To protect the iden--es of pediatric transgender, nonbinary, and gender diverse pa-ents, city names and clinical sites

where
research subjects have been treated are redacted from this version of the report.

GENDER-AFFIRMING MEDICAL TREATMENTS FOR

PEDIATRIC PATIENTS WITH GENDER DYSPHORIA
PART I:
PHARMACOLOGICAL AGENTS
GUIDELINES
SYSTEMATIC REVIEWS
BIBLIOGRAPHY OF INCLUDED STUDIES
EXPERIMENTAL AND OBSERVATIONAL STUDIES
DESCRIPTIVE STUDIES

PART II:
LONG-TERM OUTCOMES

Submitted to
Utah Department of Health and Human Services

Jennifer Strohecker, PharmD, BCPS Michelle Hofman, MD, MPH, MHCDS, FAAP
Medicaid Director Medical Director
Director, Division of Integrated Healthcare Utah Department of Health and Human Services
[email protected] [email protected]

Submitted by
Joanne LaFleur, PharmD, MSPH
Director, Drug Regimen Review Center
Associate Professor, Department of Pharmacotherapy
University of Utah, College of Pharmacy
[email protected]

August 6, 2024

University of Utah College of Pharmacy, Drug Regimen Review Center.

Copyright © 2024 by University of Utah College of Pharmacy, Salt Lake City, Utah.
All rights reserved.
CONTENTS
CONTENTS ..................................................................................................................................................... ii
LIST OF FIGURES .......................................................................................................................................... vii
LIST OF TABLES ........................................................................................................................................... viii
REPORT CONTRIBUTORS ............................................................................................................................ xiii
FUNDING AND FINANCIAL CONFLICTS OF INTEREST ................................................................................. xiii
ABBREVIATIONS ......................................................................................................................................... xiv
PART I ............................................................................................................................................................ 1
I.1.0 INTRODUCTION ................................................................................................................................ 2
I.1.1 Gender Dysphoria and the Utah Context .................................................................................. 2
I.1.2 Objectives .................................................................................................................................. 2
I.1.3 Deliverables Based on a Hierarchy of Evidence ........................................................................ 3
I.1.4 Terms Used in This Report ........................................................................................................ 4
I.1.4.1 Populations ......................................................................................................................... 4
I.1.4.2 Treatment protocols and agents ........................................................................................ 5
I.2.0 AGENTS USED OR RECOMMENDED FOR USE IN PEDIATRIC TGNB PATIENTS ................................. 6
I.2.1 Off-label Use of Drugs in Pediatric Patients .............................................................................. 6
I.2.2 Methods .................................................................................................................................... 6
I.2.3 Results ....................................................................................................................................... 7
I.2.3.1 Agents used for gender-affirming hormonal therapy (GAHT) in TGNB
adolescents ......................................................................................................................... 7
I.2.3.1.1 FDA-approved indications ......................................................................................... 8
I.2.3.1.2 Indications for off-label use from reputed pharmacy compendia ............................ 9
I.3.0 EVIDENCE SYNTHESIS METHODS ................................................................................................... 12
I.3.1 Protocol ................................................................................................................................... 12
I.3.2 Systematic Search Methods .................................................................................................... 12
I.3.2.1 Eligibility criteria ............................................................................................................... 12
I.3.2.2 Search strategies ............................................................................................................... 16
I.3.3 Study Relevance Assessment Methods ................................................................................... 16
I.3.3.1 Title/Abstract screening .................................................................................................... 16
I.3.3.2 Full-text screening and tagging ......................................................................................... 17
I.3.4 Study Design-specific Methods ............................................................................................... 17
I.3.4.1 Guideline-specific methods .............................................................................................. 17
I.3.4.1.1 Final full-text eligibility assessment ......................................................................... 17
I.3.4.1.2 Data collection ......................................................................................................... 18

ii
 I.3.4.1.3 Risk of bias assessment............................................................................................ 19
I.3.4.2 Systematic review-specific methods ................................................................................ 19
I.3.4.2.1 Final full-text eligibility assessment ......................................................................... 19
I.3.4.2.2 Data collection ......................................................................................................... 20
I.3.4.2.3 Risk-of-bias assessment ........................................................................................... 20
I.3.4.3 Methods for the bibliography of all relevant studies ....................................................... 22
I.3.4.4 Experimental study-specific methods............................................................................... 22
I.3.4.4.1 Clinicaltrials.gov search ........................................................................................... 22
I.3.4.4.2 Final full-text eligibility ............................................................................................ 23
I.3.4.4.3 Data collection ......................................................................................................... 23
I.3.4.4.4 Risk-of-bias assessment ........................................................................................... 23
I.3.4.5 Observational study-specific methods ............................................................................. 23
I.3.4.5.1 Final full-text eligibility assessment and tagging ..................................................... 23
I.3.4.5.2 Data extraction and record annotation ................................................................... 24
I.3.4.5.3 Risk-of-bias assessment ........................................................................................... 25
I.3.4.6 Descriptive study-specific methods .................................................................................. 27
I.3.4.6.1 Descriptive study full-text eligibility assessment..................................................... 27
I.3.4.6.2 Data extraction and record annotation ................................................................... 28
I.3.4.6.3 Risk-of-bias assessment ........................................................................................... 29
I.4.0 RESULTS OF EVIDENCE SYNTHESIS ................................................................................................. 33
I.4.1 Search Results ......................................................................................................................... 33
I.4.1.1 Ovid Medline search results ............................................................................................. 33
I.4.1.2 Embase search results ...................................................................................................... 33
I.4.1.3 PRISMA.............................................................................................................................. 33
I.4.1.4 Publication year ................................................................................................................ 35
I.4.2 Guidelines ................................................................................................................................ 35
I.4.2.1 Included guidelines ........................................................................................................... 35
I.4.2.2 Guideline recommendations ............................................................................................ 35
I.4.2.2.1 Overview of reviewed guidelines ............................................................................ 35
I.4.2.2.2 Key guideline hormonal therapy recommendations ............................................... 36
I.4.2.2.3 Considerations for interpretation of guideline recommendations ......................... 36
I.4.3 Systematic Reviews ................................................................................................................. 38
I.4.3.1 High-priority systematic reviews ...................................................................................... 38
I.4.3.2 Systematic review risks of bias (ROB) ............................................................................... 42
I.4.4 Bibliography of Included Publications ..................................................................................... 44
I.4.5 Included Relevant Clinical Studies ........................................................................................... 44
I.4.5.1 Characteristics of relevant clinical studies ........................................................................ 44

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 I.4.5.2 Relevant clinical studies from US populations .................................................................. 44
I.4.5.3 Relevant clinical studies from Dutch populations ............................................................ 49
I.4.5.4 Relevant clinical studies from Canada, Australia, the United Kingdom, and
Europe ............................................................................................................................... 50
I.4.5.5 Relevant clinical studies published in other populations ................................................. 53
I.4.5.6 Risk of bias analyses .......................................................................................................... 54
I.4.6 Experimental Studies ............................................................................................................... 63
I.4.6.1 Experimental studies as defined by Gehlbach's taxonomy .............................................. 64
I.4.6.2 Experimental studies as defined by authors..................................................................... 65
I.4.6.3 Experimental studies according to trial registries ............................................................ 66
I.4.6.3.1 US Clinical Trials Register ......................................................................................... 66
I.4.6.3.2 International Standard Randomized Controlled Trial Register................................ 66
I.4.6.4 Prospective studies of treatments for pediatric gender dysphoria .................................. 66
I.4.7 Observational Studies.............................................................................................................. 71
I.4.7.1 TGNB patients compared to other TGNB subgroups ........................................................ 71
I.4.7.2 TGNB compared to cisgender peers ................................................................................. 77
I.4.7.3 Summary of observational studies ................................................................................... 77
I.4.7.4 Outcomes addressed with comparisons of TGNB adolescents to other TGNB
subgroups ......................................................................................................................... 77
I.4.7.5 Outcomes addressed with comparisons of TGNB patients to their cisgender
peers ................................................................................................................................. 78
I.4.8 Descriptive Studies .................................................................................................................. 78
I.4.8.1 Longitudinal, pre-post comparisons ................................................................................. 79
I.4.8.2 Summary of longitudinal, pre-post descriptive studies .................................................... 79
I.4.8.3 Outcomes addressed with longitudinal, pre-post comparisons ....................................... 82
I.5.0 OBJECTIVE 4: PERSISTENCE, DESISTANCE, AND REGRETS ............................................................. 83
I.6.0 CONCLUSIONS ................................................................................................................................ 90
I.7.0 LIMITATIONS .................................................................................................................................. 91
PART I REFERENCES ..................................................................................................................................... 92
APPENDIX I.A: PHARMACOLOGIC AGENTS BY DRUG CLASS ................................................................... 155
APPENDIX I.B: SEARCH STRATEGIES OF BIBLIOGRAPHIC DATABASES .................................................... 194
APPENDIX I.C: STUDIES EXCLUDED AT FULL-TEXT SCREENING, BY CRITERION ...................................... 262
APPENDIX I.D: CLINICAL PRACTICE GUIDELINE DATA EXTRACTION TABLES .......................................... 297
APPENDIX I.E: SYSTEMATIC REVIEW DATA EXTRACTION TABLES .......................................................... 307
APPENDIX I.F: BIBLIOGRAPHY OF ALL INCLUDED STUDIES .................................................................... 342
APPENDIX I.G: CHARACTERISTICS OF INCLUDED RELEVANT CLINICAL STUDIES .................................... 489

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APPENDIX I.H: MENTAL HEALTH ASESSMENT TOOLS USED IN INCLUDED CLINICAL STUDIES ............... 538
APPENDIX I.I: RISK OF BIAS ANALYSIS OF EXTRACTED INCLUDED CLINICAL STUDIES ........................... 551
APPENDIX I.J: DATA EXTRACTED FROM STUDIES COMPARING TGNB PATIENTS TO OTHER TGNB
PATIENTS, ORGANIZED BY OUTCOME ......................................................................................... 630
APPENDIX I.K: DATA EXTRACTED FROM STUDIES COMPARING TGNB PATIENTS TO THEIR
CISGENDER PEERS, ORGANIZED BY OUTCOME ........................................................................... 771
APPENDIX I.L: DATA EXTRACTED FROM STUDIES COMPARING TGNB PATIENTS BEFORE AND
AFTER (PRE-POST) INTERVENTION, ORGANIZED BY OUTCOME .................................................. 807
PART II ....................................................................................................................................................... 898
II.1.0 INTRODUCTION ............................................................................................................................ 899
II.1.1 Objective ............................................................................................................................... 899
II.2.0 EVIDENCE SYNTHESIS METHODS ................................................................................................. 899
II.2.1 Search Strategy...................................................................................................................... 899
II.2.2 Study Eligibility Assessment .................................................................................................. 899
II.2.2.1 Title/Abstract screening .................................................................................................. 900
II.2.2.1.1 Population.............................................................................................................. 900
II.2.2.1.2 Length of Treatment .............................................................................................. 900
II.2.2.2 Full-text Screening and Tagging ...................................................................................... 900
II.2.2.3 Re-screening of Included Studies .................................................................................... 901
II.2.3 Deliverable-specific Methods ................................................................................................ 901
II.2.3.1 Observational Study-specific Methods ........................................................................... 901
II.2.3.1.1 Final Full-text Eligibility Assessment and Tagging ................................................. 901
II.2.3.1.2 Data Extraction and Record Annotation ................................................................ 902
II.2.3.1.3 Risk of Bias Assessment ......................................................................................... 902
II.2.3.2 Descriptive Study-specific Methods ............................................................................... 902
II.2.3.2.1 Final Full-text Eligibility Assessment and Tagging ................................................. 902
II.2.3.2.2 Data Extraction and Record Annotation ................................................................ 902
II.2.3.2.3 Risk of Bias Assessment ......................................................................................... 902
II.3.0 RESULTS OF EVIDENCE SYNTHESIS ............................................................................................... 903
II.3.1 Search and Rescreening Results ............................................................................................ 903
II.3.1.1 PRISMA............................................................................................................................ 903
II.3.2 Included Relevant Clinical Studies ......................................................................................... 904
II.3.2.1 Characteristics of Relevant Clinical Studies .................................................................... 904
II.3.2.2 Risk of Bias Analyses ....................................................................................................... 904
II.3.3 Observational Studies............................................................................................................ 906
II.3.3.1 TGNB Patients Compared to Other TGNB Subgroups .................................................... 907

v
 II.3.3.2 TGNB Patients Compared to Cisgender Peers ................................................................ 907
II.3.3.3 Summary of Outcomes of Observational Studies ........................................................... 907
II.3.3.3.1 Transgender Men versus Transgender Women .................................................... 911
II.3.3.3.2 TGNB versus Cisgender Peers ................................................................................ 911
II.3.3.3.3 Hormonally Treated versus Untreated TGNB Cohorts .......................................... 911
II.3.3.3.4 Differences in Treatments ..................................................................................... 911
II.3.3.3.5 Other TGNB versus TGNB Comparisons ................................................................ 911
II.3.4 Descriptive Studies ................................................................................................................ 912
II.3.4.1 Descriptive Study Outcomes ........................................................................................... 912
II.3.4.2 Summary of Outcomes for Descriptive Studies .............................................................. 912
II.3.4.2.1 Mental Health and Psychosocial Functioning ........................................................ 913
II.3.4.2.2 Cardiovascular, Bone Health and Body Change Outcomes ................................... 913
II.3.4.2.3 Body Image Outcomes ........................................................................................... 913
II.3.4.2.4 Cancer .................................................................................................................... 913
II.3.4.2.5 Mortality ................................................................................................................ 914
II.4.0 CONCLUSIONS .............................................................................................................................. 914
II.5.0 LIMITATIONS ................................................................................................................................ 915
PART II REFERENCES CITED ....................................................................................................................... 916
APPENDIX II.A: STUDIES EXCLUDED AT FULL-TEXT SCREENING, BY CRITERION ...................................... 919
APPENDIX II.B: ROB SUMMARY OF TGNB VS TGNB OBSERVATIONAL STUDIES ..................................... 958
APPENDIX II.C: ROB SUMMARY FOR LONGITUDINAL, PRE-POST DESCRIPTIVE STUDIES, OR
SINGLE-ARM TRIALS ..................................................................................................................... 966
APPENDIX II.D: INCLUDED STUDIES ......................................................................................................... 976
APPENDIX II.E: EVIDENCE TABLES FOR TGNB VERSUS TGNB LONG-TERM OUTCOMES ......................... 992
APPENDIX II.F: EVIDENCE TABLES FOR TGNB VERSUS CISGENDER PEER LONG-TERM OUTCOMES ..... 1003
APPENDIX II.G: EVIDENCE TABLES FOR PRE-POST LONG-TERM OUTCOMES ........................................ 1005

vi
LIST OF FIGURES
In Part I
Figure I.1. Relevant clinical study designs included in the report grouped according to
Gehlbach's taxonomic definitions ........................................................................................... 15
Figure I.2. Top ten indexed major MeSH headings in all first- and second- corpus Ovid Medline
results ...................................................................................................................................... 33
Figure I.3. PRISMA flow chart for study selection .................................................................................... 34
Figure I.4. Number of included publications per year, 2010-2023 (N = 277)........................................... 35

In Part II
Figure II.1. PRISMA diagram .................................................................................................................... 903

vii
LIST OF TABLES
In Part I Report Body

Table I.1. Eligibility criteria for relevant publications in the search and screening phases .................... 13
Table I.2. Explanations for ROB items included in the AMSTAR-2 tool for SR quality ............................ 20
Table I.3. Explanations for ROB items included in the NOS tool for observational study quality .......... 26
Table I.4. Explanations for ROB items included in the NIH/NHLBI tool for longitudinal, pre-post
descriptive studies ................................................................................................................... 30
Table I.5. Characteristics of 7 systematic reviews addressing high-priority outcomes associated
with gender-affirming hormone therapy (GAHT) in adolescents ........................................... 39
Table I.6. Summary of AMSTAR-2 ROB domains43 for 7 SRs examining relevant/included
outcomes associated with GD therapy in TGNB children/adolescents ................................... 43
Table I.7. Disposition of N=11 likely-relevant primary studies excluded from one recent SR that
searched 13 different databases ............................................................................................. 43
Table I.8. Summary of N = 118 relevant clinical studies conducted in pediatric TGNB
populations in the US .............................................................................................................. 45
Table I.9. Summary of N = 43 relevant clinical studies conducted in pediatric TGNB
populations in the Netherlands............................................................................................... 49
Table I.10. Summary of N = 60 relevant clinical studies conducted in pediatric TGNB
populations in Canada, Australia, the United Kingdom, and Europe ...................................... 50
Table I.11. Summary of N = 9 relevant, English-language clinical studies conducted in other
pediatric TGNB populations .................................................................................................... 53
Table I.12. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB cohort
studies ..................................................................................................................................... 54
Table I.13. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB cross-
sectional studies ...................................................................................................................... 55
Table I.14. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB case-
control studies ......................................................................................................................... 57
Table I.15. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs Peer cohort
studies ..................................................................................................................................... 57
Table I.16. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs Peer cross-
sectional studies ...................................................................................................................... 57
Table I.17. NIH Quality Assessment Tool ROB data for Pre-Post studies.................................................. 59
Table I.18. Four competing criteria for classifying experimental studies ................................................. 64
Table I.19. High-priority comparison types used for extracting findings from experimental
studies ..................................................................................................................................... 64
Table I.20. Comparison types reported in experimental studies as defined by Gehlbach's
taxonomy................................................................................................................................. 65
Table I.21. Comparison types reported in experimental studies as defined by study authors ................ 65
Table I.22. Comparison types reported in experimental studies as defined by ISRCT registration.......... 66

viii
Table I.23. Comparison types reported in experimental studies as defined by prospective study
design, assuming that treatments are regarded as "experimental" ....................................... 67
Table I.24. Comparison types reported in observational studies that underwent full data
extraction ................................................................................................................................ 72
Table I.25. Comparison types reported in descriptive studies that underwent full data
extraction ................................................................................................................................ 79
Table I.26. Included studies that addressed issues related to persistence and desistance with
GAHT in pediatric GD patients................................................................................................. 83

In Part I Appendixes

Table I.A.1. Indications for gonadotropin-releasing hormone analogs used for gender dysphoria ......... 156
Table I.A.2. Indications for gonadotropin-releasing hormone antanalogs used for gender
dysphoria ............................................................................................................................... 158
Table I.A.3. Indications for antiandrogens used for gender dysphoria .................................................... 159
Table I.A.4. Indications for single-ingredient sex hormone agents used for gender dysphoria ............... 161
Table I.A.5. Indications for single-ingredient progestin agents used for gender dysphoria ..................... 168
Table I.A.6. Indications for combination sex-hormone/progestin products used for gender
dysphoria ............................................................................................................................... 173
Table I.A.7. Indications for aromatase inhibitors used for gender dysphoria .......................................... 187
Table I.A.8. Indications for selective estrogen receptor modulators (SERMs) used for gender
dysphoria ............................................................................................................................... 189
Table I.A.9. Indications for miscellaneous other agents used for gender dysphoria ............................... 192
Table I.B.1. Summary of searches uploaded to Covidence, March 9, 2023 through June 5, 2023 .......... 195
Table I.B.2. MeSH-only search of Ovid Medline for guidelines and systematic reviews, initially
March 9, 2023; rerun April 11, 2023 ..................................................................................... 198
Table I.B.3. MeSH-only search of Ovid Medline for randomized controlled trials, initially March
20, 2023; rerun April 11, 2023 .............................................................................................. 201
Table I.B.4. MeSH-only search of Ovid Medline for randomized controlled trials and other
experimental studies (eg, controlled clinical trials), initially March 22, 2023; rerun
April 11, 2023 ........................................................................................................................ 203
Table I.B.5. MeSH-only search of Ovid Medline for observational and descriptive studies, initially
March 22, 2023; rerun April 11, 2023 ................................................................................... 206
Table I.B.6. MeSH-only search of Ovid Medline for qualitative studies, initially March 23, 2023;
rerun April 11, 2023 .............................................................................................................. 210
Table I.B.7. Emtree-only searches of Embase for systematic reviews, initially March 21, 2023;
rerun April 11, 2023 .............................................................................................................. 214
Table I.B.8. Emtree-only searches of Embase for guidelines, initially March 23, 2023; rerun April
11, 2023 ................................................................................................................................. 217
Table I.B.9. Emtree-only searches of Embase for experimental studies (eg, randomized
controlled trials, controlled clinical trials), initially March 31, 2023; rerun April 11,
2023 ....................................................................................................................................... 220

ix
Table I.B.10. Emtree-only searches of Embase for observational and descriptive studies, initially
April 7, 2023; rerun April 11, 2023 ........................................................................................ 223
Table I.B.11. Emtree-only searches of Embase for qualitative studies, initially April 7, 2023; rerun
April 11, 2023 ........................................................................................................................ 227
Table I.B.12. Free text and controlled vocabulary search of Ovid Medline for systematic reviews,
May 15, 2023 ......................................................................................................................... 231
Table I.B.13. Free text and controlled vocabulary search of Ovid Medline for guidelines, May 15,
2023 ....................................................................................................................................... 234
Table I.B.14. Free text and controlled vocabulary search of Ovid Medline for randomized
controlled trials, May 22, 2023 ............................................................................................. 236
Table I.B.15. Free text and controlled vocabulary search of Ovid Medline for randomized
controlled trials, May 22, 2023 ............................................................................................. 238
Table I.B.16. Free text and controlled vocabulary search of Ovid Medline for observational and
descriptive studies, May 22, 2023 ......................................................................................... 241
Table I.B.17. Free text and controlled vocabulary search of Ovid Medline for qualitative studies,
June 5, 2023........................................................................................................................... 244
Table I.B.18. Free text and controlled vocabulary search of Embase for systematic reviews, May
15, 2023 ................................................................................................................................. 247
Table I.B.19. Free text and controlled vocabulary search of Embase for guidelines, May 15, 2023 ........ 250
Table I.B.20. Free text and controlled vocabulary search of Embase for experimental studies (eg,
randomized controlled trials, controlled clinical trials), May 22, 2023 ................................. 253
Table I.B.21. Free text and controlled vocabulary search of Embase for observational and
descriptive studies, May 22, 2023 ......................................................................................... 256
Table I.B.22. Free text and controlled vocabulary search of Embase for qualitative studies, June
5, 2023 ................................................................................................................................... 259
Table I.D.1. Overview of development methodology and level of evidence (LOE) for
recommendations by guidelines or position statements addressing gender-affirming
hormonal therapies (GAHT) .................................................................................................. 298
Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-
blocking therapy (GAHT) in TGNB youth ............................................................................... 299
Table I.D.3. Overview of GAHT monitoring addressed by guidelines or position statements ................ 306
Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews
addressing included outcomes associated with medical treatments of TGNB
adolescents ............................................................................................................................ 308
Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority
outcomes associated with GD treatments in TGNB children/adolescents ........................... 315
Table I.E.3. Systematic reviews examining mental health outcomes (eg, anxiety, depression,
suicidality) associated with GD treatments in TGNB children/adolescents .......................... 323
Table I.E.4. Systematic reviews examining psychosocial outcomes (eg, QOL, behavioral/social
functioning, GD, body image) associated with GD treatments in TGNB
children/adolescents ............................................................................................................. 326

x
Table I.E.5. Systematic reviews addressing body changes (eg, endogenous hormones, growth,
fat/lean/body mass, breast development, testicular volume) associated with GD
treatments in TGNB children/adolescents ............................................................................ 330
Table I.E.6. Systematic reviews examining bone health (eg, bone density, bone turnover
measures) associated with GD treatments in TGNB children/adolescents .......................... 335
Table I.E.7. Systematic reviews addressing cardiovascular/metabolic risk factors (eg,
thrombotic/thromboembolic, insulin sensitivity, blood pressure, cholesterol, liver,
and kidney outcomes) in TGNB adolescents who receive GnRH analogs for puberty
suppression ........................................................................................................................... 338
Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB
populations in the US, chronologically by site ...................................................................... 490
Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB
populations in the Netherlands, chronologically by site ....................................................... 516
Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB
populations in Canada, Australia, the United Kingdom, and Europe, chronologically
by site .................................................................................................................................... 524
Table I.G.4. Characteristics of N = 9 relevant, English-language clinical studies conducted in other
pediatric TGNB populations, chronologically by site ............................................................ 536
Table I.H.1. Psychological assessment tools utilized in included studies ................................................. 539
Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients,
using the Newcastle-Ottawa Quality Assessment Scale (NOS) ............................................. 552
Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB
patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS) .............................. 573
Table I.I.3. Risk of bias in extracted case-control studies comparing TGNB patients to TGNB
patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS) .............................. 589
Table I.I.4. Risk of bias in extracted cohort studies comparing TGNB patients to their cisgender
peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS) .................................. 590
Table I.I.5. Risk of bias in extracted cross-sectional studies comparing TGNB patients to their
cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS) .................. 595
Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients
before and after intervention (pre-post), using the NIH Quality Assessment Tool .............. 599
Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health
outcomes ............................................................................................................................... 631
Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial
functioning ............................................................................................................................ 676
Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change
outcomes ............................................................................................................................... 710
Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image
outcomes ............................................................................................................................... 733
Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health
outcomes ............................................................................................................................... 743

xi
Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular
outcomes ............................................................................................................................... 755
Table I.K.1. Clinical studies comparing TGNB to cisgender peers regarding mental health
outcomes ............................................................................................................................... 772
Table I.K.2. Clinical studies comparing TGNB to cisgender peers regarding psychosocial outcomes ...... 776
Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change
outcomes ............................................................................................................................... 781
Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular
outcomes ............................................................................................................................... 791
Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients ........... 808
Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients ............. 819
Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients ............. 836
Table I.L.4. Longitudinal pre-post studies evaluating body image outcomes in TGNB patients .............. 859
Table I.L.5. Longitudinal pre-post studies evaluating bone health outcomes in TGNB patients .............. 865
Table I.L.6. Longitudinal pre-post studies evaluating cardiovascular outcomes in TGNB patients .......... 885

In Part II Report Body

Table II.1. Summary of N=27 Relevant, Long-term Clinical Studies Conducted in Mixed Pediatric
and Adult TGNB Populations ................................................................................................. 904
Table II.2. Newcastle-Ottawa Quality Assessment Scale Data for TGNB vs TGNB Cohort
Observational Studies............................................................................................................ 905
Table II.3. Newcastle-Ottawa Quality Assessment Scale Data for TGNB vs TGNB or TGNB vs
Peer Cross-sectional Observational Studies .......................................................................... 905
Table II.4. Quality Assessment of Included Pre-post Studies Using the NIH Quality Assessment
Tool for Before-after Studies with No Control Group ........................................................... 906
Table II.5. Comparison Types Reported in Observational Studies that Underwent Full Data
Extraction .............................................................................................................................. 908
Table II.6. Comparison Types Reported in Descriptive Studies that Underwent Full Data
Extraction .............................................................................................................................. 909

In Part II Appendixes

Table II.B.1. Newcastle-Ottawa Quality Assessment Scale (NOS) for Cohort Studies .............................. 959
Table II.B.2. Newcastle-Ottawa Quality Assessment Scale (NOS) adapted for cross-sectional
studies ................................................................................................................................... 963
Table II.C.1. NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control
Group ..................................................................................................................................... 967
Table II.E.1. Clinical Studies with Between-TGNB-group Comparisons .................................................... 993
Table II.F.1. Clinical Studies with TGNB vs Peer Comparisons ................................................................ 1004
Table II.G.1. Clinical studies with before and after (pre-post) comparisons .......................................... 1006

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REPORT CONTRIBUTORS
Joanne LaFleur, PharmD, MSPH Director, DRRC
Lauren Heath, PharmD, MS, BCACP Clinical Pharmacist, DRRC
Valerie Gonzales, PharmD Clinical Pharmacist, DRRC
Monet Luloh, PharmD Clinical Pharmacist, DRRC
Rebecca Henkels, PharmD candidate Pharmacist Intern
Ary Vadipour, PharmD candidate Pharmacist Intern
Danielle Nguyen, PharmD, PhD candidate Graduate Research Assistant
Xi Liang, PharmD, PhD candidate Graduate Research Assistant
Tami Haines, RPh Clinical Pharmacist
Kristin Knippenberg, MFA Project Administrator

FUNDING AND FINANCIAL CONFLICTS OF INTEREST

The writing of this report was sponsored by funding from the Utah Department of Health and Human
Services. The report contributors have no other conflicts of interest to declare.

xiii

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ABBREVIATIONS
Alphabetized by Abbreviation

AAP American Academy of Pediatrics

ABCL Adult Behavior Checklist
aBMD Areal bone mineral density
ACOG American College of Obstetricians and Gynecologists
ACoG Amsterdam Cohort of Gender Dysphoria
ADHD Attention deficit hyperactivity disorder
AFAB Assigned female at birth
AIDS Acquired immune deficiency syndrome
ALP Alkaline phosphatase
ALT Alanine transaminase
AMA American Medical Association
AMAB Assigned male at birth
AMSTAR A MeaSurement Tool to Assess systematic Reviews
AMSTAR-2 A MeaSurement Tool to Assess systematic Reviews, Version 2
Amsterdam UMC Amsterdam University Medical Center
aOR Adjusted odds ratio
ASQ Ask Suicide Screening Questions
ASR Adult self-report
AST Aspartate transaminase
BA Bone age
BCE Before common era
BDI Beck Depression Inventory
BDI-(Y) Beck Depression Inventory (for Youth)
BDI-II Beck Depression Inventory-II
BES Body Esteem Scale for Adolescents and Adults
BIS Body Image Scale
BMAD Bone mineral apparent density
BMC Bone mineral content
BMD Bone mineral density
BMI Body mass index
BP Blood pressure
BTM(s) Bone turnover marker(s)
C-SSRS Columbia Suicide Severity Rating Scale
CA Chronological age
CADTH Canada's Drug and Health Technology Agency
CBCL Child Behavior Checklist

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CBD Cortical BMD
CCT Controlled clinical trial
CD-RISC Connor-Davidson Resilience Scale
CDC Center for Disease Control and Prevention
CDI Children's Depression Inventory
CEGD Center of Expertise on Gender Dysphoria
CEOAE(s) Click-evoked otoacoustic emission(s)
CESD-R Center for Epidemiologic Studies Depression Scale
CF Cystic fibrosis
CGAS Children's Global Assessment Scale
CHEO Children's Hospital of Eastern Ontario
CHLA Children's Hospital Los Angeles
CI Confidence interval
cLDL Low-density lipoprotein cholesterol
cm Centimeter(s)
CML Chronic myelogenous leukemia
COI Conflict of interest
CPP Central precocious puberty
CSH Cross-sex hormones
CSHT Cross-sex hormone therapy
DC District of Columbia
DFAB Designated female at birth
dL Deciliter
DLPFC Dorsolateral prefrontal cortex
DM Diabetes mellitus
DMAB Designated male at birth
DRRC Drug Regimen Review Center
DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision
DVT Deep vein thrombophlebitis
DXA Dual-energy radiograph absorptiometry
ED Endocortical diameter
EDE-Q Eating Disorders Examination Questionnaire
EROS Erotic Response and Orientation Scale
ES Endocrine Society
ESSM European Society for Sexual Medicine
ET-FMR Extremities/Trunk fat mass ratio
FBeK Fragebofen zur Beurteilung des eisenen Körpers (Body image assessment
questionnaire)
FDA US Food and Drug Administration

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FDAMA Food and Drug Administration Modernization Act of 1997
FEV Forced expiratory volume
fMRI Functional magnetic resonance imaging
FN Femoral neck
FTM Female-to-male, or assigned female at birth transitioning to male
GAD-7 General Anxiety Disorder-7
GAET Gender-affirming estrogen treatment
GAH Gender-affirming hormone(s)
GAHT Gender-affirming hormone therapy
GAS Gender-affirming surgery
GD Gender dysphoria
GDAAY Gender Diversity and Affirming Action for Youth Clinic of the Health Sciences
Center, Winnipeg, Manitoba
GENECIS Children's Health GENder Education and Care Interdisciplinary Support program
GGT Gamma-glutamyl transferase
GIDS Gender Identity Development Service
GIDYQ Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults
GIQ-Ad Gender Identity Questionnaire for Adolescents
GIS Gender Identity Service
GMSR-A Gender Minority Stress and Resilience Measure for Adolescents
GnRH Gonadotropin-releasing hormone
GnRH analog Gonadotropin-releasing hormone analog/analogue/agonist
GnRH antagonist Gonadotropin-releasing hormone antagonist
GRADE Grading of Recommendations, Assessment, Development, and Evaluations
GRS Gender reassignment surgery
GWBS General Well-being Schedule
HB Hemoglobin
HCP(s) Healthcare professional(s)
HCT Hematocrit
Hg Mercury
HRQOL Health-related quality of life
HT Hormonal therapy
HTN Hypertension
ICD International Classification of Diseases
IOM Institute of Medicine
IQ Intelligence quotient
IRB Institutional Review Board
ISRCTN International Standard Randomized Controlled Trial Number Register
ITS Interrupted time series
IUD Intrauterine device

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IV Intravenous
K6 Kessler Psychological Distress Scale
kg Kilogram(s)
KIDSCREEN-27 KIDSCREEN Health Related Quality of Life Questionnaire for Children and Young
People and their Parents, Short Version
KP Kaiser Permanente
KZcG Kennis- en Zorgcentrum Genderdysforie
L Liter(s)
LA Long-acting
LBM Lean body mass
LGBTQ Lesbian gay bisexual transgender queer
LGI Leeds General Infirmary
LH Luteinizing hormone
LHRH Luteinizing hormone-releasing hormone
LOE(s) Level(s) of evidence
LS Lumbar spine
LSAS Liebowitz Social Anxiety Scale
LT-FMR Legs/Total fat mass ratio
LTH Left total hip
LUMC Leiden University Medical Center
m Meter(s)
MA Meta-analysis
MacCAT-T MacArthur Competence Assessment Tool for Treatment
mBMI Median body mass index
MDC Medical decision-making competence
MDS Modified Depression Scale
MeSH Medical Subject Headings for National Library of Medicine
mFG Modified Ferriman-Gallwey
MHP(s) Mental health professional(s)
MI Myocardial infarction
mIU Milli-international unit(s)
mL Milliliter(s)
mm Millimeter(s)
mmol Millimole(s)
MRI Magnetic resonance imaging
MRT Mental rotation task
MSPSS Multi-dimensional Scale of Perceived Social Support
MTF Male-to-female, or assigned male at birth transitioning to female
N/A Not applicable
N/R Not reported

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N/S Not significant
ng Nanogram(s)
NHANES National Health and Nutrition Examination Survey
NHLBI National Heart, Lung, and Blood Institute
NHS National Health Service
NIH National Institutes of Health
NOS Newcastle-Ottawa Scale
NRI Network of Relationships Inventory―Relationship Qualities
NRSI Non-randomized studies of interventions
NSSI Non-suicidal self-injury
OASIS Overall Anxiety Severity and Impairment Score
OATP Organic anion transporting polypeptide
OC Osteocalcin
OGD Other gender-diverse
OR Odds ratio
OTC Over-the-counter
PAH Predicted adult height
PAQ-C Physical Activity Questionnaire for Older Children
PB Puberty blocker(s)
PE Pulmonary embolism
PEDSnet A Clinical Research Network in the National Patient-Centered Clinical Research
Network
pg Picogram(s)
PHQ Patient Health Questionnaire
PHQ-9 Patient Health Questionnaire Modified for Teens
PICO Population Intervention Control Group and Outcome
POTS Postural orthostatic tachycardic syndrome
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses
PRL Prolactin
PROMIS Patient Reported Outcomes Measurement Information System
PS Puberty suppression
Q-LES-Q-SF Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form
QIDS Quick Inventory of Depressive Symptoms
QOL Quality of life
QRS A Q wave (downward deflection), followed by an R wave (upward deflection),
followed by an S wave (another downward deflection after the R wave), on an
electrocardiogram
QT Time from the beginning of the QRS complex to the end of the T wave on
electrocardiogram
QTc Rate-corrected QT interval
RCGI Recalled Childhood Gender Identity/Gender Role Questionnaire

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RCMAS-2 Revised Children's Manifest Anxiety Scale, Second Edition
RCT(s) Randomized controlled trial(s)
REP Rochester Epidemiology Project
RLPFC Rostrolateral prefrontal cortex
ROB Risk of bias, or risk-of-bias
ROBINS-I Risk Of Bias In Non-randomised Studies - of Interventions
ROI Region of interest
SAIFI Italian Gender Identity Development Service
SB Senate Bill
SBP Systolic blood pressure
SBQ-R Suicide Behaviors Questionnaire-Revised
SCARED Screen for Child Anxiety Related Disorders
SCr Serum creatinine
SD Standard deviation
SERM(s) Selective estrogen receptor modulator(s)
SHI Self-harm Index
SHQ Sexual History Questionnaire
SHS Subjective Happiness Scale
SI Suicidal ideation
SOC Standard of care
SOE Strength of evidence
SPPA Harter Self Perception Profile for Adolescents
SPRM(s) Selective progestin receptor modulator(s)
SPW Subperiosteal width (SPW)
SR(s) Systematic review(s)
SRMA(s) Systematic review(s) and meta-analysis(es)
SRS-2 Social Responsiveness Scale, Second Edition
STAI Spielberger State-Trait Anxiety Inventory
STRONG cohort Study of Transition Outcomes and Gender cohort of Kaiser Permanente
SubQ Subcutaneous
SWLS Satisfaction With Life Scale
T Testosterone
T1DM Type 1 diabetes mellitus
TBD Trabecular BMD
TBF Total body fat
TBLH Total body less head
TC Total cholesterol
TCS Transgender Congruence Scale
TG Triglycerides
TGD Transgender/Gender diverse

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TGF Transgender female
TGM Transgender male
TGNB Transgender non-binary or gender-diverse
TGNB Transgender/Nonbinary
TH Total hip
TIAB Title and Abstract
TOL Tower of London
TPI Spielberger State-Trait Anger Expression Inventory
TRICARE Healthcare payer for US military personnel and their families
TT-FMR Trunk/Total fat mass ratio
TYC Transgender Youth Clinic
UCLH University College London Hospital
UCSF University California San Francisco
UDHHS Utah Department of Health and Human Services
UGDS Utrecht Gender Dysphoria Scale
UK United Kingdom
UMC, VUmc VUmc location of Amsterdam University Medical Center
US United States
USC University of Southern California
UTIGPA Unidad de Tratamiento de Identidad de Género del Principado de Asturias
VTE Venous thromboembolism
VUMC Vrije Universiteit Amsterdam, VU University Medical Center
WHO-QOL-Brief World Health Organization Quality of Life Brief Version
WHR Waist-hip ratio
WISC Wechsler Intelligence Scale for Children
WPATH World Professional Association for Transgender Health
yr Year(s)
YSR Youth Self Report
μg Microgram(s)

Alphabetized by Name

Acquired immune deficiency syndrome AIDS

Adjusted odds ratio aOR
Adult Behavior Checklist ABCL
Adult self-report ASR
Alanine transaminase ALT
Alkaline phosphatase ALP
American Academy of Pediatrics AAP

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American College of Obstetricians and Gynecologists ACOG
American Medical Association AMA
Amsterdam Cohort of Gender Dysphoria ACoG
Amsterdam University Medical Center Amsterdam UMC
Areal bone mineral density aBMD
Ask Suicide Screening Questions ASQ
Aspartate transaminase AST
Assigned female at birth AFAB
Assigned male at birth AMAB
Attention deficit hyperactivity disorder ADHD
Beck Depression Inventory BDI
Beck Depression Inventory (for Youth) BDI-(Y)
Beck Depression Inventory-II BDI-II
Before common era BCE
Blood pressure BP
Body Esteem Scale for Adolescents and Adults BES
Body Image Scale BIS
Body mass index BMI
Bone age BA
Bone mineral apparent density BMAD
Bone mineral content BMC
Bone mineral density BMD
Bone turnover marker(s) BTM(s)
Canada's Drug and Health Technology Agency CADTH
Center for Disease Control and Prevention CDC
Center for Epidemiologic Studies Depression Scale CESD-R
Center of Expertise on Gender Dysphoria CEGD
Centimeter(s) cm
Central precocious puberty CPP
Child Behavior Checklist CBCL
Children's Depression Inventory CDI
Children's Global Assessment Scale CGAS
Children's Health GENder Education and Care Interdisciplinary Support program GENECIS
Children's Hospital Los Angeles CHLA
Children's Hospital of Eastern Ontario CHEO
Chronic myelogenous leukemia CML
Chronological age CA
Click-evoked otoacoustic emission(s) CEOAE(s)
A Clinical Research Network in the National Patient-Centered Clinical Research PEDSnet
Network

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Columbia Suicide Severity Rating Scale C-SSRS
Confidence interval CI
Conflict of interest COI
Connor-Davidson Resilience Scale CD-RISC
Controlled clinical trial CCT
Cortical BMD CBD
Cross-sex hormone therapy CSHT
Cross-sex hormones CSH
Cystic fibrosis CF
Deciliter dL
Deep vein thrombophlebitis DVT
Designated female at birth DFAB
Designated male at birth DMAB
Diabetes mellitus DM
Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition DSM-5
District of Columbia DC
Dorsolateral prefrontal cortex DLPFC
Drug Regimen Review Center DRRC
Dual-energy radiograph absorptiometry DXA
Eating Disorders Examination Questionnaire EDE-Q
Endocortical diameter ED
Endocrine Society ES
Erotic Response and Orientation Scale EROS
European Society for Sexual Medicine ESSM
Extremities/Trunk fat mass ratio ET-FMR
Female-to-male, or assigned female at birth transitioning to male FTM
Femoral neck FN
Food and Drug Administration Modernization Act of 1997 FDAMA
Forced expiratory volume FEV
Fragebofen zur Beurteilung des eisenen Körpers (Body image assessment FBeK
questionnaire)
Functional magnetic resonance imaging fMRI
Gamma-glutamyl transferase GGT
Gender Diversity and Affirming Action for Youth Clinic of the Health Sciences GDAAY
Center, Winnipeg, Manitoba
Gender dysphoria GD
Gender Identity Development Service GIDS
Gender Identity Questionnaire for Adolescents GIQ-Ad
Gender Identity Service GIS

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Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults GIDYQ
Gender Minority Stress and Resilience Measure for Adolescents GMSR-A
Gender reassignment surgery GRS
Gender-affirming estrogen treatment GAET
Gender-affirming hormone(s) GAH
Gender-affirming hormone therapy GAHT
Gender-affirming surgery GAS
General Anxiety Disorder-7 GAD-7
General Well-being Schedule GWBS
Gonadotropin-releasing hormone GnRH
Gonadotropin-releasing hormone analog/analogue/agonist GnRH analog
Gonadotropin-releasing hormone antagonist GnRH antagonist
Grading of Recommendations, Assessment, Development, and Evaluations GRADE
Harter Self Perception Profile for Adolescents SPPA
Health-related quality of life HRQOL
Healthcare payer for US military personnel and their families TRICARE
Healthcare professional(s) HCP(s)
Hematocrit HCT
Hemoglobin HB
Hormonal therapy HT
Hypertension HTN
Institute of Medicine IOM
Institutional Review Board IRB
Intelligence quotient IQ
International Classification of Diseases ICD
International Standard Randomized Controlled Trial Number Register ISRCTN
Interrupted time series ITS
Intrauterine device IUD
Intravenous IV
Italian Gender Identity Development Service SAIFI
Kaiser Permanente KP
Kennis- en Zorgcentrum Genderdysforie KZcG
Kessler Psychological Distress Scale K6
KIDSCREEN Health Related Quality of Life Questionnaire for Children and Young KIDSCREEN-27
People and their Parents, Short Version
Kilogram(s) kg
Lean body mass LBM
Leeds General Infirmary LGI
Left total hip LTH
Legs/Total fat mass ratio LT-FMR

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Leiden University Medical Center LUMC
Lesbian gay bisexual transgender queer LGBTQ
Level(s) of evidence LOE(s)
Liebowitz Social Anxiety Scale LSAS
Liter(s) L
Long-acting LA
Low-density lipoprotein cholesterol cLDL
Lumbar spine LS
Luteinizing hormone LH
Luteinizing hormone-releasing hormone LHRH
MacArthur Competence Assessment Tool for Treatment MacCAT-T
Magnetic resonance imaging MRI
Male-to-female, or assigned male at birth transitioning to female MTF
A MeaSurement Tool to Assess systematic Reviews AMSTAR
A MeaSurement Tool to Assess systematic Reviews, Version 2 AMSTAR-2
Median body mass index mBMI
Medical decision-making competence MDC
Medical Subject Headings for National Library of Medicine MeSH
Mental health professional(s) MHP(s)
Mental rotation task MRT
Mercury Hg
Meta-analysis MA
Meter(s) m
Microgram(s) μg
Milli-international unit(s) mIU
Milliliter(s) mL
Millimeter(s) mm
Millimole(s) mmol
Modified Depression Scale MDS
Modified Ferriman-Gallwey mFG
Multi-dimensional Scale of Perceived Social Support MSPSS
Myocardial infarction MI
Nanogram(s) ng
National Health and Nutrition Examination Survey NHANES
National Health Service NHS
National Heart, Lung, and Blood Institute NHLBI
National Institutes of Health NIH
Network of Relationships Inventory―Relationship Qualities NRI
Newcastle-Ottawa Scale NOS
Non-randomized studies of interventions NRSI

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Non-suicidal self-injury NSSI
Not applicable N/A
Not reported N/R
Not significant N/S
Odds ratio OR
Organic anion transporting polypeptide OATP
Osteocalcin OC
Other gender-diverse OGD
Over-the-counter OTC
Overall Anxiety Severity and Impairment Score OASIS
Patient Health Questionnaire PHQ
Patient Health Questionnaire Modified for Teens PHQ-9
Patient Reported Outcomes Measurement Information System PROMIS
Physical Activity Questionnaire for Older Children PAQ-C
Picogram(s) pg
Population Intervention Control Group and Outcome PICO
Postural orthostatic tachycardic syndrome POTS
Predicted adult height PAH
Preferred Reporting Items for Systematic Reviews and Meta-analyses PRISMA
Prolactin PRL
Puberty blocker(s) PB
Puberty suppression PS
Pulmonary embolism PE
A Q wave (downward deflection), followed by an R wave (upward deflection), QRS
followed by an S wave (another downward deflection after the R wave), on an
electrocardiogram
Quality of life QOL
Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form Q-LES-Q-SF
Quick Inventory of Depressive Symptoms QIDS
Randomized controlled trial(s) RCT(s)
Rate-corrected QT interval QTc
Recalled Childhood Gender Identity/Gender Role Questionnaire RCGI
Region of interest ROI
Revised Children's Manifest Anxiety Scale, Second Edition RCMAS-2
Risk Of Bias In Non-randomised Studies - of Interventions ROBINS-I
Risk of bias, or risk-of-bias ROB
Rochester Epidemiology Project REP
Rostrolateral prefrontal cortex RLPFC
Satisfaction With Life Scale SWLS
Screen for Child Anxiety Related Disorders SCARED

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Selective estrogen receptor modulator(s) SERM(s)
Selective progestin receptor modulator(s) SPRM(s)
Self-harm Index SHI
Senate Bill SB
Serum creatinine SCr
Sexual History Questionnaire SHQ
Social Responsiveness Scale, Second Edition SRS-2
Spielberger State-Trait Anger Expression Inventory TPI
Spielberger State-Trait Anxiety Inventory STAI
Standard deviation SD
Standard of care SOC
Strength of evidence SOE
Study of Transition Outcomes and Gender cohort of Kaiser Permanente STRONG cohort
Subcutaneous SubQ
Subjective Happiness Scale SHS
Subperiosteal width (SPW) SPW
Suicidal ideation SI
Suicide Behaviors Questionnaire-Revised SBQ-R
Systematic review(s) SR(s)
Systematic review(s) and meta-analysis(es) SRMA(s)
Systolic blood pressure SBP
Testosterone T
Time from the beginning of the QRS complex to the end of the T wave on QT
electrocardiogram
Title and Abstract TIAB
Total body fat TBF
Total body less head TBLH
Total cholesterol TC
Total hip TH
Tower of London TOL
Trabecular BMD TBD
Transgender Congruence Scale TCS
Transgender female TGF
Transgender male TGM
Transgender non-binary or gender-diverse TGNB
Transgender Youth Clinic TYC
Transgender/Gender diverse TGD
Transgender/Nonbinary TGNB
Triglycerides TG
Trunk/Total fat mass ratio TT-FMR

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Type 1 diabetes mellitus T1DM
Unidad de Tratamiento de Identidad de Género del Principado de Asturias UTIGPA
United Kingdom UK
United States US
University California San Francisco UCSF
University College London Hospital UCLH
University of Southern California USC
US Food and Drug Administration FDA
Utah Department of Health and Human Services UDHHS
Utrecht Gender Dysphoria Scale UGDS
Venous thromboembolism VTE
Vrije Universiteit Amsterdam, VU University Medical Center VUMC
VUmc location of Amsterdam University Medical Center UMC, VUmc
Waist-hip ratio WHR
Wechsler Intelligence Scale for Children WISC
World Health Organization Quality of Life Brief Version WHO-QOL-Brief

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 PART I
PHARMACOLOGICAL AGENTS
GUIDELINES
SYSTEMATIC REVIEWS
BIBLIOGRAPHY OF INCLUDED STUDIES
EXPERIMENTAL AND OBSERVATIONAL STUDIES
DESCRIPTIVE STUDIES

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I.1.0 INTRODUCTION
I.1.1 Gender Dysphoria and the Utah Context
In recent years, there has been a growing public awareness about the challenges faced by individuals
suffering from gender dysphoria. According to the 5th Edition of the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5), this condition is defined as a disparity between an individual's perceptions
about their own gender identity relative to their assigned gender at birth, resulting in psychological
distress. The incorporation of the diagnostic term gender dysphoria into the DSM-5 was added only
recently (2013).1 However, that diagnostic term was preceded by the term gender identity disorder in
the DSM-3 (1980),2 and the condition itself has been reported in the medical literature as long ago as
the 1800s.3 Outside the medical literature, transgender individuals have been mentioned in western
literature for more than 2 thousand years; for example, as early as the 1st century BCE, the Roman poet
Ovid wrote a collection of stories and myths, The Metamorphoses, which included a myth about a
transgender figure, Tiresias.4

The recent increase in public awareness has coincided with a great deal of public discourse in which
individuals from across the political spectrum have opined publicly and privately about whether gender
dysphoria should be medically treated, and if so, how. Much of the discourse has focused on the issue of
whether transgender children should receive the same medical interventions that are offered to adult
patients.5,6 A 2018 guideline by the American Academy of Pediatrics (AAP) advocated for the importance
of gender-affirming medical care in transgender adolescents,7 citing evidence that gender-affirming care
may reduce depression, anxiety, eating disorders, self-harm, and suicide.8-13

Utah state legislators passed a law on January 28, 2023 prohibiting newly-diagnosed transgender and
gender-diverse minors from receiving gender-affirming medical interventions;14 Utah was the fifth state
to pass legislation banning gender-affirming care for transgender minors.15 Senate Bill (SB) 16 refers to
the ban as a moratorium, and charges the Utah Department of Health and Human Services (UDHHS) to
undertake a systematic review of the medical evidence about gender-affirming hormonal and hormone-
blocking agents and to use that as the basis for making a recommendation to the legislature about
whether the moratorium on use of these treatments in minors should be lifted.14

I.1.2 Objectives
The purpose of this review is to provide evidence to support the UDHHS in its recommendations about
gender-affirming care in transgender, nonbinary, or other gender diverse (TGNB) adolescents, including
the questions listed below:
1. Objectives addressed by the compilation of Pharmacological Agents:
a. What hormones and hormone blockers are used in gender-affirming care of pediatric patients
with gender dysphoria (GD)?
b. What is the regulatory status of the treatments? (ie, are they approved by the US Food and Drug
Administration [FDA] for use in pediatric patients?)
c. What are the indications and contraindications for their use?
d. What are off-label pediatric indications listed in pharmacy compendia for hormones and
hormone blockers?

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2. Objectives addressed by the compilation of Guidelines:
a. What recent clinical practice guidelines address medical interventions for gender-affirming
treatment in pediatric gender dysphoria patients?
b. What recommendations related to hormonal and hormonally active medications for treatment
of GD are made in the guidelines?
c. What are the levels of evidence (LOEs) that support the guideline recommendations?
3. Objectives addressed by the compilation of Systematic Reviews and Clinical Studies (ie,
Experimental Studies, Observational Studies, and Descriptive Studies):
a. What systematic reviews and meta-analyses (SRs/MAs), randomized controlled clinical trials
(RCTs), and observational studies address short- and long-term safety and efficacy outcomes of
hormonal and hormone-blocking agents used for gender-affirming care in pediatric patients?
b. What are the primary and secondary findings of primary studies, including experimental,
observational, and descriptive studies?
c. What is the quality (or risk-of-bias [ROB]) of the evidence?
4. Additional objectives:
a. Among pediatric patients who initiate a hormone or hormone blocker, what are the short- and
long-term rates of discontinuation?

I.1.3 Deliverables Based on a Hierarchy of Evidence

This work was completed on a short timeline. With the goal of providing the highest-quality evidence as
quickly as possible, the work was organized into the following deliverables, in this order:
1. The first deliverable comprised the identification of all specific hormonal and hormonally-active
pharmacological agents that are approved for any use in the US, and that are used (or
recommended for use) as a component of gender-affirming care in the US, based on secondary and
tertiary literature sources. FDA-approved pediatric indications, relevant off-label uses, and
contraindications are provided for each drug. This step was an essential prerequisite to the
remaining work.
2. The second deliverable comprised a tabular summary of recent clinical practice guidelines (since
2010) that address treatment of pediatric gender dysphoria, as identified in bibliographic database
searches. Guidelines were included if they were intended for an audience of practicing clinicians,
and if they were released by organizations that are widely regarded as authorities in their given
specialty (eg, the Endocrine Society for the treatment of endocrine diseases). Authors of these
guidelines typically rate the strength of evidence behind their recommendations, and they may
provide a high- to low-ranking of the recommendations that they make based on the quality of the
underlying evidence. To create high-quality guidelines, such authors often utilize systematic reviews
and primary studies to inform their recommendations, and tend to comprise one of the most
rigorous compilations of evidence for clinical care available. Clinicians rely on guidelines for standard
courses of treatment, to determine options available for nonstandard patients and certain
populations, and to understand which aspects of treatment are uncertain.
3. The third deliverable comprises evidence tables of systematic reviews and/or meta-analyses
(SRMAs), as identified in bibliographic database searches. Systematic reviews have, ideally, rigorous
search terms and attempt to capture all primary studies meeting criteria that will help answer their

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 given research questions. If enough primary studies comparing the same interventions and
outcomes in similar populations are available, these reviews may also include meta-analyses, which
quantitatively analyze and synthesize outcomes across studies to obtain more precision in estimates
of treatment effects, and to improve power for small treatment effects. In this deliverable, a
summary of SRMA findings and an appropriate risk-of-bias (ROB) assessment are provided for each
review.
The guidelines and SRMAs together represent the highest order of available evidence, in that they
draw on the consensus of all the patient-level evidence that their authors found in searches like
ours. To the extent that our highly exhaustive searches experimental, observational, and descriptive
studies yielded many studies that were not cited by many guidelines and SRs, our report has the
potential to more reliably capture the true consensus of the evidence compared to some of the
other top-of-the-pyramid evidence summaries found in guidelines and SRMAs. The conventional
wisdom has long been that there is not a great deal of evidence to support use of these treatments
for pediatric gender dysphoria, but the results of our searches are likely to undermine that particular
narrative. The body of evidence that we have uncovered exceeds the amount of evidence that often
serves as the basis of FDA approval for many high-risk, new drugs approved in pediatric populations
in the US, including recent gene therapies.
4. Of greater urgency to our timeline was a complete bibliography of all included studies identified in
our systematic search bibliographic databases, grouped into relevant publication types. This
bibliography includes all guidelines, systematic reviews, and experimental, observational, and
descriptive/qualitative studies that met our inclusion criteria, even if we did not ultimately perform
data extraction on all of them due to time restrictions for this report. The studies in this bibliography
have passed all of the eligibility screenings: highly sensitive searches, duplicate title and abstract
screening, and duplicate full-text screening.
5. We next delivered detailed evidence tables for all explanatory studies, including experimental (eg,
randomized controlled trial) and observational (ie, cohort, case-control, and cross-sectional)
studies. These evidence tables summarize primary and secondary safety and efficacy findings, as
well as an ROB assessment of comparisons between treated and untreated TGNB adolescents, and
between TGNB adolescents and cisgender peers.
6. Finally, we submitted detailed evidence tables for relevant descriptive studies identified in
bibliographic database searches. These include the notably important, longitudinal, pre-post studies
from The Netherlands that follow pediatric transgender patients into adulthood, as much as 40
years of follow-up in some cases. These also include a large body of evidence from US populations
comprising well over 18,000 TGNB children and adolescents.

I.1.4 Terms Used in This Report

I.1.4.1 Populations
For the purposes of this evidence synthesis, we consider those who have not started puberty as
"children" and those who have started puberty as "adolescents." This distinction matters more than an
exact age because puberty onset (variable as to age) is consistently the time at which one's appearance
and hormones become more gendered, which in turn is a major factor in the intensification or
alleviation of gender dysphoria.

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Because the terms used to refer to gender-diverse people change over time and across place, there is no
consistent naming terminology in the evidence presented. We do not attempt to correct these terms in
the data we extract from primary studies; rather, we present here the terms we have chosen to use. We
use the acronym "TGNB", short for transgender non-binary, as an inclusive, umbrella term that indicates
we are talking about a population of gender-diverse patients, or all patients who may identify as
transgender, nonbinary, or otherwise gender diverse. Where it is otherwise ambiguous, we use the term
"natal" to qualify the terms "male" or "female" when referring to assigned-at-birth gender. We may also
use acronyms for "assigned male at birth" (AMAB) and "assigned female at birth" (AFAB). The terms
"FTM" (female-to-male) and "MTF" (male-to-female) are used to refer, respectively, to natal females
who identify as transgender males, and natal males who identify as transgender females.

Much of the literature may lead readers to believe that the goal for most gender transitions is from
entirely female to entirely male, or vice versa. Although such TGNB patients may be the easiest for study
purposes, their majority is shrinking.16,17 Many gender-diverse patients may need treatments and
procedures so that they are neither male- nor female-presenting, or so they present with the traits of
both genders. In the clinical presentation of gender dysphoria and transgenderism, it should be noted
that gender identity, presentation, and embodiment are highly individual and are guided by the
patient's ultimate alleviation of dysphoria, and ideally, quality of life.

I.1.4.2 Treatment protocols and agents

Numerous means are available to TGNB people wishing to transition. "Social transition"—meaning
everything from wearing gender non-conforming clothes, to hair and makeup, to mannerisms, habits,
and activities, to name and pronoun changes—is flexible, reversible, and available to anyone, including
pre-pubertal children. Gender-affirming surgery (GAS) is another well-known means. In this report, we
address only pharmacologic/hormonal means of transition, also referred to as "medical," for pubertal
adolescent GD patients <18 years. This evidence synthesis found no evidence that pharmacologic/
hormonal treatments are offered to pre-pubertal children with GD.

The terms referring to pharmacologic protocols for puberty suppression, cross-sex hormone therapy, or
both also vary from study to study. For example, some studies use "gender-affirming hormone therapy"
(GAHT) to refer to cross-sex hormone therapy only, while other studies use this term to refer to the arc
starting with puberty-delaying hormones and ending with cross-sex hormones.

The terms we use throughout this report are "puberty suppression" (PS) for the phase of treatment
typically done with GnRH analogs; "cross-sex hormone therapy" (CSHT) for treating natal males with
estrogen-based hormones and natal females with testosterone-based hormones; and "gender-affirming
hormone therapy" (GAHT) to refer to the full arc encompassing both phases.

Finally, we address the various terms referring to gonadotropin-releasing hormone agents used to
suppress puberty: agonists, analog(ue)s, or their abbreviations, GnRHa or GnRH(a). The term we use
throughout the report for these puberty-suppression agents is "GnRH analog," rather than agonists,
analogues, GnRHa, or GnRH(a). "GnRH antagonists" are used for puberty initiation and are referred to as
such the few times they appear in this report.

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I.2.0 AGENTS USED OR RECOMMENDED FOR USE IN PEDIATRIC TGNB
PATIENTS
I.2.1 Off-label Use of Drugs in Pediatric Patients
Off-label use of drugs is commonplace in the US.18 "Off-label use" refers to the practice of prescribing
drugs that are approved for use in the United States (US), by the Food and Drug Administration (FDA),
but using them to treat indications that are not expressly approved by the FDA.19 Off-label use of
medications is widely accepted and often becomes a standard of care.19

The extent of off-label use varies across populations, but worldwide estimates range from 3.2% to
95%.18,20 In US pediatric patients, estimates for off-label use are reportedly as high as 38.1% of
prescriptions,20 and as many as 78.9% of children.21,22 Common medications used off label in pediatric
patients include antibiotics, anticoagulants, beta blockers, and psychiatric drugs.20 Studies examining the
safety of pediatric off-label prescribing in the US are limited, but one study showed no differences in the
risk of adverse events.23

A key driver of this high off-label use prevalence is the substantial financial investment required to get
additional uses approved; because off-label use is otherwise common and legal, drug companies rarely
go to the effort without a financial incentive to offset this cost burden.19,24

The Pediatric Studies of Drugs, Section 505A of the Food and Drug Administration Modernization Act
(FDAMA)(1997), was one attempt to incentivize the practice of getting additional approved indications
for pediatric patients.25 This act allows drug companies to obtain a 6-month patent extension for a
product (upon FDA approval), effectively preventing competitors from marketing generic versions within
that timeframe.25,26 However, many drugs used in pediatric gender dysphoria were off patent long
before that law came into existence, which makes them ineligible for the incentive.

I.2.2 Methods
We first compiled a list of US drugs that, according to reputable pharmacy compendia, are used or
recommended for use in the treatment of pediatric patients diagnosed with gender dysphoria, or who
are transgender, nonbinary, or gender-diverse (ie, TGNB). We also summarize the FDA-approved
indications of these agents in children and adults, as well as off-label indications that are indexed in
reputable pharmacy compendia.

Standard tertiary databases (eg, Micromedex, UpToDate, and the FDA Orange Book) were searched to
identify a comprehensive list of all drug product hormones and hormonally active agents that are used
in pediatric TGNB patients in the United States. Information in these databases that addresses the
relevant questions above will be extracted; for example, the FDA Orange Book was the primary source
for identifying FDA-approved indications.

We identified medications that are used for gender-affirming hormone therapy (GAHT) from
recommendations in clinical practice guidelines, and from relevant citations identified during the full-
text screening of bibliographic database search results. The US FDA-approved indications, off-label uses,
and contraindications for each agent were obtained from the pharmacy compendia, Micromedex27 and

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Lexicomp.28 We included any pediatric off-label uses for identified agents of interest; but we only
included adult off-label uses that specifically addressed a gender transition-related use, including
menstrual suppression.

Generally, the FDA approval date for each agent was obtained from Lexicomp. If Lexicomp did not
provide an FDA approval date for an agent, it was then obtained from the Approved Drug Products with
Therapeutic Equivalence Evaluations29 (commonly referred to as the Orange Book) by noting the oldest
approval date among all entries for a particular agent. Notably, the Orange Book does not provide a
specific date for agents approved prior to 1982, which was the year that the FDA began requiring
approval dates on New Drug Applications. If a discrepancy in the initial date of approval existed between
Lexicomp and the Orange Book, we deferred to the date listed in the Orange Book, which is published by
the FDA.

Agents were arranged into multiple tables, organized by drug class. Agents in some drug classes may not
be included in the tables for several reasons:
They were not found to be used for GAHT, including combination products of included individual
agents (eg, letrozole in combination with ribociclib, finasteride in combination with tadalafil).
They were withdrawn from the market in the US before the date of this report (eg, leuprolide in
combination with norethindrone, oxandrolone).
They were not approved for any use by the FDA (eg, esterified estrogens in combination with
methyltestosterone, cyproterone acetate).

I.2.3 Results
I.2.3.1 Agents used for gender-affirming hormonal therapy (GAHT) in
TGNB adolescents
We identified 66 unique prescription drug entities from 10 different therapeutic classes that are used off
label or recommended for off-label use (according to Micromedex and/or Lexicomp) in patients with
gender dysphoria, and that are available in the US. These are summarized below and detailed in
Appendix I.A.
Gonadotropin releasing hormone (GnRH) analogs (5 agents)
GnRH antagonists (5 agents)
Antiandrogens (6 agents)
Single-ingredient estrogen and testosterone products (10 agents)
Single-ingredient progestin agents (ie, not in combination with another agent; 7 agents)
Combination sex hormone/progestin products (20 agents)
Aromatase inhibitors (3 agents)
Selective estrogen receptor modulators (SERMs; 6 agents)
Androgens (2 agents)
Vasodilators (1 agent)
Selective progestin receptor modulators (SPRMs; 1 agent)

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I.2.3.1.1 FDA-approved indications

None of the identified agents have specifically been approved by the FDA to treat gender dysphoria in
pediatric or adult patients. However, these agents have other various FDA-approved indications; note
that some labeled indications may be approved for use in both adult and pediatric patients or in only
one of these populations.

I.2.3.1.1.1 Pediatric FDA indications

Of the identified agents, 24 have at least one FDA-approved, pediatric labeled indication, as listed
below:
Central precocious puberty (4 agents)
Abnormal uterine bleeding (1 agent)
Post-menarche contraception, including emergency (17 agents)
Acne vulgaris (4 agents)
Premenstrual dysphoric disorder (2 agents)
Folate supplementation (1 agent)
Hypogonadism (3 agents) or delayed puberty (2 agents)
Endometriosis (1 agent)
Hypertension (1 agent)

I.2.3.1.1.2 Adult FDA indications

All 66 identified agents have at least one FDA-approved indication in adults. The various indicated
disease states for these are listed below with the corresponding count of included agents:
Breast cancer (12 agents) or fibrocystic breast changes (1 agent)
Endometriosis, including treatment of associated pain (8 agents)
Hypoplasia of the endometrium (1 agent)
Prostate cancer (13 agents)
Anemia related to uterine leiomyomata (1 agent)
Female infertility (3 agents) or assisted reproductive technology (1 agent)
Benign prostatic hyperplasia (2 agents)
Male pattern alopecia (2 agents)
Ascites due to cirrhosis (1 agent)
Edema (nephrotic syndrome) (1 agent)
Heart failure with reduced ejection fraction (1 agent)
Hypertension (2 agents)
Hyperaldosteronism (1 agent)
Menopause-related symptoms (dyspareunia, vasomotor, atrophy) (15 agents)
Postmenopausal osteoporosis (9 agents)
Hypogonadism (7 agents), hypoestrogenism (5 agents), or delayed puberty (1 agent)

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 Abnormal uterine bleeding (5 agents)
Contraception, including emergency (18 agents)
Menorrhagia (3 agents)
Acene vulgaris (4 agents)
Premenstrual dysphoric disorder (2 agents)
Folate supplementation (1 agent)
Endometrial cancer (1 agent)
Prevention of estrogen therapy-associated endometrial hyperplasia (3 agents)
Renal cell carcinoma (1 agent)
Secondary amenorrhea, diagnostic aid (3 agents)
Prevention of hereditary angioedema (1 agent)

I.2.3.1.2 Indications for off-label use from reputed pharmacy compendia

Overall, 19 agents had off-label indications indexed in Micromedex, and 24 had off-label indications in
Lexicomp.

I.2.3.1.2.1 Pediatric off-label indications

In Micromedex, 14 identified agents had a pediatric off-label indication, and no pediatric off-label
indications were listed in Lexicomp. Of these, the following 6 agents specifically had an indexed off-label
use related to gender dysphoria:
Triptorelin pamoate
Estradiol
Testosterone
Testosterone undecanoate
Testosterone cypionate
Testosterone enanthate

Except for triptorelin, which is classified as "effective," all others are classified as "evidence favors
efficacy" and are recommended based on Category B evidencea (per Micromedex).

Other recommended pediatric off-label indications for the remaining agentsb include the following:
Precocious puberty (1 agent)
Hyperaldosteronism (1 agent)
Bronchopulmonary dysplasia of newborn (1 agent)
Hemorrhagic cystitis (1 agent)
Postoperative hemorrhage (1 agent)

a
Category B evidence is based on meta-analyses of randomized controlled trials (RCTs) with conflicting results, RCTs
with critical limitations (eg, bias, small sample size), or non-randomized studies.
b
Note that some agents may be indexed for ≥ 1 off-label indication

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 Turner syndrome (1 agent)
Alveolar hypoventilation (1 agent)
Central precocious puberty (1 agent)
Gynecomastia (1 agent)
Polyostotic fibrous dysplasia of bone (1 agent)
Retinoblastoma (1 agent)
Retroperitoneal fibrosis (1 agent)

Note that 4 agents had recommendations against their use for certain off-label uses in the pediatric
population due to inconclusive evidence for that particular indication(s), as listed below:
Triptorelin pamoate: growth hormone deficiency, short stature disorder (idiopathic)
Flutamide: congenital adrenal hyperplasia
Danazol: thrombocytopenic purpura (idiopathic or immune)
Anastrozole: pubertal gynecomastia

I.2.3.1.2.2 Adult off-label indications

All 24 agents indexed in Lexicomp and 13 of the 19 agents indexed in Micromedex had an off-label use
related to GAHT in adults. Both Micromedex and Lexicomp recommended the use of 6 agents in male-
to-female (MTF) transgender adults with gender dysphoria, as listed below:
Goserelin
Leuprolide
Spironolactone
Estradiol
Estradiol cypionatec
Estradiol valerate

For female-to-male (FTM) transgender individuals with gender dysphoria, the following agents were
recommended to be used off-label in both Micromedex and Lexicomp:
Testosterone
Testosterone undecanoate
Testosterone cypionate
Testosterone enanthate

Although the listed agents with an adult off-label use for GAHT tended to be the same across the 2
pharmacy compendia, slight variations were observed. For example, conjugated estrogens and
nilutamide were only indexed in Micromedex with an off-label GAHT use in adults. Furthermore, none of
the agents indexed in Micromedex were specifically for the off-label use of menstrual suppression in
FTM transgender adults, but 14 agents were listed in Lexicomp, listed below:

c
Although Micromedex and Lexicomp list a off-label use for this agent in male-to-female transgender adults with
gender dysphoria, no efficacy or recommendation is reported in Micromedex, but this use is supported by guideline
evidence as noted in Lexicomp.

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 Estradiol valerate and dienogest
Ethinyl estradiol and drospirenone
Ethinyl estradiol and desogestrel
Ethinyl estradiol and norethindrone
Ethinyl estradiol and norgestimate
Ethinyl estradiol and levonorgestrel
Ethinyl estradiol and norelgestromin
Ethinyl estradiol and norgestrel
Ethinyl estradiol and ethynodiol diacetate
Ethinyl estradiol, drospirenone, and levomefolate
Medroxyprogesterone (acetate)
Norethindrone
Norethindrone acetate
Levonorgestrel, specifically the intrauterine device

Notably, despite that included agents are recommended in reviewed sources, use of a few is
discouraged in some compendia. For example, Micromedex recommends against the use of finasteride
in MTF transgender adults with gender dysphoria, citing a lack of efficacy.

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I.3.0 EVIDENCE SYNTHESIS METHODS
I.3.1 Protocol
We conducted the current work according to pre-specified, internal protocols for the searches, eligibility
assessment, and data extraction tasks.

I.3.2 Systematic Search Methods

We planned a systematic search to address most of the questions specified in Senate Bill (SB) 16,
including those addressed by guidelines, prior systematic reviews, and inferential and descriptive
studies. We planned a comprehensive search of at least 2 standard bibliographic medical databases,
including Medline and Embase. While we also considered options to search Cochrane CENTRAL,
PsycInfo, and ClinicalTrials.gov if time allowed, and if needed, but as of the date of this report, we have
conducted bibliographic database searches only in Ovid Medline, Embase, and ClinicalTrials.gov.

Several organizations have articulated standards for systematic reviews (SRs) such as the present study.
The most common such guideline is the Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA).30 We have followed the PRISMA guidance as closely as possible given the
abbreviated timeline and the broad scope of the current work.

I.3.2.1 Eligibility criteria

Details of the broad eligibility criteria used to identify studies of interest during the search and screening
phases are summarized in Table I.1. In short, after identifying the comprehensive list of pharmacological
agents, we planned to search for full-text publications that addressed these treatments as either study
exposures/interventions/comparators, study eligibility criteria, or study outcomes (or a function of an
outcome). We identified 66 agents in 10 different drug classes, including sex hormones (testosterones
and estrogens), progestins, gonadotropin-releasing hormone (GnRH) analogs and antagonists, selective
estrogen/progestin inhibitors (SERMs/SPRMs), and others.

The study population of interest was adolescents (ie, patients < 18 years of age, or cohorts with a mean
age of < 18 years, or long-term follow-up studies of patients who initiated treatment at < 18 years of age
or in cohorts with a mean age of < 18 years, and who were transgender, nonbinary, or gender diverse).
Publication types of interest included guidelines, systematic reviews (SRs), experimental studies,
observational studies, and descriptive studies.

We limited study eligibility to papers that were published since 2010 to facilitate the identification of
modern studies, to include those that may have informed the addition of the diagnostic term for gender
dysphoria in DSM-5, and to include recent studies that likely inform modern treatment choices. We
chose not to restrict eligibility based on comparator, outcome, or publication language; however, some
otherwise eligible studies were included but did not undergo data collection for these reasons and
others. These are nonetheless provided in the bibliography of included studies.

After relevant studies were identified in the search and screening phases of the work, further eligibility
criteria were applied by the lead author for each category of evidence (ie, guideline, systematic review,
or experimental, observational, or descriptive study) before the data extraction phase in order to ensure

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Table I.1. Eligibility criteria for relevant publications in the search and screening phases
Publication types and study designs
Guidelines
We included guidelines that met the IOM definition of a clinical practice guideline,31 listed below, if they were
written or published by a well-recognized medical authority, and if they provided recommendations about the use
of treatments of interest in the population of interest. For treatments and populations of interest, see below
under Intervention and Population, respectively.
Clinical practice guideline definition: "…statements that include recommendations intended to optimize
patient care that are informed by a systematic review of evidence and an assessment of the benefits and
harms of alternative care options."

Clinical studies
Study designs (S) of interest included systematic reviews or cohort-type reviews, experimental studies,
observational studies, and descriptive studies. To simplify the task of classifying patient-level clinical studies, we
used simple categories devised by Gehlbach,32 summarized in Figure I.1. In short, each publication type or study
design of interest is defined as follows:
Systematic reviews: We included review articles that described a systematic search in 1 or more bibliographic
database, which were described by authors as a "systematic review" or has having a "systematic search" or a
"comprehensive search," or reviews that were cohort-type meta-analyses (eg, prospective meta-analyses or
other full cohort of studies identified before any results were known)
Experimental studies: We included any RCTs or pseudo-randomized studies (ie, those that were not
randomized, but in which the intent was to randomize patients), or non-randomized experimental studies. We
also included single-arm clinical trials, but these were grouped with descriptive studies (below) in keeping with
our chosen study design taxonomy (ie, Gehlbach's taxonomy).32
Observational studies: We included all eligible cohort, case-control, and cross-sectional studies. Because these
may not use standard terminology to describe the study designs (eg, a "retrospect database analysis"), we
used definitions from Gehlbach's taxonomy for making these classifications.32 In short, observational studies
included any non-experimental study in which inferential statistics were used to compare either (a) study
outcomes between 2 or more exposure groups, or (b) study exposures between 2 or more outcome groups.
These were included if subjects from our population of interest (see below under Population) were included in
one or more exposure or outcome group, and in which study exposures or outcomes included an intervention
of interest (see below under Intervention).
Descriptive studies: We included all eligible case reports and case series if they addressed the population and
interventions of interest. Initially we had planned to extract data for all descriptive study designs, including
case reports that contained a statement about IRB (or other ethics board) review and approval/exemption, or
specified that informed consent was obtained from study subjects for research or publication. However, due to
time constraints and the number of relevant publications, only longitudinal, pre-post descriptive studies
underwent data collection. Other descriptive studies lacking such pre-post comparisons were included in the
bibliography only.

Population
The population of interest was pediatric patients (ie, ages < 18 years) described as having gender
dysphoria/transition/diversity or being non-binary and/or transgender (ie, pediatric TGNB patients). We included
studies that mixed TGNB children and adults if the studies met at least one of the following conditions:
Findings were reported separately for minors (ie, ages < 18 years).

Table abbreviations: IOM, Institute of Medicine; RCT, randomized controlled trials; IRB, investigational review
board; US, United States; TGNB transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing
hormone; SERM, selective estrogen receptor modulator; SPRM, selective progestin receptor modulator
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 32
Figure I.1. Relevant clinical study designs included in the report grouped according to
Gehlbach's taxonomic definitions

Table abbreviations: TGNB, transgender, nonbinary, or other gender diverse

that the most relevant evidence was highlighted, and to ensure that the scope of the work was
manageable within our abbreviated timeline. These additional eligibility criteria are described in the
methods sections specific to guidelines, SRs, experimental studies, observational studies, and descriptive
studies.

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I.3.2.2 Search strategies
Search strategies for bibliographic databases were developed and conducted according to best-practice
standards. We planned to employ both structured vocabulary searches (eg, medical subject headings
[MeSH] for Medline and Emtree for Embase) and unstructured keyword terms in relevant database
fields. Searches were implemented in phases, including structured-vocabulary-only searches in the first
phase, and complete searches in the second.

The relevant citations identified in the structured-vocabulary-only searches are collectively referred to
as "first-corpus" citations where applicable throughout this narrative. These included structured
vocabulary terms for gender dysphoria (eg, Gender Dysphoria/ or Transgender Persons/ or Gender
Identity/ or Transsexualism/), pediatrics (eg, Pediatrics/ or Child/ or Minors/ or Adolescent/ or
Puberty/), and interventions of interest (eg, Gonadotropin-releasing hormone/ or Gonadal Steroid
Hormones/ or Hormone Replacement Therapy/ or Androgens/ or Estrogens/ or exp Progesterone/).

Complete searches, which were designed to find remaining studies, are collectively referred to as
"second- corpus" citations. These included a combination of all structured-vocabulary terms from first-
corpus searches, plus free-text terms. The inclusion of free-text terms ensures the identification of
relevant in-process citations and citations that were incorrectly or incompletely indexed.

All searches, including both first- and second- corpus searches, were limited to relevant citations
published since 2010 to ensure that studies leading up to the 2013 addition of the term gender
dysphoria in the DSM-5 were retrieved. Search strategies also used validated, high-quality filters for
publication types (ie, guidelines, systematic reviews, experimental studies, observational studies,
qualitative studies, and descriptive studies).33-37 We also used a validated filter to exclude non-human
studies.38 Searches were conducted between March 9 and June 5, 2023. All searches were peer
reviewed internally before implementation. Complete searches for Medline and Embase are
summarized in Appendix I.B.

I.3.3 Study Relevance Assessment Methods

As searches were completed, meta-data for potentially relevant bibliographic references were
downloaded into Covidence, an online tool designed to support systematic review work (Covidence.org,
Veritas Health Innovation, Melbourne, Australia). Two phases of study eligibility screening were then
conducted, including (1) title/abstract screening, and (2) full-text screening, described below.

I.3.3.1 Title/Abstract screening

Title and abstract (TIAB) screening was conducted in duplicate in Covidence using the eligibility criteria
given in Table I.1. Reviewers were instructed to assess eligibility on the basis of the population,
intervention, and study design (or publication type) only. Studies that otherwise met population and
study-design eligibility criteria were included if treatments of interest were included in any of the
following ways:
1. It was an intervention or comparator
2. It was an outcome or a function of an outcome
3. It was an eligibility criterion

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At this stage, all potentially-relevant studies were included, regardless of outcomes and language of
publication. Disagreement between reviewers about the relevance of any citations was resolved by
consensus or by a third reviewer.

I.3.3.2 Full-text screening and tagging

All citations that were deemed to be potentially relevant in TIAB screening were retrieved in full text and
underwent duplicate full-text screening in Covidence. While eligibility criteria did not change for the
identification of relevant studies, we began to identify studies that would be included in the
bibliography, but that would not undergo data collection. These are defined as follows:
Potentially-relevant, non-English studies of all types did not undergo data extraction, but were
included in the bibliography.
Descriptive studies (ie, case reports and case series) that lacked a statement about ethics review or
institutional review board (IRB) review and approval/exemption, or a statement about obtaining
informed consent for research, did not undergo data extraction, but were included in the
bibliography.

Disagreement about eligibility between two independent authors at the full-text screening stage was
resolved by consensus or by a third reviewer when consensus could not be reached.

Studies that did not meet eligibility criteria as defined in Table I.1 were excluded at this stage, and a
reason for exclusion was selected. Included studies underwent additional full-text screening before data
extraction, as described in the study design-specific methods below.

A single study design category was assigned to each primary study using a simple taxonomy
(Gehlbach’s).32 While many studies can meet the criteria for multiple study designs, we used a gestalt
method of assigning the design, which was based on which types of comparisons seemed to be the
major point of the paper. Studies in which the major point of the paper seemed to be to make between-
group comparisons were assigned as experimental or observational studies, and studies in which the
major point seemed to be to make within-group comparisons were assigned as descriptive studies.

I.3.4 Study Design-specific Methods

Study design-specific methods (including additional study design-specific full-text eligibility
assessments), data-collection methods, and risk-of-bias assessment methods for each study design are
summarized in the sections below.

I.3.4.1 Guideline-specific methods

I.3.4.1.1 Final full-text eligibility assessment

Included guidelines met eligibility criteria in Table I.1. The published guideline text, supplementary
materials, and publishing organization website, when available, were assessed to determine guideline
inclusion. To meet the inclusion criteria of performing a systematic review, guidelines were required to
report performing a systematic review for at least 1 part of the guideline. If a guideline did not report

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performing a systematic review for a section in which recommendations were extracted, we required
that the guideline at least cite and discuss published literature supporting each recommendation.

Guidelines with recommendations that were not formed by the publishing organization were excluded
(eg, publication from a medical authority that summarized recommendations from another authority's
guideline). Guidelines that only addressed intervention/outcome pairs that were excluded after the
stage of full-text eligibility were also excluded at this stage. For example, we excluded from
consideration any evidence that addressed menstrual suppression with common treatments that would
also be offered to cis women who required menstrual suppression. Consequently, we only considered
guidelines that addressed menstrual suppression if they included recommendations about use of
testosterone for menstrual suppression, as testosterone is the only one of the available options that
would not be offered to cisgender women.

I.3.4.1.2 Data collection

Published guideline text, supporting appendices, and the guideline organization's website (for guideline
construction methodology only) were searched for relevant information to extract. A single author of
this report reviewed guidelines for relevant information. Formal guideline recommendations (ie,
recommendations or statements created by consensus of the guideline authors, and when part of the
guideline methodology, assigned a risk-of-bias [ROB] or level-of-evidence [LOE] rating) or informal
recommendations (eg, non-consensus statements provided as supplementary text) were eligible for
extraction.

The primary extraction focus was hormonal/hormone-blocking (see list in Table I.1) treatment
information about who should be treated, which agent(s) are recommended, and when the treatment
should be started and/or stopped for the target population (TGNB youth). In addition, guideline
development methodology was extracted. Recommendation strengths and/or LOE ratings for each
hormonal treatment recommendation were extracted when provided. Lastly, an overview of guideline
recommendations about safety and efficacy monitoring for hormonal/hormone-blocking therapies, and
the recommended population to receive the monitoring were extracted.

Some reviewed guidelines addressing both youth and adults do not state whether a hormonal therapy
recommendation is intended for youth, adults, or both. When applicable, only recommendations
pertaining to youth were extracted (eg, relevant recommendations from the section of the guideline
devoted to adolescents). If a guideline including all ages did not specify an age for a hormonal therapy
recommendation, we interpreted that recommendation as applying to both adolescents and adults.

Extracted information other than about guideline development methodology is from the following
guideline chapters or sections:
World Professional Association for Transgender Health (WPATH; 2022): chapter 2 (medical necessity
of treatment), chapter 7 (lack of hormonal therapy for pre-pubertal TGNB children), chapter 6
(assessment and treatment of TGNB adolescents), and chapter 12 (hormonal therapy treatment
recommendations for adolescents and adults).39
American College of Obstetricians and Gynecologists (ACOG; 2022): This guideline only addresses
menstrual suppression. Information on the section about transgender and gender-diverse patients
was extracted.40

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 European Society for Sexual Medicine (ESSM; 2020): sections "Assessment of gender diverse
children and adolescents," "Hormone therapy in trans AFAB [assigned female at birth] people," and
"Hormone therapy in trans AMAB [assigned male at birth] people."41
Endocrine Society (ES; 2017): sections "Evaluation of youth and adults," "Treatment of adolescents,"
"Adverse outcome prevention and long-term care," and "Surgery for sex reassignment and gender
confirmation" (for a single non-graded statement about the recommended duration of GAHT).42

I.3.4.1.3 Risk of bias assessment

A risk-of-bias assessment was not conducted on guidelines as part of the current work because we
restricted inclusion to recognized medical authorities who published evidence-based guidlines.
However, we exctracted information about any ROB assesssment of the primary evidence that was
made by guideline authors.

I.3.4.2 Systematic review-specific methods

I.3.4.2.1 Final full-text eligibility assessment

Systematic reviews (SRs) that met the eligibility described in Table I.1 were included in the SR
deliverable. Further full-text eligibility assessment was then conducted by one author of this review to
limit data collection to the highest-quality subset of reviews, including the following criteria:
Potentially relevant SRs that were published in a non-English language, but which had an English-
language abstract suggesting they met inclusion criteria, were listed in the bibliography only and did
not undergo data extraction.
SRs that did not include one or more of the following highest-priority outcomes were included in the
bibliography only and did not undergo data extraction:
o Mental health (eg, depression, anxiety, suicidality)
o Psychosocial functioning (eg, executive function, brain activity, education, quality of life)
o Body changes (eg, changes in height, fat/lean/body mass changes, development of secondary
sex characteristics such as breast development or deepening voice, menstruation)
o Body image (eg, body dysphoria/gender dysphoria, body satisfaction)
o Bone health (eg, bone density, bone turnover measures)
o Cardiovascular risk factors (eg, thrombotic changes, insulin sensitivity, blood pressure, obesity)
o Cancer
SRs that did not report results of their search, such as those that only included a narrative synthesis
but without descriptions of the primary studies included, were included in the bibliography only and
did not undergo data extraction.
SRs that did not search at least 2 bibliographic databases were included in the bibliography only and
did not undergo data extraction. (For this criterion, Medline was considered a single database,
whether it was searched via PubMed or Ovid; Ovid Medline contains a subset of all PubMed
citations.)

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I.3.4.2.2 Data collection

Data collection was conducted by a single author. Data that were extracted included for each SR
included a purpose statement, the type of synthesis conducted (ie, narrative vs quantitative),
bibliographic databases that were searched, dates of the searches, numbers of primary studies that
examined treatments in TGNB children and/or adolescents, total numbers of TGNB children and/or
adolescents that were represented in the primary studies, the treatments examined in each SR, the
outcomes examined in each SR along with the specific measures that were used in the primary study,
and relevant study-level findings reported in each SR.

I.3.4.2.3 Risk-of-bias assessment

An ROB assessment of each SR was conducted by a single author using the complete AMSTAR-2, a 16-
item checklist designed to assist readers of SRs in assessing the ROB.43 Relevant items in AMSTAR are
summarized in Table I.2. A subset of the items deemed "critical" by the AMSTAR-2 authors are also
indicated.

Table I.2. Explanations for ROB items included in the AMSTAR-2 tool for SR 43

quality
Item Item description Critical
number Explanation domain

Did the authors use a well-specified research question and inclusion criteria?
The PICO framework (ie, (population, intervention, control group, and outcome) is
1 commonly used to define a focused research question for systematic reviews. A well-
specified research question reduces the risk that the search strategy and the authors'
objectives will not be well-matched, and it reduces the risk that the authors will make
biased study eligibility decisions.

Did the authors use methods that were established prior to beginning the work?
2 SRs are observational studies of other studies. Best practices for all observational studies
are that a protocol should be created in advance, reducing the risk of bias in the findings.

Did the authors justify their study design restrictions?

Some questions can only be answered with nonrandomized studies, such as effects of a
policy change, or studies of interventions in a vulnerable population without other
3 treatment options. Other questions require only experimental studies. However, most
research questions can only be well-answered by including all study types. If authors
restrict eligibility to only a particular study design, they should give a justification for that
restriction.

Did the authors use a comprehensive search strategy?

SRs can only reveal the true consensus of the evidence if one of 2 conditions is met: (1)
4
they must include all the relevant studies; or (2) they must include a completely random
sample of all relevant studies. Because of the difficulty obtaining the second type of
sample, the best practice is to find everything. Because of bias in publishing, it can be

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Table I.2. Explanations for ROB items included in the AMSTAR-2 tool for SR 43

quality
Item Item description Critical
number Explanation domain
very difficult to find all the relevant studies without a comprehensive and exhaustive
search strategy.

Did the authors perform duplicate study selection?

Authors can easily make mistakes in determining study eligibility, or can inadvertently
5 allow bias to creep into their eligibility assessment. To minimize the risk of this
happening, best practice for SRs are that review authors should conduct title/abstract
and full-text eligibility screening in duplicate.

Did the authors perform duplicate data extraction?

6 Data extraction can be very complex and error-prone. For this reason, best practice is
that data collection should be performed in duplicate, with a plan for resolving any
disagreement.

Did the authors provide a list of excluded studies?

Because of the subjectivity inherent in evidence synthesis, best practice for review
7 authors is that they should provide a list of studies excluded at the stage of full-text
review along with reasons for exclusion. This enables readers to determine whether
some excluded studies should have been included.

Did the authors adequately describe included studies?

Heterogeneity of included studies (eg, major differences in population characteristics
8 across studies) can distort review findings. That's why best practices for review authors
are that they should provide key details about the populations, interventions,
comparators, outcome measures, study designs, and settings of included studies. The
provision of these details enables readers to make judgments about study heterogeneity.

Did the authors assess study-level ROB?

9 All primary studies are subject to bias. A good systematic review will make assessments
of ROB in the primary studies so that they can consider whether bias is distorting the
review's findings.

Did the authors report on the sources of funding for primary studies?
10 Funding source tends to be highly correlated with systematic differences in the nature
and direction of study results. That's why best practice for review authors is that they
examine sources of funding in the primary studies.

Did the authors use appropriate methods for statistical combination of results?
In the presence of heterogeneity, review authors should be very careful about which
11 approach they use to calculate quantitative summaries of treatment effects, if it is even
appropriate to do so. This item may be irrelevant when authors use a narrative or
qualitative synthesis only.

12 Did the authors assess the impact of primary-study ROB on their findings?

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Table I.2. Explanations for ROB items included in the AMSTAR-2 tool for SR 43

quality
Item Item description Critical
number Explanation domain
Because study-level ROB can distort a review's finding, review authors should go beyond
just assessing study-level ROB; they should conduct sensitivity and subgroup analyses to
examine the extent to which study-level ROB is distorting their findings. This item may be
irrelevant when authors use a narrative or qualitative synthesis only.

Did the authors address study-level ROB when interpreting/discussing their findings?
Because of the importance of study-level ROB, investigators should go beyond assessing
13 primary-study ROB and examining its impact on their findings. They should discuss its
effects on their findings in their narrative. This item may be irrelevant when authors use
a narrative or qualitative synthesis only.

Did the authors explain and discussion any observed heterogeneity?

Because heterogeneity can distort review findings, review authors should go beyond
14 simply measuring heterogeneity; they should also examine potential sources of
heterogeneity, and theorize about the impact it may have on their findings. This item
may be irrelevant when authors use a narrative or qualitative synthesis only.

Did the authors investigate small study bias and discuss its impact on their findings?
The effects of several reporting biases, such as publication bias, can be seen by
15 examining funnel plot asymmetry. A statistical or visual examination asymmetry can
reveal the presence of bias in the review's findings. This item may be irrelevant when
authors use a narrative or qualitative synthesis only.

Did the authors report their own funding sources or conflict of interest?
16 Because of the strong correlation between funding source and study findings, review
authors are asked to report any financial conflicts of interest.

I.3.4.3 Methods for the bibliography of all relevant studies

To compile this bibliography, all relevant sources passed 3 levels of screening: search screening, title and
abstract screening, and full-text screening. The eligibility criteria specific to guidelines and systematic
reviews are detailed above in Sections I.3.3.1 and I.3.3.2, respectively. The eligibility criteria specific to
experimental studies, observational studies, and descriptive studies are presented in Sections I.3.3.4,
I.3.3.5, and I.3.3.6, respectively.

I.3.4.4 Experimental study-specific methods

I.3.4.4.1 Clinicaltrials.gov search

While it was not a part of the contracted work, we planned to search ClinicalTrials.gov if few clinical
trials were found in bibliographic database searches.

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I.3.4.4.2 Final full-text eligibility

Experimental studies that met eligibility criteria according to Table I.1 were to be included in this review.
Experimental studies that did not examine relevant outcomes of interest (listed below) were tagged for
inclusion in the bibliography only.
Mental health (eg, depression, anxiety, suicidality)
Psychosocial functioning (eg, executive function, brain activity, education, quality of life)
Body changes (eg, changes in height, fat/lean/body mass changes, development of secondary sex
characteristics such as breast development or deepening voice, menstruation)
Body image (eg, body dysphoria/gender dysphoria, body satisfaction)
Bone health (eg, bone density, bone turnover measures)
Cardiovascular risk factors (eg, thrombotic changes, insulin sensitivity, blood pressure, obesity)
Cancer

I.3.4.4.3 Data collection

Data collection for experimental studies was combined with data collection for other study designs.
Experimental studies that made between-group comparisons underwent data collection with
observational studies based on the comparison type (ie, between-TGNB-group or TGNB vs peer-group
comparisons). Single-arm experimental studies underwent data collection with descriptive studies (ie,
longitudinal, pre-post, within-group comparisons).

I.3.4.4.4 Risk-of-bias assessment

When it was possible to do so, ROB assessment for non-randomized experimental studies was combined
with ROB assessment for other study designs. Experimental studies that made between-group
comparisons (eg, TGNB patients who received an intervention vs cisgender patients who did not)
underwent ROB assessment with similar observational studies as described below. Single-arm
experimental studies underwent data collection with descriptive studies as described below.

I.3.4.5 Observational study-specific methods

I.3.4.5.1 Final full-text eligibility assessment and tagging

Observational studies that met eligibility according to Table I.1 were included in this review. Potentially-
relevant, non-English publications with English-language abstracts that met inclusion criteria were also
assigned to the bibliography only. Observational studies that did not examine high-priority outcomes of
interest (listed below) were tagged for inclusion in the bibliography only.
Mental health (eg, depression, anxiety, suicidality)
Psychosocial functioning (eg, executive function, brain activity, education, quality of life)
Body changes (eg, changes in height, fat/lean/body mass changes, development of secondary sex
characteristics such as breast development or deepening voice, menstruation)
Body image (eg, body dysphoria/gender dysphoria, body satisfaction)
Bone health (eg, bone density, bone turnover measures)

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 Cardiovascular/metabolic risk factors: thrombotic/thromboembolic, insulin sensitivity, obesity,
blood pressure, cholesterol, liver, and kidney outcomes
Cancer

Included studies were further examined to determine the study design (ie, cohort study, case-control
study, or cross-sectional study), and were categorized further according to the types of between-group
comparisons made, including the following:
A. Between-TGNB-group comparisons: These studies made inferential comparisons between 2 or more
TGNB groups. For example, a study that compared treated TGNB children with untreated TGNB
children (eg, comparisons between treated and untreated TGNB children).
B. TGNB vs cisgender peer group comparisons: These studies made inferential comparisons between 1
or more TGNB groups and one or more cisgender control groups from the general population.
C. TGNB vs other populations: These studies made inferential comparisons between 1 or more TGNB
groups and one or more special populations, such as patients with sex developmental disorders.

Comparison types A and B above (ie, between-TGNB-group comparisons and between TGNB-group vs
peer group comparisons) were considered 2 of the 3 highest-priority comparisons to evaluate for this
evidence synthesis and were tagged for data extraction, as long as they also examined the identified
high-priority outcomes. Those studies that lacked high-priority outcomes, along with type C above (ie,
studies in which TGNB patients were compared to special populations, such as patients with a
developmental sex disorder) were assigned to the bibliography only. For type C studies, the decision to
exclude them was a function of the large number of higher-priority studies with relevant comparisons of
interest in the context of the limited time available for this review.

Some observational studies had comparisons that met more than 1 of the group comparison types listed
above. If these had high-priority outcomes, these were assigned to data collection in multiple stages.

I.3.4.5.2 Data extraction and record annotation

Because there were so many observational studies, data extraction was conducted by a team of authors
in multiple phases, staged according to the comparison types described above.

For each phase, a data collection tool was developed in Excel and piloted to standardize the data
collection process among the multiple authors. There were 5 steps in the data collection, listed below:
1. Confirm data collection tasks: During this data collection step, authors collected 3 types of data:
a. Confirmation of between-group comparisons: Authors confirmed that there was 1 or more or
more between-group comparison of the type specified, regardless of outcomes. For example,
during the phase of data extraction for between-TGNB-group comparisons, authors were asked
to confirm that there was one or more inferential finding reported that compared 1 group of
TGNB subjects to another.
b. Identification of relevant comparisons: Authors listed each inferential between-group
comparison reported of the type specified (ie, comparison type A, B, and/or C), regardless of
outcomes. For example, during the phase of data extraction for between-TGNB-group
comparisons, authors were asked to list the comparisons in the following format: [Outcome list]
was compared between [exposure group] vs [comparator group] at [time]. Bracketed phrases

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 were replaced by the outcome, exposure definition, comparator definition, or timeframe for
follow-up (eg, baseline or 6 months).
c. Identification of included comparisons: Authors were asked to indicate which between-group
comparisons required data collection (ie, comparison type A and/or B) because they pertained
to a high-priority outcome (ie, outcomes 1-6, above). For example, during the phase of data
extraction for between-TGNB-group comparisons, and if a study reported findings for 2
inferential between-TGNB-group comparisons, but only one included an outcome of interest,
authors highlighted only the one that included the outcome of interest.
4. Extract details for the included comparisons: During this data collection step, authors collected 3
types of data:
a. Give the number of included comparisons: Authors were asked to indicate the number of
relevant inferential comparisons that required data extraction. This number should match the
number of highlighted comparisons described in step 1c, above.
b. Extract details of included comparisons: For each included comparison, authors extracted data
on the population studied; number of subjects included; eligibility criteria; setting; sampling
method; subset definition (if the extracted comparison was conducted in a subset of the whole
study population); and summary baseline characteristics overall, for the subset (if relevant), and
for each comparison group. They also extracted details of exposure and comparator definitions
and numbers in each group, outcome definitions and numbers with each outcome (if
dichotomous) or mean values (if continuous), and a summary of the hypothesis test findings.
c. Manuscript annotation: Authors were asked to annotate the PDFs of each study to highlight
relevant and included comparisons, including additional comparisons to be addressed in other
data extraction phases. For example, during between-TGNB group data collection, authors
highlighted comparisons that would need to be extracted during the phase of TGNB vs peer data
collection, if any.
5. Complete ROB assessment: Authors completed the ROB assessment for the study overall, or for a
primary included comparison if no included comparisons were conducted in the full study cohort,
using an appropriate tool as described below.
6. Identify any other treatment-related, inferential comparisons that will need to be extracted in
other phases. Authors were asked to indicate what other inferential comparisons were reported in
the study that would need to be examined during other data-extraction phases. For example, during
between-TGNB-group data extraction, if authors saw an inferential pre-post comparison (eg, a value
at follow-up was compared to a value at baseline in the same group), then they would indicate that
a "pre-post descriptive" comparison remained to be addressed during the data collection task for
descriptive studies.

I.3.4.5.3 Risk-of-bias assessment

The Newcastle-Ottawa Scale (NOS) was used for ROB assessment.44 The NOS has two versions: one for
cohort studies, and another for case-control studies. We applied the NOS to all observational study
types, adapting it for cross-sectional studies by excluding items that were relevant to the duration of
follow-up. We decided not exclude items related to the temporality requirement for cohort and case-
control studies (ie, that all measured exposures must precede measured outcomes), as this is a clear
weakness of cross-sectional studies that increases the ROB for those studies relative to cohort studies.

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The NOS is a validated tool with good inter- and intra-rater reliability. It comprises 8 items each for
cohort and case-control studies, as described in Table I.3. The NOS contains items in each of 4 domains,
including 3 each for cohort studies (selection bias, comparability, and outcome assessment) and case-
control studies (selection bias, comparability, and exposure assessment). A summary score for each
domain can be calculated, ranging from 0-5 stars for the selection domain with cohort studies, and 0-4
stars for the selection domain with case-control studies, 0-1 star for the; comparability domain for both
study types, and 0-3 stars for the outcome domain for both study types. Overall scores range from 0 to 8
stars for cohort studies, and 0-7 stars for case-control studies.

Table I.3. Explanations for ROB items included in the NOS tool for observational study 44

quality
Domain Item # Cohort study items Case-control study items Scoring
Domain: Selection
Item 1 Representativeness of the exposed Case definition 0-1 stars
cohort Asks whether the case definition is with
Asks whether the exposed cohort was regards to identifying the outcome. This
representative of the larger population relates to a question of accurate
from which the sample was drawn. This outcome classification, an issue of
relates to selection bias as a question of information bias.
generalizability.

Item 2 Selection of the nonexposed cohort Representativeness of cases 0-1 stars

Asks whether the comparator group was Asks whether all cases were included, or
drawn from the same community as the whether a cherry-picked subset of cases
exposed cohort. This relates to a type of were included. This concerns
selection bias that can introduce confounding bias, which occurs when
confounding bias into the study. other causes of the outcome are ignored.

Item 3 Ascertainment of exposure Control selection 0-1 stars

Asks how the exposure was assessed, Asks how controls were selected,
whether by secure records, interviews, whether they came from the same
self-report, or other. This item is in the population that gave rise to the cases, or
selection bias domain for the NOS, but whether they came from different
misclassified exposures (or outcomes) are populations. The latter can introduce
classically a concern about information confounding bias.
bias.

Item 4 Outcome temporality requirement Control definition 0-1 stars

Asks if the authors of the primary study Asks whether controls were selected
demonstrated that the outcome was not from all non-cases (eg, cumulative
present at the beginning of the study; sampling), or whether some other
including patients not at risk for the sampling method was used (ie, case-
outcome is classic selection bias. cohort or risk-set sampling). Cumulative
sampling may bias a study away from the
null hypothesis if the outcome is

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Table I.3. Explanations for ROB items included in the NOS tool for observational study 44

quality
Domain Item # Cohort study items Case-control study items Scoring
common, but this item awards a point
for that method.

Domain: Comparability
Item 1 Comparability of (exposure/comparator) Comparability of (case/control) groups 0-1 stars
cohorts Asks if study investigators controlled for
Asks if study investigators controlled for one or more key confounding factors,
one or more key confounding factors, whether by a study design method (ie,
whether by a study design method (ie, matching, restriction, stratification), or a
matching, restriction, stratification), or a statistical method.
statistical method.

Domain: Outcome
Item 1 Outcome assessment Exposure ascertainment 0-1 stars
Asks how outcomes were classified, a Asks about the data source used for
factor that concerns information bias. exposure ascertainment; this item
concerns information bias.

Item 2 Duration of follow-up Comparability of exposure 0-1 stars

Asks whether the study duration is ascertainment method
sufficiently long for an outcome to occur This item asks whether exposure
as a result of the exposure. ascertainment was the same in both
cases and controls; this item concerns
either differential information bias or
confounding bias or both.

Item 3 Attrition Non-response rate 0-1 stars

Asks whether any patients were lost to This item asks about percentage of study
follow-up during the study period; if so, subjects who do not respond to surveys,
confounding bias can be introduced. or who lack data on exposures.
Depending on how a lack of response is
handled by investigators, nonresponse
may introduce either information bias or
selection bias.

I.3.4.6 Descriptive study-specific methods

I.3.4.6.1 Descriptive study full-text eligibility assessment

Descriptive studies that met eligibility according to Table I.1 were included in this review. Potentially-
relevant, non-English publications with English-language abstracts that met inclusion criteria were also
assigned to the bibliography only. Descriptive studies that did not examine high-priority outcomes
(listed below) were tagged for inclusion in the bibliography only.

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1. Mental health (eg, depression, anxiety, suicidality)
2. Psychosocial functioning (eg, executive function, brain activity, education, quality of life)
3. Body changes (eg, changes in height, fat/lean/body mass changes, development of secondary sex
characteristics such as breast development or deepening voice, menstruation)
4. Body image (eg, body dysphoria/gender dysphoria, body satisfaction)
5. Bone health (eg, bone density, bone turnover measures)
6. Cardiovascular/metabolic risk factors: thrombotic/thromboembolic, insulin sensitivity, obesity,
blood pressure, cholesterol, liver, and kidney outcomes
7. Cancer

Due to an overwhelming volume of descriptive studies to examine within our very limited time
constraints, we ultimately restricted data extraction to only 2 types of descriptive studies (ie, single-arm
clinical trials and longitudinal, pre-post descriptive studies). All case series, case reports, and other
descriptive studies that did not assess high-priority outcomes at 2 or more time points did not undergo
data extraction. Potentially relevant, non-English descriptive studies were also assigned to the
bibliography only.

In the bibliography, we also distinguish between case series/reports that include a statement about
IRB/ethics board review or subjects' consent, and those that do not have such statements. This is to
indicate which studies certainly used real patients and those that may or may not have used fictional or
composite patients; the latter studies are sometimes written for educational purposes.

I.3.4.6.2 Data extraction and record annotation

A data collection tool was developed in Excel and piloted to standardize the data collection process,
which was to be completed by multiple authors. There were 5 steps in the data collection, listed below:
1. Confirm data collection tasks: During this data collection step, authors collected 3 types of data:
a. Confirmation of relevant and/or included comparisons: Reviewers confirmed that there was 1
or more or more within-TGNB-group comparison, regardless of outcomes. For example,
reviewers were asked to confirm that there was one or more inferential finding reported that
compared mean outcome measures in a TGNB study sample both before and after a treatment
was initiated.
b. Identification of relevant comparisons: Reviewers listed each inferential within-group, pre-post
comparison that was reported, regardless of outcomes. For example, reviewers were asked to
list the comparisons in the following format: [Outcome list] was compared at [time 1 (eg, "12
months")] vs [time 0 (eg, "baseline")] in [population] who received [exposure]. Bracketed
phrases were replaced by the outcome, exposure definition, population, or timeframe for
follow-up.
c. Identification of included comparisons: Authors were asked to indicate which within-group,
pre-post comparisons required data collection. For example, if a study reported findings for 2
inferential within-TGNB-group comparisons, but only one included an outcome of interest,
authors highlighted the one that included the outcome of interest.
8. Extract details for the included comparisons: During this data collection step, reviewers collected 3
types of data:

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 a. Give the number of included comparisons: Reviewers were asked to indicate the number of
relevant inferential comparisons that required data extraction. This number should match the
number of highlighted comparisons described in step 1c, above.
b. Extract details of included comparisons: For each included comparison, reviewers extracted
data on the population studied; number of subjects included; eligibility criteria; setting;
sampling method; subset definition (if the extracted comparison was conducted in a subset of
the whole study population); and summary baseline characteristics overall, for the subset (if
relevant), and for each comparison group. They also extracted details of exposure definitions
and numbers in each treatment group, outcome definitions and numbers with each outcome (if
dichotomous) or mean values (if continuous), and a summary of the hypothesis test findings.
c. Manuscript annotation: Reviewers were asked to annotate the PDFs of each study to highlight
relevant and included comparisons, including additional comparisons to be addressed in other
data extraction phases. For example, reviewers highlighted comparisons that would need to be
extracted during the phase of TGNB vs peer data collection, if any.
9. Complete ROB assessment: Reviewers completed an ROB assessment for the study overall, or for a
primary included comparison if no included comparisons were conducted in the full study cohort,
using the National Institutes of Health (NIH) Quality Assessment Tool for Before-After (Pre-Post)
Studies with No Control Group,45 as described below.
10. Extract information on funding and financial conflicts of interest: Reviewers extracted data from
the manuscript about 2 types of financial conflicts of interest: (A) funding for the study, and (B)
other financial conflicts of interest.
11. Identify any other treatment-related, inferential comparisons that will need to be extracted in
other phases: Reviewers were asked to indicate what other inferential comparisons were reported
in the study that would need to be examined during other data-extraction phases. For example,
during between-TGNB-group data extraction, if authors saw an inferential pre-post comparison (eg,
a value at follow-up was compared to a value at baseline in the same group), then they would
indicate that a "pre-post descriptive" comparison remained to be addressed during the data
collection task for descriptive studies.

I.3.4.6.3 Risk-of-bias assessment

The NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group was used for
ROB assessment of longitudinal, pre-post descriptive studies.45 This tool was developed jointly by
methodologists from the National Heart, Lung, and Blood Institute (NHLBI) and Research Triangle
Institute International. This NIH tool is a 12-item questionnaire, with questions designed to help
reviewers focus on the key concepts for evaluating the internal validity of a study. They are not intended
to create a list from which to add up items to judge a study's quality (ie, a "summary score.") The
questions in this quality assessment tool, as well as their descriptions, are listed in Table I.4.

The tool includes items for evaluating potential flaws in study methods or implementation, including
sources of bias (eg, patient selection, performance, attrition, and detection), confounding, study power,
the strength of causality in the association between interventions and outcomes, and other factors.
Reviewers could select "yes," "no," or "cannot determine/not reported/not applicable" in response to
each item on the tool. For each item where "no" was selected, reviewers were instructed to consider

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the potential risk of bias that could be introduced by that flaw in the study design or implementation.
"Cannot determine" and "not reported" were also noted as representing potential flaws. The greater the
risk of bias, the lower the quality rating of the study.

Table I.4. Explanations for ROB items included in the NIH/NHLBI tool for longitudinal, pre- 45

post descriptive studies

Domain
(Item no) Description
Question

Study question This item asks reviewers to assess whether the authors adequately and
clearly described their research goal for the study.
(Item 1)
Was the study question or objective High-quality research studies should have a hypothesis, defined a
clearly stated? priori, and an a priori research plan that is designed to test the
prespecified hypothesis. It is easy to come up with a hypothesis after-
the fact that fits the study's findings, but such hypotheses are usually
biased.

Eligibility criteria and study population This item asks reviewers to assess whether the authors adequately and
clearly described the eligibility criteria that were applied to study
(Item 2) subjects.
Were eligibility/selection criteria for the
study population prespecified and clearly Eligibility criteria should be described in sufficient detail to make the
described? study's findings reproducible. Well-defined and explicit eligibility
criteria are important because, without them, we cannot know which
to patients the study applies.

Selection This item asks reviewers whether study subjects are representative of
the population in which the study's findings will be applied.
(Item 3)
Were the participants in the study Studies on tiny, unique demographic subgroups may not apply to
representative of those who would be broader populations. For example, studies that focus on autistic TGNB
eligible for the test/service/intervention in subpopulations may not always be relevant to allistic TGNB
the general or clinical population of adolescents.
interest?

All eligible participants enrolled This item asks reviewers whether the investigators developed eligibility
criteria before they began recruiting subjects, and whether all eligible
(Item 4) subjects, or a representative sample (ie, a random sample) of subjects
Were all eligible participants that met the was included.
prespecified entry criteria enrolled?
This item is intended to help reviewers identify studies in which
included subjects are a cherry-picked subset of all eligible subjects, in
whom the treatment effects may be different.

Sample size This item asks reviewers to assess whether study authors adequately
and clearly justified their reasons for selecting or recruiting the number
(Item 5) of individuals included in the study. Reviewers were asked to look for a
Was the sample size sufficiently large to samples size calculation, and if so, to assess whether the study was
provide confidence in the findings? powered to detect a clinically meaningful difference.

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Table I.4. Explanations for ROB items included in the NIH/NHLBI tool for longitudinal, pre- 45

post descriptive studies

Domain
(Item no) Description
Question
It is uncommon for non-experimental studies to include a
power/sample size calculation in the methods section. Most
observational and descriptive studies include all eligible subjects, so
authors frequently neglect the question of power on the rationale that
they can do nothing about it if their study is underpowered. However,
this question is highly relevant for readers of studies that show no
significant difference. An underpowered study that shows no
difference is interpreted differently from a well-powered study that
shows no difference.

Intervention clearly described This item asks reviewers whether the intervention is adequately and
clearly defined, and whether study authors gave any indication that it
(Item 6) was consistently administered to study subjects.
Was the test/service/intervention clearly
described and delivered consistently The purpose of this item is to determine the likelihood that study
across the study population? outcomes resulted from the administration of study interventions. If
participants received outside (ie, non-study) interventions, study
results could be biased.

Outcome measures clearly described, This item asks reviewers to assess whether study outcomes were
valid, and reliable defined in sufficient detail, and whether appropriate and reliable tools
for measuring outcomes were used.
(Item 7)
Were the outcome measures prespecified, Some outcome measures are more objective, accurate, and reliable
clearly defined, valid, reliable, and than others, such as measuring death, or lab levels. These examples
assessed consistently across all study would get a "yes." Other measures that are more subjective, such as
participants? self-reports, would get a "no" answer. This question is important
influences the reader's confidence in the validity of study results.

Blinding of outcome assessors This item asks reviewers to evaluate if study outcomes assessors were
blinded to the exposures/interventions.
(Item 8)
Were the people assessing the outcomes Often there is insufficient detail provided for reviewers to make this
blinded to the participants' assessment, in which case they would respond that it is "unclear."
exposures/interventions? Blinding is critical for a study's internal validity because unblinded
investigators are more likely to assess outcomes differentially in
different treatment groups. The risk of bias is higher if outcomes are
also subjective.

Follow-up rate This item asks reviewers to assess the amount of attrition (ie, "loss-to-
follow-up") in a longitudinal study.
(Item 9)
Was the loss to follow-up after baseline Studies have repeatedly shown that reasons for attrition tend to be
20% or less? Were those lost to follow-up systematically associated with exposures and outcomes, which means
accounted for in the analysis? that studies with higher rates of attrition are more likely to produce
biased results. An acceptable rate of follow-up rate is usually ≥ 80% of

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Table I.4. Explanations for ROB items included in the NIH/NHLBI tool for longitudinal, pre- 45

post descriptive studies

Domain
(Item no) Description
Question
participants whose interventions or exposures were measured at
baseline.

Statistical analysis This item asks reviewers if formal statistical tests were used to assess
the significance of the changes in the outcome measures between the
(Item 10) before and after time periods. The reported study results should
Did the statistical methods examine present values for statistical tests, such as P values or 95% confidence
changes in outcome measures from intervals (CIs), to document the statistical significance (or lack thereof)
before to after the intervention? Were for any observed outcome changes.
statistical tests done that provided P
values for the pre-to-post changes?

Multiple outcome measures This item asks reviewers to evaluate whether outcome measures for
each person were measured more than once in the study follow-up
(Item 11) period.
Were outcome measures of interest taken
multiple times before the intervention and Multiple measurements with the same result increase confidence that
multiple times after the intervention (i.e., the outcomes were accurately measured.
did they use an interrupted time-series
design)?

Group-level interventions and individual- This item asks reviewers to assess whether statistical analyses
accounted for any group-level effects, such as when interventions were
level outcome efforts
provided at the clinic level in cases where the clinics may differ in the
(Item 12) intensity of the interventions.
If the intervention was conducted at a
group level (eg, a whole hospital, a Group-level interventions are usually not relevant for clinical
community, etc.) did the statistical interventions in which the interventions are applied at the individual
analysis take into account the use of patient level. In those cases, the questions were coded as "N/A" in the
individual-level data to determine effects assessment tool.
at the group level?

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I.4.0 RESULTS OF EVIDENCE SYNTHESIS
I.4.1 Search Results
I.4.1.1 Ovid Medline search results
All Ovid Medline searches yielded a total of N = 1,731 records. After deduplication, there were N = 769
(44.4%) unique citations in Ovid Medline that underwent title/ abstract screening. Before screening, we
noted that no single major MeSH heading was widely used to index retrieved citations, and that indexing
seemed to be relatively heterogenous compared to other medical topics. As shown in Figure I.2, the
most common major MeSH terms were Transgender Persons, Gender Dysphoria, Transsexualism, and
Gender Identity, which occurred in 335 (43.5%), 159 (20.7%), 156 (20.3%), and 127 (16.5%), respectively.

Figure I.2. Top ten indexed major MeSH headings in all first- and second- corpus Ovid Medline results

Transgender Persons
Gender Dysphoria
Transsexualism
Gender Identity
Sex Reassignment Procedures
Testosterone
Fertility Preservation
Puberty
Gonadal Steroid Hormones
Gonadotropin-Releasing Hormone
0 50 100 150 200 250 300 350
Number of citations
Figure abbreviations: MeSH, medical subject headings, structured vocabulary keyword terms used to index
bibliographic records in Medline

I.4.1.2 Embase search results

An analysis of major keyword headings from Embase was not done since Embase does not use a major-
topic indicator for their indexed keywords.

I.4.1.3 PRISMA
As shown in the PRISMA diagram in Figure I.3, a total of N = 4980 citations were identified. These
included 1731 Ovid Medline and 3062 Embase citations that were uploaded to Covidence. Outside of
Covidence, we identified another 171 citations from reference lists of included studies, 12 citations from
clinical trial registries, and 4 citations recommended by experts in the field. In total, after removing
duplicates, N = 1425 studies were eligible to be screened for relevance in the title/abstract (TIAB)
screening stage.

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Figure I.3. PRISMA flow chart for study selection

n = 4980 total records identified in 4 sources

Identification

Ovid Medline (n = 1731)

Embase (n = 3062)
n = 3555 duplicate citations removed
Reference lists of relevant studies (n = 171)
Registries (n = 12)
Contacted experts (n = 4)

n = 1425 unique citations underwent TIAB screening n = 803 irrelevant citations excluded
Screening

n = 345 citations excluded

206 wrong patient population
n = 622 citations examined in full text 91 wrong study design/publication type
46 no intervention of interest
2 article withdrawn or outdated (eg, guidelines)

n = 277 citations summarizing results from 269 studies

n = 101 citations underwent data extraction n = 176 citations included in bibliography only:
93 studies lacking high-priority group comparisons, ie:
46 case studies
Included

44 descriptive studies lacking pre-post comparisons

3 observational studies comparing between TGNB
Guidelines Single-arm adolescents and special populations
(4) clinical trials/ 41 studies lacking high-priority outcomes
Observational/ 18 “systematic” review articles lacking adequate
longitudinal,
experimental reporting of searches or results
pre-post
studies 16 likely-relevant, non-English language publications
descriptive
SRs (58) with English-language abstracts
studies
(7) (32) 6 repeat publications of included articles
2 corrections or commentaries on included articles

Figure abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses; TIAB, title
and abstract; SR, systematic review; TGNB, transgender, nonbinary, or gender diverse

During TIAB screening, 803 irrelevant citations were excluded, leaving 622 (43.6%) that underwent full-
text review. Of these, 345 (55.4%) citations were excluded, leaving 277 separate publications that
represented 269 unique studies. These included 101 citations that underwent data extraction as
described in the sections that follow, and 176 citations that were included in the bibliography only.

Appendix I.C contains a list of all studies examined in full-text review that were excluded from eligibility,
along with reasons for exclusion.

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I.4.1.4 Publication year
The publication year of N=277 included studies is summarized in Figure I.4. Most of the studies (88%)
were published in 2016 or later; the largest number of studies (N=46) was published in 2022. As of the
end date of our searches (June 5, 2023), there were already N=27 studies published in 2023.

Figure I.4. Number of included publications per year, 2010-2023 (N = 277)

I.4.2 Guidelines
I.4.2.1 Included guidelines
A total of 5 guidelines was identified in bibliographic database searches that were eligible for inclusion in
the bibliography, including 1 non-English (German-language) guideline that is included in the
bibliography only. The remaining included guidelines comprised 3 guidelines that made drug-therapy-
related recommendations for treatment of GD in pediatric TGNB patients and 1 guideline with
recommendations pertinent to people who menstruate. Appendix I.D includes summary tables of
information extracted from these English-language guidelines.

I.4.2.2 Guideline recommendations

I.4.2.2.1 Overview of reviewed guidelines
We identified 4 clinical practice guidelines or position statements that met our inclusion criteria for
data extraction (see Table I.1 and Section I.3.3.1 for criteria).
Reviewed guidelines were published by the following organizations: the World Professional
Association for Transgender Health (WPATH; 2022),39 the Endocrine Society (ES; 2017),42 the

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 European Society for Sexual Medicine (ESSM; 2020),41 and the American College of Obstetricians
and Gynecologists (ACOG; 2022).40

I.4.2.2.2 Key guideline hormonal therapy recommendations

Guidelines providing hormone therapy recommendations do not recommend starting hormonal
therapies in pre-pubertal children.39,41,42 The WPATH, ES, and ESSM provided hormonal therapy
recommendations for adolescents,39,41,42 defined by the WPATH guideline as youth who reached
puberty (ie, at least sexual maturity of Tanner stage ≥ 2) and are less than 18 years old (or age of
majority).39 ACOG guideline recommendations for menstrual suppression are non-specific to age.40
Generally, hormonal therapies for TGNB adolescents desiring treatment include puberty-
suppression agents (eg, gonadotropin-hormone releasing [GnRH] analogs) and cross-sex hormone
therapies (CSHT; eg, estradiol or testosterone).39,41,42
Evidence tables for reviewed guidelines are provided in Appendix I.D. Table I.D.1 describes
guideline development methodology, including criteria used for level of evidence (LOE) ratings.
Table I.D.2 shows recommended eligibility criteria for use of hormone or hormone-blocking GAHT
for TGNB adolescents, recommended hormonal therapy by drug class or specific medication, and
recommendations for starting or stopping hormonal treatments. Table I.D.3 provides an overview of
hormonal treatment monitoring parameters addressed by guidelines.

I.4.2.2.3 Considerations for interpretation of guideline recommendations

Most guidelines are broad,39,41,42 addressing many aspects of TGNB care outside the scope of this
report, such as provider training or background, non-pharmacologic treatments for pre-pubescent
children, surgical treatment, and counseling recommendations (eg, regarding benefits or risks of
medications). The guideline evidence tables in this report focus on guideline development methods
and pharmacologic hormone or hormone-blocking therapy recommendations for minors. Please
refer to the guidelines for details about other important aspects of TGNB care across the lifespan.
According to WPATH (page S7), "The goal of gender-affirming care is to partner with TGD
[transgender and gender diverse] people to holistically address their social, mental, and medical
health needs and well-being while respectfully affirming their gender identity."39 Medically
necessary care should be provided to TGNB people; medical necessity is defined by WPATH using
criteria by the American Medical Association (page S16-S17):
"'Health care services that a physician and/or healthcare professional, exercising
prudent clinical judgment, would provide to a patient for the purpose of preventing,
evaluating, diagnosing or treating an illness, injury, disease or its symptoms, and that
are: (a) in accordance with generally accepted standards of medical practice; (b)
clinically appropriate, in terms of type, frequency, extent, site and duration, and
considered effective for the patient's illness, injury, or disease; and (c) not primarily for
the convenience of the patient, physician, or other health care provider, and not more
costly than an alternative service or sequence of services at least as likely to produce
equivalent therapeutic or diagnosis results as to the diagnosis or treatment of that
patient's illness, injury or disease.' The treating HCP [healthcare professional] asserts
and documents that a proposed treatment is medically necessary for the treatment of
the condition."39

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 Both the WPATH and ES guidelines recommended adolescents meet specific criteria to receive
hormonal therapy (see eligibility criteria in the left column of Table I.D.2). An important criterion to
start hormonal therapy is collecting informed consent (or assent) from the adolescent and
guardian(s) (in most cases).39,42
o To provide informed consent/assent, adolescents must be informed of the possible risks and
benefits of hormonal therapies, including the reversibility of therapies and possible fertility
risks.39,41,42 Guidelines consider the effects of puberty suppression with GnRH analogs to be
"fully reversible" whereas CSHT is "partially reversible."39,42
o Adolescents should be capable of providing informed consent/assent to initiate hormonal
therapies.39,41,42 WPATH and ESSM guidelines do not specify an age at which all adolescents can
consent to hormonal therapy, but the consenting adolescent must have the "capacity" for
consent.39,41 See the WPATH guideline for suggestions on how to assess an adolescent's capacity
to consent to treatment.
o Similar to WPATH and ESSM guidelines, the ES requires adolescents to consent to hormonal
therapy once they have sufficient capacity. Unlike the other guidelines, the ES specifies an age at
which most adolescents can consent to GAHT. According to the ES, most adolescents have
sufficient capacity to consent to CSHT by age 16; however, there are compelling reasons to start
earlier than 16, which may be possible for some adolescents.42
ES and ESSM guidelines did not provide separate recommendations for TGNB sub-populations (eg,
non-binary),41,42 whereas the WPATH developed separate recommendations for tailoring hormonal
therapy and other care to other gender-diverse populations (ie, non-binary, Eunuch, people who are
TGNB and intersex),d asserting that hormonal therapies should be accessible to all gender-diverse
people (not only people identifying as male or female) who would benefit from gender-affirming
treatments.39
Guidelines providing hormonal therapy recommendations for TGNB adolescents are generally in
agreement about recommended therapies and treatment approach (see Table I.D.2). GAHT given to
TGNB adolescents may include agents for suppression of endogenous puberty (eg, GnRH analogs),
and CSHT with feminizing sex hormones (eg, 17-β-estradiol) or masculinizing sex hormones (eg,
testosterone). To receive therapy, youth should meet eligibility criteria (see left column of Table
I.D.2) and not have any contraindications to treatment. The approach to therapy depends on an
individual's pubertal developmental stage (eg, early puberty vs near-complete endogenous puberty
completion) and treatment goals.39,41,42 Medication interventions are not intended to be
implemented using an all-or-nothing approach: treatments should be tailored to the individual.39
o Puberty suppression may begin as soon as early puberty (Tanner stage 2). Guidelines
recommend puberty suppression with GnRH analogs.39,41,42
o For youth presenting in early puberty (eg, Tanner stage 2), CSHT typically follows a period of
monotherapy with puberty suppression agents in youth meeting eligibility criteria. CSHT may
start as early as Tanner stage 2 in adolescents meeting additional guideline eligibility criteria
(see left column of guideline evidence Table I.D.2).39,41 WPATH describes "When considering the
timing and initiation of gender-affirming [ie, cross-sex] hormones, providers should compare the

d
Recommendations for how to adapt hormonal therapies to people with specific gender diverse
identities/expression were not extracted from the 2022 WPATH guideline; please see this guideline for additional
information regarding the use of hormonal therapy in these populations.

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 potential physical and psychological benefits and risks of starting treatment with the potential
risks and benefits of delaying treatment" (page S66).39
 Eligible TGNB youth assigned female at birth desiring masculinizing therapy are typically
treated with testosterone therapy.39,41,42
 Eligible TGNB youth assigned male at birth desiring feminizing therapy are typically treated
with estrogen therapy, and possibly, anti-androgen therapy (eg, spironolactone or GnRH
analogs)39,41,42.
Generally, CSHT in adolescents is started at low doses and gradually titrated to a maintenance dose
that achieves physiologic sex hormone levels similar to cisgender peers.39,41,42 For youth presenting
for care after completion or near completion of puberty, more rapid CSHT dose escalation can be
considered. When levels can be measured, serum sex hormone levels should be monitored during
therapy.39,42 Refer to the WPATH (2022) and ES (2017) guidelines for suggested CSHT puberty
induction dosing regimens in youth.
Recommendations for specific medications by guidelines do not account for availability of that
medication in the United States.
Generally, guidelines recommend that healthcare professionals providing gender-affirming care to
TGNB youth have sufficient general and gender-specific training to deliver care effectively.39,41,42
Access to experts should not be a barrier to care. Multidisciplinary care is often necessary for
assessment of youth seeking GAHT.39

I.4.3 Systematic Reviews

A total of 38 reviews met our criteria for population and interventions as well as our broad criteria for
"systematic" review (ie, those that describe a systematic search in 1 or more bibliographic database or
that were described by authors as "systematic"). Of these, 31 (81.6%) were subsequently determined to
be of low priority for data extraction for the reasons listed below. These were assigned to the
bibliography only.
10 reviews lacked a description of either the search strategy, search results, or both.
8 were based on searches conducted in only a single bibliographic database.
7 lacked high-priority outcomes.
4 were likely-relevant but published in a language other than English.
2 were duplicate publications of reviews counted elsewhere.

I.4.3.1 High-priority systematic reviews

Detailed summaries of findings from the N=7 reviews that underwent data extraction are included in
Appendix I.E. Table I.5 summarizes some key characteristics of these reviews. While 2 reviews primarily
addressed GnRH analogs, all included primary studies of patients who had received subsequent CSHT.
The number of primary studies in each review ranged from 9 to 91, but when considering only primary
studies of TGNB adolescents, the range was 4 to 24.

As summarized in Table I.5, most of the extracted reviews addressed a majority of our high-priority
outcomes. Psychosocial outcomes, a key indicator of treatment efficacy, were addressed by all 7
extracted reviews.46-52 Body changes, a key goal of therapy for many TGNB patients, and bone health, an

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Table I.5. Characteristics of 7 systematic reviews addressing high-priority outcomes associated with gender-affirming hormone therapy
(GAHT) in adolescents
First author (Year) Primary studies
Treatments addressed Outcomes addressed Funding source
Purpose Patients
Baker (2021)46 Primary studies: Out of 20 primary In pediatric patients, Mental health (anxiety, death by suicide, World Professional
studies, 3 addressed adolescents in 4 GnRH analogs for puberty depression) and psychosocial outcomes Association for
To examine the effects
publications suppression with or (QOL) Transgender Health
of CSHT on mental
without subsequent CSHT
health and psychosocial Patients: Includes longitudinal
(anti-androgens
outcomes in TGNB experience from N=143 adolescents.
[including GnRH analogs],
adults and adolescent
estrogens, progestins,
and the effect of GnRH
and testosterone)
analogs for puberty
suppression in TGNB In adult or mixed
adolescents pediatric/adult
populations, CSHT

Chew (2018) 47 Primary studies: 11 out of 13 Unspecified GnRH Body changes (endogenous hormone levels, Royal Children's
primary studies included only patient analogs for puberty height, growth velocity, lean and fat body Hospital Foundation,
To examine the impact
groups with mean ages <18 years, suppression with or mass); Bone health (BMD); psychosocial Melbourne Children's
of GAHT on physical and
including 1 study that did not without subsequent CSHT outcomes (executive functioning, mental Clinician Scientist
mental health of TGNB
mention the age of participants but (anti-androgens, rotation, global functioning, anger, behavioral Fellowship Scheme,
adolescents and young
referred to them collectively as estrogens, progestins, or and emotional problems gender and body Apex Foundation for
adults
"adolescents;" 1 study's transgender testosterone) and CSHT dysphoria); and mental health outcomes Research into
male participants met this criterion, (anxiety, depression) intellectual Disability,
but not it's trans female participants. and William Collie
One study included patients with a Trust at University of
mean age >18; we did not extract Melbourne
results from this study.
Patients: Includes longitudinal
experience from N=649 adolescents
plus short-term or cross-sectional
experience from N=178 more.

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Table I.5. Characteristics of 7 systematic reviews addressing high-priority outcomes associated with gender-affirming hormone therapy
(GAHT) in adolescents
First author (Year) Primary studies
Treatments addressed Outcomes addressed Funding source
Purpose Patients
D’hoore (2022)48 Primary studies: Out of 91 primary Unspecified GnRH Mental health, psychosocial outcomes (body Not reported
studies, 21 addressed adolescents, 1 analogs for puberty image); body changes (body composition);
To identify recent
addressed both adolescents and suppression, CSHT cardiovascular and metabolic outcomes
information from larger
adults, and 69 addressed adults only. (antiandrogens [including (insulin resistance, cardiovascular and
cohorts on modern
GnRH analogs], thromboembolic safety); bone health; cancer
GAHT regimens in adult Patients: Includes experience from
testosterones and risk
and adolescent TGNB more than N=4052 patients.
estrogens), progestins,
patients
spironolactone

Ludvigsson (2023)49 Primary studies: 24 primary studies Unspecified GnRH Mental health (anxiety, depression, acute Swedish Agency for
were included out of 36 retrieved analogs in young distress, suicidality, self-harm, psychotropic Health Technology
To examine the effect of
studies. adolescents with or medication use, mental health service Assessment and
puberty suppression and
without subsequent CSHT utilization); Psychosocial outcomes (global Assessment of Social
CSHT on body changes, Patients: Includes experience from
in older adolescents functioning, anger, cognitive function, Services
bone health, mental N=6552 TGNB adolescents.
executive function, QOL); Body changes
health, psychosocial
(height, height velocity weight, BMI,
outcomes, and
subperiosteal width, endocortical diameter,
metabolic changes in
lean body mass); Bone (BMD); Cardiovascular
pediatric TGNB patients
risk factors and metabolic changes (BMI, BP,
SBP, DBP, liver enzymes, creatinine, glucose,
HbA1c, insulin, cholesterol, triglycerides,
HOMA, hematocrit, thrombosis); Other
outcomes (medication use, mental health
utilization)

Mahfouda (2019)50 Primary studies: N=12 studies that GnRH analogs for puberty Psychosocial outcomes (gender dysphoria, University of
examined GAHT (plus N=5 studies suppression in young global functioning, cognitive effects); Western Australia,
To examine the effects
examining surgical interventions) adolescents with or cardiovascular risk factors (hematological Perth Children's
of medical (GnRH
without subsequent CSHT effects, cholesterol); bone health (BMD, bone Hospital Fund, Raine
analogs and CSHT) and
in older adolescents and turnover markers); body changes (lean mass, Medical Foundation,
surgical interventions on
CSHT. fat mass, BMI, waist-to-hip ratio, body/facial Australian National
mental health,

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Table I.5. Characteristics of 7 systematic reviews addressing high-priority outcomes associated with gender-affirming hormone therapy
(GAHT) in adolescents
First author (Year) Primary studies
Treatments addressed Outcomes addressed Funding source
Purpose Patients
psychosocial outcomes, Patients: Includes longitudinal hair changes, breast development, testicular Health and Medical
cardiovascular and experience of N=778 TGNB patients volume) Research Council
metabolic effects, bone and N=41 cisgender patients.
health, and body
changes in TGNB
adolescents

Ramos (2021)51 Primary studies: Out of 11 primary GnRH analogs (including Mental health (suicide, general mental Authors reported
studies, 3 addressed adolescents in 4 triptorelin and other health); psychosocial outcomes (GD and body that there was no
To examine the effects
publications unspecified agents) for image); body changes (fat mass, lean mass, funding for this work.
of GnRH analogs for
puberty suppression in waist-to-hip ratio); bone health (BMD, BMAD,
puberty suppression Patients: Includes longitudinal
young adolescents with bone turnover markers)
(with or without experience from N=143 adolescents.
or without subsequent
subsequent CSHT) on
CSHT (testosterone ester,
mental health,
17estradiol, or other
psychosocial function,
unspecified agents)
body changes, and liver
and kidney function in
TGNB youths with
“gender incongruity”

Rew (2021)52 Primary studies: 9 primary studies GnRH analogs Mental health (anxiety, depression, suicide Authors reported
(triptorelin, leuprorelin, ideation, affect); psychosocial outcomes that there was no
To examine the impact Patients: Includes longitudinal
and other unspecified (anger, emotional and behavioral problems, funding for this work.
of GnRH analogs with or experience from N=702 TGNB
agents) with or without IQ, social life); body changes
without CSHT on mental patients.
subsequent CSHT (feminization/masculinization, testicular
and psychosocial
(testosterone, estradiol) volume, menstrual outcomes, lean mass, fat
outcomes, body
mass, growth/height velocity); bone health
changes, bone health,
(BMD, bone turnover markers); metabolic
metabolic changes, and
changes (liver function, creatinine); and other
other safety outcomes in
safety outcomes
TGNB youths

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important safety outcome, were addressed by 6 reviews.47-52 Mental health outcomes, our last key
efficacy indicator, were addressed by 5 reviews.46,48,49,51,52 Cardiovascular and metabolic outcomes were
addressed in 4 reviews.48-50,52 Cancer was only addressed in 2 reviews47,48; neither review found any
studies examining cancer risk in TGNB adolescents.

I.4.3.2 Systematic review risks of bias (ROB)

A summary of the ROB for SRs that underwent data extraction is given in in Table I.6. A complete
summary of all ROB details is given in Appendix I.E.

The recent SR by Ludvigsson (2023),49 was an outlier in terms of several key methods. Ludvigsson and
co-authors were the only reviewers to exclude one-third of all relevant studies from consideration for
inclusion in their review. They justified this choice by stating that they were only excluding studies with
the highest risk of study-level bias, but this choice is a violation of best practices for systematic
reviewers. ROB assessment is a highly subjective process, which makes this choice highly susceptible to
investigator bias. In addition, it is well-known that the many tools available for assessing study-level bias
are highly variable in terms of how they group the studies into high-and low-risk categories. Thus, even
in the absence of any investigator manipulation of their results, authors that use different ROB tools on
the same set of studies and then exclude some studies from inclusion based on the resultant ROB
findings will end up including different subsets of the same studies, and consequently coming to
different conclusions. Consequently, the best practice is to assess ROB using the tool selected by the
investigators a priori, and then rather than excluding studies with a high ROB, assessing the impact of
study-level differences in ROB on their findings.

Ludvigsson and colleagues were also the only review authors who did not include a summary of findings
in the individual primary studies. Rather, they reported what outcomes were assessed by reviewers, and
then reported only their conclusions about the body of evidence as a whole. This was a highly irregular
choice; best practices are for systematic reviewers to include a summary of study-level findings on which
they based their conclusions.

Ludvigsson and colleagues were also the only review authors who did not base their conclusions about
key outcomes on all of their included studies. Instead, they based their conclusions on only a subset of
the included studies. Taken together, these irregularities suggest that the conclusions drawn by
Ludvigsson might best be considered unhelpful.

Nonetheless, Ludvigsson and colleagues found the largest number of primary studies (N=36) out of all
SRs included in this report. As mentioned previously, the authors excluded 12 primary studies that they
considered to have a high ROB and reported their findings based only on a subset.53 Consequently, we
checked the excluded references to ensure that any relevant studies excluded by Ludvigsson were
included in our report, a practice that is supported by best practices. Table I.7 lists N=11 excluded
studies along with their disposition in this review; a twelfth excluded study was not provided in the
authors’ list.54

The 11 studies listed in Table I.7 included 8 relevant studies that we included in evidence tables, 2 likely-
relevant studies that we included in the bibliography only, and 1 irrelevant study that we excluded
during title/abstract screening.

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Table I.6. Summary of AMSTAR-2 ROB domains43 for 7 SRs examining relevant/included outcomes
associated with GD therapy in TGNB children/adolescents
Baker Chew D'hoore Ludvigsson Mahfouda Ramos Rew
AMSTAR-2 Item
(2021)46 (2018)47 (2022)48 (2023)49 (2019)50 (2021)51 (2021)52

1. Well-specified research question Yes Yes Yes Yes No Partial yes Yes

2. Pre-specified protocol Yes Yes No Yes No No No

3. Study design restrictions No No No No No No Yes

4. Comprehensive search strategy No Partial yes No Partial yes Partial yes Partial yes No

5. Duplicate study selection Yes Yes Yes Yes No No No

6. Duplicate data extraction Yes Yes No Unclear No Unclear No

7. Excluded studies list No No No No No No No

8. Described included studies Yes Partial yes No No Partial yes No Partial yes

9. Assessed study-level ROB Yes Unclear No Yes No Yes Yes

10. Assessed primary study funding No No No No No No No

11. Appropriate synthesis method N/A N/A N/A N/A N/A N/A N/A

12. Assessed ROB impact Yes Yes No No No No No

13. Discussed ROB impact Yes Yes No No No No No

14. Discussed heterogeneity N/A N/A N/A N/A N/A N/A N/A

15. Assessed small-study effects N/A N/A N/A N/A N/A N/A N/A

16. Review authors conflicts Yes Yes Yes Yes Yes Yes Yes

Table I.7. Disposition of N=11 likely-relevant primary studies excluded from one recent SR that
searched 13 different databases
Author (year) Disposition in this review
Cohort study found in bibliographic database searches and cited in other SRs; included in
Achille (2020)55
evidence tables for between-TGNB group and longitudinal, pre-post comparisons.

Descriptive study not found in bibliographic database searches, but cited in other SRs;
Allen (2019)56
included in evidence tables for longitudinal, pre-post comparisons.

Descriptive study found in bibliographic database searches and cited in other SRs; included
de Vries (2011)57
in evidence tables for longitudinal, pre-post and between-TGNB group comparisons.

Descriptive study found in bibliographic database searches; included in evidence tables for
Ghelani (2020)58
longitudinal, pre-post comparisons.

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Table I.7. Disposition of N=11 likely-relevant primary studies excluded from one recent SR that
searched 13 different databases
Author (year) Disposition in this review
Descriptive study found in bibliographic database searches and cited in other SRs; included
Hannema (2017)59
in evidence tables for longitudinal, pre-post comparisons.

Cohort study found in bibliographic database searches; included in evidence tables for
Jensen (2019)60
between-TGNB group comparisons.

SR not found in bibliographic database searches; included in bibliography only due to an

Karalexi (2020)61
inadequate search strategy (ie, a single database).

López de Lara
Non-English descriptive study found in bibliographic database searches.
(2020)62

Cohort study found in bibliographic database searches; excluded from consideration during
Millington (2020)63
title/abstract screening due to the absence of relevant treatments.

Descriptive study found in bibliographic database searches; included in evidence tables for
Neyman (2019)64
longitudinal, pre-post comparisons.

Cross-sectional study not found in bibliographic database searches but cited in other SRs;
Zucker (2011)65
included in evidence tables for between-TGNB-group comparisons.

Table abbreviations: SR, systematic review; TGNB, transgender, nonbinary, or gender-diverse

I.4.4 Bibliography of Included Publications

The bibliography of all included studies–that is, guidelines, systematic reviews, and experimental,
observational, and descriptive studies that passed the search screening, the title and abstract screening,
and the full-text screening–is in Appendix I.F.

I.4.5 Included Relevant Clinical Studies

I.4.5.1 Characteristics of relevant clinical studies
We found relevant, English-language clinical studies about populations from all over the world, including
the US, Canada, the United Kingdom, Europe, Australia, Brazil, and the middle east (eg, Israel, Turkey). A
summary of the characteristics of included studies is given below, by geographic region, and the basic
characteristics of each study can be found in Appendix I.G. In all, there were N=134 primary clinical
studies reporting findings in TGNB populations all over the world, including the experience of more than
N=28,056 pediatric TGNB patients.

I.4.5.2 Relevant clinical studies from US populations

By far, the largest numbers of unique studies, clinical sites, and subjects, including the largest number of
TGNB youths, were from the United States. Table I.8 includes a summary of the numbers of clinical
studies, sites, and subjects for these studies. These included a total of N = 118 studies examining

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outcomes in at least 62 discrete samples of TGNB adolescents. The total number of subjects included
was nearly 65,000, of which at least 18,561 were TGNB youths.

When considering geographic regions among the US studies, the largest subsets of studies (25) and
unique patient samples (13) were conducted among the nationally-representative or multi-state subset
of studies. This subset included observations from nearly 60,000 subjects, including at least 13,995
TGNB children and adolescents.

In the studies conducted among individual US states or territories, there were 93 unique studies
conducted among 49 unique sites across 21 states and the District of Columbia (DC). Collectively, these
studies included more than N = 5,081 subjects, including more than N = 4,367 pediatric TGNB children
and adolescents. Notably, although New York and California both had largest number of individual
practice sites in any state (ie, 6 and 7 sites, respectively), neither of them contributed as many individual
publications as came from the 4 sites in the state of Massachusetts (15 studies). The key characteristics
of the 118 US studies we found, grouped by geographic area and site, are found in Appendix I.G.

Table I.8. Summary of N = 118 relevant clinical studies conducted in pediatric TGNB populations in
the US
Number of sites,
State/Geographic Number of studies/ Pediatric
samples, or unique All subjects
Area publications TGNB subjects
populations
Multi-state/ 13 (listed below) 25 ≥ 59,551 ≥ 14,143
National
1. National internet survey ≥ 3235

2. National internet survey 156

3. US Youth Risk Behavior Survey ≥ 3494

4. Children's Hospital Association's Pediatric Health and Information ≥ 264

System
5. Military Healthcare Data Repository ≥ 952

6. Cystic Fibrosis care center survey 30

7. Trans Youth Project in 23 states and Canada 317

8. A dataset from PEDSnet (a pediatric learning health system 4172

network), comprising data from 7 PEDSnet participating institutions
≥ 391

22

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Table I.8. Summary of N = 118 relevant clinical studies conducted in pediatric TGNB populations in
the US
Number of sites,
State/Geographic Number of studies/ Pediatric
samples, or unique All subjects
Area publications TGNB subjects
populations
116

12. STRONG cohort 958

13. 36

Unspecified/ 2 (listed below) 2 54 54

Inconclusive
locations 1

2. A regional, referral-based adolescent specialty clinic for dependent 53

children of military service members
Arizona 1 (listed below) 1 260 ≥ 13

≥ 13

California 7 (listed below) 9 ≥ 885 ≥ 783

≥ 66

14

417

106

119

60

Colorado 2 (listed below) 4 ≥ 363 ≥ 255

≥ 35

220

Connecticut 2 (listed below) 2 31 31

23

Delaware 1 (listed below) 3 ≥ 133 ≥ 133

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Table I.8. Summary of N = 118 relevant clinical studies conducted in pediatric TGNB populations in
the US
Number of sites,
State/Geographic Number of studies/ Pediatric
samples, or unique All subjects
Area publications TGNB subjects
populations
≥ 133

Georgia 1 (listed below) 1 60 60

60

Illinois 1 (listed below) 5 ≥ 105 ≥ 105

≥ 105

Indiana 1 (listed below) 1 13 13

13

Iowa 1 (listed below) 1 1 1

Massachusetts 4 (listed below) 15 ≥ 1153 ≥ 1129

≥ 1124

Michigan 1 (listed below) 1 30 30

30

Minnesota 1 (listed below) 1 2 2

Missouri 2 (listed below) 4 ≥ 114 ≥ 114

47

≥ 67

New York 6 (listed below) 7 195 193

139

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Table I.8. Summary of N = 118 relevant clinical studies conducted in pediatric TGNB populations in
the US
Number of sites,
State/Geographic Number of studies/ Pediatric
samples, or unique All subjects
Area publications TGNB subjects
populations
1

50

Ohio 2 (listed below) 10 735 690

611

79

Oklahoma 2 (listed below) 3 222 119

118

Oregon 1 (listed below) 1 80 80

80

Pennsylvania 2 (listed below) 6 151 71

64

P 7

Rhode Island 1 (listed below) 1 5 5

Texas 4 (listed below) 7 ≥ 371 ≥ 371

192

≥ 148

30

Washington 1 (listed below) 5 104 104

104

Washington DC 1 (listed below) 3 68 68

68

Total 62 118 ≥ 64,656 ≥ 18,561

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I.4.5.3 Relevant clinical studies from Dutch populations
Studies from the Netherlands are those with the longest duration of follow-up, including at least 4
studies of more than 40 years duration,66-69 one of which counted N = 1360 TGNB children/adolescents
and more than N = 6,793 subjects overall, as summarized in Table I.9 and Appendix I.G.67

Table I.9. Summary of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the
Netherlands
Number of Pediatric TGNB
Site All subjects
studies subjects
36 ≥ 8831 ≥ 1766

6 ≤ 8831 ≤ 1766

30 Nested in but unaffiliated with ACOG

4 ≥ 143 ≥ 143

3 ≥ 36 ≥ 14

Total 43 ≥ 9010 ≥ 1923

The treatment and study of TGNB patients in the Netherlands stretches back to 1972. Most such care
and investigation were done at
In 2002, established a gender identity clinic for children and adolescents,
called
which incidentally centralized records of all TGNB patients seen at the since 1972.
Youth diagnosed with gender dysphoria in other mental health or medical settings are able to start or
continue medical treatment at treats TGNB youth from all over the world.

Studies on TGNB patients seen at have been conducted on an ongoing basis. However, a
study of the entire TGNB patient population was not published until This study comprised
persons with some form of GD/TGNB diagnosis and at least 1 visit to
patients in this cohort are referred to as the Cohort of Gender Dysphoria (ACOG). This study
counted 6793 gender dysphoric/TGNB visiting patients, of which
A more recent study, updates the
ACOG's number from to

In 2018, t merged with and was renamed

the Of the two medical centers
the former remains the locus of gender dysphoria referral, diagnosis, and

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treatment, and is now called Most, but not all, studies published
after this period use "

University in the Netherlands, has developed its own gender identity treatment and
research program. The was established in 1998, with the
Clinic serving as the intake point for young, gender
dysphoric patients. A dedicated gender clinic was established Research has
been conducted on TGNB youths seen at this clinic, in collaboration and separately.

I.4.5.4 Relevant clinical studies from Canada, Australia, the United

Kingdom, and Europe
We present here in Table I.10 the 59 relevant, English-language studies from Canada, Australia, New
Zealand, the UK, and Europe. For more information, please see Appendix I.G.

Table I.10. Summary of N = 60 relevant clinical studies conducted in pediatric TGNB populations in
Canada, Australia, the United Kingdom, and Europe
Number of sites,
Country/ Number of studies/ Pediatric
samples, or unique All subjects
Geographic Area publications TGNB subjects
populations
Multinational 2 2 3087 3087

316

2771

Australia 3 6 418 408

10

39

355

Belgium 1 1 27 27

27

Canada 11 16 1063 843

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Table I.10. Summary of N = 60 relevant clinical studies conducted in pediatric TGNB populations in
Canada, Australia, the United Kingdom, and Europe
Number of sites,
Country/ Number of studies/ Pediatric
samples, or unique All subjects
Geographic Area publications TGNB subjects
populations
Multi-site 35

174

Alberta 33

British Columbia 84

21

21

Ontario 1

172

300

Quebec 1

Finland 2 2 176 176

124

52

France 2 2 5 5

Germany 4 6 425 214

82

22

75

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Table I.10. Summary of N = 60 relevant clinical studies conducted in pediatric TGNB populations in
Canada, Australia, the United Kingdom, and Europe
Number of sites,
Country/ Number of studies/ Pediatric
samples, or unique All subjects
Geographic Area publications TGNB subjects
populations
35

Italy 2 2 127 127

125

Poland 1 1 166 166

166

Slovenia 1 1 1 1

Spain 5 7 378 125

80

23

20

Switzerland 2 2 56 56

80

United Kingdom 7 12 5715 2242

Multisite 668

360

980

England 95

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Table I.10. Summary of N = 60 relevant clinical studies conducted in pediatric TGNB populations in
Canada, Australia, the United Kingdom, and Europe
Number of sites,
Country/ Number of studies/ Pediatric
samples, or unique All subjects
Geographic Area publications TGNB subjects
populations
12

36

Scotland 91

Total 43 59 11,644 7476

I.4.5.5 Relevant clinical studies published in other populations

Table I.11 describes the remaining published, English-language studies captured in our searches and
meeting inclusion criteria. They are from Brazil, Israel, and Turkey. Their details are in Appendix I.G.

Table I.11. Summary of N = 9 relevant, English-language clinical studies conducted in other pediatric
TGNB populations
Number of sites,
Country/ Number of studies/ Pediatric
samples, or unique All subjects
Geographic Area publications TGNB subjects
populations
Brazil 3 3 659 44

28

15

Israel 1 3 106 106

106

Turkey 3 3 36 36

30

Total 7 9 801 96

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I.4.5.6 Risk of bias analyses
Tables I.12 through I.16 summarize the risk of bias for all studies with an observational comparison (ie,
TGNB vs TGNB or TGNB vs cisgender peer) that underwent data extraction. The Newcastle-Ottawa
Scales for cohort and case-control studies, and an adapted version for cross-sectional studies, were used
as described in Section I.3.3.5.3. Cohort, cross-sectional, and case-control studies are listed separately
due to differences in the risk of bias analysis. They are further separated by comparison type (ie, TGNB
vs TGNB or TGNB vs cisgender peer). The ROB details are in Appendix I.I.

Table I.17 summarizes the risk of bias for studies with a descriptive, longitudinal, pre-post comparison.
The NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group was used
(see description in Section I.3.3.6.3). We found some limitations with this tool for assessing the studies:
Question 5 asked whether the sample size was large enough, but in these types of studies, a power
calculation is not normally done. For this question, we answered “unclear” on many of the studies,
however; this is only relevant if no difference was found. When a finding is statistically significant
(ie, p-value <0.05), then we can rest assured that the study was adequately powered to detect a
difference of the magnitude observed. However, when a finding is statistically nonsignificant, then
the question of whether or not the study was adequately powered to detect a clinically-meaningful
difference becomes relevant.
Question 8 asked about assessor blinding. Due to the fact that the pre-post comparisons that we
were extracting all had to have an intervention of interest, it was usually not feasible for the
assessors to be blinded, as all of the participants had taken an intervention of interest. The ROB
details are in Appendix I.I.

Table I.12. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB cohort studies
Cohort Study Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆☆ max ☆☆ max ☆☆☆ max
Achille (2020)55 ☆☆☆☆ ☆ ☆☆ 7/9
Allen (2019)56 ☆☆ ☆ ☆☆ 5/9
Arnoldussen (2022) 71
☆☆☆☆ ☆ ☆☆ 7/9
Becker-Hebly (2021)72 ☆☆☆ ☆☆ 5/9
Boogers (2022) 66
☆☆☆☆ ☆ ☆☆☆ 8/9
Carmichael (2021)73 ☆☆☆☆ ☆ ☆☆ 7/9
Cantu (2020) 74
☆☆☆ ☆ 4/9
Chen (2023)75 ☆☆☆☆ ☆☆ ☆☆ 8/9
Chiniara (2018) 76
☆☆☆☆ ☆☆ 6/9
Costa (2015)77 ☆☆☆☆ ☆ 5/9
de Vries (2010) 78
☆☆☆ ☆☆ 5/9
de Vries (2011)57 ☆☆☆☆ ☆ 5/9

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Table I.12. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB cohort studies
Cohort Study Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆☆ max ☆☆ max ☆☆☆ max
de Vries (2014)79 ☆☆☆☆ ☆ ☆ 6/9
Eitel (2023) 80
☆☆☆☆ ☆☆ 6/9
Grimstad (2021)81 ☆☆☆☆ ☆☆☆ 7/9
Khatchadourian (2014)82 ☆☆☆ ☆☆☆ 6/9
Klaver (2018)83 ☆☆☆☆ ☆ ☆☆ 7/9
Laurenzano (2021)84 ☆☆☆☆ ☆☆ 6/9
Lee (2020)85 ☆☆☆☆ ☆☆ ☆☆ 8/9
Martinez-Martin (2023)86 ☆☆☆☆ ☆☆ ☆☆ 8/9
Marwa (2022)87 ☆☆☆☆ ☆ ☆☆☆ 8/9
Millington (2019)88 ☆☆☆☆ ☆☆☆ 7/9
Millington (2021)89 ☆☆☆☆ ☆ ☆☆ 7/9
Millington (2022)90 ☆☆☆☆ ☆ ☆☆☆ 8/9
Mullins (2021)91 ☆☆☆☆ ☆☆☆ 7/9
Navabi (2021)92 ☆☆☆ ☆ ☆☆☆ 7/9
Olson-Kennedy (2021)93 ☆☆☆☆ ☆☆ ☆☆☆ 9/9
Schagen (2018) ☆☆☆ ☆☆ 5/9
Schagen (2020)94 ☆☆ ☆☆ ☆☆ 6/9
Schulmeister (2022)95 ☆☆☆ ☆ ☆☆☆ 7/9
Tordoff (2022)96 ☆☆☆☆ ☆ ☆ 6/9
Valentine (2021)97 ☆☆ ☆ ☆ 4/9
Valentine (2022)98 ☆☆☆ ☆☆ ☆☆ 7/9
Vlot (2017)99 ☆☆☆ ☆ ☆☆☆ 7/9
Low risk of bias (higher quality): 7-9 stars; Fair risk of bias: 5-6 stars; High risk of bias: 1-4 stars.
Selection Criteria composed of questions about: Representativeness of the exposed cohort, selection of the nonexposed
cohort, ascertainment of exposure, and outcome temporality requirements. Comparability criteria composed of question
about: comparability of exposure/comparator cohorts-controlling for most important factors (age, sex) and additional
factors. Outcome criteria composed of questions about: method of outcome assessment, duration of follow-up, attrition.

Table I.13. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB cross-sectional
studies
Cross-sectional Studies Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆ max ☆☆ max ☆ max
Arnoldussen (2020)100 ☆☆☆ ☆ 4/6
Avila (2019)101 ☆☆☆ 3/6

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Table I.13. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB cross-sectional
studies
Cross-sectional Studies Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆ max ☆☆ max ☆ max
Bauer (2021)102 ☆☆☆ ☆ 4/6
Becker (2018) 103
☆☆ ☆ 3/6
Chen (2021)104 ☆☆☆ 3/6
Conn (2023) 105
☆☆ ☆☆ 4/6
de Vries (2011)106 ☆☆☆ ☆ ☆ 5/6
de Vries (2016) 107
☆☆ ☆☆ 4/6
de Graaf (2022)108 ☆☆ ☆☆ 4/6
Durwood (2017) 109
☆☆ 2/6
Grannis (2021)110 ☆☆☆ ☆ 4/6
Green (2022) 111
☆☆ ☆☆ 4/6
Karakilic Ozturan (2023)112 ☆☆☆ ☆ ☆ 5/6
Mirabella (2022) 113
☆☆☆ ☆ 4/6
Morningstar (2023)114 ☆☆☆ ☆ ☆ 5/6
Nahata (2017) 115
☆☆☆ 3/6
Olsavsky (2023)116 ☆☆☆ ☆☆ 5/6
Segev-Becker (2020)117 ☆☆☆ ☆ 4/6
Sorbara (2020)118 ☆☆☆ ☆☆ 5/6
Staphorius (2015)119 ☆☆ ☆ 3/6
Tollit (2023)120 ☆☆☆ ☆ 4/6
Turban (2020)121 ☆☆ ☆☆ 4/6
Turban (2022)122 ☆☆ ☆☆ 4/6
van der Grift (2020)123 ☆☆ ☆☆ 4/6
van der Miesen (2020)124 ☆☆ ☆ 3/6
Vehmas (2022)125 ☆☆☆ ☆ 4/6
Vrouenraets (2021)126 ☆☆☆ 3/6
Willemsen (2023)127 ☆☆☆ ☆ ☆ 5/6
Zucker (2010)65 ☆☆☆ ☆☆ ☆ 6/6
Low risk of bias (higher quality): 5-6 stars, Fair risk of bias: 3-4 stars, High risk of bias: 1-2 stars.
Selection Criteria composed of questions about: Representativeness of the exposed cohort, selection of the nonexposed
cohort, ascertainment of exposure, and outcome temporality requirements. Comparability criteria composed of question
about: comparability of exposure/comparator cohorts-controlling for most important factors (age, sex) and additional
factors. Outcome criteria composed of questions about: method of outcome assessment, duration of follow-up, attrition.
The outcome temporality requirement, duration of follow-up, and attrition questions were excluded.

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Table I.14. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs TGNB case-control
studies
Case-control studies Selection Comparability Exposure
Total Stars
First Author (year) ☆☆☆ max ☆☆ max ☆ max
Maru (2021)128 ☆☆☆ ☆ 4/6
Low risk of bias (higher quality): 5-6 stars, Fair risk of bias: 3-4 stars, High risk of bias: 1-2 stars.
Selection Criteria composed of questions about: Adequacy of the case definition, representativeness of the cases, selection
of controls, and definition of controls. Comparability criteria composed of question about: Comparability of cohorts on
the basis of design or analysis. Outcome criteria composed of questions about: Assessment of exposure, same method of
ascertainment for cases and controls, and non-response rates.

Table I.15. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs Peer cohort studies
Cohort Studies Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆☆ max ☆☆ max ☆☆☆ max
Beking (2020)129 ☆☆☆☆ ☆ ☆☆☆ 8/9
Burke (2016) 130
☆☆☆☆ ☆☆ ☆☆☆ 9/9
Costa (2015)77 ☆☆☆ ☆ 4/9
López de Lara (2020) 62
☆☆☆☆ ☆ ☆☆ 7/9
Millington (2022)90 ☆☆☆ ☆ ☆☆ 6/9
Nokoff (2020)131 ☆☆☆ ☆ ☆☆ 6/9
Schulmeister (2022)95 ☆☆ ☆ ☆☆☆ 6/9
Valentine (2021)97 ☆☆☆☆ ☆ ☆☆ 7/9
Low risk of bias (higher quality): 7-9 stars, Fair risk of bias: 5-6 stars, High risk of bias 1-4 stars.
Selection Criteria composed of questions about: Representativeness of the exposed cohort, selection of the nonexposed
cohort, ascertainment of exposure, and outcome temporality requirements. Comparability criteria composed of questions
about: comparability of exposure/comparator cohorts-controlling for most important factors (age, sex) and additional
factors. Outcome criteria composed of questions about: method of outcome assessment, duration of follow-up, attrition.

Table I.16. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs Peer cross-sectional
studies
Cross-sectional Studies Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆ max ☆☆ max ☆ max
Alvares (2022)132 ☆ ☆ 2/6
Burke (2015)133 ☆☆☆ ☆ ☆ 5/6
Durwood (2017) 109
☆ 1/6
Nokoff (2021)134 ☆ ☆☆ ☆ 4/6
Staphorius (2015) 119
☆☆☆ ☆ ☆ 5/6

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Table I.16. Newcastle-Ottawa Quality Assessment Scale ROB data for TGNB vs Peer cross-sectional
studies
Cross-sectional Studies Selection Comparability Outcome
Total Stars
First Author (year) ☆☆☆ max ☆☆ max ☆ max
Valentine (2022)98 ☆☆☆ ☆☆ ☆ 6/6
Van der Miesen (2020) 124
☆ 1/6
Low risk of bias (higher quality): 5-6 stars, Fair risk of bias: 3-4 stars, High risk of bias: 1-2 stars.
Selection Criteria composed of questions about: Representativeness of the exposed cohort, selection of the nonexposed
cohort, ascertainment of exposure, and outcome temporality requirements. Comparability criteria composed of questions
about: comparability of exposure/comparator cohorts-controlling for most important factors (age, sex) and additional
factors. Outcome criteria composed of questions about: method of outcome assessment, duration of follow-up, and
attrition. Outcome temporality requirement, duration of follow-up, and attrition questions are excluded.

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Table I.17. NIH Quality Assessment Tool ROB data for Pre-Post studies
Pre-post study NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group Quality
Author (Year) (Total "Yes" answers)
Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12
Achille (2020)55 Y Y U Y U N Y N N Y U N/A 5/11

Allen (2019)56 Y Y U Y U N Y N Y Y N N/A 6/11

Arnoldussen (2022)135 Y Y N Y U N Y N Y Y N N/A 6/11

Alvares (2022)132 Y Y Y N N N U N Y U N N/A 4/11

Becker-Hebly (2021)72 Y Y U Y U N Y N U Y N N/A 5/11

Beking (2020)129 Y U U N U Y Y U Y Y N N/A 5/11

Boogers (2022)66 Y Y U Y U Y Y N N Y N N/A 6/11

Cantu (2020)74 Y Y Y N N N Y N Y Y N N/A 6/11

Carmichael (2021)73 Y Y Y Y U Y Y N U Y N N/A 7/11

Chen (2023)75 Y Y Y U U U Y N Y Y N N/A 6/11

Costa (2015)77 Y Y Y Y U U Y N Y Y N N/A 7/11

De Vries (2010)78 Y N N N U Y Y N N Y N N/A 4/11

2013.0Q1: Was the study question or objective clearly stated?, Q2: Were eligibility/selection criteria for the study population prespecified and clearly
described?, Q3: Were the participants in the study representative of those who would be eligible for the test/service/ intervention in the general or clinical
population of interest?, Q4: Were all eligible participants that met the prespecified entry criteria enrolled?, Q5: Was the sample size sufficiently large to
provide confidence in the findings?, Q6: Was the test/service/intervention clearly described and delivered consistently across the study population?, Q7:
Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed consistently across all study participants?, Q8: Were the people
assessing the outcomes blinded to the participants' exposures/interventions?, Q9: Was the loss to follow-up after baseline 20% or less? Were those lost to
follow-up accounted for in the analysis?, Q10: Did the statistical methods examine changes in outcome measures from before to after the intervention? Were
statistical tests done that provided p values for the pre-to-post changes? Q11: Were outcome measures of interest taken multiple times before the
intervention and multiple times after the intervention (i.e., did they use an interrupted time-series design)?, Q12: If the intervention was conducted at a
group level (e.g., a whole hospital, a community, etc.) did the statistical analysis take into account the use of individual-level data to determine effects at the
group level?
Good: Met 8+ criteria, Fair: Met 5-7 criteria, Poor: met < 4 criteria.
Y = Yes, N = No, U = Unclear, N/A = not applicable, NIH = National Institutes of Health
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Table I.17. NIH Quality Assessment Tool ROB data for Pre-Post studies
Pre-post study NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group Quality
Author (Year) (Total "Yes" answers)
Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12
De Vries (2011)57 Y Y U N U U Y N Y Y N N/A 5/11

De Vries (2014)79 Y Y U N U U Y N Y Y N N/A 5/11

Ghelani (2020)58 Y N Y Y U Y Y Y Y Y N N/A 8/11

Hannema (2017)59 Y Y U U N Y Y N N Y N N/A 5/11

Jarin (2017)136 Y Y Y Y U Y Y U Y Y N N/A 8/11

Joseph (2019)137 Y N U Y U Y Y U N Y N N/A 5/11

Kaltiala (2020)138 Y Y Y Y U N Y N Y Y N N/A 7/11

Klaver (2018)83 Y Y Y Y U Y Y N N Y Y N/A 8/11

Klaver (2020)139 Y Y U U U Y Y N Y Y N N/A 6/11

Klink (2015)140 Y Y Y Y U Y Y N N Y N N/A 7/11

Kuper (2020)141 Y Y N Y U Y Y N N Y N N/A 6/11

Lavender (2023)142 Y Y N Y Y N Y N N Y N N/A 6/11

2013.0Q1: Was the study question or objective clearly stated?, Q2: Were eligibility/selection criteria for the study population prespecified and clearly
described?, Q3: Were the participants in the study representative of those who would be eligible for the test/service/ intervention in the general or clinical
population of interest?, Q4: Were all eligible participants that met the prespecified entry criteria enrolled?, Q5: Was the sample size sufficiently large to
provide confidence in the findings?, Q6: Was the test/service/intervention clearly described and delivered consistently across the study population?, Q7:
Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed consistently across all study participants?, Q8: Were the people
assessing the outcomes blinded to the participants' exposures/interventions?, Q9: Was the loss to follow-up after baseline 20% or less? Were those lost to
follow-up accounted for in the analysis?, Q10: Did the statistical methods examine changes in outcome measures from before to after the intervention? Were
statistical tests done that provided p values for the pre-to-post changes? Q11: Were outcome measures of interest taken multiple times before the
intervention and multiple times after the intervention (i.e., did they use an interrupted time-series design)?, Q12: If the intervention was conducted at a
group level (e.g., a whole hospital, a community, etc.) did the statistical analysis take into account the use of individual-level data to determine effects at the
group level?
Good: Met 8+ criteria, Fair: Met 5-7 criteria, Poor: met < 4 criteria.
Y = Yes, N = No, U = Unclear, N/A = not applicable, NIH = National Institutes of Health
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Table I.17. NIH Quality Assessment Tool ROB data for Pre-Post studies
Pre-post study NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group Quality
Author (Year) (Total "Yes" answers)
Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12
Laurenzano (2021)84 Y Y Y U U Y Y N Y Y U N/A 7/11

López de Lara (2020)62 Y Y Y Y U Y Y N Y Y N N/A 8/11

Millington (2022)90 Y N U U U Y Y N N Y N N/A 4/11

Millington (2021)89 Y N Y Y U N U U U Y N N/A 4/11

Navabi (2021)92 Y Y Y U U Y Y N N Y N N/A 6/11

Neyman (2019)64 Y Y U Y N Y Y N Y N Y N/A 7/11

Olson-Kennedy (2021)93 Y Y Y Y U U Y N Y Y U N/A 7/11

Olson-Kennedy (2018)143 Y Y Y Y N U Y N N Y U N/A 6/11

Perl (2020)144 Y Y N Y U Y Y N Y Y N N/A 7/11

Perl (2021)145 Y Y Y Y U Y Y N Y Y N N/A 8/11

Roy (2023)146 Y N N U N Y Y N Y U N N/A 4/11

Schagen (2018)147 Y Y Y Y U Y Y N U Y N N/A 7/11

2013.0Q1: Was the study question or objective clearly stated?, Q2: Were eligibility/selection criteria for the study population prespecified and clearly
described?, Q3: Were the participants in the study representative of those who would be eligible for the test/service/ intervention in the general or clinical
population of interest?, Q4: Were all eligible participants that met the prespecified entry criteria enrolled?, Q5: Was the sample size sufficiently large to
provide confidence in the findings?, Q6: Was the test/service/intervention clearly described and delivered consistently across the study population?, Q7:
Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed consistently across all study participants?, Q8: Were the people
assessing the outcomes blinded to the participants' exposures/interventions?, Q9: Was the loss to follow-up after baseline 20% or less? Were those lost to
follow-up accounted for in the analysis?, Q10: Did the statistical methods examine changes in outcome measures from before to after the intervention? Were
statistical tests done that provided p values for the pre-to-post changes? Q11: Were outcome measures of interest taken multiple times before the
intervention and multiple times after the intervention (i.e., did they use an interrupted time-series design)?, Q12: If the intervention was conducted at a
group level (e.g., a whole hospital, a community, etc.) did the statistical analysis take into account the use of individual-level data to determine effects at the
group level?
Good: Met 8+ criteria, Fair: Met 5-7 criteria, Poor: met < 4 criteria.
Y = Yes, N = No, U = Unclear, N/A = not applicable, NIH = National Institutes of Health
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Table I.17. NIH Quality Assessment Tool ROB data for Pre-Post studies
Pre-post study NIH Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group Quality
Author (Year) (Total "Yes" answers)
Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Q12
Schagen (2016)148 Y Y Y Y U Y Y N U Y N N/A 7/11

Schagen (2020)94 Y N U U U Y Y U U Y N N/A 4/11

Stoffers (2019)149 Y Y Y Y U Y Y U N Y N N/A 7/11

Tack (2017)150 Y Y U U U Y Y U N Y N N/A 5/11

Tordoff (2022)96 Y Y Y N U Y Y N N Y Y N/A 7/11

Valentine (2021)97 Y Y N N U Y Y U N Y N N/A 5/11

Van der Loos (2021)69 Y Y Y Y U Y Y N Y Y N N/A 8/11

Vlot (2017)99 Y Y U N U Y Y U N Y N N/A 5/11

Willemsen (2023)127 Y Y Y Y U U N N Y N N N/A 5/11

2013.0Q1: Was the study question or objective clearly stated?, Q2: Were eligibility/selection criteria for the study population prespecified and clearly
described?, Q3: Were the participants in the study representative of those who would be eligible for the test/service/ intervention in the general or clinical
population of interest?, Q4: Were all eligible participants that met the prespecified entry criteria enrolled?, Q5: Was the sample size sufficiently large to
provide confidence in the findings?, Q6: Was the test/service/intervention clearly described and delivered consistently across the study population?, Q7:
Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed consistently across all study participants?, Q8: Were the people
assessing the outcomes blinded to the participants' exposures/interventions?, Q9: Was the loss to follow-up after baseline 20% or less? Were those lost to
follow-up accounted for in the analysis?, Q10: Did the statistical methods examine changes in outcome measures from before to after the intervention? Were
statistical tests done that provided p values for the pre-to-post changes? Q11: Were outcome measures of interest taken multiple times before the
intervention and multiple times after the intervention (i.e., did they use an interrupted time-series design)?, Q12: If the intervention was conducted at a
group level (e.g., a whole hospital, a community, etc.) did the statistical analysis take into account the use of individual-level data to determine effects at the
group level?
Good: Met 8+ criteria, Fair: Met 5-7 criteria, Poor: met < 4 criteria.
Y = Yes, N = No, U = Unclear, N/A = not applicable, NIH = National Institutes of Health
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I.4.6 Experimental Studies
The term "experimental study" can refer to several different types of study designs. In addition to the
archetypal design that we are all familiar with (ie, the prospective, randomized or non-randomized,
blinded or unblinded, crossover- or parallel-group, interventional studies with 2 or more comparison
groups), the category can also include either single-arm clinical trials or experimental case studies.151

According to Gehlbach's taxonomy, which we used to facilitate study eligibility assessment and to
organize our team's data extraction tasks, experimental trials must include at least 2 treatment groups,
and treatments must be assigned by the study investigators.32 This definition is most consistent with the
archetypal experimental study design. However, this taxonomy groups single-arm clinical trials and
experimental case studies with descriptive studies, and treats them as non-inferential studies.32
However, we must be clear that longitudinal, pre-post descriptive studies, which include single-arm
clinical trials, are considered to be inferential in nature by many experts other than Gehlbach, and may
also be considered experimental studies, especially when the interventions of interest are still deemed
to be experimental. Such single-arm, experimental trials serve as the basis of US FDA market approval
for many drugs that lack effective alternative interventions, including pediatric cancer treatments,152
and even a recently-approved, novel gene therapy for the treatment of spinal muscular atrophy (SMA).
The latter drug was FDA-approved using data from only 2 single-arm clinical trials including the
experience of N = 36 patients in total.153 Certainly, the amount of evidence available for treating
pediatric GD patients with GAHT far exceeds the quantity that supported the use of SMA gene therapy
upon FDA approval.

The question of whether hormonal treatments for pediatric gender dysphoria are still considered to be
experimental is the subject of some debate. Most experts, including WPATH and USPATH, argue that the
treatments are no longer experimental; rather they say, the treatments are well-established with
decades of clinical research supporting their use, and they are safe and effective options for pediatric
GD patients.39,154 Nonetheless, others argue that the treatments are still experimental,155-158 a
designation that they may posit invalidates the treatments' use in children. It should be noted that the
experimental status of any drug does not preclude its use in children, particularly for conditions like GD,
which have no other effective interventions. In fact, if pediatric patients were routinely excluded from
receiving experimental treatments, we would never have non-experimental treatments to offer them in
any disease state.

In one recent SR by Ludvigsson and colleagues,49 based on what may be an arbitrary subset of the
evidence, authors concluded that the treatments should still be considered experimental.49 If so, we
may regard any prospective study in which patients were treated and data were collected according to a
protocol as an experimental study for the purposes of this report. Thus, in the subsections that follow,
we provide a list of relevant experimental studies as those that meet one or more of the criteria listed in
Table I.18. As these definitions are hierarchical, with the first definitions being most restrictive and the
last being least so, studies that meet any of the definitions for experimental studies will be listed in the
first appropriate subsection.

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 Table I.18. Four competing criteria for classifying experimental studies
No Definition
1. Gehlbach's taxonomy defines experimental studies as any study in which 2 or more treatment groups
are compared, and in which study investigators assigned patients to receive the treatments of interest.

2. Authors' statements can be used to identify experimental studies as any in which investigators describe
their studies using terms such as "experimental," "pseudo-experimental," "quasi-experimental," or
"clinical trial."

3. Trial registries, such as clinicaltrials.gov,159 can be used to identify experimental studies or clinical trials.

4. Experimental treatments: This definition classifies single- or multiple-arm studies as experimental if they
are conducted prospectively, and if patients were treated and data were collected according to an a
priori protocol (eg, most of the Dutch studies).

Findings from most experimental studies meeting each of these 4 criteria are summarized in evidence
tables that are grouped according to high-priority comparison types, listed in Table I.19, rather than
according to study design. Thus, experimental studies (along with observational and descriptive studies)
may have findings reported in more than one place.

Table I.19. High-priority comparison types used for extracting findings from experimental studies

Group
Study designs
comparison types
Between-TGNB Experimental studies that compare 2 or more groups of TGNB patients (eg, treated versus
group comparisons untreated TGNB patients) are found in these evidence tables (Appendix I.J).

TGNB/cisgender Experimental studies that compare 1 or more group of TGNB patients to 1 or more groups
peer group of cisgender patients (eg, brain imaging studies of TGNB patients, cisgender males, and
comparisons cisgender females who were exposed to pheromones) are included in these evidence tables
(Appendix I.K).

Longitudinal, pre- Single- or multiple-arm experimental studies that examine within-group changes over time
post, within-group (eg, an examination of changes over time in a single group of pediatric TGNB patients who
comparisons were given GnRH analogs for puberty suppression) are included in these evidence tables
(Appendix I.L).

Experimental case studies, and other descriptive studies that lacked longitudinal, within-group
comparisons, did not undergo data extraction due to time and scope limitations. These studies that
lacked high-priority comparisons are listed in the bibliography only.

I.4.6.1 Experimental studies as defined by Gehlbach's taxonomy

Searches yielded only 1 study that met our eligibility criteria for population, intervention, and
comparator, and that was regarded as an experimental study according to Gehlbach's taxonomy (which
uses the most restrictive criteria; Table I.20).129 The study is summarized in Appendix I.K, Table I.K.3,
and Appendix I.L, Table I.L.3.

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Table I.20. Comparison types reported in experimental studies as defined by Gehlbach's taxonomy

TGNB/TGNB TGNB/Peer Pre-post

Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
Authors used a quasi-experimental design in which
Dutch, transgender boys and cisgender girls and
boys underwent laboratory assays (salivary
testosterone levels), face-matching tests, and fMRI X X
Beking (2020)129
imaging in sessions conducted before and after the
transgender boys had received exogenous
testosterone.

Table abbreviations: TGNB, transgender, nonbinary, gender-diverse; TGNB/TGNB, between-TGNB comparisons;

TGNB/Peer, TGNB versus cisgender peer group comparisons

I.4.6.2 Experimental studies as defined by authors

Searches yielded only 2 studies that met our eligibility criteria for population, intervention, and
comparator and that were described by study authors as either experimental or as clinical trials (Table
I.21).119,132 Alvares is listed in Appendix I.K, Table I.K.3, and Appendix I.L, Table I.L.3, and Staphorsius is
listed in Appendix I.J, Table I.J.2, and Appendix I.K, Table I.K.2.

Table I.21. Comparison types reported in experimental studies as defined by study authors

TGNB/TGNB TGNB/Peer Pre-post

Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
Authors described having used an experimental
protocol to conduct cardiopulmonary assessment
in transgender women who started treatments as
adolescents, and cisgender men and women who
did not. They also underwent laboratory assays
Alvares (2022)132 X X
(hemoglobin, hematocrit, and levels of FSH, LH,
estradiol, and testosterone), physical activity
assessments, anthropometric and body
composition measurement, and muscle strength
tests.

Authors described having used an experimental

Staphorsius design to examine executive functioning in
X X
(2015)119 adolescents with GD who were given cognitive
tasks to perform as they underwent fMRI imaging.

Table abbreviations: TGNB, transgender, nonbinary, gender-diverse; TGNB/TGNB, between-TGNB comparisons;

TGNB/Peer, TGNB versus cisgender peer group comparisons

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I.4.6.3 Experimental studies according to trial registries
I.4.6.3.1 US Clinical Trials Register

A search of ClinicalTrials.gov conducted on September 6, 2023 yielded 7 studies conducted in TGNB

patients that were described as clinical trials. Abstracts of each were examined, and all 7 were excluded
from this report as irrelevant because they included only adult subjects (wrong population). Thus, no
experimental studies were found in the US clinical trial registry.

I.4.6.3.2 International Standard Randomized Controlled Trial Register

Four studies from the same geographic location (Netherlands, Amsterdam, Vrije) each reported that
they were registered as clinical trials in the International Standard Randomized Controlled Trial Register
(ISRCT) and were assigned an ISRCT number (ISRCTN), which they shared. These are listed in Table I.22.

Table I.22. Comparison types reported in experimental studies as defined by ISRCT registration

TGNB/TGNB TGNB/Peer Pre-post

Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
Authors examined changes in growth, body
composition, and endogenous hormone levels in
Schagen (2016)148 X
N = 116 TGNB adolescents who were treated with
GnRH analogs for 1 year (ISRCTN 81574253).

Authors examined changes in endogenous

hormone levels, anthropometric measures, bone,
Hannema blood pressure measures among N = 28 X
(2017)59 transgender girls treated with estradiol (ISRCTN
81574253).

Authors examined changes in endogenous

Schagen (2018) 147 hormones during puberty suppression and CSHT in X X
adolescents with GD (ISRCTN 81574253).

Authors examined bone changes over time in

94 N = 121 TGNB patients who started treatment at X X
Schagen (2020)
different pubertal stages (ISRCTN 81574253).160

Table abbreviations: ISRCT, International Standard Randomized Controlled Trial Register (ISRCT); TGNB,
transgender, nonbinary, gender-diverse; TGNB/TGNB, between-TGNB comparisons; TGNB/Peer, TGNB versus
cisgender peer group comparisons

I.4.6.4 Prospective studies of treatments for pediatric gender dysphoria

In addition to the 7 studies listed above, searches yielded 29 additional prospective studies that may be
considered to be experimental studies under the premise that the treatments are still considered
experimental in children. These are listed in Table I.23.

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Table I.23. Comparison types reported in experimental studies as defined by prospective study design,
assuming that treatments are regarded as "experimental"
TGNB/TGNB TGNB/Peer Pre-post
Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
Authors examined mental health outcomes in
Achille (2020)55 X X
N = 50 TGNB adolescents.

Authors examined educational achievement

Arnoldussen (2022) 71 after puberty suppression with GnRH analogs X
and GAHT in N = 72 TGNB adolescents.

Authors examined characteristics and mental

Bauer (2021)102 X
health needs between N = 174 TGNB patients.

Authors examined the effect of hormones and

GnRH analogs on body image outcomes in
Becker (2018)103 X
TNGB adolescents (N = 82) and adults
(N = 112).

Authors examined the effect of unspecified

GnRH analogs and CSHT on psychosocial
Becker-Hebly (2021)72 X X
functioning in treated versus untreated TGNB
youth.

Authors examined effects of testosterone on

fMRI outcomes in N = 36 TGNB youth (17
Burke (2015)133 X
AFAB and 19 AMAB children) vs N = 39 age-
and sex-matched cisgender controls.

Authors examined the effects of testosterone

Burke (2016) 130 on fMRI outcomes in TGNB adolescents vs X
age- and sex-matched controls.

Authors examined short-term (ie, 1-3 years)

bone and psychosocial outcomes in N = 44
Carmichael (2021)73 TGNB youths (including 25 AMAB and 19 AFAB X X
children) ages 12-15 years who received GnRH
analog monotherapy

Authors examined mental health outcomes in

Chen (2021)104 N = 95 TGNB youth initiating treatment with X
GnRH analogs or GAH.

Authors examined mental health and

psychosocial outcomes in TGNB adolescents
Chen (2023)75 after 2 years of CSHT and mental health X X
outcomes between early- and late-treated
adolescents.

Table abbreviations: TGNB, transgender, nonbinary, or gender-diverse; TGNB/TGNB, comparisons between 2 or

more TGNB patient groups; TGNB/Peer, comparisons between 1 or more TGNB group and 1 or more cisgender
peer groups; GnRH, gonadotropin-releasing hormone; GAHT, gender-affirming hormone therapy, including
puberty suppression and/or cross-sex hormone therapy; CSHT, cross-sex hormone therapy; fMRI, functional
magnetic resonance imaging; AFAB, assigned female at birth; AMAB, assigned male at birth; WPATH, World
Professional Association for Transgender Health
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Table I.23. Comparison types reported in experimental studies as defined by prospective study design,
assuming that treatments are regarded as "experimental"
TGNB/TGNB TGNB/Peer Pre-post
Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
Authors examined mental health changes in
N = 201 TGNB adolescents, including a
comparison between transgender males vs
Costa (2015)77 transgender females treated with unspecified X X X
GnRH analogs according to the WPATH
guideline. They also looked at changes over
time within groups.

Authors examined treatment satisfaction,

de Vries (2010) 78 social functioning, sexual functioning, and
X X
quality of life in N = 27 transgender males who
Thesis (C7)
initiated treatment as adolescents.

Authors examined mental health outcomes in

de Vries (2011) 57 N = 70 TGNB patients treated with GnRH X X
analogs

Authors examined psychosocial functioning

de Vries (2014)79 after GnRH analogs, CSHT, and surgery among X X
TGNB adolescents.

Authors examined mental health and self-

worth outcomes between TGNB treatment
Durwood (2017)109 X X
groups and between TGNB adolescents versus
controls (ie, siblings and community controls).

Authors examined body composition changes

Ghelani (2020) 58 in N = 36 TGNB adolescents receiving X
triptorelin for puberty suppression.

Authors examined depression and anxiety

Grannis (2021) 110 severity in N = 42 treated vs untreated X
transgender boys.

Authors examined changes in body

dissatisfaction and mental health
Kuper (2020)161 (anxiety/depression) among N = 148 TGNB X
adolescents receiving puberty suppression
and/or CSHT.

Authors examined changes in bone between

Lee (2020)85 N = 63 TGNB patients treated with GnRH X
analogs.

Table abbreviations: TGNB, transgender, nonbinary, or gender-diverse; TGNB/TGNB, comparisons between 2 or

more TGNB patient groups; TGNB/Peer, comparisons between 1 or more TGNB group and 1 or more cisgender
peer groups; GnRH, gonadotropin-releasing hormone; GAHT, gender-affirming hormone therapy, including
puberty suppression and/or cross-sex hormone therapy; CSHT, cross-sex hormone therapy; fMRI, functional
magnetic resonance imaging; AFAB, assigned female at birth; AMAB, assigned male at birth; WPATH, World
Professional Association for Transgender Health
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Table I.23. Comparison types reported in experimental studies as defined by prospective study design,
assuming that treatments are regarded as "experimental"
TGNB/TGNB TGNB/Peer Pre-post
Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
Authors examined psychosocial outcomes in
23 TGNB patients who attend a pediatric
Lopez de Lara (2020)62 endocrinology clinic before and after one-year X X
of cross hormonal therapy (CHT).

Authors examined growth, body composition,

and cholesterol changes in N = 269 TGNB
Millington (2021)89 X X
adolescents (83 AMAB and 186 AFAB children)
receiving CSHT.

Authors examined changes in kidney function

Millington (2022) 90 measures in N = 286 TGNB adolescents (194 X X X
AFAB and 92 AMAB children) receiving GAHT.

Authors examined neural responses to peer X

Morningstar (2013)114 and caregiver voices between N = 44 CSHT-
treated or untreated transgender boys.

Authors examined insulin and DEXA outcomes

between N = 35 TGNB patients versus N = 108 X
Nokoff (2020)131
cisgender peers.

Authors examined insulin sensitivity and

Nokoff (2021) 134 glycemic control outcomes between N = 17 X
TGNB youths versus N = 31 cisgender peers.

In this protocol, authors describe that they

plan to examine growth and bone density in
Olsen-Kennedy N = 90 TGNB adolescents starting puberty
suppression, and N = 301 patients starting
(2019)162
CSHT. No high-priority results were included,
so it was included only in the bibliography.

Authors examined red blood cells in N = 15

Roy (2023) 146 transgender boys receiving testosterone X
therapy

Authors examined height velocity (ie, growth)

in TGNB patients who initiated GnRH analog
Schulmeister (2022)95 X X
puberty suppression at the various Tanner
stages.

Authors examined mental health outcomes X X

Tordoff (2022)96 (depression/anxiety) in N = 104 TGNB

Table abbreviations: TGNB, transgender, nonbinary, or gender-diverse; TGNB/TGNB, comparisons between 2 or

more TGNB patient groups; TGNB/Peer, comparisons between 1 or more TGNB group and 1 or more cisgender
peer groups; GnRH, gonadotropin-releasing hormone; GAHT, gender-affirming hormone therapy, including
puberty suppression and/or cross-sex hormone therapy; CSHT, cross-sex hormone therapy; fMRI, functional
magnetic resonance imaging; AFAB, assigned female at birth; AMAB, assigned male at birth; WPATH, World
Professional Association for Transgender Health
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Table I.23. Comparison types reported in experimental studies as defined by prospective study design,
assuming that treatments are regarded as "experimental"
TGNB/TGNB TGNB/Peer Pre-post
Author (year) Description
Appendix I.J Appendix I.K Appendix I.L
adolescents and young adults receiving
puberty suppression, CSHT, or both.

Authors examined medical competence and

Vrouenraets (2021)126 related outcomes in N = 74 TGNB adolescents X

Table abbreviations: TGNB, transgender, nonbinary, or gender-diverse; TGNB/TGNB, comparisons between 2 or

more TGNB patient groups; TGNB/Peer, comparisons between 1 or more TGNB group and 1 or more cisgender
peer groups; GnRH, gonadotropin-releasing hormone; GAHT, gender-affirming hormone therapy, including
puberty suppression and/or cross-sex hormone therapy; CSHT, cross-sex hormone therapy; fMRI, functional
magnetic resonance imaging; AFAB, assigned female at birth; AMAB, assigned male at birth; WPATH, World
Professional Association for Transgender Health
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I.4.7 Observational Studies
A total of 83 studies that were primarily observational (though some had descriptive components) met
eligibility criteria, including 1 that was a repeat publication of another included study, 3 studies without
high-priority group comparisons of interest, and 22 studies that lacked any high-priority outcomes of
interest: these were all relegated to the bibliography only. Thus, 57 observational studies had at least
one high-priority outcome of interest, made high-priority group comparisons, and underwent data
extraction. These were divided into categories according to the types of comparisons made, listed below
(studies could have comparisons in both categories; Table I.24):
A. Between-TGNB-group comparisons: 50 studies
B. TGNB vs cisgender peer comparisons: 12 studies

Outcomes of interest included the following:

Mental health (eg, depression, anxiety, suicidality)
Psychosocial functioning (eg, executive function, brain activity, education, quality of life)
Body changes (eg, changes in height, fat/lean/body mass changes, development of secondary sex
characteristics such as breast development or deepening voice, menstruation)
Body image (eg, body dysphoria/gender dysphoria, body satisfaction)
Bone health (eg, bone density, bone turnover measures)
Cardiovascular risk factors (eg, thrombotic changes, insulin sensitivity, blood pressure, obesity)
Cancer

I.4.7.1 TGNB patients compared to other TGNB subgroups

Overall, we identified 50 observational studies with comparisons between TGNB youth and other TGNB
subgroups with at least one outcome of interest (Table I.24; see Appendix I.J). Of these, 9 studies also
had longitudinal, pre-post descriptive comparisons of interest. Their detailed findings are in Appendix
I.L.

None of the reviewed TGNB vs TGNB observational studies had cancer-related outcomes, but the
remaining outcomes of interest were reported in the following number of studies (note that more than
1 outcome of interest may have been reported in a single study):
Mental health: 25
Psychosocial functioning: 22
Body changes: 15
Body image: 9
Bone health: 7
Cardiovascular risk factors: 10

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Table I.24. Comparison types reported in observational studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix I.L
I.K
Authors examined mental health outcomes in
Achille (2020)55 X X
N = 50 TGNB adolescents.
Authors compared cardiopulmonary capacity
and muscle strength (ie, determinants of
Alvares (2022)132 physical performance) in Brazilian transgender X X
women versus cisgender men and women,
none of whom were athletes.
Authors examined the association between
Arnoldussen birth-assigned sex and psychosocial functioning
X
(2020)100 in N = 1072 TGNB adolescents, including 404
AFAB and 668 AMAB children.
Authors examined educational achievement
Arnoldussen (2022)71 after puberty suppression with GnRH analogs X
and GAHT in N = 72 TGNB adolescents.
Authors compared EDE-Q (eating disorder
Avila (2019)101 scale) scores between treated and untreated X
TGNB subjects
Authors examined characteristics and mental
Bauer (2021)102 X
health needs between N = 174 TGNB patients.
Authors examined the effect of hormones and
Becker (2018)103 GnRH analogs on body image outcomes in X
TNGB adolescents (N = 82) and adults (N = 112).
Authors examined the effect of unspecified
Becker-Hebly GnRH analogs and CSHT on psychosocial
X X
(2021)72 functioning in treated versus untreated TGNB
youth.
Authors compared dosages, growth, bone age,
IGF-1 levels, and more outcomes between
Boogers (2022)66 X X
N = 161 trans females with different hormone
treatments and dosages.
Authors examined effects of testosterone on
fMRI outcomes in N = 36 TGNB youth (17 AFAB
Burke (2015)133 X
and 19 AMAB children) vs N = 39 age- and sex-
matched cisgender controls.
Authors examined the effects of testosterone
Burke (2016)130 on fMRI outcomes in TGNB adolescents vs age- X
and sex-matched controls.
Authors examined mental health outcomes in
Chen (2021)104 N = 95 TGNB youth initiating treatment with X
GnRH analogs or GAH.
Authors examined baseline mental health in
Chiniara (2018)76 X
N = 79 TGNB AFAB vs AMAB children
Authors examined risk factors for mental health
Conn (2023)105 outcomes in N = 315 TGNB adolescents from X
the Trans Youth Care Study.

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Table I.24. Comparison types reported in observational studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix I.L
I.K
Authors examined mental health changes in
N = 201 TGNB adolescents, including a
comparison between transgender males vs
Costa (2015)77 transgender females treated with unspecified X X X
GnRH analogs according to the WPATH
guideline. They also looked at changes over
time within groups.
Authors examined mental health characteristics
of TGNB patients who were referred (ie, for
De Graaf (2022)108 X
GnRH analog treatment) versus non-referred
across 3 clinics
Authors examined psychosocial functioning
de Vries (2014)79 after GnRH analogs, CSHT, and surgery among X X
TGNB adolescents.
Authors examined mental health characteristics
of TGNB patients who were referred (ie, for
de Vries (2016)107 X
GnRH analog treatment) versus non-referred
across 2 clinics
A cross-sectional study examining mental
health diagnoses among AFAB vs AMAB TGNB
De Vries (2011)106 X
adolescents, and between treated vs untreated
TGNB patients
Authors examined mental health and self-
worth outcomes between TGNB treatment
Durwood (2017)109 X X
groups and between TGNB adolescents versus
controls (ie, siblings and community controls).
Authors compared hormone levels and puberty
suppression outcomes between N = 48
Eitel (2023)80 X
transgender youths (16 AFAB and 32 AMAB
children) receiving Lupron vs Eligard
Authors examined depression and anxiety
Grannis (2021)110 severity in N = 42 treated vs untreated X
transgender boys.
Authors compared demographic and mental
health characteristics between N = 5753
Green (2022)111 adolescents and young adults who self- X
reported receiving GAHT versus not, including
N = 3235 adolescents ages 13-17 years
Authors compared menstrual suppression
outcomes in N = 232 transgender boys in
different GnRH analogs and hormone
Grimstad (2021)81 X
treatment groups. Also makes case-control-
type comparisons examining risk factors for
breakthrough bleeding in transgender males.
Authors examined body changes and
Karakilic Ozturan
endogenous hormone levels in TGNB X
(2023)112
adolescents

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Table I.24. Comparison types reported in observational studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix I.L
I.K
Authors compared demographic characteristics,
adverse effects, GnRH analog/CSHT initiation,
Khatchadourian
Tanner stages, and psychiatric comorbidities X
(2014)82
between N = 84 MTF and FTM transgender
youth.
Authors examined changes in bone between
Lee (2020)85 N = 63 TGNB patients treated with GnRH X
analogs.
Authors compared blood pressure outcomes in
Martinez-Martin N = 302 young transgender patients receiving
X
(2023)86 different hormone therapies, including
treatment groups with mean ages < 18 years.
Authors examined risk factors for type I DM,
Maru (2021)128 including age at presentation, and hormone X
therapy.
Authors examined differences in bone density
in N = 119 TGNB patients based on natal sex,
Marwa (2022)87 X
including N = 46 AMAB and N = 73 AFAB
children
Authors examined the risk of hyperkalemia
Millington (2019)88 associated with spironolactone in N = 85 X
transfeminine or nonbinary adolescents
Authors examined gender identity changes
between AMAB vs AFAB TGNB subjects, and
Mirabella (2022)113 X
between trans binary vs nonbinary TGNB
subjects.
Authors examined neural responses to peer
Morningstar (2023)114 and caregiver voices between N = 44 CSHT- X
treated or untreated transgender boys.
Authors examined thrombosis risk factors and
outcomes in N = 611 TGNB adolescents
91 initiating GAHT. [No thrombosis events were
Mullins (2021) X
observed and too few observations had any of
the relevant outcomes for inferential
comparisons.]
Authors examined mental health and
Nahata (2017)115 psychosocial outcomes between transgender X
males and transgender females
Authors examined baseline and follow-up
changes in bone mass, body composition,
vitamin D, and puberty suppression outcomes
Navabi (2021)92 between N = 172 transgender male vs female X X
youths who received GnRH analogs. Also
looked at changes from baseline within each
group.

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Table I.24. Comparison types reported in observational studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix I.L
I.K
Authors examined insulin and DEXA outcomes
Nokoff (2020)131 between N = 35 TGNB patients versus N = 108 X
cisgender peers.
Authors examined insulin sensitivity and
Nokoff (2021)134 glycemic control outcomes between N = 17 X
TGNB youths versus N = 31 cisgender peers.
Authors examined associations between
Olsavsky (2023)116 treatments and mental health outcomes among X
N = 75 TGNB adolescents
Authors compared puberty suppression
Olson-Kennedy outcomes in N = 66 TGNB subjects receiving
X X
(2021)93 two forms of histrelin (Vantas vs SupprelinLA).
Also examined within-group outcomes.
Authors compared bone changes over time for
TGNB subjects at different pubertal stages. Also
examined changes over time in N = 121 TGNB
Schagen (2020)94 X X
patients. The study was registered with the
International Standard Randomized Controlled
Trial Number register (ISRCTN 81574253).
Authors examined height velocity (ie, growth)
in TGNB patients who initiated GnRH analog
Schulmeister (2022)95 X X
puberty suppression at the various Tanner
stages.
Authors examined mental health and
Segev-Becker
behavioral outcomes in N = 106 transgender X
(2020)117
boys vs girls
Authors examined mental health problems in
Sorbara (2020)118 older- versus younger-presenting TGNB X
adolescents
Authors analyzed of the impact of GAHT on
Staphorius (2015)119 X X
executive function in N = 40 TGNB adolescents
Authors examined characteristics of AFAB vs
Tollit (2023)120 AMAB TGNB adolescents, including mental X
health and psychosocial parameters
Authors examined mental health outcomes
(depression/anxiety) in N = 104 TGNB
Tordoff (2022)96 X X
adolescents and young adults receiving puberty
suppression, CSHT, or both.
Authors conducted a secondary analysis of the
2015 US Transgender Survey, (N = 27,715 TGNB
respondents), restricted to those who wanted
Turban (2020)121 puberty suppression hormones (n = 3494). They X
examined associations between adolescent and
adult mental health outcomes, including
measures of suicidality.

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Table I.24. Comparison types reported in observational studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix I.L
I.K
Authors conducted a secondary analysis of the
2015 US Transgender Survey (N = 27,715 TGNB
respondents), restricted to those who desired
GAHT (n = 21.598). They examined associations
between access to GAHT during early
Turban (2022)122 X
adolescence (age 14–15), late adolescence (age
16–17), or adulthood (age > 18) and adult
mental health outcomes, with participants who
desired but never accessed GAHT as the
reference group.
Authors examined cardiometabolic parameters
in N = 44 transgender adolescents receiving
Valentine (2021)97 testosterone versus N = 82 cisgender females. X X
The study also compares outcomes between
transgender treatment groups.
Authors compared cardiometabolic parameters
between N = 4172 TGNB adolescents, (N = 2766
98 AFAB and N = 1407 AMAB) versus N = 16648
Valentine (2022) X X
controls (N = 11130 AFAB and N = 5518 AMAB),
and between TGNB adolescents receiving
different treatments
Authors compared surgical outcomes between
3 TGNB groups: (a) youths who received early
Van de Grift (2020)123 puberty suppression, (b) youths who received X
late puberty suppression, and (c) TGNB adults
who did not receive puberty suppression.
Authors compared bone outcomes in N = 322
TGNB adolescents compared to cisgender
Van der Loos (2021)69 X
controls and a pre-post descriptive study
reporting on bone changes over time
Authors compared mental health outcomes in
treated versus untreated TGNB adolescents;
Van der Miesen
also compares mental health outcomes X X
(2020)124
between TGNB adolescents and cisgender
peers
Authors examined characteristics of N = 124
Vehmas (2022)125 pediatric TGNB patients presenting for X
treatment.
Authors examined medical competence and
Vrouenraets (2021)126 X
related outcomes in N = 74 TGNB adolescents
Authors examined correlates of puberty
Zucker (2010)65 X
suppressive treatment

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I.4.7.2 TGNB compared to cisgender peers
Overall, we identified 12 observational studies with comparisons between TGNB youth and cisgender
peer groups with at least one outcome of interest (see Table I.24; see Appendix I.K) Of these, 3 also had
a longitudinal, pre-post descriptive component. Their detailed findings are in Appendix I.L.

None of the reviewed TGNB vs peer observational studies had cancer-related, body image, or bone
health outcomes, but the remaining outcomes of interest were reported in the following number of
studies (note that more than 1 outcome of interest may have been reported in a single study):
Mental health: 2
Body changes: 6
Psychosocial functioning: 4
Cardiovascular risk factors: 5

I.4.7.3 Summary of observational studies

Table I.24 contains all observational studies that underwent data extraction, including TGNB vs TGNB
and TGNB versus cisgender peer comparisons, and where data can be found for each study. Some
observational studies also have pre-post comparisons and have data included in Appendix I.L.

I.4.7.4 Outcomes addressed with comparisons of TGNB adolescents to

other TGNB subgroups
See Appendix I.J for evidence tables regarding study details and findings, organized by outcome of
interest. Note that some studies evaluated more than one outcome of interest and are represented in
more than one table. Some studies also have TGNB vs cisgender peer data or pre-post comparison
within the study, and may be included in Appendixes I.K and I.L. ROB assessment is provided in Section
I.4.5.6.

Some limited take-aways based on the findings from included observational studies with TGNB patients
compared to other TGNB subgroups, organized by outcome of interest:
Mental health:
o Generally, rates of depression and suicidal thoughts/self-harm tended to be lower among
hormonally treated transgender youth compared to untreated transgender individuals.
o Starting hormone therapy earlier tended to have a neutral to positive effect on mental health
outcomes.
o Transgender youth exhibit a relatively high prevalence of mental health comorbidities, including
anxiety, depression, and/or suicidality.
o Transmasculine adolescents tend to report more severe symptoms of depression and anxiety
compared to transfeminine adolescents.
Psychosocial Functioning:
o Generally, psychosocial functioning tended to be comparable between natal males and natal
females

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 o In general, when compared to untreated TGNB adolescents, TGNB youth who used hormone
therapy tended to see a decrease in problem scores and an increase in functioning and quality
of life scores.
Body changes:
o Typically, transgender females and transgender males had comparable body compositions.
Body image:
o In general, natal females reported a greater degree of gender dysphoria compared to natal
males
o Compared to untreated transgender individuals, those who received hormonal treatment
tended to have improvements in body image satisfaction
Bone health:
o Transgender females tend to have lower levels of bone mineral density compared to
transgender males
Cardiovascular risk factors:
o As a rule, some cardiovascular risk factors increase for transgender patients when they start
CSHT. However, these risk factors tend to be within the reference range for transgender
patients compared to that of the affirmed sex.

I.4.7.5 Outcomes addressed with comparisons of TGNB patients to their

cisgender peers
See Appendix I.K for evidence tables regarding study details and findings, organized by outcome of
interest. Note that some studies evaluated more than one outcome of interest and are represented in
more than one table. Some studies also have TGNB vs TGNB data or pre-post comparison within the
study and may be included in Appendixes I.J and I.L.

Due to fewer studies, with varied outcomes, there are few generalizations to make for the TGNB vs.
cisgender peer studies.

I.4.8 Descriptive Studies

A total of 144 descriptive studies met eligibility criteria, including 35 case reports (2 of which were not in
English), 14 case series (1 of which was not in English), 4 other non-English studies with abstracts in
English that warranted inclusion, 1 commentary on another included study, 2 repeat publications of
included studies, 12 studies that lacked any high-priority outcomes of interest, and 44 studies that
lacked high priority comparisons. These were all relegated to the bibliography only (see Appendix I.F).
The remainder, 32 studies, had a high-priority comparison and at least one high-priority outcome of
interest and thus had their data extracted. The non-English and lacking studies can be found only in the
Bibliography of Included Studies, Appendix I.F.

See Appendix I.L for evidence tables regarding details and findings of the descriptive studies that had
their data extracted in full, organized by outcome of interest. Note that some studies evaluated more
than one outcome of interest and are represented in more than one table.

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Outcomes of interest included the following:
Mental health (eg, depression, anxiety, suicidality)
Psychosocial functioning (eg, executive function, brain activity, education, quality of life)
Body image (eg, body dysphoria/gender dysphoria, body satisfaction)
Body changes (eg, changes in height, fat/lean/body mass changes, development of secondary sex
characteristics such as breast development or deepening voice, menstruation)
Bone health (eg, bone density, bone turnover measures)
Cardiovascular risk factors (eg, thrombotic changes, insulin sensitivity, blood pressure, obesity)
Cancer

I.4.8.1 Longitudinal, pre-post comparisons

None of the reviewed descriptive studies had cancer-related outcomes, but the remaining outcomes of
interest were reported in the following number of studies (note that more than 1 outcome of interest
may have been reported in a single study):
Mental health: 11
Psychosocial functioning: 11
Body image: 5
Body changes: 22
Bone health: 7
Cardiovascular risk factors: 14

I.4.8.2 Summary of longitudinal, pre-post descriptive studies

Table I.25 below contains all included descriptive studies with high-priority, pre-post comparisons and
where extracted data can be found (see Appendix I.L). Some descriptive studies also had observational
comparisons; the observational comparisons are summarized above in Section I.4.7, and their extracted
data can be found in Appendixes I.J and I.K.

Overall, we identified 39 descriptive studies with longitudinal pre-post comparisons, 31 of which had at
least one high priority outcome of interest (Table I.25). Thirteen of these longitudinal pre-post studies
also had an observational component (see Appendix I.L).

Table I.25. Comparison types reported in descriptive studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix
I.K I.L
Authors examined mental health and suicidality
Allen (2019)56 outcomes among N = 47 TGNB adolescents who X X
received GnRH analogs followed by CSHT vs CSHT only.
Authors examined changes in psychosocial outcomes
Arnoldussen
in TGNB adolescents before (while on hormonal X
(2022)135
treatments only) vs after gender-affirming surgery.

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Table I.25. Comparison types reported in descriptive studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix
I.K I.L
Authors examined changes in anxiety and depression
in treated and untreated TGNB youth. Also compares
Cantu (2020)74 X X
differences in changes over time between TGNB
groups.
Authors examined short-term (ie, 1-3 years) bone and
psychosocial outcomes in N = 44 TGNB youths
Carmichael (2021)73 X X
(including 25 AMAB and 19 AFAB children) ages 12-15
years who received GnRH analog monotherapy
Authors examined mental health and psychosocial
outcomes in TGNB adolescents after 2 years of CSHT
Chen (2023)75 X X
and mental health outcomes between early- and late-
treated adolescents.
Authors examined treatment satisfaction, social
de Vries (2010)78 functioning, sexual functioning, and quality of life in
X X
Thesis (C7) N = 27 transgender males who initiated treatment as
adolescents.
de Vries (2011)57 Authors examined mental health outcomes in N = 70 X X
TGNB patients treated with GnRH analogs
Authors examined body composition changes in
Ghelani (2020)58 N = 36 TGNB adolescents receiving triptorelin for X
puberty suppression.
Authors examined changes in endogenous hormone
levels, anthropometric measures, bone, blood
Hannema (2017)59 X
pressure measures among N = 28 transgender girls
treated with estradiol
Authors examined cardiovascular and metabolic
Jarin (2017)136 changes associated with CSHT in N = 116 adolescents X
with gender dysphoria
Authors examined bone outcomes in N = 31 TGNB
Joseph (2019)137 X
adolescents treated with GnRH analogs
Authors examined psychosocial functioning in N = 52
Kaltiala (2020)138 X
TGNB adolescents before and after 1-year of CSHT
Authors examined body composition changes over
Klaver (2018)83 time in N = 192 transgender patients who received X X
unspecified GnRH analogs and CSHT
Authors compared changes in cardiovascular risk
factors between TGNB subjects who received surgical
Klaver (2020)139 vs GnRH analog gonadal suppression, and between X
transwomen and transmen. Also examined within-
group changes over time.
Authors examined patient characteristics and bone
Klink (2015)140 outcomes over time in N = 34 GnRH analog and CSHT- X
treated adolescents with GD
Authors examined changes in body dissatisfaction and
Kuper (2020)141 X
mental health (anxiety/depression) among N = 148

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Table I.25. Comparison types reported in descriptive studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix
I.K I.L
TGNB adolescents receiving puberty suppression
and/or CSHT.
Authors examined endogenous hormone levels,
menstrual outcomes, and body changes in N = 119
Laurenzano (2021)84 X X
transmasculine and gender-diverse adolescents
treated with subcutaneous testosterone
Authors examined changes in mental health and
Lavender (2023)142 suicidality for N = 38 TGNB youths after initiating X
unspecified GnRH analogs and CSHT.
Authors examined psychosocial outcomes in 23 TGNB
Lopez de Lara patients who attend a pediatric endocrinology clinic
X X
(2020) 62 before and after one-year of cross hormonal therapy
(CHT).
Authors examined growth, body composition, and
Millington (2021)89 cholesterol changes in N = 269 TGNB adolescents (83 X X
AMAB and 186 AFAB children) receiving CSHT.
Authors examined changes in kidney function
Millington (2022)90 measures in N = 286 TGNB adolescents (194 AFAB and X X X
92 AMAB children) receiving GAHT.
Authors reported on clinical and laboratory
characteristics of N = 13 transfeminine patients
Neyman (2019)64 treated with the antiandrogen bicalutamide as an X
androgen blocker after insurance denials of claims for
GnRH analogs
Authors examined cardiovascular and metabolic
Olson-Kennedy
outcomes over time in N = 101 transmasculine and X
(2018)143
transfeminine adolescents
Authors examined blood pressure outcomes in N = 15
transgender males receiving puberty-suppressing
Perl (2020)144 X
GnRH analogs, N = 9 of which went on to receive CSHT
with testosterone
Authors examined blood pressure, weight, and
hormone levels in N = 19 adolescents who received
Perl (2021)145 X
GnRH analogs for puberty suppression, N = 15 of
which also went on to receive CSHT with estradiol
146 Authors examined red blood cells in N = 15
Roy (2023) X
transgender boys receiving testosterone therapy
Authors examined growth, body composition, and
Schagen (2016)148 endogenous hormone levels in N = 116 TGNB X
adolescents who received GnRH analogs for 1 year
Authors examined changes in endogenous hormones
Schagen (2018)147 during puberty suppression and CSHT in adolescents X X
with GD.
Authors examined body changes, growth,
Stoffers (2019)149 cardiovascular risk factors, and metabolic outcomes in X
testosterone-treated adolescents with GD

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Table I.25. Comparison types reported in descriptive studies that underwent full data extraction
Author (year) Description TGNB/TGNB TGNB/peer Pre-post
Appendix I.J Appendix Appendix
I.K I.L
Authors examined growth, cardiovascular risk factors,
and metabolic changes in N = 27 transgender female
Tack (2017)150 X
adolescents taking estrogen with an antiandrogen not
available in the US (cyproterone)
Authors examined bone changes over time with
Vlot (2017)99 puberty suppression and CSHT in N = 70 TGNB X X
adolescents
Authors examined height and weight outcomes in
Willemsen (2023)127 N = 146 TGNB adolescents who initiated GnRH analogs X X
before age 16 years.

I.4.8.3 Outcomes addressed with longitudinal, pre-post comparisons

See Appendix I.L for evidence tables regarding descriptive study details and findings, organized by
outcome of interest. Below are some limited takeaways based on the findings from included pre-post
descriptive studies of within-TGNB population comparisons, organized by outcome of interest:
Mental health:
o Generally, rates of suicidal thoughts/self-harm tended to be lower when followed up after
treatment
o Scores for anxiety and depressive symptoms tended to either have no change, or decrease while
on treatment
o Scores for gender dysphoria tended to decline after treatment
Psychosocial functioning:
o Generally, there was an increase in scores for psychosocial functioning, and a decrease in
behavioral and emotional problem scores after treatment
Body image:
o In general, there was a decrease in body dissatisfaction scores in patients after treatment
Body changes:
o Body composition tended to change (fat distribution, lean body mass) towards the affirmed sex
with CSH treatment
Bone health:
o There were changes in bone mineral density, usually with a drop in z-scores, often leveling out
over time. This was more apparent in transgender girls.
Cardiovascular risk factors:
o Cardiovascular risk factors tended to increase for transgender patients when they started
therapy, but still often stayed within normal range. However, many of these risk factors often
plateaued or returned to normal after more time on therapy. Transgender boys tended to have
more changes to their cardiovascular health.

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I.5.0 OBJECTIVE 4: PERSISTENCE, DESISTANCE, AND REGRETS
Persistence, desistance, and regret were not among our high-priority outcome categories for this
review. However, these concepts were pointedly of interest to the legislature, per Utah SB 16,14 so we
examined the evidence in the retrieved studies. We found 32 studies that addressed persistence,
desistance, and/or regret. Findings from these studies that relate to rates of persistence and desistance
are summarized in Table I.26.

Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
163
Barnard (2019) N=11 TGNB presented at an academic fertility clinic for fertility preservation. Of
these,
2 (18%) paused GAHT for fertility preservation.
Brik (2020)164 N=143 TGNB adolescents were seen at a clinic in the Netherlands and started GnRH
analog therapy between November 2010 and January 2018. There were n=105 trans
boys (median age 16.1 years) and n=38 trans girls (median age 15.0 years). Of this
group,
After a median duration of 0.8 years on GnRH analogs, n=125 started GAHT
5 had not yet started GAHT because they were not yet eligible due to their age at
the time of data collection, 6 had been referred to a gender clinic elsewhere
Of those who started GnRH analogs, 9 (6%) discontinued:
o 5 (3.5%) no longer wished to pursue gender-affirming treatment.
o 4 (2.3%) discontinued, but then later restarted GAHT.
Butler (2022)165 N=1151 TGNB children were referred to 1 of 2 British gender identity clinics in 2008-
2021; N=1089 were followed until 2022. Of these,
999 (91.7%) persisted with their initial gender identity variant.
32 (2.9%) reverted to their birth gender and never started GAHT.
58 (5.3%) reverted to their birth gender after initiating GAHT.
Carmichael (2021)73 N=44 TGNB youth on GnRH analog monotherapy at a gender clinic in Brazil. Bone
data was assessed. Of these,
1 (2.3%) chose not to start CSHT.
Clark (2020)166 N= 21 trans youth (aged 14-18) and their parents, residing in British Columbia,
Canada, were interviewed about the decision-making process related to initiating
GAHT between August 2016 and February 2017. Of these youth,
0 (0%) expressed regret about the decision to start hormone therapy, though
some wished the process had unfolded differently. In particular, those who
wished the process had unfolded differently were those who had been denied

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing

hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
puberty blockers and who had developed unwanted secondary sex characteristics
while waiting for care.
Cohen (2023)167 N=68 out of 130 TGNB children requesting GAHT or surgery in a US, national hospital-
based gender identity clinic were interviewed over time to assess patterns of change
in requests for GAHT or surgery. Of these,
20 (29%) experienced a shift in their treatment requests related to gender
identity:
o 4 (5.9%) withdrew their request before starting treatment.
o 2 (2.9%) withdrew their requests after starting treatment.
o 14 (20.6%), withdrew their request and then subsequently re-requested
treatment.
Cohen-Kettenis (2011)168 N=1 transgender male followed up over 22 years. He was treated with GnRH analogs
at 13 years of age, was eligible for androgen treatment at age 17 years, and had
gender reassignment surgeries at 20 and 22 years. At follow-ups, he expressed a lack
of regret about undergoing his treatment.

De Vries (2010) (Chapter N=27 TGNB youths presented to a Dutch gender identity clinic, underwent GAHT and
7)78 gender reassignment surgery, and were followed up at a mean age of 20 years. Of
these,
0 (0%) expressed feelings of regret with either GAHT or surgery.
De Vries (2014)79 N=55 TGNB adults at a Dutch gender identity clinic had initiated puberty suppression
during adolescence and undergone assessments at 3 times: (1) before the start of
puberty suppression (mean age 13.6 years), (2) when CSHT was introduced (mean
age 16.7 years), and (3) at least 1 year after gender reassignment surgery (mean age
20.7 years). Psychological functioning (GD, body image, global functioning,
depression, anxiety, emotional and behavioral problems) and objective (social and
educational/professional functioning) and subjective (quality of life, satisfaction with
life and happiness) well-being were investigated. Of these,
55 (100%) of young adults were generally satisfied with their physical appearance.
0 (0%) regretted treatment.
Expösito-Campos (2022)169 N=1 transgender female (age 16 years) presented at a Spanish gender identity clinic
with severe GD in 2014. She was prescribed GAHT with cyproterone and estradiol. In
2016, she legally changed her name to a feminine-affirming name. Vaginoplasty was
delayed for unrelated reasons, but after starting a sexual relationship with a male
partner, she desisted from pursuing surgery in 2017 and discontinued cyproterone. In
2018, she discontinued hormonal treatment completely, saying that she "does not
need [hormones] to be a woman." At the time of publication, she continues to persist
in her transfeminine gender identity.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing

hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
Hannema (2017)59 N=28 TGNB girls at a Dutch gender identity clinic were treated with oral estrogen for
1+ year. Tanner stage, anthropometry, laboratory parameters, bone age, and body
composition were evaluated. Of this group,
0 (0%) discontinued estrogen treatment
Jensen (2019)60 N=83 patients at a pediatric gender clinic who were receiving GAHT before March of
2016. 17 out of 83 patients were taking GnRH analogs. Of these,
10 (59%) of patients discontinued use of GnRH analogs, most commonly due to a
loss of insurance coverage.
Laurenzano (2021)84 N= 119 TNGB youth at a California hospital started GAHT between 2012 and 2020
with subcutaneous testosterone at ages 13-19 years and were evaluated for side
effects, dosage, and response to treatment. Of the 119 youth,
3 (2.5 %) stopped GAHT altogether due to desire to end masculinizing therapy.
2 (1.7%) stopped because they were satisfied with the effects they had achieved.
1 (0.8%) stopped within 6 months of starting after reassessing their gender
identity and concerns about a potential impact on fertility.
Karakilic Ozturan (2023)112 N=30 TGNB adolescents referred for GD to a clinic in Turkey had their charts reviewed
for clinical findings. Of these,
1 (3.3%) had their GD resolve and did not continue with CSHT after GnRH analogs.
1 (3.3%) developed depression due to body dissatisfaction related to cosmetic
appearance after a gender-affirming surgery and treatments were discontinued.
Khatchadourian (2014)82 N=84 TNGB adolescents (median age 16.9 years) seen in a British Columbia hospital
were included in a chart review study from 1998 through 2011. Of these,
1 (1.2%) patient with undecided gender was prescribed GnRH analogs but
discontinued after 13 months and chose not to pursue transition.
63 (75%) were treated with CSHT during the observation period.
o 0 (0%) of the 63 discontinued treatment permanently.
o 3 (4.8%) temporarily paused treatment and later restarted.
 2 due to concomitant psychiatric comorbidities
 1 due to distress over androgenic alopecia
141
Kuper (2020) N=148 TGNB participants (mean age 14.9 years) were receiving GAHT in a program in
Texas. Participants completed surveys assessing various mental health outcomes at
baseline and 1 year (11-18 months) after initial assessment. Of this group,
0 (0%) participants discontinued feminizing or masculinizing hormone therapy
during study period
Masic (2022)170 N=439 TGNB youths who presented to a British gender identity clinic in 2017-2018
were followed until November 2020. Of these,

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing

hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
30 (6.8%) discontinued GAHT or chose not to start it for the following reasons:
o 13 (3.0%) stopped/did not start for unknown reasons.
o 5 (1.1%) stopped/did not start for health reasons.
o 4 (0.9%) paused to preserve fertility.
o 4 (0.9%) transferred to a private provider.
o 3 (0.7%) stopped/did not start because they felt unsure about starting GAHT.
o 1 (0.2%) stopped/did not start for mental health reasons.
McCallion (2021)171 N=91 TGNB patients (median age 14.6 years) were referred to a pediatric
endocrinology clinic for GD, of whom 79 (87%) started treatment with GnRH analogs.
Of those who started GnRH analogs,
6 (8%) discontinued GnRH analogs after a median of 6 months.
41 (51.9%) started CSHT.
1 (1.3%) discontinued CSHT.
172
Nieder (2021) N=75 TGNB adolescents ages 11-21 years who presented to a German gender identity
service were assessed for satisfaction of care, social support, reasons for regret and
termination of transition related care and (dis)satisfaction with transition-related
medical interventions. Of these,
0 (0%) adolescents regretted undergoing treatment at follow-up
13 (17.3%) participants had suspended or terminated their care at the clinic-
reasons related to mental health issues were most often listed, followed by
reasons unrelated to direct treatment experience (eg, long distance to clinic)
o 9 (12%) had not started medical interventions
o 3 (4%) were taking GAHT
o 1 (1.3%) was at the stage for gender-affirming surgery
Nos (2022)173 N=434 TGNB patients (mean age 15.4) presented with GD at a US military healthcare
system. Of these,
70 (16.1%) were prescribed GnRH analogs.
"Few" discontinued treatment.
O’Bryan (2018)174 N=139 TNGB youths enrolled in a registry at a rural gender identity clinic. Of these,
121 (87.7%) had socially transitioned.
123 (89.1%) had begun medically transitioning.
20 (14.4%) had undergone a gender-affirming surgical procedure.
1 (0.7%) reverted to their birth-assigned sex after starting CSHT.
1 (0.7%) stopped GnRH analogs and subsequently resumed them.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing

hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
1 (0.7%) continued to take GnRH analogs while exploring an emerging gender
identity.
1 (0.7%) desisted after taking GnRH analogs.
Olson (2022)175 N=317 TNGB children (mean age 8.1 years) participating in the longitudinal Trans
Youth Project were followed for 5 years after an initial social transition. Of these,
298 (94.0%) still identified as a binary transgender youth.
o 23 (7.3%) had retransitioned at least once.
o 4 (1.3%) had retransitioned to another identity before returning to their binary
transgender identity.
11 (3.5%) identified as nonbinary.
8 (2.5%) identified as cisgender 5 years after their initial social transition.
o A cisgender identity 5 years after the social transition was more likely in
patients whose social transition occurred before age 6 years.
Pullen Sansfaçon (2019)176 N=35 Canadian TGNB youths ages 9-17 years who participated in semi-structured
interviews through clinics where they had received or were waiting for GAHT. Of
these,
0 (0%) of youth regretted their choice to undergo the interventions even though
some described unwanted medication side-effects and others said they had
questioned their transition trajectory at certain moments in the past.
Schagen (2016)148 N=116 TGNB youth seen in a Dutch clinic were treated with triptorelin. Physical
examination took place every 3 months and blood samples were drawn at 0, 3, and 6
months and every 6 months after. After 12 months of treatment, of this group,
0 (0%) of the subjects discontinued GnRH analogs.
Segev Becker (2020)117 N=106 TGNB youth at an Israeli gender clinic (median age at referral 15.5 years) from
March 2013 through December 2018 were retrospectively assessed for psychiatric
comorbidities, behavioral characteristics, fertility preservation and treatment. Of the
pubertal group (n=96),
77 (80%) began on GnRH analog treatment (mean [SD] age of 15.6 [1.6] years)
during the observation period.
o 61 (83%) of the patients who began on GnRH analog treatment were started on
GAHT either concurrently or later, at a mean (SD) age of 16.5 (1.3) years
o At the time of study analysis, some chose not to pursue treatment with GAHT.
 12 (16%) lacked a complete GD diagnosis by a health care provider
 3 (3.9%) lacked parental consent
 1 (1.3%) was delaying treatment for the purpose of fertility preservation
 3 (3.9%) had other reasons for not pursuing GAHT at that time

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing

hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
2 (2%) of the 96 patients in the pubertal group expressed regret. 2 transgender
females who had been on GnRH analogs and low-dose estrogen for 3 months
chose not to continue transition and discontinued treatment. One of those had
autistic spectrum disorder, and the other identified as a homosexual male and
was lost to follow-up.
Singh (2021)177 N=139 birth assigned males were assessed at a gender identity service in Canada
around the mean age of 7.49 years at the mean year of 2002. In childhood, 88
(63.3%) of the boys met the criteria for gender identity disorder; the remaining 51
(36.7%) were subthreshold for the criteria. Gender identity/dysphoria was assessed
via multiple methods. At follow-up, when patients were a mean age of 20.58, after an
interval of mean 12.88 years, of the 139 participants,
17 (12.2%) were classified as persisters
122 (87.8%) were classified as desisters
Of the 88 participants who met the full diagnostic criteria for GID in childhood,
12 (13.6%) were classified as persisters
76 (86.4%) were classified as desisters
Tollit (2023)120 N=359 TGNB patients (median age at presentation, 14.3 years) who had had an
appointment with a large Australian pediatric gender service from Jan 2001-Dec 2016
and had either a self-reported gender which differed from what was presumed for
them at birth or sought guidance regarding gender identity/expression had their
charts reviewed for data. Of the 359 patients, 234 received medical interventions. Of
the 234 patients,
54/234 (23%) were treated with GnRH analogs.
o 1 (1.9%) patient stopped without progressing to CSHT during the study period
48/234 (20.5%) were treated with CSHT
o 1 (2.1%) patient stopped GAH unexpectedly during the study period
Turban (2018)178 N=1 TGNB girl who presented to a multidisciplinary clinic at the age of 15. She
received a puberty blocker (histrelin GnRH analog implant.) At age 16, she started
estrogen therapy at a small dose, with a plan to escalate to adult dosing over a
prolonged period of time. Four months later, the patient adopted nonbinary
pronouns they, them and their and did not wish to increase the dose of estrogen any
further, nor did they wish to stop estrogen. The patient then decided they did not
identify as a boy or girl and chose to discontinue estrogen therapy and remove their
puberty blocker with the understanding that they would go through male puberty.
They continued to be followed and continues to identify as gender nonbinary. The
patient sometimes expresses a desire to have no secondary sex characteristics but
overall are happy with their decisions.

van der Loos (2022)68 N= 720 TGNB adolescents seen at a Dutch gender identity clinic (from the ACOG data
set), from 1972 to 2018, of whom 220 (31%) were assigned male at birth and 500
(69%) were assigned female at birth. At the start of GnRH analog treatment, the
Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing
hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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Table I.26. Included studies that addressed issues related to persistence and desistance with GAHT in
pediatric GD patients
Author (year) Findings
median age was 14.1 years for people assigned male at birth and 16·0 years for
people assigned female at birth. Median age at end of data collection was 20.2 years
for people assigned male at birth and 19.2 years for those assigned female at birth.
Of the 720 adolescents:
704 (98%) people who had started GAHT in adolescence continued to use GAHT at
follow-up.
van der Loos (2023)70 N=1766 TGNB children and adolescents seen at a Dutch clinic from 1972 to 2018 for
gender dysphoria . Of possibly eligible adolescents who had their first visit before age
10 years, nearly half started GnRH analogs vs around two-thirds who had their first
visit at or after age 10 years. The proportion starting GnRH analogs rose only for
those first visiting before age 10. Of those that started GnRH analogs,
1.4% stopped GnRH analogs, mostly because of remission of gender dysphoria
Vrouenraets (2022)179 N= 8 TGNB adolescents who proceeded with GAMT after PS ("continuers") and N=6
adolescents who discontinued PS ("discontinuers") participated in structured
interviews about their experience. All patients were seen at a Dutch gender identity
clinic.
All informants considered inhibition of development of secondary sex
characteristics an important function of PS.
Most continuers saw PS as the first step of GAMT. Nevertheless, some were glad
that the effects were reversible even if they didn’t expect to change their minds.
Some discontinuers did experience PS as an expanded diagnostic phase.
One continuer used the time on PS to get used to living in the affirmed gender
role, and several parents found the time helpful to adapt to their child’s new
gender role.
PS provided clinicians more time for diagnostic assessment.
Wiepjes(2018)67 N=6793 TGNB people who visited a single Dutch gender identity clinic from 1972 to
2015. From this group:
0.6 % of transwomen and 0.3% of transmen who underwent gonadectomy who
started HT after the age of 18 had regret.
No cases of regret were observed among the 1360 individuals who were first seen
before the age of 18 years. 1.9% of adolescents who started PS (n=812) stopped
PS and did not start HT

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; GnRH, gonadotropin-releasing

hormone; GAHT, gender-affirming hormone therapy; CSHT, cross-sex hormone therapy; US, United States; GD,
gender dysphoria;
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I.6.0 CONCLUSIONS
The conventional wisdom among non-experts has long been that there are limited data on the use of
GAHT in pediatric patients with GD. However, results from our exhaustive literature searches have led
us to the opposite conclusion.

We found more than 277 individual, full-text citations that met eligibility for study design, population,
and treatments of interest, including N=230 primary clinical studies reporting on the patient-level
experience of at least N=28,056 pediatric GD patients all over the world. We provide in this report
extracted findings and ROB assessments for N=89 English-language clinical studies that included high-
priority comparisons and outcomes (listed below). Another 127 English-language clinical observational
studies, descriptive studies, and case studies that did not undergo data extraction are also provided in a
bibliography. Due to the extremely limited time available for this work, we were forced to deprioritize
studies that lacked our high-priority comparison types (n=93) and outcomes (n=41).
High-priority comparison types: Between TGNB-group; TGNB versus cisgender peer group; and
TGNB within-group, before-after (pre-post) comparisons
High-priority outcomes: Mental health and psychosocial changes; body changes; body image; bone
health; cardiovascular risk factors and metabolic changes; and cancer.

We were not contracted to include a synthesis of the evidence that we found: only to assess ROB and
provide evidence tables summarizing safety and efficacy findings. However, after having spent many
months searching for, reading, and evaluating the available literature, it was impossible for us to avoid
drawing some high-level conclusions. Namely, the consensus of the evidence supports that the
treatments are effective in terms of mental health, psychosocial outcomes, and the induction of body
changes consistent with the affirmed gender in pediatric GD patients. The evidence also supports that
the treatments are safe in terms of changes to bone density, cardiovascular risk factors, metabolic
changes, and cancer. With regards to these safety outcomes, reviewed studies show that any patient-
level changes are minimal, and that despite any small improvements or decrements in individual disease
risk factors, the average patient’s values remain within the bounds of normal, non-pathological ranges
for human populations. For example, transgender women typically realize adult BMD levels that, while
lower than their pre-treatment potential, remain in the normal range for healthy cisgender women.

With respect to guidelines, we used the IOM’s definition, which enabled us to ignore a vast body of
opinion-based position statements and editorials from interested groups across the political spectrum.
We considered only publications focused on optimizing patient care that came from a recognized
medical authority, and that provided graded recommendations based on a systematic review of the
available evidence. We found 5 guidelines that met these criteria, in addition to also meeting our
population and intervention criteria. We extracted data from 4 guidelines; the fifth was not in English
and is included in the bibliography only.

Reviewed guidelines generally recommend use of puberty suppressing drugs in GD patients during early
puberty (but not earlier) and using CSHT in older adolescents. They also address some key
considerations that are outside the scope of this report, but that are nonetheless important, such as
provider training recommendations, non-pharmacologic treatments for pre-pubescent children,

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counseling recommendations, and surgical treatments. (The latter are typically only recommended in
adulthood, especially genital surgeries.) The consensus of guideline recommendations acknowledges the
validity of medically treating pediatric GD patients after puberty.

With regards to any misgivings that stakeholders may have about allowing pediatric patients to receive
pharmacologic (and frequently surgical) treatments over concerns about future regret, we found (based
on the N=32 studies that addressed it) that there is virtually no regret associated with receiving the
treatments, even in the very small percentages of patients who ultimately discontinued them. Reasons
for discontinuing GAHT are varied, but changed minds about gender identities is only a very minor
proportion overall.

We found 39 reviews that described themselves as "systematic" or that included search terms for ≥1
bibliographic database, but we only extracted data from the 7 reviews that conducted systematic,
reproducible searches in 2 or more databases, reported search results and findings, and addressed our
high-priority outcomes. Most reviewed SRs supported the conclusion that GAHT in pediatric GD patients
is generally effective in terms of mental health, psychosocial outcomes, and/or producing the desired
body changes; they also supported the conclusion that the treatments are generally safe in terms of
cardiovascular risk factors, metabolic changes, bone health, and/or cancer. One SR notably concluded
that the treatments should be regarded as experimental,49 but this conclusion was based on what
evidence remained after excluding a third of the eligible, retrieved studies, which violates best practices
for systematic review authors.30,43

Notably, our searches yielded a larger number of primary studies than any of the systematic reviews
that underwent data extraction. Ludvigsson (2023) found the largest number of studies (36) in their
search of 13 databases using eligibility criteria that broadly included all study designs, including case
studies.49 Thanks to the skills of our evidence retrieval experts, we found more than 200 studies
(including case studies) and extracted data from 89 primary experimental studies, observational studies,
and longitudinal, pre-post studies of high-priority outcomes.

Based on the reviewed evidence included in this report, it is our expert opinion that policies to prevent
access to and use of GAHT for treatment of GD in pediatric patients cannot be justified based on the
quantity or quality of medical science findings or concerns about potential regret in the future, and
that high-quality guidelines are available to guide qualified providers in treating pediatric patients
who meet diagnostic criteria.

I.7.0 LIMITATIONS
We performed no formal synthesis. Conclusions are those of DRRC authors who reviewed the
individual studies.
Data extraction was not performed in duplicate; but a pharmacist author double-checked all
extracted data performed by other authors.
We may have overlooked some studies due to our abbreviated timeline, but given that we have
found a more exhaustive set of studies than any included systematic review or guideline, our report
is likely the most comprehensive to date.
We would have liked to extract data from clinical case studies and other descriptive studies.
However, due to time constraints, the best we can do is provide those studies in the bibliography.

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195. US Food and Drug Administration. Degarelix: FDA Uses, Non-FDA Uses, and Contraindications
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207. US Food and Drug Administration. Finasteride (Lexi-Drugs): Uses (Labeled Indications and Off-
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236. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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237. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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238. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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239. US Food and Drug Administration. Estradiol: FDA Uses, Non-FDA Uses, and Contraindications (In-
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240. US Food and Drug Administration. Estradiol (Systemic) (Lexi-Drugs): Uses (Labeled Indications
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241. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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242. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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243. US Food and Drug Administration. Estradiol Acetate: FDA Uses, Non-FDA Uses, and
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244. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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245. US Food and Drug Administration. Estradiol Cypionate: FDA Uses, Non-FDA Uses, and
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246. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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247. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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248. US Food and Drug Administration. Estradiol Valerate: FDA Uses, Non-FDA Uses, and
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249. US Food and Drug Administration. Estradiol Valerate and Estradiol Valerate/Dienogest: FDA
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250. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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251. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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252. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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253. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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254. US Food and Drug Administration. Testosterone: FDA Uses, Non-FDA Uses, and
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255. US Food and Drug Administration. Testosterone (Lexi-Drugs): Uses (Labeled Indications and Off-
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256. US Food and Drug Administration. Testosterone Cypionate: FDA Uses, Non-FDA Uses, and
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257. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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258. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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259. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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260. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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261. US Food and Drug Administration. Testosterone Enanthate: FDA Uses, Non-FDA Uses, and
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262. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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263. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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264. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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265. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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266. US Food and Drug Administration. Testosterone Undecanoate: FDA Uses, Non-FDA Uses, and
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267. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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268. US Food and Drug Administration. Drospirenone (Lexi-Drugs): Uses (Labeled Indications and Off-
label), Warnings & Precautions (Contraindications), and FDA Approval Date. Lexicomp.com;
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269. US Food and Drug Administration. Drospirenone: FDA Uses, Non-FDA Uses, and
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270. US Food and Drug Administration. Etonogestrel (Lexi-Drugs): Uses (Labeled Indications and Off-
label), Warnings & Precautions (Contraindications), and FDA Approval Date. Lexicomp.com;
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271. US Food and Drug Administration. Etonogestrel: FDA Uses, Non-FDA Uses, and Contraindications
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272. US Food and Drug Administration. Levonorgestrel: FDA Uses, Non-FDA Uses, and
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273. US Food and Drug Administration. Levonorgestrel (IUD) (Lexi-Drugs): Uses (Labeled Indications
and Off-label), Warnings & Precautions (Contraindications), and FDA Approval Date.

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 Lexicomp.com; 2023. Last Updated February 27, 2023. Accessed March 31, 2023. Available at
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274. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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275. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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276. US Food and Drug Administration. Norethindrone: FDA Uses, Non-FDA Uses, and
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277. US Food and Drug Administration. Norethindrone (Lexi-Drugs): Uses (Labeled Indications and
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278. US Food and Drug Administration. Norethindrone Acetate: FDA Uses, Non-FDA Uses, and
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279. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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280. US Food and Drug Administration. Progesterone: FDA Uses, Non-FDA Uses, and
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281. US Food and Drug Administration. Progesterone (Lexi-Drugs): Uses (Labeled Indications and Off-
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282. US Food and Drug Administration. Conjugated Estrogens/Medroxyprogesterone Acetate: FDA

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283. US Food and Drug Administration. Estrogens (Conjugated/Equine) and Medroxyprogesterone

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284. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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285. US Food and Drug Administration. Drospirenone/Estradiol: FDA Uses, Non-FDA Uses, and
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286. US Food and Drug Administration. Drospirenone and Estradiol (Lexi-Drugs): Uses (Labeled
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287. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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288. US Food and Drug Administration. Estradiol and Levonorgestrel (Lexi-Drugs): Uses (Labeled
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289. US Food and Drug Administration. Estradiol/Levonorgestrel: FDA Uses, Non-FDA Uses, and
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290. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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291. US Food and Drug Administration. Estradiol/Norethindrone Acetate: FDA Uses, Non-FDA Uses,
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292. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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294. US Food and Drug Administration. Estradiol and Norgestimate (Lexi-Drugs): Uses (Labeled
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295. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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296. US Food and Drug Administration. Estradiol/Progesterone: FDA Uses, Non-FDA Uses, and
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297. US Food and Drug Administration. Estradiol and Progesterone (Lexi-Drugs): Uses (Labeled
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298. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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299. US Food and Drug Administration. Elagolix, Estradiol, and Norethindrone (Lexi-Drugs): Uses
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300. US Food and Drug Administration. Elagolix/Estradiol/Norethindrone Acetate and Elagolix: FDA
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301. US Food and Drug Administration. Relugolix, Estradiol, and Norethindrone (Lexi-Drugs): Uses
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302. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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303. US Food and Drug Administration. Desogestrel/Ethinyl Estradiol: FDA Uses, Non-FDA Uses, and
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304. US Food and Drug Administration. Ethinyl Estradiol and Desogestrel (Lexi-Drugs): Uses (Labeled
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305. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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306. US Food and Drug Administration. Drospirenone/Ethinyl Estradiol: FDA Uses, Non-FDA Uses, and
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307. US Food and Drug Administration. Ethinyl Estradiol and Drospirenone (Lexi-Drugs): Uses
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308. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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309. US Food and Drug Administration. Ethinyl Estradiol/Ethynodiol Diacetate: FDA Uses, Non-FDA
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310. US Food and Drug Administration. Ethinyl Estradiol and Ethynodiol Diacetate (Lexi-Drugs): Uses
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311. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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312. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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 2023. Available at
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313. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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314. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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315. US Food and Drug Administration. Ethinyl Estradiol/Etonogestrel: FDA Uses, Non-FDA Uses, and
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316. US Food and Drug Administration. Ethinyl Estradiol and Etonogestrel (Lexi-Drugs): Uses (Labeled
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317. US Food and Drug Administration. Ethinyl Estradiol/Levonorgestrel: FDA Uses, Non-FDA Uses,
and Contraindications (In-Depth Answers). MicromedexSolutions.com; 2023. Last Updated
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318. US Food and Drug Administration. Ethinyl Estradiol and Levonorgestrel (Lexi-Drugs): Uses
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319. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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Levonorgestrel). AccessData.FDA.gov; 2023. Last Updated April 2023. Accessed April 7, 2023.
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320. US Food and Drug Administration. Ethinyl Estradiol/Norethindrone: FDA Uses, Non-FDA Uses,
and Contraindications (In-Depth Answers). MicromedexSolutions.com; 2023. Last Updated
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321. US Food and Drug Administration. Ethinyl Estradiol and Norethindrone (Lexi-Drugs): Uses
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 Lexicomp.com; 2023. Last Updated March 31, 2023. Accessed March 31, 2023. Available at
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322. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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323. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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324. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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325. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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326. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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327. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
Equivalence Evaluations; Product Details for NDA 017565 - Norinyl 1+35 21-Day (Ethinyl
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017565#1959

328. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
Equivalence Evaluations; Product Details for NDA 017919 - Ortho-Novum 1/35-28 (Ethinyl
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 https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=
017919#2120

329. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
Equivalence Evaluations; Product Details for NDA 017489 - Ortho-Novum 1/35-21 (Ethinyl
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330. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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331. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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332. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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333. US Food and Drug Administration. Ethinyl Estradiol/Norelgestromin: FDA Uses, Non-FDA Uses,
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334. US Food and Drug Administration. Ethinyl Estradiol and Norelgestromin (Lexi-Drugs): Uses
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335. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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336. US Food and Drug Administration. Ethinyl Estradiol/Norgestimate: FDA Uses, Non-FDA Uses, and
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337. US Food and Drug Administration. Ethinyl Estradiol and Norgestimate (Lexi-Drugs): Uses
(Labeled Indications and Off-label) and Warnings & Precautions (Contraindications).
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338. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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339. US Food and Drug Administration. Ethinyl Estradiol/Norgestrel: FDA Uses, Non-FDA Uses, and
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340. US Food and Drug Administration. Ethinyl Estradiol and Norgestrel (Lexi-Drugs): Uses (Labeled
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341. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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342. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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343. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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344. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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345. US Food and Drug Administration. Segesterone Acetate/Ethinyl Estradiol: FDA Uses, Non-FDA
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346. US Food and Drug Administration. Segesterone Acetate and Ethinyl Estradiol (Lexi-Drugs): Uses
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347. US Food and Drug Administration. Drospirenone/Ethinyl Estradiol/Levomefolate Calcium and

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348. US Food and Drug Administration. Ethinyl Estradiol, Drospirenone, and Levomefolate (Lexi-
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349. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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350. US Food and Drug Administration. Anastrozole: FDA Uses, Non-FDA Uses, and Contraindications
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351. US Food and Drug Administration. Anastrozole (Lexi-Drugs): Uses (Labeled Indications and Off-
label), Warnings & Precautions (Contraindications), and FDA Approval Date. Lexicomp.com;
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352. US Food and Drug Administration. Exemestane (Lexi-Drugs): Uses (Labeled Indications and Off-
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353. US Food and Drug Administration. Exemestane: FDA Uses, Non-FDA Uses, and Contraindications
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354. US Food and Drug Administration. Letrozole: FDA Uses, Non-FDA Uses, and Contraindications
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355. US Food and Drug Administration. Letrozole (Lexi-Drugs): Uses (Labeled Indications and Off-
label), Warnings & Precautions (Contraindications), and FDA Approval Date. Lexicomp.com;
2023. Last Updated April 4, 2023. Accessed April 12, 2023. Available at http://online.lexi.com

356. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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 https://www.accessdata.fda.gov/scripts/cder/ob/results_product.cfm?Appl_Type=N&Appl_No=
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357. US Food and Drug Administration. Conjugated Estrogens/Bazedoxifene Acetate: FDA Uses, Non-
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358. US Food and Drug Administration. Clomiphene (Lexi-Drugs): Uses (Labeled Indications and Off-
label), Warnings & Precautions (Contraindications), and FDA Approval Date. Lexicomp.com;
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359. US Food and Drug Administration. Clomiphene: FDA Uses, Non-FDA Uses, and Contraindications
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360. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic
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361. US Food and Drug Administration. Ospemifene (Lexi-Drugs): Uses (Labeled Indications and Off-
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362. US Food and Drug Administration. Ospemifene: FDA Uses, Non-FDA Uses, and Contraindications
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363. US Food and Drug Administration. Raloxifene (Lexi-Drugs): Uses (Labeled Indications and Off-
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364. US Food and Drug Administration. Raloxifene: FDA Uses, Non-FDA Uses, and Contraindications
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365. US Food and Drug Administration. Tamoxifen (Lexi-Drugs): Uses (Labeled Indications and Off-
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366. US Food and Drug Administration. Tamoxifen: FDA Uses, Non-FDA Uses, and Contraindications
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367. US Food and Drug Administration. Toremifene (Lexi-Drugs): Uses (Labeled Indications and Off-
label), Warnings & Precautions (Contraindications), and FDA Approval Date. Lexicomp.com;
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368. US Food and Drug Administration. Toremifene: FDA Uses, Non-FDA Uses, and Contraindications
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APPENDIX I.A: PHARMACOLOGIC AGENTS BY DRUG CLASS

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Table I.A.1. Indications for gonadotropin-releasing hormone analogs used for gender dysphoria a
Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Active ingredient FDA-approved uses
(Efficacy; Recommendation [SOE]c) (LOE)d
Original FDA-approval dateb
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Goserelin acetate180,181 None Breast cancer Precocious puberty Gender dysphoria–MTF transgender None Gender dysphoria–MTF transgender
individuals; adjunct individuals LOE: G
December 29, 1989 Endometriosis Evidence favors efficacy
Hypoplasia of the endometrium Effective
Recommended, in some cases (B)
Prostate cancer Recommended, in most cases (B)

Contraindications for use

Hypersensitivity to the active ingredient, any excipient, GnRH, or GnRH analog analogs
Treating endometriosis or endometrial thinning during pregnancy
Histrelin acetatee,182,183 Central precocious puberty Prostate cancer None None
December 24, 1991184 Contraindications for use
Hypersensitivity to the active ingredient, any excipient, GnRH, or GnRH analog analogs
Pregnancy
Leuprolide185,186 Central precocious pubertyf Anemia related to uterine None Gender dysphoria–MTF transgender None Gender dysphoria–MTF transgender
leiomyomata (fibroids) individuals; adjunct individuals LOE: G
April 9, 1985187
Endometriosis Evidence favors efficacy
Prostate cancer Recommended, in some cases (B)

Contraindications for use

Hypersensitivity to the active ingredient, any excipient, GnRH, or GnRH analog analogs
Pregnancy
Undiagnosed abnormal uterine bleeding
Nafarelin acetate 188,189 Central precocious puberty Endometriosis None None

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book).
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Vantas, a brand name product of histrelin, was indicated for the palliative treatment of advanced prostate cancer, but this product has been discontinued in the US for more than 1 year. However, Supprelin LA continues to be on the market for the treatment of
central precocious puberty in children aged 2 years and older.
f Treatment of central precocious puberty is indicated only for certain formulations of leuprolide: Lupron Depot-Ped and Fensolvi
g Of the available products for triptorelin, only Triptodur is approved for the treatment of central precocious puberty
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; RCTs, randomized controlled trials
156

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Table I.A.1. Indications for gonadotropin-releasing hormone analogs used for gender dysphoria a
Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Active ingredient FDA-approved uses
(Efficacy; Recommendation [SOE]c) (LOE)d
Original FDA-approval dateb
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
February 13, 1990 Breastfeeding or pregnancy
Hypersensitivity to the active ingredient, any excipient, GnRH, or GnRH analog analogs
Undiagnosed abnormal vaginal bleeding
Triptorelin pamoate 190,191 Central precocious pubertyg Prostate cancer Drug treatment to suppress puberty None None
in gender dysphoria
June 15, 2000
Effective
Recommended, in most cases (B)
Growth hormone deficiency
Evidence is inconclusive
Not Recommended (B)
Short stature disorder, idiopathic
Evidence is inconclusive
Not Recommended (B)

Contraindications for use

Hypersensitivity to the active ingredient, any excipient, GnRH, or GnRH analog analogs
Pregnancy

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book).
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Vantas, a brand name product of histrelin, was indicated for the palliative treatment of advanced prostate cancer, but this product has been discontinued in the US for more than 1 year. However, Supprelin LA continues to be on the market for the treatment of
central precocious puberty in children aged 2 years and older.
f Treatment of central precocious puberty is indicated only for certain formulations of leuprolide: Lupron Depot-Ped and Fensolvi
g Of the available products for triptorelin, only Triptodur is approved for the treatment of central precocious puberty
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; RCTs, randomized controlled trials
157

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Table I.A.2. Indications for gonadotropin-releasing hormone antanalogs used for gender dysphoria a

Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Cetrorelix acetate192,193 None Ovulation induction, controlled None None
August 11, 2000 ovarian stimulation; adjunct

Contraindications for use

Breastfeeding or pregnancy
Hypersensitivity to the active ingredient, any excipient, extrinsic peptide hormones, mannitol, GnRH, or any other GnRH analogs
Severe renal impairment
Degarelix acetate194,195 None Prostate cancer None None
December 24, 2008 Contraindications for use
Hypersensitivity to the active ingredient or any excipient
Elagolix sodium196,197 None Endometriosis related pain None None
July 23, 2018198 Contraindications for use
Concomitant use with strong OATP 1B1 inhibitors
Hypersensitivity to the active ingredient or any excipient
Osteoporosis
Pregnancy
Severe hepatic impairment
Ganirelix acetate199,200 None Female infertility, adjunct to None None
July 29, 1999 controlled ovarian
hyperstimulation

Contraindications for use

Hypersensitivity to the active ingredient, any excipient, GnRH, or any other GnRH analogs
Pregnancy
Relugolix201,202 None Prostate cancer None None
December 18, 2020 Contraindications for use
Hypersensitivity to the active ingredient or any excipient

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; OATP, organic anion transporting polypeptide; RCTs, randomized controlled trials
158

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Table I.A.3. Indications for antiandrogens used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Bicalutamide203,204 None Prostate cancer None None
October 4, 1995 Contraindications for use
Hypersensitivity to the active ingredient or any excipient
Use in women, including during pregnancy
Dutasteride186,205 None Benign prostatic hyperplasia None None
November 20, 2001 Contraindications for use
Clinically significant hypersensitivity (eg, serious skin reactions, angioedema) to the active ingredient, any excipient, or other 5-alpha-reductase inhibitors
Pregnancy
Finasteride206,207 None Benign prostatic hyperplasia None Gender dysphoria–MTF transgender None
individuals; adjunct
June 19, 1992 Male pattern alopecia
Ineffective
Not Recommended (B)

Contraindications for use

Hypersensitivity to the active ingredient or any excipient
Pregnancy
Flutamide208,209 None Prostate cancer Congenital adrenal hyperplasia None None
January 27, 1989 Evidence is inconclusive
Not Recommended (B)

Contraindications for use

Hypersensitivity to the active ingredient or any excipient
Severe hepatic impairment

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; RCTs, randomized controlled trials.
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Table I.A.3. Indications for antiandrogens used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Nilutamide210,211 None Prostate cancer None Drug-induced feminization– None
transgender individuals
September 19, 1996
Evidence is inconclusive
Recommended, in some cases (B)

Contraindications for use

Hypersensitivity to the active ingredient or any excipient
Severe hepatic impairment
Severe respiratory insufficiency
Spironolactone212,213 None Ascites due to cirrhosis Hyperaldosteronism Gender dysphoria–MTF transgender None Gender dysphoria–MTF transgender
individuals; adjunct individuals LOE: G
January 21, 1960 Edema − Nephrotic syndrome Effective
Heart failure with reduced Evidence is inconclusive
Recommended, in most cases (B)
ejection fraction Bronchopulmonary dysplasia of Recommended, in some cases (B)
Hypertension newborn
Primary hyperaldosteronism Evidence is inconclusive
Recommended, in some cases (B)

Contraindications for use

Addison disease
Concomitant eplerenone use
Hyperkalemia

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; RCTs, randomized controlled trials.
160

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Conjugated estrogens214,215 None Abnormal uterine bleeding Hemorrhagic cystitis Gender dysphoria–MTF transgender None
individuals
Approved prior to January 1, Breast cancer Evidence favors efficacy
1982216-218 Female hypogonadism syndrome Evidence favors efficacy
Recommended, in some cases (B)
Menopause-related dyspareunia Postoperative hemorrhage Recommended, in some cases (B)

Menopause-related vasomotor Evidence favors efficacy

symptoms
Recommended, in some cases (B)
Menopause-related vulvar and
Turner syndrome
vaginal atrophy
Evidence favors efficacy
Postmenopausal osteoporosis;
prophylaxis Recommended, in some cases (B)
Prostate cancer
Secondary amenorrhea,
hypoestrogenism

Contraindications for use

Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Angioedema or anaphylactic reaction to the active ingredient or any excipient
Breast cancer (known, suspected, or history of); except in appropriately selected patients being treated for metastatic disease
Estrogen-dependent neoplasia
Hepatic disease or impairment
Pregnancy
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

161

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Esterified estrogens219,220 None Menopause-related vasomotor None None
Approved prior to January 1, symptoms
1982221-238 Menopause-related vulvar and
vaginal atrophy
Metastatic breast cancer
Prostate cancer
Secondary amenorrhea,
hypoestrogenism

Contraindications for use

Active or prior history of DVT or PE
Active or recent history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of); except in appropriately selected patients being treated for metastatic disease
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity to the active ingredient or any excipient
Pregnancy
Undiagnosed abnormal genital bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

162

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Estradiol239,240 None Breast cancer Gender dysphoria–MTF transgender Gender dysphoria–MTF transgender None Gender dysphoria–MTF transgender
individuals individuals individuals LOE: G
Approved prior to January 1, Menopause-related dyspareunia
1982241,242 Menopause-related vasomotor Evidence favors efficacy Evidence favors efficacy
symptoms Recommended, in most cases (B) Recommended, in some cases (B)
Menopause-related vulvar,
urethral, and vaginal atrophy
Postmenopausal osteoporosis,
prophylaxis
Prostate cancer
Secondary amenorrhea,
hypoestrogenism

Contraindications for use

Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Breast cancer (known, suspected, or history of); except in appropriately selected patients being treated for metastatic disease
Estrogen-dependent neoplasia
Hepatic disease or impairment
Known angioedema, anaphylactic reaction, or hypersensitivity to the active ingredient or any excipient
Pregnancy
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding
Estradiol acetate243 None Menopause-related vasomotor None None
March 20, 2003244 symptoms
Menopause-related vulvar and
vaginal atrophy

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

163

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Contraindications for use
Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Known angioedema, anaphylactic reaction, or hypersensitivity to the active ingredient or any excipient
Pregnancy
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding
Estradiol cypionate245 None Female hypogonadism syndrome None Gender dysphoria–MTF transgender None Gender dysphoria–MTF transgender
individuals individuals LOE: G
Approved prior to January 1, Menopause-related vasomotor
1982246,247 symptoms No efficacy or recommendation is
reported

Contraindications for use

Active or prior history of DVT or PE
Active or recent history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity to the active ingredient or any excipient
Pregnancy
Undiagnosed abnormal genital bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

164

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Estradiol valerate248,249 None Menopause-related vasomotor None Gender dysphoria–MTF transgender None Gender dysphoria–MTF transgender
symptoms individuals individuals LOE: G
Approved prior to January 1,
1982250-253 Menopause-related vulvar and Evidence favors efficacy
vaginal atrophy
Recommended, in some cases (B)
Prostate cancer
Secondary amenorrhea,
hypoestrogenism

Contraindications for use

Active or prior history of DVT or PE
Active or recent history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity to the active ingredient
Pregnancy
Undiagnosed abnormal genital bleeding
Testosterone254,255 None Hypogonadism, male Gender dysphoria–FTM transgender Gender dysphoria–FTM transgender None Gender dysphoria–FTM transgender
individuals individuals individuals LOE: G
December 24, 1953
Evidence favors efficacy Effective
Recommended, in some cases (B) Recommended, in most cases (B)

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

165

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Breast cancer (males)
Breastfeeding
Hypersensitivity to the active ingredient or any excipient
Pregnancy, or those who may become pregnant
Prostate cancer (known or suspected)
Testosterone cypionate256 Primary hypogonadism, male Gender dysphoria–FTM transgender Gender dysphoria–FTM transgender None Gender dysphoria–FTM transgender
individuals individuals individuals LOE: G
Approved prior to January 1,
1982257-260 Evidence favors efficacy Effective
Recommended, in some cases (B) Recommended, in most cases (B)

Contraindications for use

Breast cancer (males)
Hypersensitivity to the active ingredient or any excipient
Pregnancy, or those who may become pregnant
Prostate cancer (known or suspected)
Serious cardiac, renal, or hepatic disease
Testosterone enanthatee,261 Delayed puberty, male Hypogonadism, male Gender dysphoria–FTM transgender Gender dysphoria–FTM transgender None Gender dysphoria–FTM transgender
individuals individuals individuals LOE: G
Approved prior to January 1, Hypogonadism, male Metastatic breast cancer, female
1982262-265 Evidence favors efficacy Effective
Recommended, in some cases (B) Recommended, in most cases (B)

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

166

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Table I.A.4. Indications for single-ingredient sex hormone agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Breast cancer (males)
Hypersensitivity to the active ingredient or any excipient
Hypogonadal conditions that are not attributed to genetic or structural etiologies (eg, age-related hypogonadism)
Pregnancy, or those who may become pregnant
Prostate cancer (known or suspected)
Testosterone undecanoate266 None Hypogonadism, male Gender dysphoria–FTM transgender Gender dysphoria–FTM transgender None Gender dysphoria–FTM transgender
individuals individuals individuals LOE: G
March 5, 2014267
Evidence favors efficacy Effective
Recommended, in some cases (B) Recommended, in most cases (B)

Contraindications for use

Breast cancer (males)
Breastfeeding
Hypersensitivity to the active ingredient or any excipient
Hypogonadal conditions that are not attributed to genetic or structural etiologies (eg, age-related hypogonadism)
Pregnancy, or those who may become pregnant
Prostate cancer (known or suspected)

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Only the intramuscular injection of testosterone enanthate is FDA-approved in adolescent males to treat delayed puberty and hypogonadism
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MTF, male-to-female; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary
embolism; FTM, female-to-male; RCTs, randomized controlled trials

167

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Table I.A.5. Indications for single-ingredient progestin agents used for gender
dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Drospirenone268,269 Contraception (post-menarche) None None
May 23, 2019 Contraindications for use
Active or prior history of cervical cancer or progestin-sensitive cancers
Adrenal insufficiency
Benign or malignant hepatic tumors
Renal or hepatic impairment
Undiagnosed abnormal uterine bleeding
Etonogestrel270,271 None Contraception None None
July 17, 2006 Contraindications for use
Active hepatic disease
Active or prior history of progestin-sensitive cancer
Active or prior history of thrombosis or thromboembolic disorders
Benign or malignant hepatic tumors
Breast cancer (known, suspected, or history of)
Hypersensitivity to the active ingredient or any excipient
Pregnancy
Undiagnosed abnormal genital bleeding
Levonorgestrel272,273 Contraception (post-menarche) Contraception None None Menstrual suppression–FTM
transgender individualse (IUD)
December 10, 1990274,275 Postcoital contraception (post- Menorrhagia
menarche) Postcoital contraception LOE: C

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who do not desire or are not ready to start masculinizing hormones
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; FTM, female-to-male; IUD, intrauterine device; AIDS, acquired immune deficiency syndrome; MI, myocardial infarction; DVT, deep vein thrombophlebitis;
PE, pulmonary embolism; MTF, male-to-female; PE, pulmonary embolism; RCTs, randomized controlled trials

168

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Table I.A.5. Indications for single-ingredient progestin agents used for gender
dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Active or prior history of breast cancer (known or suspected), or hormone-sensitive cancer (known or Known or suspected pregnancy
suspected), including progestin Post-partum endometritis
Active or prior history of PID, or active endometritis, except in cases where there has been a subsequent Unremoved IUD
pregnancy within the uterus
Unresolved abnormal Pap smear
Active thrombophlebitis or thromboembolic disorders
Untreated vaginitis or cervicitis, including bacterial vaginosis or other lower genital tract infections
Benign or malignant hepatic tumors, or acute hepatic disease
Use of intrauterine system as emergency contraception
Conditions that increase infection vulnerability (eg, AIDS, leukemia)
Uterine anomaly (acquired or congenital), including fibroids, that disrupts the uterine cavity making proper
Genital or uterine bleeding of unknown cause intrauterine placement incompatible
Hypersensitivity to the active ingredient or any excipient Uterine or cervical neoplasia (known or suspected)
Infected abortion in the past 3 months
Medroxyprogesterone Contraception Abnormal uterine bleeding Alveolar hypoventilation None None Menstrual suppression–FTM
(acetate)185 transgender individuals LOE: C
Endometriosis (SC suspension Contraception Evidence favors efficacy
June 18, 1959 only) Endometrial cancer Recommended, in some cases (B)
Endometriosis Central precocious puberty
Estrogen therapy-associated Evidence is inconclusive
endometrial hyperplasia,
Recommended, in some cases (B)
prophylaxis
Renal cell carcinoma
Secondary amenorrhea, diagnostic
aid

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who do not desire or are not ready to start masculinizing hormones
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; FTM, female-to-male; IUD, intrauterine device; AIDS, acquired immune deficiency syndrome; MI, myocardial infarction; DVT, deep vein thrombophlebitis;
PE, pulmonary embolism; MTF, male-to-female; PE, pulmonary embolism; RCTs, randomized controlled trials

169

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Table I.A.5. Indications for single-ingredient progestin agents used for gender
dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Active or prior history of thromboembolic conditions, cerebral vascular disease, or thrombophlebitis
Breast cancer (known, suspected, or history of)
Estrogen- or progesterone-dependent neoplasia (known or suspected)
Hepatic disease or impairment
Known angioedema, anaphylactic reaction, or hypersensitivity to the active ingredient or any excipient
Pregnancy
Undiagnosed abnormal vaginal or genital bleeding
Norethindrone276,277 Contraception (post-menarche) None None Menstrual suppression–FTM
transgender individualsf LOE: C
January 2, 1973
Contraindications for use
Acute hepatic disease
Benign or malignant hepatic tumors
Breast cancer (known, suspected, or history of)
Hypersensitivity to the active ingredient or any excipient
Pregnancy
Undiagnosed abnormal genital bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who do not desire or are not ready to start masculinizing hormones
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; FTM, female-to-male; IUD, intrauterine device; AIDS, acquired immune deficiency syndrome; MI, myocardial infarction; DVT, deep vein thrombophlebitis;
PE, pulmonary embolism; MTF, male-to-female; PE, pulmonary embolism; RCTs, randomized controlled trials

170

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Table I.A.5. Indications for single-ingredient progestin agents used for gender
dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Norethindrone acetate278 None Abnormal uterine bleeding None None Menstrual suppression–FTM
transgender individualsf LOE: C
Approved prior to January 1, Endometriosis
1982279 Estrogen therapy-associated
endometrial hyperplasia,
prophylaxis
Secondary amenorrhea, diagnostic
aid

Contraindications for use

Active or prior history of DVT or PE
Active or recent history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of)
Hepatic disease or impairment
Hypersensitivity to the active ingredient or any excipient
Pregnancy
Undiagnosed abnormal vaginal bleeding
Use as a diagnostic pregnancy test
Progesterone280,281 None Abnormal uterine bleeding None None
May 11, 1978 Assisted reproductive technology
Estrogen therapy-associated
endometrial hyperplasia,
prophylaxis
Secondary amenorrhea, diagnostic
aid

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who do not desire or are not ready to start masculinizing hormones
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; FTM, female-to-male; IUD, intrauterine device; AIDS, acquired immune deficiency syndrome; MI, myocardial infarction; DVT, deep vein thrombophlebitis;
PE, pulmonary embolism; MTF, male-to-female; PE, pulmonary embolism; RCTs, randomized controlled trials

171

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Table I.A.5. Indications for single-ingredient progestin agents used for gender
dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Active or prior history of arterial thromboembolic disease (eg, MI, stroke) or thromboembolic disorders (eg, Hepatic disease or impairment
DVT, PE) Hypersensitivity to the active ingredient or any excipient
Active or prior history of cerebral apoplexy Pregnancy
Breast cancer (known, suspected, or history of) Thrombophlebitis (known or history of)
Ectopic pregnancy or missed abortion Undiagnosed abnormal genital or vaginal bleeding
Genital cancer (known or suspected)

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who do not desire or are not ready to start masculinizing hormones
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; FTM, female-to-male; IUD, intrauterine device; AIDS, acquired immune deficiency syndrome; MI, myocardial infarction; DVT, deep vein thrombophlebitis;
PE, pulmonary embolism; MTF, male-to-female; PE, pulmonary embolism; RCTs, randomized controlled trials

172

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Conjugated/equine None Menopause-related vasomotor None None
estrogens and symptoms
medroxyprogesterone
Menopause-related vulvar and
acetate282,283
vaginal atrophy
December 30, 1994284
Postmenopausal osteoporosis;
prophylaxis

Contraindications for use

Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Angioedema or anaphylactic reaction to the active ingredients or any excipient
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Pregnancy
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding
Estradiol and None Menopause-related vasomotor None None
drospirenone285,286 symptoms
September 28, 2005287 Menopause-related vulvar and
vaginal atrophy

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

173

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Active or prior history of arterial thromboembolic disease (eg, MI, stroke) Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Active or prior history of DVT or PE Pregnancy
Adrenal insufficiency Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Breast cancer (known, suspected, or history of) Renal impairment
Estrogen-dependent neoplasia Undiagnosed abnormal genital bleeding
Hepatic disease or impairment
Estradiol and None Menopause-related vasomotor None None
levonorgestrel288,289 symptoms
November 21, 2003290 Postmenopausal osteoporosis,
prophylaxis

Contraindications for use

Active or prior history of DVT or PE
Active or recent history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

174

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Estradiol and norethindrone None Menopause-related vasomotor None None
acetate291 symptoms
August 7, 1998292 Menopause-related vulvar and
vaginal atrophy
Postmenopausal osteoporosis,
prophylaxis
Secondary amenorrhea,
hypoestrogenism

Contraindications for use

Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding
Estradiol and None Menopause-related vasomotor None None
norgestimate293,294 symptoms
October 22, 1999295 Menopause-related vulvar and
vaginal atrophy
Postmenopausal osteoporosis,
prophylaxis

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

175

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Contraindications for use
Active or prior history of DVT or PE
Active or recent history of arterial thromboembolic disease (eg, MI, stroke)
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity to the active ingredients or any excipient
Pregnancy
Undiagnosed abnormal genital bleeding
Estradiol and None Menopause-related vasomotor None None
progesterone296,297 symptoms
October 28, 2018298 Contraindications for use
Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Breast cancer (known, suspected, or history of)
Estrogen-dependent neoplasia
Hepatic disease or impairment
Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Undiagnosed abnormal genital bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

176

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Estradiol, elagolix, and None Menorrhagia associated with None None
norethindrone299,300 uterine leiomyoma
May 29, 2020 (premenopausal women)

Contraindications for use

Active or prior history of DVT or PE Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Breast cancer (active, or history of) or other hormonally-sensitive malignancies, and those with increased risk Osteoporosis
for hormonally-sensitive malignancies Pregnancy
Concomitant use with OATP 1B1 inhibitors Smoking and > 35 years of age
Headaches with focal neurological symptoms, or migraine headaches with aura if > 35 years of age Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Hepatic disease or impairment Uncontrolled hypertension
High risk of thrombotic or thromboembolic conditions (venous or arterial) Undiagnosed abnormal uterine bleeding
Hypercoagulopathies (acquired or inherited) Vascular disease (eg, coronary artery disease)
Estradiol, relugolix, and None Endometriosis related pain None None
norethindrone301
Menorrhagia associated with
May 26, 2021 uterine leiomyoma
(premenopausal women)

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

177

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Active or prior history of DVT or PE Osteoporosis
Breast cancer (active, or history of) or other hormonally-sensitive malignancies, and those with increased risk Pregnancy
for hormonally-sensitive malignancies Smoking and > 35 years of age
Headaches with focal neurological symptoms, or migraine headaches with aura if > 35 years of age Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Hepatic disease or impairment Uncontrolled hypertension
High risk of thrombotic or thromboembolic conditions (venous or arterial) Undiagnosed abnormal uterine bleeding
Hypercoagulopathies (acquired or inherited) Vascular disease (eg, coronary artery disease)
Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Estradiol valerate and Abnormal uterine bleeding, without organic pathology (post-menarche) Likely Nonee None Menstrual suppression–FTM
dienogest 249 transgender individualsf LOE: C
Contraception (post-menarche)
May 6, 2010302
Contraindications for use
Active or prior history of breast cancer, or other progestin- or estrogen-sensitive cancer High risk of thrombotic conditions (venous or arterial)
Active or prior history of DVT or PE Hypercoagulopathies (acquired or inherited)
Benign or malignant hepatic tumors, or hepatic disease Pregnancy
Cerebrovascular or coronary artery disease Smoking and > 35 years of age
Diabetes mellitus with vascular disease Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Headaches with focal neurological symptoms or migraine headaches without or with aura if > 35 years of age Uncontrolled hypertension
Undiagnosed abnormal uterine bleeding
Ethinyl estradiol and Contraception (post-menarche) None None Menstrual suppression–FTM
desogestrel303,304 transgender individualsf LOE: C

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

178

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
December 10, 1992305 Benign or malignant hepatic tumors, or hepatic disease Hypersensitivity to the active ingredient or any excipient
Breast cancer (known, suspected, or history of) Hypertension (systolic: ≥ 160 mm Hg; diastolic: ≥ 100 mm Hg), uncontrolled or severe
Cerebrovascular or coronary artery disease Jaundice with previous oral hormonal contraceptive pill use or cholestatic jaundice of pregnancy
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Major surgery with prolonged immobilization
Diabetes mellitus with vascular disease Pregnancy
Endometrial cancer, or other estrogen-dependent neoplasia (known or suspected) Prior history of DVT or other thromboembolic conditions
Headaches with focal neurological symptoms Smoking and > 35 years of age
Hepatocellular disease with abnormal liver function Thrombophlebitis, thromboembolic disorders, or known thrombophilic disorders
Hypercoagulopathies (acquired or inherited) Undiagnosed abnormal genital bleeding
Valvular cardiac disease with thrombogenic complications
Ethinyl estradiol and Acne vulgaris, moderate to severe ( ≥ 14 years of age) None None Menstrual suppression–FTM
drospirenone306,307 transgender individualsf LOE: C
Contraception (post-menarche)
May 11, 2001308 Premenstrual dysphoric disorder (post-menarche)

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

179

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Active or prior history of breast cancer, or other progestin- or estrogen-sensitive cancer Diabetes mellitus with vascular disease
Active or prior history of DVT or PE Hepatic or renal impairment
Adrenal insufficiency Hypercoagulopathies (acquired or inherited)
Benign or malignant hepatic tumors Pregnancy
Cerebrovascular or coronary artery disease Smoking and > 35 years of age
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Headaches with focal neurological symptoms or migraine headaches without or with aura if > 35 years of age Uncontrolled hypertension
Undiagnosed abnormal uterine bleeding
Ethinyl estradiol and Contraception (post-menarche) None None Menstrual suppression–FTM
ethynodiol diacetate309,310 transgender individualsf LOE: C
Approved prior to Contraindications for use
January 1, 1982311-314
Benign or malignant hepatic tumors or hepatic disease Cerebrovascular or coronary artery disease, or MI
Breast cancer (known, suspected, or history of) Jaundice with previous oral hormonal contraceptive pill use or cholestatic jaundice of pregnancy
Carcinoma of the female reproductive organs (known or suspected), or estrogen-dependent neoplasia (current, Pregnancy
suspected, or history of) Prior history of DVT or other thromboembolic conditions
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Thrombophlebitis or thromboembolic disorders
Undiagnosed abnormal genital bleeding
Ethinyl estradiol and Contraception (post-menarche) None None
etonogestrel315,316
Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

180

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
October 3, 2001 Active or prior history of DVT or PE High risk of thrombotic conditions (venous or arterial)
Benign or malignant hepatic tumors, or hepatic disease Hypercoagulopathies (acquired or inherited)
Breast cancer (known, suspected, or history of), or other estrogen- or progestin-sensitive neoplasia Hypersensitivity to the active ingredient or any excipient
Cerebrovascular or coronary artery disease Hypertension, uncontrolled
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Pregnancy
Diabetes mellitus with vascular disease Smoking and > 35 years of age
Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches if > 35 Thrombogenic rhythm or thrombogenic valvular cardiac diseases
years of age Undiagnosed abnormal uterine bleeding
Ethinyl estradiol and Contraception (post-menarche) None None Menstrual suppression–FTM
levonorgestrel317,318 transgender individualsf LOE: C

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

181

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
May 10, 1982319 Benign or malignant hepatic tumors, or hepatic disease (eg, acute viral hepatitis or severe decompensated Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches with or
cirrhosis) without aura if > 35 years of age
BMI ≥ 30 kg/m² (patch only) Hypersensitivity to the active ingredient or any excipient
Breast cancer (known, suspected, or history of) Hypertension, uncontrolled
Cerebrovascular or coronary artery disease Jaundice with previous oral hormonal contraceptive pill use or cholestatic jaundice of pregnancy
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Major surgery with prolonged immobilization
Current or prior history of DVT or other thromboembolic conditions (eg, PE) Pregnancy
Diabetes mellitus with hypertension, vascular disease, or other end-organ injury; > 35 years of age; or a disease Smoking and > 35 years of age
duration of > 20 years Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Endometrial cancer, or other estrogen- or progestin-sensitive neoplasia (known or suspected) Thrombophlebitis, thromboembolic disorders, or thrombophilias (acquired or hereditary)
Hypercoagulopathies (acquired or inherited) Undiagnosed abnormal genital or uterine bleeding
Valvular cardiac disease with thrombogenic complications
Ethinyl estradiol and Acne vulgaris, moderate to severe Acne vulgaris, moderate to severe None None Menstrual suppression–FTM
norethindrone320,321 ( ≥ 15 years of age) transgender individualsf LOE: C
Contraception
Approved prior to Contraception (post-menarche) Menopause-related vasomotor
January 1, 1982322-332
symptoms
Postmenopausal osteoporosis,
prophylaxis

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

182

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Benign or malignant hepatic tumors, or hepatic disease Hypersensitivity to the active ingredient or any excipient
Breast cancer (known, suspected, or history of) Hypertension (systolic: ≥ 160 mm Hg; diastolic: ≥ 100 mm Hg), uncontrolled or severe
Cerebrovascular or coronary artery disease Jaundice with previous oral hormonal contraceptive pill use or cholestatic jaundice of pregnancy
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Major surgery with prolonged immobilization
Diabetes mellitus with vascular disease Pregnancy
Endometrial cancer, or other estrogen- or progestin-sensitive neoplasia (known or suspected) Prior history of DVT or other thromboembolic conditions
Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches if > 35 Smoking and > 35 years of age
years of age Thrombophlebitis, thromboembolic disorders, or known thrombophilic disorders
Hepatocellular disease with abnormal liver function Undiagnosed abnormal genital bleeding
Hypercoagulopathies (acquired or inherited) Valvular cardiac disease with thrombogenic complications
Ethinyl estradiol and Contraception (post-menarche) None None Menstrual suppression–FTM
norelgestromin333,334 transgender individualsf LOE: C
November 20, 2001335 Contraindications for use
Active or prior history of DVT or PE Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches with or
Benign or malignant hepatic tumors, or hepatic disease without aura if > 35 years of age

BMI ≥ 30 kg/m² Hypercoagulopathies (acquired or inherited)

Breast cancer, or other estrogen- or progestin-sensitive neoplasia (known or history of) Hypertension, uncontrolled

Cerebrovascular or coronary artery disease Pregnancy

Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Smoking and > 35 years of age

Diabetes mellitus with vascular disease Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Undiagnosed abnormal uterine bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Ethinyl estradiol and Acne vulgaris, moderate to severe ( ≥ 15 years of age) None None Menstrual suppression–FTM
norgestimate336,337 transgender individualsf LOE: C
Contraception (post-menarche)
December 29, 1989338
Contraindications for use
Active or prior history of DVT or PE Diabetes mellitus with vascular disease
Benign or malignant hepatic tumors, or hepatic disease High risk of thrombotic conditions (venous or arterial)
Breast cancer (known, suspected, or history of), or other estrogen- or progestin-sensitive neoplasia Hypercoagulopathies (acquired or inherited)
Cerebrovascular or coronary artery disease Hypertension, uncontrolled
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Pregnancy
Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches if > 35 Smoking and > 35 years of age
years of age Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Undiagnosed abnormal uterine bleeding
Ethinyl estradiol and Contraception (post-menarche) None None Menstrual suppression–FTM
norgestrel339,340 transgender individualsf LOE: C

Contraindications for use

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

184

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Approved prior to January 1, Benign or malignant hepatic tumors, or hepatic disease Hypertension, uncontrolled
1982341-344
Breast cancer (known, suspected, or history of) Jaundice with previous oral hormonal contraceptive pill use or cholestatic jaundice of pregnancy
Cerebrovascular or coronary artery disease Major surgery with prolonged immobilization
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Pregnancy
Diabetes mellitus with vascular disease Prior history of DVT or other thromboembolic conditions
Endometrial cancer, or other estrogen-dependent neoplasia (known or suspected) Smoking and > 35 years of age
Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches with or Thrombogenic rhythm or thrombogenic valvular cardiac diseases
without aura if > 35 years of age Thrombophlebitis, thromboembolic disorders, or thrombophilias (acquired or hereditary)
Hypersensitivity to the active ingredient or any excipient Undiagnosed abnormal genital or uterine bleeding
Valvular cardiac disease with thrombogenic complications
Ethinyl estradiol and Contraception (post-menarche) None None
segesterone acetate345,346
Contraindications for use
August 10, 2018
Active or prior history of DVT or PE Headaches with focal neurological symptoms, migraine headaches with aura, or migraine headaches with or
Benign or malignant hepatic tumors, or hepatic disease (eg, acute viral hepatitis or severe decompensated without aura if > 35 years of age
cirrhosis) Hypercoagulopathies (acquired or inherited)
Breast cancer (current or history of), or other estrogen- or progestin-sensitive neoplasia Hypersensitivity to the active ingredient or any excipient
Cerebrovascular or coronary artery disease Hypertension, uncontrolled or with vascular disease
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Pregnancy
Diabetes mellitus with hypertension, vascular disease, or other end-organ injury; > 35 years of age; or a disease Smoking and > 35 years of age
duration of > 20 years Thrombogenic rhythm or thrombogenic valvular cardiac diseases
High risk of thrombotic conditions (venous or arterial) Undiagnosed abnormal uterine bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

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Table I.A.6. Indications for combination sex-hormone/progestin products used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Ethinyl estradiol, Acne vulgaris ( ≥ 14 years of age) None None Menstrual suppression–FTM
drospirenone, and transgender individualsf LOE: C
Contraception (post-menarche)
levomefolate347,348
Folate supplementation (post-menarche)
September 24, 2010349
Premenstrual dysphoric disorder (post-menarche)

Contraindications for use

Active or prior history of DVT or PE Diabetes mellitus with vascular disease
Adrenal insufficiency Hypercoagulopathies (acquired or inherited)
Benign or malignant hepatic tumors or hepatic disease Hypertension, uncontrolled
Breast cancer (current or history of), or other estrogen- or progestin-sensitive neoplasia Pregnancy
Cerebrovascular or coronary artery disease Renal impairment
Concomitant use of hepatitis C regimens containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir Smoking and > 35 years of age
Headaches with focal neurological symptoms or migraine headaches with or without aura if > 35 years of age Thrombogenic rhythm or thrombogenic valvular cardiac diseases
Undiagnosed abnormal uterine bleeding

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Off-label uses for the combination product of estradiol and dienogest were based on the 'Quick Answers' view in the database; note that some off-label uses are only displayed in the 'In-Depth Answers' view, which was unable to be displayed appropriately for
this combination product.
f According to Lexicomp, this agent may be used based on clinical experience to suppress menstruation in FTM transgender adults who experience continual menstrual bleeding while taking testosterone or progestogen treatment (and who are not against
receiving estrogen if applicable)
Table abbreviations: FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein thrombophlebitis; PE, pulmonary embolism; OATP, organic
anion transporting polypeptide; FTM, female-to-male; RCTs, randomized controlled trials

186

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Table I.A.7. Indications for aromatase inhibitors used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Anastrozole350,351 None Advanced breast cancer, following Pubertal gynecomastia None None
December 27, 1995 disease progression on tamoxifen
Evidence is inconclusive
(postmenopausal women)
Not Recommended (B)
Early hormone receptor-positive
breast cancer, adjuvant
(postmenopausal women)
Hormone receptor-positive or -
unknown, metastatic or locally
advanced breast cancer
(postmenopausal women), first-
line

Contraindications for use

Hypersensitivity to the active ingredient or any excipient

Exemestane352,353 None Advanced breast cancer, following None None

October 21, 1999 disease progression on tamoxifen
(postmenopausal women)
Estrogen receptor-positive breast
cancer, adjuvant (following 2 to 3
years of tamoxifen;
postmenopausal women)

Contraindications for use

Hypersensitivity to the active ingredient or any excipient

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book).
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports.
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: FDA, Food-and Drug Administration; LOE, level of evidence; SOE, strength of evidence; TGNB, transgender, nonbinary, or gender diverse; RCTs, randomized controlled trials
187

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Table I.A.7. Indications for aromatase inhibitors used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Letrozole354,355 None Advanced breast cancer, following None None
July 25, 1997356 disease progression on
antiestrogen therapy
(postmenopausal women)
Breast cancer, extended adjuvant
(following 5 years of tamoxifen;
postmenopausal women)
Early hormone receptor-positive
breast cancer, adjuvant
(postmenopausal women)
Hormone receptor-positive or -
unknown, metastatic or locally
advanced breast cancer
(postmenopausal women), first-
line

Contraindications for use

Hypersensitivity to the active ingredient or any excipient
Pregnancy

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book).
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports.
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: FDA, Food-and Drug Administration; LOE, level of evidence; SOE, strength of evidence; TGNB, transgender, nonbinary, or gender diverse; RCTs, randomized controlled trials
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Table I.A.8. Indications for selective estrogen receptor modulators (SERMs) used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Bazedoxifene acetate and None Menopause-related vasomotor None None
conjugated/equine symptoms
estrogens357
Postmenopausal osteoporosis,
October 3, 2013 prophylaxis

Contraindications for use

Active or prior history of arterial thromboembolic disease (eg, MI, stroke) Hepatic disease or impairment
Active or prior history of DVT or PE Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredients or any excipient
Breast cancer (known, suspected, or history of) Pregnancy
Breastfeeding Protein S, protein C, or antithrombin deficiency, or other thrombophilic condition
Estrogen-dependent neoplasia Undiagnosed abnormal uterine bleeding

Clomiphene citrate358,359 None Female infertility, ovulatory None None

Approved prior to dysfunction
January 1, 1982360
Contraindications for use
Abnormal uterine bleeding of unknown cause
Hepatic disease or history of hepatic impairment
Hypersensitivity to the active ingredient or any excipient
Organic intracranial lesion (eg, pituitary tumor)
Ovarian cysts, or enlargement of ovarian cysts not due to polycystic ovarian syndrome
Pregnancy
Uncontrolled adrenal or thyroid dysfunction

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE):Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: SERM, selective estrogen receptor modulator; FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein
thrombophlebitis; PE, pulmonary embolism; RCTs, randomized controlled trials
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Table I.A.8. Indications for selective estrogen receptor modulators (SERMs) used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Ospemifene361,362 None Dyspareunia due to menopause- None None
February 26, 2013 related vulvar and vaginal atrophy
Vaginal dryness due to
menopause-related vulvar and
vaginal atrophy

Contraindications for use

Active or prior history of arterial thromboembolic disease (eg, MI, stroke)
Active or prior history of DVT or PE
Estrogen-dependent neoplasia
Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredient or any excipient
Pregnancy, or those who may become pregnant
Undiagnosed abnormal genital bleeding

Raloxifene None Postmenopausal osteoporosis, None None

hydrochloride363,364 treatment and prophylaxis
December 9, 1997 Risk reduction for invasive breast
cancer (postmenopausal women
at high-risk or with osteoporosis)

Contraindications for use

Active or prior history of venous thromboembolic conditions (eg, DVT, PE, retinal vein thrombosis)
Pregnancy

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE):Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: SERM, selective estrogen receptor modulator; FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein
thrombophlebitis; PE, pulmonary embolism; RCTs, randomized controlled trials
190

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Table I.A.8. Indications for selective estrogen receptor modulators (SERMs) used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
Original FDA-approval dateb (Efficacy; Recommendation [SOE]c) (LOE)d
Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Tamoxifen citrate365,366 None Breast cancer, adjunct Gynecomastia None None
December 30, 1977 Breast cancer, ductal carcinoma in Evidence favors efficacy
situ
Recommended, in some cases (B)
Breast cancer, prophylaxis in Polyostotic fibrous dysplasia of
those at high-risk bone
Metastatic breast cancer
Evidence favors efficacy
Recommended, in some cases (B)
Retinoblastoma
Evidence favors efficacy
Recommended, in some cases (C)
Retroperitoneal fibrosis
Evidence favors efficacy
Recommended, in some cases (C)

Contraindications for use

Hypersensitivity (eg, angioedema, anaphylactic reaction) to the active ingredient or any excipient
The following contraindications only apply when used for breast cancer risk reduction in high-risk patients, or in those treated for ductal carcinoma in situ of the breast:
o Concomitant warfarin use
o History of DVT or PE

Toremifene citrate367,368 None Metastatic breast cancer None None

May 29, 1997 (postmenopausal women)

Contraindications for use

Hypersensitivity to the active ingredient or any excipient
Hypokalemia
Hypomagnesemia
QT prolongation (acquired or congenital)

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b US FDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE):Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or
possibly faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
Table abbreviations: SERM, selective estrogen receptor modulator; FDA, Food and Drug Administration; SOE, strength of evidence; LOE, level of evidence; TGNB, transgender, nonbinary, or gender diverse; MI, myocardial infarction; DVT, deep vein
thrombophlebitis; PE, pulmonary embolism; RCTs, randomized controlled trials
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Table I.A.9. Indications for miscellaneous other agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
(Drug class) (Efficacy; Recommendation [SOE]c) (LOE)d
Original FDA-approval dateb Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Danazol369,370 None Endometriosis Thrombocytopenic purpura, None None
(Androgen) idiopathic or immune
Fibrocystic breast changes
June 21, 1976 Evidence is inconclusive
Hereditary angioedema,
prophylaxis Not Recommended (B)

Contraindications for use

Active or prior history of thrombosis or thromboembolic disease
Androgen-dependent neoplasia
Breastfeeding or pregnancy
Hypersensitivity to the active ingredient or any excipient
Porphyria
Significantly impaired cardiac, renal, or hepatic function
Undiagnosed abnormal genital bleeding

Methyltestosteronee,371,372 Delay in puberty and/or sexual Delay in puberty and/or sexual None None
(Androgen) development (males) development (males)
Approved prior to January 1, Hypogonadotropic or primary Hypogonadotropic or primary
1982373-402 hypogonadism hypogonadism
Metastatic breast cancer (natal
females who are 1 to 5 years
postmenopausal)

Contraindications for use

Breast cancer (males)
Pregnancy
Prostate cancer (known or suspected)

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b USFDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports;
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Although methyltestosterone is FDA-approved to treat metastatic breast cancer, delayed puberty, and hypogonadism (primary or hypogonadotropic), Lexicomp notes that other agents are often used to treat these conditions due to concerns of hepatic toxicity

with chronic use.

Table abbreviations: FDA, Food and Drug Administration; LOE, level of evidence; SOE, strength of evidence; TGNB, transgender, nonbinary, or gender diverse; SPRM, selective progestin receptor modulator; OTC, over-the-counter; RCTs, randomized controlled
trials
192

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Table I.A.9. Indications for miscellaneous other agents used for gender a

dysphoria
Active ingredient FDA-approved uses Micromedex-indexed off-label uses Lexicomp-indexed off-label uses
(Drug class) (Efficacy; Recommendation [SOE]c) (LOE)d
Original FDA-approval dateb Any pediatric indications Any adult indications Any pediatric uses Adult TGNB uses Any pediatric uses Adult TGNB uses
Minoxidil403-405 Hypertension Hypertension None None
(Vasodilator) Male-pattern alopecia, including
October 18, 1979 in natal females

Contraindications for use

Hypersensitivity to the active ingredient or any excipient
Per OTC labeling for the topical formulation:
o Apply other medications to the scalp
o Hair loss does not correspond to product labeling
o Hair loss is sudden and/or patchy, related to childbirth, or unknown etiology
o Labeled products for males should not be used on natal females
o No family history of hair loss
o Patients < 18 years of age
o Scalp is irritated, inflamed, red, infected, or painful
Pheochromocytoma

Ulipristal acetate406,407 Postcoital contraception (post-menarche) None None

(SPRM)
Contraindications for use
August 13, 2010
Pregnancy

a Information is reported based on Lexicomp and Micromedex. Because the indications and contraindications vary based on the formulation of the product, please refer to the drug-specific product labeling (ie, package inserts) for complete details.
b USFDA approval date for each agent was obtained from either Lexicomp or the Approved Drug Products with Therapeutic Equivalence Evaluations (often referred to as the Orange Book). Notably, the Orange Book does not provide an approval date for agents
approved before January 1, 1982.
c Micromedex categories for the strength of evidence (SOE): Category A: based on consistent results from meta-analyses of RCTs or several well-conducted, large RCTs; Category B: based on meta-analyses of RCTs with conflicting results, RCTs with critical
limitations (eg, bias, small sample size), or non-randomized studies; Category C: based on expert consensus or opinion, case series or case reports;
d Lexicomp level of evidence (LOE) definitions: A: based on consistent evidence from well-conducted RCTs, or substantial evidence (other than RCTs) supporting the off-label use. Estimate of effect is unlikely to change with additional evidence.; B: based on RCTs
with significant limitations (eg, methodological weaknesses, inconsistent results), or very strong evidence of another design. Estimate of effect may change with additional evidence.; C: based on observational studies, unsystematic clinical experience, or possibly
faulty RCTs. Estimate of effect is uncertain.; G: use has been substantiated through its incorporation into either an evidence- or consensus-based clinical practice guideline.
e Although methyltestosterone is FDA-approved to treat metastatic breast cancer, delayed puberty, and hypogonadism (primary or hypogonadotropic), Lexicomp notes that other agents are often used to treat these conditions due to concerns of hepatic toxicity

with chronic use.

Table abbreviations: FDA, Food and Drug Administration; LOE, level of evidence; SOE, strength of evidence; TGNB, transgender, nonbinary, or gender diverse; SPRM, selective progestin receptor modulator; OTC, over-the-counter; RCTs, randomized controlled
trials
193

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APPENDIX I.B: SEARCH STRATEGIES OF BIBLIOGRAPHIC DATABASES
Bibliographic database searches were conducted in phases over a period of months and are summarized
in Table I.B.1.

Initial searches (ie, "first- corpus" searches) included structured vocabulary only (ie, medical subject
headings [MeSH] in Medline and Emtree in Embase) and were initially conducted between March 9 and
23, 2023. We first ran these initial searches with filters for guidelines and systematic reviews, followed
by searches for experimental, observational, descriptive, and qualitative studies.

While screening the citations that were retrieved in these initial searches, we discovered that we had
excluded some additional agents that are used in patients with gender dysphoria. After adding search
terms for those agents, all the structured vocabulary searches were rerun on April 11, 2023. Details of
the searches with structured vocabulary only are in Table I.B.2 through Table I.B.6 (searches of Ovid
Medline) and Table I.B.7 through Table I.B.11 (searches of Embase).

Comprehensive searches (ie, "second- corpus" searches, or those that included a combination of
structured vocabulary and free text keywords) were run after the screening was complete for the MeSH-
and Emtree-only searches, between May 15 and June 5, 2023. The combination of structured vocabulary
and free-text terms is a best practice for comprehensive searches. Free text terms increase the
sensitivity of searches and also increase the likelihood of identifying relevant citations that are
incorrectly or incompletely indexed. These also included searches for additional guidelines and SRs, as
well as additional experimental, observational, descriptive, and qualitative studies. Details of these
searches are summarized in Table I.B.12 through Table I.B.17 (Ovid Medline) and Table I.B.18 through
Table I.B.22 (Embase).

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Table I.B.1. Summary of searches uploaded to Covidence, March 9, 2023 through June 5, 2023
Search Rerun/ # # # # Added to
Database Search File Name (*.ris) Study Type Search Term Type
Date Redo? References Duplicates Merged Screening
3/9/2023 MEDLINE Ovid 41 Guidelines Mesh-Only 3.9.23.ris Guideline MeSH only 41 0 0 41

3/9/2023 MEDLINE Ovid 12 SRs Mesh-Only 3.9.23.ris Systematic MeSH only 12 3 0 9

Review

3/20/2023 MEDLINE Ovid 3 RCTs Mesh-Only 3.20.23.ris RCT MeSH only 3 0 0 3

3/21/2023 Embase Embase 31 SRs Emtree Search 3.21.23.ris Systematic Emtree only 31 4 0 27
Review

3/22/2023 MEDLINE Gender Dysphoria_Ovid-Medline MESH- RCT-CCT MeSH only 25 5 0 20

only search_results with RCT-CCT
filter_3.22.23.ris

3/22/2023 MEDLINE Gender Dysphoria_Ovid-Medline MESH- Observational MeSH only 190 29 0 161
only search_observational filter_
3.22.23.ris

3/23/2023 Embase Embase 110 Guidelines Emtree-only Guideline Emtree only 110 33 0 77
3.23.23.ris

3/23/2023 MEDLINE MeshOnly_Qualitative_GenderDysphoria. Qualitative MeSH only 72 42 0 30

ris

3/31/2023 Embase Embase 55 Experimental Studies Emtree- Experimental Emtree only 55 27 0 28

only Search 3.31.23.ris

4/7/2023 Embase Embase 448 Observational_Descriptive Observational/ Emtree only 448 181 0 267
Emtree-only Search 4.7.23.ris Descriptive

4/7/2023 Embase Embase 158 Qualitative Emtree-only Qualitative Emtree only 158 131 0 27
Search 4.7.23.ris

4/11/2023 MEDLINE Ovid 13 SRs Reran Mesh-Only Search Systematic MeSH only Yes 13 12 0 1
4.11.23.ris Review

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug Regimen Review Center; SR, systematic review;
CADTH, Canada's Drug and Health Technology Agency; RCT, randomized controlled trial; CCT, controlled clinical trial

195
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Table I.B.1. Summary of searches uploaded to Covidence, March 9, 2023 through June 5, 2023
Search Rerun/ # # # # Added to
Database Search File Name (*.ris) Study Type Search Term Type
Date Redo? References Duplicates Merged Screening
4/11/2023 MEDLINE Ovid 41 Guidelines Reran Mesh-Only Guideline MeSH only Yes 41 41 0 0
Search 4.11.23.ris

4/11/2023 MEDLINE Ovid 3 RCTs Reran Mesh-Only Search RCT MeSH only Yes 3 3 0 0
4.11.23.ris

4/11/2023 MEDLINE Ovid 25 RCT-CCT Reran Mesh-Only RCT-CCT MeSH only Yes 25 25 0 0
Search 4.11.23.ris

4/11/2023 MEDLINE Ovid 197 Observational Re-ran Mesh- Observational MeSH only Yes 197 197 0 0
Only Search 4.11.23.ris

4/11/2023 MEDLINE Ovid 72 Qualitative Re-ran Mesh-Only Qualitative MeSH only Yes 72 72 0 0
Search 4.11.23.ris

4/11/2023 Embase Embase 158 Qualitative Re-ran Emtree- Qualitative Emtree only Yes 158 158 0 0
Only Search 4.11.23.ris

4/11/2023 Embase Embase 449 Observational Re-ran Observational Emtree only Yes 449 448 0 1
Emtree-Only Search 4.11.23.ris

4/11/2023 Embase Embase 56 Experimental Re-ran Emtree- Experimental Emtree only Yes 56 56 0 0
Only Search 4.11.23.ris

4/11/2023 Embase Embase 110 Guidelines Re-ran Emtree- Guideline Emtree only Yes 110 110 0 0
Only Search 4.11.23.ris

4/11/2023 Embase Embase 31 SRs Re-ran Emtree-Only Systematic Emtree only Yes 31 31 0 0
Search 4.11.23.ris Review

5/15/2023 Embase Embase 67 SRs free text + controlled Systematic free text + controlled 67 30 0 37
vocabulary_5.15.23.ris Review vocabulary

5/15/2023 Embase Embase 192 Guidelines free text + Guideline free text + controlled 192 128 0 64
controlled vocabulary_5.15.23.ris vocabulary

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug Regimen Review Center; SR, systematic review;
CADTH, Canada's Drug and Health Technology Agency; RCT, randomized controlled trial; CCT, controlled clinical trial

196
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Table I.B.1. Summary of searches uploaded to Covidence, March 9, 2023 through June 5, 2023
Search Rerun/ # # # # Added to
Database Search File Name (*.ris) Study Type Search Term Type
Date Redo? References Duplicates Merged Screening
5/15/2023 MEDLINE Ovid 54 SRs free text + controlled Systematic free text + controlled 54 37 0 17
vocabulary_5.15.23.ris Review vocabulary

5/15/2023 MEDLINE Ovid 112 Guidelines free text + controlled Guideline free text + controlled 112 93 0 19
vocabulary_5.15.23.ris vocabulary

5/22/2023 Embase Embase 93 Experimental studies free text Experimental free text + controlled 93 67 0 26
+ controlled vocabulary_5.22.23.ris vocabulary

5/22/2023 Embase Embase 400 Observational_Descriptive Observational/ free text + controlled Batch 1 400 297 0 103
(batch 1) studies free text + controlled Descriptive vocabulary
vocabulary_5.22.23.ris

5/22/2023 Embase Embase 324 Observational_Descriptive Observational/ free text + controlled Batch 2 324 233 0 91
(batch 2) studies free text + controlled Descriptive vocabulary
vocabulary_5.22.23.ris

5/22/2023 MEDLINE Ovid Medline 14 RCTs free text + RCT free text + controlled 14 13 0 1
controlled vocabulary_5.22.23.ris vocabulary

5/22/2023 MEDLINE Ovid Medline 61 RCT-CCT free text + RCT-CCT free text + controlled 61 54 0 7
controlled vocabulary_5.22.23.ris vocabulary

5/22/2023 MEDLINE Ovid Medline 499 Observational_ Observational/ free text + controlled 499 429 0 70
Descriptive studies free text + controlled Descriptive vocabulary
vocabulary_5.22.23.ris

6/5/2023 Embase Embase 380 Qualitative studies free text Qualitative free text + controlled 380 300 0 80
+ controlled vocabulary_6.05.23.ris vocabulary

6/5/2023 MEDLINE Ovid 297 Qualitative studies free text + Qualitative free text + controlled 297 268 0 29
controlled vocabulary_6.05.23.ris vocabulary

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug Regimen Review Center; SR, systematic review;
CADTH, Canada's Drug and Health Technology Agency; RCT, randomized controlled trial; CCT, controlled clinical trial

197
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MeSH-only Searches of Ovid Medline Conducted between March 9 and
April 11, 2023

Table I.B.2. MeSH-only search of Ovid Medline for guidelines and systematic reviews, initially March 9,
2023; rerun April 11, 2023
Search step Query Results
For the systema c review filter, we combined our tradi onal DRRC SR filter with a University of Texas SR filter to
broaden our results.37 The search also uses the CADTH broad guideline filter for Medline/Embase/PsycInfo.33

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 28,992

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,139,986
#3 1 and 2 9,126
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 347,472
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,833
Cyproterone/ or Spironolactone/
#6 4 or 5 365,884
#7 3 and 6 549
#8 7 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs or 546
mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#9 limit 8 to yr = "2010 -Current" 370
#10 (((comprehensive* or integra ve or systema c*) adj3 (bibliographic* or review* or 706,329
literature)) or ("research synthesis" or ((informa on or data) adj3 synthesis) or (data adj2
extract*))). ,ab. or (cinahl or embase or medline or psyclit or (psycinfo not "psycinfo
database") or pubmed or scopus or "sociological abstracts" or "web of science").ab. or
("cochrane database of systema c reviews" or evidence report technology assessment or
evidence report technology assessment summary).jn. or Evidence Report: Technology
Assessment*.jn. or ((review adj5 (ra onale or evidence)). ,ab. and review.pt.) or meta-
analysis as topic/ or Meta-Analysis.pt. or meta-analysis/ or (metaanaly$ or meta-
analy$). ,ab,kw,kf. or "Systema c Review"/ or ((systema c* adj3 review*) or (systema c*
adj2 search*) or cochrane$ or (overview adj4 review)). ,ab,kw,kf. or (cochrane$ or
systema c-review?).jw. or systema c review.tw. or meta-analysis.pt.
#11 exp clinical pathway/ or exp clinical protocol/ or clinical protocols/ or exp consensus/ or 736,217
exp consensus development conference/ or exp consensus development conferences as
topic/ or cri cal pathways/ or exp guideline/ or guidelines as topic/ or exp prac ce
guideline/ or prac ce guidelines as topic/ or health planning guidelines/ or Clinical
Decision Rules/ or (guideline or prac ce guideline or consensus development conference
or consensus development conference, NIH).pt. or (posi on statement* or policy
statement* or prac ce parameter* or best prac ce*). ,ab,kf. or (standards or guideline or
guidelines). ,kf. or ((prac ce or treatment* or clinical) adj guideline*).ab. or (CPG or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

198
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Table I.B.2. MeSH-only search of Ovid Medline for guidelines and systematic reviews, initially March 9,
2023; rerun April 11, 2023
Search step Query Results
CPGs). . or consensus*. ,kf. or consensus*.ab. /freq = 2 or ((cri cal or clinical or prac ce)
adj2 (path or paths or pathway or pathways or protocol*)). ,ab,kf. or recommendat*. ,kf.
or guideline recommenda on*.ab. or (care adj2 (standard or path or paths or pathway or
pathways or map or maps or plan or plans)). ,ab,kf. or (algorithm* adj2 (screening or
examina on or test or tested or tes ng or assessment* or diagnosis or diagnoses or
diagnosed or diagnosing)). ,ab,kf. or (algorithm* adj2 (pharmacotherap* or
chemotherap* or chemotreatment* or therap* or treatment* or interven on*)). ,ab,kf.
or (guideline* or standards or consensus* or recommendat*).au.
#12 9 and 10 12
#13 9 and 11 41
We re-ran all searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug class per Lexicomp. Deduplica on was performed in Covidence.

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,210

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,147,994
#3 1 and 2 9,170
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 348,064
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,939
Cyproterone/ or Spironolactone/
#6 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,359
#7 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,557
Ospemifene/ or Bazedoxifene/
#8 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,571
#9 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#10 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,153
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#11 4 or 5 or 6 or 7 or 8 or 9 or 10 398,775
#12 3 and 11 558
#13 12 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 555
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#14 limit 13 to yr = "2010 -Current" 378
#15 (((comprehensive* or integra ve or systema c*) adj3 (bibliographic* or review* or 714,668
literature)) or ("research synthesis" or ((informa on or data) adj3 synthesis) or (data adj2
extract*))). ,ab. or (cinahl or embase or medline or psyclit or (psycinfo not "psycinfo
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

199
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Table I.B.2. MeSH-only search of Ovid Medline for guidelines and systematic reviews, initially March 9,
2023; rerun April 11, 2023
Search step Query Results
database") or pubmed or scopus or "sociological abstracts" or "web of science").ab. or
("cochrane database of systema c reviews" or evidence report technology assessment or
evidence report technology assessment summary).jn. or Evidence Report: Technology
Assessment*.jn. or ((review adj5 (ra onale or evidence)). ,ab. and review.pt.) or meta-
analysis as topic/ or Meta-Analysis.pt. or meta-analysis/ or (metaanaly$ or meta-
analy$). ,ab,kw,kf. or "Systema c Review"/ or ((systema c* adj3 review*) or (systema c*
adj2 search*) or cochrane$ or (overview adj4 review)). ,ab,kw,kf. or (cochrane$ or
systema c-review?).jw. or systema c review.tw. or meta-analysis.pt.
#16 exp clinical pathway/ or exp clinical protocol/ or clinical protocols/ or exp consensus/ or 740,221
exp consensus development conference/ or exp consensus development conferences as
topic/ or cri cal pathways/ or exp guideline/ or guidelines as topic/ or exp prac ce
guideline/ or prac ce guidelines as topic/ or health planning guidelines/ or Clinical
Decision Rules/ or (guideline or prac ce guideline or consensus development conference
or consensus development conference, NIH).pt. or (posi on statement* or policy
statement* or prac ce parameter* or best prac ce*). ,ab,kf. or (standards or guideline or
guidelines). ,kf. or ((prac ce or treatment* or clinical) adj guideline*).ab. or (CPG or
CPGs). . or consensus*. ,kf. or consensus*.ab. /freq = 2 or ((cri cal or clinical or prac ce)
adj2 (path or paths or pathway or pathways or protocol*)). ,ab,kf. or recommendat*. ,kf.
or guideline recommenda on*.ab. or (care adj2 (standard or path or paths or pathway or
pathways or map or maps or plan or plans)). ,ab,kf. or (algorithm* adj2 (screening or
examina on or test or tested or tes ng or assessment* or diagnosis or diagnoses or
diagnosed or diagnosing)). ,ab,kf. or (algorithm* adj2 (pharmacotherap* or
chemotherap* or chemotreatment* or therap* or treatment* or interven on*)). ,ab,kf.
or (guideline* or standards or consensus* or recommendat*).au.
#17 14 and 15 13
#18 14 and 16 41

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

200
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Table I.B.3. MeSH-only search of Ovid Medline for randomized controlled trials, initially March 20,
2023; rerun April 11, 2023
Search step Query Results
For randomized controlled trials.

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,069

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,142,313
#3 1 and 2 9,141
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 347,631
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,854
Cyproterone/ or Spironolactone/
#6 4 or 5 366,060
#7 3 and 6 549
#8 7 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 546
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#9 limit 8 to yr = "2010 -Current" 370
#10 (randomized controlled trial or controlled clinical trial).pt. or randomi#ed.ab. or 1,555,480
placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial. .
#11 9 and 10 3
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,210

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,147,994
#3 1 and 2 9,170
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 348,064
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,939
Cyproterone/ or Spironolactone/
#6 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,359
#7 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,557
Ospemifene/ or Bazedoxifene/
#8 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,571
#9 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

201
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Table I.B.3. MeSH-only search of Ovid Medline for randomized controlled trials, initially March 20,
2023; rerun April 11, 2023
Search step Query Results
#10 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,153
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#11 4 or 5 or 6 or 7 or 8 or 9 or 10 398,775
#12 3 and 11 558
#13 12 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 555
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#14 limit 13 to yr = "2010 -Current" 378
#15 (randomized controlled trial or controlled clinical trial).pt. or randomi#ed.ab. or 1,560,821
placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial. .
#16 14 and 15 3

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

202
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Table I.B.4. MeSH-only search of Ovid Medline for randomized controlled trials and other experimental
studies (eg, controlled clinical trials), initially March 22, 2023; rerun April 11, 2023
Search step Query Results
For a more sensi ve search for experimental studies, we used the CADTH RCT/CCT filter for Medline/Embase/
PsycInfo.33

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,103

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,144,053
#3 1 and 2 9,149
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 347,736
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,880
Cyproterone/ or Spironolactone/
#6 4 or 5 366,181
#7 3 and 6 549
#8 7 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs or 546
mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#9 limit 8 to yr = "2010 -Current" 370
#10 (Randomized Controlled Trial or Controlled Clinical Trial or Pragma c Clinical Trial or 684,464
Equivalence Trial or Clinical Trial, Phase III).pt.
#11 Randomized Controlled Trial/ 589,274
#12 exp Randomized Controlled Trials as Topic/ 164,947
#13 "Randomized Controlled Trial (topic)"/ 0
#14 Controlled Clinical Trial/ 95,223
#15 exp Controlled Clinical Trials as Topic/ 170,651
#16 "Controlled Clinical Trial (topic)"/ 0
#17 Randomiza on/ 106,911
#18 Random Alloca on/ 106,911
#19 Double-Blind Method/ 174,672
#20 Double Blind Procedure/ 0
#21 Double-Blind Studies/ 174,672
#22 Single-Blind Method/ 32,582
#23 Single Blind Procedure/ 0
#24 Single-Blind Studies/ 32,582
#25 Placebos/ 35,926
#26 Placebo/ 0

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

203
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Table I.B.4. MeSH-only search of Ovid Medline for randomized controlled trials and other experimental
studies (eg, controlled clinical trials), initially March 22, 2023; rerun April 11, 2023
Search step Query Results
#27 Control Groups/ 1,925
#28 Control Group/ 1,925
#29 (random* or sham or placebo*). ,ab,hw,kf. 1,785,429
#30 ((singl* or doubl*) adj (blind* or dumm* or mask*)). ,ab,hw,kf. 265,145
#31 ((tripl* or trebl*) adj (blind* or dumm* or mask*)). ,ab,hw,kf. 1,550
#32 (control* adj3 (study or studies or trial* or group*)). ,ab,kf. 1,203,930
#33 (Nonrandom* or non random* or non-random* or quasi-random* or 53,609
quasirandom*). ,ab,hw,kf.
#34 allocated. ,ab,hw. 82,266
#35 ((open label or open-label) adj5 (study or studies or trial*)). ,ab,hw,kf. 43,828
#36 ((equivalence or superiority or non-inferiority or noninferiority) adj3 (study or studies or 11,756
trial*)). ,ab,hw,kf.
#37 (pragma c study or pragma c studies). ,ab,hw,kf. 580
#38 ((pragma c or prac cal) adj3 trial*). ,ab,hw,kf. 7,511
#39 ((quasiexperimental or quasi-experimental) adj3 (study or studies or trial*)). ,ab,hw,kf. 11,801
#40 (phase adj3 (III or "3") adj3 (study or studies or trial*)). ,hw,kf. 34,820
#41 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 2,560,367
or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40
#42 9 and 41 25
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,210

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,147,994
#3 1 and 2 9,170
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 348,064
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,939
Cyproterone/ or Spironolactone/
#6 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,359
#7 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,557
Ospemifene/ or Bazedoxifene/
#8 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,571

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

204
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Table I.B.4. MeSH-only search of Ovid Medline for randomized controlled trials and other experimental
studies (eg, controlled clinical trials), initially March 22, 2023; rerun April 11, 2023
Search step Query Results
#9 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#10 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ or 22,153
Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#11 4 or 5 or 6 or 7 or 8 or 9 or 10 398,775
#12 3 and 11 558
#13 12 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 555
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#14 limit 13 to yr = "2010 -Current" 378
#15 (Randomized Controlled Trial or Controlled Clinical Trial or Pragma c Clinical Trial or 2,568,334
Equivalence Trial or Clinical Trial, Phase III).pt. or Randomized Controlled Trial/ or exp
Randomized Controlled Trials as Topic/ or "Randomized Controlled Trial (topic)"/ or
Controlled Clinical Trial/ or exp Controlled Clinical Trials as Topic/ or "Controlled Clinical
Trial (topic)"/ or Randomiza on/ or Randomiza on/ or Double-Blind Method/ or Double
Blind Procedure/ or Double-Blind Studies/ or Single-Blind Method/ or Single Blind
Procedure/ or Single-Blind Studies/ or Placebos/ or Placebo/ or Control Groups/ or Control
Group/ or (random* or sham or placebo*). ,ab,hw,kf. or ((singl* or doubl*) adj (blind* or
dumm* or mask*)). ,ab,hw,kf. or ((tripl* or trebl*) adj (blind* or dumm* or
mask*)). ,ab,hw,kf. or (control* adj3 (study or studies or trial* or group*)). ,ab,kf. or
(Nonrandom* or non random* or non-random* or quasi-random* or
quasirandom*). ,ab,hw,kf. or allocated. ,ab,hw. or ((open label or open-label) adj5 (study
or studies or trial*)). ,ab,hw,kf. or ((equivalence or superiority or non-inferiority or
noninferiority) adj3 (study or studies or trial*)). ,ab,hw,kf. or (pragma c study or
pragma c studies). ,ab,hw,kf. or ((pragma c or prac cal) adj3 trial*). ,ab,hw,kf. or
((quasiexperimental or quasi-experimental) adj3 (study or studies or trial*)). ,ab,hw,kf. or
(phase adj3 (III or "3") adj3 (study or studies or trial*)). ,hw,kf.
#16 14 and 15 25

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

205
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Table I.B.5. MeSH-only search of Ovid Medline for observational and descriptive studies, initially March
22, 2023; rerun April 11, 2023
Search step Query Results
For observa onal and descrip ve studies, we used the CADTH observa onal studies filter for
Medline/Embase/PsycInfo.34

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,103

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,144,053
#3 1 and 2 9,149
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 347,736
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,880
Cyproterone/ or Spironolactone/
#6 4 or 5 366,181
#7 3 and 6 549
#8 7 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs or 546
mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#9 limit 8 to yr = "2010 -Current" 370
#10 epidemiologic methods.sh. 31,613
#11 epidemiologic studies.sh. 9,285
#12 observa onal study/ 139,665
#13 observa onal studies as topic/ 8,597
#14 clinical studies as topic/ 784
#15 controlled before-a er studies/ 718
#16 cross-sec onal studies/ 460,566
#17 historically controlled study/ 225
#18 interrupted me series analysis/ 1,793
#19 exp seroepidemiologic studies/ 27,779
#20 na onal longitudinal study of adolescent health/ 103
#21 cohort studies/ 326,279
#22 cohort analysis/ 326,279
#23 longitudinal studies/ 163,864
#24 longitudinal study/ 163,864
#25 prospec ve studies/ 654,181
#26 prospec ve study/ 654,181
#27 follow-up studies/ 690,498

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

206
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Table I.B.5. MeSH-only search of Ovid Medline for observational and descriptive studies, initially March
22, 2023; rerun April 11, 2023
Search step Query Results
#28 follow up/ 0
#29 followup studies/ 0
#30 retrospec ve studies/ 1,103,777
#31 retrospec ve study/ 1,103,777
#32 case-control studies/ 326,734
#33 exp case control study/ 1,401,173
#34 cross-sec onal study/ 460,566
#35 observa onal study/ 139,665
#36 quasi experimental methods/ 0
#37 quasi experimental study/ 1,060
#38 single-case studies as topic/ 98
#39 (observa onal study or valida on studies or clinical study).pt. 145,080
#40 (observa onal adj3 (study or studies or design or analysis or analyses)). ,ab,kf. 213,523
#41 cohort*. ,ab,kf. 834,281
#42 (prospec ve adj7 (study or studies or design or analysis or analyses)). ,ab,kf. 523,640
#43 ((follow up or followup) adj7 (study or studies or design or analysis or analyses)). ,ab,kf. 166,904
#44 ((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or 339,131
analyses or data)). ,ab,kf.
#45 (retrospec ve adj7 (study or studies or design or analysis or analyses or data or 662,831
review)). ,ab,kf.
#46 ((case adj control) or (case adj comparison) or (case adj controlled)). ,ab,kf. 156,914
#47 (case-referent adj3 (study or studies or design or analysis or analyses)). ,ab,kf. 636
#48 (popula on adj3 (study or studies or analysis or analyses)). ,ab,kf. 228,792
#49 (descrip ve adj3 (study or studies or design or analysis or analyses)). ,ab,kf. 106,255
#50 ((mul dimensional or (mul adj dimensional)) adj3 (study or studies or design or analysis 4,842
or analyses)). ,ab,kf.
#51 (cross adj sec onal adj7 (study or studies or design or research or analysis or analyses or 422,893
survey or findings)). ,ab,kf.
#52 ((natural adj experiment) or (natural adj experiments)). ,ab,kf. 3,184
#53 (quasi adj (experiment or experiments or experimental)). ,ab,kf. 19,759
#54 ((non experiment or nonexperiment or non experimental or nonexperimental) adj3 (study 1,677
or studies or design or analysis or analyses)). ,ab,kf.
#55 (prevalence adj3 (study or studies or analysis or analyses)). ,ab,kf. 48,580

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

207
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Table I.B.5. MeSH-only search of Ovid Medline for observational and descriptive studies, initially March
22, 2023; rerun April 11, 2023
Search step Query Results
#56 case series. ,ab,kf. 101,005
#57 case reports.pt. 2,325,255
#58 case report/ 0
#59 case study/ 2,325,255
#60 (case adj3 (report or reports or study or studies or histories)). ,ab,kf. 963,322
#61 organiza onal case studies.sh. 12,633
#62 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 6,713,161
or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or
41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56
or 57 or 58 or 59 or 60 or 61
#63 9 and 62 190
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,210

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,147,994
#3 1 and 2 9,170
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 348,064
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,939
Cyproterone/ or Spironolactone/
#6 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,359
#7 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,557
Ospemifene/ or Bazedoxifene/
#8 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,571
#9 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#10 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ or 22,153
Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#11 4 or 5 or 6 or 7 or 8 or 9 or 10 398,775
#12 3 and 11 558
#13 12 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 555
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#14 limit 13 to yr = "2010 -Current" 378

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

208
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Table I.B.5. MeSH-only search of Ovid Medline for observational and descriptive studies, initially March
22, 2023; rerun April 11, 2023
Search step Query Results
#15 (epidemiologic methods or epidemiologic studies).sh. or observa onal study/ or 6,733,172
observa onal studies as topic/ or clinical studies as topic/ or controlled before-a er
studies/ or cross-sec onal studies/ or historically controlled study/ or interrupted me
series analysis/ or exp seroepidemiologic studies/ or na onal longitudinal study of
adolescent health/ or cohort studies/ or cohort analysis/ or longitudinal studies/ or
longitudinal study/ or prospec ve studies/ or prospec ve study/ or follow-up studies/ or
follow up/ or followup studies/ or retrospec ve studies/ or retrospec ve study/ or case-
control studies/ or exp case control study/ or cross-sec onal study/ or observa onal
study/ or quasi experimental methods/ or quasi experimental study/ or single-case studies
as topic/ or (observa onal study or valida on studies or clinical study).pt. or (observa onal
adj3 (study or studies or design or analysis or analyses)). ,ab,kf. or cohort*. ,ab,kf. or
(prospec ve adj7 (study or studies or design or analysis or analyses)). ,ab,kf. or ((follow up
or followup) adj7 (study or studies or design or analysis or analyses)). ,ab,kf. or
((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or
analyses or data)). ,ab,kf. or (retrospec ve adj7 (study or studies or design or analysis or
analyses or data or review)). ,ab,kf. or ((case adj control) or (case adj comparison) or (case
adj controlled)). ,ab,kf. or (case-referent adj3 (study or studies or design or analysis or
analyses)). ,ab,kf. or (popula on adj3 (study or studies or analysis or analyses)). ,ab,kf. or
(descrip ve adj3 (study or studies or design or analysis or analyses)). ,ab,kf. or
((mul dimensional or (mul adj dimensional)) adj3 (study or studies or design or analysis
or analyses)). ,ab,kf. or (cross adj sec onal adj7 (study or studies or design or research or
analysis or analyses or survey or findings)). ,ab,kf. or ((natural adj experiment) or (natural
adj experiments)). ,ab,kf. or (quasi adj (experiment or experiments or
experimental)). ,ab,kf. or ((non experiment or nonexperiment or non experimental or
nonexperimental) adj3 (study or studies or design or analysis or analyses)). ,ab,kf. or
(prevalence adj3 (study or studies or analysis or analyses)). ,ab,kf. or case series. ,ab,kf. or
case reports.pt. or case report/ or case study/ or (case adj3 (report or reports or study or
studies or histories)). ,ab,kf. or organiza onal case studies.sh.
#16 14 and 15 197

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

209
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Table I.B.6. MeSH-only search of Ovid Medline for qualitative studies, initially March 23, 2023; rerun
April 11, 2023
Search step Query Results
To find qualita ve studies, we used the pragma cally-validated filters from CADTH.35,36

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,072

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,143,449
#3 1 and 2 9,144
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 366,143
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or
Dutasteride/ or exp Cyproterone/ or Spironolactone/ or Sex Reassignment Procedures/
#5 3 and 4 550
#6 limit 5 to yr = "2010 -Current" 373
#7 6 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs or 371
mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#8 exp Empirical Research/ or Interviews as Topic/ or Personal Narra ves as Topic/ or Focus 177,777
Groups/ or exp Narra on/ or Nursing Methodology Research/ or Narra ve Medicine/
#9 (Interview or Personal Narra ve).pt. 36,749
#10 interview*. ,ab,kf. 444,084
#11 qualita ve. ,ab,kf,jw. 317,319
#12 (theme* or thema c). ,ab,kf. 161,783
#13 ethnological research. ,ab,kf. 8
#14 ethnograph*. ,ab,kf. 13,677
#15 ethnomedicine. ,ab,kf. 961
#16 ethnonursing. ,ab,kf. 127
#17 phenomenol*. ,ab,kf. 33,195
#18 (grounded adj (theor* or study or studies or research or analys?s)). ,ab,kf. 14,941
#19 life stor*. ,ab,kf. 1,539
#20 (emic or e c or hermeneu c* or heuris c* or semio c*). ,ab,kf. 21,585
#21 (data adj1 saturat$). ,ab,kf. 1,989
#22 par cipant observ*. ,ab,kf. 5,419
#23 (social construct* or postmodern* or post-structural* or post structural* or 4,212
poststructural* or post modern* or post-modern*). ,ab,kf.
#24 (ac on research or coopera ve inquir* or co opera ve inquir* or co-opera ve 5,571
inquir*). ,ab,kf.
#25 (humanis c or existen al or experien al or paradigm*). ,ab,kf. 190,077
#26 (field adj (study or studies or research or work)). ,ab,kf. 21,124
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

210
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Table I.B.6. MeSH-only search of Ovid Medline for qualitative studies, initially March 23, 2023; rerun
April 11, 2023
Search step Query Results
#27 (human science or social science). ,ab,kf. 6,702
#28 biographical method. ,ab,kf. 22
#29 theore cal sampl*. ,ab,kf. 901
#30 ((purpos* adj4 sampl*) or (focus adj group*)). ,ab,kf. 81,883
#31 (open-ended or narra ve* or textual or texts or semi-structured). ,ab,kf. 173,375
#32 (life world* or life-world* or conversa on analys?s or personal experience* or theore cal 17,855
satura on). ,ab,kf.
#33 ((lived or life) adj experience*). ,ab,kf. 18,266
#34 cluster sampl*. ,ab,kf. 9,331
#35 observa onal method*. ,ab,kf. 967
#36 content analysis. ,ab,kf. 41,472
#37 (constant adj (compara ve or comparison)). ,ab,kf. 5,903
#38 ((discourse* or discurs*) adj3 analys?s). ,ab,kf. 3,163
#39 (heidegger* or colaizzi* or spiegelberg* or merleau* or husserl* or foucault* or ricoeur or 4,723
glaser*). ,ab,kf.
#40 (van adj manen*). ,ab,kf. 530
#41 (van adj kaam*). ,ab,kf. 44
#42 (corbin* adj2 strauss*). ,ab,kf. 433
#43 or/8-42 1,147,921
#44 "Surveys and Ques onnaires"/ 556,176
#45 Health Care Surveys/ 33,997
#46 self report/ 42,485
#47 ques onnaire*. ,ab,kf. 652,803
#48 survey*. ,ab,kf. 823,578
#49 or/44-48 1,521,538
#50 43 or 49 2,420,873
#51 50 and 7 72
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,210

#2 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,147,994
#3 1 and 2 9,170

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

211
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Table I.B.6. MeSH-only search of Ovid Medline for qualitative studies, initially March 23, 2023; rerun
April 11, 2023
Search step Query Results
#4 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 348,064
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/
#5 exp Androgen antagonists/ or Bicalutamide/ or Finasteride/ or Dutasteride/ or exp 27,939
Cyproterone/ or Spironolactone/
#6 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,359
#7 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,557
Ospemifene/ or Bazedoxifene/
#8 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,571
#9 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#10 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ or 22,153
Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#11 4 or 5 or 6 or 7 or 8 or 9 or 10 398,775
#12 3 and 11 558
#13 12 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 555
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#14 limit 13 to yr = "2010 -Current" 378
#15 exp Empirical Research/ or Interviews as Topic/ or Personal Narra ves as Topic/ or Focus 1,153,851
Groups/ or exp Narra on/ or Nursing Methodology Research/ or Narra ve Medicine/ or
(Interview or Personal Narra ve).pt. or interview*. ,ab,kf. or qualita ve. ,ab,kf,jw. or
(theme* or thema c). ,ab,kf. or ethnological research. ,ab,kf. or ethnograph*. ,ab,kf. or
ethnomedicine. ,ab,kf. or ethnonursing. ,ab,kf. or phenomenol*. ,ab,kf. or (grounded adj
(theor* or study or studies or research or analys?s)). ,ab,kf. or life stor*. ,ab,kf. or (emic
or e c or hermeneu c* or heuris c* or semio c*). ,ab,kf. or (data adj1 saturat$). ,ab,kf.
or par cipant observ*. ,ab,kf. or (social construct* or postmodern* or post-structural* or
post structural* or poststructural* or post modern* or post-modern*). ,ab,kf. or (ac on
research or coopera ve inquir* or co opera ve inquir* or co-opera ve inquir*). ,ab,kf. or
(humanis c or existen al or experien al or paradigm*). ,ab,kf. or (field adj (study or
studies or research or work)). ,ab,kf. or (human science or social science). ,ab,kf. or
biographical method. ,ab,kf. or theore cal sampl*. ,ab,kf. or ((purpos* adj4 sampl*) or
(focus adj group*)). ,ab,kf. or (open-ended or narra ve* or textual or texts or semi-
structured). ,ab,kf. or (life world* or life-world* or conversa on analys?s or personal
experience* or theore cal satura on). ,ab,kf. or ((lived or life) adj experience*). ,ab,kf. or
cluster sampl*. ,ab,kf. or observa onal method*. ,ab,kf. or content analysis. ,ab,kf. or
(constant adj (compara ve or comparison)). ,ab,kf. or ((discourse* or discurs*) adj3
analys?s). ,ab,kf. or (heidegger* or colaizzi* or spiegelberg* or merleau* or husserl* or
foucault* or ricoeur or glaser*). ,ab,kf. or (van adj manen*). ,ab,kf. or (van adj
kaam*). ,ab,kf. or (corbin* adj2 strauss*). ,ab,kf.

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

212
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Table I.B.6. MeSH-only search of Ovid Medline for qualitative studies, initially March 23, 2023; rerun
April 11, 2023
Search step Query Results
#16 "Surveys and Ques onnaires"/ or Health Care Surveys/ or self report/ or 1,528,319
ques onnaire*. ,ab,kf. or survey*. ,ab,kf.
#17 15 or 16 2,432,307
#18 14 and 17 72

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

213
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Emtree-only Searches of Embase Conducted between March 21 and April
11, 2023

Table I.B.7. Emtree-only searches of Embase for systematic reviews, initially March 21, 2023; rerun
April 11, 2023
Search step Query Results

#1 'conference abstract'/it OR 'conference review'/it 4,724,785

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,111,455
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,712,617
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,337,688
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 922,017
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 35,827
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,475
#8 #7 NOT (#1 OR #2 OR #3) 996
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 757
#10 'systema c review':jt,ab,kw OR 'meta-analy*':jt,ab,kw OR metaanalys*:jt,ab,kw OR 858,830
(((systema c* OR comprehensive*) NEAR/3 (review* OR overview* OR literature OR
bibliographic)): ,ab,kw) OR ((systema c* NEAR/2 search*): ,ab,kw) OR ((methodologic*
NEAR/3 (review* OR overview*)): ,ab,kw) OR ((quan ta ve NEAR/3 (review* OR
overview* OR synthes*)): ,ab,kw) OR ((research NEAR/3 (integra * OR
overview*)): ,ab,kw) OR ((integra ve NEAR/3 (review* OR overview*)): ,ab,kw) OR
((collabora ve NEAR/3 (review* OR overview*)): ,ab,kw) OR ((pool* NEAR/3
analy*): ,ab,kw) OR 'data synthes*': ,ab,kw OR 'data extrac on*': ,ab,kw OR 'data
abstrac on*': ,ab,kw OR handsearch*: ,ab,kw OR 'hand search*': ,ab,kw OR 'mantel

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

214
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Table I.B.7. Emtree-only searches of Embase for systematic reviews, initially March 21, 2023; rerun
April 11, 2023
Search step Query Results
haenszel': ,ab,kw OR peto: ,ab,kw OR 'der simonian': ,ab,kw OR dersimonian: ,ab,kw OR
'fixed effect*': ,ab,kw OR 'la n square*': ,ab,kw OR 'met analy*': ,ab,kw OR
metanaly*: ,ab,kw OR 'technology assessment*': ,ab,kw OR hta: ,ab,kw OR htas: ,ab,kw
OR 'technology overview*': ,ab,kw OR 'technology appraisal*': ,ab,kw OR 'meta
regression*': ,ab,kw OR metaregression*: ,ab,kw OR medline: ,ab OR cochrane: ,ab OR
pubmed: ,ab OR medlars: ,ab OR embase: ,ab OR cinahl: ,ab OR psyclit:ab OR
(psycinfo:ab NOT 'psycinfo database':ab) OR scopus:ab OR 'sociological abstracts':ab OR
'web of science':ab OR cochrane:it OR ((health NEXT/2 'technology assessment'):it) OR
'evidence report':it OR ((compara ve NEXT/3 (efficacy OR effec veness)): ,ab,kw) OR
'outcomes research': ,ab,kw OR 'rela ve effec veness': ,ab,kw OR (((indirect OR 'indirect
treatment' OR 'mixed treatment' OR bayesian) NEXT/3 comparison*): ,ab,kw) OR ((mul *
NEXT/3 treatment NEXT/2 comparison*): ,ab,kw) OR 'umbrella review*': ,ab,kw OR
((mul paramet* NEXT/3 synthesis): ,ab,kw) OR (('mul paramet*' NEXT/3
synthesis): ,ab,kw)
#11 'systema c review'/exp OR 'meta analysis'/exp OR 'systema c review (topic)'/exp OR 'meta 593,824
analysis (topic)'/exp OR 'biomedical technology assessment'/exp
#12 #10 OR #11 988,917
#13 #9 AND #12 31
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 'conference abstract'/it OR 'conference review'/it 4,744,219

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,116,941
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,726,726
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,724
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 989,250
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp OR 'gonadorelin
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

215
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Table I.B.7. Emtree-only searches of Embase for systematic reviews, initially March 21, 2023; rerun
April 11, 2023
Search step Query Results
antagonist'/exp OR 'elagolix'/exp OR 'degarelix'/exp OR 'ganirelix'/exp OR 'elagolix plus
estradiol plus norethisterone acetate'/exp OR 'aromatase inhibitor'/exp OR 'selec ve
estrogen receptor modulator'/exp OR 'an estrogen'/exp OR 'progesterone receptor
modulator'/de OR 'ulipristal'/exp OR 'hormonal contracep ve agent'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,130
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,503
#8 #7 NOT (#1 OR #2 OR #3) 1,002
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 763
#10 'systema c review':jt,ab,kw OR 'meta-analy*':jt,ab,kw OR metaanalys*:jt,ab,kw OR 864,611
(((systema c* OR comprehensive*) NEAR/3 (review* OR overview* OR literature OR
bibliographic)): ,ab,kw) OR ((systema c* NEAR/2 search*): ,ab,kw) OR ((methodologic*
NEAR/3 (review* OR overview*)): ,ab,kw) OR ((quan ta ve NEAR/3 (review* OR
overview* OR synthes*)): ,ab,kw) OR ((research NEAR/3 (integra * OR
overview*)): ,ab,kw) OR ((integra ve NEAR/3 (review* OR overview*)): ,ab,kw) OR
((collabora ve NEAR/3 (review* OR overview*)): ,ab,kw) OR ((pool* NEAR/3
analy*): ,ab,kw) OR 'data synthes*': ,ab,kw OR 'data extrac on*': ,ab,kw OR 'data
abstrac on*': ,ab,kw OR handsearch*: ,ab,kw OR 'hand search*': ,ab,kw OR 'mantel
haenszel': ,ab,kw OR peto: ,ab,kw OR 'der simonian': ,ab,kw OR dersimonian: ,ab,kw OR
'fixed effect*': ,ab,kw OR 'la n square*': ,ab,kw OR 'met analy*': ,ab,kw OR
metanaly*: ,ab,kw OR 'technology assessment*': ,ab,kw OR hta: ,ab,kw OR htas: ,ab,kw
OR 'technology overview*': ,ab,kw OR 'technology appraisal*': ,ab,kw OR 'meta
regression*': ,ab,kw OR metaregression*: ,ab,kw OR medline: ,ab OR cochrane: ,ab OR
pubmed: ,ab OR medlars: ,ab OR embase: ,ab OR cinahl: ,ab OR psyclit:ab OR
(psycinfo:ab NOT 'psycinfo database':ab) OR scopus:ab OR 'sociological abstracts':ab OR
'web of science':ab OR cochrane:it OR ((health NEXT/2 'technology assessment'):it) OR
'evidence report':it OR ((compara ve NEXT/3 (efficacy OR effec veness)): ,ab,kw) OR
'outcomes research': ,ab,kw OR 'rela ve effec veness': ,ab,kw OR (((indirect OR 'indirect
treatment' OR 'mixed treatment' OR bayesian) NEXT/3 comparison*): ,ab,kw) OR ((mul *
NEXT/3 treatment NEXT/2 comparison*): ,ab,kw) OR 'umbrella review*': ,ab,kw OR
((mul paramet* NEXT/3 synthesis): ,ab,kw) OR (('mul paramet*' NEXT/3
synthesis): ,ab,kw)
#11 'systema c review'/exp OR 'meta analysis'/exp OR 'systema c review (topic)'/exp OR 'meta 597,972
analysis (topic)'/exp OR 'biomedical technology assessment'/exp
#12 #10 OR #11 995,437
#13 #9 AND #12 31

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

216
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Table I.B.8. Emtree-only searches of Embase for guidelines, initially March 23, 2023; rerun April 11,
2023
Search step Query Results

#1 'conference abstract'/it OR 'conference review'/it 4,727,606

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,112,070
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp 7,714,271
OR 'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,339,393
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex 922,697
hormone'/exp OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR
'gender affirming hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal
therapy'/exp OR 'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 35,864
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,482
#8 #7 NOT (#1 OR #2 OR #3) 996
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 757
#10 'clinical protocol'/exp OR 'consensus'/exp OR 'consensus development'/exp OR 'clinical 1,156,211
pathway'/exp OR 'guideline'/exp OR 'prac ce guideline'/exp OR 'clinical decision rule'/exp
OR 'posi on statement*': ,ab,kw OR 'policy statement*': ,ab,kw OR 'prac ce
parameter*': ,ab,kw OR 'best prac ce*': ,ab,kw OR 'standards': ,kw OR 'guideline': ,kw
OR 'guidelines': ,kw OR ((('prac ce' OR 'treatment*' OR 'clinical') NEXT/1 'guideline*'):ab)
OR 'cpg': OR 'cpgs': OR 'consensus*': ,kw OR ((('cri cal' OR 'clinical' OR 'prac ce')
NEXT/2 ('path' OR 'paths' OR 'pathway' OR 'pathways' OR 'protocol*')): ,ab,kw) OR
'recommendat*': ,kw OR 'guideline recommenda on*':ab OR (('care' NEAR/2 ('standard'
OR 'path' OR 'paths' OR 'pathway' OR 'pathways' OR 'map' OR 'maps' OR 'plan' OR
'plans')): ,ab,kw) OR (('algorithm*' NEAR/2 ('screening' OR 'examina on' OR 'test' OR
'tested' OR 'tes ng' OR 'assessment*' OR 'diagnosis' OR 'diagnoses' OR 'diagnosed' OR
'diagnosing')): ,ab,kw) OR (('algorithm*' NEAR/2 ('pharmacotherap*' OR 'chemotherap*'

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

217
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Table I.B.8. Emtree-only searches of Embase for guidelines, initially March 23, 2023; rerun April 11,
2023
Search step Query Results
OR 'chemotreatment*' OR 'therap*' OR 'treatment*' OR 'interven on*')): ,ab,kw) OR
'guideline*':au OR 'standards':au OR 'consensus*':au OR 'recommendat*':au
#11 #9 AND #10 110
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 'conference abstract'/it OR 'conference review'/it 4,744,219

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,116,941
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp 7,726,726
OR 'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,724
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex 989,250
hormone'/exp OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR
'gender affirming hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal
therapy'/exp OR 'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp OR
'gonadorelin antagonist'/exp OR 'elagolix'/exp OR 'degarelix'/exp OR 'ganirelix'/exp OR
'elagolix plus estradiol plus norethisterone acetate'/exp OR 'aromatase inhibitor'/exp OR
'selec ve estrogen receptor modulator'/exp OR 'an estrogen'/exp OR 'progesterone
receptor modulator'/de OR 'ulipristal'/exp OR 'hormonal contracep ve agent'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,130
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,503
#8 #7 NOT (#1 OR #2 OR #3) 1,002
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 763
#10 'clinical protocol'/exp OR 'consensus'/exp OR 'consensus development'/exp OR 'clinical 1,160,702
pathway'/exp OR 'guideline'/exp OR 'prac ce guideline'/exp OR 'clinical decision rule'/exp
OR 'posi on statement*': ,ab,kw OR 'policy statement*': ,ab,kw OR 'prac ce
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

218
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Table I.B.8. Emtree-only searches of Embase for guidelines, initially March 23, 2023; rerun April 11,
2023
Search step Query Results
parameter*': ,ab,kw OR 'best prac ce*': ,ab,kw OR 'standards': ,kw OR 'guideline': ,kw
OR 'guidelines': ,kw OR ((('prac ce' OR 'treatment*' OR 'clinical') NEXT/1 'guideline*'):ab)
OR 'cpg': OR 'cpgs': OR 'consensus*': ,kw OR ((('cri cal' OR 'clinical' OR 'prac ce')
NEXT/2 ('path' OR 'paths' OR 'pathway' OR 'pathways' OR 'protocol*')): ,ab,kw) OR
'recommendat*': ,kw OR 'guideline recommenda on*':ab OR (('care' NEAR/2 ('standard'
OR 'path' OR 'paths' OR 'pathway' OR 'pathways' OR 'map' OR 'maps' OR 'plan' OR
'plans')): ,ab,kw) OR (('algorithm*' NEAR/2 ('screening' OR 'examina on' OR 'test' OR
'tested' OR 'tes ng' OR 'assessment*' OR 'diagnosis' OR 'diagnoses' OR 'diagnosed' OR
'diagnosing')): ,ab,kw) OR (('algorithm*' NEAR/2 ('pharmacotherap*' OR 'chemotherap*'
OR 'chemotreatment*' OR 'therap*' OR 'treatment*' OR 'interven on*')): ,ab,kw) OR
'guideline*':au OR 'standards':au OR 'consensus*':au OR 'recommendat*':au
#11 #9 AND #10 110

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

219
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Table I.B.9. Emtree-only searches of Embase for experimental studies (eg, randomized controlled trials,
controlled clinical trials), initially March 31, 2023; rerun April 11, 2023
Search step Query Results

#1 'conference abstract'/it OR 'conference review'/it 4,736,809

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,114,206
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,719,652
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,344,127
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 924,277
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,036
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,497
#8 #7 NOT (#1 OR #2 OR #3) 998
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 759
#10 'randomized controlled trial'/exp OR 'randomized controlled trial (topic)'/exp OR 4,431,083
'controlled clinical trial'/exp OR 'controlled clinical trial (topic)'/exp OR 'clinical trial'/exp
OR 'clinical trial (topic)'/exp OR 'noninferiority trial'/exp OR 'randomiza on'/de OR
'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind
procedure'/exp OR 'placebo'/exp OR 'control group'/exp OR 'random*': ,ab,de,kw OR
'sham': ,ab,de,kw OR 'placebo*': ,ab,de,kw OR ((('singl*' OR 'doubl*') NEXT/1 ('blind*' OR
'dumm*' OR 'mask*')): ,ab,de,kw) OR ((('tripl*' OR 'trebl*') NEXT/1 ('blind*' OR 'dumm*'
OR 'mask*')): ,ab,de,kw) OR (('control*' NEAR/3 ('study' OR 'studies' OR 'trial*' OR
'group*')): ,ab,kw) OR 'nonrandom*': ,ab,de,kw OR 'non-random*': ,ab,de,kw OR 'quasi-
random*': ,ab,de,kw OR 'quasirandom*': ,ab,de,kw OR 'allocated': ,ab,de OR (('open-
label' NEAR/5 ('study' OR 'studies' OR 'trial*')): ,ab,de,kw) OR ((('equivalence' OR
'superiority' OR 'non-inferiority' OR 'noninferiority') NEAR/3 ('study' OR 'studies' OR
'trial*')): ,ab,de,kw) OR 'pragma c study': ,ab,de,kw OR 'pragma c studies': ,ab,de,kw
OR ((('pragma c' OR 'prac cal') NEAR/3 trial*): ,ab,de,kw) OR ((('quasiexperimental' OR
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

220
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Table I.B.9. Emtree-only searches of Embase for experimental studies (eg, randomized controlled trials,
controlled clinical trials), initially March 31, 2023; rerun April 11, 2023
Search step Query Results
'quasi-experimental') NEAR/3 ('study' OR 'studies' OR 'trial*')): ,ab,de,kw) OR ((('phase'
NEAR/3 ('iii' OR '3')): ,de,kw) AND ('study': ,de,kw OR 'studies': ,de,kw OR
'trial*': ,de,kw))
#11 #9 AND #10 55
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 'conference abstract'/it OR 'conference review'/it 4,744,219

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,116,941
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,726,726
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,724
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 989,250
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp OR 'gonadorelin
antagonist'/exp OR 'elagolix'/exp OR 'degarelix'/exp OR 'ganirelix'/exp OR 'elagolix plus
estradiol plus norethisterone acetate'/exp OR 'aromatase inhibitor'/exp OR 'selec ve
estrogen receptor modulator'/exp OR 'an estrogen'/exp OR 'progesterone receptor
modulator'/de OR 'ulipristal'/exp OR 'hormonal contracep ve agent'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,130
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,503
#8 #7 NOT (#1 OR #2 OR #3) 1,002
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 763
#10 'randomized controlled trial'/exp OR 'randomized controlled trial (topic)'/exp OR 4,437,758
'controlled clinical trial'/exp OR 'controlled clinical trial (topic)'/exp OR 'clinical trial'/exp
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

221
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Table I.B.9. Emtree-only searches of Embase for experimental studies (eg, randomized controlled trials,
controlled clinical trials), initially March 31, 2023; rerun April 11, 2023
Search step Query Results
OR 'clinical trial (topic)'/exp OR 'noninferiority trial'/exp OR 'randomiza on'/de OR
'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind
procedure'/exp OR 'placebo'/exp OR 'control group'/exp OR 'random*': ,ab,de,kw OR
'sham': ,ab,de,kw OR 'placebo*': ,ab,de,kw OR ((('singl*' OR 'doubl*') NEXT/1 ('blind*' OR
'dumm*' OR 'mask*')): ,ab,de,kw) OR ((('tripl*' OR 'trebl*') NEXT/1 ('blind*' OR 'dumm*'
OR 'mask*')): ,ab,de,kw) OR (('control*' NEAR/3 ('study' OR 'studies' OR 'trial*' OR
'group*')): ,ab,kw) OR 'nonrandom*': ,ab,de,kw OR 'non-random*': ,ab,de,kw OR 'quasi-
random*': ,ab,de,kw OR 'quasirandom*': ,ab,de,kw OR 'allocated': ,ab,de OR (('open-
label' NEAR/5 ('study' OR 'studies' OR 'trial*')): ,ab,de,kw) OR ((('equivalence' OR
'superiority' OR 'non-inferiority' OR 'noninferiority') NEAR/3 ('study' OR 'studies' OR
'trial*')): ,ab,de,kw) OR 'pragma c study': ,ab,de,kw OR 'pragma c studies': ,ab,de,kw
OR ((('pragma c' OR 'prac cal') NEAR/3 trial*): ,ab,de,kw) OR ((('quasiexperimental' OR
'quasi-experimental') NEAR/3 ('study' OR 'studies' OR 'trial*')): ,ab,de,kw) OR ((('phase'
NEAR/3 ('iii' OR '3')): ,de,kw) AND ('study': ,de,kw OR 'studies': ,de,kw OR
'trial*': ,de,kw))
#11 #9 AND #10 56

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

222
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Table I.B.10. Emtree-only searches of Embase for observational and descriptive studies, initially April
7, 2023; rerun April 11, 2023
Step search Query Results

#1 'conference abstract'/it OR 'conference review'/it 4,742,383

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR 3,116,800
castoris: OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs:
OR equine: OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR
mouse: OR murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*:
OR purebred: OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR
thoroughbred: OR veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp 7,726,377
OR 'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,298
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex 925,060
hormone'/exp OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR
'gender affirming hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal
therapy'/exp OR 'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,122
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR
'gender variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp
OR 'transsexuality'/exp
#7 #4 AND #5 AND #6 1,500
#8 #7 NOT (#1 OR #2 OR #3) 1,001
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 762
#10 'epidemiology'/de OR 'observa onal study'/de OR 'clinical study'/exp OR 'cross-sec onal 19,514,851
study'/exp OR 'seroepidemiology'/exp OR 'na onal longitudinal study of adolescent
health'/de OR 'cohort analysis'/de OR 'longitudinal study'/de OR 'prospec ve study'/de
OR 'follow up'/de OR 'retrospec ve study'/de OR 'case control study'/exp OR 'quasi
experimental study'/de OR 'single-case study'/de OR 'valida on study'/de OR 'pilot
study'/de OR 'controlled study'/de OR 'pretest pos est control group design'/de OR
'compara ve study'/de OR 'compara ve effec veness'/de OR (('observa onal' NEAR/3
('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR
'cohort*': ,ab,kw OR (('prospec ve' NEAR/7 ('study' OR 'studies' OR 'design' OR
'analysis' OR 'analyses')): ,ab,kw) OR ((('follow up' OR 'followup') NEAR/7 ('study' OR
'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR ((('longitudinal' OR
'longterm' OR 'long-term') NEAR/7 ('study' OR 'studies' OR 'design' OR 'analysis' OR
'analyses' OR 'data')): ,ab,kw) OR (('retrospec ve' NEAR/7 ('study' OR 'studies' OR
'design' OR 'analysis' OR 'analyses' OR 'data' OR 'review')): ,ab,kw) OR (('case' NEXT/1
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

223
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Table I.B.10. Emtree-only searches of Embase for observational and descriptive studies, initially April
7, 2023; rerun April 11, 2023
Step search Query Results
'control'): ,ab,kw) OR (('case' NEXT/1 'comparison'): ,ab,kw) OR (('case' NEXT/1
'controlled'): ,ab,kw) OR (('case-referent' NEAR/3 ('study' OR 'studies' OR 'design' OR
'analysis' OR 'analyses')): ,ab,kw) OR (('popula on' NEAR/3 ('study' OR 'studies' OR
'analysis' OR 'analyses')): ,ab,kw) OR (('descrip ve' NEAR/3 ('study' OR 'studies' OR
'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR ((('mul dimensional' OR 'mul -
dimensional') NEAR/3 ('study' OR 'studies' OR 'design' OR 'analysis' OR
'analyses')): ,ab,kw) OR (('cross-sec onal' NEAR/7 ('study' OR 'studies' OR 'design' OR
'research' OR 'analysis' OR 'analyses' OR 'survey' OR 'findings')): ,ab,kw) OR (('natural'
NEXT/1 'experiment'): ,ab,kw) OR (('natural' NEXT/1 'experiments'): ,ab,kw) OR
(('quasi' NEXT/1 ('experiment' OR 'experiments' OR 'experimental')): ,ab,kw) OR ((('non
experiment' OR 'nonexperiment' OR 'non experimental' OR 'nonexperimental') NEAR/3
('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR (('prevalence'
NEAR/3 ('study' OR 'studies' OR 'analysis' OR 'analyses')): ,ab,kw) OR 'case
series': ,ab,kw OR 'case report'/de OR 'case study'/exp OR (('case' NEAR/3 ('report' OR
'reports' OR 'study' OR 'studies' OR 'histories')): ,ab,kw) OR 'health services
research'/de
#11 #9 AND #10 448
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 'conference abstract'/it OR 'conference review'/it 4,744,219

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR 3,116,941
castoris: OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs:
OR equine: OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR
mouse: OR murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*:
OR purebred: OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR
thoroughbred: OR veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp 7,726,726
OR 'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,724
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex 989,250
hormone'/exp OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR
'gender affirming hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal
therapy'/exp OR 'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp OR
'gonadorelin antagonist'/exp OR 'elagolix'/exp OR 'degarelix'/exp OR 'ganirelix'/exp OR

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

224
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Table I.B.10. Emtree-only searches of Embase for observational and descriptive studies, initially April
7, 2023; rerun April 11, 2023
Step search Query Results
'elagolix plus estradiol plus norethisterone acetate'/exp OR 'aromatase inhibitor'/exp OR
'selec ve estrogen receptor modulator'/exp OR 'an estrogen'/exp OR 'progesterone
receptor modulator'/de OR 'ulipristal'/exp OR 'hormonal contracep ve agent'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,130
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR
'gender variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp
OR 'transsexuality'/exp
#7 #4 AND #5 AND #6 1,503
#8 #7 NOT (#1 OR #2 OR #3) 1,002
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 763
#10 'epidemiology'/de OR 'observa onal study'/de OR 'clinical study'/exp OR 'cross-sec onal 19,517,871
study'/exp OR 'seroepidemiology'/exp OR 'na onal longitudinal study of adolescent
health'/de OR 'cohort analysis'/de OR 'longitudinal study'/de OR 'prospec ve study'/de
OR 'follow up'/de OR 'retrospec ve study'/de OR 'case control study'/exp OR 'quasi
experimental study'/de OR 'single-case study'/de OR 'valida on study'/de OR 'pilot
study'/de OR 'controlled study'/de OR 'pretest pos est control group design'/de OR
'compara ve study'/de OR 'compara ve effec veness'/de OR (('observa onal' NEAR/3
('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR
'cohort*': ,ab,kw OR (('prospec ve' NEAR/7 ('study' OR 'studies' OR 'design' OR
'analysis' OR 'analyses')): ,ab,kw) OR ((('follow up' OR 'followup') NEAR/7 ('study' OR
'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR ((('longitudinal' OR
'longterm' OR 'long-term') NEAR/7 ('study' OR 'studies' OR 'design' OR 'analysis' OR
'analyses' OR 'data')): ,ab,kw) OR (('retrospec ve' NEAR/7 ('study' OR 'studies' OR
'design' OR 'analysis' OR 'analyses' OR 'data' OR 'review')): ,ab,kw) OR (('case' NEXT/1
'control'): ,ab,kw) OR (('case' NEXT/1 'comparison'): ,ab,kw) OR (('case' NEXT/1
'controlled'): ,ab,kw) OR (('case-referent' NEAR/3 ('study' OR 'studies' OR 'design' OR
'analysis' OR 'analyses')): ,ab,kw) OR (('popula on' NEAR/3 ('study' OR 'studies' OR
'analysis' OR 'analyses')): ,ab,kw) OR (('descrip ve' NEAR/3 ('study' OR 'studies' OR
'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR ((('mul dimensional' OR 'mul -
dimensional') NEAR/3 ('study' OR 'studies' OR 'design' OR 'analysis' OR
'analyses')): ,ab,kw) OR (('cross-sec onal' NEAR/7 ('study' OR 'studies' OR 'design' OR
'research' OR 'analysis' OR 'analyses' OR 'survey' OR 'findings')): ,ab,kw) OR (('natural'
NEXT/1 'experiment'): ,ab,kw) OR (('natural' NEXT/1 'experiments'): ,ab,kw) OR
(('quasi' NEXT/1 ('experiment' OR 'experiments' OR 'experimental')): ,ab,kw) OR ((('non
experiment' OR 'nonexperiment' OR 'non experimental' OR 'nonexperimental') NEAR/3
('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR (('prevalence'
NEAR/3 ('study' OR 'studies' OR 'analysis' OR 'analyses')): ,ab,kw) OR 'case
series': ,ab,kw OR 'case report'/de OR 'case study'/exp OR (('case' NEAR/3 ('report' OR
'reports' OR 'study' OR 'studies' OR 'histories')): ,ab,kw) OR 'health services
research'/de
#11 #9 AND #10 449

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

225
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Table I.B.11. Emtree-only searches of Embase for qualitative studies, initially April 7, 2023; rerun April
11, 2023
Search step Query Results

#1 'conference abstract'/it OR 'conference review'/it 4,742,383

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,116,800
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,726,377
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,298
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 925,060
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,122
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,500
#8 #7 NOT (#1 OR #2 OR #3) 1,001
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 762
#10 'empirical research'/exp OR 'interview'/exp OR 'literature'/exp OR 'focus group'/exp OR 4,231,970
'informa on processing'/exp OR 'verbal communica on'/exp OR 'nursing methodology
research'/de OR 'narra ve medicine'/de OR 'interview*': ,ab,kw OR 'qualita ve': ,ab,kw,jt
OR 'theme*': ,ab,kw OR 'thema c': ,ab,kw OR 'ethnological research': ,ab,kw OR
'ethnograph*': ,ab,kw OR 'ethnomedicine': ,ab,kw OR 'ethnonursing': ,ab,kw OR
'phenomenol*': ,ab,kw OR (('grounded' NEXT/1 ('theor*' OR 'study' OR 'studies' OR
'research' OR 'analys?s')): ,ab,kw) OR 'life stor*': ,ab,kw OR 'emic': ,ab,kw OR
'e c': ,ab,kw OR 'hermeneu c*': ,ab,kw OR 'heuris c*': ,ab,kw OR 'semio c*': ,ab,kw
OR (('data' NEAR/1 'saturat*'): ,ab,kw) OR 'par cipant observ*': ,ab,kw OR 'social
construct*': ,ab,kw OR 'postmodern*': ,ab,kw OR 'post-structural*': ,ab,kw OR
'poststructural*': ,ab,kw OR 'post-modern*': ,ab,kw OR 'ac on research': ,ab,kw OR
'coopera ve inquir*': ,ab,kw OR 'co-opera ve inquir*': ,ab,kw OR 'humanis c': ,ab,kw
OR 'existen al': ,ab,kw OR 'experien al': ,ab,kw OR 'paradigm*': ,ab,kw OR (('field'
NEXT/1 ('study' OR 'studies' OR 'research' OR 'work')): ,ab,kw) OR 'human
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

227
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Table I.B.11. Emtree-only searches of Embase for qualitative studies, initially April 7, 2023; rerun April
11, 2023
Search step Query Results
science': ,ab,kw OR 'social science': ,ab,kw OR 'biographical method': ,ab,kw OR
'theore cal sampl*': ,ab,kw OR (('purpos*' NEAR/4 'sampl*'): ,ab,kw) OR (('focus' NEXT/1
'group*'): ,ab,kw) OR 'open-ended': ,ab,kw OR 'narra ve*': ,ab,kw OR 'textual': ,ab,kw
OR 'texts': ,ab,kw OR 'semi-structured': ,ab,kw OR 'life-world*': ,ab,kw OR 'conversa on
analys?s': ,ab,kw OR 'personal experience*': ,ab,kw OR 'theore cal satura on': ,ab,kw
OR ((('lived' OR 'life') NEXT/1 'experience*'): ,ab,kw) OR 'cluster sampl*': ,ab,kw OR
'observa onal method*': ,ab,kw OR 'content analysis': ,ab,kw OR (('constant' NEXT/1
('compara ve' OR 'comparison')): ,ab,kw) OR ((('discourse*' OR 'discurs*') NEAR/3
'analys?s'): ,ab,kw) OR 'heidegger*': ,ab,kw OR 'colaizzi*': ,ab,kw OR
'spiegelberg*': ,ab,kw OR 'merleau*': ,ab,kw OR 'husserl*': ,ab,kw OR
'foucault*': ,ab,kw OR 'ricoeur': ,ab,kw OR 'glaser*': ,ab,kw OR (('van' NEXT/1
'manen*'): ,ab,kw) OR (('van' NEXT/1 'kaam*'): ,ab,kw) OR (('corbin*' NEAR/2
'strauss*'): ,ab,kw)
#11 'ques onnaire'/exp OR 'health care survey'/de OR 'self report'/de OR 2,055,085
'ques onnaire*': ,ab,kw OR 'survey*': ,ab,kw
#12 #10 OR #11 5,744,629
#13 #9 AND #12 158
We re-ran the searches to include addi onal agents for menstrual suppression that were missing from our ini al
literature searches. We used informa on from Grimstad et al (2021)81 to inform which agents should be included,
and we added other agents in the same drug classes (per Lexicomp).28 Deduplica on was performed in Covidence.

#1 'conference abstract'/it OR 'conference review'/it 4,744,219

#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,116,941
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,726,726
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'pediatrics'/exp OR 'pediatric'/exp OR 4,348,724
'child'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp OR
'preadolescence'/exp
#5 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 989,250
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'gender dysphoria'/exp/dd_dt OR 'puberty suppression'/exp OR 'gonadorelin
antagonist'/exp OR 'elagolix'/exp OR 'degarelix'/exp OR 'ganirelix'/exp OR 'elagolix plus
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

228
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Table I.B.11. Emtree-only searches of Embase for qualitative studies, initially April 7, 2023; rerun April
11, 2023
Search step Query Results
estradiol plus norethisterone acetate'/exp OR 'aromatase inhibitor'/exp OR 'selec ve
estrogen receptor modulator'/exp OR 'an estrogen'/exp OR 'progesterone receptor
modulator'/de OR 'ulipristal'/exp OR 'hormonal contracep ve agent'/exp
#6 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,130
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#7 #4 AND #5 AND #6 1,503
#8 #7 NOT (#1 OR #2 OR #3) 1,002
#9 #7 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 763
#10 'empirical research'/exp OR 'interview'/exp OR 'literature'/exp OR 'focus group'/exp OR 4,232,886
'informa on processing'/exp OR 'verbal communica on'/exp OR 'nursing methodology
research'/de OR 'narra ve medicine'/de OR 'interview*': ,ab,kw OR 'qualita ve': ,ab,kw,jt
OR 'theme*': ,ab,kw OR 'thema c': ,ab,kw OR 'ethnological research': ,ab,kw OR
'ethnograph*': ,ab,kw OR 'ethnomedicine': ,ab,kw OR 'ethnonursing': ,ab,kw OR
'phenomenol*': ,ab,kw OR (('grounded' NEXT/1 ('theor*' OR 'study' OR 'studies' OR
'research' OR 'analys?s')): ,ab,kw) OR 'life stor*': ,ab,kw OR 'emic': ,ab,kw OR
'e c': ,ab,kw OR 'hermeneu c*': ,ab,kw OR 'heuris c*': ,ab,kw OR 'semio c*': ,ab,kw
OR (('data' NEAR/1 'saturat*'): ,ab,kw) OR 'par cipant observ*': ,ab,kw OR 'social
construct*': ,ab,kw OR 'postmodern*': ,ab,kw OR 'post-structural*': ,ab,kw OR
'poststructural*': ,ab,kw OR 'post-modern*': ,ab,kw OR 'ac on research': ,ab,kw OR
'coopera ve inquir*': ,ab,kw OR 'co-opera ve inquir*': ,ab,kw OR 'humanis c': ,ab,kw
OR 'existen al': ,ab,kw OR 'experien al': ,ab,kw OR 'paradigm*': ,ab,kw OR (('field'
NEXT/1 ('study' OR 'studies' OR 'research' OR 'work')): ,ab,kw) OR 'human
science': ,ab,kw OR 'social science': ,ab,kw OR 'biographical method': ,ab,kw OR
'theore cal sampl*': ,ab,kw OR (('purpos*' NEAR/4 'sampl*'): ,ab,kw) OR (('focus' NEXT/1
'group*'): ,ab,kw) OR 'open-ended': ,ab,kw OR 'narra ve*': ,ab,kw OR 'textual': ,ab,kw
OR 'texts': ,ab,kw OR 'semi-structured': ,ab,kw OR 'life-world*': ,ab,kw OR 'conversa on
analys?s': ,ab,kw OR 'personal experience*': ,ab,kw OR 'theore cal satura on': ,ab,kw
OR ((('lived' OR 'life') NEXT/1 'experience*'): ,ab,kw) OR 'cluster sampl*': ,ab,kw OR
'observa onal method*': ,ab,kw OR 'content analysis': ,ab,kw OR (('constant' NEXT/1
('compara ve' OR 'comparison')): ,ab,kw) OR ((('discourse*' OR 'discurs*') NEAR/3
'analys?s'): ,ab,kw) OR 'heidegger*': ,ab,kw OR 'colaizzi*': ,ab,kw OR
'spiegelberg*': ,ab,kw OR 'merleau*': ,ab,kw OR 'husserl*': ,ab,kw OR
'foucault*': ,ab,kw OR 'ricoeur': ,ab,kw OR 'glaser*': ,ab,kw OR (('van' NEXT/1
'manen*'): ,ab,kw) OR (('van' NEXT/1 'kaam*'): ,ab,kw) OR (('corbin*' NEAR/2
'strauss*'): ,ab,kw)
#11 'ques onnaire'/exp OR 'health care survey'/de OR 'self report'/de OR 2,055,402
'ques onnaire*': ,ab,kw OR 'survey*': ,ab,kw
#12 #10 OR #11 5,745,753

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

229
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Table I.B.11. Emtree-only searches of Embase for qualitative studies, initially April 7, 2023; rerun April
11, 2023
Search step Query Results
#13 #9 AND #12 158

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

230
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Free Text and Controlled Vocabulary Searches of Ovid Medline
Conducted between May 15 and June 5, 2023

Table I.B.12. Free text and controlled vocabulary search of Ovid Medline for systematic reviews, May
15, 2023
Search step Query Results
#1 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,154,915
#2 (adolescen* or boy* or girl* or child or children or juvenile or minors or paediatr* or 2,138,237
pediatr* or pre-pubertal or prepubertal or pre-pubesc* or prepubesc* or pubesc* or
pubertal or puberty or teen* or youth* or school-aged). ,ab,kw,kf.
#3 (adolescen* or child* or paediatr* or pediatr*).jn. 295,441
#4 1 or 2 or 3 4,019,870
#5 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 367,058
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/ or exp Androgen antagonists/ or
Bicalutamide/ or Finasteride/ or Dutasteride/ or exp Cyproterone/ or Spironolactone/
#6 Gender dysphoria/dt or Gender dysphoria/th or Transsexualism/dt or Transsexualism/th 983
#7 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,360
#8 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,589
Ospemifene/ or Bazedoxifene/
#9 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,600
#10 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#11 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,197
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#12 (gn-rh* or gnrh* or gonadotropin-releasing hormone* or 5-alpha reductase inhibitor* 35,168
or 5alpha reductase inhibitor* or goserelin or histrelin or leuprolide or leuprorelin or
nafarelin or triptorelin or elagolix or cetrorelix or degarelix or ganirelix or
relugolix). ,ab,kw,kf.
#13 (puberty adj3 (inhibit* or block* or suppress*)). ,ab,kw,kf. 455
#14 (an androgen* or an -androgen* or bicalutamide or finasteride or dutasteride or 21,514
spironolactone or flutamide or nilutamide). ,ab,kw,kf.
#15 (androgen adj3 (antagonist* or inhibit* or block*)). ,ab,kw,kf. 5,895
#16 (sex hormon* or sex steroid hormon* or gonadal steroid* or androgen* or androst* or 447,368
estrogen* or oestrogen* or estradiol* or oestradiol* or dehydroepiandrosterone or
prasterone or dhea or dihydrotestosterone or dht or dihydroprogesterone or
dihydroepitestosterone or epiandrosterone or epitestosterone or epiestriol or equilenin
or equilin or estrane* or estrenolone or estrone or e ocholanolone or folliculin or
gestagen* or hermaphrodiol or hydroxyestrone* or hydroxypregnenolone* or
hydroxysteroid* or hydroxytestosterone* or isotestosterone or ketosteroid* or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

231
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Table I.B.12. Free text and controlled vocabulary search of Ovid Medline for systematic reviews, May
15, 2023
Search step Query Results
medroxyprogesterone or mestranol or methyltestosterone or danazol or nandrolone or
nortestosterone or oxosteroid* or pregnenolone* or progesta onal hormon* or
progest* or quinestrol or stanolone or testosterone or dydrogesterone or levonorgestrel
or dienogest or norethindrone or norges mate or drospirenone or desogestrel or
etonogestrel or norelgestromin or norgestrel or segesterone or ethynodiol). ,ab,kw,kf.
#17 (hormon* adj3 (replacement or suppress* or therap* or treat* or cross-sex or gender- 80,109
affirming)). ,ab,kw,kf.
#18 (gender-affirming pharmaceu cal* or contracep ve*). ,ab,kw,kf. 65,678
#19 (aromatase inhibitor* or anastrozole or exemestane or letrozole). ,ab,kw,kf. 11,606
#20 (selec ve estrogen receptor modulator* or serm or an estrogen* or an -estrogen* or 40,545
bazedoxifene or clomiphene or clomifene or ospemifene or raloxifene or tamoxifen or
toremifene). ,ab,kw,kf.
#21 (proges n receptor modulator* or ulipristal or minoxidil). ,ab,kw,kf. 2,784
#22 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 676,692
21
#23 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,387
#24 (gender dysphor* or 'gender minorit* or gender divers* or gender iden ty or gender 18,789
incongruenc* or gender transi on* or trans-female* or transfemale* or trans-feminine
or transfeminine or trans-gender* or transgender* or trans-sexual* or transsex* or
trans-male* or transmale* or trans-masculine or transmasculine or transboy* or
transgirl*). ,ab,kw,kf.
#25 (gender adj1 (affirm* or confirm* or reassign*)). ,ab,kw,kf. 2,964
#26 ((sex or medical) adj1 (reassign* or transi on*)). ,ab,kw,kf. 887
#27 23 or 24 or 25 or 26 37,984
#28 4 and 22 and 27 1,686
#29 28 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or 1,667
dogs or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#30 limit 29 to yr = "2010 -Current" 1,133
#31 (((comprehensive* or integra ve or systema c*) adj3 (bibliographic* or review* or 721,963
literature)) or ("research synthesis" or ((informa on or data) adj3 synthesis) or (data
adj2 extract*))). ,ab. or (cinahl or embase or medline or psyclit or (psycinfo not
"psycinfo database") or pubmed or scopus or "sociological abstracts" or "web of
science").ab. or ("cochrane database of systema c reviews" or evidence report
technology assessment or evidence report technology assessment summary).jn. or
Evidence Report: Technology Assessment*.jn. or ((review adj5 (ra onale or
evidence)). ,ab. and review.pt.) or meta-analysis as topic/ or Meta-Analysis.pt. or meta-
analysis/ or (metaanaly$ or meta-analy$). ,ab,kw,kf. or "Systema c Review"/ or
((systema c* adj3 review*) or (systema c* adj2 search*) or cochrane$ or (overview

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

232
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Table I.B.12. Free text and controlled vocabulary search of Ovid Medline for systematic reviews, May
15, 2023
Search step Query Results
adj4 review)). ,ab,kw,kf. or (cochrane$ or systema c-review?).jw. or systema c
review.tw. or meta-analysis.pt.
#32 30 and 31 54

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

233
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Table I.B.13. Free text and controlled vocabulary search of Ovid Medline for guidelines, May 15, 2023
Search step Query Results
#1 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,154,915
#2 (adolescen* or boy* or girl* or child or children or juvenile or minors or paediatr* or 2,138,237
pediatr* or pre-pubertal or prepubertal or pre-pubesc* or prepubesc* or pubesc* or
pubertal or puberty or teen* or youth* or school-aged). ,ab,kw,kf.
#3 (adolescen* or child* or paediatr* or pediatr*).jn. 295,441
#4 1 or 2 or 3 4,019,870
#5 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 367,058
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/ or exp Androgen antagonists/ or
Bicalutamide/ or Finasteride/ or Dutasteride/ or exp Cyproterone/ or Spironolactone/
#6 Gender dysphoria/dt or Gender dysphoria/th or Transsexualism/dt or Transsexualism/th 983
#7 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,360
#8 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,589
Ospemifene/ or Bazedoxifene/
#9 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,600
#10 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#11 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,197
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#12 (gn-rh* or gnrh* or gonadotropin-releasing hormone* or 5-alpha reductase inhibitor* or 35,168
5alpha reductase inhibitor* or goserelin or histrelin or leuprolide or leuprorelin or
nafarelin or triptorelin or elagolix or cetrorelix or degarelix or ganirelix or
relugolix). ,ab,kw,kf.
#13 (puberty adj3 (inhibit* or block* or suppress*)). ,ab,kw,kf. 455
#14 (an androgen* or an -androgen* or bicalutamide or finasteride or dutasteride or 21,514
spironolactone or flutamide or nilutamide). ,ab,kw,kf.
#15 (androgen adj3 (antagonist* or inhibit* or block*)). ,ab,kw,kf. 5,895
#16 (sex hormon* or sex steroid hormon* or gonadal steroid* or androgen* or androst* or 447,368
estrogen* or oestrogen* or estradiol* or oestradiol* or dehydroepiandrosterone or
prasterone or dhea or dihydrotestosterone or dht or dihydroprogesterone or
dihydroepitestosterone or epiandrosterone or epitestosterone or epiestriol or equilenin
or equilin or estrane* or estrenolone or estrone or e ocholanolone or folliculin or
gestagen* or hermaphrodiol or hydroxyestrone* or hydroxypregnenolone* or
hydroxysteroid* or hydroxytestosterone* or isotestosterone or ketosteroid* or
medroxyprogesterone or mestranol or methyltestosterone or danazol or nandrolone or
nortestosterone or oxosteroid* or pregnenolone* or progesta onal hormon* or progest*
or quinestrol or stanolone or testosterone or dydrogesterone or levonorgestrel or
dienogest or norethindrone or norges mate or drospirenone or desogestrel or
etonogestrel or norelgestromin or norgestrel or segesterone or ethynodiol). ,ab,kw,kf.
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

234
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Table I.B.13. Free text and controlled vocabulary search of Ovid Medline for guidelines, May 15, 2023
Search step Query Results
#17 (hormon* adj3 (replacement or suppress* or therap* or treat* or cross-sex or gender- 80,109
affirming)). ,ab,kw,kf.
#18 (gender-affirming pharmaceu cal* or contracep ve*). ,ab,kw,kf. 65,678
#19 (aromatase inhibitor* or anastrozole or exemestane or letrozole). ,ab,kw,kf. 11,606
#20 (selec ve estrogen receptor modulator* or serm or an estrogen* or an -estrogen* or 40,545
bazedoxifene or clomiphene or clomifene or ospemifene or raloxifene or tamoxifen or
toremifene). ,ab,kw,kf.
#21 (proges n receptor modulator* or ulipristal or minoxidil). ,ab,kw,kf. 2,784
#22 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 676,692
#23 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,387
#24 (gender dysphor* or 'gender minorit* or gender divers* or gender iden ty or gender 18,789
incongruenc* or gender transi on* or trans-female* or transfemale* or trans-feminine
or transfeminine or trans-gender* or transgender* or trans-sexual* or transsex* or trans-
male* or transmale* or trans-masculine or transmasculine or transboy* or
transgirl*). ,ab,kw,kf.
#25 (gender adj1 (affirm* or confirm* or reassign*)). ,ab,kw,kf. 2,964
#26 ((sex or medical) adj1 (reassign* or transi on*)). ,ab,kw,kf. 887
#27 23 or 24 or 25 or 26 37,984
#28 4 and 22 and 27 1,686
#29 28 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 1,667
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#30 limit 29 to yr = "2010 -Current" 1,133
#31 exp clinical pathway/ or exp clinical protocol/ or clinical protocols/ or exp consensus/ or 743,713
exp consensus development conference/ or exp consensus development conferences as
topic/ or cri cal pathways/ or exp guideline/ or guidelines as topic/ or exp prac ce
guideline/ or prac ce guidelines as topic/ or health planning guidelines/ or Clinical
Decision Rules/ or (guideline or prac ce guideline or consensus development conference
or consensus development conference, NIH).pt. or (posi on statement* or policy
statement* or prac ce parameter* or best prac ce*). ,ab,kf. or (standards or guideline
or guidelines). ,kf. or ((prac ce or treatment* or clinical) adj guideline*).ab. or (CPG or
CPGs). . or consensus*. ,kf. or consensus*.ab. /freq = 2 or ((cri cal or clinical or prac ce)
adj2 (path or paths or pathway or pathways or protocol*)). ,ab,kf. or recommendat*. ,kf.
or guideline recommenda on*.ab. or (care adj2 (standard or path or paths or pathway or
pathways or map or maps or plan or plans)). ,ab,kf. or (algorithm* adj2 (screening or
examina on or test or tested or tes ng or assessment* or diagnosis or diagnoses or
diagnosed or diagnosing)). ,ab,kf. or (algorithm* adj2 (pharmacotherap* or
chemotherap* or chemotreatment* or therap* or treatment* or interven on*)). ,ab,kf.
or (guideline* or standards or consensus* or recommendat*).au.
#32 30 and 31 112
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

235
Return to TOC
Table I.B.14. Free text and controlled vocabulary search of Ovid Medline for randomized controlled
trials, May 22, 2023
Search step Query Results
#1 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,156,084
#2 (adolescen* or boy* or girl* or child or children or juvenile or minors or paediatr* or 2,140,449
pediatr* or pre-pubertal or prepubertal or pre-pubesc* or prepubesc* or pubesc* or
pubertal or puberty or teen* or youth* or school-aged). ,ab,kw,kf.
#3 (adolescen* or child* or paediatr* or pediatr*).jn. 295,801
#4 1 or 2 or 3 4,022,329
#5 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 367,170
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/ or exp Androgen antagonists/ or
Bicalutamide/ or Finasteride/ or Dutasteride/ or exp Cyproterone/ or Spironolactone/
#6 Gender dysphoria/dt or Gender dysphoria/th or Transsexualism/dt or Transsexualism/th 981
#7 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,360
#8 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,603
Ospemifene/ or Bazedoxifene/
#9 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,611
#10 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#11 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,202
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#12 (gn-rh* or gnrh* or gonadotropin-releasing hormone* or 5-alpha reductase inhibitor* or 35,198
5alpha reductase inhibitor* or goserelin or histrelin or leuprolide or leuprorelin or
nafarelin or triptorelin or elagolix or cetrorelix or degarelix or ganirelix or
relugolix). ,ab,kw,kf.
#13 (puberty adj3 (inhibit* or block* or suppress*)). ,ab,kw,kf. 455
#14 (an androgen* or an -androgen* or bicalutamide or finasteride or dutasteride or 21,533
spironolactone or flutamide or nilutamide). ,ab,kw,kf.
#15 (androgen adj3 (antagonist* or inhibit* or block*)). ,ab,kw,kf. 5,898
#16 (sex hormon* or sex steroid hormon* or gonadal steroid* or androgen* or androst* or 447,681
estrogen* or oestrogen* or estradiol* or oestradiol* or dehydroepiandrosterone or
prasterone or dhea or dihydrotestosterone or dht or dihydroprogesterone or
dihydroepitestosterone or epiandrosterone or epitestosterone or epiestriol or equilenin or
equilin or estrane* or estrenolone or estrone or e ocholanolone or folliculin or gestagen*
or hermaphrodiol or hydroxyestrone* or hydroxypregnenolone* or hydroxysteroid* or
hydroxytestosterone* or isotestosterone or ketosteroid* or medroxyprogesterone or
mestranol or methyltestosterone or danazol or nandrolone or nortestosterone or
oxosteroid* or pregnenolone* or progesta onal hormon* or progest* or quinestrol or
stanolone or testosterone or dydrogesterone or levonorgestrel or dienogest or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

236
Return to TOC
Table I.B.14. Free text and controlled vocabulary search of Ovid Medline for randomized controlled
trials, May 22, 2023
Search step Query Results
norethindrone or norges mate or drospirenone or desogestrel or etonogestrel or
norelgestromin or norgestrel or segesterone or ethynodiol). ,ab,kw,kf.
#17 (hormon* adj3 (replacement or suppress* or therap* or treat* or cross-sex or gender- 80,188
affirming)). ,ab,kw,kf.
#18 (gender-affirming pharmaceu cal* or contracep ve*). ,ab,kw,kf. 65,705
#19 (aromatase inhibitor* or anastrozole or exemestane or letrozole). ,ab,kw,kf. 11,634
#20 (selec ve estrogen receptor modulator* or serm or an estrogen* or an -estrogen* or 40,576
bazedoxifene or clomiphene or clomifene or ospemifene or raloxifene or tamoxifen or
toremifene). ,ab,kw,kf.
#21 (proges n receptor modulator* or ulipristal or minoxidil). ,ab,kw,kf. 2,792
#22 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 677,117
#23 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,396
#24 (gender dysphor* or 'gender minorit* or gender divers* or gender iden ty or gender 18,839
incongruenc* or gender transi on* or trans-female* or transfemale* or trans-feminine or
transfeminine or trans-gender* or transgender* or trans-sexual* or transsex* or trans-
male* or transmale* or trans-masculine or transmasculine or transboy* or
transgirl*). ,ab,kw,kf.
#25 (gender adj1 (affirm* or confirm* or reassign*)). ,ab,kw,kf. 2,980
#26 ((sex or medical) adj1 (reassign* or transi on*)). ,ab,kw,kf. 887
#27 23 or 24 or 25 or 26 38,036
#28 4 and 22 and 27 1,688
#29 28 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 1,669
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#30 limit 29 to yr = "2010 -Current" 1,135
#31 (randomized controlled trial or controlled clinical trial).pt. or randomi#ed.ab. or 1,568,977
placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial. .
#32 30 and 31 14

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

237
Return to TOC
Table I.B.15. Free text and controlled vocabulary search of Ovid Medline for randomized controlled
trials, May 22, 2023
Search step Query Results
#1 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,156,084
#2 (adolescen* or boy* or girl* or child or children or juvenile or minors or paediatr* or 2,140,449
pediatr* or pre-pubertal or prepubertal or pre-pubesc* or prepubesc* or pubesc* or
pubertal or puberty or teen* or youth* or school-aged). ,ab,kw,kf.
#3 (adolescen* or child* or paediatr* or pediatr*).jn. 295,801
#4 1 or 2 or 3 4,022,329
#5 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 367,170
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/ or exp Androgen antagonists/ or
Bicalutamide/ or Finasteride/ or Dutasteride/ or exp Cyproterone/ or Spironolactone/
#6 Gender dysphoria/dt or Gender dysphoria/th or Transsexualism/dt or Transsexualism/th 981
#7 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,360
#8 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,603
Ospemifene/ or Bazedoxifene/
#9 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,611
#10 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#11 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,202
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#12 (gn-rh* or gnrh* or gonadotropin-releasing hormone* or 5-alpha reductase inhibitor* or 35,198
5alpha reductase inhibitor* or goserelin or histrelin or leuprolide or leuprorelin or
nafarelin or triptorelin or elagolix or cetrorelix or degarelix or ganirelix or
relugolix). ,ab,kw,kf.
#13 (puberty adj3 (inhibit* or block* or suppress*)). ,ab,kw,kf. 455
#14 (an androgen* or an -androgen* or bicalutamide or finasteride or dutasteride or 21,533
spironolactone or flutamide or nilutamide). ,ab,kw,kf.
#15 (androgen adj3 (antagonist* or inhibit* or block*)). ,ab,kw,kf. 5,898
#16 (sex hormon* or sex steroid hormon* or gonadal steroid* or androgen* or androst* or 447,681
estrogen* or oestrogen* or estradiol* or oestradiol* or dehydroepiandrosterone or
prasterone or dhea or dihydrotestosterone or dht or dihydroprogesterone or
dihydroepitestosterone or epiandrosterone or epitestosterone or epiestriol or equilenin or
equilin or estrane* or estrenolone or estrone or e ocholanolone or folliculin or gestagen*
or hermaphrodiol or hydroxyestrone* or hydroxypregnenolone* or hydroxysteroid* or
hydroxytestosterone* or isotestosterone or ketosteroid* or medroxyprogesterone or
mestranol or methyltestosterone or danazol or nandrolone or nortestosterone or
oxosteroid* or pregnenolone* or progesta onal hormon* or progest* or quinestrol or
stanolone or testosterone or dydrogesterone or levonorgestrel or dienogest or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

238
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Table I.B.15. Free text and controlled vocabulary search of Ovid Medline for randomized controlled
trials, May 22, 2023
Search step Query Results
norethindrone or norges mate or drospirenone or desogestrel or etonogestrel or
norelgestromin or norgestrel or segesterone or ethynodiol). ,ab,kw,kf.
#17 (hormon* adj3 (replacement or suppress* or therap* or treat* or cross-sex or gender- 80,188
affirming)). ,ab,kw,kf.
#18 (gender-affirming pharmaceu cal* or contracep ve*). ,ab,kw,kf. 65,705
#19 (aromatase inhibitor* or anastrozole or exemestane or letrozole). ,ab,kw,kf. 11,634
#20 (selec ve estrogen receptor modulator* or serm or an estrogen* or an -estrogen* or 40,576
bazedoxifene or clomiphene or clomifene or ospemifene or raloxifene or tamoxifen or
toremifene). ,ab,kw,kf.
#21 (proges n receptor modulator* or ulipristal or minoxidil). ,ab,kw,kf. 2,792
#22 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 677,117
#23 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,396
#24 (gender dysphor* or 'gender minorit* or gender divers* or gender iden ty or gender 18,839
incongruenc* or gender transi on* or trans-female* or transfemale* or trans-feminine or
transfeminine or trans-gender* or transgender* or trans-sexual* or transsex* or trans-
male* or transmale* or trans-masculine or transmasculine or transboy* or
transgirl*). ,ab,kw,kf.
#25 (gender adj1 (affirm* or confirm* or reassign*)). ,ab,kw,kf. 2,980
#26 ((sex or medical) adj1 (reassign* or transi on*)). ,ab,kw,kf. 887
#27 23 or 24 or 25 or 26 38,036
#28 4 and 22 and 27 1,688
#29 28 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 1,669
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#30 limit 29 to yr = "2010 -Current" 1,135
#31 (Randomized Controlled Trial or Controlled Clinical Trial or Pragma c Clinical Trial or 2,583,567
Equivalence Trial or Clinical Trial, Phase III).pt. or Randomized Controlled Trial/ or exp
Randomized Controlled Trials as Topic/ or "Randomized Controlled Trial (topic)"/ or
Controlled Clinical Trial/ or exp Controlled Clinical Trials as Topic/ or "Controlled Clinical
Trial (topic)"/ or Randomiza on/ or Randomiza on/ or Double-Blind Method/ or Double
Blind Procedure/ or Double-Blind Studies/ or Single-Blind Method/ or Single Blind
Procedure/ or Single-Blind Studies/ or Placebos/ or Placebo/ or Control Groups/ or Control
Group/ or (random* or sham or placebo*). ,ab,hw,kf. or ((singl* or doubl*) adj (blind* or
dumm* or mask*)). ,ab,hw,kf. or ((tripl* or trebl*) adj (blind* or dumm* or
mask*)). ,ab,hw,kf. or (control* adj3 (study or studies or trial* or group*)). ,ab,kf. or
(Nonrandom* or non random* or non-random* or quasi-random* or
quasirandom*). ,ab,hw,kf. or allocated. ,ab,hw. or ((open label or open-label) adj5 (study
or studies or trial*)). ,ab,hw,kf. or ((equivalence or superiority or non-inferiority or
noninferiority) adj3 (study or studies or trial*)). ,ab,hw,kf. or (pragma c study or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

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Table I.B.15. Free text and controlled vocabulary search of Ovid Medline for randomized controlled
trials, May 22, 2023
Search step Query Results
pragma c studies). ,ab,hw,kf. or ((pragma c or prac cal) adj3 trial*). ,ab,hw,kf. or
((quasiexperimental or quasi-experimental) adj3 (study or studies or trial*)). ,ab,hw,kf. or
(phase adj3 (III or "3") adj3 (study or studies or trial*)). ,hw,kf.
#32 30 and 31 61

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

240
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Table I.B.16. Free text and controlled vocabulary search of Ovid Medline for observational and
descriptive studies, May 22, 2023
Search step Query Results
#1 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,156,084
#2 (adolescen* or boy* or girl* or child or children or juvenile or minors or paediatr* or 2,140,449
pediatr* or pre-pubertal or prepubertal or pre-pubesc* or prepubesc* or pubesc* or
pubertal or puberty or teen* or youth* or school-aged). ,ab,kw,kf.
#3 (adolescen* or child* or paediatr* or pediatr*).jn. 295,801
#4 1 or 2 or 3 4,022,329
#5 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 367,170
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/ or exp Androgen antagonists/ or
Bicalutamide/ or Finasteride/ or Dutasteride/ or exp Cyproterone/ or Spironolactone/
#6 Gender dysphoria/dt or Gender dysphoria/th or Transsexualism/dt or Transsexualism/th 981
#7 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,360
#8 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,603
Ospemifene/ or Bazedoxifene/
#9 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,611
#10 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#11 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,202
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#12 (gn-rh* or gnrh* or gonadotropin-releasing hormone* or 5-alpha reductase inhibitor* or 35,198
5alpha reductase inhibitor* or goserelin or histrelin or leuprolide or leuprorelin or
nafarelin or triptorelin or elagolix or cetrorelix or degarelix or ganirelix or
relugolix). ,ab,kw,kf.
#13 (puberty adj3 (inhibit* or block* or suppress*)). ,ab,kw,kf. 455
#14 (an androgen* or an -androgen* or bicalutamide or finasteride or dutasteride or 21,533
spironolactone or flutamide or nilutamide). ,ab,kw,kf.
#15 (androgen adj3 (antagonist* or inhibit* or block*)). ,ab,kw,kf. 5,898
#16 (sex hormon* or sex steroid hormon* or gonadal steroid* or androgen* or androst* or 447,681
estrogen* or oestrogen* or estradiol* or oestradiol* or dehydroepiandrosterone or
prasterone or dhea or dihydrotestosterone or dht or dihydroprogesterone or
dihydroepitestosterone or epiandrosterone or epitestosterone or epiestriol or equilenin or
equilin or estrane* or estrenolone or estrone or e ocholanolone or folliculin or gestagen*
or hermaphrodiol or hydroxyestrone* or hydroxypregnenolone* or hydroxysteroid* or
hydroxytestosterone* or isotestosterone or ketosteroid* or medroxyprogesterone or
mestranol or methyltestosterone or danazol or nandrolone or nortestosterone or
oxosteroid* or pregnenolone* or progesta onal hormon* or progest* or quinestrol or
stanolone or testosterone or dydrogesterone or levonorgestrel or dienogest or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

241
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Table I.B.16. Free text and controlled vocabulary search of Ovid Medline for observational and
descriptive studies, May 22, 2023
Search step Query Results
norethindrone or norges mate or drospirenone or desogestrel or etonogestrel or
norelgestromin or norgestrel or segesterone or ethynodiol). ,ab,kw,kf.
#17 (hormon* adj3 (replacement or suppress* or therap* or treat* or cross-sex or gender- 80,188
affirming)). ,ab,kw,kf.
#18 (gender-affirming pharmaceu cal* or contracep ve*). ,ab,kw,kf. 65,705
#19 (aromatase inhibitor* or anastrozole or exemestane or letrozole). ,ab,kw,kf. 11,634
#20 (selec ve estrogen receptor modulator* or serm or an estrogen* or an -estrogen* or 40,576
bazedoxifene or clomiphene or clomifene or ospemifene or raloxifene or tamoxifen or
toremifene). ,ab,kw,kf.
#21 (proges n receptor modulator* or ulipristal or minoxidil). ,ab,kw,kf. 2,792
#22 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 677,117
#23 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,396
#24 (gender dysphor* or 'gender minorit* or gender divers* or gender iden ty or gender 18,839
incongruenc* or gender transi on* or trans-female* or transfemale* or trans-feminine or
transfeminine or trans-gender* or transgender* or trans-sexual* or transsex* or trans-
male* or transmale* or trans-masculine or transmasculine or transboy* or
transgirl*). ,ab,kw,kf.
#25 (gender adj1 (affirm* or confirm* or reassign*)). ,ab,kw,kf. 2,980
#26 ((sex or medical) adj1 (reassign* or transi on*)). ,ab,kw,kf. 887
#27 23 or 24 or 25 or 26 38,036
#28 4 and 22 and 27 1,688
#29 28 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 1,669
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#30 limit 29 to yr = "2010 -Current" 1,135
#31 (epidemiologic methods or epidemiologic studies).sh. or observa onal study/ or 6,771,779
observa onal studies as topic/ or clinical studies as topic/ or controlled before-a er
studies/ or cross-sec onal studies/ or historically controlled study/ or interrupted me
series analysis/ or exp seroepidemiologic studies/ or na onal longitudinal study of
adolescent health/ or cohort studies/ or cohort analysis/ or longitudinal studies/ or
longitudinal study/ or prospec ve studies/ or prospec ve study/ or follow-up studies/ or
follow up/ or followup studies/ or retrospec ve studies/ or retrospec ve study/ or case-
control studies/ or exp case control study/ or cross-sec onal study/ or observa onal
study/ or quasi experimental methods/ or quasi experimental study/ or single-case studies
as topic/ or (observa onal study or valida on studies or clinical study).pt. or
(observa onal adj3 (study or studies or design or analysis or analyses)). ,ab,kf. or
cohort*. ,ab,kf. or (prospec ve adj7 (study or studies or design or analysis or
analyses)). ,ab,kf. or ((follow up or followup) adj7 (study or studies or design or analysis or
analyses)). ,ab,kf. or ((longitudinal or longterm or (long adj term)) adj7 (study or studies

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

242
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Table I.B.16. Free text and controlled vocabulary search of Ovid Medline for observational and
descriptive studies, May 22, 2023
Search step Query Results
or design or analysis or analyses or data)). ,ab,kf. or (retrospec ve adj7 (study or studies
or design or analysis or analyses or data or review)). ,ab,kf. or ((case adj control) or (case
adj comparison) or (case adj controlled)). ,ab,kf. or (case-referent adj3 (study or studies or
design or analysis or analyses)). ,ab,kf. or (popula on adj3 (study or studies or analysis or
analyses)). ,ab,kf. or (descrip ve adj3 (study or studies or design or analysis or
analyses)). ,ab,kf. or ((mul dimensional or (mul adj dimensional)) adj3 (study or studies
or design or analysis or analyses)). ,ab,kf. or (cross adj sec onal adj7 (study or studies or
design or research or analysis or analyses or survey or findings)). ,ab,kf. or ((natural adj
experiment) or (natural adj experiments)). ,ab,kf. or (quasi adj (experiment or
experiments or experimental)). ,ab,kf. or ((non experiment or nonexperiment or non
experimental or nonexperimental) adj3 (study or studies or design or analysis or
analyses)). ,ab,kf. or (prevalence adj3 (study or studies or analysis or analyses)). ,ab,kf. or
case series. ,ab,kf. or case reports.pt. or case report/ or case study/ or (case adj3 (report
or reports or study or studies or histories)). ,ab,kf. or organiza onal case studies.sh.
#32 30 and 31 499

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

243
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Table I.B.17. Free text and controlled vocabulary search of Ovid Medline for qualitative studies, June 5,
2023
Search step Query Results
#1 Pediatrics/ or Child/ or Minors/ or Adolescent/ or Puberty/ 3,158,365
#2 (adolescen* or boy* or girl* or child or children or juvenile or minors or paediatr* or 2,144,528
pediatr* or pre-pubertal or prepubertal or pre-pubesc* or prepubesc* or pubesc* or
pubertal or puberty or teen* or youth* or school-aged). ,ab,kw,kf.
#3 (adolescen* or child* or paediatr* or pediatr*).jn. 296,222
#4 1 or 2 or 3 4,026,855
#5 exp Gonadotropin-releasing hormone/ or exp Gonadal Steroid Hormones/ or exp 367,444
Hormone Replacement Therapy/ or exp Androgens/ or exp Estrogens/ or exp
Progesterone/ or Sex Reassignment Procedures/ or exp Androgen antagonists/ or
Bicalutamide/ or Finasteride/ or Dutasteride/ or exp Cyproterone/ or Spironolactone/
#6 Gender dysphoria/dt or Gender dysphoria/th or Transsexualism/dt or Transsexualism/th 982
#7 Elagolix/ or Cetrorelix/ or Degarelix/ or Ganirelix/ or Relugolix/ or Danazol/ 2,360
#8 Selec ve Estrogen Receptor Modulators/ or exp Tamoxifen/ or exp Clomiphene/ or 29,611
Ospemifene/ or Bazedoxifene/
#9 Aromatase Inhibitors/ or Letrozole/ or Anastrozole/ or Exemestane/ 8,618
#10 Selec ve progesterone receptor modulator EC313/ or Ulipristal/ or Ulipristal acetate/ 0
#11 Contracep ve Agents, Hormonal/ or Proges ns/ or Etonogestrel/ or exp Norethindrone/ 22,211
or Drospirenone/ or Desogestrel/ or Ethynodiol diacetate/ or Norelgestromin/ or exp
Norgestrel/ or Norges mate/ or Segesterone acetate/
#12 (gn-rh* or gnrh* or gonadotropin-releasing hormone* or 5-alpha reductase inhibitor* or 35,258
5alpha reductase inhibitor* or goserelin or histrelin or leuprolide or leuprorelin or
nafarelin or triptorelin or elagolix or cetrorelix or degarelix or ganirelix or
relugolix). ,ab,kw,kf.
#13 (puberty adj3 (inhibit* or block* or suppress*)). ,ab,kw,kf. 456
#14 (an androgen* or an -androgen* or bicalutamide or finasteride or dutasteride or 21,562
spironolactone or flutamide or nilutamide). ,ab,kw,kf.
#15 (androgen adj3 (antagonist* or inhibit* or block*)). ,ab,kw,kf. 5,907
#16 (sex hormon* or sex steroid hormon* or gonadal steroid* or androgen* or androst* or 448,236
estrogen* or oestrogen* or estradiol* or oestradiol* or dehydroepiandrosterone or
prasterone or dhea or dihydrotestosterone or dht or dihydroprogesterone or
dihydroepitestosterone or epiandrosterone or epitestosterone or epiestriol or equilenin or
equilin or estrane* or estrenolone or estrone or e ocholanolone or folliculin or gestagen*
or hermaphrodiol or hydroxyestrone* or hydroxypregnenolone* or hydroxysteroid* or
hydroxytestosterone* or isotestosterone or ketosteroid* or medroxyprogesterone or
mestranol or methyltestosterone or danazol or nandrolone or nortestosterone or
oxosteroid* or pregnenolone* or progesta onal hormon* or progest* or quinestrol or
stanolone or testosterone or dydrogesterone or levonorgestrel or dienogest or

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

244
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Table I.B.17. Free text and controlled vocabulary search of Ovid Medline for qualitative studies, June 5,
2023
Search step Query Results
norethindrone or norges mate or drospirenone or desogestrel or etonogestrel or
norelgestromin or norgestrel or segesterone or ethynodiol). ,ab,kw,kf.
#17 (hormon* adj3 (replacement or suppress* or therap* or treat* or cross-sex or gender- 80,291
affirming)). ,ab,kw,kf.
#18 (gender-affirming pharmaceu cal* or contracep ve*). ,ab,kw,kf. 65,776
#19 (aromatase inhibitor* or anastrozole or exemestane or letrozole). ,ab,kw,kf. 11,646
#20 (selec ve estrogen receptor modulator* or serm or an estrogen* or an -estrogen* or 40,601
bazedoxifene or clomiphene or clomifene or ospemifene or raloxifene or tamoxifen or
toremifene). ,ab,kw,kf.
#21 (proges n receptor modulator* or ulipristal or minoxidil). ,ab,kw,kf. 2,796
#22 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 677,878
#23 Gender Dysphoria/ or Transgender Persons/ or Gender Iden ty/ or Transsexualism/ 29,449
#24 (gender dysphor* or 'gender minorit* or gender divers* or gender iden ty or gender 18,951
incongruenc* or gender transi on* or trans-female* or transfemale* or trans-feminine or
transfeminine or trans-gender* or transgender* or trans-sexual* or transsex* or trans-
male* or transmale* or trans-masculine or transmasculine or transboy* or
transgirl*). ,ab,kw,kf.
#25 (gender adj1 (affirm* or confirm* or reassign*)). ,ab,kw,kf. 3,007
#26 ((sex or medical) adj1 (reassign* or transi on*)). ,ab,kw,kf. 888
#27 23 or 24 or 25 or 26 38,167
#28 4 and 22 and 27 1,694
#29 28 not ((exp animals/ not humans/) or (animal* or canine* or crustacean* or dog or dogs 1,674
or mice or monkey* or mouse or murine or primate* or rat or rats or ra us). .)
#30 limit 29 to yr = "2010 -Current" 1,140
#31 exp Empirical Research/ or Interviews as Topic/ or Personal Narra ves as Topic/ or Focus 1,166,909
Groups/ or exp Narra on/ or Nursing Methodology Research/ or Narra ve Medicine/ or
(Interview or Personal Narra ve).pt. or interview*. ,ab,kf. or qualita ve. ,ab,kf,jw. or
(theme* or thema c). ,ab,kf. or ethnological research. ,ab,kf. or ethnograph*. ,ab,kf. or
ethnomedicine. ,ab,kf. or ethnonursing. ,ab,kf. or phenomenol*. ,ab,kf. or (grounded adj
(theor* or study or studies or research or analys?s)). ,ab,kf. or life stor*. ,ab,kf. or (emic
or e c or hermeneu c* or heuris c* or semio c*). ,ab,kf. or (data adj1 saturat$). ,ab,kf.
or par cipant observ*. ,ab,kf. or (social construct* or postmodern* or post-structural* or
post structural* or poststructural* or post modern* or post-modern*). ,ab,kf. or (ac on
research or coopera ve inquir* or co opera ve inquir* or co-opera ve inquir*). ,ab,kf. or
(humanis c or existen al or experien al or paradigm*). ,ab,kf. or (field adj (study or
studies or research or work)). ,ab,kf. or (human science or social science). ,ab,kf. or
biographical method. ,ab,kf. or theore cal sampl*. ,ab,kf. or ((purpos* adj4 sampl*) or
(focus adj group*)). ,ab,kf. or (open-ended or narra ve* or textual or texts or semi-

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

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Table I.B.17. Free text and controlled vocabulary search of Ovid Medline for qualitative studies, June 5,
2023
Search step Query Results
structured). ,ab,kf. or (life world* or life-world* or conversa on analys?s or personal
experience* or theore cal satura on). ,ab,kf. or ((lived or life) adj experience*). ,ab,kf. or
cluster sampl*. ,ab,kf. or observa onal method*. ,ab,kf. or content analysis. ,ab,kf. or
(constant adj (compara ve or comparison)). ,ab,kf. or ((discourse* or discurs*) adj3
analys?s). ,ab,kf. or (heidegger* or colaizzi* or spiegelberg* or merleau* or husserl* or
foucault* or ricoeur or glaser*). ,ab,kf. or (van adj manen*). ,ab,kf. or (van adj
kaam*). ,ab,kf. or (corbin* adj2 strauss*). ,ab,kf.
#32 "Surveys and Ques onnaires"/ or Health Care Surveys/ or self report/ or 1,543,405
ques onnaire*. ,ab,kf. or survey*. ,ab,kf.
#33 31 or 32 2,457,803
#34 30 and 33 297

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

246
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Free Text and Controlled Vocabulary Searches of Embase Conducted
between May 15 and June 5, 2023

Table I.B.18. Free text and controlled vocabulary search of Embase for systematic reviews, May 15,
2023
Search step Query Results
#1 'conference abstract'/it OR 'conference review'/it 4,782,437
#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,126,975
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,753,850
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'juvenile'/de OR 'child'/de OR 'pediatrics'/exp 3,426,389
OR 'pediatric'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp
OR 'preadolescence'/exp
#5 'adolescen*': ,ab,kw OR 'boy*': ,ab,kw OR 'girl*': ,ab,kw OR 'child': ,ab,kw OR 3,268,795
'children': ,ab,kw OR 'juvenile': ,ab,kw OR 'minors': ,ab,kw OR 'paediatr*': ,ab,kw OR
'pediatr*': ,ab,kw OR 'pre-pubertal': ,ab,kw OR 'prepubertal': ,ab,kw OR 'pre-
pubesc*': ,ab,kw OR 'prepubesc*': ,ab,kw OR 'pubesc*': ,ab,kw OR 'pubertal': ,ab,kw
OR 'puberty': ,ab,kw OR 'teen*': ,ab,kw OR 'youth*': ,ab,kw OR 'school-aged': ,ab,kw
OR 'adolescen*':jt OR 'child*':jt OR 'paediatr*':jt OR 'pediatr*':jt
#6 #4 OR #5 4,677,465
#7 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 929,685
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'puberty suppression'/exp OR 'gender dysphoria'/exp/dm_dt OR 'gender
dysphoria'/exp/dm_th
#8 'gn-rh*': ,ab,kw OR 'gnrh*': ,ab,kw OR 'gonadotropin-releasing hormone*': ,ab,kw OR 46,093
'5-alpha reductase inhibitor*': ,ab,kw OR '5alpha reductase inhibitor*': ,ab,kw OR
'goserelin': ,ab,kw OR 'histrelin': ,ab,kw OR 'leuprolide': ,ab,kw OR 'leuprorelin': ,ab,kw
OR 'nafarelin': ,ab,kw OR 'triptorelin': ,ab,kw OR 'elagolix': ,ab,kw OR
'cetrorelix': ,ab,kw OR 'degarelix': ,ab,kw OR 'ganirelix': ,ab,kw OR 'relugolix': ,ab,kw
#9 ('puberty' NEAR/3 ('inhibit*' OR 'block*' OR 'suppress*')): ,ab,kw 636
#10 'an androgen*': ,ab,kw OR 'an -androgen*': ,ab,kw OR 'bicalutamide': ,ab,kw OR 31,484
'finasteride': ,ab,kw OR 'dutasteride': ,ab,kw OR 'spironolactone': ,ab,kw OR
'flutamide': ,ab,kw OR 'nilutamide': ,ab,kw

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

247
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Table I.B.18. Free text and controlled vocabulary search of Embase for systematic reviews, May 15,
2023
Search step Query Results
#11 ('androgen' NEAR/3 ('antagonist*' OR 'inhibit*' OR 'block*')): ,ab,kw 8,639
#12 'sex hormon*': ,ab,kw OR 'sex steroid hormon*': ,ab,kw OR 'gonadal steroid*': ,ab,kw 569,723
OR 'androgen*': ,ab,kw OR 'androst*': ,ab,kw OR 'estrogen*': ,ab,kw OR
'oestrogen*': ,ab,kw OR 'estradiol*': ,ab,kw OR 'oestradiol*': ,ab,kw OR
'dehydroepiandrosterone': ,ab,kw OR 'prasterone': ,ab,kw OR 'dhea': ,ab,kw OR
'dihydrotestosterone': ,ab,kw OR 'dht': ,ab,kw OR 'dihydroprogesterone': ,ab,kw OR
'dihydroepitestosterone': ,ab,kw OR 'epiandrosterone': ,ab,kw OR
'epitestosterone': ,ab,kw OR 'epiestriol': ,ab,kw OR 'equilenin': ,ab,kw OR
'equilin': ,ab,kw OR 'estrane*': ,ab,kw OR 'estrenolone': ,ab,kw OR 'estrone': ,ab,kw OR
'e ocholanolone': ,ab,kw OR 'folliculin': ,ab,kw OR 'gestagen*': ,ab,kw OR
'hermaphrodiol': ,ab,kw OR 'hydroxyestrone*': ,ab,kw OR
'hydroxypregnenolone*': ,ab,kw OR 'hydroxysteroid*': ,ab,kw OR
'hydroxytestosterone*': ,ab,kw OR 'isotestosterone': ,ab,kw OR 'ketosteroid*': ,ab,kw
OR 'medroxyprogesterone': ,ab,kw OR 'mestranol': ,ab,kw OR
'methyltestosterone': ,ab,kw OR 'danazol': ,ab,kw OR 'nandrolone': ,ab,kw OR
'nortestosterone': ,ab,kw OR 'oxosteroid*': ,ab,kw OR 'pregnenolone*': ,ab,kw OR
'progesta onal hormon*': ,ab,kw OR 'progest*': ,ab,kw OR 'quinestrol': ,ab,kw OR
'stanolone': ,ab,kw OR 'testosterone': ,ab,kw OR 'dydrogesterone': ,ab,kw OR
'levonorgestrel': ,ab,kw OR 'dienogest': ,ab,kw OR 'norethindrone': ,ab,kw OR
'norges mate': ,ab,kw OR 'drospirenone': ,ab,kw OR 'desogestrel': ,ab,kw OR
'etonogestrel': ,ab,kw OR 'norelgestromin': ,ab,kw OR 'norgestrel': ,ab,kw OR
'segesterone': ,ab,kw OR 'ethynodiol': ,ab,kw
#13 ('hormon*' NEAR/3 ('replacement' OR 'suppress*' OR 'therap*' OR 'treat*' OR 'cross-sex' 113,288
OR 'gender-affirming')): ,ab,kw
#14 'gender-affirming pharmaceu cal*': ,ab,kw OR 'contracep ve*': ,ab,kw 73,316
#15 'aromatase inhibitor*': ,ab,kw OR 'anastrozole': ,ab,kw OR 'exemestane': ,ab,kw OR 20,333
'letrozole': ,ab,kw
#16 'selec ve estrogen receptor modulator*': ,ab,kw OR 'serm': ,ab,kw OR 59,823
'an estrogen*': ,ab,kw OR 'an -estrogen*': ,ab,kw OR 'bazedoxifene': ,ab,kw OR
'clomiphene': ,ab,kw OR 'clomifene': ,ab,kw OR 'ospemifene': ,ab,kw OR
'raloxifene': ,ab,kw OR 'tamoxifen': ,ab,kw OR 'toremifene': ,ab,kw
#17 'proges n receptor modulator*': ,ab,kw OR 'ulipristal': ,ab,kw OR 'minoxidil': ,ab,kw 4,111
#18 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 1,185,819
#19 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,608
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#20 'gender dysphor*': ,ab,kw OR 'gender minorit*': ,ab,kw OR 'gender divers*': ,ab,kw OR 24,167
'gender iden ty': ,ab,kw OR 'gender incongruenc*': ,ab,kw OR 'gender
transi on*': ,ab,kw OR 'trans-female*': ,ab,kw OR 'transfemale*': ,ab,kw OR 'trans-
Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

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Table I.B.18. Free text and controlled vocabulary search of Embase for systematic reviews, May 15,
2023
Search step Query Results
feminine': ,ab,kw OR 'transfeminine': ,ab,kw OR 'trans-gender*': ,ab,kw OR
'transgender*': ,ab,kw OR 'trans-sexual*': ,ab,kw OR 'transsex*': ,ab,kw OR 'trans-
male*': ,ab,kw OR 'transmale*': ,ab,kw OR 'trans-masculine': ,ab,kw OR
'transmasculine': ,ab,kw OR 'transboy*': ,ab,kw OR 'transgirl*': ,ab,kw
#21 ('gender' NEAR/1 ('affirm*' OR 'confirm*' OR 'reassign*')): ,ab,kw 4,058
#22 (('sex' OR 'medical') NEXT/1 ('reassign*' OR 'transi on*')): ,ab,kw 1,248
#23 #19 OR #20 OR #21 OR #22 42,539
#24 #6 AND #18 AND #23 2,585
#25 #24 NOT (#1 OR #2 OR #3) 1,865
#26 #24 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 1,372
#27 'systema c review':jt,ab,kw OR 'meta-analy*':jt,ab,kw OR metaanalys*:jt,ab,kw OR 874,065
(((systema c* OR comprehensive*) NEAR/3 (review* OR overview* OR literature OR
bibliographic)): ,ab,kw) OR ((systema c* NEAR/2 search*): ,ab,kw) OR ((methodologic*
NEAR/3 (review* OR overview*)): ,ab,kw) OR ((quan ta ve NEAR/3 (review* OR
overview* OR synthes*)): ,ab,kw) OR ((research NEAR/3 (integra * OR
overview*)): ,ab,kw) OR ((integra ve NEAR/3 (review* OR overview*)): ,ab,kw) OR
((collabora ve NEAR/3 (review* OR overview*)): ,ab,kw) OR ((pool* NEAR/3
analy*): ,ab,kw) OR 'data synthes*': ,ab,kw OR 'data extrac on*': ,ab,kw OR 'data
abstrac on*': ,ab,kw OR handsearch*: ,ab,kw OR 'hand search*': ,ab,kw OR 'mantel
haenszel': ,ab,kw OR peto: ,ab,kw OR 'der simonian': ,ab,kw OR dersimonian: ,ab,kw
OR 'fixed effect*': ,ab,kw OR 'la n square*': ,ab,kw OR 'met analy*': ,ab,kw OR
metanaly*: ,ab,kw OR 'technology assessment*': ,ab,kw OR hta: ,ab,kw OR htas: ,ab,kw
OR 'technology overview*': ,ab,kw OR 'technology appraisal*': ,ab,kw OR 'meta
regression*': ,ab,kw OR metaregression*: ,ab,kw OR medline: ,ab OR cochrane: ,ab OR
pubmed: ,ab OR medlars: ,ab OR embase: ,ab OR cinahl: ,ab OR psyclit:ab OR
(psycinfo:ab NOT 'psycinfo database':ab) OR scopus:ab OR 'sociological abstracts':ab OR
'web of science':ab OR cochrane:it OR ((health NEXT/2 'technology assessment'):it) OR
'evidence report':it OR ((compara ve NEXT/3 (efficacy OR effec veness)): ,ab,kw) OR
'outcomes research': ,ab,kw OR 'rela ve effec veness': ,ab,kw OR (((indirect OR 'indirect
treatment' OR 'mixed treatment' OR bayesian) NEXT/3 comparison*): ,ab,kw) OR ((mul *
NEXT/3 treatment NEXT/2 comparison*): ,ab,kw) OR 'umbrella review*': ,ab,kw OR
((mul paramet* NEXT/3 synthesis): ,ab,kw) OR (('mul paramet*' NEXT/3
synthesis): ,ab,kw)
#28 'systema c review'/exp OR 'meta analysis'/exp OR 'systema c review (topic)'/exp OR 605,165
'meta analysis (topic)'/exp OR 'biomedical technology assessment'/exp
#29 #27 OR #28 1,006,136
#30 #26 AND #29 67

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

249
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Table I.B.19. Free text and controlled vocabulary search of Embase for guidelines, May 15, 2023
Search step Query Results
#1 'conference abstract'/it OR 'conference review'/it 4,782,437
#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,126,975
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,753,850
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'juvenile'/de OR 'child'/de OR 'pediatrics'/exp 3,426,389
OR 'pediatric'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp
OR 'preadolescence'/exp
#5 'adolescen*': ,ab,kw OR 'boy*': ,ab,kw OR 'girl*': ,ab,kw OR 'child': ,ab,kw OR 3,268,795
'children': ,ab,kw OR 'juvenile': ,ab,kw OR 'minors': ,ab,kw OR 'paediatr*': ,ab,kw OR
'pediatr*': ,ab,kw OR 'pre-pubertal': ,ab,kw OR 'prepubertal': ,ab,kw OR 'pre-
pubesc*': ,ab,kw OR 'prepubesc*': ,ab,kw OR 'pubesc*': ,ab,kw OR 'pubertal': ,ab,kw
OR 'puberty': ,ab,kw OR 'teen*': ,ab,kw OR 'youth*': ,ab,kw OR 'school-aged': ,ab,kw
OR 'adolescen*':jt OR 'child*':jt OR 'paediatr*':jt OR 'pediatr*':jt
#6 #4 OR #5 4,677,465
#7 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 929,685
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'puberty suppression'/exp OR 'gender dysphoria'/exp/dm_dt OR 'gender
dysphoria'/exp/dm_th
#8 'gn-rh*': ,ab,kw OR 'gnrh*': ,ab,kw OR 'gonadotropin-releasing hormone*': ,ab,kw OR 46,093
'5-alpha reductase inhibitor*': ,ab,kw OR '5alpha reductase inhibitor*': ,ab,kw OR
'goserelin': ,ab,kw OR 'histrelin': ,ab,kw OR 'leuprolide': ,ab,kw OR 'leuprorelin': ,ab,kw
OR 'nafarelin': ,ab,kw OR 'triptorelin': ,ab,kw OR 'elagolix': ,ab,kw OR
'cetrorelix': ,ab,kw OR 'degarelix': ,ab,kw OR 'ganirelix': ,ab,kw OR 'relugolix': ,ab,kw
#9 ('puberty' NEAR/3 ('inhibit*' OR 'block*' OR 'suppress*')): ,ab,kw 636
#10 'an androgen*': ,ab,kw OR 'an -androgen*': ,ab,kw OR 'bicalutamide': ,ab,kw OR 31,484
'finasteride': ,ab,kw OR 'dutasteride': ,ab,kw OR 'spironolactone': ,ab,kw OR
'flutamide': ,ab,kw OR 'nilutamide': ,ab,kw
#11 ('androgen' NEAR/3 ('antagonist*' OR 'inhibit*' OR 'block*')): ,ab,kw 8,639
#12 'sex hormon*': ,ab,kw OR 'sex steroid hormon*': ,ab,kw OR 'gonadal steroid*': ,ab,kw 569,723
OR 'androgen*': ,ab,kw OR 'androst*': ,ab,kw OR 'estrogen*': ,ab,kw OR
'oestrogen*': ,ab,kw OR 'estradiol*': ,ab,kw OR 'oestradiol*': ,ab,kw OR

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

250
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Table I.B.19. Free text and controlled vocabulary search of Embase for guidelines, May 15, 2023
Search step Query Results
'dehydroepiandrosterone': ,ab,kw OR 'prasterone': ,ab,kw OR 'dhea': ,ab,kw OR
'dihydrotestosterone': ,ab,kw OR 'dht': ,ab,kw OR 'dihydroprogesterone': ,ab,kw OR
'dihydroepitestosterone': ,ab,kw OR 'epiandrosterone': ,ab,kw OR
'epitestosterone': ,ab,kw OR 'epiestriol': ,ab,kw OR 'equilenin': ,ab,kw OR
'equilin': ,ab,kw OR 'estrane*': ,ab,kw OR 'estrenolone': ,ab,kw OR 'estrone': ,ab,kw OR
'e ocholanolone': ,ab,kw OR 'folliculin': ,ab,kw OR 'gestagen*': ,ab,kw OR
'hermaphrodiol': ,ab,kw OR 'hydroxyestrone*': ,ab,kw OR
'hydroxypregnenolone*': ,ab,kw OR 'hydroxysteroid*': ,ab,kw OR
'hydroxytestosterone*': ,ab,kw OR 'isotestosterone': ,ab,kw OR 'ketosteroid*': ,ab,kw
OR 'medroxyprogesterone': ,ab,kw OR 'mestranol': ,ab,kw OR
'methyltestosterone': ,ab,kw OR 'danazol': ,ab,kw OR 'nandrolone': ,ab,kw OR
'nortestosterone': ,ab,kw OR 'oxosteroid*': ,ab,kw OR 'pregnenolone*': ,ab,kw OR
'progesta onal hormon*': ,ab,kw OR 'progest*': ,ab,kw OR 'quinestrol': ,ab,kw OR
'stanolone': ,ab,kw OR 'testosterone': ,ab,kw OR 'dydrogesterone': ,ab,kw OR
'levonorgestrel': ,ab,kw OR 'dienogest': ,ab,kw OR 'norethindrone': ,ab,kw OR
'norges mate': ,ab,kw OR 'drospirenone': ,ab,kw OR 'desogestrel': ,ab,kw OR
'etonogestrel': ,ab,kw OR 'norelgestromin': ,ab,kw OR 'norgestrel': ,ab,kw OR
'segesterone': ,ab,kw OR 'ethynodiol': ,ab,kw
#13 ('hormon*' NEAR/3 ('replacement' OR 'suppress*' OR 'therap*' OR 'treat*' OR 'cross-sex' 113,288
OR 'gender-affirming')): ,ab,kw
#14 'gender-affirming pharmaceu cal*': ,ab,kw OR 'contracep ve*': ,ab,kw 73,316
#15 'aromatase inhibitor*': ,ab,kw OR 'anastrozole': ,ab,kw OR 'exemestane': ,ab,kw OR 20,333
'letrozole': ,ab,kw
#16 'selec ve estrogen receptor modulator*': ,ab,kw OR 'serm': ,ab,kw OR 59,823
'an estrogen*': ,ab,kw OR 'an -estrogen*': ,ab,kw OR 'bazedoxifene': ,ab,kw OR
'clomiphene': ,ab,kw OR 'clomifene': ,ab,kw OR 'ospemifene': ,ab,kw OR
'raloxifene': ,ab,kw OR 'tamoxifen': ,ab,kw OR 'toremifene': ,ab,kw
#17 'proges n receptor modulator*': ,ab,kw OR 'ulipristal': ,ab,kw OR 'minoxidil': ,ab,kw 4,111
#18 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 1,185,819
#19 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,608
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#20 'gender dysphor*': ,ab,kw OR 'gender minorit*': ,ab,kw OR 'gender divers*': ,ab,kw OR 24,167
'gender iden ty': ,ab,kw OR 'gender incongruenc*': ,ab,kw OR 'gender
transi on*': ,ab,kw OR 'trans-female*': ,ab,kw OR 'transfemale*': ,ab,kw OR 'trans-
feminine': ,ab,kw OR 'transfeminine': ,ab,kw OR 'trans-gender*': ,ab,kw OR
'transgender*': ,ab,kw OR 'trans-sexual*': ,ab,kw OR 'transsex*': ,ab,kw OR 'trans-
male*': ,ab,kw OR 'transmale*': ,ab,kw OR 'trans-masculine': ,ab,kw OR
'transmasculine': ,ab,kw OR 'transboy*': ,ab,kw OR 'transgirl*': ,ab,kw
#21 ('gender' NEAR/1 ('affirm*' OR 'confirm*' OR 'reassign*')): ,ab,kw 4,058

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

251
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Table I.B.19. Free text and controlled vocabulary search of Embase for guidelines, May 15, 2023
Search step Query Results
#22 (('sex' OR 'medical') NEXT/1 ('reassign*' OR 'transi on*')): ,ab,kw 1,248
#23 #19 OR #20 OR #21 OR #22 42,539
#24 #6 AND #18 AND #23 2,585
#25 #24 NOT (#1 OR #2 OR #3) 1,865
#26 #24 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 1,372
#27 'clinical protocol'/exp OR 'consensus'/exp OR 'consensus development'/exp OR 'clinical 1,170,181
pathway'/exp OR 'guideline'/exp OR 'prac ce guideline'/exp OR 'clinical decision rule'/exp
OR 'posi on statement*': ,ab,kw OR 'policy statement*': ,ab,kw OR 'prac ce
parameter*': ,ab,kw OR 'best prac ce*': ,ab,kw OR 'standards': ,kw OR 'guideline': ,kw
OR 'guidelines': ,kw OR ((('prac ce' OR 'treatment*' OR 'clinical') NEXT/1 'guideline*'):ab)
OR 'cpg': OR 'cpgs': OR 'consensus*': ,kw OR ((('cri cal' OR 'clinical' OR 'prac ce')
NEXT/2 ('path' OR 'paths' OR 'pathway' OR 'pathways' OR 'protocol*')): ,ab,kw) OR
'recommendat*': ,kw OR 'guideline recommenda on*':ab OR (('care' NEAR/2 ('standard'
OR 'path' OR 'paths' OR 'pathway' OR 'pathways' OR 'map' OR 'maps' OR 'plan' OR
'plans')): ,ab,kw) OR (('algorithm*' NEAR/2 ('screening' OR 'examina on' OR 'test' OR
'tested' OR 'tes ng' OR 'assessment*' OR 'diagnosis' OR 'diagnoses' OR 'diagnosed' OR
'diagnosing')): ,ab,kw) OR (('algorithm*' NEAR/2 ('pharmacotherap*' OR 'chemotherap*'
OR 'chemotreatment*' OR 'therap*' OR 'treatment*' OR 'interven on*')): ,ab,kw) OR
'guideline*':au OR 'standards':au OR 'consensus*':au OR 'recommendat*':au
#28 #26 AND #27 192

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

252
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Table I.B.20. Free text and controlled vocabulary search of Embase for experimental studies (eg,
randomized controlled trials, controlled clinical trials), May 22, 2023
Search step Query Results
#1 'conference abstract'/it OR 'conference review'/it 4,794,639
#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,128,633
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,758,077
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'juvenile'/de OR 'child'/de OR 'pediatrics'/exp 3,429,175
OR 'pediatric'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp
OR 'preadolescence'/exp
#5 'adolescen*': ,ab,kw OR 'boy*': ,ab,kw OR 'girl*': ,ab,kw OR 'child': ,ab,kw OR 3,271,977
'children': ,ab,kw OR 'juvenile': ,ab,kw OR 'minors': ,ab,kw OR 'paediatr*': ,ab,kw OR
'pediatr*': ,ab,kw OR 'pre-pubertal': ,ab,kw OR 'prepubertal': ,ab,kw OR 'pre-
pubesc*': ,ab,kw OR 'prepubesc*': ,ab,kw OR 'pubesc*': ,ab,kw OR 'pubertal': ,ab,kw
OR 'puberty': ,ab,kw OR 'teen*': ,ab,kw OR 'youth*': ,ab,kw OR 'school-aged': ,ab,kw
OR 'adolescen*':jt OR 'child*':jt OR 'paediatr*':jt OR 'pediatr*':jt
#6 #4 OR #5 4,681,266
#7 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 930,567
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'puberty suppression'/exp OR 'gender dysphoria'/exp/dm_dt OR 'gender
dysphoria'/exp/dm_th
#8 'gn-rh*': ,ab,kw OR 'gnrh*': ,ab,kw OR 'gonadotropin-releasing hormone*': ,ab,kw OR 46,126
'5-alpha reductase inhibitor*': ,ab,kw OR '5alpha reductase inhibitor*': ,ab,kw OR
'goserelin': ,ab,kw OR 'histrelin': ,ab,kw OR 'leuprolide': ,ab,kw OR 'leuprorelin': ,ab,kw
OR 'nafarelin': ,ab,kw OR 'triptorelin': ,ab,kw OR 'elagolix': ,ab,kw OR
'cetrorelix': ,ab,kw OR 'degarelix': ,ab,kw OR 'ganirelix': ,ab,kw OR 'relugolix': ,ab,kw
#9 ('puberty' NEAR/3 ('inhibit*' OR 'block*' OR 'suppress*')): ,ab,kw 640
#10 'an androgen*': ,ab,kw OR 'an -androgen*': ,ab,kw OR 'bicalutamide': ,ab,kw OR 31,534
'finasteride': ,ab,kw OR 'dutasteride': ,ab,kw OR 'spironolactone': ,ab,kw OR
'flutamide': ,ab,kw OR 'nilutamide': ,ab,kw
#11 ('androgen' NEAR/3 ('antagonist*' OR 'inhibit*' OR 'block*')): ,ab,kw 8,658
#12 'sex hormon*': ,ab,kw OR 'sex steroid hormon*': ,ab,kw OR 'gonadal steroid*': ,ab,kw 570,233
OR 'androgen*': ,ab,kw OR 'androst*': ,ab,kw OR 'estrogen*': ,ab,kw OR

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

253
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Table I.B.20. Free text and controlled vocabulary search of Embase for experimental studies (eg,
randomized controlled trials, controlled clinical trials), May 22, 2023
Search step Query Results
'oestrogen*': ,ab,kw OR 'estradiol*': ,ab,kw OR 'oestradiol*': ,ab,kw OR
'dehydroepiandrosterone': ,ab,kw OR 'prasterone': ,ab,kw OR 'dhea': ,ab,kw OR
'dihydrotestosterone': ,ab,kw OR 'dht': ,ab,kw OR 'dihydroprogesterone': ,ab,kw OR
'dihydroepitestosterone': ,ab,kw OR 'epiandrosterone': ,ab,kw OR
'epitestosterone': ,ab,kw OR 'epiestriol': ,ab,kw OR 'equilenin': ,ab,kw OR
'equilin': ,ab,kw OR 'estrane*': ,ab,kw OR 'estrenolone': ,ab,kw OR 'estrone': ,ab,kw OR
'e ocholanolone': ,ab,kw OR 'folliculin': ,ab,kw OR 'gestagen*': ,ab,kw OR
'hermaphrodiol': ,ab,kw OR 'hydroxyestrone*': ,ab,kw OR
'hydroxypregnenolone*': ,ab,kw OR 'hydroxysteroid*': ,ab,kw OR
'hydroxytestosterone*': ,ab,kw OR 'isotestosterone': ,ab,kw OR 'ketosteroid*': ,ab,kw
OR 'medroxyprogesterone': ,ab,kw OR 'mestranol': ,ab,kw OR
'methyltestosterone': ,ab,kw OR 'danazol': ,ab,kw OR 'nandrolone': ,ab,kw OR
'nortestosterone': ,ab,kw OR 'oxosteroid*': ,ab,kw OR 'pregnenolone*': ,ab,kw OR
'progesta onal hormon*': ,ab,kw OR 'progest*': ,ab,kw OR 'quinestrol': ,ab,kw OR
'stanolone': ,ab,kw OR 'testosterone': ,ab,kw OR 'dydrogesterone': ,ab,kw OR
'levonorgestrel': ,ab,kw OR 'dienogest': ,ab,kw OR 'norethindrone': ,ab,kw OR
'norges mate': ,ab,kw OR 'drospirenone': ,ab,kw OR 'desogestrel': ,ab,kw OR
'etonogestrel': ,ab,kw OR 'norelgestromin': ,ab,kw OR 'norgestrel': ,ab,kw OR
'segesterone': ,ab,kw OR 'ethynodiol': ,ab,kw
#13 ('hormon*' NEAR/3 ('replacement' OR 'suppress*' OR 'therap*' OR 'treat*' OR 'cross-sex' 113,417
OR 'gender-affirming')): ,ab,kw
#14 'gender-affirming pharmaceu cal*': ,ab,kw OR 'contracep ve*': ,ab,kw 73,365
#15 'aromatase inhibitor*': ,ab,kw OR 'anastrozole': ,ab,kw OR 'exemestane': ,ab,kw OR 20,361
'letrozole': ,ab,kw
#16 'selec ve estrogen receptor modulator*': ,ab,kw OR 'serm': ,ab,kw OR 59,866
'an estrogen*': ,ab,kw OR 'an -estrogen*': ,ab,kw OR 'bazedoxifene': ,ab,kw OR
'clomiphene': ,ab,kw OR 'clomifene': ,ab,kw OR 'ospemifene': ,ab,kw OR
'raloxifene': ,ab,kw OR 'tamoxifen': ,ab,kw OR 'toremifene': ,ab,kw
#17 'proges n receptor modulator*': ,ab,kw OR 'ulipristal': ,ab,kw OR 'minoxidil': ,ab,kw 4,123
#18 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 1,186,884
#19 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,718
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#20 'gender dysphor*': ,ab,kw OR 'gender minorit*': ,ab,kw OR 'gender divers*': ,ab,kw OR 24,274
'gender iden ty': ,ab,kw OR 'gender incongruenc*': ,ab,kw OR 'gender
transi on*': ,ab,kw OR 'trans-female*': ,ab,kw OR 'transfemale*': ,ab,kw OR 'trans-
feminine': ,ab,kw OR 'transfeminine': ,ab,kw OR 'trans-gender*': ,ab,kw OR
'transgender*': ,ab,kw OR 'trans-sexual*': ,ab,kw OR 'transsex*': ,ab,kw OR 'trans-

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

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Table I.B.20. Free text and controlled vocabulary search of Embase for experimental studies (eg,
randomized controlled trials, controlled clinical trials), May 22, 2023
Search step Query Results
male*': ,ab,kw OR 'transmale*': ,ab,kw OR 'trans-masculine': ,ab,kw OR
'transmasculine': ,ab,kw OR 'transboy*': ,ab,kw OR 'transgirl*': ,ab,kw
#21 ('gender' NEAR/1 ('affirm*' OR 'confirm*' OR 'reassign*')): ,ab,kw 4,100
#22 (('sex' OR 'medical') NEXT/1 ('reassign*' OR 'transi on*')): ,ab,kw 1,249
#23 #19 OR #20 OR #21 OR #22 42,685
#24 #6 AND #18 AND #23 2,594
#25 #24 NOT (#1 OR #2 OR #3) 1,868
#26 #24 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 1,375
#27 'randomized controlled trial'/exp OR 'randomized controlled trial (topic)'/exp OR 4,470,992
'controlled clinical trial'/exp OR 'controlled clinical trial (topic)'/exp OR 'clinical trial'/exp
OR 'clinical trial (topic)'/exp OR 'noninferiority trial'/exp OR 'randomiza on'/de OR
'crossover procedure'/exp OR 'double blind procedure'/exp OR 'single blind
procedure'/exp OR 'placebo'/exp OR 'control group'/exp OR 'random*': ,ab,de,kw OR
'sham': ,ab,de,kw OR 'placebo*': ,ab,de,kw OR ((('singl*' OR 'doubl*') NEXT/1 ('blind*' OR
'dumm*' OR 'mask*')): ,ab,de,kw) OR ((('tripl*' OR 'trebl*') NEXT/1 ('blind*' OR 'dumm*'
OR 'mask*')): ,ab,de,kw) OR (('control*' NEAR/3 ('study' OR 'studies' OR 'trial*' OR
'group*')): ,ab,kw) OR 'nonrandom*': ,ab,de,kw OR 'non-random*': ,ab,de,kw OR 'quasi-
random*': ,ab,de,kw OR 'quasirandom*': ,ab,de,kw OR 'allocated': ,ab,de OR (('open-
label' NEAR/5 ('study' OR 'studies' OR 'trial*')): ,ab,de,kw) OR ((('equivalence' OR
'superiority' OR 'non-inferiority' OR 'noninferiority') NEAR/3 ('study' OR 'studies' OR
'trial*')): ,ab,de,kw) OR 'pragma c study': ,ab,de,kw OR 'pragma c studies': ,ab,de,kw
OR ((('pragma c' OR 'prac cal') NEAR/3 trial*): ,ab,de,kw) OR ((('quasiexperimental' OR
'quasi-experimental') NEAR/3 ('study' OR 'studies' OR 'trial*')): ,ab,de,kw) OR ((('phase'
NEAR/3 ('iii' OR '3')): ,de,kw) AND ('study': ,de,kw OR 'studies': ,de,kw OR
'trial*': ,de,kw))
#28 #26 AND #27 93

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

255
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Table I.B.21. Free text and controlled vocabulary search of Embase for observational and descriptive
studies, May 22, 2023
Search step Query Results
#1 'conference abstract'/it OR 'conference review'/it 4,794,639
#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,128,633
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp 7,758,077
OR 'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'juvenile'/de OR 'child'/de OR 3,429,175
'pediatrics'/exp OR 'pediatric'/exp OR 'puberty'/exp OR 'sexual development'/exp OR
'adolescence'/exp OR 'preadolescence'/exp
#5 'adolescen*': ,ab,kw OR 'boy*': ,ab,kw OR 'girl*': ,ab,kw OR 'child': ,ab,kw OR 3,271,977
'children': ,ab,kw OR 'juvenile': ,ab,kw OR 'minors': ,ab,kw OR 'paediatr*': ,ab,kw OR
'pediatr*': ,ab,kw OR 'pre-pubertal': ,ab,kw OR 'prepubertal': ,ab,kw OR 'pre-
pubesc*': ,ab,kw OR 'prepubesc*': ,ab,kw OR 'pubesc*': ,ab,kw OR 'pubertal': ,ab,kw
OR 'puberty': ,ab,kw OR 'teen*': ,ab,kw OR 'youth*': ,ab,kw OR 'school-aged': ,ab,kw
OR 'adolescen*':jt OR 'child*':jt OR 'paediatr*':jt OR 'pediatr*':jt
#6 #4 OR #5 4,681,266
#7 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex 930,567
hormone'/exp OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR
'gender affirming hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal
therapy'/exp OR 'puberty suppression'/exp OR 'gender dysphoria'/exp/dm_dt OR 'gender
dysphoria'/exp/dm_th
#8 'gn-rh*': ,ab,kw OR 'gnrh*': ,ab,kw OR 'gonadotropin-releasing hormone*': ,ab,kw OR 46,126
'5-alpha reductase inhibitor*': ,ab,kw OR '5alpha reductase inhibitor*': ,ab,kw OR
'goserelin': ,ab,kw OR 'histrelin': ,ab,kw OR 'leuprolide': ,ab,kw OR 'leuprorelin': ,ab,kw
OR 'nafarelin': ,ab,kw OR 'triptorelin': ,ab,kw OR 'elagolix': ,ab,kw OR
'cetrorelix': ,ab,kw OR 'degarelix': ,ab,kw OR 'ganirelix': ,ab,kw OR 'relugolix': ,ab,kw
#9 ('puberty' NEAR/3 ('inhibit*' OR 'block*' OR 'suppress*')): ,ab,kw 640
#10 'an androgen*': ,ab,kw OR 'an -androgen*': ,ab,kw OR 'bicalutamide': ,ab,kw OR 31,534
'finasteride': ,ab,kw OR 'dutasteride': ,ab,kw OR 'spironolactone': ,ab,kw OR
'flutamide': ,ab,kw OR 'nilutamide': ,ab,kw
#11 ('androgen' NEAR/3 ('antagonist*' OR 'inhibit*' OR 'block*')): ,ab,kw 8,658
#12 'sex hormon*': ,ab,kw OR 'sex steroid hormon*': ,ab,kw OR 'gonadal steroid*': ,ab,kw 570,233
OR 'androgen*': ,ab,kw OR 'androst*': ,ab,kw OR 'estrogen*': ,ab,kw OR

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

256
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Table I.B.21. Free text and controlled vocabulary search of Embase for observational and descriptive
studies, May 22, 2023
Search step Query Results
'oestrogen*': ,ab,kw OR 'estradiol*': ,ab,kw OR 'oestradiol*': ,ab,kw OR
'dehydroepiandrosterone': ,ab,kw OR 'prasterone': ,ab,kw OR 'dhea': ,ab,kw OR
'dihydrotestosterone': ,ab,kw OR 'dht': ,ab,kw OR 'dihydroprogesterone': ,ab,kw OR
'dihydroepitestosterone': ,ab,kw OR 'epiandrosterone': ,ab,kw OR
'epitestosterone': ,ab,kw OR 'epiestriol': ,ab,kw OR 'equilenin': ,ab,kw OR
'equilin': ,ab,kw OR 'estrane*': ,ab,kw OR 'estrenolone': ,ab,kw OR 'estrone': ,ab,kw
OR 'e ocholanolone': ,ab,kw OR 'folliculin': ,ab,kw OR 'gestagen*': ,ab,kw OR
'hermaphrodiol': ,ab,kw OR 'hydroxyestrone*': ,ab,kw OR
'hydroxypregnenolone*': ,ab,kw OR 'hydroxysteroid*': ,ab,kw OR
'hydroxytestosterone*': ,ab,kw OR 'isotestosterone': ,ab,kw OR 'ketosteroid*': ,ab,kw
OR 'medroxyprogesterone': ,ab,kw OR 'mestranol': ,ab,kw OR
'methyltestosterone': ,ab,kw OR 'danazol': ,ab,kw OR 'nandrolone': ,ab,kw OR
'nortestosterone': ,ab,kw OR 'oxosteroid*': ,ab,kw OR 'pregnenolone*': ,ab,kw OR
'progesta onal hormon*': ,ab,kw OR 'progest*': ,ab,kw OR 'quinestrol': ,ab,kw OR
'stanolone': ,ab,kw OR 'testosterone': ,ab,kw OR 'dydrogesterone': ,ab,kw OR
'levonorgestrel': ,ab,kw OR 'dienogest': ,ab,kw OR 'norethindrone': ,ab,kw OR
'norges mate': ,ab,kw OR 'drospirenone': ,ab,kw OR 'desogestrel': ,ab,kw OR
'etonogestrel': ,ab,kw OR 'norelgestromin': ,ab,kw OR 'norgestrel': ,ab,kw OR
'segesterone': ,ab,kw OR 'ethynodiol': ,ab,kw
#13 ('hormon*' NEAR/3 ('replacement' OR 'suppress*' OR 'therap*' OR 'treat*' OR 'cross-sex' 113,417
OR 'gender-affirming')): ,ab,kw
#14 'gender-affirming pharmaceu cal*': ,ab,kw OR 'contracep ve*': ,ab,kw 73,365
#15 'aromatase inhibitor*': ,ab,kw OR 'anastrozole': ,ab,kw OR 'exemestane': ,ab,kw OR 20,361
'letrozole': ,ab,kw
#16 'selec ve estrogen receptor modulator*': ,ab,kw OR 'serm': ,ab,kw OR 59,866
'an estrogen*': ,ab,kw OR 'an -estrogen*': ,ab,kw OR 'bazedoxifene': ,ab,kw OR
'clomiphene': ,ab,kw OR 'clomifene': ,ab,kw OR 'ospemifene': ,ab,kw OR
'raloxifene': ,ab,kw OR 'tamoxifen': ,ab,kw OR 'toremifene': ,ab,kw
#17 'proges n receptor modulator*': ,ab,kw OR 'ulipristal': ,ab,kw OR 'minoxidil': ,ab,kw 4,123
#18 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 1,186,884
#19 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,718
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#20 'gender dysphor*': ,ab,kw OR 'gender minorit*': ,ab,kw OR 'gender divers*': ,ab,kw OR 24,274
'gender iden ty': ,ab,kw OR 'gender incongruenc*': ,ab,kw OR 'gender
transi on*': ,ab,kw OR 'trans-female*': ,ab,kw OR 'transfemale*': ,ab,kw OR 'trans-
feminine': ,ab,kw OR 'transfeminine': ,ab,kw OR 'trans-gender*': ,ab,kw OR
'transgender*': ,ab,kw OR 'trans-sexual*': ,ab,kw OR 'transsex*': ,ab,kw OR 'trans-

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

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Table I.B.21. Free text and controlled vocabulary search of Embase for observational and descriptive
studies, May 22, 2023
Search step Query Results
male*': ,ab,kw OR 'transmale*': ,ab,kw OR 'trans-masculine': ,ab,kw OR
'transmasculine': ,ab,kw OR 'transboy*': ,ab,kw OR 'transgirl*': ,ab,kw
#21 ('gender' NEAR/1 ('affirm*' OR 'confirm*' OR 'reassign*')): ,ab,kw 4,100
#22 (('sex' OR 'medical') NEXT/1 ('reassign*' OR 'transi on*')): ,ab,kw 1,249
#23 #19 OR #20 OR #21 OR #22 42,685
#24 #6 AND #18 AND #23 2,594
#25 #24 NOT (#1 OR #2 OR #3) 1,868
#26 #24 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 1,375
#27 'epidemiology'/de OR 'observa onal study'/de OR 'clinical study'/exp OR 'cross-sec onal 19,666,362
study'/exp OR 'seroepidemiology'/exp OR 'na onal longitudinal study of adolescent
health'/de OR 'cohort analysis'/de OR 'longitudinal study'/de OR 'prospec ve study'/de
OR 'follow up'/de OR 'retrospec ve study'/de OR 'case control study'/exp OR 'quasi
experimental study'/de OR 'single-case study'/de OR 'valida on study'/de OR 'pilot
study'/de OR 'controlled study'/de OR 'pretest pos est control group design'/de OR
'compara ve study'/de OR 'compara ve effec veness'/de OR (('observa onal' NEAR/3
('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR
'cohort*': ,ab,kw OR (('prospec ve' NEAR/7 ('study' OR 'studies' OR 'design' OR 'analysis'
OR 'analyses')): ,ab,kw) OR ((('follow up' OR 'followup') NEAR/7 ('study' OR 'studies' OR
'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR ((('longitudinal' OR 'longterm' OR 'long-
term') NEAR/7 ('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses' OR
'data')): ,ab,kw) OR (('retrospec ve' NEAR/7 ('study' OR 'studies' OR 'design' OR 'analysis'
OR 'analyses' OR 'data' OR 'review')): ,ab,kw) OR (('case' NEXT/1 'control'): ,ab,kw) OR
(('case' NEXT/1 'comparison'): ,ab,kw) OR (('case' NEXT/1 'controlled'): ,ab,kw) OR
(('case-referent' NEAR/3 ('study' OR 'studies' OR 'design' OR 'analysis' OR
'analyses')): ,ab,kw) OR (('popula on' NEAR/3 ('study' OR 'studies' OR 'analysis' OR
'analyses')): ,ab,kw) OR (('descrip ve' NEAR/3 ('study' OR 'studies' OR 'design' OR
'analysis' OR 'analyses')): ,ab,kw) OR ((('mul dimensional' OR 'mul -dimensional')
NEAR/3 ('study' OR 'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR (('cross-
sec onal' NEAR/7 ('study' OR 'studies' OR 'design' OR 'research' OR 'analysis' OR
'analyses' OR 'survey' OR 'findings')): ,ab,kw) OR (('natural' NEXT/1
'experiment'): ,ab,kw) OR (('natural' NEXT/1 'experiments'): ,ab,kw) OR (('quasi' NEXT/1
('experiment' OR 'experiments' OR 'experimental')): ,ab,kw) OR ((('non experiment' OR
'nonexperiment' OR 'non experimental' OR 'nonexperimental') NEAR/3 ('study' OR
'studies' OR 'design' OR 'analysis' OR 'analyses')): ,ab,kw) OR (('prevalence' NEAR/3
('study' OR 'studies' OR 'analysis' OR 'analyses')): ,ab,kw) OR 'case series': ,ab,kw OR
'case report'/de OR 'case study'/exp OR (('case' NEAR/3 ('report' OR 'reports' OR 'study'
OR 'studies' OR 'histories')): ,ab,kw) OR 'health services research'/de
#28 #26 AND #27 724

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

258
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Table I.B.22. Free text and controlled vocabulary search of Embase for qualitative studies, June 5, 2023
Search step Query Results
#1 'conference abstract'/it OR 'conference review'/it 4,804,537
#2 animal*: OR beaver*: OR beef: OR bovine: OR breeding: OR canine: OR castoris: 3,133,289
OR cat: OR ca le: OR cats: OR chicken*: OR cow: OR dog: OR dogs: OR equine:
OR foal: OR foals: OR fish: OR insect*: OR livestock: OR mice: OR mouse: OR
murine: OR plant: OR plants: OR pork: OR porcine: OR protozoa*: OR purebred:
OR rabbit*: OR rat: OR rats: OR rodent*: OR sheep: OR thoroughbred: OR
veterinar*: ,ab,de
#3 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 7,770,424
'animal ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR
'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal
ssue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human
cell'/de))
#4 'minor (person)'/exp OR 'adolescent'/exp OR 'juvenile'/de OR 'child'/de OR 'pediatrics'/exp 3,438,008
OR 'pediatric'/exp OR 'puberty'/exp OR 'sexual development'/exp OR 'adolescence'/exp
OR 'preadolescence'/exp
#5 'adolescen*': ,ab,kw OR 'boy*': ,ab,kw OR 'girl*': ,ab,kw OR 'child': ,ab,kw OR 3,281,856
'children': ,ab,kw OR 'juvenile': ,ab,kw OR 'minors': ,ab,kw OR 'paediatr*': ,ab,kw OR
'pediatr*': ,ab,kw OR 'pre-pubertal': ,ab,kw OR 'prepubertal': ,ab,kw OR 'pre-
pubesc*': ,ab,kw OR 'prepubesc*': ,ab,kw OR 'pubesc*': ,ab,kw OR 'pubertal': ,ab,kw
OR 'puberty': ,ab,kw OR 'teen*': ,ab,kw OR 'youth*': ,ab,kw OR 'school-aged': ,ab,kw
OR 'adolescen*':jt OR 'child*':jt OR 'paediatr*':jt OR 'pediatr*':jt
#6 #4 OR #5 4,692,643
#7 'sex hormones therapeu c use'/exp OR 'gonadorelin deriva ve'/exp OR 'sex hormone'/exp 932,377
OR 'an androgen'/exp OR 'steroid 5alpha reductase inhibitor'/exp OR 'gender affirming
hormone therapy'/exp OR 'gender affirming care'/exp OR 'hormonal therapy'/exp OR
'puberty suppression'/exp OR 'gender dysphoria'/exp/dm_dt OR 'gender
dysphoria'/exp/dm_th
#8 'gn-rh*': ,ab,kw OR 'gnrh*': ,ab,kw OR 'gonadotropin-releasing hormone*': ,ab,kw OR 46,208
'5-alpha reductase inhibitor*': ,ab,kw OR '5alpha reductase inhibitor*': ,ab,kw OR
'goserelin': ,ab,kw OR 'histrelin': ,ab,kw OR 'leuprolide': ,ab,kw OR 'leuprorelin': ,ab,kw
OR 'nafarelin': ,ab,kw OR 'triptorelin': ,ab,kw OR 'elagolix': ,ab,kw OR
'cetrorelix': ,ab,kw OR 'degarelix': ,ab,kw OR 'ganirelix': ,ab,kw OR 'relugolix': ,ab,kw
#9 ('puberty' NEAR/3 ('inhibit*' OR 'block*' OR 'suppress*')): ,ab,kw 641
#10 'an androgen*': ,ab,kw OR 'an -androgen*': ,ab,kw OR 'bicalutamide': ,ab,kw OR 31,589
'finasteride': ,ab,kw OR 'dutasteride': ,ab,kw OR 'spironolactone': ,ab,kw OR
'flutamide': ,ab,kw OR 'nilutamide': ,ab,kw
#11 ('androgen' NEAR/3 ('antagonist*' OR 'inhibit*' OR 'block*')): ,ab,kw 8,679
#12 'sex hormon*': ,ab,kw OR 'sex steroid hormon*': ,ab,kw OR 'gonadal steroid*': ,ab,kw 571,157
OR 'androgen*': ,ab,kw OR 'androst*': ,ab,kw OR 'estrogen*': ,ab,kw OR
'oestrogen*': ,ab,kw OR 'estradiol*': ,ab,kw OR 'oestradiol*': ,ab,kw OR

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

259
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Table I.B.22. Free text and controlled vocabulary search of Embase for qualitative studies, June 5, 2023
Search step Query Results
'dehydroepiandrosterone': ,ab,kw OR 'prasterone': ,ab,kw OR 'dhea': ,ab,kw OR
'dihydrotestosterone': ,ab,kw OR 'dht': ,ab,kw OR 'dihydroprogesterone': ,ab,kw OR
'dihydroepitestosterone': ,ab,kw OR 'epiandrosterone': ,ab,kw OR
'epitestosterone': ,ab,kw OR 'epiestriol': ,ab,kw OR 'equilenin': ,ab,kw OR
'equilin': ,ab,kw OR 'estrane*': ,ab,kw OR 'estrenolone': ,ab,kw OR 'estrone': ,ab,kw OR
'e ocholanolone': ,ab,kw OR 'folliculin': ,ab,kw OR 'gestagen*': ,ab,kw OR
'hermaphrodiol': ,ab,kw OR 'hydroxyestrone*': ,ab,kw OR
'hydroxypregnenolone*': ,ab,kw OR 'hydroxysteroid*': ,ab,kw OR
'hydroxytestosterone*': ,ab,kw OR 'isotestosterone': ,ab,kw OR 'ketosteroid*': ,ab,kw
OR 'medroxyprogesterone': ,ab,kw OR 'mestranol': ,ab,kw OR
'methyltestosterone': ,ab,kw OR 'danazol': ,ab,kw OR 'nandrolone': ,ab,kw OR
'nortestosterone': ,ab,kw OR 'oxosteroid*': ,ab,kw OR 'pregnenolone*': ,ab,kw OR
'progesta onal hormon*': ,ab,kw OR 'progest*': ,ab,kw OR 'quinestrol': ,ab,kw OR
'stanolone': ,ab,kw OR 'testosterone': ,ab,kw OR 'dydrogesterone': ,ab,kw OR
'levonorgestrel': ,ab,kw OR 'dienogest': ,ab,kw OR 'norethindrone': ,ab,kw OR
'norges mate': ,ab,kw OR 'drospirenone': ,ab,kw OR 'desogestrel': ,ab,kw OR
'etonogestrel': ,ab,kw OR 'norelgestromin': ,ab,kw OR 'norgestrel': ,ab,kw OR
'segesterone': ,ab,kw OR 'ethynodiol': ,ab,kw
#13 ('hormon*' NEAR/3 ('replacement' OR 'suppress*' OR 'therap*' OR 'treat*' OR 'cross-sex' 113,632
OR 'gender-affirming')): ,ab,kw
#14 'gender-affirming pharmaceu cal*': ,ab,kw OR 'contracep ve*': ,ab,kw 73,483
#15 'aromatase inhibitor*': ,ab,kw OR 'anastrozole': ,ab,kw OR 'exemestane': ,ab,kw OR 20,411
'letrozole': ,ab,kw
#16 'selec ve estrogen receptor modulator*': ,ab,kw OR 'serm': ,ab,kw OR 59,941
'an estrogen*': ,ab,kw OR 'an -estrogen*': ,ab,kw OR 'bazedoxifene': ,ab,kw OR
'clomiphene': ,ab,kw OR 'clomifene': ,ab,kw OR 'ospemifene': ,ab,kw OR
'raloxifene': ,ab,kw OR 'tamoxifen': ,ab,kw OR 'toremifene': ,ab,kw
#17 'proges n receptor modulator*': ,ab,kw OR 'ulipristal': ,ab,kw OR 'minoxidil': ,ab,kw 4,137
#18 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 1,189,104
#19 'gender dysphoria'/exp OR 'gender affirma on'/exp OR 'gender iden ty'/exp OR 'gender 36,860
incongruence'/exp OR 'gender nonconformity'/exp OR 'sex reassignment'/exp OR 'gender
variance'/exp OR 'transgender and gender nonbinary'/exp OR 'transgender'/exp OR
'transsexuality'/exp
#20 'gender dysphor*': ,ab,kw OR 'gender minorit*': ,ab,kw OR 'gender divers*': ,ab,kw OR 24,440
'gender iden ty': ,ab,kw OR 'gender incongruenc*': ,ab,kw OR 'gender
transi on*': ,ab,kw OR 'trans-female*': ,ab,kw OR 'transfemale*': ,ab,kw OR 'trans-
feminine': ,ab,kw OR 'transfeminine': ,ab,kw OR 'trans-gender*': ,ab,kw OR
'transgender*': ,ab,kw OR 'trans-sexual*': ,ab,kw OR 'transsex*': ,ab,kw OR 'trans-
male*': ,ab,kw OR 'transmale*': ,ab,kw OR 'trans-masculine': ,ab,kw OR
'transmasculine': ,ab,kw OR 'transboy*': ,ab,kw OR 'transgirl*': ,ab,kw
#21 ('gender' NEAR/1 ('affirm*' OR 'confirm*' OR 'reassign*')): ,ab,kw 4,142

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

260
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Table I.B.22. Free text and controlled vocabulary search of Embase for qualitative studies, June 5, 2023
Search step Query Results
#22 (('sex' OR 'medical') NEXT/1 ('reassign*' OR 'transi on*')): ,ab,kw 1,251
#23 #19 OR #20 OR #21 OR #22 42,882
#24 #6 AND #18 AND #23 2,604
#25 #24 NOT (#1 OR #2 OR #3) 1,875
#26 #24 NOT (#1 OR #2 OR #3) AND [2010-2023]/py 1,382
#27 'empirical research'/exp OR 'interview'/exp OR 'literature'/exp OR 'focus group'/exp OR 4,303,354
'informa on processing'/exp OR 'verbal communica on'/exp OR 'nursing methodology
research'/de OR 'narra ve medicine'/de OR 'interview*': ,ab,kw OR 'qualita ve': ,ab,kw,jt
OR 'theme*': ,ab,kw OR 'thema c': ,ab,kw OR 'ethnological research': ,ab,kw OR
'ethnograph*': ,ab,kw OR 'ethnomedicine': ,ab,kw OR 'ethnonursing': ,ab,kw OR
'phenomenol*': ,ab,kw OR (('grounded' NEXT/1 ('theor*' OR 'study' OR 'studies' OR
'research' OR 'analys?s')): ,ab,kw) OR 'life stor*': ,ab,kw OR 'emic': ,ab,kw OR
'e c': ,ab,kw OR 'hermeneu c*': ,ab,kw OR 'heuris c*': ,ab,kw OR 'semio c*': ,ab,kw
OR (('data' NEAR/1 'saturat*'): ,ab,kw) OR 'par cipant observ*': ,ab,kw OR 'social
construct*': ,ab,kw OR 'postmodern*': ,ab,kw OR 'post-structural*': ,ab,kw OR
'poststructural*': ,ab,kw OR 'post-modern*': ,ab,kw OR 'ac on research': ,ab,kw OR
'coopera ve inquir*': ,ab,kw OR 'co-opera ve inquir*': ,ab,kw OR 'humanis c': ,ab,kw
OR 'existen al': ,ab,kw OR 'experien al': ,ab,kw OR 'paradigm*': ,ab,kw OR (('field'
NEXT/1 ('study' OR 'studies' OR 'research' OR 'work')): ,ab,kw) OR 'human
science': ,ab,kw OR 'social science': ,ab,kw OR 'biographical method': ,ab,kw OR
'theore cal sampl*': ,ab,kw OR (('purpos*' NEAR/4 'sampl*'): ,ab,kw) OR (('focus' NEXT/1
'group*'): ,ab,kw) OR 'open-ended': ,ab,kw OR 'narra ve*': ,ab,kw OR 'textual': ,ab,kw
OR 'texts': ,ab,kw OR 'semi-structured': ,ab,kw OR 'life-world*': ,ab,kw OR 'conversa on
analys?s': ,ab,kw OR 'personal experience*': ,ab,kw OR 'theore cal satura on': ,ab,kw
OR ((('lived' OR 'life') NEXT/1 'experience*'): ,ab,kw) OR 'cluster sampl*': ,ab,kw OR
'observa onal method*': ,ab,kw OR 'content analysis': ,ab,kw OR (('constant' NEXT/1
('compara ve' OR 'comparison')): ,ab,kw) OR ((('discourse*' OR 'discurs*') NEAR/3
'analys?s'): ,ab,kw) OR 'heidegger*': ,ab,kw OR 'colaizzi*': ,ab,kw OR
'spiegelberg*': ,ab,kw OR 'merleau*': ,ab,kw OR 'husserl*': ,ab,kw OR
'foucault*': ,ab,kw OR 'ricoeur': ,ab,kw OR 'glaser*': ,ab,kw OR (('van' NEXT/1
'manen*'): ,ab,kw) OR (('van' NEXT/1 'kaam*'): ,ab,kw) OR (('corbin*' NEAR/2
'strauss*'): ,ab,kw)
#28 'ques onnaire'/exp OR 'health care survey'/de OR 'self report'/de OR 2,081,019
'ques onnaire*': ,ab,kw OR 'survey*': ,ab,kw
#29 #27 OR #28 5,833,354
#30 #26 AND #29 380

Table abbreviations: MeSH, medical subject headings (ie, structured vocabulary for Medline); DRRC, Drug
Regimen Review Center; SR, systematic review; CADTH, Canada's Drug and Health Technology Agency; RCT,
randomized controlled trial; CCT, controlled clinical trial

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APPENDIX I.C: STUDIES EXCLUDED AT FULL-TEXT SCREENING, BY
CRITERION
Excluded because Wrong Patient Population
182,184-193,195,196,198,200-203,205,206,208,210-215,220,222,223,225-229,231,235-238,244,247,249,251,253,256,259-261,263,264,266-270,272-275,278,281,283,284,286-291,294,299-301,303,305-307,309,312,316-318,322-325,328-330,332,334-336,339,340,342-344
4-7,10,13-21,23-28,30,32,34,37,39-42,45,46,48,50,51,53,55,57,58,61,65,66,70,72,73,76-80,84,89-92,95,96,100,101,105-109,112-116,118,119,121,123-128,131,132,134,136,138,140-142,144,146,148,151,153,155,156,158,159,161,163,166,167,169,171,173-175,177-

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Excluded because Wrong Study Design or Publication Type

2,3,8,9,12,22,31,33,36,38,43,44,47,49,54,56,60,62,63,68,71,74,75,81,85-88,93,94,97-99,102,104,110,117,120,122,130,149,152,154,157,162,170,172,176,194,199,204,209,217,219,221,224,230,234,239,241-243,245,248,250,252,254,255,258,262,265,271,279,280,282,292,293,297,298,302,310,311,313-315,320,321,331,337,338,341

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Excluded because No Intervention of Interest 11,29,35,52,59,67,69,82,83,103,111,129,133,135,137,139,143,145,147,150,160,164,165,168,183,197,207,216,218,232,233,240,246,257,276,277,285,295,296,304,308,319,326,327,333,345

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APPENDIX I.D: CLINICAL PRACTICE GUIDELINE DATA EXTRACTION
TABLES

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Table I.D.1. Overview of development methodology and level of evidence (LOE) for recommendations by guidelines or position statements addressing gender-affirming hormonal therapies (GAHT)
Guideline/Statement Name Organization; publication year Overview of Development Methods and LOE Rating
Standards of Care for the Health of World Professional Association for Guideline Development Methodology: Formal recommendations were informed by a systematic review of the evidence performed by expert methodologists and expert opinion.
Transgender and Gender Diverse Transgender Health (WPATH); 2022 Methodologists evaluated the risk of bias of included evidence and graded the evidence using the GRADE system. A multidisciplinary guideline team of experts who completed COI
People, Version 839 statements and were not compensated for their service defined guideline questions, drafted chapters, and voted on recommendations using Delphi-consensus (requiring that ≥ 75%
of voters agreed). Guideline development was funded by a grant by the Tawani Foundation and WPATH.
LOE Ratings: Formal recommendations were not assigned a specific LOE. The recommendations strengths (strong or weak) correlate with the LOE.
Strength of recommendations:
Strong, worded as "we recommend": Formal recommendations supported by (1) high evidence quality; (2) high certainty of effectiveness; (3) comparatively few risks; and (4)
high acceptance by the community.
Weak, worded as "we suggest": Formal recommendations supported or limited by (1) evidence with weaknesses; (2) doubt about effectiveness in regular care; (3) requirement
for careful balance of the risks vs benefits; and (4) acceptance by the community varies.
Endocrine Treatment of Gender- Endocrine Society (ES); 2017 Guideline Development Methodology: The guideline was developed by experts, a medical writer, and a methodologist. Guideline developer's COI were declared. Guideline
Dysphoric/Gender-Incongruent development was funded by the ES. Two systematic reviews were commissioned for the guideline; these reviews addressed the effects of sex steroid hormonal therapy on (1)
Persons42 cardiovascular and lipid outcomes or (2) bone health in transgender people. Recommendations were based on "…the best available research evidence" (page 3872) and were
assigned strength of recommendation and quality of evidence using the GRADE approach.408
LOE Ratings: Very-low quality: primarily based one unsystematic observations or indirect evidence; low quality: evidence from flawed RCTs or observational studies, or indirect
evidence; moderate quality: RCT-level evidence with limitations or strong observational study evidence lacking bias; high quality: evidence from good-quality RCTs or very strong
observational studies lacking bias.409
Strength of recommendations:
Strong, worded as "we recommend": Most patients will receive greater benefits than harms by following this recommendation.
Weak, worded as "we suggest": Determine whether to follow this recommendation by considering each patient's unique values and circumstances.
Other, "Ungraded Good Practice Statement": These are basic principles; evidence for the statement was either lacking, or outside the scope of the guideline.
Assessment and Hormonal European Society for Sexual Medicine Guideline Development Methodology: An interdisciplinary team of 7 experts with clinical or research experience on transgender patient healthcare (ie, including areas of
Management in Adolescent and Adult Position Statement (ESSM); 2020 endocrinology, psychology, psychiatry, surgery, sociology) developed consensus-based recommendations informed by a systematic literature review. COI were disclosed, and the
Trans People, With Attention for guideline was developed with funding from the European Society of Sexual Medicine. Experts voted on "General Statements" pertaining to transgender healthcare, revising
Sexual Function and Satisfaction41 statements until they achieved 100% consensus. It was described that "The available literature for a direct recommendation was limited, and most of the literature was used as
background or indirect evidence" (page 572).
LOE Ratings: No formal LOE ratings provided for each recommendation. Recommendations are consensus-based with inference from the literature.
Strength of recommendations: No rating strength provided. Recommendation statements include "We advise…"
General Approaches to Medical The American College of Obstetricians and Guideline Development Methodology: The guideline is consensus-based, informed by a systematic review of the literature using a hierarchy-of-evidence approach with an emphasis
Management of Menstrual Gynecologists (ACOG); 2022 on systematic reviews, randomized controlled trials, and observational studies. No risk of bias assessment or LOE rating was performed. The committee of about 20 ACOG members
Suppression40 including members with subspecialty expertise (eg, adolescents) reviewed compiled literature and voted on consensus statements informed by the literature, or based on expert
opinion if evidence was limited. Included recommendation statements required at least 75% agreement among voting committee members. Committee members were required to
disclose COI; no information about funding was provided in the guideline publication.
LOE Ratings: No LOE ratings performed or provided for each recommendation. Recommendations are consensus-based with inference from the literature.
Strength of recommendations: No rating strength provided.
Table abbreviations: ACOG, American College of Obstetricians and Gynecologists; COI, conflict of interest; GRADE, Grading of Recommendations, Assessment, Development and Evaluations; LOE, level of evidence; WPATH, World Professional Association for
Transgender Health.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
Guidelines
Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 (2022);
World Professional Association for Transgender Health (WPATH)39
Target population: All persons with a gender identity differing from the identity typically associated with the gender assigned at birth. This includes transgender and gender-diverse persons, including but not limiting to the following: gender nonconforming,
nonbinary, and identities or expressions not typically recognized by Western culture.
Adolescents: People who have reached puberty and who are < 18 years old (or age of majority).
Children: People who are pre-pubescent.
Adolescents should meet ALL OF THE FOLLOWING criteria to receive gender-affirming medical General Treatment Recommendation for all age groups:
treatments (rated together as strong):
"We recommend health care systems should provide medically necessary gender-affirming health care for transgender and gender diverse people" (page
"The adolescent meets the diagnostic criteria for gender incongruence as per the ICD-11 in situations S16).39 (strong)
where a diagnosis is necessary to access health care…" (page S48) Hormonal therapy recommendations for children:
"The experience of gender diversity/incongruence is marked and sustained over time" (page S48)
Hormone or hormone-blocking treatments are not recommended before puberty (ie, before Tanner Stage 2) (non-graded).
"The adolescent demonstrates the emotional and cognitive maturity required to provide informed
Recommendations for when to begin hormonal therapies in eligible adolescents for pubertal suppression or CSHT:
consent/assent for the treatment" (page S48)
May begin pubertal hormonal suppression after reaching Tanner stage 2 (strong)
"The adolescent's mental health concerns (if any) that may interfere with diagnostic clarity, capacity to
consent, and gender-affirming medical treatments have been addressed" (page S48) o Use of GnRH analog for pubertal suppression is only considered for Tanner stage 1 (pre-pubescent youth) if the youth is also experiencing
constitutional delay of growth. Youth with constitutional delay of growth eligible for hormonal therapy may start CSHT with GnRH analog therapy.
"The adolescent has been informed of the reproductive effects, including the potential loss of fertility
(non-graded)
and the available options to preserve fertility, and these have been discussed in the context of the
adolescent's stage of pubertal development" (page S48) GnRH analog is suggested if the adolescent is developed beyond Tanner stage 3, and there is a desire to delay sex hormone replacement (weak).
"The adolescent has reached Tanner stage 2 of puberty for pubertal suppression to be initiated" (page May begin sex hormone replacement therapy (CSHT) if ≥ Tanner stage 2; parental involvement is recommended unless it is considered detrimental or
S48) unnecessary (strong)
"The adolescent had at least 12 months of gender-affirming hormone therapy or longer, if required, to The following hormonal treatments are suggested or recommended as part of pubertal suppression or CSHT for eligible TBNB people:
achieve the desired surgical result for gender-affirming procedures, including breast augmentation, GnRH analogs recommended for adolescents when puberty suppression is indicated (strong)
orchiectomy, vaginoplasty, hysterectomy, phalloplasty, metoidioplasty, and facial surgery as part of
gender-affirming treatment unless hormone therapy is either not desired or is medically
contraindicated" (page S48)39

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
Recommendation for assessment of adolescents for hormonal therapies (strong): o Progestins (oral or injectable depot) are an alternative for puberty suppression in youth when GnRH analogs are not accessible (weak). There is a lack
of information about the safety (for bone development) of treatment with GnRH analog monotherapy after age 14 (non-graded), which is potentially
"We recommend health care professionals involve relevant disciplines, including mental health and
another reason to consider alternative pubertal suppression therapies.
medical professionals, to reach a decision about whether puberty suppression, hormone initiations, or
gender-related surgery for gender diverse and transgender adolescents are appropriate and remain Feminizing CSHT for people with testes:
indicated through the course of treatment until the transition is made to adult care" (page S56).39 o 17-β-estradiol recommended for pubertal induction in adolescents with testes (non-graded)
o Transdermal estrogen for adults/adolescents receiving GAET at higher risk for VTE (eg, age > 45 years or a history of VTE) (weak)
o Testosterone-lowering therapies (cyproterone acetate, spironolactone, or GnRH analog) for adults/adolescents desiring sex hormone levels like
cisgender women (strong)
Masculinizing CSHT for people with ovaries:
o Testosterone-ester injection is often recommended by experts for pubertal induction in adolescents due to availability and history of use (non-graded)
The following hormonal therapies are NOT recommended as part of CSHT for eligible adults or adolescents:
Ethinyl estradiol (strong) (17-β-estradiol is a preferred option due to lower thromboembolism risk [non-graded])
Conjugated estrogen if estradiol is available (weak)
Progestins (other than cyproterone acetate) for feminizing treatment (eg, additional breast development) are not suggested for most adults/adolescents
since there is a lack of evidence of benefits and a potential for harm. Evaluate response within 1 year if used. (non-graded)
Bicalutamide (an anti-androgen) or 5α-reductase inhibitors (except for treating alopecia associated with high dihydrotestosterone levels) are not
recommended for "routine use" page S124 (non-graded)
Menstrual cycle suppression for eligible adolescents:
Menstrual suppression agents (progestogens or GnRH analogs) are recommended for people with a uterus not receiving testosterone, or in the case of
breakthrough bleeding with testosterone therapy alone. Menstrual suppression may reduce menstruation-related gender dysphoria (strong).
o Progestins, or GnRH analogs in youth meeting criteria for puberty suppression, are options for primary or adjunctive menstrual suppression to
testosterone (non-graded)
Recommendations for continuation of hormonal therapies for eligible TGNB people:
Due to potential adverse effects on bone health, the duration of GnRH analog monotherapy in adolescents should be decided based on various clinical
factors (eg, bone mass, bone age, pubertal stage) and psychosocial factors (eg, maturity, and development relative to peers). (non-graded)

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
Generally, GnRH analogs may be continued in adolescents with ovaries who started them until testosterone levels are sufficient to suppress estrogen
(non-graded). For adolescents with testes, GnRH analogs (or an alternative testosterone-blocking therapy) should be continued until gonadectomy (if
indicated). (non-graded)
Testosterone-lowing therapies (including GnRH analogs or other agents) are usually continued in people with testes until gonadectomy, if desired (non-
graded)
After gonadectomy, it is important to continue sex hormone replacement therapy for bone and mental health (non-graded)
Initiate and continue CSHT for eligible adolescents/adults "…due to demonstrated improvement in psychosocial functioning and quality of life," page
S12639 (strong)
Continue hormonal therapy for eligible adolescents/adults if "…mental health deteriorates and assess the reason for the deterioration, unless
contraindicated," page S12639 (strong)
Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons (2017);
Endocrine Society (ES)42
Target population: Individuals with gender dysphoria (ie, meeting the DSM-5 definition) or gender incongruence (people identifying as a gender or with gender expression different from the natal gender)
Criteria for Adolescents to Receive GnRH analog treatment (non-graded; copied by ES from 2017 WPATH Hormonal therapy recommendations for children:
SOC):
Hormone or hormone-blocking treatments for pubertal suppression for gender-affirming treatment are not recommended before puberty (Strong; low
"A qualified MHP has confirmed that:" LOE).
o "the adolescent has demonstrated a long-lasting and intense pattern of gender nonconformity or Recommendations for when to begin hormonal therapies in eligible adolescents:
gender dysphoria (whether suppressed or expressed)"
Pubertal suppression is suggested as the initial treatment (Weak, Low LOE)
o "gender dysphoria worsened with the onset of puberty,"
Suggest beginning pubertal suppression after exhibiting initial signs of puberty (ie, Tanner stages G2/B2) (Weak, Low LOE)
o "any coexisting psychological, medical, or social problems that could interfere with treatment (e.g.,
o Authors considered early puberty (Tanner stage 2) to be the optimal time to initiate pubertal suppression. Pubertal suppression can be initiated in later
that may compromise treatment adherence) have been addressed, such as that the adolescent's
stages of puberty for menstrual suppression and prevention of facial hair growth. (non-graded)
situation and functioning are stable enough to start treatment,"
o "the adolescent has sufficient mental capacity to give informed consent to this (reversible) Sex hormone replacement therapy (CSHT) may be initiated at a low dose and up titrated once the adolescent has capacity to give informed consent (as
treatment" confirmed by a multidisciplinary care team); in most cases, capacity is reached by age 16 (Strong, Low LOE)

"And the adolescent:" Sex hormone replacement therapy (CSHT) may be started before age 16 (although there is little data for starting earlier than 13.5-14 years) under
compelling circumstances when managed by multidisciplinary care team (Strong, Very Low LOE)

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
o "has been informed of the effects and side effects of treatment (including potential loss of fertility if o Specific criteria for "compelling cases" are not provided; potential examples listed for special cases are when there may be harm from delaying sex
the individual subsequently continues with sex hormone treatment) and options to preserve hormone therapy (eg, bone harm due to starting GnRH analogs at a very early age, or psychological harm from delayed growth relative to peers)
fertility," The following hormonal treatments are suggested or recommended for eligible adolescents:
o "has given informed consent and (particularly when the adolescent has not reached the age of legal
GnRH analogs are the recommended agents for pubertal suppression (Strong, Low LOE)
medical consent, depending on applicable legislation), the parents and other caretakers or guardians
have consented to the treatment and are involved in supporting the adolescent throughout the Long-acting GnRH analogs preferred to GnRH antagonists due to less evidence for use of antagonists use in adolescents (non-graded)
treatment process" Oral or depot progestins, or an anti-androgen in transgender female patients, are alternatives if GnRH analogs are inaccessible (non-graded)
"And a pediatric endocrinologist or other clinician experienced in pubertal assessment" Suggested feminizing hormones include oral or transdermal 17-β-estradiol (non-graded)
o "agrees with the indication for GnRH analog treatment," Suggested masculinizing hormones include intramuscular or subcutaneous testosterone esters (non-graded)
o "has confirmed that puberty has started in the adolescent (Tanner stage ≥ G2/B2),"
Recommendations for continuation of hormonal therapies in eligible adolescents:
o "has confirmed that there are no medical contraindications to GnRH analog treatment" (page
3878)42 Continue GnRH analogs after starting CSHT, until gonadectomy. Alternatively for transgender male patients, the GnRH analogs may be continued until
Criteria for Adolescents to Receive Sex Hormone Replacement (non-graded; copied by ES from 2017 reaching an adult testosterone dose; a progestin may be added for breakthrough menstrual bleeding. Transgender female patients wishing to stop GnRH
WPATH SOC): analogs may consider starting an anti-androgen instead. (non-graded)

"A qualified MHP has confirmed:" Adults/adolescents who undergo gonadectomy require chronic hormone replacement or surveillance to prevent adverse effects from sex hormone
deficiency (non-graded)
o "the persistence of gender dysphoria,"
o "any coexisting psychological, medical, or social problems that could interfere with treatment (e.g.,
that may compromise treatment adherence) have been addressed, such that the adolescent's
situation and functioning are stable enough to start sex hormone treatment,"
o "the adolescent has sufficient mental capacity (which most adolescents have by age 16 years) to
estimate the consequences of this (partly) irreversible treatment, weigh the benefits and risks, and
give informed consent to this (partly) reversible treatment,"
"And the adolescent:
o "has been informed of the (irreversible) effects and side effects of treatment (including potential loss
of fertility and options to preserve fertility),
o "has given informed consent and (particularly when the adolescent has not reached the age of legal
medical consent, depend on applicable legislation) the parents and other caretakers or guardians

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
have consented to the treatment and are involved in supporting the adolescent through the
treatment process,"
"And a pediatric endocrinologist or other clinicians experienced in pubertal induction:"
o "agrees with the indication for sex hormone treatment,"
o "has confirmed that there are no medical contraindications to sex hormone treatment." (page
3878)42
Assessment and Hormonal Management in Adolescent and Adult Trans People, with Attention for Sexual Function and Satisfaction (2020);
European Society for Sexual Medicine41
Target population: People with a gender identity differing from their natal sex; the term "trans" was used broadly to recognize diverse gender identities, including people identifying as female, male, nonbinary, agender or other.
Hormone-therapy Related Assessment Statements for Gender Diverse Adolescents: Hormonal therapy recommendations for children:
For pubertal adolescents: HCPs should "…inform and explore all nonmedical and medical options, No information was provided about pharmacologic treatment of children. However, recommendations for puberty suppression and CSHT were for
including the effect that GAMIs [gender-affirming medical interventions] (puberty blockers, hormones "adolescents" specifically.
as well as surgical) may have on sexuality and fertility and if indicated, facilitate GAMIs [gender- Recommendations for beginning hormone therapy in adolescents (formal consensus):
41
affirming medical interventions]" (page 573) (formal consensus)
Hormonal puberty suppression suggested after Tanner stage G2 when adolescents may give consent and after addressing other assessment criteria (ie,
o Supporting information (informal) about assessment criteria for pubertal adolescents used in
assessment of gender identity and managing other psychosocial challenges when possible)
effectiveness studies evaluating puberal suppression therapies (page 573)41:
Puberty induction with CSHT is advised for adolescents desiring masculinizing or feminizing therapy, respectively, once the individual can give informed
 "(i) the adolescents show a persistent and long-lasting GIC [gender incongruence] that usually
consent
intensified or began around the start of puberty (and did not remit),
The following hormonal treatments are suggested or recommended for eligible adolescents or adults:
 (ii) the adolescents' co-occurring psychosocial difficulties should not interfere or hamper
assessment or treatment, GnRH analogs are options for adolescent pubertal suppression (informal information)
 (iii) the adolescent understands the pros and cons of [gender-affirming medical intervention] and Pubertal induction with testosterone (with gradual dose up-titration) advised for interested trans adolescents AFAB when the adolescent can give
has sufficient capacity to give informed consent, informed consent (formal consensus)
 (iv) the adolescent has sufficient family or other social support to pursue [gender-affirming o Examples of suggested hormone treatment options for people AFAB (listed without regarded to age) (informal information):
medical intervention], and
 Progestins: oral lynestrenol or medroxyprogesterone; parenteral medroxyprogesterone

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
 (v) the adolescent has actually experienced of the first physical puberal changes (Tanner stage G2)  Testosterone: intramuscular testosterone esters or testosterone undecanoate; subcutaneous testosterone esters; transdermal androgen gel; oral
because blocking is not necessary before that time and the experience of puberty is deemed testosterone undecanoate
important for gender identity development." Feminizing hormone therapy as pubertal induction with 17-β-estradiol (with gradual dose up-titration) advised for interested adolescents AMAB when the
adolescent can give informed consent. Feminizing therapy with estrogens and/or anti-androgens is suggested without specifying a target age. (both
formal consensus statements).
o Examples of suggested hormonal treatment options for people AMAB (listed without regarded to age) (informal information):
 Estrogens: oral estradiol (17-β-estradiol valerate); intramuscular estradiol valerate or estradiol cypionate; or transferal estradiol patch or gel.
Guideline authors consider oral or transdermal 17-β-estradiol to be the treatment of choice.
 Anti-androgens: spironolactone, cyproterone acetate
 GnRH analog: intramuscular or subcutaneous triptorelin
Menstrual suppression for AFAB (informal information):
During later adolescent puberty, a progestin is usually used (inferred that this is in place of GnRH analogs due to potential AEs from GnRH analogs)
"If induction of amenorrhea is desired and does not occur with testosterone treatment alone, the addition of a pregestational agent or GnRH analog may
be considered"41 (page 577; provided without regard to age)
Continuation of therapy recommendations for eligible adolescents and/or adults (informal information):
Therapies for menstrual suppression can be stopped after hysteron-oophorectomy
"If started, GnRH analogs are advised to be continued at least until the maintenance dosage of testosterone is reached and to be continued until
gonadectomy" (page 576).41
For people AFAB, testosterone therapy is usually life-long
For people AMAB, estrogen should be continued after gonadectomy. There is a lack of consensus in the medical literature about whether estrogen should
be stopped at ages matching postmenopausal ages in cisgender women.

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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Table I.D.2. Guideline recommendations for use of gender-affirming hormonal or hormone-blocking therapy (GAHT) in TGNB youth
Eligibility or Assessment Criteria for Youth to Receive Gender-affirming Hormone or Hormone-
Recommendations for Gender-Affirming Hormone or Hormone-blocking Therapy (GAHT)a,d in Youth (Strength/LOE)c
Blocking Therapy (GAHT)a,b (Strength/LOE)c
General Approaches to Medical Management of Menstrual Suppression (2022);
The American College of Obstetricians and Gynecologists40
Target population: All people desiring menstrual suppression, including a special section on transgender or gender-diverse people. Only recommendations for unique considerations for transgender people were extracted.
Not addressed General menstrual suppression recommendation for transgender or gender diverse people, without specified age (formal consensus):
"Transgender and gender-diverse individuals may benefit from menstrual suppression to decrease gender dysphoria associated with menses" (page
536)41
Agents recommended for menstrual suppression therapy that would not be used by cisgender women (formal consensus):
Testosterone therapy as part of CSHT is an option for amenorrhea

aExtracted information from guidelines is focused on eligibility criteria for children or adolescents to receive hormonal or hormone-blocking GAHT (left column) and information about initiation or cessation of GAHT, including preferences for particular GAHT
(right column). Depending on the structure of the guideline, information about GAHT (right column) was extracted from the adolescent section or from a combined hormonal therapy section non-specific to age. If recommendations did not specify an age or were
not from a text section on adolescents only, we indicated the recommendation may apply to either adolescents or adults.
b Although not an explicit eligibility criterion by all guidelines, youth should also not have a contraindication to receiving a given hormonal therapy. Refer to prescribing information for each treatment for contraindications. WPATH explicitly states that co-
treatment with antiretroviral medications is not a contraindication to GAHT (strong recommendation). Additionally, WPATH recommends screening for conditions which may be worsened during GAHT therapy before treatment (for example, to assist with
lowering the risk for adverse events).
cGuidelines used different approaches for rating recommendations or statements. 'Formal' recommendations include those assigned a ROB rating, LOE rating, or formed by consensus vote. In contrast, 'non-graded' or 'informal' statements were not formally
evaluated to form official statements but were typically provided as supportive text elaborating on formal recommendations. Non-graded/informal information was extracted when it answered questions of adolescent eligibility, or which and when hormonal
treatments are recommended.
dRefer to Appendix I.A for a list of medications belonging to each drug class. This report uses hormone terminology consistent with each guideline; in some cases, multiple words are used to refer to similar medications. For example, progestins are a synthetic
subtype of progestogens.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; COI, conflict of interest; CSHT, cross-sex hormonal therapy; GAET, gender-affirming estrogen treatment; GAHT, gender-affirming hormonal therapy; GnRH, gonadotropin
releasing hormone; HCPs, healthcare professionals; ICD, International Classification of Diseases; LOE, level of evidence; MHP, mental health professional; ROB, risk of bias; SOC, standard of care; TGNB, transgender, non-binary or gender diverse; VTE, venous
thromboembolism.

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 a
Table I.D.3. Overview of GAHT monitoring addressed by guidelines or position statements
Guideline/Statement Name Organization (publication year) Hormonal Therapy Monitoring Addressed Target Population(s) for Statementb
Standards of Care for the Health of Transgender World Professional Association for Measurement of sex hormone levels during treatment Everyone receiving sex hormone replacement
and Gender Diverse People, Version 839 Transgender Health (WPATH); 2022
Monitoring for physical and laboratory adverse effects Everyone receiving sex hormone replacement
Hematocrit (or hemoglobin) monitoring Everyone receiving testosterone replacement
Endocrine Treatment of Gender-Dysphoric/Gender- Endocrine Society (ES); 2017 Monitoring parameters and monitoring frequency during pubertal suppression treatment (eg, BP, height, Adolescents receiving puberty suppression therapy
Incongruent Persons42 weight, hormonal levels, vitamin D level, bone density) Adolescents receiving puberty induction therapy
Monitoring parameters and monitoring frequency during sex hormone (ie, puberty induction) treatment Everyone receiving sex hormone therapy
(eg, BP, height, weight, hormone-specific laboratory parameters, bone density)
Everyone receiving spironolactone therapy
Monitoring for physical and laboratory adverse effects from sex hormones
Laboratory monitoring parameters for spironolactone
Assessment and Hormonal Management in European Society for Sexual Medicine (ESSM); Measurement of sex hormone levels during treatment Everyone receiving sex hormone replacement
Adolescent and Adult Trans People, With Attention 2020
Monitoring for desired effects of sex hormone therapies (ie, virilization with testosterone, feminization Everyone receiving sex hormone replacement
for Sexual Function and Satisfaction41
for estrogens and/or anti-androgen therapy) Everyone receiving testosterone replacement
Laboratory monitoring of hematocrit People AFAB who stop testosterone therapy and
Osteoporosis screening have other risk factors for bone loss
General Approaches to Medical Management of The American College of Obstetricians and None specific to gender diverse people Not applicable
Menstrual Suppression40 Gynecologists (ACOG); 2022
a Extracted information is very general, with a focus on the nature of hormone/hormone-blocking therapy monitoring recommendations. Refer to guidelines for details about the 'how' and 'when' of monitoring recommendations.
bStatements in the right column are matched for the type of monitoring addressed in same row of the left-adjacent column. For example, measuring sex hormone levels is recommended by WPATH for everyone receiving puberty suppression and/or sex hormone
therapy replacement.
Table abbreviations: AFAB, assigned female at birth; BP, blood pressure.

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APPENDIX I.E: SYSTEMATIC REVIEW DATA EXTRACTION TABLES

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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
Baker (2021)46 1. Yes Purpose well-specified? Population, intervention, comparators, and outcomes were well-specified.
Type: Systematic review, narrative synthesis 2. Yes A priori protocol? Protocol published on PROSPERO (CRD42018115379)
Databases: PubMed, Embase, PsycINFO
3. No Study designs justified? Case reports were excluded without justification.
Search dates: Through October 2018 through
June 10, 2020 4. No Comprehensive search strategy? Authors searched 3 bibliographic databases and gray-literature sources without publication and language restrictions. They also searched reference lists of
relevant studies. They did not describe consulting with experts or searching trial registries. They did not publish search strategies or terms in either the publication or protocol.

5. Yes Performed study selection in duplicate? Duplicate screening was described.

6. Yes Performed data extraction in duplicate? ROB assessment of primary studies was conducted in duplicate; data collection was conducted by a single reviewer with a second reviewer checking
accuracy.

7. No List of excluded studies? No list of excluded studies was provided.

8. Yes Detailed description of included studies? Authors described populations (with key details), interventions and comparators (with key details), outcomes, research designs, settings, and timeframe
for follow-up.

9. Yes Assessed study-level ROB? Authors used the revised Cochrane risk-of-bias tool for RCTs and ROBINS-I for NRSIs.

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. Yes Impact of ROB on results assessed? Authors assessed the impact of primary-study ROB on their findings.

13. Yes Impact of ROB on results discussed? Authors discussed the impact of primary-study ROB on their findings.

14. N/A Impact of heterogeneity explained and discussed? No pooled synthesis was conducted.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? Authors stated that the work was funded by WPATH.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
Chew (2018)47 1. Yes Purpose well-specified? Populations, interventions, outcomes, and study designs were well-specified in the protocol. Comparators were not defined in advance because all were considered.
Type: Systematic review, narrative synthesis; a 2. Yes A priori protocol? Protocol published on PROSPERO (42017056670).
quantitative synthesis was planned, but there
were too few studies. 3. No Study designs justified? No justification for including all study designs was provided.
Databases: Medline, Embase, PubMed 4. Partial yes Comprehensive search strategy? Authors searched 2 bibliographic databases (counting Medline and PubMed as one) without language restrictions and provided search terms. They also conducted
Search dates: 1946 through June 10, 2017 the search within 24 months of publication. They also searched reference lists of relevant studies. However, authors did not justify exclusion of unpublished studies, search in registries or other
grey literature sources, or consult experts.

5. Yes Performed study selection in duplicate? Duplicate screening was described.

6. Yes Performed data extraction in duplicate? Duplicate data extraction was described.

7. No List of excluded studies? No list of excluded studies was provided.

8. Partial yes Detailed description of included studies? Authors described populations, interventions, comparators, outcomes, research designs, and timeframe for follow-up. They left out settings and key
details of the population, interventions, and comparators.

9. Unclear Assessed study-level ROB? Authors used a modified QUIPS, an ROB tool for prognostic studies

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. Yes Impact of ROB on results assessed? Authors did not assess the impact of primary-study ROB on their findings.

13. Yes Impact of ROB on results discussed? Authors did not discuss the impact of primary-study ROB on their findings.

14. N/A Impact of heterogeneity explained and discussed? No pooled synthesis was conducted.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? The work was funded by the Royal Children's Hospital Foundation, the Melbourne Children's Clinician Scientist Fellowship Scheme, the
Apex Foundation for Research into Intellectual Disability, and the William Collie Trust at the University of Melbourne. They reported no conflicts of interest.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
D'hoore (2022)48 1. Yes Purpose well-specified? Population, outcomes, and study designs were well-specified. interventions and comparators were not defined in advance.
Type: Systematic review, narrative synthesis 2. No A priori protocol? Protocol not mentioned.
Databases: PubMed Medline and Embase
3. No Study designs justified? No justification for including only cohort or cross-sectional studies and RCTs.
Search dates: 2015 through April 16, 2021
4. No Comprehensive search strategy? Authors searched 2+ bibliographic databases (Medline and Embase) and provided both search terms. They also conducted the search within 24 months of
publication. However, authors did not justify publication and language restrictions (they included only English-language studies and excluded studies not available in full text at their institution).
The made no mention of searching reference lists of relevant studies or in registries or other grey literature sources, or consulting experts.

5. Yes Performed study selection in duplicate? Duplicate screening was described.

6. No Performed data extraction in duplicate? Data extraction was performed by a single author.

7. No List of excluded studies? No list of excluded studies was provided.

8. No Detailed description of included studies? Authors did not describe populations, interventions, comparators, outcomes, research designs, settings, or timeframe for follow-up.

9. No Assessed study-level ROB? Authors did not describe any ROB assessment method.

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. No Impact of ROB on results assessed? Authors did not assess the impact of primary-study ROB on their findings.

13. No Impact of ROB on results discussed? Authors did not discuss the impact of primary-study ROB on their findings.

14. N/A Impact of heterogeneity explained and discussed? No pooled synthesis was conducted.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? The authors reported no conflicts in this work.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
310

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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
Ludvigsson (2023)49 1. Yes Purpose well-specified? Population, intervention, outcomes, and study designs were well-specified. Comparators were not defined in advance because all were accepted.
Type: Systematic review, narrative synthesis 2. Yes A priori protocol? A priori protocol was published on the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) website.410
Databases: CINAHL, Cochrane, EMBASE,
3. No Study designs justified? No justification for including both RCTs and NRSIs was provided.
PsycINFO, PubMed, Scopus, SocINDEX, Campbell
Library, Epistemonikos, Evidence Search, 4. Partial yes Comprehensive search strategy? Authors searched 13 bibliographic databases (CINAHL, Cochrane Library, EMBASE, PsycINFO, PubMed, Scopus, SocINDEX, Campbell Library, Epistemonikos,
International HTA database, Database of Evidence Search, International HTA database, Database of Abstracts of Reviews of Effects (DARE), Health and Technology Assessment (HTA), NHS Economic Evaluation Database (EED), and
Abstracts of Reviews of Effects (DARE), Health PROSPERO) and provided complete search strategies.411 They also conducted the search within 24 months of publication. However, authors did not justify language restrictions (they included only
and Technology Assessment (HTA), NHS English-language studies). The made no mention of searching reference lists of relevant studies or in registries or other grey literature sources, or consulting experts. However, while their search
Economic Evaluation Database (EED), PROSPERO strategy was robust, they used an arbitrary threshold on their study-level ROB assessment to exclude a third of the studies retrieved, which goes against best practices.30,43,412
Search dates: Through November 9, 2021
5. Yes Performed study selection in duplicate? Duplicate screening was described.

6. Unclear Performed data extraction in duplicate? Data extraction was performed by 2 authors, but it was unclear whether the 2 authors performed extraction in duplicate.

7. No List of excluded studies? Authors stated that they provided a list of 12 studies that were excluded due to a high risk of bias on the SBU website.54 However, the list only included 11 studies. In
addition, authors also failed to provide a list of 159 studies examined in full text and subsequently excluded.

8. No Detailed description of included studies? Authors described populations, interventions, comparators, outcomes, research designs, and timeframe for follow-up, but they did not describe settings,
nor did they describe the populations, interventions, and comparators in detail. They did not describe study-level findings.

9. Yes Assessed study-level ROB? The authors used ROBINS-I to assess study-level ROB.413 ROBINS-I addresses all 4 required ROB domains and several more that are not included in the AMSTAR-2 tool.
Notably, the authors excluded studies that had a high ROB according to ROBINS-I, which means that some studies may have been excluded because they had a high ROB on dimensions not
considered key domains in the AMSTAR-2.

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. No Impact of ROB on results assessed? Authors did not assess the impact of primary-study ROB on their findings. Rather, they simply excluded studies that had a high ROB according to ROBINS-I.

13. No Impact of ROB on results discussed? Authors did not discuss the impact of primary-study ROB on their findings. Authors excluded studies with a high ROB.

14. N/A Impact of heterogeneity explained and discussed? No pooled synthesis was conducted.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? The authors reported that their work was funded by the Swedish Agency for Health Technology Assessment and Assessment of Social
Services.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
311

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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
Mahfouda (2019)50 1. No Purpose well-specified? Population and outcomes were well-specified. Comparators were described as "gender-affirming CSHs," but were not listed by name. In fact, authors ended up also
including GnRH analogs, which are not considered CHST. Outcomes were described in categories (eg, "mental health" and "physical effects," but were not well-described in advance. Comparators
Type: Systematic review, narrative synthesis
were not specified in advance.
Databases: Medline and Embase
2. No A priori protocol? No explicit statement was made that the protocol was written in advance.
Search dates: Through June 9, 2018
3. No Study designs justified? All explanatory studies were potentially eligible; case studies were excluded. No justification was given

4. Partial yes Comprehensive search strategy? Authors searched 2 bibliographic databases (Medline and Embase) and they provided keyword search terms. They also conducted the search within 24 months of
publication, without language restrictions, and searched the references of relevant studies. They did not describing having searched in registries or other grey literature sources.

5. No Performed study selection in duplicate? No mention of duplicate eligibility screening.

6. No Performed data extraction in duplicate? No mention of duplicate data extraction.

7. No List of excluded studies? No list of excluded studies was provided.

8. Partial yes Detailed description of included studies? Authors described populations (with details), interventions (with details), outcomes, research designs, settings, and time frames for follow-up. Their
report lacked key details about comparators (when between-group comparisons were made).

9. No Assessed study-level ROB? Authors did not describe ROB assessment using any ROB measurement tool that addresses key bias domains.

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. No Impact of ROB on results assessed? Authors did not describe the impact of primary-study ROB on their findings.

13. No Impact of ROB on results discussed? Authors did not discuss the impact of primary-study ROB on their findings.

14. N/A Impact of heterogeneity explained and discussed? No pooled synthesis was conducted.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? Authors declared no conflicts of interest, and reported that the work was funded by University of Western Australia, Perth Children’s
Hospital Fund, Raine Medical Foundation, and Australian National Health and Medical Research Council.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
312

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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
Ramos (2021)51 1. Yes Purpose well-specified? Population and interventions were well-specified. Comparators and outcomes were not defined in advance because all were accepted.
Type: Systematic review, narrative synthesis 2. No A priori protocol? No explicit statement was made that the protocol was written in advance.
Databases: Medline and Embase: Medline and
3. No Study designs justified? All experimental and non-experimental studies were potentially eligible, but no justification was provided..
Embase
Search dates: 2009-2019 4. Partial yes Comprehensive search strategy? Authors searched 2+ bibliographic databases (Medline and Embase) and they provided keyword search terms. They also conducted the search within 24 months of
publication without language restrictions However, authors did not justify publication restrictions (they included only published studies), and they did not search in registries or other grey literature
sources. It was unclear if they searched the reference lists of published studies or if they consulted experts.

5. No Performed study selection in duplicate? No mention of duplicate eligibility screening.

6. Yes Performed data extraction in duplicate? 2 reviewers extracted data and resolved discrepancies..

7. No List of excluded studies? No list of excluded studies was provided.

8. Partial yes Detailed description of included studies? Authors described populations (with details), interventions, outcomes, research designs, and settings. Their report lacked key details about the
interventions, and comparators were not described in adequate detail. The timeframe for follow-up was not described. .

9. Yes Assessed study-level ROB? Authors used the Cochrane ROB tool for observational and intervention studies, which addresses selection bias, performance bias, selective outcome reporting,
detection bias, attrition bias, and potential confounding.

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. Yes Impact of ROB on results assessed? Authors described the impact of primary-study ROB on their findings.

13. Yes Impact of ROB on results discussed? Authors discuss the impact of primary-study ROB on their findings.

14. Partial yes Impact of heterogeneity explained and discussed? Although no quantitative pooled synthesis was conducted, authors describe the potential impact of heterogeneity on review findings.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? No conflicts to report; no funding.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
313

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Table I.E.1. ROB, purpose, and search details for relevant first-corpus systematic reviews addressing included outcomes associated with medical treatments of TGNB adolescents
First author (Year) ROB assessment (AMSTAR-2)43
Search details
Rew (2021)52 1. Partial yes Purpose well-specified? Population was well-specified. Intervention (GnRH analogs) were specified by class only. All study designs were listed. No comparators or outcomes were specified a priori.
study designs were well-specified. Comparators (ie, specific GnRH analogs) and outcomes were not defined in advance because all were accepted.
Type: Systematic review, narrative synthesis
Databases: PubMed and Embase 2. No A priori protocol? Protocol not mentioned

Search dates: 2009-2/6/2019 3. No Study designs justified? Authors did not justify their choice to include all study designs, but all study designs were included.

4. Partial yes Comprehensive search strategy? Authors searched 2 bibliographic databases without restricting by language, provided search terms and a complete search strategy, and published within 2 years
of conducting the search. However, authors neither searched reference lists of relevant studies nor did they search in registries or other grey literature sources, search within 24 months of
publication.

5. No Performed study selection in duplicate? Duplicate screening was not described.

6. Unclear Performed data extraction in duplicate? There is no mention of duplicate data extraction in the applicable section; there is a statement that data extraction was performed in duplicate in the
section that describes ROB assessment, but it is unclear whether that statement applies to all data extraction or to ROB assessment only.

7. No List of excluded studies? No list of excluded studies was provided.

8. No Detailed description of included studies? Authors did not include study details in a tabular format; some study details were described in the narrative, but not uniformly.

9. Yes Assessed study-level ROB? Authors used the Cochrane ROB tool.

10. No Described funding sources for primary sources? No funding sources were described.

11. N/A Appropriate meta-analytic methods? No quantitative pooled synthesis was conducted.

12. No Impact of ROB on results assessed? Authors did not assess the impact of primary-study ROB on their findings.

13. No Impact of ROB on results discussed? Authors did not discuss the impact of primary-study ROB on their findings.

14. N/A Impact of heterogeneity explained and discussed? No pooled synthesis was conducted.

15. N/A Small-study effects (eg, publication bias) examined and discussed? No pooled synthesis was conducted.

16. Yes Potential review author conflicts of interest addressed? Authors reported that the work was unfunded and that there were no conflicts of interest.

Table abbreviations: TGNB; transgender, nonbinary, or other gender diverse; ROB, risk of bias; AMSTAR, A Measurement Tool to Assess Systematic Reviews; GAHT, gender-affirming hormone therapy including testosterone in transgender males, estrogen or anti-
androgens in transgender females, or GnRH analogs in all TGNB individuals; WPATH, World Professional Association for Transgender Health; GnRH, gonadotropin releasing hormone; RCT, randomized controlled trial; ROBINS-I, Cochrane risk-of-bias tool for
NRSIs; NRSI; non-randomized studies of interventions
314

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
55
Achille (2020)
Mental health
Prospective, longitudinal, pre-post study found in bibliographic database searches
(second-corpus); included in evidence tables for longitudinal, pre-post, within- Psychosocial outcomes
group and between-TGNB-group comparisons.

Asscheman (2011)414
Found in first-corpus bibliographic database searches; excluded at full-text Mental health
screening (wrong population).

Asscheman (1989)415
Not found in bibliographic database searches; categorically excluded from Mental health
consideration (publication year <2010).

Auer (2018)416 NCT01072825

Prospective cohort study cited in Clinicaltrials.gov;417 not found in bibliographic Not specified (metabolic
database searches; excluded from eligibility during title-abstract screening (wrong changes)
population).

Becerra-Culqui (2018)418
Not found in bibliographic database searches; excluded at full-text screening (no Mental health
intervention of interest).

Becker (2018)103
Cohort study found in bibliographic database searches (second corpus); included Psychosocial outcomes
in evidence tables for between-TGNB group comparisons.

Becker-Hebly (2021)72
Cohort study found in bibliographic database searches (first corpus); included in Mental health
evidence tables for between-TGNB group and longitudinal, pre-post, within-group
comparisons.

Bultynck (2017)419 NCT01072825

Prospective cohort study cited in Clinicaltrials.gov;417 found in bibliographic Not specified
database searches (second corpus); excluded from eligibility during title-abstract (Psychosocial)
screening (wrong population).

Burke (2016)130
Psychosocial outcomes
Cohort study found in bibliographic database searches (first corpus); included in Psychosocial outcomes
Other
evidence tables for TGNB/cisgender peer group comparisons.

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
315

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
74
Cantu (2020)
Descriptive study found in bibliographic database searches (second corpus); Mental health
included in evidence tables for between-TGNB group comparisons and
longitudinal, pre-post, within-group comparisons.

Carmichael (2021)73
Mental health
Descriptive study found in bibliographic database searches (first-corpus); included Mental health
in evidence tables for longitudinal, pre-post, within-group and between-TGNB Bone health
group comparisons.

Cohen-Kettenis (2011)168
Body changes
Case report found in bibliographic database searches (first corpus); excluded from
Metabolic changes
data extraction due to a lack of high-priority comparison types.

Colizzi (2014)10
Not found in bibliographic database searches; excluded at full-text screening Mental health
(wrong population).

Costantino (2013)420
Not found in bibliographic database searches; excluded at full-text screening Mental health
(wrong population).

Costa (2015)77
Cohort study found in bibliographic database searches (first corpus); included in Psychosocial outcomes Psychosocial outcomes Mental health Psychosocial outcomes
evidence tables for between-TGNB-group, TGNB/cisgender peer group, and
longitudinal, pre-post, within-group comparisons.

de Vries (2011)57
Mental health Body changes Mental health
Descriptive study found in bibliographic database searches (first corpus); included Mental health
Psychosocial outcomes Psychosocial outcomes Psychosocial outcomes
in longitudinal, pre-post, within-group, and between-TGNB-group results.

de Vries (2014)79
Mental health
Cohort study found in bibliographic database searches (first corpus); included in Mental health Mental health Psychosocial outcomes
Psychosocial outcomes
between-TGNB and longitudinal, pre-post, within-group comparisons.

de Vries (2016)107
Cross-sectional study not found in bibliographic database searches; included in Mental health
evidence tables for between-TGNB group comparisons.

Defreyne (2018)421
Cohort study found in bibliographic database searches (first-corpus); excluded at Mental health
title/abstract screening (irrelevant).

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
316

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
Delemarre-van de Waal (2006) 422 Body changes

Not found in bibliographic database searches; categorically excluded from Bone health
consideration (publication year <2010). Metabolic changes

Fisher (2016)423
Not found in bibliographic database searches; excluded at full-text screening Mental health
(wrong population).

Fisher (2017)424
Mental health
Found in bibliographic database searches (second corpus); excluded at
Psychosocial outcomes
title/abstract screening (no interventions of interest).

Fuss (2015)425
Mental health
Cohort study found in bibliographic database searches (first-corpus); excluded at
full-text screening (wrong population).

Gava (2016)426
Mental health
Not found in bibliographic database searches; excluded at full-text screening
Psychosocial outcomes
(wrong population).

Gava (2018)427
Not found in bibliographic database searches; excluded at full-text screening Psychosocial outcomes
(wrong population).

Giovanardi (2019)428
Qualitative descriptive study found in bibliographic database searches (first Other
corpus); excluded at title-abstract screening (wrong population).

Gómez-Gil (2012)429
Cross-sectional study found in bibliographic database searches (second-corpus); Mental health
excluded at full-text screening (wrong population).

Gorin-Lazard (2012)430
Not found in bibliographic database searches; excluded at full-text screening Mental health
(wrong population).

Guss (2017)431
Found in bibliographic database searches (first corpus); excluded at title/abstract
screening (no intervention of interest).

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
317

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
59
Hannema (2017)
Body changes
Descriptive study found in bibliographic database searches (first corpus); included Other
CV risk factors
in evidence tables for longitudinal, pre-post, within-group comparisons.

Hisle-Gorman (2021)432
Cohort study found in bibliographic database searches (second-corpus); excluded Mental health
at full-text screening (wrong population).

Jarin (2017)136 Body changes

CV risk factors
Descriptive study found in bibliographic database searches (first corpus); included CV risk factors CV risk factors CV risk factors
Metabolic changes
in evidence tables for longitudinal, pre-post, within-group comparisons. Metabolic changes

Joseph (2019)137
Descriptive study found in bibliographic database searches (first corpus); included Bone health
in evidence tables for longitudinal, pre-post, within-group comparisons.

Khatchadourian (2014)82 Mental health

Mental health
Cohort study found in bibliographic database searches (second corpus); included Safety
Other
in evidence tables for between-TGNB group comparisons. Other

Klaver (2018)83
Descriptive study found in bibliographic database searches (first corpus); included Body changes Body changes Body changes Body changes Body changes
in evidence tables for longitudinal, pre-post, within-group, and between-TGNB
group comparisons.

Klaver (2020)139 Body changes

Descriptive study found in bibliographic database searches (first corpus); included CV risk factors Metabolic changes
in evidence tables for longitudinal, pre-post, within-group comparisons. CV risk factors

Klink (2013)433
Descriptive study not found in bibliographic database searches; excluded from Bone health
consideration due to publication type (abstract only).

Klink (2015)140
Body changes
Descriptive study found in bibliographic database searches (first corpus); included Bone health Bone health Bone health Bone health
Bone health
in evidence tables for longitudinal, pre-post, within-group comparisons.

Kuper (2020)141
Mental health
Descriptive study found in bibliographic database searches (second-corpus);
Psychosocial outcomes
included in evidence tables for longitudinal, pre-post, within-group comparisons.

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
318

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
434
Leavitt (1980)
Not found in bibliographic database searches; categorically excluded from Mental health
consideration (publication year <2010).

Lee (2020)85
Cohort study found in bibliographic database searches (second-corpus); included Bone health
in evidence tables for between-TGNB group comparisons.

Lopez (2018)435
Descriptive study found in bibliographic database searches (first corpus); included Other
in bibliography only due to a lack of high-priority group comparisons.

López de Lara (2020)62

Likely-relevant, non-English study found in bibliographic database searches (first- Mental health
corpus; included in bibliography only.

Manieri (2014)436
Not found in bibliographic database searches; excluded at full-text screening Psychosocial outcomes
(wrong population).

Metzger (2019)437
Cohort study found in bibliographic database searches (first-corpus); excluded at Mental health
title/abstract screening (irrelevant).

Motta (2018)438
Not found in bibliographic database searches; excluded at full-text screening Mental health
(wrong population).

Mueller (2005)439
Not found in bibliographic database searches; categorically excluded from
consideration (publication year <2010).

Mullins (2021)91
Cohort study found in bibliographic database searches (first-corpus); included in CV risk factors
evidence tables for between-TGNB group comparisons.

Nahata (2017)115
Cross-sectional study found in bibliographic database searches (second corpus); Other
included in evidence tables for between-TGNB group comparisons.

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
319

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
92
Navabi (2021)
Cohort study found in bibliographic database searches (first corpus); included in Bone health
evidence tables for between-TGNB group and longitudinal, pre-post, within-group
comparisons.

Nokoff (2020)131
Body changes
Prospective cohort study found in bibliographic database searches (second Body changes
Metabolic changes
corpus); included in evidence tables for TGNB/cisgender peer group comparisons.

Olson (2014)440
Body changes
Descriptive study found in bibliographic database searches (second corpus);
Metabolic changes
excluded at full-text screening (wrong population).

Olson-Kennedy (2018)143
Descriptive study found in bibliographic database searches (first corpus); excluded Metabolic parameters?
at full-text screening (wrong population).

Pelusi (2014)441
Not found in bibliographic database searches; excluded at full-text screening Psychosocial outcomes
(wrong population).

Perl (2020)144
Body changes
Descriptive study found in bibliographic database searches (first corpus); included CV risk factors
CV risk factors
in evidence tables for longitudinal, pre-post, within-group comparisons.

Schagen (2016)148
Body changes Body changes Body changes
Descriptive study found in bibliographic database searches (second corpus); Body changes Body changes
Metabolic changes Metabolic changes Metabolic changes
included in evidence tables for longitudinal, pre-post, within-group comparisons.

Schagen (2020)94
Prospective cohort study found in bibliographic database searches (first corpus); Bone health Bone health
included in evidence tables for between-TGNB-group and longitudinal, pre-post,
within-group comparisons.

Schneider (2017)442
Case report found in bibliographic database searches (second corpus); included in Psychosocial outcomes
bibliography only due to a lack of high-priority group comparisons.

Schulmeister (2022)95
Prospective cohort study found in bibliographic database searches (first corpus); Body changes
included in evidence table between-TGNB group and TGNB/cisgender peer group
comparisons.

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
320

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
443
Sequeira (2017)
Not found in bibliographic database searches; categorically excluded from Psychosocial outcomes
eligibility due to publication type (abstract only).

Shadid (2020)444 NCT01072825

Prospective cohort study cited in clinicaltrials.gov;417 was not found in Not specified (metabolic
bibliographic database searches; excluded from eligibility during title-abstract changes)
screening (wrong population).

Staphorsius (2015)119
Prospective cohort study found in bibliographic database searches (first-corpus); Psychosocial outcomes Mental health
included in evidence tables for between-TGNB-group and longitudinal, pre-post,
within-group comparisons.

Smith (2001)445
Not found in bibliographic database searches; categorically excluded from Psychosocial outcomes
consideration (publication year <2010).

Stoffers (2019)149
Descriptive study found in bibliographic database searches (first corpus); included Bone health Bone health
in evidence tables for longitudinal, pre-post, within-group comparisons.

Tack (2016)446 Body changes Body changes CV risk factors

Descriptive study found in bibliographic database searches (second-corpus); CV risk factors CV risk factors Metabolic changes
excluded at full-text screening (wrong population) because treatments were
initiated at ages 18+. Metabolic changes Mental health Other

Tack (2017)150 Body changes

CV risk factors
Descriptive study found in bibliographic database searches (first corpus); included CV risk factors Body changes
Metabolic changes
in evidence tables for longitudinal, pre-post, within-group comparisons. Metabolic change

Tack (2018)447
Body changes
Observational study found in bibliographic database searches (second corpus);
excluded at full-text screening (wrong interventions) for evaluating only Bone health
interventions not approved for use in the US (cyproterone and lynestrenol).

Tankersley (2021)448
SR not found in bibliographic database searches; included in bibliography only
(wrong outcomes).

Trotman (2014)449
CV risk factors
Not found in bibliographic database searches; categorically excluded from
Metabolic changes
consideration due to publication type (abstract only).

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
321

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Table I.E.2. Disposition of primary studies included in first-corpus SRs examining high-priority outcomes associated with GD treatments in TGNB children/adolescents
First author (year) Systematic reviews
Disposition in this DRRC review Baker (2021)46 Chew (2018)47 D'hoore (2022)48 Ludvigsson (2023)49 Mahfouda (2019)50 Ramos (2021)51 Rew (2021)52
450
Turan (2018)
Not found in bibliographic database searches; excluded at full-text screening Mental health
(wrong population).

Turban (2020)121
Cross-sectional study found in bibliographic database searches (first corpus); Mental health
included in evidence tables for between-TGNB group comparisons.

van der Loos (2021)69

Descriptive study found in bibliographic database searches (first corpus); included Bone health Bone health
in evidence tables for longitudinal, pre-post, within-group comparisons.

van der Miesen (2020)124

Mental health
Cohort study found in bibliographic database searches (second corpus); included
in evidence tables for between-TGNB group and TGNB/cisgender peer group Psychosocial functioning
comparisons.

Vlot (2017)99
Bone health
Descriptive study found in bibliographic database searches (first corpus); included Bone health Bone health Bone health Bone health Bone health
in evidence tables for longitudinal, pre-post, within-group, and between-TGNB Body changes
group comparisons.

Vrouenraets (2016)451
Descriptive study found in bibliographic database searches (first corpus); included Other
in bibliography only due to a lack of high-priority group comparisons.

Warrier (2020)452
Not found in bibliographic database searches; excluded at full-text screening
(wrong population).

Wierckx (2011)453
Cross-sectional study found in bibliographic database searches (second corpus); Mental health
excluded at full-text screening (wrong population).

Table abbreviations: SR, systematic review; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse;
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Table I.E.3. Systematic reviews examining mental health outcomes (eg, anxiety, depression, suicidality) associated with GD treatments in TGNB children/adolescents
First author (Year)
Findings from primary studies
Primary studies
46
Baker (2021) Anxiety
Primary studies: TGNB patients, pre-post: GnRH analogs with or without CSHT were associated with a statistically significant decrease in mean anxiety scores versus baseline in 1 out of 3 primary studies; any changes were nonsignificant in 2 others. No study
Mental health found that hormone therapy increased anxiety. Authors concluded that hormone therapy may decrease anxiety in TGNB adolescents.
outcomes were GnRH analog therapy for puberty suppression for an average of 1.88 years had no significant effect on STAI trait subscale scores in N=41 treatment-naïve, Danish TGNB adolescents with a mean age of 14.8 years (p=NS) in de Vries (2011).57
assessed in 4 primary
studies of 3 TGNB o In a subset of N=32 patients (mean age 14.8 years) who went on to receive CSHT for an average duration of 5.9 years, there was no significant change in STAI trait subscale scores versus baseline in de Vries (2014).79
adolescent cohorts. GnRH analog therapy plus CSHT for a treatment duration of 12 months was associated with a decrease in mean (SD) STAI trait subscale score from 33.0 (7.2) to 18.5 (8.4) in N=38 Spanish, TGNB adolescents with a mean age of 16 years
(p<0.001) ) in López de Lara (2020).62
Conclusions:
Hormone therapy may Depression
decrease depression TGNB patients, pre-post: GnRH analogs with or without CSHT were associated with a statistically significant decrease in mean depression scores versus baseline in 3 out of 4 primary studies; any change was nonsignificant in 1 other. No study
and anxiety in TGNB found that hormone therapy increased depression. Authors concluded that hormone therapy may decrease depression in TGNB adolescents.
adolescents; no GnRH analog therapy for puberty suppression for an average of 1.88 years was associated with decrease in mean (SD) BDI score from 8.31 (7.12) to 4.95 (6.72) in N=41 treatment-naïve, Danish TGNB adolescents with a mean age of 14.8
conclusions can be years (p=0.004) in de Vries (2011).57
drawn about suicidality.
o In a subset of N=32 patients who went on to receive CSHT for an average duration of 5.9 years, there was no significant differences in BDI score (mean age 14.8 years) in de Vries (2014).79
GnRH analog therapy plus CSHT for a treatment duration of 12 months was associated with a decrease in mean CESD-R decrease from 21.4 to 13.9 (p<0.001) in N=47 US-based, TGNB adolescents with a mean age of 16.2 years. (A score of
16 indicates no clinical depression.) Mean PHQ-9 score decreased from 9.0 to 5.4 over the same period (p<0.001) in Achille (2020).55
GnRH analog therapy plus CSHT for a treatment duration of 12 months was associated with a decrease in mean (SD) BDI score from 19.3 (5.5) to 9.7 (3.9) in N=38 Spanish, TGNB adolescents with a mean age of 16 years (p<0.001) in López
de Lara (2020).62
Suicide
Investigators looked for but did not find primary studies that addressed suicide-related outcomes in TGNB adolescents.
Chew (2018)46 Anxiety
Primary studies: TGNB patients, pre-post: GnRH analogs were associated with a nonsignificant decrease in anxiety and anger versus baseline in 1 primary study that examined it.
Mental health GnRH analog therapy for puberty suppression for an average (SD) of 1.88 (1.05) years was associated with a nonsignificant decrease in a composite of depression and anxiety among N=70 Danish TGNB adolescents with a mean (SD) age of
outcomes were 13.65 (1.85) years (p=NS) in de Vries (2011).57
assessed in 1 primary
study including TGNB Depression
adolescents. TGNB patients, pre-post: GnRH analogs were associated with a statistically significant decrease in mean depression scores versus baseline in 1 primary study that examined it.
Authors conclusions GnRH analog therapy for puberty suppression for an average (SD) of 1.88 (1.05) years was associated with significant decrease in depression among N=70 Danish TGNB adolescents with a mean (SD) age of 13.65 (1.85) years (p<0.05) in de
Vries (2011).57
GnRH analogs were
associated with
improvements in
depression, but impact
on anxiety remains
unclear. No research
was found examining
the effects of progestin,
antiandrogens,
estrogens, and
testosterone.

D’hoore (2022) ADHD

Table abbreviations: GAHT, gender-affirming hormone therapy; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males,
estrogen in transgender females; BDI, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; PHQ-9, Patient Health Questionnaire Modified for Teens; STAI, State-Trait Anxiety Inventory; US, United States;
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Table I.E.3. Systematic reviews examining mental health outcomes (eg, anxiety, depression, suicidality) associated with GD treatments in TGNB children/adolescents
First author (Year)
Findings from primary studies
Primary studies
Primary studies: TGNB patients vs cisgender peers: Untreated TGNB youth have higher rates of ADHD compared to cisgender peer groups in 1 primary study.
Mental health No treatment was associated with higher rates of ADHD (15% in transfeminine and 16% in transmasculine patients compared to age-matched cisgender peer groups in Becerra-Culqui et al (2018).418
outcomes were
assessed in 5 primary Anxiety
studies including TGNB TGNB patients, pre-post: GAHT was associated with improved anxiety in 1 primary study.
adolescents. GAHT was associated with improvements in anxiety among TGNB patients (mean age 14.9) in Kuper (2020).141
Depression
TGNB patients vs cisgender peers: Untreated TGNB youth had higher rates of depression than cisgender peers in 1 primary study.
No treatment was associated with higher rates of depressive disorders (49% in transfeminine and 62% in transmasculine adolescents) compared to age-matched cisgender peer groups in Becerra-Culqui et al (2018).418
TGNB patients, pre-post: GAHT was associated with improved depression in 1 primary study.
GAHT was associated with improvements in depression among TGNB patients (mean age 14.9) in Kuper (2020).141
Psychological functioning
TGNB vs cisgender peers: Untreated TGNB patients had worse psychological functioning compared to cisgender peers in 1 primary study; GAHT was associated with psychosocial functioning that was similar to or better than that of peers in
another.
No treatment was associated with worse psychological functioning compared to a cisgender peer group in Fisher (2017).424
GAHT was associated with psychosocial functioning was that was similar to or better than that of peers in van der Miesen (2020).124
TGNB patients, pre-post: GAHT was associated with improved mental health outcomes in 2 primary studies.
GAHT was associated with improved mental health problems among London trans adolescents (mean age 13.6) Carmichael (2021).73
Puberty blockers were associated with improvements in behavioral and emotional problems in van der Miesen (2020).124
Suicide ideation/behavior
TGNB patients vs cisgender peers: Untreated TGNB youth have higher rates suicidal ideation compared to cisgender peer groups in 1 primary study.
No treatment was associated with higher rates of lifetime suicidal ideation (7.5% in transfeminine and 10.4% in transmasculine adolescents) among n = 1388 TGNB youth ages 3-17 years (588 transfeminine and 745 transmasculine, ages 3-
17 years) compared to age-matched cisgender peer groups in Becerra-Culqui et al (2018).418
Ludvigsson (2023)49 Anxiety
Primary studies: TGNB patients, pre-post: Authors concluded from 2 primary studies that GAHT was associated with no changes in anxiety.
Mental health GnRH analogs for 1 year followed by subsequent CSHT for 4 years were assessed for changes/differences anxiety (STAI) among N=196 TGNB patients (mean age 13.6 years) in de Vries (2014).79
outcomes were GnRH analogs followed by subsequent CSHT were assessed for changes/differences in anxiety (GAD-7) among N=80 TGNB patients (mean age 15 years) in Cantu (2020).74a
assessed in 5 primary
studies out of 24 Depression
included by review TGNB patients, pre-post: Review authors concluded from 2 primary studies that GAHT was associated with no changes in depression.
authors. Authors drew GnRH analogs for 1 year followed by subsequent CSHT for 4 years were assessed for changes/differences in depression (BDI) among N=196 TGNB patients (mean age 13.6 years) in de Vries (2014).79
conclusions about GnRH analogs followed by subsequent CSHT were assessed for changes/differences in acute distress and suicidality among N=80 TGNB patients (mean age 15 years) in Cantu (2020).74b
mental health
outcomes based on 3 Suicide ideation
primary studies, TGNB patients, pre-post: Review authors concluded from 1 primary study that GAHT was associated with no changes in suicide ideation; authors omitted 1 included study that also addressed suicidality.

a
Publication year was erroneously listed as 2019 in the review authors’ reference lists.
b
Publication year was erroneously listed as 2019 in the review authors’ reference lists.
Table abbreviations: GAHT, gender-affirming hormone therapy; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males,
estrogen in transgender females; BDI, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; PHQ-9, Patient Health Questionnaire Modified for Teens; STAI, State-Trait Anxiety Inventory; US, United States;
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Table I.E.3. Systematic reviews examining mental health outcomes (eg, anxiety, depression, suicidality) associated with GD treatments in TGNB children/adolescents
First author (Year)
Findings from primary studies
Primary studies
omitting any findings GnRH analogs followed by subsequent CSHT were assessed for changes/differences in suicidality among N=80 TGNB patients (mean age 15 years) in Cantu (2020).74c
from 2. 1 other included primary study that assessed suicidality was omitted by review authors when drawing their conclusions.
Author conclusions: CSHT for a mean of 12 months were assessed for changes/differences in height, weight, and BMI, triglycerides, cholesterol, suicide, and side effects among N=43 TGNB adolescents (ages 15-17 years at start of treatment) in Tack (2016).446
GnRH analogs have no
effect on depression,
anxiety, or suicide
ideation.

Ramos (2021)51 Suicide behaviors

Primary studies: TGNB patients, pre-post: GnRH analog therapy for puberty suppression was associated with a decrease in suicidality in 1 primary study.
Mental health GnRH analog therapy for puberty suppression or monitoring in a GD clinic was associated with a decline in suicide attempts from 12% to 5% among N=84 TGNB youths in Khatchadourian et al (2014).82
outcomes were
assessed in 2 primary General mental health
studies including TGNB TGNB patients, pre-post: GnRH analog therapy for puberty suppression was associated with improved mental health in 1 primary study.
adolescents. GnRH analogs for puberty suppression were associated with significant improvement in mental health in N=70 TGNB youths who received in de Vries et al (2011).57
Rew (2021)52 Anxiety
Primary studies: AFAB vs AMAB transgender adolescents: 1 primary study showed that AFAB patients had more anxiety than AMAB patients who received GnRH analogs.
Mental health was AFAB patients who received unspecified GnRH analogs had more anxiety compared to AMAB who received them among N=70 TGNB adolescents (mean age 13.6 years) in de Vries (2011). 69
examined in 4 out of 9
primary studies Depression
addressing TGNB TGNB patients, pre-post: 1 primary study showed decreased depressive symptoms associated with GnRH analogs.
adolescents. GnRH analogs were associated with decreases in depressive symptoms in both AMAB and AFAB patients among N=70 TGNB adolescents (mean age 13.6 years) in de Vries (2011). 69
Mood and affect
Case findings: Leuprorelin was associated with improved affect in one case; another patient case had to discontinue due to mood swings and emotional liability.
1 patient who received GnRH analogs followed discontinued due to mood swings and emotional lability among N=84 TGNB adolescents (age between 11.4-19.8 years) in Khatchadourian (2014).82
Leuprorelin was associated with improvement in affective and social life in N=1 TGNB patient in Schneider (2017).442
TGNB patients, pre-post: 1 primary study showed decreased psychological distress in patients who started puberty suppression between ages 9 and 16 years.
Unspecified puberty blockers were associated with reduced past-month psychological distress among N=89 TGNB patients who started treatment between ages 9 and 16 in Turban (2020).121

Suicide ideation
TGNB patients, pre-post: 1 primary study showed reduced suicide ideation in patients who started puberty suppression between ages 9 and 16 years.
Unspecified puberty blockers were associated with decreased lifetime suicide ideation in N=89 TGNB adolescents who started treatment between ages 9 and 16 in Turban (2020).121

c
Publication year was erroneously listed as 2019 in the review authors’ reference lists.
Table abbreviations: GAHT, gender-affirming hormone therapy; GD, gender dysphoria; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males,
estrogen in transgender females; BDI, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; PHQ-9, Patient Health Questionnaire Modified for Teens; STAI, State-Trait Anxiety Inventory; US, United States;
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Table I.E.4. Systematic reviews examining psychosocial outcomes (eg, QOL, behavioral/social functioning, GD, body image) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
Baker (2021)46 QOL
Primary studies TGNB patients, pre-post: No change in QOL from baseline in 1 primary study; no study found that hormone therapy decreased QOL.
Psychosocial and GnRH analog therapy plus CSHT for a treatment duration of 12 months was associated no change from baseline in mean Q-LES-Q-SF in N=38 Spanish, TGNB adolescents with a mean age of 16 years (p=NS) in López de Lara (2020).62
emotional outcomes
were assessed in 1
primary study of TGNB
adolescents.
Authors conclusions
Hormone therapy was
associated with
improved QOL.

Chew (2018)47 Anger

Primary studies: TGNB patients, pre-post: GnRH analogs were associated with a nonsignificant decrease in anger and anxiety in 1 primary study.
Psychosocial and GnRH analog therapy for puberty suppression for an average (SD) of 1.88 (1.05) years was associated with a nonsignificant decrease in a composite of anger and depression among N=70 Danish TGNB adolescents with a mean (SD) age of
emotional outcomes 13.65 (1.85) years (p=NS) in de Vries (2011).57
were assessed in 4
primary studies among Behavioral and emotional outcomes
3 cohorts of TGNB TGNB patients, pre-post: GnRH analogs were associated with significant improvement in total and internalizing and externalizing CBCL and YSR scores in 1 primary study, and nonsignificant improvements in another primary study that included
adolescents. a subset of the patients included in the first.
Authors conclusions GnRH analog therapy for puberty suppression over an average (SD) of 1.88 (1.05) years was associated with a statistically significant decreases (improvements) in CBCL total and internalizing scores (p<0.05) and externalizing scores
(p<0.05) among N=70 Danish TGNB adolescents with a mean (SD) age of 13.65 (1.85) years (p<0.05). It was also associated with statistically significant decreases (improvements) in YSR total and internalizing scores (p<0.05) and
GnRH analogs
externalizing scores (p<0.05) in de Vries (2011).57
significantly improve
global functioning and o In a subset of the same cohort who went on to receive CSHT, GnRH analog therapy for puberty suppression over an average (SD) of 1.88 (1.05) years was associated with nonsignificant decreases (improvements) in CBCL externalizing
behavioral/emotional scores (P=NS) as well as in YSR externalizing scores among N=55 Danish TGNB adolescents with a mean (SD) age of 14.75 (1.92) years (p=NS) in de Vries (2014).79
problems. The effects Gender dysphoria and body image
on anger remain
TGNB patients, pre-post: There was no significant improvement in body image in 1 primary study, but the assessment tool was not designed to assess changes related to unwanted secondary sex characteristics.
unclear. Treatment had
no significant effect on GnRH analog therapy for puberty suppression over an average (SD) of 1.88 (1.05) years was associated with no significant changes in GD and body image among N=70 Danish TGNB adolescents with a mean (SD) age of 13.65 (1.85) years
GD and body image. No (p=NS) in de Vries (2011).57
research was found Global functioning
examining the effects
TGNB patients, pre-post: GnRH analogs were associated with significant improvement in global functioning in 1 primary study, and nonsignificant improvement in another primary study. A third primary study reported improvement but did not
of progestin,
report significance.
antiandrogens,
GnRH analog therapy for puberty suppression over an average (SD) of 1.88 (1.05) years was associated with a statistically significant increase in global functioning among N=70 Danish TGNB adolescents with a mean (SD) age of 13.65
estrogens, and
(1.85) years (p<0.05) in de Vries (2011).57
testosterone.
o In a subset of the same cohort who went on to receive CSHT, GnRH analog therapy for puberty suppression over an average (SD) of 1.88 (1.05) years was associated with nonsignificant improvement in global functioning among N=55
Danish TGNB adolescents with a mean (SD) age of 14.75 (1.92) years (p=NS) in de Vries (2014).79
GnRH analog therapy for puberty suppression over an average (SD) duration of 0.75 (0.59) years was associated with improvement in global functioning among N=201 TGNB adolescents with a mean (SD) age of 15.52 (1.41) years (p=N/R)
in Costa (2015).77
D'hoore (2022)48 Body image

Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
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Table I.E.4. Systematic reviews examining psychosocial outcomes (eg, QOL, behavioral/social functioning, GD, body image) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
Primary studies: TGNB patients, pre-post: GAHT was associated with improved body image in 2 primary studies.
Mental health GAHT was associated with improvements in body dissatisfaction among TGNB adolescents (mean age 14.9) in Kuper (2020).141
outcomes in TGNB
adolescents were GAHT was associated with significant improvement in body image in treated adolescents in Becker (2018).103
assessed in 5 primary TGNB patients vs cisgender peers: Untreated TGNB patients had worse body image compared to cisgender peers in 1 primary study.
studies out of 91 that No treatment was associated with significantly higher levels of body uneasiness among N = 46 Italian TGNB patients (mean age = 16.0 ± 1.49) compared to a cisgender peer group in Fisher (2017).424
addressed a variety of
Global/psychosocial functioning
outcomes in TGNB
populations. TGNB patients, pre-post: GnRH analogs were associated with improved global functioning in 1 primary study.
Puberty suppression with GnRH analogs was associated with improved global functioning in n = 201 UK patients in Costa (2015).77
TGNB patients vs cisgender peers: Untreated TGNB patients had worse psychosocial functioning vs cisgender peers; after starting GAHT, they had comparable or better psychosocial functioning in 1 primary study.
Untreated TGNB patients had worse psychosocial functioning vs cisgender peers; after starting GAHT psychosocial functioning was similar or better than that of peers in van der Miesen (2020).124
Ludvigsson (2023)49 Cognition
Primary studies: Authors concluded from 1 primary study that GAHT was associated with no change in cognition.
Psychosocial outcomes GnRH analogs for a mean of 1.6 years were assessed for changes/differences in cognitive function (executive function task test) among N=41 patients (ages 12+ years) in Staphorsius (2015).119
were assessed in 7 Gender dysphoria
primary studies out of
Authors concluded from 2 primary studies that GAHT was associated with no change in GD as assessed with UGDS; authors omitted 1 included study that also looked at GD using UGDS.
24 included by review
authors. Review GnRH analogs for 1 year were assessed for changes/differences in GD among N=436 TGNB patients (mean age 15.5 years) in Costa (2015).77
authors based their GnRH analogs for a mean of 31 months were assessed for changes/differences in GD among N=44 TGNB patients (mean age 13.6 years) in Carmichael (2021).73
conclusions about Other included studies that also looked at GD:
psychosocial outcomes
GnRH analogs for 1 year followed by subsequent CSHT for 4 years were assessed for changes/differences in depression (BDI), anxiety (STAI), GD (UGDS), global functioning (CGAS), anger (TPI) among N=196 TGNB patients (mean age 13.6
on only 5 primary
years) in de Vries (2014).79
studies, omitting any
results from 2. Global/psychosocial function
Authors conclusions Authors concluded from 4 primary studies that GAHT was associated with improved global functioning as assessed with CGAS. Authors omitted 1 primary study that assessed psychosocial functioning with other measures.
GnRH analogs improve GnRH analogs for 1 year followed by subsequent CSHT for 4 years were assessed for changes/differences in global/psychosocial functioning among N=196 TGNB patients (mean age 13.6 years) in de Vries (2014).79
global function, but GnRH analogs for 1 year were assessed for changes/differences in global/psychosocial functioning among N=436 TGNB patients (mean age 15.5 years) in Costa (2015).77
have no effect on
GnRH analogs for a mean of 31 months were assessed for changes/differences in global/psychosocial functioning among N=44 TGNB patients (mean age 13.6 years) in Carmichael (2021).73
cognition. They also
improve quality of life. GnRH analogs for 0.5-4 years followed by CSHT for 0.5-0.4 years were assessed for changes/differences global/psychosocial functioning among N=434 TGNB patients (mean age 15.5 years) in Becker-Hebly (2020).72
Other included primary studies that assessed suicide ideation that the authors omitted when drawing their conclusions:
GnRH analogs followed by subsequent CSHT were assessed for changes/differences in psychosocial functioning (PHQ-9), anxiety (GAD-7), acute distress, suicidality, among N=80 TGNB patients (mean age 15 years) in Cantu (2020). d74
QOL
Authors concluded from 2 primary studies that GAHT was associated with improved of QOL.
GnRH analogs for a mean of 31 months were assessed for changes/differences in HRQOL (Kidscreen52) among N=44 TGNB patients (mean age 13.6 years) in Carmichael (2021).73
GnRH analogs for 0.5-4 years followed by CSHT for 0.5-0.4 years were assessed for changes/differences in global functioning (CGAS), psychosocial function (YSR/ASR) among N=434 TGNB patients (mean age 15.5 years) in Becker-Hebly
(2020).72

d
Publication year was erroneously listed as 2019 in the review authors’ reference lists.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
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Table I.E.4. Systematic reviews examining psychosocial outcomes (eg, QOL, behavioral/social functioning, GD, body image) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
Mahfouda (2019)50 Body dissatisfaction
Primary studies: TGNB patients, pre-post: 1 primary study found improvements in body dissatisfaction associated with unspecified GAHT.
Psychosocial outcomes Unspecified GAHT was associated with improvements in body dissatisfaction among N=50 TGNB adolescents (mean ages 14.3 years for transgender males and 15.7 years for transgender females) in Sequeira (2017).443
were examined in 3 out
of 12 primary studies Cognitive functioning
that addressed TGNB TGNB patients vs cisgender peers: 1 primary study found no differences in cognitive function associated with GnRH analogs and subsequent CSHT.
adolescents. Puberty suppression with GnRH analogs followed by CSHT was associated with no difference in cognitive function among N=21 transgender males (mean age at baseline 16.1 years) vs N=20 age-matched cisgender males and N=21 age-
matched cisgender females in Burke (2016).130
Disordered eating
TGNB patients, pre-post: 1 primary study found improvements in disordered eating associated with unspecified GAHT.
Unspecified GAHT was associated with improvements in body dissatisfaction among N=50 TGNB adolescents (mean ages 14.3 years for transgender males and 15.7 years for transgender females) in Sequeira (2017).443
Gender dysphoria
TGNB patients, pre-post: 1 primary study found improvements in GD associated with GnRH analogs and subsequent CSHT.
GnRH analogs for puberty suppression and unspecified CSHT was associated with reduced GD among N=55 transgender males (mean age 13.7 years at baseline) and N=22 transgender females (mean age 13.6 years at baseline) in de Vries
(2014).79
Global functioning
TGNB patients, pre-post: 1 primary study found improvements in global functioning associated with GnRH analogs and subsequent CSHT.
GnRH analogs for puberty suppression and unspecified CSHT was associated with reduced global functioning among N=55 transgender males and N=22 transgender females in de Vries (2014).79
Ramos (2021)51 Psychosocial outcomes:
Primary studies: Transgender males versus females: One primary study found AFAB patients were less satisfied with secondary sex characteristic changes associated with GnRH analogs vs AMAB patients.
Psychosocial outcomes De Vries et al (2011)57 found AFAB patients who received GnRH analog puberty suppression were less satisfied with secondary sex characteristics than AMAB patients who received the same treatments in N=70 TGNB youths.57
were examined in 2
TGNB patients, pre-post: One primary study found no difference in GD and body image scales associated with GnRH analogs; another found improvements in psychosocial functioning when the treatment was accompanied by psychological
primary studies that
support.
included adolescents.
De Vries et al (2011)57 found no differences in GD and body image scales vs baseline in N=70 patients who received GnRH analog puberty suppression.57
Costa et al (2015)77 found improvements in psychosocial functioning in N 200 TGNB adolescents undergoing GnRH analog puberty suppression along with psychological support.77
52
Rew (2021) Gender dysphoria
Primary studies: AMAB vs AFAB TGNB patients: 1 primary study showed that AFAB patients who received GnRH analogs had more problem behaviors than AMAB patients who received them.
Psychosocial outcomes AFAB patients who received unspecified GnRH analogs had more problem behaviors vs AMAB patients among N=70 TGNB adolescents (mean age 13.6 years) in de Vries (2011). 69
were examined in 3 out
TGNB patients, pre-post: 1 primary study showed no change in GD associated with GnRH analogs.
of 9 primary studies
addressing TGNB GnRH analogs were associated with no change in GD among N=70 TGNB adolescents (mean age 13.6 years) in de Vries (2011). 69
adolescents. Emotional and behavior problems
TGNB patients, pre-post: 1 primary study showed that GnRH analogs were associated with fewer emotional and behavior problems.
GnRH analogs were associated with significantly fewer emotional and behavior problems among N=70 TGNB adolescents (mean age 13.6 years) in de Vries (2011). 69
Global functioning
TGNB patients, pre-post: 1 primary study showed GnRH analogs were associated with improved global functioning.
GnRH analogs were associated with increases in global functioning among N=70 TGNB adolescents (mean age 13.6 years) in de Vries (2011). 69

Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
328

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Table I.E.4. Systematic reviews examining psychosocial outcomes (eg, QOL, behavioral/social functioning, GD, body image) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
Global IQ
Case findings: 1 patient experienced a decrease in global IQ after starting leuprorelin.
Leuprorelin was associated with a decrease in global IQ in N=1 TGNB patient in Schneider (2017).442
Social functioning
Case findings: Leuprorelin was associated with improved social life in 1 case report.
Leuprorelin was associated with improved social life in N=1 TGNB patient in Schneider (2017).442
Substance abuse
TGNB patients, pre-post: Puberty suppression was associated with decreases in binge drinking and illicit drug use in 1 primary study.
Unspecified puberty blockers were associated with decreased past-month binge drinking and lower lifetime illicit drug use in N=89 TGNB patients who started treatments between ages 9 and 16 years in Turban (2020).121

Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
329

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Table I.E.5. Systematic reviews addressing body changes (eg, endogenous hormones, growth, fat/lean/body mass, breast development, testicular volume) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
Chew (2018)47 Endogenous hormone levels
Primary studies: Body TGNB patients, pre-post: GnRH analogs, which are used for puberty suppression, tended to suppress gonadotropin hormone, LH, FSH, and sex hormones (testosterone and estrogen) in 3 out of 3 primary studies, although 1 study showed a
changes were assessed decrease in testosterone levels for transgender females but not transgender males. CSHT tended to produce changes in endogenous hormone levels that were consistent with that of the affirmed gender in 3 out of 3 primary studies.
in 7 primary studies, Studies in transgender females:
including 1 for which
only the transgender GnRH analog therapy for puberty suppression over 2+ years was associated with decreases in gonadotropin (p=N/R) and testosterone levels (p=N/R) among N=10 transgender females (mean age not given) in Delemarre-van de Waal
female adolescents met (2006).422
our eligibility criteria. GnRH analog therapy for puberty suppression over a mean of 1.3 years was associated with a statistically significant decrease in testosterone (p<0.05), LH (p<0.05), and FSH (p<0.05), and a nonsignificant decrease in androstenedione
One primary study that (p=NS) in N=15 transgender female adolescents with a mean (SD) age of 14.9 (1.9) years in Klink (2015).140
included young adults
GnRH analog therapy for puberty suppression over at least 3 months was associated with nonsignificant decreases in gonadotropin (p=NS), estradiol (p=NS), testosterone (p=NS), LH (p=NS), and FSH (p=NS) among N=49 transgender
was excluded.
female adolescents with a mean (SD) age of 13.6 years (p=NS) in Schagen (2016).148
Authors conclusions Estrogen in combination with cyproterone e over a mean of 1.3 years was associated with a statistically significant decrease in testosterone (p<0.05), fT (p<0.05), LH (p<0.05), a statistically significant increase in estradiol (p<0.05) and SHBG
GnRH analogs were (p<0.05), a nonsignificant decrease in FSH (p=NS), and no significant change in DHEA (p=NS) among N=27 Danish transgender female adolescents with a mean age of 16.5 years at the start of GnRH analog treatment and 17.6 years at the
associated with start of CSHT in Tack (2017).150
decreased growth
velocity, increased Studies in transgender males
body fat percentage, GnRH analog therapy for puberty suppression over a mean of 1.5 years was associated with statistically significant decreases in estradiol (p<0.05), LH (p<0.05), and FSH (p<0.05), and a non-significant decrease in androstenedione (p=NS),
increased BMI, and but no change in testosterone levels (p=NS) in N=19 transgender male adolescents with a mean (SD) age of 15.0 (2.0) years in Klink (2015).140
decreased lean body
Testosterone in combination with lynestrenol f over a mean of 0.95 years was associated with a statistically significant decrease in LH and FSH (p<0.05) and increase in testosterone and fT (p<0.05), a nonsignificant decrease in SHBG
mass. Lynestrenol
(p=NS), and a nonsignificant increase in estradiol (p=NS) among N=38 transgender male adolescents with a mean age of 15.8 years in Tack (2016).446
significantly increases
weight and BMI. Testosterone over 1-3 months was associated with a nonsignificant increase in testosterone (p=NS) and a nonsignificant decrease in estradiol (p=NS) among N=transgender male adolescents with a mean age of 16 years in Jarin (2017).136
Cyproterone decreases Body composition
growth velocity without
TGNB patients, pre-post: GnRH analogs increased fat mass and decreased lean mass in both transgender males (1 out of 1 primary study) and females (2 out of 2 primary studies).
affecting body weight
and BMI after 12 Studies transgender females:
months. Estrogen in GnRH analog therapy for puberty suppression over 2+ years was associated with increased fat mass percentage (p=N/R) and decreased lean body mass percentage (p=N/R) among N=10 transgender females (mean age not given) in
combination with Delemarre-van de Waal (2006).422
cyproterone resulted in
GnRH analog therapy for puberty suppression over at least 3 months was associated with a statistically significant increase in fat percentage (p<0.05) and a decrease in lean mass percentage (p<0.05) N=49 transgender female adolescents
reduced growth and
with a mean (SD) age of 13.6 years (p=NS in Schagen (2016).148
increases in total BMI.
Testosterone Studies in transgender males:
monotherapy increased GnRH analog therapy for puberty suppression over at least 3 months was associated with a statistically significant increase in fat percentage (p<0.05) and a decrease in lean mass percentage (p<0.05) among N=49 transgender female
growth velocity and adolescents with a mean (SD) age of 13.6 years (p=NS) in Schagen (2016).148
increased BMI.
Growth
TGNB patients, pre-post: GnRH analogs therapy tended to decrease growth velocity in transgender males and females compared with age- and puberty-matched peers. CSHT tended to accelerate growth in both transgender males and
females. No studies showed whether in individuals who received GnRH analogs would achieve their predicted final height after starting CSHT.
Studies transgender females:

e Cyproterone is an antiandrogen not available in the US.

f Lynestrenol is an androgenic progesterone not available in the US.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
330

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Table I.E.5. Systematic reviews addressing body changes (eg, endogenous hormones, growth, fat/lean/body mass, breast development, testicular volume) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
GnRH analog therapy for puberty suppression over 2+ years was associated with decreases in height velocity (p=N/R) and height variance (p=N/R) among N=10transgender females (mean age not given) in Delemarre-van de Waal
(2006).422
GnRH analog therapy for puberty suppression over a mean of 1.3 years was associated with a statistically significant increase in height (p<0.05), weight (p<0.05), and BMI (p<0.05), and a significant decrease in standardized height for trans
female adolescents (p<0.05) as well as a nonsignificant change in BMI variance (p=NS) among N=15 transgender female adolescents with a mean (SD) age of 14.9 (1.9) years in Klink (2015).140
GnRH analog therapy for puberty suppression over at least 3 months was associated with a statistically a significant increase in height (p<0.05), weight (p<0.05), BMI (p<0.05), and BMI variance (p<0.05), and a significant decrease in height
variance (p<0.05) and among N=49 transgender female adolescents with a mean (SD) age of 13.6 years (p=NS) in Schagen (2016).148
GnRH analog therapy for puberty suppression over an unspecified duration was associated with an increase in height (p=N/R) and weight (p=N/R) among N=28 transgender female adolescents with a mean age of 13.5 years in Vlot
(2017).99
Estrogen CSHT for an unspecified duration was associated with increases in height (p=N/R) among N=28 transgender female adolescents with a mean age at start of CSHT of 16.0 years in Vlot (2017).99
Estrogen in combination with cyproterone g over a mean of 1.3 years was associated with a statistically significant increase in height (p<0.05), a decrease in height relative to male peers (p<0.05), and an increase in BMI after 6-12 months
(p<0.05), though BMI was still lower than that of Flemish male peers, among N=27 Danish transgender female adolescents with a mean age of 16.5 years at the start of GnRH analog treatment and 17.6 years at the start of CSHT in Tack
(2017).150
Studies in transgender males:
GnRH analog therapy for puberty suppression over a mean of 1.5 years was associated with a statistically significant increase in height (p<0.05), weight (p<0.05), ), and BMI (p<0.05), and a nonsignificant decrease in standardized height
(p=NS) as well as a nonsignificant change in BMI variance (p=NS) for transgender male adolescents among N=19transgender male adolescents with a mean (SD) age of 15.0 (2.0) years in Klink (2015).140
GnRH analog therapy for puberty suppression over at least 3 months was associated with a statistically significant increase in height (p<0.05), weight (p<0.05), BMI (p<0.05), and BMI variance (p<0.05), and a nonsignificant decrease in
standardized height (p=NS) among N=67 transgender male adolescents with a mean (SD) age of 14.2 years in Schagen (2016).148
GnRH analog therapy for puberty suppression over an unspecified duration was associated with an increase in height (p=N/R) and weight (p=N/R) among N=42 transgender male adolescents with a mean age of 15.1 years in Vlot (2017).99
Testosterone in combination with lynestrenol h over a mean of 0.95 years was associated with an increase in height (p=N/R) and statistically significant increases in weight (p<0.05) and BMI (p<0.05) among N=38 male adolescents with a
mean age of 15.8 years in Tack (2016).446
Testosterone CSHT over an unspecified duration was associated with an increase in height (p=N/R) and weight (p=N/R) among N=42 transgender male adolescents with a mean age at the start of CSHT of 16.3 years in Vlot (2017).99
Testosterone over 1-3 months was associated with a nonsignificant increase in BMI (p=NS) among N=72 transgender male adolescents with a mean age of 16 years in Jarin (2017).136
Secondary sex characteristics
TGNB patients, pre-post: GnRH analogs tended to decrease unwanted secondary sex characteristics in 3 out of 3 primary studies. Estrogen produced changes in transgender females that were consistent with the affirmed sex.
Testicular volume:
GnRH analog therapy for puberty suppression over 2+ years was associated with decreases in testicular volume (p=N/R) in N=10 transgender females (mean age not given) in Delemarre-van de Waal (2006).422
GnRH analog therapy for puberty suppression over a mean of 1.3 years was associated with a statistically significant decrease in testicular volume in N=15 transgender female adolescents with a mean (SD) age of 14.9 (1.9) years in Klink
(2015).140
Feminization:
Estrogen in combination with cyproterone i over a mean of 1.3 years was associated with a decreased need for shaving in 71.4% (p=N/R), breast development at Tanner stage B3 in 66.7% or B4 in 9.5% (p=N/R), breast tenderness in 57.1%,
emotionality in 28.6%, and hot flashes in 14.3% among N=27 Danish transgender female adolescents with a mean age of 16.5 years at the start of GnRH analog treatment and 17.6 years at the start of CSHT in Tack (2017).150
Virilization

g Cyproterone is an antiandrogen not available in the US.

h Lynestrenol is an androgenic progesterone not available in the US.
i Cyproterone is an antiandrogen not available in the US.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
331

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Table I.E.5. Systematic reviews addressing body changes (eg, endogenous hormones, growth, fat/lean/body mass, breast development, testicular volume) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
GnRH analog therapy for puberty suppression over at least 3 months was associated with a cessation of menses in N=67 transgender male adolescents with a mean (SD) age of 14.2 years in Schagen (2016).148
48
D'hoore (2022) Body composition
Primary studies: Body TGNB patients, pre-post: GnRH puberty suppression (1 primary study), progestins (2 primary studies), and cross-sex hormone treatments (3 primary studies) were effective in producing body changes consistent with the affirmed gender in 6
changes in TGNB primary studies.
adolescents were GnRH analog monotherapy in trans girls (n = 49, median age = 13.6) and trans boys (n = 67, median age = 14.2) was associated with increased height, weight, fat mass, and BMI, and decreased lean body mass in the first year of treatment
assessed in 6 studies in Schagen (2016).148
out of 22 that
addressed adolescent Progestins in late-pubertal adolescents were associated with reduced endogenous hormone effects in Tack (2017).150
TGNB populations. Progestins for a mean <12 months were associated with increased lean mass and grip strength among n = 44 Belgian trans boys. Similarly, progestins decreased lean mass and grip strength and increased fat mass in n = 21 trans girls in
Tack (2018).447
Authors conclusions
Estradiol led to breast development within 3 months in 83% of trans girls (n = 22). At 3 years, 86% had Tanner breast stage 4-5. Hip circumference increased and waist-to-hip ratio decreased in Hannema (2017).59
In n = 121 trans boys and n = 71 trans girls who started GAHT at age 16 years, waist-to-hip ratio and body composition changed toward the affirmed sex by age 22. In trans girls, total body fat increased, and lean body mass and waist-to-
hip ratio decreased. In trans boys, total body fat decreased, and lean body mass and waist-to-hip ratio increased in Klaver (2018).83
In n = 19 Colorado trans boys (mean age 17), 3+ months of testosterone resulted in body composition changes consistent with the affirmed gender, and no difference in insulin sensitivity versus cis controls. in n = 14 trans girls (mean age
16.3), 3+ months of estradiol also produced the desired body composition changes, but trans girls became more insulin resistant than cis boys in Nokoff (2020).131
Ludvigsson (2023)49 Anthropometric measurements
Primary studies: Weight and BMI: Authors concluded from 1 primary study that GnRH analogs were associated with increases in weight and BMI. Authors omitted from their conclusions 6 other included primary studies that also looked at weight and/or BMI.
Body changes were Authors did not draw separate conclusions for AFAB vs AMAB adolescents, who would be expected to respond differently to the treatments.
assessed in 13 primary GnRH analogs for a mean of 1.5 years followed by CSHT for a mean of 2.9 years were assessed for changes/differences in weight and BMI by age 22 years among N=192 TGNB adolescents (mean age 15 years at start of treatment) in Klaver
studies out of 24 (2018).454
included primary Other included primary studies that assessed weight and/or BMI in patients who received GnRH analogs that were omitted by the authors when drawing their conclusions:
studies that addressed GnRH analogs for 1+ years were assessed for changes/differences weight and BMI among N=70 TGNB adolescents (mean age 13 years at start of treatment) in Joseph (2019).137
TGNB adolescents.
Authors drew GnRH analogs for 3-12 were assessed for changes/differences in weight and BMI among N=138 TGNB adolescents (mean age 14 years at start of treatment) in Schagen (2016).148
conclusions about body GnRH analogs for 10-14 months were assessed for changes/differences in BMI among N=92 TGNB adolescents (mean age 11.5 years at start of treatment) in Schulmeister (2022). j95
changes based on only GnRH analogs for a mean of 1.5 years followed by CSHT for a mean of 2.5 years were assessed for changes/differences in BMI by age 22 years among N=192 TGNB adolescents (mean age 14.9 years at start of treatment) in Klaver
4 included primary (2020).139
studies, omitting any
results from 9. GnRH analogs for 2-4 months followed by CSHT for 2-6 months were assessed for changes/differences in BMI among N=48 TGNB adolescents (mean age 14 years at start of treatment) in Perl (2020).144
GnRH analogs followed by CSHT were assessed for changes/differences in BMI among N=116 TGNB adolescents (ages 10+ years at start of treatment) after an average follow-up for 2 years in Jarin (2017).136
Author conclusions
GnRH analogs were Body composition
associated with Lean body mass: Authors concluded from 3 primary studies that GnRH analogs were associated with decreased lean body mass. Authors did not report findings separately for AFAB and AMAB youth, who would be expected to respond
increased weight and differently to treatments. Authors did not draw conclusions about other measures of body composition, such as fat mass and WHR, which were addressed in X of their included primary studies.
BMI as well as GnRH analogs for 3-12 were assessed for changes/differences in lean mass among N=138 TGNB adolescents (mean age 14 years at start of treatment) in Schagen (2016).148
decreased lean body
mass and growth GnRH analogs for 0.5-5.8 years were assessed for changes/differences in % lean mass among N=17 TGNB adolescents (mean age 12 years at start of treatment) in Nokoff (2020). k131
velocity.

j
Publication year is erroneously listed as 2021 in Ludvigsson’s results tables, but actual publication year is 2022.
k
Publication year is erroneously listed as 2021 in Ludvigsson tables, but actual publication year is 2020.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
332

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Table I.E.5. Systematic reviews addressing body changes (eg, endogenous hormones, growth, fat/lean/body mass, breast development, testicular volume) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
GnRH analogs for a mean of 1.5 years followed by CSHT for a mean of 2.9 years were assessed for changes/differences in total body % by age 22 years among N=192 TGNB adolescents (mean age 15 years at start of treatment) in Klaver
(2018).454
Other body composition measures that were addressed in 2 included primary studies were ignored by review authors when they drew their conclusions:
GnRH analogs for 0.5-5.8 years were assessed for changes/differences in insulin, glucose, HbA1c, HOMA-IR, body fat, % lean mass among N=17 TGNB adolescents (mean age 12 years at start of treatment) in Nokoff (2020). l131
GnRH analogs for a mean of 1.5 years followed by CSHT for a mean of 2.9 years were assessed for changes/differences in weight, BMI, total body %, WHR by age 22 years among N=192 TGNB adolescents (mean age 15 years at start of
treatment) in Klaver (2018).454
Growth velocity
Authors concluded from 1 primary study that GnRH analogs were associated with reduced growth velocity.
GnRH analogs for 10-14 months were assessed for changes/differences in height velocity among N=92 TGNB adolescents (mean age 11.5 years at start of treatment) in Schulmeister (2022). m95
Mahfouda (2019)50 Body composition changes
Primary studies: Body TGNB patients, pre-post: 1 primary study found GnRH analogs and subsequent CSHT were associated with changes towards the affirmed gender. .
changes were Puberty suppression with GnRH analogs and CSHT were associated with body changes towards the affirmed gender by age 22 years among N=192 TGNB patients (mean ages at start of treatment were 15.3 years for transgender male sand
examined in 1 out of 12 14.5 years for transgender females); this was characterized by increased fat mass, decreased lean mass, and decreased waist-to-hip ratio in transgender males, and decreased fat mass, increased lean mass, and increased waist-to-hip ratio
primary studies that in transgender females in Klaver (2018).83
addressed TGNB
adolescents.

Ramos (2021)51 Body composition changes:

Primary studies: Body TGNB patients, pre-post: One primary study found all body composition changes were more like the affirmed gender in transgender women who underwent GnRH analog therapy followed by CSHT. Transgender men experienced increases in
changes were assessed mass and waist to hip ration, but body composition was more like that of cisgender women than cisgender men. Earlier initiation of therapy improved outcomes in transgender men.
in 2 primary studies Studies in transgender women
that assessed it out of 3
studies/4 publications GnRH analog puberty suppression followed by CSHT given during adolescence was associated with an increase in body fat and a decline in lean mass and waist-hip ratio among N=71 transgender women assessed at age 22 years, resulting
that addressed in a body composition that was similar to that of cisgender women in Klaver (2018).83
adolescent TGNB Studies in transgender men
patients.
GnRH analog puberty suppression followed by CSHT given during adolescence was associated with increases in lean mass and waist-hip ratio among N=121 transgender men, but body composition at age 22 was more similar to that of
cisgender women than cisgender men. In a subset of transgender men who initiated treatment earlier, body composition at age 22 was more similar to that of cisgender men in Klaver (2018).83
Endogenous hormone changes:
TGNB patients, pre-post: One primary study found endogenous hormone changes during GnRH analog therapy along with adequate puberty suppression.
GnRH analog puberty suppression for between 3 months and 3 years was associated with endogenous gonadotropin decreases in the first 3 months of treatment, after which there were no more changes. Testosterone and estradiol
decreased after 3 months of treatment, with no signs of insufficient puberty suppression among TGNB patients in Schagen (2016).148

Rew (2021)52 Anthropometric measurements

Primary studies: Case findings: Triptorelin at age 13.7 years followed by testosterone and subsequent gonadectomy were associated with normal anthropometric measurements at 35 years in 1 case report.
Body changes were Triptorelin at age 13.7 years, testosterone at 18.6 years, and subsequent gonadectomy were associated normal anthropometric measurements at age 35 years in N=1 AFAB patient in Cohen-Kettenis (2011).168
examined in 3 primary Body composition
studies out of 9

l
Publication year is erroneously listed as 2021 in Ludvigsson tables, but actual publication year is 2020.
m
Publication year is erroneously listed as 2021 in Ludvigsson's results tables, but actual publication year is 2022.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
333

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Table I.E.5. Systematic reviews addressing body changes (eg, endogenous hormones, growth, fat/lean/body mass, breast development, testicular volume) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
addressing TGNB TGNB patients vs cisgender peers: GnRH analogs and subsequent CSHT were associated with changes consistent with the affirmed gender in 1 primary study.
adolescents. GnRH analogs followed by CSHT were associated with higher body fat in MTF and lower body fat in FTM patients compared to cisgender peers among N=192 TGNB adolescents who started puberty suppression before age 16 years in
Klaver (2018).83
TGNB patients, pre-post: Triptorelin was associated with decreased average lean mass and increased average fat mass in 1 primary study, but review authors did not report findings separately for AMAB and AFAB youth, which makes these
findings difficult to interpret.
Triptorelin was associated with decreased lean mass and increased fat mass among N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148
Endogenous hormone levels
Case findings: 21 years after starting treatment, a patient who had received triptorelin followed by subsequent testosterone and gonadectomy had elevated endogenous hormone levels in 1 primary study.
Triptorelin at age 13.7 years, testosterone at 18.6 years, and subsequent gonadectomy were associated with elevated FSHS and LH at age 35 years in N=1 AFAB patient in Cohen-Kettenis (2011).168
TGNB patients, pre-post: Triptorelin suppressed endogenous hormone levels in 1 primary study.
Triptorelin was associated with suppressed gonadotropin and sex steroid levels among N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148
Growth
TGNB patients, pre-post: Triptorelin was associated with slower growth in 1 primary study, but findings were not summarized separately for AMAB and AFAB youth.
Triptorelin was associated with decreased height velocity among N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148
Menstruation
TGNB patients, pre-post: Triptorelin was associated with cessation of menses in 1 primary study.
Triptorelin was associated with cessation of menses volume in the FTM subset of N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148
Testicular volume
TGNB patients, pre-post: Triptorelin was associated with decreased testicular volume in 1 primary study.
Triptorelin was associated with decreased testicular volume in the MTF subset of N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148

Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
334

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Table I.E.6. Systematic reviews examining bone health (eg, bone density, bone turnover measures) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
Chew (2018)47 BMD
Primary studies: Bone TGNB patients, pre-post: GnRH analog therapy was associated with no change or nonsignificant decreases in BMD among transgender females in 2 out of 2 primary studies. In transgender males, GnRH analog therapy was associated with a
changes were assessed mix of significant and nonsignificant decreases in 2 out of 2 primary studies. CSHT was associated with statistically increases in BMD among both transgender males and females in 1 out of 1 primary study.
in 3 primary studies out Studies in transgender females
of 11 that addressed
TGNB adolescents. GnRH analog therapy for puberty suppression over 2+ years was associated with no change in BMD values (p=N/R), and a decrease in BMD z scores (p=N/R) among N=10 transgender females (mean age not given) in Delemarre-van de
Waal (2006).422
Authors conclusions
GnRH analog therapy for puberty suppression over a mean of 1.3 years was associated with no significant change in BMD value (p=NS) and a nonsignificant decrease in BMD z score (p=NS) at the lumbar spine among N=15 transgender
GnRH analogs resulted
female adolescents with a mean (SD) age of 14.9 (1.9) years; it was also associated with nonsignificant decreases in both BMD values and z scores at the nondominant femur (p=NS) in Klink (2015).140
in no changes in
carbohydrate or lipid Estrogen CSHT for an unspecified duration was associated statistically significant increases in BMD values (p<0.05) and BMD z scores (p<0.05) at the lumbar spine among N=28 transgender female adolescents with a mean age at start of
metabolism or CSHT of 16.0 years; it was also associated with no significant changes in hip bone density (p=N/R) in Vlot (2017).99
cholesterol levels. It Studies in transgender males
may affect LFTs.
Progestins adversely GnRH analog therapy for puberty suppression over a mean of 1.5 years was associated with a nonsignificant decrease in BMD values (p=NS) and a statistically significant decrease (p<0.05) in z score at the lumbar spine among transgender
affect lipid profile, but male adolescents among N=19 transgender male adolescents with a mean (SD) age of 15.0 (2.0) years; it was also associated with nonsignificant decreases both BMD values and z scores and the nondominant femur (p=NS) in Klink
have no effect on (2015).140
glucose metabolism. GnRH analog therapy for puberty suppression over an unspecified duration was associated with statistically significant decreases in BMD values (p<0.05) and z scores (p<0.05) at the hip for older bone age among N=42 transgender male
LFTs resulted in non- adolescents with a mean age of 15.1 years; it was also associated with statistically significant decreases in BMD values (p<0.05) and z scores (p<0.05) at the lumbar spine for older bone age, and statistically significant decreases in BMD
clinically-significant values (p<0.05) and z scores (p<0.05) at the lumbar spine for younger bone age in Vlot (2017).99
changes. Cyproterone
Testosterone CSHT over an unspecified duration was associated with statistically significant increases in bone density values (p<0.05) and z scores (p<0.05) at the hip and in bone density values (p<0.05) and z scores (p<0.05) at the lumbar
reduced triglycerides
spine among N=42 transgender male adolescents with a mean age at the start of CSHT of 16.3 years in Vlot (2017).99
but did not affect other
lipids; it had no effect
on LFTs. Estrogen and
testosterone had no
effect on carbohydrate
or lipid metabolism or
LFTs.

D'hoore (2022)48 Bone health:

Primary studies: Bone TNGB patients, pre-post: GnRH analog therapy was associated with no (2 studies) or nonsignificant (4 studies) decreases in bone growth; GAHT was associated with significant increases in 3 primary studies, but 1 study showed bone density at
health outcomes in age 22 was nonsignificantly lower compared to pretreatment levels.
TGNB adolescents were Primary studies
assessed in 6 studies
out of 22 that GnRH analog monotherapy was associated with no change in 12-month LS BMD among n = 44 London transgender adolescents with persistent, severe GD (ages 12-15-years). At 24 months, LS bone mineral content and BMD were higher
addressed TGNB versus baseline. No change from baseline in TH BMD at 34 and 36 months in Carmichael (2021).73
populations. GnRH analog monotherapy showed that BMAD stabilized or showed a nonsignificant decrease in n = 121 transgender adolescents (51 trans girls and 70 trans boys), but Z-scores (and bone markers) decreased in all groups. GnRH
analog/GAHT combination therapy was associated with significant BMAD increases over 3 years, but Z-scores remained lower in trans girls and normalized in trans boys in Schagen (2020).94
Cyproterone n monotherapy was associated with limited normal bone expansion and pubertal bone mass accrual at the LS during a mean of 10.6 months (range 5–31) in n = 21 trans girls in Tack (2018).447

n
Cyproterone is an antiandrogen not available in the US.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
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Table I.E.6. Systematic reviews examining bone health (eg, bone density, bone turnover measures) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
GnRH analog monotherapy was associated with nonsignificant Z-score decreases ( 0.8 to 1.4) among n = 15 trans girls (median age 14.9); during CSHT, absolute LS BMD increased in these patients, but mean Z-score at age 22 was
nonsignificantly decreased compared to pre-treatment. GnRH analog monotherapy was associated with nonsignificant decreases in both LS and FN BMD (Z- among n = 19 trans boys (median age 15.0); CSHT showed
increases by age 22, but LS BMD Z-scores were nonsignificantly lower compared pre-treatment levels. Notably, the pretreatment LS BMD Z-score in trans women was below the population mean at the start of the treatment in Klink
140
(2015).
24 months of GnRH analog monotherapy was associated with decreased bone turnover markers (P1NP and 1CTP) in younger transgender adolescents (<14 years) and decreased LS BMAD Z- scores. Subsequent CSHT was associated with
further bone turnover markers decreased further in all groups except for trans boys >14 years old, but the BMAD increased and Z-scores returned to normal, especially at the LS among n = 56 Amsterdam transgender adolescents (34
transmasculine [median age 15.1] and 22 transfeminine individuals [median age 13.5]) in Vlot (2017).99
Between-TGNB group comparisons: Earlier initiation of GnRH puberty suppression was associated with bone changes that were more consistent with the affirmed gender in 1 primary study.
In 2+ years of GnRH and subsequent CSHT, earlier (vs later) treatment initiation was associated with measures of bone growth (sub-periosteal width and endocortical diameter) that were more similar to the affirmed gender; participants
who started treatment later remained within the reference curve of the natal sex among n = 322 transgender adolescents (106 trans girls and 216 trans boys) in van der Loos (2021).69
o Similarly, pretreatment bone density in n = 62 trans boys was also lower than the population mean in Stoffers (2019).149 Authors attributed it to lower participation in sports activities among trans girls, which negatively impacted
mechanical loading, and lower vitamin D levels in the sample.
Ludvigsson (2023)49 Bone mineral density
Primary studies: Puberty blockers: Authors concluded from 5 primary studies that puberty suppression was associated with no change in bone density. Patients in 4 out of the 5 primary studies also received CSHT, which is expected to build bone more rapidly in
Bone health was AMAB patients (versus AFAB); authors did not draw separate conclusions by sex. Authors omitted from their conclusions 2 included primary studies that also examined BMD.
assessed in 9 primary GnRH analogs for 1.5-4 years followed by CSHT for 3 years were assessed for changes/differences in BMAD among N=127 TGNB adolescents (mean age 14 at start of treatment) in Schagen (2020).94
studies out of 24 GnRH analogs for 0.25-8 years followed by CSHT for up to 8 years were assessed for changes/differences BMD, BMAD among N=34 adolescents by age 22 (mean age 15 years at start of treatment) in Klink (2015).140
included studies
GnRH analogs for 1+ years followed by CSHT were assessed for changes/differences in BMAD among N=213 TGNB adolescents (mean age 14 years at start of treatment) in Vlot (2017).99
addressing TGNB
adolescents. Authors GnRH analogs for 1+ years were assessed for changes/differences BMD and BMAD among N=70 TGNB adolescents (mean age 13 years at start of treatment) in Joseph (2019).137
drew conclusions about GnRH analogs for 3 months-3 years followed by CSHT for 5 months-3 years were assessed for changes/differences in BMD among N=64 transgender males (mean age 16 years at start of treatment) in Stoffers (2019).149
bone effects based on
Other primary studies that also evaluated BMD or BMAD
only 6 primary studies,
omitting any results GnRH analogs for 0.5-2 years followed by CSHT were assessed for changes/differences in BMD, BMAD, and Z-score (hip, LS) among N=193 TGNB adolescents (mean age 15 years at start of treatment) in Navabi (2021).92
from 3. GnRH analogs for 2 months were assessed for changes/differences in BMD, BMAD, and Z-score (hip, LS) among N=95 TGNB adolescents (mean age 11.5 years at start of treatment) in Lee (2020).85
Authors conclusions BMD Z-scores (ie, relative to reference mean)
Bone density remains Puberty blockers: Authors concluded from 5 primary studies that puberty suppression was associated with decreases in bone density relative to the reference population. Patients in 4 out of the 5 primary studies also received CSHT, which is
unchanged during expected to build bone more rapidly in AMAB patients (versus AFAB); authors did not draw separate conclusions by sex. Authors omitted from their conclusions 3 other studies that examined Z-scores in patients who had received GnRH
puberty blocking, but is analogs.
decreased over time GnRH analogs for 0.25-8 years followed by CSHT for up to 8 years were assessed for changes/differences in Z-score among N=34 adolescents by age 22 (mean age 15 years at start of treatment) in Klink (2015).140
relative to cisgender
peers. Bone density GnRH analogs for 1+ years followed by CSHT were assessed for changes/differences in Z-score among N=213 TGNB adolescents (mean age 14 years at start of treatment) in Vlot (2017).99
after CSHT is recovered GnRH analogs for 1+ years were assessed for changes/differences in Z-score (hip, spine) among N=70 TGNB adolescents (mean age 13 years at start of treatment) in Joseph (2019).137
in the hip but not at the
GnRH analogs for 3 months-3 years followed by CSHT for 5 months-3 years were assessed for changes/differences in Z-score (FN, LS) among N=64 transgender males (mean age 16 years at start of treatment) in Stoffers (2019).149
LS.
GnRH analogs for 0.5-2 years followed by CSHT were assessed for changes/differences in Z-score (hip, LS) among N=193 TGNB adolescents (mean age 15 years at start of treatment) in Navabi (2021).92
Puberty blockers: 3 others of their included primary studies that also examined BMD Z-score changes associated with GnRH analogs were omitted from their conclusions.
GnRH analogs for 1.5-4 years followed by CSHT for 3 years were assessed for changes/differences in aBMD and Z-score (hip) among N=127 TGNB adolescents (mean age 14 at start of treatment) in Schagen (2020).94
GnRH analogs for 2 months were assessed for changes/differences in BMD, aBMAD, and Z-score (hip, LS) among N=95 TGNB adolescents (mean age 11.5 years at start of treatment) in Lee (2020).85

Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
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Table I.E.6. Systematic reviews examining bone health (eg, bone density, bone turnover measures) associated with GD treatments in TGNB children/adolescents
First author (Year) Findings
Primary studies
GnRH analogs for 10-14 months were assessed for changes/differences in height velocity, BMI, Z-score N=92 TGNB adolescents (mean age 11.5 years at start of treatment) in Schulmeister (2022). o95
CSHT: Authors concluded from 3 primary studies that CSHT was associated with recovered bone density at the hip but not the LS, according to Z-scores. Authors did not draw conclusions separately by sex. Authors omitted 3 other included
studies that examined Z-scores that examined Z-scores in patients who had received CSHT.
GnRH analogs for 0.25-8 years followed by CSHT for up to 8 years were assessed for changes/differences in Z-score among N=34 adolescents by age 22 (mean age 15 years at start of treatment) in Klink (2015).140
GnRH analogs for 3 months-3 years followed by CSHT for 5 months-3 years were assessed for changes/differences in Z-score (FN, LS) among N=64 transgender males (mean age 16 years at start of treatment) in Stoffers (2019).149
GnRH analogs for 0.5-2 years followed by CSHT were assessed for changes/differences in Z-score (hip, LS) among N=193 TGNB adolescents (mean age 15 years at start of treatment) in Navabi (2021).92
CSHT: 3 others of their included primary studies also examined BMD Z-score changes associated with CSHT were omitted from their conclusions.
GnRH analogs for 1+ years followed by CSHT were assessed for changes/differences in height, BMAD, Z-score (hip, LS), bone markers (P1NP, OC, ICTP) among N=213 TGNB adolescents (mean age 14 years at start of treatment) in Vlot
(2017).99
GnRH analogs for 0.5-2 years followed by CSHT were assessed for changes/differences in BMD, aBMAD, and Z-score (hip, LS) among N=193 TGNB adolescents (mean age 15 years at start of treatment) in Navabi (2021).92
GnRH analogs for 1.5-4 years followed by CSHT for 3 years were assessed for changes/differences in aBMD and Z-score (hip) among N=127 TGNB adolescents (mean age 14 at start of treatment) in Schagen (2020).94
Mahfouda (2019)50 Bone health
Primary studies: Bone TGNB patients, pre-post: 1 primary study found increases in bone density associated with CSHT; another found average BMD was below pretreatment potential after GnRH analogs and subsequent CSHT; in the latter study, review authors did
health was examined in not report findings separately for transgender males and transgender females, so it is difficult to interpret this finding.
2 out of 12 primary Puberty suppression with GnRH analogs and subsequent CSHT were associated with changes in BMD among N=34 TGNB adolescents (mean ages at start of treatment 15.0 years for transgender males and 14.9 years for transgender
studies that addressed females); this was characterized by either delayed attainment of peak bone mass, or by attenuation of peak bone mass in Klink (2015).140
TGNB adolescents.
CSHT was associated with increases in BMAD and BMAD Z-scores at the LS, and decreases in bone turnover markers at 24 months among N=70 TGNB adolescents (mean age at baseline 13.5 years for transgender females and 15.1 years
for transgender males) in Vlot (2017).99
Ramos (2021)51 Bone health:
Primary studies: Bone Transgender women versus cisgender men: One primary study showed no significant difference in BMD at age 22 after GnRH analog puberty suppression and CSHT.
health was assessed in GnRH analog puberty suppression with triptorelin in early adolescence followed by CSHT in later adolescence were associated with no effect on BMD changes in N=16 transgender women vs N=19 cisgender men at age 22 years in Klink
3 primary studies out of (2013).433
3 reviewed studies/4
reviewed publications TGNB patients, pre-post: 1 primary study showed a decline in BMD associated with GnRH analogs followed by CSHT in both TGNB males and females; another primary showed declining bone turnover markers during GnRH analog therapy with
no change in BMAD, which was followed by a return to normal after initiating CSHT.
that addressed
adolescent TGNB GnRH analog puberty suppression with triptorelin in early adolescence followed by CSHT was associated with a decline in Z-scores from - 0.8 to - 1.4 among transgender women and a decline from 0.2 to - 0.3 in transgender men. Authors
patients. concluded that BMD was below pre-treatment potential at age 22 years in both groups in Klink (2015).140
GnRH analog therapy was associated with a decrease in bone turnover markers among N=28 transgender women and N=42 transgender men, with no change in BMAD; subsequent CSHT was associated with increased BMAD and Z-scores
among both groups in Vlot (2017).99

Rew (2021)52 Bone turnover markers

Primary studies: TGNB patients, pre-post: Triptorelin and subsequent CSHT were associated with decreases in bone turnover markers in 1 primary study.
Bone health was Triptorelin puberty suppression followed by CSHT with testosterone or estradiol was associated with decreases in ICTP and P1NP among N=70 TGNB adolescents in Vlot (2017).99
examined in 1 primary Bone mineral density
study out of 9 that TGNB patients, pre-post: Triptorelin and subsequent CSHT were associated with decreases in LS BMAD Z scores in 1 primary study; findings were not separated out for AMAB vs AFAB youth.
addressed TGNB
Triptorelin puberty suppression followed by CSHT with testosterone or estradiol was associated with decreases in LS BMAD Z scores among N=70 TGNB adolescents; pretreatment Z scores in most patients had not fully recovered after 24
adolescents.
months on CSHT in Vlot (2017).99

o
Publication year is erroneously listed as 2021 in Ludvigsson's results tables, but actual publication year is 2022.
Table abbreviations: GD, gender dysphoria; QOL, quality of life; TGNB; transgender, nonbinary, or other gender diverse; GnRH, gonadotropin-releasing hormone; CSHT, cross-sex hormone therapy (ie, testosterone in transgender males, estrogen in transgender
females; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form; CBCL, Child Behavior Checklist; YSR, Youth Self Report; NS, nonsignificant; SD, standard deviation; NR, not reported; GGT, gamma-glutamyl transferase; AST, aspartate
transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase;
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Table I.E.7. Systematic reviews addressing cardiovascular/metabolic risk factors (eg, thrombotic/thromboembolic, insulin sensitivity, blood pressure, cholesterol, liver, and kidney outcomes) in TGNB adolescents who receive GnRH
analogs for puberty suppression
First author (Year) Findings
Primary studies
Chew (2018)47 Cholesterol
Primary studies: TNGB patients, pre-post: Estrogen CSHT was associated with no changes in cholesterol and TG levels in transgender females in 1 out of 1 primary study. Testosterone was associated with no significant changes in TC, LDL, or TG in 2 out of 2
Cardiovascular and primary studies, but HDL was significantly decrease in 1 out of 2 primary studies.
metabolic outcomes Studies in transgender females
were assessed in 3 out
of 11 primary studies Estrogen in combination with cyproterone p over a mean of 1.3 years was associated with no significant changes in TC (p=NS), LDL (p=NS), HDL (p=NS), or TG (p=NS) levels among N=27 Danish transgender female adolescents with a mean
that addressed TGNB age of 16.5 years at the start of GnRH analog treatment and 17.6 years at the start of CSHT in Tack (2017).150
adolescents. Studies in transgender males
Testosterone in combination with lynestrenol q over a mean of 0.95 years was associated with no significant changes in TC (p=NS), TG (p=NS), HDL (p=NS), or LDL (p=NS) among N=38 transgender male adolescents with a mean age of 15.8
years in Tack (2016).446
Testosterone over 1-3 months was associated with no significant changes in TC (p=NS), LDL (p=NS), TG (p=NS), TG-to-HDL ratio (p=NS), and a statistically significant decrease in HDL (p=<0.05) among N=72 transgender male adolescents
with a mean age of 16 years in Jarin (2017).136
Liver and kidney effects
TGNB patients, pre-post:
Studies in transgender females
GnRH analog therapy for puberty suppression over at least 3 months was associated no significant changes in GGT (p=NS), AST (p=NS), or ALT (p=NS), and a statistically significant decrease in ALP (p<0.05) among N=49 transgender female
adolescents with a mean (SD) age of 13.6 years (p=NS) in Schagen (2016).148
Estrogen in combination with cyproterone r over a mean of 1.3 years was associated with no significant changes in creatinine (p=NS), AST (p=NS), or ALT (p=NS) among N=27 Danish transgender female adolescents with a mean age of 16.5
years at the start of GnRH analog treatment and 17.6 years at the start of CSHT in Tack (2017).150
Studies in transgender males
GnRH analog therapy for puberty suppression over at least 3 months was associated with a statistically significant decrease in creatinine (p=<0.05), no significant change in GGT (p=NS), AST (p=NS), or ALT (p=NS), and a statistically
significant decrease in AP (p<0.05) among N=67 transgender male adolescents with a mean (SD) age of 14.2 years in Schagen (2016).148
Testosterone in combination with lynestrenol s over a mean of 0.95 years was associated with statistically significant increases in creatinine (p<0.05) and in ALT (p<0.05) and AST (p<0.05), though both of the latter remained in the normal
range for males, among N=38 transgender male adolescents with a mean age of 15.8 years in Tack (2016).446
Testosterone over 1-3 months was associated with no significant changes in creatinine (p=NS), prolactin (p=NS), or AST (p=NS), and a nonsignificant decrease in ALT (p=<0.05), which returned to baseline after 4-6 months, among N=72
transgender male adolescents with a mean age of 16 years in Jarin (2017).136
Thrombotic changes:
TGNB patients, pre-post:
Studies in transgender females:
Estrogen in combination with cyproterone t over a mean of 1.3 years was associated with no significant changes in Hb (p=NS) or HCT (p=NS) among N=27 Danish transgender female adolescents with a mean age of 16.5 years at the start of
GnRH analog treatment and 17.6 years at the start of CSHT in Tack (2017).150

p
Cyproterone is an antiandrogen not available in the US.
q Lynestrenol is an androgenic progesterone not available in the US.
r Cyproterone is an antiandrogen not available in the US.
s Lynestrenol is an androgenic progesterone not available in the US.
t Cyproterone is an antiandrogen not available in the US.

Table abbreviations: AP, alkaline phosphatase; CI, confidence interval; DBP, diastolic blood pressure ;DFAB, defined female at birth; DMAB, defined male at birth; GD, gender dysphoria; HDL high-density lipoproteins; ITS, interrupted time series; LDL, low-density
lipoproteins; N/A, not applicable; N/R, not reported; SCr, serum creatinine; SD, standard deviation; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; TGNB, transgender, non-binary, or gender-diverse.
338

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Table I.E.7. Systematic reviews addressing cardiovascular/metabolic risk factors (eg, thrombotic/thromboembolic, insulin sensitivity, blood pressure, cholesterol, liver, and kidney outcomes) in TGNB adolescents who receive GnRH
analogs for puberty suppression
First author (Year) Findings
Primary studies
Studies in transgender males:
Testosterone in combination with lynestrenol u over a mean of 0.95 years was associated with statistically significant increases in HB (p<0.05) and HCT levels among N=38 transgender male adolescents with a mean age of 15.8 years in
Tack (2016).446
Testosterone over 1-3 months was associated with statistically significant increases in Hb (p<0.05) and HCT (p<0.05) among N=72 transgender male adolescents with a mean age of 16 years in Jarin (2017).136
Thyroid changes:
Studies in transgender females:
Estrogen in combination with cyproterone v over a mean of 1.3 years was associated with no significant changes in thyrotropin (p=NS) and free thyroxin (p=NS), and a statistically significant decrease in prolactin (p=NS) among N=27 Danish
transgender female adolescents with a mean age of 16.5 years at the start of GnRH analog treatment and 17.6 years at the start of CSHT in Tack (2017).150
Studies in transgender males:
Testosterone in combination with lynestrenol w over a mean of 0.95 years was associated with a nonsignificant decrease thyroxine (p=NS) and a statistically significant decrease in fT4 (p<0.05) among N=38 transgender male adolescents
with a mean age of 15.8 years in Tack (2016).446
D'hoore (2022)48 x Cardiovascular and thromboembolic safety
Primary studies: TGNB patients, pre-post: CSHT (ie, oral estrogen) was associated with no BP changes in 2 primary studies. Transmasculine individuals in 1 primary study who received androgenic progestins with or without testosterone experienced a
Cardiovascular risk significant decrease in HDL; the lipid profile was worse in those who received androgenic progestin monotherapy versus those who received progestin/testosterone combination therapy. Transmasculine adolescents who received testosterone
factor outcomes were also experienced significant increases in hemoglobin/hematocrit in 1 primary study. Transfeminine individuals who received estrogen experienced no changes in HDL, hemoglobin, or hematocrit in 1 primary study.
assessed in 4 out of 22 12+ months of oral estrogen in n = 28 transfeminine individuals was associated with no significant changes in blood pressure in Hannema (2017).59
studies that addressed
No changes in blood pressure were observed with GnRH analog therapy in n = 19 transfeminine individuals, or with estrogen in n = 15 who continued with estrogen treatment in Perl (2020)144
TGNB populations.
GAHT was associated with a significant decrease in mean HDL-cholesterol level (from 50.2 to 45.0 mg/dl) in n = 72 transmasculine adolescents (mean age 16); in the subset who were received androgenic progestin monotherapy (ie,
lynestrenol y), the lipid profile was significantly more unfavorable compared to those who received progestin/testosterone combination therapy. Testosterone (with or without androgenic progestins) was also associated with significant
increases in hemoglobin (from 13.5 to 15.0 g/dl) and hematocrit (from 39.4% to 44.5%). No HDL or hemoglobin/hematocrit changes were associated with GAHT in n = 44 transfeminine individuals in Jarin (2017).136
TGNB patients vs cisgender peers: GnRH analogs were associated with improvements in metabolic and CV risk factors that were similar to or more favorable than that of cisgender peers in 1 primary study.
Pretreatment obesity prevalence was 9.9% among n = 81 trans girls 6.6% in and n = 121 trans boys, compared to 2.2% and 3.0% in cis girls and boys, respectively. GnRH analog therapy started at a mean age of 15 years was associated with
changes in BMI, SBP/DPB, glucose, HOMA-IR, and lipid values that were similar to or more favorable than that of cisgender peers by age 22 in Klaver (2020).139
Ludvigsson (2023)49 Metabolic measures
Primary studies: Authors concluded from 2 primary studies that GnRH analogs were associated with no changes in serum lipids or blood pressure, insulin level is increased in MTF patients, and there was decreased insulin sensitivity
Cardiovascular and GnRH analogs for 0.5-5.8 years were assessed for changes/differences in insulin, glucose, HbA1c, HOMA-IR, body fat, % lean mass among N=17 TGNB adolescents (mean age 12 years at start of treatment) in Nokoff (2020). z131
metabolic changes GnRH analogs for a mean of 1.5 years followed by CSHT for a mean of 2.5 years were assessed for changes/differences in BMI, SDP, DBP, glucose, insulin, HOMA-IR, cholesterol, and triglycerides by age 22 years among N=192 TGNB
were assessed in 7 adolescents (mean age 14.9 years at start of treatment) in Klaver (2020).139
primary studies out of
Other included primary studies that examined lipids, blood pressure, insulin levels, and/or insulin sensitivity associated with GnRH analogs
24 included by review

u Lynestrenol is an androgenic progesterone not available in the US.

v Cyproterone is an antiandrogen not available in the US.
w Lynestrenol is an androgenic progesterone not available in the US.
x
D'hoore looked for but did not find studies addressing cancer risk in TGNB adolescents.
y Lynestrenol is an androgenic progesterone not available in the US.

z
Publication year is erroneously listed as 2021 in Ludvigsson tables, but actual publication year is 2020.
Table abbreviations: AP, alkaline phosphatase; CI, confidence interval; DBP, diastolic blood pressure ;DFAB, defined female at birth; DMAB, defined male at birth; GD, gender dysphoria; HDL high-density lipoproteins; ITS, interrupted time series; LDL, low-density
lipoproteins; N/A, not applicable; N/R, not reported; SCr, serum creatinine; SD, standard deviation; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; TGNB, transgender, non-binary, or gender-diverse.
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Table I.E.7. Systematic reviews addressing cardiovascular/metabolic risk factors (eg, thrombotic/thromboembolic, insulin sensitivity, blood pressure, cholesterol, liver, and kidney outcomes) in TGNB adolescents who receive GnRH
analogs for puberty suppression
First author (Year) Findings
Primary studies
authors. Review GnRH analogs for 3 months-3 years followed by CSHT for 5 months-3 years were assessed for changes/differences in height, BP, BMD, Z-score (FN, LS) among N=64 transgender males (mean age 16 years at start of treatment) in Stoffers
authors based their (2019).149
conclusions about
GnRH analogs for 2-4 months followed by CSHT for 2-6 months were assessed for changes/differences in BMI and BP among N=48 TGNB adolescents (mean age 14 years at start of treatment) in Perl (2020).144
psychosocial outcomes
on only 3 primary GnRH analogs followed by CSHT were assessed for changes/differences in BMI, BP, hematocrit, Hb, and cholesterol among N=116 TGNB adolescents (ages 10+ years at start of treatment) after an average follow-up for 2 years in Jarin
studies, omitting any (2017).136
results from 4. Blood pressure
Author conclusions Authors concluded from 1 primary study that GnRH analogs were associated with changes in BP.
GnRH analogs were GnRH analogs for 2-4 months followed by CSHT for 2-6 months were assessed for changes/differences in BP among N=48 TGNB adolescents (mean age 14 years at start of treatment) in Perl (2020).144
associated with no Other included primary studies that also examined changes in BP associated with GnRH analogs
change in lipids or
GnRH analogs for 3 months-3 years followed by CSHT for 5 months-3 years were assessed for changes/differences in height, BP, BMD, Z-score (FN, LS) among N=64 transgender males (mean age 16 years at start of treatment) in Stoffers
blood pressure,
(2019).149
increased insulin levels
in MTF patients, and GnRH analogs for a mean of 1.5 years followed by CSHT for a mean of 2.5 years were assessed for changes/differences in BMI, SDP, DBP, glucose, insulin, HOMA-IR, cholesterol, and triglycerides by age 22 years among N=192 TGNB
decreased insulin adolescents (mean age 14.9 years at start of treatment) in Klaver (2020).139
sensitivity. They are GnRH analogs followed by CSHT were assessed for changes/differences in BMI, BP, hematocrit, Hb, and cholesterol among N=116 TGNB adolescents (ages 10+ years at start of treatment) after an average follow-up for 2 years in Jarin
also associated with a (2017).136
change in blood
pressure (direction
unspecified).

Mahfouda (2019)50 Hematocrit

Primary studies: CV risk TGNB patients, pre-post:
factors and metabolic Unspecified GAHT was associated with significant changes in hematocrit in N=14 transgender males but not in N=6 transgender females; no other metabolic factors were affected in Trotman (2014).449
outcomes were
examined in 5 out of 12 Metabolic parameters
primary studies that TGNB patients, pre-post:
addressed TGNB Puberty suppression with lynestrenol aa followed by testosterone CSHT was associated with no major changes in unspecified liver enzymes among N=70 transgender males (mean age 15.8 years) in Tack (2016).446
adolescents.
CSHT was associated with safe short-term metabolic parameter levels in N=116 TGNB adolescents (mean age 16 years for transgender males and 18 years for transgender females) in Jarin (2017).136
Puberty suppression with cyproterone bb followed by estradiol CSHT was associated with transient increases in ALT and AST that did not require treatment discontinuation among N=27 transgender females (mean age 16.5 years at start of
therapy) in Tack (2017).150
GAHT (including GnRH analogs and subsequent CSHT) for 2 years was associated with no clinically significant changes in "laboratory parameters" among N=101 TGNB adolescents (mean age at start of treatment 18 years) in Olson-
Kennedy (2018).143
Cardiovascular parameters
CSHT was associated with safe short-term CV parameter levels in N=116 TGNB adolescents (mean age 16 years for transgender males and 18 years for transgender females) in Jarin (2017).136
Ramos (2021)51 Metabolic changes:
Primary studies: TGNB patients, pre-post: One primary study showed no changes in key markers of metabolism and renal function.
Metabolic changes

aa Lynestrenol is an androgenic progesterone not available in the US.

bb Cyproterone is an antiandrogen not available in the US.

Table abbreviations: AP, alkaline phosphatase; CI, confidence interval; DBP, diastolic blood pressure ;DFAB, defined female at birth; DMAB, defined male at birth; GD, gender dysphoria; HDL high-density lipoproteins; ITS, interrupted time series; LDL, low-density
lipoproteins; N/A, not applicable; N/R, not reported; SCr, serum creatinine; SD, standard deviation; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; TGNB, transgender, non-binary, or gender-diverse.
340

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Table I.E.7. Systematic reviews addressing cardiovascular/metabolic risk factors (eg, thrombotic/thromboembolic, insulin sensitivity, blood pressure, cholesterol, liver, and kidney outcomes) in TGNB adolescents who receive GnRH
analogs for puberty suppression
First author (Year) Findings
Primary studies
were examined in 1 GnRH analog puberty suppression for 3 months to 3 years was associated with no changes in AST, ALT, FA, GT, or creatinine among TGNB patients in Schagen (2016).148
primary study out of 3
reviewed studies/4
reviewed publications
that addressed
adolescent TGNB
patients.

Rew (2021)52 "Fasting labs"

Primary studies: Case findings:
Metabolic changes Triptorelin puberty suppression at age 13.7 years followed by CSHT with testosterone at age 18.6 was associated with fasting labs "within normal limits" in N=1 AFAB patient in Cohen-Kettenis (2011).168
were examined in 2
Creatinine
primary studies out of 9
that addressed TGNB TGNB patients, pre-post:
adolescents. Triptorelin was associated with no sustained creatinine abnormalities among N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148
Liver function
TGNB patients, pre-post:
Triptorelin was associated with no sustained LFT abnormalities among N=116 TGNB patients (age range 11.1-18.6 years) in Schagen (2016).148

Table abbreviations: AP, alkaline phosphatase; CI, confidence interval; DBP, diastolic blood pressure ;DFAB, defined female at birth; DMAB, defined male at birth; GD, gender dysphoria; HDL high-density lipoproteins; ITS, interrupted time series; LDL, low-density
lipoproteins; N/A, not applicable; N/R, not reported; SCr, serum creatinine; SD, standard deviation; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; TGNB, transgender, non-binary, or gender-diverse.
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APPENDIX I.F: BIBLIOGRAPHY OF ALL INCLUDED STUDIES
Guidelines 10,54,101,245

American College of Obstetricians, Gynecologists' Committee on Clinical Consensus-Gynecology. General

Approaches to Medical Management of Menstrual Suppression: ACOG Clinical Consensus No. 3.
Obstet Gynecol. 2022;140(3):528-541. doi:10.1097/AOG.0000000000004899 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36356248

Abstract: The purpose of this document is to review currently available management options,
general principles, and counseling approaches for reproductive-aged patients requesting
menstrual suppression. It includes considerations for unique populations, including adolescents,
patients with physical or cognitive disabilities or both, and those with limited access to health
care. Gynecologists should be familiar with the use of hormonal therapy for menstrual
suppression (including combined oral contraceptive pills, combined hormonal patches, vaginal
rings, progestin-only pills, depot medroxyprogesterone acetate, the levonorgestrel-releasing
intrauterine device, and the etonogestrel implant). Approaches to counseling should be
individualized based on patient preferences and goals, average treatment effectiveness, and
contraindications or risk factors for adverse events. Counseling regarding the choice of
hormonal medication for menstrual suppression should be approached with the utmost respect
for patient autonomy and be free of coercion. Complete amenorrhea may be difficult to
achieve; thus, obstetrician-gynecologists and other clinicians should counsel patients and
caregivers, if applicable, about realistic expectations.

Annotation: Guidelines for managing menstrual suppression, including in TGNB patients

Coleman E, Radix AE, Bouman WP, et al. Standards of Care for the Health of Transgender and Gender
Diverse People, Version 8. Int J Transgend Health. 2022;23(Suppl 1):S1-S259.
doi:10.1080/26895269.2022.2100644 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36238954

Abstract: Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the

last decade, there has been an unprecedented increase in the number and visibility of
transgender and gender diverse (TGD) people seeking support and gender-affirming medical
treatment in parallel with a significant rise in the scientific literature in this area. The World
Professional Association for Transgender Health (WPATH) is an international, multidisciplinary,
professional association whose mission is to promote evidence-based care, education, research,
public policy, and respect in transgender health. One of the main functions of WPATH is to
promote the highest standards of health care for TGD people through the Standards of Care
(SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in
2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the
Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care
professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective
pathways to achieving lasting personal comfort with their gendered selves with the aim of
optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods:
The SOC-8 is based on the best available science and expert professional consensus in
transgender health. International professionals and stakeholders were selected to serve on the
SOC-8 committee. Recommendation statements were developed based on data derived from

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 independent systematic literature reviews, where available, background reviews and expert
opinions. Grading of recommendations was based on the available evidence supporting
interventions, a discussion of risks and harms, as well as the feasibility and acceptability within
different contexts and country settings. Results: A total of 18 chapters were developed as part
of the SOC-8. They contain recommendations for health care professionals who provide care
and treatment for TGD people. Each of the recommendations is followed by explanatory text
with relevant references. General areas related to transgender health are covered in the
chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters
developed for the diverse population of TGD people include Assessment of Adults, Adolescents,
Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional
Environments. Finally, the chapters related to gender-affirming treatment are Hormone
Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care,
Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are
intended to be flexible to meet the diverse health care needs of TGD people globally. While
adaptable, they offer standards for promoting optimal health care and guidance for the
treatment of people experiencing gender incongruence. As in all previous versions of the SOC,
the criteria set forth in this document for gender-affirming medical interventions are clinical
guidelines; individual health care professionals and programs may modify these in consultation
with the TGD person.

Annotation: WPATH’s best practices for treating TGNB patients

Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/Gender-

Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab.
2017;102(11):3869-3903. doi:10.1210/jc.2017-01658 Accessed May 18, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28945902

Abstract: OBJECTIVE: To update the "Endocrine Treatment of Transsexual Persons: An Endocrine

Society Clinical Practice Guideline," published by the Endocrine Society in 2009. PARTICIPANTS:
The participants include an Endocrine Society-appointed task force of nine experts, a
methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed
using the Grading of Recommendations, Assessment, Development, and Evaluation approach to
describe the strength of recommendations and the quality of evidence. The task force
commissioned two systematic reviews and used the best available evidence from other
published systematic reviews and individual studies. CONSENSUS PROCESS: Group meetings,
conference calls, and e-mail communications enabled consensus. Endocrine Society committees,
members and cosponsoring organizations reviewed and commented on preliminary drafts of the
guidelines. CONCLUSION: Gender affirmation is multidisciplinary treatment in which
endocrinologists play an important role. Gender-dysphoric/gender-incongruent persons seek
and/or are referred to endocrinologists to develop the physical characteristics of the affirmed
gender. They require a safe and effective hormone regimen that will (1) suppress endogenous
sex hormone secretion determined by the person's genetic/gonadal sex and (2) maintain sex
hormone levels within the normal range for the person's affirmed gender. Hormone treatment
is not recommended for prepubertal gender-dysphoric/gender-incongruent persons. Those
clinicians who recommend gender-affirming endocrine treatments-appropriately trained
diagnosing clinicians (required), a mental health provider for adolescents (required) and mental
health professional for adults (recommended)-should be knowledgeable about the diagnostic
criteria and criteria for gender-affirming treatment, have sufficient training and experience in
assessing psychopathology, and be willing to participate in the ongoing care throughout the

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 endocrine transition. We recommend treating gender-dysphoric/gender-incongruent
adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with
gonadotropin-releasing hormone agonists. Clinicians may add gender-affirming hormones after
a multidisciplinary team has confirmed the persistence of gender dysphoria/gender
incongruence and sufficient mental capacity to give informed consent to this partially
irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize
that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years,
although there is minimal published experience treating prior to 13.5 to 14 years of age. For the
care of peripubertal youths and older adolescents, we recommend that an expert
multidisciplinary team comprised of medical professionals and mental health professionals
manage this treatment. The treating physician must confirm the criteria for treatment used by
the referring mental health practitioner and collaborate with them in decisions about gender-
affirming surgery in older adolescents. For adult gender-dysphoric/gender-incongruent persons,
the treating clinicians (collectively) should have expertise in transgender-specific diagnostic
criteria, mental health, primary care, hormone treatment, and surgery, as needed by the
patient. We suggest maintaining physiologic levels of gender-appropriate hormones and
monitoring for known risks and complications. When high doses of sex steroids are required to
suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically
removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor
both transgender males (female to male) and transgender females (male to female) for
reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians
should persistently monitor adverse effects of sex steroids. For gender-affirming surgeries in
adults, the treating physician must collaborate with and confirm the criteria for treatment used
by the referring physician. Clinicians should avoid harming individuals (via hormone treatment)
who have conditions other than gender dysphoria/gender incongruence and who may not
benefit from the physical changes associated with this treatment.

Annotation: A guideline for treating gender dysphoria

T'Sjoen G, Arcelus J, De Vries ALC, et al. European Society for Sexual Medicine Position Statement
"Assessment and Hormonal Management in Adolescent and Adult Trans People, With Attention
for Sexual Function and Satisfaction". J Sex Med. 2020;17(4):570-584.
doi:10.1016/j.jsxm.2020.01.012 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32111534

Abstract: BACKGROUND: There is a general lack of recommendations for and basic information
tailored at sexologists and other health-care professionals for when they encounter trans people
in their practice. AIM: We present to clinicians an up-to-date overview of clinical consensus
statements on trans health care with attention for sexual function and satisfaction. METHODS:
The task force consisted of 7 clinicians experienced in trans health care, selected among
European Society for Sexual Medicine (ESSM) scientific committee. The consensus was guided
by clinical experience and a review of the available literature and by interactive discussions on
trans health, with attention for sexual function and satisfaction where available. OUTCOMES:
The foci of the study are assessment and hormonal aspects of trans health care. RESULTS: As the
available literature for direct recommendations was limited, most of the literature was used as
background or indirect evidence. Clinical consensus statements were developed based on
clinical experiences and the available literature. With the multiple barriers to care that many
trans people experience, basic care principles still need to be stressed. We recommend that
health-care professionals (HCPs) working with trans people recognize the diversity of genders,

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 including male, female, and nonbinary individuals. In addition, HCPs assessing gender diverse
children and adolescents should take a developmental approach that acknowledges the
difference between prepubescent gender diverse children and pubescent gender diverse
adolescents and trans adults. Furthermore, trans people seeking gender-affirming medical
interventions should be assessed by HCPs with expertise in trans health care and gender-
affirming psychological practice. If masculinization is desired, testosterone therapy with
monitoring of serum sex steroid levels and signs of virilization is recommended. Similarly, if
feminization is desired, we recommend estrogens and/or antiandrogen therapy with monitoring
of serum sex steroid levels and signs of feminization. HCPs should be aware of the influence of
hormonal therapy on sexual functioning and satisfaction. We recommend HCPs be aware of
potential sexual problems during all surgical phases of treatment. CLINICAL IMPLICATIONS: This
is an up-to-date ESSM position statement. STRENGTHS & LIMITATIONS: These statements are
based on the data that are currently available; however, it is vital to recognize that this is a
rapidly changing field and that the literature, particularly in the field of sexual functioning and
satisfaction, is limited. CONCLUSION: This ESSM position statement provides relevant
information and references to existing clinical guidelines with the aim of informing relevant
HCPs on best practices when working with transgender people. T'Sjoen G, Arcelus J, De Vries
ALC, et al. European Society for Sexual Medicine Position Statement "Assessment and Hormonal
Management in Adolescent and Adult Trans People, With Attention for Sexual Function and
Satisfaction". J Sex Med 2020;17:570-584.

Annotation: Clinical guidelines for working with transgender patients

Systematic Reviews 15,44,60,143,144,204,207

Baker KE, Wilson LM, Sharma R, Dukhanin V, McArthur K, Robinson KA. Hormone Therapy, Mental
Health, and Quality of Life Among Transgender People: A Systematic Review. J Endocr Soc.
2021;5(4):bvab011. doi:10.1210/jendso/bvab011 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33644622

Abstract: We sought to systematically review the effect of gender-affirming hormone therapy

on psychological outcomes among transgender people. We searched PubMed, Embase, and
PsycINFO through June 10, 2020 for studies evaluating quality of life (QOL), depression, anxiety,
and death by suicide in the context of gender-affirming hormone therapy among transgender
people of any age. We excluded case studies and studies reporting on less than 3 months of
follow-up. We included 20 studies reported in 22 publications. Fifteen were trials or prospective
cohorts, one was a retrospective cohort, and 4 were cross-sectional. Seven assessed QOL, 12
assessed depression, 8 assessed anxiety, and 1 assessed death by suicide. Three studies included
trans-feminine people only; 7 included trans-masculine people only, and 10 included both.
Three studies focused on adolescents. Hormone therapy was associated with increased QOL,
decreased depression, and decreased anxiety. Associations were similar across gender identity
and age. Certainty in this conclusion is limited by high risk of bias in study designs, small sample
sizes, and confounding with other interventions. We could not draw any conclusions about
death by suicide. Future studies should investigate the psychological benefits of hormone
therapy among larger and more diverse groups of transgender people using study designs that
more effectively isolate the effects of hormone treatment.

Annotation: A systematic review examining mental health outcomes in TGNB children,

adolescents, and adults.

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Chew D, Anderson J, Williams K, May T, Pang K. Hormonal Treatment in Young People With Gender
Dysphoria: A Systematic Review. Pediatrics. 2018;141(4)doi:10.1542/peds.2017-3742 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/29514975

Abstract: CONTEXT: Hormonal interventions are being increasingly used to treat young people
with gender dysphoria, but their effects in this population have not been systematically
reviewed before. OBJECTIVE: To review evidence for the physical, psychosocial, and cognitive
effects of gonadotropin-releasing hormone analogs (GnRHa), gender-affirming hormones,
antiandrogens, and progestins on transgender adolescents. DATA SOURCES: We searched
Medline, Embase, and PubMed databases from January 1, 1946, to June 10, 2017. STUDY
SELECTION: We selected primary studies in which researchers examined the hormonal
treatment of transgender adolescents and assessed their psychosocial, cognitive, and/or
physical effects. DATA EXTRACTION: Two authors independently screened studies for inclusion
and extracted data from eligible articles using a standardized recording form. RESULTS: Thirteen
studies met our inclusion criteria, in which researchers examined GnRHas (n = 9), estrogen (n =
3), testosterone (n = 5), antiandrogen (cyproterone acetate) (n = 1), and progestin (lynestrenol)
(n = 1). Most treatments successfully achieved their intended physical effects, with GnRHas and
cyproterone acetate suppressing sex hormones and estrogen or testosterone causing
feminization or masculinization of secondary sex characteristics. GnRHa treatment was
associated with improvement across multiple measures of psychological functioning but not
gender dysphoria itself, whereas the psychosocial effects of gender-affirming hormones in
transgender youth have not yet been adequately assessed. LIMITATIONS: There are few studies
in this field and they have all been observational. CONCLUSIONS: Low-quality evidence suggests
that hormonal treatments for transgender adolescents can achieve their intended physical
effects, but evidence regarding their psychosocial and cognitive impact are generally lacking.
Future research to address these knowledge gaps and improve understanding of the long-term
effects of these treatments is required.

Annotation: A systematic review examining the impact of GnRH analogues, with or without
cross-sex hormones, antiandrogens, and progestins, on body changes (eg, endogenous hormone
levels, height, growth velocity, lean and fat body mass), gender and body dysphoria, BMD,
safety, and cognitive (eg, executive functioning, mental rotation), psychosocial (eg, global
functioning, anger, behavioral and emotional problems), and mental health (eg, anxiety,
depression) outcomes in TGNB adolescents and young adults.

D’hoore L, T'Sjoen G. Gender-affirming hormone therapy: An updated literature review with an eye on
the future. J Intern Med. 2022;291(5):574-592. doi:10.1111/joim.13441 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/34982475

Abstract: In line with increasing numbers of transgender (trans) and gender nonbinary people
requesting hormone treatment, the body of available research is expanding. More clinical
research groups are presenting data, and the numbers of participants in these studies are rising.
Many previous review papers have focused on all available data, as these were scarce, but a
more recent literature review is timely. Hormonal regimens have changed over time, and older
data may be less relevant for today's practice. In recent literature, we have found that even
though mental health problems are more prevalent in trans people compared to cisgender
people, less psychological difficulties occur, and life satisfaction increases with gender-affirming
hormone treatment (GAHT) for those who feel this is a necessity. With GAHT, body composition
and contours change towards the affirmed sex. Studies in bone health are reassuring, but

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 special attention is needed for adolescent and adult trans women, aiming at adequate dosage of
hormonal supplementation and stimulating therapy compliance. Existing epidemiological data
suggest that the use of (certain) estrogens in trans women induces an increased risk of
myocardial infarction and stroke, the reason that lifestyle management can be an integral part
of trans health care. The observed cancer risk in trans people does not exceed the known
cancer-risk differences between men and women. Now it is time to integrate the mostly
reassuring data, to leave the overly cautious approach behind, to not copy the same research
questions repeatedly, and to focus on longer follow-up data with larger cohorts.

Annotation: A systematic review examining recent information from larger cohorts of adult and
adolescent TGNB patients taking modern GAHT regimens. Outcomes include cognitive (eg,
executive functioning, mental rotation), psychosocial (eg, global functioning, anger, behavioral
and emotional problems), mental health (anxiety, depression), and gender and body dysphoria
outcomes.

Ludvigsson JF, Adolfsson J, Höistad M, Rydelius PA, Kriström B, Landén M. A systematic review of
hormone treatment for children with gender dysphoria and recommendations for research.
Acta Paediatrica, International Journal of Paediatrics. 2023, 10.1111/apa.16791:ePub ahead of
print. doi:10.1111/apa.16791 Accessed September 15, 2023. Available at
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/apa.16791?download=true

Abstract: Aim: The aim of this systematic review was to assess the effects on psychosocial and
mental health, cognition, body composition, and metabolic markers of hormone treatment in
children with gender dysphoria. Methods: Systematic review essentially follows PRISMA. We
searched PubMed, EMBASE and thirteen other databases until 9 November 2021 for English-
language studies of hormone therapy in children with gender dysphoria. Of 9934 potential
studies identified with abstracts reviewed, 195 were assessed in full text, and 24 were relevant.
Results: In 21 studies, adolescents were given gonadotropin-releasing hormone analogues
(GnRHa) treatment. In three studies, cross-sex hormone treatment (CSHT) was given without
previous GnRHa treatment. No randomised controlled trials were identified. The few
longitudinal observational studies were hampered by small numbers and high attrition rates.
Hence, the long-term effects of hormone therapy on psychosocial health could not be
evaluated. Concerning bone health, GnRHa treatment delays bone maturation and bone mineral
density gain, which, however, was found to partially recover during CSHT when studied at age
22 years. Conclusion: Evidence to assess the effects of hormone treatment on the above fields in
children with gender dysphoria is insufficient. To improve future research, we present the
GENDHOR checklist, a checklist for studies in gender dysphoria.

Annotation: A systematic review of GAHT for TGNB adolescents

Mahfouda S, Moore JK, Siafarikas A, et al. Gender-affirming hormones and surgery in transgender
children and adolescents. Lancet Diabetes Endocrinol. 2019;7(6):484-498. doi:10.1016/S2213-
8587(18)30305-X Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30528161

Abstract: The Endocrine Society Clinical Practice Guidelines on the treatment of gender
incongruent people recommend the use of gender-affirming cross-sex hormone (CSH)
interventions in transgender children and adolescents who request this treatment, who have
undergone psychiatric assessment, and have maintained a persistent transgender identity. The

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 intervention can help to affirm gender identity by inducing masculine or feminine physical
characteristics that are congruent with an individual's gender expression, while aiming to
improve mental health and quality-of-life outcomes. Some transgender individuals might also
wish to access gender-affirming surgeries during adolescence; however, research to inform best
clinical practice for surgeons and other medical professionals is scarce. This Review explores the
available published evidence on gender-affirming CSH and surgical interventions in transgender
children and adolescents, amalgamating findings on mental health outcomes, cognitive and
physical effects, side-effects, and safety variables. The small amount of available data suggest
that when clearly indicated in accordance with international guidelines, gender-affirming CSHs
and chest wall masculinisation in transgender males are associated with improvements in
mental health and quality of life. Evidence regarding surgical vaginoplasty in transgender
females younger than age 18 years remains extremely scarce and conclusions cannot yet be
drawn regarding its risks and benefits in this age group. Further research on an international
scale is urgently warranted to clarify long-term outcomes on psychological functioning and
safety.

Annotation: A systematic review examining psychological benefits of cross-sex hormone

therapy in TGNB adolescents.

Ramos GGF, Mengai ACS, Daltro CAT, Cutrim PT, Zlotnik E, Beck APA. Systematic Review: Puberty
suppression with GnRH analogues in adolescents with gender incongruity. J Endocrinol Invest.
2021;44(6):1151-1158. doi:10.1007/s40618-020-01449-5 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33111215

Abstract: CONTEXT: Gender incongruence is defined as disharmony between assigned gender

and gender identity. Several interventions are liable in this case including genital affirming
surgery among other surgical interventions such as harmonization, and also the use of
gonadotropin-releasing hormone agonists (GnRHa) for gonadal shielding. This aids in preventing
the development of secondary sexual characteristics related to the genetic sex. OBJECTIVE:
Systematically review the treatment of gender incongruity with GnRHa analogues. DATA
SOURCES: The data source of this research is from Pubmed-Medline and Embase. STUDY
SELECTION: Articles published between 2009 and 2019 which studied transgender adolescents
treated with GnRHa were carefully selected. DATA EXTRACTION: Were extracted: design, sample
size, study context, targeted subjects of intervention, outcome measures, and results. RESULTS:
Eleven studies were included. The use of GnRHa seems to be well tolerated by the studied
population. When started in pubertal transition, it was associated with a more distinct
resemblance to body shape than to the affirmed sex. In addition to preventing the irreversible
phenotypic changes that occur in cross-hormonal therapy, the use of GnRHa can equally
contribute to the mental health of these adolescents. LIMITATION: There are few consistent
studies on the use of GnRHa for gender incongruence. CONCLUSION: As the population of
transgender children and adolescents grows, they acquire knowledge and greater access to the
various forms and stages of treatment for sex reassignment. The medical community needs to
be adequately prepared to better serve this population and offer the safest resources available.

Annotation: A systematic review examining mental health, psychosocial function, body changes,
and liver and kidney function outcomes in TGNB adolescents who receive GnRH analogues.

Rew L, Young CC, Monge M, Bogucka R. Review: Puberty blockers for transgender and gender diverse
youth-a critical review of the literature. Child Adolesc Ment Health. 2021;26(1):3-14.

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 doi:10.1111/camh.12437 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33320999

Abstract: BACKGROUND: Increasingly, early adolescents who are transgender or gender diverse
(TGD) are seeking gender-affirming healthcare services. Pediatric healthcare providers
supported by professional guidelines are treating many of these children with gonadotropin-
releasing hormone agonists (GnRHa), which reversibly block pubertal development, giving the
child and their family more time in which to explore the possibility of medical transition.
METHODS: We conducted a critical review of the literature to answer a series of questions
about criteria for using puberty-blocking medications, the specific drugs used, the risks and
adverse consequences and/or the positive outcomes associated with their use. We searched
four databases: LGBT Life, PsycINFO, PubMed, and Web of Science. From an initial sample of 211
articles, we systematically reviewed 9 research studies that met inclusion/exclusion criteria.
RESULTS: Studies reviewed had samples ranging from 1 to 192 (N = 543). The majority (71%) of
participants in these studies required a diagnosis of gender dysphoria to qualify for puberty
suppression and were administered medication during Tanner stages 2 through 4. Positive
outcomes were decreased suicidality in adulthood, improved affect and psychological
functioning, and improved social life. Adverse factors associated with use were changes in body
composition, slow growth, decreased height velocity, decreased bone turnover, cost of drugs,
and lack of insurance coverage. One study met all quality criteria and was judged 'excellent', five
studies met the majority of quality criteria resulting in 'good' ratings, whereas three studies
were judged fair and had serious risks of bias. CONCLUSION: Given the potentially life-saving
benefits of these medications for TGD youth, it is critical that rigorous longitudinal and mixed
methods research be conducted that includes stakeholders and members of the gender diverse
community with representative samples.

Annotation: A systematic review examining physical and psychologial outcomes associated with
puberty blockers in TGNB children.

Experimental Studies
22

Beking T, Burke SM, Geuze RH, et al. Testosterone effects on functional amygdala lateralization: A study
in adolescent transgender boys and cisgender boys and girls. Psychoneuroendocrinology.
2020;111:104461. doi:10.1016/j.psyneuen.2019.104461 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31630051

Abstract: The influence of testosterone on the development of human brain lateralization has
been subject of debate for a long time, partly because studies investigating this are necessarily
mostly correlational. In the present study we used a quasi-experimental approach by assessing
functional brain lateralization in trans boys (female sex assigned at birth, diagnosed with Gender
Dysphoria, n = 21) before and after testosterone treatment, and compared these results to the
functional lateralization of age-matched control groups of cisgender boys (n = 20) and girls (n =
21) around 16 years of age. The lateralization index of the amygdala was determined with
functional magnetic resonance imaging (fMRI) during an emotional face matching task with
angry and fearful faces, as the literature indicates that boys show more activation in the right
amygdala than girls during the perception of emotional faces. As expected, the lateralization
index in trans boys shifted towards the right amygdala after testosterone treatment, and the
cumulative dose of testosterone treatment correlated significantly with amygdala lateralization
after treatment. However, we did not find any significant group differences in lateralization and

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 endogenous testosterone concentrations predicted rightward amygdala lateralization only in
the cis boys, but not in cis girls or trans boys. These inconsistencies may be due to sex
differences in sensitivity to testosterone or its metabolites, which would be a worthwhile course
for future studies.

Annotation: A quasi-experimental study examining the effects of testosterone on amygdala

lateralization between transgender boys and cis boys/girls.

Observational Studies
2,9,11,12,14,19-21,26,30,31,39,45,57,59,65,67,68,70,79,81,93-95,115,118,135,149-151,165-167,169,171,173,178,179,183,186,223,225,229,235,238,248,249,251-255,258,260,262,266,276

Achille C, Taggart T, Eaton NR, et al. Longitudinal impact of gender-affirming endocrine intervention on
the mental health and well-being of transgender youths: preliminary results. Int J Pediatr
Endocrinol. 2020;2020(1):8. doi:10.1186/s13633-020-00078-2 Accessed June 28, 2023. Available
at https://www.ncbi.nlm.nih.gov/pubmed/32368216

Abstract: BACKGROUND/AIMS: Transgender youths experience high rates of depression and

suicidal ideation compared to cisgender peers. Previous studies indicate that endocrine and/or
surgical interventions are associated with improvements to mental health in adult transgender
individuals. We examined the associations of endocrine intervention (puberty suppression
and/or cross sex hormone therapy) with depression and quality of life scores over time in
transgender youths. METHODS: At approximately 6-month intervals, participants completed
depression and quality of life questionnaires while participating in endocrine intervention.
Multiple linear regression and residualized change scores were used to compare outcomes.
RESULTS: Between 2013 and 2018, 50 participants (mean age 16.2 + 2.2 yr) who were naive to
endocrine intervention completed 3 waves of questionnaires. Mean depression scores and
suicidal ideation decreased over time while mean quality of life scores improved over time.
When controlling for psychiatric medications and engagement in counseling, regression analysis
suggested improvement with endocrine intervention. This reached significance in male-to-
female participants. CONCLUSION: Endocrine intervention may improve mental health in
transgender youths in the US. This effect was observed in both male-to-female and female-to-
male youths, but appears stronger in the former.

Annotation: A US-based observational study examining the effect of hormonal treatments on

mental health outcomes in TGNB adolescents.

Alvares LAM, Santos MR, Souza FR, et al. Cardiopulmonary capacity and muscle strength in transgender
women on long-term gender-affirming hormone therapy: a cross-sectional study. Br J Sports
Med. 2022;56(22):1292-1298. doi:10.1136/bjsports-2021-105400 Accessed September 15, 2023.
Available at https://bjsm.bmj.com/content/bjsports/56/22/1292.full.pdf

Abstract: OBJECTIVE: For transgender women (TW) on oestrogen therapy, the effects of prior
exposure to testosterone during puberty on their performance, mainly cardiopulmonary
capacity (CPC), while exerting physical effort are unknown. Our objective was to evaluate CPC
and muscle strength in TW undergoing long-term gender-affirming hormone therapy.
METHODS: A cross-sectional study was carried out with 15 TW (34.2±5.2 years old), 13 cisgender
men (CM) and 14 cisgender women (CW). The TW received hormone therapy for 14.4±3.5 years.
Bioimpedance, the hand grip test and cardiopulmonary exercise testing on a treadmill with an
incremental effort were performed. RESULTS: The mean VO2peak (L/min) was 2606±416.9 in
TW, 2167±408.8 in CW and 3358±436.3 in CM (TW vs CW, p<0.05; TW vs CM, p<0.0001; CW vs

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 CM, p<0.0001). The O2 pulse in TW was between that in CW and CM (TW vs CW, p<0.05, TW vs
CM, p<0.0001). There was a high correlation between VO2peak and fat-free mass/height2
among TW (r=0.7388; p<0.01), which was not observed in the other groups. The mean strength
(kg) was 35.3±5.4 in TW, 29.7±3.6 in CW and 48.4±6.7 in CM (TW vs CW, p<0.05; TW vs CM,
p<0.0001). CONCLUSION: CPC in non-athlete TW showed an intermediate pattern between that
in CW and CM. The mean strength and VO2 peak in non-athlete TW while performing physical
exertion were higher than those in non-athlete CW and lower than those in CM.

Annotation: A cross-sectional study comparing cardiopulmonary capacity and muscle strength

(ie, determinants of physical performance) in Brazilian transgender women versus cisgender
men and women, none of whom were athletes

Arnoldussen M, Hooijman EC, Kreukels BP, de Vries AL. Association between pre-treatment IQ and
educational achievement after gender-affirming treatment including puberty suppression in
transgender adolescents. Clin Child Psychol Psychiatry. 2022;27(4):1069-1076.
doi:10.1177/13591045221091652 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35638479

Abstract: BACKGROUND: Concerns exist regarding effects of puberty suppression on

neurodevelopment. Intelligence is strongly correlated with educational achievement in the
general population. This study aimed to examine the association between pre-treatment
intelligence and educational achievement after gender-affirming treatment including puberty
suppression in transgender adolescents to contribute to the emerging understanding of the
effect that gender-affirming treatment including puberty suppression may have on cognitive
development. METHODS: IQ was measured in 72 adolescents (45 trans boys, 27 trans girls) at
clinical entry (mean age 12.78 years), educational achievement was evaluated after gender-
affirming treatment (mean age 20.40 years). RESULTS: IQ pre-treatment and educational
achievement post-treatment were positively associated (Nagelkerke R = 0.71). DISCUSSION: The
association between IQ pre-treatment and educational achievement post-treatment in
transgender adolescents who received gender-affirming medical treatment including puberty
suppression appears to be similar to the general population. This may reflect that gender-
affirming medical treatment including puberty suppression does not negatively affect the
association between IQ and educational achievement.

Annotation: Examines changes in IQ and educational achievement after puberty suppression

with GnRH agonists and GAHT in TGNB adolescents from a gender specialty clinic

Arnoldussen M, Steensma TD, Popma A, van der Miesen AIR, Twisk JWR, de Vries ALC. Re-evaluation of
the Dutch approach: are recently referred transgender youth different compared to earlier
referrals? Eur Child Adolesc Psychiatry. 2020;29(6):803-811. doi:10.1007/s00787-019-01394-6
Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305255/pdf/787_2019_Article_1394.pdf

Abstract: The background of this article is to examine whether consecutively transgender clinic-
referred adolescents between 2000 and 2016 differ over time in demographic, psychological,
diagnostic, and treatment characteristics. The sample under study consisted of 1072
adolescents (404 assigned males, 668 assigned females, mean age 14.6 years, and range 10.1–
18.1 years). The data regarding the demographic, diagnostic, and treatment characteristics were
collected from the adolescents’ files. Psychological functioning was measured by the Child

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 Behaviour Check List and the Youth Self-Report, intensity of gender dysphoria by the Utrecht
Gender Dysphoria Scale. Time trend analyses were performed with 2016 as reference year.
Apart from a shift in sex ratio in favour of assigned females, no time trends were observed in
demographics and intensity of dysphoria. It was found, however, that the psychological
functioning improved somewhat over time (CBCL β − 0.396, p < 0.001, 95% CI − 0.553 to − 0.240,
YSR β − 0.278, p < 0.001, 95% CI − 0.434 to − 0.122). The percentage of referrals diagnosed with
gender dysphoria (mean 84.6%, range 75–97.4%) remained the same. The percentage of
diagnosed adolescents that started with affirmative medical treatment (puberty suppression
and/or gender-affirming hormones) did not change over time (mean 77.7%; range 53.8–94.9%).
These findings suggest that the recently observed exponential increase in referrals might reflect
that seeking help for gender dysphoria has become more common rather than that adolescents
are referred to gender identity services with lower intensities of gender dysphoria or more
psychological difficulties.

Annotation: A cohort study examining the association between birth-assigned sex and
psychosocial functioning in TGNB adolescents, including 404 AFAB and 668 AMAB youths.

Avila JT, Golden NH, Aye T. Eating Disorder Screening in Transgender Youth. J Adolesc Health.
2019;65(6):815-817. doi:10.1016/j.jadohealth.2019.06.011 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31500946

Abstract: PURPOSE: Body dissatisfaction in transgender youth (TY) may increase the risk for
eating disorders. This is the first study using the Eating Disorders Examination Questionnaire
(EDE-Q) to assess for eating disorder psychopathology in TY. METHODS: Youth aged 13-22 years
(n = 106) presenting to a gender clinic from January 2018 to January 2019 completed the EDE-Q
and answered questions on weight manipulation for gender-affirming purposes. RESULTS:
Respondents identified as transmasculine (61%), transfeminine (28%), or nonbinary (11%).
Mean age was 16.5 years (standard deviation = 2.0), mean weight was 119.9% median body
mass index (standard deviation = 32.9), and 32% were on hormonal therapy. Of the participants,
15% had elevated EDE-Q scores. Most (63%) disclosed weight manipulation for gender-affirming
purposes, with 11% of assigned females doing so for menstrual suppression. These behaviors
had poor concordance with elevated EDE-Q scores (kappa = .137 and .148). CONCLUSIONS:
Disordered eating behaviors are relatively common among TY. Further studies are needed to
validate the EDE-Q in TY and establish meaningful cutoff score values.

Annotation: Cross-sectional study comparing eating disorder outcome scores (EDE-Q; see
Appendix H) between treated and untreated TGNB subjects

Bauer GR, Pacaud D, Couch R, et al. Transgender Youth Referred to Clinics for Gender-Affirming Medical
Care in Canada. Pediatrics. 2021;148(5)doi:10.1542/peds.2020-047266 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/34620727

Abstract: BACKGROUND AND OBJECTIVES: Referrals of transgender and gender-diverse (trans)

youth to medical clinics for gender-affirming care have increased. We described characteristics
of trans youth in Canada at first referral visit. METHODS: Baseline clinical and survey data (2017-
2019) were collected for Trans Youth CAN!, a 10-clinic prospective cohort of n = 174 pubertal
and postpubertal youth <16 years with gender dysphoria, referred for hormonal suppression or
hormone therapy, and 160 linked parent-participants. Measures assessed health, demographics,
and visit outcome. RESULTS: Of youth, 137 were transmasculine (assigned female) and 37

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 transfeminine (assigned male); 69.0% were aged 14 to 15, 18.8% Indigenous, 6.6% visible
minorities, 25.7% from immigrant families, and 27.1% low income. Most (66.0%) were gender-
aware before age 12. Only 58.1% of transfeminine youth lived in their gender full-time versus
90.1% of transmasculine (P < .001). Although transmasculine youth were more likely than
transfeminine youth to report depressive symptoms (21.2% vs 10.8%; P = .03) and anxiety
(66.1% vs 33.3%; P < .001), suicidality was similarly high overall (past-year ideation: 34.5%,
attempts: 16.8%). All were in school; 62.0% reported strong parental gender support, with
parents the most common support persons (91.9%). Two-thirds of families reported external
gender-related stressors. Youth had met with a range of providers (68.5% with a family
physician). At clinic visit, 62.4% were prescribed hormonal suppression or hormone therapy,
most commonly depot leuprolide acetate. CONCLUSIONS: Trans youth in Canada attending
clinics for hormonal suppression or gender-affirming hormones were generally healthy but with
depression, anxiety, and support needs.

Annotation: A Canadian study comparing characteristics and mental health needs between
TGNB groups.

Becker I, Auer M, Barkmann C, et al. A Cross-Sectional Multicenter Study of Multidimensional Body

Image in Adolescents and Adults with Gender Dysphoria Before and After Transition-Related
Medical Interventions. Arch Sex Behav. 2018;47(8):2335-2347. doi:10.1007/s10508-018-1278-4
Accessed September 15, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/30088234

Abstract: Persistent feelings of gender dysphoria (GD) are accompanied by distress and body
dissatisfaction in most clinically referred adolescents and adults. Transition-related medical
interventions (e.g., puberty suppression, hormones, or surgery) may alleviate body
dissatisfaction. The aim of the present cross-sectional study was to compare multidimensional
body image across clinically referred adolescents and adults undergoing different transition-
related medical interventions. Two clinical samples of adolescents (n = 82) and adults (n = 120)
referred to specialized departments of four different transgender health services in Germany
participated in the study. In total, 202 individuals from the female-to-male (FtM individuals) and
male-to-female (MtF individuals) spectrum aged 14-74 years were included at different stages of
their transition. Four scales assessing multidimensional aspects of body image (measured by the
Body Image Assessment Questionnaire, FBeK) were compared across three groups: sample,
gender, and medical interventions (while controlling for age and treatment duration). The
results indicated less favorable body image scores compared with the norm in both adolescents
and adults with GD. Individuals who had undergone transition-related medical interventions
presented a significantly better body image on two of the four scales. Differences according to
gender and age were also present. These findings suggest that medical interventions, especially
gender-affirming hormones and surgery, are generally beneficial to the body image in
individuals with GD. However, not all of the less favorable outcomes in multidimensional body
image were positively influenced by the treatment conditions and may thus benefit from
additional integrative counseling before and during transition.

Annotation: A cross-sectional study examining the effect of hormones and GnRH analogues on
body image outcomes in TNGB adolescents

Becker-Hebly I, Fahrenkrug S, Campion F, Richter-Appelt H, Schulte-Markwort M, Barkmann C.

Psychosocial health in adolescents and young adults with gender dysphoria before and after
gender-affirming medical interventions: a descriptive study from the Hamburg Gender Identity

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 Service. Eur Child Adolesc Psychiatry. 2021;30(11):1755-1767. doi:10.1007/s00787-020-01640-2
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32990772

Abstract: Empirical evidence concerning the psychosocial health outcomes after puberty
suppression and gender-affirming (GA) medical interventions of adolescents with gender
dysphoria (GD) is scarce. The aim of the present study was to describe how dimensions of
psychosocial health were distributed among different intervention groups of adolescents with a
GD diagnosis from the Hamburg Gender Identity Service before and after treatment.
Participants included n = 75 adolescents and young adults from a clinical cohort sample,
measured at their initial intake and on average 2 years later (M treatment duration = 21.4
months). All cases were divided into four different intervention groups, three of which received
medical interventions. At baseline, both psychological functioning and quality of life scores were
significantly below the norm mean for all intervention groups. At follow-up, adolescents in the
gender-affirming hormone (GAH) and surgery (GAS) group reported emotional and behavioral
problems and physical quality of life scores similar to the German norm mean. However, some
of the psychosocial health outcome scores were still significantly different from the norm.
Because this study did not test for statistically significant differences between the four
intervention groups or before and after treatment, the findings cannot be generalized to other
samples of transgender adolescents. However, GA interventions may help to improve
psychosocial health outcomes in this sample of German adolescents. Long-term treatment
decisions during adolescence warrant careful evaluation and informed, participatory decision-
making by a multidisciplinary team and should include both medical interventions and
psychosocial support. The present study highlights the urgent need for further ongoing
longitudinal research.

Annotation: A cohort study examining the effect of unspecified GnRH analogues and cross-sex
hormone therapy on psychosocial functioning in treated versus untreated TGNB youth. Also
contains within-group longitudinal comparisons vs baseline (pre-post descriptive study).

Boogers LS, Wiepjes CM, Klink DT, et al. Transgender Girls Grow Tall: Adult Height Is Unaffected by GnRH
Analogue and Estradiol Treatment. J Clin Endocrinol Metab. 2022;107(9):e3805-e3815.
doi:10.1210/clinem/dgac349 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35666195

Abstract: CONTEXT: Transgender adolescents can receive gonadotropin-releasing hormone

analogues (GnRH) and gender-affirming hormone therapy (GAHT), but little is known about
effects on growth and adult height. This is of interest since height differs between sexes and
some transgender girls wish to limit their growth. OBJECTIVE: This work aims to investigate the
effects of GnRHa and GAHT on growth, and the efficacy of growth-reductive treatment.
METHODS: This retrospective cohort study took place at a specialized tertiary gender clinic. A
total of 161 transgender girls were treated with GnRHa and estradiol at a regular dose (2 mg) or
high growth-reductive doses of estradiol (6 mg) or ethinyl estradiol (EE, 100-200 microg). Main
outcome measures included growth, adult height, and the difference from predicted adult
height (PAH) and target height. RESULTS: Growth velocity and bone maturation decreased
during GnRHa, but increased during GAHT. Adult height after regular-dose treatment was 180.4
+/- 5.6 cm, which was 1.5 cm below PAH at the start GnRHa (95% CI, 0.2 cm to 2.7 cm), and
close to target height (-1.1 cm; 95% CI, -2.5 cm to 0.3 cm). Compared to regular-dose treatment,
high-dose estradiol and EE reduced adult height by 0.9 cm (95% CI, -0.9 cm to 2.8 cm) and 3.0
cm (95% CI, 0.2 cm to 5.8 cm), respectively. CONCLUSION: Growth decelerated during GnRHa

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 and accelerated during GAHT. After regular-dose treatment, adult height was slightly lower than
predicted at start of GnRHa, likely due to systematic overestimation of PAH as described in boys
from the general population, but not significantly different from target height. High-dose EE
resulted in greater reduction of adult height than high-dose estradiol, but this needs to be
weighed against possible adverse effects.

Annotation: A cohort study comparing dosages, growth, bone age, IGF-1 levels, and more
outcomes among transgender females with different hormone treatments and dosages from a
gender specialty clinic

Burke SM, Bakker J. The Role of Pubertal Hormones in the Development of Gender Identity: fMRI
Studies. In: Bourguignon J-P, Carel J-C, Christen Y, eds. Research and Perspectives in Endocrine
Interactions. Springer Cham; 2015:29-43:chap 3. Accessed May 17, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L601349832&from=export

Burke SM, Kreukels BP, Cohen-Kettenis PT, Veltman DJ, Klink DT, Bakker J. Male-typical visuospatial
functioning in gynephilic girls with gender dysphoria - organizational and activational effects of
testosterone. J Psychiatry Neurosci. 2016;41(6):395-404. doi:10.1503/jpn.150147 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/27070350

Abstract: BACKGROUND: Sex differences in performance and regional brain activity during
mental rotation have been reported repeatedly and reflect organizational and activational
effects of sex hormones. We investigated whether adolescent girls with gender dysphoria (GD),
before and after 10 months of testosterone treatment, showed male-typical brain activity
during a mental rotation task (MRT). METHODS: Girls with GD underwent fMRI while performing
the MRT twice: when receiving medication to suppress their endogenous sex hormones before
onset of testosterone treatment, and 10 months later during testosterone treatment. Two age-
matched control groups participated twice as well. RESULTS: We included 21 girls with GD, 20
male controls and 21 female controls in our study. In the absence of any group differences in
performance, control girls showed significantly increased activation in frontal brain areas
compared with control boys (p(FWE) = 0.012). Girls with GD before testosterone treatment
differed significantly in frontal brain activation from the control girls (p(FWE) = 0.034),
suggesting a masculinization of brain structures associated with visuospatial cognitive functions.
After 10 months of testosterone treatment, girls with GD, similar to the control boys, showed
increases in brain activation in areas implicated in mental rotation. LIMITATIONS: Since all girls
with GD identified as gynephilic, their resemblance in spatial cognition with the control boys,
who were also gynephilic, may have been related to their shared sexual orientation rather than
their shared gender identity. We did not account for menstrual cycle phase or contraceptive use
in our analyses. CONCLUSION: Our findings suggest atypical sexual differentiation of the brain in
natal girls with GD and provide new evidence for organizational and activational effects of
testosterone on visuospatial cognitive functioning.

Annotation: A cohort study examining effects of testosterone on fMRI outcomes in TGNB

adolescents vs age- and sex-matched controls

Chen D, Abrams M, Clark L, et al. Psychosocial Characteristics of Transgender Youth Seeking Gender-
Affirming Medical Treatment: Baseline Findings From the Trans Youth Care Study. J Adolesc
Health. 2021;68(6):1104-1111. doi:10.1016/j.jadohealth.2020.07.033 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/32839079

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 Abstract: PURPOSE: This study aimed to characterize two developmental cohorts of transgender
and nonbinary youth enrolled in the Trans Youth Care Network Study and describe their gender
identity-related milestones and baseline mental health and psychosocial functioning. METHODS:
Trans Youth Care participants were recruited from four pediatric academic medical centers in
the U.S. before initiating medical treatment for gender dysphoria either with gonadotropin-
releasing hormone agonists (GnRHa) or gender-affirming hormones (GAH). GnRHa cohort data
were collected from youth and a parent; GAH cohort data were collected from youth only.
RESULTS: A total of 95 youth were enrolled in the GnRHa cohort. Mean age was 11.22 years
(standard deviation = 1.46), and the majority were white (52.6%) and designated male at birth
(51.6%). Elevated depression symptoms were endorsed by 28.6% of GnRHa cohort youth, and
22.1% endorsed clinically significant anxiety. Approximately one fourth (23.6%) endorsed
lifetime suicidal ideation, with 7.9% reporting a past suicide attempt. A total of 316 youth were
enrolled in the GAH cohort. The mean age was 16.0 years (standard deviation = 1.88), and the
majority were white (62%) and designated female at birth (64.9%). Elevated depression
symptoms were endorsed by 51.3% of the GAH cohort, and 57.3% endorsed clinically significant
anxiety. Two-thirds (66.6%) endorsed lifetime suicidal ideation, with 24.6% reporting a past
suicide attempt. Life satisfaction was lower among both cohorts compared with population-
based norms. CONCLUSIONS: GnRHa cohort youth appear to be functioning better from a
psychosocial standpoint than GAH cohort youth, pointing to possible benefits of accessing
gender-affirming treatment earlier in life.

Annotation: Cross-sectional study examining psychosocial outcomes in TGNB youth initiating

treatment with GnRH agonists or CSHT.

Chiniara LN, Bonifacio HJ, Palmert MR. Characteristics of Adolescents Referred to a Gender Clinic: Are
Youth Seen Now Different from Those in Initial Reports? Horm Res Paediatr. 2018;89(6):434-
441. doi:10.1159/000489608 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29920505

Abstract: BACKGROUND/AIMS: To examine characteristics, including mental health

comorbidities, among adolescents presenting to a transgender clinic and to compare these data
to previous reports. METHODS: Retrospective chart review among youth seen at The Hospital
for Sick Children between January 2014 and June 2016. Demographic data, clinical
characteristics, and mental health comorbidities were assessed. Baseline and repeat blood work
were also examined. RESULTS: Charts from 203 adolescents aged 12-18 years were reviewed
(156 assigned female at birth [AFAB] (77%) aged 16.3 +/- 1.63 years, 47 assigned male at birth
[AMAB] aged 16.1 +/- 1.70 years). There was no statistically significant difference between
gender groups except for Tanner stage (AFAB, mean 4.42 +/- 0.8 and AMAB, mean 4.03 +/- 1.1,
p = 0.040). Individuals from racial/ethnic minority populations were under-represented
compared to the background population. Self-report and baseline psychological questionnaires
showed high levels of gender dysphoria, mood disorders, and suicidal ideation, with higher
levels of anxiety detected on questionnaires among AFAB (p = 0.03). Laboratory abnormalities
identified on baseline and repeat testing were minor; on cross-sex hormones, hemoglobin levels
increased slightly in AFAB (p = 0.002, highest = 166 g/L) and decreased among AMAB (p = 0.02,
lowest = 132 g/L). CONCLUSION: Our study supports an evolving demographic trend with more
AFAB than AMAB youth now presenting to gender clinics. The data also corroborate studies
indicating that extensive laboratory testing may not be a necessary part of caring for these
youths. Why more AFAB are now presenting to clinic and racial/ethnic minorities are

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 underrepresented is not clear, but these trends have important implications for clinical care and
warrant further study.

Annotation: A Toronto-based study examining mental health in TGNB youth

Conn BM, Chen D, Olson-Kennedy J, et al. High Internalized Transphobia and Low Gender Identity Pride
Are Associated With Depression Symptoms Among Transgender and Gender-Diverse Youth. J
Adolesc Health. 2023;72(6):877-884. doi:10.1016/j.jadohealth.2023.02.036 Accessed September
15, 2023. Available at https://www.jahonline.org/article/S1054-139X(23)00146-5/pdf

Abstract: Purpose: Prior studies have identified a significant relationship between internalized
transphobia and poor mental health among transgender and gender-diverse (TGD) adults;
however, this relationship has not been extensively examined among youth. Further, little
research has sought to explore protective factors, such as identity pride, and their influence on
this relationship. We examined the association between internalized transphobia and
depression and anxiety symptoms among TGD youth and explored the moderating role of
gender identity pride on these associations. Methods: Participants were 315 TGD youth ages
12–20 years (mean = 16; standard deviation = 1.89) seeking gender-affirming hormone
treatment at one of four major pediatric hospitals across the United States. At the time of
enrollment, participants were naïve to gender-affirming hormone treatment. Participants self-
reported mental health, internalized transphobia, and identity pride. Multiple regression models
were used with depression and anxiety symptoms as outcomes and age, designated sex at birth,
and perceived parental support included as covariates. Results: Greater internalized transphobia
was associated with greater depressive symptoms, and gender identity pride moderated this
relationship, such that greater gender identity pride was associated with fewer depressive
symptoms. Greater internalized transphobia was significantly associated with greater anxiety
symptoms; no moderation effect was observed for this relationship. Discussion: Gender identity
pride influenced mental health symptoms for youth experiencing internalized transphobia and
represents a potential key protective factor. These results support efforts to further develop,
test, and implement clinical inventions to bolster identity pride for TGD youth.

Annotation: A pair of case reports, including one transfeminine and one transmasculine
adolescent

Costa R, Dunsford M, Skagerberg E, Holt V, Carmichael P, Colizzi M. Psychological Support, Puberty

Suppression, and Psychosocial Functioning in Adolescents with Gender Dysphoria. J Sex Med.
2015;12(11):2206-2214. doi:10.1111/jsm.13034 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/26556015

Abstract: INTRODUCTION: Puberty suppression by gonadotropin-releasing hormone analogs

(GnRHa) is prescribed to relieve the distress associated with pubertal development in
adolescents with gender dysphoria (GD) and thereby to provide space for further exploration.
However, there are limited longitudinal studies on puberty suppression outcome in GD. Also,
studies on the effects of psychological support on its own on GD adolescents' well-being have
not been reported. AIM: This study aimed to assess GD adolescents' global functioning after
psychological support and puberty suppression. METHODS: Two hundred one GD adolescents
were included in this study. In a longitudinal design we evaluated adolescents' global
functioning every 6 months from the first visit. MAIN OUTCOME MEASURES: All adolescents
completed the Utrecht Gender Dysphoria Scale (UGDS), a self-report measure of GD-related

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 discomfort. We used the Children's Global Assessment Scale (CGAS) to assess the psychosocial
functioning of adolescents. RESULTS: At baseline, GD adolescents showed poor functioning with
a CGAS mean score of 57.7 +/- 12.3. GD adolescents' global functioning improved significantly
after 6 months of psychological support (CGAS mean score: 60.7 +/- 12.5; P < 0.001). Moreover,
GD adolescents receiving also puberty suppression had significantly better psychosocial
functioning after 12 months of GnRHa (67.4 +/- 13.9) compared with when they had received
only psychological support (60.9 +/- 12.2, P = 0.001). CONCLUSION: Psychological support and
puberty suppression were both associated with an improved global psychosocial functioning in
GD adolescents. Both these interventions may be considered effective in the clinical
management of psychosocial functioning difficulties in GD adolescents.

Annotation: A London-based cohort study examining mental health changes in TGNB

adolescents, including a comparison between transgender males vs transgender females treated
with unspecified GnRH agonists according to the WPATH guideline. Only natal sexes were
reported: 76 AMAB and 125 AFAB adolescents. They also looked at changes over time within
groups.

de Graaf NM, Steensma TD, Carmichael P, et al. Suicidality in clinic-referred transgender adolescents.
Eur Child Adolesc Psychiatry. 2022;31(1):67-83. doi:10.1007/s00787-020-01663-9 Accessed
September 15, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33165650

Abstract: Gender and sexually diverse adolescents have been reported to be at an elevated risk
for suicidal thoughts and behaviors. For transgender adolescents, there has been variation in
source of ascertainment and how suicidality was measured, including the time-frame (e.g., past
6 months, lifetime). In studies of clinic-referred samples of transgender adolescents, none
utilized any type of comparison or control group. The present study examined suicidality in
transgender adolescents (M age, 15.99 years) seen at specialty clinics in Toronto, Canada,
Amsterdam, the Netherlands, and London, UK (total N = 2771). Suicidality was measured using
two items from the Child Behavior Checklist (CBCL) and the Youth Self-Report (YSR). The
CBCL/YSR referred and non-referred standardization samples from both the U.S. and the
Netherlands were used for comparative purposes. Multiple linear regression analyses showed
that there was significant between-clinic variation in suicidality on both the CBCL and the YSR; in
addition, suicidality was consistently higher among birth-assigned females and strongly
associated with degree of general behavioral and emotional problems. Compared to the U.S.
and Dutch CBCL/YSR standardization samples, the relative risk of suicidality was somewhat
higher than referred adolescents but substantially higher than non-referred adolescents. The
results were discussed in relation to both gender identity specific and more general risk factors
for suicidality.

Annotation: A cross-sectional study examining mental health characteristics of TGNB patients

who were referred (ie, for GnRH analogue treatment) versus non-referred across 3 clinics. Only
natal sexes were reported: 937 AMAB and 1834 AFAB.

de Vries AL, Doreleijers TA, Steensma TD, Cohen-Kettenis PT. Psychiatric comorbidity in gender
dysphoric adolescents. J Child Psychol Psychiatry. 2011;52(11):1195-1202. doi:10.1111/j.1469-
7610.2011.02426.x Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/21671938

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 Abstract: BACKGROUND: This study examined psychiatric comorbidity in adolescents with a
gender identity disorder (GID). We focused on its relation to gender, type of GID diagnosis and
eligibility for medical interventions (puberty suppression and cross-sex hormones). METHODS:
To ascertain DSM-IV diagnoses, the Diagnostic Interview Schedule for Children (DISC) was
administered to parents of 105 gender dysphoric adolescents. RESULTS: 67.6% had no
concurrent psychiatric disorder. Anxiety disorders occurred in 21%, mood disorders in 12.4%
and disruptive disorders in 11.4% of the adolescents. Compared with natal females (n = 52),
natal males (n = 53) suffered more often from two or more comorbid diagnoses (22.6% vs. 7.7%,
p = .03), mood disorders (20.8% vs. 3.8%, p = .008) and social anxiety disorder (15.1% vs. 3.8%, p
= .049). Adolescents with GID considered to be 'delayed eligible' for medical treatment were
older [15.6 years (SD = 1.6) vs. 14.1 years (SD = 2.2), p = .001], their intelligence was lower [91.6
(SD = 12.4) vs. 99.1 (SD = 12.8), p = .011] and a lower percentage was living with both parents
(23% vs. 64%, p < .001). Although the two groups did not differ in the prevalence of psychiatric
comorbidity, the respective odds ratios ('delayed eligible' adolescents vs. 'immediately eligible'
adolescents) were >1.0 for all psychiatric diagnoses except specific phobia. CONCLUSIONS:
Despite the suffering resulting from the incongruence between experienced and assigned
gender at the start of puberty, the majority of gender dysphoric adolescents do not have co-
occurring psychiatric problems. Delayed eligibility for medical interventions is associated with
psychiatric comorbidity although other factors are of importance as well.

Annotation: A cross-sectional study examining mental health diagnoses among AFAB vs AMAB
TGNB adolescents, and between treated vs untreated TGNB patients

de Vries AL, McGuire JK, Steensma TD, Wagenaar EC, Doreleijers TA, Cohen-Kettenis PT. Young adult
psychological outcome after puberty suppression and gender reassignment. Pediatrics.
2014;134(4):696-704. doi:10.1542/peds.2013-2958 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25201798

Abstract: BACKGROUND: In recent years, puberty suppression by means of gonadotropin-

releasing hormone analogs has become accepted in clinical management of adolescents who
have gender dysphoria (GD). The current study is the first longer-term longitudinal evaluation of
the effectiveness of this approach. METHODS: A total of 55 young transgender adults (22
transwomen and 33 transmen) who had received puberty suppression during adolescence were
assessed 3 times: before the start of puberty suppression (mean age, 13.6 years), when cross-
sex hormones were introduced (mean age, 16.7 years), and at least 1 year after gender
reassignment surgery (mean age, 20.7 years). Psychological functioning (GD, body image, global
functioning, depression, anxiety, emotional and behavioral problems) and objective (social and
educational/professional functioning) and subjective (quality of life, satisfaction with life and
happiness) well-being were investigated. RESULTS: After gender reassignment, in young
adulthood, the GD was alleviated and psychological functioning had steadily improved. Well-
being was similar to or better than same-age young adults from the general population.
Improvements in psychological functioning were positively correlated with postsurgical
subjective well-being. CONCLUSIONS: A clinical protocol of a multidisciplinary team with mental
health professionals, physicians, and surgeons, including puberty suppression, followed by
cross-sex hormones and gender reassignment surgery, provides gender dysphoric youth who
seek gender reassignment from early puberty on, the opportunity to develop into well-
functioning young adults.

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 Annotation: A cohort study examining psychosocial functioning after GnRHas, cross-sex
hormones, and surgery among TGNB adolescents.

de Vries AL, Steensma TD, Cohen-Kettenis PT, VanderLaan DP, Zucker KJ. Poor peer relations predict
parent- and self-reported behavioral and emotional problems of adolescents with gender
dysphoria: a cross-national, cross-clinic comparative analysis. Eur Child Adolesc Psychiatry.
2016;25(6):579-588. doi:10.1007/s00787-015-0764-7 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/26373289

Abstract: This study is the third in a series to examine behavioral and emotional problems in
children and adolescents with gender dysphoria in a comparative analysis between two clinics in
Toronto, Ontario, Canada and Amsterdam, the Netherlands. In the present study, we report
Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) data on adolescents assessed in the
Toronto clinic (n = 177) and the Amsterdam clinic (n = 139). On the CBCL and the YSR, we found
that the percentage of adolescents with clinical range behavioral and emotional problems was
higher when compared to the non-referred standardization samples but similar to the referred
adolescents. On both the CBCL and the YSR, the Toronto adolescents had a significantly higher
Total Problem score than the Amsterdam adolescents. Like our earlier studies of CBCL data of
children and Teacher's Report Form data of children and adolescents, a measure of poor peer
relations was the strongest predictor of CBCL and YSR behavioral and emotional problems in
gender dysphoric adolescents.

Annotation: A cross-sectional study examining mental health characteristics of TGNB patients

who were referred (ie, for GnRH analogue treatment) versus non-referred across 2 clinics. Only
natal sexes were reported: 173 AMAB and 143 AFAB

Durwood L, McLaughlin KA, Olson KR. Mental Health and Self-Worth in Socially Transitioned
Transgender Youth. J Am Acad Child Adolesc Psychiatry. 2017;56(2):116-123 e112.
doi:10.1016/j.jaac.2016.10.016 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28117057

Abstract: OBJECTIVE: Social transitions are increasingly common for transgender children. A
social transition involves a child presenting to other people as a member of the "opposite"
gender in all contexts (e.g., wearing clothes and using pronouns of that gender). Little is known
about the well-being of socially transitioned transgender children. This study examined self-
reported depression, anxiety, and self-worth in socially transitioned transgender children
compared with 2 control groups: age- and gender-matched controls and siblings of transgender
children. METHOD: As part of a longitudinal study (TransYouth Project), children (9-14 years old)
and their parents completed measurements of depression and anxiety (n = 63 transgender
children, n = 63 controls, n = 38 siblings). Children (6-14 years old; n = 116 transgender children,
n = 122 controls, n = 72 siblings) also reported on their self-worth. Mental health and self-worth
were compared across groups. RESULTS: Transgender children reported depression and self-
worth that did not differ from their matched-control or sibling peers (p = .311), and they
reported marginally higher anxiety (p = .076). Compared with national averages, transgender
children showed typical rates of depression (p = .290) and marginally higher rates of anxiety (p =
.096). Parents similarly reported that their transgender children experienced more anxiety than
children in the control groups (p = .002) and rated their transgender children as having
equivalent levels of depression (p = .728). CONCLUSION: These findings are in striking contrast
to previous work with gender-nonconforming children who had not socially transitioned, which

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 found very high rates of depression and anxiety. These findings lessen concerns from previous
work that parents of socially transitioned children could be systematically underreporting
mental health problems.

Annotation: A cross-sectional study comparing mental health and self-worth outcomes between
TGNB treatment groups and between TGNB adolescents versus controls

Eitel KB, Hodax JK, DiVall S, Kidd KM, Salehi P, Sequeira GM. Leuprolide Acetate for Puberty Suppression
in Transgender and Gender Diverse Youth: A Comparison of Subcutaneous Eligard Versus
Intramuscular Lupron. J Adolesc Health. 2023;72(2):307-311.
doi:10.1016/j.jadohealth.2022.09.017 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36404242

Abstract: PURPOSE: To compare the efficacy of intramuscular Lupron and subcutaneous Eligard,
two formulations of leuprolide, for puberty suppression in transgender and gender diverse
(TGD) youth. METHODS: A retrospective chart review of TGD youth receiving Lupron or Eligard
22.5 mg every 3 months was conducted to determine hormone levels obtained 1 hour after an
injection (1hrPost) and patient-reported clinical puberty suppression. RESULTS: Forty eight
patients were analyzed: 33% assigned female at birth of which 25% were premenarchal, mean
age at first injection 13.7 years, and 50% received concurrent gender affirming hormones. Of
these, 13% received Lupron, 52% Eligard, and 35% initially received Lupron then transitioned to
Eligard due to drug shortages. There were 55 incidents of 1hrPost levels, 42 after Eligard and 13
after Lupron. Clinical puberty suppression occurred in all patients; however, biochemical
suppression occurred in 90% of Eligard and 69% of Lupron (p = .06). DISCUSSION: Eligard and
Lupron were both effective in suppressing clinical puberty progression in our population of TGD
youth, of which 50% were receiving concurrent gender affirming hormones.

Annotation: A cohort study comparing hormone levels and puberty suppression outcomes
between transgender youths receiving Lupron vs Eligard.

Grannis C, Leibowitz SF, Gahn S, et al. Testosterone treatment, internalizing symptoms, and body image
dissatisfaction in transgender boys. Psychoneuroendocrinology. 2021;132:105358.
doi:10.1016/j.psyneuen.2021.105358 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34333318

Abstract: OBJECTIVE: Many transgender adolescents experience clinically elevated anxiety and
depression. Testosterone (T), used as a gender affirming treatment, may reduce symptoms of
anxiety and depression. We assessed the effect of gender affirming T treatment on internalizing
symptoms, body image dissatisfaction, and activation patterns within the amygdala-prefrontal
cortex circuit in transgender adolescent boys. METHOD: Symptoms of generalized anxiety, social
anxiety, depression, suicidality and body image dissatisfaction were measured by self-report and
brain activation was measured during a face processing task with functional MRI in a group of 19
adolescent transgender boys receiving T treatment and 23 not receiving gonadal hormone
treatment (UT). RESULTS: Severity of anxiety and depression was significantly lower in the T
treated group relative to the UT group, along with a trend of lower suicidality. The T group also
reported less distress with body features and exhibited stronger connectivity within the
amygdala-prefrontal cortex circuit compared to the UT group. Finally, group differences on
depression and suicidality were directly associated with body image dissatisfaction, and anxiety
symptoms were moderated by amygdala-prefrontal cortex connectivity differences between

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 groups. CONCLUSION: T treatment is associated with lower levels of internalizing symptoms
among transgender adolescent boys. T is also associated with greater body satisfaction and
greater connectivity in a neural circuit associated with anxiety and depression. Satisfaction with
body image was found to overlap with the association between T and both depression and
suicidality, and amygdala-prefrontal co-activation moderated the role of T on anxiety.

Annotation: A cohort study comparing depression and anxiety severity between treated and
untreated transgender boys.

Green AE, DeChants JP, Price MN, Davis CK. Association of Gender-Affirming Hormone Therapy With
Depression, Thoughts of Suicide, and Attempted Suicide Among Transgender and Nonbinary
Youth. J Adolesc Health. 2022;70(4):643-649. doi:10.1016/j.jadohealth.2021.10.036 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/34920935

Abstract: PURPOSE: There are no large-scale studies examining mental health among
transgender and nonbinary youth who receive gender-affirming hormone therapy (GAHT). The
purpose of this study is to examine associations among access to GAHT with depression,
thoughts of suicide, and attempted suicide among a large sample of transgender and nonbinary
youth. METHODS: Data were collected as part of a 2020 survey of 34,759 lesbian, gay, bisexual,
transgender, queer, and questioning youth aged 13-24, including 11,914 transgender or
nonbinary youth. Adjusted logistic regression assessed whether receipt of GAHT was associated
with lower levels of depression, thoughts of suicide, and attempted suicide among those who
wanted to receive GAHT. RESULTS: Half of transgender and nonbinary youth said they were not
using GAHT but would like to, 36% were not interested in receiving GAHT, and 14% were
receiving GAHT. Parent support for their child's gender identity had a strong relationship with
receipt of GAHT, with nearly 80% of those who received GAHT reporting they had at least one
parent who supported their gender identity. Use of GAHT was associated with lower odds of
recent depression (adjusted odds ratio [aOR] = .73, p < .001) and seriously considering suicide
(aOR = .74, p < .001) compared to those who wanted GAHT but did not receive it. For youth
under age 18, GAHT was associated with lower odds of recent depression (aOR = .61, p < .01)
and of a past-year suicide attempt (aOR = .62, p < .05). CONCLUSIONS: Findings support a
relationship between access to GAHT and lower rates of depression and suicidality among
transgender and nonbinary youth.

Annotation: A US-based cross-sectional study comparing demographic and mental health

characteristics between TGNB patients who self-reported receiving GAHT versus not.

Grimstad F, Kremen J, Shim J, Charlton BM, Boskey ER. Breakthrough Bleeding in Transgender and
Gender Diverse Adolescents and Young Adults on Long-Term Testosterone. J Pediatr Adolesc
Gynecol. 2021;34(5):706-716. doi:10.1016/j.jpag.2021.04.004 Accessed June 28, 2023. Available
at https://www.ncbi.nlm.nih.gov/pubmed/33910088

Abstract: STUDY OBJECTIVE: Amenorrhea is a goal of many transgender and gender diverse
adolescent and young adult (TGD AYA) patients on testosterone gender-affirming hormone
therapy (T-GAHT). Breakthrough bleeding can contribute to worsening gender dysphoria. Our
objective was to evaluate breakthrough bleeding in TGD AYA on T-GAHT. DESIGN: Institutional
review board-approved retrospective cohort. SETTING: Tertiary-care children's hospital.
PARTICIPANTS: TGD AYA on T-GAHT >1 year. INTERVENTIONS: None; observational. MAIN
OUTCOME MEASURES: Presence of, and risk factors for, breakthrough bleeding. RESULTS: Of the

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 232 patients who met inclusion criteria, one-fourth (n = 58) had 1 or more episodes of
breakthrough bleeding, defined as bleeding after more than 1 year on T-GAHT. In comparing
patients with breakthrough bleeding to those without, there were no significant differences
between age of initiation, body mass index (BMI), race/ethnicity, testosterone type used, use of
additional menstrual suppression, serum testosterone, or estradiol levels. Patients with
breakthrough bleeding patients were on T-GAHT longer (37.3 +/- 17.0 vs 28.5 +/- 14.6 months, P
< .001) and were more likely to have endometriosis (P = .049). Breakthrough bleeding began at a
mean of 24.3 +/- 17.2 months after T-GAHT initiation. Of those with breakthrough bleeding, 46
(79.3%) had no known cause, 10 (17.2%) bled only with missed T-GAHT doses, and 2 (3.4%) bled
only when withdrawing from concomitant menstrual suppression. No breakthrough bleeding
management method was found to be superior. CONCLUSION: Breakthrough bleeding is
relatively common (25%) on T-GAHT despite early amenorrhea. Most cases do not have an
identifiable cause. Our data did not show superiority of any 1 method for managing
breakthrough bleeding on T-GAHT.

Annotation: A cohort study comparing menstrual suppression outcomes in transgender boys in

different GnRHa and hormone treatment groups.

Karakilic Ozturan E, Ozturk AP, Bas F, et al. Endocrinological Approach to Adolescents with Gender
Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. J
Clin Res Pediatr Endocrinol. 2023, 10.4274/jcrpe.galenos.2023.2023-1-
13doi:10.4274/jcrpe.galenos.2023.2023-1-13 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36987788

Abstract: OBJECTIVE: A significant rise in the number of trans adolescents seeking medical
interventions has been reported in recent years. In this study, we aimed to report the clinical
features, treatment, and follow-up of adolescents with gender dysphoria (GD) with our
increased experience. METHODS: Twenty-six male-to-female (MTF) and twenty-seven female-
to-male (FTM) adolescents who were referred to our GD-outpatient clinic between the years
2016 and 2022 were reviewed. The clinical and laboratory findings of thirty transgender
adolescents (15FTM /15 MTF) who received medical intervention were evaluated
retrospectively. RESULTS: The vast majority of individuals (60.4%) were admitted between 2020
and 2022, and the remaining (39.6%) were admitted between 2016 and 2019. At the referral
time, median age was 16.3 years (IQR,1.53; range, 13.2-19.4) in 26 MTF, and 16.4 years
(IQR,1.74; range, 11.7-21.6) in 27 FTM adolescents. The median age of the pubertal blockage
with gonadotropin-releasing hormone analog (GnRHa) and androgen receptor blocker was 16.4
years (IQR,1.4; range, 11.7-17.8) in 22 adolescents (9 MTF,13 FTM), and 17.4 years (IQR,1.4;
range, 15.5-19.4) in 6 MTF individuals, respectively. The cross-sex hormone therapy (CSH) was
commenced in 21 adolescents (12 MTF, 9 FTM) at the median age of 17.7 years (IQR,0.61;
range,16-19.5). Fifteen individuals (8 MTF, 7 FTM) have been transferred to the adult
endocrinology department in transition clinics. CONCLUSION: All treatments were well tolerated
and effective including bicalutamide, no side effects were observed. Besides, transition clinics
play an important role in the better management of gender reassignment processes.

Annotation: Examines body changes and endogenous hormone levels in TGNB adolescents

Khatchadourian K, Amed S, Metzger DL. Clinical management of youth with gender dysphoria in
Vancouver. J Pediatr. 2014;164(4):906-911. doi:10.1016/j.jpeds.2013.10.068 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/24315505

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 Abstract: OBJECTIVE: To describe patient characteristics at presentation, treatment, and
response to treatment in youth with gender dysphoria. STUDY DESIGN: A retrospective chart
review of 84 youth with a diagnosis of gender dysphoria seen at BC Children's Hospital from
1998-2011. RESULTS: Of the 84 patients, 45 (54%) identified as female-to-male (FtM), 37 (44%)
as male-to-female (MtF), and 2 (2%) as natal males who were undecided. Median age of
presentation was 16.9 years (range 11.4-19.8 years) and 16.6 years (range 12.3-22.5 years) for
FtM and MtF youth, respectively. Gonadotropin-releasing hormone analog treatment was
prescribed in 27 (32%) patients. One FtM patient developed sterile abscesses with leuprolide
acetate; he was switched to triptorelin and tolerated this well. Cross-sex hormones were
prescribed in 63 of 84 patients (39 FtM vs 24 MtF, P < .02). Median age at initiation of
testosterone injections in FtM patients was 17.3 years (range 13.7-19.8 years); median age at
initiation of estrogen therapy in MtF patients was 17.9 years (range 13.3-22.3 years). Three
patients stopped cross-sex hormones temporarily due to psychiatric comorbidities (2 FtM) and
distress over androgenic alopecia (1 FtM). No severe complications were noted in patients
treated with testosterone or estrogen. CONCLUSION: Treatment with gonadotropin-releasing
hormone analog and/or cross-sex hormones, in collaboration with transgender-competent
mental health professionals, is an intervention that appears to be appropriate in carefully
selected youth with gender dysphoria. Long-term follow-up studies are needed to determine
the safety of these treatments in this age group.

Annotation: A cohort study comparing demographic characteristics, adverse effects, GnRH

agonist/cross-sex hormone initiation, Tanner stages, and psychiatric comorbidites between MTF
and FTM transgender youth.

Lee JY, Finlayson C, Olson-Kennedy J, et al. Low Bone Mineral Density in Early Pubertal
Transgender/Gender Diverse Youth: Findings From the Trans Youth Care Study. J Endocr Soc.
2020;4(9):bvaa065. doi:10.1210/jendso/bvaa065 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32832823

Abstract: CONTEXT: Transgender youth may initiate GnRH agonists (GnRHa) to suppress
puberty, a critical period for bone-mass accrual. Low bone mineral density (BMD) has been
reported in late-pubertal transgender girls before gender-affirming therapy, but little is known
about BMD in early-pubertal transgender youth. OBJECTIVE: To describe BMD in early-pubertal
transgender youth. DESIGN: Cross-sectional analysis of the prospective, observational,
longitudinal Trans Youth Care Study cohort. SETTING: Four multidisciplinary academic pediatric
gender centers in the United States. PARTICIPANTS: Early-pubertal transgender youth initiating
GnRHa. MAIN OUTCOME MEASURES: Areal and volumetric BMD Z-scores. RESULTS: Designated
males at birth (DMAB) had below-average BMD Z-scores when compared with male reference
standards, and designated females at birth (DFAB) had below-average BMD Z-scores when
compared with female reference standards except at hip sites. At least 1 BMD Z-score was < -2
in 30% of DMAB and 13% of DFAB. Youth with low BMD scored lower on the Physical Activity
Questionnaire for Older Children than youth with normal BMD, 2.32 +/- 0.71 vs. 2.76 +/- 0.61 (P
= 0.01). There were no significant deficiencies in vitamin D, but dietary calcium intake was
suboptimal in all youth. CONCLUSIONS: In early-pubertal transgender youth, BMD was lower
than reference standards for sex designated at birth. This lower BMD may be explained, in part,
by suboptimal calcium intake and decreased physical activity-potential targets for intervention.
Our results suggest a potential need for assessment of BMD in prepubertal gender-diverse
youth and continued monitoring of BMD throughout the pubertal period of gender-affirming
therapy.

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 Annotation: A US-based cohort study examining changes in bone between TGNB patients
treated with GnRHa.

Martinez-Martin FJ, Kuzior A, Hernandez-Lazaro A, et al. Incidence of hypertension in young transgender

people after a 5-year follow-up: association with gender-affirming hormonal therapy. Hypertens
Res. 2023;46(1):219-225. doi:10.1038/s41440-022-01067-z Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36229533

Abstract: In order to assess the risk of hypertension development, we performed a

retrospective analysis of the clinical records of consecutive transgender patients who began
gender-affirming hormonal therapy in our Outpatient Gender Identity Clinic with <30 years of
age and had a follow-up >5 years. 149 transgender women treated with estradiol and 153
transgender men treated with testosterone were included; 129 of the transgender women
received also androgen blockers (54 spironolactone, 49 cyproterone acetate and 26 LHRH
agonists). The annual incidence of hypertension in young transgender men (1.18%) seemed
comparable to that of the general population. In young transgender women, it seemed higher
(2.14%); we found that the choice of androgen blocker had a remarkable effect, with a highly
significant increase in patients treated with cyproterone acetate (4.90%) vs. the rest (0.80%); the
adjusted hazard-ratio was 0.227 (p = 0.001). Correlation, logistic regression and mediation
analyses were performed for the associations of the available clinical variables with the increase
in systolic blood pressure and the onset of hypertension, but besides the use of cyproterone
acetate, only the ponderal gain was found significant (Spearman's r: 0.361, p < 0.001); with a
36.7% mediation effect (31.2-42.3%). Cyproterone acetate has additional known risks, such as
meningioma; although we cannot conclusively prove that it has a role in the development of
hypertension, we conclude that the use of cyproterone acetate for this indication should be
reconsidered.

Annotation: A cohort study comparing blood pressure outcomes in young transgender patients
receiving different hormone therapies.

Maru J, Millington K, Carswell J. Greater Than Expected Prevalence of Type 1 Diabetes Mellitus Found in
an Urban Gender Program. Transgend Health. 2021;6(1):57-60. doi:10.1089/trgh.2020.0027
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33644323

Abstract: The prevalence of type 1 diabetes mellitus among transgender and gender diverse
(TGD) youth is nearly five times higher than in the general pediatric population (9.9 per 1000
people vs. 1.93 per 1000 people). We hypothesize that minority stress experienced by TGD
youth may lead to a higher prevalence of diabetes.

Annotation: A Boston-based cross-sectional study examining treatment exposures in TGNB

youth with type I DM versus those without.

Marwa A, Misra M, Lopez X. Determinants of Bone Mineral Density in Transgender Youth. Transgend
Health. 2022;7(3):213-218. doi:10.1089/trgh.2020.0111 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36643057

Abstract: PURPOSE: We aimed to study determinants of bone health in transgender youth in

anticipation of or shortly after initiating puberty suppression and/or gender-affirming hormone
therapy. METHODS: This was a retrospective review of records of transgender adolescents in
our institution between June 2014 and June 2019. Dual energy X-ray absorptiometry was used

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 to assess bone mineral density (BMD). Baseline characteristics were collected and included in a
multilinear regression model to assess determinants of lumbar spine (LS) BMD Z-scores adjusted
for age and height and accounting for race. Welch's t-test was used to compare characteristics
across genders. RESULTS: One hundred nineteen patient records were analyzed. Forty-six
patients (38.7%) were assigned male at birth (AMAB) and 73 patients (61.3%) were assigned
female at birth (AFAB). Mean (+/-standard deviation [SD]) age (years) was 14.7+/-2.6 for AMAB
and 15.0+/-2.2 for AFAB. The adjusted LS BMD Z-score was lower in the AMAB population with a
mean (+SD) of -0.605+/-1.42 compared with 0.043+/-1.09 in AFAB (p=0.010). In a multivariate
model, AMAB gender, vitamin D deficiency, and lower body mass index (BMI) z-scores were
determinants of lower LS BMD Z-scores (R (2)=0.206). Age, race, ethnicity, insurance status, and
Tanner stage were not determinants of BMD. However, post hoc analysis did show that pubertal
status modified the results. CONCLUSION: AMAB transgender adolescents have lower BMD
compared with AFAB patients, before or shortly after starting puberty suppression and/or
gender-affirming hormone therapy. Lower BMI and vitamin D deficiency were determinants of
lower BMD. Further studies are needed to explore etiology for bone health discrepancy in this
population.

Annotation: A US-based cohort study examining differences in bone density between TGNB
patients based on natal sex.

Millington K, Liu E, Chan YM. The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking
Spironolactone. J Endocr Soc. 2019;3(5):1031-1038. doi:10.1210/js.2019-00030 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/31065620

Abstract: CONTEXT: Current guidelines recommend close monitoring of electrolytes in

transgender patients using spironolactone given the risk of hyperkalemia from mineralocorticoid
antagonism. In patients taking spironolactone for other conditions, the rate of hyperkalemia is
low, and the utility of frequent monitoring has been questioned. OBJECTIVE: We hypothesized
that the rate of hyperkalemia in gender-diverse adolescents taking spironolactone is low and,
when present, clinically insignificant. DESIGN AND OUTCOMES: A retrospective chart review of
adolescents seen in a specialty gender clinic at a tertiary care pediatric hospital over 10 years
identified patients prescribed spironolactone for gender transition. Study outcomes were the
incidence of hyperkalemia, defined as serum potassium concentration >5.0 mmol/L, and the
relationship between potassium levels and spironolactone dose and duration. RESULTS: Records
were reviewed for 85 subjects with a mean +/- SD age of 16.6 +/- 1.7 years. There were a total
of 269 potassium measurements (80 prior to spironolactone initiation and 189 during
spironolactone treatment). Six potassium measurements in five subjects were >5.0 mmol/L,
indicating a rate of hyperkalemia of 2.2%. None of the subjects had symptoms of hyperkalemia,
and all elevated measurements were normal when repeated. Only one subject discontinued
spironolactone after an elevated potassium measurement. There was no relationship between
hyperkalemia and spironolactone dose. Potassium measurements decreased with increasing
treatment duration. CONCLUSIONS: Hyperkalemia in patients taking spironolactone for gender
transition is rare and when present is transient and asymptomatic. In the absence of other
medical comorbidities, routine electrolyte monitoring in this population may be unnecessary.

Annotation: Cohort study examining the risk of hyperkalemia associated with spironolactone in
transfeminine or nonbinary adolescents in a pediatric gender specialty clinic

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Mirabella M, Piras I, Fortunato A, et al. Gender Identity and Non-Binary Presentations in Adolescents
Attending Two Specialized Services in Italy. J Sex Med. 2022;19(6):1035-1048.
doi:10.1016/j.jsxm.2022.03.215 Accessed September 15, 2023. Available at
https://academic.oup.com/jsm/article-abstract/19/6/1035/6961405?redirectedFrom=fulltext

Abstract: Background: Recently, the variability and heterogeneity of gender presentations in

transgender youths have gained significant attention worldwide. Alongside this, specialized
gender services have reported an increase in referrals of youths reporting non-binary identities.
In Italy, studies investigating gender identity and expression in gender non-conforming youths
are lacking, as are data regarding the non-binary population. Aim: The present study aimed at
dimensionally exploring how transgender and non-binary Italian adolescents identify and
express their gender. Outcomes: Gender expression in trans binary youths and non-binary
youths. Methods: The Gender Diversity Questionnaire (GDQ; Twist & de Graaf, 2019) was used
to investigate gender identity, gender fluidity, and gender expression in a sample of 125
adolescent patients from the Gender Identity Development Service (SAIFIP) in Rome and the
Gender Incongruence Unit of the Careggi Hospital in Florence, between April 2019–June 2021.
Results: The majority of participants (74.4%) identified as trans* binary and the remaining
(25.6%) participants identified as non-binary. Trans binary participants reported a stable gender
identity, whereas non-binary participants reported a more fluid gender identity across time and
contexts. Almost all participants rated external appearance as important to their gender
expression, yet trans binary participants attributed more importance to the body in this respect.
Body discomfort and pubertal stage emerged as the most influential factors in participants’
experiences of gender. Participants who were assigned male at birth expressed significantly
more desire for puberty blockers, whereas those who were assigned female at birth had a
stronger desire to engage in breast/chest surgery. Non-binary participants sought different
medical interventions relative to trans binary participants. Clinical Implications: These results
may be useful for clinicians working with transgender youths as they provide awareness
regarding the features of young people who identify within and outside of binary constructions
of gender. Strengths & Limitations: This study provides useful data in gaining insight into
understanding the variety of experiences and challenges of gender non-conforming youths.
However as the sample was recruited from specialized services, it may not represent the entire
gender non-conforming population in Italy. Conclusion: The results describe the range of gender
identities and expressions among gender non-conforming youths attending gender specialized
services in Italy, thereby improving our understanding of the variety of identities experienced
and the specific medical needs of both trans binary and non-binary adolescents. Mirabella M,
Piras I, Fortunato A, et al. Gender Identity and Non-Binary Presentations in Adolescents
Attending Two Specialized Services in Italy. J Sex Med 2022;19:1035–1048.

Annotation: A study examining gender identity changes between AMAB vs AFAB TGNB subjects,
and between trans binary vs nonbinary TGNB subjects. Only natal sexes reported: 40 AMAB and
85 AFAB.

Morningstar M, Thomas P, Anderson AM, et al. Exogenous testosterone administration is associated

with differential neural response to unfamiliar peer's and own caregiver's voice in transgender
adolescents. Dev Cogn Neurosci. 2023;59:101194. doi:10.1016/j.dcn.2022.101194 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36634500

Abstract: Changes in gonadal hormones during puberty are thought to potentiate adolescents'
social re-orientation away from caregivers and towards peers. This study investigated the effect

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 of testosterone on neural processing of emotional (vocal) stimuli by unfamiliar peers vs. parents,
in transgender boys receiving exogenous testosterone as a gender-affirming hormone (GAH+) or
not (GAH-). During fMRI, youth heard angry and happy vocal expressions spoken by their
caregiver and an unfamiliar teenager. Youth also self-reported on closeness with friends and
parents. Whole-brain analyses (controlling for age) revealed that GAH+ youth showed blunted
neural response to caregivers' angry voices-and heightened response to unfamiliar teenage
angry voices-in the anterior cingulate cortex. This pattern was reversed in GAH- youth, who also
showed greater response to happy unfamiliar teenager vs. happy caregiver voices in this region.
Blunted ACC response to angry caregiver voices-a pattern characteristic of GAH+ youth-was
associated with greater relative closeness with friends over parents, which could index more
"advanced" social re-orientation. Consistent with models of adolescent neurodevelopment,
increases in testosterone during adolescence may shift the valuation of caregiver vs. peer
emotional cues in a brain region associated with processing affective information.

Annotation: A cross-sectional study comparing neural responses to peer and caregiver voices
between TGNB groups.

Mullins ES, Geer R, Metcalf M, et al. Thrombosis Risk in Transgender Adolescents Receiving Gender-
Affirming Hormone Therapy. Pediatrics. 2021;147(4)doi:10.1542/peds.2020-023549 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33753543

Abstract: BACKGROUND AND OBJECTIVES: Many transgender youth experience gender

dysphoria, a risk factor for suicide. Gender-affirming hormone therapy (GAHT) ameliorates this
risk but may increase the risk for thrombosis, as seen from studies in adults. The aim with this
study was to examine thrombosis and thrombosis risk factors among an exclusively adolescent
and young adult transgender population. METHODS: This retrospective chart review was
conducted at a pediatric hospital-associated transgender health clinic. The primary outcome was
incidence of arterial or venous thrombosis during GAHT. Secondary measures included the
prevalence of thrombosis risk factors. RESULTS: Among 611 participants, 28.8% were
transgender women and 68.1% were transgender men. Median age was 17 years at GAHT
initiation. Median follow-up time was 554 and 577 days for estrogen and testosterone users,
respectively. Individuals starting GAHT had estradiol and testosterone levels titrated to
physiologic normal. Multiple thrombotic risk factors were noted among the cohort, including
obesity, tobacco use, and personal and family history of thrombosis. Seventeen youth with risk
factors for thrombosis were referred for hematologic evaluation. Five individuals were treated
with anticoagulation during GAHT: 2 with a previous thrombosis and 3 for thromboprophylaxis.
No participant developed thrombosis while on GAHT. CONCLUSIONS: In this study, we examined
thrombosis and thrombosis risk factors in an exclusively adolescent and young adult population
of transgender people receiving GAHT. These data suggest that GAHT in youth, titrated within
physiologic range, does not carry a significant risk of thrombosis in the short-term, even with the
presence of preexisting thrombosis risk factors.

Annotation: A cohort study examining thrombosis risk factors and outcomes in TGNB
adolescents initiating GAHT

Nahata L, Quinn GP, Caltabellotta NM, Tishelman AC. Mental Health Concerns and Insurance Denials
Among Transgender Adolescents. LGBT health. 2017;4(3):188-193. doi:10.1089/lgbt.2016.0151
Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L621194440&from=export

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 Abstract: RESULTS: Seventy-nine records (51 transgender males, 28 transgender females) met
inclusion criteria (median age: 15 years, range: 9-18). Seventy-three subjects (92.4%) were
diagnosed with one or more of the following conditions: depression, anxiety, post-traumatic
stress disorder, eating disorders, autism spectrum disorder, and bipolar disorder. Fifty-nine
(74.7%) reported suicidal ideation, 44 (55.7%) exhibited self-harm, and 24 (30.4%) had one or
more suicide attempts. Forty-six (58.2%) subjects reported school victimization. Of the 27
patients prescribed gonadotropin-releasing hormone analogues, only 8 (29.6%) received
insurance coverage.CONCLUSION: Transgender youth face significant barriers in accessing
appropriate hormone therapy. Given the high rates of mental health concerns, self-injurious
behavior, and school victimization among this vulnerable population, healthcare professionals
must work alongside policy makers toward insurance coverage reform.PURPOSE: Transgender
youth are at high risk for mental health morbidities. Based on treatment guidelines, puberty
blockers and gender-affirming hormone therapy should be considered to alleviate distress due
to discordance between an individual's assigned sex and gender identity. The goals of this study
were to examine the: (1) prevalence of mental health diagnoses, self-injurious behaviors, and
school victimization and (2) rates of insurance coverage for hormone therapy, among a cohort
of transgender adolescents at a large pediatric gender program, to understand access to
recommended therapy.METHODS: An IRB-approved retrospective medical record review (2014-
2016) was conducted of patients with ICD 9/10 codes for gender dysphoria referred to pediatric
endocrinology within a large multidisciplinary gender program. Researchers extracted the
following details: demographics, age, assigned sex, identified gender, insurance
provider/coverage, mental health diagnoses, self-injurious behavior, and school victimization.

Annotation: A cross-sectional study examining mental health and psychosocial outcomes

between transgender males and transgender females

Navabi B, Tang K, Khatchadourian K, Lawson ML. Pubertal Suppression, Bone Mass, and Body
Composition in Youth With Gender Dysphoria. Pediatrics. 2021;148(4)doi:10.1542/peds.2020-
039339 Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/34497118

Abstract: BACKGROUND AND OBJECTIVES: Puberty onset and development contribute

substantially to adolescents' bone mass and body composition. Our objective with this study
was to examine the effects of gonadotropin-releasing hormone agonists (GnRHa) on these
puberty-induced changes among youth with gender dysphoria (GD). METHODS: Medical records
of the endocrine diversity clinic in an academic children's hospital were reviewed for youth with
GD seen from January 2006 to April 2017 with at least 1 baseline dual-energy radiograph
absorptiometry measurement. RESULTS: At baseline, transgender females had lower lumbar
spine (LS) and left total hip (LTH) areal bone mineral density (aBMD) and LS bone mineral
apparent density (BMAD) z scores. Only 44.7% of transgender youth were vitamin D sufficient.
Baseline vitamin D status was associated with LS, LTH aBMD, and LS BMAD z scores. Post-GnRHa
assessments revealed a significant drop in LS and LTH aBMD z scores (transgender males and
transgender females) without fractures and LS BMAD (transgender males), an increase in gynoid
(fat percentage), and android (fat percentage) (transgender males and transgender females),
and no changes in BMI z score. CONCLUSIONS: GnRHa monotherapy negatively affected bone
mineral density of youth with GD without evidence of fractures or changes in BMI z score.
Transgender youth body fat redistribution (android versus gynoid) were in keeping with their
affirmed gender. The majority of transgender youth had vitamin D insufficiency or deficiency
with baseline status associated with bone mineral density. Vitamin D supplementation should
be considered for all youth with GD.

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 Annotation: A cohort study examining baseline and follow-up changes in bone mass, body
composition, vitamin D, and pubertal suppression outcomes between transgender males vs
transgender females who received GnRH agonists. Note that this was also a descriptive study
that looked at changes from baseline in each group.

Nokoff NJ, Scarbro SL, Moreau KL, et al. Body Composition and Markers of Cardiometabolic Health in
Transgender Youth Compared With Cisgender Youth. J Clin Endocrinol Metab. 2020;105(3):e704-
714. doi:10.1210/clinem/dgz029 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31544944

Abstract: CONTEXT: As many as 1.8% of adolescents identify as transgender and many more
seek care, yet the impact of gender-affirming hormone therapy (GAHT) on cardiometabolic
health is unknown. OBJECTIVE: To determine insulin sensitivity and body composition among
transgender females (TF) and males (TM) on estradiol or testosterone, compared with cisgender
females (CF) and males (CM). DESIGN: Pilot, cross-sectional study conducted from 2016-2018.
SETTING: Academic regional transgender referral center. PARTICIPANTS: Transgender
adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen
TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF
were matched to 23 CF and 13 TF to 24 CM on age and BMI. MAIN OUTCOME MEASURES:
1/[fasting insulin] and body composition (dual-energy x-ray absorptiometry). RESULTS: Total
body fat was lower in TM than CF mean +/- SD: (29% +/- 7% vs 33% +/- 7%; P = 0.002) and higher
than in CM (28% +/- 7% vs 24% +/- 9%; P = 0.047). TM had higher lean mass than CF (68% +/- 7%
vs 64% +/- 7%, P = 0.002) and lower than CM (69% +/- 7% vs 73% +/- 8%; P = 0.029). Insulin
sensitivity was not different between the groups.TF had lower body fat than CF (31% +/- 7% vs
35% +/- 8%; P = 0.033) and higher than CM (28% +/- 6% vs 20% +/- 10%; P = 0.001). TF had
higher lean mass than CF (66% +/- 6% vs 62% +/- 7%; P = 0.032) and lower than CM (69% +/- 5%
vs 77% +/- 9%; P = 0.001). TF were more insulin resistant than CM (0.078 +/- 0.025 vs 0.142 +/-
0.064 mL/muU; P = 0.011). CONCLUSIONS: Transgender adolescents on GAHT have significant
differences in body composition compared with cisgender controls, with a body composition
intermediate between BMI-matched CMs and CFs. These changes in body composition may
have consequences for the cardiometabolic health of transgender adolescents.
CLINICALTRIALS.GOV: NCT02550431.

Annotation: A cohort study comparing insulin and DEXA outcomes between TGNB patients
versus cisgender peers.

Nokoff NJ, Scarbro SL, Moreau KL, et al. Body Composition and Markers of Cardiometabolic Health in
Transgender Youth on Gonadotropin-Releasing Hormone Agonists. Transgend Health.
2021;6(2):111-119. doi:10.1089/trgh.2020.0029 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33937527

Abstract: Purpose: Up to 1.8% of youth identify as transgender; many will be treated with a
gonadotropin-releasing hormone agonist (GnRHa). The impact of GnRHa on insulin sensitivity
and body composition in transgender youth is understudied. We aimed to evaluate differences
in insulin sensitivity and body composition in transgender youth on GnRHa therapy compared
with cisgender youth. Methods: Transgender participants were matched to cisgender
participants on age, body mass index, and sex assigned at birth. Transgender males (n=9, ages
10.1-16.0 years) on GnRHa (mean+/-standard deviation duration of exposure: 20.9+/-19.8
months) were compared with cisgender females (n=14, ages 10.6-16.2). Transgender females

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 (n=8, ages 12.6-16.1) on GnRHa (11.3+/-7 months) were compared with cisgender males (n=17,
ages 12.5-15.5). Differences in insulin sensitivity (1/[fasting insulin], homeostatic model of
insulin resistance [HOMA-IR]), glycemia (hemoglobin A1C [HbA1c], fasting glucose), and body
composition (dual-energy X-ray absorptiometry) were evaluated using a mixed linear regression
model. Results: Transgender males had lower 1/fasting insulin and higher HOMA-IR (p=0.031,
p=0.01, respectively), fasting glucose (89+/-4 vs. 79+/-13 mg/dL, p=0.012), HbA1c (5.4+/-0.2 vs.
5.2+/-0.2%, p=0.039), and percent body fat (36+/-7 vs. 32+/-5%, p=0.042) than matched
cisgender females. Transgender females had lower 1/fasting insulin and higher HOMA-IR
(p=0.028, p=0.035), HbA1c (5.4+/-0.1% vs. 5.1+/-0.2%, p=0.007), percent body fat (31+/-9 vs.
24+/-10%, p=0.002), and lower percent lean mass (66+/-8 vs. 74+/-10%, p<0.001) than matched
cisgender males. Conclusion: Transgender youth on a GnRHa have lower estimated insulin
sensitivity and higher glycemic markers and body fat than cisgender controls with similar
characteristics. Longitudinal studies are needed to understand the significance of these changes.
Clinical Trial.gov ID: NCT02550431.

Annotation: A cohort study comparing insulin sensitivity and glycemic control outcomes
between transgender males versus cisgender females

Olsavsky AL, Grannis C, Bricker J, et al. Associations Among Gender-Affirming Hormonal Interventions,
Social Support, and Transgender Adolescents' Mental Health. J Adolesc Health. 2023;72(6):860-
868. doi:10.1016/j.jadohealth.2023.01.031 Accessed September 15, 2023. Available at
https://www.jahonline.org/article/S1054-139X(23)00097-6/pdf

Abstract: Purpose: We aimed to examine the concurrent associations of gender-affirming

hormonal interventions (i.e., puberty blockers, testosterone, estrogen), as well as family and
friend social support, on transgender and nonbinary (TNB) adolescents' reports of anxiety
symptoms, depressive symptoms, nonsuicidal self-injury (NSSI), and suicidality. We
hypothesized that gender-affirming hormonal interventions and greater social support would be
associated with lower levels of mental health concerns. Methods: Participants (n = 75; aged 11–
18; Mage = 16.39 years) were recruited for this cross-sectional study from a gender-affirming
multidisciplinary clinic. Fifty-two percent were receiving gender-affirming hormonal
interventions. Surveys assessed anxiety and depressive symptoms, NSSI and suicidality in the
past year, and social support from family, friends, and significant others. Hierarchical linear
regression models examined associations between gender-affirming hormonal interventions
and social support (i.e., family, friend) with mental health while accounting for nonbinary
gender identity. Results: Regression models explained 15%–23% of variance in TNB adolescents'
mental health outcomes. Gender-affirming hormonal interventions were associated with fewer
anxiety symptoms (β = −0.23; p < .05). Family support was associated with fewer depressive
symptoms (β = −0.33; p = .003) and less NSSI (β = −0.27; p = .02). Friend support was associated
with fewer anxiety symptoms (β = −0.32; p = .007) and less suicidality (β = −0.25; p = .03).
Discussion: TNB adolescents had better mental health outcomes in the context of receiving
gender-affirming hormonal interventions and having greater support from family and friends.
Findings highlight the important role of quality family and friend support for TNB mental health.
Providers should aim to address both medical and social factors to optimize TNB mental health
outcomes.

Annotation: A cross-sectional study examining associations between treatments and mental

health outcomes among TGNB adolescents

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Olson-Kennedy J, Streeter LH, Garofalo R, Chan YM, Rosenthal SM. Histrelin Implants for Suppression of
Puberty in Youth with Gender Dysphoria: A Comparison of 50 mcg/Day (Vantas) and 65 mcg/Day
(SupprelinLA). Transgend Health. 2021;6(1):36-42. doi:10.1089/trgh.2020.0055 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33644320

Abstract: Purpose: Development of incongruent secondary sex characteristics in transgender

youth can intensify or trigger the onset of gender dysphoria. Guidelines from professional
organizations recommend gonadotropin-releasing hormone agonists, including histrelin
implants (Vantas and SupprelinLA) to suppress endogenous puberty. Although Vantas does not
have a pediatric indication, it is anecdotally being used in pediatric gender centers throughout
the United States because of its substantially lower cost. This retrospective study aimed to
determine if both implants were effective in suppressing the hypothalamic-pituitary-gonadal
axis in early-to-mid pubertal youth with gender dysphoria. Methods: Youth with gender
dysphoria receiving care at the Center for Transyouth Health and Development at Children's
Hospital Los Angeles (CHLA) or participants from an ongoing observational trial with a histrelin
implant placed for pubertal suppression at Tanner stage 2 or 3 were included. Sex steroid
(testosterone or estradiol) and gonadotropin measurements at baseline (T0) and then 2 to 12
months following implant placement (T1) were abstracted from medical records. Results: Of the
66 eligible participants, 52% were designated female at birth. Most participants were white
(60.6%). Twenty participants (30.3%) had a Vantas implant and 46 (69.7%) had a SupprelinLA
implant. Mean age of insertion was 11.3 years. Gonadotropin and sex steroid levels were
significantly decreased at T1 (2-12 months after insertion of implant), with no differences
between implants. Conclusion: These results indicate that both implants are effective in
suppressing puberty in early-to-mid pubertal youth with gender dysphoria. These data may
inform decisions about insurance coverage of Supprelin and/or Vantas for youth with gender
dysphoria.

Annotation: A cohort study comparing puberty suppression outcomes in TGNB subjects

receiving two forms of histrelin (Vantas vs SupprelinLA).

Schagen SEE, Wouters FM, Cohen-Kettenis PT, Gooren LJ, Hannema SE. Bone Development in
Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming
Hormones. J Clin Endocrinol Metab. 2020;105(12):e4252-4263. doi:10.1210/clinem/dgaa604
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32909025

Abstract: CONTEXT: Hormonal interventions in adolescents with gender dysphoria may have
adverse effects, such as reduced bone mineral accrual. OBJECTIVE: To describe bone mass
development in adolescents with gender dysphoria treated with gonadotropin-releasing
hormone analogues (GnRHa), subsequently combined with gender-affirming hormones. DESIGN:
Observational prospective study. SUBJECTS: 51 transgirls and 70 transboys receiving GnRHa and
36 transgirls and 42 transboys receiving GnRHa and gender-affirming hormones, subdivided into
early- and late-pubertal groups. MAIN OUTCOME MEASURES: Bone mineral apparent density
(BMAD), age- and sex-specific BMAD z-scores, and serum bone markers. RESULTS: At the start of
GnRHa treatment, mean areal bone mineral density (aBMD) and BMAD values were within the
normal range in all groups. In transgirls, the mean z-scores were well below the population
mean. During 2 years of GnRHa treatment, BMAD stabilized or showed a small decrease,
whereas z-scores decreased in all groups. During 3 years of combined administration of GnRHa
and gender-affirming hormones, a significant increase of BMAD was found. Z-scores normalized
in transboys but remained below zero in transgirls. In transgirls and early pubertal transboys, all

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 bone markers decreased during GnRHa treatment. CONCLUSIONS: BMAD z-scores decreased
during GnRHa treatment and increased during gender-affirming hormone treatment. Transboys
had normal z-scores at baseline and at the end of the study. However, transgirls had relatively
low z-scores, both at baseline and after 3 years of estrogen treatment. It is currently unclear
whether this results in adverse outcomes, such as increased fracture risk, in transgirls as they
grow older.

Annotation: A cohort study comparing bone changes over time for TGNB subjects at different
pubertal stages. This was also a pre-post descriptive study examining changes over time in
treated patients.

Schulmeister C, Millington K, Kaufman M, et al. Growth in Transgender/Gender-Diverse Youth in the

First Year of Treatment With Gonadotropin-Releasing Hormone Agonists. J Adolesc Health.
2022;70(1):108-113. doi:10.1016/j.jadohealth.2021.06.022 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34315674

Abstract: PURPOSE: Transgender/gender-diverse (TGD) youth are treated with gonadotropin-

releasing hormone agonists (GnRHas) to halt endogenous puberty and prevent the development
of secondary sex characteristics discordant with their gender identity. This treatment may have
significant impact on growth and height velocity (HV). METHODS: Participants were recruited
prior to GnRHa initiation from four gender specialty clinics in the U.S. Anthropometric,
laboratory, and Tanner-stage data were abstracted from medical records. RESULTS: Fifty-five
TGD youth (47% designated male at birth) with a mean +/- standard deviation age of 11.5 +/- 1.2
years were included in the analysis. HV in the first year of GnRHa use was median (interquartile
range) 5.1 (3.7-5.6) cm/year. Later Tanner stage at GnRHa initiation was associated with lower
HV: 5.3 (4.4-5.6) cm/year for Tanner stage II, 4.4 (3.3-6.0) cm/year for Tanner stage III, and 1.6
(1.5-2.9) cm/year for Tanner stage IV (p = .001). When controlled for age, there was not a
significant difference in mean HV between TGD youth and prepubertal youth; however, when
stratified by Tanner stage individuals starting GnRHa at Tanner stage IV had an HV below that of
prepubertal youth, 1.6 (1.5-2.9) versus 6.1 (4.3-6.5) cm/year, p = .006. CONCLUSIONS: Overall,
TGD youth treated with GnRHa have HV similar to that of prepubertal children, but TGD youth
who start GnRHa later in puberty have an HV below the prepubertal range. Ongoing follow-up of
this cohort will determine the impact of GnRHa treatment on adult height.

Annotation: A cohort study comparing height velocity (ie, growth) in TGNB patients who
initiated GnRHa puberty suppression at the various Tanner stages.

Segev-Becker A, Israeli G, Elkon-Tamir E, et al. Children and Adolescents with Gender Dysphoria in Israel:
Increasing Referral and Fertility Preservation Rates. Endocr Pract. 2020;26(4):423-428.
doi:10.4158/EP-2019-0418 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32045294

Abstract: Objective: To describe patient characteristics at presentation, management, and

fertility preservation rates among a cohort of Israeli children and adolescents with gender
dysphoria (GD). Methods: We performed a retrospective chart review of 106 consecutive
children and adolescents with GD (<18 years) referred to and followed at the multidisciplinary
Israeli Pediatric Gender Dysphoria Clinic from March 2013 through December 2018. Results: Of
the 106 patients, 10 were prepubertal (9 prepubertal transgender females), and 96 were
pubertal (38 pubertal transgender females). The GD population increased 11-fold since the

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 establishment of our clinic in 2013. The subject's median age at referral was 15.5 years (range,
4.6 to 18 years). At the time of referral, 91 (95%) of the pubertal group had completed sexual
maturation in their assigned gender at birth. Thirteen (13.5%) patients had attempted suicide,
and 11 (11.5%) reported having had suicidal thoughts. Fourteen (45%) pubertal transgender
females and 3 (6.5%) pubertal transgender males completed fertility preservation.
Gonadotropin-releasing hormone analog treatment was prescribed in 77 (80%) patients at a
mean age of 15.9 +/- 1.6 years. Gender-affirming hormones were prescribed in 61 (64%)
patients at a mean age of 16.5 +/- 1.3 years. No severe side effects were recorded. Two (2%) of
the pubertal group expressed regret about medical treatment. Conclusion: Children and
adolescents with GD are presenting for medical attention at increasing rates. Israeli adolescents
with GD have high fertility preservation rates, perhaps attributable to cultural perspectives.
Taking advantage of the option to preserve fertility can be achieved when proper counseling is
both available and promoted by medical personnel. Abbreviations: GAH = gender-affirming
hormone; GD = gender dysphoria; GnRHa = gonadotropin-releasing hormone analog; MHP =
mental health professional.

Annotation: Examines mental health and behavioral outcomes in transgender boys vs girls

Sorbara JC, Chiniara LN, Thompson S, Palmert MR. Mental Health and Timing of Gender-Affirming Care.
Pediatrics. 2020;146(4)doi:10.1542/peds.2019-3600 Accessed September 15, 2023. Available at
https://watermark.silverchair.com/peds_20193600.pdf

Abstract: BACKGROUND: Gender-incongruent (GI) youth have high rates of mental health
problems. Although gender-affirming medical care (GAMC) provides psychological benefit, some
GI youth present to care at older ages. Whether a relationship exists between age of
presentation to GAMC and mental health difficulties warrants study., METHODS: A cross-
sectional chart review of patients presenting to GAMC. Subjects were classified a priori as
younger presenting youth (YPY) (<15 years of age at presentation) or older presenting youth
(OPY) (>=15 years of age). Self-reported rates of mental health problems and medication use
were compared between groups. Binary logistic regression analysis was used to identify
determinants of mental health problems. Covariates included pubertal stage at presentation,
social transition status, and assigned sex., RESULTS: Of 300 youth, there were 116 YPY and 184
OPY. After presentation, more OPY than YPY reported a diagnosis of depression (46% vs 30%),
had self-harmed (40% vs 28%), had considered suicide (52% vs 40%), had attempted suicide
(17% vs 9%), and required psychoactive medications (36% vs 23%), with all P < .05. After
controlling for covariates, late puberty (Tanner stage 4 or 5) was associated with depressive
disorders (odds ratio 5.49; 95% confidence interval [CI]: 1.14-26.32) and anxiety disorders (odds
ratio 4.18 [95% CI: 1.22-14.49]), whereas older age remained associated only with psychoactive
medication use (odd ratio 1.31 [95% CI: 1.05-1.63])., CONCLUSIONS: Late pubertal stage and
older age are associated with worse mental health among GI youth presenting to GAMC,
suggesting that this group may be particularly vulnerable and in need of appropriate care.
Copyright © 2020 by the American Academy of Pediatrics.

Annotation: A Toronto-based cross-sectional study examining mental health problems in older-

versus younger-presenting TGNB adolescents

Staphorsius AS, Kreukels BP, Cohen-Kettenis PT, et al. Puberty suppression and executive functioning: An
fMRI-study in adolescents with gender dysphoria. Psychoneuroendocrinology. 2015;56:190-199.

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 doi:10.1016/j.psyneuen.2015.03.007 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25837854

Abstract: Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing
hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted)
secondary sex characteristics. Since adolescence marks an important period for the
development of executive functioning (EF), we determined whether the performance on the
Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when
treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual
differentiation of the brain, we determined whether untreated adolescents with GD showed
sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa
on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-
to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa
treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the
suppressed MFs had significantly lower accuracy scores than the control groups and the
untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in
control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral
precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated
adolescents with GD did not show significant sex differences in task load-related activation and
had intermediate activation levels compared to the two control groups. GnRHa treated
adolescents with GD showed sex differences in neural activation similar to their natal sex control
groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also
significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings
suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD,
and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents
with GD.

Annotation: A cohort or cross-sectional analysis of the impact of GAH hormones on executive

function.

Tollit MA, May T, Maloof T, et al. The clinical profile of patients attending a large, Australian pediatric
gender service: A 10-year review. International journal of transgender health. 2023;24(1):59-69.
doi:10.1080/26895269.2021.1939221 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9879187/pdf/WIJT_24_1939221.pdf

Abstract: Objectives: To better understand the clinical profile of patients attending a large
Australian pediatric gender service. Retrospective clinical audit of patients seen at the Royal
Children's Hospital Gender Service (RCHGS) over 10 years (2007-16). Setting: The RCHGS:
Australia's largest pediatric gender service. Participants: Patients were eligible for inclusion if
they had an appointment with the RCHGS between January 2007 - December 2016, and had
either a self-reported gender which differed from what was presumed for them at birth or
sought guidance regarding gender identity/expression. Main outcome measures:
Demographic/developmental history, clinical presentation including information about gender
identity/dysphoria, comorbidities, self-harm, suicidal ideation, gender-affirming treatment,
psychosocial functioning. Results: 359 patients were first seen during the study period. Assigned
females (54%) slightly outnumbered assigned males (46%), and presented at an older age (14.8
vs 12.4 years. Patients predominantly identified as transgender (87.2%) or non-binary (7.2%).
Across the cohort, gender diversity was evident from a young age (median age 3), and
symptoms of gender dysphoria were noted earlier in assigned males (median age 4) than

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 assigned females (median age 11). Although 81% of patients met eligibility for GD, rates of
hormonal treatment were much lower, with 29% of young people >=10 years of age receiving
puberty blocking treatment and 38% of adolescents >= 16 years of age receiving gender-
affirming hormones (i.e. testosterone or estrogen). Many patients had mental health difficulties
and/or neurodevelopment disorders, including major depressive disorder/low mood (51%), self-
harm (25%), suicidal ideation (30%) and autism spectrum disorder (16%). Conclusion: This audit
illustrates the complex profile and needs of transgender and gender diverse children and
adolescents presenting to specialist gender services. Supplemental data for this article is
available online at https://doi.org/10.1080/26895269.2021.1939221 . Copyright © 2021 Taylor
& Francis Group, LLC.

Annotation: An cross-sectional study examining characteristics of AFAB vs AMAB TGNB

adolescents, including mental health and psychosocial parameters. Natal genders were
reported: 166 AMAB and 193 AFAB.

Tordoff DM, Wanta JW, Collin A, Stepney C, Inwards-Breland DJ, Ahrens K. Mental Health Outcomes in
Transgender and Nonbinary Youths Receiving Gender-Affirming Care. JAMA Netw Open.
2022;5(2):e220978. doi:10.1001/jamanetworkopen.2022.0978 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/35212746

Abstract: IMPORTANCE: Transgender and nonbinary (TNB) youths are disproportionately

burdened by poor mental health outcomes owing to decreased social support and increased
stigma and discrimination. Although gender-affirming care is associated with decreased long-
term adverse mental health outcomes among these youths, less is known about its association
with mental health immediately after initiation of care. OBJECTIVE: To investigate changes in
mental health over the first year of receiving gender-affirming care and whether initiation of
puberty blockers (PBs) and gender-affirming hormones (GAHs) was associated with changes in
depression, anxiety, and suicidality. DESIGN, SETTING, AND PARTICIPANTS: This prospective
observational cohort study was conducted at an urban multidisciplinary gender clinic among
TNB adolescents and young adults seeking gender-affirming care from August 2017 to June
2018. Data were analyzed from August 2020 through November 2021. EXPOSURES: Time since
enrollment and receipt of PBs or GAHs. MAIN OUTCOMES AND MEASURES: Mental health
outcomes of interest were assessed via the Patient Health Questionnaire 9-item (PHQ-9) and
Generalized Anxiety Disorder 7-item (GAD-7) scales, which were dichotomized into measures of
moderate or severe depression and anxiety (ie, scores >/=10), respectively. Any self-report of
self-harm or suicidal thoughts over the previous 2 weeks was assessed using PHQ-9 question 9.
Generalized estimating equations were used to assess change from baseline in each outcome at
3, 6, and 12 months of follow-up. Bivariate and multivariable logistic models were estimated to
examine temporal trends and investigate associations between receipt of PBs or GAHs and each
outcome. RESULTS: Among 104 youths aged 13 to 20 years (mean [SD] age, 15.8 [1.6] years)
who participated in the study, there were 63 transmasculine individuals (60.6%), 27
transfeminine individuals (26.0%), 10 nonbinary or gender fluid individuals (9.6%), and 4 youths
who responded "I don't know" or did not respond to the gender identity question (3.8%). At
baseline, 59 individuals (56.7%) had moderate to severe depression, 52 individuals (50.0%) had
moderate to severe anxiety, and 45 individuals (43.3%) reported self-harm or suicidal thoughts.
By the end of the study, 69 youths (66.3%) had received PBs, GAHs, or both interventions, while
35 youths had not received either intervention (33.7%). After adjustment for temporal trends
and potential confounders, we observed 60% lower odds of depression (adjusted odds ratio
[aOR], 0.40; 95% CI, 0.17-0.95) and 73% lower odds of suicidality (aOR, 0.27; 95% CI, 0.11-0.65)

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 among youths who had initiated PBs or GAHs compared with youths who had not. There was no
association between PBs or GAHs and anxiety (aOR, 1.01; 95% CI, 0.41, 2.51). CONCLUSIONS
AND RELEVANCE: This study found that gender-affirming medical interventions were associated
with lower odds of depression and suicidality over 12 months. These data add to existing
evidence suggesting that gender-affirming care may be associated with improved well-being
among TNB youths over a short period, which is important given mental health disparities
experienced by this population, particularly the high levels of self-harm and suicide.

Annotation: A cohort study examining mental health outcomes (depression/anxiety) in TGNB

adolescents and young adults receiving puberty blockers, cross-sex hormones, or both.

Turban JL, King D, Carswell JM, Keuroghlian AS. Pubertal Suppression for Transgender Youth and Risk of
Suicidal Ideation. Pediatrics. 2020;145(2)doi:10.1542/peds.2019-1725 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/31974216

Abstract: BACKGROUND AND OBJECTIVES: Gonadotropin-releasing hormone analogues are

commonly prescribed to suppress endogenous puberty for transgender adolescents. There are
limited data regarding the mental health benefits of this treatment. Our objective for this study
was to examine associations between access to pubertal suppression during adolescence and
adult mental health outcomes. METHODS: Using a cross-sectional survey of 20 619 transgender
adults aged 18 to 36 years, we examined self-reported history of pubertal suppression during
adolescence. Using multivariable logistic regression, we examined associations between access
to pubertal suppression and adult mental health outcomes, including multiple measures of
suicidality. RESULTS: Of the sample, 16.9% reported that they ever wanted pubertal suppression
as part of their gender-related care. Their mean age was 23.4 years, and 45.2% were assigned
male sex at birth. Of them, 2.5% received pubertal suppression. After adjustment for
demographic variables and level of family support for gender identity, those who received
treatment with pubertal suppression, when compared with those who wanted pubertal
suppression but did not receive it, had lower odds of lifetime suicidal ideation (adjusted odds
ratio = 0.3; 95% confidence interval = 0.2-0.6). CONCLUSIONS: This is the first study in which
associations between access to pubertal suppression and suicidality are examined. There is a
significant inverse association between treatment with pubertal suppression during adolescence
and lifetime suicidal ideation among transgender adults who ever wanted this treatment. These
results align with past literature, suggesting that pubertal suppression for transgender
adolescents who want this treatment is associated with favorable mental health outcomes.

Annotation: A cross-sectional survey study including cisgender and transgender adolescent

respondents from 2017 and 2019, including an examination of the association between self-
reported GnRH agonist use and suicide ideation in TGNB adolescents

Turban JL, King D, Kobe J, Reisner SL, Keuroghlian AS. Access to gender-affirming hormones during
adolescence and mental health outcomes among transgender adults. PLoS One.
2022;17(1):e0261039. doi:10.1371/journal.pone.0261039 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35020719

Abstract: OBJECTIVE: To examine associations between recalled access to gender-affirming

hormones (GAH) during adolescence and mental health outcomes among transgender adults in
the U.S. METHODS: We conducted a secondary analysis of the 2015 U.S. Transgender Survey, a
cross-sectional non-probability sample of 27,715 transgender adults in the U.S. Using

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 multivariable logistic regression adjusting for potential confounders, we examined associations
between access to GAH during early adolescence (age 14-15), late adolescence (age 16-17), or
adulthood (age >/=18) and adult mental health outcomes, with participants who desired but
never accessed GAH as the reference group. RESULTS: 21,598 participants (77.9%) reported ever
desiring GAH. Of these, 8,860 (41.0%) never accessed GAH, 119 (0.6%) accessed GAH in early
adolescence, 362 (1.7%) accessed GAH in late adolescence, and 12,257 (56.8%) accessed GAH in
adulthood. After adjusting for potential confounders, accessing GAH during early adolescence
(aOR = 0.4, 95% CI = 0.2-0.6, p < .0001), late adolescence (aOR = 0.5, 95% CI = 0.4-0.7, p < .0001),
or adulthood (aOR = 0.8, 95% CI = 0.7-0.8, p < .0001) was associated with lower odds of past-
year suicidal ideation when compared to desiring but never accessing GAH. In post hoc analyses,
access to GAH during adolescence (ages 14-17) was associated with lower odds of past-year
suicidal ideation (aOR = 0.7, 95% CI = 0.6-0.9, p = .0007) when compared to accessing GAH
during adulthood. CONCLUSION: Access to GAH during adolescence and adulthood is associated
with favorable mental health outcomes compared to desiring but not accessing GAH.

Annotation: A cross-sectional study examining the association between self-reported GnRHa

use and suicide ideation in TGNB adolescents.

Valentine A, Davis S, Furniss A, et al. Multicenter Analysis of Cardiometabolic-related Diagnoses in

Transgender and Gender-Diverse Youth: A PEDSnet Study. J Clin Endocrinol Metab.
2022;107(10):e4004-e4014. doi:10.1210/clinem/dgac469 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35945152

Abstract: CONTEXT: Studies on cardiometabolic health in transgender and gender-diverse youth

(TGDY) are limited to small cohorts. OBJECTIVE: This work aimed to determine the odds of
cardiometabolic-related diagnoses in TGDY compared to matched controls in a cross-sectional
analysis, using a large, multisite database (PEDSnet). METHODS: Electronic health record data
(2009-2019) were used to determine odds of cardiometabolic-related outcomes based on
diagnosis, anthropometric, and laboratory data using logistic regression among TGDY youth vs
controls. The association of gender-affirming hormone therapy (GAHT) with these outcomes
was examined separately among TGDY. TGDY (n = 4172) were extracted from 6 PEDSnet sites
and propensity-score matched on 8 variables to controls (n = 16 648). Main outcomes measures
included odds of having cardiometabolic-related diagnoses among TGDY compared to matched
controls, and among TGDY prescribed GAHT compared to those not prescribed GAHT. RESULTS:
In adjusted analyses, TGDY had higher odds of overweight/obesity (1.2; 95% CI, 1.1-1.3) than
controls. TGDY with a testosterone prescription alone or in combination with a gonadotropin-
releasing hormone agonist (GnRHa) had higher odds of dyslipidemia (1.7; 95% CI, 1.3-2.3 and
3.7; 95% CI, 2.1-6.7, respectively) and liver dysfunction (1.5; 95% CI, 1.1-1.9 and 2.5; 95% CI, 1.4-
4.3) than TGDY not prescribed GAHT. TGDY with a testosterone prescription alone had higher
odds of overweight/obesity (1.8; 95% CI, 1.5-2.1) and hypertension (1.6 95% CI, 1.2-2.2) than
those not prescribed testosterone. Estradiol and GnRHa alone were not associated with greater
odds of cardiometabolic-related diagnoses. CONCLUSION: TGDY have increased odds of
overweight/obesity compared to matched controls. Screening and tailored weight management,
sensitive to the needs of TGDY, are needed.

Annotation: A cohort study comparing cardiometabolic parameters between testosterone-

treated transgender males and cisgender females. This study also compares testosterone-
treated vs untreated TGNB youth.

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Valentine A, Nokoff N, Bonny A, et al. Cardiometabolic Parameters Among Transgender Adolescent
Males on Testosterone Therapy and Body Mass Index-Matched Cisgender Females. Transgend
Health. 2021;6(6):369-373. doi:10.1089/trgh.2020.0052 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34993308

Abstract: Limited data are available on changes in metabolic parameters in transgender youth
on testosterone therapy in comparison with cisgender females. Data from 42 transgender males
on testosterone therapy were retrospectively analyzed. Body mass index (BMI) and lipid profile
changes were compared with BMI-matched females. There was a significant increase in BMI
over time in the transgender males as compared with the cisgender females, and a decrease in
high-density lipoprotein in the transgender males after starting testosterone therapy.
Longitudinal prospective studies with cisgender controls are needed to better define effects of
testosterone therapy in adolescents.

Annotation: A cohort study examining cardiometabolic parameters in TGNB adolescents

receiving testosterone versus not. Note thte study also compares TGNB versus cis-gender peers.

van de Grift TC, van Gelder ZJ, Mullender MG, Steensma TD, de Vries ALC, Bouman MB. Timing of
Puberty Suppression and Surgical Options for Transgender Youth. Pediatrics.
2020;146(5)doi:10.1542/peds.2019-3653 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33106340

Abstract: OBJECTIVES: Puberty suppression (PS) is a cornerstone of treatment in youth

experiencing gender dysphoria. In this study, we aim to inform prescribing professionals on the
long-term effects of PS treatment on the development of sex characteristics and surgical
implications. METHODS: Participants received PS according to the Endocrine Society guideline at
Tanner 2 or higher. Data were collected from adolescents who received PS between 2006 and
2013 and from untreated transgender controls. Data collection pre- and post-PS and before
surgery included physical examination and surgical information. RESULTS: In total, 300
individuals (184 transgender men and 116 transgender women) were included. Of these, 43
individuals started PS treatment at Tanner 2/3, 157 at Tanner 4/5, and 100 used no PS
(controls). Breast development was significantly less in transgender men who started PS at
Tanner 2/3 compared with those who started at Tanner 4/5 and controls. Mastectomy was
more frequently omitted or less invasive after PS. In transgender women, the mean penile
length was significantly shorter in the PS groups compared with controls (by 4.8 cm [Tanner 2/3]
and 2.1 cm [Tanner 4/5]). As a result, the likelihood of undergoing intestinal vaginoplasty was
increased (odds ratio = 84 [Tanner 2/3]; odds ratio = 9.8 [Tanner 4/5]). CONCLUSIONS: PS
reduces the development of sex characteristics in transgender adolescents. As a result,
transgender men may not need to undergo mastectomy, whereas transgender women may
require an alternative to penile inversion vaginoplasty. These surgical implications should inform
decision-making when initiating PS.

Annotation: Compares surgical outcomes between TGNB youths who received early versus late
puberty suppression.

van der Loos MA, Hellinga I, Vlot MC, Klink DT, den Heijer M, Wiepjes CM. Development of Hip Bone
Geometry During Gender-Affirming Hormone Therapy in Transgender Adolescents Resembles
That of the Experienced Gender When Pubertal Suspension Is Started in Early Puberty. J Bone

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 Miner Res. 2021;36(5):931-941. doi:10.1002/jbmr.4262 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33507568

Abstract: Bone geometry can be described in terms of periosteal and endocortical growth and is
partly determined by sex steroids. Periosteal and endocortical apposition are thought to be
regulated by testosterone and estrogen, respectively. Gender-affirming hormone (GAH)
treatment with sex steroids in transgender people might affect bone geometry. However, in
adult transgender people, no change in bone geometry during GAH was observed. In this study,
we investigated changes in bone geometry among transgender adolescents using a
gonadotropin-releasing hormone agonist (GnRHa) and GAH before achieving peak bone mass.
Transgender adolescents treated with GnRHa and subsequent GAH before the age of 18 years
were eligible for inclusion. Participants were grouped based on their Tanner stage at the start of
GnRHa treatment and divided into early, mid, and late puberty groups. Hip structure analysis
software calculating subperiosteal width (SPW) and endocortical diameter (ED) was applied to
dual-energy X-ray absorptiometry scans performed at the start of GnRHa and GAH treatments,
and after >/=2 years of GAH treatment. Mixed-model analyses were performed to study
differences over time. Data were visually compared with reference values of the general
population. A total of 322 participants were included, of whom 106 were trans women and 216
trans men. In both trans women and trans men, participants resembled the reference curve for
SPW and ED of the experienced gender but only when GnRHa was started during early puberty.
Those who started during mid and late puberty remained within the reference curve of the
gender assigned at birth. A possible explanation might be sought in the phenomenon of
programming, which conceptualizes that stimuli during critical windows of development can
have major consequences throughout one's life span. Therefore, this study adds insights into
sex-specific bone geometry development during puberty of transgender adolescents treated
with GnRHa, as well as the general population. (c) 2021 The Authors. Journal of Bone and
Mineral Research published by American Society for Bone and Mineral Research.

Annotation: Reports on bone changes over time in TGNB adolescents seen in a gender specialty
clinic. Reports the size of the ACOG as 8210 patients in 2018, up from 6793 patients in 2015.

Van der Miesen AIR, Steensma TD, de Vries ALC, Bos H, Popma A. Psychological Functioning in
Transgender Adolescents Before and After Gender-Affirmative Care Compared With Cisgender
General Population Peers. J Adolesc Health. 2020;66(6):699-704.
doi:10.1016/j.jadohealth.2019.12.018 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32273193

Abstract: PURPOSE: Transgender adolescents are at risk for internalizing and externalizing
problems, along with high suicidality rates, and poor peer relations. The present study
compared transgender adolescents before and after gender-affirmative care with a sample of
nonclinical age-equivalent cisgender adolescents from the general population on psychological
well-being and aimed to investigate the possible effect of transgender care involving puberty
suppression. METHODS: In this cross-sectional study, emotional and behavioral problems were
assessed by the Youth Self-Report in a sample of 272 adolescents referred to a specialized
gender identity clinic who did not yet receive any affirmative medical treatment and compared
with 178 transgender adolescents receiving affirmative care consisting of puberty suppression
and compared with 651 Dutch high school cisgender adolescents from the general population.
RESULTS: Before medical treatment, clinic-referred adolescents showed more internalizing
problems and reported increased self-harm/suicidality and poorer peer relations compared with

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 their age-equivalent peers. Transgender adolescents receiving puberty suppression had fewer
emotional and behavioral problems than the group that had just been referred to transgender
care and had similar or fewer problems than their same-age cisgender peers on the Youth Self-
Report domains. CONCLUSIONS: Transgender adolescents show poorer psychological well-being
before treatment but show similar or better psychological functioning compared with cisgender
peers from the general population after the start of specialized transgender care involving
puberty suppression.

Annotation: A study comparing mental health outcomes in treated versus untreated TGNB
adolescents; also compares mental health outcomes between TGNB adolescents and cisgender
peers

Vehmas N, Holopainen E, Suomalainen L, Savolainen-Peltonen H. Somatic Health and Psychosocial

Background Among Finnish Adolescents with Gender Dysphoria Seeking Hormonal
Interventions. Transgend Health. 2022;7(6):505-513. doi:10.1089/trgh.2021.0084 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36644116

Abstract: PURPOSE: Although the number of young adults suffering from gender dysphoria (GD)
is increasing, reports focusing on their somatic health remain scarce. We studied the somatic
health, pubertal development, psychosocial background, and interest regarding gender-
affirming surgical treatment of Finnish adolescents seeking gender-affirming hormonal
treatment (GAHT). METHODS: In this retrospective register study at an adolescent gynecology
clinic in Helsinki University Hospital, Finland we included 124 adolescents diagnosed with GD
and referred to GAHT between January 1, 2011 and December 31, 2018. This cohort covered
two thirds of all Finnish adolescents referred to GAHT during the follow-up. Data on the general
adolescent population were obtained from the Finnish School Health Promotion (SHP) study of
year 2017. RESULTS: Most adolescents were assigned female at birth. Sex ratio increased from
1.2 in 2012 to 5.2 in 2017. One-third of the patients were overweight or obese (body mass index
[BMI] >25 kg/m(2)). Other somatic comorbidities were rare. Interest toward reconstructive
genital surgery was more common among male-to-female than female-to-male patients (80%
vs. 22%, respectively, p<0.001). Depression (29%) and anxiety (19%) were common psychiatric
comorbidities. Parental divorce rate (57%) was higher than in the general adolescent population
in Finland (23%, p<0.001). CONCLUSION: Finnish adolescents diagnosed with GD-seeking GAHT
have good somatic health, but a higher proportion of overweight, depression, and anxiety than
the general adolescent population. Prospective follow-up of this cohort will provide an
opportunity to evaluate the somatic and psychosocial outcomes and quality of life during GAHT.

Annotation: A cross-sectional study examining characteristics of TGNB patients presenting for

treatment.

Vrouenraets LJJJ, de Vries ALC, de Vries MC, van der Miesen AIR, Hein IM. Assessing Medical Decision-
Making Competence in Transgender Youth. Pediatrics. 2021;148(6)doi:10.1542/peds.2020-
049643 Accessed September 15, 2023. Available at
https://watermark.silverchair.com/peds_2020049643.pdf

Abstract: BACKGROUND: According to international transgender care guidelines, an important

prerequisite for puberty suppression (PS) is transgender adolescents' competence to give
informed consent (IC). In society, there is doubt whether transgender adolescents are capable of
this, which in some countries has even led to limited access to this intervention. Therefore, this

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 study examined transgender adolescents' medical decision-making competence (MDC) to give IC
for starting PS in a structured, replicable way. Additionally, potential associated variables on
MDC, such as age, intelligence, sex, psychological functioning, were investigated. METHODS: A
cross-sectional semistructured interview study with 74 transgender adolescents (aged 10-18
years; 16 birth-assigned boys, 58 birth-assigned girls) within two Dutch specialized gender-
identity clinics was performed. To assess MDC, judgements based on the reference standard
(clinical assessment) and the MacArthur Competence Assessment Tool for Treatment (MacCAT-
T), a validated semistructured interview, were used. RESULTS: Of the transgender adolescents,
93.2% (reference standard judgements; 69 of 74) and 89.2% (MacCAT-T judgements; 66 of 74)
were assessed competent to consent. Intermethod agreement was 87.8% (65 of 74). Interrater
agreements of the reference standard and MacCAT-T-based judgements were 89.2% (198 of
222) and 86.5% (192 of 222), respectively. IQ and sex were both significantly related to MacCAT-
T total score, whereas age, level of emotional and behavioral challenges, and diagnostic
trajectories duration were not. CONCLUSIONS: By using the MacCAT-T and clinicians'
assessments, 93.2% and 89.2%, respectively, of the transgender adolescents in this study were
assessed competent to consent for starting PS.

Annotation: A cross-sectional study examining medical competence and related outcomes in

TGNB adolescents. Natal sexes reported only: 16 AMAB and 58 AFAB.

Zucker KJ, Bradley SJ, Owen-Anderson A, Singh D, Blanchard R, Bain J. Puberty-Blocking Hormonal
Therapy for Adolescents with Gender Identity Disorder: A Descriptive Clinical Study. Journal of
Gay & Lesbian Mental Health. 2010;15(1):58-82. doi:10.1080/19359705.2011.530574 Accessed
June 12, 2023. Available at
https://www.tandfonline.com/doi/abs/10.1080/19359705.2011.530574

Abstract: The use of puberty-delaying or blocking hormonal treatment of adolescents with

gender identity disorder (GID) has become increasingly common. In the present study, we
examined demographic, behavior problem, and psychosexual measures to see if any of them
correlated with the clinical decision to recommend, or not recommend, puberty-blocking
hormonal therapy in a consecutive series of 109 adolescents (55 females, 54 males) with GID
evaluated between 2000 and 2009. Of the 109 adolescents, 66 (60.6%) were recommended for
puberty-blocking hormonal therapy and 43 (39.4%) were not. A combination of five (of 15)
demographic, behavior problem, and psychosexual measures were identified in a logistic
regression analysis to significantly predict this clinical recommendation. The quantitative data
were complemented by clinical case descriptions and some follow-up information. We discuss
our data in relation to the Dutch model of early biomedical treatment for youth with GID and
consider areas that require further clinical and empirical examination.

Annotation: A cross-sectional study examining correlates of puberty suppressive treatment in

treated vs untreated TGNB patients. Only natal sexes were reported: 54 AMAB and 55 AFAB.

Longitudinal Pre-Post Descriptive Studies

8,13,36,37,41,71,75,91,98,109,111,112,120-122,128,131,132,141,162,163,175,187,195,196,214,221,222,241,246,263,273

Allen LR, Watson LB, Egan AM, Moser CN. Well-being and suicidality among transgender youth after
gender-affirming hormones. Clinical Practice in Pediatric Psychology. 2019;7(3):302-311.
doi:10.1037/cpp0000288 Accessed September 15, 2023. Available at
https://psycnet.apa.org/record/2019-52280-009

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 Abstract: Objective: This study is a longitudinal evaluation of the effectiveness of gender-
affirming hormones for improving psychological well-being and decreasing suicidality among
transgender youth referred to a transgender health specialty clinic at a large Midwest children’s
hospital. Method: Forty-seven youth (13.73–19.04 years; M = 16.59, SD = 1.19) who received
gender-affirming hormones were assessed at least 2 times: before the start of treatment and at
least 3 months after treatment. Results: After gender-affirming hormones, a significant increase
in levels of general well-being and a significant decrease in levels of suicidality were observed.
Conclusion: These findings suggest that gender-affirming hormones are a valuable medical
intervention with promising psychosocial outcomes for transgender youth. (PsycInfo Database
Record (c) 2022 APA, all rights reserved)

Annotation: Examines mental health and suicidality outcomes among TGNB adolescents who
received GnRH agonists followed by CSHT vs CSHT only

Arnoldussen M, van der Miesen AIR, Elzinga WS, et al. Self-Perception of Transgender Adolescents After
Gender-Affirming Treatment: A Follow-Up Study into Young Adulthood. LGBT health.
2022;9(4):238-246. doi:10.1089/lgbt.2020.0494 Accessed September 15, 2023. Available at
https://www.liebertpub.com/doi/pdf/10.1089/lgbt.2020.0494?download=true

Abstract: Purpose: Early medical treatment for transgender adolescents should contribute to
healthy psychological development, including the development of positive self-perception.
However, at present, there are no longitudinal studies that have examined whether current
treatment approaches meet this expectation. Therefore, the aim of this single-arm retrospective
study was to examine transgender adolescents' self-perception changes over the course of
irreversible medical gender-affirming treatment. Methods: The total study sample consisted of
70 adolescents (49 trans men and 21 trans women). Self-perception was assessed before the
start of gender-affirming hormone treatment (mean age = 14.65, standard deviation (SD) = 2.08)
and at least 6 months after gender-affirming surgeries (mean age = 20.70, SD = 1.49) by Self-
Perception Profile for Adolescents (SPPA). The SPPA is a self-report measure that examines self-
perception on seven different domains: Scholastic competence, social acceptance, athletic
competence, physical appearance, behavioral conduct, close friendship, and global self-worth.
Multilevel modeling (random intercepts model) was conducted to determine the effect of time
for all domains of self-perception. Results: It was found that the domains of physical appearance
and global self-worth improved significantly over the course of treatment. No domain worsened
significantly over the course of treatment. The domains of scholastic competence, social
acceptance, athletic competence, and close friendship remained stable over time. Conclusion:
This study provides the first suggestive evidence that irreversible gender-affirming treatment for
adolescents could contribute to the development of a more positive self-perception.

Annotation: Examines changes in psychosocial outcomes in TGNB adolescents before (while on

hormonal treatments only) vs after gender-affirming surgery.

Cantu AL, Moyer DN, Connelly KJ, Holley AL. Changes in Anxiety and Depression from Intake to First
Follow-Up Among Transgender Youth in a Pediatric Endocrinology Clinic. Transgend Health.
2020;5(3):196-200. doi:10.1089/trgh.2019.0077 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33644311

Abstract: Monitoring acute distress in transgender youth initiating gender-affirming care is

important given their increased risk for significant mental health symptoms. The current study

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 examined changes in anxiety, depression, and suicidality from initial appointment to first follow-
up in 80 youth, ages 11-18. Average time between visits was approximately 4 months but varied
across participants. Results revealed no change in acute distress from intake to follow-up.
Neither distance from medical center nor initiation of hormone therapy was associated with
symptom changes. While research shows decreased distress with initiation of hormones, study
findings suggest changes may actually take longer to occur.

Annotation: Examines changes in anxiety and depression in treated and untreated TGNB youths

Carmichael P, Butler G, Masic U, et al. Short-term outcomes of pubertal suppression in a selected cohort
of 12 to 15 year old young people with persistent gender dysphoria in the UK. PLoS One.
2021;16(2):e0243894. doi:10.1371/journal.pone.0243894 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33529227

Abstract: BACKGROUND: In adolescents with severe and persistent gender dysphoria (GD),
gonadotropin releasing hormone analogues (GnRHa) are used from early/middle puberty with
the aim of delaying irreversible and unwanted pubertal body changes. Evidence of outcomes of
pubertal suppression in GD is limited. METHODS: We undertook an uncontrolled prospective
observational study of GnRHa as monotherapy in 44 12-15 year olds with persistent and severe
GD. Prespecified analyses were limited to key outcomes: bone mineral content (BMC) and bone
mineral density (BMD); Child Behaviour CheckList (CBCL) total t-score; Youth Self-Report (YSR)
total t-score; CBCL and YSR self-harm indices; at 12, 24 and 36 months. Semistructured
interviews were conducted on GnRHa. RESULTS: 44 patients had data at 12 months follow-up,
24 at 24 months and 14 at 36 months. All had normal karyotype and endocrinology consistent
with birth-registered sex. All achieved suppression of gonadotropins by 6 months. At the end of
the study one ceased GnRHa and 43 (98%) elected to start cross-sex hormones. There was no
change from baseline in spine BMD at 12 months nor in hip BMD at 24 and 36 months, but at 24
months lumbar spine BMC and BMD were higher than at baseline (BMC +6.0 (95% CI: 4.0, 7.9);
BMD +0.05 (0.03, 0.07)). There were no changes from baseline to 12 or 24 months in CBCL or
YSR total t-scores or for CBCL or YSR self-harm indices, nor for CBCL total t-score or self-harm
index at 36 months. Most participants reported positive or a mixture of positive and negative
life changes on GnRHa. Anticipated adverse events were common. CONCLUSIONS: Overall
patient experience of changes on GnRHa treatment was positive. We identified no changes in
psychological function. Changes in BMD were consistent with suppression of growth. Larger and
longer-term prospective studies using a range of designs are needed to more fully quantify the
benefits and harms of pubertal suppression in GD.

Annotation: A London-based pre-post descriptive study examining short-term (ie, 1-3 years)
bone and psychosocial outcomes in TGNB youths ages 12-15 years who received GnRH analogue
monotherapy. Only natal sexes were reported: 25 AMAB and 19 AFAB

Chen D, Berona J, Chan YM, et al. Psychosocial Functioning in Transgender Youth after 2 Years of
Hormones. N Engl J Med. 2023;388(3):240-250. doi:10.1056/NEJMoa2206297 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36652355

Abstract: BACKGROUND: Limited prospective outcome data exist regarding transgender and
nonbinary youth receiving gender-affirming hormones (GAH; testosterone or estradiol).
METHODS: We characterized the longitudinal course of psychosocial functioning during the 2
years after GAH initiation in a prospective cohort of transgender and nonbinary youth in the

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 United States. Participants were enrolled in a four-site prospective, observational study of
physical and psychosocial outcomes. Participants completed the Transgender Congruence Scale,
the Beck Depression Inventory-II, the Revised Children's Manifest Anxiety Scale (Second Edition),
and the Positive Affect and Life Satisfaction measures from the NIH (National Institutes of
Health) Toolbox Emotion Battery at baseline and at 6, 12, 18, and 24 months after GAH
initiation. We used latent growth curve modeling to examine individual trajectories of
appearance congruence, depression, anxiety, positive affect, and life satisfaction over a period
of 2 years. We also examined how initial levels of and rates of change in appearance congruence
correlated with those of each psychosocial outcome. RESULTS: A total of 315 transgender and
nonbinary participants 12 to 20 years of age (mean [+/-SD], 16+/-1.9) were enrolled in the study.
A total of 190 participants (60.3%) were transmasculine (i.e., persons designated female at birth
who identify along the masculine spectrum), 185 (58.7%) were non-Latinx or non-Latine White,
and 25 (7.9%) had received previous pubertal suppression treatment. During the study period,
appearance congruence, positive affect, and life satisfaction increased, and depression and
anxiety symptoms decreased. Increases in appearance congruence were associated with
concurrent increases in positive affect and life satisfaction and decreases in depression and
anxiety symptoms. The most common adverse event was suicidal ideation (in 11 participants
[3.5%]); death by suicide occurred in 2 participants. CONCLUSIONS: In this 2-year study involving
transgender and nonbinary youth, GAH improved appearance congruence and psychosocial
functioning. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and
Human Development.).

Annotation: Examines mental health and psychosocial outcomes in TGNB adolescents after 2
years of CSHT. Also compares mental health outcomes between early- and late-treated
adolescents.

de Vries AL, Steensma TD, Doreleijers TA, Cohen-Kettenis PT. Puberty suppression in adolescents with
gender identity disorder: a prospective follow-up study. J Sex Med. 2011;8(8):2276-2283.
doi:10.1111/j.1743-6109.2010.01943.x Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/20646177

Abstract: INTRODUCTION: Puberty suppression by means of gonadotropin-releasing hormone

analogues (GnRHa) is used for young transsexuals between 12 and 16 years of age. The purpose
of this intervention is to relieve the suffering caused by the development of secondary sex
characteristics and to provide time to make a balanced decision regarding actual gender
reassignment. AIM: To compare psychological functioning and gender dysphoria before and
after puberty suppression in gender dysphoric adolescents. METHODS: Of the first 70 eligible
candidates who received puberty suppression between 2000 and 2008, psychological
functioning and gender dysphoria were assessed twice: at T0, when attending the gender
identity clinic, before the start of GnRHa; and at T1, shortly before the start of cross-sex
hormone treatment. MAIN OUTCOME MEASURES: Behavioral and emotional problems (Child
Behavior Checklist and the Youth-Self Report), depressive symptoms (Beck Depression
Inventory), anxiety and anger (the Spielberger Trait Anxiety and Anger Scales), general
functioning (the clinician's rated Children's Global Assessment Scale), gender dysphoria (the
Utrecht Gender Dysphoria Scale), and body satisfaction (the Body Image Scale) were assessed.
RESULTS: Behavioral and emotional problems and depressive symptoms decreased, while
general functioning improved significantly during puberty suppression. Feelings of anxiety and
anger did not change between T0 and T1. While changes over time were equal for both sexes,
compared with natal males, natal females were older when they started puberty suppression

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 and showed more problem behavior at both T0 and T1. Gender dysphoria and body satisfaction
did not change between T0 and T1. No adolescent withdrew from puberty suppression, and all
started cross-sex hormone treatment, the first step of actual gender reassignment.
CONCLUSION: Puberty suppression may be considered a valuable contribution in the clinical
management of gender dysphoria in adolescents.

Annotation: Examines mental health outcomes in TGNB patients treated with GnRH agonists.
Only natal sex reported: 33 AMAB and 37 AFAB

de Vries ALC. Puberty Suppression Followed by Cross-sex Hormones and Gender Reassignment Surgery:
A Prospective Follow-up of Gender Dysphoric Adolescents into Adulthood. Gender Dysphoria in
Adolescents. PhD Thesis. Vrije Universiteit Amsterdam; 2010:91-106:chap 7. Accessed June 12,
2023. Available at https://research.vu.nl/en/publications/gender-dysphoria-in-adolescents-
mental-health-and-treatment-evalu

Ghelani R, Lim C, Brain C, Fewtrell M, Butler G. Sudden sex hormone withdrawal and the effects on body
composition in late pubertal adolescents with gender dysphoria. J Pediatr Endocrinol Metab.
2020;33(1):107-112. doi:10.1515/jpem-2019-0045 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31834861

Abstract: Background Sex hormones initiate profound physical and physiological changes during
the pubertal process, but to what extent are they responsible for continuing the body
composition changes of late adolescence and what happens to body composition on sudden sex
hormone withdrawal? Methods Thirty-six healthy, phenotypically and chromosomally normal
late and post-pubertal individuals aged 15-17 years with gender dysphoria (transgirls - birth-
registered males identifying as female n = 11; and transboys - birth-registered females
identifying as male n = 25) underwent Tanita body composition analysis at 0, 6 and 12 months
during reproductive hormone suppression with Triptorelin as part of the standard therapeutic
protocol. Results and conclusions In the transgirl cohort, paired t-test analysis demonstrated a
significant decrease in height and lean mass standard deviation scores over the 12-month
period, going against an expected trajectory over that time. In contrast, oestrogen suppression
appeared not to affect the body composition of transboys; their measurements were not
significantly different at baseline and after 12 months of treatment. The withdrawal of sex
hormone secretion does not appear to have a significant impact on female post-pubertal body
composition, in contrast to that seen at the menopause. This suggests that other factors may
preserve normal body balance in adolescents in the absence of sex steroids.

Annotation: A London-based study examining body composition changes in TGNB adolescents

receiving triptorelin for puberty suppression

Hannema SE, Schagen SEE, Cohen-Kettenis PT, Delemarre-van de Waal HA. Efficacy and Safety of
Pubertal Induction Using 17beta-Estradiol in Transgirls. J Clin Endocrinol Metab.
2017;102(7):2356-2363. doi:10.1210/jc.2017-00373 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28419243

Abstract: CONTEXT: Puberty suppression using gonadotropin-releasing hormone agonists,

followed by induction of the desired sex characteristics using sex steroids, has been
recommended by the current guidelines as the treatment of choice for gender dysphoric
adolescents, although little evidence is available. AIM: To evaluate the efficacy and safety of
estrogen treatment for pubertal induction in transgirls (female-identifying adolescents assigned

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 male at birth). METHODS: Twenty-eight adolescents treated with oral estrogen for >/=1 year
were included. The Tanner stage, anthropometry, laboratory parameters, bone age, and body
composition were evaluated. RESULTS: Breast development started within 3 months in 83% of
adolescents, and after 3 years, 86% had Tanner breast stage 4 to 5. The hip circumference
increased and the waist/hip ratio decreased. The median serum estradiol was 100 pmol/L
(range, 24 to 380) at the standard adult dose of 2 mg of 17beta-estradiol. The adult height
standard deviation score was +1.9 (for females). The body mass index standard deviation score,
lean body mass percentage, fat percentage, and blood pressure did not change. No
abnormalities of creatinine or liver enzymes were detected, and the hematocrit and hemoglobin
A1c did not change. One individual developed hyperprolactinemia during high-dose
ethinylestradiol treatment to limit growth. CONCLUSIONS: Pubertal induction using estradiol is
effective; however, an adult dose of 2 mg does not always result in appropriate serum estradiol
levels. Monitoring renal function, liver enzymes, hematocrit, and hemoglobin A1c during
pubertal induction with estradiol is not necessary. Further studies are needed to establish
effective and safe methods to limit growth.

Annotation: Examines changes in endogenous hormone levels, anthropometric measures, bone,

blood pressure measures among transgender girls treated with estradiol seen in a gender
specialty clinic

Jarin J, Pine-Twaddell E, Trotman G, et al. Cross-Sex Hormones and Metabolic Parameters in Adolescents
With Gender Dysphoria. Pediatrics. 2017;139(5)doi:10.1542/peds.2016-3173 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/28557738

Abstract: BACKGROUND AND OBJECTIVES: The Endocrine Society states that adolescents with
gender dysphoria may start cross-sex hormones. The goal of this study was to identify patterns
in metabolic parameters in transgender adolescents receiving cross-sex hormones. METHODS:
Data from adolescents aged 14 to 25 years seen in 1 of 4 clinical sites between 2008 and 2014
were retrospectively analyzed. Subjects were divided into affirmed male (female-to-male)
patients taking testosterone and affirmed female (male-to-female) patients taking estrogen.
Previously recorded measurements of blood pressure, BMI, testosterone, estradiol, prolactin,
lipids, electrolytes, liver function tests, hemoglobin/hematocrit, and hemoglobin A1c were
reviewed. These values were obtained from before the start of therapy, at 1 to 3 months after
initiation, at 4 to 6 months, and at 6 months and beyond. Repeated measures analysis of
variance models were used to evaluate changes over time. RESULTS: One hunderd and sixteen
adolescents were included (72 female-to-male subjects and 44 male-to-female subjects). Of the
72 subjects taking testosterone, a significant increase in hemoglobin/hematocrit levels and BMI,
as well as a decrease in high-density lipoprotein level, was recorded at each visit. No significant
changes in any other parameter tested were found. Of the 44 subjects taking estrogen, no
statistically significant changes were noted in the measured metabolic parameters.
CONCLUSIONS: Testosterone use was associated with increased hemoglobin and hematocrit,
increased BMI, and lowered high-density lipoprotein levels; estrogen was associated with lower
testosterone and alanine aminotransferase levels. Otherwise, cross-sex hormone administration
in adolescents was not associated with significant differences in the selected metabolic
parameters over time.

Annotation: Examines cardiovascular and metabolic changes associated with CSHT in

adolescents with gender dysphoria

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Joseph T, Ting J, Butler G. The effect of GnRH analogue treatment on bone mineral density in young
adolescents with gender dysphoria: findings from a large national cohort. J Pediatr Endocrinol
Metab. 2019;32(10):1077-1081. doi:10.1515/jpem-2019-0046 Accessed June 28, 2023. Available
at https://www.ncbi.nlm.nih.gov/pubmed/31472062

Abstract: Background More young people with gender dysphoria (GD) are undergoing hormonal
intervention starting with gonadotropin-releasing hormone analogue (GnRHa) treatment. The
impact on bone density is not known, with guidelines mentioning that bone mineral density
(BMD) should be monitored without suggesting when. This study aimed to examine a cohort of
adolescents from a single centre to investigate whether there were any clinically significant
changes in BMD and bone mineral apparent density (BMAD) whilst on GnRHa therapy. Methods
A retrospective review of 70 subjects aged 12-14 years, referred to a national centre for the
management of GD (2011-2016) who had yearly dual energy X-ray absorptiometry (DXA) scans.
BMAD scores were calculated from available data. Two analyses were performed, a complete
longitudinal analysis (n=31) where patients had scans over a 2-year treatment period, and a
larger cohort over the first treatment year (n=70) to extend the observation of rapid changes in
lumbar spine BMD when puberty is blocked. Results At baseline transboys had lower BMD
measures than transgirls. Although there was a significant fall in hip and lumbar spine BMD and
lumbar spine BMAD Z-scores, there was no significant change in the absolute values of hip or
spine BMD or lumbar spine BMAD after 1 year on GnRHa and a lower fall in BMD/BMAD Z-
scores in the longitudinal group in the second year. Conclusions We suggest that reference
ranges may need to be re-defined for this select patient cohort. Long-term BMD recovery
studies on sex hormone treatment are needed.

Annotation: A Britain-based pre-post descriptive study examining bone outcomes in TGNB

adolescents treated with GnRHa.

Kaltiala R, Heino E, Tyolajarvi M, Suomalainen L. Adolescent development and psychosocial functioning

after starting cross-sex hormones for gender dysphoria. Nord J Psychiatry. 2020;74(3):213-219.
doi:10.1080/08039488.2019.1691260 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31762394

Abstract: Purpose: To assess how adolescent development progresses and psychiatric

symptoms develop among transsexual adolescents after starting cross-sex hormone
treatment.Materials and methods: Retrospective chart review among 52 adolescents who came
into gender identity assessment before age 18, were diagnosed with transsexualism and started
hormonal gender reassignment. The subjects were followed over the so-called real-life phase of
gender reassignment.Results: Those who did well in terms of psychiatric symptoms and
functioning before cross-sex hormones mainly did well during real-life. Those who had
psychiatric treatment needs or problems in school, peer relationships and managing everyday
matters outside of home continued to have problems during real-life.Conclusion: Medical
gender reassignment is not enough to improve functioning and relieve psychiatric comorbidities
among adolescents with gender dysphoria. Appropriate interventions are warranted for
psychiatric comorbidities and problems in adolescent development.

Annotation: A Finnish pre-post study examining psychosocial functioning before and after 1-
year of treatment with cross-sex hormones.

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Klaver M, de Mutsert R, van der Loos M, et al. Hormonal Treatment and Cardiovascular Risk Profile in
Transgender Adolescents. Pediatrics. 2020;145(3)doi:10.1542/peds.2019-0741 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32102929

Abstract: BACKGROUND AND OBJECTIVES: The effects of endocrinological treatment on

cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort
study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in
transgender adolescents at 22 years compared with peers. METHODS: Changes in BMI, systolic
blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment
for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of
obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who
started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a
subsequent addition of sex hormones (17 years). RESULTS: In transwomen, changes in BMI
(+3.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (-2 mm Hg; 95% CI -7 to 3), DBP (+10 mm Hg;
95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI -0.2 to 0.2), HOMA-IR (+0.6; 95% CI -0.6 to 1.9), and
lipid values were similar or more favorable compared with peers. The same was true for
transmen regarding changes in BMI (+2.3; 95% CI 1.7 to 2.9), SBP (+7 mm Hg; 95% CI 3 to 10),
DBP (+7 mm Hg; 95% CI 5 to 10), glucose (+0.1 mmol/L; 95% CI -0.1 to 0.3), HOMA-IR (-0.2; 95%
CI -0.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in
transmen, 2.2% in ciswomen, and 3.0% in cismen. CONCLUSIONS: Generally, endocrinological
treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is
more prevalent in transgender adolescents compared with peers, body weight management
should be important during the medical trajectory.

Annotation: A cohort study comparing changes in cardiovascular risk factors between TGNB
subjects who received surgical vs GnRHa gonadal suppression. Note that this is also (1) a cohort
study comparing these outcomes between TGNB subjects vs cisgender peers, and (2) a pre-post
descriptive study.

Klaver M, de Mutsert R, Wiepjes CM, et al. Early Hormonal Treatment Affects Body Composition and
Body Shape in Young Transgender Adolescents. J Sex Med. 2018;15(2):251-260.
doi:10.1016/j.jsxm.2017.12.009 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29425666

Abstract: BACKGROUND: Transgender adolescents aspiring to have the body characteristics of

the affirmed sex can receive hormonal treatment. However, it is unknown how body shape and
composition develop during treatment and whether transgender persons obtain the desired
body phenotype. AIM: To examine the change in body shape and composition from the start of
treatment with gonadotropin-releasing hormone agonists (GnRHa) until 22 years of age and to
compare these measurements at 22 years with those of age-matched peers. METHODS: 71
transwomen (birth-assigned boys) and 121 transmen (birth-assigned girls) who started
treatment from 1998 through 2014 were included in this retrospective study. GnRHa treatment
was started and cross-sex hormonal treatment was added at 16 years of age. Anthropometric
and whole-body dual-energy x-ray absorptiometry data were retrieved from medical records.
Linear mixed model regression was performed to examine changes over time. SD scores (SDS)
were calculated to compare body shape and composition with those of age-matched peers.
OUTCOMES: Change in waist-hip ratio (WHR), total body fat (TBF), and total lean body mass
(LBM) during hormonal treatment. SDS of measures of body shape and composition compared
with age-matched peers at 22 years of age. RESULTS: In transwomen, TBF increased (+10%, 95%

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 CI = 7-11) while total LBM (-10%, 95% CI = -11 to -7) and WHR (-0.04, 95% CI = -0.05 to -0.02)
decreased. Compared with ciswomen, SDS at 22 years of age were +0.3 (95% CI = 0.0-0.5) for
WHR, and 0.0 (95% CI = -0.2 to 0.3) for TBF. Compared with cismen, SDS were -1.0 (95% CI = -1.3
to -0.7) for WHR, and +2.2 (95% CI = 2.2-2.4) for TBF. In transmen, TBF decreased (-3%, 95% CI =
-4 to -1), while LBM (+3%, 95% CI = 1-4) and WHR (+0.03, 95% CI = 0.01-0.04) increased.
Compared with ciswomen, SDS at 22 years of age were +0.6 (95% CI = 0.4-0.8) for WHR, and -1.1
(95% CI = -1.4 to -0.9) for TBF. Compared with cismen, SDS were -0.5 (95% CI = -0.8 to -0.3) for
WHR, and +1.8 (95% CI = 1.6-1.9) for TBF. CLINICAL IMPLICATIONS: Knowing body shape and
composition outcomes at 22 years of age will help care providers in counseling transgender
youth on expectations of attaining the desired body phenotype. STRENGTHS AND LIMITATIONS:
This study presents the largest group of transgender adults to date who started treatment in
their teens. Despite missing data, selection bias was not found. CONCLUSIONS: During
treatment, WHR and body composition changed toward the affirmed sex. At 22 years of age,
transwomen compared better to age-matched ciswomen than to cismen, whereas transmen
were between reference values for ciswomen and cismen. Klaver M, de Mutsert R, Wiepjes CM,
et al. Early Hormonal Treatment Affects Body Composition and Body Shape in Young
Transgender Adolescents. J Sex Med 2018;15:251-260.

Annotation: An Amsterdam-based cohort study examining body composition outcomes in

patients who received unspecified GnRH analogues and cross-sex hormones, including
comparisons between TGNB patients and cisgender peers.

Klink D, Caris M, Heijboer A, van Trotsenburg M, Rotteveel J. Bone mass in young adulthood following
gonadotropin-releasing hormone analog treatment and cross-sex hormone treatment in
adolescents with gender dysphoria. J Clin Endocrinol Metab. 2015;100(2):E270-275.
doi:10.1210/jc.2014-2439 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25427144

Abstract: CONTEXT: Sex steroids are important for bone mass accrual. Adolescents with gender
dysphoria (GD) treated with gonadotropin-releasing hormone analog (GnRHa) therapy are
temporarily sex-steroid deprived until the addition of cross-sex hormones (CSH). The effect of
this treatment on bone mineral density (BMD) in later life is not known. OBJECTIVE: This study
aimed to assess BMD development during GnRHa therapy and at age 22 years in young adults
with GD who started sex reassignment (SR) during adolescence. DESIGN AND SETTING: This was
a longitudinal observational study at a tertiary referral center. PATIENTS: Young adults
diagnosed with gender identity disorder of adolescence (DSM IV-TR) who started SR in puberty
and had undergone gonadectomy between June 1998 and August 2012 were included. In 34
subjects BMD development until the age of 22 years was analyzed. INTERVENTION: GnRHa
monotherapy (median duration in natal boys with GD [transwomen] and natal girls with GD
[transmen] 1.3 and 1.5 y, respectively) followed by CSH (median duration in transwomen and
transmen, 5.8 and 5.4 y, respectively) with discontinuation of GnRHa after gonadectomy.
MAJOR OUTCOME MEASURES: How BMD develops during SR until the age of 22 years. RESULTS
AND CONCLUSION: Between the start of GnRHa and age 22 years the lumbar areal BMD z score
(for natal sex) in transwomen decreased significantly from -0.8 to -1.4 and in transmen there
was a trend for decrease from 0.2 to -0.3. This suggests that the BMD was below their
pretreatment potential and either attainment of peak bone mass has been delayed or peak
bone mass itself is attenuated.

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 Annotation: Examines patient characteristics and bone outcomes over time in GnRH agonist-
and CSHT-treated adolescents in a gender specialty clinic

Kuper LE, Stewart S, Preston S, Lau M, Lopez X. Body Dissatisfaction and Mental Health Outcomes of
Youth on Gender-Affirming Hormone Therapy. Pediatrics. 2020;145(4)doi:10.1542/peds.2019-
3006 Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32220906

Abstract: OBJECTIVES: Our first aim was to examine baseline differences in body dissatisfaction,
depression, and anxiety symptoms by gender, age, and Tanner (ie, pubertal) stage. Our second
aim was to test for changes in youth symptoms over the first year of receiving gender-affirming
hormone therapy. Our third aim was to examine potential differences in change over time by
demographic and treatment characteristics. Youth experiences of suicidal ideation, suicide
attempt, and nonsuicidal self-injury (NSSI) are also reported. METHODS: Participants (n = 148;
ages 9-18 years; mean age 14.9 years) were receiving gender-affirming hormone therapy at a
multidisciplinary program in Dallas, Texas (n = 25 puberty suppression only; n = 123 feminizing
or masculinizing hormone therapy). Participants completed surveys assessing body
dissatisfaction (Body Image Scale), depression (Quick Inventory of Depressive Symptoms), and
anxiety (Screen for Child Anxiety Related Emotional Disorders) at initial presentation to the clinic
and at follow-up. Clinicians completed the Quick Inventory of Depressive Symptoms and
collected information on youth experiences of suicidal ideation, suicide attempt, and NSSI.
RESULTS: Affirmed males reported greater depression and anxiety at baseline, but these
differences were small (P < .01). Youth reported large improvements in body dissatisfaction (P <
.001), small to moderate improvements in self-report of depressive symptoms (P < .001), and
small improvements in total anxiety symptoms (P < .01). No demographic or treatment-related
characteristics were associated with change over time. Lifetime and follow-up rates were 81%
and 39% for suicidal ideation, 16% and 4% for suicide attempt, and 52% and 18% for NSSI,
respectively. CONCLUSIONS: Results provide further evidence of the critical role of gender-
affirming hormone therapy in reducing body dissatisfaction. Modest initial improvements in
mental health were also evident.

Annotation: A US-based pre-post descriptive study examining changes in body dissatisfaction

and mental health (anxiety/depression) among adolescents receiving GAH.

Laurenzano SE, Newfield RS, Lee E, Marinkovic M. Subcutaneous Testosterone Is Effective and Safe as
Gender-Affirming Hormone Therapy in Transmasculine and Gender-Diverse Adolescents and
Young Adults: A Single Center's 8-Year Experience. Transgend Health. 2021;6(6):343-352.
doi:10.1089/trgh.2020.0103 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34988290

Abstract: Purpose: To describe our Center's 8-year experience with subcutaneous testosterone
(SC-T) as gender-affirming hormone therapy (GAHT) in transmasculine and gender-diverse
(TM/GD) youth. Methods: An Institutional Review Board (IRB)-approved retrospective study for
119 TM/GD subjects who started SC-T at age 13-19 and received SC-T for >6 months between
2012 and 2020. Results: SC-T was typically started at 25-50 mg biweekly and dose was escalated
at provider's discretion. Over 96% of subjects were on 100-320 mg monthly (divided weekly or
biweekly) at last follow-up. There was an overall increase in mean total and free testosterone (T)
over the dose range (p=0.003), with mean total and free T levels of 460 ng/dL and 92 pg/mL,
respectively, at a monthly SC-T dose of 200 mg. For subjects on SC-T without additional
menstrual suppression, 54% had cessation of menses at 140 mg monthly and 97% at 200 mg

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 monthly. On average, menses stopped 4.7 (standard deviation 3.0) months after starting SC-T.
There was a decrease in high-density lipoprotein and increase in hematocrit from baseline to
follow-up. Body mass index Z-scores did not change significantly with treatment. Mild acne was
common; severe acne and significant injection site reactions were uncommon. Sustained
hypertension, transaminitis, and dyslipidemia were infrequent. Conclusions: SC-T is well
tolerated and effective in reaching recommended T levels and stopping menses in TM/GD
youth. Occurrence of serious adverse effects is low and inability to tolerate injections is very
uncommon. SC-T is a safe and effective alternative to intramuscular testosterone in initiation
and maintenance of GAHT in TM/GD youth.

Annotation: Examines endogenous hormone levels, menstrual outcomes, and body changes in
transmasculine and gender-diverse adolescents treated with subcutaneous testosterone

Lavender R, Shaw S, Maninger JK, et al. Impact of Hormone Treatment on Psychosocial Functioning in
Gender-Diverse Young People. LGBT Health. 2023,
10.1089/lgbt.2022.0201doi:10.1089/lgbt.2022.0201 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36989498

Abstract: Purpose: Few studies have assessed the effects of hormonal treatments such as
gonadotropin-releasing hormone agonists (GnRHa) and gender-affirming hormones (GAH) on
mental health outcomes in clinically referred gender-diverse young people from a younger age.
Where this research has been conducted, findings have been mixed. This study investigated a
cohort of young people before treatment, 1 year into GnRHa, and 1 year into GAH treatment to
understand psychological and behavioral impacts over time. Methods: Thirty-eight young
people (28 assigned female and 10 assigned male) referred to endocrinology, younger than 15
years at/beyond Tanner stage two, who received GnRHa followed by GAH treatment, were
assessed in a retrospective analysis study. Young people completed the Youth Self Report (YSR),
the Body Image Scale, and the Utrecht Gender Dysphoria Scale, while caregivers completed the
Child Behavior Checklist (CBCL) and the Social Responsiveness Scale-2 at all time points. Results:
Dissatisfaction with primary sexual characteristics (p = 0.02), gender dysphoria (p = 0.01), and
social motivation (p = 0.04) improved significantly over time. Self-harm and suicidality also
showed a general decrease. Caregivers reported a significant reduction in internalizing (p = 0.03)
behaviors on the CBCL after GnRHa. Other subcategories of the YSR and CBCL were within
normal ranges with no significant difference (p > 0.05). Conclusion: These findings demonstrate
some improvements in psychological and behavioral outcomes in young people concurrently
receiving psychosocial support and hormone treatment. Future research with larger and more
diverse samples is warranted to further understand generalizability.

Annotation: A London-based pre-post study examining changes in mental health and suicidality
for patients after initiating unspecified GnRH analogues and cross-sex hormones.

Lopez de Lara D, Perez Rodriguez O, Cuellar Flores I, et al. [Psychosocial assessment in transgender
adolescents]. An Pediatr (Engl Ed). 2020;93(1):41-48. doi:10.1016/j.anpedi.2020.01.019
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32144041

Abstract: OBJECTIVES: To evaluate the psychosocial status of the patients who attend a
paediatric endocrinology clinic due to gender incongruity (GI), and to establish the impact on
this after one-year of cross hormonal therapy (CHT). MATERIAL AND METHODS: An analytical
and prospective study conducted on adolescents between 14 and 18 years old with GI, and who

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 attended the Endocrinology clinic during 2018-2019. The sample included 23 transgender cases
(16 male and 7 female cases) and 30 cisgender controls. Study variables were collected at T0
(pre-treatment) and T1 (after one year of CHT) and included sociodemographic data, Utrecht
test, SDQ-Cas test, family APGAR test, STAI scale-anxiety Grade, and BDI-II depression
assessment test. RESULTS: A significant improvement (P<.05) was found between T0 and T1 in
the transgender group in terms of emotional symptoms, behaviour problems, hyperactivity
symptoms, pro-social conduct, as well as in the degree of anxiety and depression measured by
the SDQ-Cas test, the STAI and the BDI-II scale. There were significant differences in these scales
between the transgender group and the controls at T0, however, the scores equalised at T1. The
families in this sample of transgender patients provided a very favourable environment
according to the scores obtained on the family APGAR scale. CONCLUSIONS: The rates of
anxiety, emotional and behaviour distress, depressive symptomatology, as well as the feeling of
gender dysphoria of these transgender patients were similar to those of non-transsexual
population of the same age after one year of CHT initiated at ages between 14-18 years old.

Annotation: Examines psychosocial outcomes in TGNB patients who attend a pediatric

endocrinology clinic before and after one-year of cross hormonal therapy (CHT). In Spanish.

Millington K, Barrera E, Daga A, et al. The effect of gender-affirming hormone treatment on serum
creatinine in transgender and gender-diverse youth: implications for estimating GFR. Pediatr
Nephrol. 2022;37(9):2141-2150. doi:10.1007/s00467-022-05445-0 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/35083530

Abstract: BACKGROUND: Equations for estimated glomerular filtration rate (eGFR) based on
serum creatinine include terms for sex/gender. For transgender and gender-diverse (TGD)
youth, gender-affirming hormone (GAH) treatment may affect serum creatinine and in turn
eGFR. METHODS: TGD youth were recruited for this prospective, longitudinal, observational
study prior to starting GAH treatment. Data collected as part of routine clinical care were
abstracted from the medical record. RESULTS: For participants designated male at birth (DMAB,
N = 92), serum creatinine decreased within 6 months of estradiol treatment (mean +/- SD 0.83
+/- 0.12 mg/dL to 0.76 +/- 0.12 mg/dL, p < 0.001); for participants designated female at birth
(DFAB, n = 194), serum creatinine increased within 6 months of testosterone treatment (0.68 +/-
0.10 mg/dL to 0.79 +/- 0.11 mg/dL, p < 0.001). Participants DFAB treated with testosterone had
serum creatinine similar to that of participants DMAB at baseline, whereas even after estradiol
treatment, serum creatinine in participants DMAB remained higher than that of participants
DFAB at baseline. Compared to reference groups drawn from the National Health and
Nutritional Examination Survey, serum creatinine after 12 months of GAH was more similar
when compared by gender identity than by designated sex. CONCLUSION: GAH treatment leads
to changes in serum creatinine within 6 months of treatment. Clinicians should consider a
patient's hormonal exposure when estimating kidney function via eGFR and use other methods
to estimate GFR if eGFR based on serum creatinine is concerning.

Annotation: A cohort study comparing kidney function measures between TGNB adolescents
receiving gender-affirming hormone therapy versus a cohort of other adolescents from NHANEs.

Millington K, Finlayson C, Olson-Kennedy J, Garofalo R, Rosenthal SM, Chan YM. Association of High-
Density Lipoprotein Cholesterol With Sex Steroid Treatment in Transgender and Gender-Diverse
Youth. JAMA Pediatr. 2021;175(5):520-521. doi:10.1001/jamapediatrics.2020.5620 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33587098

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 Abstract: This cohort study analyzes the association of sex steroids with cholesterol in different
sex-chromosome contexts.

Annotation: A research letter examining growth, body composition, and cholesterol changes in
TGNB adolescents receiving CSHT. Only natal sex reported (N = 83 AMAB and N = 186 AFAB).

Neyman A, Fuqua JS, Eugster EA. Bicalutamide as an Androgen Blocker With Secondary Effect of
Promoting Feminization in Male-to-Female Transgender Adolescents. J Adolesc Health.
2019;64(4):544-546. doi:10.1016/j.jadohealth.2018.10.296 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30612811

Abstract: PURPOSE: The purpose of the study was to describe the novel use of bicalutamide in
transgender youth. METHODS: This is a retrospective review of patients with gender dysphoria
followed in the pediatric endocrine clinic at Riley Hospital for Children. RESULTS: Of 104 patients
with gender dysphoria, 23 male-to-female adolescents received bicalutamide 50 mg daily as a
second-line puberty blocker after insurance company denial of a gonadotropin-releasing
hormone analog. Six patients received estrogen concurrently. Of 13 patients treated exclusively
with bicalutamide seen in follow-up, 84.6% had breast development within 6 months, the
majority being >/= Tanner stage III. CONCLUSIONS: Bicalutamide may be an alternative to
gonadotropin-releasing hormone analogs in transgender male-to-female youth who are also
ready to undergo physical transition.

Annotation: Clinical and laboratory characteristics of transfeminine patients treated with the
antiandrogen bicalutamide as an androgen blocker after insurance denials of claims for GnRH
agonists

Olson-Kennedy J, Warus J, Okonta V, Belzer M, Clark LF. Chest Reconstruction and Chest Dysphoria in
Transmasculine Minors and Young Adults: Comparisons of Nonsurgical and Postsurgical Cohorts.
JAMA Pediatr. 2018;172(5):431-436. doi:10.1001/jamapediatrics.2017.5440 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/29507933

Abstract: IMPORTANCE: Transmasculine youth, who are assigned female at birth but have a
gender identity along the masculine spectrum, often report considerable distress after breast
development (chest dysphoria). Professional guidelines lack clarity regarding referring minors
(defined as people younger than 18 years) for chest surgery because there are no data
documenting the effect of chest surgery on minors. OBJECTIVE: To examine the amount of chest
dysphoria in transmasculine youth who had had chest reconstruction surgery compared with
those who had not undergone this surgery. DESIGN, SETTING, AND PARTICIPANTS: Using a novel
measure of chest dysphoria, this cohort study at a large, urban, hospital-affiliated ambulatory
clinic specializing in transgender youth care collected survey data about testosterone use and
chest distress among transmasculine youth and young adults. Additional information about
regret and adverse effects was collected from those who had undergone surgery. Eligible youth
were 13 to 25 years old, had been assigned female at birth, and had an identified gender as
something other than female. Recruitment occurred during clinical visits and via telephone
between June 2016 and December 2016. Surveys were collected from participants who had
undergone chest surgery at the time of survey collection and an equal number of youth who had
not undergone surgery. MAIN OUTCOMES AND MEASURES: Outcomes were chest dysphoria
composite score (range 0-51, with higher scores indicating greater distress) in all participants;
desire for chest surgery in patients who had not had surgery; and regret about surgery and

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 complications of surgery in patients who were postsurgical. RESULTS: Of 136 completed surveys,
68 (50.0%) were from postsurgical participants, and 68 (50.0%) were from nonsurgical
participants. At the time of the survey, the mean (SD) age was 19 (2.5) years for postsurgical
participants and 17 (2.5) years for nonsurgical participants. Chest dysphoria composite score
mean (SD) was 29.6 (10.0) for participants who had not undergone chest reconstruction, which
was significantly higher than mean (SD) scores in those who had undergone this procedure (3.3
[3.8]; P < .001). Among the nonsurgical cohort, 64 (94%) perceived chest surgery as very
important, and chest dysphoria increased by 0.33 points each month that passed between a
youth initiating testosterone therapy and undergoing surgery. Among the postsurgical cohort,
the most common complication of surgery was loss of nipple sensation, whether temporary
(59%) or permanent (41%). Serious complications were rare and included postoperative
hematoma (10%) and complications of anesthesia (7%). Self-reported regret was near 0.
CONCLUSIONS AND RELEVANCE: Chest dysphoria was high among presurgical transmasculine
youth, and surgical intervention positively affected both minors and young adults. Given these
findings, professional guidelines and clinical practice should consider patients for chest surgery
based on individual need rather than chronologic age.

Annotation: Examines the amount of chest dysphoria in transmasculine youth who had had
chest reconstruction surgery compared with those who had not undergone this surgery.

Perl L, Elkon-Tamir E, Segev-Becker A, Israeli G, Brener A, Oren A. Blood pressure dynamics after
pubertal suppression with gonadotropin-releasing hormone analogs followed by estradiol
treatment in transgender female adolescents: a pilot study. J Pediatr Endocrinol Metab.
2021;34(6):741-745. doi:10.1515/jpem-2021-0172 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33823098

Abstract: OBJECTIVES: The benefits of gonadotropin-releasing hormone analogues (GnRHa) in

the treatment of central precocious puberty are well established, and their use is regarded as
both safe and effective. Possible adverse effects on blood pressure (BP) and cardiac outcomes,
body composition, bone health and brain development, however, continue to be of some
concern. The aim of this study was to analyze BP changes in transgender female adolescents
before and after receiving GnRHa and after adding estrogen treatment. METHODS: This was a
retrospective pilot study. We analyzed systolic BP (SBP) and diastolic BP (DBP) before and after
GnRHa initiation and after adding estrogen. RESULTS: Nineteen transgender female adolescents
received GnRHa and 15 continued to estrogen treatment. Their baseline SBP and DBP
percentiles did not change significantly after either GnRHa or the addition of estrogen
treatment. CONCLUSIONS: Blood pressure is apparently not affected by GnRHa or GnRHa +
estrogen treatment in transgender female adolescents. Further larger studies are indicated to
confirm these findings.

Annotation: Examines blood pressure, weight, and hormone levels in transfeminine adolescents
who received GnRH analogues for puberty suppression, 15 of whom went on to receive CSHT
with estradiol

Perl L, Segev-Becker A, Israeli G, Elkon-Tamir E, Oren A. Blood Pressure Dynamics After Pubertal
Suppression with Gonadotropin-Releasing Hormone Analogs Followed by Testosterone
Treatment in Transgender Male Adolescents: A Pilot Study. LGBT Health. 2020;7(6):340-344.
doi:10.1089/lgbt.2020.0026 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32735503

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 Abstract: Purpose: We analyzed blood pressure (BP) changes in transgender male adolescents
treated with gonadotropin-releasing hormone analogs (GnRHa) and after adding testosterone
treatment. Methods: This was a retrospective pilot study. Outcome measures included systolic
BP (SBP) and diastolic BP (DBP) before and after GnRHa initiation and after adding testosterone.
Results: Fifteen transgender male adolescents received GnRHa. DBP percentiles increased
significantly after GnRHa treatment (from 55.9% +/- 26.4 to 73.6% +/- 9.4, p = 0.019). BP levels
did not meet criteria for hypertension. DBP percentiles were restored after adding testosterone.
Conclusion: GnRHa may increase DBP in transgender male adolescents, and testosterone
treatment may restore it. Further larger studies are indicated.

Annotation: Examines blood pressure outcomes in transgender males receiving puberty-

suppressing GnRH analogues, followed by CSHT for 9 of them

Roy MK, Wilkerson RB, Alexander K, Nokoff NJ, Cree-Green M, D'Alessandro A. Longitudinal metabolic
study of red blood cells from patients undergoing gender-affirming testosterone therapy. Blood
Adv. 2023;7(16):4269-4277. doi:10.1182/bloodadvances.2022008061 Accessed September 15,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36001490

Annotation: A research letter reporting findings from a Colorado-based, longitudinal, pre-post

study of transgender boys receiving testosterone therapy.

Schagen SE, Cohen-Kettenis PT, Delemarre-van de Waal HA, Hannema SE. Efficacy and Safety of
Gonadotropin-Releasing Hormone Agonist Treatment to Suppress Puberty in Gender Dysphoric
Adolescents. J Sex Med. 2016;13(7):1125-1132. doi:10.1016/j.jsxm.2016.05.004 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/27318023

Abstract: INTRODUCTION: Puberty suppression using gonadotropin-releasing hormone agonists

(GnRHas) is recommended by current guidelines as the treatment of choice for gender dysphoric
adolescents. Although GnRHas have long been used to treat precocious puberty, there are few
data on the efficacy and safety in gender dysphoric adolescents. Therefore, the Endocrine
Society guideline recommends frequent monitoring of gonadotropins, sex steroids, and renal
and liver function. AIM: To evaluate the efficacy and safety of GnRHa treatment to suppress
puberty in gender dysphoric adolescents. METHODS: Forty-nine male-to-female and 67 female-
to-male gender dysphoric adolescents treated with triptorelin were included in the analysis.
MAIN OUTCOME MEASURES: Physical examination, including assessment of Tanner stage, took
place every 3 months and blood samples were drawn at 0, 3, and 6 months and then every 6
months. Body composition was evaluated using dual energy x-ray absorptiometry. RESULTS:
GnRHa treatment caused a decrease in testicular volume in 43 of 49 male-to-female subjects. In
one of four female-to-male subjects who presented at Tanner breast stage 2, breast
development completely regressed. Gonadotropins and sex steroid levels were suppressed
within 3 months. Treatment did not have to be adjusted because of insufficient suppression in
any subject. No sustained abnormalities of liver enzymes or creatinine were encountered.
Alkaline phosphatase decreased, probably related to a slower growth velocity, because height
SD score decreased in boys and girls. Lean body mass percentage significantly decreased during
the first year of treatment in girls and boys, whereas fat percentage significantly increased.
CONCLUSION: Triptorelin effectively suppresses puberty in gender dysphoric adolescents. These
data suggest routine monitoring of gonadotropins, sex steroids, creatinine, and liver function is
not necessary during treatment with triptorelin. Further studies should evaluate the extent to

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 which changes in height SD score and body composition that occur during GnRHa treatment can
be reversed during subsequent cross-sex hormone treatment.

Annotation: Examines growth, body composition, and endogenous hormone levels in TGNB
adolescents who received GnRH agonists for 1 year in a gender specialty clinic

Schagen SEE, Lustenhouwer P, Cohen-Kettenis PT, Delemarre-van de Waal HA, Hannema SE. Changes in
Adrenal Androgens During Puberty Suppression and Gender-Affirming Hormone Treatment in
Adolescents With Gender Dysphoria. J Sex Med. 2018;15(9):1357-1363.
doi:10.1016/j.jsxm.2018.07.017 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30224022

Abstract: INTRODUCTION: Gender-affirming hormone treatment is known to affect adrenal

androgen levels in adult individuals with gender dysphoria (GD). This may be clinically relevant
because the adrenal gland plays a critical role in many different metabolic processes. AIM: This
study aims to assess the effects of gonadotropin-releasing hormone analogs (GnRHa) treatment
and gender-affirming hormone treatment on adrenal androgen levels in adolescents with GD.
METHODS: In this prospective study, dehydroepiandrosterone-sulfate (DHEAS) and
androstenedione values were measured every 6 months during 2 years of GnRHa treatment
only, and 2 years of GnRHa combined with gender-affirming hormone treatment (estradiol or
testosterone) in 73 transgirls and 54 transboys. To determine trends in adrenal androgen levels
a linear mixed model was used to approximate androgen levels. MAIN OUTCOME MEASURES:
DHEAS and androstenedione levels were the main outcome measures. RESULTS: DHEAS levels
rose in transboys during GnRHa treatment, which may represent the normal increase during
adolescence. In transgirls no change in DHEAS levels during GnRHa treatment was found.
Gender-affirming hormone treatment did not affect DHEAS levels in either sex. In transboys
androstenedione levels decreased during the first year of GnRHa treatment, which may reflect
reduced ovarian androstenedione synthesis, and rose during the first year of gender-affirming
hormone treatment, possibly due to conversion of administered testosterone. In transgirls
androstenedione levels did not change during either GnRHa or gender-affirming hormone
treatment. CLINICAL IMPLICATIONS: No deleterious effects of treatment on adrenal androgen
levels were found during approximately 4 years of follow-up. STRENGTHS & LIMITATIONS: This is
one of the largest cohort of adolescents with GD, treated using a uniform protocol, with
standardized follow-up. The lack of a control group is a limitation. CONCLUSION: The changes in
androstenedione levels during GnRHa and gender-affirming hormone treatment in transboys
may not be of adrenal origin. The absence of changes in androstenedione levels in transgirls or
DHEAS levels in either sex during gender-affirming hormone treatment suggests that gender-
affirming hormone treatment does not significantly affect adrenal androgen production.
Schagen SEE, Lustenhouwer P, Cohen-Kettenis PT, et al. Changes in Adrenal Androgens During
Puberty Suppression and Gender-Affirming Hormone Treatment in Adolescents With Gender
Dysphoria. J Sex Med 2018;15:1357-1363.

Annotation: Examines changes in endogenous hormones during puberty suppression and CSHT
in adolescents with GD

Stoffers IE, de Vries MC, Hannema SE. Physical changes, laboratory parameters, and bone mineral
density during testosterone treatment in adolescents with gender dysphoria. J Sex Med.
2019;16(9):1459-1468. doi:10.1016/j.jsxm.2019.06.014 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31405768

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 Abstract: INTRODUCTION: Current treatment guidelines for adolescents with gender dysphoria
recommend therapy with gonadotropin-releasing hormone agonists (GnRHa) and testosterone
in transgender males. However, most evidence on the safety and efficacy of testosterone is
based on studies in adults. AIM: This study aimed to investigate the efficacy and safety of
testosterone treatment in transgender adolescents. METHODS: The study included 62
adolescents diagnosed with gender dysphoria who had started GnRHa treatment and had
subsequently received testosterone treatment for more than 6 months. MAIN OUTCOME
MEASURE: Virilization, anthropometry, laboratory parameters, and bone mineral density (BMD)
were analyzed. RESULTS: Adolescents were treated with testosterone for a median duration of
12 months. Voice deepening began within 3 months in 85% of adolescents. Increased hair
growth was first reported on the extremities, followed by an increase of facial hair. Acne was
most prevalent between 6 and 12 months of testosterone therapy. Most adolescents had
already completed linear growth; body mass index and systolic blood pressure increased but
diastolic blood pressure did not change. High-density lipoprotein (HDL) cholesterol and sex
hormone binding globulin significantly decreased, but hematocrit, hemoglobin, prolactin,
androstenedione, and dehydroepiandrosterone sulfate significantly increased, although not all
changes were clinically significant. Other lipids and HbA1c did not change. Vitamin D deficiency
was seen in 32-54% throughout treatment. BMD z-scores after 12 to 24 months of testosterone
treatment remained below z-scores before the start of GnRHa treatment. CLINICAL
IMPLICATIONS: Adolescents need to be counseled about side effects with potential longer term
implications such as increased hematocrit and decreased HDL cholesterol and decreased BMD z-
scores. They should be advised on diet, including adequate calcium and vitamin D intake;
physical exercise; and the use of tobacco and alcohol to avoid additional risk factors for
cardiovascular disease and osteoporosis. STRENGTHS & LIMITATIONS: Strengths are the
standardized treatment regimen and extensive set of safety parameters investigated.
Limitations are the limited duration of follow-up and lack of a control group so some of the
observed changes may be due to normal maturation rather than to treatment. CONCLUSION:
Testosterone effectively induced virilization beginning within 3 months in the majority of
adolescents. Acne was a common side effect, but no short-term safety issues were observed.
The increased hematocrit, decreased HDL cholesterol, and decreased BMD z-scores are in line
with previous studies. Further follow-up studies will need to establish if the observed changes
result in adverse outcomes in the long term. Stoffers IE, de Vries MC, Hannema SE. Physical
Changes, Laboratory Parameters, and Bone Mineral Density During Testosterone Treatment in
Adolescents with Gender Dysphoria. J Sex Med 2019;16:1459-1468.

Annotation: Examines body changes, growth, cardiovascular risk factors, and metabolic
outcomes in testosterone-treated adolescents with GD

Tack LJW, Heyse R, Craen M, et al. Consecutive Cyproterone Acetate and Estradiol Treatment in Late-
Pubertal Transgender Female Adolescents. J Sex Med. 2017;14(5):747-757.
doi:10.1016/j.jsxm.2017.03.251 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28499525

Abstract: BACKGROUND: Cyproterone acetate (CA) is an antiandrogenic progestin commonly

used in adult transwomen to suppress endogenous androgens, often in combination with
estrogens to induce feminization. AIM: To assess the (side) effects and biochemical changes of
CA alone and in combination with estrogens in adolescent trans-girls. METHODS: This study was
a retrospective analysis of clinical and biochemical data from 27 trans-girls who presented at
Tanner stage G4 and were treated with CA monotherapy for at least 6 months (mean = 12

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 months) and then in combination with incremental doses of estrogens (CA + E; mean = 16
months). Statistical analysis of data included paired or unpaired Student t-test or Wilcoxon
signed-ranks or Mann-Whitney U-test as appropriate. OUTCOMES: Anthropometrics, reported
beneficial and side effects, safety parameters, and hormone levels. RESULTS: Physical changes
included decrease of facial and non-facial hair growth. One third showed breast development
under CA (Tanner stages B2-B3), which increased to Tanner stages B3 and B4 in 66.7% and 9.5%
respectively, during CA + E. Reported side effects during CA and CA + E were breast tenderness,
emotionality, fatigue, and flushes. No relevant weight changes were observed. Main safety
parameters showed the following changes. Hemoglobin and hematocrit decreased and liver
enzymes transiently and modestly increased during CA. Triglycerides and cholesterol levels
slightly decreased during CA but returned to baseline during CA + E; glucose metabolism was
unaffected. Relevant hormonal changes included a decrease in gonadotropins during CA + E and
in total and free testosterone levels throughout treatment. Prolactin levels increased during CA
and were restored during CA + E. CLINICAL IMPLICATIONS: CA produced modest feminizing
effects in trans-girls and therefore might be a valuable alternative in situations in which
gonadotropin-releasing hormone analogues are not the treatment of choice and/or are not
reimbursed. STRENGTHS AND LIMITATIONS: This is the first study to report on the effects of CA
in the treatment of trans-girls and one of the few to report on the use of estrogens in this
population. Limitations are the modest sample size and the retrospective nature of this study.
CONCLUSION: Treatment with CA in late-pubertal trans-girls overall was safe and well tolerated
and induced mild clinical and biochemical feminizing changes. Rapid further feminization was
observed with incremental doses of E. Tack LJW, Heyse R, Craen M, et al. Consecutive
Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents.
J Sex Med 2017;14:747-757.

Annotation: A Belgian pre-post, descriptive study examining growth, cardiovascular risk factors,
and metabolic changes in transgender female adolescents taking estrogen with an antiandrogen
not available in the US (cyproterone)

Vlot MC, Klink DT, den Heijer M, Blankenstein MA, Rotteveel J, Heijboer AC. Effect of pubertal
suppression and cross-sex hormone therapy on bone turnover markers and bone mineral
apparent density (BMAD) in transgender adolescents. Bone. 2017;95:11-19.
doi:10.1016/j.bone.2016.11.008 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/27845262

Abstract: Puberty is highly important for the accumulation of bone mass. Bone turnover and
bone mineral density (BMD) can be affected in transgender adolescents when puberty is
suppressed by gonadotropin-releasing hormone analogues (GnRHa), followed by treatment with
cross-sex hormone therapy (CSHT). We aimed to investigate the effect of GnRHa and CSHT on
bone turnover markers (BTMs) and bone mineral apparent density (BMAD) in transgender
adolescents. Gender dysphoria was diagnosed based on diagnostic criteria according to the
DSM-IV (TR). Thirty four female-to-male persons (transmen) and 22 male-to-female persons
(transwomen)were included. Patients were allocated to a young (bone age of <15years in
transwomen or <14 in transmen) or old group (bone age of >/=15years in transwomen or
>/=14years in transmen). All were treated with GnRHa triptorelin and CSHT was added in
incremental doses from the age of 16years. Transmen received testosterone esters (Sustanon,
MSD) and transwomen received 17-beta estradiol. P1NP, osteocalcin, ICTP and BMD of lumbar
spine (LS) and femoral neck (FN) were measured at three time points. In addition, BMAD and Z-
scores were calculated. We found a decrease of P1NP and 1CTP during GnRHa treatment,

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 indicating decreased bone turnover (young transmen 95% CI -74 to -50%, p=0.02, young
transwomen 95% CI -73 to -43, p=0.008). The decrease in bone turnover upon GnRHa treatment
was accompanied by an unchanged BMAD of FN and LS, whereas BMAD Z-scores of
predominantly the LS decreased especially in the young transwomen. Twenty-four months after
CSHT the BTMs P1NP and ICTP were even more decreased in all groups except for the old
transmen. During CSHT BMAD increased and Z-scores returned towards normal, especially of
the LS (young transwomen CI 95% 0.1 to 0.6, p=0.01, old transwomen 95% CI 0.3 to 0.8, p=0.04).
To conclude, suppressing puberty by GnRHa leads to a decrease of BTMs in both transwomen
and transmen transgender adolescents. The increase of BMAD and BMAD Z-scores
predominantly in the LS as a result of treatment with CSHT is accompanied by decreasing BTM
concentrations after 24months of CSHT. Therefore, the added value of evaluating BTMs seems
to be limited and DXA-scans remain important in follow-up of bone health of transgender
adolescents.

Annotation: Examines bone changes over time with puberty suppression and CSHT in TGNB
adolescents in a gender specialty clinic

Willemsen LA, Boogers LS, Wiepjes CM, et al. Just as Tall on Testosterone; a Neutral to Positive Effect on
Adult Height of GnRHa and Testosterone in Trans Boys. The Journal of clinical endocrinology and
metabolism. 2023;108(2):414-421. doi:10.1210/clinem/dgac571 Accessed September 15, 2023.
Available at https://watermark.silverchair.com/dgac571.pdf

Abstract: CONTEXT: Growth is an important topic for many transgender boys. However, few
studies have investigated the impact of puberty suppression (PS) and gender-affirming hormone
treatment (GAHT) on growth and adult height. OBJECTIVE: To evaluate the effect of PS and
GAHT on growth and adult height. DESIGN: Retrospective cohort study. SETTING: Specialized
gender identity clinic. PARTICIPANTS: A total of 146 transgender boys treated with GnRH
analogues and testosterone who reached adult height. MAIN OUTCOME MEASURES: Growth,
bone age (BA), adult height, and difference between adult height and predicted adult height
(PAH) and midparental height. RESULTS: In those with BA ≤14 years at start (n = 61), a decrease
in growth velocity and bone maturation during PS was followed by an increase during GAHT.
Adult height was 172.0 ± 6.9 cm; height SD score was similar to baseline (0.1; 95% CI, -0.2 to
0.4). Adult height was 3.9 ± 6.0 cm above midparental height and 3.0 ± 3.6 cm above PAH at
start of PS. A younger BA at start PS was associated with an adult height significantly further
above PAH. CONCLUSION: During PS, growth decelerated followed by an acceleration during
GAHT. Although adult height SD score was similar to baseline, adult height was taller than
predicted based on BA at baseline, especially in those who started treatment at a younger BA. It
is reassuring that PS and GAHT do not have a negative impact on adult height in transgender
boys and might even lead to a slightly taller adult height, especially in those who start at a
younger age.

Annotation: A longitudinal, pre-post descriptive study examining height and weight outcomes in
TGNB adolescent boys who initiated GnRH agonists before age 16 years.

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Eligible Studies Lacking High-priority Comparisons: Case Studies
(Bibliography Only) 3,5,17,18,23,27,35,38,40,49,53,62,64,78,80,82,83,86,96,107,119,134,138,142,146,147,155,164,174,182,189-191,194,198,209,218-220,224,232,233,237,250,274,277

Adeleye AJ, Stark BA, Jalalian L, Mok-Lin E, Smith JF. Evidence of Spermatogenesis in the Presence of
Hypothalamic Suppression and Low Testosterone in an Adolescent Transgender Female: A Case
Report. Transgender Health. 2023;8(1):104-107. doi:10.1089/trgh.2021.0034 Accessed
September 15, 2023. Available at https://www.liebertpub.com/doi/10.1089/trgh.2021.0034

Abstract: Objective: To report a novel case of semen cryopreservation after testicular sperm
extraction in an adolescent transgender female without cessation of gonadotropin-releasing
hormone (GnRH) agonist therapy and feminizing hormone therapy. Methods: This is a case
report of a 16-year-old transgender female using leuprolide acetate for 4 years and estradiol for
3 years requesting semen cryopreservation at the time of gender-affirming orchiectomy. She
desired to proceed without cessation of gender affirming hormone therapy. The patient’s
consent was obtained for written publication. Results: The patient underwent testicular sperm
extraction followed by orchiectomy. The sample was processed and cryopreserved in a 1:1 Test
Yolk Buffer. Multiple early and late spermatids were identified as well as spermatagonium in the
TESE specimen. Conclusion(s): Advanced spermatogenesis may occur in the presence of a GnRH
agonist. Cessation of GnRH agonist therapy may not be essential for semen cryopreservation in
adolescent transgender females.

Annotation: Examines treatment course and outcomes in a transgender female adolescent with
spermatogenesis during hypothalamic suppression and low testosterone

Akgül S, Tuzun Z, Pehlivanturk Kizilkan M, Ozon ZA. Menstrual Suppression in Gender Minority Youth. J
Clin Res Pediatr Endocrinol. 2022;14(4):463-468. doi:10.4274/jcrpe.galenos.2021.2020.0283
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/34044500

Abstract: The purpose of this case series was to evaluate menstrual suppression in sex assigned
at birth female adolescents identifying as male or gender non-conforming. A retrospective chart
review of four gender minority youth (GMY), age 14-17, was performed for gender identity
history, type and success of menstrual suppression, method satisfaction, side effects and
improvement in menstrual distress. Menstrual suppression was successful in three patients, one
patient discontinued use due to side effects that caused an increase in gender dysphoria.
Menstrual distress and bleeding pattern improved in the majority of GMY in this series but side
effects, as well as contraindications, may limit their use. In conclusion, menstrual dysphoria can
be life-threatening for GMY and it is important that clinicians consider menstrual suppression in
GMY with menstrual dysphoria. This series emphasizes the importance of individualized
treatment plans.

Annotation: A case series reporting on use of GnRHa for menstrual suppression in 4 Turkish
gender minority youth.

Barnard EP, Dhar CP, Rothenberg SS, et al. Fertility Preservation Outcomes in Adolescent and Young
Adult Feminizing Transgender Patients. Pediatrics. 2019;144(3)doi:10.1542/peds.2018-3943
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/31383814

Abstract: BACKGROUND: Fertility preservation enables patients undergoing gonadotoxic

therapies to retain the potential for biological children and now has broader implications in the

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 care of transgender individuals. Multiple medical societies recommend counseling on fertility
preservation before initiating therapy for gender dysphoria; however, outcome data pre- and
posttreatment are limited in feminizing transgender adolescents and young adults. METHODS:
The University of Pittsburgh Institutional Research Board approved this study. Data were
collected retrospectively on transgender patients seeking fertility preservation between 2015
and 2018, including age at initial consultation and semen analysis parameters. RESULTS: Eleven
feminizing transgender patients accepted a referral for fertility preservation during this time;
consultation occurred at median age 19 (range 16-24 years). Ten patients attempted and
completed at least 1 semen collection. Eight patients cryopreserved semen before initiating
treatment. Of those patients, all exhibited low morphology with otherwise normal median
semen analysis parameters. In 1 patient who discontinued leuprolide acetate to attempt fertility
preservation, transient azoospermia of 5 months' duration was demonstrated with subsequent
recovery of spermatogenesis. In a patient who had previously been treated with spironolactone
and estradiol, semen analysis revealed persistent azoospermia for the 4 months leading up to
orchiectomy after discontinuation of both medications. CONCLUSIONS: Semen cryopreservation
is a viable method of fertility preservation in adolescent and young adult transgender individuals
and can be considered in patients who have already initiated therapy for gender dysphoria.
Further research is needed to determine the optimal length of time these therapies should be
discontinued to facilitate successful semen cryopreservation.

Annotation: Reports fertility-preservation outcomes in TGNB patients, including 2 who were <
18 years of age at the fertility preservation consult, 4 who were < 18 at the time of their initial
GD consultation, and 7 who were < 18 at the time of GD onset.

Barthel EM, Werny DM, Hayden LL, Salehi P. Gender Affirming Hormone Replacement for the
Adolescent and Young Adult Cancer Survivor with Hypogonadism. J Adolesc Young Adult Oncol.
2020;9(1):128-131. doi:10.1089/jayao.2019.0070 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31580768

Abstract: Hypogonadism is a known late effect of cancer treatment. Hypogonadism requires

replacement of sex steroids to ensure appropriate development of secondary sex
characteristics, growth, and other beneficial health effects. We present a cancer survivor with
hypogonadotropic hypogonadism and gender dysphoria. The patient received gender affirming
care in our gender clinic with a multidisciplinary team that included an endocrinologist. This is
not an isolated case at our institution. Survivorship oncologists must include a discussion about
gender concurrently with conversations about survivors' development of puberty. Conversations
should start early to ensure appropriate referrals and gender affirming hormone replacement.

Annotation: A transgender female adolescent cancer survivor with hypogonadism in a pediatric

gender specialty clinic (no IRB).

Bentsianov S, Gordon L, Goldman A, Jacobs A, Steever J. Use of Copper Intrauterine Device in

Transgender Male Adolescents. Contraception. 2018;98(1):74-75.
doi:10.1016/j.contraception.2018.02.010 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29490287

Abstract: Transgender men need contraception if engaging in intercourse with a cis-gender male
partner. The copper IUD is an effective, non-hormonal contraceptive well suited for trans-males

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 even while utilizing gender affirming hormone therapy. A gender-neutral medical facility with
well-trained and sensitive staff is the ideal setting to provide such contraceptive care.

Annotation: A trio of case reports on use of hormones and copper IUDs in transgender young
men, including one that was age 17 upon presentation

Boris JR, McClain ZBR, Bernadzikowski T. Clinical Course of Transgender Adolescents with Complicated
Postural Orthostatic Tachycardia Syndrome Undergoing Hormonal Therapy in Gender Transition:
A Case Series. Transgend Health. 2019;4(1):331-334. doi:10.1089/trgh.2019.0041 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/31754630

Abstract: Purpose: Postural orthostatic tachycardia syndrome (POTS), an increasingly recognized

dysautonomia, may affect as many as 3,000,000 Americans. Concurrently, prevalence estimates
suggest 10% of individuals identify as lesbian, gay, bisexual, transgender, or questioning/queer.
The preponderance of female POTS patients implies hormonal differences between natal sexes
and their role in POTS. Transgender POTS patients using hormone therapies may offer further
insight into the mechanism of POTS. There have been no previously published studies of
transgender patients with POTS undergoing gender-affirming hormone therapy. Methods: We
reviewed our electronic health record for clinical histories of transgender patients in our POTS
Database. Results: Three patients who transitioned from female to male demonstrated clinical
improvement of their POTS symptoms with the addition of testosterone therapy. Conclusion:
We present our clinical experience of three transgender POTS patients who transitioned from
female to male with hormone therapy, all of whom demonstrated clinical improvement with
testosterone. This may give further insight into the pathophysiology of POTS. However, the
authors do not endorse the use of hormone therapy as primary therapy for the symptoms of
POTS.

Annotation: Transgender adolescents presenting with complicated POTS and undergoing

hormonal treatment

Campos-Munoz L, Lopez-De Lara D, Rodriguez-Rojo ML, Conde-Taboada A, Lopez-Bran E. Transgender

adolescents and acne: A cases series. Pediatr Dermatol. 2018;35(3):e155-e158.
doi:10.1111/pde.13448 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29575091

Abstract: We describe the difficulties of treating acne in a series of female-to-male transgender

adolescents, including concerns about potential hepatotoxicity with concomitant use of
testosterone with isotretinoin or tetracyclines. Acne is a foreseeable adverse effect of
testosterone treatment in transgender adolescents, so monitoring for acne is advised. The
treatment of acne in transgender adolescents is important given that severe acne and
transgenderism are associated with higher rates of depression and suicide.

Annotation: A pediatric case series reporting on transgender male adolescents presenting with
acne (no IRB)

Cesur E, Yuksel S, Basar K, Kaptan S. Clinical Follow-up of Two Adolescents Diagnosed with Gender
Dysphoria. Turk Psikiyatri Derg. 2022;33(3):214-219. doi:10.5080/u26795 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36148573

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 Abstract: Rapid physical, psychological and sexual changes in adolescents due to the
developmental process differentiate the approach to adolescents with gender dysphoria (GD)
from the approach to adults. In this article, two adolescents who applied for GD and followed up
for a long time are presented. The first case was assigned male at birth and defined herself as
female. At the age of fifteen, a gonadotropin-releasing hormone analog was started for puberty
suppression, and sex hormone was started in the follow-up. The second case's assigned sex was
female and defined himself as male. At the age of sixteen years and six months, puberty
suppressive treatment was started, followed by sex hormones. Both cases were able to continue
their psychosocial development without any problems after the psychiatric and physical
treatments they could reach on time. Although GD in adolescents cannot be resolved with
puberty suppression alone, it creates time to resolve the acute problems and to search for
appropriate treatment approaches in the future. Puberty suppression partially relieves and
prevents the exacerbation of the dysphoria experienced by the youth diagnosed as GD, and
creates time to search appropriate treatment approaches in the follow-up. Through these two
cases, it is aimed to introduce the gender affirmation processes of adolescents with GD, to
discuss the medical interventions in adolescence and the psychosocial effects of the process on
individuals. Keywords: Gender dysphoria, gender incongruence, adolescence, gender affirmation
process, puberty supression, puberty blockers.

Annotation: A pair of case reports of Turkish, transgender adolescents with long-term follow-up

Chen D, Bernardi LA, Pavone ME, Feinberg EC, Moravek MB. Oocyte cryopreservation among
transmasculine youth: a case series. J Assist Reprod Genet. 2018;35(11):2057-2061.
doi:10.1007/s10815-018-1292-4 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30136015

Abstract: None

Annotation: Examines fertility preservation outcomes in transmasculine youths undergoing

oocyte cryopreservation

Churcher Clarke A, Spiliadis A. 'Taking the lid off the box': The value of extended clinical assessment for
adolescents presenting with gender identity difficulties. Clin Child Psychol Psychiatry.
2019;24(2):338-352. doi:10.1177/1359104518825288 Accessed September 15, 2023. Available
at
https://www.embase.com/search/results?subaction=viewrecord&id=L627311211&from=export

Abstract: As the number of young people referred to specialist gender identity clinics in the
western world increases, there is a need to examine ways of making sense of the range and
diversity of their developmental pathways and outcomes. This article presents a joint case
review of the authors caseloads over an 18-month period, to identify and describe those young
people who presented to the Gender Identity Development Service (GIDS) with gender
dysphoria (GD) emerging in adolescence, and who, during the course of assessment, ceased
wishing to pursue medical (hormonal) interventions and/or who arrived at a different
understanding of their embodied distress. From the 12 cases identified, 2 case vignettes are
presented. Implications for the development of clinical practice, service delivery and research
are considered.

Annotation: A case series reporting on TGNB patients seen in the UK's Tavistock & Portman
Gender Identity Development Service (GIDS)

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Cohen-Kettenis PT, Schagen SE, Steensma TD, de Vries AL, Delemarre-van de Waal HA. Puberty
suppression in a gender-dysphoric adolescent: a 22-year follow-up. Arch Sex Behav.
2011;40(4):843-847. doi:10.1007/s10508-011-9758-9 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/21503817

Abstract: Puberty suppression by means of gonadotropin releasing hormone (GnRH) analogs is

considered a diagnostic aid in gender dysphoric adolescents. However, there are also concerns
about potential risks, such as poor outcome or post-surgical regret, adverse effects on metabolic
and endocrine status, impaired increment of bone mass, and interference with brain
development. This case report is on a 22-year follow-up of a female-to-male transsexual, treated
with GnRH analogs at 13 years of age and considered eligible for androgen treatment at age 17,
and who had gender reassignment surgery at 20 and 22 years of age. At follow-up, he indicated
no regrets about his treatment. He was functioning well psychologically, intellectually, and
socially; however, he experienced some feelings of sadness about choices he had made in a
long-lasting intimate relationship. There were no clinical signs of a negative impact on brain
development. He was physically in good health, and metabolic and endocrine parameters were
within reference ranges. Bone mineral density was within the normal range for both sexes. His
final height was short as compared to Dutch males; however, his body proportions were within
normal range. This first report on long-term effects of puberty suppression suggests that
negative side effects are limited and that it can be a useful additional tool in the diagnosis and
treatment of gender dysphoric adolescents.

Annotation: A case report following a Dutch adolescent who received puberty suppresion 22
years earlier.

Daniolos PT, Telingator CJ. Engendering identity. J Am Acad Child Adolesc Psychiatry. 2013;52(12):1245-
1247. doi:10.1016/j.jaac.2013.09.003 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/24290454

Abstract: None

Annotation: Case report of the clinical findings in one transgender male adolescent

Day DS, Saunders JJ, Matorin A. Gender Dysphoria and Suicidal Ideation: Clinical Observations from a
Psychiatric Emergency Service. Cureus. 2019;11(11):e6132. doi:10.7759/cureus.6132 Accessed
September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903884/pdf/cureus-0011-00000006132.pdf

Abstract: Adolescent gender dysphoria is increasingly common. There has been documentation
of the association of gender dysphoria with numerous other psychiatric conditions as well as
attempted and completed suicide. The literature is unsettled on specific risk factors for self-
harm within this population. Though there are published recommendations, there appears to be
a need for additional clinical evidence for the determination of the safest and most effective
treatment strategies for adolescent gender dysphoria. This clinical observation describes the
unique case of an adolescent with gender dysphoria, severe body dysmorphia, and suicidal
ideation who presented for emergency psychiatric evaluation. Gender-affirming hormone
therapy had been administered to this patient at the age of 13, well earlier than published
guidelines, though it was discontinued after a short course due to persistent gender uncertainty
and distress. This case provides an opportunity to consider the complexity of adolescent gender
dysphoria, including the unique individual features that affect the risk for self-harm and how

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 treatment history may be related. With an increasing prevalence of gender dysphoria in this
population, it is essential that every provider who cares for adolescents be well informed and
prepared to recognize and respond to these risks. Copyright © 2019, Day et al.

Annotation: A transgender boy presents to an academic emergency department with mental

health crisis after detransitioning

Donaldson AA, Hall A, Neukirch J, et al. Multidisciplinary care considerations for gender nonconforming
adolescents with eating disorders: A case series. Int J Eat Disord. 2018;51(5):475-479.
doi:10.1002/eat.22868 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29740834

Abstract: Gender nonconforming youth are at risk for body dissatisfaction and disordered
eating. Currently, only a small body of literature addresses this high-risk group. The five cases in
this series highlight important themes for this patient population from an interdisciplinary
perspective. Identified themes include increased risk for self-harm/suicide, complex psychiatric,
and medical implications of delay to treatment for either gender dysphoria or disordered eating,
and the importance of collaborative management to maximize care and facilitate healthy
development to adulthood. The purpose of this case series is to expand the interdisciplinary
discussion regarding the breadth of presentation and management considerations for gender
nonconforming adolescents with disordered eating. An interdisciplinary approach to care might
enhance access to comprehensive, collaborative treatment for disordered eating, and gender
dysphoria in this unique population.

Annotation: Eating disorders, suicidality, and self-harm behaviors in TGNB cases

Eisenberg L. Minor Patient, Major Decisions: Caring for a Rural Child With Gender Dysphoria. Am J
Bioeth. 2019;19(7):64-65. doi:10.1080/15265161.2019.1619346 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/31237514

Abstract: None

Annotation: A US-based case report of a transgender male adolescent (no IRB).

Expösito-Campos P, Gomez-Balaguer M, Hurtado-Murillo F, Garcia-Moreno RM, Morillas-Arino C.

Medical detransition following transgender identity reaffirmation: two case reports. Sex Health.
2022;18(6):498-501. doi:10.1071/SH21089 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34883041

Abstract: Background Recently, increased social and scientific attention has been paid to gender
detransition, a phenomenon in which individuals discontinue gender-affirming medical
interventions (GAMI) aimed at alleviating gender dysphoria (GD). Yet, clinical knowledge of
detransitioners and their experiences is still scarce. Case reports published in the literature
suggest that both internal and external factors may influence this decision. Methods Two
transgender individuals treated for GD at a gender identity unit presented with a desire to
discontinue GAMI. A description of their clinical evolution is presented. Results Increased body
satisfaction, self-esteem, self-acceptance, and self-empowerment with respect to their
transgender identity were mentioned by the patients as reasons for discontinuing gender-
affirming treatments. Coinciding factors included reduced GD, positive changes in social
environments, better interpersonal functioning, and higher levels of psychological well-being in

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 general. Conclusions Gender detransition is an under-researched phenomenon. These cases
highlight the need for a more nuanced approach to gender-related clinical presentations, which
involves providing individuals the opportunity to work on their social ecosystems and explore
alternative options to manage GD before initiating GAMI.

Annotation: Two case reports of Spanish transgender patients presenting for medical
detransition, one of whom was an AMAB adolescent

Fan EM, Gordner C, Luty J. Venous Thromboembolism in a Transgender Adolescent on Testosterone

Therapy: A Case Report and Literature Review. J Pediatr Hematol Oncol. 2020;42(5):e352-e354.
doi:10.1097/MPH.0000000000001755 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32079984

Abstract: The incidence of pediatric venous thromboembolism (VTE) has been increasing in the
past few decades and can be associated with significant mortality and morbidity. There are
known risk factors associated with VTE, including estrogen therapy. However, the relationship
between testosterone and VTE remains unclear. Here, we present a 17-year-old female-to-male
transgender patient without a history of inherited thrombophilia, who developed pulmonary
embolism while receiving testosterone injections for gender dysphoria. Despite the limited data
on testosterone and the risk of VTE, health care providers should counsel patients and family
about the possible increased risk of VTE when starting testosterone.

Annotation: A US-based case report of venous thromboembolism (VTE) in a transgender male

adolescent on testosterone therapy (no IRB).

Fung R, Greenaway MK, McEvenue G. Gynecomastia in a Transgender Boy: A Case Report. AACE clinical
case reports. 2021;7(6):350-352. doi:10.1016/j.aace.2021.05.003 Accessed September 15, 2023.
Available at https://www.aaceclinicalcasereports.com/article/S2376-0605(21)00065-1/pdf

Abstract: OBJECTIVE: To describe the case of a 17-year-old transgender boy who experienced
breast development while on testosterone, having been suppressed with a gonadotropin-
releasing hormone (GnRH) agonist prior to testosterone therapy., CASE REPORT: A 17-year-old
transgender boy presented with breast development after having been on a GnRH agonist and
then testosterone since the age of 11 years, having never experienced breast development
before, which was consistent with pubertal gynecomastia. A small decrease in the testosterone
dose resulted in a significant reduction of gynecomastia. Despite the improvement, he went on
to undergo chest surgery with the removal of the breast tissue., DISCUSSION: Pubertal
gynecomastia is a common phenomenon in the cisgender male population. However, it has not
been previously described in transgender boys. The potential mechanisms for its occurrence
were discussed., CONCLUSION: Transgender boys who undergo GnRH agonist treatment for
puberty suppression and subsequently receive testosterone therapy for puberty induction may
develop gynecomastia. Judicious adjustment of the testosterone therapy may lead to an
improvement. Copyright © 2021 AACE. Published by Elsevier Inc.

Annotation: A Toronto-based case report of a 17-year-old transgender boy experiencing

gynecomastia during ongoing testosterone therapy, after having received puberty suppression

Grimstad F, Moyer Q, Williams CR, Kremen J. A Body-Neutral and Gender-Neutral Modified Ferriman-
Gallwey Diagram. J Pediatr Adolesc Gynecol. 2022;35(3):375-378.

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 doi:10.1016/j.jpag.2021.10.015 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34748917

Abstract: BACKGROUND: The modified Ferriman-Gallwey (mFG) diagram for scoring hirsutism
uses images with traditionally Eurocentric feminine features. No reports have documented its
utility in patients with other gender identities. CASE: A 16-year-old nonbinary masculine patient,
assigned female sex at birth, was seen for hyperandrogenism and irregular menses. They
declined an exam, citing body dysphoria, and declined self-documenting on the mFG diagram,
expressing anxiety with gendered images. We subsequently developed a novel, gender-inclusive
mFG diagram, which the patient was then comfortable using to document their hair pattern.
SUMMARY AND CONCLUSION: This case documents how the binary gendered characteristics of
the mFG diagram can impact the care of patients. As gender expression is highly individual, we
created the first gender-inclusive version of the mFG diagram to enhance care for all patients.

Annotation: A US-based case report of hirsutism in a nonbinary masculine adolescent assigned

female at birth (no IRB).

Insogna IG, Ginsburg E, Srouji S. Fertility Preservation for Adolescent Transgender Male Patients: A Case
Series. J Adolesc Health. 2020;66(6):750-753. doi:10.1016/j.jadohealth.2019.12.004 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32001141

Abstract: This case series from a hospital-based academic in vitro fertilization clinic outlines the
feasibility of oocyte cryopreservation for transgender male adolescents after varying degrees of
exposure to pubertal blockers and/or testosterone. A description of each patient's oocyte
cryopreservation cycle is reviewed, including prior exposure to pubertal blockers and/or
testosterone, anti-Mullerian hormone level, stimulation medications, trigger injections, number
of oocytes retrieved and cryopreserved, and complications. All patients tolerated stimulation
and retrieval well and had mature oocytes cryopreserved in each cycle. There were no
complications. Adolescent transgender males who choose to undergo oocyte cryopreservation
tolerate the process well, reinforcing the importance of fertility preservation in providing
comprehensive care for transgender patients.

Annotation: Describes fertility-preservation outcomes in transgender males presenting for a

fertility consultation. Authors did not report gender identities for most subjects, but all subjects
were AFAB.

Khazal S, Abdel-Azim H, Kapoor N, Mahadeo KM. Overcoming psychosocial and developmental barriers
to blood and marrow transplantation (BMT) in an adolescent/young adult (AYA) transgender
patient with chronic myelogenous leukemia. Pediatr Hematol Oncol. 2014;31(8):765-767.
doi:10.3109/08880018.2014.909914 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/24854505

Abstract: Adolescents/young adults (AYAs) afflicted with cancer face unique barriers to
potentially standard curative therapies, such as blood and marrow transplantation (BMT).
Transgender AYAs face additional barriers and there is a dearth of published literature regarding
their oncology-related experience. We present the case of an AYA male-to-female (MTF)
transgender patient on cross-sex hormone therapy, with a history of Chronic Myelogenous
Leukemia (CML) and significant psychosocial barriers, which initially served as a barrier to BMT
at two different centers; we modified our standard consent and education process and was able
to successfully proceed with BMT and subsequently cure her CML. Despite unique challenges,

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 AYA and transgender patients with significant psychosocial barriers may achieve successful
outcomes with BMT. Research is needed regarding guidelines for cross-sex hormone therapy
administration for patients undergoing BMT and other issues, which may be unique to the
transgender experience.

Annotation: A US-based case report on a transgender adolescent with chronic myelogenous

leukemia (CML) (no IRB).

Lee G, Ferri-Huerta R, Greenberg KB, Somers KE. Acne fulminans in a transgender boy after an increase
in testosterone dosage. JAAD Case Rep. 2022;21:32-34. doi:10.1016/j.jdcr.2021.11.029 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/35141385

Abstract: None

Annotation: Acne fulminans in a transgender boy receiving testosterone CSHT

Lin AJ, Baranski T, Chaterjee D, Chapman W, Foltz G, Kim H. Androgen-receptor-positive hepatocellular

carcinoma in a transgender teenager taking exogenous testosterone. Lancet.
2020;396(10245):198. doi:10.1016/S0140-6736(20)31538-5 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32682485

Abstract: None

Annotation: A 17-year-old, testosterone-treated transgender male presenting with androgen-

receptor positive hepatocellular carcinoma

Lopez X, Stewart S, Jacobson-Dickman E. Approach to Children and Adolescents with Gender Dysphoria.
Pediatr Rev. 2016;37(3):89-96; quiz 97-88. doi:10.1542/pir.2015-0032 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/26933223

Abstract: None

Annotation: A potential US-based case report of an adolescent presenting with gender

dysphoria (no IRB).

Margolin EA, Mason RH. Female-to-male transgender patient with idiopathic intracranial hypertention. J
Neurol Sci. 2020;415:116970. doi:10.1016/j.jns.2020.116970 Accessed June 28, 2023. Available
at https://www.ncbi.nlm.nih.gov/pubmed/32521344

Abstract: None

Annotation: A Toronto-based case of a transgender male adolescent with idiopathic intracranial

hypertension (no IRB).

Martin CE, Lewis C, Omurtag K. Successful oocyte cryopreservation using letrozole as an adjunct to
stimulation in a transgender adolescent after GnRH agonist suppression. Fertil Steril.
2021;116(2):522-527. doi:10.1016/j.fertnstert.2021.02.025 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33795140

Abstract: OBJECTIVE: To report a successful case of ovarian hyperstimulation and oocyte

cryopreservation in a transgender male adolescent after suppression with a gonadotropin-
releasing hormone (GnRH) agonist while using the aromatase inhibitor letrozole to maintain low

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 serum estradiol. DESIGN: Case report. SETTING: Division of Reproductive Endocrinology and
Infertility, Washington University in St. Louis School of Medicine, St Louis, Missouri. PATIENT(S):
A 15-year-old Tanner II transgender male adolescent with a GnRH agonist implant.
INTERVENTION(S): The GnRH agonist implant was removed. The patient was given letrozole (5
mg daily) while undergoing ovarian stimulation with an antagonist protocol. After oocyte
retrieval, the patient began taking testosterone. MAIN OUTCOME MEASURE(S): Successful
oocyte cryopreservation with minimal changes in breast budding. RESULT(S): The patient's peak
serum estradiol concentration was 510 pg/mL. Twenty-two mature oocytes were cryopreserved.
Small increases in breast budding occurred between baseline and the time of oocyte retrieval.
CONCLUSION(S): We successfully used letrozole to maintain low serum estradiol in a
transgender male adolescent during ovarian stimulation. Maintaining low estradiol to minimize
pubertal development and possibly prevent gender dysphoria symptoms may make oocyte
cryopreservation more desirable for transgender male adolescents.

Annotation: A US-based case report of successful oocyte cryopreservation in a transgender

male adolescent (no IRB).

Maxwell S, Noyes N, Keefe D, Berkeley AS, Goldman KN. Pregnancy Outcomes After Fertility
Preservation in Transgender Men. Obstet Gynecol. 2017;129(6):1031-1034.
doi:10.1097/AOG.0000000000002036 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28486372

Abstract: BACKGROUND: Transgender individuals, individuals whose gender identity does not
align with their sex assigned at birth, undergoing gender-affirming hormonal or surgical
therapies may experience loss of fertility. Assisted reproductive technologies have expanded
family-building options for transgender men who were assigned female at birth. CASES: Three
transgender men underwent oocyte cryopreservation before gender-affirming hormonal
therapy. One patient underwent fertility preservation as an adolescent. Two adult patients had
children using their cryopreserved oocytes, with the pregnancies carried by their sexually
intimate partners. CONCLUSION: Transgender men with cryopreserved gametes can build
families in a way that affirms their gender identity. Obstetrician-gynecologists should be familiar
with the fertility needs of transgender patients so appropriate discussions and referrals can be
made.

Annotation: A New York-based case series reporting on pregnancy outcomes in 3 transgender

men (1 adolescent) who underwent fertility preservation

Millington K, Hayes K, Pilcher S, et al. A serous borderline ovarian tumour in a transgender male
adolescent. Br J Cancer. 2021;124(3):567-569. doi:10.1038/s41416-020-01129-4 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33106582

Abstract: Here we present a transgender male adolescent with an androgen receptor-positive

serous borderline ovarian tumour in the setting of testosterone treatment for medical gender
transition. To our knowledge, this is the second report of borderline tumour in a transgender
individual and the first in an adolescent, an age group in which borderline tumours are
extremely rare. We discuss the specific considerations of treating ovarian tumours in the
transgender male population, the incompletely understood role of androgens in the genesis of
ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients
based on patient anatomy.

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 Annotation: A transgender male adolescent on CSHT with a serous borderline ovarian tumor

Nayman T, Hebert M, Ospina LH. Idiopathic intracranial hypertension in a pediatric transgender patient.
Am J Ophthalmol Case Rep. 2021;24:101208. doi:10.1016/j.ajoc.2021.101208 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/34622090

Abstract: PURPOSE: Androgens given for gender affirmation have been implicated in the
pathophysiology of idiopathic intracranial hypertension (IIH) in transgender patients. 10 cases of
transgender adults with IIH have been published but this association has not been described in
younger patients. Herein we describe the first case of IIH in an adolescent transgender patient.
OBSERVATIONS: A 17-year-old non-obese female-to-male transgender patient on subcutaneous
testosterone since age 13 presented with a two-month history of transient visual obscuration
and frontal headaches. Ophthalmological examination revealed Frisen grade 2 papilledema with
preserved visual function. Lumbar puncture confirmed elevated opening pressure. Papilledema
resolved with oral acetazolamide and reduction of testosterone therapy. CONCLUSIONS AND
IMPORTANCE: The use of cross-sex hormone therapy (CSH) for gender affirmation may increase
the risk of IIH. Awareness of this association is important as the number of younger transgender
patients seeking CSH is increasing significantly.

Annotation: A case report of intracranial hypertension in a 17-year-old transgender male

O'Connell MA, Nguyen TP, Ahler A, Skinner SR, Pang KC. Approach to the Patient: Pharmacological
Management of Trans and Gender-Diverse Adolescents. J Clin Endocrinol Metab.
2022;107(1):241-257. doi:10.1210/clinem/dgab634 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34476487

Abstract: Internationally, increasing numbers of children and adolescents with gender dysphoria
are presenting for care. In response, gender-affirming therapeutic interventions that seek to
align bodily characteristics with an individual's gender identity are more commonly being used.
Depending on a young person's circumstances and goals, hormonal interventions may aim to
achieve full pubertal suppression, modulation of endogenous pubertal sex hormone effects,
and/or development of secondary sex characteristics congruent with their affirmed gender. This
is a relatively novel therapeutic area and, although short-term outcomes are encouraging,
longer term data from prospective longitudinal adolescent cohorts are still lacking, which may
create clinical and ethical decision-making challenges. Here, we review current treatment
options, reported outcomes, and clinical challenges in the pharmacological management of
trans and gender-diverse adolescents.

Annotation: A pair of case reports, including one transfeminine and one transmasculine
adolescent

Pang KC, Nguyen TP, Upreti R. Case Report: Successful Use of Minoxidil to Promote Facial Hair Growth in
an Adolescent Transgender Male. Front Endocrinol (Lausanne). 2021;12:725269.
doi:10.3389/fendo.2021.725269 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34659117

Abstract: Increasing numbers of trans and gender diverse young people are presenting to health
services seeking gender-affirming medical care. While testosterone therapy in transgender
males is generally effective in inducing masculinization, some adolescents encounter barriers to
accessing such treatment or may not wish to experience all the changes that usually accompany

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 testosterone. Here, we describe the case of a 17 year old trans male who presented with gender
dysphoria but was initially unable to start testosterone therapy. Due to a desire for facial hair,
he was therefore treated with topical minoxidil, an easily accessible, over-the-counter
medication that has been used to treat androgenic alopecia for several decades. In this case,
minoxidil was applied regularly to the lower face and, after three months of treatment, he
developed obvious pigmented facial hair that was sufficient to help him avoid being
misgendered. The only reported side effect was excessive skin dryness. Unexpectedly, despite
no direct application to other areas, there was also an increase in pigmented body hair,
suggestive of systemic absorption and effect. Given its long-standing use and safety record in
the management of alopecia, minoxidil might thus represent a useful treatment option for trans
males who desire an increase in facial hair.

Annotation: A case report of minoxidil use to promote facial hair growth in a transgender male
adolescent

Pang KC, Notini L, McDougall R, et al. Long-term Puberty Suppression for a Nonbinary Teenager.
Pediatrics. 2020;145(2)doi:10.1542/peds.2019-1606 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31974217

Abstract: Many transgender and gender-diverse people have a gender identity that does not
conform to the binary categories of male or female; they have a nonbinary gender. Some
nonbinary individuals are most comfortable with an androgynous gender expression. For those
who have not yet fully progressed through puberty, puberty suppression with gonadotrophin-
releasing hormone agonists can support an androgynous appearance. Although such treatment
is shown to ameliorate the gender dysphoria and serious mental health issues commonly seen in
transgender and gender-diverse young people, long-term use of puberty-suppressing
medications carries physical health risks and raises various ethical dilemmas. In this Ethics
Rounds, we analyze a case that raised issues about prolonged pubertal suppression for a patient
with a nonbinary gender.

Annotation: A case report describing outcomes in a nonbinary patient receiving long-term

puberty suppression

Parikh N, Chattha A, Gargollo P, Granberg C. Fertility Preservation: A Tale of Two Testicles. Urology.
2021;153:298-300. doi:10.1016/j.urology.2020.11.011 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33221414

Abstract: OBJECTIVE: The transgender population has long been marginalized by society.
Societal stigmata, fear to seek care, and dearth of provider knowledge regarding transgender
health issues has caused disparities to widen. The purpose of this case study is to call to
attention the often-overlooked aspect of transgender care: the importance of fertility
preservation prior to undergoing therapy. METHODS: 13 and 16-year old genetically XY patients
presented to a tertiary care facility for gender affirmation. Both self-identified as female since a
young age and successfully socially transitioned. Impending onset and/or progression of puberty
prompted patients to seek hormonal therapy. Fortunately, physicians in transgender clinic were
aware of fertility struggles after undergoing hormone therapy and referred for consultation.
RESULTS: Sperm cryopreservation via open gonadal biopsy, tissue cryopreservation, and semen
sample were discussed. Though invasive, biopsy relieves patients of the psychological impact of
sample production and is indicated in pubertal immaturity. After further discussion with

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 patients and parents, the 13-year-old decided to undergo testicular biopsy while the 16-year old
opted for semen sample. Both patients had success and their genetic material was
cryopreserved for future assisted reproduction. CONCLUSION: Gender affirming procedures and
hormone therapy affect the long-term reproductive potential of transgender individuals. While
cost concerns and insurance coverage regarding oncofertility is a prominent area of discussion,
the transgender community is often excluded. With more individuals beginning medical and
surgical therapy at a younger age, fertility preservation discussions are essential but often
overlooked, depriving these individuals the joy of becoming a biological parent.

Annotation: Transgender females undergoing sperm cryopreservation

Penney SW, Jung JH, Ballantyne AJ, Parekh DS, Klein DA, Viola SA. Affirming Hormone Treatment for a
Transgender Adolescent After a Venous Thromboembolic Event. J Pediatr Hematol Oncol.
2022;44(5):E892-E895. doi:10.1097/MPH.0000000000002442 Accessed September 15, 2023.
Available at
https://www.ingentaconnect.com/content/wk/jpho/2022/00000044/00000005/art00019

Abstract: Background: Medical affirmation, including gender-affirming hormones, is an essential

component in the treatment of many transgender and gender-diverse youth. The risk of venous
thromboembolism (VTE) during testosterone therapy for gender-affirming care is not fully
elucidated. Observation: The case describes a 17-year-old transgender male treated with
testosterone therapy who presented with an occlusive deep vein thrombosis of right axillary and
subclavian veins. Testosterone level was 920 ng/dL at the time of the deep vein thrombosis, and
he had no risk factors for VTE. A complete hypercoagulable workup was negative. Conclusions:
The possibility of testosterone therapy as a risk factor for VTE may suggest the need to include
this information during informed consent discussions. Long-term anticoagulation may be
considered for those restarting testosterone therapy.

Annotation: A 17 year-old transgender male diagnosed with VTE who went on to receive
testosterone therapy

Pham A, Kasenic A, Hayden L, et al. A Case Series on Disordered Eating Among Transgender Youth With
Autism Spectrum Disorder. J Adolesc Health. 2021;68(6):1215-1219.
doi:10.1016/j.jadohealth.2020.12.143 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33707147

Abstract: Transgender youth with autism spectrum disorder (ASD) may experience complex
relationships with eating because of cognitive rigidity, including inflexible thoughts and
behaviors around food and/or their body. Yet, there is no research that provides guidance to
clinicians providing care for youth with the unique triad of gender dysphoria, ASD, and
disordered eating. This case series discusses trends in presentation and management of three
cases from a multidisciplinary gender care clinic. All three individuals endorsed rigid thoughts
around food and/or body appearance, which affected nutritional intake; however, their
presenting eating disorder behaviors, described etiology for disordered thoughts, diagnosis, and
level of engagement in a multidisciplinary treatment model varied. Based on these cases we
hypothesize several strategies including early engagement with ASD specialists, proactive
screening and discussions around eating with all transgender youth with suspected/confirmed
ASD, continued discussions throughout care, as disordered eating behaviors may change after
the initiation of gender-affirming medications, dietician visits early in treatment regardless of

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 endorsed thoughts and behaviors, tailored management to the unique needs of each individual
and their eating thoughts/behaviors, and consistent multidisciplinary collaboration.

Annotation: A trio of clinical cases of autistic, transgender, pediatric patients with eating
disorders

Ristori J, Fisher AD, Castellini G, et al. Gender Dysphoria and Anorexia Nervosa Symptoms in Two
Adolescents. Arch Sex Behav. 2019;48(5):1625-1631. doi:10.1007/s10508-019-1396-7 Accessed
September 15, 2023. Available at https://link.springer.com/article/10.1007/s10508-019-1396-7

Abstract: The co-occurrence of gender dysphoria and anorexia nervosa has been described in
the scientific literature. This paper presents two adolescents with gender dysphoria and
pathological eating behaviors and questions with longitudinal observations the clinical meaning
of anorexia nervosa symptoms (e.g., restricting eating behaviors and fear of gaining weight) in
adolescents with gender dysphoria. Both received psychological evaluations at different times:
at first admission to the gender dysphoria clinic (T0) and 6 months after starting treatment with
gonadotropin-releasing analogues (GnRHa; T1). In both cases, treatment with GnRHa not only
improved psychological functioning, but also resolved pathological eating behaviors. In fact,
both adolescents reported quick restoring of healthy food habits with restricting eating
behaviors as well as intensive exercise no longer needed after treatment with GnRHa.
Therefore, pathological eating behaviors (e.g., food avoidance and weight loss) could be
assessed as a dysfunctional coping strategy adopted to gain control over a body developing in an
unwanted direction and to block irreversible physical pubertal changes. This psychopathological
conceptualization of pathological eating behaviors in adolescents with gender dysphoria
stresses the importance of providing, in selected cases, early medical intervention such as
pubertal suppression with GnRHa. Mental health professionals should therefore perform a
specific and detailed assessment on gender identity within the evaluation of apparent eating
disorders in adolescents. Restrictive eating behaviors as well as the intense fear of gaining
weight or of becoming fat may, in fact, be considered secondary to a gender dysphoria diagnosis
instead of anorexia nervosa symptoms.

Annotation: A pair of case reports about the occurrence of anorexia nervosa in TGNB
adolescents

Salvatore L, Dancyger I, Shadianloo S, Fornari V. Caring for Transgender Youth with Eating Disorders in a
Day Treatment Program. Adolesc Psychiatry. 2022;12(3):196-206.
doi:10.2174/2210676613666221027124554 Accessed June 28, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L2018683391&from=expo
rt

Abstract: Background: The treatment of transgender youth with an eating disorder presents
particular considerations due to the unique combination of body dissatisfaction, drive for
thinness, malnutrition coupled with the evolving gender identity in the midst of biological and
physical changes. At this time, public awareness, societal acknowledgment and legislative
initiatives have led to wider acceptance of Lesbian, Gay, Bi-sexual and Transgender rights.
However, at the same time, transgender youth are at increased risk for mental health problems,
including eating disorders. Objective: To describe two cases of trans adolescents with anorexia
nervosa treated in a day treatment program. Methods: This paper will discuss the two clinical
vignettes of the transgender adolescent with anorexia nervosa. The focused care included

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 specific attention to the initial disclosure of gender identity in a safe space, name and pronoun
preferences, and wardrobe and hairstyle changes. In addition, treatment focused on the
reduction of social anxiety around meal consumption, with special attention given to the impact
of weight on the development of secondary sex characteristics. Themes of identity, rejection
and secrecy were explored. Conclusion: In summary, treating transgender youth with anorexia
nervosa requires additional considerations is more complex than treating cis gender youth.
Additional issues, such as hormonal treatments, the development of secondary sexual
characteristics, and social and cultural factors, can exacerbate eating disorder symptoms.
Treatment should focus on understanding the disorder's etiology and trajectory within this lens.

Annotation: Anorexia nervosa in transgender females who were ages < 18 years when they first
sought treatment, but who were seen for eating disorders in a tertiary care center

Sanchez Lorenzo I, Mora Mesa JJ, Oviedo de Lucas O. Psychomedical care in gender identity dysphoria
during adolescence. Revista de psiquiatria y salud mental. 2017;10(2):96-103.
doi:10.1016/j.rpsm.2015.04.002 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/26055932

Abstract: INTRODUCTION: In the clinical literature, the term gender dysphoria is used to define
the perception of rejection that a person has to the fact of being male or female. In children and
adolescents, gender identity dysphoria is a complex clinical entity. The result of entity is variable
and uncertain, but in the end only a few will be transsexuals in adulthood., OBJECTIVES:
METHODOLOGY: RESULTS AND CONCLUSIONS. Copyright © 2015 SEP y SEPB. Publicado por
Elsevier Espana, S.L.U. All rights reserved.

Annotation: A Spanish clinical case report on the presentation, assessment, findings, and
treatment of a 16-year-old transgender boy

Sayeem M, Carter B, Phulwani P, Zempsky WT. Gender Dysphoria and Chronic Pain in Youth. Pediatrics.
2021;148(4)doi:10.1542/peds.2021-050128 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34561268

Abstract: Chronic pain in youth with gender dysphoria (GD) is poorly understood. The aim of our
study was to review the clinical presentation of 8 youth with GD in a multidisciplinary chronic
pain clinic. A single center retrospective chart review was conducted to obtain information on
demographics, clinical care, previous diagnoses, and validated clinical measures. We present the
trajectory of pain in this population with treatment of GD. Recognition and treatment of GD in
youth with pain may improve pain outcomes.

Annotation: Describes pain and functionality outcomes in TGNB youths with gender dysphoria
presenting in a pain clinic

Schneider MA, Spritzer PM, Soll BMB, et al. Brain Maturation, Cognition and Voice Pattern in a Gender
Dysphoria Case under Pubertal Suppression. Front Hum Neurosci. 2017;11:528.
doi:10.3389/fnhum.2017.00528 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29184488

Abstract: Introduction: Gender dysphoria (GD) (DMS-5) is a condition marked by increasing

psychological suffering that accompanies the incongruence between one's experienced or
expressed gender and one's assigned gender. Manifestation of GD can be seen early on during

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 childhood and adolescence. During this period, the development of undesirable sexual
characteristics marks an acute suffering of being opposite to the sex of birth. Pubertal
suppression with gonadotropin releasing hormone analogs (GnRHa) has been proposed for
these individuals as a reversible treatment for postponing the pubertal development and
attenuating psychological suffering. Recently, increased interest has been observed on the
impact of this treatment on brain maturation, cognition and psychological performance.
Objectives: The aim of this clinical report is to review the effects of puberty suppression on the
brain white matter (WM) during adolescence. WM Fractional anisotropy, voice and cognitive
functions were assessed before and during the treatment. MRI scans were acquired before, and
after 22 and 28 months of hormonal suppression. Methods: We performed a longitudinal
evaluation of a pubertal transgender girl undergoing hormonal treatment with GnRH analog.
Three longitudinal magnetic resonance imaging (MRI) scans were performed for diffusion tensor
imaging (DTI), regarding Fractional Anisotropy (FA) for regions of interest analysis. In parallel,
voice samples for acoustic analysis as well as executive functioning with the Wechsler
Intelligence Scale (WISC-IV) were performed. Results: During the follow-up, white matter
fractional anisotropy did not increase, compared to normal male puberty effects on the brain.
After 22 months of pubertal suppression, operational memory dropped 9 points and remained
stable after 28 months of follow-up. The fundamental frequency of voice varied during the first
year; however, it remained in the female range. Conclusion: Brain white matter fractional
anisotropy remained unchanged in the GD girl during pubertal suppression with GnRHa for 28
months, which may be related to the reduced serum testosterone levels and/or to the patient's
baseline low average cognitive performance.Global performance on the Weschler scale was
slightly lower during pubertal suppression compared to baseline, predominantly due to a
reduction in operational memory. Either a baseline of low average cognition or the hormonal
status could play a role in cognitive performance during pubertal suppression. The voice pattern
during the follow-up seemed to reflect testosterone levels under suppression by GnRHa
treatment.

Annotation: Describes brain maturation, cognition, and voice pattern in a patient with GD
receiving GnRH agonist therapy for puberty suppression

Shumer DE, Tishelman AC. The Role of Assent in the Treatment of Transgender Adolescents. Int J
Transgend. 2015;16(2):97-102. doi:10.1080/15532739.2015.1075929 Accessed September 15,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/27175107

Annotation: Ethics of assent to treatment in a transgender female patient.

Silverstein L, Zander E, Middleman AB. Adolescent identity: The importance of the social history. SAGE
Open Med Case Rep. 2020;8:2050313X20952980. doi:10.1177/2050313X20952980 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32922796

Abstract: This is a unique case of a patient with trichotillomania, depression, and anxiety for 2
years, serving as coping strategies for underlying gender dysphoria. To our knowledge, a case of
a patient presenting with this unique constellation of comorbid conditions has not previously
been reported. This case stresses the importance of providers obtaining a full social history
consistently and repeatedly while providing a nonjudgmental environment for patients to
disclose sensitive and potentially fluid information related to gender identity and sexuality.

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 Annotation: A transmasculine adolescent with gender dysphoria and comorbid trichotillomania,
depression, and anxiety

Stanley K, Cooper J. Hormone Therapy and Venous Thromboembolism in a Transgender Adolescent. J

Pediatr Hematol Oncol. 2018;40(1):e38-e40. doi:10.1097/MPH.0000000000000984 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/28945660

Abstract: Venous thromboembolism can be precipitated by both genetic and acquired factors,
but the role of testosterone therapy is less clear. Here, we present a 17-year-old transgender
adolescent, transitioning from female to male, receiving both estrogen and testosterone
therapy, who developed a pulmonary embolism without an underlying genetic thrombophilic
condition. As transgender medical care evolves, the use of testosterone as cross-sex hormone
therapy in adolescents is likely to increase. Our review suggests that care must be taken when
initiating treatment with testosterone, and modification of other thrombophilic risks should be
explored before starting therapy in this population.

Annotation: A 17-year-old transgender male presenting with venous thromboembolism

Turban JL, Carswell J, Keuroghlian AS. Understanding Pediatric Patients Who Discontinue Gender-
Affirming Hormonal Interventions. JAMA Pediatr. 2018;172(10):903-904.
doi:10.1001/jamapediatrics.2018.1817 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30178056

Abstract: None

Annotation: A transfeminine child's clinical presentation and treatment with histrelin for
puberty suppression at age 15 and estrogen CSHT at age 16

Wolf-Gould CS, Riley MR, Carswell JM. A Trans-Feminine Youth with a BRCA1 Mutation: Case Study.
LGBT health. 2018;5(4):270-272. doi:10.1089/lgbt.2017.0148 Accessed September 15, 2023.
Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L626215648&from=export

Annotation: Reports on one US-based, transfeminine youth with a BRCA-1 mutation

Zupanič S, Kruljac I, Sostaric Zvonar M, Drobnic Radobuljac M. Case Report: Adolescent With Autism and
Gender Dysphoria. Front Psychiatry. 2021;12:671448. doi:10.3389/fpsyt.2021.671448 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/34122187

Abstract: There is increasing clinical evidence of an association between gender variability,

gender dysphoria (GD), and autism spectrum disorder (ASD). This seems to be a two-way
relationship, a person with GD is more likely to be diagnosed with ASD and vice versa. In youth,
it is important to distinguish whether the presented symptoms are a manifestation of ASD focus
on special interests or symptoms of co-occurring GD. This distinction is crucial in the process of
planning reversible and especially irreversible medical procedures in the context of treatment.
We present the case of a birth-assigned female adolescent with GD, who enrolled in our clinic at
the age of 16.5 years with "being transgender" as her main complaint accompanied by a wish
for surgical breast removal. His (as the patient prefers to use male pronouns) medical and
developmental history involved obesity, hyperlipidemia, delays in social and language
development and specific interests and rituals. He presented with half a year of untreated

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 depression, suicidal thoughts and non-suicidal self-injuring, social phobia and relative social
isolation. Comprehensive clinical assessments revealed a female karyotype (46, XX), normal
female genitalia and unremarkable hormonal status. Clinical psychological assessments reported
GD, ASD with average intellectual abilities and co-occurring symptoms of depression and
anxiety. Other disorders, such as psychosis, personality disorder and dysmorphophobia, were
excluded during longer-term diagnostic and psychotherapeutic processes. Our first aim was to
build a good therapeutic alliance with the patient and treat depression and suicidality. He
refused to take sertraline, but took a St. John's Wort over-the-counter peroral preparation in the
form of infusions. His mood improved, he was no longer suicidal and started social transitioning,
yet he remained socially phobic. At the time of writing, he is 20 years old, waiting for bilateral
mastectomy and receiving regular triptorelin depot and testosterone depot intramuscular
injections. Even though the diagnostic procedures and transition process in autistic gender
diverse adolescents may take longer than in non-autistic individuals, ASD is not a
contraindication to the gender transition process. We present a well-documented case of a slow
social and medical transition resulting in gradual improvement of co-occurring symptoms of GD.

Annotation: A case report of a transgender male adolescent with autism

Eligible Studies Lacking High-priority Comparisons: Descriptive Studies

without Pre-post Comparisons (Bibliography Only)
1,28,29,33,43,50,51,61,69,88,90,97,99,103,105,114,117,127,139,140,153,156,168,170,181,184,192,197,201,202,205,208,231,236,239,240,242,257,264,265,267,269-271

Abu-Ghname A, Grome L, Raj S, Axelrad ME, Chapman SG. Health Care Services Utilization by
Transgender Patients in a Medicaid Managed Program. J Health Care Poor Underserved.
2021;32(1):435-448. doi:10.1353/hpu.2021.0033 Accessed September 15, 2023. Available at
https://muse.jhu.edu/article/783119

Abstract: While challenges related to health care utilization among transgender individuals have
been discussed, studies examining health services under Medicaid are limited. A retrospective
review was performed on all patients who presented with Gender Dysphoria from 2013-2018 to
one Medicaid managed program. Utilization rates of distinct services and interventions were
analyzed. A total of 192 patients, with 787 encounters, were identified. Mean patient age was
15 years old. Mean number of encounters per patient was 4.1. The average number of distinct
specialties seen was 1.4. Behavioral health (BH) services were most commonly utilized (50%).
Endocrinology and surgical services were encountered less frequently. Medications were
prescribed for 25% of patients; hormonal treatment was prescribed for 6.7%. This study
highlights the deficiencies in services this population is receiving under one managed Medicaid
program. While behavioral health services are widely employed, underutilization of medical and
surgical consultations compromises patient awareness of available interventions.

Annotation: Examines GD-related utilization in a cohort of TGNB adolescents seen in a state-

managed Medicaid program. Affirmed genders were not reported, only natal sexes (N = 70
AMAB and N = 122 AFAB).

Brik T, Vrouenraets L, de Vries MC, Hannema SE. Trajectories of Adolescents Treated with
Gonadotropin-Releasing Hormone Analogues for Gender Dysphoria. Arch Sex Behav.
2020;49(7):2611-2618. doi:10.1007/s10508-020-01660-8 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32152785

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 Abstract: Gonadotropin-releasing hormone analogues (GnRHa) are recommended as initial
treatment for adolescents diagnosed with gender dysphoria, providing time to follow gender
identity development and consider further treatment wishes without distress caused by
unwanted pubertal changes. This has been described as an extended diagnostic phase.
However, there are also concerns about the physical, neurocognitive, and psychosocial effects
of this treatment. In this retrospective study, we document trajectories after the initiation of
GnRHa and explore reasons for extended use and discontinuation of GnRHa. Treatment was
considered appropriate in 143 (67%) of the 214 adolescents eligible for GnRHa treatment by
virtue of their age/pubertal status, and all started GnRHa (38 transgirls, 105 transboys; median
age, 15.0 years [range, 11.1-18.6] and 16.1 years [range, 10.1-17.9]). After a median duration of
0.8 years (0.3-3.8) on GnRHa, 125 (87%) started gender-affirming hormones (GAH). Nine (6%)
discontinued GnRHa, five of whom no longer wished gender-affirming treatment. Thirteen had
used GnRHa for longer than required by protocol for reasons other than logistics and regularly
met with a mental health professional during this time, supporting the use of GnRHa treatment
as an extended diagnostic phase. In conclusion, the vast majority who started GnRHa proceeded
to GAH, possibly due to eligibility criteria that select those highly likely to pursue further gender-
affirming treatment. Due to the observational character of the study, it is not possible to say if
GnRHa treatment itself influenced the outcome. Few individuals discontinued GnRHa, and only
3.5% no longer wished gender-affirming treatment.

Annotation: A Dutch descriptive study examining GnRHa treatment trajectories in n=143 TGNB
adolescents

Brik T, Vrouenraets L, Schagen SEE, Meissner A, de Vries MC, Hannema SE. Use of Fertility Preservation
Among a Cohort of Transgirls in the Netherlands. J Adolesc Health. 2019;64(5):589-593.
doi:10.1016/j.jadohealth.2018.11.008 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30691936

Abstract: PURPOSE: The primary aims of the study are to examine the rate of attempted fertility
preservation (FP) among a Dutch cohort of transgirls who started gonadotropin-releasing
hormone analog treatment and the reasons why adolescents did or did not choose to attempt
FP. METHODS: The study was a single-center retrospective review of medical records of 35
transgirls who started gonadotropin-releasing hormone analog treatment between 2011 and
2017. RESULTS: Ninety-one percent of adolescents were counseled on the option of FP. Thirty-
eight percent of counseled adolescents attempted FP, and 75% of them were able to
cryopreserve sperm suitable for intrauterine insemination or intracytoplasmic sperm injection.
Younger and Caucasian transgirls were less likely to attempt FP. No specific reason for declining
FP was known in 33% adolescents, 32% of adolescents were not able to produce a semen
sample because of early puberty, 17% felt uncomfortable with masturbation, 17% did not want
to have children, and 13% wanted to adopt. CONCLUSIONS: One third of adolescents attempted
FP, which is much more than the percentage reported in previous studies from the United
States. One third of the transgirls could not make use of FP because they were unable to
produce a semen sample because of early pubertal stage. For these adolescents, alternatives
need to be explored.

Annotation: Examines use of fertility preservation among transgender girls

Butler G, Adu-Gyamfi K, Clarkson K, et al. Discharge outcome analysis of 1089 transgender young people
referred to paediatric endocrine clinics in England 2008-2021. Arch Dis Child.

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 2022;107(11):1018-1022. doi:10.1136/archdischild-2022-324302 Accessed September 15, 2023.
Available at https://adc.bmj.com/content/107/11/1018

Abstract: Introduction The destination of transgender and gender variant young people referred
by the National Health Service (NHS) Gender Identity Development Service (GIDS) to, and
discharged from the two English paediatric endocrine liaison clinics is not known. Methods 1151
young people referred after full assessment by the GIDS; 827 to University College London
Hospital since 2008; 324 to Leeds Children's Hospital since 2013. Discharge categorisation was
by agreed criteria. Eleven emigrated and 51 self-discharged. 1089 had known outcomes. Results
999/1089 (91.7%) continued identifying as gender variant. 867/999 (86.8%) were discharged to
adult gender identity clinics (GICs). 166/867 (19.1%) of these were <16 years and 701/867
(80.9%) ≥16 years at initial endocrine referral. No sex differences were seen. 38/999 (3.8%)
opted for non-NHS services. 90/1089 ceased identifying as gender variant. In 32/1089 (2.9%),
this was subsequent to their first clinic appointment. 58/1089 (5.3%) stopped treatment either
with the gonadotropin releasing hormone analogue (GnRHa) or gender-affirming hormones
(GAH) and reverted to their birth gender: <16 years (20/217; 9.2%); ≥16 years (38/872; 4.4%).
Subdividing further, 16/217 (7.4%) <16 years ceased GnRHa and 4/217 (1.8%) after GAH. Of
those ≥16 years, 33/872 (3.8%) ceased GnRHa and 5/872 (0.6%) GAH. Conclusions At discharge,
91.7% continued as transgender or gender variant, 86.8% sought ongoing care through NHS
GICs. 2.9% ceased identifying as transgender after an initial consultation prior to any endocrine
intervention and 5.3% stopped treatment either with GnRHa or GAH, a higher proportion in the
<16 year compared with the ≥16 year groups.

Annotation: A descriptive study examining gender identities of TGNB adolescents after

discharge from 2 English children's hospitals for GD-related treatments. Only natal genders were
reported: 329 AMAB and 651 AFAB adolescents < 18 years.

Chen D, Simons L, Johnson EK, Lockart BA, Finlayson C. Fertility Preservation for Transgender
Adolescents. J Adolesc Health. 2017;61(1):120-123. doi:10.1016/j.jadohealth.2017.01.022
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/28363716

Abstract: PURPOSE: To describe fertility preservation (FP) utilization by transgender adolescents

within a pediatric gender clinic between July 2013 and July 2016. METHODS: A retrospective
chart review was conducted to abstract demographic and clinical information among
adolescents initiating gender-affirming hormones, including patient age at initial FP
consultation, birth-assigned sex, race/ethnicity, and outcome of FP consultation. RESULTS: In
our sample of 105 transgender adolescents, a total of 13 (seven transgender men and six
transgender women) between the age of 14.2 and 20.6 years were seen in formal consultation
for FP before initiating hormones. Of these adolescents, four completed sperm cryopreservation
and one completed oocyte cryopreservation. CONCLUSIONS: Rates of FP utilization among
transgender youth were low, which is consistent with a recently published report of FP
utilization among transgender youth at another pediatric institution. Identified barriers to FP in
our sample included cost, invasiveness of procedures, and desire not to delay medical transition.

Annotation: Examines fertility consultation outcomes in TGNB adolescents

Clark BA, Marshall SK, Saewyc EM. Hormone therapy decision-making processes: Transgender youth and
parents. J Adolesc. 2020;79:136-147. doi:10.1016/j.adolescence.2019.12.016 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/31972534

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 Abstract: INTRODUCTION: This study explored how transgender (trans) youth and parents of
trans youth made decisions around hormone therapy initiation as well as trans youth
experiences of barriers to care. METHODS: Participants included 21 trans youth (ages 14-18) and
15 parents of trans youth who resided in British Columbia, Canada. Data for this grounded
theory research consisted of transcripts and lifeline drawings collected through semi-structured
interviews conducted August 2016 through February 2017. RESULTS: The decision-making
processes of youth and of parents are illustrated in three-phase temporal models, starting with
discovery, leading to (inter)action while seeking care, and reflection after hormone therapy
initiation. Youth who sought hormone therapy were clear about their decision to access this
care. Throughout these processes, youth experienced numerous parent- and system-related
barriers to care. Youth with the lowest levels of parent support experienced more system
barriers, with non-binary/genderfluid youth experiencing greater barriers and less support for
hormone therapy than youth with binary genders. A new barrier identified in this study was
health care provider imposed requirements for parental involvement and/or approval, which
rendered some youth unable access to hormone therapy. CONCLUSIONS: Health care providers
should be aware of the deliberation and information-seeking in which youth engage prior to
seeking care as well as the temporally misaligned decision-making processes of youth and
parents. Understanding the challenges trans youth experience due to insufficient parental
support and system barriers can provide important context for health care providers striving to
provide accessible, gender-affirming care and decision-making support for trans youth.

Annotation: A Canadian descriptive study examining the hormone treatment decision-making

process with TGNB adolescents and their parents

Clark BA, Virani A, Marshall SK, Saewyc EM. Conditions for shared decision making in the care of
transgender youth in Canada. Health Promot Int. 2021;36(2):570-580.
doi:10.1093/heapro/daaa043 Accessed September 15, 2023. Available at
https://academic.oup.com/heapro/article-abstract/36/2/570/5864519?redirectedFrom=fulltext

Abstract: Information is lacking on the role shared decision making plays in the care of
transgender (trans) youth. This qualitative, descriptive study explored how trans youth, parents
and health care providers engaged or did not engage in shared decision-making practices
around hormone therapy initiation and what conditions supported shared decision-making
approaches in clinical practice. Semi-structured interviews were conducted with 47 participants
in British Columbia, Canada, and analyzed using a constructivist grounded theory approach.
While formal shared decision-making models were not used in practice, many participants
described elements of such approaches when asked about their health care decision-making
processes. Others described health care interactions that were not conducive to a shared
decision-making approach. The key finding that emerged through this analysis was a set of five
conditions for supporting shared decision making when making decisions surrounding initiation
of hormone therapy with trans youth. Both supportive relationships and open communication
were necessary among participants to support shared decision making. All parties needed to
agree regarding what decisions were to be made and what role each person would play in the
process. Finally, adequate time was needed for decision-making processes to unfold. When
stakeholders meet these five conditions, a gender-affirming and culturally safer shared decision-
making approach may be used to support decision making about gender-affirming care.
Implications for clinical practice and future research are discussed.

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 Annotation: A qualitative descriptive study examining aspects of decision-making in TGNB
youths

Daley T, Grossoehme D, McGuire JK, Corathers S, Conard LA, Lipstein EA. "I Couldn't See a Downside":
Decision-Making About Gender-Affirming Hormone Therapy. J Adolesc Health. 2019;65(2):274-
279. doi:10.1016/j.jadohealth.2019.02.018 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31196783

Abstract: PURPOSE: The aim of the article was to understand adolescents' and parents' decision-
making process related to gender-affirming hormone therapy (GAHT). METHODS: We conducted
qualitative semistructured interviews with transgender adolescents who began testosterone for
GAHT in the prior year and the parents of such adolescents. Questions focused on decision-
making roles, steps in the decision process, and factors considered in the decision. Participants
used pie charts to describe the division of responsibility for the decision. All interviews were
coded by at least two members of the research team with disagreements resolved through
discussion. Thematic analysis was used to analyze the data. RESULTS: Seventeen adolescents
and 13 parents were interviewed (12 dyads). The process of deciding about GAHT involves a
series of small conversations, typically with the adolescent advocating to start treatment and
the parent feeling hesitant. In most cases, after seeking information from the Internet,
healthcare providers and personal contacts move toward acceptance and agree to start
treatment. Although adolescents have some short-term concerns, such as about needles,
parents' concerns relate more to long-term risks. Ultimately, for both parents and adolescents,
the benefits of treatment outweigh any concerns, and they are in agreement about the goals of
personal confidence, comfort in one's body and happiness. CONCLUSIONS: To the extent that
the decision about GAHT is a medical decision, the decision process is similar to others.
However, decisions about GAHT are much more about gender identity than medical risks,
suggesting that interventions based in a medical framework may not aid in supporting decision-
making.

Annotation: A qualitative study of pediatric transmasculine patients and their parents, focusing
on decision-making around the initiation GAHT

de Vries AL, Noens IL, Cohen-Kettenis PT, van Berckelaer-Onnes IA, Doreleijers TA. Autism spectrum
disorders in gender dysphoric children and adolescents. J Autism Dev Disord. 2010;40(8):930-
936. doi:10.1007/s10803-010-0935-9 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/20094764

Abstract: Only case reports have described the co-occurrence of gender identity disorder (GID)
and autism spectrum disorders (ASD). This study examined this co-occurrence using a systematic
approach. Children and adolescents (115 boys and 89 girls, mean age 10.8, SD = 3.58) referred
to a gender identity clinic received a standardized assessment during which a GID diagnosis was
made and ASD suspected cases were identified. The Dutch version of the Diagnostic Interview
for Social and Communication Disorders (10th rev., DISCO-10) was administered to ascertain
ASD classifications. The incidence of ASD in this sample of children and adolescents was 7.8% (n
= 16). Clinicians should be aware of co-occurring ASD and GID and the challenges it generates in
clinical management.

Annotation: Examines the prevalence of autism and autism traits in TGNB children and
adolescents. Only natal sex reported: 115 AMAB and 89 AFAB

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Garborcauskas G, Boskey ER, Guss CE, Grimstad FW. Retrospective Review of Sexual and Reproductive
Health Conversations During Initial Visits of Adolescents Seeking Gender-Affirming Testosterone.
J Pediatr Adolesc Gynecol. 2023;36(1):25-32. doi:10.1016/j.jpag.2022.09.004 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36162722

Abstract: STUDY OBJECTIVE: To use a retrospective review of sexual and reproductive health
(SRH) counseling that occurred during initial visits of adolescents seeking testosterone gender-
affirming hormone therapy to determine the feasibility of using such visits to manage SRH
DESIGN: Retrospective chart review SETTING: Children's hospital, multidisciplinary gender clinic
PARTICIPANTS: Transgender male and nonbinary patients assigned female at birth (TGD-M) aged
15-17 seen for initiation of testosterone between January 1, 2010, and December 31, 2019
INTERVENTIONS: Not applicable MAIN OUTCOME MEASURE(S): Counseling on (1) testosterone
impact on fertility and (2) fertility preservation; assessment of (3) desire for gender-affirming
surgery, (4) sexual activity, (5) sexual orientation, and (6) human papilloma virus vaccination as
documented during the initial visit. RESULTS: Of 195 patients who met the inclusion criteria,
only 3 (1.5%) had all 6 measures addressed. The median number addressed was 4 out of 6 (IQR
= 2-5/6), with fertility counseling (95.9%, n = 187) being most common, followed by assessment
of surgery desire (74.4%, n = 145), sexual orientation (69.2%, n = 135), and sexual activity
(69.2%, n = 135). The odds of being asked about sexual orientation were 5.3 times higher in
patients who endorsed sexual activity than in those who did not (P < .001; 95% CI, 9.8-10.3).
CONCLUSION: Providers of adolescent gender-affirming hormone therapy regularly assess and
counsel on certain aspects of SRH as part of their initial visits for those seeking testosterone. Our
data suggest that these initial visits for patients seeking testosterone represent an opportunity
to expand SRH assessment and counseling among TGD-M adolescents.

Annotation: Examines characteristics and counseling topics in TGNB adolescents seeking

testosterone CSHT

Gawlik A, Antosz A, Kasparek K, Nowak Z, Grabski B. Gender confirmation hormonal treatment use in
young Polish transgender binary and non-binary persons. Endokrynol Pol. 2022;73(6):922-927.
doi:10.5603/EP.a2022.0088 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36519648

Abstract: INTRODUCTION: Gender confirmation hormonal treatment (GCHT) is a cornerstone of

medical treatments for persistent gender dysphoria, which is expected and required by many
transgender binary and non-binary individuals. Many protocols have been published, and the
qualification process is guided by the World Professional Association for Transgender Health
Standards of Care. The standards and other documents such as the Endocrine Society Clinical
Practice Guideline provide gender confirmation hormonal care also for minors. However, the
issue of starting these treatments in younger populations is still marked by controversy. This
preliminary study aimed to inquire into GCHT (medications used, timing of its initiation, its
tolerance, and sources of information on the treatment) in a convenience sample of young
Polish transgender binary and non-binary persons. MATERIAL AND METHODS: A total of 166
adult transgender participants answered our online questionnaire between November 2020 and
December 2021. The population was divided into 2 groups: assigned male at birth (AMB, n = 37)
and assigned female at birth (AFB, n = 126). Subsequently, division into binary and non-binary
was applied to these groups. RESULTS: Most patients (91.9% AMB and 92.2% AFB) did not use
gender confirmation medical treatments before the age of 18 years. The most common
medication used for GCHT before the age of 18 was cyproterone acetate for AMB and

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 testosterone for AFB. When asked about their opinion on the timing (age) of initiating GCHT,
73.1% of the AMB and 59.2% of the AFB participants shared the view that it had been initiated
much too late. By far the most common source of information on GCHT and gender
confirmation surgery (GCS) was the Internet (92.2%). CONCLUSIONS: These treatments
(including pubertal blocking) seem to be rarely commenced in Poland before the age of 18
years. In adults, treatment consists mostly of either testosterone or oestradiol, and cyproterone
acetate and, more seldom, spironolactone are used as antiandrogens in persons assigned male
at birth. In turn, gonadotropin-releasing hormone agonists are barely used at all. Specialists
need to be more aware that withholding treatment in minors with gender dysphoria is not a
health-neutral option. Gonadotropin-releasing hormone agonists should also be more often
considered as an alternative to cyproterone acetate in the context of long-term safety.

Annotation: A survey-based, descriptive study of Polish TGNB young adults with self-reported
testosterone and GnRH analogue treatment initiation before age 16, before age 18, and current
use.

Handler T, Hojilla JC, Varghese R, Wellenstein W, Satre DD, Zaritsky E. Trends in Referrals to a Pediatric
Transgender Clinic. Pediatrics. 2019;144(5)doi:10.1542/peds.2019-1368 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/31619510

Abstract: OBJECTIVES: We characterized referral trends over time at a transgender clinic within
an integrated health system in Northern California. We identified the transition-related requests
of pediatric transgender and gender-nonconforming patients and evaluated differences in
referrals by age group. METHODS: Medical records were analyzed for all patients <18 years of
age in the Kaiser Permanente Northern California health system who were referred to a
specialty transgender clinic between February 2015 and June 2018. Trends in treatment
demand, demographic data, service requests, and surgical history were abstracted from medical
charts and analyzed by using descriptive statistics. RESULTS: We identified 417 unique
transgender and gender-nonconforming pediatric patients. The median age at time of referral
was 15 years (range 3-17). Most (62%) identified on the masculine spectrum. Of the 203
patients with available ethnicity data, 68% were non-Hispanic. During the study period, the clinic
received a total of 506 referrals with a significant increase over time (P < .001). Most referrals
were for requests to start cross-sex hormones and/or blockers (34%), gender-affirming surgery
(32%), and mental health (27%). Transition-related requests varied by age group: younger
patients sought more mental health services, and older patients sought hormonal and surgical
services. Eighty-nine patients underwent gender-affirming surgeries, mostly before age 18 and
most frequently mastectomies (77%). CONCLUSIONS: The increase in referrals supports the
need for expanded and accessible health care services for this population. The transition-related
care of patients in this large sample varied by age group, underscoring the need for an
individualized approach to gender-affirming care.

Annotation: A California-based descriptive study examining trends in TGNB referrals and

requests for cross-sex hormones, puberty blockers, and surgery.

Harris RM, Kolaitis IN, Frader JE. Ethical issues involving fertility preservation for transgender youth. J
Assist Reprod Genet. 2020;37(10):2453-2462. doi:10.1007/s10815-020-01873-9 Accessed
September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550448/pdf/10815_2020_Article_1873.pdf

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 Abstract: Purpose: To investigate ethical issues associated with fertility preservation (FP) in
transgender youth based on reports of patients and their parents. Methods: Our qualitative
study involved in-person interviews with 54 subjects (35 patients and 19 parents). Interviews
were audio recorded, transcribed, and verified. Each subject completed a demographic
questionnaire, and each patient’s medical chart was reviewed for additional information. We
analyzed the data using inductive thematic content analysis. Results: Themes that emerged
included a range of desires and ambivalence about having genetically related children, variability
in understanding the potentially irreversible impact of gender affirming hormones (GAHs) on
fertility, use of adoption, and the impact of age on decision-making. Subjects (patients and
parents) noted barriers to FP, such as cost and insurance coverage. Several parents expressed
concern that their transgender children may have future regret about not attempting FP. Both
transgender youth and their parents felt FP was an important precaution. Conclusions: Our
study took advantage of the richness of personal narratives to identify ongoing ethical issues
associated with fertility preservation in transgender youth. Transgender youth and their parents
did not fully understand the process of FP, especially regarding the effects of GAHs, had fears
that FP could reactivate gender dysphoria, and noted barriers to FP, such as cost, highlighting
economic disparity and lack of justice. These findings highlight ethical issues involving the
adequacy of informed consent and economic injustice in access to FP despite expressed interest
in the topic.

Annotation: A qualitative, descriptive interview study examining ethical considerations related

to fertility preservation in TGNB youth and their parents

Hewitt JK, Paul C, Kasiannan P, Grover SR, Newman LK, Warne GL. Hormone treatment of gender
identity disorder in a cohort of children and adolescents. Med J Aust. 2012;196(9):578-581.
doi:10.5694/mja12.10222 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/22621149

Abstract: OBJECTIVE: To describe the experience of hormone treatment of gender identity

disorder (GID) in children and adolescents within a specialist clinic. DESIGN, PATIENTS AND
SETTING: Cohort study by medical record review of children aged 0-17 years referred during
2003-2011 for management at the GID clinic in a tertiary paediatric referral centre - the Royal
Children's Hospital, Melbourne, Victoria. MAIN OUTCOME MEASURES: Clinical characteristics of
the patient population, hormone treatment provided, frequency of referrals with time.
RESULTS: Thirty-nine children and adolescents were referred for gender dysphoria. Seventeen
individuals were pubertal with persistent GID, and were considered eligible for hormone
treatment. Seven patients, comprising three biological males and four biological females, had
legally endorsed hormone treatment. In this group, gender dysphoria was first noted at 3-6
years of age. Hormone treatment with GnRH analogue to suppress pubertal progression (phase
1) was given at 10-16 years of age. Treatment with cross-sex hormones (phase 2) was given at
15.6-16 years. One patient purchased cross-sex hormone treatment overseas. One patient
received oestrogen and progesterone for menstrual suppression before phase 1. The annual
frequency of new referrals increased continuously over the study period. CONCLUSIONS:
Hormone treatment for pubertal suppression and subsequent gender transition needs to be
individualised within stringent protocols in multidisciplinary specialist units.

Annotation: An Australia-based descriptive study reporting on pediatric TGNB cases and their
treatments.

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Hobson BJ, Lett E, Hawkins LA, Swendiman RA, Nance ML, Dowshen NL. Transgender Youth Experiences
with Implantable GnRH Agonists for Puberty Suppression. Transgend Health. 2022;7(4):364-368.
doi:10.1089/trgh.2021.0006 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36033209

Abstract: This descriptive study reports caregiver experiences with GnRH agonist implants
among a cohort of youth followed in a pediatric hospital-based gender clinic. We administered a
survey to 36 of 55 eligible caregivers ascertaining demographics and satisfaction, with a medical
record review of any surgical complications. The overwhelming majority (97.1%) reported
satisfaction with the procedure and would undergo the implant procedure again (94.4%). The
most frequent challenges noted were about affordability (39.8%) and insurance denials (39.8%).
Implantable GnRH agonist can be used successfully in pediatric patients with gender dysphoria.
Future policy should seek to address concerns regarding insurance approval and
reimbursement.

Annotation: A qualitative study examining patient and parent preferences in TGNB patients with
implantable GnRH agonists for puberty suppression. Investigators did not report affirmed
gender identities; only natal sex reported (N = 15 AMAB and N = 21 AFAB).

Kanj RV, Conard LAE, Corathers SD, Trotman GE. Hormonal contraceptive choices in a clinic-based series
of transgender adolescents and young adults. Int J Transgend. 2019;20(4):413-420.
doi:10.1080/15532739.2019.1631929 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32999626

Abstract: Aims: To describe the use of hormonal contraceptives for menstrual management
and/or pregnancy prevention in a clinic-based series of transgender adolescents and young
adults who were assigned female at birth (transmasculine identity). Methods: We performed a
chart review of post-menarchal transgender assigned-female-at-birth (AFAB) patients, age 10-25
years, seen at CCHMC Transgender Health Clinic for at least 2 visits between July 1, 2013 and
September 17, 2016, and who were not on a puberty suppression method. We collected data
including choice of hormonal contraceptive and indication (menstrual suppression, pregnancy
prevention, or both), duration of use, initiation of sexual activity, reported sexual partners, and
use of gender-affirming hormone therapy (i.e., testosterone). We present simple descriptive
statistics. Results: A total of 231 patients met inclusion criteria, with ages from 11 to 25 years. Of
those, 135 (59%) were using a hormonal contraceptive method. Most patients (67%) used
hormonal contraception for the indication of menstrual suppression. Most commonly used
method was depot medroxyprogesterone (DMPA) (49 patients), followed by combined oral
contraceptives (COC) and norethindrone (progestin-only pill, POP) (34 patients each). Thirteen
patients used 52 mg levonorgestrel IUD (LNG-IUD). Of the total sample (n = 231), 82 (36%)
reported sexual activity, 35 of whom (43% of sexually active patients) reported sexual
intercourse with assigned-male-at-birth (AMAB) partners and/or penile-vaginal intercourse.
Among 35 patients at risk for pregnancy, only 21 (60%) were using hormonal contraception.
Over half (54%) of sexually active patients taking testosterone discontinued their hormonal
contraceptive method once they stopped having menses. Discussion: Within a sample of
transgender AFAB adolescents, half of whom were taking testosterone, a variety of
contraceptives were used, including depot medroxyprogesterone, combined oral
contraceptives, and levonorgestrel IUD. Among those taking testosterone, many patients
discontinued contraception once they stopped having menses.

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 Annotation: Examines oral contraceptive use in transgender males

Kerman HM, Pham A, Crouch JM, et al. Gender Diverse Youth on Fertility and Future Family: A
Qualitative Analysis. J Adolesc Health. 2021;68(6):1112-1120.
doi:10.1016/j.jadohealth.2021.01.002 Accessed September 15, 2023. Available at
https://www.jahonline.org/article/S1054-139X(21)00004-5/fulltext

Abstract: Purpose: Gender-affirming treatment for transgender and nonbinary adolescents has
been shown to decrease anxiety, depression, and suicidality, but treatments have medical
consequences. Specifically, hormone replacement and pubertal blocking may impact patients'
fertility and childbearing capabilities. We interviewed gender diverse adolescents regarding
their thoughts on family and fertility. Methods: We completed semistructured interviews with
23 gender diverse adolescents recruited from the Seattle Children's Gender Clinic. Interviewees
included transfeminine, transmasculine, and nonbinary youth. Interviews were recorded,
transcribed, and analyzed using Braun and Clarke's theory of thematic analysis, a flexible
framework for qualitative analysis. Results: Gender diverse adolescents have myriad views on
fertility, but four main themes were identified: (1) an interest in future family, including ideas
regarding adoption and biological children; (2) barriers to fertility, including cost and procedure-
related dysphoria; (3) factors unique to the developmental stage of adolescents, including the
age discordance of making fertility decisions as a teenager and parental influence on decision-
making; and (4) suggestions for clinicians approaching fertility counseling with adolescents
considering hormone therapy. Conclusions: Many gender diverse youth asserted an interest in
building families, although the process of fertility preservation remains fraught. Relative to
other studies, our participants were hopeful, imaginative, and interested in having children.
Participants wanted to receive specific counseling on fertility, to receive help navigating the
logistics of fertility preservation, and to be listened to when their hopes for children (or no
children) were stated. Further research is needed to create care paradigms that address fertility
of transgender youth in an affirming, developmentally appropriate manner.

Annotation: A qualitative survey study examining fertility attitudes among TGNB children seen
in a pediatric gender clinic

Krishna V, Lee SL, DeUgarte DA. Optimizing pediatric histrelin implantation to improve success rates in
clinic without sedation. J Pediatr Endocrinol Metab. 2021;34(11):1443-1448. doi:10.1515/jpem-
2021-0432 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34407329

Abstract: OBJECTIVES: The purpose of this study was to review our success rate performing the
histrelin implant procedure in clinic without sedation. METHODS: A retrospective study was
performed for histrelin implant procedures done at our institution from 2008 to 2020. Wilcoxon
rank-sum test or Fisher's exact test was utilized to identify significant differences (p<0.05).
RESULTS: A total of 73 patients underwent 184 histrelin implant procedures from 2008 to 2020.
In the past few years, there has been a decrease in procedures for precocious puberty and an
increase for gender dysphoria. The majority of procedures were performed in clinic without
sedation (82%). The only risk factor associated with requiring sedation was younger age (median
9 vs. 10 years; p<0.003). Complications (i.e. implant fracture or need for counter-incision) were
noted in 10 of the procedures (5%). The only risk factor identified for a procedural complication
during implant removal/replacement was interval time from insertion (21 vs. 13 months;
p<0.01). The only documented wound problem reported was dermatitis in 1 patient (no suture

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 granuloma, dehiscence, or implant extravasation). CONCLUSIONS: Procedural refinements and
distraction therapy have enabled us to perform the majority of procedures in clinic without
sedation. In our experience, procedural difficulty and complications appear to increase with
prolonged implant duration. Histrelin implantation is increasingly being performed for gender
dysphoria.

Annotation: Examines on characteristics and temporal trends in use of histrelin implants in

pediatric patients, including patients with GD

Lopez CM, Solomon D, Boulware SD, Christison-Lagay E. Trends in the "Off-Label" Use of GnRH Agonists
Among Pediatric Patients in the United States. Clin Pediatr (Phila). 2018;57(12):1432-1435.
doi:10.1177/0009922818787260 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30003804

Abstract: BACKGROUND: Gonadotropin-releasing hormone (GnRH) agonists are FDA approved

for the treatment of precocious puberty. The therapy consists of histrelin acetate (Supprelin), a
surgically implanted device, or Lupron injections. In recent years, the use of these agents has
been extended to include the off-label treatment of children with normally timed puberty.
Trends in the off-label use of GnRH agonists in children across the U.S. have not been previously
described in the literature. METHODS: We analyzed data on the use of Supprelin and Lupron
reported to the Pediatric Health Information System (PHIS) from 2013 to 2016 to determine the
trends in both the FDA-approved and off-label uses of these medications. RESULTS: We
identified a stable cohort of 39 children's hospitals administering GnRH agonist therapies from
2013 to 2016. During this period, the annual number of children treated with these medications
for precocious puberty increased modestly, from 283 to 303; meanwhile, the fraction of children
receiving therapy for an off-label indication more than doubled, from 12% (39 of 322 total
patients) to 29% (125 of 428 total patients). Privately insured patients were more likely to be
treated for an off-label indication (13%; 119 out of 883 patients) than Medicaid patients (8%; 58
out of 706 patients; chi(2)[1] = 10.97, P = .00093). CONCLUSION: From 2013 to 2016, the
proportion of children treated with GnRH agonists for an off-label indication notably increased.
The number of children treated for precocious puberty modestly increased. Private insurance
coverage was associated with higher rates of off-label use.

Annotation: Examines off-label use of GnRH agonists among pediatric patients with GD or
developmental sex disorders. Neither affirmed genders nor birth-assigned sexes were reported.

Lopez CM, Solomon D, Boulware SD, Christison-Lagay ER. Trends in the use of puberty blockers among
transgender children in the United States. J Pediatr Endocrinol Metab. 2018;31(6):665-670.
doi:10.1515/jpem-2018-0048 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29715194

Abstract: BACKGROUND: The objective of the study was to identify national trends in the
utilization of histrelin acetate implants among transgender children in the United States.
METHODS: We analyzed demographic, diagnostic and treatment data from 2004 to 2016 on the
use of histrelin acetate reported to the Pediatric Health Information System (PHIS) to determine
the temporal trends in its use for transgender-related billing diagnoses, e.g. "gender identity
disorder". Demographic and payer status data on this patient population were also collected.
RESULTS: Between 2004 and 2016, the annual number of implants placed for a transgender-
related diagnosis increased from 0 to 63. The average age for placement was 14 years.

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 Compared to natal females, natal males were more likely to receive implants (57 vs. 46) and
more likely to have implants placed at an older age (62% of natal males vs. 50% of natal females
were >/=;13 years; p<0.04). The majority of children were White non-Hispanic (White: 60,
minority: 21). When compared to the distribution of patients treated for precocious puberty
(White: 1428, minority: 1421), White non-Hispanic patients were more likely to be treated with
a histrelin acetate implant for a transgender-related diagnosis than minority patients (p<0.001).
This disparity was present even among minority patients with commercial insurance (p<0.001).
CONCLUSIONS: Utilization of histrelin acetate implants among transgender children has
increased dramatically. Compared to natal females, natal males are more likely to receive
implants and also more likely to receive implants at an older age. Treated transgender patients
are more likely to be White when compared to the larger cohort of patients being treated with
histrelin acetate for central precocious puberty (CPP), thus identifying a potential racial disparity
in access to medically appropriate transgender care.

Annotation: Examines use of GnRH analogues in pediatric patients, including TGNB children and
cis children with CPP. Authors did not report affirmed gender ratios, only natal sex (N = 52
AMAB, N = 39 AFAB, and 1 whose natal sex was unknown).

Masic U, Butler G, Carruthers P, Carmichael P. Trajectories of transgender adolescents referred for

endocrine intervention in England. Arch Dis Child. 2022;107(11):1012-1017.
doi:10.1136/archdischild-2022-324283 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35902230

Abstract: OBJECTIVES: Some gender-diverse young people (YP) who experience clinically
significant gender-related distress choose to pursue endocrine treatment alongside
psychotherapeutic support to suppress pubertal development using gonadotropin-releasing
hormone analogues (GnRHa), and then to acquire the secondary sex characteristics of their
identified gender using gender affirming hormones (GAH). However, little is known about the
demographics of transgender adolescents accessing paediatric endocrinology services while
under the specialist Gender Identity Development Service (GIDS) in England. DESIGN:
Demographics of referrals from the GIDS to affiliated endocrinology clinics to start GnRHa or
GAH between 2017 and 2019 (cohort 1), with further analysis of a subgroup of this cohort
referred in 2017-2018 (cohort 2) were assessed. RESULTS: 668 adolescents (227 assigned male
at birth (AMAB) and 441 assigned female at birth (AFAB)) were referred to endocrinology from
2017 to 2019. The mean age of first GIDS appointment for cohort 1 was 14.2 (+/-2.1) years and
mean age of referral to endocrinology postassessment was 15.4 (+/-1.6) years. Further detailed
analysis of the trajectories was conducted in 439 YP in cohort 2 (154 AMAB; 285 AFAB). The
most common pathway included a referral to access GnRHa (98.1%), followed by GAH when
eligible (42%), and onward referral to adult services when appropriate (64%). The majority (54%)
of all adolescents in cohort 2 had a pending or completed referral to adult services.
CONCLUSIONS: This study highlights the trajectories adolescents may take when seeking
endocrine treatments in child and adolescent clinical services and may be useful for guiding
decisions for gender-diverse YP and planning service provision.

Annotation: A London-based descriptive study examining treatment trajectories in TGNB

adolescents referred for treatment with GnRHa and cross-sex hormones.

McCallion S, Smith S, Kyle H, Shaikh MG, Wilkinson G, Kyriakou A. An appraisal of current service
delivery and future models of care for young people with gender dysphoria. Eur J Pediatr.

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 2021;180(9):2969-2976. doi:10.1007/s00431-021-04075-2 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33855617

Abstract: The clinical needs of young people with gender dysphoria (GD) have outpaced the
capacity of health services to provide appropriate care. The study aimed to explore the interface
of Paediatric Endocrinology and young people with GD, detailing the clinical characteristics and
the clinical care provided, in order to inform future service development. Medical records of all
young people with GD (n=91, 59 (65%) birth-assigned females and 32 (35%) birth-assigned
males) referred to Paediatric Endocrinology during 2011-2019 for puberty suppression were
reviewed. Median age at initial assessment was 14.6 years (range 8.8-17.6 years). There was a
threefold increase from 2016 (n=22) to 2019 (n=73). Mental health disorders were present in 34
(37%) and autistic spectrum disorder in 21 (23%), while 54 (59%) had at least one comorbidity.
Sixty-four (70%) young people fulfilled the criteria for consideration of fertility preservation,
with 6 (9%) of them preserving their gametes. Seventy-nine (87%) young people commenced
treatment with gonadotrophin-releasing hormone analogue, at a median age of 14.8 years
(range 9.7-18.0 years). Six (8%) of those discontinued treatment, following a median duration of
6 months (range 6-18 months). Forty-one young people commenced gender-affirming
hormones. One (2%) of those who started gender-affirming hormones discontinued
treatment.Conclusions: We have witnessed increasing numbers of young people with GD
attending Paediatric Endocrinology, with an over-representation of comorbidities, necessitating
provision of an individualised approach to treatment. Addressing young people's acceptability of
fertility services and ongoing close collaboration between endocrinology and mental health
professionals require innovative models of multidisciplinary care. What is Known: * A worldwide
increase in presentation of gender dysphoria has been mirrored in our service, with majority
assigned female at birth and post-pubertal. * An over-representation of comorbidities exists,
notably mental health disorders and autistic spectrum disorder. What is New: * Coordination of
interprofessional care to meet complex needs, at an individual level, while improving efficiency
of working, at a systemic level, can be met by the development of specialist centres. * The
reasons for low uptake of fertility services demand further exploration.

Annotation: A Scotland-based descriptive study of characteristics of pediatric patients referred

to a pediatric gender care clinic.

Morrison A, Olezeski C, Cron J, Kallen AN. A Pilot Study to Assess Attitudes Toward Future Fertility and
Parenthood in Transgender and Gender Expansive Adolescents. Transgender Health.
2020;5(2):129-137. doi:10.1089/trgh.2019.0075 Accessed June 28, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L632152015&from=export

Abstract: Purpose: In this pilot study, we sought to characterize the knowledge about fertility
and attitudes about future parenthood in a sample of transgender and gender expansive (TGE)
youth attending an academic, university-affiliated adolescent gender program. Methods: A 22-
item cross-sectional survey assessing knowledge of fertility issues and attitudes toward future
parenthood was administered to 23 transgender adolescents, 12-22 years of age, who reported
gender identity incongruent with birth-assigned sex, and who were seen at our university-
affiliated clinic during an 11-month period between October 2016 and August 2017. Knowledge
scores and ranked responses on selected topics in fertility and reproduction were evaluated.
Results: Participants were well informed overall about fertility topics related to their gender
care (mean score of 3.8±0.8 out of 5), but over half of participants lacked specific knowledge
regarding basic fertility principles and overestimated the ability of physicians to predict the

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 effects of gender-affirming hormone therapy on fertility. The majority of participants (15/23)
preferred nonbiological parenthood in the form of adoption. Participants who ranked future
parenthood as unimportant had the greatest concern about becoming a parent (p<0.05), and
over one-third were also concerned about interrupting their gender-affirming hormone therapy
to preserve fertility. Conclusion: TGE youth would benefit from fertility-related counseling that
both assesses baseline understanding of reproduction and also acknowledges the limitations of
current data on gender-affirming hormones and future fertility. Counseling should also be
comprehensive and explore both biological and nonbiological forms of parenthood.

Annotation: A US-based descriptive study reporting on survey results about fertility preference
in N=23 transgender children seen at a university-affiliated clinic.

Nahata L, Chen D, Quinn GP, et al. Reproductive Attitudes and Behaviors Among Transgender/Nonbinary
Adolescents. J Adolesc Health. 2020;66(3):372-374. doi:10.1016/j.jadohealth.2019.09.008
Accessed September 15, 2023. Available at https://www.jahonline.org/article/S1054-
139X(19)30451-3/fulltext

Abstract: Purpose: The aim of the study was to examine reproductive health attitudes and
behaviors related to contraception use, provider counseling, parenthood goals, and fertility
preservation (FP) in TNB adolescents. Methods: A 24-item survey was administered to 44 TNB
adolescents aged 12–19 years. Results: Contraceptive use was variable even among the 46%
who reported sexual activity. Half denied or were unsure if they had been offered options from
their provider to prevent sexually transmitted infections, and more than one third denied or
were unsure about the offer of pregnancy prevention options. Importantly, the majority did not
desire more information about contraceptive options. Few used FP, although many thought
their feelings about parenthood may change in the future. Conclusions: TNB adolescents are at
risk for sexually transmitted infections, unplanned pregnancies, and future infertility, yet many
do not desire more information about contraception or FP. Tailored counseling strategies should
be developed and researched to protect this vulnerable group of youth.

Annotation: Examines gender identity, sexual orientation, contraception counseling, and

attitudes towards fertility among TGNB adolescents seen in 4 gender clinics across 3 states

O'Bryan J, Leon K, Wolf-Gould C, Scribani M, Tallman N, Gadomski A. Building a Pediatric Patient Registry
to Study Health Outcomes Among Transgender and Gender Expansive Youth at a Rural Gender
Clinic. Transgend Health. 2018;3(1):179-189. doi:10.1089/trgh.2018.0023 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/30581991

Abstract: Purpose: Significant knowledge gaps regarding outcomes of gender-affirming therapy

in transgender (TG) and gender expansive (GE) youth impede an evidence-based approach to
these patients. The Gender Wellness Center (GWC) Pediatric Patient Registry was established in
2017 to enable systematic, longitudinal research to describe the physical, mental, and quality-
of-life outcomes of these youth. Methods: All TG/GE youth, ages 8-21 years, presenting to the
GWC were recruited on site. Ten research questions guided the creation of data fields. The
following 131 variables were abstracted from electronic medical records: demographics, weight,
height, body mass index, gender identity, sexual orientation, coexisting diagnoses, substance
use, Tanner stage, sexual activity, medications, fertility preservation, Gonadotropin Releasing
Hormone (GnRH) analog use, hormone therapy, surgery, and related outcomes. Health-related
quality of life is assessed using the Child Health Questionnaire-87 for ages <18 and the Short

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 Form-36 for ages 18-21. Results: To date, 139 TG and GE youth (90% white and 93% non-
Hispanic), have enrolled in the registry. Average age at enrollment was 17.5 years (+/-3.1, range:
8-21). Two-thirds of youth identified on the trans masculine spectrum (n=90), 28.8% identified
on the trans feminine spectrum (n=40), and 6.5% identified as nonbinary/gender nonconforming
(n=9). Nearly, all youth had socially transitioned (n=121, 87.7%) and were medically transitioning
(n=123, 89.1%). Conclusion: As one of the first rural-based registries, the GWC Registry has
helped to delineate health outcomes attributable to gender-affirming care in a unique patient
population of TG/GE youth. Our results will be used to describe treatment outcomes that will
contribute to evidence-based guidelines.

Annotation: A US-based descriptive study examining characteristics (including medication use)

in a cohort of TGNB adolescents.

Olson KR, Durwood L, Horton R, Gallagher NM, Devor A. Gender Identity 5 Years After Social Transition.
Pediatrics. 2022;150(2)doi:10.1542/peds.2021-056082 Accessed September 15, 2023. Available
at https://www.ncbi.nlm.nih.gov/pubmed/35505568

Abstract: BACKGROUND AND OBJECTIVES: Concerns about early childhood social transitions
among transgender youth include that these youth may later change their gender identification
(ie, retransition), a process that could be distressing. The current study aimed to provide the
first estimate of retransitioning and to report the current gender identities of youth an average
of 5 years after their initial social transitions. METHODS: The current study examined the rate of
retransition and current gender identities of 317 initially transgender youth (208 transgender
girls, 109 transgender boys; M = 8.1 years at start of study) participating in a longitudinal study,
the Trans Youth Project. Data were reported by youth and their parents through in-person or
online visits or via e-mail or phone correspondence. RESULTS: We found that an average of 5
years after their initial social transition, 7.3% of youth had retransitioned at least once. At the
end of this period, most youth identified as binary transgender youth (94%), including 1.3% who
retransitioned to another identity before returning to their binary transgender identity. A total
of 2.5% of youth identified as cisgender and 3.5% as nonbinary. Later cisgender identities were
more common among youth whose initial social transition occurred before age 6 years; their
retransitions often occurred before age 10 years. CONCLUSIONS: These results suggest that
retransitions are infrequent. More commonly, transgender youth who socially transitioned at
early ages continued to identify that way. Nonetheless, understanding retransitions is crucial for
clinicians and families to help make retransitions as smooth as possible for youth.

Annotation: A nationwide survey study examining gender identities 5 years after initial
presentation

Parks MA, Zwayne N, Temkit M. Bleeding Patterns among Adolescents Using the Levonorgestrel
Intrauterine Device: A Single Institution Review. J Pediatr Adolesc Gynecol. 2020;33(5):555-558.
doi:10.1016/j.jpag.2020.04.006 Accessed September 15, 2023. Available at
https://www.jpagonline.org/article/S1083-3188(20)30223-0/fulltext

Abstract: Study Objective: To describe the bleeding patterns associated with the use of the
levonorgestrel intrauterine device (IUD) in adolescents. Design, Setting, and Participants: A
retrospective chart review of postmenarchal adolescent patients ages 8-19 years who had the
levonorgestrel IUD inserted at Phoenix Children's Hospital from 2012 to 2018. Interventions:
Insertion of the 52-mg and 13.5-mg levonorgestrel IUD. Main Outcome Measures: The rate of

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 amenorrhea and other bleeding patterns after insertion of the levonorgestrel IUD and the
factors that might predict those bleeding patterns. Results: A total of 260 charts were identified
with 221/260 (85.0%) patients choosing the 52-mg IUD and 39/260 (15.0%) patients choosing
the 13.5-mg IUD to be inserted. Follow-up data were available for 166 patients. The overall rate
of amenorrhea among IUD users was 39.8% (n = 66) with no difference between 52-mg and
13.5-mg IUD users (P = .656). Regularity and flow of menstrual cycle, history of bleeding
disorder, history of developmental delay, and current treatment with testosterone for gender
dysphoria before IUD insertion did not appear to have a significant effect on the rate of
amenorrhea or bleeding patterns post-IUD insertion. Conclusion: The levonorgestrel IUD can be
successfully used to control abnormal uterine bleeding and suppress menses in adolescents.
Menstrual cycle characteristics pre-IUD insertion did not result in predictable post-IUD bleeding
patterns.

Annotation: Examines menstrual outcomes in adolescents who received levonorgestrel IUDs,

including transgender male patients

Persky RW, Gruschow SM, Sinaii N, Carlson C, Ginsberg JP, Dowshen NL. Attitudes Toward Fertility
Preservation Among Transgender Youth and Their Parents. J Adolesc Health. 2020;67(4):583-
589. doi:10.1016/j.jadohealth.2020.02.027 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32359942

Abstract: PURPOSE: While gender-affirming hormones (GAH) may impact the fertility of
transgender and gender diverse (TGGD) youth, few pursue fertility preservation (FP). The
objective of this study is to understand youth and parent attitudes toward FP decision-making.
METHODS: This study is a cross-sectional survey of youth and parents in a pediatric, hospital-
based gender clinic from April to December 2017. Surveys were administered electronically,
containing 34 items for youth and 31 items for parents regarding desire for biological children,
willingness to delay GAH for FP, and factors influencing FP decisions. RESULTS: The mean age of
youth (n = 64) was 16.8 years, and 64% assigned female at birth; 46 parents participated. Few
youth (20%) and parents (13%) found it important to have biological children or grandchildren,
and 3% of youth and 33% of parents would be willing to delay GAH for FP. The most common
factor influencing youth FP decision-making was discomfort with a body part they do not
identify with (69%), and for the parents, whether it was important to their child (61%). In paired
analyses, youth and their parents answered similarly regarding youth desire for biological
children and willingness to delay GAH for FP. CONCLUSIONS: The majority of TGGD youth and
parents did not find having biological offspring important and were not willing to delay GAH for
FP. Discomfort with reproductive anatomy was a major influencing factor for youth FP decision-
making and their child's wishes was a major factor for parents. Future qualitative research is
needed to understand TGGD youth and parent attitudes toward FP and to develop shared
decision-making tools.

Annotation: A US-based descriptive study examining characteristics, attittudes, and beliefs

about fertility and GAH in N=41 TGNB youth/parent pairs.

Pullen Sansfaçon A, Temple Newhook J, Douglas L, et al. Experiences and Stressors of Parents of Trans
and Gender-Diverse Youth in Clinical Care from Trans Youth CAN! Health Soc Work.
2022;47(2):92-101. doi:10.1093/hsw/hlac003 Accessed September 15, 2023. Available at
https://academic.oup.com/hsw/article-abstract/47/2/92/6544691?redirectedFrom=fulltext

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 Abstract: Parents of trans and gender-diverse youth can experience challenges navigating
gender-affirming (GA) care such as stigma, transphobia, and lack of support. There is little
information available about stressors, worries, and positive feelings of parents as they try to
support their youth accessing GA care. This article presents baseline survey data on experiences
and stressors of 160 parents/caregivers in the Trans Youth CAN! cohort study, which examined
medical, social, and family outcomes in youth age 16 years or younger considering puberty
blockers or GA hormones. Data were collected at 10 Canadian gender clinics. Authors report on
participating parents' characteristics, levels of support toward youth, stressors, worries,
concerns, and positive feelings related to youth's gender. Most parent participants were White
(85.1 percent), female (85.1 percent), birth or adoptive parents (96.1 percent), and reported
strong support for youth's gender. Participants' concerns included their youth facing rejection
(81.9 percent), generalized transphobia (74.6 percent), or encountering violence (76.4 percent).
Parents also reported positive feelings about seeing their youth grow more confident. Most
parental worries and stressors were situated outside the family, reflecting the systemic
discrimination faced by youth and their families. Social workers could address these by
developing systems-focused interventions and by further taking into account intersectional
health disparities.

Annotation: A Canada-based, descriptive survey study (Trans Youth CAN!) examining stressors
in TGNB adolescents who were referred for puberty suppression and/or hormones and their
parents

Pullen Sansfaçon A, Temple-Newhook J, Suerich-Gulick F, et al. The experiences of gender diverse and
trans children and youth considering and initiating medical interventions in Canadian gender-
affirming speciality clinics. Int J Transgend. 2019;20(4):371-387.
doi:10.1080/15532739.2019.1652129 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32999623

Abstract: Background: Canadian specialty clinics offering gender-affirming care to trans and
gender diverse children and youth have observed a significant increase in referrals in recent
years, but there is a lack of information about the experiences of young people receiving care.
Furthermore, treatment protocols governing access to gender-affirming medical interventions
remain a topic of debate. Aims: This qualitative research aims to develop a deeper
understanding of experiences of trans youth seeking and receiving gender-affirming care at
Canadian specialty clinics, including their goals in accessing care, feelings about care and
medical interventions they have undergone, and whether they have any regrets about these
interventions. Methods: The study uses an adapted Grounded Theory methodology from social
determinants of health perspective. Thirty-five trans and gender diverse young people aged 9 to
17 years were recruited to participate in semi-structured interviews through the specialty clinics
where they had received or were waiting for gender-affirming medical interventions such as
puberty blockers, hormone therapy, and surgery. Results: Young people felt positively overall
about the care they had received and the medical interventions they had undergone, with many
recounting an improvement in their well-being since starting care. Most commonly shared
frustrations concerned delays in accessing interventions due to clinic waiting lists or treatment
protocols. Some youth described unwanted medication side-effects and others said they had
questioned their transition trajectory at certain moments in the past, but none regretted their
choice to undergo the interventions. Discussion : The results suggest that trans youth and
gender diverse children are benefiting from medical gender-affirming care they receive at
specialty clinics, providing valuable insight into their decision-making processes in seeking care

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 and specific interventions. Providers might consider adjusting aspects of treatment protocols
(such as age restrictions, puberty stage, or mental health assessments) or applying them on a
more flexible, case-by-case basis to reduce barriers to access.

Annotation: A Canadian, multi-province, interview-based, qualitative, descriptive study

examining the decision and initiation of GD treatment

Razzak M. Pediatrics: evaluation and management of gender identity disorder--an American tale. Nat
Rev Urol. 2012;9(4):175. doi:10.1038/nrurol.2012.36 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/22410681

Abstract: None

Annotation: A research letter describing the experience of a pediatric gender specialty clinic,
and the Tanner stages of children presenting for care. Investigators did not report the affirmed
gender of their patients, only natal sex (N = 43 AMAB and N = 54 AFAB).

Riggs DW, Bartholomaeus C, Sansfacon AP. 'If they didn't support me, I most likely wouldn't be here':
Transgender young people and their parents negotiating medical treatment in Australia.
International journal of transgender health. 2020;21(1):3-15.
doi:10.1080/15532739.2019.1692751 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430428/pdf/WIJT_21_1692751.pdf

Abstract: Background: It is increasingly recognized that transgender young people require

affirming medical care, however the provision of such care may be mitigated by the availability
of services and the views of parents. Aims: This study aimed to explore the views of Australian
transgender young people (aged 11-17) and their parents with regards to medical treatment.
Methods: Ten qualitative interviews were conducted with parent-child dyads in two Australian
states. Thematic analysis was undertaken on responses to interview questions related to family
relationships, views about medical treatment (specifically hormone blockers and hormones),
and the relationship between medical treatment and sense of self. Results: Themes developed
focused on the importance of strong supportive parent-child relationships, the meaning of and
access to hormone blockers, and the meaning of and access to hormones. Discussion: The paper
concludes by discussing the implications of the findings for clinical services, particularly in
relation to supporting parents to be affirming of a transgender child, the need to prepare
transgender young people and their parents for the passage of time in regards to medical
treatment, and the need to focus on expectations in regards to sense of self in relation to
medical treatment. Copyright © 2019 Taylor & Francis Group, LLC.

Annotation: A qualitative, descriptive interview study that examined the views of TGNB
adolescents and their parents about medical treatments.

Shim JY, Laufer MR, Grimstad FW. Dysmenorrhea and Endometriosis in Transgender Adolescents. J
Pediatr Adolesc Gynecol. 2020;33(5):524-528. doi:10.1016/j.jpag.2020.06.001 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32535219

Abstract: STUDY OBJECTIVE: To study the presentation of dysmenorrhea and endometriosis in

transmasculine adolescents and review their treatment outcomes. DESIGN: A retrospective
review. SETTING: Boston Children's Hospital. PARTICIPANTS: Transmasculine persons younger
than 26 years old who were diagnosed with dysmenorrhea and treated between January 1, 2000

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 and March 1, 2020. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: An electronic
medical record review of the clinical characteristics, transition-related care, and treatment
outcomes. RESULTS: Dysmenorrhea was diagnosed in 35 transmasculine persons. Mean age was
14.9 years +/- 1.9 years. Twenty-nine (82.9%) were diagnosed after social transition. Twenty-
three of 35 (65.7%) were first treated with combined oral contraceptives, but 14/23 (61%)
discontinued or transitioned to alternative therapy. Twelve patients with dysmenorrhea alone
initiated testosterone treatment, and 4/12 (33.3%) experienced persistent symptoms. Seven of
35 patients with dysmenorrhea (20.0%) were laparoscopically evaluated for endometriosis, and
it was confirmed in all seven. Six had stage I disease, and one had stage II. Three of the 7 (42.9%)
were diagnosed after social transition, with one diagnosed 20 months after initiating
testosterone treatment. Their endometriosis was treated with combined oral contraceptives,
danazol, or progestins; four experienced suboptimal response during treatment with these
therapies alone. Two of those with suboptimal response subsequently resolved their
dysmenorrhea when using testosterone. Five patients with endometriosis initiated testosterone
treatment, and of the 5 (40%) experienced persistent symptomatology with combined
testosterone and progestin therapies. CONCLUSION: To our knowledge, this is the first study to
characterize endometriosis in transmasculine persons. Evaluation for endometriosis was
underutilized in transmasculine persons with dysmenorrhea, despite those who underwent
laparoscopic evaluation and had disease confirmation. Although testosterone treatment can
resolve symptoms in some, others might require additional suppression. Endometriosis should
be considered in transmasculine persons with symptoms even when they are using
testosterone.

Annotation: Examining treatment trajectories, risk factors, and endometriosis in transgender

males with dysmenorrhea

Spack NP, Edwards-Leeper L, Feldman HA, et al. Children and adolescents with gender identity disorder
referred to a pediatric medical center. Pediatrics. 2012;129(3):418-425. doi:10.1542/peds.2011-
0907 Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/22351896

Abstract: OBJECTIVES: To describe the patients with gender identity disorder referred to a
pediatric medical center. We identify changes in patients after creation of the multidisciplinary
Gender Management Service by expanding the Disorders of Sex Development clinic to include
transgender patients. METHODS: Data gathered on 97 consecutive patients <21 years, with
initial visits between January 1998 and February 2010, who fulfilled the following criteria: long-
standing cross-gender behaviors, provided letters from current mental health professional, and
parental support. Main descriptive measures included gender, age, Tanner stage, history of
gender identity development, and psychiatric comorbidity. RESULTS: Genotypic male:female
ratio was 43:54 (0.8:1); there was a slight preponderance of female patients but not significant
from 1:1. Age of presentation was 14.8 +/- 3.4 years (mean +/- SD) without sex difference (P =
.11). Tanner stage at presentation was 4.1 +/- 1.4 for genotypic female patients and 3.6 +/- 1.5
for genotypic male patients (P = .02). Age at start of medical treatment was 15.6 +/- 2.8 years.
Forty-three patients (44.3%) presented with significant psychiatric history, including 20
reporting self-mutilation (20.6%) and suicide attempts (9.3%). CONCLUSIONS: After
establishment of a multidisciplinary gender clinic, the gender identity disorder population
increased fourfold. Complex clinical presentations required additional mental health support as
the patient population grew. Mean age and Tanner Stage were too advanced for pubertal
suppressive therapy to be an affordable option for most patients. Two-thirds of patients were
started on cross-sex hormone therapy. Greater awareness of the benefit of early medical

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 intervention is needed. Psychological and physical effects of pubertal suppression and/or cross-
sex hormones in our patients require further investigation.

Annotation: A US-based descriptive study reporting on characteristics and treatment tragjectory

of N=97 patients with gender dysphoria, including percentages starting cross-sex hormone
treatment.

Steensma TD, Biemond R, de Boer F, Cohen-Kettenis PT. Desisting and persisting gender dysphoria after
childhood: a qualitative follow-up study. Clin Child Psychol Psychiatry. 2011;16(4):499-516.
doi:10.1177/1359104510378303 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/21216800

Abstract: The aim of this qualitative study was to obtain a better understanding of the
developmental trajectories of persistence and desistence of childhood gender dysphoria and the
psychosexual outcome of gender dysphoric children. Twenty five adolescents (M age 15.88,
range 14-18), diagnosed with a Gender Identity Disorder (DSM-IV or DSM-IV-TR) in childhood,
participated in this study. Data were collected by means of biographical interviews. Adolescents
with persisting gender dysphoria (persisters) and those in whom the gender dysphoria remitted
(desisters) indicated that they considered the period between 10 and 13 years of age to be
crucial. They reported that in this period they became increasingly aware of the persistence or
desistence of their childhood gender dysphoria. Both persisters and desisters stated that the
changes in their social environment, the anticipated and actual feminization or masculinization
of their bodies, and the first experiences of falling in love and sexual attraction had influenced
their gender related interests and behaviour, feelings of gender discomfort and gender
identification. Although, both persisters and desisters reported a desire to be the other gender
during childhood years, the underlying motives of their desire seemed to be different.

Annotation: A interview-based, qualitatively-analyzed descriptive study of desisting or persisting

Dutch TGNB adolescents

Stevens J, Gomez-Lobo V, Pine-Twaddell E. Insurance Coverage of Puberty Blocker Therapies for

Transgender Youth. Pediatrics. 2015;136(6):1029-1031. doi:10.1542/peds.2015-2849 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/26527547

Abstract: None

Annotation: Examines insurance barriers to treatment access among TGNB children seen in 2
University-based pediatric clinics (MedStar Washington Hospital Center and Chase Brexton
Health Care)

Strang JF, Jarin J, Call D, et al. Transgender Youth Fertility Attitudes Questionnaire: Measure
Development in Nonautistic and Autistic Transgender Youth and Their Parents. J Adolesc Health.
2018;62(2):128-135. doi:10.1016/j.jadohealth.2017.07.022 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29033160

Abstract: PURPOSE: The objective of this study was to assess transgender youth and parent
attitudes regarding (1) the potential impact of gender-affirming hormone therapy on fertility
and (2) fertility preservation (FP) options. METHODS: The Transgender Youth Fertility Attitudes
Questionnaire was developed through a multistage participatory process with gender specialists
and key stakeholders (transgender youth and their parents, N = 35). As up to 25% of youth

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 gender referrals have co-occurring autism, measure development included a well-characterized
supplementary sample of autistic transgender youth to maximize the applicability of the
questionnaire. Following its development and refinement, the Transgender Youth Fertility
Attitudes Questionnaire was pilot tested with transgender youth (nonautistic and autistic) and
their parents (N = 51). RESULTS: The participatory process produced parallel child and parent
questionnaires addressing fertility and FP knowledge and attitudes. In the pilot trial, youth and
parents expressed generally similar attitudes about fertility and FP. Most youth (92%) reported
learning about gender-affirming hormone therapy-related fertility issues online. Although many
transgender youth endorsed a wish to parent children at some point, few (24%) expressed
desire to have their own biological child. However, many youth wondered, or did not know, if
their feelings about having a biological child might change in the future. CONCLUSIONS: This
study presents a novel procedure for developing instruments for use with transgender youth.
Although a majority of transgender youth in this study were uninterested in using FP, extending
exploration of this topic with young people may be useful given findings of their openness to the
idea that fertility attitudes may change in adulthood.

Annotation: A qualitative comparison of attitudes about fertility preservation between autistic

and allistic TGNB youths

van der Loos M, Klink DT, Hannema SE, et al. Children and adolescents in the Amsterdam Cohort of
Gender Dysphoria: trends in diagnostic- and treatment trajectories during the first 20 years of
the Dutch Protocol. J Sex Med. 2023;20(3):398-409. doi:10.1093/jsxmed/qdac029 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36763938

Abstract: BACKGROUND: Twenty years ago, the Dutch Protocol-consisting of a gonadotropin-

releasing hormone agonist (GnRHa) to halt puberty and subsequent gender-affirming hormones
(GAHs)-was implemented to treat adolescents with gender dysphoria. AIM: To study trends in
trajectories in children and adolescents who were referred for evaluation of gender dysphoria
and/or treated following the Dutch Protocol. METHODS: The current study is based on a
retrospective cohort of 1766 children and adolescents in the Amsterdam Cohort of Gender
Dysphoria. OUTCOMES: Outcomes included trends in number of intakes, ratio of assigned sex at
birth, age at intake, age at start of GnRHa and GAH, puberty stage at start of GnRHa, proportions
of adolescents starting and stopping GnRHa, reasons for refraining from GnRHa, and proportions
of people undergoing gender-affirming surgery. RESULTS: A steep increase in referrals was
observed over the years. A change in the AMAB:AFAB ratio (assigned male at birth to assigned
female at birth) was seen over time, tipping the balance toward AFAB. Age at intake and at start
of GnRHa has increased over time. Of possibly eligible adolescents who had their first visit
before age 10 years, nearly half started GnRHa vs around two-thirds who had their first visit at
or after age 10 years. The proportion starting GnRHa rose only for those first visiting before age
10. Puberty stage at start of GnRHa fluctuated over time. Absence of gender dysphoria diagnosis
was the main reason for not starting GnRHa. Very few stopped GnRHa (1.4%), mostly because of
remission of gender dysphoria. Age at start of GAH has increased mainly in the most recent
years. When a change in law was made in July 2014 no longer requiring gonadectomy to change
legal sex, percentages of people undergoing gonadectomy decreased in AMAB and AFAB.
CLINICAL IMPLICATIONS: A substantial number of adolescents did not start medical treatment.
In the ones who did, risk for retransitioning was very low, providing ongoing support for medical
interventions in comprehensively assessed gender diverse adolescents. STRENGTHS AND
LIMITATIONS: Important topics on transgender health care for children and adolescents were
studied in a large cohort over an unprecedented time span, limited by the retrospective design.

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 CONCLUSION: Trajectories in diagnostic evaluation and medical treatment in children and
adolescents referred for gender dysphoria are diverse. Initiating medical treatment and need for
surgical procedures depends on not only personal characteristics but societal and legal factors
as well.

Annotation: Examines characteristics, treatment trajectories, and temporal trends in TGNB

adolescents over 20 years of applying the Dutch protocol in an Amsterdam clinic. Authors did
not specify affirmed gender identities, only natal sex: N = 689 AMAB and N = 1077 AFAB.
Reports the size of the ACOG as 8831 patients in 2018, up from 8210 in previous publication.

Vrouenraets LJ, Fredriks AM, Hannema SE, Cohen-Kettenis PT, de Vries MC. Perceptions of Sex, Gender,
and Puberty Suppression: A Qualitative Analysis of Transgender Youth. Arch Sex Behav.
2016;45(7):1697-1703. doi:10.1007/s10508-016-0764-9 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/27251640

Abstract: International guidelines recommend the use of Gonadotropin-Releasing Hormone

(GnRH) agonists in adolescents with gender dysphoria (GD) to suppress puberty. Little is known
about the way gender dysphoric adolescents themselves think about this early medical
intervention. The purpose of the present study was (1) to explicate the considerations of gender
dysphoric adolescents in the Netherlands concerning the use of puberty suppression; (2) to
explore whether the considerations of gender dysphoric adolescents differ from those of
professionals working in treatment teams, and if so in what sense. This was a qualitative study
designed to identify considerations of gender dysphoric adolescents regarding early treatment.
All 13 adolescents, except for one, were treated with puberty suppression; five adolescents
were trans girls and eight were trans boys. Their ages ranged between 13 and 18 years, with an
average age of 16 years and 11 months, and a median age of 17 years and 4 months.
Subsequently, the considerations of the adolescents were compared with views of clinicians
treating youth with GD. From the interviews with the gender dysphoric adolescents, three
themes emerged: (1) the difficulty of determining what is an appropriate lower age limit for
starting puberty suppression. Most adolescents found it difficult to define an appropriate age
limit and saw it as a dilemma; (2) the lack of data on the long-term effects of puberty
suppression. Most adolescents stated that the lack of long-term data did not and would not stop
them from wanting puberty suppression; (3) the role of the social context, for which there were
two subthemes: (a) increased media-attention, on television, and on the Internet; (b) an
imposed stereotype. Some adolescents were positive about the role of the social context, but
others raised doubts about it. Compared to clinicians, adolescents were often more cautious in
their treatment views. It is important to give voice to gender dysphoric adolescents when
discussing the use of puberty suppression in GD. Otherwise, professionals might act based on
assumptions about adolescents' opinions instead of their actual considerations. We encourage
gathering more qualitative research data from gender dysphoric adolescents in other countries.

Annotation: Examines perceptions and attitudes about gender in transgender youths

Vrouenraets LJJJ, de Vries ALC, Arnoldussen M, et al. Medical decision-making competence regarding
puberty suppression: perceptions of transgender adolescents, their parents and clinicians. Eur
Child Adolesc Psychiatry. 2022;32(11):2343-2361. doi:10.1007/s00787-022-02076-6 Accessed
September 15, 2023. Available at https://link.springer.com/content/pdf/10.1007/s00787-022-
02076-6.pdf

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 Abstract: According to international transgender care guidelines, transgender adolescents
should have medical decision-making competence (MDC) to start puberty suppression (PS) and
halt endogenous pubertal development. However, MDC is a debated concept in adolescent
transgender care and little is known about the transgender adolescents’, their parents’, and
clinicians’ perspectives on this. Increasing our understanding of these perspectives can improve
transgender adolescent care. A qualitative interview study with adolescents attending two
Dutch gender identity clinics (eight transgender adolescents who proceeded to gender-affirming
hormones after PS, and six adolescents who discontinued PS) and 12 of their parents, and focus
groups with ten clinicians was conducted. From thematic analysis, three themes emerged
regarding transgender adolescents’ MDC to start PS: (1) challenges when assessing MDC, (2)
aspects that are considered when assessing MDC, and (3) MDC’s relevance. The four criteria one
needs to fulfill to have MDC—understanding, appreciating, reasoning, communicating a
choice—were all, to a greater or lesser extent, mentioned by most participants, just as MDC
being relative to a specific decision and context. Interestingly, most adolescents, parents and
clinicians find understanding and appreciating PS and its consequences important for MDC.
Nevertheless, most state that the adolescents did not fully understand and appreciate PS and its
consequences, but were nonetheless able to decide about PS. Parents’ support of their child was
considered essential in the decision-making process. Clinicians find MDC difficult to assess and
put into practice in a uniform way. Dissemination of knowledge about MDC to start PS would
help to adequately support adolescents, parents and clinicians in the decision-making process.

Annotation: A qualitative interview/focus group study of TGNB adolescents who either

continued or discontinued treatment, and their parents. TGNB natal sexes reported only: 5
AMAB and 9 AFAB.

Vrouenraets LJJJ, de Vries MC, Hein IM, Arnoldussen M, Hannema SE, de Vries ALC. Perceptions on the
function of puberty suppression of transgender adolescents who continued or discontinued
treatment, their parents, and clinicians. International journal of transgender health.
2022;23(4):428-441. doi:10.1080/26895269.2021.1974324 Accessed September 15, 2023.
Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9621271/pdf/WIJT_23_1974324.pdf

Abstract: Purpose: Treatment of transgender adolescents with puberty suppression (PS) was
developed to provide time for exploration before pursuing gender affirming medical treatment
(GAMT) with irreversible effects. It may also result in a more satisfactory physical outcome for
those who continue with GAMT. Despite being the current first choice treatment, little research
has examined the function of PS from the perspectives of transgender adolescents, their
parents, and clinicians. Insight into the perceived functions of PS will help to adequately support
adolescents in their decision-making process and give them the care they need. Methods:
Qualitative study using interviews with eight transgender adolescents who proceeded with
GAMT after PS ("continuers"), six adolescents who discontinued PS ("discontinuers") and 12
parents, and focus groups with ten clinicians. Results: All informants considered inhibition of
development of secondary sex characteristics an important function of PS. Most continuers saw
PS as the first step of GAMT. Nevertheless, some were glad that the effects were reversible even
if they didn't expect to change their minds. Some discontinuers did experience PS as an
expanded diagnostic phase. One continuer used the time on PS to get used to living in the
affirmed gender role, and several parents found the time helpful to adapt to their child's new
gender role. PS provided clinicians more time for diagnostic assessment. Conclusions:
Adolescents, parents and clinicians do not all report the same functions of PS. Although

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 international guidelines emphasize providing time for exploration of gender identity as an
important reason for PS, many adolescents nowadays seem to have clear ideas about their
gender identity and treatment wishes, and experience PS as the first step of GAMT. For some
discontinuers however, PS offered a valued period of exploration. Guidelines could be modified
to provide more customized care, taking adolescents' and parents' ideas about the functions of
PS into account. Copyright © 2021 Leiden University Medical Center (LUMC). Published with
license by Taylor & Francis Group, LLC.

Annotation: A qualitative study examining perceptions about the function of puberty

suppression in TGNB adolescents who continued vs discontinued treatment, their parents, and
clinicians. TGNB natal sexes reported only: 5 AMAB and 9 AFAB.

Waldner RC, Doulla M, Atallah J, Rathwell S, Grimbly C. Leuprolide Acetate and QTc Interval in Gender-
Diverse Youth. Transgender Health. 2023;8(1):84-88. doi:10.1089/trgh.2021.0102 Accessed
September 15, 2023. Available at https://www.liebertpub.com/doi/10.1089/trgh.2021.0102

Abstract: Background: Puberty suppression is a standard of care for gender-affirming therapy in

gender-diverse youth. Leuprolide acetate is a gonadotropin-releasing hormone agonist (GnRHa)
commonly used for pubertal suppression. There are concerns that GnRHa agents prolong the
rate-corrected QT interval (QTc) when used as androgen deprivation therapy in management of
prostate cancer; however, there is a paucity of literature regarding the effect of leuprolide
acetate on QTc intervals in gender-diverse youth. Aim: To determine the proportion of gender-
diverse youth with QTc prolongation on leuprolide acetate therapy. Methods: A retrospective
chart review of gender-diverse youth initiated on leuprolide acetate between July 1, 2018 and
December 31, 2019 was conducted at a tertiary care pediatric hospital in Alberta, Canada. Youth
aged 9–18 years were included if a 12-lead electrocardiogram was completed after initiating
leuprolide acetate. The proportion of adolescents with clinically significant QTc prolongation
was assessed, defined as QTc > 460 milliseconds (ms). Results: Thirty-three pubertal youth were
included. The cohort had a mean age of 13.7 years (standard deviation [SD] 2.1) and 69.7%
identified as male (assigned female at birth). The mean post-leuprolide acetate QTc was 415 ms
(SD 27, range 372–455). Twenty-two (66.7%) of youth were prescribed concomitant
medications, including QTc-prolonging medications in 15.2%. None of the 33 youth on
leuprolide acetate had QTc prolongation. Only 24.2% patients had a borderline QTc (QTc 440–
460 ms). Conclusion: No gender-diverse youth on leuprolide acetate demonstrated clinically
significant QTc prolongation.

Annotation: A descriptive study examining QTc intervals of TGNB youths on leuprolide acetate

Warwick RM, Araya AC, Shumer DE, Selkie EM. Transgender Youths' Sexual Health and Education: A
Qualitative Analysis. J Pediatr Adolesc Gynecol. 2022;35(2):138-146.
doi:10.1016/j.jpag.2021.09.011 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34619356

Abstract: STUDY OBJECTIVE: To characterize transgender adolescents' sexual behaviors,

identities, and their perceived experiences with sex education. DESIGN: Semi-structured
interviews were conducted and addressed sexual experiences and perceptions of sex education
received from family, school educators, and healthcare providers. Interviews were audio
recorded, transcribed, and analyzed utilizing NVivo 12 software for thematic analysis. SETTING:
Child and adolescent gender services clinic at a Midwestern university-based medical center in

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 the United States. PARTICIPANTS: 30 transgender adolescents between the ages of 15 to 20.
INTERVENTIONS AND MAIN OUTCOME MEASURES: Themes generated during semi-structured
interviews. RESULTS: Sexual orientations were inclusive of attractions to a spectrum of gender
identities. Libido was perceived to be impacted by gender-affirming hormone therapy, which
was unanticipated for some adolescents. Family and school-based sex education was perceived
to be relevant only for heterosexual and cisgender adolescents. Inclusive education for
transgender adolescents was desired. Counseling provided by gender-affirming providers on
sexual health was trusted and other healthcare providers were perceived to lack training on
gender-inclusive care. CONCLUSION: This study demonstrated that families and school
educators did not provide sex education perceived to be applicable to transgender adolescents.
Similarly, healthcare providers of transgender adolescents were perceived to not provide
inclusive or comprehensive medical care in comparison to physicians who routinely provide
gender-affirming care. Gaps in education and healthcare could be improved with sex education
outreach or training for families and school educators as well as the development and
implementation of professional competencies for pediatricians on transgender adolescent
healthcare.

Annotation: Qualitative study examining sexual health and education outcomes in transgender
adolescents

Wiepjes CM, Nota NM, de Blok CJM, et al. The Amsterdam Cohort of Gender Dysphoria Study (1972-
2015): Trends in Prevalence, Treatment, and Regrets. J Sex Med. 2018;15(4):582-590.
doi:10.1016/j.jsxm.2018.01.016 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29463477

Abstract: BACKGROUND: Over the past decade, the number of people referred to gender
identity clinics has rapidly increased. This raises several questions, especially concerning the
frequency of performing gender-affirming treatments with irreversible effects and regret from
such interventions. AIM: To study the current prevalence of gender dysphoria, how frequently
gender-affirming treatments are performed, and the number of people experiencing regret of
this treatment. METHODS: The medical files of all people who attended our gender identity
clinic from 1972 to 2015 were reviewed retrospectively. OUTCOMES: The number of (and
change in) people who applied for transgender health care, the percentage of people starting
with gender-affirming hormonal treatment (HT), the estimated prevalence of transgender
people receiving gender-affirming treatment, the percentage of people who underwent
gonadectomy, and the percentage of people who regretted gonadectomy, specified separately
for each year. RESULTS: 6,793 people (4,432 birth-assigned male, 2,361 birth-assigned female)
visited our gender identity clinic from 1972 through 2015. The number of people assessed per
year increased 20-fold from 34 in 1980 to 686 in 2015. The estimated prevalence in the
Netherlands in 2015 was 1:3,800 for men (transwomen) and 1:5,200 for women (transmen). The
percentage of people who started HT within 5 years after the 1st visit decreased over time, with
almost 90% in 1980 to 65% in 2010. The percentage of people who underwent gonadectomy
within 5 years after starting HT remained stable over time (74.7% of transwomen and 83.8% of
transmen). Only 0.6% of transwomen and 0.3% of transmen who underwent gonadectomy were
identified as experiencing regret. CLINICAL IMPLICATIONS: Because the transgender population
is growing, a larger availability of transgender health care is needed. Other health care providers
should familiarize themselves with transgender health care, because HT can influence diseases
and interact with medication. Because not all people apply for the classic treatment approach,
special attention should be given to those who choose less common forms of treatment.

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 STRENGTHS AND LIMITATIONS: This study was performed in the largest Dutch gender identity
clinic, which treats more than 95% of the transgender population in the Netherlands. Because of
the retrospective design, some data could be missing. CONCLUSION: The number of people with
gender identity issues seeking professional help increased dramatically in recent decades. The
percentage of people who regretted gonadectomy remained small and did not show a tendency
to increase. Wiepjes CM, Nota NM, de Blok CJM, et al. The Amsterdam Cohort of Gender
Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets. J Sex Med
2018;15:582-590.

Annotation: First describes the Dutch ACOG cohort, adults, adolescents, and children with a
GD/TGNB diagnosis and at least one CEGD visit. Examines temporal trends in diagnosis,
treatment, and surgical interventions, as well as reporting on the proportions of subjects who
reported regret after gonadectomy in N=6793 transgender patients, including N=812
adolescents.

Eligible Studies Lacking High-priority Comparisons: Observational

Studies of TGNB Youth versus Special Populations (Bibliography Only)
77,157,261

Dilday EA, Bukulmez O, Saner K, Lopez X, Jarin J. Sperm Cryopreservation Outcomes in Transgender
Adolescents Compared with Adolescents Receiving Gonadotoxic Therapy. Transgend Health.
2022;7(6):528-532. doi:10.1089/trgh.2021.0037 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36644123

Abstract: PURPOSE: The target population for fertility preservation recently has been expanded
from adolescents with cancer undergoing gonadotoxic chemotherapy to include transgender
youth before initiating gender-affirming hormone therapy. Patients and providers may have
knowledge deficits regarding options for fertility preservation, accessibility, and feasibility of its
techniques, and impact of treatment on future fertility. This study describes outcomes of sperm
cryopreservation in transgender male-to-female (affirmed female) youth and compares semen
parameters with adolescents diagnosed with cancer. METHODS: Medical records of
transgender-affirmed female adolescents and adolescent males diagnosed with cancer who
underwent sperm cryopreservation at the Fertility and Advanced Reproductive Medicine clinic
of the University of Texas (UT) Southwestern Medical Center between March 2015 and March
2020 were reviewed. Demographic data were recorded and values for sperm parameters
(volume, count, total count, motility (%), total motile) were collected. When available, hormone
levels (luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol) and
Tanner stages were also assessed. The two populations were compared using chi-square
analysis and two-sample student's t-test. Data are presented as mean+/-standard deviation.
RESULTS: While semen quality parameters trended lower in transgender youth compared with
adolescents with cancer, there was no statistically significant difference between groups. While
four out of 18 patients in the transgender group had azoospermia, mean semen quality
parameters fell within normal adult reference ranges for both groups. CONCLUSION: Sperm
cryopreservation for transgender youth and adolescents with cancer is feasible, inexpensive,
and does not result in significant treatment delays. This information can improve counseling and
access to these procedures, particularly in the transgender population.

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 Annotation: A US-based cross-sectional study comparing sperm quality outcomes between
transgender females vs a special population (ie, cisgender males with cancer) at baseline (before
initiating treatment with gender-affirming hormones).

Mejia-Otero JD, White P, Lopez X. Effectiveness of Puberty Suppression with Gonadotropin-Releasing

Hormone Agonists in Transgender Youth. Transgend Health. 2021;6(1):31-35.
doi:10.1089/trgh.2020.0007 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33614957

Abstract: Purpose: To analyze the effectiveness of gonadotropin-releasing hormone agonists

(GnRHa) in suppressing the hypothalamic-pituitary gonadal (HPG) axis in transgender
adolescents. Methods: Retrospective review of electronic medical records of transgender youth
and children with central precocious puberty (CPP) treated with GnRHa. Blood levels of
luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and/or estradiol at
baseline and during treatment were compared between groups. Results: Data from 30
transgender and 30 patients with CPP were analyzed. Transgender patients were older with a
mean age of 13.0+/-2.1 years versus 7.7+/-2.3 years in the CPP group, p<0.001. There were
more patients assigned male at birth (AMAB) in the transgender group (56.7%) than males in the
CPP group (30%), p<0.001. The transgender group had more patients with advanced puberty
with 56% of patients having a Tanner stage of IV-V, versus none in the CPP group, p<0.01.
GnRHa treatment resulted in LH, FSH, and testosterone levels that were similar in males with
CPP versus transgender patients AMAB; suppression of LH and FSH levels was similar in females
with CPP versus transgender patients assigned female at birth, but estradiol levels were higher
in the latter (1.8+/-1.8 pg/mL vs. 9.4+/-9.7 pg/mL, respectively, p<0.001). FSH levels were lower
in the transgender group treated with histrelin (0.8+/-0.8 mIU/mL vs. 1.9+/-1.2 mIU/mL in the
leuprolide group, p=0.004). Conclusions: GnRHa are effective in suppressing the HPG axis in
transgender youth, similar to that observed in children with CPP.

Annotation: Compares puberty suppression outcomes in TGNB youth versus those with central
precocious puberty (CPP).

Van Donge N, Schvey NA, Roberts TA, Klein DA. Transgender Dependent Adolescents in the U.S. Military
Health Care System: Demographics, Treatments Sought, and Health Care Service Utilization. Mil
Med. 2019;184(5-6):e447-e454. doi:10.1093/milmed/usy264 Accessed September 15, 2023.
Available at https://watermark.silverchair.com/usy264.pdf

Abstract: INTRODUCTION: Transgender and gender-diverse (TGD) youth are at greater risk for
mental health and medical conditions than their cisgender peers; however, poor health
outcomes and identity-based discrimination can be minimized in the context of optimal support.
Approximately 1.7 million youth may be eligible for care covered by the Military Health System,
which includes mental health and gender-affirming medications. The purpose of the current
study is to identify sociodemographic characteristics, the psychosocial and behavioral risk
profile, and health care utilization patterns of TGD dependent youth cared for in the U.S.
military system to inform provider training and resource allocation. MATERIALS AND METHODS:
We performed a retrospective chart review by searching all medical records between July 1,
2014 and July 1, 2017 for diagnoses suggesting visits for TGD-services at a regional referral-
based adolescent medicine clinic which cares for dependent children of active duty, activated
selected reserve, and retired military service members between the ages of 9 and 24 years for a
wide range of health care needs. RESULTS: Fifty-three participants were included in this study.

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 Sixty-four percent reported a transmasculine identity, 21% a transfeminine identity, and 15% a
non-binary or undecided identity. The mean age at first gender-related visit was 14.5 years (SD
3.2). The mean number of primary care physicians and specialists seen by a given individual in a
military treatment facility for any visit type since the implementation of the medical record
system in 2005 was 12 (SD 6.8) and 10.2 (SD 7.8), respectively. Thirty-three percent of all
patients assigned as female at birth were on testosterone therapy and 23% of all patients
assigned as male at birth were on estrogen therapy at their most recent clinic visit. Twelve
patients were undergoing pubertal suppression with an injectable or implantable gonadotropin-
releasing hormone agonist. Seventy percent reported a history of suicidal ideation, 42% self-
harm, 21% at least one suicide attempt, and 33% psychiatric hospitalization. Having strongly
supportive parents was significantly associated with recognizing, disclosing and seeking
treatment for gender nonconformity at an earlier age (ps ≤ 0.03) and marginally associated with
less likelihood of current suicidal ideation (p = 0.06) compared to those with less supportive
parents. CONCLUSIONS: This study elucidated the sociodemographic and behavioral risk profile
of a sample of TGD youth in the MHS. Military and non-military health care providers across a
broad spectrum of specialties should be knowledgeable about the unique psychosocial and
medical needs, requisite sensitivity, and available referral options in the care of TGD youth.
Assumptions about one's gender identity, sexual orientation, gender expression, or behaviors
cannot be made based on birth-assigned sex. Further research is needed to investigate the
health and wellbeing of TGD military-affiliated youth over time and to determine quality
transgender-related services in support of this vulnerable and underserved population.

Annotation: A cross-sectional study examining mental health outcomes in TGNB adolescent

dependents of active-duty or retired US military personnel

Eligible Studies without High-priority Outcomes (Bibliography Only)

4,6,16,32,42,46,48,52,66,89,92,106,108,110,123,129,130,133,136,152,172,176,177,180,185,203,210,213,215,216,226-228,230,234,243,247,256,259,268,275

Akgül S, Bonny AE, Ford N, Holland-Hall C, Chelvakumar G. Experiences of Gender Minority Youth With
the Intrauterine System. J Adolesc Health. 2019;65(1):32-38.
doi:10.1016/j.jadohealth.2018.11.010 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30691940

Abstract: PURPOSE: The aim of the study was to evaluate the experience of menstruating
adolescents identifying as male or gender nonconforming with the levonorgestrel-releasing
intrauterine system (LNG-IUS) as a method of menstrual suppression and compare to that of
cisgender youth (CGY) using the LNG-IUS for noncontraceptive indications. METHODS: A
retrospective chart review of gender minority youth (GMY), aged 12-22 years, who self-selected
the 52 mg LNG-IUS for menstrual suppression between June 2014 and January 2018. GMY were
then matched for age and time of insertion with CGY. Subjects were contacted by telephone to
further explore LNG-IUS experience such as if the device was still in place, method satisfaction,
current bleeding patterns, and for GMY improvement in menstrual distress. RESULTS: Thirty
GMY had the LNG-IUS inserted during the study period, and 20 GMY were matched with CGY for
age and time of insertion. GMY were significantly more likely to receive sedation for LNG-IUS
insertion (50% vs. 15%, p = .04). Otherwise, the LNG-IUS experience was similar between
groups, including mean number of telephone/office visit encounters for an LNG-IUS concern,
expulsion and reinsertion rates, and need for additional medications to control bleeding. On
average, the mean months of use was 14.5 +/- 8.6 months in GMY and 14.6+/-11.5 in CGY (p =
.97). LNG-IUS removal was documented in three (15%) of GMY and five (25%) of CGY.

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 Improvement in menstrual distress was reported by 80% of GMY after the insertion of the LNG-
IUS. CONCLUSIONS: Overall experience with the LNG-IUS was similar for GMY and CGY, and
menstrual distress and bleeding pattern improved in the majority of GMY who self-selected this
method for menstrual suppression.

Annotation: A US cohort study examining menstrual suppression in transmasculine versus

cisgender adolescents.

Alaniz VI, Sheeder JL, Whitmore GT, et al. Menstrual Suppression in Adolescent and Young Adult
Transgender Males. J Pediatr Adolesc Gynecol. 2023;36(2):116-121.
doi:10.1016/j.jpag.2022.10.007 Accessed June 28, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L2021591277&from=expo
rt

Abstract: Objective: To describe time to cessation of menses in adolescent and young adult
transgender males with testosterone and/or other hormonal therapies Design: Retrospective
chart review Setting: Tertiary children's hospital Participants: Patients, aged 10-24, who began
gender-affirming hormonal therapy between January 2013 and January 2019 (n = 220)
Intervention(s): None Main Outcome Measure(s): Time to cessation of menses Results: Most
patients identified as transgender male or transmasculine (211/220, 95.9%), with an average
age of 15.8 (±1.9) years. Approximately 53.6% (118/220) of patients reported regular menstrual
cycles; 18.2% (40/220) reported irregular cycles. Median time to cessation of menses for all
patients was 182 days. Patients treated with testosterone alone (n = 105) reported a median
time to cessation of menses of 151 days. Patients who concurrently began testosterone and
norethindrone acetate (NETA) (n = 5) had a median time to cessation of menses of 188 days,
compared with 168 days for those on testosterone and depot medroxyprogesterone acetate
(DMPA, n = 15). In 15 patients who began testosterone, a progestin therapy was later added to
induce menstrual suppression, and the median time to cessation of menses was 168 days
(+DMPA, n = 4) or 56 days (+NETA, n = 11). Patients treated with NETA (n = 14) or depot
leuprolide (n = 11) reported a median time to cessation of menses of 78 days or 77 days,
respectively. Considerable variability in prescribing patterns was noted in the remaining 36.4%
of patients (n = 80). Conclusion: Patients used a variety of different hormonal regimens for
menstrual suppression. Less than half achieved cessation of menses within 6 months. NETA and
depot leuprolide users reported the most rapid cessation of menses.

Annotation: Examines time to menstrual suppression in transmasculine and gender expansive

youths receiving GAHT, including testosterone

Baram S, Myers SA, Yee S, Librach CL. Fertility preservation for transgender adolescents and young
adults: a systematic review. Hum Reprod Update. 2019;25(6):694-716.
doi:10.1093/humupd/dmz026 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31633751

Abstract: BACKGROUND: Many transgender individuals choose to undergo gender-affirming

hormone treatment (GAHT) and/or sex reassignment surgery (SRS) to alleviate the distress that
is associated with gender dysphoria. Although these treatment options often succeed in
alleviating such symptoms, they can also negatively impact future reproductive potential.
OBJECTIVE AND RATIONALE: The purpose of this systematic review was to synthesize the
available psychosocial and medical literature on fertility preservation (FP) for transgender

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 adolescents and young adults (TAYAs), to identify gaps in the current research and provide
suggestions for future research directions. SEARCH METHODS: A systematic review of English
peer-reviewed papers published from 2001 onwards, using the preferred reporting items for
systematic reviews and meta-analyses protocols (PRISMA-P) guidelines, was conducted. Four
journal databases (Ovid MEDLINE, PubMed Medline, Ovid Embase and Ovid PsychINFO) were
used to identify all relevant studies exploring psychosocial or medical aspects of FP in TAYAs.
The search strategy used a combination of subject headings and generic terms related to the
study topic and population. Bibliographies of the selected articles were also hand searched and
cross-checked to ensure comprehensive coverage. All selected papers were independently
reviewed by the co-authors. Characteristics of the studies, objectives and key findings were
extracted, and a systematic review was conducted. OUTCOMES: Included in the study were 19
psychosocial-based research papers and 21 medical-based research papers that explore fertility-
related aspects specific for this population. Key psychosocial themes included the desire to have
children for TAYAs; FP discussions, counselling and referrals provided by healthcare providers
(HCPs); FP utilization; the attitudes, knowledge and beliefs of TAYAs, HCPs and the
parents/guardians of TAYAs; and barriers to accessing FP. Key medical themes included fertility-
related effects of GAHT, FP options and outcomes. From a synthesis of the literature, we
conclude that there are many barriers preventing TAYAs from pursuing FP, including a lack of
awareness of FP options, high costs, invasiveness of the available procedures and the potential
psychological impact of the FP process. The available medical data on the reproductive effects of
GAHT are diverse, and while detrimental effects are anticipated, the extent to which these
effects are reversible is unknown. WIDER IMPLICATIONS: FP counselling should begin as early as
possible as a standard of care before GAHT to allow time for informed decisions. The current
lack of high-quality medical data specific to FP counselling practice for this population means
there is a reliance on expert opinion and extrapolation from studies in the cisgender population.
Future research should include large-scale cohort studies (preferably multi-centered),
longitudinal studies of TAYAs across the FP process, qualitative studies of the parents/guardians
of TAYAs and studies evaluating the effectiveness of different strategies to improve the
attitudes, knowledge and beliefs of HCPs.

Annotation: A systematic review examining fertility outcomes in TGNB adolescents and young
adults.

Burke SM, van Heesewijk JO, Menks WM, et al. Postnatal Effects of Sex Hormones on Click-Evoked
Otoacoustic Emissions: A Study of Adolescents with Gender Dysphoria. Arch Sex Behav.
2020;49(2):455-465. doi:10.1007/s10508-020-01652-8 Accessed September 15, 2023. Available
at https://orbi.uliege.be/bitstream/2268/259356/1/BurkeArchSexBehav%202020.pdf

Abstract: Click-evoked otoacoustic emissions (CEOAEs) are echo-like sounds, generated by the
inner ear in response to click-stimuli. A sex difference in emission strength is observed in
neonates and adults, with weaker CEOAE amplitudes in males. These differences are assumed to
originate from testosterone influences during prenatal male sexual differentiation and to remain
stable throughout life. However, recent studies suggested activational, postnatal effects of sex
hormones on CEOAEs. Adolescents diagnosed with gender dysphoria (GD) may receive
gonadotropin-releasing hormone analogs (GnRHa) in order to suppress endogenous sex
hormones and, therefore, pubertal maturation, followed by cross-sex hormone (CSH) treatment.
Using a cross-sectional design, we examined whether hormonal interventions in adolescents
diagnosed with GD (62 trans boys, assigned female at birth, self-identifying as male; 43 trans
girls, assigned male at birth, self-identifying as female), affected their CEOAEs compared to age-

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 and sex-matched controls (44 boys, 37 girls). Sex-typical differences in CEOAE amplitude were
observed among cisgender controls and treatment-naïve trans boys but not in other groups with
GD. Treatment-naïve trans girls tended to have more female-typical CEOAEs, suggesting
hypomasculinized early sexual differentiation, in support of a prominent hypothesis on the
etiology of GD. In line with the predicted suppressive effects of androgens, trans boys receiving
CSH treatment, i.e., testosterone plus GnRHa, showed significantly weaker right-ear CEOAEs
compared with control girls. A similar trend was seen in trans boys treated with GnRHa only.
Unexpectedly, trans girls showed CEOAE masculinization with addition of estradiol. Our findings
show that CEOAEs may not be used as an unequivocal measure of prenatal androgen exposure
as they can be modulated postnatally by sex hormones, in the form of hormonal treatment.

Annotation: A cross-sectional study examining the effect of GnRH agonists and sex hormones on
click-evoked otoacoustic emissions in TGNB adolescents. Also compares TGNB adolescents to
cisgender peers.

Chen D, Matson M, Macapagal K, et al. Attitudes Toward Fertility and Reproductive Health Among
Transgender and Gender-Nonconforming Adolescents. J Adolesc Health. 2018;63(1):62-68.
doi:10.1016/j.jadohealth.2017.11.306 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29503031

Abstract: PURPOSE: Little is known about the reproductive desires of transgender and gender-
nonconforming (TGNC) adolescents who may seek gender-affirming medical care that leads to
infertility. The current study addressed this gap by examining attitudes toward fertility and
family formation in a diverse sample of TGNC youth. METHOD: An online survey about
sexual/reproductive health in sexual and gender minority (SGM) adolescents ages 14-17 years
was conducted from September to October 2016. RESULTS: A total of 156 TGNC adolescents
(M(age) = 16.1 years; 83.3% assigned female at birth; 58.3% youth of color) responded. Overall,
70.5% of TGNC adolescents were interested in adoption and 35.9% in biological parenthood;
more gender-nonconforming youth (43.8%) than transgender youth (25.8%) expressed interest
in biological fertility. Discussions with health-care providers about fertility and reproductive
health were uncommon-only 20.5% of youth had discussed fertility in general and only 13.5%
had discussed effects of hormones on fertility. However, 60.9% of respondents were interested
in learning more about their fertility and family building options. Key themes emerging from
qualitative comments included concerns related to fertility/reproductive health (e.g., stigma of
SGM parenthood, effect of gender-affirming treatments on fertility), and the need for additional
reproductive health information both tailored to their individual experience and for SGM
individuals more generally. DISCUSSION: TGNC adolescents expressed interest in multiple family
building options, including adoption and biological parenthood, and identified a need for more
information about these options. Thus, clinicians working with adolescents should be aware of
the unique fertility and reproductive health needs of TGNC youth.

Annotation: A survey study examining attitudes about fertility among TGNB adolescents who
were participants in a larger study about sexual health and HIV prevention

Chiniara LN, Viner C, Palmert M, Bonifacio H. Perspectives on fertility preservation and parenthood
among transgender youth and their parents. Arch Dis Child. 2019;104(8):739-744.
doi:10.1136/archdischild-2018-316080 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30894340

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 Abstract: OBJECTIVE: The aim of this study was to investigate the views of young people (YP)
with gender dysphoria and their parents concerning fertility preservation and reproductive and
life priorities. DESIGN: A cross-sectional questionnaire-based study assessed knowledge of
potential effects of treatments for gender dysphoria on fertility, current and future life priorities
and preferences regarding future fertility/parenting options among YP and parents. RESULTS: A
total of 79 YP (81% assigned female at birth [AFAB], 19% assigned male at birth [AMAB], aged
12-18 years, 68% between ages 16 years and 18 years) and 73 parents participated. The top
current life priority for YP among eight options was being in good health; the least important
priority was having children. Anticipated life priorities 10 years from now were ranked similarly.
Parents' rankings paralleled the YP responses; however, parents ranked having children as a
significantly higher priority for AFAB compared with AMAB YP in 10 years. The majority of YP
(66% AFAB, 67% AMAB) want to be a parent in the future. However, most do not envision
having a biological child. A large majority (72% AFAB, 80% AMAB) were open to adoption. None
of the YP surveyed pursued fertility preservation. CONCLUSION: Fertility is a low current and
future life priority for transgender YP. The majority of YP wish to become parents but are open
to alternative strategies for building a family. These data may explain in part the reported low
rates of fertility preservation among this population. Further studies are needed to assess if life
priorities change over time.

Annotation: A Toronto-based cross-sectional study of TGNB adolescents and their parents

examining fertility- and treatment-related questionnaire responses

Chu L, Gold S, Harris C, et al. Incidence and Factors Associated With Acne in Transgender Adolescents on
Testosterone: A Retrospective Cohort Study. Endocr Pract. 2023;29(5):353-355.
doi:10.1016/j.eprac.2023.02.002 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36889581

Abstract: OBJECTIVE: This retrospective cohort study aimed to assess incidence and predictors
of acne among transgender adolescents receiving testosterone. METHODS: We analyzed records
of patients aged <18 years, assigned female at birth, seen at Children's Healthcare of Atlanta
Pediatric Endocrinology clinic for testosterone initiation between January 1, 2016, and January
1, 2019, with at least 1-year follow-up documented. Bivariable analyses to determine the
association of clinical and demographic factors with new acne diagnosis were performed.
RESULTS: Of 60 patients, 46 (77%) did not have baseline acne, but of those 46 patients, 25 (54%)
developed acne within 1 year of testosterone initiation. Overall incidence proportion was 70% at
2 years; patients who used progestin prior to or during follow-up were more likely to develop
acne than nonusers (92% vs 33%, P <.001). CONCLUSION: Transgender adolescents starting
testosterone, particularly those taking progestin, should be monitored for acne development
and treated proactively by hormone providers and dermatologists.

Annotation: Examines acne outcomes in transmasculine adolescents receiving testosterone in a

pediatric endocrinology clinic

Cohen A, Gomez-Lobo V, Willing L, et al. Shifts in Gender-Related Medical Requests by Transgender and
Gender-Diverse Adolescents. J Adolesc Health. 2023;72(3):428-436.
doi:10.1016/j.jadohealth.2022.10.020 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36529618

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 Abstract: PURPOSE: Gender-affirming hormones and/or surgeries seeking to change the body
can have potentially lasting effects. Changes in requests for these therapies among gender-
diverse youth are not well-understood. The study aim is to characterize factors associated with
shifts in gender-related medical requests. METHODS: This mixed-methods study used
retrospective chart review and qualitative interviews with clinicians. Of 130 youth receiving
clinical gender care at Children's National Hospital, 68 met inclusion criteria. Qualitative
interview analysis was performed to identify patterns and themes around shifts in gender-
related medical requests over time. Statistical analysis employed chi-square and t-tests to
compare characteristics in the shift versus no-shift groups and kappa statistics to calculate
qualitative coding agreement. RESULTS: Of the 68 youth followed over time (mean age 15.11
years, 47% autistic, 22% nonbinary), 20 (29%) reported a shift in request. No significant
differences were found by age, autism status, or designated sex at birth. More youth with shifts
were nonbinary (p = .012). Six shift profiles were identified from qualitative interviews with
excellent reliability (kappa = 0.865). Four of the profiles reflect shifts in request prior to starting
treatment (85% sample); two involved shifts after commencing treatment (15%). The most
common profile reflected a medical request that was made, withdrawn, and re-requested
(45%). DISCUSSION: Shifts in gender-affirming medical requests by gender-diverse youth may
not be uncommon during the adolescent's gender discernment process, and may more likely
occur among nonbinary youth. Many individuals who experience shifts away from medical
treatment may later resume the request.

Annotation: A case-control study examining potential predictors of GD treatment

discontinuation in TGNB adolescents in a gender services program. Only natal sex (29 AMAB and
39 AFAB) and transbinary/nonbinary were reported.

de Nie I, Mulder CL, Meissner A, et al. Histological study on the influence of puberty suppression and
hormonal treatment on developing germ cells in transgender women. Hum Reprod.
2022;37(2):297-308. doi:10.1093/humrep/deab240 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34791270

Abstract: STUDY QUESTION: Can transgender women cryopreserve germ cells obtained from
their orchiectomy specimen for fertility preservation, after having used puberty suppression
and/or hormonal treatment? SUMMARY ANSWER: In the vast majority of transgender women,
there were still immature germ cells present in the orchiectomy specimen, and in 4.7% of
transgender women-who all initiated medical treatment in Tanner stage 4 or higher-mature
spermatozoa were found, which would enable cryopreservation of spermatozoa or testicular
tissue after having used puberty suppression and/or hormonal treatment. WHAT IS KNOWN
ALREADY: Gender affirming treatment (i.e. puberty suppression, hormonal treatment, and
subsequent orchiectomy) impairs reproductive function in transgender women. Although semen
cryopreservation is generally offered during the transition process, this option is not feasible for
all transgender women (e.g. due to incomplete spermatogenesis when initiating treatment in
early puberty, in case of inability to masturbate, or when temporary cessation of hormonal
treatment is too disruptive). Harvesting mature spermatozoa, or testicular tissue harboring
immature germ cells, from orchiectomy specimens obtained during genital gender-affirming
surgery (gGAS) might give this group a chance of having biological children later in life. Previous
studies on spermatogenesis in orchiectomy specimens showed conflicting results, ranging from
complete absence of germ cells to full spermatogenesis, and did not involve transgender women
who initiated medical treatment in early- or late puberty. STUDY DESIGN, SIZE, DURATION:
Histological and immunohistochemical analyses were performed on orchiectomy specimens

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 from 214 transgender women who underwent gGAS between 2006 and 2018. Six subgroups
were identified, depending on pubertal stage at initiation of medical treatment (Tanner stage 2-
3, Tanner stage 4-5, adult), and whether hormonal treatment was continued or temporarily
stopped prior to gGAS in each of these groups. PARTICIPANTS/MATERIALS, SETTING, METHODS:
All transgender women used a combination of estrogens and testosterone suppressing therapy.
Orchiectomy specimen sections were stained with Mayer's hematoxylin and eosin and
histologically analyzed to assess the Johnsen score and the ratio of most advanced germ cell
types in at least 50 seminiferous tubular cross-sections. Subsequently, immunohistochemistry
was used to validate these findings using spermatogonia, spermatocytes or spermatids markers
(MAGE-A3/A4, gammaH2AX, Acrosin, respectively). Possibilities for fertility preservation were
defined as: preservation of spermatozoa, preservation of spermatogonial stem cells or no
possibilities (in case no germ cells were found). Outcomes were compared between subgroups
and logistic regression analyses were used to assess the association between the duration of
hormonal treatment and the possibilities for fertility preservation. MAIN RESULTS AND THE
ROLE OF CHANCE: Mature spermatozoa were encountered in 4.7% of orchiectomy specimens,
all from transgender women who had initiated medical treatment in Tanner stage 4 or higher. In
88.3% of the study sample orchiectomy specimens only contained immature germ cells (round
spermatids, spermatocytes or spermatogonia, as most advanced germ cell type). In 7.0%, a
complete absence of germ cells was observed, all these samples were from transgender women
who had initiated medical treatment in adulthood. Cessation of hormonal treatment prior to
gGAS did not affect the presence of germ cells or their maturation stage, nor was there an effect
of the duration of hormonal treatment prior to gGAS. LIMITATIONS, REASONS FOR CAUTION:
Since data on serum hormone levels on the day of gGAS were not available, we were unable to
verify if the transgender women who were asked to temporarily stop hormonal treatment 4
weeks prior to surgery actually did so, and if people with full spermatogenesis were compliant
to treatment. WIDER IMPLICATIONS OF THE FINDINGS: There may still be options for fertility
preservation in orchiectomy specimens obtained during gGAS since a small percentage of
transgender women had full spermatogenesis, which could enable cryopreservation of mature
spermatozoa via a testicular sperm extraction procedure. Furthermore, the vast majority still
had immature germ cells, which could enable cryopreservation of testicular tissue harboring
spermatogonial stem cells. If maturation techniques like in vitro spermatogenesis become
available in the future, harvesting germ cells from orchiectomy specimens might be a promising
option for those who are otherwise unable to have biological children. STUDY
FUNDING/COMPETING INTEREST: None. TRIAL REGISTRATION NUMBER: N/A.

Annotation: A cohort study comparing potential for fertility preservation in transgender

women, including adolescents, who initiated cross-sex hormones at different pubertal stages at
a gender specialty clinic

Garborcauskas G, McCabe E, Boskey ER, Grimstad FW. Family Building Perspectives of Assigned Female
at Birth Transgender and Gender Diverse Adolescents Seeking Testosterone Gender-Affirming
Hormone Therapy. LGBT Health. 2022;9(7):463-470. doi:10.1089/lgbt.2022.0004 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/35802494

Abstract: Purpose: The purpose of this study was to assess the future family building desires of
assigned female at birth (AFAB) transgender and gender diverse (TGD) adolescents initiating
hormone therapy, and to characterize the individuals interested in adoption. Methods: This was
a retrospective chart review of AFAB TGD adolescents ages 15-17 years old initiating
testosterone gender-affirming hormone therapy between 2010 and 2019, analyzing interest in

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 adoption, demographics, and gender-affirming care. Results: Of 195 AFAB TGD adolescents
asked about family planning goals, 58% (n = 113) indicated desire for adoption in their future,
and 13.3% (n = 26) had no desire for children. There was no difference between those who did
and did not want to adopt in terms of age at time of first visit (p = 0.22), or race distribution (p =
0.45); however, straight-identified patients were more likely to desire adoption (p = 0.02) than
people with other sexual orientations. Fifty-nine percent (n = 110) of those who did not have a
history of adoption and/or experience with the child welfare system desired adoption,
compared with 22% (n = 2) of those with a history (odds ratio, 5.14; 95% confidence interval,
1.04-25.39; p = 0.05). Conclusion: Some AFAB TGD adolescents endorse adoption as their
desired pathway to parenthood. Clinicians should be sensitive to the complexities of parenthood
desires of AFAB TGD patients and have resources to direct patients to more information. Further
research is needed to better understand why many AFAB TGD adolescents desire adoption, how
this changes with age, and the barriers they face in achieving their goals.

Annotation: Cohort study examining predictors of fertility beliefs and attitudes in testosterone-
treated TGNB adolescents ages 15-17 years

Gilani M, Wallach P, Kyriakou A. Levels of physical activity and barriers to sport participation in young
people with gender dysphoria. J Pediatr Endocrinol Metab. 2021;34(6):747-753.
doi:10.1515/jpem-2021-0007 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33818040

Abstract: OBJECTIVES: To determine the levels of physical activity (PA) in young people with
gender dysphoria (GD) and help identify factors which deter participation. METHODS: Fifty-six
young people who attended paediatric endocrinology because of GD, June to October 2019, and
were on treatment with gonadotrophin-releasing hormone (GnRH) analogue were approached
to participate in a survey. RESULTS: A total of 55 young people (98%) responded to the survey.
Thirty-eight (69%) participated in PA for >1 h/week. Thirty-two (58%) reported high motivation
level for exercise. Those had median age of 15.9 years (10.7, 18.7) at the time of survey, and
13.6 years (9.7, 17.6) at start of GnRH analogue compared to 16.7 years (13.9, 18.5) (p, 0.047)
and 15.4 years (11.2, 18.0) (p, 0.009) of the 23 (42%) who reported low motivation. Forty-one
(74.5%) reported barriers when accessing PA, such as not being as good as others (75%),
revealing sports clothing (73%) and not satisfied with body image (47%). Those were older (16.4
years [10.9, 18.7] vs. 14.7 years [10.7, 18.4] [p, 0.011]) at the time of survey and at start of GnRH
analogue (14.9 years [9.7, 18.0] vs. 12.5 years [10.6, 15.2] [p, 0.0001]) than those 14 (25.5%)
who reported facing no barriers. Twelve (85.7%) of those reporting no barriers stated high
motivation levels compared to 20 (48.8%) of those reporting barriers (p, 0.026). CONCLUSIONS:
Strategies aimed at improving participation are twofold: first to improve motivation, especially
in post-pubertal young people, and secondly to achieve societal change to help eliminate
barriers.

Annotation: A Scotland-based cross-sectional study examining sports participation and

motivation levels in TGNB adolescents treated with GnRHa and a subset with cross-sex
hormones.

Hranilovich JA, Millington K. Headache prevalence in transgender and gender diverse youth: A single-
center case-control study. Headache. 2023;63(4):517-522. doi:10.1111/head.14493 Accessed
June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36988085

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 Abstract: OBJECTIVE: Assess the prevalence of headache in transgender and gender-diverse
adolescents, comparing prevalence with and without exposure to gender-affirming hormone
therapy. BACKGROUND: Transgender and gender-diverse youth are an understudied group in
whom we can study the effects of sex steroids on adolescents' development of headache. We
hypothesized that transfeminine adolescents treated with estrogen would have higher odds of
headache than those not treated, and that transmasculine adolescents treated with
testosterone would have lower odds of headache than those not treated. METHODS: This
retrospective case-control study analyzed all patients seen at the Boston Children's Hospital
Gender Multispecialty Service clinic from 2007 to 2017. Cases were defined as patients with
headache, controls as those without headache, and exposure as treatment with gender-
affirming hormone therapy (i.e., estrogen or testosterone). A computerized search identified
cases that were then validated by chart review. RESULTS: Fifty-two of the 763 transgender and
gender-diverse patients seen were confirmed to have headache. Of 273 transfeminine patients
45% (123/273) received estrogen treatment. Transfeminine patients receiving estrogen were
more likely to have headache than those not receiving estrogen (7% [9/123] vs. 1% [2/150]; odd
ratio [OR] 5.84 (95% confidence interval [CI] 1.24-27.6), p = 0.026). Of 490 transmasculine
patients, 46% (227/490) received testosterone. Transmasculine patients receiving testosterone
were more likely to have headache than those not receiving testosterone (12% [28/227] vs. 5%
(13/263); OR 2.71 (95% CI 1.37-5.4), p = 0.005). CONCLUSION: Among transfeminine and
transmasculine youth, those who received gender-affirming hormone therapy had higher odds
of headache compared to those not taking gender-affirming hormone therapy. Further
prospective studies to guide headache care of transgender and gender-diverse youth and adults
are needed. Our results could be generalizable to other pediatric gender management clinics
and may be worth discussing with patients considering treatment.

Annotation: A cumulative case-control study comparing risks of headache in TGNB patients

receiving testosterone/estrogen versus not.

James HA, Chang AY, Imhof RL, et al. A community-based study of demographics, medical and
psychiatric conditions, and gender dysphoria/incongruence treatment in transgender/gender
diverse individuals. Biol Sex Differ. 2020;11(1):55. doi:10.1186/s13293-020-00332-5 Accessed
September 15, 2023. Available at https://bsd.biomedcentral.com/counter/pdf/10.1186/s13293-
020-00332-5.pdf

Abstract: BACKGROUND: Current understanding about health care in the gender diverse
population is limited by the lack of community-based, longitudinal data, especially in the USA.
We sought to characterize a community-based cohort of transgender individuals including
demographics, gender identities, social characteristics, psychiatric and medical conditions, and
medical therapy for gender dysphoria/incongruence. PATIENTS AND METHODS: We performed a
retrospective chart review of gender diverse residents of Olmsted County, Minnesota, who
sought gender-specific healthcare from January 1, 1974, through December 31, 2015, using an
infrastructure that links medical records of Olmsted County residents from multiple institutions.
RESULTS: The number of patients seeking gender-specific healthcare increased from 1 to 2 per
5-year interval during the 1970s-1990s to 41 from 2011 to 2015 (n = 82). Forty-nine (59.8%)
were assigned male sex at birth (AMAB), 31 (37.8%) were assigned female (AFAB), and 2 (2.4%)
were intersex. Gender identities evolved over time in 16.3% and 16.1% of patients AMAB and
AFAB, respectively, and at most recent follow-up, 8.2% and 12.9% of patients AMAB and AFAB,
respectively, were non-binary. Depression affected 78%, followed by anxiety (62.2%),
personality disorder (22%), and post-traumatic stress disorder (14.6%). 58.5% experienced

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 suicidal ideation, 22% attempted suicide, and 36.6% were victims of abuse. The most prevalent
medical conditions and cardiovascular (CV) risk factors included obesity (42.7%), tobacco use
(40.2%), fracture [34.1% (86.2% traumatic)], hypertension (25.6%), hyperlipidemia (25.6%), and
hypertriglyceridemia (15.9%). 67.3% of patients AMAB used feminizing and 48.4% of patients
AFAB used masculinizing hormone therapy. When compared to US CDC National Health
Statistics, there was a significantly greater prevalence of depression and anxiety but no
difference in the prevalence of obesity, hypertension, hypercholesterolemia, type 2 diabetes, or
stroke. CONCLUSION: Transgender and gender diverse individuals represent a population who
express various gender identities and are seeking gender-specific healthcare at increasing rates.
Psychiatric illness is highly prevalent compared to the US population but there is no difference in
the prevalence of CV risk factors including obesity, type 2 diabetes, hypertension, and
dyslipidemia.

Annotation: Examines changes in gender identity between AFAB and AMAB TGNB patients,
including adolescents. Outcomes of interest were not reported separately for adolescents.

Jensen RK, Jensen JK, Simons LK, Chen D, Rosoklija I, Finlayson CA. Effect of Concurrent Gonadotropin-
Releasing Hormone Agonist Treatment on Dose and Side Effects of Gender-Affirming Hormone
Therapy in Adolescent Transgender Patients. Transgend Health. 2019;4(1):300-303.
doi:10.1089/trgh.2018.0061 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31663037

Abstract: This retrospective chart review aims to address gaps in the literature regarding the
efficacy and interaction of gonadotropin-releasing hormone agonists (GnRHa) and gender-
affirming hormone therapies in medical transition regimens in transgender adolescents. We
abstracted and reviewed data from 83 patients at our pediatric gender clinic, and found that
patients who initiated treatment with GnRHa before gender-affirming hormones (estrogen,
testosterone) required lower doses of those hormones than those who did not use GnRHa. The
results of this preliminary research provide a foundation for future long-term prospective
studies aimed to better understand these relationships.

Annotation: A cohort study comparing demographic characteristics, adverse effects, and

estrogen/testosterone dosages between transgender patients receiving GnRH agonists versus
not.

Komorowski AS, Fisher AR, Jungheim ES, Lewis CS, Omurtag KR. Fertility preservation discussions,
referral and follow-up in male-to-female and female-to-male adolescent transgender patients.
Hum Fertil (Camb). 2021, 10.1080/14647273.2021.2015804:1-5.
doi:10.1080/14647273.2021.2015804 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34915792

Abstract: The number of patients seeking transgender healthcare is growing, and there is a
potential impact of gender-affirming therapies on fertility. The use of fertility preservation (FP),
particularly among transgender adolescents, has been limited. We aimed to examine differences
in FP counselling, referral and utilisation between male-to-female (MtF) and female-to-male
(FtM) transgender adolescents. A retrospective review of the medical records of patients ages
12-17 seen at an academic medical centre between 2012 and 2017 with a diagnosis of gender
dysphoria was conducted. A total of 22 MtF and 45 FtM adolescents were included. The
counselling on the potential fertility impact of gender-affirming therapy was documented in

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 55%, and of those counselled, 73% were counselled before receiving medication. There was no
significant difference between the timing of counselling for MtF versus FtM adolescents. Of
patients with documented reproductive wishes, 77% reported either desire for adopted children
or no desire for biological children. Among patients offered FP referral, 2 (22.2%) MtF and 3
(12.5%) FtM patients accepted; both MtF patients cryopreserved sperm. While most
adolescents were counselled on the fertility impact of gender-affirming therapy, there is room
for improvement as 45% of patients had no documented counselling. The rate of transgender
adolescents pursuing FP consultation and gamete cryopreservation was low, consistent with
prior studies in this population.

Annotation: A US-based cohort study examining fertility-related outcomes in n=67 TGNB

adolescents seen in a specialty clinic.

Kyweluk MA, Sajwani A, Chen D. Freezing for the future: Transgender youth respond to medical fertility
preservation. International Journal of Transgenderism. 2018;19(4):401-416.
doi:10.1080/15532739.2018.1505575 Accessed September 15, 2023. Available at
https://doi.org/10.1080/15532739.2018.1505575

Annotation: A qualitative, descriptive interview study examining ethical considerations related

to fertility preservation in TGNB youth and their parents

Lambert A, Pratt A, Conard LAE, et al. Supporting Gender-Related Medical Decision Making for
Transgender and Gender-Diverse Individuals: A Scoping Review. Transgend Health.
2023;8(2):113-123. doi:10.1089/trgh.2021.0030 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/37013094

Abstract: PURPOSE: Transgender and gender-diverse (TGD) individuals and their families face
numerous challenging decisions. To better understand their decision processes, we conducted a
scoping review of the existing literature and of decision-support tools in use at pediatric gender-
care clinics. METHODS: We searched PubMed, EMBASE, Scopus CINAHL, PsychINFO, and EBM
Reviews for studies that were original research focused on decisions, decision making, or
decision support for TGD individuals and/or their families. All studies were reviewed for
inclusion by at least two researchers. Additionally, we reviewed clinical tools used to support
decision making by TGD youth and their families. RESULTS: We retrieved 3306 articles. Thirty-
two met criteria for data extraction. Studies focused on three major decisions: gender-
confirming surgery, fertility preservation, and gender-affirming hormone therapy. Several
themes that cut across clinical topics emerged: decision-making processes, decision-making
roles, and sources of decision support. Only three articles focused on decision-support
interventions, two of which discussed development of support tools and one evaluated a class
designed to help with surgical decision making. None of the clinical tools reviewed met criteria
for a decision aid. CONCLUSIONS: There is a dearth of studies related to decision support
interventions, an absence validated by the resources currently in clinical use. This scoping
review suggests an opportunity for the development of tools to aid in the decision-making
processes for TGD youth and their families.

Annotation: A scoping review examining components of decision-making for TGNB individuals.

Lawlis SM, Donkin HR, Bates JR, Britto MT, Conard LAE. Health Concerns of Transgender and Gender
Nonconforming Youth and Their Parents Upon Presentation to a Transgender Clinic. J Adolesc

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 Health. 2017;61(5):642-648. doi:10.1016/j.jadohealth.2017.05.025 Accessed September 15,
2023. Available at https://www.jahonline.org/article/S1054-139X(17)30254-9/fulltext

Abstract: Purpose The purpose of the study was to determine the frequency of specific health
concerns identified by transgender and gender nonconforming patients and their parents at
initial clinic visit. Methods Checklists were developed in an iterative process and distributed to
both patients and parents at their initial visit to a transgender clinic. Retrospective chart review
and secondary data analyses were performed to determine the number of items endorsed,
frequency with which each item was endorsed, and provider domain of each item endorsed:
physician, social work, or both physician and social work. Results Checklists were collected from
118 patients and 103 parents. Patients endorsed a mean of 8.4 concerns (range 0–22) and
parents 7.9 concerns (range 0–20). The most commonly endorsed patient concerns included use
of gender-affirming hormones, steps for transition, gender-affirming surgery, restroom/dressing
room use, and legal issues. Common parent concerns included general resources, child safety at
school, acute mental health concerns, restroom/dressing room use, and steps for transition. Of
the concerns endorsed by patients, 44% were in the social work domain, 37% in the physician
domain, and 19% in both the social work and physician domain. Of the concerns endorsed by
parents, 40% were in the social work domain, 31% in the physician domain, and 29% in the
social work and physician domain. Conclusions Although patients and parents had similar
numbers of concerns, they primarily focused on different topics. Youth were more interested in
hormones and transition, while parents were more interested with transition and acceptance.
Many concerns for both patients and parents fell within the social work domain.

Annotation: A cross-sectional study comparing attitudes about GD drug treatments between

TGNB youths and their parents

Lee WG, Butler G, Carmichael P, et al. Urological and Gynaecological Considerations for the Use of
Gonadotropin-releasing Hormone Analogues in Transgender and Nonbinary Adolescents: A
Narrative Review. Eur Urol Focus. 2023;9(1):35-41. doi:10.1016/j.euf.2022.11.002 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36396559

Abstract: CONTEXT: Gonadotropin-releasing hormone analogues (GnRHAs) delay the

progression of puberty in transgender and nonbinary (TGNB) adolescents and reduce the impact
of dysphoria due to ongoing physical development. The intervention remains contentious
despite growing evidence to support this practice. OBJECTIVE: To stimulate discussion on this
topical issue in the urological and gynaecological community given potential ramifications for
future fertility, physical development, and options for gender affirmation surgery (GAS).
EVIDENCE ACQUISITION: We conducted searches of the MEDLINE (from 1946) and Embase
(from 1974) databases for the benefits and potential challenges of hormone blockade in TGNB
adolescents on February 1, 2022. Evidence with a primary focus on clinical issues of interest to
urologists and gynaecologists was objectively synthesised and reported. EVIDENCE SYNTHESIS:
The onset of puberty represents a period of distress for TGNB adolescents as secondary sexual
characteristics develop. GnRHAs are prescribed to inhibit sex hormone production, but the
decision to treat should be balanced against the known (and unknown) adverse effects. Fertility
preservation is more likely to be successful if GnRHA treatment is delayed for as long as
possible. Some adolescents may decide to stop GnRHA use to harvest spermatozoa or oocytes
before starting gender-affirming hormone treatment. Transfeminine individuals should consider
that options for genital GAS may become more limited, as vaginoplasty with penile skin
inversion requires an adequate stretched penile length. Transmasculine individuals may no

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 longer require chest reconstruction for breast development. CONCLUSIONS: Offers of GnRHA
treatment to TGNB adolescents should be balanced by careful preparation and counselling.
Urologists and gynaecologists can complement the expertise of specialist psychosocial and
adolescent endocrinology teams, and should be involved early in and throughout the treatment
pathway to maximise future functional and surgical outcomes. PATIENT SUMMARY: Puberty
blockers for transgender and nonbinary adolescents have benefits, but timing is important to
preserve fertility and surgical options.

Annotation: A systematic review examining fertility outcomes associated with GnRH analogues
in TGNB adolescents.

Maschião LF, Bastos FI, Wilson E, et al. Nonprescribed Sex Hormone Use Among Trans Women: The
Complex Interplay of Public Policies, Social Context, and Discrimination. Transgend Health.
2020;5(4):205-215. doi:10.1089/trgh.2020.0012 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33644312

Abstract: Purpose: Trans women are systematically excluded from basic human rights, possibly
due to social contexts of transphobia. In health care, such barriers may result in nonprescribed
sex hormone use and lead to significant health complications. As few studies investigated this
phenomenon, we analyzed factors associated with nonprescribed sex hormone use by trans
women in seven municipalities of Sao Paulo, Brazil. Methods: Muriel was a cross-sectional study
(2014/2015), in which 673 transgender people answered a face-to-face survey. This analysis
focused on trans women (n=616). Poisson regression models were used to assess factors
associated with nonprescribed sex hormone use. A direct acyclic graph was built with a priori
knowledge on the matter and was used for covariate selection. Results: A total of 90.7% of
participants reported ever taking sex hormones. Most of those detailed nonprescribed use,
which was associated with sex work, starting to use hormones before 18, identifying as travesti
and lower education. Having the chosen name honored in public health services was found to
be protective against this outcome. Conclusion: A high proportion of nonprescribed sex
hormone use was observed in our sample. Our findings suggest barriers to health care and the
need for trans women to resort to medically unsupervised transition procedures. Among sex
workers, this may also be due to higher economic and access needs than other groups. Ensuring
social rights and providing adequate health care services may lessen nonprescribed sex
hormone use, preventing subsequent risks and resulting in better health outcomes for trans
women.

Annotation: A Brazil-based cross-sectional study examining correlates (ie, "risk factors") for use
of non-prescribed sex hormones.

Nasomyont N, Meisman AR, Ecklund K, et al. Changes in Bone Marrow Adipose Tissue in Transgender
and Gender Non-Conforming Youth Undergoing Pubertal Suppression: A Pilot Study. J Clin
Densitom. 2022;25(4):485-489. doi:10.1016/j.jocd.2022.06.006 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/36064698

Abstract: Pubertal suppression with gonadotropin-releasing hormone (GnRH) agonists in

transgender and gender non-conforming (TGNC) youth may affect acquisition of peak bone
mass. Bone marrow adipose tissue (BMAT) has an inverse relationship with bone mineral
density (BMD). To evaluate the effect of pubertal suppression on BMAT, in this pilot study we
prospectively studied TGNC youth undergoing pubertal suppression and cisgender control

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 participants with similar pubertal status over a 12-month period. BMD was measured by dual-
energy X-ray absorptiometry and peripheral quantitative computed tomography. Magnetic
Resonance T1 relaxometry (T1-R) and spectroscopy (MRS) were performed to quantify BMAT at
the distal femur. We compared the change in BMD, T1-R values, and MRS lipid indices between
the two groups. Six TGNC (two assigned female and four assigned male at birth) and three
female control participants (mean age 10.9 and 11.7 years, respectively) were enrolled. The
mean lumbar spine BMD Z-score declined by 0.29 in the TGNC group, but increased by 0.48 in
controls (between-group difference 0.77, 95% CI: 0.05, 1.45). Similar findings were observed
with the change in trabecular volumetric BMD at the 3% tibia site (-4.1% in TGNC, +3.2% in
controls, between-group difference 7.3%, 95% CI: 0.5%-14%). Distal femur T1 values declined
(indicative of increased BMAT) by 7.9% in the TGNC group, but increased by 2.1% in controls
(between-group difference 10%, 95% CI: -12.7%, 32.6%). Marrow lipid fraction by MRS increased
by 8.4% in the TGNC group, but declined by 0.1% in controls (between-group difference 8.5%,
95% CI: -50.2%, 33.0%). In conclusion, we observed lower bone mass acquisition and greater
increases in BMAT indices by MRI and MRS in TGNC youth after 12 months of GnRH agonists
compared with control participants. Early changes in BMAT may underlie an alteration in bone
mass acquisition with pubertal suppression, including alterations in mesenchymal stem cells
within marrow.

Annotation: Examines changes in bone marrow adipose tissue among TGNB youths undergoing
puberty suppression. Also an observational study comparing findings to controls not undergoing
puberty suppression. Only natal sexes were reported (N = 4 AMAB and N = 2 AFAB).

Ni J, Chi C, Aye T. Review of implant gonadotrophin-releasing hormone agonist use: experience in a

single academic center. Horm Res Paediatr. 2023, 10.1159/000529733doi:10.1159/000529733
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36791687

Abstract: BACKGROUND: Gonadotrophin-releasing hormone agonists (GnRHa) are used for

puberty suppression in central precocious puberty (CPP) and gender dysphoria (GD). Guidelines
on biochemical monitoring are not defined. OBJECTIVES: To evaluate the utility of biochemical
monitoring of GnRHa therapy in patients with CPP or GD. METHODS: Retrospective chart review
of patients 18 years or younger who received GnRHa therapy from 1/1/2018 to 3/2/2021.
RESULTS: 103 patients were evaluated, 43 with CPP and 60 with GD. Using thresholds of basal
luteinizing hormone (LH) <2 IU/L and stimulated LH <4 IU/L, biochemical pubertal suppression
occurred in all but two patients. Basal LH frequently remained above prepubertal range.
CONCLUSIONS: Laboratory assessment for puberty suppression on GnRHa therapy may be
unnecessary in CPP and GD patients monitored with physical exams.

Annotation: Examining endogenous hormone levels associated with implantable GnRH agonist
therapy in TGNB adolescents. Only natal sex reported (N = 63 AFAB and N = 40 AMAB).

Nieder TO, Mayer TK, Hinz S, Fahrenkrug S, Herrmann L, Becker-Hebly I. Individual Treatment Progress
Predicts Satisfaction With Transition-Related Care for Youth With Gender Dysphoria: A
Prospective Clinical Cohort Study. J Sex Med. 2021;18(3):632-645.
doi:10.1016/j.jsxm.2020.12.010 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33642235

Abstract: BACKGROUND: The number of adolescents presenting with gender dysphoria (GD) in
healthcare services has increased significantly, yet specialized services offering transition-

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 related care (TRC) for trans youth is lacking. AIM: To investigate satisfaction with TRC, regret,
and reasons for (dis)satisfaction with transition-related medical interventions (TRMIs) in trans
adolescents who had presented to the Hamburg Gender Identity Service for children and
adolescents (Hamburg GIS). METHODS: Data were collected from a clinical cohort sample of 75
adolescents and young adults diagnosed with GD (81% assigned female at birth) aged 11 to 21
years (M = 17.4) at baseline and follow-up (on a spectrum of ongoing care, on average 2 years
after initial consultation). To determine progress of the youth's medical transitions, an individual
treatment progress score (ITPS) was calculated based on number of desired vs received TRMIs.
OUTCOMES: Main outcome measures were satisfaction with TRC at the time of follow-up, ITPS,
social support, reasons for regret and termination of TRC, and (dis)satisfaction with TRMIs.
RESULTS: Participants underwent different stages of TRMIs, such as gender-affirming hormone
treatment or surgeries, and showed overall high satisfaction with TRC received at the Hamburg
GIS. Regression analysis indicated that a higher ITPS (an advanced transition treatment stage)
was predictive of higher satisfaction with TRC. Sex assigned at birth, age, and time since initial
consultation at the clinic showed no significant effects for satisfaction with TRC, while degree of
social support showed a trend. No adolescents regretted undergoing treatment at follow-up.
Additional analysis of free-text answers highlighted satisfaction mostly with the physical results
of TRMI. CLINICAL IMPLICATIONS: Because youth were more satisfied with TRC when their
individual transition (ITPS) was more progressed, treatment should start in a timely manner to
avoid distress from puberty or long waiting lists. STRENGTHS AND LIMITATIONS: This study is
one of the first to report on treatment satisfaction among youth with GD from Europe. The ITPS
allowed for a more detailed evaluation of TRMI wishes and experiences in relation to
satisfaction with TRC and may close a gap in research on these treatments in adolescent
populations. However, all participants were from the same clinic, and strict treatment eligibility
criteria may have excluded certain trans adolescents from the study. Low identification rates
with non-binary identities prevented comparisons between non-binary and binary genders.
CONCLUSION: The study highlights the role of TRMI and individual treatment or transition
progress for youth's overall high satisfaction with TRC received at the Hamburg GIS. Nieder TO,
Mayer TK, Hinz S, et al. Individual Treatment Progress Predicts Satisfaction With Transition-
Related Care for Youth With Gender Dysphoria: A Prospective Clinical Cohort Study. J Sex Med
2021;18:632-645.

Annotation: A Germany-based cohort study examining patients satisfaction with transition-

related care (TRC) over time and with various treatments.

Nos AL, Klein DA, Adirim TA, et al. Association of Gonadotropin-Releasing Hormone Analogue Use With
Subsequent Use of Gender-Affirming Hormones Among Transgender Adolescents. JAMA Netw
Open. 2022;5(11):e2239758. doi:10.1001/jamanetworkopen.2022.39758 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36318207

Abstract: IMPORTANCE: Gonadotropin-releasing hormone analogue (GnRHa) use during puberty

improves mental health among transgender and gender-diverse (TGD) adolescents. In previous
studies, most (96.5%-98.1%) TGD adolescents who started GnRHa subsequently started gender-
affirming hormones (GAH), raising concerns that GnRHa use promotes later use of GAH.
OBJECTIVE: To determine whether GnRHa use among TGD adolescents is associated with
increased subsequent GAH use. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective
cohort study of administrative records collected between 2009 and 2018. The current analysis
was completed in August 2022. Participants were enrolled in the US Military Healthcare System
(MHS) with an initial TGD-related encounter occurring between ages 10 and 17 years.

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 EXPOSURES: GnRHa use. MAIN OUTCOMES AND MEASURES: Initiation of GAH. RESULTS: The
434 patients were a mean (SD) of 15.4 (1.6) years old at the time of their first TGD-related
encounter; 312 (71.9%) were assigned female at birth, and 300 (69.1%) had an enlisted
insurance sponsor. GnRHa use was more common among patients who were assigned male at
birth (28 patients [23.0%]) than those assigned female (42 patients [13.5%]), but GAH use was
not. Socioeconomic status was not associated with GnRHa or GAH use. Compared with older
patients (aged 14-17 years), those who were younger (aged 10-13 years) at the time of the
initial TGD-related encounter had a higher rate of GnRHa use (32 patients [57.1%] vs 38 patients
[10.1%]) and a longer median time to starting GAH. The median interval from the date of the
initial encounter to starting GAH decreased over time, from 2.3 years (95% CI, 1.7-2.8 years)
between October 2009 and December 2014 to 0.6 years (95% CI, 0.5-0.6 years) between
September 2016 and April 2018. Patients who were prescribed GnRHa had a longer median time
to starting GAH (1.8 years; 95% CI, 1.1-2.4 years) than patients who were not (1.0 years; 95% CI,
0.8-1.2 years) and were less likely to start GAH during the 6 years after their first TGD-related
encounter (hazard ratio, 0.52; 95% CI, 0.37-0.71). Among 54 younger (aged 10-13 years) patients
who were not eligible to start GAH at their first encounter, GnRHa use was associated with a
longer median time to starting GAH, but age at the first TGD-related visit was not.
CONCLUSIONS AND RELEVANCE: In this cohort study of TGD adolescents, GnRHa use was not
associated with increased subsequent GAH use. These findings suggest that clinicians can offer
the benefits of GnRHa treatment without concern for increasing rates of future GAH use.

Annotation: A cohort study examining the risk of GAH use in TGNB adolescents who used
GnRHa.

Olson-Kennedy J, Chan Y-M, Garofalo R, et al. Impact of Early Medical Treatment for Transgender Youth:
Protocol for the Longitudinal, Observational Trans Youth Care Study. JMIR research protocols.
2019;8(7):e14434. doi:10.2196/14434 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31290407

Abstract: BACKGROUND: Transgender children and adolescents (ie, those who experience
incongruence between assigned sex at birth and internal gender identity) are poorly understood
and an understudied population in the United States. Since 2008, medical care for transgender
youth has generally followed guidelines developed by professional consensus, given the paucity
of empirical research, particularly in the US setting., OBJECTIVE: The objective of this research
was to provide evidence-based data to inform clinical care for transgender youth. The study
aims (1) to evaluate the impact of gonadotropin-releasing hormone agonists administered for
puberty suppression on mental health, psychological well-being, and metabolic and physiologic
parameters including bone health in a cohort of children and adolescents (Tanner stages 2-4)
with gender dysphoria, comparing baseline and follow-up assessments, and (2) to determine the
impact of gender-affirming hormones (eg, estradiol and testosterone) administered for
phenotypic gender transition on mental health, psychological well-being, and metabolic and
physiologic parameters in a cohort of adolescents with gender dysphoria, comparing baseline
and follow-up assessments., METHODS: The study uses a longitudinal observational design to
examine the outcomes of existing medical treatment protocols for gender dysphoria in two
distinct cohorts: youth initiating puberty suppression and youth pursuing a phenotypic gender
transition. Data on routine anthropometric and physiologic parameters are collected through
chart abstraction, questionnaires, and research interviews in the 24-month study period. Audio
computer-assisted self-interview and individual interview survey instruments are used to collect
demographic, mental health, psychosocial, and behavioral data from parents and youth in the

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 blocker cohort and only from youth in the gender-affirming hormone cohort at baseline and 6,
12, 18, and 24 months., RESULTS: Participant recruitment commenced in July 2016, and
enrollment was completed in September 2018. A total of 90 participants were enrolled in the
blocker cohort and 301 participants were enrolled in the gender-affirming hormone cohort.
Findings based on baseline data are expected to be submitted for publication in 2019.,
CONCLUSIONS: This longitudinal, observational study is collecting critical data on the existing
models of care for transgender youth that have been used in clinical settings for close to a
decade, although with limited empirical research to support them. This research is a direct
response to the Institute of Medicine report calling for such studies as well as the needs of
clinicians and patients. Results from this study have the potential to significantly impact the
medical and mental health services provided to transgender youth by making available rigorous
scientific evidence on the impact and safety of early treatment based on the sexual
development stage. Ultimately, we aim to understand if early medical intervention reduces the
health disparities well known to disproportionately affect transgender individuals across their
lifespan., INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/14434.
Copyright ©Johanna Olson-Kennedy, Yee-Ming Chan, Robert Garofalo, Norman Spack, Diane
Chen, Leslie Clark, Diane Ehrensaft, Marco Hidalgo, Amy Tishelman, Stephen Rosenthal.
Originally published in JMIR Research Protocols (http://www.researchprotocols.org),
09.07.2019.

Annotation: Examines growth and bone density in TGNB adolescents starting puberty
suppression and TGNB adolescents starting CSHT

Quain KM, Kyweluk MA, Sajwani A, et al. Timing and Delivery of Fertility Preservation Information to
Transgender Adolescents, Young Adults, and Their Parents. J Adolesc Health. 2021;68(3):619-
622. doi:10.1016/j.jadohealth.2020.06.044 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32826153

Abstract: PURPOSE: This study aimed to examine transgender adolescents and young adults'
(AYA) and their parents' preferences regarding fertility preservation (FP) information provision
and discussion timing. METHODS: Data were derived from two separate studies: an online
survey and semistructured qualitative interviews. Survey data were analyzed using descriptive
statistics and interview data using conventional content analysis. RESULTS: Survey participants
(AYA: 88% and parents: 93%) preferred gender clinic physicians provide FP information, and
nearly one-third endorsed mental health professionals (AYA: 28% and parents: 26%) or fertility
specialists (AYA: 23% and parents: 30%). Interview participants' FP discussion timing preferences
ranged from the initial clinic visit, follow-up visits, before medical intervention, to mentioning FP
early but deferring in-depth discussion to follow-up visits. CONCLUSIONS: Gender clinic
physicians, mental health professionals, and fertility specialists should be prepared to discuss FP
with transgender AYA and their parents. Opinions varied regarding when to provide FP
information; therefore, discussion timing may need to be individualized.

Annotation: A qualitative, descriptive study examining timing and delivery of fertility

preservation information provided to TGNB youths and their parents

Roberts CM, Klein DA, Adirim TA, Schvey NA, Hisle-Gorman E. Continuation of Gender-affirming
Hormones Among Transgender Adolescents and Adults. J Clin Endocrinol Metab.
2022;107(9):e3937-e3943. doi:10.1210/clinem/dgac251 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35452119

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 Abstract: INTRODUCTION: Concerns about future regret and treatment discontinuation have led
to restricted access to gender-affirming medical treatment for transgender and gender-diverse
(TGD) minors in some jurisdictions. However, these concerns are merely speculative because
few studies have examined gender-affirming hormone continuation rates among TGD
individuals. METHODS: We performed a secondary analysis of 2009 to 2018 medical and
pharmacy records from the US Military Healthcare System. We identified TGD patients who
were children and spouses of active-duty, retired, or deceased military members using
International Classification of Diseases-9/10 codes. We assessed initiation and continuation of
gender-affirming hormones using pharmacy records. Kaplan-Meier and Cox proportional hazard
analyses estimated continuation rates. RESULTS: The study sample included 627 transmasculine
and 325 transfeminine individuals with an average age of 19.2 +/- 5.3 years. The 4-year gender-
affirming hormone continuation rate was 70.2% (95% CI, 63.9-76.5). Transfeminine individuals
had a higher continuation rate than transmasculine individuals 81.0% (72.0%-90.0%) vs 64.4%
(56.0%-72.8%). People who started hormones as minors had higher continuation rate than
people who started as adults 74.4% (66.0%-82.8%) vs 64.4% (56.0%-72.8%). Continuation was
not associated with household income or family member type. In Cox regression, both
transmasculine gender identity (hazard ratio, 2.40; 95% CI, 1.50-3.86) and starting hormones as
an adult (hazard ratio, 1.69; 95% CI, 1.14-2.52) were independently associated with increased
discontinuation rates. DISCUSSION: Our results suggest that >70% of TGD individuals who start
gender-affirming hormones will continue use beyond 4 years, with higher continuation rates in
transfeminine individuals. Patients who start hormones, with their parents' assistance, before
age 18 years have higher continuation rates than adults.

Annotation: A cohort study examining adherence and persistence outcomes between

transmasculine and transfeminine TGNB individuals.

Rogers C, Webberley M, Mateescu R, El Rakhawy Y, Daly-Gourdialsing A, Webberley H. A retrospective

study of positive and negative determinants of gamete storage in transgender and gender-
diverse patients. International journal of transgender health. 2021;22(1-2):167-178.
doi:10.1080/26895269.2020.1848693 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040686/pdf/WIJT_22_1848693.pdf

Abstract: Background: GenderGP is a novel, online telemedicine service for transgender and
gender-diverse individuals. As part of the service, people are offered fertility counseling in
regard to gamete storage. Aims: This study aims to formally categorize the reasons that
transgender and gender-diverse people do and not store gametes prior to hormonal treatments.
We hope to use this data and subsequent research to inform healthcare policy, improve the
healthcare experience for transgender and gender-diverse people, and inform legislation for
permanent change in UK healthcare. Methods: Data sets (electronic medical records) from June
2015 - April 2020 were derived from the GenderGP patient database. All patients starting
treatment with GenderGP and undergoing routine fertility counseling were included in the
study. Results: Of 3667 patients aged 10-85, 2722 (74.2%) were aged 18-45. 151 (5.4%) patients
stored gametes. 678 (18.5%) patients wanted to store: 268 (39.5%) could not afford gamete
storage, 84 (12.4%) had no local services, 307 (45.3%) did not want to delay hormone
treatment. 2085 patients did not want to undertake gamete storage, 480 (23.0%) hoped to
adopt, 1605 (77.1%) did not want children. All ages showed similar patterns. Discussion:
Financial barriers mean many transgender and gender-diverse people cannot access fertility
healthcare. Many participants suffered low self-esteem and struggled to envisage an accepting
healthcare system, making them less likely to seek advice. Many patients favored adoption over

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 gamete storage. Younger patients (<18) often had very definite views on gamete storage. Many
older patients without children would consider gamete storage and adoption, once their
transition is complete. Copyright © 2020 Taylor & Francis Group, LLC.

Annotation: A database, cohort study examining predictors of gamete storage in TGNB patients
from the UK, including adolescents at the time of the study

Rozga M, Linsenmeyer W, Cantwell Wood J, Darst V, Gradwell EK. Hormone therapy, health outcomes
and the role of nutrition in transgender individuals: A scoping review. Clin Nutr ESPEN.
2020;40:42-56. doi:10.1016/j.clnesp.2020.08.011 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/33183572

Abstract: OBJECTIVE: The objective of this scoping review is to describe the extent, range, and
nature of available literature examining nutrition-related intermediate and long-term health
outcomes in individuals who are transgender. Specific sub-topics examined include 1) dietary
intake, 2) nutrition-related health disparities, 3) validity and reliability of nutrition assessment
methods, 4) the effects of nutrition interventions/exposures, and 5) hormone therapy.
METHODS: A literature search was conducted using MEDLINE, Embase, PsycINFO, CINAHL, Web
of Science, and other databases for peer-reviewed articles published from January 1999 until
December 5, 2019 to identify studies addressing the research objective and meeting eligibility
criteria. Conference abstracts and registered trials published or registered in the five years prior
to the search were also included. Findings were reported in a study characteristics table, a
bubble chart and heat maps. RESULTS: The search of the databases identified 5403 studies,
including full peer-reviewed studies, systematic reviews, conference abstracts and registered
trials. Following title/abstract screening, 189 studies were included in the narrative analysis. Ten
studies reported dietary intake in transgender individuals, 64 studies reported nutrition-related
health disparities in transgender compared to cisgender individuals, one study examined validity
and reliability of nutrition assessment methods, two studies reported nutrition interventions,
and 127 studies reported on the intermediate and health effects of hormone therapy.
CONCLUSION: Individuals who are transgender have unique nutrition needs, which may vary
according to the stage and type of gender-affirmative therapy that they are undergoing. There is
scant research examining effective nutrition therapy methods for nutrition professionals
working with transgender individuals. More research is needed in order to inform evidence-
based clinical practice guidelines for nutrition practitioners working with transgender
individuals.

Annotation: A systematic review examining nutrition-related outcomes in TGNB children,

adolescents, and adults.

Russell I, Pearson B, Masic U. A Longitudinal Study of Features Associated with Autism Spectrum in Clinic
Referred, Gender Diverse Adolescents Accessing Puberty Suppression Treatment. J Autism Dev
Disord. 2021;51(6):2068-2076. doi:10.1007/s10803-020-04698-8 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/32936414

Abstract: Literature has documented inflated rates of features associated with autism spectrum
(AS) in clinic referred, gender diverse young people. This study examined scores on the Social
Responsiveness Scale, Second Edition (SRS-2) over time in a group of clinic referred, gender
diverse adolescents accessing gonadotropin-releasing hormone analogues (GnRHa) to supress
puberty. Primary caregivers of 95 adolescents presenting to the Gender Identity Development

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 Service (GIDS) completed the SRS-2 prior to receiving endocrine input (mean age: 13.6 +/- SEM:
0.11) and after approximately one year of accessing GnRHa (mean age: 14.6 +/- SEM: 0.13). No
significant differences in SRS-2 scores over time and between birth assigned sex were found. No
interactions between time and birth assigned sex were established for SRS-2 subscales or total
scores.

Annotation: A London-based pre-post descriptive study examining autism-related

characteristics before and after 1 year of GnRH analogue therapy in TGNB adolescents with
autism. Only natal sexes were reported: 38 AMAB and 57 AFAB.

Schwartz BI, Bear B, Kazak AE. Menstrual Management Choices in Transgender and Gender Diverse
Adolescents. J Adolesc Health. 2023;72(2):207-213. doi:10.1016/j.jadohealth.2022.09.023
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/36443161

Abstract: PURPOSE: Transgender and gender diverse patients who are assigned female at birth
may request menstrual management to alleviate an increased dysphoria due to menses. The
objective of this study is to describe the initiation and use over time of menstrual management
methods (MMMs) in transgender and gender diverse adolescents. METHODS: A retrospective
chart review was conducted of patients in a multidisciplinary pediatric gender program from
March 2015 to December 2020 who were assigned female at birth, identified as transgender or
gender diverse, and had achieved menarche. A descriptive statistical analysis was performed.
RESULTS: Of 133 patients, 119 (90%) identified as transgender male, 11 (8%) as gender
nonbinary, and 3 (2%) as another gender identity. Mean age was 15 (standard deviation 1.6)
years. Only 12 (9%) patients had ever been sexually active. During the study period, 48 (36%)
used gender-affirming testosterone. At the initial visit, 114 (86%) patients were not using an
MMM. Of 80 patients who initiated a new MMM, 3 (4%) chose continuous oral contraceptive
pills, 65 (83%) used norethindrone acetate (NETA), and 9 (11%) planned levonorgestrel
intrauterine device (IUD) insertion. At 1 year, 56 patients were using NETA and 20 had an IUD in
place. DISCUSSION: This study provides data on MMM choice in transgender and gender diverse
adolescents using these methods almost exclusively for menstrual management and not
contraception. Although few patients were using an MMM at baseline, most opted to start a
method when given the opportunity. The most common methods were NETA or an
levonorgestrel IUD.

Annotation: Examines menstrual suppression outcomes in transmasculine and gender-diverse

adolescents receiving various menstrual management treatments in a gender specialty clinic

Schwartz BI, Bear B, Short VL, Kazak AE. Outcomes of Menstrual Management Use in Transgender and
Gender-Diverse Adolescents. Obstet Gynecol. 2023;141(4):748-755.
doi:10.1097/AOG.0000000000005123 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36897186

Abstract: OBJECTIVE: To describe and compare the outcomes of various menstrual-management

methods, including method choice, continuation, bleeding patterns, amenorrhea rates, effect on
moods and dysphoria, and side effects, in transgender and gender-diverse adolescents.
METHODS: This was a retrospective chart review of all patients seen in a multidisciplinary
pediatric gender program from March 2015 to December 2020 who were assigned female at
birth, had achieved menarche, and used a menstrual-management method during the study
period. Data were abstracted on patient demographics and menstrual-management method

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 continuation, bleeding patterns, side effects, and satisfaction at 3 months (T1) and 1 year (T2).
Outcomes were compared between method subgroups. RESULTS: Among the 101 included
patients, 90% chose either oral norethindrone acetate or a 52-mg levonorgestrel (LNG)
intrauterine device (IUD). There were no differences in continuation rates for these methods at
either follow-up time. Almost all patients had improved bleeding at T2 (96% for norethindrone
acetate and 100% for IUD users), with no difference between subgroups. Amenorrhea rates
were 84% for norethindrone acetate and 67% for IUD at T1 and 97% and 89%, respectively, at
T2, with no differences at either point. The majority of patients had improved pain, menstrually
related moods, and menstrually related dysphoria at both follow-up points. There were no
differences in side effects between subgroups. There were no differences in method satisfaction
between the groups at T2. CONCLUSION: Most patients chose norethindrone acetate or an LNG
IUD for menstrual management. Continuation, amenorrhea, and improved bleeding, pain, and
menstrually related moods and dysphoria were high for all patients, indicating that menstrual
management is a viable intervention for gender-diverse patients who experience increased
dysphoria related to menses.

Annotation: Examines menstrual suppression outcomes in transmasculine and gender-diverse

adolescents receiving various progestins in a gender specialty clinic

Schwartz BI, Effron A, Bear B, et al. Experiences with Menses in Transgender and Gender Nonbinary
Adolescents. J Pediatr Adolesc Gynecol. 2022;35(4):450-456. doi:10.1016/j.jpag.2022.01.015
Accessed September 15, 2023. Available at https://www.jpagonline.org/article/S1083-
3188(22)00037-7/fulltext

Abstract: STUDY OBJECTIVE: To describe menstrual history, associated dysphoria, and desire for
menstrual management in transgender male and gender diverse adolescents who were assigned
female at birth DESIGN: Retrospective chart review SETTING: Tertiary care children's hospital
PARTICIPANTS: All patients seen in a multidisciplinary pediatric gender program from March
2015 through December 2020 who were assigned female at birth, identified as transgender
male or gender nonbinary, and had achieved menarche INTERVENTION: None MAIN OUTCOME
MEASURES: Patient demographics, menstrual history, interest in and prior experiences with
menstrual management, parental support, and concerns about menstrual management
RESULTS: Of the 129 included patients, 116 (90%) identified as transgender male and 13 (10%)
as gender nonbinary, with an average age of 15 (SD 1.6) years. Almost all (93%) patients
reported menstrual-related dysphoria. Most (88%) were interested in menstrual suppression.
The most common reasons for desiring suppression were achievement of amenorrhea (97%)
and improvement of menstrual-related dysphoria (63%)., CONCLUSIONS: Most gender diverse
patients assigned female at birth reported dysphoria associated with menses and desired
menstrual suppression. This information can encourage physicians to raise this topic and offer
menstrual management for gender diverse patients who experience distress related to menses,
especially for those who are not ready for or do not desire gender-affirming hormonal
treatment. Future research is needed to better understand patients' experiences with menses
and to determine the optimal menstrual management methods. This could be an important
intervention to improve outcomes for this vulnerable population. Copyright © 2022. Published
by Elsevier Inc.

Annotation: Compares menstrual history and menstrual management methods between

transgender males and nonbinary patients

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Shaffer LR, McCormack E, Sawicki GS, Keller A, Jain R. Understanding the Intersection between Gender
Transition and Health Outcomes in Cystic Fibrosis. Ann Am Thorac Soc. 2022;19(3):504-506.
doi:10.1513/AnnalsATS.202105-535RL Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/34469707

Abstract: None

Annotation: A research letter summarizing findings from a research study examining 1-second
FEV values in TGNB adolescents with CF from a national sample of centers

Singh D, Bradley SJ, Zucker KJ. A Follow-Up Study of Boys With Gender Identity Disorder. Front
Psychiatry. 2021;12:632784. doi:10.3389/fpsyt.2021.632784 Accessed September 15, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/33854450

Abstract: This study reports follow-up data on the largest sample to date of boys clinic-referred
for gender dysphoria (n = 139) with regard to gender identity and sexual orientation. In
childhood, the boys were assessed at a mean age of 7.49 years (range, 3.33-12.99) at a mean
year of 1989 and followed-up at a mean age of 20.58 years (range, 13.07-39.15) at a mean year
of 2002. In childhood, 88 (63.3%) of the boys met the DSM-III, III-R, or IV criteria for gender
identity disorder; the remaining 51 (36.7%) boys were subthreshold for the criteria. At follow-
up, gender identity/dysphoria was assessed via multiple methods and the participants were
classified as either persisters or desisters. Sexual orientation was ascertained for both fantasy
and behavior and then dichotomized as either biphilic/androphilic or gynephilic. Of the 139
participants, 17 (12.2%) were classified as persisters and the remaining 122 (87.8%) were
classified as desisters. Data on sexual orientation in fantasy were available for 129 participants:
82 (63.6%) were classified as biphilic/androphilic, 43 (33.3%) were classified as gynephilic, and 4
(3.1%) reported no sexual fantasies. For sexual orientation in behavior, data were available for
108 participants: 51 (47.2%) were classified as biphilic/androphilic, 29 (26.9%) were classified as
gynephilic, and 28 (25.9%) reported no sexual behaviors. Multinomial logistic regression
examined predictors of outcome for the biphilic/androphilic persisters and the gynephilic
desisters, with the biphilic/androphilic desisters as the reference group. Compared to the
reference group, the biphilic/androphilic persisters tended to be older at the time of the
assessment in childhood, were from a lower social class background, and, on a dimensional
composite of sex-typed behavior in childhood were more gender-variant. The
biphilic/androphilic desisters were more gender-variant compared to the gynephilic desisters.
Boys clinic-referred for gender identity concerns in childhood had a high rate of desistance and a
high rate of a biphilic/androphilic sexual orientation. The implications of the data for current
models of care for the treatment of gender dysphoria in children are discussed.

Annotation: A cohort study examining changes in gender identity over time among TGNB
children who presented for treatment at a pediatric gender identity clinic during childhood. Only
natal gender was reported: 139 AMAB.

Strang JF, Powers MD, Knauss M, et al. "They Thought It Was an Obsession": Trajectories and
Perspectives of Autistic Transgender and Gender-Diverse Adolescents. J Autism Dev Disord.
2018;48(12):4039-4055. doi:10.1007/s10803-018-3723-6 Accessed September 15, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/30140984

Abstract: Despite research exploring autism in gender-diverse adolescents, no studies have

elicited these individuals' perspectives. In-depth interviews with 22 well-characterized autistic

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 gender-diverse adolescents revealed critical themes, including: recollections of pre-pubertal
gender nonconformity; vivid experiences of gender dysphoria; a fear of social gender expression
due to perceived animosity toward transgender people; and specific challenges that result from
the interplay of gender diversity and neurodiversity. During the ~ 22 month study social gender
affirmation increased in six participants and gender dysphoria attenuated in four participants.
Given the ethical imperative to understand and prioritize the voiced perspectives and needs of
autistic gender minority adolescents as well as the discovery of shared themes and experiences
in this population, results should inform clinical research approaches and priorities.

Annotation: A qualitative examination of trajectories and perspectives of children diagnosed

with both autism and gender dysphoria

Tankersley AP, Grafsky EL, Dike J, Jones RT. Risk and Resilience Factors for Mental Health among
Transgender and Gender Nonconforming (TGNC) Youth: A Systematic Review. Clin Child Fam
Psychol Rev. 2021;24(2):183-206. doi:10.1007/s10567-021-00344-6 Accessed September 15,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33594611

Abstract: In recent years, there has been a proliferation of research regarding transgender and
gender nonconforming (TGNC) people. The stigma and legal discriminations that this population
faces have obvious and documented repercussions for mental health. In 2015, the American
Psychological Association (APA) published Guidelines for Psychological Practice with TGNC
People. The APA noted that due to the nuances of working with TGNC youth and the dearth of
related literature, the guidelines focus primarily on TGNC adults. To date, there has not been a
systematic review of risk and resilience factors for mental health among TGNC children,
adolescents, and young adults under the age of 25. Forty-four peer-reviewed articles met
inclusion criteria for this systematic review, and were evaluated for their methodological rigor
and their findings. Common risk factors for negative mental health variables included physical
and verbal abuse, exposure to discrimination, social isolation, poor peer relations, low self-
esteem, weight dissatisfaction, and age. Across studies, older children and adolescents tended
to report higher rates of psychological distress. Resilience-promoting factors for mental health
were also documented, including parent connectedness, social support, school safety and
belonging, and the ability to use one's chosen name. By synthesizing the existing literature using
a resilience-focused and minority stress framework, the present review provides clinicians and
researchers with a coherent evidence-base to better equip them to promote psychological
adaptation and wellbeing among TGNC youth.

Annotation: A review of the risk and resilience factors of living as a TGNB youth.

van der Loos M, Hannema SE, Klink DT, den Heijer M, Wiepjes CM. Continuation of gender-affirming
hormones in transgender people starting puberty suppression in adolescence: a cohort study in
the Netherlands. Lancet Child Adolesc Health. 2022;6(12):869-875. doi:10.1016/S2352-
4642(22)00254-1 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36273487

Abstract: BACKGROUND: In the Netherlands, treatment with puberty suppression is available to

transgender adolescents younger than age 18 years. When gender dysphoria persists
testosterone or oestradiol can be added as gender-affirming hormones in young people who go
on to transition. We investigated the proportion of people who continued gender-affirming
hormone treatment at follow-up after having started puberty suppression and gender-affirming

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 hormone treatment in adolescence. METHODS: In this cohort study, we used data from the
Amsterdam Cohort of Gender dysphoria (ACOG), which included people who visited the gender
identity clinic of the Amsterdam UMC, location Vrije Universiteit Medisch Centrum,
Netherlands, for gender dysphoria. People with disorders of sex development were not included
in the ACOG. We included people who started medical treatment in adolescence with a
gonadotropin-releasing hormone agonist (GnRHa) to suppress puberty before the age of 18
years and used GnRHa for a minimum duration of 3 months before addition of gender-affirming
hormones. We linked this data to a nationwide prescription registry supplied by Statistics
Netherlands (Centraal Bureau voor de Statistiek) to check for a prescription for gender-affirming
hormones at follow-up. The main outcome of this study was a prescription for gender-affirming
hormones at the end of data collection (Dec 31, 2018). Data were analysed using Cox regression
to identify possible determinants associated with a higher risk of stopping gender-affirming
hormone treatment. FINDINGS: 720 people were included, of whom 220 (31%) were assigned
male at birth and 500 (69%) were assigned female at birth. At the start of GnRHa treatment, the
median age was 14.1 (IQR 13.0-16.3) years for people assigned male at birth and 16.0 (14.1-
16.9) years for people assigned female at birth. Median age at end of data collection was 20.2
(17.9-24.8) years for people assigned male at birth and 19.2 (17.8-22.0) years for those assigned
female at birth. 704 (98%) people who had started gender-affirming medical treatment in
adolescence continued to use gender-affirming hormones at follow-up. Age at first visit, year of
first visit, age and puberty stage at start of GnRHa treatment, age at start of gender-affirming
hormone treatment, year of start of gender-affirming hormone treatment, and gonadectomy
were not associated with discontinuing gender-affirming hormones. INTERPRETATION: Most
participants who started gender-affirming hormones in adolescence continued this treatment
into adulthood. The continuation of treatment is reassuring considering the worries that people
who started treatment in adolescence might discontinue gender-affirming treatment. FUNDING:
None.

Annotation: A cohort study comparing baseline characteristics and continuation rates between
transgender males and transgender females, with and without treatment.

Van Der Miesen AI, Hurley H, De Vries AL. Gender dysphoria and autism spectrum disorder: A narrative
review. Int Rev Psychiatry. 2016;28(1):70-80. doi:10.3109/09540261.2015.1111199 Accessed
September 15, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/26753812

Abstract: The current literature shows growing evidence of a link between gender dysphoria
(GD) and autism spectrum disorder (ASD). This study reviews the available clinical and empirical
data. A systematic search of the literature was conducted using the following databases:
PubMed, Web of Science, PsycINFO and Scopus; utilizing different combinations of the following
search terms: autism, autism spectrum disorder (ASD), Asperger's disorder (AD), co-morbidity,
gender dysphoria (GD), gender identity disorder (GID), transgenderism and transsexualism. In
total, 25 articles and reports were selected and discussed. Information was grouped by found
co-occurrence rates, underlying hypotheses and implications for diagnosis and treatment. GD
and ASD were found to co-occur frequently - sometimes characterized by atypical presentation
of GD, which makes a correct diagnosis and determination of treatment options for GD difficult.
Despite these challenges there are several case reports describing gender affirming treatment of
co-occurring GD in adolescents and adults with ASD. Various underlying hypotheses for the link
between GD and ASD were suggested, but almost all of them lack evidence.

Annotation: Examining the links between autism and gender dysphoria

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Wagner S, Panagiotakopoulos L, Nash R, et al. Progression of Gender Dysphoria in Children and
Adolescents: A Longitudinal Study. Pediatrics. 2021;148(1)doi:10.1542/peds.2020-027722
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/34099504

Abstract: BACKGROUND AND OBJECTIVES: The progression of gender-expansive behavior to

gender dysphoria and to gender-affirming hormonal treatment (GAHT) in children and
adolescents is poorly understood. METHODS: A cohort of 958 gender-diverse (GD) children and
adolescents who did not have a gender dysphoria-related diagnosis (GDRD) or GAHT at index
were identified. Rates of first GDRD and first GAHT prescription were compared across
demographic groups. RESULTS: Overall, 29% of participants received a GDRD and 25% were
prescribed GAHT during the average follow-up of 3.5 years (maximum 9 years). Compared with
youth assigned male sex at birth, those assigned female sex at birth were more likely to receive
a diagnosis and initiate GAHT with hazard ratio (95% confidence interval) estimates of 1.3 (1.0-
1.7), and 2.5 (1.8-3.3), respectively. A progression to diagnosis was more common among those
aged >/=15 years at initial presentation compared with those aged 10 to 14 years and those
aged 3 to 9 years (37% vs 28% vs 16%, respectively). By using the youngest group as a reference,
the adjusted hazard ratios (95% confidence interval) for a GDRD were 2.0 (1.3-3.0) for age 10 to
14 years and 2.7 (1.8-3.9) for age >/=15 years. Racial and ethnic minorities were less likely to
receive a diagnosis or be prescribed GAHT. CONCLUSIONS: This study characterized the
progression of GD behavior in children and adolescents. Less than one-third of GD youth receive
an eventual GDRD, and approximately one-quarter receive GAHT. Female sex at birth, older age
of initial GD presentation to medical care, and non-Hispanic white race and ethnicity increased
the likelihood of receiving diagnosis and treatment.

Annotation: Cohort study examining predictors of GD diagnosis and of CSHT initiation in gender-
diverse children. Only natal sex reported (N = 531 AMAB and N = 527 AFAB).

Wright T, Candy B, King M. Conversion therapies and access to transition-related healthcare in

transgender people: a narrative systematic review. BMJ Open. 2018;8(12):e022425.
doi:10.1136/bmjopen-2018-022425 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/30580262

Abstract: OBJECTIVES: Conversion is a term for treatments that seek to suppress or change a
person's sexual orientation or gender. Our review focuses on transgender and gender-diverse
(TGD) people. Our aims were to (1) describe the frequency, nature and structure of conversion
practices; (2) document difficulties in accessing transition-related healthcare and (3) evaluate
the mental health consequences of such practices and access barriers. METHOD: Systematic
review and narrative synthesis using the Critical Appraisals Skills Programme and Joanne Briggs
Institute critical appraisal tools. Data sources include Embase, MEDLINE, PsychINFO,
PsychARTICLES and Web of Science between 1990 and June 2017. PARTICIPANTS: Studies were
included that (1) document use of conversion therapies or access barriers to transition-related
healthcare; and/or (2) describe how such therapeutic practices and access barriers have been
applied and/or (3) evaluate the mental health impacts of such therapies and difficulties
accessing transition-related healthcare. Two reviewers screened papers for eligibility. Data were
then grouped according to the objectives. Narratives and themes were presented per study.
RESULTS: Seven studies met inclusion criteria. Four reports were on 'realignment', involving case
studies or case series. Two involved psychoanalysis, one self-exposure therapy and one open-
ended play psychotherapy. All four studies concerning 'realignment' were of poor
methodological quality. The other three studies explored access barriers from the view point of

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 TGD youth, their parents and healthcare providers. All papers reported access barriers, such as
inability to access puberty-delaying medications. The papers concerning barriers to access were
of good methodological quality. CONCLUSION: We found limited published evidence on use,
nature, structure and/or health consequences of conversion therapies and access barriers to
transition in TGD people. However, reports of restriction to access may indicate a more
widespread problem. Research is needed into TGD people's experiences of conversion therapy
and access barriers to transition-related healthcare TRIAL REGISTRATION NUMBER:
CRD42017062149.

Annotation: A systematic review examining conversion therapy and access to transition care in
TGNB people.

Eligible "Systematic" Reviews Lacking Adequate Reporting of Searches

or Results (Bibliography Only) 7,24,25,34,47,55,58,63,87,113,116,126,137,145,154,211,212,272

Alegria CA. Gender nonconforming and transgender children/youth: Family, community, and
implications for practice. J Am Assoc Nurse Pract. 2016;28(10):521-527. doi:10.1002/2327-
6924.12363 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/27031444

Abstract: PURPOSE: The aim of this article is to provide foundational knowledge on gender
nonconforming/transgender children/youth. With this knowledge, providers' confidence and
ability to address the needs of patients/families can increase. DATA SOURCES: Academic Search
Premier, Cinahl, PubMed, World Professional Association for Transgender Health.
CONCLUSIONS: The number of gender nonconforming/transgender children/youth presenting
to healthcare providers is increasing. The situation presents a myriad of challenges to families.
The identity trajectory of gender nonconforming children is variable, and watchful waiting while
providing support to the child and family is advised. If gender dysphoria persists as puberty
approaches, treatment with puberty blockers is recommended. This provides youth time to
further explore their identity, while alleviating the distress of developing unwanted secondary
natal sex characteristics. For these individuals, cross-sex hormones may be started at age 16.
IMPLICATIONS FOR PRACTICE: The complexities of providing care to gender nonconforming
children/youth and their families are best met through an interdisciplinary approach.
Consultation with and/or referral to specialists knowledgeable about transgender health care is
advised. Beyond a basic understanding of gender nonconformance, of primary importance to
patients/families is being heard and supported by their providers. Establishing a safe and
welcome environment is paramount. Resources are provided.

Annotation: A systematic review examining prevalence, trajectory, family and social networks,
treatments, and implications for clinical practice in TGNB children and adolescents.

Biggs M. Gender Dysphoria and Psychological Functioning in Adolescents Treated with GnRHa:
Comparing Dutch and English Prospective Studies. Arch Sex Behav. 2020;49(7):2231-2236.
doi:10.1007/s10508-020-01764-1 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32594279

Abstract: None

Annotation: A systematic review examining mental health in Dutch and English TGNB youth.

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Bonifacio JH, Maser C, Stadelman K, Palmert M. Management of gender dysphoria in adolescents in
primary care. CMAJ. 2019;191(3):E69-E75. doi:10.1503/cmaj.180672 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/30665976

Abstract: Adolescents with gender dysphoria present in a variety of health care settings,
including primary care. Gender dysphoria is the distress experienced by an individual when their
gender identity and their gender assigned at birth are discordant. Many tertiary pediatric
centres across Canada and the Unites States have opened gender clinics for adolescents with
gender dysphoria.1 However, high demand often exceeds the capacity of these clinics, and
many youth are prevented from accessing such centres for a variety of reasons (e.g., lack of
parental or physician support, geographical distance). Primary care providers are well placed to
provide critical support for youth with gender dysphoria and their caregivers and families.
However, primary care providers often lack exposure to trans health issues in training, and may
lack experience in managing gender dysphoria in youth. A recent Canadian national survey
found that less than 50% of transgender youth felt comfortable discussing their trans-related
health care needs with their family doctor.2 We provide an overview of the management of
gender dysphoria in postpubertal adolescents, including practical advice on approaches to social
and medical transitioning, aimed at supporting primary care practitioners in supporting youth
with gender dysphoria in their practices. We use the current Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria when referring to gender dysphoria.
Because definitions and approaches to care have changed over the past 2 decades, we focus
mainly on recent research that reflects the current diagnostic criteria, studies that apply
contemporary assessment and measurement strategies, and findings that are applicable across
multiple clinical settings. Our approach to gathering evidence used in this review is presented in
Box 1. Box 2 defines commonly used terms.

Annotation: How to manage gender dysphoria in adolescents in a primary care setting

Byne W, Bradley SJ, Coleman E, et al. Report of the American Psychiatric Association Task Force on
Treatment of Gender Identity Disorder. Arch Sex Behav. 2012;41(4):759-796.
doi:10.1007/s10508-012-9975-x Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/22736225

Abstract: Both the diagnosis and treatment of Gender Identity Disorder (GID) are controversial.
Although linked, they are separate issues and the DSM does not evaluate treatments. The Board
of Trustees (BOT) of the American Psychiatric Association (APA), therefore, formed a Task Force
charged to perform a critical review of the literature on the treatment of GID at different ages,
to assess the quality of evidence pertaining to treatment, and to prepare a report that included
an opinion as to whether or not sufficient credible literature exists for development of
treatment recommendations by the APA. The literature on treatment of gender dysphoria in
individuals with disorders of sex development was also assessed. The completed report was
accepted by the BOT on September 11, 2011. The quality of evidence pertaining to most aspects
of treatment in all subgroups was determined to be low; however, areas of broad clinical
consensus were identified and were deemed sufficient to support recommendations for
treatment in all subgroups. With subjective improvement as the primary outcome measure,
current evidence was judged sufficient to support recommendations for adults in the form of an
evidence-based APA Practice Guideline with gaps in the empirical data supplemented by clinical
consensus. The report recommends that the APA take steps beyond drafting treatment
recommendations. These include issuing position statements to clarify the APA's position

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 regarding the medical necessity of treatments for GID, the ethical bounds of treatments of
gender variant minors, and the rights of persons of any age who are gender variant, transgender
or transsexual.

Annotation: A systematic review conducted to support development of a guideline for the

treatment of gender dysphoria from the American Psychiatric Association (APA).

Chou K, Johnson B. Working with Transgender Adolescents: Essential Guidelines and Applications.
Adolesc Psychiatry. 2022;12(3):159-173. doi:10.2174/2210676611666210831161929 Accessed
September 15, 2023. Available at https://www.eurekaselect.com/article/117582

Abstract: Background: There has been a rise in the numbers of adolescents identifying as
transgender and seeking medical treatment for gender dysphoria. While gender clinics are
developing across the country, not all transgender adolescents have access to these centers.
There is, therefore, an increased need for other clinicians to be aware of interventions and
guidelines to help transgender youth and their families. Objective: The aim of this article is to
provide an overview of current literature and guidelines for treating transgender adolescents
with gender dysphoria. Methods: Using keywords “gender”, “gender dysphoria”, “transgender”,
“trans*”, “adolescent trans*”, the authors searched PubMed to gather current literature on
treating transgender adolescents. Additionally, sources from primary transgender resources
online were obtained, including current endocrine and psychological guidelines. Results: This
article discusses important gender concepts that are relevant to treating all transgender
individuals. It describes models of engagement with transgender adolescents seeking treatment,
including assenting and consenting to medical intervention. Finally, we discuss the assessment
of transgender adolescents’ needs and present an overview of the various guidelines outlining
both non-medical and medical interventions targeted to treat gender dysphoria in this
population. Conclusion: Knowledge of treating adolescents with gender dysphoria is imperative
as gender dysphoria presents more commonly in practice. Multidisciplinary collaboration is
required to provide comprehensive treatment to this population. Guidelines from professional
organizations such as the World Professional Association for Transgender Health and the
Endocrine Society provide instructions for clinical practice while the evidence base in this field
continues to expand.

Annotation: Principles for working with gender dysphoric adolescents with psychiatric
comorbidities

Conard LE. Supporting and caring for transgender and gender nonconforming youth in the urology
practice. J Pediatr Urol. 2017;13(3):300-304. doi:10.1016/j.jpurol.2017.02.019 Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/28645619

Abstract: INTRODUCTION: Gender identity is a person's internal sense of gender, which may be
different than the sex they were assigned at birth. Pediatric urologists are starting to see more
transgender and gender non-conforming (TGN) youth and need to be able to provide culturally
competent and appropriate care for these patients and their caregivers. This review will discuss
common transgender terminology, specific health concerns and treatment options. METHODS
AND MATERIALS: A systematic literature review was performed on Medline((R)), PubMed((R)),
and Google Scholar for key words transgender, gender dysphoria and gender identity disorder.
Original research articles and relevant reviews were examined as well as transgender treatment
guidelines from several organizations. These studies and expert opinion are summarized in this

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 review. RESULTS: In this rapidly growing area of medicine, there is very little literature and few
evidence-based studies. Treatment guidelines are based on small studies and expert opinion.
CONCLUSION: Transgender and gender nonconforming youth are at high risk for mental health
concerns and other health disparities based on their gender identity. Pediatric urologists can
create a safe and welcoming environment for these patients and their caregivers to discuss
these matters. Providers who are able to provide competent care for TGN youth can improve
outcomes for this group.

Annotation: A systematic review examining etiology, presentation, common comorbidities,

treatments, and surgeries for GD in TGNB children and adolescents.

Connolly MD, Zervos MJ, Barone CJ, 2nd, Johnson CC, Joseph CL. The Mental Health of Transgender
Youth: Advances in Understanding. J Adolesc Health. 2016;59(5):489-495.
doi:10.1016/j.jadohealth.2016.06.012 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/27544457

Abstract: This review provides an update on the growing body of research related to the mental
health of transgender youth that has emerged since the 2011 publication of the Institute of
Medicine report on the health of lesbian, gay, bisexual, and transgender people. The databases
PubMed and Ovid Medline were searched for studies that were published from January 2011 to
March 2016 in English. The following search terms were used: transgender, gender
nonconforming, gender minority, gender queer, and gender dysphoria. Age limits included the
terms youth, child, children, teenager*, and adolescen*. The combined search produced 654
articles of potential relevance. The resulting abstracts went through a tiered elimination system,
and the remaining 15 articles, which presented quantitative data related to the prevalence of
transgender youth and their mental health, were included in the present review. In addition to
providing new estimates of the number of young people who identify as transgender (.17%-
1.3%), studies since 2011 have shown that transgender youth have higher rates of depression,
suicidality and self-harm, and eating disorders when compared with their peers. Gender-
affirming medical therapy and supported social transition in childhood have been shown to
correlate with improved psychological functioning for gender-variant children and adolescents.
Recent research has demonstrated increased rates of psychiatric morbidity among transgender
youth compared to their peers. Future work is needed to understand those youth who identify
as gender nonbinary, improve methods to capture and understand diverse gender identities and
related health disparities, and delineate the social determinants of such disparities.

Annotation: A systematic review examining mental health outcomes in TGNB youth.

Davidge-Pitts C, Clarke BL. Transgender bone health. Maturitas. 2019;127:35-42.

doi:10.1016/j.maturitas.2019.05.002 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/31351518

Abstract: Gonadal sex steroids play a pivotal role in bone health. Medical and surgical therapies
for gender dysphoria in both adolescents and adults can lead to skeletal changes. This review
evaluates the literature on transgender bone health, and how the data can be translated into
clinical practice.

Annotation: A systematic review examining bone health associated with therapies in patients
with gender dysphoria.

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Fuss J, Auer MK, Briken P. Gender dysphoria in children and adolescents: a review of recent research.
Curr Opin Psychiatry. 2015;28(6):430-434. doi:10.1097/YCO.0000000000000203 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/26382161

Abstract: PURPOSE OF REVIEW: With the advent of medical treatments such as puberty
suppression and cross-sex hormones in gender dysphoric minors, there has been a debate
around questions of gender identity and brain development. This review aimed to identify
recent empirical studies that addressed this controversial topic. RECENT FINDINGS:
Epidemiological data from several countries indicate that gender dysphoria in children and
adolescents is far more common than initially anticipated. This is in line with the currently
observed steady increase in referrals to gender clinics. Minors with gender dysphoria are a
vulnerable population as they may face a high psychopathological burden. Recently published
data on the long-term outcome of puberty suppression and subsequent hormonal and surgical
treatment indicate that young people with gender dysphoria may benefit substantially with
regard to psychosocial outcomes. Brain development studied by neuroimaging methods seems
not to be disturbed by puberty suppression. SUMMARY: The first reports about long-term
outcome in adolescents having undergone puberty suppression have shown promising results.
However, in a substantial part of gender dysphoric minors, puberty suppression is not indicated
so far because of psychiatric comorbidity and long-term follow-up data from these patients are
still scarce.

Annotation: A systematic review examining epidemiology, comorbidity, and puberty

suppression in TGNB children and adolescents.

Kameg BN, Nativio DG. Gender dysphoria in youth: An overview for primary care providers. J Am Assoc
Nurse Pract. 2018;30(9):493-498. doi:10.1097/JXX.0000000000000068 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/30095668

Abstract: BACKGROUND AND PURPOSE: Primary care providers who encounter children are
often the first line of contact for individuals with gender dysphoria, which occurs when sex
assigned at birth is incongruent with one's true, expressed sexual identity. Because those with
untreated gender dysphoria are at risk of a variety of negative outcomes, including mood
symptomatology, suicidality, substance use disorders, and other psychosocial risk factors, it is
critical that health care providers are adept in the provision of holistic, patient-centered care.
The purpose of this report is to provide an updated review of the current evidence from the
literature pertaining to the identification, treatment, and coordination of care among children
with gender dysphoria within the primary care setting or medical home. METHODS: Using
PubMed and CINAHL, a literature review spanning from 2012 to the present was conducted
using the following key words: gender dysphoria, transgender health, LGBT health, and hormone
therapy. Reference lists of identified articles were also explored for relevance. CONCLUSIONS:
Treatment may include a social transition, hormone antagonist therapy, or the administration of
cross-sex hormone therapy, with a medical home needed to facilitate coordination of care. Best
practice guidelines vary across pediatric and developmental groups and include both reversible
and nonreversible modalities. Screening for negative psychosocial sequelae must be completed
to include mood symptomatology, suicidality, substance use disorders, and risky sexual
behavior, so that appropriate screening, identification, and treatment interventions can be
implemented. IMPLICATIONS FOR PRACTICE: The primary care medical home must act as a
foundation for the identification of gender dysphoria and/or associated comorbidities and must
treat, when able, or refer, when indicated. In addition, because of structural barriers and

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 stigmatization, public policy often fails the transgender community and can exacerbate the
aforementioned psychosocial comorbidities faced by the transgender youth community. Health
care providers, particularly nurse practitioners, are in a unique position to expand on the face-
to-face care provided to the community and engage in advocacy efforts to dismantle structural
barriers impeding transgender individuals and communities while also providing primary health
care, anticipatory guidance, and care coordination.

Annotation: A systematic review examining prevalence, treatment considerations, risk factors,

and comorbidities among TGNB children and adolescents.

Karalexi MA, Georgakis MK, Dimitriou NG, et al. Gender-affirming hormone treatment and cognitive
function in transgender young adults: a systematic review and meta-analysis.
Psychoneuroendocrinology. 2020;119:104721. doi:10.1016/j.psyneuen.2020.104721 Accessed
September 15, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32512250

Abstract: BACKGROUND: Previous studies have examined whether steroid hormone treatment
in transgender individuals may affect cognitive function; yet, their limited power does not allow
firm conclusions to be drawn. We leveraged data from to-date literature aiming to explore the
effect of gender-affirming hormone administration on cognitive function in transgender
individuals. METHODS: A search strategy of MEDLINE was developed (through June 1, 2019)
using the key terms transgender, hormone therapy and cognitive function. Eligible were (i)
cohort studies examining the longitudinal effect of hormone therapy on cognition, and (ii) cross-
sectional studies comparing the cognitive function between treated and non-treated individuals.
Standardized mean differences (Hedges' g) were pooled using random-effects models. Study
quality was evaluated using the Newcastle-Ottawa Scale. OUTCOMES: Ten studies (seven cohort
and three cross-sectional) were eligible representing 234 birth-assigned males (aM) and 150
birth-assigned females (aF). The synthesis of cohort studies (n = 5) for visuospatial ability
following hormone treatment showed a statistically significant enhancement among aF (g =
0.55, 95% confidence intervals [CI]: 0.29, 0.82) and an improvement with a trend towards
statistical significance among aM (g = 0.28, 95%CI: -0.01, 0.58). By contrast, no adverse effects
of hormone administration were shown. No heterogeneity was evident in most meta-analyses.
INTERPRETATION: Current evidence does not support an adverse impact of hormone therapy on
cognitive function, whereas a statistically significant enhancing effect on visuospatial ability was
shown in aF. New longitudinal studies with longer follow-up should explore the long-term
effects of hormone therapy, especially the effects on younger individuals, where there is greater
scarcity of data.

Annotation: An analysis of studies investigating cognitive function in adolescents who are

treated for gender dysphoria

Kreukels BP, Cohen-Kettenis PT. Puberty suppression in gender identity disorder: the Amsterdam
experience. Nat Rev Endocrinol. 2011;7(8):466-472. doi:10.1038/nrendo.2011.78 Accessed June
28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/21587245

Abstract: The use of gonadotropin-releasing hormone analogs (GnRHa) to suppress puberty in

adolescents with gender dysphoria is a fairly new intervention in the field of gender identity
disorders or transsexualism. GnRHa are used to give adolescents time to make balanced
decisions on any further treatment steps, and to obtain improved results in the physical
appearance of those who opt to continue with sex reassignment. The effects of GnRHa are

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 reversible. However, concerns have been raised about the risk of making the wrong treatment
decisions, as gender identity could fluctuate during adolescence, adolescents in general might
have poor decision-making abilities, and there are potential adverse effects on health and on
psychological and psychosexual functioning. Proponents of puberty suppression emphasize the
beneficial effects of GnRHa on the adolescents' mental health, quality of life and of having a
physical appearance that makes it possible for the patients to live unobtrusively in their desired
gender role. In this Review, we discuss the evidence pertaining to the debate on the effects of
GnRHa treatment. From the studies that have been published thus far, it seems that the benefits
outweigh the risks. However, more systematic research in this area is needed to determine the
safety of this approach.

Annotation: A systematic review focused on developing a protocol for puberty suppression,

based on the Dutch experience.

Leibowitz S, de Vries ALC. Gender dysphoria in adolescence. International review of psychiatry

(Abingdon, England). 2016;28(1):21-35. doi:10.3109/09540261.2015.1124844 Accessed
September 15, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/26828376

Abstract: Adolescents presenting with gender-related concerns are increasingly seeking support
from providers from a variety of disciplines within health care settings across the world. For
those treating young people who meet the criteria for the DSM 5 diagnosis of gender dysphoria
(GD), complex decisions in clinical care are common. Defining best practice with this population
with respect to interventions that span mental health, physical, and surgical domains can be
challenging, given a relative dearth of empirical data available; yet practice guidelines have
emerged from different professional organizations which can aid with this. For this review
paper, a broad literature search was performed to identify relevant studies pertaining to the
care of adolescents with GD. In addition, an overview of trends in clinical practice, including
shifts in conceptualization of how clinicians and patients define care that is considered affirming
when working with this population, is described. This paper explores the characteristics of
referral patterns to specialized clinics, provides a brief overview of gender identity development
in adolescence, and then describes the phenomenology of known aetiological factors and co-
occurring psychiatric issues in adolescents with GD. Additionally, clinical management
considerations that detail assessment aims and common treatment interventions across
disciplines will be explored.

Annotation: A systematic review of gender dysphoria diagnostic criteria

Mahfouda S, Moore JK, Siafarikas A, Zepf FD, Lin A. Puberty suppression in transgender children and
adolescents. Lancet Diabetes Endocrinol. 2017;5(10):816-826. doi:10.1016/S2213-
8587(17)30099-2 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28546095

Abstract: The World Professional Association for Transgender Health's standards of care
recommend suspending puberty, preferably with the use of gonadotropin-releasing hormone
agonists, in certain gender non-conforming minors (aged under 18 years) who have undergone a
psychiatric assessment and have reached at least Tanner stage II of puberty. This approach
seeks to lessen the discordance between assigned natal sex and gender identity by temporarily
halting the development of secondary sexual characteristics, essentially widening the temporal
window for gender clarification. Despite promising preliminary evidence on the clinical utility of

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 this approach, there is a dearth of research to inform evidence-based practice. In view of these
challenges, we review the available empirical evidence on the cognitive, physical, and surgical
implications of puberty suppression in gender-incongruent children and adolescents. We also
explore the historical underpinnings and clinical impetus for suspending puberty in this
population, and propose key research priorities.

Annotation: A systematic review examining puberty suppression in TGNB children and

adolescents.

Mason KA, Schoelwer MJ, Rogol AD. Androgens During Infancy, Childhood, and Adolescence: Physiology
and Use in Clinical Practice. Endocr Rev. 2020;41(3):421-456. doi:10.1210/endrev/bnaa003
Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/32115641

Abstract: We provide an in-depth review of the role of androgens in male maturation and
development, from the fetal stage through adolescence into emerging adulthood, and discuss
the treatment of disorders of androgen production throughout these time periods.
Testosterone, the primary androgen produced by males, has both anabolic and androgenic
effects. Androgen exposure induces virilization and anabolic body composition changes during
fetal development, influences growth and virilization during infancy, and stimulates
development of secondary sexual characteristics, growth acceleration, bone mass accrual, and
alterations of body composition during puberty. Disorders of androgen production may be
subdivided into hypo- or hypergonadotropic hypogonadism. Hypogonadotropic hypogonadism
may be either congenital or acquired (resulting from cranial radiation, trauma, or less common
causes). Hypergonadotropic hypogonadism occurs in males with Klinefelter syndrome and may
occur in response to pelvic radiation, certain chemotherapeutic agents, and less common
causes. These disorders all require testosterone replacement therapy during pubertal
maturation and many require lifelong replacement. Androgen (or gonadotropin) therapy is
clearly beneficial in those with persistent hypogonadism and self-limited delayed puberty and is
now widely used in transgender male adolescents. With more widespread use and newer
formulations approved for adults, data from long-term randomized placebo-controlled trials are
needed to enable pediatricians to identify the optimal age of initiation, route of administration,
and dosing frequency to address the unique needs of their patients.

Annotation: A systematic review examining the use of androgens during infancy, childhood, and
adolescents.

Roden RC. Reversible interventions for menstrual management in adolescents and young adults with
gender incongruence. Ther Adv Reprod Health. 2023;17:26334941231158251.
doi:10.1177/26334941231158251 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36938373

Abstract: The newly released World Professional Association for Transgender Health Standards
of Care, 8th Edition specify that adolescents should be offered menstrual suppression as part of
their treatment plans to suppress menses and alleviate dysphoria, provide contraception, or
improve irregular bleeding on testosterone therapy. This is a review of current evidence-based
options for reversible interventions for menstrual suppression in adolescents with gender
dysphoria or incongruence. Shared decision-making should be used by the clinician at all times,
and the clinician should be intentional in prioritizing the patient's stated needs and desires when
offering interventions. No method should be withheld due to the experience of gender

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 incongruence alone. Contraceptive options offering menstrual suppression include depot-
medroxyprogesterone acetate, levonorgestrel intrauterine systems, progestin-only
contraceptive pills, and combined hormonal contraceptives. Non-contraceptive options include
norethindrone acetate, oral medroxyprogesterone acetate, gonadotropin-releasing hormone
analogues/agonists, and danazol. Certain patients may also benefit from non-pharmacologic
interventions, such as specialty menstrual underwear. PLAIN LANGUAGE SUMMARY: Using
medicine to stop Menstrual periods in teens with gender incongruence Summary: Newly
released recommendations for the care of teens and young adults with gender dysphoria or
incongruence specifically recommend using medications to get rid of menstrual periods if
desired or medically necessary. Patients may ask for this to help improve dysphoria, as a feature
they want in birth control, or simply because they do not want to have periods. Because
temporarily getting rid of periods is something that doctors can do for any patient old enough to
have periods, patients with gender dysphoria should also be able to have their periods
temporarily stopped using medications if requested. Doctors should ensure that they always
help the patient make a decision that is right for them instead of prescribing what they think is
right without considering the patient's input. Options for temporarily getting rid of periods can
include birth control, such as oral contraceptive pills, patches, or rings; intrauterine devices; or
shots, and it can also be done with things that are not birth control, such a progesterone pills or
puberty blockers. Finally, some patients may only need improved period hygiene with period
underwear to feel better in their bodies.

Annotation: A systematic review examining menstrual outcomes associated with menstrual

suppression treatments and testosterone in adolescents and young adults with gender
dysphoria.

Rodriguez-Wallberg K, Obedin-Maliver J, Taylor B, Van Mello N, Tilleman K, Nahata L. Reproductive

health in transgender and gender diverse individuals: A narrative review to guide clinical care
and international guidelines. Int J Transgend Health. 2023;24(1):7-25.
doi:10.1080/26895269.2022.2035883 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/36713139

Abstract: BACKGROUND: Hormonal treatments and surgical interventions practiced with the
aim to affirm gender identity in transgender and gender diverse patients may impact their
future reproductive ability, family building, and family planning options. Whereas it is
recommended by international guidelines to discuss the potential risks of infertility and to
present fertility preservation (FP) options to transgender individuals and their families prior to
initiating any of these treatments, many barriers still remain. Further, transgender and gender
diverse individuals often experience barriers to accessing contraception, abortion, pre-
conception care, and comprehensive perinatal care. AIMS: In this review we summarize the
current literature on reproductive healthcare issues reported in transgender people including
fertility issues, fertility preservation (FP), contraception, pregnancy and lactation and perinatal
health. METHODS: A narrative literature search of major databases (Pubmed, Medline, PsycInfo,
Google Scholar, Web of Science) was conducted. Given the paucity and heterogeneity of studies,
summative review tactics were not available. The literature was critically reviewed by
international experts in the field with focus on the impact of gender-affirming medical
interventions on future fertility, current FP options and reproductive health issues in
transgender people. RESULTS: The current literature supports that transgender and gender
diverse individuals may wish to have genetically related children in the future, rendering the
issue of FP relevant to this patient group. The cryopreservation of mature gametes is an

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 efficacious option for FP for post-pubertal adolescents and adults. It is recommended to discuss
these options at time of planning for gender-affirming hormonal therapy (GAHT) or engaging
with other gender-affirming procedures that can limit future fertility. Discontinuation of GAHT
may allow individuals to undergo FP later, but data are limited and there is the concern of
symptoms and consequences of stopping GAHT. For pre-pubertal and early pubertal children, FP
options are limited to the cryopreservation of gonadal tissue. At present the tissue can become
functional only after re-transplantation, which might be undesirable by transgender individuals
in the future. Preconception counseling, prenatal surveillance, perinatal support, contraceptive,
and pregnancy termination related healthcare need to be meaningfully adapted for this patient
population, and many knowledge gaps remain. DISCUSSION: Specialized FP reproductive
healthcare for transgender and gender diverse individuals is in early evolution. Research should
be conducted to examine effects of medical interventions on fertility, timing of FP, gamete
preservation and outcome of the fertility treatments. Strategies to inform and educate
transgender and gender diverse patients can lead to optimization of reproductive care and
counseling and decision making of FP for this population.

Annotation: A narrative review of fertility management when counseling TGNB patients

Wilhelm S, Kelsberg G, Safranek S. How does gender-affirming hormone therapy affect QOL in
transgender patients? The Journal of family practice. 2022;71(10):442-444.
doi:10.12788/jfp.0521 Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L640249400&from=export

Abstract: There are modest effects on depression but not anxiety. Gender-affirming hormone
therapy (GAHT) is associated with modest improvements in standardized scores for quality of
life (QOL) and depression in adult male-to-female and female-to-male transgender people and
modest improvements in depression scores in transgender adolescents, but the effect on
anxiety is uncertain (strength of recommendation [SOR]: B, based on a preponderance of low-
quality prospective cohort studies with inconsistent results). GAHT is associated with reduced
gender dysphoria and decreased suicidality (SOR: B, based on a prospective cohort study).
However, there is insufficient evidence to determine any effect on suicide completion. No
studies associated GAHT with worsened QOL, depression, or anxiety scores.

Annotation: The impact of GAHT on quality of life for TGNB youth

Likely Eligible Studies Published in Other Languages but with English

Abstracts (Bibliography Only)
56,84,85,124,148,158-161,188,193,199,200,206,217,244

Condat A, Bekhaled F, Mendes N, Lagrange C, Mathivon L, Cohen D. Gender dysphoria in children and
adolescents: French history and clinical observations. Neuropsychiatr Enfance Adolesc.
2016;64(1):7-15. doi:10.1016/j.neurenf.2015.06.001 Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L605213392&from=export

Abstract: Background: While specialized consultations in the clinical evaluation and

management of sexual identity disorders in children and adolescents have developed since the
1970s abroad, access to information and specialized care is not yet well established in France.
Gender dysphoria is a rare disorder and in the context of a lack of specialized center, every
French child psychiatrist has met about 2 to 4 cases during his career. Also, in the absence of in-
depth clinical experience or integrated thinking, many French child psychiatrists or psychologists

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 have tried to formulate own views and ideas from isolated observations, in a context where the
clinical issues raised by these complex cases are crossed by societal debates about gender, sex,
procreation and human rights. We recently created a consultation specialized in sexual identity
in a Parisian university hospital to provide children and adolescents questioning their sexual
identity, with or without disorder of sex development, and their families a diagnostic evaluation,
information and if necessary treatment. Methods: We reviewed available medical information,
proposed care and international recommendations. In addition, we also reviewed the history of
the interests in gender dysphoria in France. Finally, we report four clinical observations that
meet all DSM-criteria of gender dysphoria and appeared paradigmatic of the diversity of issues
and clinical expressions. Results: The review of both the international and the French literatures
confirms that the debates, passions and issues are similar across culture and context despite
specific local variations that may explain why French child psychiatry appeared reluctant to
follow international changes until recently. The four cases that included 2 boys and two girls
aged 17, 16 (= 2) and 10 years, all asking for a change of sex, show (1) the clinical diversity in
terms of main expression (school refusal and anxiety, suicidal behaviors, anorexia), age of onset,
and medical context (with or without disorder of sex development); and (2) the relevance of a
multidisciplinary clinical approach taking into account the genetic, hormonal, psychological,
developmental, family and social dimensions. Conclusion: Besides the validity of gender
dysphoria as a clinical category, the diversity of the issues and clinical expression promotes a
dimensional approach of the cases. Many clinical and research questions need to be addressed
in the future: should we propose subgroups based on age of onset or comorbidities? What are
the consequences of hormonal suppression on child development and adolescence both in
terms of somatic and psychological milestones? Does social transition in child and adolescent
favour latter transsexual choices in adulthood? What is the right balance between hormonal
treatment and psychological therapies?

Annotation: A French case series reporting on 2 AMAB and 2 AFAB with gender dysphoria

Fernandez M, Guerra P, Martin E, Martinez N, Alvarez-Diz JA, Grupo G. [Health care for adolescents with
gender dysphoria]. Rev Esp Salud Publica. 2018;92Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/29493565

Abstract: OBJECTIVE: Dysphoria gender treatment in adolescents is recent. Studies of

adolescents treated with analogs are reduced. To ensure the quality of care and safety of the
child, follow-up studies are necessary. The aim of the present research was to describe the
characteristics of the process of medical and psychological attention in adolescents with the DG
in the Gender Identity Treatment Unit of Asturias in the period 2007-2015. METHODS: The
sample included 20 minors attended in the Gender Identity Treatment Unit of Asturias in the
period 2007-2015. The clinical history was made to collect the variables. It was made descriptive
analysis. RESULTS: 10% of adolescents abandoned in the process of psychological counseling,
80% began to be valued by endocrinology and 10% continued exclusively in psychological
consultations. Of the medical treated adolescents, 13.3% were treated with analogues and
86.7% received cross-hormonal treatment (THC) directly. The most prevalent secondary effects
were dermatological problems (40%), followed by mastodynia without galactorrhea (26.7%) and
hot flashes (20%). 20% performed gender confirmation surgeries. CONCLUSIONS: The profile of
the adolescent treated in the unit of Asturias is a subject that begins hormonal treatment after
psychological accompaniment and endocrinological evaluation. The minor has adverse effects
after treatment. Once the hormonal treatment has been established, they do not abandon the
process.

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 Annotation: A survey of TGNB youth on their treatment decisions after they presented
complaints of gender dysphoria. In Spanish.

Fernandez Rodriguez M, Guerra Mora P, Martin Sanchez E, Grupo G. [Characteristics of Adolescents with
Gender Dysphoria Referred to the Gender Identity Treatment Unit]. Rev Esp Salud Publica.
2017;91Accessed June 28, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/28141788

Abstract: OBJECTIVE: The demand for treatment among people with gender dys-phoria has
increased during the last years. The aim of the present research was to carry out an analysis of
the demand of the teenagers that requested consultation at the UTIGPA (Gender Identity
Treatment Unit of Principality of Asturias) as they presented complains of gender dysphoria.
METHODS: The sample included 20 minors that were treated between March 2007 and
December 2015. The clinical history was made to collect informa-tion. It was made descriptive
analysis and the reason sex/gender was used. RESULTS: The 20 teenagers represented the
14,6% of the whole sample (of 137 demands). The age average was 15,20 years (SD=1,473) and
the range of years was between 12-17. The reason sex/gender was 1/1 (10 into the man to
woman group and 10 into the woman to man group). At the arrival at the Treatment Unit, 100%
of the individuals lived with their nuclear or extended family and in the 60% of the cases, their
parents were separated. 70% of the cases were referred from mental health services. 10% hadn
t got any past medical history and 35% had never received any prescription for a
psychopharmacological treatment. 95% hadn't done any hormonal self-treatment. 100%
defined themselves as heterosexual. 25% requested exclusively for psychological interventions
and 75% asked for medical treatments. CONCLUSIONS: The profile of the minor was a teenager
of approximately 15 years old that was referred from mental health services. Contrary to the fin-
dings of other national and international researches, the rate sex/gender was equated in our
research. The minor had got a past medical history and their prio-rity request was for medical
treatments, both hormonal and surgical therapies.

Annotation: A survey of TGNB youth who requested consultation as they presented complaints
of gender dysphoria. In Spanish.

Korte A, Beier KM, Wermuth I, Bosinski HAG. The treatment of gender dysphoria (gender identity
disorders) in childhood and adolescence open-outcome psychotherapeutic support or early
setting of therapy course with the introduction of hormonal therapy? Padiatrische Praxis.
2017;88(1):67-87. Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L617597046&from=export

Abstract: Child and adolescent psychiatrists experience more and more patients who are
uncertain or dissatisfied in regard to their birth sex; some wish to join the opposite sex. Within
the framework of the recently revised DSM, DSM-5(2013), this article discusses the diagnostic
classification gender dysphoria (GD), in particular the question of the persistence of GD and the
therapeutic implications. It reviews at length the different approaches for treatment, especially
the pros and cons of early hormonal therapy. The study is based on a selective Medline
literature search, national and international guidelines, and the results of a debate among
experts in multiple relevant disciplines. Strong evidence indicates that only a minority of
children with GD manifest an irreversible transsexualism in adulthood. This indicates the use of
age-differentiated therapy with an open outcome, a treatment approach which in the case of
younger children primarily aims at strengthening the sense of concordance with their birth sex
and which in principle uses developmental tasks beyond the gender identity issue for all age

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 groups, and takes possible comorbid psychiatric disorders into account, for adolescents with
transsexualism in statu nascendi a real-life test under psychotherapeutical supervision is
indicated. The treatment with developmental- and bodyaltering hormones should be initiated
only after the juvenile's somato- and psychosexual development has been completed. The
article also debates the medical ethics involved here.

Annotation: A review of the applications of the gender dysphoria diagnostic criteria.

Martinez S, Mazoyer AV. Impacts of the sexual reassignment on the parenthood. Ann Med Psychol
(Paris). 2017;175(9):797-802. doi:10.1016/j.amp.2017.09.001 Accessed September 15, 2023.
Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L618996605&from=export

Abstract: Nous avons cherché à comprendre le vécu parental après une réassignation sexuelle
(male to female) d'un sujet. Après avoir exposé les différents travaux cliniques consacrés à la
transidentité (ou transsexualisme) et défini la parentalité, nous avons analysé les données
cliniques issues d'un entretien clinique de recherche et d'une passation d'une épreuve
projective, le TAT, étayée par une méthodologie innovante développée par des projectivistes
(Lintanff et Verdon, 2014). Nous avons rencontré une femme, Mme L., qui a été père par trois
fois et qui a décidé de changer de sexe après des événements traumatiques et somatiques et
une longue période de travestisme. Mme L. a peu évoqué son propre vécu de père, si ce n'est
que la réassignation sexuelle a occasionné une rupture des liens avec ses enfants de leur plein
gré. Elle a surtout évoqué son histoire de vie et son vécu d'enfant, d'adolescent et d'adulte
confronté à la transidentité et les aménagements qu'elle a pu mettre en œuvre pour soulager
une identité de genre non conforme à l'identité biologique. Le TAT a pu souligner la précarité
identificatoire, rendant complexe le rapport aux polarités : masculine, féminine, paternelle,
maternelle. La réassignation sexuelle vers le sexe féminin n'a pas occasionné une meilleure
qualité des identifications féminines et maternelles. Nous soulignons la valeur heuristique des
épreuves projectives dans la clinique de la transidentité. Objectives We tried to understand the
parental real-life experience after a hormonal and surgical sex reassignment (male to female).
Patients and methods After exposed research on transidentity and defined the parenthood, we
analyzed the clinical data from interviewing and projective test: TAT. Our research is based on
the French interpretation of this test, and on the show both the BM and the GF cards (Lintanff
and Verdon, 2014). We met a woman, Mrs L., who was a father by three times and who decided
to change sex after traumatic and somatic events and long period of transvestitism. Results The
reassignment caused a loss of contacts with his children. Mrs L. (now) little evoked his life story,
except his suffering when child, he repudiates his body's sex, which he oppose to his gender. We
analyse (TAT) wavering of female and maternal identifications even after reassignment.
Conclusion Projective tests provide a particularly heuristic solution for understanding the
weaknesses and psychic resources of subjects having changed gender.

Annotation: A TGNB parent of 3 children reviews her youth and decision to transition. In French.

Mendes N, Lagrange C, Condat A. Gender dysphoria in children and adolescents: Literature review.
Neuropsychiatr Enfance Adolesc. 2016;64(4):240-254. doi:10.1016/j.neurenf.2016.04.003
Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L610761157&from=export

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 Abstract: Background Today in France, specialised consultations for gender dysphoria in children
and adolescents are just being developed although specialised teams already address this public
abroad since decades. Their experience inspired the medical care in a remarkable way. Methods
To illustrate the present state of research in child and adolescents with gender dysphoria, we
first made a review of Zucker and al. publication (2013). We then compiled further researches
available on the subject (post 2013) as well as precursor works on transsexualism or gender
concept in general. We also took into consideration the most recent publications available in
scientific journals and the most relevant clinical trials. Results This research allows us to
highlight the evolution of diagnostic criteria, prevalence data, comorbidity and associated
psychopathologies, biological factors, and available treatments. We also discuss
psychodynamics observations and more generic issues based on available data. Conclusion The
recurrence of anxious and depressive signs and suicide risk in the studied population
demonstrate the need to consider gender dysphoria when providing medical and psychological
care to these children and adolescents. The recommended treatments also need to consider
possible comorbidity and the frequent related difficulties (such as social ostracism, anxiety,
etc.). Currently, there is an urgent need to develop specialised centres and platforms in France
to allow clinical practitioners to share their knowledge and researches results.

Annotation: A review of gender dysphoria in adolescents and children

Meyenburg B. [Gender dysphoria in adolescents: difficulties in treatment]. Prax Kinderpsychol

Kinderpsychiatr. 2014;63(6):510-522. Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25296511

Abstract: In many children and adolescents with gender dysphoria only minor or no
psychopathology is found. 43% of patients seen in the Frankfurt University Gender Identity Clinic
for children and adolescents suffer from major psychopathology. To demonstrate difficulties in
treatment of these patients courses of treatment in four such patients are presented. In two
natal females major psychopathology made decision for reassignment very difficult. Two natal
males were in addition not able to follow recommended treatment steps, in these patients
diagnostic doubts arose.

Annotation: Reviews treatment course for TGNB youth in a gender identity clinic. In German.

Meyenburg B, Korte A, Moller B, Romer G, Deutsche Gesellschaft fur Kinder- und Jugendpsychiatrie PuP.
[Gender identity disorders in childhood and adolescence (F64)]. Prax Kinderpsychol
Kinderpsychiatr. 2014;63(6):542-552. Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25296513

Annotation: Reviews treatment course for TGNB youth in a gender identity clinic. In German.

Meyenburg B, Kroger A, Neugebauer R. [Gender dysphoria in children and adolescents - treatment

guidelines and follow-up study]. Z Kinder Jugendpsychiatr Psychother. 2015;43(1):47-55.
doi:10.1024/1422-4917/a000332 Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25536896

Abstract: Treatment guidelines for transidentity in children and adolescents are presently under
discussion. We present an overview of the various treatment modalities. Further, follow-up data
on children and adolescents referred for gender-identity problems are presented. Of the 84
patients seen for the first time more than 3 years before follow-up, 37 mailed in the completed

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 questionnaires. In addition, 33 patients agreed to answer some short follow-up questions. We
assessed steps of treatment, gender role, psychopathology, and psychotherapy. We compared
differences in psychopathology in patients with vs. without gender role change and in patients
with intense vs. less intense psychotherapy. A total of 22 patients had completely changed
gender role, and some had started hormonal treatment und sex reassignment surgery. Most
patients were satisfied with the treatment results. All patients showed less psychopathology on
follow-up, independent of role change or intensity of psychotherapy. In general, the patients
reported little psychopathology. Our follow-up results support the present treatment approach.
In patients with little psychopathology, low-frequency supportive treatment appears sufficient
to obtain safe judgement on hormonal of surgical treatment.

Annotation: Survey of prior GD pediatric patients after 3 years, who did or did not transition. In
German.

Pamfile D, Soldati L, Brovelli S, et al. [Role of the psychiatrist-psychotherapist in the assessment and
treatment of gender dysphoria]. Rev Med Suisse. 2020;16(709):1877-1880. Accessed September
15, 2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/33026731

Abstract: This article is the result of the joint work of psychiatrists-psychotherapists working
with patients with gender dysphoria (children, adolescents and adults) in Lausanne and Geneva
university hospitals. It emphasizes the importance of their clinical interventions when hormone
therapy and sex reassignment surgery are requested.

Annotation: Practice guidelines for the mental health specialist for gender dysphoric
adolescents

Pauli D, Günthard M, Schenker T, et al. The Zurich Specialist Clinic for Adolescent with Gender Dysphoria
- Preliminary Follow-up Results. Prax Kinderpsychol Kinderpsychiatr. 2020;69(6):570-589.
doi:10.13109/prkk.2020.69.6.570 Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L633037474&from=export

Abstract: The Zurich Specialist Clinic for Adolescent with Gender Dysphoria - Preliminary Follow-
up Results The specialist clinic for children and adolescents with gender dysphoria (GD) of the
Psychiatric University Hospital of Zurich shows an increasing number of referrals since its
foundation in 2009. Since 2014 we started an observational study including adolescents aged 13
years and older. At the time of the first appointment (T0) N = 77 participants completed a
battery of questionnaires assessing demographic factors, general psychopathology, quality of
life as well as gender identity, social transitioning and GD treatment modalities. Few of the
adolescents were socially transitioned and had hormone therapy but 77.9 % wished to get
hormone therapy. Follow up assessment T1 was performed after at least one year of treatment
in our specialist clinic. 51 adolescents completed an online follow-up examination including the
same questionnaires and baseline parameters as well as a scale measuring treatment
satisfaction. At T0, 77.3 % of the adolescents scored in the clinical range of the Youth Self Report
(YSR) total score, which did not decrease significantly until T1 in our preliminary follow up
sample. Puberty blocking before T0 correlated negatively with the YSR score, indicating less
psychopathology in treated patients. Preliminary longitudinal analysis suggests that social
transitioning influences quality of life (Kidscreen subscale autonomy and parental relationship).
At T1, 52 % of the adolescents were socially transitioned in all contexts and 70 % received

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 gender affirming hormonal treatment. Gender identity changed between T0 and T1 in about 18
% of the cases. Treatment satisfaction in most cases was high.

Annotation: A pre-post follow up study of adolescents presenting with GD at a gender specialty

clinic. In German.

Pierce S, Mazziotta A, Möller-Kallista B. Experiences of Children with Gender Dysphoria/Gender

Incongruence and their Parents with the Health Care System in Germany. Prax Kinderpsychol
Kinderpsychiatr. 2022;71(7):597-619. doi:10.13109/prkk.2022.71.7.597 Accessed September 15,
2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L639549895&from=export

Abstract: The aim of the study is to describe experiences within the health care system of
children and adolescents with gender dysphoria/gender incongruence (GD/GI) as well as their
parents in Germany.The findings are intended to improve health care of children and
adolescents with GD/GI and their families and have been incorporated into the development of
the new S3 Guidelines "Gender Incongruence and Gender Dysphoria in Childhood and
Adolescence: Diagnosis and Treatment". A total of 78 people, 35 children, adolescents, and
young adults (6- 21 years) with GD/GI as well as 33mothers and 10 fathers, were interviewed.
Seventeen semistructured individual interviews and five focus groups were conducted. Many of
the participants reported waiting times of several months or years as well as inadequately
trained doctors and therapists. A trans*identity, especially amongst smaller children and their
parents, was often dismissed by health care providers, as a temporary phenomenon or an
imagination of the child or the parents. Trans*ident children, adolescents and young adults as
well as their parents were rarely perceived as experts in their own right. Recommendations for
an affirmative care of trans* children and adolescents are formulated.

Annotation: A qualitative, interview survey of TGNB youths and their parents. In German

Poirier F, Condat A, Laufer L, Rosenblum O, Cohen D. Non-binary gender and transgender youth: A
literature review. Neuropsychiatr Enfance Adolesc. 2019;67(5-6):268-285.
doi:10.1016/j.neurenf.2018.08.004 Accessed September 15, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L2001164253&from=expo
rt

Abstract: Background: Recently international scientific literature has been increasingly

interested in situations where gender identity is unconventional – neither male nor female,
part-time male part-time female, male and female. Binary transgender identity and gender
dysphoria are now well recognized. However, this is not the case for non-binary gender
identities. Objective: In the current report, we aim at reviewing the literature on non-binary
gender and genderqueer identities in order to appreciate the interest of this recognition in
medicine and its understanding by the health professionals. Methods: The article is based on a
literature review on non-binary gender and genderqueer identities and on the accompaniment
of binary and non-binary transgender youth. The results are presented within different themes.
Results: Research shows that non-binary/genderqueer people tend to be young, urban, have a
higher level of education, and to remain often as students or unemployed. If non-binary trans
people are mostly teenagers and young adults between the ages of 14 and 25, it is not simply a
question of considering non-binary gender identity as an adolescent process, or even simply a
recent societal phenomenon. Indeed, the issues that are facing these adolescents and young

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 people are very specific, starting with marginalization and precariousness. According to previous
studies, psychic difficulties (including self-aggressive gestures, suicidal thoughts and behaviors,
eating disorders, anxiety and depression) are more or less equal or superior to those of binary
transgender people. It is necessary to consider the different methodological biases, or the
cultural and geographical context of a study. The rate of indecision is particularly high among
non-binary youth, but access to care is more complicated when they are ready to make a
change. Then, the physical transformations desired will vary, depending on the needs, but
frequently only the cross-sex hormones and/or top surgery are needed. In that way, non-binary
gender youth tend to have a better relationship with their own bodies than binary transgender
youth. Conclusion: The scientific literature is increasingly trying to raise the question of the
inclusivity of all genres in national surveys and in the accompaniment of people. A better
understanding of these questions will allow better support of young people questioning their
gender in a binary or non-binary perspective.

Annotation: A review of the literature concerning TGNB youth.

Rebetez N. [I want an accepting society]. Krankenpfl Soins Infirm. 2014;107(11):56-57. Accessed June 28,
2023. Available at https://www.ncbi.nlm.nih.gov/pubmed/25438414

Abstract: None

Annotation: A TGNB youth discusses her transition. In French.

Rutzen KM, Nieder TO, Schreier H, Moller B. [Clinical treatment of children and adolescents with gender
dysphoria from international experts' point of view]. Prax Kinderpsychol Kinderpsychiatr.
2014;63(6):449-464. Accessed June 28, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/25296508

Abstract: The clinical treatment of children and adolescents with gender dysphoria is still a
controversial issue. The aim of this study was to get an overview of the knowledge and
experience of international experts and to highlight shared views as well as differences in
theoretical convictions and treatment approaches. Half-structured, guide-line based interviews
were carried out with international experts in the field. The interviews were analyzed using
qualitative content analysis (Mayring, 2010).

Annotation: The clinical treatment of children and adolescents with gender dysphoria

Strittmatter E, Holtmann M. [Gender identities in transition]. Z Kinder Jugendpsychiatr Psychother.

2020;48(2):93-102. doi:10.1024/1422-4917/a000724 Accessed September 15, 2023. Available at
https://www.ncbi.nlm.nih.gov/pubmed/32162593

Abstract: Gender identities in transition Abstract. In recent years, the healthcare system has
been confronted with an increasing number of children and adolescents with gender
nonconformity, gender incongruence, and gender dysphoria. Medical professionals are still
debating how to interpret this phenomenon and how best to meet the healthcare needs of this
diverse group of young people. Meanwhile, the transgender and gender nonconforming youths
themselves face enormous challenges in finding appropriate support and treatment in the
mental healthcare system. This article reviews the available epidemiological data, the paradigm
shift in the social, legal, and medical systems, the developments in diagnostic classifications
(DSM-5, ICD-11) as well as important aspects of the AWMF S3 guideline for adults with gender

486

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 incongruence and gender dysphoria. In addition, it describes the complexity of working with
transgender, gender nonconforming, and gender-questioning youth in the context of the
current discourse and the underlying ethical dilemmas. In conclusion, this article outlines the
challenges facing child and adolescent psychiatry and psychotherapy in this complex
environment.

Annotation: A review of the diagnosis and treatment of gender dysphoria

Repeat Publications of Included Studies (Bibliography Only) 72-74,76,100,125

de Vries ALC. Autism Spectrum Disorders in Gender Dysphoric Children and Adolescents. Gender
Dysphoria in Adolescents. PhD Thesis. Vrije Universiteit Amsterdam; 2010:51-62:chap 4.
Accessed June 12, 2023. Available at https://research.vu.nl/en/publications/gender-dysphoria-
in-adolescents-mental-health-and-treatment-evalu

de Vries ALC. Gender Dysphoria in Adolescents. PhD Thesis. Vrije Universiteit Amsterdam; 2010.
Accessed June 12, 2023. Available at https://research.vu.nl/en/publications/gender-dysphoria-
in-adolescents-mental-health-and-treatment-evalu

de Vries ALC. Psychiatric Comorbidity in Gender Dysphoric Adolescents. Gender Dysphoria in

Adolescents. PhD Thesis. Vrije Universiteit Amsterdam; 2010:63-76:chap 5. Accessed June 12,
2023. Available at https://research.vu.nl/en/publications/gender-dysphoria-in-adolescents-
mental-health-and-treatment-evalu

de Vries ALC. Puberty Suppression in Adolescents with Gender Identity Disorder: A Prospective Follow-
up Study. Gender Dysphoria in Adolescents. PhD Thesis. Vrije Universiteit Amsterdam; 2010:77-
90:chap 6. Accessed June 12, 2023. Available at https://research.vu.nl/en/publications/gender-
dysphoria-in-adolescents-mental-health-and-treatment-evalu

Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/Gender-

Incongruent Persons: An Endocrine Society Clinical Practice Guideline. Endocr Pract.
2017;23(12):1437. doi:10.4158/1934-2403-23.12.1437 Accessed September 15, 2023. Available
at https://www.ncbi.nlm.nih.gov/pubmed/29320642

Annotation: A guideline for treating gender dysphoria

Korte A, Beier KM, Wermuth I, Bosinski HAG. The treatment of gender dysphoria (gender identity
disorders) in childhood and adolescence open-outcome psychotherapeutic support or early
setting of therapy course with the introduction of hormonal therapy? Gynakologische Praxis.
2018;43(2):303-323. Accessed June 28, 2023. Available at
https://www.embase.com/search/results?subaction=viewrecord&id=L617597046&from=export

Abstract: Child and adolescent psychiatrists experience more and more patients who are
uncertain or dissatisfied in regard to their birth sex; some wish to join the opposite sex. Within
the framework of the recently revised DSM, DSM-5(2013), this article discusses the diagnostic
classification gender dysphoria (GD), in particular the question of the persistence of GD and the
therapeutic implications. It reviews at length the different approaches for treatment, especially
the pros and cons of early hormonal therapy. The study is based on a selective Medline
literature search, national and international guidelines, and the results of a debate among
experts in multiple relevant disciplines. Strong evidence indicates that only a minority of

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 children with GD manifest an irreversible transsexualism in adulthood. This indicates the use of
age-differentiated therapy with an open outcome, a treatment approach which in the case of
younger children primarily aims at strengthening the sense of concordance with their birth sex
and which in principle uses developmental tasks beyond the gender identity issue for all age
groups, and takes possible comorbid psychiatric disorders into account, for adolescents with
transsexualism in statu nascendi a real-life test under psychotherapeutical supervision is
indicated. The treatment with developmental- and bodyaltering hormones should be initiated
only after the juvenile's somato- and psychosexual development has been completed. The
article also debates the medical ethics involved here.

Annotation: Gender development in children and implications for gender dysphoria

Commentaries on or Corrections of Included Studies (Bibliography Only)

102,104

Hembree WC, Cohen-Kettenis PT, Gooren L, et al. CORRIGENDUM FOR "Endocrine Treatment of Gender-
Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline". J Clin
Endocrinol Metab. 2018;103(7):2758-2759. doi:10.1210/jc.2018-01268 Accessed June 28, 2023.
Available at https://www.ncbi.nlm.nih.gov/pubmed/29905821

Abstract: In the Summary of Recommendations, 1.0 Evaluation of youth and adults,

Recommendation 1.1 on page 3870 and in Recommendations for Those Involved in the Gender-
Affirming Hormone Treatment of Individuals With GD/Gender Incongruence on page 3877, the
Recommendation was originally: 1.1. We advise that only trained mental health professionals
(MHPs) who meet the following criteria should diagnose gender dysphoria (GD)/gender
incongruence in adults: (1) competence in using the Diagnostic and Statistical Manual of Mental
Disorders (DSM) and/or the International Statistical Classification of Diseases and Related Health
Problems (ICD) for diagnostic purposes, (2) the ability to diagnose GD/gender incongruence and
make a distinction between GD/gender incongruence and conditions that have similar features
(e.g., body dysmorphic disorder), (3) training in diagnosing psychiatric conditions, (4) the ability
to undertake or refer for appropriate treatment, (5) the ability to psychosocially assess the
persons understanding, mental health, and social conditions that can impact gender-affirming
hormone therapy, and (6) a practice of regularly attending relevant professional meetings.
(Ungraded Good Practice Statement).

Annotation: A correction to a guideline for treating gender dysphoria

Hewitt JK, Paul C, Newman LK. Author Reply to Conway, et al. regarding “Hormone treatment of gender
identity disorder in a cohort of children and adolescents”. Med J Aust. 2012;197(5):274.
doi:10.5694/mja12.10911 Accessed June 16, 2023. Available at
https://pubmed.ncbi.nlm.nih.gov/22938117/

Annotation: Author’s reply to comment on prior article, “Hormone treatment of gender identity
disorder in a cohort of children and adolescents”

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APPENDIX I.G: CHARACTERISTICS OF INCLUDED RELEVANT CLINICAL
STUDIES

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Multistate/national studies
National internet survey, n ≥ 3235 TGNB youths
Green (2022)111 All subjects: 5,753 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 5,753 Mental health TGNB)
Observational cross-sectional study
TGNB youths: 3,235
Study period: 10/2020–12/2020 Risk of bias details in Appendix I.I
Nationwide, cross-sectional, survey study comparing demographic and mental health characteristics between Transmasculine: 2,547
adolescents and young adults who self-reported receiving GAHT versus not, including TGNB adolescents ages 13- Transfeminine: 702 Follow-up duration: N/A
17 years recruited from an unspecified number of US states via ads on social media OGD: 2,504

National internet survey, n ≥ 156 TGNB youths

Chen (2018)455 All subjects: 156 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 156 Attitudes towards fertility
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 156
Study period: 9/2016–10/2016 not have data extracted due to time constraints
A survey study examining attitudes about fertility among TGNB adolescents who were participants in a larger study Transmasculine: 57
about sexual health and HIV prevention Transfeminine: 9 Follow-up duration: N/A
OGD: 90

US Youth Risk Behavior Survey, n ≥ 3494 TGNB youths

Turban (2020)121 All subjects: 20,619 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 3,494 Mental health TGNB)
Observational cross-sectional study
TGNB youths: 3,494 Self-harm Risk of bias details in Appendix I.I
A cross-sectional survey study including cisgender and transgender adolescent respondents from 2017 and 2019, Transmasculine: 1,213
including an examination of the association between self-reported GnRH analog use and suicide ideation in TGNB Transfeminine: 1,385 Study period: 8/2015–9/2015
adolescents OGD: 896 Follow-up duration: N/A
Cisgender peers/others: 17,125

Turban (2022)122 All subjects: 27,715 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 27,715 Mental health TGNB)
Observational cross-sectional study
TGNB youths: 481 Psychosocial metrics Risk of bias details in Appendix I.I
A cross-sectional study of 2015 Youth Behavioral Risk Survey respondents including transgender adults who
started treatment in early adolescence, late adolescence, or adulthood; examines the risk of mental health Study period: 8/2015–9/2015
problems associated with the age of treatment initiation. Follow-up duration: N/A

Children's Hospital Association's Pediatric Health and Information System,a n ≥ 264 TGNB youths
Lopez (2018)456 All subjects: 1,506 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 264

a Includes up to 43 institutions.

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
490

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Descriptive study TGNB youths: 264 FDA-approved indications and off- Studies that did not make one of our three highest-priority
Cisgender peers/others: 1,242 label uses comparisons did not have data extracted due to time
Examines off-label use of GnRH analogs among pediatric patients with GD or developmental sex disorders. Neither
constraints
affirmed genders nor birth-assigned sexes were reported. Study period: 2013–2016
Follow-up duration: N/A

Lopez (2018)435 All subjects: 2,332 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 92 Utilization of histrelin acetate
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 92 implants comparisons did not have data extracted due to time
Examines use of GnRH analogs in pediatric patients, including TGNB children and cis children with CPP. Authors did Transmasculine: N/R
Study period: 2004–2016 constraints
not report affirmed gender ratios, only natal sex (N = 52 AMAB, N = 39 AFAB, and 1 whose natal sex was Transfeminine: N/R
unknown). OGD: N/R Follow-up duration: N/R
Cisgender peers/others: 2,240

Military Healthcare Data Repository, n = 952 TGNB youths

Roberts (2022)457 All subjects: 952 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 952 Initiation and continuation of GAH
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 952
Study period: 2009–2018 not have data extracted due to time constraints
A US, multi-state cohort study examining treatment continuation in N = 952 transmasculine vs transfeminine TGNB Transmasculine: 627
dependents of US military personnel Transfeminine: 325 Follow-up duration: 4.4 years

Nos (2022)173 All subjects: 434 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 434 Likelihood of initiation of GAH
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 434
Study period: 10/2009–4/2018 not have data extracted due to time constraints
Cohort study examining the risk of CSHT use in TGNB adolescents who used GnRH analogs and had the TRICARE
benefit. Only natal sexes reported (N = 122 AMAB and N = 312 AFAB). Follow-up duration: N/R

Cystic Fibrosis care centers surveyed, N = 30 TGNB youths

Shaffer (2022)458 All subjects: 30 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 30 1-second FEV values
Longitudinal, pre-post descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 30
Study period: 12/2019–2/2020 not have data extracted due to time constraints
A research letter summarizing findings from a research study examining 1-second FEV values in TGNB adolescents Transmasculine: 13
with CF from a national sample of centers Transfeminine: 11 Follow-up duration: 24 months
OGD: 6

Trans Youth Project in 23 states and Canada, N = 317 TGNB youths

Durwood (2017)109 All subjects: 310 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 116 Mental health TGNB), Appendix I.K (TGNB vs cisgender peers)
Observational cross-sectional study
TGNB youths: 116
Study period: 3/2015–2/2016 Risk of bias details in Appendix I.I
Transmasculine: 48

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
491

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Cross-sectional study comparing mental health and self-worth outcomes between TGNB treatment groups and Transfeminine: 68 Follow-up duration: N/A
between TGNB adolescents versus controls (ie, siblings and community controls). Cisgender peers/others: 194

Olson (2022)175 All subjects: 317 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 317
Descriptive study Study period: 7/2013–12/2017 Studies that did not make one of our three highest-priority
TGNB youths: 317
comparisons did not have data extracted due to time
A nationwide survey study examining gender identities 5 years after initial presentation Transmasculine: 109 Follow-up duration: N/A
constraints
Transfeminine: 208

A dataset from PEDSnet (a pediatric learning health system network), comprising data from 7 PEDSnet participating institutions , N = 4172 TGNB youths
Valentine (2022)98 All subjects: 20,625 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 4,172 Cardiometabolic parameters TGNB), Appendix I.K (TGNB vs cisgender peers)
Observational cohort and cross-sectional study
TGNB youths: 4,172
Study period: 2009–2019 Risk of bias details in Appendix I.I
Cross-sectional, database study comparing cardiometabolic parameters between TGNB adolescents and controls, Cisgender peers/others: 16,648
as well as between TGNB adolescents receiving different treatments. Only natal sexes reported (N = 2766 AFAB Follow-up duration: N/A
and N = 1407 AMAB).

Trans Youth Care Study Hospitals),b n ≥ 391 TGNB youths

Olson-Kennedy (2019)162 All subjects: 481 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 391 Mental health
Longitudinal, pre-post descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 391 Physiologic/Metabolic parameters not have data extracted due to time constraints
Examines growth and bone density in TGNB adolescents starting puberty suppression and TGNB adolescents Bone health
starting CSHT
Study period: 7/2016–9/2018
Follow-up duration: 24 months
85
Lee (2020) All subjects: 63 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 63 BMD Z-scores TGNB)
Observational cohort study
TGNB youths: 63
Study period: N/R Risk of bias details in Appendix I.I
Examines changes in bone between TGNB patients treated with GnRH analogs. Authors did not specify affirmed Transmasculine: N/R
gender identities other than to specify 58 as binary and 5 nonbinary. They also specified natal sexes (N = 33 AMAB Transfeminine: N/R Follow-up duration: N/A
and N = 30 AFAB) OGD: 5

Nahata (2020)459 All subjects: 44 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 44 Sexual attitudes and behaviors
Descriptive studya Studies that did not make one of our three highest-priority
TGNB youths: 44 Attitudes towards fertility comparisons did not have data extracted due to time
Study period: N/R constraints

b Sites include

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
492

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Examines gender identity, sexual orientation, contraception counseling, and attitudes towards fertility among Follow-up duration: N/A
TGNB adolescents seen in 4 gender clinics across 3 states

Chen (2021)104 All subjects: 95 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 95 Psychosocial TGNB)
Observational cross-sectional study
TGNB youths: 95
Study period: 7/2016–9/2018 Risk of bias details in Appendix I.I
Cross-sectional study examining psychosocial outcomes in TGNB youth initiating treatment with GnRH analogs or Transmasculine: 41
CSHT. Transfeminine: 45 Follow-up duration: N/A
OGD: 9

Millington (2021)89 All subjects: 269 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 269 Cholesterol changes TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 269 Body changes/Growth Risk of bias details in Appendix I.I
A research letter examining growth, body composition, and cholesterol changes in TGNB adolescents receiving
CSHT. Only natal sex reported (N = 83 AMAB and N = 186 AFAB). Study period: 7/2016–9/2018
Follow-up duration: 12 months
Millington (2022)90 All subjects: 286 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 286 Kidney function metrics TGNB), Appendix I.K (TGNB vs cisgender peers), and
Descriptive, longitudinal pre-post study
TGNB youths: 286 Appendix I.L (pre-post comparisons)
Examines changes in kidney function measures in TGNB adolescents receiving GAHT. Study period: N/R
Transmasculine: 181
Risk of bias details in Appendix I.I
Transfeminine: 87 Follow-up duration: 24 months
OGD: 18

Schulmeister (2022)95 All subjects: 55 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 55 Growth TGNB), Appendix I.K (TGNB vs cisgender peers)
Observational cohort study
TGNB youths: 55 Height velocity Risk of bias details in Appendix I.I
Multi-state cohort study comparing height velocity (ie, growth) in TGNB patients who initiated GnRH analogs for Transmasculine: 28
puberty suppression at the various Tanner stages. Transfeminine: 24 Study period: 7/2016–9/2018
OGD: 3 Follow-up duration: 14 months

Chen (2023)75 All subjects: 315 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 315 Mental health TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 315 Psychosocial functioning Risk of bias details in Appendix I.I
Examines mental health and psychosocial outcomes in TGNB adolescents after 2 years of CSHT. Also compares Transmasculine: 190
mental health outcomes between early- and late-treated adolescents. Transfeminine: 106 Study period: 7/2016–6/2019
OGD: 19 Follow-up duration: 24 months
Conn (2023)105 All subjects: 315 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 315 Mental health TGNB)
Observational cross-sectional study
TGNB youths: 315
Risk of bias details in Appendix I.I
Transmasculine: 190

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
493

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Examines risk factors for mental health outcomes in TGNB adolescents from the Trans Youth Care Study. Transfeminine: 106 Gender Minority Stress and
OGD 19 Resilience Measure for Adolescents
(GMSR-A)
Study period: 7/2016–9/2018
Follow-up duration: N/R

which links medical records at multiple health care sites throughout , n = 22 TGNB youths
James (2020)460 All subjects: 80 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 80 Health risk factors
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 22 Mental health risk factors not have data extracted due to time constraints
Examines changes in gender identity between AFAB and AMAB TGNB patients, including adolescents. Outcomes of Transmasculine: 29 Gender identity
interest were not reported separately for adolescents. Transfeminine: 32
OGD: 19 Study period: 1974–2015
Follow-up duration: Median 40.5
months
,c n = 116 TGNB youths
Jarin (2017)136 All subjects: 116 Relevant outcomes Details of data extraction available in Appendix I.L (pre-post
TNGB patients: 116 Cardiovascular risk factors comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 116 Metabolic parameters Risk of bias details in Appendix I.I
Examines cardiovascular and metabolic changes associated with CSHT in adolescents with gender dysphoria Transmasculine: 72
Transfeminine: 44 Study period: 2008–2014
Follow-up duration: Max of 35 months

STRONG cohort, n = 958 TGNB youths

Wagner (2021)461 All subjects: 958 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 958 Predictors of GD diagnosis
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 958 Predictors of CSHT not have data extracted due to time constraints
Cohort study examining predictors of GD diagnosis and of CSHT initiation in gender-diverse children. Only natal sex
reported (N = 531 AMAB and N = 527 AFAB). Study period: 1/2006–12/2014
Follow-up duration: Mean 3.5 years

c Sites include the .

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
494

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
n = 36 TGNB youths
Stevens (2015)462 All subjects: 36 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 36 Insurance coverage patterns
Observational study Studies that did not make one of our three highest-priority
TGNB youths: 36
Study period: 2010–2015 comparisons did not have data extracted due to time
Examines insurance barriers to treatment access among TGNB children seen in 2 University-based pediatric clinics
constraints
Follow-up duration: N/R

Unspecified or inconclusive locations in the US

Either a, n ≥ 1 TGNB youth
Penney (2022)463 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 VTE events after testosterone
Case reporta Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
A 17 year-old transgender male diagnosed with VTE who went on to receive testosterone therapy Transmasculine: 1
due to time constraints
Follow-up duration: N/R

A regional, referral-based adolescent specialty clinic that cares for dependent children of active duty, activated selected reserve, and retired military service members, n ≥ 53 TGNB youth
Van Donge (2019)464 All subjects: 53 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 53 Mental health outcomes
Observational study Studies that did not make one of our three highest-
TGNB youths: 53 Psychosocial outcomes priority comparisons did not have data extracted due to
A cross-sectional study examining mental health outcomes in TGNB adolescent dependents of active-duty or Healthcare utilization time constraints
retired US military personnel
Study period: 7/2014–7/2017
Follow-up duration: N/A

Arizona
clinic, n ≥ 13 TGNB youths
Parks (2020)465 All subjects: 260 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 13 Menstruation patterns
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 13
Study period: 2012–2018 priority comparisons did not have data extracted due to
Examines menstrual outcomes in adolescents who received levonorgestrel IUDs, including transgender male Transmasculine: 13
time constraints
patients Follow-up duration: N/R

California

n ≥ 66 TGNB youths

Khazal (2014)466 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Blood and marrow transplantation
Case report
Psychosocial

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
495

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
A transgender adolescent with chronic myelogenous leukemia (CML) TGNB youths: 1 Study period: N/A Case reports and series do not contain high-priority
Transfeminine: 1 comparisons and therefore did not have data extracted,
Follow-up duration: 18 months due to time constraints
No ethics review, IRB, or consent for research was
described

Olson-Kennedy (2018)143 All subjects: 59 Relevant outcomes Details of data extraction available in Appendix I.L (pre-post
TNGB patients: 59 Body changes comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 59 Testosterone utilization Risk of bias details in Appendix I.I
Examines the amount of chest dysphoria in transmasculine youth who had had chest reconstruction surgery Transmasculine: 34
compared with those who had not undergone this surgery. Transfeminine: 25 Study period: 6/2016–12/2016
Follow-up duration: N/A
93
Olson-Kennedy (2021) All subjects: 66 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 66 Body change prevention TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort study
TGNB youths: 66
Study period: N/R Risk of bias details in Appendix I.I
Cohort study comparing puberty suppression outcomes in TGNB subjects receiving two forms of histrelin (Vantas Transmasculine: 32
vs Supprelin LA), and examining changes in the same outcomes within-TGNB groups Transfeminine: 34 Follow-up duration: 12 months

n = 14 TGNB youths

Krishna (2021)467 All subjects: 73 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 14 Success of utilization
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 14 Adverse events comparisons did not have data extracted due to time
Examines on characteristics and temporal trends in use of histrelin implants in pediatric patients, including Transmasculine: 14
Study period: 2008–2020 constraints
patients with GD Cisgender peers/others: 59
Follow-up duration: 37 months

California

n = 417 TGNB youths

Handler (2019)468 All subjects: 417 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 417 Referral and request trends
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 417
Study period: 2/2015–6/2018 comparisons did not have data extracted due to time
Examines trends in TGNB referrals and requests for cross-sex hormones, puberty blockers, and surgery Transmasculine: 257
constraints Descriptive studies that did not measure
Transfeminine: 102 Follow-up duration: Median > 2 years
outcomes at multiple time-points were excluded from data
OGD: 58
extraction due to time constraints.

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
496

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
California

n = 106 TGNB youths

Avila (2019)101 All subjects: 106 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 106 Eating disorder metrics TGNB)
Observational cross-sectional study
TGNB youths: 106 Body satisfaction Risk of bias details in Appendix I.I
Cross-sectional study comparing eating disorder outcome scores (see Appendix I.H) between treated and Transmasculine: 64
untreated TGNB subjects Transfeminine: 30 Study period: 1/2018–1/2019
OGD: 12 Follow-up duration: N/A

California

n = 119 TGNB youths

Laurenzano (2021)84 All subjects: 119 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 119 Body and hormone changes TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 119
Study period: 8/2012–2/2020 Risk of bias details in Appendix I.I
Examines endogenous hormone levels, menstrual outcomes, and body changes in transmasculine and gender- Transmasculine: 110
diverse adolescents treated with subcutaneous testosterone OGD: 9 Follow-up duration: Up to 5.5 years

California

urology department, n = 1 TGNB youth

Adeleye (2023)469 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Semen cryopreservation; fertility
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/R comparisons and therefore did not have data extracted,
Examines treatment course and outcomes in a transgender female adolescent with spermatogenesis during Transfeminine: 1
due to time constraints
hypothalamic suppression and low testosterone Follow-up duration: N/R

California

, n = 60 TGNB youths

Ni (2023)470 All subjects: 103 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 103 Utility of biochemical monitoring
Longitudinal, pre-post descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 60
Study period: 1/2018–3/2021 not have data extracted due to time constraints
Examining endogenous hormone levels associated with implantable GnRH analog therapy in TGNB adolescents.
Only natal sex reported (N = 63 AFAB and N = 40 AMAB). Follow-up duration: Median 135 days

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
497

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Colorado

n = 35 TGNB youths

Nokoff (2020)131 All subjects: 143 Relevant outcomes Details of data extraction available in Appendix I.K (TGNB vs
TNGB patients: 35 Insulin sensitivity cisgender peers)
Observational cohort study
TGNB youths: 35 Body composition Risk of bias details in Appendix I.I
Cohort study comparing insulin and body composition outcomes between TGNB patients on estradiol or Transmasculine: 21
testosterone and cisgender peers Transfeminine: 14 Study period: 2016–2018
Cisgender peers/others: 108 Follow-up duration: N/A

Nokoff (2021)134 All subjects: 48 Relevant outcomes Details of data extraction available in Appendix I.K (TGNB vs
TNGB patients: 17 Insulin sensitivity/glycemic control cisgender peers)
Observational study
TGNB youths: 17 Body composition Risk of bias details in Appendix I.I
Study comparing insulin sensitivity and glycemic control outcomes between TGNB youths on GnRH analogs and Transmasculine: 9
cisgender peers Transfeminine: 8 Study period: 2016–2019
Cisgender peers/others: 31 Follow-up duration: N/A
146
Roy (2023) ClinicalTrials.gov All subjects: 15 Relevant outcomes Details of data extraction available in Appendix I.L (pre-post
TNGB patients: 15 Metabolic changes comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 15
Study period: 6/2018–8/2019 Risk of bias details in Appendix I.I
A research letter reporting findings from a Colorado-based, longitudinal, pre-post study of transgender boys Transmasculine: 15
receiving testosterone therapy. Follow-up duration: 12 months

n = 220 TGNB youths

Alaniz (2023)471 All subjects: 220 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 220 Time to menstrual suppression
Longitudinal, pre-post descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 220
Study period: 1/2013–1/2019 not have data extracted due to time constraints
Examines time to menstrual suppression in transmasculine and gender expansive youths receiving GAHT, including Transmasculine: 212
testosterone OGD: 8 Follow-up duration: N/R

Connecticut a

a n = 8 TGNB youths
Sayeem (2021)472 All subjects: 8 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 8 Pain and functionality
Case seriesa Case reports and series do not contain high-priority
TGNB youths: 8
Study period: 1/2017–9/2019 comparisons and therefore did not have data extracted,
Describes pain and functionality outcomes in TGNB youths with gender dysphoria presenting in a pain clinic Transmasculine: 6
due to time constraints
Transfeminine: 2 Follow-up duration: N/R

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
498

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
No ethics review, IRB, or consent for research was
described

Connecticut

, n = 23 TGNB youths

Morrison (2020)473 All subjects: 23 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 23 Fertility preferences
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 23
Study period: 8/2016–8/2017 comparisons did not have data extracted due to time
Cross-sectional survey results about fertility preference in transgender children seen at a university-affiliated clinic. Transmasculine: 15
constraints
Transfeminine: 6 Follow-up duration: N/A
OGD: 2

Delaware

n ≥ 133 TGNB youths

Schwartz (2022)474 All subjects: 129 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 129 Menstruation, menstrual dysphoria Studies that did not evaluate our high-priority outcomes did
Observational, cross-sectional study
TGNB youths: 129
Study period: 3/2015–12/2020 not have data extracted due to time constraints
Compares menstrual history and menstrual management methods between transgender males and nonbinary Transmasculine: 116
patients OGD: 13 Follow-up duration: N/R

Schwartz (2023)475 All subjects: 101 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 101 Menstrual suppression
Longitudinal, pre-post descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 101
Study period: 3/2015–12/2020 not have data extracted due to time constraints
Examines menstrual suppression outcomes in transmasculine and gender-diverse adolescents receiving various Transmasculine: 90
progestins in a gender specialty clinic OGD: 11 Follow-up duration: 18 months
476
Schwartz (2023) All subjects: 133 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 133 Menstrual management methods
Longitudinal, pre-post descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 133
Study period: 3/2015–12/2020 not have data extracted due to time constraints
Examines menstrual suppression outcomes in transmasculine and gender-diverse adolescents receiving various Transmasculine: 119
menstrual management treatments in a gender specialty clinic OGD: 14 Follow-up duration: 18 months

Georgia

n = 60 TGNB youths
477
Chu (2023) All subjects: 60 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 60 Acne
Descriptive study
Predictors of acne

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
499

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Examines acne outcomes in transmasculine adolescents receiving testosterone in a pediatric endocrinology clinic TGNB youths: 60 Study period: 1/2016–12/2018 Studies that did not evaluate our high-priority outcomes did
Transmasculine: 60 not have data extracted due to time constraints
Follow-up duration: 24 months

Illinois

n ≥ 105 TGNB youths

Chen (2017)478 All subjects: 105 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 105 Fertility preservation utilization
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 105
Study period: 7/2013–7/2016 comparisons did not have data extracted due to time
Examines fertility consultation outcomes in TGNB adolescents Transmasculine: 77
constraints
Transfeminine: 28 Follow-up duration: N/R

Chen (2018)479 All subjects: 5 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 5 Fertility preservation
Case seriesa Case reports and series do not contain high-priority
TGNB youths: 3
Study period: N/R comparisons and therefore did not have data extracted,
Examines fertility preservation outcomes in transmasculine youths undergoing oocyte cryopreservation Transmasculine: 5
due to time constraints
Follow-up duration: N/A

Kyweluk (2018)480 All subjects: 18 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 18 Opinions on medical care
Descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 7 Opinions on fertility preservation not have data extracted due to time constraints
A qualitative, descriptive interview study examining ethical considerations related to fertility preservation in TGNB Transmasculine: 5
youth and their parents Transfeminine: 2 Study period: 12/2016–8/2017
Follow-up duration: N/A
60
Jensen (2019) All subjects: 83 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 83 GnRH analog efficacy
Observational studya Studies that did not evaluate our high-priority outcomes did
TGNB youths: 83 CSHT doses not have data extracted due to time constraints
Cohort study comparing demographic characteristics, adverse effects, and estrogen/testosterone dosages Transmasculine: 61
between transgender patients receiving GnRH analogs versus not Transfeminine: 22 Study period: 3/2016–1/2018
Follow-up duration: Median 24 or 29
months on or off GnRH analogs,
respectively

Harris (2020)481 All subjects: 54 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 35 Ethical views of fertility
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 35 preservation comparisons did not have data extracted due to time
A qualitative, descriptive interview study examining ethical considerations related to fertility preservation in TGNB Transmasculine: 24
Study period: 12/2016–5/2017 constraints
youth and their parents Transfeminine: 10

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
500

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
OGD: 1 Follow-up duration: N/A
Parents: 19

Indiana

, n = 13 TGNB youths

Neyman (2019)64 All subjects: 13 Relevant outcomes Details of data extraction available in Appendix I.L (pre-post
TNGB patients: 13 Clinical and lab characteristics comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 13 Body changes Risk of bias details in Appendix I.I
Clinical and laboratory characteristics of transfeminine patients treated with the antiandrogen bicalutamide as an Transfeminine: 13
androgen blocker after insurance denials of claims for GnRH analogs Study period: N/R
Follow-up duration: 29 months

Iowa

n = 1 TGNB youth

Daniolos (2013)482 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Mental health
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/R comparisons and therefore did not have data extracted,
Case report of the clinical findings in one transgender male adolescent Transmasculine: 1
due to time constraints
Follow-up duration: N/R
No ethics review, IRB, or consent for research was
described

Massachusetts

n ≥ 1124 TGNB youths

Razzak (2012)483 All subjects: 97 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 97 Mental health
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 97 Gender-specific characteristics comparisons did not have data extracted due to time
A research letter describing the experience of a pediatric gender specialty clinic, and the Tanner stages of children
Study period: N/A constraints
presenting for care. Investigators did not report the affirmed gender of their patients, only natal sex (N = 43 AMAB
and N = 54 AFAB). Follow-up duration: N/R No ethics review, IRB, or consent for research was
described

Spack (2012)484 All subjects: 97 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 97 Gender history
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 97 Mental health comparisons did not have data extracted due to time
Study period: 1/1998–2/2010 constraints

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
501

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Reports on characteristics, baseline mental health status, and treatment trajectory of patients with gender Follow-up duration: N/R
dysphoria, including percentages starting CSHT in a pediatric gender specialty clinic. Affirmed genders were not
reported, only natal sex (N = 43 AMAB and N = 54 AFAB).

Shumer (2015)485 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Ethics of assent
Case reporta Case reports and series do not contain high-priority
TGNB youths: 1 Decision-making comparisons and therefore did not have data extracted,
Ethics of assent to treatment in a transgender female patient. Transfeminine: 1
Study period: N/A due to time constraints

Follow-up duration: N/R

88
Millington (2019) All subjects: 85 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 85 Risk of hyperkalemia TGNB)
Observational cohort study
TGNB youths: 85
Study period: 2007–2017 Risk of bias details in Appendix I.I
Cohort study examining the risk of hyperkalemia associated with spironolactone in transfeminine or nonbinary Transfeminine: 82
adolescents in a pediatric gender specialty clinic OGD: 3 Follow-up duration: 7 years

Shim (2020)486 All subjects: 35 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 35 Risk factors for dysmenorrhea
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 35 Menstrual changes after treatment comparisons did not have data extracted due to time
Examining treatment trajectories, risk factors, and endometriosis in transgender males with dysmenorrhea Transmasculine: 35
Study period: 1/2000–3/2020 constraints

Follow-up duration: N/R

Grimstad (2021)81 All subjects: 232 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 232 Menstrual suppression TGNB)
Observational cohort study
TGNB youths: 232 Breakthrough bleeding Risk of bias details in Appendix I.I
Cohort study comparing menstrual suppression outcomes in transgender boys in different GnRH analog and Transmasculine: 232
hormone treatment groups. Also makes case-control-type comparisons examining risk factors for breakthrough Study period: 2010–2020
bleeding in transgender males. Follow-up duration: N/R

Grimstad (2021)487 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Hirsutism
Case report Case reports and series do not contain high-priority
TGNB youths: 1 Response to modified Ferriman- comparisons and therefore did not have data extracted,
Hirsutism in a nonbinary, masculine AFAB adolescent OGD: 1 Gallwey (mFG) diagram due to time constraints
Study period: N/A No ethics review, IRB, or consent for research was
Follow-up duration: 12 weeks described

Maru (2021)128 All subjects: 1124 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 1124 Risk factors for T1DM TGNB)

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
502

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Observational case-control study TGNB youths: 1124 Stress Risk of bias details in Appendix I.I
Transmasculine: 671
A case-control study examining risk factors for T1DM, including age at presentation, and hormone therapy. Study period: 1/2007–12/2018
Transfeminine: 355
OGD: 98 Follow-up duration: 12 months

Millington (2021)488 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Tumor treatment in TGNB
Case report Case reports and series do not contain high-priority
TGNB youths: 1 population comparisons and therefore did not have data extracted,
A transgender male adolescent on CSHT with a serous borderline ovarian tumor Transmasculine: 1 Cancer risk due to time constraints
Study period: N/A
Follow-up duration: 6 months
489
Garborcauskas (2022) All subjects: 195 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 195 Predictors of family planning beliefs Studies that did not evaluate our high-priority outcomes did
Observational study
TGNB youths: 195 and desires not have data extracted due to time constraints
Cohort study examining predictors of fertility beliefs and attitudes in testosterone-treated TGNB adolescents ages Transmasculine: 195
Study period: 1/2010–12/2019
15-17 years
Follow-up duration: N/R
490
Garborcauskas (2023) All subjects: 195 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 195 Sexual, gender, and reproductive
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 195 counseling comparisons did not have data extracted due to time
Examines characteristics and counseling topics in TGNB adolescents seeking testosterone CSHT Transmasculine: 195
Study period: 1/2010–12/2019 constraints
Follow-up duration: N/R

Hranilovich (2023)491 All subjects: 763 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 763 Prevalence of headache with and
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 763 without CSHT not have data extracted due to time constraints
Cumulative case-control study comparing risks of headache in TGNB patients receiving testosterone/estrogen Transmasculine: 490
Study period: 2007–2017
versus not in a pediatric gender specialty hospital Transfeminine: 273
Follow-up duration: N/R

n ≥ 3 TGNB youths

Insogna (2020)492 All subjects: 27 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 27 Fertility preservation
Case series Case reports and series do not contain high-priority
TGNB youths: 3+
Study period: 1/2016–2/2019 comparisons and therefore did not have data extracted,
Describes fertility-preservation outcomes in transgender males presenting for a fertility consultation. Authors did
due to time constraints
not report gender identities for most subjects, but all subjects were AFAB. Follow-up duration: N/A

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
503

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
n = 1 TGNB youth
178
Turban (2018) All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Body and hormonal changes
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
A transfeminine child's clinical presentation and treatment with histrelin for puberty suppression at age 15 and Transfeminine: 1
due to time constraints
estrogen CSHT at age 16 Follow-up duration: N/R
No ethics review, IRB, or consent for research was
described

Massachusetts

n = 1 TGNB youth

Fan (2020)493 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Risks of VTE
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
Venous thromboembolism (VTE) in a transgender male adolescent on testosterone CSHT Transmasculine: 1
due to time constraints
Follow-up duration: N/R
No ethics review, IRB, or consent for research was
described

Michigan

n = 30 TGNB youth

Warwick (2022)494 All subjects: 30 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 30 Sexual behaviors and education
Descriptive studya Studies that did not make one of our three highest-priority
TGNB youths: 30
Study period: N/R comparisons did not have data extracted due to time
Qualitative study examining sexual health and education outcomes in transgender adolescents Transmasculine: 18
constraints
Transfeminine: 12 Follow-up duration: N/A

Minnesota

n = 2 TGNB youth

Parikh (2021)495 All subjects: 2 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 2 Sperm cryopreservation
Case series Case reports and series do not contain high-priority
TGNB youths: 2
Study period: N/A comparisons and therefore did not have data extracted,
Transgender females undergoing sperm cryopreservation Transfeminine: 2
due to time constraints
Follow-up duration: N/A

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
504

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
No ethics review, IRB, or consent for research was
described

Missouri

n ≥ 47 TGNB youths

Allen (2019)56 All subjects: 47 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 47 Mental health TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 47
Study period: 2015–2018 Risk of bias details in Appendix I.I
Examines mental health and suicidality outcomes among TGNB adolescents who received GnRH analogs followed
by CSHT vs CSHT only Follow-up duration: Mean of 349 days

Missouri

n ≥ 67 TGNB youths

Lin (2020)496 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Disease progression
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
A 17-year-old, testosterone-treated transgender male presenting with androgen-receptor positive hepatocellular Transmasculine: 1
due to time constraints
carcinoma Follow-up duration: N/R

Komorowski (2021)497 All subjects: 67 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 67 Fertility counselling, referral, and
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 67 utilization not have data extracted due to time constraints
Cohort study examining fertility-related outcomes in TGNB adolescents seen in a pediatric endocrinology specialty Transmasculine: 45
Study period: 1/2012–1/2017
clinic Transfeminine: 22
Follow-up duration: N/R
498
Martin (2021) All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Fertility preservation
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: 12/2019–8/2020 comparisons and therefore did not have data extracted,
Successful oocyte cryopreservation in a transgender male adolescent Transmasculine: 1
due to time constraints
Follow-up duration: 8 months
No ethics review, IRB, or consent for research was
described

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
505

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
New York
a, n = 2 TGNB youths
499
Salvatore (2022) All subjects: 2 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 2 Eating disorder outcomes
Case reporta Case reports and series do not contain high-priority
TGNB youths: 2
Study period: N/A comparisons and therefore did not have data extracted,
Anorexia nervosa in transgender females who were ages < 18 years when they first sought treatment, but who Transfeminine: 2
due to time constraints
were seen for eating disorders in a tertiary care center Follow-up duration: 5 years

New York

n = 1 TGNB youth

Bentsianov (2018)500 All subjects: 3 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 3 IUD outcomes
Case reporta Case reports and series do not contain high-priority
TGNB youths: 1 Hormonal outcomes comparisons and therefore did not have data extracted,
A trio of case reports on use of hormones and copper IUDs in transgender young men, including one that was age Transmasculine: 1
Study period: N/A due to time constraints
17 upon presentation
Follow-up duration: up to 24 months

n = 1 TGNB youth

Maxwell (2017)501 All subjects: 3 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 3 Fertility/Pregnancy outcomes
Case series Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
A New York-based case series reporting on pregnancy outcomes in 3 transgender men (1 adolescent) who Transfeminine: 1
due to time constraints
underwent fertility preservation Follow-up duration: 9 years

New York

n = 139 TGNB youths

O'Bryan (2018)174 All subjects: 139 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 139 General health parameters
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 139 Quality of life comparisons did not have data extracted due to time
Examines characteristics (including medication use) in a cohort of TGNB adolescents Transmasculine: 90
Study period: N/R constraints
Transfeminine: 40
OGD: 9 Follow-up duration: N/R

Wolf-Gould (2018)502 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Risks of BRCA-1 mutation
Case reporta

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
506

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Reports on one US-based, transfeminine youth with a BRCA-1 mutation TGNB youths: 1 Study period: N/A Case reports and series do not contain high-priority
Transfeminine: 1 comparisons and therefore did not have data extracted,
Follow-up duration: N/R due to time constraints

New York

, n = 1 TGNB youth

Lee (2022)503 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Acne fulminans
Case reporta Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
Acne fulminans in a transgender boy receiving testosterone CSHT Transmasculine: 1
due to time constraints
Follow-up duration: 12 months

New York

, n = 50 TGNB youth

Achille (2020)55 All subjects: 50 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 50 Mental health TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort study
TGNB youths: 50
Study period: 12/2013–12/2018 Risk of bias details in Appendix I.I
Examines the effect of hormonal treatments on mental health outcomes in TGNB adolescents Transmasculine: 33
Transfeminine: 17 Follow-up duration: 12 months

Ohio

, n ≥ 611 TGNB youths

Daley (2019)504 All subjects: 30 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 17 GAHT decision-making
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 17
Study period: N/R comparisons did not have data extracted due to time
A qualitative study of pediatric transmasculine patients and their parents, focusing on decision-making around the Transmasculine 17
constraints
initiation of GAHT Parents: 13 Follow-up duration: N/A

Kanj (2019)505 All subjects: 231 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 231 Menstrual management
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 231 Pregnancy prevention comparisons did not have data extracted due to time
Examines oral contraceptive use in transgender males Transmasculine 231
Study period: 7/2013–9/2016 constraints

Follow-up duration: > 6 months for 60%

of subjects

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
507

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Mullins (2021)91 All subjects: 611 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 611 Thrombosis risk factors TGNB)
Observational cohort study
TGNB youths: 611 Thrombosis Risk of bias details in Appendix I.I
A cohort study examining thrombosis risk factors and outcomes in TGNB adolescents initiating CSHT Transmasculine: 416
Transfeminine: 176 Study period: 7/2013–3/2019
OGD: 19 Follow-up duration: Median 554 days
for estrogen, 577 days testosterone

Nasomyont (2022)506 All subjects: 9 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 6 Bone marrow adipose tissue
Descriptive, longitudinal pre-post study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 6 BMD not have data extracted due to time constraints
Examines changes in bone marrow adipose tissue among TGNB youths undergoing puberty suppression. Also an Cisgender peers/others: 3
observational study comparing findings to controls not undergoing puberty suppression. Only natal sexes were Study period: N/R
reported (N = 4 AMAB and N = 2 AFAB). Follow-up duration: 12 months

Ohio

, n ≥ 79 TGNB youths

Nahata (2017)115 All subjects: 79 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 79 Mental health conditions TGNB)
Observational cross-sectional studya
TGNB youths: 79 Psychosocial metrics Risk of bias details in Appendix I.I
A cross-sectional study examining mental health and psychosocial outcomes between transgender males and Transmasculine: 51
transgender females Transfeminine: 28 Study period: 2014–2016
Follow-up duration: N/A

Akgül (2019)507 All subjects: 50 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 30 Menstrual suppression
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 30
Study period: 6/2014–1/2018 not have data extracted due to time constraints
Cohort study examining menstrual suppression in transmasculine versus cisgender adolescents Transmasculine: 30
Cisgender peers/others: 20 Follow-up duration: N/R

Grannis (2021)110 All subjects: 42 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 42 Mental health TGNB)
Observational cross-sectional study a
TGNB youths: 42
Study period: 12/2018–3/2020 Risk of bias details in Appendix I.I
Compares depression and anxiety severity in treated vs untreated transgender boys Transmasculine: 42
Follow-up duration: 12 months

Valentine (2021)97 All subjects: 124 Relevant outcomes Details of data extraction available in Appendix I.K (TGNB vs
TNGB patients: 42 Cardiometabolic parameters cisgender peers) and Appendix I.L (pre-post comparisons)
Observational cohort study a
TGNB youths: 42
Risk of bias details in Appendix I.I

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
508

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Cohort study examining cardiometabolic parameters in transgender adolescents receiving testosterone versus Transmasculine 42 Study period: 2014–2018
cisgender females. The study also compares outcomes between transgender treatment groups. Cisgender peers/others: 82
Follow-up duration: Max of 25.7
months

Morningstar (2023)114 All subjects: 44 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 44 Hormonal/Neural response to TGNB)
Observational cross-sectional studya
TGNB youths: 44 known voices Risk of bias details in Appendix I.I
Cross-sectional study comparing neural responses to peer and caregiver voices between CSHT-treated or Transmasculine: 44 fMRI results
untreated transgender boys.
Study period: N/R
Follow-up duration: N/A

Olsavsky (2023)116 All subjects: 75 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 75 Mental health conditions TGNB)
Observational cross-sectional study a
TGNB youths: 75
Study period: 12/2018–3/2020 and Risk of bias details in Appendix I.I
A cross-sectional study examining associations between treatments and mental health outcomes among TGNB Transmasculine: 41
3/2021–2/2022
adolescents Transfeminine: 28
OGD: 6 Follow-up duration: N/A

Oklahoma

n = 1 TGNB youth
Eisenberg (2019)508 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Quality of GD medical and mental
Case report Case reports and series do not contain high-priority
TGNB youths: 1 health care comparisons and therefore did not have data extracted,
A transgender male adolescent treated in the rural setting Transmasculine: 1
Study period: N/A due to time constraints
Follow-up duration: N/R No ethics review, IRB, or consent for research was
described

Oklahoma
a, n = 118 TGNB youth
509
Lawlis (2017) All subjects: 221 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 118 Frequency and types of health and Studies that did not evaluate our high-priority outcomes did
Observational studya
TGNB youths: 118 social concerns not have data extracted due to time constraints
A cross-sectional study comparing attitudes about GD drug treatments between TGNB youths and their parents Parents: 103
Study period: N/R
Follow-up duration: N/R

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
509

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Silverstein (2020)510 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Trichotillomania outcomes
Case reporta Case reports and series do not contain high-priority
TGNB youths: 1 Mental health outcomes comparisons and therefore did not have data extracted,
A transmasculine adolescent with gender dysphoria and comorbid trichotillomania, depression, and anxiety Transmasculine: 1
Study period: N/A due to time constraints

Follow-up duration: 16 months

Oregon

n = 80 TGNB youths
74
Cantu (2020) All subjects: 80 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 80 Mental health TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 80
Study period: 9/2017–6/2019 Risk of bias details in Appendix I
Examines changes in anxiety and depression in treated and untreated TGNB youths Transmasculine: 58
Transfeminine: 15 Follow-up duration: Mean of 20.4
OGD: 7 weeks

Pennsylvania

n ≥ 64
511
Boris (2019) All subjects: 3 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 3 POTS characteristics on hormonal
Case series Case reports and series do not contain high-priority
TGNB youths: 3 treatment comparisons and therefore did not have data extracted,
Transgender adolescents presenting with complicated POTS and undergoing hormonal treatment Transmasculine: 3
Study period: N/A due to time constraints
Follow-up duration: N/R No ethics review, IRB, or consent for research was
described

Persky (2020)512 All subjects: 110 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 64 Fertility attitudes
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 64
Study period: 4/2017–12/2017 comparisons did not have data extracted due to time
Survey of characteristics, attitudes, and beliefs about fertility and GAHT in TGNB youth and their parents Transmasculine: 37
constraints
Transfeminine: 23 Follow-up duration: N/A
OGD: 4
Parents: 46

Quain (2021)513 All subjects: 141 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 82 Timing and delivery of fertility
Descriptive study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 64 information not have data extracted due to time constraints
Parents: 59

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
510

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
A qualitative, descriptive study examining timing and delivery of fertility preservation information provided to Study period: N/R
TGNB youths and their parents
Follow-up duration: N/A

Hobson (2022)514 All subjects: 36 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 36 Parent and patient preferences for Studies that did not make one of our three highest-priority
Descriptive study
TGNB youths: 36 implantable GnRH analogs comparisons did not have data extracted due to time
A qualitative study examining patient and parent preferences in TGNB patients with implantable GnRH analogs for Parents: 36
Study period: 2/2019–5/2019 constraints
puberty suppression. Investigators did not report affirmed gender identities; only natal sex reported (N = 15 AMAB
and N = 21 AFAB). Follow-up duration: N/A

Pennsylvania

n ≥ 7 TGNB youths

Stanley (2018)515 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 VTE events
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
A 17-year-old transgender male presenting with venous thromboembolism Transmasculine: 1
due to time constraints
Follow-up duration: N/R
No ethics review, IRB, or consent for research was
described

Barnard (2019)163 All subjects: 10 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 10 Fertility preservation
Case series Case reports and series do not contain high-priority
TGNB youths: 7
Study period: 1/2015–9/2018 comparisons and therefore did not have data extracted,
Reports fertility-preservation outcomes in TGNB patients, including 2 who were < 18 years of age at the fertility Transfeminine: 10
due to time constraints
preservation consult, 4 who were < 18 at the time of their initial GD consultation, and 7 who were < 18 at the time Follow-up duration: 4 months
of GD onset.

Rhode Island

, n = 5 TGNB youths

Donaldson (2018)516 All subjects: 5 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 5 Eating disorders
Case series Case reports and series do not contain high-priority
TGNB youths: 5 Self-harm/Suicidality comparisons and therefore did not have data extracted,
Eating disorders, suicidality, and self-harm behaviors in TGNB cases Transmasculine: 3
Study period: 1/2012–1/2017 due to time constraints
Transfeminine: 1
OGD: 1 Follow-up duration: Up to 5 years

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
511

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Texas (Statewide)

, n ≥ 192 TGNB youths

Abu-Ghname (2021)517 All subjects: 192 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 192 Healthcare utilization for GD
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 192
Study period: 2013–2018 comparisons did not have data extracted due to time
Examines GD-related utilization in a cohort of TGNB adolescents seen in a state-managed Medicaid program.
constraints
Affirmed genders were not reported, only natal sexes (N = 70 AMAB and N = 122 AFAB). Follow-up duration: N/R

Texas

n ≥ 148 TGNB youths

Lopez (2016)518 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Mental Health
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
An adolescent presenting with gender dysphoria Transfeminine: 1
due to time constraints
Follow-up duration: N/R
No ethics review, IRB, or consent for research was
described

Kuper (2020)141 All subjects: 148 Relevant outcomes Details of data extraction available in Appendix I.L (pre-post
TNGB patients: 148 Mental health comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 148
Study period: 8/2017–3/2018 Risk of bias details in Appendix I
Examines changes in body dissatisfaction and mental health (anxiety/depression) among TGNB adolescents Transmasculine: 90
receiving puberty suppression and/or CSHT Transfeminine: 54 Follow-up duration: 12 months
OGD: 3

Dilday (2022)519 All subjects: 45 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 18 Sperm quality
Observational study Studies that did not make one of our three highest-priority
TGNB youths: 18
Study period: 3/2015–3/2020 comparisons did not have data extracted due to time
Cross-sectional study comparing sperm quality outcomes between transgender females vs cisgender males with Transfeminine: 18
constraints
cancer receiving gonadotoxic therapy Cisgender peers/others: 27 Follow-up duration: N/A
87
Marwa (2022) All subjects: 119 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 119 Bone mineral density TGNB)
Observational cohort study
TGNB youths: 119
Study period: 6/2014–6/2019 Risk of bias details in Appendix I
Cohort study examining differences in bone density in TGNB patients based on natal sex (N = 46 AMAB and N = 73
AFAB). Follow-up duration: N/R

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
512

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
n = 30 TGNB youths
520
Mejia-Otero (2021) All subjects: 60 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 30 Blood hormonal metrics
Observational study Studies that did not make one of our three highest-priority
TGNB youths: 30
Study period: 1/2014–6/2018 comparisons did not have data extracted due to time
Cohort study comparing puberty suppression outcomes in TGNB youth versus youth with CPP Transmasculine: 13
constraints
Transfeminine: 17 Follow-up duration: 9 months
Cisgender peers/others: 30

Texas
a, n ≥ 1 TGNB youth

Day (2019)521 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Mental health
Case reporta Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data extracted,
A transgender boy presents to an academic emergency department with mental health crisis after detransitioning Transmasculine: 1
due to time constraints
Follow-up duration: N/A

Washington

n ≥ 104 TGNB youths

Barthel (2020)522 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Hypogonadism
Case report Case reports and series do not contain high-priority
TGNB youths: 1 Complications of GD treatment due comparisons and therefore did not have data extracted,
A transgender female adolescent cancer survivor with hypogonadism in a pediatric gender specialty clinic Transfeminine: 1 to comorbidities due to time constraints
Study period: N/A No ethics review, IRB, or consent for research was
Follow-up duration: 10 months described

Kerman (2021)523 All subjects: 23 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 23 Attitudes towards family and
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 23 fertility comparisons did not have data extracted due to time
A qualitative survey study examining fertility attitudes among TGNB children seen in a pediatric gender clinic Transmasculine: 9
Study period: N/R constraints
Transfeminine: 10
OGD: 4 Follow-up duration: N/A

Pham (2021)524 All subjects: 3 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 3 Eating disorders
Case series
TGNB youths: 3 Characteristics of presentation
A trio of clinical cases of autistic, transgender, pediatric patients with eating disorders

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from ; CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
513

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Transmasculine: 1 Study period: 1/2018–1/2019 Case reports and series do not contain high-priority
Transfeminine: 2 comparisons and therefore did not have data extracted,
Follow-up duration: > 2 years due to time constraints

Tordoff (2022)96 All subjects: 104 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB vs
TNGB patients: 104 Mental health TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort study
TGNB youths: 104
Study period: 8/2017–11/2021 Risk of bias details in Appendix I
Cohort study examining mental health outcomes (depression/anxiety) in TGNB adolescents and young adults Transmasculine: 63
receiving puberty blockers, cross-sex hormones, or both Transfeminine: 27 Follow-up duration: 12 months
OGD: 14

Eitel (2023)80 All subjects: 55 Relevant outcomes Appendix I.J: Observational Study Data Extraction Tables
TNGB patients: 55 Hormone levels
Observational cohort study
TGNB youths: 55 Puberty suppression
Cohort study comparing hormone levels and puberty suppression outcomes between transgender youths
receiving Lupron vs Eligard. Only natal sex was reported (N = 16 AFAB and N = 32 AMAB). Study period: 7/1/2014–Unknown
Follow-up duration: > 15 months

n ≥ 68
525
Strang (2018) All subjects: 51 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 25 Fertility preservation attitudes
Descriptive study Studies that did not make one of our three highest-priority
TGNB youths: 25
Study period: N/R comparisons did not have data extracted due to time
A qualitative comparison of attitudes about fertility preservation between autistic and allistic TGNB youths Transmasculine: 14
constraints
Transfeminine: 10 Follow-up duration: N/A
OGD: 1
Parents: 26

Strang (2018)526 All subjects: 22 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 22 Critical themes/preoccupations for Studies that did not evaluate our high-priority outcomes did
Descriptive studya
TGNB youths: 22 autistic GD patients not have data extracted due to time constraints
A qualitative examination of trajectories and perspectives of children diagnosed with both autism and gender Transmasculine: 6
Study period: N/R
dysphoria Transfeminine: 14
OGD: 2 Follow-up duration: 22 months

Cohen (2023)167 All subjects: 68 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 68 Predictors of GD treatment
Observational study Studies that did not evaluate our high-priority outcomes did
TGNB youths: 68 discontinuation not have data extracted due to time constraints
Transmasculine: N/R
Study period: 2010–2021

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
514

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Table I.G.1. Characteristics of N = 118 relevant clinical studies conducted in pediatric TGNB populations in the US, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
A case-control study examining potential predictors of GD treatment discontinuation in TGNB adolescents in a Transfeminine: N/R Follow-up duration: Up to 15 years
gender services program. Only natal sex (29 AMAB and 39 AFAB) and transbinary/nonbinary were reported. OGD: 15

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: US, United States; TGNB, transgender, nonbinary, or otherwise gender-diverse; GAHT, gender-affirming hormone therapy; OGD, other gender-diverse; GnRH, gonadotropin releasing hormone; AMAB, assigned male at birth; AFAB, assigned
female at birth; GD, gender dysphoria; CPP, central precocious puberty; TRICARE, healthcare payer for US military personnel and their families; CSHT, cross-sex hormone therapy; FEV, forced expiratory volume; CF, cystic fibrosis; PEDSnet, a Clinical Research
Network in, the National Patient-Centered Clinical Research Network; DC, District of Columbia; STRONG cohort, Study of Transition, Outcomes, and Gender from CML, chronic
myelogenous leukemia; LA, long-acting; IRB, investigational review board; DM, diabetes mellitus; VTE, venous thromboembolism; POTS, postural orthostatic tachycardic syndrome; GENECIS, Children's Health GENder, Education and Care Interdisciplinary
Support program
515

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description

n ≥ 1766 TGNB youths

Wiepjes (2018)67 All subjects: 6,793 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 6,793 GD diagnosis, treatment, and surgical
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 1,360 interventions priority comparisons did not have data extracted due to
First describes cohort, adults, adolescents, and children with a GD/TGNB diagnosis and at least one Transmasculine: 2,361 Regrets time constraints
visit. Examines temporal trends in diagnosis, treatment, and surgical interventions, as well as reporting on the Transfeminine: 4,432
proportions of subjects who reported regret after gonadectomy Study period: 1972–2015
Follow-up duration: Median of 6.4 years

van der Loos (2021)69 All subjects: 322 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 322 Changes in bone geometry post comparisons)
Observational study
TGNB youths: 322 Subperiosteal width (SPW) Risk of bias details in Appendix I
Reports on bone changes over time in TGNB adolescents seen in a gender specialty clinic. Reports the size of Transmasculine: 216 Endocortical diameter (ED)
the as 8210 patients in 2018, up from 6793 patients in 2015. Transfeminine: 106
Study period: 1972–2018
Follow-up duration: censored at
12/31/2018

Boogers (2022)66 All subjects: 161 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 161 Dosages vs TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort and descriptive, longitudinal pre-post study
TGNB youths: 161 Metabolic and growth parameters Risk of bias details in Appendix I
A cohort study comparing dosages, growth, bone age, IGF-1 levels, and more outcomes among transgender Transfeminine: 161
females with different hormone treatments and dosages from a gender specialty clinic Study period: 1972–2018
Follow-up duration: "Until adult height
was reached"

van der Loos (2022)68 All subjects: 720 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 720 GAH continuation/discontinuation
Observational study Studies that did not evaluate our high-priority outcomes
TGNB youths: 720
Study period: 1972–2018 did not have data extracted due to time constraints
Cohort study comparing baseline characteristics and continuation rates between transgender males and
transgender females in subjects, with and without treatment, from a gender specialty clinic. Only natal sexes Follow-up duration: censored at
were reported: 220 AMAB and 500 AFAB 12/31/2018

van der Loos (2023)70 All subjects: 1,766 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1,766 Trajectories of adolescents treated
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 1,766 with Dutch protocol priority comparisons did not have data extracted due to
Examines characteristics, treatment trajectories, and temporal trends in TGNB adolescents over 20 years of
Study period: 1972–2018 time constraints
applying the Dutch protocol in clinic. Authors did not specify affirmed gender identities, only
natal sex: N = 689 AMAB and N = 1077 AFAB. Reports the size of the as 8831 patients in 2018, up from Follow-up duration: censored at
8210 in previous publication. 12/31/2018

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
516

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Willemsen (2023)127 All subjects: 146 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 146 Growth, bone age, adult height vs TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 146 Differences among height, predicted Risk of bias details in Appendix I
A longitudinal, pre-post descriptive study examining height and weight outcomes in TGNB adolescent boys who Transmasculine: 146 height, parental height
initiated GnRH analogs before age 16 years.
Study period: 1972–2018
Follow-up duration: censored at
12/31/2018

Non studies
Although these studies do not affiliate with the formal as described above, their patient populations, including all TGNB youths, should be counted as nesting in the population above. They are counted by study below, but they do not contribute
further to the total patients at this location.
de Vries (2010)527 All subjects: 204 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 204 Autism, autistic traits
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 204
Study period: 4/2004–10/2007 priority comparisons did not have data extracted due to
Examines the prevalence of autism and autism traits in TGNB children and adolescents. Only natal sex reported:
time constraints
115 AMAB and 89 AFAB Follow-up duration: N/A
528
de Vries (2010) All subjects: Variable Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: Variable Psychological functioning
Thesis with various study designs, by chapter Concurrent/dual publications occur when one study is
TGNB youths: Variable Treatment outcomes published in two different publications. Second
A PhD thesis comprising studies of gender dysphoria in adolescents.
Study period: before 2010 publications were noted in the bibliography but not
extracted.
Follow-up duration: Variable

de Vries (2010)529 Thesis, Chapter 4 All subjects: 204 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 204 Incidence of autism spectrum disorder Concurrent/dual publications occur when one study is
Descriptive study
TGNB youths: 182
Study period: 4/2004–10/2007 published in two different publications. Second
A survey study of children and adolescents referred to a gender identity clinic who received diagnoses of GD
publications were noted in the bibliography but not
and ASD. Only natal sexes were reported: 70 AMAB children, 45 AMAB adolescents, 38 AFAB children, and 51 Follow-up duration: N/A
extracted.
AFAB adolescents.

de Vries (2010)530 Thesis, Chapter 5 All subjects: 105 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 105 Psychiatric comorbidities
Observational study Concurrent/dual publications occur when one study is
TGNB youths: 105
Study period: 4/2002–12/2009 published in two different publications. Second
A survey study examining psychiatric comorbidity in TGNB adolescents, according to their parents. Only natal Parents: 105
publications were noted in the bibliography but not
sexes were reported for TGNB subjects: 53 AMAB and 52 AFAB. Follow-up duration: N/A
extracted.

de Vries (2010)531 Thesis, Chapter 6 All subjects: 70 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 70 Psychological functioning
Longitudinal, pre-post descriptive study Concurrent/dual publications occur when one study is
TGNB youths: 70 GD severity published in two different publications. Second
Compares psychological functioning and gender dysphoria before and after puberty suppression in gender
dysphoric adolescents who progress to CSHT. Only natal sexes reported: 33 AMAB and 37 AFAB Study period: 2000–2008

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
517

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Follow-up duration: Mean of 1.9 years publications were noted in the bibliography but not
extracted.

de Vries (2010)78 Thesis, Chapter 7 All subjects: 27 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 27 Psychological functioning vs TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 27 Psychosocial functioning Risk of bias details in Appendix I
Assessed long-term outcome of adolescents with a gender identity disorder (GID), from initial intake at gender Transmasculine: 11 GD severity
identity clinic until post-treatment at least 1 year after gender reassignment surgery. Transfeminine: 16
Study period:
Follow-up duration: Mean of 7.4 years

Cohen-Kettenis (2011168) All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Regret/Satisfaction
Case report Case reports and series do not contain high-priority
TGNB youths: 1 Metabolic and endocrine parameters comparisons and therefore did not have data extracted,
Reports on 22-year outcomes in an adolescent who received puberty suppression Transfeminine: 1
Study period: N/A due to time constraints

Follow-up duration: 22 years

de Vries (2011)106 All subjects: 105 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 105 Mental Health vs TGNB)
Observational cross-sectional study
TGNB youths: 105
Study period: 4/2002–12/2009 Risk of bias details in Appendix I
A cross-sectional study examining mental health diagnoses among AFAB vs AMAB TGNB adolescents, and
between treated vs untreated TGNB patients Follow-up duration: N/A

de Vries (2011)57 All subjects: 70 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 70 Mental health vs TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort study
TGNB youths: 70
Study period: 2000–2008 Risk of bias details in Appendix I
Examines mental health outcomes in TGNB patients treated with GnRH analogs. Only natal sex reported: 33
AMAB and 37 AFAB Follow-up duration: mean of 3 years

Steensma (2011)532 All subjects: 25 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 25 GD treatment desistance/persistence
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 25 Factors influencing desistance/ priority comparisons did not have data extracted due to
A interview-based, qualitatively-analyzed descriptive study of desisting or persisting Dutch TGNB adolescents persistence time constraints
Study period: 1/2000–1/2007
Follow-up duration: 7-8 years

de Vries (2014)79 All subjects: 55 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 55 Psychosocial functioning vs TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort study
TGNB youths: 55 Mental health Risk of bias details in Appendix I
A cohort study examining psychosocial functioning after GnRH analogs for puberty suppression, CSHT, and Transmasculine: 33
surgery among TGNB adolescents. Also reports within-group comparisons vs baseline of psychosocial Transfeminine: 22 Study period: 2000–2012
functioning (pre-post descriptive) Follow-up duration: Mean of 7.1 years

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
518

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Burke (2015)133 All subjects: 75 Relevant outcomes Details of data extraction available in Appendix I.K
TNGB patients: 36 Hypothalamic activation (TGNB vs cisgender peers)
Observational cross-sectional study
TGNB youths: 36 fMRI outcomes Risk of bias details in Appendix I
A cohort study examining effects of testosterone on fMRI outcomes in TGNB youth vs age- and sex-matched Cisgender peers/others: 39
cisgender controls seen in a specialty gender clinic. Only natal sex of TGNB youth was reported: 17 AFAB and 19 Study period: N/R
AMAB Follow-up duration: N/R
140
Klink (2015) All subjects: 34 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 34 Bone mineral density post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 34
Study period: 6/1998–8/2012 Risk of bias details in Appendix I
Examines patient characteristics and bone outcomes over time in GnRH analog- and CSHT-treated adolescents Transmasculine: 19
in a gender specialty clinic Transfeminine: 15 Follow-up duration: Median of 6.9 years

Staphorsius (2015)119 All subjects: 41 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 40 Executive functioning on tasks vs TGNB), Appendix I.K (TGNB vs cisgender peers)
Observational cross-sectional study
TGNB youths: 40 Region-of-interest analysis Risk of bias details in Appendix I
Cross-sectional study of the impact of GAHT on executive function in TGNB adolescents Transmasculine: 22
Transfeminine: 18 Study period: N/R
Cisgender peers/others 45 Follow-up duration: N/R

Burke (2016)130 All subjects: 62 Relevant outcomes Details of data extraction available in Appendix I.K
TNGB patients: 21 fMRI outcomes (TGNB vs cisgender peers)
Observational cohort study
TGNB youths: 21 gender-typical mental rotation task Risk of bias details in Appendix I
A cohort study examining effects of testosterone on fMRI outcomes in TGNB adolescents vs age- and sex- Transmasculine: 21
matched controls Cisgender peers/others: 41 Study period: N/R
Follow-up duration: 10 months
148
Schagen (2016) All subjects: 116 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 116 Body changes post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 116 Hormone levels Risk of bias details in Appendix I
Examines growth, body composition, and endogenous hormone levels in TGNB adolescents who received GnRH Transmasculine: 67
analogs for 1 year in a gender specialty clinic Transfeminine: 49 Study period: 1988–2009
Follow-up duration: 24 months

Hannema (2017)59 All subjects: 28 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 28 Hormone levels post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 28 Body changes Risk of bias details in Appendix I
Examines changes in endogenous hormone levels, anthropometric measures, bone, blood pressure measures Transfeminine: 28 Bone changes
among transgender girls treated with estradiol seen in a gender specialty clinic
Blood biomarkers
Study period: 1998–2006
Follow-up duration: 3 years

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
519

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Vlot (2017)99 All subjects: 70 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 70 Bone turnover markers vs TGNB) and Appendix I.L (pre-post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 70
Study period: N/R Risk of bias details in Appendix I
Examines bone changes over time with puberty suppression and CSHT in TGNB adolescents in a gender Transmasculine: 42
specialty clinic Transfeminine: 28 Follow-up duration: 24 months

Klaver (2018)454 All subjects: 192 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 192 Body composition vs TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 192
Study period: 1998–2015 Risk of bias details in Appendix I
Examines body composition changes over time in transgender patients who received unspecified GnRH analogs Transmasculine: 121
and CSHT Transfeminine: 71 Follow-up duration: Mean of 7 years

Schagen (2018)147 All subjects: 127 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 127 Adrenal androgen levels vs TGNB) and Appendix I.L (pre-post comparisons)
Descriptive, longitudinal pre-post study
TGNB youths: 127
Study period: 1998–2009 Risk of bias details in Appendix I
Examines changes in endogenous hormones during puberty suppression and CSHT in adolescents with GD Transmasculine: 73
Transfeminine: 54 Follow-up duration: 4 years

Arnoldussen (2020)100 All subjects: 1072 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 1072 Psychosocial functioning vs TGNB)
Observational cross-sectional study
TGNB youths: 1072 Demographic, diagnostic, treatment Risk of bias details in Appendix I
A cohort study examining the association between birth-assigned sex and psychosocial functioning in TGNB characteristics
adolescents, including 404 AFAB and 668 AMAB youths.
Study period: 2000–2016
Follow-up duration: Time-trend analysis
with reference year of 2016

Beking (2020)129 All subjects: 62 Relevant outcomes Details of data extraction available in Appendix I.K
TNGB patients: 21 Brain development (TGNB vs cisgender peers) and Appendix I.L (pre-post
Experimental study
TGNB youths: 21 fMRI outcomes comparisons)
Examines the effects of testosterone on amygdala lateralization between transgender boys seen and cisgender Transmasculine: 21
Study period: N/R Risk of bias details in Appendix I
boys/girls Cisgender peers/others: 41
Follow-up duration: 12 months

Burke (2020)533 All subjects: 186 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 105 Sex differences in click-evoked
Observational study Studies that did not evaluate our high-priority outcomes
TGNB youths: 105 otoacoustic emissions (CEOAEs) did not have data extracted due to time constraints
A cross-sectional study examining the effect of GnRH analogs and sex hormones on click-evoked otoacoustic Transmasculine: 62
Study period: N/R
emissions in TGNB adolescents. Also compares TGNB adolescents to cisgender peers. Transfeminine: 43
Cisgender peers/others: 81 Follow-up duration: N/A

Klaver (2020)139 All subjects: 192 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 192 Cardiovascular risk factors post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 192 Body composition

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
520

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
A pre-post descriptive study examining cardiovascular risk factors and body changes in TGNB subjects over Transmasculine: 121 Study period: 1998–2015 Risk of bias details in Appendix I
time. Transfeminine: 71
Follow-up duration: Mean of 7 years

Schagen (2020)94 All subjects: 121 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 121 Bone changes vs TGNB) and Appendix I.L (pre-post comparisons)
Observational cohort studya
TGNB youths: 121
Study period: 1998–2009 Risk of bias details in Appendix I
A cohort study comparing bone changes over time for TGNB subjects at different pubertal stages. Also a pre- Transmasculine: 70
post descriptive study examining changes over time in TGNB patients. The study was registered with the Transfeminine: 51 Follow-up duration: 36 months
International Standard Randomized Controlled Trial Number register (ISRCTN 81574253).

Van de Grift (2020)123 All subjects: 300 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 300 Surgery outcomes vs TGNB)
Observational cross-sectional study
TGNB youths: 300
Study period: 2006–2013 Risk of bias details in Appendix I
Compares surgical outcomes between TGNB youths who received early versus late puberty suppression. Transmasculine: 184
Transfeminine: 116 Follow-up duration: Mean of 8 years

Van der Miesen (2020)124 All subjects: 1101 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 450 Mental health vs TGNB), Appendix I.K (TGNB vs cisgender peers)
Observational cross-sectional study
TGNB youths: 450
Study period: 2012–2015 Risk of bias details in Appendix I
A study comparing mental health outcomes in treated versus untreated TGNB adolescents; also compares Cisgender peers/others: 651
mental health outcomes between TGNB adolescents and cisgender peers Follow-up duration: N/A

Arnoldussen (2022)71 All subjects: 72 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 72 IQ vs TGNB)
Observational cohort study
TGNB youths: 72 Educational level Risk of bias details in Appendix I
Examines changes in IQ and educational achievement after puberty suppression with GnRH analogs and CSHT in Transmasculine: 45
TGNB adolescents from a gender specialty clinic Transfeminine: 27 Study period: Before 2010
Follow-up duration: N/R

Arnoldussen (2022)135 All subjects: 70 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 70 Psychosocial outcomes post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 70
Study period: 2000–2013 Risk of bias details in Appendix I
Examines changes in psychosocial outcomes in TGNB adolescents before (while on hormonal treatments only) Transmasculine: 49
vs after gender-affirming surgery. Transfeminine: 21 Follow-up duration: Mean of 6 years

de Nie (2022)534 All subjects: 214 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 214 Fertility preservation
Observational study Studies that did not evaluate our high-priority outcomes
TGNB youths: 78 Histological parameters did not have data extracted due to time constraints
A cohort study comparing potential for fertility preservation in transgender women, including adolescents, who Transfeminine: 78
initiated cross-sex hormones at different pubertal stages at a gender specialty clinic Study period: 2006–2018
Follow-up duration: N/A

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
521

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
the Netherlands, n = 143
Vrouenraets (2016)451 All subjects: 13 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 13 Perceptions and attitudes about
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 13 gender priority comparisons did not have data extracted due to
Examines perceptions and attitudes about gender in transgender youths Transmasculine: 8
Study period: 10/2013–8/2014 time constraints
Transfeminine: 5
Follow-up duration: N/A

Brik (2019)535 All subjects: 35 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 35 Fertility preservation
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 35
Study period: 6/2011–8/2017 priority comparisons did not have data extracted due to
Examines use of fertility preservation among transgender girls Transfeminine: 35
time constraints
Follow-up duration: N/R

Stoffers (2019)149 All subjects: 62 Relevant outcomes Details of data extraction available in Appendix I.L (pre-
TNGB patients: 62 Body changes/growth post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 62 Metabolic biomarkers Risk of bias details in Appendix I
Examines body changes, growth, cardiovascular risk factors, and metabolic outcomes in testosterone-treated Transmasculine: 62 Cardiovascular risk factors
adolescents with GD
Study period: 11/2010–8/2018
Follow-up duration: 24 months

Brik (2020)164 All subjects: 143 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 143 Physical, neurocognitive, and
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 143 psychosocial effects of GD treatment priority comparisons did not have data extracted due to
Examines GnRH analog treatment trajectories in TGNB adolescents Transmasculine: 105 Persistence/Desistence time constraints
Transfeminine: 38
Study period: 11/2010–12/2017
Follow-up duration: 8.67 years

Multisite: N ≥ 36
Vrouenraets (2021)126 All subjects: 74 Relevant outcomes Details of data extraction available in Appendix I.J (TGNB
TNGB patients: 74 Medical decision-making competence vs TGNB)
Observational cross-sectional study
TGNB youths: 74
Study period: 2016–2017 Risk of bias details in Appendix I
A cross-sectional study examining medical competence and related outcomes in TGNB adolescents. Natal sexes
reported only: 16 AMAB and 58 AFAB. Follow-up duration: N/A

Vrouenraets (2022)536 All subjects: 26 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 14 Treatment continuation/
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 14 discontinuation priority comparisons did not have data extracted due to
A qualitative interview/focus group study of TGNB adolescents who either continued or discontinued Parents: 12
Study period: 1/2019–9/2019 time constraints
treatment, and their parents. TGNB natal sexes reported only: 5 AMAB and 9 AFAB.
Follow-up duration: N/A

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
522

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Table I.G.2. Characteristics of N = 43 relevant clinical studies conducted in pediatric TGNB populations in the Netherlands, chronologically by site
Author (Year) Participants Relevant outcomes Disposition in this review
Study design Study period
Description
Vrouenraets (2022)179 All subjects: 36 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 14 Perceptions and attitudes towards
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 14 puberty suppression priority comparisons did not have data extracted due to
A qualitative study examining perceptions about the function of puberty suppression in TGNB adolescents who Parents: 12 Treatment continuation/ time constraints
continued vs discontinued treatment, their parents, and clinicians. TGNB natal sexes reported only: 5 AMAB and Healthcare providers: 10 discontinuation
9 AFAB.
Study period: 1/2019–9/2019
Follow-up duration: N/A

a Site unconfirmed; inferred from author affiliations.

Table abbreviations: TGNB, transgender, nonbinary, or otherwise gender-diverse; AMAB, assigned male at birth; AFAB, assigned female at birth; GnRH, gonadotropin releasing-hormone; OGD, other gender-diverse; CSHT, cross-sex hormone therapy; fMRI,
functional magnetic resonance imagery; GAHT, gender-affirming hormone therapy; GD, gender dysphoria
523

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
Multinational: Canada and the Netherlands
Canada, n = 177
the Netherlands, n = 139
de Vries (2016)107 All subjects: 316 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 316 Behavioral, psychosocial, and (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 316 emotional problems Risk of bias details in Appendix I
A cross-sectional study examining mental health characteristics of TGNB patients who were referred (ie, for GnRH analog treatment) versus
Study period: 1980–2010
non-referred across 2 clinics. Only natal sexes were reported: 173 AMAB and 143 AFAB
Follow-up duration: N/A

Multinational: Canada UK , and the Netherlands

, Canada, n = 260
the Netherlands, n = 266
London, UK, n = 2245
De Graaf (2022)108 All subjects: 2771 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 2771 Mental health (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 2771 Suicidality Risk of bias details in Appendix I
A cross-sectional study examining mental health characteristics of TGNB patients who were referred (ie, for GnRH analog treatment) versus
non-referred across 3 clinics. Only natal sexes were reported: 937 AMAB and 1834 AFAB. Study period: 1978–2017
Follow-up duration: N/A

Australia
South Australia, n = 10
Riggs (2020)537 All subjects: 20 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 10 Views of GD treatments
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 10
Study period: 5/2019–7/2019 priority comparisons did not have data extracted
A qualitative, descriptive interview study that examined the views of TGNB adolescents and their parents about medical treatments. Transmasculine 5
due to time constraints
Transfeminine 4 Follow-up duration: N/A
OGD: 1
Parents: 10

Victoria, n ≥ 39
Hewitt (2012)538,539 All subjects: 39 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 39 GD treatment experience
Descriptive study plus commentary Studies that did not make one of our three highest-
TGNB youths: 39
Study period: 2003–2011 priority comparisons did not have data extracted
A descriptive study reporting on characteristics of pediatric TGNB cases and their treatments
due to time constraints
Follow-up duration: Max of 8.2
years Commentaries or corrections of included studies did
not have their data extracted due to time
constraints

Pang (2020)540 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Androgynous appearance

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
Case report TGNB youths: 1 Mental health Case reports and series do not contain high-priority
OGD: 1 Health risks comparisons and therefore did not have data
A case report describing outcomes in a nonbinary patient receiving long-term puberty suppression
extracted, due to time constraints
Study period: N/A
No ethics review, IRB, or consent for research was
Follow-up duration: N/R
described

Pang (2021)541 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Facial hair growth
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data
A case report of minoxidil use to promote facial hair growth in a transgender male adolescent Transmasculine 1
extracted, due to time constraints
Follow-up duration: 2 years
542
O'Connell (2022) All subjects: 2 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 2 Modulating GD treatment
Case report Case reports and series do not contain high-priority
TGNB youths: 2 towards patient goals comparisons and therefore did not have data
A pair of case reports, including one transfeminine and one transmasculine adolescent Transmasculine: 1
Study period: N/A extracted, due to time constraints
Transfeminine: 1
Follow-up duration: N/R No ethics review, IRB, or consent for research was
described

Victoria, n ≥ 359
Tollit (2023)120 All subjects: 359 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 359 GD characteristics (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 359 Comorbidities Risk of bias details in Appendix I
An cross-sectional study examining characteristics of AFAB vs AMAB TGNB adolescents, including mental health and psychosocial Transmasculine: N/R Mental health
parameters. Natal genders were reported: 166 AMAB and 193 AFAB. Transfeminine: N/R
Psychosocial functioning
OGD: 35
Cisgender peers/others: 4 Study period: 2007–2016
Follow-up duration: N/A

Belgium
Ghent, n = 27
Tack (2017)150 All subjects: 27 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 27 Body and metabolic changes (pre-post comparisons)
Longitudinal, pre-post descriptive
TGNB youths: 27 Cardiovascular risk factors Risk of bias details in Appendix I
A Belgian pre-post, descriptive study examining growth, cardiovascular risk factors, and metabolic changes in transgender female Transfeminine: 27
adolescents taking estrogen with an antiandrogen not available in the US (cyproterone) Study period: 2008–2016
Follow-up duration: 12 months

Canada
Multisite: , n = 35
Pullen Sansfaçon (2019)176 All subjects: 70 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 35 GD treatment decision-
Descriptive study
TGNB youths: 35 making

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
A Canadian, multi-province, interview-based, qualitative, descriptive study examining the decision and initiation of GD treatment Transmasculine: 22 GD initiation Studies that did not make one of our three highest-
Transfeminine: 14 priority comparisons did not have data extracted
Study period: 11/2017–8/2018
Parents 35 due to time constraints
Follow-up duration: N/A

Multisite ) Trans Youth Can!, n ≥ 174

Bauer (2021)102 All subjects: 174 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 174 Mental health (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 174
Study period: 9/2017–6/2019 Risk of bias details in Appendix I
A Canadian study comparing characteristics and mental health needs between TGNB groups. Transmasculine: 137
Transfeminine: 37 Follow-up duration: N/A

Pullen Sansfaçon (2022)543 All subjects: 319 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 160 Psychosocial stressors
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 160
Study period: 2017–2019 priority comparisons did not have data extracted
A Canada-based, descriptive survey study (Trans Youth CAN!) examining stressors in TGNB adolescents who were referred for puberty Parents: 159
due to time constraints
suppression and/or hormones and their parents Follow-up duration: N/A

Alberta, n = 33
Waldner (2023)544 All subjects: 33 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 33 Prolonged QTc intervals
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 33
A descriptive study examining QTc intervals of TGNB youths on leuprolide acetate Study period: 7/2018–12/2019 priority comparisons did not have data extracted
Transmasculine: 23
due to time constraints
Transfeminine: 10 Follow-up duration: N/R

British Columbia, n = 84
Khatchadourian (2014)82 All subjects: 84 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 84 Treatment regimens (TGNB vs TGNB)
Observational cohort study
TGNB youths: 84 Treatment response Risk of bias details in Appendix I
A Canadian cohort study comparing demographic characteristics, adverse effects, GnRH analog/cross-sex hormone initiation, Tanner stages, Transmasculine: 45 Adverse effects
and psychiatric comorbidities between MTF and FTM transgender youth. Transfeminine: 37
OGD: 2 Study period: 1/1998–12/2011
Follow-up duration: Mean of 2.3
years

, British Columbia, n = 21
Clark (2020)166 All subjects: 36 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 21 Treatment decision-making Studies that did not make one of our three highest-
Descriptive study
TGNB youths: 21 Barriers to care priority comparisons did not have data extracted
A Canadian descriptive study examining the hormone treatment decision-making process with TGNB adolescents and their parents Transmasculine: 8
Transfeminine: 8 Study period: 8/2016–2/2017 due to time constraints
OGD: 5 Follow-up duration: N/A
Parents: 15

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
British Columbia, n = 21
Clark (2021)545 All subjects: 47 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 21 Treatment decision-making Studies that did not make one of our three highest-
Descriptive study
TGNB youths: 21 Barriers to care priority comparisons did not have data extracted
A qualitative descriptive study examining aspects of decision-making in TGNB youths Parents: 15
Study period: N/R due to time constraints
Healthcare providers: 11
Follow-up duration: N/A

, Ontario, n = 1
Fung (2021)546 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Gynecomastia outcomes
Case report Case reports and series do not contain high-priority
TGNB youths: 1 Breast development comparisons and therefore did not have data
A -based case report of a 17-year-old transgender boy experiencing gynecomastia during ongoing testosterone therapy, after having Transmasculine: 1
Study period: N/A extracted, due to time constraints
received puberty suppression
Follow-up duration: N/R

Ontario, n = 172
Navabi (2021)92 All subjects: 172 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 172 Body changes and (TGNB vs TGNB) and Appendix I.L (pre-post
Observational cohort study
TGNB youths: 172 composition comparisons)
A Canadian cohort study examining baseline and follow-up changes in bone mass, body composition, vitamin D, and pubertal suppression Transmasculine: 119 Pubertal suppression Risk of bias details in Appendix I
outcomes between transgender male vs female youths who received GnRH analogs. Also a pre-post descriptive study that looked at Transfeminine: 51
changes from baseline in each group. OGD: 2 Study period: 1/2006–4/2017
Follow-up duration: 18 months

Ontario, n ≥ 139
Zucker (2010)65 All subjects: 109 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 109 Mental and behavioral (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 109 problems Risk of bias details in Appendix I
A cross-sectional study examining correlates of puberty suppressive treatment in treated vs untreated TGNB patients. Only natal sexes were Psychosexual outcomes
reported: 54 AMAB and 55 AFAB.
Study period: 2000–2009
Follow-up duration: N/A

Singh (2021)177 All subjects: 139 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 139 Cognitive functioning
Observational study Studies that did not evaluate our high-priority
TGNB youths: 139 Gender alignment outcomes did not have data extracted due to time
A cohort study examining changes in gender identity over time among TGNB children who presented for treatment at a pediatric gender Sexual orientation constraints
identity clinic during childhood. Only natal gender was reported: 139 AMAB.
Study period: 1975–2009
Follow-up duration: Mean of 13
years

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
, Ontario, n ≥ 300
Chiniara (2018)76 All subjects: 79 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 79 Mental health (TGNB vs TGNB)
Observational cohort study
TGNB youths: 79
Study period: 1/2014–6/2016 Risk of bias details in Appendix I
A study examining mental health in TGNB youth Transmasculine: 60
Transfeminine: 14 Follow-up duration: up to 30
OGD: 5 months

Chiniara (2019)547 All subjects: 152 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 79 Fertility
Observational study Studies that did not evaluate our high-priority
TGNB youths: 79 GD treatment outcomes did not have data extracted due to time
A cross-sectional study of TGNB adolescents and their parents examining fertility- and treatment-related questionnaire responses Transmasculine: 60
Transfeminine: 14 Study period: 10/2016–5/2017 constraints
OGD: 5 Follow-up duration: N/A
Parents: 73

Sorbara (2020)118 All subjects: 300 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 300 Mental health (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 300
A cross-sectional study examining mental health problems in older- versus younger-presenting TGNB adolescents Study period: 10/2013–6/2016 Risk of bias details in Appendix I
and 8/2017 - 6/2018
Follow-up duration: N/A

, Ontario, n = 1
Margolin (2020)548 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Intracranial hypertension
Case report Case reports and series do not contain high-priority
TGNB youths: 1 resolution comparisons and therefore did not have data
A case of a transgender male adolescent with idiopathic intracranial hypertension Transmasculine: 1
Study period: N/A extracted, due to time constraints
Follow-up duration: 2 years No ethics review, IRB, or consent for research was
described

, Quebec, n = 1
Nayman (2021)549 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Intracranial hypertension
Case report Case reports and series do not contain high-priority
TGNB youths: 1 resolution comparisons and therefore did not have data
A case report of intracranial hypertension in a 17-year-old transgender male Transmasculine: 1
Study period: N/A extracted, due to time constraints
Follow-up duration: 10 months

Finland
, n ≥ 124
Vehmas (2022)125 All subjects: 124 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 124 (TGNB vs TGNB)
Observational cross-sectional study
124

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
A cross-sectional study examining characteristics of pediatric TGNB patients presenting for treatment. TGNB youths: 104 Mental and physical Risk of bias details in Appendix I
Transmasculine: 20 comorbidities
Transfeminine: Pubertal development
Psychosocial background
Study period: 2011–2018
Follow-up duration: N/R

n = 52
Kaltiala (2020)138 All subjects: 52 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 52 Psychosocial functioning (pre-post comparisons)
Longitudinal pre-post descriptive study
TGNB youths: 52
Study period: 2011–2017 Risk of bias details in Appendix I
A pre-post study examining psychosocial functioning in TGNB adolescents before and after 1-year of CSHT Transmasculine: 41
Transfeminine: 11 Follow-up duration: 1 year

France
n=4
Condat (2016)550 All subjects: 4 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 4 Gender dysphoria
Case series Despite having abstracts in English that obviously
TGNB youths: 4 characteristics met inclusion criteria, non-English language studies
A French case series reporting on 2 AMAB and 2 AFAB with gender dysphoria. In French. Transfeminine: 4
Study period: N/A could not have their data extracted
Follow-up duration: N/A Case reports and series do not contain high-priority
comparisons and therefore did not have data
extracted, due to time constraints

, France, n = 1
Martinez (2017)551 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Unavailable
Case report Despite having abstracts in English that obviously
TGNB youths: 1
Study period: N/A met inclusion criteria, non-English language studies
A TGNB parent of 3 children reviews her youth and decision to transition. In French. Transfeminine: 1
could not have their data extracted
Follow-up duration: N/A
Case reports and series do not contain high-priority
comparisons and therefore did not have data
extracted, due to time constraints

Germany
Multiple sites n = 82
Becker (2018)103 All subjects: 202 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 202 Body image (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 82
A cross-sectional study examining the effect of hormones and GnRH analogs on body image outcomes in TNGB adolescents Study period: 9/2013–12/2015 Risk of bias details in Appendix I
Transmasculine: 62
Transfeminine: 20 Follow-up duration: N/A

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
n ≥ 22
Meyenburg (2014)552 All subjects: 4 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 4 Unavailable
Case series Despite having abstracts in English that obviously
TGNB youths: 4
Study period: N/A met inclusion criteria, non-English language studies
Reviews treatment course for TGNB youth in a gender identity clinic. In German. Transmasculine: 2
could not have their data extracted
Transfeminine: 2 Follow-up duration: Unavailable
Case reports and series do not contain high-priority
comparisons and therefore did not have data
extracted, due to time constraints

Meyenburg (2015)553 All subjects: 70 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 22 Gender identity outcomes
Guideline and Descriptive study Despite having abstracts in English that obviously
TGNB youths: 22 Psychosocial and mental met inclusion criteria, non-English language studies
Survey of prior GD pediatric patients after 3 years, who did or did not transition. In German. health could not have their data extracted
Study period: Unavailable
Follow-up duration: 3 years

n = 75
Becker-Hebly (2021)72 All subjects: 75 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 75 Psychosocial functioning (TGNB vs TGNB) and Appendix I.L (pre-post
Observational cohort study
TGNB youths: 75 comparisons)
A cohort study examining the effect of unspecified GnRH analogs and cross-sex hormone therapy on psychosocial functioning in treated Study period: 9/2013–6/2017
Transmasculine: 64
Risk of bias details in Appendix I
versus untreated TGNB youth. Also contains within-group longitudinal comparisons vs baseline (pre-post descriptive study). Transfeminine: 11 Follow-up duration: up to 48
months

Nieder (2021)172 All subjects: 75 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 75 GD treatment/care
Observational study Studies that did not evaluate our high-priority
TGNB youths: 75
Study period: 9/2013–6/2017 outcomes did not have data extracted due to time
A cohort study examining patient satisfaction with transition-related care (TRC) over time and with various treatments in adolescents and
constraints
young adults with a mean age of 17.4 years. Only natal sexes reported: 61 AFAB and 14 AMAB. Follow-up duration: 48 months

n = 35
Pierce (2022)554 All subjects: 78 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 35 Unavailable
Descriptive study Despite having abstracts in English that obviously
TGNB youths: 35
Study period: Unavailable met inclusion criteria, non-English language studies
A qualitative, interview survey of TGNB youths and their parents. In German Parents: 43
could not have their data extracted
Follow-up duration: Unavailable

Italy
Multisite: , n = 125
Mirabella (2022)113 All subjects: 125 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 125 Gender identity expression (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 125

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
A study examining gender identity changes between AMAB vs AFAB TGNB subjects, and between trans binary vs nonbinary TGNB subjects. Transmasculine: N/R Study period: 4/2019–6/2021 Risk of bias details in Appendix I
Only natal sexes reported: 40 AMAB and 85 AFAB. Transfeminine: N/R
OGD: 32 Follow-up duration: N/A

n=2
Ristori (2019)555 All subjects: 2 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 2 Eating disorder outcomes
Case series Case reports and series do not contain high-priority
TGNB youths: 2
Study period: N/A comparisons and therefore did not have data
A pair of case reports about the occurrence of anorexia nervosa in TGNB adolescents Transmasculine: 1
extracted, due to time constraints
Transfeminine: 1 Follow-up duration: 6 months

Poland
n = 166
Gawlik (2022)556 All subjects: 166 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 166 GD treatments
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 166 Opinions on GD treatment priority comparisons did not have data extracted
A survey-based, descriptive study of Polish TGNB young adults with self-reported testosterone and GnRH analog treatment initiation before Transmasculine: 95
age 16, before age 18, and current use. Transfeminine: 34 Study period: 11/2020–12/2021 due to time constraints
OGD: 37 Follow-up duration: N/A

Slovenia
n=1
Zupanič (2021)557 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Mental health
Case report Case reports and series do not contain high-priority
TGNB youths: 1 GD treatment comparisons and therefore did not have data
A case report of a transgender male adolescent with autism Transmasculine: 1
Study period: N/A extracted, due to time constraints

Follow-up duration: 4.5 years

Spain
Spain, n = 1
Sanchez Lorenzo (2017)558 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Mental health
Case report Case reports and series do not contain high-priority
TGNB youths: 1 Body image comparisons and therefore did not have data
A Spanish clinical case report on the presentation, assessment, findings, and treatment of a 16-year-old transgender boy Transmasculine: 1
Study period: N/A extracted, due to time constraints

Follow-up duration: 2 years

, Spain, n = 80
Martinez-Martin (2023)86 All subjects: 302 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 302 Blood pressure (TGNB vs TGNB)
Observational cohort study
TGNB youths: 80
Study period: 3/2000–3/2020 Risk of bias details in Appendix I

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
A Spanish cohort study comparing blood pressure outcomes in young transgender patients receiving different hormone therapies, including Follow-up duration: 5 years
treatment groups with mean ages < 18 years.

Spain, n ≥ 23
Campos-Munoz (2018)559 All subjects: 5 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 5 Acne outcomes
Case series Case reports and series do not contain high-priority
TGNB youths: 5
Study period: 2016–2017 comparisons and therefore did not have data
A pediatric case series reporting on transgender male adolescents presenting with acne (no IRB) Transmasculine: 5
extracted, due to time constraints
Follow-up duration: Up to 12
months No ethics review, IRB, or consent for research was
described

Lopez de Lara (2020)62 All subjects: 53 Relevant outcomes Details of data extraction available in Appendix I.K
TNGB patients: 23 Treatment outcomes (TGNB vs cisgender peers), and Appendix I.L (pre-
Descriptive study
TGNB youths: 23 Psychosocial outcomes post comparisons)
Examines psychosocial outcomes in TGNB patients who attend a pediatric endocrinology clinic before and after one-year of cross hormonal Cisgender peers/others: 30
Study period: 2018–2019 Risk of bias details in Appendix I
therapy (CHT). In Spanish.
Follow-up duration: 1 year

Spain, n ≥ 20
Fernandez Rodriguez (2017)560 All subjects: 20 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 20 Medical history
Descriptive study Despite having abstracts in English that obviously
TGNB youths: 20 Mental health history met inclusion criteria, non-English language studies
A survey of TGNB youth who requested consultation as they presented complaints of gender dysphoria. In Spanish.
Study period: 3/2007–12/2015 could not have their data extracted
Follow-up duration: N/A

Fernandez (2018)561 All subjects: 20 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 20 GD treatment decisions
Descriptive study Despite having abstracts in English that obviously
TGNB youths: 20 Adverse effects met inclusion criteria, non-English language studies
A survey of TGNB youth on their treatment decisions after they presented complaints of gender dysphoria. In Spanish.
Study period: 3/2007–12/2015 could not have their data extracted
Follow-up duration: Unavailable

Spain, n = 1
Expösito-Campos (2022)169 All subjects: 2 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 2 Reasons for detransition
Case report Case reports and series do not contain high-priority
TGNB youths: 1
Study period: N/A comparisons and therefore did not have data
Two case reports of Spanish transgender patients presenting for medical detransition, one of whom was an AMAB adolescent
extracted, due to time constraints
Follow-up duration: 2 years

Switzerland
Switzerland, n = 1
Rebetez (2014)562 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
Case report TGNB youths: 1 Unavailable Despite having abstracts in English that obviously
Transfeminine 1 met inclusion criteria, non-English language studies
A TGNB youth discusses her transition. In French. Study period: N/A
could not have their data extracted
Follow-up duration: N/A
Case reports and series do not contain high-priority
comparisons and therefore did not have data
extracted, due to time constraints

n = 51
Pauli (2020)563 All subjects: 51 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 51 Mental health
Descriptive study. In German. Despite having abstracts in English that obviously
TGNB youths: 51 GD severity met inclusion criteria, non-English language studies
A pre-post follow up study of adolescents presenting with GD at a gender specialty clinic. In German. Treatment decisions could not have their data extracted
Study period: 2014–onward
Follow-up duration: at least 1
year

United Kingdom (UK)

Multisite: England, Wales, and Ireland, n ≥ 668
Costa (2015)77 All subjects: 201 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 201 Mental health (TGNB vs TGNB), Appendix I.K (TGNB vs cisgender
Observational cohort study
TGNB youths: 201 peers), and Appendix I.L (pre-post comparisons)
A -based cohort study examining mental health changes in TGNB adolescents, including a comparison between transgender males vs Study period: 2010–2014
Risk of bias details in Appendix I
transgender females treated with unspecified GnRH analogs according to the WPATH guideline. Only natal sexes were reported: 76 AMAB Follow-up duration: 18 months
and 125 AFAB adolescents. They also looked at changes over time within groups.

Carmichael (2021)73 All subjects: 44 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 44 Bone outcomes (TGNB vs TGNB) and Appendix I.L (pre-post
Descriptive, longitudinal pre-post study
TGNB youths: 44 Psychosocial outcomes comparisons)
A -based pre-post descriptive study examining short-term (ie, 1-3 years) bone and psychosocial outcomes in TGNB youths ages 12-15
Study period: 6/2011–4/2014 Risk of bias details in Appendix I
years who received GnRH analog monotherapy. Only natal sexes were reported: 25 AMAB and 19 AFAB
Follow-up duration: 48 months

Masic (2022)170 All subjects: 668 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 668 GD treatment trajectories
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 668
A -based descriptive study examining treatment trajectories in TGNB adolescents referred for treatment with GnRH analogs and Study period: 1/2017–12/2019 priority comparisons did not have data extracted
due to time constraints
cross-sex hormones. Only natal sexes were reported: N = 227 AMAB and N = 441 AFAB. Follow-up duration: 2017-
onward

Lavender (2023)142 All subjects: 38 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 38 Mental health (pre-post comparisons)
Longitudinal pre-post descriptive study
TGNB youths: 38
Study period: 2014–10/2021 Risk of bias details in Appendix I

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
A based, pre-post, descriptive study examining changes in mental health and suicidality for TGNB youths after initiating unspecified Follow-up duration: 2 years
GnRH analogs and CSHT. Only natal sexes were reported: N = 28 AFAB and N = 10 AMAB.

Multisite: England, Northern Ireland, Scotland, and Wales, n ≥ 360

Rogers (2021)564 All subjects: 3667 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 3667 Fertility preservation
Observational study Studies that did not evaluate our high-priority
TGNB youths: 360 Reasons for fertility decisions outcomes did not have data extracted due to time
A database, cohort study examining predictors of gamete storage in TGNB patients from the UK, including adolescents at the time of the
Study period: 6/2015–4/2020 constraints
study
Follow-up duration: N/A

Multisite: England, n = 980

Butler (2022)165 All subjects: 1089 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1089 Gender identity decisions
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 980 post-discharge priority comparisons did not have data extracted
A descriptive study examining gender identities of TGNB adolescents after discharge from 2 English children's hospitals for GD-related
Study period: 2008–2021 due to time constraints
treatments. Only natal genders were reported: 329 AMAB and 651 AFAB adolescents < 18 years.
Follow-up duration: up to age 18

Indeterminate site: England, n = 95

Russell (2021)565 All subjects: 97 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 97 Social responsiveness scores Studies that did not evaluate our high-priority
Longitudinal pre-post descriptive study
TGNB youths: 95 (see Appendix I.H) outcomes did not have data extracted due to time
A -based pre-post descriptive study examining autism-related characteristics before and after 1 year of GnRH analog therapy in
Study period: N/R constraints
TGNB adolescents with autism. Only natal sexes were reported: 38 AMAB and 57 AFAB.
Follow-up duration: 1 year

England, n = 12
Churcher Clarke (2019)566 All subjects: 12 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 12 Desistance
Case series Case reports and series do not contain high-priority
TGNB youths: 12 Reasons for desistance comparisons and therefore did not have data
A case series reporting on TGNB patients seen in the Transmasculine: 6
Transfeminine: 3 Study period: 10/2015–4/2017 extracted, due to time constraints
OGD: 3 Follow-up duration: 18 months

England, n ≥ 36
Joseph (2019)137 All subjects: 31 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 31 Bone outcomes (pre-post comparisons)
Longitudinal pre-post descriptive study
TGNB youths: 31
Study period: 2011–2016 Risk of bias details in Appendix I
A based pre-post descriptive study examining bone outcomes in TGNB adolescents treated with GnRH analogs Transmasculine: 21
Transfeminine: 10 Follow-up duration: 3 years

Ghelani (2020)58 All subjects: 36 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 36 Body composition (pre-post comparisons)
Longitudinal pre-post descriptive study
TGNB youths: 36

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Table I.G.3. Characteristics of N = 60 relevant clinical studies conducted in pediatric TGNB populations in Canada, Australia, the United Kingdom, and Europe, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
A based study examining body composition changes in TGNB adolescents receiving triptorelin for puberty suppression Transmasculine: 25 Study period: 2013–2015 Risk of bias details in Appendix I
Transfeminine: 11
Follow-up duration: 12 months

Scotland, n ≥ 91
Gilani (2021)567 All subjects: 55 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 55 Sports/Physical activity
Observational study Studies that did not evaluate our high-priority
TGNB youths: 55 participation outcomes did not have data extracted due to time
A Scotland-based, cross-sectional, survey study examining sports participation and motivation levels in TGNB adolescents treated with Barriers to participation constraints
GnRH analogs, including a subset who were treated with CSHT. Only natal sex was reported: N = 39 AFAB and N = 16 AMAB.
Study period: 6/2019–10/2019
Follow-up duration: N/A

McCallion (2021)171 All subjects: 91 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 91 Endocrine medical care
Descriptive study Studies that did not make one of our three highest-
TGNB youths: 91 Pubertal-early adulthood priority comparisons did not have data extracted
A Scotland-based descriptive study of characteristics of pediatric TGNB patients referred to a pediatric gender care clinic. Only natal sexes and treatment trajectory due to time constraints
were reported: 59 AFAB and 32 AMAB.
Study period: 2011–2019
Follow-up duration: 18 months

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Table I.G.4. Characteristics of N = 9 relevant, English-language clinical studies conducted in other pediatric TGNB populations, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
Brazil
Brazil, n = 1
Schneider (2017)442 All subjects: 1 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 1 Brain and cognition
Case report Case reports and series do not contain high-priority
TGNB youths: 1 development comparisons and therefore did not have data
Describes brain maturation, cognition, and voice pattern in a patient with GD receiving GnRH analog therapy for puberty suppression Transfeminine: 1 Vocal development extracted, due to time constraints
Study period: N/A
Follow-up duration: 28 months

7 municipalities in Brazil, n = 28
Maschião (2020)568 All subjects: 616 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 616 Risk factors for non-
Observational study Studies that did not evaluate our high-priority
TGNB youths: 28 prescribed GD treatment outcomes did not have data extracted due to time
A cross-sectional/case -control study examining risk factors for use of non-prescribed sex hormones in transgender females Transfeminine: 28
Study period: 2014–2015 constraints
Follow-up duration: N/A

Brazil, n = 15
Alvares (2022)132 All subjects: 42 Relevant outcomes Details of data extraction available in Appendix I.K
TNGB patients: 15 Cardiopulmonary capacity (TGNB vs cisgender peers) and Appendix I.L (pre-
Observational cross-sectional study
TGNB youths: 15 Muscle strength post comparisons)
A cross-sectional study comparing cardiopulmonary capacity and muscle strength (ie, determinants of physical performance) in Brazilian Transfeminine: 15
Study period: N/R Risk of bias details in Appendix I
transgender women versus cisgender men and women, none of whom were athletes Cisgender peers/others: 27
Follow-up duration: N/A

Israel
Israel, n = 106
Segev-Becker (2020)117 All subjects: 106 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 106 Mental health (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 106 Behavioral outcomes Risk of bias details in Appendix I
Examines mental health and behavioral outcomes in transgender boys vs girls Transmasculine: 59
Transfeminine: 47 Study period: 3/2013–12/2018
Follow-up duration: Max of 5.1
years

Perl (2020)144 All subjects: 15 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 15 Blood pressure (pre-post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 15
Study period: 2013–2018 Risk of bias details in Appendix I
Examines blood pressure outcomes in transgender males receiving puberty-suppressing GnRH analogs, followed by CSHT for 9 of them Transmasculine: 15
Follow-up duration: Mean of 7
months

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Table I.G.4. Characteristics of N = 9 relevant, English-language clinical studies conducted in other pediatric TGNB populations, chronologically by site
Author (Year)
Study design Participants Relevant Outcomes Disposition in this Review
Description
Perl (2021)145 All subjects: 19 Relevant outcomes Details of data extraction available in Appendix I.L
TNGB patients: 19 Blood pressure (pre-post comparisons)
Longitudinal, pre-post descriptive study
TGNB youths: 19 Hormone biomarkers Risk of bias details in Appendix I
Examines blood pressure, weight, and hormone levels in transfeminine adolescents who received GnRH analogs for puberty suppression, 15 Transfeminine: 19 Body weight
of whom went on to receive CSHT with estradiol
Study period: 2/2013–12/2020
Follow-up duration: Max of 63
months

Turkey
, Turkey, n = 4
Akgül (2022)569 All subjects: 4 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 4 Menstrual suppression
Case series Case reports and series do not contain high-priority
TGNB youths: 4
Study period: 9/2018–5/2020 comparisons and therefore did not have data
Reports on use of GnRH analogs for menstrual suppression in Turkish gender minority youth Transmasculine: 3
extracted, due to time constraints
ONB: 1 Follow-up duration: N/R

Turkey, n = 30
Karakilic Ozturan (2023)112 All subjects: 30 Relevant outcomes Details of data extraction available in Appendix I.J
TNGB patients: 30 Body changes (TGNB vs TGNB)
Observational cross-sectional study
TGNB youths: 30 Hormone levels Risk of bias details in Appendix I
Examines body changes and endogenous hormone levels in TGNB adolescents Transmasculine: 15
Transfeminine: 15 Study period: 2016–2022
Follow-up duration: Max of 45
months

Turkey, n = 2
Cesur (2022)570 All subjects: 2 Relevant outcomes Bibliography only (Appendix I.F)
TNGB patients: 2 Gender identity trajectory
Case report Case reports and series do not contain high-priority
TGNB youths: 2 Response to puberty comparisons and therefore did not have data
A pair of case reports of Turkish, transgender adolescents with long-term follow-up Transmasculine: 1 suppression extracted, due to time constraints
Transfeminine: 1
Study period: N/A No ethics review, IRB, or consent for research was
Follow-up duration: 35 months described

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APPENDIX I.H: MENTAL HEALTH ASESSMENT TOOLS USED IN INCLUDED
CLINICAL STUDIES

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
ASR Adult Self-report The Adult Self-Report (ASR), a component of the ASEBA, is Achenbach TM, Rescorla LA. Manual for the ASEBA
specifically designed to assess psychopathology in Adult Forms & Profiles. Burlington, VT: University of
individuals aged 18 to 59. Ratings of problem items are Vermont, Research Center for Children, Youth, &
summed to yield scores on eight statistically derived Families; 2003455
narrow-band syndrome scales (e.g., Anxious/Depressed),
Used by de Vries et al. 201479
three broad-band scales (Internalizing, Externalizing, and
Total Problems), six DSM-oriented scales, as well as a
Friends and Spouse/Partner scale. The ASR is utilized for
self-assessment.

ASQ Ask Question-Screening A questionnaire is used to assess suicidality. Horowitz, L. M., Bridge, J. A., Teach, S. J., Ballard, E.,
Questions Klima, J., Rosenstein, D. L., . . . Pao, M. (2012). Ask
Suicide-Screening Questions (ASQ): A brief instrument
for the pediatric emergency department. Archives of
Pediatrics & Adolescent Medicine, 166, 1170–1176.456
Used by Allen et al. 201956
BDI-(Y) Beck Depression 20-item questionnaire used to measure used to assess Beck JS, Beck AT, Jolly JB. Beck youth inventories, 2nd
Inventory-for youth presence and severity of depressive symptoms in youth. edition. San Antonio (TX): Pearson Assessments;
Each item was rated on a 4- point scale. Scores were 2005.457
summed and compared to standardized cutoffs reflecting
minimal, mild, moderate, or severe depression. Used by Chen et al. 2021104
BDI-II Beck Depression 21-item questionnaire used to measure depression. Each Beck, et al. Manual for Beck Depression Inventory-II.
Inventory-II item was rated on a 4-point scale, summed and compared 1996.458
to standardized cutoffs reflecting minimal (0-13), mild (14-
Used in Chen et al. 202375
19), moderate (20-28), or severe depression symptoms (29-
63).

BES Body Esteem Scale for 22-item questionnaire with items that assess general Mendelson BK, Mendelson MJ, White DR. Body-esteem
Adolescents perceptions about appearance (“I’m pretty happy with the scale for adolescents and adults. Journal of Personality
way I look.”), weight (“I am satisfied with my weight.”), and
how others view one’s body or appearance (“Young people
my age like my looks.”). Each item was rated on a 4-point

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
scale and summed, with higher scores indicating greater Assessment. 2001;76(1):90–106. [PubMed:
body esteem. 11206302]459

Used by Chen et al. 2021104

BIS Body Image Scale Tool is designed to assess body imaging or dissatisfaction. Lindgren and Pauly. A body image scale for evaluating
30-item self-report measure assessing BIS or transsexuals. Arch Sex Behav. 1975;4(6):639–656.460
dissatisfaction. Thirty body features are listed, and
Used in Lavender et al. 2023142, and Grannis et al.
satisfaction is rated on a 5-point Likert scale. A total score
2021110
and three subscale scores for primary sexual
characteristics, secondary sexual characteristics (both of
which are affected by sex hormones), and "neutral"
characteristics are calculated. Higher scores represent
more body dissatisfaction

CESD-R Center for 20-item questionnaire with scores ranging from 0 to 60. Eaton, et al. Center for Epidemiologic Studies
Epidemiologic Studies Individual items are scored on a 4-level scale that ranges Depression Scale: Review and Revision (CESD and CESD-
Depression Scale from 0 (for "Not at all or less than one day") to 3 (for "5-7 R). In: The Use of Psychological Testing for Treatment
days" and/or "nearly every day for 2 weeks"). A total CESD- Planning and Outcomes Assessment: Instruments for
R score less than 16 implies no clinical depression. Adults, Vol. 3. 3rd ed. Lawrence Erlbaum Associates
Publishers; 2004:363–77.461
Haroz, et al. Psychometric evaluation of a self-report
scale to measure adolescent depression: the CESDR-10
in two national adolescent samples in the United States.
J Affect Disord. 2014;158:154-160.462

CBCL Child Behavior Checklist Tool is designed as a parent report as a general measure of Crijnen, et al. Comparisons of problems reported by
psychological functioning. Part of ASEBA (www.aseba.org). parents of children in 12 cultures: Total problems,
externalizing, and internalizing. J Am Acad Child Adolesc
112-item caregiver-reported measures of psychological and
Psychiatry. 1997;36(9):1269–1277.463
behavioral functioning of young people. Generated scores
reflect six DSM-V orientated categories: Depressive,
Anxiety, Somatic, Attention Deficit/Hyperactivity,
Oppositional Defiant, and Conduct problems. Internalizing

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
behaviors (such as depression and anxiety) and Achenbach System of Empirically Based Assessment
externalizing behaviors (such as aggression and conduct (ASEBA). Updated 2022. Available at
issues) are measured. https://aseba.org/455
Used in Lavender et al. 2023142
CGAS Children's Global Used to assess adolescent's global functioning via clinician's Shaffer D, Gould MS, Brasic J, et al. A children’s global
Assessment Tool reports. Designed to measure how children and assessment scale (CGAS). Arch Gen Psychiatry.
adolescents' function in daily life and can be used to assess 1983;40(11): 1228–1231464
psychosocial/psychiatric outcomes, socio-cognitive
Used by de Vries et al. 201479
competence, and changes due to interventions. It is divided
into 10-point intervals from 10 to 100, with higher scores
(above 80) indicating good global functioning.

CDI Children’s Depression Children's depression inventory-The CDI consists of 27 Figueras Masip A, Amador-Campos JA, Gómez-Benito J,
Inventory items rated from 0-2; the clinical cutoff suggestive of del Barrio Gándara V. Psychometric properties of the
depression is a sum of 20 or higher. Children’s Depression Inventory in community and
clinical sample. Span J Psychol 2010;13:990e9.465
Used in Olsavsky et al. 2023116
Kovacs, M., 1985. The children’s depression inventory
(CDI). Psychopharmacol. Bull. 21 (4), 995–998.466
Used by Grannis et al. 2021110
C-SSRS Columbia Suicide Questions used to assess suicidal ideation Posner K, Brown GK, Stanley B, et al. The Columbia-
Severity Rating Scale suicide severity rating scale: Initial validity and internal
consistency findings from three multisite studies with
adolescents and adults. Am J Psychiatry
2011;168:1266e77.467
Used in Olsavsky et al. 2023116
CD-RISC Connor-Davidson The Connor-Davidson Resilience Scale is a test that Neyer et al. Validity, Reliability, and Differential Item
Resilience Scale measures resilience or how well one is equipped to bounce Functioning of English and French Versions of the 10-
back after stressful events, tragedy, or trauma. Resilience Item Connor-Davidson Resilience Scale in Systemic
gives us the ability to thrive in the face of adversity

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
Sclerosis: A Scleroderma Patient-Centered Intervention
Network Cohort Study. Arthritis Care Res. 2023.468

N/A Draw -a-person test Draw-a-Person test-after each youth had drawn a house Bieliauskas, V. J. (1960). Sexual identification in
and a tree, he or she was asked to “draw a person” and to children’s drawings of human figure. Journal of Clinical
identify its sex. The youth was then asked to draw a person Psychology, 16, 42–44.469
of the sex opposite to that of the first drawing. Used by Zucker et al. 2012470
EDE-Q Eating Disorder Tool is designed to assess eating disorder-related (1) Fairburn CG, Beglin SJ. Assessment of eating
Examination psychopathology in TGNB subjects. disorders: Interview of self-report questionnaire? Int J
Questionnaire Eat Disord 1994; 16:363-70.471
(2) Berg KC, Peterson CB, Frazier P, Crow SJ.
Psychometric evaluation of the eating disorder
examination and eating disorder examination-
questionnaire: A systematic review of the literature. Int
J Eat Disord 2012;45:428e38.472
(3) Swenne I. Changes and predictive value for
treatment outcome of the compulsive exercise test
(CET) during a family-based intervention for adolescents
eating disorders. BMC Psychol 2018;6:55.473
All used by Avila et al. 2019101
EROS Erotic Response and Erotic Response and Orientation Scale-a 16-item self- Storms, M. D. (1980). Theories of sexual orientation.
Orientation Scale report measure assessing sexual orientation in fantasy over Journal of Personality and Social Psychology, 38, 783–
the past six months. Half of the questions pertained to 792.474
heterosexual fantasy (e.g., for females, “How often have Used by Zucker et al. 2012470
you had any sexual feelings (even the slightest) while
looking at a boy?”) and the other half pertained to
homosexual fantasy (e.g., for females, “How often have you
had any sexual feelings (even the slightest) while looking at
a girl?”). Each item was rated on a 5-point scale for
frequency of occurrence, ranging from “none” to “almost
every day.”
FBeK “Fragebofen zur The FBeK is one of the most frequently used Dahne A, Assmann B, Ettrich C, Hinz A. [Norm values for
Beurteilung des eisenen multidimensional body questionnaires in the German the questionnaire to assess the own body (Fragebogen

542

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
Körpers” (Body image language, providing an assessment of body experience that zur Beurteilung des eigenen Korpers, FBeK) for
assessment is especially relevant to the study of the importance of adolescents]. Prax Kinderpsychol Kinderpsychiatr.
questionnaire) body image in clinical samples. It is a self-report measure 2004;53(7):483-496.475
with response options of either 1 (“I agree”) or 0 (“I Used by Becker et al. 2018103
disagree“).
GIQ-Ad Gender Identity Gender Identity Questionnaire for Adolescents -13- item Johnson LL, Bradley SJ, Birkenfeld-Adams AS, Kuksis MA,
Questionnaire for parent-report questionnaire pertaining to various aspects Maing DM, Mitchell JN, Zucker KJ. A parent-report
Adolescents of concurrent sex-typed behavior (e.g., sex-of-peer gender identity questionnaire for children. Arch Sex
affiliation preference, masculine vs. feminine interests, Behav. 2004;33(2):105-116.
cross-dressing, the desire to be of the other sex). Eleven of doi:10.1023/b:aseb.0000014325.68094.f3476
the items were rated on a 5-point scale (e.g., from “never”
to “every day”), one item was rated on a 4-point scale, and
one item was calculated as a difference score based on the
number of male versus female close friends.
GIDYQ Gender Identity/Gender Gender Identity/Gender Dysphoria Questionnaire for Deogracias, J. J., Johnson, L. L., Meyer-Bahlburg, H. F. L.,
Dysphoria Adolescents and Adults -Item content was based on prior Kessler, S. J., Schober, J. M., & Zucker, K. J. (2007). The
Questionnaire for measures, expert panels, and clinical experience. There are Gender Identity/Gender Dysphoria Questionnaire for
Adolescents and Adults parallel versions for males and females. Each item was Adolescents and Adults. Journal of Sex Research, 44,
rated on a 5-point response scale ranging from Never to 370–379.477
Always based on a time frame of the past 12 months. Item Used by Zucker et al. 2012470
examples include: “In the past 12 months, have you felt
unhappy about being a boy?” and “In the past 12 months,
have you wished to have an operation to change your body
into a man’s (e.g., to have your breasts removed or to have
a penis made)?” Participants’ GIDYQ total score was
calculated by summing scores on the completed items and
dividing by the number of marked responses.

GMSR-A Gender Minority Stress This tool assesses social stigma and psychosocial resilience Hidalgo MA, Petras H, Chen D, Chodzen G. The Gender
and Resilience related to gender minority identity. The GMSR-A is Minority Stress and Resilience Measure: Psychometric
Measures for comprised of nine subscales, six of which were employed in validity of an adolescent extension. Clinical Practice in
Adolescents this study. Included were four minority stress subscales
(i.e., gender identity non-affirmation; internalized

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
transphobia; negative expectations for the future; non- Pediatric Psychology. 2019;7(3):278–290. [PubMed:
disclosure of gender identity/history) and two resilience 33224698]478
subscales (i.e., pride in being a gender minority individual;
community connectedness). Items were rated on a 5-point Used by Chen et al. 2021104 and Conn et al. 2023105
scale. Sample items include “People don’t respect my
gender identity because of my appearance or body” (non-
affirmation), “If I express my gender history, I could be a
victim of crime or violence” (non-disclosure), “It is a gift
that my gender identity is different from my designated sex
at birth” (pride), and “I feel connected to other people who
share my gender identity” (community connectedness).
Subscale item responses are summed, with higher scores
indicating greater minority stress or resilience.

GAD-7 General Anxiety Designated to assess anxiety symptoms, 7-item screening Lowe, et al. Validation and standardization of the
Disorder-7 measure of anxiety. Items are rated on a 4-point scale for Generalized Anxiety Disorder Screener (GAD-7) in the
how often each symptom has occurred in the past 2 weeks general population. Med Care. 2008; 46:266–274.479
from 0 (Not at All) to 3 (Nearly Every Day).
Used in Cantu et al. 202074
GWBS General Well-being A questionnaire used to assess psychological well-being. Fazio AF. A concurrent validational study of the NCHS
Schedule General Well-Being Schedule. Vital Health Stat 2. 1977,
(73):1-53. https://www.ncbi.nlm.nih.gov/pubmed/
610049480
Used by Allen et al. 201956
SPPA Harter Self Perception The SPPA is an instrument designed to measure an Van den Bergh BR, Van Ranst N. Self-concept in
Profile for Adolescents adolescent’s overall self-esteem and feelings of children: equivalence of measurement and structure
competence in eight specific domains, namely: scholastic across gender and grade of Harter's Self-Perception
competence, social acceptance, athletic competence, Profile for Children. J Pers Assess. 1998;70(3):564-582.
physical appearance, behavioral conduct, romantic appeal, doi:10.1207/s15327752jpa7003_13481
job competence and close friendship
Used by Durwood et al. 2017109

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
K6 Kessler Psychological The Kessler Psychological Distress Scale (K6) is a simple Kessler RC, Green JG, Gruber MJ, Sampson NA, Bromet
Distress Scale measure of psychological distress which involves 6 E, Cuitan M, et al. Screening for serious mental illness in
questions about a person's emotional state. Each question the general population with the K6 screening scale:
is scored from 0 (None of the time) to 4 (All of the time). results from the WHO World Mental Health (WMH)
survey initiative. International journal of methods in
psychiatric research. 2010; 19(01):4.482
Used by Turban et al. 2022122
(n/a) KIDSCREEN-27 Youth self-report tool to assess health related quality of Ravens-Sieberer U, Herdman M, Devine J, Otto C,
life. Includes 5 subscales. Bullinger M, Rose M, Klasen F (2014) The European
KIDSCREEN approach to measure quality of life and well-
being in children: development, current application, and
future advances. Qual Life Res 23:791–803.483
Used by Becker-Hebly et al. 202172
LSAS Liebowitz Social Anxiety Standardized self-reported measure to assess social anxiety Mennin DS, Fresco DM, Heimberg RG, Schneier FR,
Scale Davies SO, Liebowitz MR. Screening for social anxiety
disorder in the clinical setting: using the Liebowitz Social
Anxiety Scale. J Anxiety Disord. 2002;16(6):661-673.
doi:10.1016/s0887-6185(02)00134-2.484
Used by Grannis et al. 2021110
MDS Modified Depression The MDS is a self-administered six-item scale designed to Dunn EC, Johnson RM, Green JG. The Modified
Scale assess the frequency of depressive symptoms (e.g., Depression Scale (MDS): A Brief, No-Cost Assessment
sadness, irritability, hopelessness, sleep disturbance, and Tool to Estimate the Level of Depressive Symptoms in
concentration difficulties) among adolescents. Students and Schools. School Ment Health.
2012;4(1):34-45. doi:10.1007/s12310-011-9066-5485

MSPSS Multi-dimensional Scale Multi-dimensional Scale of Perceived Social Support Zimet GD, Powell SS, Farley GK, Werkman S, Berkoff KA.
of Perceived Social The MSPSS assessed support from: (1) family (4 items), (2) Psychometric characteristics of the Multidimensional
Support friends (4 items), and (3) significant others (4 items). Scores Scale of Perceived Social Support. J Pers Assess.
ranged from 1e 7 (1e2.9 1⁄4 low support; 3e4.9 1⁄4 1990;55(3-4):610-617.
moderate support; 5.1e7 1⁄4 high support). Notably, the

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
significant other subscale refers to one special individual doi:10.1080/00223891.1990.9674095
such as a spouse/partner, friend, professional, or other https://www.ncbi.nlm.nih.gov/pubmed/2280326.486
family member, whereas the family and friend subscales Used by Olsavsky 2023
asked participants to describe support from these general
categories (with family being open to interpretation, e.g.,
legal, bio- logical, and/or chosen)
(n/a) NIH Toolbox-Emotional Tool used to assess different emotions. Participants are Slotkin, et al. NIH Toolbox Scoring And Interpretation
Battery asked to rate how frequently they experienced a variety of Guide. National Institutes of Health. 2012487
positive feelings over the past seven days. Each item was
Used in Chen et al. 202375, and Chen et al. 2021104
rated on a 5-point scale from 1 = "not at all" to 5 = "very
much"; higher scores indicate greater positive affect.
Participants are asked to rate how much they agree or
disagree with statements about their personal well-being."
Each item is rated on a 5-point scale from "strongly
disagree" to "strongly agree"; higher scores indicate greater
life satisfaction.

OASIS Overall Anxiety Severity The OASIS is a 5-item measure that assesses frequency of Campbell-Sills L, Norman SB, Craske MG, et al.
and Impairment Scale anxiety, intensity of anxiety symptoms, behavioral Validation of a brief measure of anxiety-related severity
avoidance, and functional impairment associated with and impairment: the Overall Anxiety Severity and
anxiety Impairment Scale (OASIS). J Affect Disord. 2009;112(1-
3):92-101. doi:10.1016/j.jad.2008.03.014488

PHQ-9 Patient Health 9-item questionnaire for depressive symptoms with scores Richardson, et al. Evaluation of the Patient Health
Questionnaire Modified ranging from 0 to 27. Individual items are scored on a 4- Questionnaire-9 Item for detecting major depression
for Teens level scale that ranges from 0 (for minimal) to 3 (severe). among adolescents. Pediatrics. 2010;126(6):1117–
PHQ-9 scores are interpreted as follows: Minimal (0-4), 1123.489
mild (5-9), moderate (10-14), moderately severe (15-19),
and severe (20-27). The item also has 4 additional
questions related to suicide ideation and life problems.

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
PROMIS Patient Reported There are 3 PROMIS negative affect item banks, consisting Irwin DE, Stucky B, Langer MM, et al. An item response
Outcomes of Depression (28 items), Anxiety (29 items), and Anger (29 analysis of the pediatric PROMIS anxiety and depressive
Measurement items). The items in the PROMIS negative affect banks use symptoms scales. Qual Life Res. 2010;19:595-607490
Information System a 7-day time frame and a 5-point rating scale that ranges
Used by Chen et al. 2021104 and Durwood et al. 2017109
from 1 (“Never”) to 5 (“Always”) The questions are used to
measure levels of negative affect across its observed
continuum.

QLES-Q-SF Quality of Life 15-item questionnaire for quality of life and enjoyment Endicott, et al. Quality of Life Enjoyment and
Enjoyment and with scores ranging from 15 to 75. Individual items are Satisfaction Questionnaire: A new measure.
Satisfaction scored on a 5-level scale that ranges from 1 (poor) to 5 Psychopharmacol Bull. 1993;29(2):321–326.491
Questionnaire (very good).

QIDS Quick Inventory of Tool is designed to assess depression-related symptoms. Rush, et al. The 16-Item Quick Inventory of Depressive
Depressive Symptoms Measures symptoms of depression that reflect the Symptomatology (QIDS), clinician rating (QIDS-C), and
Diagnostic and Statistical Manual of Mental Disorders, Fifth self-report (QIDS-SR): A psychometric evaluation in
Edition criteria for major depressive disorder. It produces a patients with chronic major depression. Biol Psychiatry.
total score that can also be grouped into clinical categories: 2003;54(5):573–583.492
not elevated (0–5), mild (6–10), moderate (11–15), and
Used in Kuper et al. 2020141
severe (16–27). Clinicians also completed the clinician
version of the QIDS.

RCGI Recalled Childhood Recalled Childhood Gender Identity/Gender Role Veale JF. Factorial Validity and Invariance Assessment of
Gender Identity/Role Questionnaire-a 23-item questionnaire pertaining to a Short Version of the Recalled Childhood Gender
Questionnaire various aspects of sex-typed behavior as well as relative Identity/Role Questionnaire. Arch Sex Behav.
closeness to mother and father during childhood. Items 2016;45(3):537-550. doi:10.1007/s10508-015-0684-0
were rated on a 5-point response scale. https://www.ncbi.nlm.nih.gov/pubmed/26864871493
Used by Zucker et al. 2012470
RCMAS2 Revised Children's This tool is designed to assess anxiety. Forty-nine items Reynolds and Richmond. Revised Children's Manifest
Manifest Anxiety Scale were rated "yes"/ "no". "Yes" responses were tallied and Anxiety Scale, 2nd ed. Last updated 2008. Available at
transformed into a T score; for this scale T scores > 60 are https://www.wpspublish.com.494
considered clinically significant
Used in Chen et al. 202375

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
SWLS Satisfaction with Life The Satisfaction With Life Scale (SWLS) is a five-item self- Diener E, Emmons RA, Larsen RJ, Griffin S. The
Scale report instrument intended to assess the respondent's Satisfaction With Life Scale. J Pers Assess. 1985
overall life satisfaction (sometimes referred to as global Feb;49(1):71–5.495
satisfaction)
Used by de Vries 2010, chapter 778
SCARED Screen for Child Anxiety Tool is designed to assess anxiety-related symptoms. Birmaher, et al. Psychometric properties of the Screen
Related Emotional Produces a total score as well as subscale scores for panic- for Child Anxiety Related Emotional Disorders (SCARED):
Disorders related, social, separation-related, generalized, and school A replication study. J Am Acad Child Adolesc Psychiatry.
avoidance–related anxiety symptoms 1999;38(10):1230–1236.496
Used in Kuper et al. 2020141, Olsavsky et al. 2023,116
Grannis et al. 2021110
(n/a) Self-harm Index Self-harm actions and thoughts were assessed through two Aitken, et al. Self-Harm and Suicidality in Children
questions in each of the CBCL (parent report) and YSR (self- Referred for Gender Dysphoria. J Am Acad Child Adolesc
report): Item 18 (I deliberately try to hurt or kill myself) and Psychiatry. 2016;55(6):513–520.497
Item 91 (I think about killing myself). Possible responses for
Van Meter, et al. Assessing for suicidal behavior in youth
each question were 0 = not true, 1 = somewhat or
using the Achenbach System of Empirically Based
sometimes true, or 2 = very true or often true. The index
Assessment. Eur Child Adolesc Psychiatry.
was calculated as the sum of the two items in each scale to
2018;27(2):159–169.498
create an index from 0 to 4 for each of the CBCL and YSR
[30–32], a higher score indicating greater self-harm Deutz, et al. The Dysregulation Profile in middle
thoughts and behavior. childhood and adolescence across reporters: factor
structure, measurement invariance, and links with self-
harm and suicidal ideation. Eur Child Adolesc Psychiatry.
2016;25(4):431–442.499
All used in Carmichael et al. 202173
SHQ Sexual History Sexual History Questionnaire-a 20-item self-report measure Langevin, R. (1985). Sexual strands: Understanding and
Questionnaire assessing sexual orientation in behavior treating sexual anomalies in men. New York:
Routledge.500
Used in Zucker 2012470

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
SRS-2 Social Responsiveness 65-item, Likert-scale, caregiver-completed measure of
Scale-Second Edition symptoms associated with autistic traits. A total score
provides a severity index for social difficulties in the autism
spectrum. Subscale scores for social awareness, social
cognition, social communication, social motivation, and
restricted interests and repetitive behavior are generated.

TPI Spielberger's Trait Administered to assess the tendency to respond with anger Azevedo FB, Wang YP, Goulart AC, Lotufo PA, Bensenor
Anger Expression to a threatening or annoying situation. (Scale ranges from IM. Application of the Spielberger's State-Trait Anger
Inventory 1-4) Expression Inventory in clinical patients. Arq
Neuropsiquiatr. 2010;68(2):231-234.
doi:10.1590/s0004-282x2010000200015501
Used by de Vries et al. 201157 and de Vries et al. 201479
STAI Spielberger's Trait Administered to assess the tendency to respond with Carey MP, Faulstich ME, Carey TC. Assessment of
Anxiety Scale anxiety to a threatening or annoying situation. (Scale anxiety in adolescents: concurrent and factorial
ranges from 1-4) validities of the Trait Anxiety scale of Spielberger's
State-Trait Anxiety Inventory for Children. Psychol Rep.
1994;75(1 Pt 1):331-338.502
Used by de Vries et al. 201157 and de Vries et al. 201479
SBQ-R Suicide Behaviors The SBQ-R generates a score between 3 and 18, with higher Osman A, Bagge CL, Gutierrez PM, et al. The Suicidal
Questionnaire-Revised scores reflecting higher risk for suicide. The score is then Behaviors questionnaire-revised (SBQ-R): Validation
collapsed into one of two categories: a score of 3-6 reflects with clinical and nonclinical samples.
a negative screening for suicide risk, and a score of 7-18 Assessment 2001;8:443e54.503
reflects a positive screening for suicide risk. Used in Olsavsky et al. 2023116 and Grannis et al. 2021110
TCS Transgender Scale to measure appearance congruence. Each item was Kozee HB, Tylka TL, Bauerband LA. Measuring
Congruence Scale rated on a 5-point scale from "strongly disagree" to transgender individuals’ comfort with gender identity
"strongly agree" and averaged. Higher scores reflect and appearance: Development and validation of the
greater appearance congruence. transgender congruence scale. Psychol Women Q.
2012;36(2):179-196.504
Used by Chen et al. 202375 and Chen et al. 2021104

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Table I.H.1. Psychological assessment tools utilized in included studies
Acronym Tool Description Citations
UGDS/UGS Utrecht Gender Tool is designed to assess gender related distress. 12- item, Steensma TD, Kreukels BP, Jurgensen M, Thyen U, De
Dysphoria Scale 5-point Likert-scale, self-report measure assessing gender- Vries AL, Cohen-Kettenis PT. The Utrecht Gender
related distress in over 12 seconds, which is specific to Dysphoria Scale: a validation study. Arch Sex Behav.
gender assigned at birth. Provisionally accepted
Used by de Vries et al. 201479
WISC Wechsler Intelligence The Wechsler Intelligence Scale for Children (WISC) is an IQ Canivez GL, Watkins MW, Dombrowski SC. Structural
Scale for Children test and assesses cognitive abilities in children between the validity of the Wechsler Intelligence Scale for Children-
ages of 6 and 16 years old. Fifth Edition: Confirmatory factor analyses with the 16
primary and secondary subtests. Psychol Assess.
2017;29(4):458-472. doi:10.1037/pas0000358505

Used by de Vries et al. 201157

WHO-QOL-Brief World Health The WHO-QOL-Brief comprises 24 questions that belong to Skevington SM, Lotfy M, O’Connell KA. The World
Organization Quality of one of four domains (Physical Health, Psychological Health, Health Organization’s WHOQOL-BRIEF quality of life
Life-Brief Social Relationships, and Environment), and two questions assessment: psychometric properties and results of the
on overall quality of life and general health. The questions international field trial. A report from the WHOQOL
have a 5-point Likert scale. Higher scores indicate a better group. Qual Life Res. 2004 Mar;13(2):299–310.506
quality of life.
Used by de Vries 201078
YSR Youth Self Report Tool is designed as a self-report for youth as a general Verhulst, et al. Comparisons of problems reported by
measure of psychological functioning. Part of ASEBA youths from seven countries. Am J Psychiatry.
(www.aseba.org). 2003;160(8):1479–1485.507
112-item self-reported measures of psychological and Used in Carmichael et al. 202173
behavioral functioning of young people. Generated scores Achenbach System of Empirically Based Assessment
reflect six DSM-V orientated categories: Depressive, (ASEBA). Updated 2022. Available at
Anxiety, Somatic, Attention Deficit/Hyperactivity, https://aseba.org/455
Oppositional Defiant, and Conduct problems. Internalizing
behaviors (such as depression and anxiety) and Used in Lavender et al. 2023142
externalizing behaviors (such as aggression and conduct
issues) are measured.

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 APPENDIX I.I: RISK OF BIAS ANALYSIS OF EXTRACTED INCLUDED
CLINICAL STUDIES

551
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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Achille (2020)55 Selection
Representativeness of the ☆ b) somewhat representative of the average While the sample is representative for patients who persist with treatment at the same clinic for at least 12 months and who are willing to complete
exposed cohort pediatric TGNB subject seen in a US-based questionnaires, the sample only included 50 out of 116 possible participants. That suggests that the eligibility criteria were restrictive.
academic endocrine gender dysphoria clinic

Selection of the ☆ a) drawn from the same community as the For the puberty suppression comparison, there were very few untreated MTF participants (N = 2)
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical They had clinic records from which to determine whether participants had received the interventions, although they did not specify that it was their information
exposure records) source. They also did not specify that medication exposures were included on the questionnaires that were used to assess outcomes, so I am left to conclude that
they used clinic data for exposures.

Outcome temporality ☆ a) yes, study was designed to ensure that the They ensured that exposures preceded outcomes, but they did not report the durations of the different treatments at each outcome measurement point.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor They specified that regression analyses controlled for baseline measures for each outcome, psychiatric medication, and engagement in psychotherapy, but they did
(exposure/comparator) not specify that models controlled for age. Because of the small sample size, it is possible that they did not. They used stratification to control for sex. They only
cohorts controlled for 1 of 2 key factors.

Outcome
Outcome assessment c) self-report Outcomes were assessed using self-administered, validated questionnaires.

Duration of follow-up ☆ a) yes, follow-up was long enough for Outcomes were measured at 12 months; however, we do not know when treatments were initiated. Not all participants initiated treatments at baseline.
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted Restricting to subjects who completed all 3 questionnaires means that there was no attrition, but this does introduce selection bias.
for

Allen (2019)56 Selection

Representativeness of the d) no description of the derivation of the Participants were recruited at the Children’s Mercy Hospital Gender Pathway Services (GPS) clinic.
exposed cohort cohort

Selection of the ☆ a) drawn from the same community as the Participants in different groups were recruited from the same clinic.
nonexposed cohort exposed cohort

Ascertainment of d) no description No clear description of how they obtained participants' medication history.
exposure

Outcome temporality ☆ a) yes, study was designed to ensure that the Not clearly stated but looks like they did retrospective review.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Not adjusted for age, but assess AFAB vs. AMAB and adjusted for duration of treatment
(exposure/comparator)
cohorts

Outcome

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome assessment c) self-report The data was collected from self-reported questionnaire responses.

Duration of follow-up ☆ a) yes, follow-up was long enough for The range of treatment length was 113-1016 days (M = 349, SD = 193). For most of the sample (90%), the duration of treatment was at, or under, 600 days. It
outcome to occur means that for some participants, treatment length between two assessments was less than 6 months, but the median treatment was just around a year.

Attrition ☆ a) complete follow up - all subjects accounted Participants were included if they had pretest and final assessment data points.
for

Arnoldussen Selection
(2022)71
Representativeness of the ☆ b) somewhat representative of the average 72 out of 119 eligible adolescents participated
exposed cohort adolescent seeking GD treatment at the
Center of Expertise on GD in the Netherlands

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ b) structured interview

exposure

Outcome temporality ☆ a) yes, study was designed to ensure that the IQ taken at initial assessment, gender affirming treatment given, then educational achievement was assessed.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important They looked at externalizing variables at start of treatment.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment c) self-report Participants completed a survey.

Duration of follow-up ☆ a) yes, follow-up was long enough for Follow-up occurred around 8 years after initial assessment
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted Based on data in results section, all patients are included in analysis
for

Becker-Hebly Selection
(2021)72
Representativeness of the c) selected group of TGNB youth in the Almost half of the participants at entry either dropped out during baseline or were excluded and there was further drop out during follow-up with only 37%
exposed cohort Hamburg gender identity service responding to questionnaires. Sex ratio changed at each step, so sample isn’t fully representative of available participants. Also, further exclusion data was
introduced when patients were not included for not completing a questionnaire. There is a high probability of selection bias.

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical

exposure records)

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the Outcomes were checked again at follow-up.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) Study did not control for any additional They looked at the raw analysis only
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment c) self-report Outcomes were assessed using self-administered, validated questionnaires.

Duration of follow-up ☆ a) yes, follow-up was long enough for Follow-up was at least six months to 4 years; average was 2 years.
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted Data only presented for those that completed the follow-up.
for

Boogers (2022)66 Selection

Representativeness of the ☆ b) somewhat representative of the average Large retrospective clinical data set was used. Inclusion and exclusion criteria not specified.
exposed cohort TGNB youth in the Center of Expertise on
Gender Dysphoria from Amsterdam

Selection of the ☆ a) drawn from the same community as the These patients were all seen at the Center of Expertise on Gender Dysphoria from Amsterdam.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Medical records were utilized.
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the All comparisons had specific timing.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) Study controlled for any additional factor They did subgroup analyses to somewhat adjust for baseline characteristics.
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Measurements were performed at center.

Duration of follow-up ☆ a) yes, follow-up was long enough for

outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted All data was collected retrospectively
for

Carmichael Selection
(2021)73
Representativeness of the ☆ b) somewhat representative of the average small sample size
exposed cohort

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
TGNB subject taking GnRH analog
monotherapy being seen by the GIDS

Selection of the ☆ a) drawn from the same community as the All participants were referred to the GIDS
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical All patients were starting GnRH analog monotherapy
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the

requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Study divided some data by Tanner stage at baseline and gender
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment b) record linkage BMD was ascertained by clinic visit, but YSR and CGAS were self-report by validated questionnaires

Duration of follow-up ☆ a) yes, follow-up was long enough for This particular comparison was made after 12 months of GnRH analog therapy
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted For this follow-up-all patients were accounted for
for

Cantu (2020)74 Selection

Representativeness of the d) no description of the derivation of the Participants were recruited from an academic medical center in the Northwestern United States between September 2017 and June 2019.
exposed cohort cohort
Unsure how many were identified and how many were excluded.

Selection of the ☆ a) drawn from the same community as the Participants on different treatments were recruited from the same center.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Medical chart was reviewed retrospectively to collect medical interventions.
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified in the article but they reviewed the chart retrospectively.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) There were no statistical adjustments.
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report PHQ-9 and GAD-7 were reported by participants to assess the mental health outcomes.

555

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Duration of follow-up b) no, follow-up was not long enough for The mean (SD) follow-up time in weeks was 20.4 (10.2).
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to A total of 80 subjects were included in analysis. All of them (N = 80) completed PHQ-9 screeners at both time points and N = 78 completed GAD-7 screeners at both
introduce bias (ie, < 5% lost to follow-up), or timepoints.
a description of those lost was provided.

Chen (2023)75 Selection

Representativeness of the ☆ a) truly representative of the average Study mentioned that they felt it was generalizable to the entire population although they were overrepresented in transmasculine, non-Latin white and multiracial
exposed cohort whereas nonbinary and black participants were underrepresented
Transgender and nonbinary youth presenting
to pediatric subspecialty gender programs

Selection of the ☆ a) drawn from the same community as the All participants were recruited the same way and divided into subgroups
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Recruited from gender clinics and specifically recruited if initiating GAH
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the

requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Trajectories were examined with the use of repeated-measures multivariate analysis of variance and mixed-effect models were used. Covariates included baseline
(exposure/comparator) age, designated sex at birth, racial and ethnic identity and early gender-affirming care.
cohorts ☆

Outcome
Outcome assessment c) self-report Participants completed various validated instruments to assess psychosocial functioning.

Duration of follow-up ☆ a) yes, follow-up was long enough for Measurements were taken at baseline and after 6, 12, 18 and 24 months
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to Data was available for 81% of all possible observations over the period of 24 months, with 238 participants (75.6%) competing all 4 visits and 162 participants
introduce bias (ie, < 5% lost to follow-up), or completing all 5. The analytic sample did not differ substantially from the overall sample.
a description of those lost was provided.

Chiniara (2018)76 Selection

Representativeness of the ☆ b) somewhat representative of the average Adolescents who did not follow up at the clinic after the first visit were excluded (n = 12). Three adolescents had their initial visit for gender dysphoria at another
exposed cohort center and were excluded from this analysis because of missing data.
Transgender participants were recruited from
the Transgender Youth Clinic at The Hospital
for Sick Children, Toronto, with their initial
visits between January 2014 and June 2016.

Selection of the ☆ a) drawn from the same community as the AFAB and AMAB participants were recruited from the same transgender clinic.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Use of medications was collected in medical records.
exposure records)

556

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified in the article but they did review retrospectively.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) The study used only univariable tests and there was no statistical adjustment.
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage In a subset of individuals, blood testing was repeated to measure lipid profile and other laboratory data while receiving gender-affirming hormones (after 6–12
months) according to the initial 2009 Endocrine Society guidelines.

Duration of follow-up ☆ a) yes, follow-up was long enough for Blood testing was repeated to measure lipid profile and other laboratory data while receiving gender-affirming hormones (after 6–12 months).
outcome to occur

Attrition c) Follow-up loss rate ≥ 5% and no description Follow-up lipid profile was only obtained in AFAB (n = 8) and AMAB (n = 4), although n = 156 assigned female and n = 47 assigned male were enrolled in the study.
of those lost

Costa (2015)77 Selection

Representativeness of the ☆ a) truly representative of the average TGNB
exposed cohort youth in the Gender identity development
service in London

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Drawn from medical center; not made clear.
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Outcomes were checked again at follow-up with baseline information provided.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) Study did not control for any additional Delayed eligible and immediately eligible would be inherently different.
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment c) self-report Outcomes were assessed using self-administered, validated questionnaires.

Duration of follow-up ☆ a) yes, follow-up was long enough for Follow-up was at 18 months.
outcome to occur

Attrition c) Follow-up rate ≥ 5% and no description of When looking at longer follow-up times, the number decreased, but this was not made clear why.
those lost

De Vries (2010)78 Selection

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Representativeness of the ☆ b) somewhat representative of the average 140 of 196 consecutively referred adolescents were considered eligible for medical intervention between 2000 and 2008 at the clinic.
exposed cohort TGNB youth from the Amsterdam gender
identity clinic of the VU University Medical
Center (VUmc).

Selection of the ☆ a) drawn from the same community as the Participants in different groups were recruited from the same clinic.
nonexposed cohort exposed cohort

Ascertainment of d) no description No clear description of how they obtained participants' medication history.
exposure

Outcome temporality ☆ a) yes, study was designed to ensure that the Not clearly stated but it's a prospective cohort study design.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) Not adjusted for age, but assessed MTFs vs. FTMs
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report The data was collected from self-reported questionnaire responses.

Duration of follow-up ☆ a) yes, follow-up was long enough for Post-treatment was assessed at least 1 year after the treatment
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted A total of 140 adolescents were eligible and 27 were included in analysis. Among 27 included in the analysis, not all of the participants had post-T data for analysis,
for so only data of adolescents who were administered questionnaires on both assessments could be used for Pre-T/Post-T comparisons (CBCL: 24, IQ: 25, UGS: 21 and
BIS: 22).

de Vries (2011)57 Selection

Representativeness of the ☆ b) somewhat representative of the average Some who entered the study did not complete the diagnostic procedures, thereby introducing some selection bias.
exposed cohort TGNB adolescent in the Amsterdam gender
identity clinic of the VUmc

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Follow-up evaluations done by provider determined if patient was qualified to continue.
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Outcomes were checked again at follow-up with baseline information provided.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Sex was included as a between-subject variable
(exposure/comparator)
cohorts

Outcome

558

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome assessment c) self-report Outcomes were assessed using self-administered, validated questionnaires.

Duration of follow-up b) no, follow-up was not long enough for Done when started on puberty suppression
outcome to occur

Attrition c) Follow-up rate ≥ 5% and no description of Only a portion finished the questionnaires.
those lost

de Vries (2014)79 Selection

Representativeness of the ☆ b) somewhat representative of the average Adolescents belonged to a group of consecutively referred adolescent, and then determined to be considered eligible for medical intervention.
exposed cohort TGNB adolescent in the Amsterdam gender
identity clinic of the VUMC

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Drawn from medical center
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Outcomes were checked again at follow-up with baseline information provided.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Gender was addressed.
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report Outcomes were assessed using self-administered, validated questionnaires.

Duration of follow-up ☆ a) yes, follow-up was long enough for Follow-up was done at 1 year.
outcome to occur

Attrition c) Follow-up rate ≥ 5% and no description of Only a portion finished the questionnaires.
those lost

Eitel (2023)80 Selection

Representativeness of the ☆ a) truly representative of the average 58 charts were reviewed and 48 patients met inclusion criteria with 55 incidents of 1hr Post levels
exposed cohort Subjects with a diagnosis of gender dysphoria
receiving leuprolide in the Seattle Children’s
Gender Clinic

Selection of the ☆ a) drawn from the same community as the Drawn from the same community as exposed group - subjects with a diagnosis of gender dysphoria receiving leuprolide in the Seattle Children’s Gender Clinic
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Collected via an electronic health record data pull. A chart review of clinician notes, laboratory values, and medications was conducted to identify baseline Tanner
exposure records) stage and laboratory values within 6 months of leuprolide initiation, evidence of clinical puberty progression, leuprolide formulation and dosing, 1hrPost LH and sex
steroid level, and other medications including hormone replacement therapy and menstrual suppression

559

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the Retrospective chart review done
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) Study did not control for any additional Does not mention any controls in the article
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment ☆ b) record linkage Clinical records and self-reported outcome were both assessed.

Duration of follow-up b) no, follow-up was not long enough for Does not mention it clearly in the article, but does provide some follow-up data for some subjects
outcome to occur

Attrition ☆ a) Complete follow-up – all patients All patient follow-up accounted for primary objective. One patient lost for further follow-up information.
accounted for

Grimstad (2021)81 Selection

Representativeness of the ☆ a) truly representative of the average TGNB Retrospective cohort identified from patients at the hospital who met inclusion criteria
exposed cohort adolescents AFAB or intersex at a Gender
Multispecialty Service (GeMS) at Boston
Children’s Hospital.

Selection of the ☆ a) drawn from the same community as the They were all seen at the same center, which have the same protocols and similar practices.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Medical records were utilized.
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Presence or lack of bleeding had to be confirmed with the medical records.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) Study did not control for any additional The analysis was raw, no adjustments were made. Since this is observational, there may be a lot of confounders that were not addressed.
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment ☆ b) record linkage This was pulled directly from the medical records.

Duration of follow-up ☆ a) yes, follow-up was long enough for Patients were on CSHT for at least one year.
outcome to occur

Attrition ☆ a) Complete follow-up – all patients Missing data was only for 5 patients, and they were already removed.
accounted for

Selection

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Khatchadourian Representativeness of the ☆ a) truly representative of the average TGNB All patients that met the broad eligibility criteria were included in the cohort. It was a small sample size, but represents those who visited the clinic during 1998 to
(2014)82 exposed cohort subjects from a Canadian -based academic 2011.
adolescent gender dysphoria clinic

Selection of the ☆ a) drawn from the same community as the All patients were sampled in the same manner. Comparator groups were drawn from the same population.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical data was extracted from clinic notes following visits.
exposure records)

Outcome temporality b) no, study was not designed to ensure that For both items of comparison, there was no exclusion criteria that stated that patients could not have come into the study with those conditions. The aim of the
requirements the timing of exposure measurement study was to understand the population.
preceded the timing of outcome
measurements

Comparability
Comparability of c) Study did not control for any additional Descriptive statistics were used and the Fisher exact test was used to determine if differences were significant. No statistical or methodology controlling for
(exposure/comparator) factors confounding was done.
cohorts

Outcome
Outcome assessment ☆ a) independent blind assessment Determined via clinic notes

Duration of follow-up ☆ a) yes, follow-up was long enough for Followed patients from that attended clinic from 1998 to 2011. Median follow up time for patients was 2.3 years.
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted Number of subjects is consistent throughout the study.
for

Klaver (2018)83 Selection

Representativeness of the ☆ b) somewhat representative of the average It's most likely that not all TGNB youth in the Netherlands were treated according to the Dutch protocol -- therefore, the results from this study are only applicable
exposed cohort TGNB youth in the Netherlands that started to those that have been treated with it. All participants got care at the VU University Medical Center in Amsterdam.
hormone treatment before turning 18

Selection of the ☆ a) drawn from the same community as the All participants were treated at the VU University Medical Center in Amsterdam.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Investigators determined when participants started hormone treatment by examining the medical records of all adolescents diagnosed with gender dysphoria at
exposure records) the VU University Medical Center in Amsterdam.

Outcome temporality ☆ a) yes, study was designed to ensure that the Measurements for each of the outcomes were taken when participants started GnRH analogs, when they added CSHT, and at 22 years old, after treatment with
requirements timing of exposure measurement preceded both.
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Participants were matched to their comparators based on natal sex. Participants were not matched based on age.
(exposure/comparator)
cohorts

Outcome

561

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome assessment ☆ b) record linkage Investigators determined outcome values by retrospectively reviewing participants' medical records.

Duration of follow-up ☆ a) yes, follow-up was long enough for All participants started hormone therapy before the age of 18, and final outcomes were determined when they turned 22.
outcome to occur

Attrition c) Follow-up loss rate ≥ 5% and no description Anthropometric data were missing for 11% of MTF and 18% of FTM for the start of GnRH analogs, 10% of MTF and 13% of FTM for the start of CHT, and 71% of MTF
of those lost and 76% for the visit at 22 years of age.
Data from measurements of body composition determined by whole-body dual-energy x-ray absorptiometry (DXA) were missing for 12% of MTF and 11% of FTM
for the start of GnRH analogs, 36% of MTF and 45% of FTM for the start of CHT, and 64% of MTF and 65% of FTM for the visit at 22 years of age.
These high values indicate significant attrition/confounding bias, but authors said that the missing data were missing at random and that analyses between people
with missing data vs. not did not indicate bias. They also said that their statistical analysis using linear mixed model regression "properly deal(s) with missing data."

Laurenzano Selection
(2021)84
Representativeness of the ☆ a) truly representative of transmasculine This study included all participants that met the criteria to begin T therapy.
exposed cohort youth in a US based gender clinic

Selection of the ☆ a) drawn from the same community as the Same sampling methods for exposed and comparator
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Medication was given at their clinic
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Outcome include those without additional menstrual suppression
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) study did not control for any confounding factors
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report This information was most likely collect via patient at the clinic

Duration of follow-up ☆ a) yes, follow-up was long enough for

outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to

introduce bias (ie, < 5% lost to follow-up), or
a description of those lost was provided.

Lee (2020)85 Selection

Representativeness of the ☆ a) truly representative of the average TGNB TGNB patients who met criteria were prospectively enrolled from the 4 study sites.
exposed cohort youth in four Children's hospitals (Children’s
Hospital Los Angeles, Lurie Children’s
Hospital, Boston Children’s Hospital, and

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
University of California San Francisco Benioff
Children’s Hospital)

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical

exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Pretreatment and post-treatment scores were analyzed
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Results were stratified by sex designated at birth or whether low BMD was present. Patient characteristics were compared among the 4 sites using ANOVA.
(exposure/comparator)
cohorts ☆

Outcome
Outcome assessment ☆ b) record linkage

Duration of follow-up ☆ a) yes, follow-up was long enough for

outcome to occur

Attrition c) Follow-up rate loss ≥ 5% and no description After initial eligibility, patients were excluded for not being assessed within the baseline time period, not getting their DXA or QCT done, and because they were at
of those lost Tanner stage 4 of puberty.

Martinez-Martin Selection
(2023)86
Representativeness of the ☆ b) somewhat representative of the average Most patients who are treated with estradiol plus LHRH analogs were previously treated with LHRH analogs as a puberty suppressor, and typically start estradiol
exposed cohort Outpatient Gender Identity Clinic since its therapy shortly after their 16th birthday, thus earlier than most other patients.
opening in March 2000
Cyproterone acetate is banned in the US.

Selection of the ☆ a) drawn from the same community as the Drawn from the same community as exposed group - a local Outpatient Gender Identity Clinic (not in the US)
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Clinical records were retrospectively reviewed
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Not specify in the article
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important For risk difference in incidence of HTN, adjusted for perceived gender, age and calendar year at the onset of gender-affirming hormonal therapy, changes in body
(exposure/comparator) confounder(s) weight, fasting plasma glucose, creatinine, LDL-cholesterol and triglycerides
cohorts ☆

Outcome
Outcome assessment ☆ b) record linkage SBP and diagnosis of HTN were obtained from clinical records.

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Duration of follow-up ☆ a) yes, follow-up was long enough for They explored a 5-yr follow up.
outcome to occur

Attrition c) Follow-up rate loss ≥ 5% and no description Out of 811 records, 168 were lost to follow-up before completing 5 years of therapy
of those lost

Marwa (2022)87 Selection

Representativeness of the ☆ b) somewhat representative of the average 314 patient records were retrospectively reviewed but only 119 patients were included in the analysis
exposed cohort TGNB youths from a multidisciplinary gender
affirming clinic in Dallas, Texas, between June
2014 and June 2019

Selection of the ☆ a) drawn from the same community as the TGD youths were selected from a multidisciplinary gender affirming clinic in Dallas, Texas, between June 2014 and June 2019
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical They reviewed electronic medical records of children and adolescents evaluated in a multidisciplinary gender-affirming clinic
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified in the article but they did review retrospectively.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Baseline characteristics were collected and included in a multilinear regression model to assess determinants of LS BMD Z-scores adjusted for age and height and
(exposure/comparator) confounder(s) accounting for race.
cohorts

Outcome
Outcome assessment ☆ b) record linkage Dual energy X-ray absorptiometry was used to assess BMD.

Duration of follow-up ☆ a) yes, follow-up was long enough for DXA scans of the LS are performed at baseline and every 1–2 years as part of standard of care guidelines in all patients being started on puberty suppression and/or
outcome to occur gender-affirming hormone therapy. Patients were included if they had had a baseline scan within 180 days of starting therapy, and had a follow-up scan done.

Attrition ☆ a) complete follow up - all subjects accounted All patients who met inclusion criteria and were not excluded were included in the analysis.
for

Millington Selection
(2019)88
Representativeness of the ☆ b) somewhat representative of the average 90 gender-diverse adolescents were prescribed spironolactone during the study period, however, only a total of 85 subjects were included in the analysis.
exposed cohort
subjects recruited from the Gender
Management Service Program at Boston
Children’s Hospital from 2007 to 2017.
Patients who were prescribed spironolactone
for the purposes of gender transition were
included in the analysis.

Selection of the ☆ a) drawn from the same community as the Subjects recruited from the same hospital were compared based on different doses of spironolactone.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical They reviewed the chart retrospectively.
exposure records)

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified in the article but they did review retrospectively.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) There were no statistical adjustments.
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Not clearly stated in the article but it looks like they did medical chart review to identify potassium measurements.

Duration of follow-up ☆ a) yes, follow-up was long enough for 36 subjects (42%) had at least one potassium measurement within the first 3 months of spironolactone therapy, and 48 subjects (56%) had a measurement within
outcome to occur the first 6 months. Potassium measurements were available for up to 7 years of spironolactone therapy.

Attrition ☆ a) complete follow up - all subjects accounted A total of 90 subjects were identified and 3 subjects without follow-up measurements were excluded. Then, after excluding subjects for other reasons, a total of 85
for were included in analysis (all of them had follow up measurements.)

Millington Selection
(2021)89
Representativeness of the ☆ b) somewhat representative of the average No information on how many people were eligible vs. how many participated, but a large sample size was included.
exposed cohort
GD adolescents being seen in large academic
medical centers

Selection of the ☆ a) drawn from the same community as the Same cohort was compared against each other.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical All participants recruited from medical centers
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Youth were recruited prior to initiating GAH
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Data was separated by male and female at birth and then separated by those with and without obesity, also looked at age, race and tobacco as modifiers
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Noted the laboratory data was collected as part of clinical care as baseline; imagine this would located in the chart.

Duration of follow-up ☆ a) yes, follow-up was long enough for Lipid levels were taken at six months.
outcome to occur

Attrition d) No information about attrition

Millington Selection
(2022)90
Representativeness of the ☆ a) truly representative of the average Eligible patients from gender clinics that consented to the study were included
exposed cohort

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
transgender youth attending gender clinics in
the USA

Selection of the ☆ a) drawn from the same community as the sample population
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Taken from medical record
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Patients were recruited before starting GAH treatment
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Study adjusted for age, and adjusted/compared the measurements from trans youth to both male and female peers
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Laboratory measurement taken from medical record

Duration of follow-up ☆ a) yes, follow-up was long enough for Participants were followed for up to 24 months
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted All patients seem to be accounted for
for

Mullins (2021)91 Selection

Representativeness of the ☆ a) truly representative of the average All patients eligible for inclusion were included within the study
exposed cohort
TGNB patient taking GAHT in the Cincinnati
children's hospital medical center

Selection of the ☆ a) drawn from the same community as the TGM and TGF were drawn from the same cohort of individuals
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Medical records were used to ascertain length of time on GAHT
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Thrombotic events were looked at before and after GAHT exposure
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) The age range was rather broad, and while separated by age, the cohorts were not matched in any way
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Medical records were reviewed retrospectively for information

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Duration of follow-up ☆ a) yes, follow-up was long enough for Patients were on GAHT for an average of over 550 days
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted Because study was retrospective, all data was included in follow-up
for

Navabi (2021)92 Selection

Representativeness of the ☆ a) truly representative of the average TGNB Retrospective review of TGNB youth with at least one DXA measurement at the clinic.
exposed cohort youth at an Endocrine diversity clinic at the
Children’s Hospital of Eastern Ontario (CHEO)
from January 2006 to April 2017

Selection of the ☆ a) drawn from the same community as the The main analysis is a pre- and post-, so this would be the same population.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical It was stated that medical records were reviewed.
exposure records)

Outcome temporality b) no, study was not designed to ensure that The GnRH analog use may have preceded the baseline DEXA scan.
requirements the timing of exposure measurement
preceded the timing of outcome
measurements

Comparability
Comparability of ☆ a) study controls for the most important The main analysis is a pre- post- analysis, so each individual serves as their own control.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage They utilized medical records.

Duration of follow-up ☆ a) yes, follow-up was long enough for The duration of treatment has to be at least 18 months
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to Earlier on in the study, it was discussed that 172 patients were included but only 170 were included in the baseline characteristics table. There is no information on
introduce bias (ie, < 5% lost to follow-up), or the 2 patients that were excluded from the analysis.
a description of those lost was provided.

Olson-Kennedy Selection
(2021)93
Representativeness of the ☆ a) truly representative of the average TGNB Participants were from a hospital in LA, as well as a nationwide study in major cities across the nation. Demographic information can be found in Table I.1. Patients
exposed cohort subjects from a US-based academic that signed the waiver and met the broad eligibility were included.
adolescent gender dysphoria clinic

Selection of the ☆ a) drawn from the same community as the All patients were sampled in the same way from their pediatric gender clinics.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Baseline and follow up information were extracted from patient charts and de-identified.
exposure records)

567

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the Baseline and follow up labs were taken. Descriptive statistics as well as statistical tests, such as Shapiro–Wilk test, Wilcoxon Signed-Rank test, and Mann Whitney U
requirements timing of exposure measurement preceded test, were used to compare the measurements between the two time periods.
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important The investigators stratified data by gender at birth, Tanner stage and type of implant. The investigators did not control for variable time period, which was between
(exposure/comparator) confounder(s) 2 and 12 months of follow up for patients.
cohorts

Outcome
Outcome assessment ☆ a) independent blind assessment Hormone levels were taken from medical record.

Duration of follow-up ☆ a) yes, follow-up was long enough for Noted timeline was between 2 and 12 months. Implants may be effective up to 24 months. For CPP, puberty progression and development stops after one month
outcome to occur on histrelin (Histrelin, Lexicomp).

Attrition ☆ b) subjects lost to follow-up are unlikely to Table I.1 describes the demographics for 66 patients. The number of patients in the other tables describe less patients, ranging from 61 to 63 patients. It was not
introduce bias (ie, < 5% lost to follow-up), or mentioned why there was a difference between the tables, whether there is simply missing data or a loss at follow-up.
a description of those lost was provided.

Schagen (2018)147 Selection

Representativeness of the ☆ a) truly representative of the average They had no exclusion criteria and included everyone in the clinic that met the diagnostic criteria.
exposed cohort pediatric transgender patient at the VU
University Medical Center in Amsterdam
between 1998-2009

Selection of the ☆ a) drawn from the same community as the All were patients of the same clinic and were selected in the same way.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Prospective trial. These patients were seen in clinic as therapy was received.
exposure records)

Outcome temporality b) no, study was not designed to ensure that

requirements the timing of exposure measurement
preceded the timing of outcome
measurements

Comparability
Comparability of c) neither (a) nor (b) there was no controlling for confounding
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage levels of hormone that were measured via lab by unblinded assessors.

Duration of follow-up ☆ a) yes, follow-up was long enough for 2 years of treatment
outcome to occur

Attrition d) No information about attrition

Schagen (2020)94 Selection

568

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Representativeness of the d) no description of the derivation of the No description of how the cohort was sampled or how they were selected.
exposed cohort cohort

Selection of the ☆ a) drawn from the same community as the All participants appeared to follow the same protocol and be derived from the same source.
nonexposed cohort exposed cohort

Ascertainment of d) no description Data was taken from previous studies. It was not mentioned how original data from participants of this study were collected.
exposure

Outcome temporality ☆ a) yes, study was designed to ensure that the Changes in bone density and bone markers were measured forward in time
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Full factorial model was conducted that included time, pubertal stage, sex and all possible interactions.
(exposure/comparator) confounder(s)
cohorts ☆

Outcome
Outcome assessment d) no description No description of how measurements were taken

Duration of follow-up ☆ a) yes, follow-up was long enough for Teens were followed as they transitioned from GnRH analogs to CSHT as determined by physician
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted

for

Schulmeister Selection
(2022)95
Representativeness of the ☆ b) somewhat representative of the average A relative lack of diversity of participants since primarily non-Hispanic white and recruited at urban academic institutions
exposed cohort Participants in treatment group from four
gender specialty clinics in the United States.

Selection of the b) drawn from a different source Participants in control group were drawn from the Bone Mineral Density in Childhood Study (BMDCS).
nonexposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Anthropometric, laboratory, and Tanner-stage data were abstracted from medical records.
exposure records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Anthropometric and laboratory data was abstracted from medical recorded and recorded prior to the participant beginning therapy.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Analysis controlled for age was conducted and within group DMAB vs. DFAB was compared. Each cohort was stratified by Tanner stages.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage HV data were abstracted from medical records.

569

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Duration of follow-up ☆ a) yes, follow-up was long enough for Anthropometric data was recorded prior to the participant beginning GnRH analogs (baseline) and at 6- and 12-month follow-up visits.
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to Of 92 youth who were enrolled prior to GnRH analog initiation, 9 participants were excluded because they did not receive GnRH analog treatment for at least 10
introduce bias (ie, < 5% lost to follow-up), or months, 12 were excluded from analysis because they did not have a documented height after 10 to 14 months of GnRH analog treatment, and 16 participants
a description of those lost was provided. were excluded because they started CSH prior to 12 months of GnRH analog treatment.

Tordoff (2022)96 Selection

Representativeness of the ☆ b) somewhat representative of the average Family support and access to care are associated with protection against poor mental health outcomes, and thus actual rates of depression, anxiety, and suicidality
exposed cohort transgender youths from a Urban in nonclinical samples of TNB youths may differ. Primarily included white and transmasculine youths, limiting the generalizability of our findings.
multidisciplinary gender clinic.

Selection of the ☆ a) drawn from the same community as the Participants in the untreated group were drawn from the same community - a Urban multidisciplinary gender clinic.
nonexposed cohort exposed cohort

Ascertainment of ☆ c) written self-report Self-reported receipt ever of PBs or CSHs at baseline or through the end of the study period.
exposure

Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified how they attained this information.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Temporal trends and potential confounders were adjusted in the model and time-varying exposure of PBs or CSHs was also controlled in model.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment c) self-report Measures of outcome were symptom-based. Depression was assessed using the Patient Health Questionnaire 9-item scale (PHQ-9), and anxiety was assessed using
the Generalized Anxiety Disorder 7-item scale (GAD-7). Self-harm and suicidal thoughts were assessed using PHQ-9 question 9.

Duration of follow-up ☆ a) yes, follow-up was long enough for The association between mental health outcomes and access to PBs or CSHs was assessed over a relatively short time frame of 1 year.
outcome to occur

Attrition c) Follow-up loss rate ≥ 5% and no description The final sample included 104 youths. Of these individuals, 84 youths (80.8%), 84 youths (80.8%), and 65 youths (62.5%) completed surveys at 3, 6, and 12 months,
of those lost respectively.

Valentine (2021)97 Selection

Representativeness of the ☆ b) somewhat representative of the average In transgender cohort, participants were predominantly white. Lack of Asian and Hispanic participants.
exposed cohort Transgender youth from a large Midwestern
pediatric academic center with a
multidisciplinary program serving
transgender and gender-diverse youth.

Selection of the b) drawn from a different source Cisgender cohort was drawn from 13 primary care centers.
nonexposed cohort

Ascertainment of d) no description Does not specify, but looks like they collected testosterone usage based on clinical records or notes
exposure

570

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the Not specify in the article
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important BMIs of the transgender male cohort, and a random number generator used these matched patients to create a 2:1 match of cisgender females to the transgender
(exposure/comparator) confounder(s) males.
cohorts

Outcome
Outcome assessment ☆ b) record linkage BMI data and lipid profile parameters were obtained from clinical records based on visits.

Duration of follow-up b) no, follow-up was not long enough for Both short- and long-term follow-ups were evaluated, with short-term follow-up assessing changes in BMI between each clinic visit, and long-term follow-up
outcome to occur
assessing changes in BMI between first and final follow-up clinic visits (on average longer than 10 months) - for adverse effects, it's not long enough.

Attrition c) Follow-up rate loss ≥ 5% and no description N = 42 were seen at least twice and, therefore, included in assessment of BMI changes. Only 28 of them had lipid panels drawn, and 18 had laboratories both pre-
of those lost and post-testosterone.

Valentine (2022)98 Selection

Representativeness of the ☆ a) truly representative of the average TGNB The data for all TGNB youth that met inclusion criteria and at least one outpatient visit were extracted from the database
exposed cohort youth from a Pediatric Learning Health
System Network

Selection of the ☆ a) drawn from the same community as the The PedsNET resource was used for all. A random sample of patients with at least one outpatient visit during the same time period who did not have a diagnosis of
nonexposed cohort exposed cohort GD were used as controls.

Ascertainment of ☆ a) secure record (eg, medical or surgical They used prescription records.
exposure records)

Outcome temporality b) no, study was not designed to ensure that The timing between the description and the diagnosis code was unclear.
requirements the timing of exposure measurement
preceded the timing of outcome
measurements

Comparability
Comparability of ☆ a) study controls for the most important They did propensity score matching and had an adjusted analysis to address for confounders.
(exposure/comparator) confounder(s)
cohorts ☆

Outcome
Outcome assessment ☆ b) record linkage They utilized the diagnosis codes.

Duration of follow-up b) no, follow-up was not long enough for Duration of therapy was unclear.
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted All data was collected retrospectively, so all subjects were accounted for
for

Vlot (2017)99 Selection

571

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Table I.I.1. Risk of bias in extracted cohort studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Representativeness of the ☆ b) somewhat representative of the average After applying these criteria to an eligible patient group of 85 transwomen and 130 transmen, a cohort of 28 transwomen and 42 transmen were included in the
exposed cohort study.
adolescents diagnosed with gender dysphoria
who were treated with GnRH analog and
CSHT were recruited at the clinic the Centre
of Expertise on Gender dysphoria at the VU
University Medical Centre, Amsterdam, the
Netherlands.

Selection of the ☆ a) drawn from the same community as the All 28 transwomen and 42 transmen which were included in this study were recruited from the same clinic and they were just categorized into a young and old
nonexposed cohort exposed cohort pubertal group, based on their bone age.

Ascertainment of d) no description No related description of how they obtained participants' medication history.
exposure

Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified in the article but they did review retrospectively.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Eligible participants were categorized into four groups based on their sex and bone ages - young transwomen, old transwomen, young transmen and old transmen.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Associated laboratory data such as a serum BTM measurement of P1NP, osteocalcin or carboxy terminal cross linked telopeptide of type I collagen were reviewed
to assess the outcomes.

Duration of follow-up ☆ a) yes, follow-up was long enough for Follow up 24 months after CSHT
outcome to occur

Attrition ☆ a) complete follow up - all subjects accounted Eligible subjects were restricted to those who have data for all baseline and follow-ups.
for

572

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Arnoldussen Selection
(2020)100
Representativeness of ☆ a) truly representative of the average They included all patients who were referred to the clinic in the time period
the exposed cohort adolescents seeking GD treatment at the
Center of Expertise on GD in the Netherlands

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Initial year of assessment evident based on the chart documentation
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor They used natal gender as a comparator
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report The CBCL and the YSR were the main outcomes.

Duration of follow-up N/A

Attrition N/A

Avila (2019)101 Selection

Representativeness of ☆ a) truly representative of the average TGNB Response applies to the inferential finding for the overall population, but not to the subgroup comparison, which was based on the subset of all participants who did
the exposed cohort subjects from a US-based academic not skip the relevant items. The highest rating is given because authors specified that only 1 subject declined to participate.
adolescent gender dysphoria clinic in the
community

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ c) written self-report Surveys were written and self-reported in surveys given onsite during clinic visit. While the investigators may have had access to information from the chart, they
exposure specified that data about exposures were collected in the survey instrument.

Outcome temporality N/A

requirements

Comparability
Comparability of c) Study did not control for any additional The study used only univariable tests, so there was no statistical adjustment. The study did not use matching. While they restricted the study to young people (age
(exposure/comparator) factors range 13 to 22 years, the range is too broad to qualify as adequate. While some of the descriptive results were stratified on natal sex (but not age), none of the
cohorts observational comparisons were stratified on either age or natal sex.

Outcome
Outcome assessment c) self-report The EDE-Q survey and additional items were self-administered via an online data collection instrument.

Duration of follow-up N/A

573

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Attrition N/A

Bauer (2021)102 Selection

Representativeness of ☆ b) somewhat representative of the average The recruitment process differed by each clinic location. The exact number in the population that were invited to participate is unknown. We know that 174 patients
the exposed cohort TGNB subjects from a Canadian-based enrolled. Patients come from various walks of life from various locations throughout Canada.
academic adolescent gender dysphoria
clinics

Selection of the ☆ a) drawn from the same community as the Information regarding exposure was taken in the same manner for all patients.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Information was taken both from a structured interview and medical record. Medications were most likely from medical record.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of c) no controls for most important P values were taken from Rao-Scott X^2 test. They did not control for confounding with methods or statistical adjustment.
(exposure/comparator) confounders or additional factors
cohorts

Outcome
Outcome assessment ☆ a) independent blind assessment They used both structured interviews and medical records to extract their information. Most likely objective data was confirmed with medical record.

Duration of follow-up N/A

Attrition N/A

Becker (2018)103 Selection

Representativeness of ☆ b) somewhat representative of the average The process of collecting data from each department in Germany was not standardized because each location had different clinical procedures, so the results cannot
the exposed cohort TGNB youth in Germany be generalized to TGNB populations outside of Germany. Additionally, this study only included TGNB who sought gender-affirming medical care, and thus does not
apply to TGNB not seeking gender-affirming medical care. Finally, the authors did not consider non-binary identities, and thus cannot generalize their results to non-
binary/gender-nonconforming people.

Selection of the ☆ a) drawn from the same community as the Participation in the study was offered to anyone applying for gender-affirming treatment.
nonexposed cohort exposed cohort

Ascertainment of c) written self-report Age and gender identity was self-reported. Medical interventions for gender affirmation was drawn from participants' medical history.
exposure

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor The study controlled for age and treatment duration in months by treating them as covariates, and used a 2 (sample) x 2 (gender) x 3 (interventions) analysis of
(exposure/comparator) covariance (ANCOVA). Investigators performed Levene tests to confirm that parametric assumptions were met.
cohorts

Outcome

574

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome assessment c) self-report Participants' FBeK scores were compared using a 2 (sample) x 2 (gender) x 3 (interventions) ANCOVA test.

Duration of follow-up N/A

Attrition N/A

Chen (2021)104 Selection

Representativeness of ☆ a) truly representative of the average TGNB Patients recruited from 4 pediatric medical centers in the US who met specific criteria
the exposed cohort youth in a pediatric academic center in the
US

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Drawn from academic medical centers for those seeking therapy.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of c) Study did not control for any additional They looked at the raw analysis. Transgender subjects were subgrouped based on medication taken and designated female or male at birth.
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment c) self-report Outcomes were assessed using self-administered, validated questionnaires.

Duration of follow-up N/A

Attrition N/A

Conn (2023)105 Selection

Representativeness of ☆ b) somewhat representative of the average Major metropolitan areas of the US are considered more liberal, inclusive, and supportive for TGNB individuals. As such, these results are not generalizable to more
the exposed cohort TGNB youth living in major metropolitan rural and/or discriminatory parts of the US. The youth are truly representative from the areas that they re from as a large cohort was gathered.
areas of the US

Selection of the ☆ a) drawn from the same community as the All participants were drawn from the same cohort originating from the Trans Youth Care Study.
nonexposed cohort exposed cohort

Ascertainment of c) written self-report Internalized transphobia was determined using the internalized transphobia subscale of the Gender Minority Stress and Resilience Measure for Adolescents (GMSR-
exposure A), a self-report measure that assesses social stigma and psychosocial resilience associated with gender minority identity that has been adapted for adolescents.

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor Age, natal sex, and perceived parental support were included as covariates.
(exposure/comparator)
cohorts ☆

575

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome
Outcome assessment c) self-report Data on anxiety and depression were collected using self-report questionnaires.

Duration of follow-up N/A

Attrition N/A

De Graaf (2022)108 Selection

Representativeness of ☆ b) somewhat representative of the average Data was collected from 3 different sites around the world-all cities are large and metropolitan. Sampling data was not provided, so we don't know if all youth that
the exposed cohort TGNB youth in large cities (Toronto, were seen in these time periods were included or a subset of youth.
Amsterdam, London)

Selection of the b) drawn from a different source Youth from each clinic were compared to each other. While they are all TGNB youth, data was collected from a wide range of years, with London having a cohort that
nonexposed cohort had been seen much more recently than the other two which could greatly impact data as views on TGNB youth and treatments have changed drastically in the last
30 years.

Ascertainment of ☆ a) secure record (eg, medical or surgical Records seem to have been used to identify youth with gender dysphoria.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor Predictors of suicidality were used to compare between groups. 9 predictors were used between the Toronto and Amsterdam group, and 6 predictors were used in
(exposure/comparator) the other comparisons.
cohorts ☆

Outcome
Outcome assessment c) self-report While record linkage was used to ascertain the data, the CBCL and YSR are self-reported measures.

Duration of follow-up N/A

Attrition N/A

de Vries (2011)106 Selection

Representativeness of ☆ b) somewhat representative of the average Note: only multidisciplinary clinic in the Netherlands
the exposed cohort transgender youth in Amsterdam

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Sex at birth and whether or not a patient is immediately eligible or delayed eligible for puberty suppression would be available from the clinic records.
exposure records)

Outcome temporality N/A

requirements

Comparability

576

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Comparability of ☆ b) study controls for any additional factor Adolescents were compared by natal sex and then by those that were immediately eligible for puberty suppression vs. those that were delayed eligible. Natal groups
(exposure/comparator) were similar based on baseline characteristics, so no additional statistical analysis was done when comparing the groups. The immediately and delayed eligible
cohorts groups had some statistically different baseline characteristic, but these were not taken into account in the analysis of the outcomes.

Outcome
Outcome assessment ☆ b) structured interview Adolescents underwent a standardized clinical assessment and completed a DISC interview and psychological assessment.

Duration of follow-up N/A

Attrition N/A

De Vries (2016)107 Selection

Representativeness of ☆ b) somewhat representative of the average No sampling method was listed, and not all of the data was available for all of the participants.
the exposed cohort TGNB youth in Amsterdam and Toronto

Selection of the b) drawn from a different source Youth were compared from 2 different clinics which may have different treatment methods. The time frames were also different for each sample.
nonexposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Youth were identified as having been diagnosed with gender dysphoria
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor 7 different predictors were used to predict the outcome of CBCL and YSR scores. Sex was also used in other comparisons. Age was similar between groups.
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report While record linkage was used to ascertain the data, the CBCL and YSR are self-reported measures.

Duration of follow-up N/A

Attrition N/A

Durwood Selection
(2017)109
Representativeness of ☆ b) somewhat representative of the average A small sample size (n = 63) completed the mental health portion of this study. 116 participants completed the self worth component of the study. This study did
the exposed cohort pediatric TGNB subject seen in a US-based include children from all around the nation, but due to small sample size of this comparison it most likely doesn’t represent the entire TGNB population for the US.
academic gender study They also reported that this population had a higher income than the average US population, which may play a role in their mental health resources.

Selection of the ☆ a) drawn from the same community as the All transgender participants were sampled in the same way.
nonexposed cohort exposed cohort

Ascertainment of c) written self-report Participants answered whether they were on medication and what type.
exposure

Outcome temporality N/A

requirements

Comparability

577

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Comparability of c) Study did not control for any additional There was no additional statistical adjustment for any factors or methods that would control for confounding factors.
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment c) self-report Participants selected answer on PROMIS scale that aligned with how they felt in the past 7 days.

Duration of follow-up N/A

Attrition N/A

Grannis (2021)110 Selection

Representativeness of ☆ b) somewhat representative of the average Reliance on caregivers for transportation and financial support may suggest an inflated level of support compared to the transgender youth population at large.
the exposed cohort minors recruited from a gender clinic

Selection of the ☆ a) drawn from the same community as the Drawn from the same community as exposed group - a gender development clinic at a large children’s hospital
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Medical chart review

exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor Sex was controlled by sample restriction. Age was included as a covariate for all other group comparisons. Results were reported after controlling for age. However, it
(exposure/comparator) is not possible to truly control for all possible factors that may differentiate treatment groups, and some of these factors may contribute to differential mental health
cohorts profiles independent of drug treatment.

Outcome
Outcome assessment c) self-report Standardized self-report measures were used and neuroimaging was used as well.

Duration of follow-up N/A

Attrition N/A

Green (2022)111 Selection

Representativeness of ☆ b) somewhat representative of the average Large scale survey with participants from all areas of the US were part of the study. Recruitment was targeted to reach all demographics. It was a long 142 question
the exposed cohort TGNB youth in the US survey and was done on a volunteer basis, so survey reflects participants that completes the survey. There was also a lower number of trans girls that responded to
the survey than trans boys.

Selection of the ☆ a) drawn from the same community as the All participants were from the same survey.
nonexposed cohort exposed cohort

Ascertainment of c) written self-report Surveys were completed on volunteer basis by participants that saw targeted ads on social media. Answers about mental health were dichotomized. Questions about
exposure demographics and additional questions were multiple choice.

Outcome temporality N/A

requirements

Comparability

578

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Comparability of ☆ a) study controls for the most important Multivariate adjusted logistic regression was performed to adjust for age, socioeconomic status, region, gender identity, sexual orientation, race/ethnicity, parent
(exposure/comparator) confounder(s) support, gender based victimization, gender identity conversion efforts and history of puberty blocker use
cohorts ☆

Outcome
Outcome assessment c) self-report Survey was self-administered online

Duration of follow-up N/A

Attrition N/A

Karakilic Ozturan Selection

(2023)112
Representativeness of ☆ b) somewhat representative of the average The data for this study was collected from a single tertiary pediatric endocrinology clinic in Istanbul, the most populous city in Turkey. People living here have more
the exposed cohort TGNB youth in Turkey access to healthcare compared to more rural parts of the country -- therefore, their clinical and laboratory findings may not reflect the experiences of TGNB youth in
the rest of the country.

Selection of the ☆ a) drawn from the same community as the All participants were drawn from patients referred to the same tertiary pediatric endocrinology clinic.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Investigators retrospectively reviewed the medical records of all adolescents diagnosed with GD that had at least 6 months of psychiatric follow-up and were referred
exposure records) to their GD outpatient clinic from 2016-2022.

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Natal sex defined comparator groups, and age was a measured outcome.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Investigators determined outcome values by retrospectively reviewing participants' medical records.

Duration of follow-up N/A

Attrition N/A

Mirabella Selection
(2022)113
Representativeness of ☆ a) truly representative of the average GD The GDQ was administered to all adolescents who had been consecutively referred to the clinic, usually during their second of three appointments.
the exposed cohort adolescent seeking treatment in
Rome/Florence

Selection of the ☆ a) drawn from the same community as the Comparisons were made between the cohort
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical

exposure records)

Outcome temporality N/A

requirements

579

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Comparability
Comparability of ☆ b) study controls for any additional factor Youth were compared by gender and whether they were trans-binary or non-binary.
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report Study used a questionnaire to assess outcomes

Duration of follow-up N/A

Attrition N/A

Morningstar Selection
(2023)114
Representativeness of ☆ a) truly representative of the average GAH+ A sample of transgender boys was recruited from the clinic
the exposed cohort transgender boy from a multidisciplinary
gender development clinic at an academic
pediatric center in the Midwest of the US.

Selection of the ☆ a) drawn from the same community as the GAH- transgender subjects were recruited from the same community as GAH+ group - a multidisciplinary gender development clinic at an academic pediatric center
nonexposed cohort exposed cohort in the Midwest of the US.

Ascertainment of ☆ a) secure record (eg, medical or surgical Information provided on medication doses and length of therapy, assumed from their medical records at the clinic.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Whole-brain analysis was controlled for age. However, variations in dose and duration of GAH administration were not controlled in the analyses.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage fMRI data were obtained and transgender subjects also self-reported relative closeness to peers and parents.

Duration of follow-up N/A

Attrition N/A

Nahata (2017)115 Selection

Representativeness of ☆ a) truly representative of the average
the exposed cohort
TGNB youth in a large, urban, midwestern
pediatric gender program from 2014-2016

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical EMRs were used to assess ICD 9/10 code
exposure records)

580

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality N/A
requirements

Comparability
Comparability of c) neither (a) or (b) Only separated by gender
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report Medical records were used-but all data came from self-report of subjects to psychiatrists

Duration of follow-up N/A

Attrition N/A

Olsavsky Selection
(2023)116
Representativeness of ☆ b) somewhat representative of the average
the exposed cohort TGNB adolescents in a large midwestern
gender-affirming clinic in the Midwest

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Patients were recruited based on their diagnosis of GD
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor Study used a multivariate linear regression model testing association between nonbinary identity, GAH, family and friend social support. Also initially tested
(exposure/comparator) correlation among age, race, and male vs female identity.
cohorts ☆

Outcome
Outcome assessment c) self-report Validated instruments were used to ascertain data

Duration of follow-up N/A

Attrition N/A

Segev-Becker Selection
(2020)117
Representativeness of ☆ a) truly representative of the average TGNB
the exposed cohort adolescent in the gender dysphoria clinic at
the Dana-Dwek Children s hospital in Tel,
Aviv Israel from 2013-2018

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

581

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Ascertainment of ☆ a) secure record (eg, medical or surgical Patients were recruited based on their referral to the GD clinic
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Study separated data by age and gender
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment c) self-report All data was from medical records, but all data was self-reported

Duration of follow-up N/A

Attrition N/A

Sorbara (2020)118 Selection

Representativeness of ☆ a) truly representative of the average Broad inclusion criteria to include those at the gender clinic that were seeking medication therapy and were diagnosed with gender dysphoria
the exposed cohort transgender youth seen at a gender clinic in
Toronto, CA

Selection of the ☆ a) drawn from the same community as the All were from the same cohort
nonexposed cohort exposed cohort

Ascertainment of ☆ b) structured interview Information was taken from both interview with patients during their visits to the clinic and their medical record. Medical history, including mental health screening
exposure was taken from patient.

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Logistic regression has performed to since which factors were associated with reported mental illness. Factors included were early or late pubertal, age at first visit,
(exposure/comparator) confounder(s) and additional confounders date cohort, social transition and assigned sex
cohorts ☆

Outcome
Outcome assessment c) self-report Mental health outcomes were self-reported

Duration of follow-up N/A

Attrition N/A

Staphorsius Selection
(2015)119
Representativeness of ☆ b) somewhat representative of the average Adolescents with gender dysphoria were recruited to participate in study. Sample size was small, so there may be some selection bias.
the exposed cohort transgender youths from VU University
Medical Center in Amsterdam.

582

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Selection of the ☆ a) drawn from the same community as the They were recruited from VU University Medical Center in Amsterdam, which is the same location.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Not really specified, but they are all located at the same medical center. Thus, medical records should be available.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important They controlled for IQ.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment d) no description They did perform the TOL test and the MRI, but it is unclear if the assessor was blinded.

Duration of follow-up N/A

Attrition N/A

Tollit (2023)120 Selection

Representativeness of ☆ a) truly representative of the average Broad inclusion criteria seems to include most patients that would be seen at the clinic. Purpose of the study was to get info on demographics.
the exposed cohort
pediatric gender diverse patient at an
Australian clinic

Selection of the ☆ a) drawn from the same community as the All were from the same cohort
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Data was collected from both face to face interviews as patients were seen in clinic as well as their medication record.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of c) neither (a) or (b) study did not control for confounding
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Both medical record and face to face methods were used

Duration of follow-up N/A

Attrition N/A

Turban (2020)121 Selection

583

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Representativeness of ☆ b) somewhat representative of the average Eligibility criteria was restricted to participants who were 36 or younger at the time of the survey, since given that pubertal suppression for transgender youth was
the exposed cohort not available in the United States until 1998, participants who were 17 or younger in 1998 would not have had health care access to GnRH analogs for pubertal
TGNB subjects completed the 2015 US
suppression. The USTS data set contains responses from 27,715 US transgender adults; however, only a sample of 20,619 participants was included in analysis.
Transgender Survey (USTS) conducted by the
National Center for Transgender Equality
(NCTE) with respondents from all 50 states,
the District of Columbia, American Samoa,
Guam, Puerto Rico, and US military bases
overseas

Selection of the ☆ a) drawn from the same community as the Pubertal suppression treated group (N = 89, 2.5%) vs. pubertal suppression untreated group (N = 3405, 97.5%)
nonexposed cohort exposed cohort

Ascertainment of c) written self-report Exposure status was examined based on self-reported history of pubertal suppression during adolescence.
exposure

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Baseline demographic variables (including level of family support, sexual orientation, education level, employment status, total household income, gender identity,
(exposure/comparator) confounder(s) and additional confounders race and relationship status) were controlled for multivariate regression models. The analysis was stratified based on age.
cohorts ☆

Outcome
Outcome assessment c) self-report Associated mental health outcomes were collected and analyzed based on survey results.

Duration of follow-up N/A

Attrition N/A

Turban (2022)122 Selection

Representativeness of ☆ b) somewhat representative of the average Participants were recruited from organizations to complete a voluntary survey. Data is dependent on those that participated, although they were able to recruit a
the exposed cohort sizeable sample.
Transgender person in the USA

Selection of the ☆ a) drawn from the same community as the Sampled in the same way/ same population
nonexposed cohort exposed cohort

Ascertainment of c) written self report Completed via online survey

exposure

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Multivariate logistical regression was performed. All models adjusted for age, partnership status, employment status, K-12 harassment and having experienced
(exposure/comparator) confounder(s) and additional confounders gender identity conversion efforts and any additional demographic and potential confounding variables that were found to be associated with each outcome
cohorts ☆

Outcome

584

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome assessment c) self report data collected from survey

Duration of follow-up N/A

Attrition N/A

van de Grift Selection

(2020)624
Representativeness of ☆ b) somewhat representative of the average The study was conducted at a single site/treatment center, and is most likely not applicable to TGNB living in more rural parts of the Netherlands.
the exposed cohort TGNB youth in the Netherlands

Selection of the b) drawn from a different source Both TGNB that used PS at Tanner 2/3 vs. 4/5 were selected using the same local registries, but TGNB that did not use PS were selected using hospital records. It is
nonexposed cohort unclear if 'local registries' and 'hospital records' are the same source.

Ascertainment of ☆ a) secure record (eg, medical or surgical Local registries and hospital records were used to identify eligible participants.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Authors made comparator groups based on natal sex, but did not control for age. There were statistically significant differences between participants' ages at the
(exposure/comparator) confounder(s) start of PS and at their first surgery. Comparator groups were also based on puberty level at beginning of treatment.
cohorts

Outcome
Outcome assessment ☆ b) record linkage The entire outcome database was completed retrospectively at follow-up during a 6-month period in 2018, using local registries.

Duration of follow-up N/A

Attrition N/A

van der Miesen Selection

(2020)124
Representativeness of ☆ b) somewhat representative of the average Since it is a single source of transgender adolescents, not sure if it is truly representative for the community.
the exposed cohort
Transgender samples consisted of
consecutive referrals to the Center of
Expertise on Gender Dysphoria of the VU
University Medical Center (VUmc) in
Amsterdam, the Netherlands, between 2012
and 2015.

Selection of the ☆ a) drawn from the same community as the Transgender adolescents referred to a specialized gender identity clinic and transgender adolescents receiving affirmative care and about to start GAH treatment
nonexposed cohort exposed cohort were recruited from the same transgender clinic.

Ascertainment of d) no description No related description of how they obtained participants' medication history.
exposure

Outcome temporality N/A

requirements

Comparability

585

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Comparability of ☆ a) study controls for the most important Multivariate GLM analysis with assigned gender at birth and a gender by group interaction as additional predictors was used to identify possible gender differences
(exposure/comparator) confounder(s) within each group.
cohorts

Outcome
Outcome assessment c) self-report c) self-report

Duration of follow-up N/A

Attrition N/A

Vehmas (2022)125 Selection

Representativeness of ☆ b) somewhat representative of the average Consecutive adolescents who had been referred to the hospital and met specific inclusion criteria were included. A much higher ratio of FTM to MTF, but that was
the exposed cohort TGNB youth gender identity services at representative of the clinic at that time.
Helsinki University Hospital

Selection of the ☆ a) drawn from the same community as the Male to female and female to male cohorts were compared
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical All patients had met criteria of being diagnosed with GD and seeking GHAT.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of c) Study did not control for any additional Appears just to be a raw analysis.
(exposure/comparator) factors
cohorts

Outcome
Outcome assessment ☆ b) record linkage They utilized medical records and some structured interviews

Duration of follow-up N/A

Attrition N/A

Vrouenraets Selection
(2021)126
Representativeness of ☆ b) somewhat representative of the average 74 adolescents participated, whereas 206 eligible adolescents were not reached or did not want to or could not participate.
the exposed cohort
Participants were transgender adolescents
visiting the Center of Expertise on Gender
Dysphoria of the Amsterdam University
Medical Centers, Location VUmc in
Amsterdam, the Netherlands, between
January 1, 2016, and December 31, 2017, or
visiting the gender-identity clinic of Leiden
University Medical Center, Leiden University
Medical Center Curium, in Leiden, the

586

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Netherlands, between March 1, 2017, and
December 31, 2017.

Selection of the ☆ a) drawn from the same community as the Birth-assigned boys and birth-assigned girls were recruited from the same clinic.
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Exposure of puberty suppression was identified through the medical files.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of c) neither (a) nor (b) Not controlled or adjusted for any factors.
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report CBCL used to assess behavioral and emotional difficulties were parent-reported.

Duration of follow-up N/A

Attrition N/A

Willemsen Selection
(2023)127
Representativeness of ☆ b) somewhat representative of the average Note: only multidisciplinary clinic in the Netherlands
the exposed cohort transgender youth in Amsterdam

Selection of the ☆ a) drawn from the same community as the

nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical Sex at birth and whether or not a patient is immediately eligible or delayed eligible for puberty suppression would be available from the clinic records.
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor Adolescents were compared by natal sex and then by those that were immediately eligible for puberty suppression vs. those that were delayed eligible. Natal groups
(exposure/comparator) were similar based on baseline characteristics, so no additional statistical analysis was done when comparing the groups. The immediately and delayed eligible
cohorts groups had some statistically different baseline characteristic, but these were not considered in the analysis of the outcomes.

Outcome
Outcome assessment ☆ b) structured interview Adolescents underwent a standardized clinical assessment and completed a DISC interview and psychological assessment.

Duration of follow-up N/A

Attrition N/A

Zucker (2010)65 Selection

587

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Table I.I.2. Risk of bias in extracted cross-sectional studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Representativeness of ☆ a) truly representative of the average Youth evaluated were consecutively referred from 2000-2009. Those that did not meet the specific criteria of GID were not included
the exposed cohort
TGNB youth with GID referred to the GIS in
Toronto, Canada from 2000-2009

Selection of the ☆ a) drawn from the same community as the The entire group was compared to each other based on demographic, behavioral and psychosocial variables
nonexposed cohort exposed cohort

Ascertainment of ☆ a) secure record (eg, medical or surgical All data was from medical records
exposure records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor 16 different factors were looked at as variables as predictors of the outcome
(exposure/comparator)
cohorts ☆

Outcome
Outcome assessment ☆ b) record linkage Outcome was assessed from medical records

Duration of follow-up N/A

Attrition N/A

588

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Table I.I.3. Risk of bias in extracted case-control studies comparing TGNB patients to TGNB patients, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Maru (2021)128 Selection
Adequacy of the case ☆ Yes, eg, Record linkage or based on self- Diagnostic codes for Type II DM were used
definition reports

Classification ☆ Consecutively or obviously representative It appears that all eligible cases (ie, those with the diagnosis) were included
series of cases

Selection of controls ☆ Community controls Controls were the “overall clinic population” (ie, case-cohort sampling)

Definition of controls No description of source With case-cohort sampling, it's likely that the comparison group included subjects who may have had type II DM, which would be an appropriate comparison, but it's
unclear.

Comparability
Comparability of No controls They did not control for age or sex
(exposure/comparator)
cohorts

Exposure

Assessment of exposure No descriptions They did not specify how they assessed exposures (eg, GD diagnosis, GD treatment)

Same method of Unclear They don't specify how exposures were assessed for cases or controls; it's unclear if they used the same for both groups.
ascertainment for cases
and controls

Non-response rate ☆ a) same rate for both groups They used chart review, so there is no difference in rates. All eligible cases and controls were included.

589

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Table I.I.4. Risk of bias in extracted cohort studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Beking (2020)129 Selection
Representativeness of the ☆ b) somewhat representative of the average Trans boys were recruited from the Venter of Expertise on Gender Dysphoria at the VU medical center. No inclusion criteria stated, or how the boys were sampled.
exposed cohort adolescent with or without gender dysphoria
in Amsterdam, the Netherlands.

Selection of the ☆ a) drawn from the same community as the They were recruited from secondary schools and/or were friends of the recruited transgender boys.
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical They were being treated there.
records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Testosterone was started after session 1.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor They were controlled for age.
(exposure/comparator)
cohorts

Outcome
Outcome assessment ☆ b) record linkage It was not clearly stated whether it was blinded, but they used brain scans for two of the reported groups of outcomes. The other one which is a bit of a baseline
characteristic and is self-report is handedness.

Duration of follow-up ☆ a) yes, follow-up was long enough for Mean duration of testosterone therapy before the measurements taken at session 2 was 9.8 months.
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to All the transgender boys were accounted for, but 3 cisgender boys and 1 cisgender girl dropped out.
introduce bias (ie, < 5% lost to follow-up), or
a description of those lost was provided.

Burke (2016)130 Selection

Representativeness of the ☆ b) somewhat representative of the average A small cohort was recruited from the Center of Expertise on Gender Dysphoria
exposed cohort youth within the VU medical center

Selection of the ☆ a) drawn from the same community as the Drawn from schools in the same geographical area, also invited friends and relatives of the appropriate age to participate in the control group.
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical Since patients were recruited within the center, assumption is that health records were used to ascertain exposure.
records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Patients started on GnRH analogs and then continued onto testosterone and test was repeated
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ b) study controls for any additional factor Study controls for sex, and age and pubertal status. Data was corrected for IQ, as that was significantly different between groups.
(exposure/comparator)
cohorts ☆

590

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Table I.I.4. Risk of bias in extracted cohort studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome
Outcome assessment ☆ b) record linkage fMRI data was used as well as performance data.

Duration of follow-up ☆ a) yes, follow-up was long enough for Patients were on treatment for an average of 10 (range 6-15) months
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to Some controls did not continue to session, but there was a description of those lost
introduce bias (ie, < 5% lost to follow-up), or
a description of those lost was provided.

Costa (2015)77 Selection

Representativeness of the ☆ b) somewhat representative of the average Patients who were referred between 2010 and 2014 to GIDS were recruited. Out of 436 referrals, 201completed the GD assessment and psychological interventions
exposed cohort TGNB adolescent at the GIDS in London and all who did took part in follow-up evaluations.

Selection of the b) drawn from a different source They were a naturalistic cohort drawn from the child and adolescent mental health services (CAMHS).
nonexposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical They were being treated at GIDS so their records were available. They were referred before treatment was initiated.
records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Puberty suppression was started 6 months after the baseline.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of c) neither (a) nor (b) Data was not controlled for anything in this comparison
(exposure/comparator)
cohorts

Outcome
Outcome assessment c) self-report Participants completed the CGAS to ascertain data

Duration of follow-up ☆ a) yes, follow-up was long enough for Follow-up was 18 months.
outcome to occur

Attrition c) Follow-up rate ≥ 5% and no description of At the end of 18 months, only about a quarter of the original cohort remain.
those lost

López de Lara Selection

(2020)62
Representativeness of the ☆ b) somewhat representative of the average Sample were volunteers from the clinic that were getting ready to start CSHT. Convenience sample as all were recruited from one clinic and were not randomly
exposed cohort TGNB youth getting ready to take CSHT in the selected.
pediatric endocrinology clinic in the San
Carlos Hospital in Spain.

Selection of the ☆ a) drawn from the same community as the Sample were volunteers from the same clinic as exposed cohort
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical Hormone therapy was prescribed by the clinic
records)

591

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Table I.I.4. Risk of bias in extracted cohort studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Outcome temporality ☆ a) yes, study was designed to ensure that the All patients were recruited before the initiation of CSHT and therefore started treatment before outcomes were measured.
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important They matched for age, ethnicity and socioeconomic status. There were no psychiatric comorbidities at baseline.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment c) self report All measures used were self-reported tools (UGDS, SDQ, STAI, BDI-II)

Duration of follow-up ☆ a) yes, follow-up was long enough for Patients were followed up for 12 months after initiation of therapy
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to All patients were accounted for in follow-up
introduce bias (ie, <5% lost to follow-up), or a
description of those lost was provided.

Millington Selection
(2022)90
Representativeness of the ☆ a) truly representative of the average Eligible patients from gender clinics that consented to the study were included
exposed cohort
transgender youth attending gender clinics in
the USA

Selection of the b) drawn from a different source Drawn as references from a National study (NHANES)
nonexposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical Taken from medical record
records)

Outcome temporality ☆ a) yes, study was designed to ensure that the TGNB participants were sampled before and after GAH therapy
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Study adjusted for age, and adjusted/compared the measurements from trans youth to both male and female peers
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage Laboratory measurement taken from medical record

Duration of follow-up ☆ a) yes, follow-up was long enough for Compared after 12 months of GAH therapy
outcome to occur

Attrition d) No information about attrition Unclear because no given information about the NHANES study

Nokoff (2020)131 Selection

592

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Table I.I.4. Risk of bias in extracted cohort studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Representativeness of the ☆ b) somewhat representative of the average They excluded patients with significant medical or psychiatric comorbidities and the examples they gave were diabetes or antipsychotic treatment,
exposed cohort pediatric transgender patient in TRUE center
for diversity at the Children’s hospital in
Colorado

Selection of the b) drawn from a different source Controls were selected from two studies at the same institution: RESISTANT and HIP.
nonexposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical They secured information about the controls from the studies, and patients at their clinic from their medical record.
records)

Outcome temporality ☆ a) yes, study was designed to ensure that the Patients with exposure had to be on therapy for at least 3 months
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important Controls were match on age and BMI. They also stratified results based on spironolactone exposure.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage investigators were not blinded. Lab values were drawn and taken from medical records.

Duration of follow-up ☆ a) yes Average treatment duration for TM was 11 months and 12 months for TF

Attrition d) no information about attrition

Schulmeister Selection
(2022)95
Representativeness of the ☆ b) somewhat representative of the average relative lack of diversity of participants since primarily non-Hispanic white and recruited at urban academic institutions
exposed cohort Participants in treatment group from four
gender specialty clinics in the United States.

Selection of the b) drawn from a different source Participants in control group were drawn from the Bone Mineral Density in Childhood Study (BMDCS).
nonexposed cohort

Ascertainment of exposure d) no description No related description of how they obtained participants' medication history.

Outcome temporality ☆ a) yes, study was designed to ensure that the Not specified in the article
requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important The HV of BMDCS and TGD youth were compared controlling for mid-age, the midpoint between the ages of the two visits used to calculate the HV. Growth data
(exposure/comparator) confounder(s) from the Centers for Disease Control and Prevention were used to determine participant height z-scores based on sex designated at birth. Comparison was stratified
cohorts by Tanner stages.

Outcome
Outcome assessment ☆ b) record linkage Anthropometric and laboratory data collected in the course of clinical care were abstracted from the medical record.

593

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Table I.I.4. Risk of bias in extracted cohort studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Duration of follow-up ☆ a) yes, follow-up was long enough for Anthropometric and laboratory data were recorded prior to the participant beginning GnRH analogs (baseline) and at 6- and 12-month follow-up visits.
outcome to occur

Attrition ☆ b) subjects lost to follow-up are unlikely to Of 92 youth who were enrolled prior to GnRH analog initiation, 9 participants were excluded because they did not receive GnRH analog treatment for at least 10
introduce bias (ie, < 5% lost to follow-up), or months, 12 were excluded from analysis because they did not have a documented height after 10 to 14 months of GnRH analog treatment, and 16 participants were
a description of those lost was provided. excluded because they started GAH prior to 12 months of GnRH analog treatment. A total of 55 individuals were included in the analysis and it looks like all of them
had follow up data.

Valentine Selection
(2021)97
Representativeness of the ☆ b) somewhat representative of the average Retrospective study of transgender males taking testosterone from 2014-2018 at center who had been seen at least twice
exposed cohort transgender males from a large Midwestern
pediatric academic center with a
multidisciplinary program serving
transgender and gender-diverse youth.

Selection of the ☆ a) drawn from the same community as the Cisgender cohort was drawn from 13 primary care centers within the same hospital system
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical Does not state it in the article but looks like they collected testosterone records based on clinical records or notes
records)

Outcome temporality ☆ a) yes, study was designed to ensure that the

requirements timing of exposure measurement preceded
the timing of outcome measurements

Comparability
Comparability of ☆ a) study controls for the most important BMIs of the transgender male cohort, and a random number generator used these matched patients to create a 2:1 match of cisgender females to the transgender
(exposure/comparator) confounder(s) males.
cohorts

Outcome
Outcome assessment ☆ b) record linkage BMI data and lipid profile parameters were obtained from clinical records based on visits.

Duration of follow-up b) no, follow-up was not long enough for Both short- and long-term follow-ups were evaluated, with short-term follow-up assessing changes in BMI between each clinic visit, and long-term follow-up
outcome to occur
assessing changes in BMI between first and final follow-up clinic visits (on average longer than 10 months) - for adverse effects, it doesn’t meet the criteria of a one-
year follow-up to ascertain effect.

Attrition ☆ a) complete follow up - all subjects N = 42 were seen at least twice and, therefore, included in assessment of BMI changes. Only 28 of them had lipid panels drawn, and 18 had laboratories both pre-
accounted for and post-testosterone. For BMI measures, all of them had follow-up data.

594

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Table I.I.5. Risk of bias in extracted cross-sectional studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Alvares (2022)132 Selection
Representativeness of the d) no description of the derivation of the Authors did not describe how the sample of transgender subjects were recruited. It is unclear whether they were sampled at random from all eligible clinic patients,
exposed cohort cohort whether they were consecutive eligible patients, etc.

Selection of the c) no description of the derivation of the There was no description of how cisgender controls were recruited.
nonexposed cohort non-exposed cohort

Ascertainment of exposure ☆ b) structured interview Exposures were assessed by trained interviewers

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Authors matched transgender patients to cisgender controls on age and activity levels
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment d) no description No choices really apply. No outcomes assessment was blinded except for the cardiopulmonary exercise tests, which we did not extract.

Duration of follow-up N/A

Attrition N/A

Burke (2015)133 Selection

Representativeness of the ☆ b) somewhat representative of the average Authors had minimal description of how cohorts were recruited, however the GD cohort was recruited from the clinic and peers were recruited from a nearby
exposed cohort adolescent with or without gender dysphoria geographical area.
in Amsterdam, the Netherlands.

Selection of the ☆ a) drawn from the same community as the Drawn from schools in the same geographical area. They also invited friends and relatives of the appropriate age to participate in the control group.
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical Since patients were recruited within the center, assumption is that health records were used to ascertain exposure.
records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Study controlled for natal sex. Age was generally matched within about a year
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage MRI data was assessed

Duration of follow-up N/A

Attrition N/A

Selection

595

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Table I.I.5. Risk of bias in extracted cross-sectional studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Durwood Representativeness of the d) no description of the derivation of the Transgender participants were enrolled in the Trans Youth Project, a national, longitudinal study of socially transitioned transgender children. No information on
(2017)109 exposed cohort cohort how this cohort was selected.

Selection of the b) drawn from a different source The matched controls were recruited through a university database of families interested in participating in child development research.
nonexposed cohort

Ascertainment of exposure d) no description Unclear how they obtained medical records including whether they were on hormonal intervention.

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Controls were age- and gender-matched.
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment c) self-report Participants reported outcomes using PROMIS scale.

Duration of follow-up N/A

Attrition N/A

Nokoff (2021)134 Selection

Representativeness of the d) no description of the derivation of the All transgender females and five transgender males were recruited from the same cross-sectional study. An additional four transgender males were recruited from a
exposed cohort cohort separate longitudinal study. Unclear whether they were sampled at random from all eligible clinic patients

Selection of the b) drawn from a different source Data on healthy cisgender controls were obtained from two studies performed at the institution: the RESistance to InSulin in Type 1 ANd Type 2 diabetes
nonexposed cohort (RESISTANT) study and the Health Influences in Puberty (HIP) study.

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical Participants being on GnRH alone was one of eligibility criteria, but they did not state how they obtained GnRH administration records. Assumed since they were
records) within a health system, records could be used to ascertain exposure.

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Transgender participants were matched to cisgender controls on age (within a year or less), BMI (within category), and sex assigned at birth.
(exposure/comparator) confounder(s)
cohorts ☆

Outcome
Outcome assessment ☆ b) record linkage BMI data and other cardiovascular parameters were obtained at each visit.

Duration of follow-up N/A

Attrition N/A

Selection

596

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Table I.I.5. Risk of bias in extracted cross-sectional studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Staphorsius Representativeness of the ☆ b) somewhat representative of the average Adolescents were recruited from the clinic, but no data was given for how they were recruited. Their peers were recruited from the same community.
(2015)119 exposed cohort
Transgender youth associated with VU
medical center in Amsterdam

Selection of the ☆ a) drawn from the same community as the Selection was from friends and peers of participants, which could introduce selection bias, but is from the same community
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical

records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ a) study controls for the most important Study controlled for sex
(exposure/comparator) confounder(s)
cohorts

Outcome
Outcome assessment ☆ b) record linkage fMRI data was used to assess data

Duration of follow-up N/A

Attrition N/A

Valentine Selection
(2022)98
Representativeness of the ☆ a) truly representative of the average All EHRs in the time period were reviewed for data on TGNB youth with GD diagnosis and then matched with a large cohort of peers
exposed cohort
Youth within the PedsNET health community

Selection of the ☆ a) drawn from the same community as the EHRs were reviewed from the same network and time period.
nonexposed cohort exposed cohort

Ascertainment of exposure ☆ a) secure record (eg, medical or surgical EHRs were reviewed for diagnosis
records)

Outcome temporality N/A

requirements

Comparability
Comparability of ☆ b) study controls for any additional factor Propensity scores were used to match control to cases (approximately 4:1.) A priori covariates used for matching include: year of birth, age at last visit, sex listed in
(exposure/comparator) chart, race, ethnicity, insurance status, duration in database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD
cohorts ☆ using a greedy match algorithm. Additional adjustments were done for data to control for overweight/obesity, depression, and antipsychotic prescription.

Outcome
Outcome assessment ☆ b) record linkage EHRs were reviewed for data

Duration of follow-up N/A

Attrition N/A

597

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Table I.I.5. Risk of bias in extracted cross-sectional studies comparing TGNB patients to their cisgender peers, using the Newcastle-Ottawa Quality Assessment Scale (NOS)
Van der Miesen Selection
(2020)124
Representativeness of the ☆ b) somewhat representative of the average transgender samples consisted of consecutive referrals to the Center of Expertise on Gender Dysphoria of the VU University Medical Center (VUmc) in Amsterdam,
exposed cohort the Netherlands, between 2012 and 2015.
transgender youth from the Center of
Expertise on Gender Dysphoria of the VU
University Medical Center (VUmc) in
Amsterdam, the Netherlands, between 2012
and 2015.

Selection of the b) drawn from a different source Cisgender adolescents from the general population were recruited by means of the help of different secondary schools in different provinces in the Netherlands.
nonexposed cohort

Ascertainment of exposure d) no description No related description of how they obtained participants' medication history.

Outcome temporality N/A

requirements

Comparability
Comparability of c) neither (a) nor (b) Although a multivariate GLM analysis with assigned gender at birth and a gender by group interaction as additional predictors was used to identify possible gender
(exposure/comparator) differences within each group, it is not used in TGNB vs. cisgender comparison.
cohorts

Outcome
Outcome assessment c) self-report The Dutch version of the YSR was used to assess internalizing and externalizing problem behavior, self-harm/suicidality, and peer relations.

Duration of follow-up N/A

Attrition N/A

598

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
Achille (2020)55 Question Answer Details and notes
1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described eligibility, including who was invited to participate, and how many ultimately completed 3 questionnaires.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unclear. Fewer than half of participants who completed at least 1 survey persisted until the 3rd survey was complete. There is likely
test/service/intervention in the general or clinical population of interest? selection bias, and it is unclear how those who persisted for 3 months may differ from the rest of the population.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All eligible participants who were invited and who completed 3 questionnaires were included.

5. Was the sample size sufficiently large to provide confidence in the findings? Other Unclear: They did not talk about a power calculation, which is common for these types of studies. It's likely that 50 patients is a
sufficient sample to see some changes in mental health outcomes after 12 months if the treatments are effective.

6. Was the test/service/intervention clearly described and delivered consistently across the No Some patients received puberty suppression with an unspecified agent, some patients received CSHT, some patients received both,
study population? and some patients received none. Treatment durations were also unclear.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated instruments to measure mental health outcomes and quality of life.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Participants answered validated surveys, but they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Loss to follow-up was more than 50%.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes The answer is given for CESD-R, PHQ-9, and QOL instrument. The answer would be "no" for suicide ideation outcomes.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Unclear Unclear. There were 3 measurement points: baseline, 6 months, and 12 months. The 6-month findings were published, but not
multiple times after the intervention (ie, did they use an interrupted time-series design)? considered in hypothesis tests. Patterns over time were consistent with a real treatment effect, but there were only 3 measures,
which is inadequate for a true ITS design.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Allen (2019)56 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Eligibility criteria were clearly described.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unclear; don’t know how many subjects were excluded.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes They state that a total of 47 participants were eligible and were included in analysis.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear if it is sufficiently large since they did not mention power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the No No specific descriptions about CSHT and GnRH analogs they were receiving.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated questionnaires to assess the outcomes. The outcome measures were clearly defined and assessed consistently
consistently across all study participants? across all study participants.

599

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
8. Were the people assessing the outcomes blinded to the participants' No Participants answered validated surveys, but they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Looks like all included participants had follow-up data.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Two mixed repeated-measures ANCOVAs were used to ascertain within-subject differences between pretest (T0) and final
intervention? Were statistical tests done that provided p values for the pre-to-post changes? assessment (T1) suicidality and general well being scores.

11. Were outcome measures of interest taken multiple times before the intervention and No They mention that participants were assessed at least 2 times; however, for analysis they only considered two time points (baseline -
multiple times after the intervention (ie, did they use an interrupted time-series design)? before start of GAH; follow up - at least 3 months after treatment)

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Arnoldussen Question Answer Details and notes

(2022)135 1. Was the study question or objective clearly stated? Yes Self-perception changes over the course of irreversible medical gender-affirming treatments in TGNB adolescents was measured

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes

3. Were the participants in the study representative of those who would be eligible for the No Unclear-adolescents were only included if pretreatment data on self-perception was available, Out of 513 referred adolescents, 179
test/service/intervention in the general or clinical population of interest? were eligible, and only 70 had pretreatment data on self-perception.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All eligible candidates that also had the pretreatment data on self-perception were enrolled

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. Did not report a power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the No Some patients had received puberty suppression at pretreatment assessment, and some had not. Patients may have received a
study population? variety of GAH treatments and surgeries.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes all patients were evaluated on the same screening questionnaire-the SPSS
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All participants had received PS, CSH and gender affirming surgery
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Since data was retrospectively obtained, all patients had all data points
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P values and confidence intervals were calculated, and multilevel modeling was conducted to determine the effect of time. Possible
intervention? Were statistical tests done that provided p values for the pre-to-post changes? confounders were also added to the model.

11. Were outcome measures of interest taken multiple times before the intervention and No ITS design was not used
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

600

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
Alvares Question Answer Details and notes
(2022)132 1. Was the study question or objective clearly stated? Yes Investigators measured mean TT levels of TGNB women 12 months before the study vs. the moment of the study, in order to better
demonstrate the extent of suppression on TT values over time.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes All inclusion/exclusion criteria are clearly listed

3. Were the participants in the study representative of those who would be eligible for the Yes All participants were adult women seeking gender-affirming care at the Gender Dysphoria Unit. The study's results will not be
test/service/intervention in the general or clinical population of interest? applicable to those under the age of 25.

4. Were all eligible participants that met the prespecified entry criteria enrolled? No The investigators do not include how many women were screened against the inclusion/exclusion criteria and excluded based on it.

5. Was the sample size sufficiently large to provide confidence in the findings? No Only 15 TGNB women were included, and the authors do not discuss the power of the study.

6. Was the test/service/intervention clearly described and delivered consistently across the No All participants were using estrogen at the time of the study, but could have been using other CSHT (like cyproterone acetate) as well.
study population? Participants were also using different doses of estrogen.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Unclear Blood tests were taken on the day of the study, but it's unclear when/how consistently blood tests were taken 12 months before the
consistently across all study participants? study.

8. Were the people assessing the outcomes blinded to the participants' No Evaluators were not blinded.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes No participants were lost to follow-up; no description is given.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Unclear It's unclear what statistical analysis the authors used for this comparison.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No A single blood test was conducted at T1; it's unclear how many blood tests were taken at T0.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Becker-Hebly Question Answer Details and notes

(2021)72 1. Was the study question or objective clearly stated? Yes Can extract population, intervention, comparison and outcome from the abstract.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Criteria listed on P5.

3. Were the participants in the study representative of those who would be eligible for the Other Only 75 out of 204 participants agreed to participate, meaning that this was a response rate of 37%. There is likely selection bias.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All eligible participants were invited.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. No power calculation was discussed.

6. Was the test/service/intervention clearly described and delivered consistently across the No It is unclear if the GnRH analog and the CSHT regimen was consistent across the population.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated instruments to measure mental health outcomes and quality of life.
consistently across all study participants?

601

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
8. Were the people assessing the outcomes blinded to the participants' No Participants answered validated surveys, but they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Unclear Unclear- they only mentioned people who had follow-up results; it was not clear what the full amount at baseline was.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes They provided P-Values.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No There were only two measurement points.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Beking (2020)129 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes They are looking at the effects of testosterone on amygdala lateralization.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Unclear They specifically list the exclusion criteria but do not really have specific inclusion criteria.

3. Were the participants in the study representative of those who would be eligible for the Unclear They are part of that group, but this looks like a convenience sample.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? No This was a convenience sample.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Power was not defined.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The protocol was provided in the study
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes The protocol was provided in the study
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Not specified
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Follow-up was 100%
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Measurements only taken twice
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

602

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
Boogers Question Answer Details and notes
(2022)66 1. Was the study question or objective clearly stated? Yes Reported data are a bit convoluted, but they still state their aim: "This work aims to investigate the effects of GnRHa [analogs] and
GAHT [CSHT] on growth, and the efficacy of growth-reductive treatment."

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Noted in the "Participants" section

3. Were the participants in the study representative of those who would be eligible for the Unclear Significant proportion were not included in the final analysis.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All eligible participants were thought to be included.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. No power calculation was discussed.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Treatment protocol and timing was clearly defined under "Measurements" and "Laboratory Investigations.”
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Treatment protocol and timing was clearly defined under "Measurements" and "Laboratory Investigations"
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No No blinding was noted
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Not clear how follow-up changed over time but a significant proportion were not included in the final analysis.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Some provided P-values, some did not provide P-values.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No There were multiple measurement points provided in the figures, but outcomes were not taken multiple times before the
multiple times after the intervention (ie, did they use an interrupted time-series design)? intervention

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Cantu (2020)74 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and recruitment process.

3. Were the participants in the study representative of those who would be eligible for the Yes They state that all youth ages 11 and older complete anxiety and depression screeners at every visit regardless of mental health
test/service/intervention in the general or clinical population of interest? diagnoses or symptom severity.

4. Were all eligible participants that met the prespecified entry criteria enrolled? No Participants were 80 youths and all of them completed PHQ-9 screeners at both time points; however, only 78 youths completed
GAD-7 screeners at both time points. They did not mention why 2 out of 80 participants did not complete GAD-7.

5. Was the sample size sufficiently large to provide confidence in the findings? No In the limitation part, they stated that power analyses revealed that the current sample would have been well powered to detect
large effects, but not small-to moderate effects, which are more likely when looking at shorter time frames.

6. Was the test/service/intervention clearly described and delivered consistently across the No Unclear about the exact time of HT initiation given the variability in how and where individuals received their treatments.
study population? Participants who started on hormone blockers only were not included in this analysis. No analyses were conducted to examine
differences between which hormone was started or for those that also initiated puberty blockers.

603

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Validated screening measures of mental health were used to assess outcomes.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Validated surveys were answered by participants and they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes One of the eligibility criteria was that participants had attended both initial visits and first follow-up appointment.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes For both PHQ-9 and GAD-7, paired sample t-tests were used to examine overall changes from initial visit to follow-up, and
intervention? Were statistical tests done that provided p values for the pre-to-post changes? independent sample t-tests were used to examine simple differences across groups. ANOVA was used to examine the role of
potential moderators (ie, initiation of HT and distance from clinic) in the changes in distress over time. P values were used for pre-to-
post changes.

11. Were outcome measures of interest taken multiple times before the intervention and No Except for baseline visit, only first follow-up appointment was analyzed.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Carmichael Question Answer Details and notes

(2021)73 1. Was the study question or objective clearly stated? Yes They very clearly stated all of their objectives and procedures for obtaining them.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly stated how they recruited their participants, the specific eligibility criteria and who was selected.

3. Were the participants in the study representative of those who would be eligible for the Yes Participants were selected from a group of TNGB youth who attended GIDS an wanted to commence hormone therapy who met
test/service/intervention in the general or clinical population of interest? specific criteria. Unclear if the group that would attend this clinic is representative of the TGNB population as a whole

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Everyone who wished to participate that met the eligibility requirements was enrolled in the study. There were some who did not
meet the criteria initially but were enrolled several months later when they did meet it.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. Did not report a power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes All patients were given GnRH analog triptorelin for pubertal suppression together with psychosocial support and therapy, from study
study population? entry until the end of the GnRH analog monotherapy pathway at age 16 or older. 3.75mg by IM injection given every 28 days during
treatment period. 2 Participants given 11.25 mg every 10 weeks.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Each outcome had clearly defined procedures and measurements.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients received the same treatments.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Unclear Patients aged out of the study at the age of 16, but when comparing data at longer interval points, the baseline mean of the
for in the analysis? participants that were followed up was calculated. There were several instances where 1,2 or 3 participants did not participate in a
data point, but it was accounted for and not a large loss for follow up.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Most measurements were taken at baseline, 12,24 and 36 mo. Each measurement was compared to baseline, but measurements
multiple times after the intervention (ie, did they use an interrupted time-series design)? could also be compared to each other to detect more or less change. Multiple measurements not taken before intervention.

604

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Chen (2023)75 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Outcomes clearly stated for this study

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes

3. Were the participants in the study representative of those who would be eligible for the Yes The study sample was representative of transgender and nonbinary youth presenting to pediatric subspecialty gender programs and
test/service/intervention in the general or clinical population of interest? generalizable to this population.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Does not clearly state in this study, but it seems like they were

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear-no power calculation stated

6. Was the test/service/intervention clearly described and delivered consistently across the Unclear All patients received GAH, but no data was available of which therapies each patient got.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients were receiving GAH
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes At least four out of five total time points were available for 75% of participants. As a result, there was high covariance coverage with
for in the analysis? data available for the majority of the sample for each variable of interest at all time points. Within sample, data exhibited skew and
were determined to be missing at random(Little’s MCAR test: χ2 [751] = 803.25, p = 0.09). This type of missing data can be
appropriately handled using maximum likelihood estimation method. Of those missing too much data, they were excluded from
analytical sample (n = 14)

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Latent growth curve model was used
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Data taken at 6,12,18 and 24 months and then put into a latent growth curve model. Multiple measurements not taken before
multiple times after the intervention (ie, did they use an interrupted time-series design)? intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Costa (2015)77 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Can extract population, intervention, comparison and outcome from the abstract.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Clearly stated

3. Were the participants in the study representative of those who would be eligible for the Yes All participants agreed to participate;.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All participants agreed to participate; from T0 to T1, there was no loss of patients. Patients started to fall off after then.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear There were no power calculations.

605

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
6. Was the test/service/intervention clearly described and delivered consistently across the Unclear No, this was unclear because the GnRH analog regimen was not specified.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated instruments to measure mental health outcomes and quality of life.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Participants answered validated surveys, but they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Patients were lost to follow-up after T1; initial was 201 and final was 71.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-Values were provided.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No There were four time periods from baseline and P-Values were provided for each one. Multiple measurements not taken before
multiple times after the intervention (ie, did they use an interrupted time-series design)? intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

De Vries Question Answer Details and notes

(2010)78 1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No Not clearly stated inclusion eligibility.

3. Were the participants in the study representative of those who would be eligible for the No 140 of 196 consecutively referred adolescents were considered eligible for medical intervention between 2000 and 2008 in the clinic.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? No A total of 140 adolescents were eligible and 27 were included in analysis.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear if it is sufficiently large since they did not mention power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated questionnaires to assess the outcomes. The outcome measures were clearly defined and assessed consistently
consistently across all study participants? across all study participants.

8. Were the people assessing the outcomes blinded to the participants' No Not clearly stated but it looks like it is not a double-blinded study
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Not all of the participants had post-treatment data for analysis, so only data of adolescents who were administered questionnaires
for in the analysis? on both assessments could be used for Pre-treatment-Post-treatment comparisons (CBCL: 24, IQ: 25, UGS: 21 and BIS: 22).

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Repeated measures ANOVA was used to ascertain within subject differences between gender dysphoria and body satisfaction at
intervention? Were statistical tests done that provided p values for the pre-to-post changes? baseline functioning (Pre-T, before the start of GnRH analogs) and after GRS (Post-T) with gender entered as a between-subject
variable. Pearson correlations were used to determine relationships between Pre-T and Post-T measures. P value is provided for
comparisons.

11. Were outcome measures of interest taken multiple times before the intervention and No Except for the baseline visit, only one follow-up assessment was analyzed.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

606

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

De Vries Question Answer Details and notes

(2014)79 1. Was the study question or objective clearly stated? Yes Can extract population, intervention, comparison and outcome from the abstract.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Located on P2- other study provides additional detail on those who were eligible

3. Were the participants in the study representative of those who would be eligible for the Unclear First 70 were included, not the whole sample. Potential selection bias.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? No Limited to the first 70

5. Was the sample size sufficiently large to provide confidence in the findings? Other There were no power calculations.

6. Was the test/service/intervention clearly described and delivered consistently across the Unclear Some were on CSH; the treatment regimen was not clearly provided.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated instruments to measure mental health outcomes and quality of life.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Participants answered validated surveys, but they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Noted when you look at the n provided by the individual results provided in the results tables.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-Values were provided.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No There were three time periods and a time linear quadratic P-value test was also provided. Multiple measurements not taken before
multiple times after the intervention (ie, did they use an interrupted time-series design)? intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

De Vries Question Answer Details and notes

(2011)57 1. Was the study question or objective clearly stated? Yes Can extract population, intervention, comparison and outcome from the abstract.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Protocol referenced provides additional detail on those who were eligible

3. Were the participants in the study representative of those who would be eligible for the Unclear First 70 were included, not the whole sample. Potential selection bias
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? No Limited to the first 70

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear There were no power calculations.

6. Was the test/service/intervention clearly described and delivered consistently across the Unclear Some were on CSH; the treatment regimen was not clearly provided.
study population?

607

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated instruments to measure mental health outcomes and quality of life.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Participants answered validated surveys, but they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Noted when you look at the n provided by the individual results provided in the results tables.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-Values were provided for the main analysis; the other ones had to be inferred.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No There were only two measurement points.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Ghelani (2020)58 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No They did not describe inclusion eligibility and sampling procedures clearly.

3. Were the participants in the study representative of those who would be eligible for the Yes It looks like they only excluded 4 subjects since they had an incomplete set of body composition data or if any other confounding
test/service/intervention in the general or clinical population of interest? factor was identified from routine clinic questioning about lifestyle that could affect the results.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Although it is not clearly stated, it looks like all of 36 participants had follow up data.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear They did not mention power calculation in the article. However, in limitation part they state one of limitations is small sample size,
especially for the trans girls (N = 11).

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They clearly state the intervention and duration of treatment.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes The outcomes were prespecified and data was recorded from routine clinic monitoring of patients. Validated tools were used for
consistently across all study participants? body composition analysis.

8. Were the people assessing the outcomes blinded to the participants' Yes They state that data was taken from this routine clinic monitoring of patients and subsequently anonymized.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes The participants included in the analysis were those who had completed follow-up data.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Changes in anthropometric and body composition variables between 0 and 12 months were tested using paired t-tests. Statistical
intervention? Were statistical tests done that provided p values for the pre-to-post changes? significance was considered to be p-value < 0.05.

11. Were outcome measures of interest taken multiple times before the intervention and No Outcomes were measured at baseline, 6 months and 12 months of GnRH treatment in TGNB subjects. Multiple measurements not
multiple times after the intervention (ie, did they use an interrupted time-series design)? taken before intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

608

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
Hannema Question Answer Details and notes
(2017)59 1. Was the study question or objective clearly stated? Yes Yes, they wanted to investigate the body changes in 28 trans girls taking long term estrogen.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes The authors stated they invited gender dysphoric adolescents at the VU University Medical Centra in Amsterdam from 1988-2009.
They included those that had been taking estrogen for over one year.

3. Were the participants in the study representative of those who would be eligible for the Unclear The exact population that was invited to participate and were seen at the clinic is unknown. It is unclear whether this population
test/service/intervention in the general or clinical population of interest? represents the clinic.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unclear because they did not mention the numbers for the total population or whether participants were excluded.

5. Was the sample size sufficiently large to provide confidence in the findings? No They had 28 participants for the first year, with participants decreasing every year. With a small sample size, it is hard to be confident
in the findings.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They took many measures from the population, but they were all described in the methods and appeared to be delivered
study population? consistently.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Laboratory values were measured in the same way. They used the same methods and devices to collect other measurements.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No The investigators were not blinded.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No At baseline there were 28 participants. At the first year, all patients are accounted for. The first year is the data they mainly analyzed.
for in the analysis? They did follow participants for up to three years. By the third year, they only had data for 16 participants. It was not mentioned why
there was a change.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes They compared values using a paired t test if normally distributed and Wilcoxon if not normally distributed. They stated that they
intervention? Were statistical tests done that provided p values for the pre-to-post changes? used these tests on the laboratory values, but p values were not given for lab values. P values that were significant were given for all
other measurements

11. Were outcome measures of interest taken multiple times before the intervention and No Baseline was established then they took annual measurements of the patients.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A No, they did not account for confounding factors.
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Jarin (2017)136 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Eligibility criteria was clearly described.

3. Were the participants in the study representative of those who would be eligible for the Yes All records of patients in that met criteria were reviewed.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All records that met criteria were reviewed

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear if it is sufficiently large since they did not mention power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population.
study population?

609

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Previously recorded measurements were retrospectively reviewed.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear if investigators were blinded to participants' intervention.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes For most of cardiovascular parameters, loss to follow-up after baseline was more than 20%.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Repeated measures analysis of variance models were used to evaluate changes in laboratory values and metabolic markers over time
intervention? Were statistical tests done that provided p values for the pre-to-post changes? for each individual subject. Although P values of pre-to-post changes for each cardiovascular parameter were not reported,
statistically significant change (P < .05) was noted.

11. Were outcome measures of interest taken multiple times before the intervention and No Values were obtained at or immediately before initiation of therapy (baseline), at 1 to 3 months after initiation, at 4 to 6 months
multiple times after the intervention (ie, did they use an interrupted time-series design)? after initiation, and at 6 months and beyond. Multiple measurements not taken before intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Joseph (2019)137 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No Not clearly stated inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the Unclear Not clearly stated. 70 patients were referred to clinic, but unclear if that is all referrals to clinic or just the group that was analyzed.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All eligible subjects with adequate data were included in this analysis

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear if it is sufficiently large since they did not mention power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes At the start and then annually during treatment during scheduled clinic visits, the subjects underwent a dual energy X-ray
consistently across all study participants? absorptiometry (DXA) scan. BMD and BMAD were valid and reliable measures of bone health outcomes.

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear if investigators were blinded to participants' intervention.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No A total of 70 participants had two scans but a total of 31 subjects had three scans. The loss to follow-up rate for scan 3 was more than
for in the analysis? 20%.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Two analyses were conducted – one assessing pure longitudinal changes in BMD and BMAD (n = 31) in those having three serial DXA
intervention? Were statistical tests done that provided p values for the pre-to-post changes? scans, and one to extend the observations in the first year on GnRH analog treatment in an additional 39 subjects (total n = 70). As
the data followed a normal distribution, paired t tests were used. A p-value less than 0.05 was considered statistically significant.

11. Were outcome measures of interest taken multiple times before the intervention and No Some participants had three scans - baseline and 2 subsequent years on GnRH analog treatment. Multiple measures of outcome not
multiple times after the intervention (ie, did they use an interrupted time-series design)? taken before intervention.

610

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Kaltiala Question Answer Details and notes

(2020)138 1. Was the study question or objective clearly stated? Yes Very clearly stated the aim of the study

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Clearly stated the criteria for which participant's chart they wanted to review.

3. Were the participants in the study representative of those who would be eligible for the Yes Yes-all patient charts that met the criteria within the gender identity service facility were reviewed.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear-no power calculation stated

6. Was the test/service/intervention clearly described and delivered consistently across the No All patients were given cross-sex hormones-but the specific drugs and amounts were not stated.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes For each data point, specific measures were listed to specify definitions and reasons for inclusion or exclusion
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients were receiving some sort of treatment
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes This study was done retrospectively, so all patients had competed all of the requirements before chart review.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Comparisons were only done from initial assessment to approximately 12 months later.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Klaver (2018)83 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Specific aim of retrospective study

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Flowchart of participant inclusion process is given

3. Were the participants in the study representative of those who would be eligible for the Yes All charts that met criteria in institution were used
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear-no power calculation stated

6. Was the test/service/intervention clearly described and delivered consistently across the Yes
study population?

611

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No No, all patients were treated with the same protocol
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Percentages of missing data for anthropometrics were 11% in transwomen and 18% in transmen for start of GnRH analogs, 10% in
for in the analysis? transwomen and 13% in transmen for start of CHT, and 71% in transwomen and 76% for visit at 22 years of age. For measurements of
body composition examined by whole-body dual-energy x-ray absorptiometry, percentages of missing data were 12% in transwomen
and 11% in transmen for start of GnRH analogs, 36% in transwomen and 45% in transmen for start of CHT, and 64% in transwomen
and 65% in transmen at 22 years of age.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Yes
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Klaver (2020)139 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Very clearly stated population, intervention, comparison and objective

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unclear - don't know how many subjects were not eligible
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unclear - don't know whether all eligible participants were enrolled

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear - power calculation was not mentioned in the article

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Intervention-related information was clearly stated in the treatment protocol part.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated clinical measures and laboratory data collected at each visit.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients were taking the same therapy.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Looks like all included participants had follow-up data.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes They performed linear mixed-model regression analyses with time as an independent variable to estimate the change in
intervention? Were statistical tests done that provided p values for the pre-to-post changes? cardiovascular risk factors over time. P values were used for changes.

11. Were outcome measures of interest taken multiple times before the intervention and No Data was obtained at 3 time points - start of GnRH analog treatment, start of CSH treatment, and 22 years. Multiple measurements
multiple times after the intervention (ie, did they use an interrupted time-series design)? not taken before intervention.

612

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Klink (2015)140 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Very clearly stated population, intervention, comparison and objective

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Study subjects were included when they were at least 21 years of age, gonadectomy had taken place in the period from June 1998 to
August 2012, and data on BMD at start of GnRH analog treatment, at start of CSH therapy, and at the age of 22 years were available.
The34 eligible subjects and their parents or legal representatives gave written consent for follow-up at start of treatment.

3. Were the participants in the study representative of those who would be eligible for the Yes This study was somewhat representative of the group. Some selection bias was likely introduced with a specific set of inclusion
test/service/intervention in the general or clinical population of interest? criteria and the need for specific metrics to have been included in past medical charts.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes It looks as if all patients who met criteria were included

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear-no power calculation stated

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Patients all followed the same protocol
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Information was given about how all data was collected.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients had been on the same treatment protocol
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Only 34 subjects were analyzed. No data provided about who was lost in follow-up.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Normally distributed data were compared with the paired sample T test with post-hoc Bonferroni correction. With data that were
intervention? Were statistical tests done that provided p values for the pre-to-post changes? not normally distributed Wilcoxon Signed Rank test was used for comparison. For correlation analyses, the Pearson’s correlation
coefficient was calculated for normally distributed data. When data were not normally distributed the Spearman’s rank correlation
coefficient was calculated. P < .05 was considered statistically significant.

11. Were outcome measures of interest taken multiple times before the intervention and No While data was collected at 3 time points, there was no data collected at multiple time points before intervention
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Kuper (2020)141 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the No Approximately 34% of families did not follow-up after the phone intake (eligible subjects must complete phone intake before the
test/service/intervention in the general or clinical population of interest? initial assessment).

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes A total of 209 eligible participants were screened and included, but there was a large loss in follow-up

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. Power calculation was not mentioned in the article.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They clearly described how many patients were on puberty suppression only, masculinizing or femininizing therapy only, or both.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Validated tools of measuring mental health and body imaging were used to assess outcomes. Survey and clinician data was used.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Validated questionnaires were answered by participants, and they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Loss to follow-up was more than 20% since 148 out of 209 eligible participants had follow-up data. They stated reasons for loss to
for in the analysis? follow-up.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes To examine change over time, QIDS, SCARED, and BIS scores were first tested for normality by using the Kolmogorov-Smirnov test.
intervention? Were statistical tests done that provided p values for the pre-to-post changes? Changes in normally distributed variables were examined by using paired t tests, and the Wilcoxon rank test was used when the
Kolmogorov-Smirnov value was significant. Cohen’s d was used as a measure of effect size (0.2 = small, 0.5 = moderate, and
0.8 = large). Changes in clinical groupings on the QIDS were also examined by using the Wilcoxon rank test. P values were provided
for associated tests.

11. Were outcome measures of interest taken multiple times before the intervention and No Except for the baseline visit, only one follow-up assessment was analyzed.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Lavender Question Answer Details and notes

(2023)142 1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the No The study has low questionnaire completion rates which could negatively affect sample representative of clinic population. Also,
test/service/intervention in the general or clinical population of interest? authors mentioned that small sample size could affect the study generalizability

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Everyone met prespecified criteria were included. Only those that completed both surveys had their data included

5. Was the sample size sufficiently large to provide confidence in the findings? Yes In methods section, authors state that a power calculation indicated that, for a medium effect size (0.25) at 80% power, a total
sample of 28 young people would be required for an ANOVA repeated-measures design (within-between interaction) for two groups
with three measurement time points.

6. Was the test/service/intervention clearly described and delivered consistently across the No No specific descriptions about CSHT and GnRH analogs they were receiving.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Validated tools of measuring mental health and psychological and behavioral functioning were used to assess outcomes.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Validated questionnaires were answered by participants and they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Loss to follow-up was more than 50% since only 38 out of 109 eligible participants completed psychosocial questionnaires at
for in the analysis? baseline, 1 year after GnRH analogs, and 1 year after CSH.

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
10. Did the statistical methods examine changes in outcome measures from before to after the Yes To assess changes in SRS-2 scores, T-scores calculated from the total score and each of the subscales was analyzed in six separate
intervention? Were statistical tests done that provided p values for the pre-to-post changes? two-factor repeated-measures ANOVAs. Changes in UGDS scores, and BIS total scores and subscale scores were analyzed in separate
two-factor repeated-measures ANOVAs. Changes in CBCL and YSR T-scores, and internalizing and externalizing T-scores were
analyzed in three two-factor repeated measures ANOVAs. P values were used for group comparisons.

11. Were outcome measures of interest taken multiple times before the intervention and No Measures were taken at three time points: at baseline, 1 year after GnRH analogs, and 1 year after CSH. There were not multiple
multiple times after the intervention (ie, did they use an interrupted time-series design)? measures taken before baseline.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Laurenzano Question Answer Details and notes

(2021)84 1. Was the study question or objective clearly stated? Yes Yes, to describe the safety and efficacy of SC-T in TM/GD youth at their clinic

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes yes, participants were under the age of 21 and had been using SC-T for at least 6 months who were seen at the clinic

3. Were the participants in the study representative of those who would be eligible for the Yes yes, all participants were taken from the clinic over an 8 year period
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear It is unclear. The study is a retrospective review aimed to include all the patients of the clinic, but the exact population or if anyone
was excluded is unknown.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear 119 seems like an appropriate size to power to be able to power the study, but no power calculation was done.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes All participants were started on the same dose of SC-T and doses were escalated by their providers at the same clinic. Participants
study population? could receive weekly or biweekly T, but the monthly amount were similar. Per chart review, 31.1% of patients slightly deviated from
schedule.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Validated tests and instruments were used to measure T levels, BMI and adverse events.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Retrospective study with the exposure as part of the inclusion criteria
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes There was no loss to follow up since the study was retrospective. When number varied in the analysis, this was disclosed.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Paired T test was used to compare pre/post lab values. P values were given.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Unclear The number of measurements per patient is unclear. They used the most recent lab values, but did not disclose the average office
multiple times after the intervention (ie, did they use an interrupted time-series design)? visits/labs taken per patients.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

López de Lara Question Answer Details and notes

(2020)62 1. Was the study question or objective clearly stated? Yes The objectives of our study were to assess the psychosocial status of patients seeking care in the pediatric endocrinology clinic for
gender incongruence and the impact on psychosocial status of cross-sex hormone therapy (CSHT) at 1 year of treatment

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Inclusion section stated criteria and selection process

3. Were the participants in the study representative of those who would be eligible for the Yes While there is some selection bias in that the patients were volunteers and not randomly selected, they still represent the clinic
test/service/intervention in the general or clinical population of interest? which they came from. The clinic itself may not fuly represent the broader population as those being treated at an earlier age have
more parental support.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Only patients that volunteered from clinic participated-there may have been more that met the criteria, but all that volunteered
were enrolled (and one criteria was that they be willing to participate)

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear No mention of power, sample size was small

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They mentioned that they use oral estradiol/intramuscular testosterone at Tanner stage 2-3. More detail could be provided, but since
study population? they are the same clinic, the same intervention is probably used.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used standardized tools to measure the outcomes (UGDS, SDQ, STAI, BDI-II)
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No No mention of blinding and all TGNB participants received treatment.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes It appears that they had all patients followed up, unless they only reported data from those that they received follow-up data from
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-values are provided
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Only baseline and 12 month measures were taken
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Millington Question Answer Details and notes

(2021)89 1. Was the study question or objective clearly stated? Yes To assess the association of CSH with lipid levels

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No Limited detail provided

3. Were the participants in the study representative of those who would be eligible for the Yes Patients seeking CSH (without GnRH analogs) were recruited from 4 children's hospitals from 2016 to 2018.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes It appears that all of them were recruited.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Power calculation was not provided.

6. Was the test/service/intervention clearly described and delivered consistently across the No There were four different children's hospitals involved.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Unclear Unclear, not all the details were provided
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear, not all the details were provided
exposures/interventions?

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Unclear It was unclear what percentage was lost to follow-up.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-Values were provided.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No The graph shows three points (0 months, 6 months, 12 months), only 0 and 6 months were provided. No measurements before
multiple times after the intervention (ie, did they use an interrupted time-series design)? intervention

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Millington Question Answer Details and notes

(2022)90 1. Was the study question or objective clearly stated? Yes Study aims to look at kidney function for transgender youth receiving GAH over a 2 year period

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No Participants were recruited prior to initiating GAH treatment at one of four study sites. Study protocol was published separately, no
eligibility criteria listed.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unknown. Study did take place at a clinic, so mostly likely representative but unclear.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unknown from given information

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Sample size was large at 286, but no power calculation was done

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Yes, followed same guidance for GAH prescribing
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes While each hospital carried out their own clinic's procedure to measure the outcomes, lab measurements are fairly reliable and all
consistently across all study participants? followed the same equations for CKD.

8. Were the people assessing the outcomes blinded to the participants' No Investigators were not blinded
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No More than 20% of participants were lost after the 6 month mark, and continue to decrease from there. Most likely lost to follow up
for in the analysis? or the patient has not reached that point in their therapy.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P value provided. Logistic regression was used.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No They did not use an ITS design
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Navabi (2021)92 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Examine the effects of GnRH analogs on bone mass and body composition

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Youth under the age of 18 seen at clinic with at least 1 DXA measurement were included in study

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
3. Were the participants in the study representative of those who would be eligible for the Yes Patients were screened at the gender diversity clinic.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unclear-not enough information given about the charts that were reviewed.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear While there was a large sample, a power calculation was not performed

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Treatment protocol and timing was clearly described under the section "CHEO Endocrine Diversity Clinic Management of Youth With
study population? GD"

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes All completed at the same facility, and the treatment protocol is the same for all.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients were on GnRH analog treatment
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Loss to follow-up was greater than 20%.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-Values were provided
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Only two time points appear to be provided.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Neyman Question Answer Details and notes

(2019)64 1. Was the study question or objective clearly stated? yes yes, to study the use of bicalutamide in MTF youth

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Yes, patients were selected from endocrine clinic from the Riley hospital if they were only taking bicalutamide

3. Were the participants in the study representative of those who would be eligible for the Unclear The patients were taken from an endocrine clinic, but this may represent a small subset that only uses bicalutamide due to insurance
test/service/intervention in the general or clinical population of interest? rejection.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes yes, population was given (103 patients) and the authors explained how they got to their 13 patients.

5. Was the sample size sufficiently large to provide confidence in the findings? No Most likely 13 patients is too small a sample to be confident in the findings.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes All patients received the same intervention and the Tanner stage was used to evaluate the outcome.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes The Tanner Stages are a classification system used among physicians. There may be a bit of gray area as it is based off observation,
consistently across all study participants? which may vary between physician.

8. Were the people assessing the outcomes blinded to the participants' No no mention of blinding
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Small population, all accounted for.
for in the analysis?

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
10. Did the statistical methods examine changes in outcome measures from before to after the No no statistical measured pre/post. No p value given
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Yes For 5 patients, there was a second visit recorded. There were most likely to be continuous visits as patients continued therapy.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Olson-Kennedy Question Answer Details and notes

(2021)93 1. Was the study question or objective clearly stated? yes Claims clearly stated

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They stated eligibility and exclusion criteria for patients that they included, but did not included numbers for the whole population.

3. Were the participants in the study representative of those who would be eligible for the Yes Patients records were taken from Gender Clinics in major cities around the nation. Although the exact population is unknown and
test/service/intervention in the general or clinical population of interest? there is a small population (n = 66), the sampling method allows for these participants to represent the population

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Patients who met criteria and who signed informed consent were enrolled in the study.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear It is possible that 66 patients would be enough to be a sufficient sample size. When evaluated in subgroups, such as transfeminine
and transmasculine there appears to be some variability and smaller sized groups. For example, when looking at baseline sex
hormone levels, there was a range of testosterone levels from 3 to 365 ng/dL.

6. Was the test/service/intervention clearly described and delivered consistently across the Unclear Patient information was taken from medical chart, therefore the outcome was not conducted by the study. Since patients were taken
study population? from either a hospital or a larger study, mostly likely labs were taken in a similar way. The study specifies that labs had to be taken
before implant, but does not specify when labs had to be taken

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes outcome for pre/post were hormone levels with units specified
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No The article does not mention that assessors were blinded to the patient's exposure
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Some of the numbers for the different outcomes varied by 1 to 3 participants, but overall they were consistent. It was not mentioned
for in the analysis? why the numbers were inconsistent, but it was most like because they may not have had all the data for each participant

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P value is provided. Wilcoxon Signed Ranked tests were used to compare hormone levels at T0 and T1
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Unclear Unknown when exactly participants hormone levels were taken and how many times they were taken.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Olson-Kennedy Question Answer Details and notes

(2018)143 1. Was the study question or objective clearly stated? yes Claims stated- prospective trial evaluating metabolic parameters of gender diverse youth

2. Were eligibility/selection criteria for the study population prespecified and clearly described? yes They clearly stated their inclusion criteria

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
3. Were the participants in the study representative of those who would be eligible for the Yes Yes, they selected patients by screening the population at the clinic
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Yes, they enrolled 101 eligible participants.

5. Was the sample size sufficiently large to provide confidence in the findings? No The participants were categorized into transfeminine or transmasculine, with groups the size of 25 and 34 people. No power
calculation was mentioned

6. Was the test/service/intervention clearly described and delivered consistently across the Unclear The intervention was unclear. It appeared that GAH was personalized based on affordability and patient characteristics. Therapy
study population? seemed consistent in the transmasculine group, but varied greatly in the transfeminine group as some were on puberty blockers,
some were taking injectable estrogen and some took oral.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes outcomes were physiological parameters that were taken from patient's medical record
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Prospective study. No mention of blinding
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No 101 patients enrolled in the study, there was data for 59 patients. Unclear why there was data for so few patients.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Yes, they used a t test to evaluate if there was a difference from baseline to 2 years of therapy.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Unclear Unknown how many measurements were taken. Looks like they used the values from the specified time frame.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Perl (2020)144 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the No Very specific inclusion criteria. Of the total of 48 cases, 15 fulfilled these study inclusion criteria and 33 were excluded, leaving room
test/service/intervention in the general or clinical population of interest? for selection bias less generalizability.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Everyone who met the inclusion criteria was included

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear: They did not talk about a power calculation. However, they only included 15 participants in the analysis.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They clearly described how many patients were puberty suppression and how many patients were added to take testosterone.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated tools to measure blood pressure. However, the BP measurements were taken at the start of each clinic visit and
consistently across all study participants? might have been affected by factors, such as anticipation and stress, associated with the visit. 24-hour ambulatory BP monitoring to
determine circadian rhythm and variability had not been performed.

8. Were the people assessing the outcomes blinded to the participants' No All patients were undergoing hormone therapy.
exposures/interventions?

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes All patients accounted for. A total of 15 participants were included in the analysis (taking GnRH analogs) and 9 out of 15 had
for in the analysis? continued to receive testosterone.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Dynamics of outcome variables over time were analyzed with repeated measures analysis of variance or, when correcting for
intervention? Were statistical tests done that provided p values for the pre-to-post changes? baseline covariate(s), with repeated measures analysis of covariance. A two-sided p-value < 0.05 was considered significant.

11. Were outcome measures of interest taken multiple times before the intervention and No The outcomes were measured after the initiation of GnRH analogs and after the addition of testosterone in those that continued on
multiple times after the intervention (ie, did they use an interrupted time-series design)? that therapy.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Perl (2021)145 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clear measures were collected from charts

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Clear inclusion criteria

3. Were the participants in the study representative of those who would be eligible for the Yes All charts of this population were reviewed for inclusion in review for this clinic-so represents this clinics population
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes All patients whose charts that met criteria were enrolled

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear No power calculation was stated, but it was a relatively small sample size

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Dosage of medication clearly defined
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Yes, all measures were reliable such as BP, hormone levels and weight/height. Although noted that sometimes BP is elevated when
consistently across all study participants? patients are nervous at appointments.

8. Were the people assessing the outcomes blinded to the participants' No All patients received GnRH analogs and some received CSH
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Since data was retrospectively obtained, all patients had all data points
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes The Kolmogorov–Smirnov test and the Shapiro–Wilk test were applied to test the normal distribution of continuous parameters.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Data was only measured at baseline and follow-up
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Roy (2023)146 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Cardiovascular parameters were evaluated in patients on testosterone therapy

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No No description of selection process

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
3. Were the participants in the study representative of those who would be eligible for the No Very small sample size
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unclear. There was no specific information on how everyone was chosen and included

5. Was the sample size sufficiently large to provide confidence in the findings? No

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Description of testosterone dosage clearly stated
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No All patients were receiving testosterone
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes All patients accounted for in data
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Unclear Unclear-significance was listed in results section, but no P values provided
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Multiple readings not taken before starting testosterone therapy
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Schagen Question Answer Details and notes

(2018)147 1. Was the study question or objective clearly stated? yes assess the effects of GnRH analogs and CSH therapy on adrenal androgen levels in adolescents with GD

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Yes, they had broad inclusion criteria to include those that had diagnosed GD and were legible for treatment.

3. Were the participants in the study representative of those who would be eligible for the Yes yes, they had a broad inclusion criteria with no exclusion criteria. It looks like they included everyone who qualified.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes With no exclusion criteria, it appears that all eligible participants were enrolled.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear They used either a t test (if the sample size was n > 30 or large enough to determine a statistical difference) or the Mann Whitney U
test. They did not have data for a few participants, so they used a linear mixed model to increase power.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They followed a consistent protocol among all participants based on age and gender.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Yes, blood samples were taken every 6 months. Androstenedione levels were determined by a coated tube radioimmunoassay with a
consistently across all study participants? limit quantification of 0.5 nmol/L. DHEAS was determined by radioimmunoassay Coat-A-Count.

8. Were the people assessing the outcomes blinded to the participants' No Prospective study.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Unclear It is unclear if there was loss to follow up. They stated that one reason for the linear mixed model was that they didn't have data at
for in the analysis? certain time points for some participants.

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
10. Did the statistical methods examine changes in outcome measures from before to after the Yes p value was provided. Independent t test or Mann Whitney U test was used.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No They took multiple measurements after intervention had started (every 6 months). They did not take multiple before the
multiple times after the intervention (ie, did they use an interrupted time-series design)? intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Schagen Question Answer Details and notes

(2016)148 1. Was the study question or objective clearly stated? Yes There is an aim section.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Listed under the protocol section.

3. Were the participants in the study representative of those who would be eligible for the Yes These patients were being seen at a gender identity clinic from a set time frame.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes It appears that all of them were enrolled.

5. Was the sample size sufficiently large to provide confidence in the findings? No Power calculation was not provided.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes There is a treatment protocol at this clinic.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes There is a treatment protocol at this clinic.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Blinding was not noted.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Other There were different populations numbers used for different parameters as data was missing from some of the patients. So there
for in the analysis? was 100% follow-up for some parameters and less for others.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes P-Values were provided.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Only two time points appear to be provided.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Schagen Question Answer Details and notes

(2020)94 1. Was the study question or objective clearly stated? Yes general research objective was clearly stated.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? No Mentioned that patients must have met DSM-IV criteria for gender dysphoria, but does not mention how or where patients were
selected. The data from 45 patients was taken from Vlot et al. and Klink et al.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unsure because it is not clear how these patients were selected. Demographic information not given.
test/service/intervention in the general or clinical population of interest?

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unclear because not sure how patients were selected to be a part of the study. Eligible population unknown.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear There were 121 participants enrolled in the study. This may be enough to correctly power the study, but no information given.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes Yes, bone density scans were calculated from DXA scans and serum bone markers were taken from blood samples.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Yes, they used aBMD and BMAD calculations. They also got their reference information for the z-scores from reliable sources.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear all participants were subject to the same exposure.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Unclear There were 121 patients, but the data they had varied since they used data from another study. Also, not all participants continued
for in the analysis? to GAH during the timeline of the study.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes The p value was provided for all pre/post outcome. BMAD changes were analyzed using linear mixed model. Differences in aBMD was
intervention? Were statistical tests done that provided p values for the pre-to-post changes? analyzed using Wilcoxon Signed Ranked test.

11. Were outcome measures of interest taken multiple times before the intervention and No They took annual measurements. They had data at baseline, 12 mo, 24 mo and 35 mo. They did not take multiple measurements
multiple times after the intervention (ie, did they use an interrupted time-series design)? before treatment/intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Stoffers Question Answer Details and notes

(2019)149 1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the Yes
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes A total of 64 patients were eligible and 2 of whom declined participation and were excluded. As a result, a total of 62 subjects were
included in the analysis.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. Power calculation was not mentioned in the article.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes They clearly described how many patients were testosterone.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated clinical measures and laboratory data.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear. Don’t know if investigators were blinded to participants' interventions.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Although a total of 62 subjects were included in the analysis, at T12, only 37 subjects had follow-up data and at T24, only 15 had
for in the analysis? data. The loss to follow-up was more than 20%.

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
10. Did the statistical methods examine changes in outcome measures from before to after the Yes Data were verified for normal distribution using the Shapiro-Wilk test. Differences between time points were analyzed by paired
intervention? Were statistical tests done that provided p values for the pre-to-post changes? samples t-test for normally distributed data and by the Wilcoxon signed-rank test for data that were not normally distributed. Results
were considered statistically significant if P < .05.

11. Were outcome measures of interest taken multiple times before the intervention and No Except for the baseline, they also assessed multiple times during 24 months of testosterone treatment (T0, T6, T12, and T24).
multiple times after the intervention (ie, did they use an interrupted time-series design)? Multiple measurements not taken before intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Tack (2017)150 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Eligibility criteria were clearly described.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unclear; don’t know how many subjects were excluded.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Unclear Unclear - don't know whether all eligible participants were enrolled

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear if it is sufficiently large since they did not mention power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population (see details in methods part)
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes They used validated clinical measures and laboratory data obtained at each visit.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear if investigators were blinded to participants' intervention.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No A total of 27 subjects were included (treated with CA for at least 6 months), however, 21 participants had been added with E and
for in the analysis? were included in the analysis of CA + E data.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Statistical tests were aimed at detecting changes in anthropometric, biochemical, and hormonal parameters at 6 and 12 months of
intervention? Were statistical tests done that provided p values for the pre-to-post changes? treatment with CA + E compared with values before the start of CA + E. A P value less than or equal to 0.05 was considered
significant.

11. Were outcome measures of interest taken multiple times before the intervention and No Two follow-up time points - change after 6 or 12 months of treatment with CA + E compared with before the start of the treatment.
multiple times after the intervention (ie, did they use an interrupted time-series design)? There were not additional measurements taken before baseline.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.)
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Tordoff (2022)96 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
3. Were the participants in the study representative of those who would be eligible for the Yes A total of 169 subjects were screened for eligibility and 161 subjects were eligible.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? No A total of 161 subjects were eligible, however, the final sample only included 104 youths.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. Power calculation was not mentioned in the article.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Validated tools for measuring mental health were used to assess outcomes.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Validated questionnaires were answered by participants and they knew what treatments they had received.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No Of these individuals included in the final sample, 84 youths (80.8%), 84 youths, and 65 youths (62.5%) completed surveys at 3, 6, and
for in the analysis? 12 months, respectively.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes They assessed the prevalence of outcomes over time and P values were reported for the pre-to-post changes.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and Yes Outcomes were measured at baseline, 3, 6, and 12 months of follow-up.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Valentine Question Answer Details and notes

(2021)97 1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Eligibility criteria were clearly described.

3. Were the participants in the study representative of those who would be eligible for the No A total of 53 TGNB males were identified and of these, 42 were included in analysis since they were seen at least twice; only 18 had
test/service/intervention in the general or clinical population of interest? laboratories both pre- and post-testosterone.

4. Were all eligible participants that met the prespecified entry criteria enrolled? No A total of 53 TGNB males were identified and of these, 42 were included in analysis since they were seen at least twice; only 18 had
laboratories both pre- and post-testosterone.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear if it is sufficiently large since they did not mention power calculation.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes While they did not clearly state lipid parameters, they retrospectively reviewed valid laboratory data for lipid profiles.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear if investigators were blinded to participants' intervention.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No 28 participants had lipid panels drawn, and only 18 had laboratories both pre- and post-testosterone.
for in the analysis?

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
10. Did the statistical methods examine changes in outcome measures from before to after the Yes P values were used for changes.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Except for the baseline visit, only one follow-up assessment was analyzed.
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Van der Loos Question Answer Details and notes

(2021)69 1. Was the study question or objective clearly stated? Yes Clearly stated in abstract

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes Listed under "Study Design and Population"

3. Were the participants in the study representative of those who would be eligible for the Yes These patients were all who visited the gender clinic between 1972 and 2018.
test/service/intervention in the general or clinical population of interest?

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes Noted in text

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Power calculation was not provided.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes There is a treatment protocol at this clinic.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes Yes, patients were chosen that had the outcomes available. Measures were consistent across patient population.
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' No Blinding was not noted.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes Having appropriate measures was an inclusion criterion.
for in the analysis?

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Implicitly- P-values do not seem to be provided but confidence intervals are.
intervention? Were statistical tests done that provided p values for the pre-to-post changes?

11. Were outcome measures of interest taken multiple times before the intervention and No Only three time points
multiple times after the intervention (ie, did they use an interrupted time-series design)?

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Vlot (2017)99 Question Answer Details and notes

1. Was the study question or objective clearly stated? Yes Clearly stated population, intervention, comparison and outcome

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes They clearly described inclusion eligibility and sampling procedures.

3. Were the participants in the study representative of those who would be eligible for the Unclear Unclear; don’t know how many subjects were excluded.
test/service/intervention in the general or clinical population of interest?

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
4. Were all eligible participants that met the prespecified entry criteria enrolled? No After applying these criteria to an eligible patient group of 85 transwomen and 130 transmen, a cohort of 28 transwomen and 42
transmen were included in the study.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear Unclear. Power calculation was not mentioned in the article.

6. Was the test/service/intervention clearly described and delivered consistently across the Yes The intervention was clearly described and delivered consistently across the population.
study population?

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed Yes
consistently across all study participants?

8. Were the people assessing the outcomes blinded to the participants' Unclear Unclear. Don’t know if investigators were blinded to participants' interventions.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted No A total of 28 transwomen and 42 transmen were included in the study, but only some of them have follow-up data. For example, only
for in the analysis? 15 transwomen (9 young transwomen and 6 old transwomen) had P1NP measurements for all three time points.

10. Did the statistical methods examine changes in outcome measures from before to after the Yes Changes in percentages of bone turnover markers and BMAD between D0, C0 and C24 were calculated as deltas (Δ) with
intervention? Were statistical tests done that provided p values for the pre-to-post changes? corresponding 95% CI and p-values.

11. Were outcome measures of interest taken multiple times before the intervention and No Data was collected at three moments in time: (1) D0: at start of GnRH analog treatment to suppress puberty, (2) C0: at start of CSHT
multiple times after the intervention (ie, did they use an interrupted time-series design)? and (3) C24: at 24 months after C0. No other measurements taken before intervention.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

Willemsen Question Answer Details and notes

(2023)127 1. Was the study question or objective clearly stated? Yes The study aimed to evaluate the effect of GnRH analogs and testosterone (CSHT) treatment on growth in transgender boys; and the
impact of timing, tempo of dose increase, and BMI on growth.

2. Were eligibility/selection criteria for the study population prespecified and clearly described? Yes

3. Were the participants in the study representative of those who would be eligible for the Yes Data were taken from the Amsterdam Cohort of Gender Dysphoria (ACOG) study, which includes the complete population of all ages
test/service/intervention in the general or clinical population of interest? seen at the gender identity clinic of Amsterdam University Medical Center from 1972 to December 2018.

4. Were all eligible participants that met the prespecified entry criteria enrolled? Yes For the most part, all eligible participants were included. One participant was excluded because they were treated with oxandrolone.

5. Was the sample size sufficiently large to provide confidence in the findings? Unclear The authors include their reasons for including 146 eligible TGNB boys (based on the inclusion/exclusion criteria), but did not discuss
statistical power.

6. Was the test/service/intervention clearly described and delivered consistently across the Unclear All participants were treated using the same treatment protocol, but treatments were still individualized by treating clinicians. This
study population? could be a potential source of information bias.

7. Were the outcome measures prespecified, clearly defined, valid, reliable, and assessed No Parental height and BA were not routinely obtained in participants in whom it was clinically obvious that they had reached adult
consistently across all study participants? height -- no description of how investigators determined clinical obviousness is given.

8. Were the people assessing the outcomes blinded to the participants' No There is no mention of blinding in the study design; data was collected retrospectively.
exposures/interventions?

9. Was the loss to follow-up after baseline 20% or less? Were those lost to follow-up accounted Yes No participants were evidently lost to follow up since this was a retrospective study, but 31% of the participants in the postpubertal
for in the analysis? group were missing values for midparental height.

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Table I.I.6. Risk of bias in extracted studies with no control group comparing TGNB patients before and after intervention (pre-post), using the NIH Quality Assessment Tool
10. Did the statistical methods examine changes in outcome measures from before to after the No Statistical methods examined changes in outcome measures from before to after the intervention, but no p-values were included.
intervention? Were statistical tests done that provided p values for the pre-to-post changes? Confidence intervals were used

11. Were outcome measures of interest taken multiple times before the intervention and No Height and weight were measured every 3-6 months from the start of PS, but BA was only determined at the start of PS and the start
multiple times after the intervention (ie, did they use an interrupted time-series design)? of CSHT. Blood draws were untimed in relation to the administration of medication since they were taken on the day of the
appointment with the clinician.

12. If the intervention was conducted at a group level (eg, a whole hospital, a community, etc.) N/A
did the statistical analysis take into account the use of individual-level data to determine effects
at the group level?

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APPENDIX I.J: DATA EXTRACTED FROM STUDIES COMPARING TGNB
PATIENTS TO OTHER TGNB PATIENTS, ORGANIZED BY OUTCOME

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Achille (2020)55 TGNB adolescents (N = 50) Mean age (yr, SD): Puberty suppression using: No puberty suppression Self-reported measures: Difference in change from baseline CESD-R:
A US NY) Eligibility: Participants were o MTF: 15.5 (1.6) o GnRH analogs and/or o MTF: n = 2 CESD-R questionnaire Puberty suppression vs. none:
pediatric endocrine recruited at the clinic, and a vast o FTM: 16.6 (2.5) antiandrogens for MTF o FTM: n = 25 o MTF: Coefficient −2.41, P value = 0.008, R² = 0.52
PHQ-9 questionnaire
gender dysphoria clinic majority consented/assented. youth (n = 15)
Depressed in the prior year: No CSH Cohort: outcomes were o FTM: Coefficient −0.02, P value NS, R² = 0.09
Sampling method: Participants o GnRH analog or
o MTF: 12 (70.6) o MTF: n = 10 measured at 12 months (wave 3) CSH vs. none:
must have completed 3 waves of medroxyprogesterone
questionnaires at 6-month o FTM: 20 (60.6) for FTM youth (n = 8) o FTM: n = 5 o MTF: Coefficient −0.56, P value NS, R² = 0.21
intervals, for a total of Reported suicidality: CSH using: o FTM: Coefficient −0.43, P value NS, R² = 0.11
approximately 12 months of
o MTF: 2 (11.8) o Estrogen for MTF youth Difference in change from baseline PHQ-9:
observation
o FTM: 3 (9.1) (n = 7) Puberty suppression vs. none:
Subset definition: Comparisons o Testosterone for FTM
Seeing a therapist: o MTF: Coefficient −1.89, P value NS, R² = 0.28
were made between treated and youth (n = 28)
untreated MTF (n = 17) and FTM o MTF: 16 (94.1) o FTM: Coefficient −0.16, P value NS, R² = 0.04
(n = 33) adolescents o FTM: 29 (87.9) CSH vs. none:
Taking psychiatric medications: o MTF: Coefficient −0.92, P value NS, R² = 0.29
o MTF: 5 (29.4) o FTM: Coefficient −0.23, P value NS, R² = 0.04
o FTM: 17 (34.0)
Allen (2019)56 N = 47 TGNB adolescents The age of the participants ranged CSH treatment CSH with previous GnRH The ASQ was used to measure Suicidality:
from 13.73 to 19.04 years analog treatment suicidality
Eligibility: Adolescents and young The findings between CSH-only and GnRH analogs + CSH
(mean = 16.59, SD = 1.19). Cohort: outcomes are measured
adults (age range 13–20 years) who were statistically significant at T1 (P < 0.05), with the GnRH
received services for GD at the The range of treatment length was after the exposure has been analog + CSH cohort having lower ASQ scores than the CSH-
clinic clinic. Participants were included if 113-1016 days (mean = 349, measured (retrospective review) only group.
they had pretest and final SD = 193).
o The estimated adjusted mean (standard error) of ASQ
assessment data points and were For most of the sample (90%), the scores for CSH-only group was 1.06 (1.3) at T0 and .33
treated with CSH for at least 3 duration of treatment was at, or (.77) at T1. The estimated adjusted mean (standard error)
months under, 600 days. of ASQ scores for GnRH analogs + CSH group was 1.08
Sampling method: A total of 47 (1.49) at T0 and .01 (.02) at T1.
eligible participants had pretest and
final assessment data. The pretest

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
631

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
for 23 participants occurred at their Assigned female at birth was n = 33
first contact with the clinic (the (70.2%) and assigned male at birth
other participants' pretest was n = 14 (29.8%).
assessment was completed at a
The majority of participants were
subsequent visits to clinic but prior
white N = 39 (83%).
to starting CSH). Thirteen of the
participants first presented to our
clinic in 2015; 19 in 2016; 14 in
2017; and one in 2018. Patients are
administered questionnaires and
screeners at the beginning of their
clinic visit, either at the time of the
diagnostic evaluation or during a
follow-up appointment with the
multidisciplinary team. Responses
are reviewed by the mental health
professional prior to meeting with
the patient.
Subset definition: Of the 47
participants, Comparisons were
made between those that were
administered GnRH analogs prior to
beginning CSH (GnRH analogs + CSH
subgroup) (n = 8) and those that
were not received GnRH analogs
prior to being administered CSH
(CSH-only subgroup) (n = 39).

Subset definition: Comparisons AFAB AMAB Suicidality:

were made between youth AMAB
A significant effect was not observed for sex assigned at birth
(n = 33) and AMAB (n = 14)
with regard to suicidality scores, after controlling for
duration of treatment, F(1, 44) = .08, P = .79, partial
η² = .002.

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
632

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
The estimated adjusted mean (standard error) of ASQ scores
for AFAB group was 1.01 (.23) at T0 and .29 (.13) at T1. The
estimated adjusted mean (standard error) of ASQ scores for
AMAB group was 1.21 (.36) at T0 and .24 (.19) at T1.
Bauer (2021)102 Pubertal and post-pubertal youth Assigned sex at birth: Pubertal and post-pubertal Pubertal and post-pubertal Self-reported measures: There was a significant difference in the MDS questionnaire
(N = 174) transfeminine youth (n = 37) transmasculine youth (n = 137) scores between the cohorts, with transmasculine youth feeling
10 Canadian medical AMAB: 37 (21.3) 5-item MDS questionnaire
depressed more often than transfeminine youth, P = .03. There
clinics located across Eligibility: GD diagnosis, < 16 yrs of
AFAB: 137 (78.7) 5-item OASIS questionnaire were no significant differences between the cohorts on any
Canada (eg, age, no previous use of estrogen,
testosterone, or GnRH analogs Age, P = NS Suicidal ideation and attempts other reported measures for mental health.
All (except contraceptives), and were evaluated using the Self-assessed mental health (n, weighted %), P = NS:
10−13 yrs old:
clinics had ≥ 1 pediatric referred for hormone use Canadian Community Health
o Transfeminine: 14 (40.6) Survey Excellent or very good:
specialist, and
Sampling method: Recruitment o Transfeminine: 16 (38.8)
resources to mental o Transmasculine: 40 (28.7) Cross-sectional:
processes differed due to the site
health physicians. 14−15 yrs old: exposures/outcomes were o Transmasculine: 27 (19.0)
location and requirements set by
the Research Ethics Board. measured at the same time
o Transfeminine: 23 (59.4) Good:
Potential eligible participants were o Transfeminine: 8 (23.4)
o Transmasculine 97 (71.3)
invited to contact the research
investigator prior to their first visit Gender identity, P < .001 o Transmasculine: 34 (22.6)
Male or primarily a boy: Fair or poor:
Subset definition: Comparisons
were made between transfeminine o Transfeminine: 1 (2.4) o Transfeminine: 13 (37.7)
(n = 37) and transmasculine o Transmasculine: 75 (58.4)
o Transmasculine: 125 (92.2)
(n = 137) participants
Female or primarily a girl: MDS ≥ 4 (depressed often or always; n, weighted %), P = .03
o Transfeminine: 32 (87.1) o Transfeminine: 4 (7.6)
o Transmasculine: 0 (0) o Transmasculine: 29 (22.0)
Nonbinary: OASIS ≥ 8 (probable anxiety; asked only participants ≥ 12
years of age; n, weighted %), P < .001:
o Transfeminine: 3 (10.5)
o Transfeminine: 10 (35.0)
o Transmasculine: 11 (7.8)
o Transmasculine: 84 (71.4)
Self-harm in the past year (n, weighted %), P = NS:

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
633

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Living in their identified gender, o Transfeminine: 18 (61.5)
P < 0.001 o Transmasculine: 92 (69.0)
All the time: Suicidal ideation (n, weighted %):
o Transfeminine: 24 (58.1) o Ever, P = NS
o Transmasculine: 122 (90.1)  Transfeminine: 19 (58.8)
Some of the time:  Transmasculine: 76 (58.0)
o Transfeminine: 11 (37.8) o In the past year, P = NS
o Transmasculine: 13 (9.9)  Transfeminine: 11 (35.1)
Not at all:  Transmasculine: 45 (34.4)
o Transfeminine: 2 (4.1) Suicide attempt (n, weighted %):
o Transmasculine: 0 (0) o Ever, P = NS
Other providers whom the adolescent  Transfeminine: 9 (30.8)
and family had met with to discuss
 Transmasculine: 44 (37.3)
gender with prior to the clinic visit:
o In the past year, P = NS
Family physician, P = NS:
 Transfeminine: 4 (12.4)
o Transfeminine: 23 (68.2)
 Transmasculine: 20 (17.9)
o Transmasculine: 85 (68.6)
Pediatrician or adolescent medicine,
P = NS:
o Transfeminine: 13 (33.4)
o Transmasculine: 39 (30.5)
Psychologist or psychiatrist, P = NS
o Transfeminine: 18 (46.2)
o Transmasculine: 64 (45.4)
Counselor, elder, religious leader,
P = NS:

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
634

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Transfeminine: 17 (50.7)
o Transmasculine: 64 (45.6)
Cantu (2020)74 N = 80 TGNB adolescents Full cohort: Participants receiving HT Participants not receiving HT PHQ-9: a 9-item screening A repeated measures factorial ANOVA did not reveal any
Eligibility: Youth were included in between initial visit and first between initial visit and first measure of depression. significant differences in depression and anxiety scores among
An academic medical the current study if they (1) were Mean (SD) age was 15.1 (1.8) follow-up appointment (n = 28 follow-up appointment (n = 51 youth who did versus did not initiate HT following their intake
center in the GAD-7: a 7-item screening
between the ages of 11 and 18 affirmed male gender, n (%), was 58 for PHQ-9, n = 27 for GAD = 7) for PHQ-9, n = 50 for GAD-7) visit.
Northwestern United years, (2) had attended both an measure of anxiety
(72.5)
States between initial visit and one follow-up Cohort: outcomes are measured PHQ-9:
September 2017 and follow-up time in weeks, mean (SD) There was no significant difference in scores between the HT
appointment, and (3) completed after the exposure has been
June 2019 was 20.4 (10.2) initiated subjects, with a mean score (SD) of 9.8 (7.1) at initial
measures assessing acute distress measured (retrospective chart
(PHQ-9 and GAD-7) at both visits Only N = 1 (1.3%) individual initiated review) visit and 10.3 (7.3) at follow-up appointment compared to
Sampling method: All youth ages HT before the initial visit those who had not initiated HT with a mean score (SD) of
11 and older complete anxiety and 11.1 (6.3) at initial visit and 10.1 (5.9) at follow-up
28 youth initiated HT between initial
depression screeners at every visit visit and first follow-up appointment, P = NS
regardless of mental health GAD-7:
diagnoses or symptom severity. o Of those 28 youth, 6 were started
Second visit is recommended 3–4 on feminizing hormones and 22 There was no significant difference in scores between the HT
months after the initial visit. were started on masculinizing. initiated subjects, with a mean score (SD) of 8.4 (6.4) at initial
Subset definition: o A total of 17 youth initiated visit and 8.5 (5.5) at follow-up appointment, compared to
N = 80 TGNB adolescents hormone blockers between their those who had no HT, with a mean score (SD) of 9.6 (5.9) at
(N = 80 youth completed PHQ-9 initial visit and first follow-up, 4 of initial visit and 9.1 (5.8) at follow-up appointment, P = NS
screeners at both time points which also initiated HT.
and N = 78 youth completed
N = 77 (96.2%) received neither HT
GAD-7 screeners at both time
nor hormone blockers at initial visit
points)
N = 38 (47.5%) received neither HT
Comparisons were made nor hormone blockers at follow up
between Participants who
appointment.
received HT between their
initial visit, and follow-up
appointment (n = 28 for PHQ-9,
n = 27 for GAD = 7), and those
who did not (n = 51 for PHQ-9,
n = 50 for GAD-7)
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
635

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Chen (2021)104 Adolescents seeking GnRH analog Mean age (yr, SD), P value = 0.002: AFAB patients seeking GnRH AMAB patients seeking GnRH Self-reported measures: There was a significant difference in total anxiety and worry
therapy (N = 95) analog therapy (n = 46) analog therapy (n = 49) scores between the AFAB and AMAB cohorts, but no other
Four pediatric AFAB: 10.76 (1.43) BDI-Y questionnaire
significant differences between groups in reported measures
academic medical Eligibility: Patients aged 8 to 20 yrs
AMAB: 11.65 (1.36) RCMAS-2 questionnaire were found.
centers in the US old, diagnosed with GD, eligible to
start GnRH analogs or CSH as Gender identity, P value = 0.000: Suicide attempts and suicidal BDI-Y (n = 91; n, %), P = NS:
deemed by the primary treatment ideation
Transmasculine/Male: o Severe depression:
team, proficient in English, and Cross-sectional:
o AFAB: 40 (87)  AFAB: 2 (4.7)
seeking care at one of the study exposures/outcomes were
clinic locations o AMAB: 1 (2) measured at the same time  AMAB: 5 (10.4)
Sampling method: Patients Transfeminine/Female: o Moderate depression:
presenting at one of the four o AFAB: 1 (2.2)  AFAB: 5 (11.6)
medical centers between July 2016
o AMAB: 44 (89.8)  AMAB: 5 (10.4)
and September 2018, desiring to
start GnRH analogs or CSH Nonbinary: o Mild depression:
treatment for GD o AFAB: 5 (10.9)  AFAB: 4 (9.3)
Subset definition: Comparisons o AMAB: 4 (8.2)  AMAB: 5 (10.4)
were made between AFAB (n = 46) o Minimal depression:
and AMAB (n = 49)
 AFAB: 32 (74.4)
 AMAB: 33 (68.8)
Mean RCMAS-2 T-score (n = 84; SD):
o Total anxiety, P = .047:
 AFAB: 45.67 (11.65)
 AMAB: 51.2 (13.38)
o Physiological anxiety T-score, P = NS:
 AFAB: 45.49 (10.6)
 AMAB: 49.15 (12.07)
o Worry T-score, P = .029:
 AFAB: 47.11 (11.57)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
636

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 AMAB: 53.2 (13.42)
o Social anxiety T-score, P = NS:
 AFAB: 45.53 (10.57)
 AMAB: 49.88 (12.87)
Suicidal ideation (n, %):
o Experienced lifetime suicidal ideation (n = 89), P = NS:
 AFAB: 7 (7.9)
 AMAB: 14 (15.7)
o Experienced lifetime suicidal ideation with plan (n = 21),
P = NS:
 AFAB: 3 (3.4)
 AMAB: 5 (5.6)
o Experienced suicidal ideation in the past 6 months
(n = 20), P = NS:
 AFAB: 3 (3.4)
 AMAB: 9 (10.1)
o Experienced suicidal ideation in the past 6 months with
plan (n = 8), P = NS:
 AFAB: 1 (1.1)
 AMAB: 3 (3.4)
Suicide attempt (n, %):
o Experienced lifetime suicide attempt (n = 18), P = NS:
 AFAB: 1 (1.1)
 AMAB: 6 (33.3)
o Experienced suicide attempt in the past 6 months (n = 8),
P = NS:

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
637

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 AFAB: 0 (0)
 AMAB: 2 (2.2)
Adolescents seeking CSH therapy Mean age (yr, SD), P = NS AFAB patients seeking CSH AMAB patients seeking CSH Self-reported measures: Youth designated female at birth attempted suicide at a
(ie, testosterone or estrogen) o AFAB: 15.87 (1.76) therapy (n = 205) therapy (n = 111) significantly higher rates than youth designated male at
BDI-II
(N = 316) birth. There were no other statistically significant differences
o AMAB: 16.23 (2.08) RCMAS-2 questionnaire between groups in mental health measures.
Eligibility: Same as above
Gender identity, P = 0.000: Suicide attempts and suicidal BDI-II (n = 308; n, %), P = NS:
Sampling method: Same as above ideation
o Transmasculine/Male: o Severe depression:
Subset definition: Comparisons  AFAB: 191 (93.72) Cross-sectional:
were made between AFAB  AFAB: 26 (13.1)
exposures/outcomes were
 AMAB: 0 (0)  AMAB: 22 (20.2)
(n = 205) and AMAB (n = 111) measured at the same time
o Transfeminine/Female: o Moderate depression:
 AFAB: 1 (0.5)  AFAB: 37 (18.6)
 AMAB: 105 (94.6)  AMAB: 20 (18.3)
o Nonbinary: o Mild depression:
 AFAB: 13 (6.3)  AFAB: 35 (17.6)
 AMAB: 6 (5.4)  AMAB: 18 (16.5)
o Minimal depression:
 AFAB: 101 (50.8)
 AMAB: 49 (44.9)
Mean RCMAS-2 T-score (n = 309; SD):
o Total anxiety, P = NS:
 AFAB: 40.32 (11.52)
 AMAB: 59.12 (11.47)
o Physiological anxiety T-score, P = NS:
 AFAB: 55.66 (11.51)
 AMAB: 54.05 (9.99)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
638

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Worry T-score, P = NS:
 AFAB: 61.89 (11.53)
 AMAB: 61.41 (11.94)
o Social anxiety T-score, P = NS:
 AFAB: 58.41 (10.74)
 AMAB: 57.36 (11.69)
Suicidal ideation (n, %):
o Experienced lifetime suicidal ideation (n = 305), P = NS:
 AFAB: 133 (43.6)
 AMAB: 70 (23.0)
o Experienced lifetime suicidal ideation with plan (n = 204),
P = NS:
 AFAB: 62 (20.3)
 AMAB: 27 (8.9)
o Experienced suicidal ideation in the past 6 months
(n = 207), P = NS:
 AFAB: 67 (22.0)
 AMAB: 41 (13.4)
o Experienced suicidal ideation in the past 6 months with
plan (n = 89), P = NS:
 AFAB: 20 (6.6)
 AMAB: 12 (3.9)
Suicide attempt (n, %):
o Experienced lifetime suicide attempt (n = 207), P = .001
 AFAB: 60 (19.7)
 AMAB: 15 (4.9)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
639

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Experienced suicide attempt in the past 6 months (n = 74),
P = NS:
 AFAB: 9 (3.0)
 AMAB: 2 (0.7)
Chen (2023 )67 TGNB adolescents (N = 315) participants were 12 to 20 years of TGNB youth starting GAH in TGNB youth starting GAH in Depression symptoms were Depression:
age (mean [ ±SD], 16 ±1.9 years.) early puberty (Tanner stages later puberty (Tanner stages 4- assessed using the 21-item Those that had ini ated GAH in early puberty had a
USA- Gender clinics at Eligibility: Participants were
1-3) (n = 24) 5) (n = 291) BDI-II. significantly lower score of 9.57 (8.26) compared to 17.00
the recruited from the gender clinics Higher percentage of those
designated female at birth (64.8%) Anxiety symptoms were (12.21) for those who ini ated GAH in later puberty at
from July 2016-June 2019. This
then male. assessed by the RCMAS2 baseline. P < .001
cohort was initiating GAH as part of
their clinical care. For minors, Cohort: outcomes were Anxiety
Mostly Non-Latinx or non-Latin white
parental consent was required to (58.1%) measured at baseline, 6, 12, 18 Those that had ini ated GAH in early puberty had a
initiate treatment. and 24 months of GAH treatment significantly lower score of 51.54 (12.20) compared to 60.75
Tanner stage at GAH ini a on: no (%) (11.15) for those who ini ated GAH in later puberty at
Sampling Method: Youth were Early n = 24
from July 2016 baseline. P < .001
recruited from 4 different sites at
through June 2019 o Stage 1: 2 (0.6)
the start of GAH therapy. They were TGNB youth identifying as TGNB youth of color (n = 105) Depression:
enrolled if they met inclusion o Stage 2: 14 (14.1) white (n = 210)
White youth had a greater decrease in depression scores
criteria o Stage 3: 9 (2.9) over 24 months of GAH therapy than youth of color with a
Subset defini on: Late n = 291 time-invariant effect on slope of 1.70, 95% CI (0.23 to 3.15)
Comparisons were made o Stage 4: 29 (9.2) Racial and ethnic identity were not associated with any other
between those designated o Stage 5: 262 (83.2) outcomes at baseline or over time
female at birth(n = 204) and
TGNB youth DFAB (n = 204) TGNB youth DMAB (n = 111) Depression:
those designated male at birth
(n = 111) Scores decreased over 24 months of GAH among those
Comparisons were made designated female at birth, but not among those designated
between those identifying as male at birth with a time-invariant effect of 1.91, 95% CI
white (n = 210) and those not (0.33 to 3.50)
identifying as white (n = 105)
Anxiety
Comparisons were made Scores decreased over 24 months of GAH among those
between those who started designated female at birth, but not among those designated
GAH in early puberty (n = 24)
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
640

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
and those who started in later male at birth with a time-invariant effect on slope of 1.56,
puberty (n = 291) 95% CI (0.01 to 3.10)
Conn (2023)105 N = 315 TGNB youth aged 12-20 Age: TGNB youth with internalized TGNB youth without Anxiety was measured using Anxiety
Eligibility: Participants had gender transphobia internalized transphobia the Revised-Children's
Four pediatric gender Mean (SD) age was 16.01 (1.87) Higher levels of anxiety were associated with greater
dysphoria as determined by a Manifest Anxiety Scale
clinics located in major Gender: internalized transphobia.
clinician, have English proficiency,
metropolitan areas of Depressive symptoms were rho = 0.427, P < 0.01
and be psychiatrically and 60.3% transmasculine/male
the US measured using the Beck
cognitively able to give informed Internalized transphobia was significantly associated with
33.6% transfeminine/female Depression Inventory-II
consent/assent to participation. greater anxiety.
The use of gender affirming 3.8% nonbinary Internalized transphobia and b = 0.47 (95% CI = 0.15-0.79), P < .01
hormones (GAH) must be gender-identity pride was
3% other Depression
appropriate and the participant measured using the Gender
must be ready to start CSH (cross- Minority Stress and Resilience Higher levels of depression were associated with greater
sex hormones; estrogen or Measure for Adolescents internalized transphobia.
testosterone) as determined by the rho = 0.436, P < 0.01
Perceived parental support
clinical team. was measured using 4 items Internalized transphobia was significantly associated with
Sampling method: Data was adapted from the Family greater depression.
collected using a computer-assisted subscale of the MSPSS b = 0.53 (95% CI = 0.37-0.69), P < .01
survey instrument. The data for this
TGNB youth AFAB (n = 204) TGNB youth AMAB (n = 111) Cross-sectional: Gender Identity pride
study came from the larger Trans
exposures/outcomes were
Youth Care Study, an ongoing, Being AFAB was associated with lower levels of gender
measured at the same time
multisite, observational study of identity pride compared to those AMAB (rho = 00.178,
before participants initiated CSH
TGNB initiating medical treatment P < .01)
with CSH. Investigators only used
TGNB youth with greater TGNB youth without greater Internalized transphobia
the CSH cohort baseline data of the
perceived parental support perceived parental support
study, which were collected before Greater perceived parental support was significantly
participants started CSH. The associated with lower internalized transphobia (rho–0.252,
baseline survey included 316 P < .01)
individuals, but one was excluded Anxiety
due to not meeting inclusion
criteria. Greater perceived parental support was significantly
associated with lower anxiety (rho = -0.209, P < .01)
Depression

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
641

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Greater perceived parental support was significantly
associated with lower depression (rho = -0.259, P < .01)
De Graaf (2022)108 Population N = 2771 TGNB Age (in years), mean (SD), P < .001 TGNB youth seen at the TGNB youth seen at the Demographic information and Demographic and General Child Behavior Checklist/ Youth Self-
adolescents Toronto clinic Amsterdam or London clinic CBCL and YSR scores were Report Metrics-univariable comparison
o Toronto: 16.66 (1.75)
obtained at the time of baseline
Eligibility: Patients referred and o Amsterdam: 15.91 (1.42) measurement prior to any On average, the Toronto clinic adolescents were significantly
assessed for GD at one of the hormonal treatment for GD. older than both the Amsterdam and London clinic
o London: 15.93 (1.07)
three clinic sites between 1978 Linear regression analysis was adolescents.
and 2017 Birth-assigned sex, N (%), P < .001 used to examine correlations and
, Ontario; the The percentage of birth-assigned females in the London clinic
Sampling method: Not specified o Male predictors of suicidality (Items 18 was significantly higher than the percentage in the Toronto
 Toronto: 129 (49.6) and 91 from CBCL and the YSR.) and Amsterdam clinics.
Subset definition: Total
Cross sectional:
population (N = 2771) patients  Amsterdam: 123 (46.2) Exposures/outcomes were The year of assessment for the London clinic adolescents
were seen at 3 clinic sites:  London: 685 (30.5) measured at the same time, at was, on average, significantly more recent than both the
o Gender Identity Service at the time of baseline assessment, Toronto and Amsterdam adolescents.
the o Female
Centre for Addiction and prior to any hormonal treatment For IQ, social class, and parent's marital status, data were
Netherlands; and Mental Health (CAMH) in  Toronto: 131 (50.4) for GD. available only from the Toronto and Amsterdam clinics. On
Toronto, Ontario (n = 260)  Amsterdam: 143 (53.8) average, the adolescents from the Toronto clinic had a
o The Center of Expertise on  London: 1560 (69.5) significantly higher IQ than the adolescents from the
Gender Dysphoria at the Netherlands but did not differ significantly with regard to
Year of assessment, mean (SD), parent's social class or marital status.
Amsterdam University range, P < .001
Medical Centers, VUmc site in On the CBCL, the adolescents from the Toronto clinic had, on
UK. Amsterdam, the Netherlands o Toronto: 2004.72 (7.59), 1978- average, more behavior problems than the adolescents from
(n = 266) 2012 the London clinic who, in turn had more behavior problems
o The Gender Identity o Amsterdam: 2004.87 (5.77), 1990- than the adolescents from the Amsterdam clinic.
Development Service at the 2012
On the YSR, the adolescents from the London clinic had, on
Tavistock and Portman o London: 2014.99 (1.77), 2009-2017 average, more behavior problems than the adolescents from
National Health Service Trust Full-Scale IQ, mean (SD), P = .005 the Toronto clinic who, in turn, had more behavior problems
in London, UK (n = 2245) than the adolescents from the Amsterdam clinic.
o Toronto:102.08 (18.85)
On the CBCL (poor) peer relations scale, the adolescents
o Amsterdam: 97.16 (16.37)
from the Toronto clinic had, on average, a higher score than
o London: N/R

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
642

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Social Class, N(%), P = NS the adolescents from both the Amsterdam and the London
o 1–2 clinic.

 Toronto: 201 (77.3) On the YSR (poor) peer relations scale, the adolescents from
the Toronto clinic and the London clinic had, on average, a
 Amsterdam: 171 (78.1) higher score than the adolescents from the Amsterdam
 London: N/R clinic.
o 3 For the CBCL gender identity item, the percentage of
 Toronto: 59 (22.7) adolescents from the London clinic who received a rating of a
1 or a 2 was significantly higher than the percentage of
 Amsterdam: 48 (21.9)
adolescents from the Toronto and Amsterdam clinics,
 London: N/R although in all clinics the percentage was ≥ 93%
Parent's marital status, N (%), P = NS On the YSR, the between-clinic difference was not significant,
o Both Parents with all percentages ≥ 95%.
 Toronto: 116 (44.6) For the suicidality composite based on parent-report, the
adolescents from the Toronto and London clinics had, on
 Amsterdam: 117 (51.1)
average, a higher score than the adolescents from the
 London: N/R Amsterdam clinic.
o Other Correlation between the CBCL and YSR suicidality sum score as
 Toronto: 144 (55.4) a function of clinic and birth-assigned sex.
 Amsterdam:112 (48.9) In the Toronto sample, the correlation for the birth-assigned
 London: N/R males (r = 0.12) was not significant, but was significant for
the birth-assigned females (r = 0.52, P < .001).
CBCL Gender N (%), P < .001
Item 110 ("Wishes to be of opposite In the Amsterdam sample, the correlation for the birth-
sex"/ "I wish I were of the opposite assigned males (r = 0.61) and birth-assigned females
sex") (r = 0.63) were both significant, P < .001.
o 0 In the London sample, the correlation for the birth-assigned
males (r = 0.02) and birth-assigned females (r = 0.07) were
 Toronto: 13 (5.8)
both not significant.
 Amsterdam: 16 (6.4)
Predictors of Suicidality-logistic regression
 London: 25 (1.8)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o 1 or 2 Toronto vs. Amsterdam:
 Toronto: 211 (94.1) Predictor of CBCL Suicidality, B, P, (95% CI)
 Amsterdam: 233 (93.5) o The adolescents from the Toronto clinic had higher
 London: 1399 (98.2) reports of suicidality than the adolescents from the
Amsterdam clinic.
YSR Gender, N(%), P = NS
Item 110 ("Wishes to be of opposite o A higher degree of suicidality was associated with birth-
sex"/"I wish I were of the opposite assigned female transgender adolescents, adolescents
sex") who lived in a family configuration classified as "Other," a
lower social class background, and more behavioral and
o 0
emotional problems in general.
 Toronto: 10 (4.2)
 Clinic: -0.260, P = .005, (-0.441, -0.078)
 Amsterdam: 8 (3.3)
 Birth-assigned sex: 0.170, P = 0.050, (0.000, 0.341)
 London: 27 (2.0)
 YOA: − 0.013, 0.056, (− 0.025, 0.000)
o 1 or 2
 Age at assessment:0.000, P = NS
 Toronto: 228 (95.7)
 Full-scale IQ:− 0.001, P = NS
 Amsterdam: 233 (93.5)
 Parent's marital status: − 0.200, P = 0.026, (− 0.375, −
 London: 1337 (98.0) 0.025)
CBCL Poor Peer Relations Scale (Sum),  Parent's social class: 0.266, P = 0.020, (0.042, 0.490)
mean (SD), P < .001
 Poor peer relations: 0.016, P = NS
o Toronto (n = 239): 2.42 (1.88)
 General behavior problems: 0.014, P < .001, (0.011,
o Amsterdam (n = 250): 1.38 (1.57) 0.018
o London (n = 1594): 1.60 (1.60) Predictor of YSR Suicidality, B, P, (95% CI)
YSR Poor Peer Relations Scale (Sum), o A higher degree of suicidality was associated with birth-
mean (SD), P < .001 assigned female transgender adolescents, poor peer
o Toronto (n = 244): 2.09 (1.68) relations, and more behavioral and emotional problems in
general.
o Amsterdam (n = 242): 1.40 (1.49)
 Clinic: -0.035, P = NS
o London (n = 1553): 2.04 (1.70)
 Birth-assigned sex: 0.212, P = .025 (0.041, 0.383)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
644

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
CBCL sum of items, mean (SD),  YOA: 0.001, P = NS
P < .001  Age at assessment: -0.01, P = NS
o Toronto (n = 240): 59.51 (30.91)  Full-scale IQ: -0.001, P = NS
o Amsterdam (n = 250): 47.48  Parent's marital status:0.022, P = NS
(27.32)
 Parent's social class: -0.028, P = NS
o London (n = 1603): 49.24 (30.15)
 Poor peer relations: 0.066, P = 0.034, (0.005, 0.127)
YSR sum of items, mean (SD), P < .001
 General behavior problems:0.020, P < .001,
o Toronto (n = 244): 63.92 (27.19) (0.016,0.024)
o Amsterdam (n = 242): 52.93 Toronto vs. London
(24.59)
Predictor of CBCL Suicidality, B, P, (95% CI)
o London (n = 1562): 68.24 (30.21)
o The adolescents from the London clinic had a higher
CBCL sum of suicidality items, mean degree of suicidality than the adolescents from the
(SD), P < .001 Toronto clinic.
o Toronto (n = 237): 0.83 (1.09) o A higher degree of suicidality was associated with birth-
o Amsterdam (n = 250): 0.43 (0.75) assigned female transgender adolescents and more
o London (n = 1562): 0.98 (1.17) behavioral and emotional problems in general.

YSR sum of suicidality items, mean  Clinic: 0.207, P < 0.001, (0.107, 0.307)
(SD), P < .001  Birth-assigned sex: 0.254, P < 0.001, (0.157, 0.352)
o Toronto (n = 244): 0.82 (1.06)  YOA: − 0.014, P = 0.059, (− 0.029, 0.001)
o Amsterdam (n = 242): 0.57 (0.93)  Age at assessment: 0.035, P = 0.076, (− 0.004, 0.073)
o London (n = 1515): 1.29 (1.33)  Poor peer relations: 0.024, P = NS
 General behavior problems: 0.021, P < .001, (0.019,
0.023)
Predictor of YSR Suicidality, , B, SE, t, P, (95% CI)
o The adolescents from the London clinic had higher reports
of suicidality than the adolescents from the Toronto clinic

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
645

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
and a higher degree of suicidality was also associated with
more behavioral and emotional problems in general.
 Clinic: 0.203, P < .001, (0.091, 0.315)
 Birth-assigned sex: 0.097, P = 0.077, (− 0.204, 0.010)
 YOA: − 0.007, P = NS
 Age at assessment:.015, P = NS
 Poor peer relations: − 0.019, P = NS
 General behavior problems: 0.027, P < .001, (0.025,
0.029)
Amsterdam vs. London
Predictor of CBCL Suicidality, , B, SE, t, P, (95% CI)
o The adolescents from the London clinic had higher reports
of suicidality than the adolescents from the Amsterdam
clinic.
o A higher degree of suicidality was associated with birth-
assigned female adolescents and more behavioral and
emotional problems in general.
 Clinic: 0.540, P < .001, (0.336, 0.744)
 Birth-assigned sex: 0.252, P < .001, (0.157, 0.347)
 YOA: − 0.013, P = NS
 Age at assessment: 0.026, P = NS
 Poor peer relations: 0.017, P = NS
 General behavior problems: 0.021, P < .001, (0.019,
0.023)
Predictor of YSR Suicidality, B, P, (95% CI)
o The adolescents from the London clinic reported a higher
degree of suicidality than the adolescents from the
Amsterdam clinic and a higher degree of suicidality was
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
646

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
also associated with more behavioral and emotional
problems in general.
 Clinic: 0.331, P = .006, (0.096, 0.566)
 Birth-assigned sex: 0.073, P = NS
 YOA: 0.000, P = NS
 Age at assessment: 0.031, P = NS
 Poor peer relations: − 0.025, P = NS
 General behavior problems: 0.028, P < .001, (0.026,
0.030)
de Vries (2011)106 N = 105 TGNB adolescents Full cohort: TGNB natal male adolescent TGNB natal female adolescent Intelligence (IQ)_ was Natal males suffered more often from two or more comorbid
Eligibility: diagnosed with GD and measure by the Dutch diagnoses, mood disorders, and social anxiety disorder. No other
mean (SD) age was 14.6 years (2.2)
seen between April 2002-December versions of the Wechsler significant differences were found.
2009. mean (SD) full-scale IQ was 97.4 Intelligence scale for Children
Sampling method: 105 out of 201 (14.2); for Full Scale IQ, P = NS
(WISC)
adolescents consecutively enrolled living arrangements, o Natal male, mean (SD): 95.4 (13.1)
Behavior Problems were
17 dropped out of the diagnosis o Natal female, mean (SD): 99.5 (15.0)
o 51.5% lived with both parents measured using T scores from
procedure
o 48.5% lived with other the CBCL Anxiety conditions, OR, P value
18 were not invited since they
parents' education status Psychiatric comorbidities Any condition, 0.64, P = NS
were included
were assessed using the DISC
o 15.5% had high o Natal male, % (n): 24.5 (13)
61 declined IV
Subset: Comparisons were made o 68.0% had medium o Natal female, % (n): 17.3 (9)
Cross-sectional:
between TGNB natal males (n = 53) o 16.5% had low exposures/outcomes were Specific phobia, 1.0, P = NS
vs TGNB natal females (n = 52) measured at the same time o Natal male, % (n): 4.5 (4)
Natal male:
around the time of intake
mean (SD) age was 14.5 years (2.2) o Natal female, % (n): 4.5 (4)

mean (SD) full-scale IQ was 95.4 Social phobia, 0.26, P = 0.049

(13.1) o Natal male, % (n): 15.1 (8)
living arrangements o Natal female, % (n): 3.8 (2)
o 56.6% lived with both parents Agoraphobia, N/A P = NS

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
647

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o 44.0% lived with other o Natal male, % (n): 1.1 (1)
parents' education status, o Natal female, % (n): 0 (0)
o 11.5% had high Separation anxiety, 3.2, P = NS)
o 71.2% had medium o Natal male, % (n): 1.9 (1)
o 17.3% had low o Natal female, % (n): 5.8 (3)
Natal female: Generalized anxiety, N/A, P = NS
mean (SD) age was 14.6 years (2.2) o Natal male, % (n): 0 (0)
mean (SD) full-scale IQ was 99.5 o Natal female, % (n): 1.9 (1)
(15.0) Mood conditions, OR, P value
living arrangements o Any, 0.15, P = .008
o 43.3% lived with both parents  Natal male, % (n): 20.8 (11)
o 56.0% lived with other  Natal female, % (n): 3.8 (2)
parents' education status o Major depression, 0.26, P = NS
o 19.6% had high, 6  Natal male, % (n): 13.2 (7)
o 4.7% had medium  Natal female, % (n): 3.8 (2)
o 15.7% had low o Dysthymia, N/A, P = NS
o There were no significant  Natal male, % (n): 7.5 (4)
differences between the groups
 Natal female, % (n): 0 (0)
Disruptive conditions, OR, P value
o Any, 0.47, P = NS
 Natal male, % (n): 15.1 (8)
 Natal female, % (n): 7.7 (4)
o ADHD combined, 2.1, P = 0.50
 Natal male, % (n): 1.9 (1)
 Natal female, % (n): 3.8 (2)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
648

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o ADHD inattentive, 1.0, P = NS
 Natal male, % (n): 1.9 (1)
 Natal female, % (n): 1.9 (1)
o ADHD hyperactive, N/A, P = NS
 Natal male, % (n): 1.9 (1)
 Natal female, % (n): 0 (0)
o Oppositional defiant, 0.48, P = NS
 Natal male, % (n): 11.3 (6)
 Natal female, % (n): 5.8 (3)
Any substance use, OR, P value
o Any, N/A, P = NS
 Natal male, % (n): 1.9 (1)
 Natal female, % (n): 0 (0)
Number of DSM-IV diagnoses, OR, P value
o One or more, 0.51 P = NS
 Natal male, % (n): 39.6 (21)
 Natal female, % (n): 25 (13)
o Two or more, 0.29, P = 0.03
 Natal male, % (n): 22.6 (12)
 Natal female, % (n): 7.7 (4)
o Three or more, 0.50, P = NS
 Natal male, % (n): 3.8 (2)
 Natal female, % (n): 1.9 (1)
N = 89 TGNB adolescents Full cohort: TGNB adolescents TGNB adolescents with delayed Intelligence (IQ)_ was Baseline comparisons, mean (SD)
Eligibility: diagnosed with GD and immediately eligible for eligibility for treatment measure by the Dutch Immediately eligible patients were younger (14.1 (2.2) vs
mean (SD) age was 14.5 years (2.2)
seen between April 2002-December treatment versions of the Wechsler 15.6 (1.6) years, P = .001), and had a higher percentage living

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
649

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
2009. mean (SD) full-scale IQ was 96.9 Intelligence scale for Children with both parents (64% vs 23%, P < .001) compared to
Sampling method: 105 out of 201 (13.1) (WISC) delayed eligible adolescents.
adolescents consecutively enrolled Psychiatric comorbidities Full Scale IQ, P = 0.011
living arrangements
17 dropped out of the diagnosis o 51.7% lived with both parents were assessed using the DISC Immediately eligible, mean (SD): 99.1 (12.8)
procedure IV
o 48.3% lived with other Delayed eligible, mean (SD): 91.6 (12.4)
18 were not invited since they Cross-sectional: o Immediately eligible participants had a significantly higher
parents' education status exposures/outcomes were
were included IQ than delayed eligible patients
o 12.6% had high measured at the same time
61 declined Anxiety conditions, OR, P value
o 69.0% had medium around the time of intake
Subset: Comparisons were made There were no significant differences in comorbidities between
between TGNB adolescents o 18.4% had low
cohorts
immediately eligible for treatment Immediately eligible
(n = 63) and delayed eligible Any Condition, 1.7, P = NS
mean (SD) age was 14.1 years (2.2)
adolescents (n = 26) o Immediately eligible % (n): 17.5 (11)
mean (SD) full-scale IQ was 99.1
(12.8) o Delayed eligible, % (n): 26.9 (7)

living arrangements, Specific phobia, 0.80, P = NS

o 63.9% lived with both parents o Immediately eligible % (n): 4.8 (3)

o 36.1% lived with other o Delayed eligible, % (n): 3.8 (1)

Social phobia, 2.8 P = NS
parents' education status
o 19.0% had high o Immediately eligible % (n): 7.9 (5)

o 68.3% had medium o Delayed eligible, % (n): 19.2 (5)

o 12.7% had low Agoraphobia, N/A, P = NS

Delayed eligible o Immediately eligible % (n): 1.6 (1)

o Delayed eligible, % (n): 0 (0)
mean (SD) age was 15.6 years (1.6)
Separation anxiety, 1.2, P = NS
mean (SD) full-scale IQ was 91.6
(12.4) o Immediately eligible % (n): 3.2 (2)
living arrangements o Delayed eligible, % (n): 3.8 (1)
o 23.1% lived with both parents Generalized anxiety, N/A, P = NS

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
650

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o 76.9% lived with other o Immediately eligible % (n): 1.6 (1)
parents' education status, o Delayed eligible, % (n): 0 (0)
o 16.7% had high Mood conditions, OR, P value
o 70.8% had medium There were no significant differences in comorbidities between
o 12.5% had low cohorts
Any, 1.5, P = NS
o Immediately eligible % (n): 11.1 (7)
o Delayed eligible, % (n): 15.4 (4)
Major depression, 1.5, P = NS
o Immediately eligible % (n): 7.9 (5)
o Delayed eligible, % (n): 11.5 (3)
Dysthymia, 1.2, P = NS
o Immediately eligible % (n): 3.2 (2)
o Delayed eligible, % (n): 3.8 (1)
Disruptive conditions, OR, P value
There were no significant differences in comorbidities between
cohorts
Any, 3.5, P = NS
o Immediately eligible % (n): 6.3 (4)
o Delayed eligible, % (n): 19.2 (5)
ADHD combined, 1.2, P = NS
o Immediately eligible % (n): 3.2 (2)
o Delayed eligible, % (n): 3.8 (1)
ADHD inattentive, 2.5, P = NS
o Immediately eligible % (n): 1.6 (1)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
651

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Delayed eligible, % (n): 3.8 (1)
ADHD hyperactive, N/A, P = NS
o Immediately eligible % (n): 0 (0)
o Delayed eligible, % (n): 3.8 (1)
Oppositional defiant, 5.5, P = NS
o Immediately eligible % (n): 3.2 (2)
o Delayed eligible, % (n): 15.4 (4)
o Number of DSM-IV diagnoses, OR, P value
One or more, 1.6, P = NS
o Immediately eligible % (n): 28.6 (18)
o Delayed eligible, % (n): 38.5 (10)
Two or more, 2.9, P = NS
o Immediately eligible % (n): 9.5 (6)
o Delayed eligible, % (n): 23.1 (6)
Three or more, N/A, P = NS
o Immediately eligible % (n): 0 (0)
o Delayed eligible, % (n): 7.7 (2)
de Vries (2011)57 Transgender adolescents (N = 70) Mean age at assessment (yr, SD), Natal males (n = 33) Natal females (n = 37) Self-reported measures: Compared with natal males, natal females reported
P = .028 significantly more feelings of anger and anxiety. There was
Eligibility: N/R BDI-II
o Natal males: 13.14 (1.55) not a significant effect between sex on depression scores.
Sampling method: First 70 TPI
o Natal females: 14.10 (1.99) Mean BDI-II score (SD), (n = 41):
transgender adolescents who were STAI
referred for medical treatment (ie, Mean age at start of GnRH analogs Before starting puberty suppression (T0):
puberty suppression) between 2000 Cohort: outcomes were
(yr, SD), P = .036 o Natal males: 5.71 (4.31)
and 2008 measured before (T0) and while
o Natal males: 14.25 (1.79) on puberty suppression, before o Natal females: 10.34 (8.24)
o Natal females: 15.21 (1.95) CSH (T1) While taking puberty suppression (T1):

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
652

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Subset definition: Comparisons Mean age at start of CSH (yr, SD), o Natal males: 3.50 (4.58)
were made between natal males P = .008 o Natal females: 6.09 (7.93)
(n = 33) and natal females (n = 37) o Natal males: 16.24 (1.21) Between-sex significance: 3.85, P = NS:
o Natal females: 16.99 (1.07) Mean TPI score (SD), (n = 41):
Mean time between start of GnRH Before starting puberty suppression (T0):
analogs and CSH (yr, SD), P
value = 0.405 o Natal males: 5.22 (2.76)

o Natal males: 1.99 (0.94) o Natal females: 6.43 (2.78)

o Natal females: 1.78 (1.16) While taking puberty suppression (T1):

o Natal males: 5.00 (3.07)
o Natal females: 6.39 (2.59)
Between-sex significance: 5.70, P = .022
Mean STAI score (SD), (n = 41):
Before starting puberty suppression (T0):
o Natal males: 4.33 (2.68)
o Natal females: 7.00 (2.36)
While taking puberty suppression (T1):
o Natal males: 4.39 (2.64)
o Natal females: 6.17 (2.62)
Between-sex significance: 16.07, P < .001
de Vries (2014)79 Transgender adults who had Mean age at assessment before Transgender women who had Transgender men who had Self-reported measures: Over time, trans men showed reduced anger and anxiety,
received puberty suppression treatment is started (yr, SD): received puberty suppression received puberty suppression whereas trans women were more stable. There was not a
BDI
during adolescence, and completed o Transgender women: 13.6 (1.8) during adolescence, and during adolescence, and significant effect between sex on depression scores.
gender reassignment surgery completed gender completed gender TPI
o Transgender men: 13.7 (2.0) Mean depression (BDI) score (SD):
(N = 55) reassignment surgery (n = 22) reassignment surgery (n = 33) STAI
Mean age at start of GnRH analogs At the start of CSH (T1):
Eligibility: Prescribed puberty Cohort: outcomes were
(yr, SD): o Transgender women: 2.25 (3.54)
Netherlands) suppression at the clinic as an measured before the start of
adolescent with GD, and received puberty suppression (pre-
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
653

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
gender reassignment surgery o Transgender women: 14.8 (2.0) treatment; T0), at the start of o Transgender men: 5.05 (7.08)
between 2004 and 2011 o Transgender men: 14.9 (1.9) CSH (T1), and at least 1 year after At least 1 year after gender reassignment surgery (T2):
gender reassignment surgery (T2)
Sampling method: This group of Mean age at start of CSH (yr, SD): o Transgender women: 3.38 (4.40)
adolescents belonged to a larger
o Transgender women: 16.5 (1.3) o Transgender men: 6.95 (9.83)
group of adolescents (n = 196) who
were referred for treatment o Transgender men: 16.8 (1.0) Mean anger (TPI) score (SD):
between 2000 and 2008. Mean age at gender reassignment At the start of CSH (T1):
Participants were recruited for the surgery (yr, SD): o Transgender women: 14.00 (3.36)
study between 2008 and 2012, at
o Transgender women: 19.6 (0.9) o Transgender men: 19.25 (5.69)
least 1 year post gender
reassignment surgery o Transgender men: 19.0 (0.8) At least 1 year after gender reassignment surgery (T2):
Subset definition: Comparisons Mean age at assessment after gender o Transgender women: 5.58 (3.92)
were made between transgender reassignment surgery (yr, SD):
o Transgender men: 16.56 (6.06)
women (n = 22) and transgender o Transgender women: 21.0 (1.1)
men (n = 33) Mean anxiety (STAI) score (SD):
o Transgender men: 20.5 (0.8)
At the start of CSH (T1):
Mean pre-treatment BDI score (SD):
o Transgender women: 31.71 (8.36)
o Transgender women (n = 12): 4.73
(4.20) o Transgender men: 41.59 (9.03)

o Transgender men (n = 20): 10.09 At least 1 year after gender reassignment surgery (T2):
(8.34) o Transgender women: 35.83 (10.22)
Mean pre-treatment anger TPI score o Transgender men: 39.20 (10.53)
(SD):
o Transgender women (n = 12):
14.17 (3.01)
o Transgender men (n = 20): 19.55
(5.96)
Mean pre-treatment anxiety (STAI)
score (SD):

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
654

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Transgender women (n = 12):
31.87 (7.42)
o Transgender men (n = 20): 44.41
(9.06)
Durwood (2017)109 Socially transitioned transgender Mean age (yr, SD; N = 63): 10.8 (1.3) Youth taking hormonal Untreated youth (n = 39) Child-reported depression Mean depression T-score (SD), P = NS:
youth (6 to 14 years of age) treatment: and anxiety measured by Youth taking CSH:
Part of a longitudinal Asserted gender:
enrolled in the Trans Youth Project NIH's PROMIS
study (Trans Youth o Boys: 33 (52.4) CSH (n = 5) o Child-reported: 48.7 (8.1)
who completed the depression and
Project) Parent-reported depression
anxiety measurements (N = 63) o Girls: 30 (47.6) Hormone blockers (n = 18) o Parent-reported: 49.3 (9.5)
and anxiety measured by a
Eligibility: Participants needed to Race or ethnicity (N = 63): proxy version of NIH's Youth taking hormone blockers:
identify as a gender opposite their o White, non-Hispanic: 37 (58.7) PROMIS o Child-reported: 48.6 (9.1)
natal sex in everyday life, socially Answers were converted to a
o Hispanic: 8 (12.7) o Parent-reported: 50.9 (8.3)
transitioned, and enrolled in the Likert type scale and then a
Trans Youth Project from March o Asian: 4 (6.3) Youth not taking CSH or hormone blockers:
standardized T score.
2015 to February 2016 o Black: 1 (1.6) o Child-reported: 48.4 (9.8)
Cross-sectional:
Sampling method: Participants o Multiracial/other: 13 (20.6) exposures/outcomes were o Parent-reported: 49.9 (9.3)
were from the larger Trans Youth measured at the same time Mean anxiety T-score (SD), P = NS:
Project. Participants were recruited
into the Trans Youth Project by Youth taking CSH:
national and local support groups, o Child-reported: 48.7 (8.8)
summer camps, online forums, and o Parent-reported: 51.0 (10.5)
word of mouth
Youth taking hormone blockers:
Subset definition: Comparisons
o Child-reported: 51.4 (8.3)
were made between transgender
youth taking hormone blockers o Parent-reported: 54.0 (8.2)
(n = 18), CSH (n = 5), and no Youth not taking CSH or hormone blockers:
treatment (n = 39). One untreated
o Child-reported: 52.6 (10.4)
child was excluded from the
comparison. o Parent-reported: 55.7 (9.4)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
655

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Grannis (2021)110 FTM adolescents (N = 42) Mean age (yr, SD), P value < 0.01: Received intramuscular Did not receive intramuscular Self-reported measures: Compared to untreated participants and after controlling for
o Treated FTM: 17.0 (1.2) testosterone cypionate testosterone cypionate (n = 23) age, those who received testosterone cypionate had
A gender Eligibility: Diagnosis of GD, 9 to 21 SCARED questionnaire
(n = 19) significantly lower mean symptom severity for:
developmental clinic at yrs of age, and able to participate in o Untreated FTM: 15.8 (1.5) LSAS questionnaire
a children's hospital MRI-based research o generalized anxiety: F(1,39) = 6.99 (measured by SCARED,
History of anxiolytics/anti-depressant CDI assessment P = .01; η² = 0.16)
Sampling method: Study sample use:
was drawn from a larger study of SBQ-R o social anxiety: F(1,39) = 17.21 (measured by LSAS,
o Treated FTM: 10 (52.6) P < .001; η² = 0.32)
transgender youth receiving gender Cross-sectional:
affirming medical care (both PB and o Untreated FTM: 18 (78.3) exposures/outcomes were o depression: F(1,39) = 7.39 (measured by CDI, P = .01;
CSH). All participants were receiving Birth control use: measured at the same time η² = 0.16)
gender affirming behavioral support
o Treated FTM: 15 (79.0) Lower rates of suicidality in the prior year trended towards
and had not been prescribed PBs
o Untreated FTM: 15 (65.2) significant in those treated with testosterone (F[1,39] = 3.85,
previously.
P = .06; η² = 0.09)
Subset definition: Comparisons Mean duration of testosterone use
(months, SD): No significant differences emerged between treated and
were made between treated untreated participants for lifetime suicidality (P = 0.27), and
(n = 19) and untreated (n = 23) FTM o Treated FTM: 13.1 (10.3) non-suicidal self-injury in the past year (P = .42) or during the
adolescents Mean testosterone dosage (mg, SD): participant's lifetime (P = .15)
o Treated FTM: 242.1 (82.3)
111
Green (2022) TGNB youth aged 13 to 17 Mean age (yr, SD), P < .001 Survey participants, aged 13 Survey participants, aged 13 to Self-reported measures: Receiving CSH therapy was associated with lower odds of
(N = 3,235) o Received CSH: 16.00 (1.03) to 17, who had received CSH 17, who had not received CSH recent depression and attempting suicide in the past year
Large US nationwide 2-item PHQ (PHQ-2)
therapy (n = 274) therapy (n = 2,961) Depression (measured by PHQ-2):
online survey Eligibility: Youth aged 13 to 24 o Did not receive CSH: 15.09 (1.36) Suicidal thoughts and
conducted between residing in the US who identified as Multivariate logistic regression (aORa; 95% CI): 0.61 (0.43 to
Gender identity, P < .001 behaviors (from the CDC's
October and December LGBTQ or gender questioning. 0.86); P < .01
Youth Risk Behavior Survey)
2020 Excluded participants included Nonbinary:
Cross-sectional: Seriously considered suicide:
those who lived outside of the US, o Received CSH: 42 (15.3)
were < 13 or > 24 years of age, and exposures/outcomes were Multivariate logistic regression (aORa; 95% CI): 0.74 (0.52 to
o Did not receive CSH: 1,382 (46.7) measured at the same time 1.03), P = NS
reported being both cisgender and
heterosexual Transgender boy/man: Attempted suicide:
Sampling method: Targeted ads o Received CSH: 205 (74.8) Multivariate logistic regression (aORa; 95% CI): 0.62 (0.40 to
from social media (ie, Instagram, o Did not receive CSH: 1,377 (46.5) 0.97), P = .04
Snapchat, Facebook) were used to

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
656

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
recruit participants. Eligible Transgender girl/woman:
participants had to complete a o Received CSH: 27 (9.9)
secured questionnaire with validity
checks. Participation was voluntary o Did not receive CSH: 202 (6.8)
and informed consent was obtained History of PBs, P < .001:
Subset definition: TGNB youth aged o Received CSH: 66 (24.4)
13 to 17 was a subset of the overall o Did not receive CSH: 37 (1.3)
survey population (N = 34,759).
Depression, P < .001:
Comparisons were made between
TGNB youth (aged 13 to 17) who o Received CSH: 167 (60.9)
received CSH therapy (n = 274) and o Did not receive CSH: 2,294 (77.9)
those who desired CSH therapy but
Seriously considered suicide, P < .001:
did not receive it (n = 2,961)
o Received CSH: 135 (51.1)
o Did not receive CSH: 1,674 (61.6)
Attempted suicide, P < .001:
o Received CSH: 42 (16.0)
o Did not receive CSH: 733 (27.7)
Khatchadourian Adolescents diagnosed with GD Mean age at first clinic visit (yr, SD): Presence of comorbid Presence of comorbid Psychiatric comorbidities Presence of psychiatric comorbidities (n, %):
(2014)82 (N = 84) o MTF: 16.8 (2.4) psychiatric conditions in MTF psychiatric conditions in FTM diagnosed by a mental health Mood disorder, P = 0.01:
adolescents adolescents professional (psychologist or
Eligibility: Pubertal development of o FTM: 16.4 (2.1) o MTF: 7 (19)
psychiatrist)
at least Tanner stage 2, previously
Mean age at start of GnRH analog Cross-sectional: o FTM: 20 (44)
seen by a mental health
treatment (yr, SD): exposures/outcomes were Anxiety disorder, P = .02:
professional at the British Columbia
Transgender Clinical Care Group, o MTF (n = 11): 14.7 (1.7) measured at the same time o MTF: 4 (11)
and confirmed diagnosis of GD o FTM: (n = 15): 14.8 (2.1) o FTM: 15 (33)
Sampling method: Data was Tanner stage at start of GnRH analog Attention-deficit/hyperactivity disorder, P = NS:
extracted from clinic notes of treatment:
patients that were seen in clinic o MTF: 6 (16)
2 to 3:
o FTM: 2 (4)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
657

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
from January 1998 to December o MTF: 5 (45) Eating disorder, P = NS:
2011 o FTM: 4 (27) o MTF: 2 (5)
Subset definition: Comparisons 4 to 5: o FTM: 2 (4)
were made between MTF (n = 37)
o MTF: 6 (55) Pervasive developmental disorder/autism spectrum disorder,
and FTM (n = 45) adolescents
o FTM: 10 (67) P = NS:

Mean age at start of CSH (yr, SD): o MTF: 4 (11)

o MTF (n = 24): 14.7 (2.2) o FTM: 2 (4)

o FTM (n = 39): 17.0 (1.6) ≥ 2 DSM-IV diagnoses, P = NS:

Tanner stage at start of CSH: o MTF: 9 (24)

2 to 3: o FTM: 12 (27)

o MTF: 1 (4) Substance abuse, P = NS:

o FTM: 6 (15) o MTF: 4 (11)

4 to 5: o FTM: 2 (4)

o MTF: 21 (88) Suicide attempt resulting in an emergency department visit,

P = NS:
o FTM: 32 (82)
o MTF before first clinic visit: 2 (5)
Mean age at start of spironolactone
(yr, SD): o FTM before first clinic visit: 6 (13)

o MTF: 17.6 (1.9) o MTF after first clinic visit: 1 (3)

o FTM: N/A o FTM after first clinic visit: 3 (7)

Tanner stage at start of Psychiatric hospitalization for posttraumatic stress disorder,

spironolactone: substance abuse, depression, psychosis, behavioral issues, or
anxiety, P = NS:
2 to 3:
o MTF before first clinic visit: 3 (8)
o MTF: 0 (0)
o FTM before first clinic visit: 7 (16)
o FTM: N/A
o MTF after first clinic visit: 0 (0)
4 to 5:
o FTM after first clinic visit: 1 (1)
o MTF: 25 (100)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
658

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o FTM: N/A Prescribed CSH (n, %), P < .02:
o MTF (oral micronized 17β-estradiol): 24 (65)
o FTM (injectable testosterone enanthate and/or
cypionate): 39 (87)
Nahata (2017)115 TGNB adolescents (N = 79) 51 (64.6%) trans gender males TGNB males (n = 51) TGNB females (n = 28) Mental health conditions Mental health conditions n(%)
28 (35.4%) transgender females were documented if they There was no significant difference in the rate of depression
large urban, Eligibility: Patients had the ICD 9/10 were formally diagnosed by a between transgender males: 42 (82.4%) and transgender
Midwestern, pediatric codes for gender dysphoria in their None of the subjects identified as psychiatrist through standard females: 20 (71.4%), P = NS
academic center from nonbinary or genderqueer.
medical records clinical practice at any time in
2014-2016 There was no significant difference in the rate of Anxiety
Median age at first endocrinology the EMR since receiving care between transgender males: 34 (66.6%) and transgender
Sampling method: Patients records visit was 15 years (range 9–18 years). in the institution. females: 26 (57.1%), P = NS
were reviewed from 2014-2106 for
Majority of patients were white, Conditions reviewed were: There was no significant difference in the rate of PTSD
participants with the ICD 9/10
codes for gender dysphoria, N = 66 (83.5%) o depression between transgender males: 13 (25.6%) and transgender
referred to a pediatric Gender-affirming hormone therapy o anxiety females: 5 (17.9%), P = NS
endocrinology multidisciplinary was initiated in N = 40 subjects There was no significant difference in the rate of eating
o post-traumatic stress
gender program for hormone disorder (PTSD) disorders between transgender males: 5 (9.8%) and
therapy. transgender females: 5 (17.9%), P = NS
o eating disorders
There was no significant difference in the rate of ASD
Subset definition: Comparisons o autism spectrum disorder
between transgender males: 3 (5.9%) and transgender
were made between transgender (ASD)
females: 2 (7.1%), P = NS
males (n = 51) and transgender o bipolar disorder
females (n = 28) There was no significant difference in the rate of bipolar
o self-injurious behavior disorder between transgender males: 3 (5.9%) and
(including suicidal ideation, transgender females: 1 (3.6%), P = NS
self-harm, and suicide
attempts)
Self-injurious behaviors
o The presence of and There was no significant difference in the rate of Suicidal
frequency of suicidal ideation between transgender males: 40 (78.4%) and
ideation, self-harm, and transgender females: 19 (67.9%), P = NS
suicide attempts were
recorded based on what

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
659

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
was documented by their There was no significant difference in the rate of Self-harm
psychiatrist. between transgender males: 31 (60.7%) and transgender
Cross-sectional study: females: 13 (46.4%), P = NS
measurements/outcomes were There was no significant difference in the rate of having one
taken at the same time or more suicide attempts between transgender males: 15
(29.4%) and transgender females: 9 (32.1%), P = NS
o There were no statistical differences between genders in
any mental health outcomes
Olsavsky (2023)116 TGNB adolescents (N = 75) Mean age: TGNB youth with nonbinary TGNB youth with binary gender Anxiety Symptoms measured Anxiety
16.39 ± 1.62 SD range (11-18) identity (n = 6) identity (n = 69) by adolescents competing the
Gender affirming Eligibility: Adolescents were eligible There was no significant correlation between TGNB youth
SCARED screening
multidisciplinary clinic if they had a GD diagnosis, were 9- Gender at birth: identifying as binary and not identifying as binary for anxiety
N = 43 (57.3%) assigned female at questionnaire
in a large, Midwestern 21 years old and were able to scores (P = NS), accounting for all other variablesc.
children's hospital participate in MRI-based research. birth Depressive symptoms
Depression
N = 32 (42.7%) assigned male at birth measure by adolescents
Sampling Method: TGNB There was no significant correlation between TGNB youth
completing the CDI
adolescents were recruited from Gender Identity: identifying as binary and not identifying as binary for
the clinic between Dec 2018-March NSSI measured by 1 question
N = 41 (54.7%) Identify as male depressive symptoms (P = NS), accounting for all other
2020, March 2021-Feb 2022. based on the SBQ-R and the
N = 28 (37.3%) Identify as female variablesc.
Adolescents who met the inclusion C-SSRS, "How often have you
criteria were reimbursed via a N = 6 (8%) identify as nonbinary harmed yourself without the NSSI
prepaid gift card. Of 101 intent of killing yourself in the TGNB youth identifying as a nonbinary was correlated with
Hormone therapy
approached, 82 participated (81%) past year?" (rated from 1- higher scores of NSSI of 0.29 compared to TGNB youth not
N = 39 (52.0%) receiving GAHT
and 7 were excluded due to never to 5-very often) identifying as nonbinary. P < .05
incomplete surveys. All adolescents o N = 32 (42.7%) receiving CSHT
Suicidality was measured by When accounting for all other variablesc, identifying as
provided informed consent/assent; (testosterone, estrogen)
asking 1 question from the nonbinary was significantly associated with fewer reports of
parental consent was obtained for o N = 9 (12%) receiving puberty SBQ-R, "How often have you NSSI (b = 0.30, P = .008)
minors. blockers thought about killing yourself
Suicidality
Subset definition: Majority (77.3%) identify as white in the last year?" (rated from
1-never to 5-very often) There was no significant correlation between TGNB youth
Comparisons were made identifying as binary and not identifying as binary for
between TGNB youth suicidality scores, accounting for all other variablesc. (P = NS)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
660

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
identifying as non-binary (n = 6) TGNB youth receiving GAHT Untreated TGNB youth (n = 36) Social support was measured Anxiety
and TGNB youth identifying as a (n = 39) using the MSPSS TGNB youth taking gender-affirming hormonal intervention
gender (n = 69) use were each associated with fewer anxiety symptoms,
Bivariate correlations were
Comparisons were made examined and then those accounting for all other variablesc. (b = -0.23, P = .046)
between GNB youth that with a significant correlation Depression
received GAHT (n = 39) and were included in a Receiving gender-affirming hormonal interventions was
those that were untreated hierarchical linear regression significantly correlated with fewer depressive symptoms
(n = 36) model. compared to those not receiving GAHT, with a correlation of
Cohort: Outcomes were -0.23 ,P < .05
measured after exposure Fewer depressive symptoms was marginally associated with
gender-affirming hormonal intervention use, accounting for
all other variablesc. (b = -0.21, P = .05)
NSSI
There was no significant correlation between TGNB youth
taking GAHT vs not taking GAHT for NSSI scores, accounting
for all other variablesc. (P = NS)
Suicidality
There was no significant correlation between TGNB youth
taking GAHT vs not taking GAHT for suicidality scores,
accounting for all other variablesc. (P = NS)
TGNB youth receiving greater TGNB youth not receiving Anxiety
social support (from friends, greater social support TGNB youth with greater friend support was correlated with
family, and significant others) fewer anxiety symptoms than those without friend support,
with a correlation of -0.28, P < .05
TGNB youth with greater friend support was associated with
fewer anxiety symptoms, accounting for all other variablesc
(b = -0.32, P = .007)
Depression

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
661

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
TGNB youth with greater significant other support was
correlated with less suicidality than those without significant
other support, with a correlation of -0.29, P < .05
TGNB youth with greater family support was correlated with
fewer depressive symptoms than those without family
support, with a correlation of -0.39, P < .01
Fewer depressive symptoms was significantly associated with
family support for TGNB youth, accounting for all other
variablesc (b = -0.33, P = .003)
NSSI
TGNB youth with greater family support was correlated with
less reports of NSSI than those without family support, with a
correlation of -0.25, P < .05
TGNB youth with greater family support was significantly
associated with fewer reports of NSSI, accounting for all
other variablesc, (b = -0.27, P = .019)
Suicidality
TGNB youth with greater friend support was correlated with
less suicidality than those without friend support, with a
correlation of -0.26, P < .05
TGNB youth with greater significant other support was
correlated with less suicidality than those without significant
other support, with a correlation of -0.32, P < .01
TGNB youth with greater family support was correlated with
less suicidality than those without family support, with a
correlation of -0.28, P < .05
TGNB youth with greater friend support was significantly
associated with less suicidality, accounting for all other
variablesc, (b = -0.25, P = .03)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
662

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o No other significant correlations or associations were
found between social support and mental health
outcomes
Segev-Becker (2020)117 pubertal TGNB adolescents (N = 95) The mean age at clinic referral: Presence of comorbid Presence of comorbid Chart reviewed for psychiatric Depression n(%)
o transgender females: 15.9 ± 1.7 psychiatric conditions in psychiatric conditions in comorbidities as recorded by a There was no significant difference in the rate of TGNB girls
Eligibility: All patients who were
years pubertal TGNB females pubertal TGNB males (n = 58) mental health professional with depression: 9 (24) compared to TGNB boys: 12 (29),
referred to the clinic between
(n = 38) P = NS
March 2013 and December 2018 o transgender males: 15.2 ± 1.7 Cross-sectional:
were eligible years exposures/outcomes were Suicidal thoughts n(%)
Israel measured at the same time There was no significant difference in the rate of TGNB girls
Sampling Method: All consecutive o transgender females were
with suicidal thoughts: 4 (10) compared to TGNB boys: 7 (12),
patients younger than 18 years of significantly older, P = .032
P = NS
age who were referred to the clinic
The mean age at presenting as Suicide attempts n(%)
between March 2013 and
transgender:
December 2018 were included in There was no significant difference in the rate of TGNB girls
the study. The majority of patients o transgender females: (13.7 ± 2.7 with suicide attempts: 3 (8) compared to TGNB boys: 10 (17),
had been evaluated by a commu- years [range, 6.5 to 17.4 years] P = NS
nity MHP and were diagnosed with o transgender males: 14 ± 1.5 years Eating disorders n(%)
GD according to the DSM 5 criteria [range, 10 to 17 years] There was no significant difference in the rate of TGNB girls
prior to their first visit to the GD o No significant difference in age with eating disorders: 3 (8) compared to TGNB boys: 2 (3.5),
clinic. P > .05 P = NS
Subset definition: comparisons At the time of referral, n (%) at School dropouts n(%)
were made between TGNB females Tanner stage 4 to 5 of puberty There was no significant difference in the rate of TGNB girls
(n = 38) and TGNB males (n = 58) with school dropouts: 12 (32) compared to TGNB boys: 12
o transgender females: 36 (89%)
(20), P = NS
o transgender males: 55 (95%)
Substance abuse n(%)
At the time of referral, 91 (95%) of
There was a significant difference in the rate of substance
the pubertal group had completed
abuse between TGNB girls: 6 (16) compared to TGNB boys: 1
sexual maturation in their assigned
(1.5) P = .01
gender at birth.
Psychiatric Medication, n(%)
77 (80%) pubertal patients began
GnRH analog treatment at a mean

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
663

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
age of 15.6 ± 1.6 years (range, 11 to There was no significant difference in the rate of TGNB girls
18.5 years). taking psychiatric medication: 12 (32) compared to TGNB
Sixty-one of the patients who began boys: 17 (29), P = NS
GnRH analog treatment (83%) were ADD/ADHD, n(%)
started on CSH treatment either There was no significant difference in the rate of TGNB girls
concurrently or later, at a mean age with ADD/ADHD: 8 (21) compared to TGNB boys: 18 (31),
of 16.5 ± 1.3 years (range, 13 to 18.9 P = NS
years).
Autistic Spectrum, n(%)
There was a significant difference in the rate of autism
spectrum between TGNB girls: 4 (10) compared to TGNB
boys: 0 (0) P = .02
Sorbara (2020)118 N = 300 TGNB youth YPY (n = 116): Younger presenting Youth to Older Presenting Youth to clinic Youth or caregiver reports of Reported Mental Illness
Eligibility: Diagnosis of gender clinic (n = 116) (n = 184) formal diagnoses of
Transgender youth o Age: 13.9 (range 12.9 to 14.5) Depression
dysphoria and seen by clinic staff. depressive, anxiety, and
clinic in Exclusion criteria was if they were o AFAB: 87 (75.0) o OPY had a higher rate of depression than YPY, P < .05.
autism spectrum disorders
not seeking CSH or had previously o Tanner stage < 3 (early puberty): were extracted from initial o OPY 46% vs. YPY 30%
Canada been on hormone blockers or CSH. 24 (20.7) visit documentation.
Sampling method: patients that Anxiety (Estimated values):
o Tanner stage > 4 (late puberty): 82 Reported active use of
were eligible from clinic o No significant difference between OPY and YPY, P = NS
Subset definition: Younger (70.7) psychoactive medication,
suicidal ideation at the time o YPY 44% vs OPY 45%
presenting youth (YPY) were < 15 o Tanner Stage not reported: 10 (8.6)
years old at presentation to clinic of or preceding the TYC visit, History of Self-harm
o Socially transitioned: 76 (65.5)
and were compared to older and history of self-harm or o OPY had a higher rate of history of self-harm than YPY,
presenting youths (OPY) were > 15 OPY (n = 184): suicide attempt were also P < .05
years when presented to clinic. o Age = 16.3 (range 15.6 to 16.8) recorded.
o OPY 40% vs. YPY 28%,
o AFAB: 142 (77.2) Cross sectional:
Measures/Outcomes taken at Current SI (Estimated values)
o Tanner Stage < 3 (early puberty): 2
same time at initial visit o No significant difference between OPY and YPY, P = NS
(1.1)
o YPY 8% vs. OPY 12%
o Tanner Stage > 4 (late puberty):
166 (90.2) History of SI
o Tanner Stage not reported: 16 (8.7)
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
664

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Socially transitioned: 149 (81.0) o OPY had more history of suicidal ideation compared to
YPY, P < .05
o OPY 52% vs. YPY 40%
Suicide Attempt
o OPY had significantly more suicide attempts than YPY,
P < .05
o YPY 9% vs. OPY 17%
Use of Psychotropic Medication
o OPY had significantly higher use of psychotropic
medications than YPY, P < .05
o YPY 23% vs. OPY 36%
TGNB youth were compared TGNB youth were compared by Pearson's X2 test or Fisher's Logistic Regression Factors Odds Ratio
by variables that increased variables that did not increase exact test was used to Depressive disorders
the odds of mental health the odds of mental health compare rates of mental Late pubertal stage youth were 5.49 times more likely to
problems. problems. health diagnoses between report the diagnosis of depressive disorders, P = .03.
YPY and OPY. Factors such as age at first visit, date cohort, social transition,
Logistic regression was used and assigned sex were not found to significantly impact the
to assess whether age at first odds of depression.
visit, pubertal stage, date Anxiety disorders
cohort, and social transition
were associated with mental Late pubertal stage youth were 4.18 times more likely to
health problems. report the diagnosis of anxiety disorders, P = .02.

Cross sectional: Factors such as age at first visit, date cohort, social transition,
Exposure/Outcomes measured at and assigned sex were not found to significantly impact the
same time at initial visit odds of having an anxiety disorder.
History of self-harm
Youth assigned female at birth were 3.41 times more likely to
have a history of self-harm, P = .006.

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
665

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Factors such as age at first visit, date cohort, social transition,
and pubertal stage were not found to significantly impact the
odds of having a history of self-harm.
Suicidal Ideation
There was no significant multicollinearity that predicted an
associated. Conditions for goodness of fit testing were not
met for the previous suicide attempt or current SI because
there were few events.
Psychoactive medication
1 year increases of age at first visit increased the odds of
psychoactive medication use by 1.31, P = .02
Factors such as pubertal stage, date cohort, social transition,
and assigned sex were not found to significantly impact the
odds of using PM.
Tollit (2023)120 N = 359 TGNB youth AMAB (n = 166): Trans females presenting at Trans males presenting at Mental Health data extracted Depression:
Eligibility: First appointment with Gender: RCHGS. (n = 166) RCHGS. (n = 193) from clinician-recorded notes TM = 74, TF = 108
clinic from January 1, 2007 to o 139 were transgender, collected at clinic
December 31, 2016, and had a self- appointments for: There were significantly more trans females reporting
reported gender identity which o 14 were non binary, depression than trans males, P = .03
gender clinic in o depressive disorder
differed from their gender at birth o 4 were cisgender and 9 weren't Eating Disorder:
Australia. o eating disorders
or sough clinical guidance on their sure.
TM = 1, TF = 4
gender identity. Age: o PTSD
Sampling method: Patients were There was no significant difference between trans males and
o Average age was 12.4 years. at GD o history of self-harm
selected if they met criteria and trans females having an eating disorder, P = NS
were a patient of the clinic. diagnosis o history of suicidal ideation
PTSD:
Subset definition: Comparisons Treatment:
TM = 1, TF = 4
were made between assigned o 126. 39 were on puberty blockers, Cross-sectional:
males at birth (n = 166) vs assigned exposures/outcomes were There was no significant difference between trans males and
females at birth (n = 193) o 7 were on anti androgens measured at the same time trans females having PTSD, P = NS
o 19 were on gender affirming Self-harm:
hormones.
TM = 25, TF = 64
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
666

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
AFAB (n = 193): There were significantly more trans females with a history of
self-harm compared to trans males, P < 0.05
Gender:
Suicidal Ideation:
o 174 were transgender,
TM = 36, TF = 70
o 12 were nonbinary,
o 2 were cisgender and 5 were not There were significantly more trans females reporting
sure. suicidal ideation than trans males, P < .05

Age:
o Average age was 14.8 years.
Treatment:
o 15 were on puberty blockers
o 57 were on menses suppression
o 29 were on gender affirming
hormones.
Tordoff (2022)96 TGNB adolescents and young adults Mean age (yr, SD; N = 104): Transgender adolescents and Transgender adolescents and Self-reported measures: After adjusting for potential confounders and temporal
(N = 104) o 15.8 (1.6) young adults who had young adults who had not trends, the odds of moderate to severe depression (PHQ-
PHQ-9 questionnaire
received PBs (eg, GnRH received PBs, CSHs, or both 9 ≥ 10) was reduced by 60% in patients treated with PBs or
Eligibility: TGNB adolescents and Gender identity (N = 104): analogs), CSHs (eg, estrogen, after 12 months (n = 35) Suicidal thoughts or self-harm CSHs compared to untreated patients (ie, not yet started PBs
young adults desiring gender-
o Male or transgender male: 63 testosterone), or both after 12 were evaluated using the or CSHs)
affirming care
(60.6) months (n = 69) PHQ-9
o aOR: 0.40; 95% CI: 0.17 to 0.95; P = .04; E-value: 2.56
Sampling method: After a referral is GAD-7 questionnaire
o Female or transgender female: 27 CSHs only: n = 50 (48.1%) After adjusting for potential confounders and temporal
received, including those initiated
(26.0) Cohort: outcomes were trends, patients treated with PBs or CSHs had a 73% lower
by the patient, a 1-hour phone PBs only: n = 5 (4.8%)
intake with a clinical social worker o Nonbinary or gender fluid: 10 (9.6) measured at 3 months (n = 84), 6 odds of suicidal thoughts or self-harm compared to those
PBs + CSHs: n = 14 (13.5%) months (n = 84), and 12 months
was required for the patient, o Don't know or missing: 4 (3.8) who had not started PBs or CSHs
caregiver, or both. After completion (n = 65)
Pharmacological intervention (at o aOR: 0.27; 95% CI: 0.11 to 0.45; P = .003; E-value = 3.25
of the phone intake, patients were
baseline or end of the study period; No significant relationship was observed for moderate to
scheduled for a clinic visit with a
N = 104): severe anxiety (GAD-7 ≥ 10) in patients who received PBs or
medical provider. All patients who
o PBs: 19 (18.2) CSHs compared to untreated patients after adjusting for
completed both the phone intake
potential confounders and temporal trends
and in-person visit between August
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
667

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
2017 and June 2018 were recruited. o CSHs: 64 (61.5) o aOR: 1.01; 95% CI: 0.41 to 2.51; P = .98
A baseline survey was completed o Androgen blockers (n = 33): 17 Subgroup analysis among patients aged 13 to 17 yrs (n = 90)
within 24 hours of their first (51.5) on the association between receiving CSH/PBs vs. those who
appointment, and were invited to did not, and mental health outcomes:
participate in follow-up surveys at o Menstrual suppression or
3, 6, and 12 months contraception: 25 (35.2) Moderate to severe depression (PHQ-9 ≥ 10):
Baseline depression (using PHQ-9; o aOR: 0.51; 95% CI: 0.19 to 1.37, P = NS
Subset definition: Comparisons
N = 104):
were made between treated Any suicidal thoughts/self-harm:
(n = 69) and untreated (n = 35) o Severe (score ≥ 20): 26 (25.0)
o aOR: 0.32; 95% CI: 0.12 to 0.88, P = .027
transgender youth o Moderately severe (score 15 to
Moderate to severe anxiety (GAD-7 ≥ 10):
19): 11 (10.6)
o aOR: 0.84; 95% CI: 0.29 to 2.40, P = NS
o Moderate (score 10 to 14): 22
(21.2)
o Mild (score 5 to 9): 27 (26.0)
o Minimal (score 0 to 4): 14 (13.5)
o Missing: 4 (3.8)
Baseline anxiety (using GAD-7;
N = 104):
o Severe (score ≥ 15): 32 (30.8)
o Moderate (score of 10 to 14): 20
(19.2)
o Mild (score of 5 to 9): 28 (26.9)
o Minimal (score of 0 to 4): 20 (19.2)
o Missing: 4 (score of 3.8)
Baseline resilience (using CD-RISC, 10-
item, higher scores indicate greater
resilience; N = 104):
o Score of 0 to 10: 8 (7.7)
o Score of 10 to 20: 35 (33.7)
aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
668

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Score of 21 to 30: 15 (14.4)
o Score of 30 to 40: 34 (32.7)
Baseline suicidal thoughts or self-
harm (N = 104): 45 (43.2)
Turban (2020)121 TGNB adults who self-reported Mean age (yr, SD), P value = 0.001: Survey respondents who Survey respondents who Past-month severe Past-month severe psychological distress (K6 ≥ 13):
wanting pubertal suppression o Received PBs: 21.7 (4.7) reported receiving PBs during reported wanting to start a PB, psychological distress o Univariate analyses (OR; 95% CI): 0.5 (0.3 to 0.8), P = .001
Survey respondents
during adolescence (N = 3,494) adolescence (9 to 16 years of but never received it
were from all 50 US o Never received PBs: 23.4 (5.0) Suicidal ideation and suicide o Multivariable analyses (aORb; 95% CI): 0.8 (0.4 to 1.4),
age; n = 89) (n = 3,405)
states, American Eligibility: TGNB adults attempts P = NS
Mean age of social transition (yr, SD),
Samoa, District of Past month binge drinking
Sampling method: Of the 27,715 P value < 0.001 Suicidal ideation:
Columbia, Guam,
respondents, 20,619 participants Lifetime illicit drug use
overseas US military o Received PBs: 15.2 (4.5) Suicidal ideation in the past 12 months:
were between 18 to 36 years old.
bases, and Puerto Rico o Never received PBs: 20.1 (5.5) Cross-sectional: o Univariate analyses (OR; 95% CI): 0.6 (0.4 to 0.8), P = .006
Analysis was further restricted to
exposures/outcomes were
those who ever wanted pubertal Mean age at beginning hormone o Multivariable analyses (aORb; 95% CI): 0.6 (0.3 to 1.1),
measured at the same time
suppression (n = 3,494) treatment, P value < 0.001 P = NS
Subset definition: Comparisons o Received PBs: 15.7 (2.4) Suicidal ideation with plan in the past 12 months:
were made between those who o Never received PBs: 22.5 (4.3) o Univariate analyses (OR; 95% CI): 0.9 (0.5 to 1.6), P = NS
received pubertal suppression with
Sex assigned at birth, P value = 0.04: Lifetime suicidal ideation:
a PB (n = 89) and those who
desired it, but never received it AFAB: o Univariate analyses (OR; 95% CI): 0.3 (0.2 to 0.5), P < .001
(n = 3,405) o Received PBs: 39 (43.8) o Multivariable analyses (aORb; 95% CI): 0.3 (0.2 to 0.6),
P = .001
o Never received PBs: 1,874 (55.0)
Suicide attempt:
AMAB:
Attempt resulting in inpatient care in the past 12 months:
o Received PBs: 50 (56.2)
o Univariate analyses (OR; 95% CI): 2.8 (0.8 to 9.4), P = NS
o Never received PBs: 1,531 (45.0)
Suicidal ideation with plan and attempt in the past 12
Gender identity, P value < 0.001:
months:
Woman:
o Univariate analyses (OR; 95% CI): 1.2 (0.6 to 2.3), P = NS
o Received PBs: 23 (25.8)
Lifetime suicide attempts:
o Never received PBs: 617 (18.2)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
669

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Man: o Univariate analyses (OR; 95% CI): 0.7 (0.4 to 1.0), P = NS
o Received PBs: 19 (21.3) Past-month binge drinking (drinking ≥ 5 standard alcoholic
o Never received PBs: 383 (11.3) drinks during 1 occasion):

Transgender women: o Univariate analyses (OR; 95% CI): 0.3 (0.8 to 2.0), P = NS

o Received PBs: 25 (28.1) Lifetime illicit drug use (excluding marijuana use):

o Never received PBs: 720 (21.3) o Univariate analyses (OR; 95% CI): 1.1 (0.7 to 1.8), P = NS

Transgender man:
o Received PBs: 16 (18.0)
o Never received PBs: 795 (23.5)
Nonbinary or genderqueer:
o Received PBs: 6 (6.7)
o Never received PBs: 866 (25.6)
Turban (2022)122 N= 21,598 survey participants No CSH but wanted (n= 8860) CSH: defined as testosterone CSH at age >18 Survey data was used to Mental Health outcomes after adjusting for confounding:
and estrogen received at ages compare mental health
2015 U.S. Transgender Eligibility: those enrolled in the 2620 were trans male Access to CSH ages 14-17 was associated with lower odds of
14-17 outcomes:
Survey (USTS) survey were >18 years. Study was past month severe psychological distress (aOR=0.6, 95% CI=
2324 were trans female
conducted a survey in restricted to only those that o past suicidal ideation in 0.5-0.8, P < .001), when compared to access to CSH during
August-September responded they had been 2829 were AFAB/NB past 12 months adulthood
2015 in transgender interested in CSH (n=21,598) 766 were AMAB/NB o past year suicidal ideation Access to CSH ages 14-17 was associated with lower odds of
adults (>18 years) with plan
Sampling method: participants 321 identified as other past year SI (aOR=0.7, 95% CI= 0.6-0.9, P = .007), when
online
were recruited online through 400 o past year suicide attempt compared to access to CSH during adulthood
135 were 18-24
community organizations o severe psychological Access to CSH ages 14-17 was associated with lower odds of
2653 were 25-44
Subset definition: Grouped by age distress measured by the past month binge drinking (aOR=0.7, 95% CI= 0.5-0.9,
of CSH initiation: (CSH 14-15), (CSH 753 were 45-64 Kessler-6 Psychological P = .001), when compared to access to CSH during adulthood
16-7) and (CSH >18) 139 were 65+ years old Distress Scale (>13) Access to CSH ages 14-17 was associated with lower odds of
CSH 14-15: (n= 119) lifetime illicit drug use (aOR=0.7, 95% CI =0.5-0.8, P = .0003)
when compared to access to CSH during adulthood

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
670

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
48 were trans male o binge drinking the month There was no significant difference (P = NS) between access
prior (more than 5 drinks to CSH at ages 14-17 vs. during adulthood when comparing
54 were trans female
on a single occasion) having an SI plan, SI attempt or SI with hospitalization
13 were AFAB/NB
Access to CSH during Wanted CSH but never took o lifetime illicit drug use Mental health outcomes after adjusting for confounders:
4 were AMAB/NB
adolescence- both early Multivariable logistic
75 were 18-24 years Access to CSH during early adolescence was associated with
adolescence (14-15) and late regression was performed,
lower odds of past month severe psychological distress
23 were 25-44, 19 were 45-64 adolescence (16-17) comparing mental health
(aOR= 0.3, 95% CI=0.2-0.4,ˆP < .0001), when compared to
outcomes for participants
2 were 65+ years old wanting CSH but never accessing them.
groups.
CSH 16-17: (n= 362) Access to CSH during early adolescence was associated with
All models adjusted for age,
lower odds of past year SI (aOR=0.4, 95% CI=0.2-0.6,
214 were trans male partnership status,
P < .001) when compared to wanting CSH but never
109 were trans female employment status, K-12
accessing them.
harassment and having
35 were AFAB/NB experienced gender identity No other detected difference for other mental health
4 were AMAB/NB conversion efforts and any variables comparing early vs no CSH.
additional demographic and Access to CSH during late adolescence was associated with
297 were 18-24 years
potential confounding lower odds of past month psychological distress (aOR=0.3,
54 were 25-44 variables that were found to 95% CI=0.3-0.4, P < .001) when compared to CSH desiring
11 were 45-64 be associated with each CSH but never accessing them
outcome.
CSH>18: (n= 12,257) Access to CSH during late adolescence was associated with
Cross sectional/Case-control- lower odds of past year suicidal ideation (aOR=0.5, 95% CI
4713 were trans male Outcomes and Exposures were =0.4-0.7, P < .0001) when compared to CSH desiring CSH but
6340 were trans female measured at the same time never accessing them.
834 were AFAB/NB No other difference detected comparing late adolescent CSH
330 were AMAB/NB treatment vs. no CSH
40 identified as other CSH: defined as testosterone CSH at age 16-17 No difference in mental health outcomes detected in
2856 were 18-24 and estrogen received at ages participants that received CSH in late vs early adolescence
14-15 (P = NS)
6285 were 25-44
2660 were 45-64

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
671

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
456 were 65+
Frequency of Mental Health Outcomes
No CSH
o Past year SI: 5144
o SI with plan: 2731
o SI with attempt: 853
o SI with hospitalization: 220
o K6>13: 4545
o binge drinking: 2083
o illicit drug use: 1918
CSH 14-15
o Past year SI: 48
o SI with plan: 29
o SI with attempt: 8
o SI with hospitalization: 1
o K6>13: 40
o binge drinking: 39
o illicit drug use: 40
CSH 16-17
o Past year SI: 40
o SI with plan: 39
o SI with attempt: 40
o SI with hospitalization: 40
o K6>12: 145
o binge drinking: 74

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
672

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o illicit drug use: 93
CSH >18:
o Past year SI: 5237
o SI with plan: 2537
o SI with attempt: 756
o SI with hospitalization: 247
o K6>12: 3419
o binge drinking: 3214
o illicit drug use: 4455
van der Miesen N = 450 TGNB adolescents referred TGNB subjects who did not started any Transgender group: on Transgender group: have not Psychological functioning Suicidality: Mean scores (SD) on the Youth Self-Report for
(2020)124 to a specialized gender identity affirmative medical treatment yet: puberty suppression and yet received any affirmative outcomes were measured suicidality
clinic Mean age (SD) in years = 14.47 (2.18); about to start unspecified CSH medical treatment (n = 272) using the Dutch version of the The adolescents at referral had significantly higher scores
116 assigned boys at birth and 156 treatment (n = 178) YSR to assess: than those using puberty suppression.
Eligibility criteria: assigned girls at birth o Self-harm/suicidality o transgender adolescents receiving affirmative care: 0.17
Not clearly stated TGNB subjects receiving affirmative care
and about to start GAH treatment: o Effect sizes Cohen's d: .80 (0.52)
the Sampling method: or higher is a large effect
Mean age (SD) in years = 16.75 (1.24); 68 o transgender adolescents who did not receive any
Netherlands, between Transgender cohort: Adolescents size, .50-.79 a medium
assigned boys at birth and 110 assigned affirmative treatment: 0.41 (0.78)
2012 and 2015 who just started the diagnostic effect size, .20-.49 small,
girls at birth o Effect sizes Cohen's d between the groups was 0.36
procedure were assessed during and effect sizes < .20 are
their first sessions at the VUmc. negligible
Adolescents diagnosed with GD
Cross-sectional:
were assessed before the start of
Exposures/outcomes measured
GAH. During both assessments,
at the same time
parents and children completed
several questionnaires during 2012
to 2015, 504 adolescents were seen
in their gender identity service. 53
participants did not complete the
assessment process and therefore,
did not participate in this study. The

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
673

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
reason for dropout was failure to
complete the questionnaire or
alternation of symptoms of GD. Of
the adolescents diagnosed with GD,
179 were about to start GAH
treatment. One participant did not
complete the questionnaire and
was thus excluded.
Subset: Comparisons were made
between TGNB adolescents
receiving affirmative care and about
to start GAH treatment: (N = 272)
and TGNB adolescents at referral,
that have not yet started
affirmative care (n = 178)
Subset: Comparisons were made Transgender subjects receiving TGNB adolescents AMAB: TGNB adolescents AFAB: have Suicidality: Mean scores (SD) on the Youth Self-Report for
between TGNB adolescents that affirmative care and about to start CSH have been receiving puberty been receiving puberty suicidality
had received puberty suppression treatment: suppression, and getting suppression, and getting ready
Gender assigned at birth had negligible effect on suicidality,
who were AMAB (n = 68) vs AFAB Mean age (SD) in years = 16.75 (1.24); 68 ready to start CSH treatment to start CSH treatment
(n = 110). (n = 68) effect size Cohen's d of -0.04
assigned boys at birth and 110 assigned (n = 110)
girls at birth o assigned boys: 0.16 (0.48)
o assigned girls: 0.18 (0.54)
Vehmas (2022)125 Transgender adolescents desiring Assigned sex at birth: Presence of comorbid Presence of comorbid The proportion of patients that Presence of psychiatric comorbidities (n, %):
gender-affirming hormonal o AMAB: n = 20 psychiatric conditions in MTF psychiatric conditions in FTM also had a diagnosis for a
Adolescent gynecology Depression, P = NS:
treatment (N = 124) adolescents (n = 20) adolescents (n = 104) psychiatric condition
clinic o AFAB: n = 104 o MTF: 5 (25.0)
Eligibility: Adolescents diagnosed Cross-sectional:
Median age at the first contact with o FTM: 31 (29.8)
(Finland) with GD, referred to gender identity exposures/outcomes were
gender identity services (yr, range; Anxiety, P = NS:
services at Helsinki University measured at the same time
N = 124):
Hospital before 18 years of age for o MTF: 4 (20.0)
GD symptoms, and further referred o 16.7 (12.1 to 18.0)
o FTM: 20 (19.2)
to the adolescent gynecology clinic Median age at GD diagnosis (yr,
range; N = 124): Attention-deficit/hyperactivity disorder, P = .14:

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
674

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Table I.J.1. Clinical studies with between-TGNB-group comparisons examining mental health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
for gender-affirming hormonal o 18.1 (14.8 to 20.1) o MTF: 2 (10.0)
assessment Median age at the time of assessment o FTM: 3 (2.9)
Sampling method: Referred by at the adolescent gynecology clinic Eating disorder, P = NS:
gender identity services (yr, range; N = 124):
o MTF: 0 (0)
Subset definition: Comparisons o 17.7 (14.6 to 19.8)
o FTM: 2 (1.9)
were made between MTF (n = 20)
and FTM (n = 104) transgender Psychotic disorder, P = NS:
adolescents o MTF: 0 (0)
o FTM: 2 (1.9)
Autism, P = NS:
o MTF: 1 (5.0)
o FTM: 1 (1.0)
Antidepressant use, P = NS
o MTF: 4 (22.2)
o FTM: 27 (26.2)

aMultivariate logistic regression adjusted for socioeconomic status, census region, age, sexual orientation, gender identity, race/ethnicity, parent support for gender identity, gender identity conversion efforts, gender identity-based victimization, and prior
puberty blocker use (Green 2022)
b Multivariable logistic regression models were adjusted for demographic variables (eg, family support, education level, employment status, sexual orientation, total household income, age); the demographic variables that were adjusted varied based on the

measured outcome (Turban 2020).

c Multivariable linear regression model used the following variables: Nonbinary identity, gender-affirming hormonal intervention use, and family and friends social support (Olsavsky, 2023).
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ADD, attention deficit disorder; ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; aOR: adjusted odds ratio; BDI-(Y), Beck Depression Inventory (for Youth); CBCL, Child Behavior
Checklist; CDC, Center for Disease Control and Prevention; CDI, Children's Depression Inventory; CD-RISC, Connor-Davidson Resilience Scale; CESD-R, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; CSH, cross sex hormones; C-SSRS,
Columbia suicide severity rating scale; DISC = IV, Diagnostic Interview Schedule for Children version IV; EMR, electronic medical record; FTM, female-to-male; GAD-7, Generalized Anxiety Disorder, 7-item; GAH, gender affirming hormones; GD, gender dysphoria;
GnRHa, gonadotropin-releasing hormone analog; GWBS, General Well-Being Scale; K6, Kessler Psychological Distress Scale; LGBTQ, lesbian, gay, bisexual, transgender, queer; LSAS, Liebowitz Social Anxiety Scale; MDS, Modified Depression Scale; MSPSS, multi-
dimensional scale of perceived social support; MRI, magnetic resonance imaging; MTF, male-to-female; N/A, not applicable; NIH, National Institutes of Health; N/R, not reported; NS, not significant; OASIS, Overall Anxiety Severity and Impairment Score; OR,
odds ratio; PBs, puberty blockers; PHQ, Patient Health Questionnaire; PROMIS, Patient Reported Outcomes Measurement Information System; RCMAS-2, Revised-Children's Manifest Anxiety Scale; SBQ-R, Suicide Behaviors Questionnaire-Revised; SCARED, Screen
for Child Anxiety Related Disorders; SD, standard deviation; STAI, Spielberger's Trait Anxiety Scale; TGNB, transgender/nonbinary; TPI, Spielberger's Trait Anger Scale; US, United States; WISC, Wechsler Intelligence Scale for Children; yr(s), year(s)
675

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Achille (2020)55 TGNB adolescents (N = 50) Mean age (yr, SD): Puberty suppression using: No puberty suppression Self-reported measures: Difference in change from baseline QLES-Q-SF:
A US NY) Eligibility: Participants were o MTF: 15.5 (1.6) o GnRH analogs and/or o MTF: n = 2 QLES-Q-SF questionnaire No significant differences between groups was found
pediatric endocrine recruited at the clinic, and a vast o FTM: 16.6 (2.5) antiandrogens for MTF o FTM: n = 25 Cohort: outcomes were Puberty suppression vs. none:
gender dysphoria clinic majority consented/assented. youth (n = 15)
Depressed in the prior year: No cross-sex hormones measured at 12 months (wave 3) o MTF: Coefficient 1.26, P = NS, R² = 0.13
Sampling method: Participants o GnRH analogs or
o MTF: 12 (70.6) medroxyprogesterone o MTF: n = 10 o FTM: Coefficient 0.71, P = NS, R² = 0.01
must have completed 3 waves of
questionnaires at 6-month o FTM: 20 (60.6) for FTM youth (n = 8) o FTM: n = 5 Cross-sex hormones vs. none:
intervals, for a total of Reported suicidality: Cross-sex hormones using: o MTF: Coefficient 0.87, P = NS, R² = 0.08
approximately 12 months of
o MTF: 2 (11.8) o Estrogen for MTF youth o FTM: Coefficient 0.93, P = NS, R² = 0.11
observation
o FTM: 3 (9.1) (n = 7)
Subset definition: Comparisons o Testosterone for FTM
were made between treated and Seeing a therapist:
youth (n = 28)
untreated MTF (n = 17) and FTM o MTF: 16 (94.1)
(n = 33) adolescents o FTM: 29 (87.9)
Taking psychiatric medications:
o MTF: 5 (29.4)
o FTM: 17 (34.0)
Allen (2019)56 N = 47 TGNB adolescents The age of the participants ranged CSH treatment CSH with previous GnRH The GWBS was used to Psychological well-being:
from 13.73 to 19.04 years analog treatment measure psychological well-
Eligibility: Adolescents and There were no significant differences in GWBS scores
(mean = 16.59, SD = 1.19). being (general well-being and
young adults (age range 13–20 between the CSH-only group and GnRH analogs + CSH group
The range of treatment length was general health)
years) who received services for at T0 and T1, P = NS
GD at the clinic. Participants 113-1016 days (mean = 349, Cohort: outcomes are measured
The estimated adjusted mean (standard error) of GWBS
were included if they had SD = 193). after the exposure has been
scores for CSH-only group was 62.75 (16.43) at T0 and 70.79
pretest and final assessment measured (retrospective review)
For most of the sample (90%), the (13.46) at T1. The estimated adjusted mean (standard error)
data points and were treated duration of treatment was at, or of GWBS scores for GnRH analogs + CSH group was 64.29
with CSH for at least 3 months under, 600 days. (8.32) at T0 and 69.2 (12.8) at T1.
Sampling method: A total of 47 Assigned female at birth was n = 33
eligible participants had pretest (70.2%) and assigned male at birth
and final assessment data. The was n = 14 (29.8%).
pretest for 23 participants
occurred at their first contact The majority of participants were
with the clinic (the other white N = 39 (83%).
participants' pretest assessment
was completed at a subsequent
visits to clinic but prior to
starting CSH). Thirteen of the

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
676

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
participants first presented to
our clinic in 2015; 19 in 2016; 14
in 2017; and one in 2018.
Patients are administered
questionnaires and screeners at
the beginning of their clinic visit,
either at the time of the
diagnostic evaluation or during
a follow-up appointment with
the multidisciplinary team.
Responses are reviewed by the
mental health professional prior
to meeting with the patient.
Subset definition: Of the 47
participants, Comparisons were
made between those that were
administered GnRH analogs
prior to beginning CSH (GnRH
analogs + CSH subgroup) (n = 8)
and those that were not
received GnRH analogs prior to
being administered CSH (CSH-
only subgroup) (n = 39).

Subset definition: Comparisons AMAB AFAB Self-reported measures: Psychological well-being:

were made between youth
5-item MDS questionnaire The predicted interaction effect of sex assigned at birth with
AMAB (n = 33) and AMAB
5-item OASIS questionnaire regard to well-being scores was non-significant, F(1,
(n = 14)
44) = 1.00, P = NS, partial η² = .02, demonstrating a small
Suicidal ideation and attempts effect size.
were evaluated using the
Canadian Community Health The estimated adjusted mean (standard error) of GWBS
Survey scores for AFAB group was 64.95 (2.66) at T0 and 70.94
(2.35) at T1. The estimated adjusted mean (standard error)
Cross-sectional: of GWBS scores for AMAB group was 58.44 (4.09) at T0 and
exposures/outcomes were 69.52 (3.62) at T1.
measured at the same time

Arnoldussen (2020)100 N = 1072 (404 natal males, 668 Full cohort: for natal gender, 37.7% are TGNB youth categorized by TGNB youth categorized by Psychological functioning Psychological Functioning (CBCL and YSR analyses) plus adding
natal females) natal males and 62.3% are natal females, year of assessment from year of assessment from 2000- measured by: time as a categorical variable from 2000-2016:
2000-2016 2016
CBCL A decreasing trend was found between 2000-2016 in the
mean total T-score of the assessed adolescents on the CBCL
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
677

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
the Eligibility: referred to the Center of Mean (SD) age at assessment was 14.64 YSR and the YSR and was still found by the analyses with time as
Netherlands Expertise on GD, potentially eligible years (2.19); a categorical variable.
Intensity of gender dysphoria
for gender affirming therapies There was no trend over time in the mean internalizing total
Parents' marital status, 54% were living measured by:
Sampling method: consecutively with both biological parents, 41.9% were T-scores on the CBCL and YSR
Utrecht Gender Dysphoria
referred, from 2000-2016. living with other, 4.1% had an unknown Scale The mean externalizing T-score on the CBCL and YSR of the
status; adolescents who applied in later years became significantly
IQ
Parents' educational level, 54.2% were lower compared to the mean score of adolescents who
Cohort study: Outcomes were applied in early years. The trend persisted through the
vocational education, 30% were higher
measured over 16 years. analyses with time as a categorical variable.
vocational and academic educated,
15.8% had an unknown status; Initial analyses showed a significant decrease for the clinical
Mean (SD) full-scale IQ was 99.15 (16.08), range total T-scores for the CBCL and YSR. The more detailed
analyses with time as a categorical variable contradicted this
In terms of diagnosis, 5.3% were not trend and showed fluctuation over the years rather than a
diagnosed with a form of GD, 84.7% were decrease.
diagnosed with a form of GD, 10% were
The clinical range internalizing total T-scores of the
unknown
adolescents on the CBCL and the YSR showed no trend over
time
In the clinical range externalizing total T-scores, a decreasing
trend was found on both parent and self-report. A similar
trend was seen in the subsequent analyses with time as a
categorical variable.
Initial regression analyses showed a decreasing trend in the
Peer Relation Scale on the CBCL and the indicating that the
quality of the peer relations of adolescents in more recent
years was assessed better compared to the quality of the
peer relations of adolescents in earlier years. Analyses with
time as a categorical variable also showed this trend for the
CBCL. On the YSR, however, this decreasing trend was less
clear.
Initial regression analyses showed no trend in time in the
score on the Suicidality Scale on the CBCL or the YSR
No interaction based on sex was found for any of the
variables
o CBCL T-score (mean)
 Total: β = -0.396, P < .001, 95% CI (-0.553, -0.240)
 Internalizing: β = -0.100, P = NS, 95% CI (-0.272, 0.071)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
678

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 Externalizing: β = -0.408, P < .001, 95% CI (-0.582, -
0.234)
 Total-clinical: OR = 0.950, P = .002, 95% CI (0.919,
0.982)
 Internalizing- clinical: OR = 0.986, P = NS, 95% CI (0.954,
1.018)
 Externalizing- clinical: OR = 0.922, P < 0.001, 95% CI
(0.892, 0.953)
 Peer Relation Scale: β = -0.017, P < .001, 95% CI (-0.024,
-0.010)
 Suicidality Scale: β = 0.007, P = NS, 95% CI (-0.005,
0.019)
o YSR T-score (mean)
 Total: β = -0.278, P < .001, 95% CI (-0.434, -0.122)
 Internalizing: β = -0.011, P = NS, 95% CI (-0.169, 0.192)
 Externalizing: β = -0.323, P < .001, 95% CI (-0.473, -
0.173)
 Total- clinical: OR = 0.968, P = 0.041, 95% CI (0.937,
0.999)
 Internalizing-clinical: OR = 1.016, P = NS, 95% CI (0.985,
1.049)
 Externalizing- clinical: OR = 0.931, P < .001, 95% CI
(0.897, 0.966)
 Peer Relation Scale: β = -0.009, P = 0.007, 95% CI (-
0.016, -0.003)
 Suicidality Scale: β = 0.006, P = NS, 95% CI (-0.001,
0.013)
 Gender Dysphoria changes over time from 2000-2016
UGDS (mean)
o The intensity of the feeling of dysphoria did not
significantly change over time
 Natal male: β = 0.055, P = NS, 95% CI (-0.214, 0.323)
 Natal female: β = -0.015, P = NS, 95% CI (-0.159, 0.129)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
679

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported

IQ changes over time from 2000-2016

Initial analyses showed that mean Full-Scale IQ of the
adolescents became higher over time (β 0.366, P = .004, 95%
CI 0.116–0.617), however, when time was used as a
categorical variable, it showed that the mean score remained
within the average range each year and thus it did not
change over time.
Arnoldussen (2022)71 TGNB adolescents (N = 72) Full cohort: Lower pre-treatment IQ score Higher pre-treatment IQ score IQ was measured using the WISC Total IQ Score:
(total, verbal and (total, verbal and performance
Eligibility: referred prior to 2010, Gender Educational achievement later in For each increase of one point in total IQ score, the chance
performance IQ) IQ)
met GD diagnostic criteria, started o 62.5% are transgender males life after gender affirming of being higher educated increased with 1.170 odds.c
PS before the age of 17 years treatment (PS, CSHT and gender- (β = 0.157, P < .001, 95% CI 1.074, 1.275)
followed by cross-sex hormonal o 37.5% are transgender females affirming surgery) was measured Verbal IQ score:
treatment and gender-affirming Adolescent living situation prior to via survey question. Educational
surgery treatment, level was dichotomized into For each increase of one point in verbal IQ score, the chance
"vocational educated" and of being higher educated increased with 1.164 odds c
Sampling method: 72 out of 119 o 72.2% lived with both biological
"higher vocational (β = 0.152, P = .001, 95% CI 1.068, 1.268)
eligible participated parents,
educated/academic educated" Performance IQ score
Subset: o 26.4% lived with other
Cohort study: Outcomes were For each increase of one point in performance IQ score, the
o 1.4% were unknown
transgender men (n = 45) measured after a mean duration chance of being higher educated increased with 1.127 odds.c
mean (SD) age at baseline: 12.78 of 7.6 years of gender-affirming (β = 0.120, P < .001, 95% CI 1.054, 1.206)
transgender women (n = 27)
years (1.48) treatment
Age, mean (SD)
o Results similar to general population.
o at the start of puberty suppression:
13.77 years (1.46) Transgender men Transgender women There was no significant difference in total, verbal or
performance IQ scores between transgender men and
o at the start of CSH: 16.22 years
transgender women, P = NS
(0.82)
o at the start of GAS: 18.70 years There was no significant difference between educational
(0.77) levels achieved between transgender men and transgender
women
o at the evaluation of educational
achievement: 20.40 years (1.03)
o between start puberty suppression
and start of CSH was 2.40 years
(1.08)
IQ, mean (SD)
o total IQ: 100.29 (15.07)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
680

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o verbal IQ: 99.53 (15.01)
o performance IQ: 100.72 (14.26)
o P = NS between trans men and
trans women
Education level achieved
o 37 were vocational educated
(51.4%)
o 35 were higher vocational
educated (48.6%).
o P = NS between trans men and
trans women
Becker-Hebly (2021)72 TGNB adolescents (N = 75) Age mean (SD) TGNB adolescents: TGNB adolescents: Emotional and behavioral Baseline Psychological Functioning
Full cohort (n = 75): problems was assessed using
Eligibility: confirmed diagnosis for not receiving medical not receiving medical At baseline, there were no significant differences found between
YSR/ASR
GD; older than 11 years old and not o Baseline: 15.56 years (1.21), treatment treatment the treatment groups on any measure
previously treated; no significant Global functioning was
o follow-up age: 17.38 years (1.69) receiving GnRH analogs receiving GnRH analogs YSR/ASR Total T-Score, mean (SD), 95% CI
psychiatric conditions assessed using the CGAS
Not receiving medical treatment receiving CSH and GnRH receiving CSH and GnRH No significant differences between groups
Sampling method: 75 out of 204 Psychological and physical
(n = 21): analogs analogs
patients (completed diagnostic dimensions of quality of life o No medical treatment (n = 21): 64.29 (9.33), 95% CI
criteria meeting inclusion criteria) o baseline: 15.50 years (1.19) receiving GA surgery and receiving GA surgery and were assessed using the (60.04, 68.53)
agreed to participate CSH at baseline and CSH at baseline and follow- Kidscreen-27
o follow-up age was 16.67 years o GnRH analogs (n = 11): 62.27 (8.96), 95% CI (56.26, 68.29)
follow-up up
(1.54) Cohort: Outcomes were o CSH and GnRH analogs (n = 32): 61.56 (9.17), 95% CI
GnRH analogs (n = 11): measured after exposure (58.26, 64.87)
o Baseline: 15.56 years (1.85) o GA surgery and CSH (n = 11): 62.18 (8.78), 95% CI (56.28,
o follow-up age was 16.57 years 68.08)
(2.02) YSR/ASR Internalizing T-Score, mean (SD), 95% CI
CSH and GnRH analogs (n = 32): No significant differences between groups
o Baseline: 15.47 years (1.04) o No medical treatment (n = 21): 65.76 (9.68), 95% CI
o follow-up age was 17.51 years (61.36, 70.17)
(1.24) o GnRH analogs (n = 11): 63.64 (10.97), 95% CI (56.87,
GA surgery and CSH (n = 11): 70.40)
o baseline was 15.96 years (1.02) o CSH and GnRH analogs (n = 32): 64.94 (11.18), 95% CI
(60.91, 68.97)
o follow-up age was 19.17 years
o GA surgery and CSH (n = 11): 65.73 (9.55), 95% CI (59.31,
Onset:
72.14)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
681

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Full cohort (n = 75): YSR/ASR Externalizing T-Score, mean (SD), 95% CI
o 80% were early onset No significant differences between groups
o 20% were late onset o No medical treatment (n = 21): 57.81 (9.07), 95% CI
Not receiving medical treatment (53.67, 61.95)
(n = 21): o GnRH analogs (n = 11): 57.73 (10.05), 95% CI (50.98,
o 62% were early onset 64.48)
o 38% were late onset o CSH and GnRH analogs (n = 32): 54.13 (7.17), 95% CI
(51.54, 56.71)
GnRH analogs (n = 11):
o GA surgery and CSH (n = 11):54.09 (7.80), 95% CI (48.85,
o 91% were early onset
59.33)
o 9% were late onset
CGAS Global Functioning, mean (SD), 95% CI
CSH and GnRH analogs (n = 32):
No significant differences between groups
o 84% were early onset
o No medical treatment (n = 21): 68.10 (11.23), 95% CI
o 16% were late onset (62.98, 73.21)
GA surgery and CSH (n = 11): o GnRH analogs (n = 11): 67.27 (11.91), 95% CI (59.27,
o 91% were early onset 75.27)
o 9% were late onset o CSH and GnRH analogs (n = 32): 73.13 (10.91), 95% CI
(69.19, 77.06)
o Gender:
o GA surgery and CSH (n = 11): 66.36 (14.33), 95% CI (56.73,
Full cohort (n = 75):
75.99)
o 85.3% were trans-male,
Health-related quality of life-mental, mean (SD), 95% CI
o 14.7% were trans-female
No significant differences between groups
Not receiving medical treatment
(n = 21): o No medical treatment (n = 21): 34.86 (6.27), 95% CI
(32.00, 37.71)
o 85.7% were trans-male
o GnRH analogs (n = 11): 39.04 (9.25), 95% CI (32.82, 45.25)
o 14.3% were trans-female
o CSH and GnRH analogs (n = 32):36.16 (6.78), 95% CI
GnRH analogs (n = 11): (33.72, 38.60)
o 72.7% were trans-male o GA surgery and CSH (n = 11):37.88 (6.53), 95% CI (33.49,
o 27.3% were trans-female 42.27)
CSH and GnRH analogs (n = 32): Health-related quality of life-physical, mean (SD), 95% CI
o 87.5% were trans-male No significant differences between groups
o 12.5% were trans-female o No medical treatment (n = 21): 37.51 (8.27), 95% CI
GA surgery and CSH (n = 11): (33.74, 41.27)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
682

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o 90.9% were trans-male o GnRH analogs (n = 11): 43.43 (8.61), 95% CI (37.65, 49.22)
o 9.1% were trans-female o CSH and GnRH analogs (n = 32): 39.12 (7.10), 95% CI
Additional psychotherapy (36.56, 41.68)
o GA surgery and CSH (n = 11): 39.88 (8.49), 95% CI (34.17,
Full cohort (n = 75):
45.59)
o 79% had additional psychotherapy
Follow-up Psychological Functioning
o 21% did not
At follow-up, TGNB adolescents who had GA surgery and
Not receiving medical treatment
were on CSH had lower internalizing, externalizing, and total
(n = 21):
YSR T-scores, a higher CGAS score and higher health related
o 71% had additional psychotherapy quality of life scores than those not receiving medical
o 29% did not treatment.
GnRH analogs (n = 11): At follow-up, TGNB adolescents who were on CSH and GnRH
analogs had lower internalizing, externalizing and total YSR T-
o 91% had additional psychotherapy
scores and a higher CGAS score than those not receiving
o 9% did not medical treatment.
CSH and GnRH analogs (n = 32): At follow-up, TGNB adolescents who were on GnRH analogs
o 81% had additional psychotherapy had a higher CGAS score than those not receiving medical
treatment.
o 19% did not
YSR/ASR Total T-Score, mean (SD), 95% CI.
GA surgery and CSH (n = 11):
o 73% had additional psychotherapy TGNB adolescents on CSH and GnRH analogs, and having GA
surgery and CSH had lower scores than those with no
o 27% did not medical treatment (P < .05)b
o No medical treatment (n = 21): 64.86 (9.68), 95% CI
(60.45, 69.26)
o GnRH analogs (n = 11): 61.91 (10.55), 95% CI (54.82,
69.00)
o CSH and GnRH analogs (n = 32): 60.09 (9.67), 95% CI
(56.61, 63.58)
o GA surgery and CSH (n = 11): 58.27 (8.72), 95% CI (52.42,
64.13)
YSR/ASR Internalizing T-Score, mean (SD), 95% CI.
TGNB adolescents on CSH and GnRH analogs, and having GA
surgery and CSH have lower scores than those with no
medical treatment (P < .05)b

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
683

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o No medical treatment (n = 21): 65.95 (8.26), 95% CI
(62.19, 69.71)
o GnRH analogs (n = 11): 61.55 (12.72), 95% CI (53.00,
70.09)
o CSH and GnRH analogs (n = 32): 59.56 (10.34), 95% CI
(55.83, 63.29)
o GA surgery and CSH (n = 11): 55.36 (8.74), 95% CI (49.49,
61.24)
YSR/ASR Externalizing T-Score, mean (SD), 95% CI.
TGNB adolescents on CSH and GnRH analogs, and having GA
surgery and CSH have lower scores than those with no
medical treatment (P < .05)b
o No medical treatment (n = 21): 56.38 (13.6), 95% CI
(59.19, 62.57)
o GnRH analogs (n = 11): 54.82 (11.37), 95% CI (47.18,
62.45)
o CSH and GnRH analogs (n = 32): 52.03 (8.43), 95% CI
(48.99, 55.07)
o GA surgery and CSH (n = 11): 45.27 (10.87), 95% CI (37.97,
52.58)
CGAS Global Functioning, mean (SD), 95% CI.
TGNB adolescents on GnRH analogs, CSH and GnRH analogs,
and having GA surgery and CSH have higher scores than
those with no medical treatment (P < .05)b
o No medical treatment (n = 21): 70.00 (12.25), 95% CI
(64.43, 75.57)
o GnRH analogs (n = 11): 81.82 (7.51), 95% CI (76.77, 86.86)
o CSH and GnRH analogs (n = 32): 85.63 (9.14), 95% CI
(82.33, 88.92)
o GA surgery and CSH (n = 11): 83.64 (8.09), 95% CI (78.20,
89.07)
Health-related quality of life-mental, mean (SD), 95% CI.
TGNB adolescents with GA surgery and CSH had higher
scores than those without medical treatment, (P < .05)b

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
684

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o No medical treatment (n = 21): 36.37 (7.71), 95% CI
(32.85, 39.88)
o GnRH analogs (n = 11): 43.17 (10.20), 95% CI (36.31,
50.01)
o CSH and GnRH analogs (n = 32):42.07 (10.74), 95% CI
(38.20, 45.94)
o GA surgery and CSH (n = 11): 43.44 (9.57), 95% CI (37.01,
49.87)
Health-related quality of life-physical, mean (SD), 95% CI.
TGNB adolescents with GA surgery and CSH had higher
scores than those without medical treatment, (P < .05)b
o No medical treatment (n = 21): 42.51 (10.40), 95% CI
(37.78, 47.25)
o GnRH analogs (n = 11): 49.57 (11.64), 95% CI (41.75,
57.39)
o CSH and GnRH analogs (n = 32): 49.36 (9.81), 95% CI
(45.82, 52.90)
o GA surgery and CSH (n = 11): 53.87 (6.15), 95% CI (49.74,
58.00)
Carmichael (2021) 73 TGNB adolescents (N = 44) Full cohort: TGNB youth registered male TGNB youth registered female Measures of Psychological YSR total T-score
Eligibility Criteria: at birth starting GnRH analogs at birth starting GnRH analogs functioning were measured TGNB youth DFAB showed no significant difference in
UK Median age was 13.6.
(n = 25) (n = 19) using the YSR (self-report.)
o Patients recruited from those Tanner stage:
outcome at 12 months compared to TGNB youth DMAB with
referred to GIDS who were Psychological and social a difference or 2.1, 95% CI (-5.2, 9.4), P = NS
between 12-15 years and had o n = 19 (43%) stage 3 functioning was assessed GCAS score
commenced GnRH analog o n = 16 (36%) stage 4 using the CGAS
treatment. TGNB youth DFAB showed no significant difference in
o n = 9 (21%), stage 5 Cohort study: Outcomes were outcome at 12 months compared to TGNB youth DMAB with
o Had been seen for at least 6 spent a median of 31 months in study compared from baseline to 12 a difference of -3.2, 95% CI (-10.0, 3.5), P = NS
months and attended at least with a median age of 16.1 at end of months on treatment
4 interviews. TGNB participants who were TGNB participants who were YSR total t-score
pathway.
Tanner stage 4 at baseline Tanner stage 3 (n = 19) or 5
o Psychological stability to 89% of patients were of white Pubertal stage at baseline showed no significant effect on
(n = 16) (n = 9) at baseline
withstand the stresses of ethnicity. outcome at 12 months.
medical treatment and o Participants starting at Tanner stage 3 at baseline showed
All participants had normal
o Displayed severe and a difference of 0.2, 95% CI (-8.3,8.7), compared to those
endocrinology, karyotype, imaging
persistent GD and actively starting at Tanner stage 4, P = NS
and clinical phenotype on physical
exam for birth-registered sex and

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
685

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
requesting pubertal normal full blood count and liver and o Participants starting at Tanner stage 5 at baseline showed
suppression renal function. a difference of 0.4, 95% CI (-9.9, 10.8), compared to those
o Able to give informed Birth registered male: starting at Tanner stage 4 P = NS
consent GCAS score
Median age 13.4
o Met physical/medical criteria Pubertal stage at baseline showed no significant effect on
spent a median 37 months in study
of being in established outcome at 12 months.
puberty and having normal Birth registered female:
o Participants starting at Tanner stage 3 at baseline showed
endocrine function and Median age 13.9 a difference of 1.6, 95% CI (-5.5,8.8), compared to those
karyotype consistent with starting at Tanner stage 4, P = NS.
spent a median 29 months in study
birth registered sex.
All patients left study following their o Participants starting at Tanner stage 5 at baseline showed
Exclusions: Inability to fully a difference of - 7.9, 95% CI (-17.6, 1.8), compared to
16th birthday when they chose
participate, BMI < 2nd those starting at Tanner stage 4, P = NS.
whether to pursue cross-sex hormone
percentile, serious psychiatric
therapy.
conditions, Inability to give
consent, low spine or hip BMD
Sampling Method: Patients
attending GIDS were provided
with information and those
wishing to find out more
discussed with their clinician.
Those likely deemed eligible
were given detailed information
and invited to a medical clinic
for discussion. Young people
needed to commit to regular
medical and psychosocial follow
up. Informed consent was
obtained. 48 young people
attended the clinics and 44
wished to participate. 8 young
people were not yet eligible, but
were able to enter the study
when sufficiently advanced in
puberty.
Subset Definition:
Comparisons between birth
registered male (N = 25) and

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
686

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
birth registered female (N = 19)
adolescents.
Comparisons between TGNB
participants who were Tanner
stage 4 at baseline (n = 16) and
TGNB participants who were
Tanner stage 3 (n = 19) or 5
(n = 9) at baseline
Chen (2021)104 Adolescents seeking GnRH analog Mean age (yr, SD), P = .002: AFAB patients seeking GnRH AMAB patients seeking GnRH Parent-reported measures: Mean NIH Toolbox Life Satisfaction T-score (n = 94) (SD)
therapy (N = 95) o AFAB: 10.76 (1.43) analog therapy (n = 46) analog therapy (n = 49) o There was no significant difference between groups
Four pediatric NIH Toolbox Life Satisfaction
academic medical Eligibility: Patients aged 8 to 20 o AMAB: 11.65 (1.36) (P = NS)
Cross-sectional:
centers in the US years old, diagnosed with GD, exposures/outcomes were  AFAB: 45.97 (9.61)
Gender identity, P = .000:
eligible to start GnRH analogs or measured at the same time  AMAB: 45.85 (12.64)
CSH as deemed by the primary Transmasculine/Male:
treatment team, proficient in o AFAB: 40 (87)
English, and seeking care at one of
o AMAB: 1 (2)
the study clinic locations
Transfeminine/Female:
Sampling method: Patients
presenting at one of the four o AFAB: 1 (2.2)
medical centers between July 2016 o AMAB: 44 (89.8)
and September 2018, desiring to
Non-binary:
start GnRH analog or CSH treatment
for GD o AFAB: 5 (10.9)

Subset definition: Comparisons o AMAB: 4 (8.2)

were made between AFAB (n = 46)
and AMAB (n = 49)

Adolescents seeking CSH therapy Mean age (yr, SD), P = 0 NS AFAB patients seeking CSH AMAB patients seeking GnRH Self-reported measures: Mean NIH Toolbox Life Satisfaction T-score (n = 313) (SD)
(ie, testosterone or estrogen) o AFAB: 15.87 (1.76) therapy (n = 205) analog therapy (n = 111) o There was no significant difference between groups
NIH Toolbox Life Satisfaction
(N = 316) (P = NS)
o AMAB: 16.23 (2.08) Cross-sectional:
Eligibility: Same as above exposures/outcomes were  AFAB: 40.37 (9.18)
Gender identity, P = .000:
Sampling method: Same as above measured at the same time  AMAB: 38.82 (13.47)
Transmasculine/Male:
Subset definition: Comparisons o AFAB: 191 (93.72)
were made between AFAB
(n = 205) and AMAB (n = 111) o AMAB: 0 (0)
Transfeminine/Female:

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
687

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o AFAB: 1 (0.5)
o AMAB: 105 (94.6)
Non-binary:
o AFAB: 13 (6.3)
o AMAB: 6 (5.4)
Chen (2023 )67 TGNB adolescents (N = 315) Participants were 12 to 20 years of TGNB youth starting GAH in TGNB youth starting GAH in Positive Effect and Life Positive affect
age (mean [ ±SD], 16 ±1.9 years.) early puberty (Tanner stages later puberty (Tanner stages 4- Satisfaction were assessed using
USA- Gender clinics at Eligibility: Participants were Those that had initiated GAH in early puberty had a
1-3) (n = 24) 5) (n = 291) measure from the NIH Toolbox—
recruited from the gender clinics Higher percentage of those significantly higher score of 50.27 (12.08) compared to 42.47
Emotion Battery.
from July 2016-June 2019. This designated female at birth (64.8%) (10.49) for those who initiated GAH in later puberty at
cohort was initiating GAH as part of then male. Cohort: outcomes were baseline. P < .001
their clinical care. For minors, Mostly Non-Latinx or non-Latin white measured at baseline, 6, 12, 18 Life satisfaction
parental consent was required to (58.1%) and 24 months of GAH therapy
initiate treatment. Those that had initiated GAH in early puberty had a higher
Tanner stage at GAH ini a on: no (%) score of 44.90 (14.13) compared to 39.35 (10.46) for those
Sampling Method: Youth were
from July 2016 Early n = 24 who initiated GAH in later puberty at baseline. P < .08
recruited from 4 different sites at
through June 2019
the start of GAH therapy. They were o Stage 1: 2 (0.6) TGNB youth DFAB (n = 204) TGNB youth DMAB (n = 111) Positive affect
enrolled if they met inclusion
o Stage 2: 14 (14.1) No significant difference after 24 months of GAH among
criteria
o Stage 3: 9 (2.9) youth designated female at birth vs youth designated male at
Subset defini on: birth
Late n = 291
Comparisons were made Life satisfaction
o Stage 4: 29 (9.2)
between those designated T scores increased over 24 months of GAH among youth
female at birth(n = 204) and o Stage 5: 262 (83.2)
designated female at birth but not among those designated
those designated male at birth male at birth with a time-invariant effect on slope of -1.86,
(n = 111) 95% CI (-3.49 to -0.24)
Comparisons were made
between those who started
GAH in early puberty (n = 24)
and those who started in later
puberty (n = 291)
Costa (2015)77 Adolescents with GD (N = 201) Mean age at baseline (yr, SD), P = NS Immediately eligible Delayed eligible adolescents for Physician-reported measure(s): Mean CGAS score (SD):
o Natal males: 15.61 (1.70) adolescents for puberty puberty suppression (n = 100) CGAS
Eligibility: Diagnosis of GD There was no significant difference between cohorts at any
suppression (n = 101)
o Natal females: 15.46 (1.22) Received psychological support Cohort: outcomes were time point
Sampling method: Participants
United Received psychological only during the study duration measured at baseline (T0), 6
were referred to the Gender Mean age at start of GnRH analogs Baseline (T0), P = NS:
Kingdom) support during the entire (18 months)
Identity Development Service (yr, SD), P = NS o Immediately eligible adolescents (N = 101): 58.72 (11.38)
study duration (18 months) +
between 2010 and 2014 and
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
688

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
completed the 6-month diagnostic o Natal males: 16.64 (1.22) 12 months of puberty months (T1), 12 months (T2), and o Delayed eligible adolescents (N = 100): 56.63 (13.14)
evaluation o Natal females: 16.39 (1.28) suppression 18 months (T3) After 6 months of psychological support in both groups (T1),
Subset definition: Comparisons Living in the role of the desired P = NS
were made between immediately gender: o Immediately eligible adolescents (N = 101): 60.89 (12.17)
eligible (n = 101) and delayed
Completely, P < .001: o Delayed eligible adolescents (N = 100): 60.29 (12.81)
eligible (n = 100) adolescents for
puberty suppression o Natal males: 29 (42.6) After 12 months of psychological support for delayed and
o Natal females: 88 (73.9) immediately eligible adolescents, with 6 months of puberty
suppression for immediately eligible adolescents only (T2),
Mean CGAS at baseline (SD), P = .03: P = NS:
o Natal males: 55.4 (12.7) o Immediately eligible adolescents (N = 60): 64.70 (13.34)
o Natal females: 59.2 (11.8) o Delayed eligible adolescents (N = 61): 62.97 (14.10)
After 18 months of psychological support for delayed and
immediately eligible adolescents, with 12 months of puberty
suppression for immediately eligible adolescents only (T3),
P = NS:
o Immediately eligible adolescents (N = 35): 67.40 (13.93)
o Delayed eligible adolescents (N = 36): 62.53 (13.54)
de Vries (2010)78 N = 27 TGNB adolescents Full cohort (N = 27): MTF TGNB adolescents FTM TGNB adolescents Quality of life was measured Quality of life:
using the WHOQOL-Brief and
Eligibility: not clearly stated Age, mean (SD) Significant gender differences were observed. In the
SWLS
Sampling method: 140 of 196 o assessment of pre-treatment: 13.5 Psychological domain of the WHOQOL-breve, MTFs reported
(1.8) with a range of 11.2–17.0. Cohort: participants are followed their quality of life as better (M = 15.9, SD = 2.1) compared to
consecutively referred
over time to monitor the FTMs (M = 13.9, SD = 2.2; U = 35.0, P < .01).
adolescents were considered o start of GnRH analogs: 14.6 (1.7) exposure status and the
eligible for medical intervention with a range of 11.5–17.9. On the SWLS, MTFs were observed to be more satisfied than
development of the outcome of
between 2000 and 2008 at the FTMs (M = 28.8, SD = 4.2 versus M = 22.9, SD = 6.7; U = 34.0,
o start of CSH: 16.6 (1.1) with a range interest (prospective review).
clinic. Of this cohort, 29 P < .01).
of 13.9–18.6. Measured pre-treatment and
adolescents who were age 16
o assessment of post treatment: 20.9 post-treatment, at least one year
years or older were prescribed
(1.0) with a range of 19.7–22.8. after gender reassignment
CSH only, and 111 adolescents
surgery.
were prescribed GnRH analogs The mean (SD) full-scale intelligence
to suppress puberty. was 98.2 (15.0) with a range of 70–
Subsequently, 70 of the 111 131.
started CSH treatment between
MTFs group (N = 11):
the years 2003 and 2009. The
first 30 young adults who had Age, mean (SD)
become age 18 and had GRS
between 2004 and 2009 were

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
689

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
invited to participate at least o assessment of pre-treatment: 13.9
one year after their last (.8).
operation. GRS was vaginoplasty o start of GnRH analogs: 15.0 (0.6).
for MTFs and hysterectomy for
FTMs, because after these o start of CSH: 16.7 (1.4).
surgeries transsexuals can o assessment of post treatment: 21.3
legally change their gender. One (1.1).
person (MTF) refused to The mean (SD) full-scale intelligence
participate and two (one FTM was 94.4(12.3).
and one MTF) failed to send
back their questionnaires. This FTMs group (N = 16):
resulted in 27 participants, 11 Age, mean (SD) age
MTFs and 16 FTMs.
o assessment of pre-treatment: 13.2
Subset definition: Comparisons (1.8).
were made between MTF
o start of GnRH analogs: 14.4 (0.3).
adolescents (n = 11) and FTM
adolescents (n = 16) o start of CSH: 16.6 (0.9).
o assessment of post treatment was
20.7 (0.8).
The mean (SD) full-scale intelligence
was 103.5 (15.2).
de Vries (2011)57 Transgender adolescents (N = 70) Mean age at assessment (yr, SD), Natal males (n = 33) Natal females (n = 37) Physician-reported measure(s): Mean CGAS score (SD; N = 41)
P = .028
Eligibility: N/R CGAS Compared with natal males, natal females had a significantly
o Natal males: 13.14 (1.55) lower score on the global assessment of functioning scale at
Sampling method: First 70 Cohort: outcomes were
o Natal females: 14.10 (1.99) measured before (T0) and while T0 and T1
transgender adolescents who were
referred for medical treatment (ie, Mean age at start of GnRH analogs on puberty suppression, before Before starting puberty suppression (T0):
puberty suppression) between 2000 (yr, SD), P = 0.036 CSH (T1) o Natal males: 73.10 (8.44)
and 2008
o Natal males: 14.25 (1.79) o Natal females: 67.25 (11.06)
Subset definition: Comparisons o Natal females: 15.21 (1.95) While taking puberty suppression (T1):
were made between natal males
(n = 33) and natal females (n = 37) Mean age at start of CSH (yr, SD), o Natal males: 77.33 (8.69)
P = .008
o Natal females: 70.30 (9.44)
o Natal males: 16.24 (1.21)
Between-sex significance: 5.77, P = .021
o Natal females: 16.99 (1.07)
Mean time between start of GnRH
analogs and CSH (yr, SD)P = NS

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
690

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o Natal males: 1.99 (0.94)
o Natal females: 1.78 (1.16)
de Vries (2014)79 Transgender adults who had Mean age at assessment before Transgender women who had Transgender men who had Physician-reported measure(s): Mean CGAS score (SD):
received puberty suppression treatment is started (yr, SD): received puberty suppression received puberty suppression
CGAS There was a significant difference in CGAS scores between
during adolescence, and completed o Transgender women: 13.6 (1.8) during adolescence, and during adolescence, and
Cohort: outcomes were natal males and females
gender reassignment surgery completed gender completed gender
(N = 55) o Transgender men: 13.7 (2.0) reassignment surgery (n = 22) reassignment surgery (n = 33) measured before the start of At the start of CSH (T1):
Mean age at start of GnRH analogs puberty suppression (pre- o Transgender women: 78.20 (9.56)
Eligibility: Prescribed puberty treatment; T0), at the start of
(yr, SD):
Netherlands) suppression at the clinic as an CSH (T1), and at least 1 year after o Transgender men: 70.65 (9.89)
adolescent with GD, and received o Transgender women: 14.8 (2.0)
gender reassignment surgery (T2) At least 1 year after gender reassignment surgery (T2):
gender reassignment surgery o Transgender men: 14.9 (1.9)
between 2004 and 2011 o Transgender women: 82.40 (8.28)
Mean age at start of CSH (yr, SD):
o Transgender men: 76.29 (14.48)
Sampling method: This group of
o Transgender women: 16.5 (1.3)
adolescents belonged to a larger
group of adolescents (n = 196) who o Transgender men: 16.8 (1.0)
were referred for treatment Mean age at gender reassignment
between 2000 and 2008. surgery (yr, SD):
Participants were recruited for the
o Transgender women: 19.6 (0.9)
study between 2008 and 2012, at
least 1 year post gender o Transgender men: 19.0 (0.8)
reassignment surgery Mean age at assessment after gender
Subset definition: Comparisons reassignment surgery (yr, SD):
were made between transgender o Transgender women: 21.0 (1.1)
women (n = 22) and transgender o Transgender men: 20.5 (0.8)
men (n = 33)
Mean pre-treatment CGAS (SD):
o Transgender women: 74.33 (7.53)
o Transgender men: 67.65 (11.87)
de Vries (2016)107 TGNB adolescents (N = 316) Age (in years), mean (SD), P = NS TGNB youth at initial clinical TGNB youth at initial clinical Ratings of psychological Behavioral and Emotional problems scored on CBCL/YSR
Eligibility: All adolescents were o Amsterdam (n = 139): 15.69 (1.46) assessment seen in assessment seen in Toronto + functioning was obtained at
For the CBCL Total Problem score, on average, the Toronto
Amsterdam + natal male natal female gender (2 the time of assessment.
seen at the clinics and met the DSM o Toronto (n = 177): 15.92 (1.27) adolescents had more behavioral and emotional problems
gender (2 comparators-clinic + comparators-clinic + sex)
criteria for gender identity disorder. Behavioral and emotional than Amsterdam adolescents, F(1, 253) = 24.63, P < .001,
Natal gender, P = NS sex)
problems were measured d = .64.
Sampling method: not specified
o Males (%) using the CBCL and YSR
o Toronto boys and girls had significantly higher
Subset definition:  Amsterdam: 79 (56.8) Internalizing T scores than the Amsterdam boys and girls
 Toronto: 94 (53.1) (respective P < .01 and < .03)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
691

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
The Amsterdam sample of o Females (%) Peer Relations Scale was o For the Externalizing T score, the Toronto boys had
(n = 139) adolescents between  Amsterdam: 60 (43.2) created from three CBCL significantly higher scores than the Amsterdam boys
the ages of 13–18 years referred items, item 25,38 and 48 (P < .001) whereas the Externalizing T scores of the
 Toronto: 83 (46.9) Amsterdam and Toronto girls were comparable.
and assessed between 1996 and All data analyzed using a 2
2008 and was compared to the M:F ratio o Post-hoc tests also showed that both the natal boys and
(Sex) x 2 (Clinic) ANOVA
Toronto sample, consisting of o Amsterdam: 1.31:1 girls from Toronto and the natal boys from Amsterdam
(n = 177) adolescents in the Cross sectional: had significantly higher Internalizing scores than
o Toronto: 1.13:1
same age range referred and Exposure/outcome was Externalizing scores (all P < .001), but the two broad-band
assessed between 1980 and Full-Scale IQ, mean (SD), P = NS measured at one point in time at scores did not differ significantly for the natal girls from
2010 o Amsterdam (n = 92): 95.79 (16.45) time of participant's initial Amsterdam.
CBCL data were available for o Toronto (n = 163): 97.76 (19.08) assessment at the clinic. For the YSR Total Problem score, on average, the Toronto
112 (80.6 %) adolescents and adolescents reported more behavioral and emotional
Social class, N (%), P = NS
YSR data were available for 106 problems than Amsterdam adolescents, F (1, 243) = 12.36,
(76.3 %) adolescents in the o I P = .001, d = .46.
Amsterdam clinic. CBCL data  Amsterdam: 52 (49.5) o Post-hoc tests showed that both the natal boys and natal
were available for 142 (80.2 %)
 Toronto: 90 (51.1) girls had a significantly higher Internalizing score than
adolescents and YSR data were
o II–III Externalizing score (P < .001 and < .01, respectively).
available for 138 (78.0 %)
adolescents in the Toronto  Amsterdam: 29 (27.6) o The natal boys had a significantly higher Internalizing
clinic. score than did the natal girls (P < .02) whereas the natal
 Toronto: 49 (27.8)
girls had a significantly higher Externalizing score than did
Comparisons were made
o IV-V the natal boys (P < .03).
between natal genders
(opposite gender within clinic  Amsterdam: 24 (22.9) Between clinics, a significantly greater percentage of
and same gender between  Toronto: 37 (21.0) adolescents scored in the clinical range in the Toronto clinic
clinics) compared to the Amsterdam clinic on the CBCL Total
Parental marital status, N (%), P = NS
Problem score, χ² (1) = 13.99, P < .001, the CBCL Internalizing
o Amsterdam males: n = 79
o Both Parents T score, χ² (1) = 12.02, P = .001, but not on the CBCL
o Amsterdam females: n = 60 Externalizing T score.
 Amsterdam: 57 (50.0)
o Toronto males: n = 94 There were no significant differences on any of the YSR
 Toronto: 77 (43.5)
o Toronto females: n = 83 measures.
o Other
CBCL and YSR Clinical range scores ( > 90% percentile)
 Amsterdam: 57 (50.0)
 Toronto: 100 (56.5) A significantly greater percentage of the Toronto girls had a
score in the clinical range for the CBCL Total problem score,
χ² (1) = 9.59, P = .002, compared to the Amsterdam girls, but
not on any of the other five measures.
The percentage of boys scoring in the clinical range was
significantly higher in the Toronto clinic than in the
Amsterdam clinic for the CBCL Total problem score, χ²

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
692

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
(1) = 4.99, P = .025, and the CBCL Internalizing T score,
χ²(1) = 10.99, P = .001, but not for the CBCL Externalizing T
score or any of the YSR problem scores.
Across both clinics, for the six measures of emotional and
behavioral problems, a significantly greater percentage of
boys scored in the clinical range compared to girls for the
CBCL and YSR Internalizing T scores, χ²(1) = 7.03, P = .008 and
χ²(1) = 10.83, P = .001, respectively, but not for the CBCL and
YSR Total Problem scores and CBCL and YSR Externalizing T
scores.
In the Amsterdam clinic, the percentage of boys scoring in
the clinical range was significantly higher than for the girls for
the CBCL and YSR Internalizing T scores, χ²(1) = 7.67, P = .006,
and χ²(1) = 6.97, P = .002, but not for the Total Problem
scores and the Externalizing T scores.
In the Toronto clinic, the percentage of boys scoring in the
clinical range was significantly higher than for the girls for the
CBCL Externalizing T score, χ²(1) = 3.87, P = .049 and for the
YSR Internalizing T score, χ²(1) = 4.03, P = .038, but not for
the other four measures.
CBCL, mean (SD), % in clinical range
Total Problems Score
o Amsterdam (n = 112): 45.59 (26.75), 55.4%
 Males (n = 63): 45.84 (26.00), 57.2%
 Females (n = 49): 45.27 (27.95), 53.1%
o Toronto (n = 142): 64.47 (31.81), 77.5%
 Males (n = 75): 69.27 (32.35), 81.3%
 Females (n = 67): 59.10 (30.55), 73.1%
Internalizing T
o Amsterdam (n = 112): 64.14 (10.89), 53.6%
 Males (n = 63): 65.11 (10.67), 65.1%
 Females (n = 49): 62.90 (11.17), 38.8%
o Toronto (n = 142): 68.78 (9.83), 74.5%
 Males (n = 75): 69.95 (8.99), 78.7%

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
693

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 Females (n = 67): 67.48 (10.61), 69.7%
Externalizing T
o Amsterdam (n = 112): 59.48 (11.62), 43.8%
 Males (n = 63): 58.14 (11.94), 39.7%
 Females (n = 49): 61.20 (11.09), 49.0%
o Toronto (n = 142): 62.89 (10.82), 48.2%
 Males (n = 75): 64.79 (11.01), 56.0%
 Females (n = 67): 60.76 (10.28), 39.4%
YSR, mean (SD), % in clinical range
Total Problems Score
o Amsterdam (n = 106): 51.62 (24.81), 40.6%
 Males (n = 58): 50.16 (25.31), 41.4%
 Females (n = 48): 53.40 (24.33), 39.6%
o Toronto (n = 138): 64.07 (28.29), 39.9%
 Males (n = 71): 66.14 (31.17), 42.3%
 Females (n = 67): 61.88 (24.92), 37.3%
Internalizing T
o Amsterdam (n = 106): 61.53 (12.52), 45.3%
 Males (n = 58): 63.02 (12.95), 56.9%
 Females (n = 48): 59.73 (11.86), 31.2%
o Toronto (n = 138): 62.41 (11.96), 46.4%
 Males (n = 71): 64.55 (13.03), 54.9%
 Females (n = 67): 60.15 (10.34), 37.3%
Externalizing T
o Amsterdam (n = 106): 54.77 (11.72), 18.9%
 Males (n = 58): 51.72 (11.75), 13.8%
 Females (n = 48): 58.46 (10.67), 25.0%
o Toronto (n = 138): 56.72 (10.89), 25.4%
 Males (n = 71): 56.49 (11.73), 22.5%
 Females (n = 67): 56.97 (9.99), 28.4%

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
694

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Peer Relations Scale
On the CBCL, on average, adolescents in Toronto had poorer
peer relations than those in Amsterdam, F (1, 253) = 16.68,
P < .001, d = .76. and boys had poorer peer relations than
girls, F (1, 253) = 11.23, P = .001, d = .39.
On the YSR, on average, adolescents in Toronto had poorer
peer relations than those in Amsterdam, F(1, 243) = 11.50,
P < .001, d = .59, and boys had poorer peer relations than
girls, F(1, 243) = 11.75, P = .003, d = .35.
CBCL, mean (SD),
o Amsterdam (n = 112): 1.52 (1.65)
 Males (n = 63): 1.83 (1.85)
 Females (n = 49): 1.12 (1.29)
o Toronto (n = 142): 2.88 (1.88)
 Males (n = 75): 3.28 (1.72)
 Females (n = 67): 2.43 (1.96)
YSR, mean (SD)
o Amsterdam (n = 106): 1.42 (1.56)
 Males (n = 58): 1.69 (1.67)
 Females (n = 48): 1.10 (1.37)
o Toronto (n = 138): 2.41 (1.78)
 Males (n = 71): 2.75 (1.75)
 Females (n = 67): 2.06 (1.75)
Same as above Same as above TGNB youth at initial clinical TGNB youth at initial clinical A multiple linear regression After a multiple linear regression analysis accounting for
assessment compared using a assessment compared using a analysis was conducted for variables:
variety of variables that would variety of variables that would the combined sample as well
For both the CBCL and the YSR Total Problem score
predict CBCL and YSR not predict having CBCL and as separately for boys and
(collapsed across natal sex of the adolescents), the Peer
behavioral and emotional YSR behavioral and emotional girls. There were seven
Relations Scale was the strongest predictor. (CBCL, B = 8.26,
problems problems independent (predictor)
P < .001; YSR, B = 8.09, P < .001)
variables:
For the CBCL Total Problem score, social class (B = 2.53,
o clinic
P = .012), Full-Scale IQ, (B = -2.66, P = .008), and Clinic (B = -
o age 2.28, P = .023), were also significant predictors. Adolescents
o Full-Scale IQ, with poorer peer relations, from a lower socioeconomic

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
695

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o parents' social class background, with a lower IQ, and from the Toronto clinic
o parents' marital status showed more behavioral and emotional problems.

o the sum of the two For boys, peer relations (B = 5.86, P < .001), social class
CBCL/YSR gender items (B = 3.29, P = .001), and Clinic (B = -2.40, P = .018), were
significant predictors .
o the CBCL/ YSR Peer
Relations Scale. For girls, peer relations (B = 5.77, P < .001), and Full-Scale IQ
(B = -2.64, P = .009), was were significant predictors.
The dependent (criterion)
variable was the CBCL/YSR For the YSR and gender, only Poor peer relations was a
Total Problem score significant predictor. (boys: B = 6.21, P < .001; girls: B = 25.25,
P < .001)
Cross sectional:
Exposure/outcome was
measured at one point in time at
time of participant's initial
assessment at the clinic.
Grannis (2021)110 FTM adolescents (N = 42) Mean age (yr, SD), P < .01: Received intramuscular Did not receive intramuscular Amygdala activation using fMRI There was a significant interaction effect between
o Treated FTM: 17.0 (1.2) testosterone cypionate testosterone cypionate (n = 23) during a face processing task testosterone treatment and amygdala connectivity regarding
A gender Eligibility: Diagnosis of GD, 9 to 21
(n = 19) generalized anxiety, but not depression or suicidality.
developmental clinic at yrs of age, and able to participate in o Untreated FTM: 15.8 (1.5) Cross-sectional:
a children's hospital MRI-based research exposures/outcomes were Participants receiving testosterone cypionate had higher
History of anxiolytics/anti-depressant activation in the left amygdala compared to untreated
measured at the same time
Sampling method: Study sample use: participants in response to threatening faces
was drawn from a larger study of
o Treated FTM: 10 (52.6)
transgender youth receiving gender A stronger connectivity in the ventromedial prefrontal cortex
affirming medical care (both o Untreated FTM: 18 (78.3) for the seed in the right amygdala was observed for treated
puberty blockers and CSH). All Birth control use: participants compared to untreated participants, but the
participants were receiving gender difference was not statistically significant
o Treated FTM: 15 (79.0)
affirming behavioral support and No significant relations were found between body image
had not been prescribed PBs o Untreated FTM: 15 (65.2)
dissatisfaction or mental health, and brain measures
previously. Mean duration of testosterone use
Subset definition: Comparisons (months, SD):
were made between treated o Treated FTM: 13.1 (10.3)
(n = 19) and untreated (n = 23) FTM Mean testosterone dosage (mg, SD):
adolescents
o Treated FTM: 242.1 (82.3)
Mirabella (2022)113 TGNB adolescents (N = 125) Total cohort: Natal male (n = 40) Natal female (n = 85) The Gender Diversity Gender fluidity (chi2, P value)
Questionnaire (GDQ) was
Center seen: There were no statistically significant differences in gender
used to evaluate the ways in
fluidity between TGNB natal males and natal females
which gender variant people

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
696

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Eligibility: referred between April o 94 were seen at SAIFIP identify and express their o Fixed gender identity- no time or context-based change:
2019 and June 2021, age between o 31 were seen at the Gender gender 3.058, P = NS
11 and 18 years Incongruence Unit of the Careggi Cross-sectional: o Fluid gender identity- context-based change: 0.178, P = NS
Sampling method: Adolescents had Hospital in Florence exposures/outcomes were o Fluid gender identity- time-based change: 2.269, P = NS
been consecutively referred. All Sex assigned at birth: measured at the same time
o Currently exploring gender identity: 4.683, P = NS
who met inclusion criteria were
o 40 natal males Factors influencing gender identity
included.
o 85 natal females
Subset Definition: No statistically significant differences in factors influencing
Natal female: gender identity between natal males and natal females
Comparisons were made between
o center seen: o Body discomfort (B%), P = NS
natal males (n = 40) and natal
females (n = 85)  61 (71.8) were seen at SAIFIP  Natal male: 90%
Comparisons were made between  24 (28.2) were seen at the  Natal female: 98.8%
trans-binary adolescents (n = 93) Gender Incongruence Unit
o Puberty (%), P = NS
and non-binary adolescents (n = 23) o age group
 Natal male: 72.5%
 19 (22.4) were in-between 11 to
 Natal female: 69.5%
14 YO and
o Friends (%), P = NS
 66 (77.6) were in-between 15 to
18 YO  Natal male: 45.1%
o Gender identity  Natal female: 27.5%
 64 (75.30) Trans binary o Family (%), P = NS
 21 (24.70) Nonbinary  Natal male: 10%

Natal male:  Natal female: 26.8%

o Center seen: o Social media (%), P = NS

 33 (82.5) were seen at SAIFIP  Natal male: 42.5%

and  Natal female: 52.4%
 7 (17.5) were seen at the o Meeting trans people (%), P = NS
Gender Incongruence Unit  Natal male: 30%
o age group:  Natal female: 35.4%
 13 (32.5) were in-between 11 to o Television programs (%), P = NS
14 YO
 Natal male: 17.5%
 27 (67.5) were in-between 15 to
18 YO  Natal female: 20.7%

o Gender identity Desired medical interventions (chi2, P value)

o Puberty blockers: 13.005, P < .001

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
697

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 29 (72.50) Trans binary  Significantly more natal males than natal female
 11 (27.50) Nonbinary participants reported that they desired puberty
blockers (estimated from figure: > 70% vs 40%)
A Chi squared test found no significant
difference in the distribution of trans o Breast/chest surgery: 36.427, P < .001
binary vs non-binary individuals between  Significantly more natal females wanted breast/chest
natal male and natal female participants surgery than natal males [n = 81 (98.8%) vs. n = 23
(57.5%)]
o Genital surgery: 4.750, P = NS
o Cross-sex hormones: 0.967, P = NS
o Other surgeries: 27.438, P = .037
Trans binary adolescents Non-binary adolescents The Gender Diversity Gender fluidity (chi^2, P value)
(n = 93) (n = 23) Questionnaire (GDQ) was
Non-binary subjects appeared to have a more fluid and less
used to evaluate the ways in
stable gender-identity both over time and across contexts
which gender variant people
compared to trans binary adolescents.
identify and express their
gender o Fixed gender identity- no time or context-based change:
23.487, P < .001
Cross-sectional:
exposures/outcomes were o Fluid gender identity- context-based change: 23.070,
measured at the same P < .001
o Fluid gender identity- time-based change: 27.942, P < .001
o Currently exploring gender identity: 16.945, P < .001
Factors influencing gender identity
No statistically significant differences in factors influencing
gender identity between natal males and natal females
o Body discomfort, P = NS
 Trans-binary: 95.7%
 Non-binary: 96.7%
o Puberty, P = NS
 Trans-binary: 69.6%
 Non-binary: 73.3%
o Friends, P = NS
 Trans-binary: exact number not reported, < 40% based
on figure

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
698

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 Non-binary: exact number not reported, ~ 50% based
on figure
o Family, P = NS
 Trans-binary: exact number not reported, < 20% based
on figure
 Non-binary: exact number not reported, ~ 30% based
on figure
o Social media, P = NS
 Trans-binary: exact number not reported, ~ 50% based
on figure
 Non-binary: exact number not reported, ~ 50% based
on figure
o Meeting trans people, P = NS
 Trans-binary: 30.4%
 Non-binary: 43.3%
o Television programs, P = NS
 Trans-binary: exact number not reported, < 20% based
on figure
 Non-binary: exact number not reported, ~ 20% based
on figure
o Other, P = NS
 Trans-binary: exact number not reported, < 5% based
on figure
 Non-binary: exact number not reported, < 5% based on
figure
Desired medical interventions (chi2, P value)
o No significant differences emerged for desired medical
interventions between non-binary and trans binary
subjects (significance determined by authors)
 Puberty blockers: 1.114, P = NS
 Breast/chest surgery: 0.116, P = NS
 Genital surgery: 0.939, P = NS
 Cross-sex hormones: 6.169, P = .013

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
699

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 Other surgeries: 21.857, P = NS
Morningstar (2023)114 FTM TGNB adolescents (N = 44) Mean age (yr, SD), P = .04: FTM adolescents treated with FTM adolescent who did not Self-reported measures: NRI questionnaire responses of those who received
o Treated FTM: 16.2 (1.1) exogenous testosterone receive exogenous testosterone compared to those who did not:
A gender development Eligibility: Participants were NRI questionnaire
(n = 19) testosterone (n = 25) o There was no significant difference between treated and
clinic at an academic excluded if they had prior use of o Untreated FTM: 15.3 (1.5) Whether testosterone
pediatric center located PBs, diagnosis of Turner's untreated FTM adolescents on self-reported NRI
History of using PBs: influences neural processing
in the US syndrome, lack a caregiver able to responses for the length of friendships and the type of
of emotional (vocal) stimuli by
provide stimuli, brain resection o Treated FTM: 0 (0) parental relationships (P = NS)
the patient's caregiver (eg,
after a tumor, or unable to o Untreated FTM: 0 (0) Neural responses of those who received testosterone
parent) compared to an
complete the MRI scan compared to those who did not:
Mean age at starting testosterone (yr, unknown teenage peer, based
Sampling method: A total of 53 range): on fMRI o In response to their caregiver's angry voice, treated FTM
FTM adolescents were recruited, Cross-sectional: had a significantly less anterior cingulate cortex response
o Treated FTM: 15.8 (13 to 18)
but after excluding 9 ineligible exposures/outcomes were compared to untreated FTM (P < .05)
participants, 44 were included in Mean duration of testosterone use
measured at the same time o Nonsignificant differences were observed between
the study population (yr, range):
treated and untreated FTM patients for anterior cingulate
o Treated FTM: 1.1 (1 month to 2.8 cortex response to an unknown teenager's angry and
Subset definition: Comparisons
were made between treated years) happy voice, and their caregiver's happy voice
(n = 19) and untreated (n = 25) FTM Testosterone dosage range Relative closeness to peers vs. parents of those who received
adolescents (mg/week): testosterone compared to those who did not:
o Treated FTM: 12.5 to 60 o Treated and untreated patients did not have significant
differences for relative closeness to peers over parents
(P = NS), closeness to peers (P value = 0.88), or closeness
to parents (P = NS)
Sorbara (2020)118 TGNB youth (N = 300) YPY (n = 116): Younger presenting youth to Older presenting youth to clinic Youth or caregiver reports The median age of recognition of gender incongruence was
clinic (n = 116) (n = 184) were extracted from initial significantly younger among YPY than OPY (5.8 years [IQR
Transgender youth Eligibility: Diagnosis of gender Age: 13.9 (range 12.9 to 14.5)
visit documentation. 3.0–11.0] vs 9.0 years [IQR 5.0–13.0]; P < .001).
clinic in dysphoria and seen by clinic staff.
AFAB: 87 (75.0)
Exclusion criteria was if they were YPY reported coming out about their gender identity at
Canada not seeking CSH or had previously Tanner stage < 3 (early puberty): 24 younger ages (12.0 years [IQR 11.0–13.0] vs 15.0 years [IQR
been on hormone blockers or CSH. (20.7) 13.0–15.0]; P < .001).
Sampling method: patients that Tanner stage > 4 (late puberty): 82 Social transition occurred earlier for YPY than for OPY (13.0
were eligible from clinic (70.7) years [IQR 12.0–13.4] vs 15.0 years [IQR 14.0–16.0]; P < .001
Tanner Stage not reported: 10 (8.6) The time from recognition of gender incongruence to first
Subset definition: Younger
presenting youth (YPY) were < 15 Socially transitioned: 76 (65.5) TYC visit was similar between YPY and OPY (7.4 years [IQR
years old at presentation to clinic OPY (n = 184): 3.1–10.4] vs 6.8 years [IQR 3.5–11.9]; P = NS)
(n = 116) were compared to older
presenting youths (OPY) were > 15 Age = 16.3 (range 15.6 to 16.8)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
700

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
years when presented to clinic AFAB: 142 (77.2) The time from recognition of gender incongruence to first
(n = 184). TYC visit was similar between YPY and OPY (7.4 years [IQR
Tanner Stage < 3 (early puberty): 2
(1.1) 3.1–10.4] vs 6.8 years [IQR 3.5–11.9]; P = NS)

Tanner Stage > 4 (late puberty): 166 The time between coming out and the first TYC visit was
(90.2) similar between YPY and OPY (1.3 years [IQR 0.9–2.0] vs 1.7
years [IQR 1.1–2.3]; P = NS
Tanner Stage not reported: 16 (8.7)
The rate of autism spectrum disorder was similar between
Socially transitioned: 149 (81.0) YPY and OPY (7 [6.0%] vs. 11 [6.0 %]; P = NS)
Staphorsius (2015)119 Adolescents with GD (N = 41a) Mean age (yr, SD): Puberty suppression using a No puberty suppression TOL performance, an TOL performance:
o MTF (n = 18): 15.1 (2.4) GnRH analog (SubQ or IV (untreated): executive functioning task,
Eligibility: Diagnosed with GD (per Mean percentage of correct trials (accuracy) (SD):
triptorelin 3.75 mg every 4 and brain activation using
DSM-IV-TR), and adolescent age. To  Treated MTF (n = 8): 15.4 (0.7) MTF: n = 10 o Treated MTF had significantly reduced mean accuracy
weeks) fMRI
Netherlands) receive a GnRH analog, patients scores than untreated FTM (P = .04)
 Untreated MTF (n = 10): 14.6 FTM: n = 10
Cross-sectional:
must be at least 12 years of age, MTF: n = 8
(3.2) exposures/outcomes were o MTF (n = 18): 79.1 (10.3)
and have breast development of
FTM: n = 12
Tanner stage B2 (natal girls) or o FTM (n = 22): 15.8 (1.9) measured at the same time  Treated MTF (n = 8): 73.9 (9.1)
genital development of Tanner  Treated FTM (n = 12): 16.1 (1.7)  Untreated MTF (n = 10): 83.4 (9.5)
stage G2 to G3 (natal boys).
 Untreated FTM (n = 10): 15.4 o FTM (n = 22): 87.1 (10.0)
Exclusion criteria included
(2.3)  Treated FTM (n = 12): 85.7 (10.5)
uncontrolled endocrine disorders,
neurological or psychiatric Mean IQ (SD):  Untreated FTM (n = 10): 88.8 (9.7)
conditions that could alter study o MTF (n = 18): 102.6 (18.5) Mean reaction time in seconds (SD):
results, contraindication for MRI
 Treated MTF (n = 8): 94.0 (10.3) o No significant differences existed between groups
scan, psychotropic medication use,
lack sufficient communication of  Untreated MTF (n = 10): 109.4 o MTF (n = 18): 10.4 (3.5)
Dutch language (21.2)
 Treated MTF (n = 8): 10.9 (4.1)
Sampling method: Participants o FTM (n = 22): 97.1 (15.4)
 Untreated MTF (n = 10): 9.9 (3.1)
were recruited from the VU  Treated FTM (n = 12): 95.8
University Medical Center in (15.6) o FTM (n = 22): 10.0 (2.6)
Amsterdam  Untreated FTM (n = 10): 98.5  Treated FTM (n = 12): 9.9 (3.1)
Subset definition: Comparisons (15.9)  Untreated FTM (n = 10): 10.0 (2.0)
were made between treated and Mean Tanner stage (SD): Brain activation:
untreated MTF (n = 18) and FTM
o MTF (n = 18): 3.9 (1.1) o There were no significant group differences based on the
(n = 22) adolescents
 Treated MTF (n = 8): 4.1 (1.0) whole-brain analyses for task load

 Untreated MTF (n = 10): 3.8 o ROI analyses showed treated MTF showed more activation
(1.1) in the bilateral precuneus, right and left DLPFC, and
bilateral RLPFC compared to treated FTM
o FTM (n = 22): 4.5 (0.9)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
701

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 Treated FTM (n = 12): 4.1 (1.1) o Compared to untreated MTF, untreated FTM showed a
 Untreated FTM (n = 10): 4.9 modest increase in right DLPFC activation (P < .10)
(0.3) o Treated MTF showed more activation in the left RLPFC and
Mean duration of triptorelin left DLPFC than untreated MTF
(Decapeptyl-CR) use (yr, SD): o Untreated FTM demonstrated greater activation of the
o Treated MTF: 1.8 (0.8) bilateral precuneus compared to treated FTM

o Treated FTM: 1.4 (1.1)

Tollit (2023)120 TGNB youth (N = 359) AMAB (n = 166): Trans females presenting at Trans males presenting at Data extracted from clinician- ADHD:
RCHGS. (n = 166) RCHGS. (n = 193) recorded notes collected at clinic
Eligibility: First appointment with Gender: There was no significant difference between trans males and
appointments for:
clinic from January 1, 2007 to o 139 were transgender, trans females with ADHD
December 31, 2016, and had a self- Neurodevelopmental o TM = 6
gender clinic in reported gender identity which o 14 were non binary, disorders including presences
Australia. differed from their gender at birth o 4 were cisgender and 9 weren't of ADHD or ASD o TF = 3
or sough clinical guidance on their sure. ASD:
School related difficulties
gender identity. Age: including peer bullying, There were significantly more trans males with ASD then
Sampling method: Patients were o Average age was 12.4 years. at GD history of school refusal or trans females, P < .05.
selected if they met criteria and diagnosis dropping out of school.
o TM = 37
were a patient of the clinic. Cross-sectional:
Treatment: o TF = 21
Subset definition: Comparisons exposures/outcomes were
o 126. 39 were on puberty blockers, measured at the same time Peer bullying:
were made between assigned
males at birth (n = 166) vs assigned o 7 were on antiandrogens There was no significant difference between trans males and
females at birth (n = 193) o 19 were on gender affirming trans females who had experienced peer bullying
hormones. o TM: 60
AFAB (n = 193): o TF = 56
o Gender: History of school refusal:
 174 were transgender, Trans females were significantly more likely to have a history
 12 were nonbinary, of school refusal than trans males, P < .05
 2 were cisgender and 5 were not o TM = 20
sure. o TF = 39
o Age: Dropped out of school:
 Average age was 14.8 years. There was no significant difference between trans males and
o Treatment: trans females who had dropped out of school. (P = NS)
 15 were on puberty blockers o TM = 17

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
702

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 57 were on menses suppression o TF = 19
 29 were on gender affirming
hormones.
van der Miesen N = 450 TGNB adolescents referred Transgender subjects who did not Transgender group: on Transgender group: have not Psychological functioning Internalizing: Mean scores (SD) on the Youth Self-Report
(2020)124 to a specialized gender identity started any affirmative medical puberty suppression and yet received any affirmative outcomes were measured using
the adolescents at referral had significantly higher scores
clinic treatment yet: about to start unspecified medical treatment (n = 272) the Dutch version of the YSR to
than the adolescents using suppression.
GAH treatment (n = 178) assess:
Eligibility criteria: Not clearly stated Mean age (SD) in years = 14.47 (2.18);
o transgender adolescents receiving affirmative care: 7.76
116 assigned boys at birth and 156 Internalizing and externalizing
Sampling method: Transgender (6.68)
assigned girls at birth problems
cohort: Adolescents who just o transgender adolescents who did not receive any
the Transgender subjects receiving Poor peer relations
started the diagnostic procedure affirmative treatment: 11.67 (8.38
Netherlands, between affirmative care and about to start
were assessed during their first Effect sizes Cohen's d: .80 or
2012 and 2015 GAH treatment:  effect sizes Cohen's d between the 2 groups was 0.52
sessions at the VUmc. Adolescents higher is a large effect size,
diagnosed with GD were assessed Mean age (SD) in years = 16.75 (1.24); Externalizing: Mean scores (SD) on the Youth Self-Report
.50-.79 a medium effect size,
before the start of GAH. During 68 assigned boys at birth and 110 .20-.49 small, and effect There was no significant difference between groups.
both assessments, parents and assigned girls at birth sizes < .20 are negligible
children completed several o transgender adolescents receiving affirmative care: 9.82
Cross-Sectional: Exposures / (5.79)
questionnaires during 2012 to
Outcomes were assessed at the
2015, 504 adolescents were seen in o transgender adolescents who did not receive any
same time.
their gender identity service. 53 affirmative treatment: 10.19 (6.33)
participants did not complete the  effect sizes Cohen's d between the 2 groups was 0.06.
assessment process and therefore,
did not participate in this study. The Peer relations: Mean scores (SD) on the Youth Self-Report
reason for dropout was failure to The adolescents at referral had significantly higher scores
complete the questionnaire or than those using puberty suppression.
alternation of symptoms of GD. Of
o transgender adolescents receiving affirmative care: 0.70
the adolescents diagnosed with GD,
(1.06)
179 were about to start GAH
treatment. One participant did not o transgender adolescents who did not receive any
complete the questionnaire and affirmative treatment: 1.08 (1.31)
was thus excluded.  Effect sizes Cohen's d between the 2 groups was 0.32
Subset: Comparisons were made
between TGNB adolescents
receiving affirmative care and about
to start GAH treatment: (N = 272)
and TGNB adolescents at referral,
that have not yet started
affirmative care (n = 178).
Comparisons were made between

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
703

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
TGNB adolescents that had received
puberty suppression who were
AMAB vs AFAB.

Subset: Comparisons were made Transgender subjects receiving TGNB adolescents AMAB: TGNB adolescents AFAB: have Psychological functioning:
between TGNB adolescents that affirmative care and about to start have been receiving puberty been receiving puberty
Gender assigned at birth had negligible effect on
had received puberty suppression GAH treatment: suppression, and getting suppression, and getting ready
psychological functioning
who were AMAB vs AFAB. ready to start GAH treatment to start GAH treatment
Mean age (SD) in years = 16.75 (1.24);
(n = 68) (n = 110) Internalizing: Mean scores (SD) on the Youth Self-Report
68 assigned boys at birth and 110
assigned girls at birth o assigned boys: 7.79 (6.76)
o assigned girls: 7.74 (6.66)
 effect size Cohen's d of 0.01.
Externalizing: Mean scores (SD) on the Youth Self-Report
o assigned boys: 10.32 (6.26)
o assigned girls: 9.51 (5.31)
 effect size Cohen's d of 0.14.
Peer relations: Mean scores (SD) on the Youth Self-Report
o assigned boys:0.91 (1.18)
o assigned girls: 0.57 (0.95)
 effect size Cohen's d of 0.32.
126
Vrouenraets (2021) TGNB adolescents (N = 74) Birth-assigned boys (n = 16, 21.6%): Birth-assigned boys starting Birth-assigned girls starting Behavioral outcomes: CBCL CBCL
puberty suppression (n = 16) puberty suppression (n = 58) was used to assess behavioral
Eligibility criteria: All adolescents Mean age (range) in years at the IC The mean CBCL total-problem T score (range) in birth-
session = 14.02 (12.02–17.11); mean and emotional difficulties. The
visiting the clinics were eligible for assigned boys group, 60.62 (44–72) was similar to the mean
total IQ (range) = 99.47 (82–131); total-problem T-score was
study participation; there was no score of the birth-assigned girls group 60.94 (42–77), P = NS.
mean duration of diagnostic calculated as age-
selection process. Not speaking
standardized measure of total The percentage in clinical range of CBCL total-problem T
Dutch and being cisgender were trajectory (range) in month = 9.25 (4–
behavioral and emotional score in birth-assigned boys group, 38.5% was similar to the
the exclusion criteria. 18)
difficulties. birth-assigned girls group, 43.7%, P = NS.
Netherlands, between Birth-assigned girls (n = 58, 78.4%):
Sampling method: The researchers
January 1, 2016, and Cross-Sectional:
identified the adolescents who Mean age (range) in years at the IC
December 31, 2017 or Exposures/Outcomes measured
were about to start PS through the session = 14.87 (10.63–18.34); mean at the same time.
medical files, and the adolescents total IQ (range) = 100.42 (66–144);
and their parents were invited by mean duration of diagnostic
the involved clinician to participate. trajectory (range) in month = 8.69 (2–
Subset: Comparisons were made 26)
between birth-assigned boys:

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
704

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
the (n = 16) and birth-assigned girls:
Netherlands, between (n = 58)
March 1, 2017, and
December 31, 2017.

Zucker (2010)65 N = 109 TGNB Adolescents N/R TGNB youth at initial clinical TGNB youth at initial clinical Whether youth was Univariable test examining the association between baseline
assessment compared assessment compared using a recommended for hormonal characteristics and HT recommendation:
Eligibility: TGNB youth referred
using a variety of variable variety of variable that would blocker therapy was
to the clinic with gender identity For the eight demographic variables, the only significant
that would predict predict not getting a ascertained and then
disorder between 2000 and difference as a function of hormonal treatment
recommendation to start recommendation to start HT compared with demographic,
2009. recommendation was that biological females were
HT behavioral and psychosocial
Sampling Method: Participants significantly more likely to receive a recommendation for
variables
were consecutively referred to, hormonal suppression than biological males.
Youth and their families or a
and then assessed in the Gender There was no significant difference on the CBCL mean sum
guardian, such as a child
Ontario, Identity Service. Referrals were score as a function of hormonal treatment recommendation,
protection agency worker)
Canada initiated either by the youth or but youth not recommended for hormonal therapy had a
were seen for a diagnostic
by parents or professionals. significantly higher YSR mean score than youth who were
assessment that typically
Youth were excluded if they recommended.
involved a family interview,
were referred for other reasons All of the psychosexual variables examined in the current
interviews with parents, and
than gender identity disorder. study showed significant differences as a function of
an interview with the youth.
Subset definition: Comparisons Parents were not involved in recommendation for hormonal therapy. Youth who were
were made between TGNB the assessment if either the recommended for hormonal therapy were more likely to
youth in which hormonal youth did not wish to have draw an opposite sex person first on the DAP, had, on
therapy was recommended them participate or the youth average, a more extreme mean score on the parent-report
(n = 66) vs. those where was in-care (e.g., in residential GIQ-Ad measure of concurrent cross-sex-typed behavior,
hormonal therapy was not treatment) or living self-reported more gender dysphoria on the GIDYQ, recalled
recommended (n = 43). Of the independently and the more cross-gender behavior during childhood on the RCGI,
total sample, n = 54 were natal parents were not available to and were more likely to be classified as homosexual (on both
males, and n = 55 were natal be seen. As part of the the EROS and the SHQ) than as non-homosexual.
females assessment, the youth were Age, mean (SD), t = 1.23, P = NS
seen for psychological testing,
o HT recommended (n = 66): 17.01 (1.74) years
which consisted of a battery
of tests and tasks, including o HT not recommended (n = 43): 16.59 (1.74) years
cognitive testing, projective Sex, n (%), c² = 7.95, P = .005
testing, and gender-specific
o Male:
measures.
 HT recommended:25 (46.3)
Eight demographic variables
were coded for the present  HT not recommended: 29 (53.7)
study: o Female:

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
705

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o (1) the patient's biological  HT recommended: 41 (74.5)
sex,  HT not recommended: 14 (25.5)
o (2) age at assessment, Year of Assessment, mean (SD), t < 1, P = NS
o (3) year of assessment o HT recommended (n = 66): 2005.83 (2.70)
(YOA),
o HT not recommended: (n = 43) 2005.63 (2.45)
o (4) Full-Scale IQ on an age-
appropriate Wechsler Full-Scale IQ, mean (SD), t < 1, P = NS
Intelligence Scale, o HT recommended (n = 65): 104.23 (17.91)
o (5) parents' social class o HT not recommended (n = 42): 101.60 (18.60)
(Hollingshead, 1975),
Social Class, n(%), c² = 4.04, P = NS
o (6) parents' marital status,
o I-II
o (7) race/ethnicity, and
 HT recommended: 38 (69.1)
o (8) whether or not the
 HT not recommended: 17 (30.9)
youth was in-care (e.g., via
a child protection society o III
and living in a group home,  HT recommended: 17 (56.7)
residential treatment, a  HT not recommended: 13 (43.3)
foster family).
o IV-V
Behavior Problems were
assessed through the CBCL  HT recommended: 11 (45.8)
and YSR  HT not recommended: 13 (54.2)
Psychosexual variables were Parent's Marital Status, n (%), c2 < 1, P = NS
assessed through the GIQ-Ad, o Both Parents
GIDYQ, RCGI, EROS and SHQ
 HT recommended: 33 (64.7)
Cross sectional:
 HT not recommended: 18 (35.3)
Exposure/outcome was
measured at one point of time- o Other
whether patient was  HT recommended: 33 (56.9)
recommended for hormonal
 HT not recommended: 25 (43.1)
blocker therapy or not was
assessed at initial clinical Ethnicity, n (%), c2 = 2.45, P = NS
assessment o Caucasian
 HT recommended: 47 (56.0)
 HT not recommended: 37 (44.0)
o Other

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
706

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 HT recommended: 19 (76.0)
 HT not recommended: 6 (24.0)
In Care, n (%), c2 = 3.11, P = NS
o Yes
 HT recommended: 6 (37.5)
 HT not recommended: 10 (62.5)
o No
 HT recommended: 60 (64.5)
 HT not recommended: 33 (35.5)

Behavior Problems
CBCL: Sum Items, mean (SD), t < 1, P = NS
o HT recommended (n = 62): 61.02 (27.17), 83.9% clinical
range
o HT not recommended (n = 39): 63.59 (32.55), 69.2%
clinical range
YSR: Sum Items, mean (SD), t = 2.78, P = .006
o HT recommended (n = 65): 60.95 (24), 40.0% clinical range
o HT not recommended (n = 42): 75.17 (28), 42.9% clinical
range

Psychosexual Measures
Draw-a-Person, n (%), c² = 3.43, P = NS
o Cross-Sex Drawn First
 HT recommended: 47 (69.1)
 HT not recommended: 21 (30.8)
o Same-Sex Drawn First
 HT recommended: 18 (48.6)
 HT not recommended: 19 (51.3)
GIQ-Ad, mean (SD), t = 5.06, P < .001
o HT recommended (n = 60): 2.17 (0.74)
o HT not recommended (n = 37): 2.94 (0.70)
GIDYQ, mean (SD), t = 4.74, P < .001

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
707

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o HT recommended (n = 60): 2.21 (035)
o HT not recommended (n = 39): 2.61 (0.47)
RCGI, mean (SD), t = 5.48, P < .001
o HT recommended (n = 65): 2.05 (0.67)
o HT not recommended (n = 42): 2.84 (0.79)
Sexual Orientation (in fantasy), n (%), c² = 7.51, P = .006
o Homosexual
 HT recommended: 45 (72.6)
 HT not recommended: 17 (28.4)
o Non-Homosexual
 HT recommended: 20 (44.4)
 HT not recommended: 25 (55.6)
Sexual Orientation (in behavior), n (%), c2 = 12.96, P < .001
o Homosexual
 HT recommended: 43 (78.2)
 HT not recommended:12 (21.8)
o Non-Homosexual
 HT recommended: 22 (42.3)
 HT not recommended:30 (57.7)

Logistical Regression Predicting Hormonal Therapy

Recommendations:
When controlling for all other covariates, of the 16 predictor
variables, 5 were significant at P < .10 (per author), with P
values ranging from .016 to .096: ethnicity, the GIDYQ, the
GIQ-Ad, the RCGI, and the YSR sum score. A recommendation
for hormonal blockers was more likely to be made when the
patients were of a visible minority ethnicity, when parent-
report indicated more concurrent cross-gender behavior,
when the patients self-reported more concurrent gender
dysphoria, recalled more cross-gender behavior in childhood,
and had a lower YSR behavior problem sum score. At P < .05,
YSR sum scores would be excluded.
o GIQ-Ad: = 1.63, SE = 0.67, P = .016

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
708

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Table I.J.2. Clinical studies with between-TGNB-group comparisons examining psychosocial functioning
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o GIQAA: = 2.79, SE = 1.23, P = .025
o RCGI: = 1.17, SE = 0.58, P .045
o Ethnicity: = 1.91, SE = 0.95, P = .047
o YSR Sum: = −0.02, SE = 0.01, P = .096
o Sex: = 0.01, SE = 0.79, P = NS
o Age at assessment: = 0.22, SE = 0.22, P = NS
o YOA: = −0.08, SE = 0.13, P = NS
o Full-Scale IQ: = 0.03, SE = 0.03, P = NS
o Parent's Marital Status: = −0.53, SE = 0.76, P = NS
o Social Class: = −0.76, SE = 0.49, P = NS
o In-Care: = 0.13, SE = 1.19, P = NS
o CBCL Sum: = −0.01, SE = 0.01, P = NS
o Draw-a-Person: = −1.20, SE = 0.91, P = NS
o EROS: = −0.18, SE = 0.82, P = NS

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
709

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
Bauer (2021)102 Pubertal and post-pubertal youth Assigned sex at birth: Pubertal and post-pubertal Pubertal and post-pubertal Weight z-scores Weighted mean for growth parameters, for sex at birth
(N = 174) o AMAB: 37 (21.3) transfeminine youth (n = 37) transmasculine youth (n = 137) (based on WHO Growth Charts for Canada, 2014 revision;
10 Canadian medical Height z-scores
SD):
clinics located across Eligibility: GD diagnosis, < 16 yrs of o AFAB: 137 (78.7) BMI z-scores
Canada (eg, age, no previous use of estrogen, There was no significant difference in height, weight or BMI
Age, P = NS Cross-sectional: z-scores between the transfeminine and transmasculine
testosterone, or GnRH analogs
All (except contraceptives), and 10−13 yrs old: exposures/outcomes were cohort based on sex assigned at birth.
clinics had ≥ 1 pediatric referred for hormone use measured at the same time
o Transfeminine: 14 (40.6) Height-for-age z-score, P = NS:
specialist, and
Sampling method: Recruitment o Transmasculine: 40 (28.7) o Transfeminine: 0.49 (0.69)
resources to mental
processes differed due to the site
health physicians 14−15 yrs old: o Transmasculine: 0.31 (0.81)
location and requirements set by
the Research Ethics Board. o Transfeminine: 23 (59.4) BMI-for-age z-score, P = NS:
Potential eligible participants were o Transmasculine 97 (71.3) o Transfeminine: 0.45 (1.01)
invited to contact the research
Gender identity, P = < 0.001 o Transmasculine: 0.71 (2.00)
investigator prior to their first visit
Male or primarily a boy: Weight-for-age z-score, P = NS:
Subset definition: Comparisons
were made between transfeminine o Transfeminine: 1 (2.4) o Transfeminine: 0.57 (0.88)
(n = 37) and transmasculine o Transmasculine: 125 (92.2) o Transmasculine: 0.66 (1.16)
(n = 137) participants Female or primarily a girl: Weighted mean for growth parameters, for gender (SD):
o Transfeminine: 32 (87.1) There was a significant difference in height and BMI z-scores
o Transmasculine: 0 (0) based on gender

Nonbinary: Height-for-age z-score, P < .001:

o Transfeminine: 3 (10.5) o Transfeminine: 1.40 (0.85)

o Transmasculine: 11 (7.8) o Transmasculine: −0.41 (0.93)

Living in their identified gender, BMI-for-age z-score, P = .02:

P < .001 o Transfeminine: 0.29 (0.96)
All the time: o Transmasculine: 0.89 (1.25)
o Transfeminine: 24 (58.1) Weight-for-age z-score, P = NS:
o Transmasculine: 122 (90.1) o Transfeminine: 0.84 (0.88)
Some of the time: o Transmasculine: 0.43 (1.22)
o Transfeminine: 11 (37.8)
o Transmasculine: 13 (9.9)
Not at all:
o Transfeminine: 2 (4.1)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
710

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o Transmasculine: 0 (0)
Other providers whom the adolescent
and family had met with to discuss
gender with prior to the clinic visit:
Family physician, P = NS:
o Transfeminine: 23 (68.2)
o Transmasculine: 85 (68.6)
Pediatrician or adolescent medicine,
P = NS:
o Transfeminine: 13 (33.4)
o Transmasculine: 39 (30.5)
Psychologist or psychiatrist, P = NS:
o Transfeminine: 18 (46.2)
o Transmasculine: 64 (45.4)
Counselor, elder, religious leader,
P = NS:
o Transfeminine: 17 (50.7)
o Transmasculine: 64 (45.6)
Boogers (2022)66 Transgender girls (N = 161) Median age at start of puberty Transgender girls who Transgender girls who received Growth Compared to regular dose treatment, high dose estradiol
suppression (yr, range): received high dose 17β- regular dose 17β-estradiol: 2 resulted in a non-significant reduction in adult height
Eligibility: Started GnRH analog Adult height
o Regular dose: 13.5 (13.2 to 14.5) estradiol: 6 mg per day mg per day (n = 47) compared to PAH of 0.9 cm ( 95% CI, -0.9 cm to 2.8 cm)
treatment before 18 years old, Predicted adult height
(n = 22)
The received estrogen therapy, and had o High dose: 13.1 (12.1 to 13.6) Duration of puberty suppression (yrs, 95% CI): 0.0 (−0.4 to
Netherlands) reached adult height Target height 0.4)
o Ethinyl estradiol: 12.4 (12.1 to
Cohort: outcomes were Bone age at start of CSHT (yrs, 95% CI): −0.7 (−1.1 to −0.3)
Sampling method: Out of the 8,831 14.0)
measured at the start of puberty
individuals in the data set, 5,350 Predicted adult height at start of CSHT (cm, 95% CI): 5.9 (2.1
Tanner stage at start of puberty suppression and then every 3 to 6
were AMAB. 176 subjects met the to 9.8)
suppression: months
inclusion criteria, but 15 were
G2: Height (cm, 95% CI):
excluded for various reasons (eg,
missing data). 161 individuals were o Regular dose: 7 (16) o Start of puberty suppression: −2.5 (−6.5 to 1.6)
included in the study, and assigned o Start of CSHT: 1.1 (−2.3 to 4.5)
o High dose: 9 (41)
to a pubertal (BA < 16 years; n = 88)
o Ethinyl estradiol: 6 (55) o Adult height: 4.8 (4.2 to 5.5)
or post-pubertal group (almost or
completely finished linear growth; G3: Male height SD score (95% CI):
n = 73) o Start of puberty suppression: 0.38 (−0.09 to 0.85)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
711

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
Subset definition: Comparisons o Regular dose: 14 (31) o Start of CSHT: 0.59 (0.12 to 1.05)
were made between pubertal o High dose: 11 (50) o Adult height: 0.69 (0.28 to 1.10)
transgender girls who received
high-dose estradiol (6 mg per day; o Ethinyl estradiol: 3 (27) o Target height: 0.68 (0.60 to 0.77)
n = 22) and regular-dose estradiol G4:
(2 mg per day; n = 47) o Regular dose: 9 (19)
Population, eligibility, and sampling o High dose: 1 (5) Transgender girls who Transgender girls who received Growth Compared to regular dose treatment, EE treatment resulted
method is the same as above. o Ethinyl estradiol: 1 (9) received ethinyl estradiol regular dose 17β-estradiol: 2 in a significant reduction in adult height compared to PAH of
Adult height
(100 or 200 ug per day; mg per day (n = 47) 3.0 cm (95% CI, 0.2 cm to 5.8 cm)
Subset definition: Comparisons G5: Predicted adult height
n = 11)
were made between pubertal Duration of puberty suppression (yrs, 95% CI): 0.2 (−0.3 to
o Regular dose: 17 (36) Target height
transgender girls who received 0.7)
ethinyl estradiol (100 or 200 ug per o High dose: 1 (5) Cohort: outcomes were Bone age at start of CSHT (yrs, 95% CI): −0.8 (−1.3 to −0.2)
day; n = 11) and regular-dose o Ethinyl estradiol: 1 (9) measured at the start of puberty
estradiol (2 mg per day; n = 47) suppression and then every 3 to 6 Predicted adult height at start of CSHT (cm, 95% CI): 4.2 (−1.6
Mean height at start of puberty to 10.0)
months
suppression (cm, SD):
Height (cm, 95% CI):
o Regular dose: 165.8 (8.4)
o Start of puberty suppression: −5.0 (−10.2 to 0.2)
o High dose: 163.4 (7.2)
o Start of CSHT: −1.9 (−6.3 to 2.4)
o Ethinyl estradiol: 160.8 (6.3)
o Adult height: 0.3 (−0.8 to 1.3)
Median BA at start of puberty
Male height SD score (95% CI):
suppression (yrs, range):
o Start of puberty suppression: 0.06 (−0.55 to 0.67)
o Regular dose: 13.5 (13.0 to 14.0)
o Start of CSHT: 0.04 (−0.55 to 0.64)
o High dose: 13.0 (12.5 to 13.5)
o Adult height: 0.05 (−0.58 to 0.47)
o Ethinyl estradiol: 13.0 (12.0 to
13.5) o Target height: 0.28 (0.12 to 0.44)
Median predicted adult height at
start of puberty suppression (cm,
range):
o Regular dose: 182.9 (177.0 to
186.7)
o High dose: 184.2 (180.7 to 188.6)
o Ethinyl estradiol: 185.2 (180.4 to
197.5)
Median target height (cm, range):

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
712

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o Regular dose: 180.0 (176.5 to
184.0)
 Missing: 5 (11)
o High dose: 184.0 (181.0 to 189.5)
 Missing: 1 (5)
o Ethinyl estradiol: 180.3 (178.5 to
186.3)
 Missing: 3 (27)
Population, eligibility, and sampling Started CSHT at a lower BA Started CSHT at a higher bone Height vs PAH
method is the same as above. age
Individuals who started CSHT at a lower BA reached an adult
Subset definition: Comparisons height that was 1.6 cm/year (95% CI, 0.6 to 2.7) further
were made between pubertal below PAH at the start of CSHT
transgender girls who started CSHT
at a lower BA vs those who started
at a higher BA

Eitel (2023)80 TGNB subjects with 1-hour post Mean age at first gender clinic visit TGNB subjects with 1-hour TGNB subjects with 1-hour Self-reported clinical Achieved self-reported clinical suppression (n, %):
injection hormone levels who self- (yrs, SD): post-injection hormone levels post-injection hormone levels suppression (defined as no o Eligard: 42 (100)
reported clinical puberty o Eligard: taking Eligard (n = 42) taking Lupron (n = 13) puberty progression)
suppression (N = 55) o Lupron: 13 (100)
 AFAB (n = 16): 12.0 (1.0) Biochemical suppression as
measured by 1-hour post- Achieved biochemical suppression (n, %), P NS:
Eligibility: Diagnosed with GD and
 AMAB (n = 26): 13.8 (2.0) o Eligard: 38 (90)
receiving leuprolide (either Lupron injection levels of LH < 4
or Eligard, both dosed at 22.5 mg o Lupron: mIU/mL, estradiol < 20 o Lupron: 9 (69)
every 3 months, intramuscularly or  AFAB (n = 1): 11.4 (0) pg/mL, or total
subcutaneously, respectively) testosterone < 30 ng/dL
 AMAB (n = 12): 14.0 (1.9)
between January 2016 and Cross-sectional:
December 2021 Mean age at first injection (yrs, SD):
exposures/outcomes were
Sampling method: 48 patients, with o Eligard: measured at the same time
55 incidents of 1-hour post injection  AFAB (n = 16): 12.2 (1.0)
levels were included in the study.  AMAB (n = 26): 14.5 (2.0)
Patients were excluded if they were
missing post-injection LH and sex o Lupron:
steroid hormone levels  AFAB (n = 1): 11.5 (0)
Subset definition: Comparisons  AMAB (n = 12): 14.7 (1.9)
were made between TGNB subjects
with 1-hour post-injection hormone

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
713

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
levels taking Eligard (n = 42) and Tanner stage on examination in the 6
those taking Lupron (n = 13) months before starting leuprolide
(N = 55):
o II: 12 (22)
o III: 8 (14.5)
o IV: 10 (18)
o V: 8 (14.5)
o Unknown: 17 (31)
Receiving concurrent CSHT:
o Eligard:
 AFAB (n = 16): 2 (12.5)
 AMAB (n = 26): 18 (69.2)
o Lupron:
 AFAB (n = 1): 0 (0)
 AMAB (n = 12): 8 (66.7)
Median baseline LH level obtained in
the 6 months before starting
leuprolide (mIU/mL, range):
o Eligard:
 AFAB (n = 16): 6.3 (4.3 to 5.3)
 AMAB (n = 26): 1.7 (0.7 to 3.8)
o Lupron:
 AFAB (n = 1): N/R
 AMAB (n = 12): 2.1 (0.7 to 4.6)
Median baseline estradiol level
obtained in the 6 months prior to
starting leuprolide (pg/mL, range):
o Eligard:
 AFAB (n = 16): 34.9 (7.2 to 39.8)
 AMAB (n = 26): N/R
o Lupron:
 AFAB (n = 1): 16.1 (N/R)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
714

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
 AMAB (n = 12): N/R
Median baseline total testosterone
level obtained in the 6 months prior
to starting leuprolide (ng/dL, range):
o Eligard:
 AFAB (n = 16): N/R
 AMAB (n = 26): 319 (16 to 704)
o Lupron:
 AFAB (n = 1): N/R
 AMAB (n = 12): 350 (37 to 616)
Grimstad (2021)81 Gender diverse adolescents or Mean age at starting testosterone Subjects taking testosterone Subjects taking testosterone Demographic characteristics Mean testosterone duration time was significantly longer for
young adults taking testosterone (yrs, SD), P = NS: for more than 1 year who did for more than 1 year who did Cross-sectional: patients who had at least one episode of breakthrough
for > 1 year for menstrual o No breakthrough bleeding: 16.3 not experience breakthrough experience breakthrough exposures/outcomes were bleeding compared to patients who did not experience any
suppression (N = 232) (1.8) bleeding (n = 174) bleeding (n = 58) measured at the same time breakthrough bleeding (P < .001)
Eligibility: AFAB or intersex with o Breakthrough bleeding: 16.3 (2.2) Endometriosis, confirmed by laparoscopy, was more
intact and functional uterus and common in patients who had breakthrough bleeding than
Testosterone duration (months, SD), those who did not (P = .049)
ovaries at the time of starting
P < .001
testosterone, seen in clinic between No significant differences were found between groups for
2010 and 2020, and taking o No breakthrough bleeding: 28.5
mean age at starting testosterone, BMI, testosterone
testosterone for > 1 year (14.6)
formulation used, and other menstrual suppression agents
Sampling method: 367 transgender o Breakthrough bleeding: 37.3 (16.9) (started before testosterone or used concomitantly with
and gender diverse natal females Testosterone formulation, P = 0.936 testosterone)
were taking testosterone for
Injectable:
gender-affirming care. After
excluding those who were taking o No breakthrough bleeding: 170
testosterone for ≤ 1 year, those (97.7)
with no documentation of uterine o Breakthrough bleeding: 51 (87.9)
bleeding, among other reasons, 232
Topical gel:
subjects were included in the study
o No breakthrough bleeding: 1 (0.6)
Subset definition: Comparisons
were made between those with no o Breakthrough bleeding: 0 (0)
breakthrough bleeding (n = 174) Injectable to subcutaneous pellets:
and those with breakthrough o No breakthrough bleeding: 1 (0.6)
bleeding (n = 58)
o Breakthrough bleeding: 3 (5.2)
Topical gel to injectable:

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
715

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o No breakthrough bleeding: 1 (0.6)
o Breakthrough bleeding: 1 (1.7)
Injectable to topical gel to
subcutaneous pellets:
o No breakthrough bleeding: 1 (0.6)
o Breakthrough bleeding: 0 (0)
Injectable to topical gel:
o No breakthrough bleeding: 0 (0)
o Breakthrough bleeding: 3 (5.2)
Mean BMI (kg/m², SD), P = NS:
o No breakthrough bleeding: 27.2
(7.1)
o Breakthrough bleeding: 26.2 (6.9)
Comorbid endometriosis, P = .04:
o No breakthrough bleeding: 1 (0.6)
o Breakthrough bleeding: 3 (5.2)
Using a GnRH analog (ie, Depo Lupron
or Histrelin implant), P = NS
o No breakthrough bleeding: 15 (8.6)
o Breakthrough bleeding: 1 (1.7)
GnRH analog and testosterone
overlap (months, SD), P = NS:
o No breakthrough bleeding: 19.1
(14.5)
o Breakthrough bleeding: 1 (N/R)
Hysterectomy, P = .047:
o No breakthrough bleeding: 10 (5.9)
o Breakthrough bleeding: 8 (13.8)
Population, eligibility, and sampling N/R Subjects who experienced Subjects who experienced Demographic characteristics Demographics at time of breakthrough bleeding:
method is the same as above. breakthrough bleeding while breakthrough bleeding while Cross-sectional:
Mean age (yr, SD), P = NS:
consistently on testosterone consistently on testosterone + exposures/outcomes were
Subset definition: Comparisons o Testosterone: 16.4 (2.6)
(n = 36) menstrual suppression (n = 10) measured at the same time
were made between subjects who

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
716

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
experienced breakthrough o Testosterone + menstrual suppression: 15.5 (0.7)
bleeding while consistently on Testosterone duration (months, SD), P = NS
testosterone (n = 36) and those
consistently on testosterone and o Testosterone: 37.7 (18.9)
menstrual suppression (n = 10) o Testosterone + menstrual suppression: 30.6 (8.8)
Mean BMI (kg/m², SD), P = NS
o Testosterone: 25.8 (7.8)
o Testosterone + menstrual suppression: 25.9 (4.6)
Estradiol (pg/mL, SD), P = .01
o The testosterone group that had breakthrough bleeding
had higher estradiol than the group with consistent
menstrual suppression.
o Testosterone: 44.3 (28.4)
o Testosterone + menstrual suppression: 24.6 (7.2)
Testosterone (ng/dL, SD), P = NS
o Testosterone: 467.8 (169.5)
o Testosterone + menstrual suppression: 433.0 (130.8)
Overlap on menstrual suppression (months, SD), P < .001
o Testosterone (n = 15): 8.9 (10.3)
o Testosterone + menstrual suppression: 26.2 (9.2)
Karakilic Ozturan TGNB adolescents (N = 28) Age, median (IQR), years: MTF adolescents that started FTM adolescents that started Physical examination done by Height, Median (IQR)
(2023)112 GnRH analogs (n = 9) GnRH analogs (n = 13) the same examiner each visit.
Eligibility: Participants must have MTF starting GnRH analogs: 16.7 (1.2) There was a significant difference in height between the MTF
Height and weight were
A tertiary pediatric been diagnosed with GD based on cohort at 176.1 (3.0) cm. vs. 160.8 (5) cm. in the FTM cohort,
FTM starting GnRH analogs: 16.7 measured, and BMI
endocrinology clinic in DSM-5 diagnostic criteria by a P < .001
(1.0), P = NS calculated.
Turkey. mental health professional after at Height SDS, Median (IQR)
least six months of psychiatric Standard deviation scores
follow-up, and must have been (SDS) were calculated There was no significant difference in the height SDS of the
referred to the GD outpatient clinic. according to natal sex MTF cohort of 0.6 (0.9) vs.: -0.2 (1.5) in the FTM cohort,
They could not start hormone P = NS
Cross Sectional:
treatment without informed Exposures/Outcomes were BMI, median (IQR)
consent from both themselves and measured at one point in time at There was no significant difference in the BMI of the MTF
their legal guardians. They must the onset of GnRH analogs cohort of 24.8 (5.8) kg/m² vs. 23.1 (4.5) kg/m²) in the FTM
have stayed below the age of 18
cohort, P = NS
during the follow-up period of the
study (3-6 months). BMI SDS, median (IQR)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
717

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
Sampling Method: Authors There was no significant difference in the BMI SDS of the
retrospectively examined the MTF cohort of 0.7 (1.5) vs. 0.7 (1.5) in the FTM cohort, P = NS
medical records of all adolescents
Age, median (IQR), years: MTF adolescents that used MTF adolescents that used Physical examination done by Height, median (IQR)
diagnosed with GD after at least 6
GnRH analogs before starting combined androgen receptor the same examiner each visit.
months of psychiatric follow-up and MTF with GnRH analog treatment: There was no significant difference in the median height of
CSH (n = 6) blockers before starting CSH Height and weight were
that were referred to their GD 17.3 (1.1) the GnRH analogs group, 177.9 (2.0) cm vs. 169.4 (3.3) in
(n = 6) measured and BMI calculated.
outpatient clinic between 2016 and the combined androgen receptor blocker group, P = NS
MTF with combined androgen
2022. Standard deviation scores Height SDS, median (IQR)
receptor blocker treatment 17.5 (1.3),
(SDS) were calculated
Subset Definition: There were P = NS There was no significant difference in the SDS of the GnRH
according to natal sex
n = 13 MTF participants and n = 15 analogs group of 0.3 (0.5) vs. 0.4 (1.3) in the combined
FTM participants. From this group, Cross-sectional: Outcomes were
androgen receptor blocker group, P = NS
comparisons were made between: measured at one point of time
before participants started CSH BMI, median (IQR)
MTF starting GnRH analogs
There was no significant difference in the BMI of the GnRH
(n = 6) vs FTM starting GnRH
analog group of 20.1 (0.7) kg/m² vs. 19.8 (5.9) kg/m² in the
analogs (n = 13)
combined androgen receptor blocker group, P = NS
MTF who took GnRH analogs
BMI SDS, median (IQR)
and then started CSH (n = 6) vs
MTF who took combined There was no significant difference in the BMI SDS of the
androgen receptor blocker and GnRH analog group of -1.2 (0.7) vs. -0.9 (2.1) in the combined
then started CSH (n = 6) androgen receptor blocker group, P = NS
MTF participants who were Age, median (IQR), years: MTF adolescents that used FTM adolescents that used Physical examination done by Height, median (IQR)
starting CSH (combined group either GnRH analogs or GnRH analogs before starting the same examiner each visit.
whose previous treatment was MTF with GnRH analog treatment: There was a significant difference in the height of the MTF
combined androgen receptor CSH (n = 9) Height and weight were
GnRH analogs and combined 17.3 (1.1) cohort [177.9 (2.0) cm and 169.4 (3.3)] compared to the FTM
blockers before starting CSH measured and BMI calculated.
androgen receptor blocker) MTF with combined androgen cohort at 164.9 (7.4) cm, P = 0.019
(n = 12)
(n = 12) vs. FTM starting CSH Standard deviation scores
receptor blocker treatment: 17.5 (1.3) Height SDS, Median (IQR)
(n = 9) (SDS) were calculated
FTM: 17.8 (0.4), P = NS according to natal sex There was a no significant difference in the height SDS of the
Cross-sectional: Outcomes and MTF cohort [0.3 (0.5) and 0.4 (1.3)] compared to the FTM
measures were taken at one cohort at -0.4 (1.4), P = NS
point in time at the start of CSH BMI, median (IQR)
There was a no significant difference in the BMI of the MTF
cohort [20.1 (0.7) kg/m² and 19.8 (5.9) kg/m²] compared to
the FTM cohort at 24.5 (6.9) kg/m², P = NS
BMI SDS, Median, IQR

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
718

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
There was a no significant difference in the BMI SDS of the
MTF cohort [1.2 (0.7) and -0.9 (2.1)] compared to the FTM
cohort at 1.1 (2.9), P = NS
Klaver (2018)83 TGNB adolescents (N = 192) FTM: TGNB women who started TGNB women who started waist-to-hip ratio (WHR): Body Composition early puberty vs. mid-puberty, Mean
hormone therapy in early hormone therapy in mid- Waist circumference was difference
Eligibility: Patients must have Mean age (SD) at the start of GnRH
puberty (n = 16) puberty (n = 21) or late puberty defined as the smallest
started hormonal treatment (either analog treatment was 15.3 (2.0), and There were no significant differences in body composition at
(n = 34) abdominal circumference.
the Netherlands GnRH analogs or cross-sex at the start of CHT was 16.9 (0.9). 22 years of age between TGNB women who started hormone
Hip circumference was
hormones (CHT)) before the age of therapy in early puberty and those that started in mid
94% were Caucasian measured at the level of the
18, started the Dutch treatment puberty.
84% had experienced menarche (but trochanter major.
protocol, underwent whole-body o waist-to-hip ratio (WHR): 0.00 (95% CI = -0.07, 0.07)
dual-energy x-ray absorptiometry data on menarche was missing for 8% total body fat (%):
(DXA) during their treatment, and of the sample). Measured using DXA. o total body fat (%): 3 (95% CI = -4, 10)
had medical checkups in young MTF: lean body mass (LBM) (%): o lean body mass (LBM) (%): -3 (95% CI = -10, 4)
adulthood (when they were over Measured using DXA. o BMI (kg/m^2): 2.9 (95% CI = -0.3, 6)
20.5 years old). Mean age (SD) at the start of GnRH
analog treatment was 14.5 (1.8), and BMI (kg/m^2): Body Composition early puberty vs. late puberty, Mean
Sampling Method: Authors at the start of CHT was 16.4 (1.1). Body height and weight were difference
reviewed the medical records of all measured at each visit.
98% were Caucasian. There were no significant differences in body composition at
adolescents seen between 1998-
Cohort Study: 22 years of age between TGNB women who started hormone
2014 diagnosed with gender
dysphoria according to the DSM-4 Outcomes were measured therapy in early puberty and those that started in late
at the VU University Medical Center when participants started puberty.
and collected data from three time GnRH analogs, started CHT, o waist-to-hip ratio (WHR): -0.03 (95% CI = -0.08, 0.02)
points: when they started GnRH and at 22 years of age.
o total body fat (%): -1 (95% CI = -6, 4)
analogs, when they added CHT, and
at 22 years of age (range 20.5-23.5 o lean body mass (LBM) (%): +1 (95% CI = -4, 6)
years). o BMI (kg/m^2): -0.4 (95% CI = -3.1, 2.3)
Subset Definition: Comparisons TGNB men who started TGNB men who started Body Composition, Mean difference
were made between trans women hormone therapy in early-mid hormone therapy in late
There was a significant difference in WHR at 22 years of age
that started treatment in early puberty (n = 11) puberty (n = 110)
between TGNB men who started on hormone therapy in
puberty (n = 16), mid-puberty
early to mid-puberty and those who started in late puberty.
(n = 21) and late puberty (n = 34).
Comparisons were made between There was no significant difference in total body fat, lean
trans men starting treatment in body mass or BMI at 22 years of age between TGNB men
early to mid-puberty (n = 11) and who started on hormone therapy in early to mid-puberty and
late puberty (n = 110) those who started in late puberty.
o waist-to-hip ratio (WHR): 0.06 (95% CI = 0.02, 0.12)
o total body fat (%): -1 (95% CI = -6, 4)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
719

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o lean body mass (LBM) (%): +1 (95% CI = -4, 6)
o BMI (kg/m^2): -1.4 (95% CI = -4.2, 1.4)
Laurenzano (2021)84 N = 119 TM/GD individuals Average age at presentation to clinic Subcutaneous testosterone Subcutaneous testosterone Timing to cessation of Timing to cessation of menses was significantly shorter with
was 16 (10.1-19.8) years. injections starting at 50 mg injections starting at 50 mg menses. the higher starting dose of testosterone. It was 5.4 (SD 2.9)
A US gender/endocrine Eligibility: Younger than 21 years
Average age of starting SC-T was 16.5 Cohort: After exposure, outcome months with the starting dose of 50 mg and 3.9 (SD 3.0)
(doesn't specify) clinic when starting T and received T for a
(13-19.9) years. was measured as time to event months with the starting dose of 100 mg (P = .025).
at minimum of 6 months, assessed by
mental health professional to make N = 110 patients were trans male,
California sure they were ready to start T and n = 3 were nonbinary, n = 6 patients
met diagnostic criteria for GD. were classified as "other."
Sampling method: Patients were 99 patients had no menstrual
selected if they met criteria and suppression before starting T,
were a patient of the clinic.
12 used GnRH analogs and 8 used
contraceptive.
Average BMI was 24.85 (SD 7.26)
Navabi (2021)92 Transgender youth with GD Mean LBM (kg, SD), P = .005 Transgender males (n = 119) Transgender females (n = 51) Demographic characteristics There were no significant differences between transgender
(N = 170) o Transgender males: 36.24 (56.14) for baseline body composition males and transgender females for LBM z-score, TBF z-score
Endocrine diversity
Cross-sectional: percentage, and BMI z-score
clinic Eligibility: Patients < 18 yrs of age o Transgender females: 45.74 (9.98)
with a clinic visit between January exposures/outcomes were Transgender females had significantly higher LBM and lower
Mean LBM z-score (SD), P = NS measured at the same time TBF percentage compared to transgender males
Ontario 2006 to April 2017, and at least 1
DXA measurement o Transgender males: −1.03 (1.22)
Sampling method: Reviewed 198 o Transgender females: −1.19 (1.45)
medical records, with 172 meeting Mean TBF percentage (SD), P < .001
eligibility criteria
o Transgender males: 37.14 (10.46)
Subset definition: Comparisons o Transgender females: 24.45 (12.48)
were made between transgender
males (n = 119) and transgender Mean TBF z-score percentage (SD),
females (n = 51) P = NS
o Transgender males: 1.68 (0.96)
o Transgender females: 1.42 (1.02)
Mean BMI (SD), P = NS
o Transgender males: 24.04 (5.17)
o Transgender females: 23.22 (6.33)
Mean BMI z-score (SD), P = NS

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
720

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o Transgender males: 0.89 (1.25)
o Transgender females: 0.62 (1.67)
Population, eligibility, and sampling N/R Baseline BMI percentile below Baseline BMI percentile above GnRH analog-induced body Mean change in BMI z-score (SD):
method is the same as above. the obesity risk threshold the obesity risk threshold composition changes o BMI ≤ 85 percentile: 0.11 (0.62)
( ≤ 85; n = 71) ( > 85; n = 47) Cross-sectional:
Subset definition: Comparisons o BMI > 85 percentile: 0.00 (0.79)
were made between patients with a exposures/outcomes were
measured at the same time  Difference (95% CI): 0.11 (−0.14 to 0.37), P = NS
BMI ≤ 85 percentile (n = 71) and
those with a BMI > 85 percentile Mean change in TBF z-score percentage (SD):
(n = 47) o BMI ≤ 85 percentile: 0.58 (0.91)
o BMI > 85 percentile: 0.19 (0.44)
 Difference (95% CI): 0.39 (0.11 to 0.67), P = NS
Mean change in LBM z-score (SD):
o BMI ≤ 85 percentile: −0.31 (0.66)
o BMI > 85 percentile: −0.15 (0.81)
 Difference (95% CI): −0.15 (−0.42 to 0.11), P = NS
Olson-Kennedy (2021)93 N = 66 participants Average age is 11.3 years. Patients who received the Patients who received Vantas LH and FSH were measured at Hormone comparison between implants
SupprelinLA at the follow up implant at T1 (n = 20). baseline and at follow up
Preexisting patients at Eligibility: histrelin implant at There were 51 (77.3%) participants in Mann-Whitney test indicated no significant difference
period T1 (n = 45). appointment
Tanner stage 2 or 3 used to treat Tanner stage 2, and 15 participants between change in LH (P = NS), and FSH (P = NS) between
gender dysphoria. They had to have (22.7%) in Tanner stage 3. Difference in testosterone the two implants.
hormone levels measured before 46 (69.7%) participants had a and estradiol levels were
In transfeminine participants, there was no significant
as well as patients implantation. Supprelin implant and 20 (30.3%) had measured respective to
difference in testosterone between the two implants
enrolled in the Trans a Vantas implant. gender identity
Sampling method: data was taken (P = NS).
Youth Care study, Cohort: direct in time is forward.
from patient charts of eligible 32 (48%) were transfeminine and In transmasculine patients there was no difference in
which was a multisite Comparison is drawn at the final
patients from CHLA clinic and Trans 32(52%) were transmasculine. estradiol between the two implants (P = NS).
observational study follow up time, comparing
Youth Care study.
conduct at major baseline (T0) to 2-12 months
hospitals in Southern Subset definition: Patients who following implantation (T1)
California, used Supprelin implant (n = 45)
were compared to those that used
the Vantas implant (n = 20)

Subset definition: Comparisons Same as above Transfeminine patients Transmasculine patients Same as above LH
were made between transfeminine treated with a histrelin treated with a histrelin implant
The median LH level was not significantly different between
patients (n = 32) and implant (n = 32) (n = 34).
transmasculine and transfeminine patients (P = NS) at
transmasculine patients (n = 34)
baseline.

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
721

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
At T1, LH was significantly higher in transfeminine patients.
FSH
At baseline, there was no significant difference in FSH
(P = NS) between transmasculine and transfeminine patients,
There was a significant difference at T1 (P < .001), with
transmasculine patients having higher levels.
Subset definition: Comparisons Same as above Participants that received Participants that received Same as above LH and FSH
were made between Participants histrelin implant at Tanner histrelin implant at Tanner
At baseline, median LH (P < .001) and median FSH (P < .005)
that received histrelin implant at stage 2 (n = 47) stage 3 (n = 14)
was significantly higher in Tanner 3 patients.
Tanner stage 2 (n = 47) and
Participants that received histrelin At T1, LH was not significantly different (P = NS), while FSH
implant at Tanner stage 3 (n = 14) was higher in Tanner 3 patients (P = .006).
Testosterone and Estradiol
In transfeminine patients, testosterone was higher at T0 in
Tanner 3 patients (P = 0.006), at T1 testosterone was still
higher in Tanner 3 patients (P = .026).
In transmasculine patients, median estradiol was higher in
Tanner 3 patients at T0 (P = .002) and T1 (P = .016).
All levels were prepubertal to early pubertal range.
Schagen (2018)147 TGNB adolescents (n = 70) from Trans girls: mean ± SD (range) TGNB males and females, who TGNB males and females (age Measurement: DHEAS
larger study of 127 TGNB had been treated for 2 years 14-16) at baseline before
Mean age at start of GnRH analogs: Mean DHEAS Trans boys:
adolescents of intramuscular injections of treatment. (n = 32)
14 ±1.6 (11.6-17.9) years androstenedione levels o 2 years of treatment in the 12–14-year-old age group was
GnRH analog triptorelin (3.75
between 1998 and Eligibility: adolescents with DSM-IV comparable to the baseline of those aged 14-16 years:
Weight- 57.4 ±12.7kg mg) at 0, 2 and 4 weeks Cohort: Outcomes were
2009. criteria for gender identity disorder 4.65 ± 1.92 µmol/L vs 3.94 ± 1.66 µmol/L, P = NS
BMI- 20.2 ± 2.2 followed by injections every 4 measured after 2 years of
and met the criteria for treatment
weeks. (n = 37) treatment. Trans girls:
according to the Endocrine Society. Tanner stage- 4 (2-5)
o after 2 years of treatment, treated girls had significantly
Sampling method: there was no length of GnRH analog treatment-
higher levels than untreated girls: 5.41 ± 1.86 µmol/L vs
exclusion criteria. Since it is a 22.8 ±11.8 mo
4.14 ± 1.98 µmol/L, P = .047
prospective study, it can be Trans boys: (mean)
assumed that those that met the Androstenedione
inclusion criteria were included. Mean age at GnRH analogs start- 14.3
Trans boys
± 2.0 (11.5-18.6) years
Subset: 1 subgroup started o Those that were treated had significantly lowered levels
treatment at 12-14 years and the weight- 56.8 kg ±14.3
than the baseline of those aged 14-16 years: 4.76 ± 1.76
other at 14 to 16 years. BMI- 21 ± 3.8 kg nmol/L vs 6.86 ± 2.96 nmol/L, P = .016

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
722

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
Trans boys 12-14 (n = 17), Tanner stage 5 (2-5) Trans girls:
untreated trans boys 14-16 length of GnRH analog treatment- o the treated group had levels that were comparable to the
(n = 18). 24.5 ± 15.3 mo untreated individuals: 3.86 ± 1.52 nmol/L vs 3.96 ± 1.33
Trans girls 12-14 (n = 20), nmol/L, P = NS
untreated trans girls 14-16 years
(n = 14)
TGNB youth that started treatment
at 12-14 years were compared after
2 years of treatment to group of 14-
16 yo TGNB youth who had not yet
began treatment.

Schagen (2020)94 Adolescents diagnosed with GD, Mean age at the start of GnRH Transgender females starting Transgender males starting Demographic characteristics Transgender males were significantly older at the start of
eligible for hormonal treatment analogs (yrs, SD), P = NS: GnRH analogs (n = 51) GnRH analogs (n = 70) Cross-sectional: CSH compared to transgender females
Setting: N/R
(N = 121) o Transgender females: 14.1 (1.7) exposures/outcomes were At the start of GnRH analogs and CSH, transgender females
Eligibility: Diagnosed with GD (per o Transgender males: 14.5 (2.0) measured at the start of GnRH were significantly taller than transgender males
DSM-IV-TR), eligible for treatment analog and CSH treatment
Mean height at the start of GnRH There were no significant differences between transgender
according to guidelines, had DXA females and transgender males at the start of GnRH analogs
analogs (cm, SD), P < .001
scans available at the start of GnRH or CSH for weight and BMI
analog treatment, and were seen o Transgender females: 169.0 (8.9)
from 1998 to 2009 o Transgender males: 162.2 (8.8)
Sampling method: N/R Mean weight at the start of GnRH
Subset definition: Comparisons analogs (kg, SD), P = NS:
were made between transgender o Transgender females: 57.9 (12.9)
females (n = 51) and transgender o Transgender males: 56.2 (14.7)
males (n = 70)
Mean BMI at the start of GnRH
analogs (kg/m², SD), P = NS
o Transgender females: 20.1 (3.3)
o Transgender males: 21.3 (4.2)
Mean age at the start of CSH (yrs, SD),
P = .005
o Transgender females: 16.2 (1.2)
o Transgender males: 16.9 (1.1)
Duration of GnRH analogs use before
starting CSH (yrs, SD), P = NS:

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
723

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o Transgender females: 2.0 (0.94)
o Transgender males: 1.8 (1.11)
Mean height at the start of CSH (cm,
SD), P = .005
o Transgender females: 176.5 (7.3)
o Transgender males: 167.1 (7.4)
Mean weight at the start of CSH (kg,
SD), P = NS:
o Transgender females: 66.7 (11.9)
o Transgender males: 63.5 (11.5)
Mean BMI at the start of CSH (kg/m²,
SD), P = NS:
o Transgender females: 21.1 (3.2)
o Transgender males: 22.8 (4.0)
Schulmeister (2022)95 TGNB youth starting GnRH analog Mean age at starting GnRH analogs Participants DMAB taking a Participants DFAB taking a Height velocity during the first DMAB participants were significantly older at the start of
treatment for puberty suppression (yrs, range), P = .01: GnRH analog (n = 26) GnRH analog (n = 29) year of GnRH analog GnRH analog therapy compared to DFAB participants
Four gender specialty
(N = 55) o DMAB: 11.9 (10.2 to 14.5) treatment (P = .01)
clinics in the US
Eligibility: Adolescents seen at one o DFAB: 11.1 (9.0 to 13.9) Cohort: outcomes were There were no significant differences between DMAB and
of four gender specialty clinics measured at the start of GnRH DFAB participants for height velocity during GnRH analog
Identified gender: analog treatment and at the 12- treatment (5.4 cm/yr vs. 4.8 cm/yr, respectively; P = NS),
between July 2016 and September
2018, and eligible to start a GnRH o Female: month visit including when controlling for Tanner stage.
analog for puberty suppression.  DMAB: 10 (38) o Median height velocity by Tanner stage at baseline (cm/yr,
Participants were excluded if they interquartile range):
 DFAB: 0 (0)
had previously received a GnRH
o Male: o Tanner stage II:
analog, had severe psychiatric
symptoms, had precocious puberty,  DMAB: 0 (0)  DMAB: 5.6 (4.7 to 5.7)
or could not read or comprehend  DFAB: 5.0 (4.2 to 5.4)
 DFAB: 15 (52)
English
o Transgender female: o Tanner stage III:
Sampling method: A total of 92  DMAB: 4.2 (2.3 to 6.4)
participants were enrolled, but 37  DMAB: 14 (54)
were excluded due to various  DFAB: 0 (0)  DFAB: 4.4 (4.0 to 5.5)
reasons (eg, missing height o Transgender male: o Tanner stage IV:
measurements, started CSH prior to  DMAB: 1.5 (1.4 to 1.6)
 DMAB: 0 (0)
12 months of GnRH analog use).
 DFAB: 13 (45)  DFAB: 2.9 (1.5 to 3.5)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
724

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
Therefore, 55 participants were o Nonbinary: There were no significant differences between DMAB
included in the study  DMAB: 2 (8) compared to DFAB participants for BMI z-scores at baseline
or 12-month follow-up
Subset definition: Comparisons  DFAB: 1 (3)
were made between participants There was no significant difference in height velocity
Tanner stage at start of GnRH
DMAB (n = 26) and DFAB (n = 29) between the 12 participants (9 DMAB, 3 DFAB) with
analogs:
ineffective blockage and those with suppressed
o II: gonadotropins (5.2 cm/yr vs. 5.1 cm/yr, respectively)
 DMAB: 21 (81) Participants concomitantly treated for ADHD (4 DMAB, 3
 DFAB: 13 (45) DFAB) had significantly lower BMI z-scores compared to
those not being treated for ADHD (−0.29 vs. 0.59,
o III:
respectively; P = .009), but height velocity was comparable
 DMAB: 3 (12) between groups (P = NS)
 DFAB: 13 (45)
o IV:
 DMAB: 2 (8)
 DFAB: 3 (10)
Mean BMI z-score at baseline (SD):
o DMAB: 0.56 (0.84)
o DFAB: 0.38 (0.94)
Mean BMI z-score at 12-month
follow-up (SD):
o DMAB: 0.68 (1.00)
o DFAB: 0.63 (0.95)
van der Grift (2020)123 N = 300 TGNB participants Gender, n (%) TGNB FTM that started PS at TGNB FTM controls not treated Routine physical examinations Mean (SD) height in meters: P = NS
o Total: P < .001 Tanner 2/3 (n = 17), FTM that with PS (n = 50) that determined height, o FTM, Tanner 2/3: 1.73 (0.08)
Eligibility: Participants were
started PS at Tanner 4/5 weight, and Tanner staging of
included if a gender dysphoria  Transgender man: 184 (61.3) o FTM, Tanner 4/5: 1.68 (0.07)
(n = 117) breasts and genitals were
diagnosis was confirmed, they were
 Transgender woman: 116 (38.7) performed by trained o FTM control: 1.68 (0.07)
at least 18 when data was collected
o Tanner 2/3: pediatric endocrinologists Mean (SD) weight in kg: P = NS
(i.e. during follow-up), they
according to clinical
were < 18 when starting PS, they  Transgender man: 17 (39.5) o FTM, Tanner 2/3: 67 (7.6)
guidelines. Preoperative
initiated and continued PS
 Transgender woman: 26 (60.5) physical exams were o FTM, Tanner 4/5: 66 (11.5)
treatment, and were not lost to
o Tanner 4/5: performed by trained o FTM control: 71 (13.6)
follow-up.
specialists and included the
Sampling Method: All adolescents  Transgender man: 117 (63.6) Mean (SD) BMI: P = 0.04
examination of breasts in FTM
that applied for gender-affirming  Transgender woman: 40 (34.5) and genitals in MTF. Physical o FTM, Tanner 2/3: 22.4 (2.1)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
725

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
medical interventions at the single o Controls: examination of the breasts o FTM, Tanner 4/5: 23.5 (3.6)
center between 2006-2013 were  Transgender man: 50 (50) included visual assessment of o FTM control: 24.8 (4.5)
screened for eligibility using local the breast cup and visual and
registries. A random sample of  Transgender woman: 50 (50) manual assessment of breast Breasts cup size, N (%): P < .001
clinical controls (TGNB that did not Age at initial assessment, median ptosis . o FTM, Tanner 2/3:
take PS) was identified with hospital (IQR), P < .001  AA, A: 7 (87.5)
records. Cross-sectional:
o Total: 16 (12-18)  greater than or equal to B: 1 (12.5)
Exposures/Outcomes were
Subset Definition: Comparisons o Tanner 2/3: 10 (9-11) measured at a single point in o FTM, Tanner 4/5:
were made between FTM that
o Tanner 4/5: 15 (12.5-16) time, immediately before  AA, A: 35 (41.2)
started PS in Tanner stages 2/3
o Controls: 19 (18-21) participants had gender-affirming
(n = 17) vs. Tanner stages 4/5  greater than or equal to B: 50 (58.8)
surgery.
(n = 117) vs. Matched TGNB FTM Age at study follow-up, mean (SD), o FTM control:
controls who did not take PS P < .001 The P values calculated also  AA, A: 3 (9.1)
(n = 50)
o Total: incorporated the results of the
 greater than or equal to B: 30 (90.9)
o Tanner 2/3: 20 (0.3) controls, which did not take PS.
Elasticity, N (%): P = 0.04
o Tanner 4/5: 22 (0.2)
o FTM, Tanner 2/3:
o Controls: 25 (0.2)
 poor, moderate: 0 (0)
Age at start of PS, mean (SD), P < .001
 good: 8 (100)
o Total: 15 (2.0)
o FTM, Tanner 4/5:
o Tanner 2/3: 12 (0.1)
 poor, moderate: 18 (30)
o Tanner 4/5: 15 (0.1)
 good: 42 (70)
o Controls: N/!
o FTM control:
Age at start of CSH, mean (SD),
 poor, moderate: 13 (46.4)
P < .001
 good: 25(53.6)
o Total: 18 (2.9)
Mean (SD) chest circumference in cm, P = NS
o Tanner 2/3: 15 (0.5)
o FTM, Tanner 2/3: 84 (1.5)
o Tanner 4/5: 17 (1.0)
o FTM, Tanner 4/5: 81 (1.4)
o Controls: 21 (2.4)
o FTM control: 83 (1.5)
Age at first surgery, median (IQR),
P < .001 Mastectomy, N (%): P < .001
o Total: 19 (18-21) o Increased likelihood of no mastectomy required among
Tanner 2/3 and Tanner 4/5 vs. controls
o FTM Tanner 2/3: 18 (18-18
o Decreased likelihood of IMF mastectomy required among
o FTM Tanner 4/5: 18 (18-19)
Tanner 2/3 and Tanner 4/5 vs. vs controls.

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
726

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
o FTM Controls: 23 (21-25) o FTM, Tanner 2/3:
Age at first surgery, mean (SD),  none required: 9 (52.9)
P < .001  periarteriolar, semicircular resection: 8 (47.1)
o Total: 21 (2.5)  IMF resection: 0 (0)
o MTF Tanner 2/3: 18 (0.8) o FTM, Tanner 4/5:
o MTF Tanner 4/5: 19 (1.3)  none required: 1 (1.0)
o MTF Controls: 23 (2.2)  periarteriolar, semicircular resection: 76 (72.4)
 IMF resection: 28 (26.7)
o FTM control:
 none required: 0 (0)
 periarteriolar, semicircular resection: 18 (48.6)
 IMF resection: 19 (51.4)
Mastectomy, mean (SD) P = .006
o FTM, Tanner 2/3:
 total weight resected in g: 144 (33)
 Total volume resected 540 g less than FTM control
group, Cohen's d (95% CI) = -2.12 (-3.09 to -1.15)
o FTM, Tanner 4/5:
 total weight resected in g: 474 (43)
 Total volume resected 209 g less than FTM control
group, Cohen's d (95%CI) = -0.45 (-0.89to -0.02)
o FTM Control:
 total weight resected in g: 684 (91)
Ptosis, N (%): P = NS
o FTM, Tanner 2/3:
 Grade 1, 2: 6 (100)
 Grade 3, 4: 0 (0)
o FTM, Tanner 4/5:
 Grade 1, 2: 44 (74.6)
 Grade 3, 4: 15 (25.4)
o FTM Control:

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
727

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
 Grade 1, 2: 20 (64.5)
 Grade 3, 4: 11 (35.5)
Genital surgery, N (%): P = NS
o FTM, Tanner 2/3:
 metoidioplasty: 0 (0)
 phalloplasty: 1 (5.9)
 surgical removal of uterus and ovaries: 11 (64.7)
 colpectomy: 6 (35.3)
o FTM, Tanner 4/5:
 metoidioplasty: 1 (0.9)
 phalloplasty: 13 (11.1)
 surgical removal of uterus and ovaries: 91 (77.8)
 colpectomy: 29 (24.8)
o FTM controls:
 metoidioplasty: 2 (4.0)
 phalloplasty: 8 (16.0)
 surgical removal of uterus and ovaries: 37 (74.0)
 colpectomy: 16 (32.0)
Same except for subset definition MTF that started PS at Tanner TGNB MTF controls not treated Mean (SD) height in meters: P = NS
2/3, MTF that started PS at with PS o MTF, Tanner 2/3: 1.81 (0.01)
Subset Definition: Comparisons
Tanner 4/5
were made between MTF that o MTF, Tanner 4/5: 1.80 (0.00)
started PS in Tanner 2/3 (n = 26) vs.
o MTF controls: 1.79 (0.01)
Tanner 4/5 (n = 40) vs. matched
TGNB MTF controls who did not Mean (SD) weight in kg: P = NS
take PS (n = 50) o MTF, Tanner 2/3: 68 (1.8)
o MTF, Tanner 4/5: 70 (2.2)
o MTF controls: 74 (1.9)
Mean (SD) BMI: P = 0.03
o MTF, Tanner 2/3: 20.7 (0.6)
o MTF, Tanner 4/5: 21.9 (0.6)
o MTF controls: 22.9 (0.5)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
728

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
Mean (SD) penile length in cm (n = 103): P = < 0.001
o MTF, Tanner 2/3: 7.9 (0.6)
 Penile length 4.8 cm shorter than control, Cohen's d
(95% CI) = -1.73 (-2.30 to -1.15)
o MTF, Tanner 4/5: 10.7 (0.5)
 Penile length 2.1 cm shorter than control, Cohen's d
(95% CI) = -0.83 (-1.29 to -0.37)
o MTF controls: 12.8 (0.3)
Testes descended, N (%): P = NS
o MTF, Tanner 2/3: 21 (91.3)
o MTF, Tanner 4/5: 31 (100)
o MTF controls: 422 (100)
Vaginoplasty, n (% of those who underwent surgery):
P < .001
o MTF, Tanner 2/3:
 intestinal vaginoplasty: 13 (68.4)
Increased likelihood compared to control, OR
(95% CI) 84 (9.29 to 768.82)
 penis inversion with FTG: 2 (10.5)
 penis inversion: 4 (21.2)
 not executed yet: 7
o MTF, Tanner 4/5:
 intestinal vaginoplasty: 6 (20)
Increased likelihood compared to control, OR
(95% CI: 9.8 (1.11 to 86.01)
 penis inversion with FTG: 2 (6.7)
 penis inversion: 22 (73.3)
 not executed yet: 10
o MTF controls:
 intestinal vaginoplasty: 1 (2.5)
 penis inversion with FTG: 5 (12.5)
 penis inversion: 34 (85)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
729

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
 not executed yet: 8
Vehmas (2022)125 Transgender adolescents desiring Assigned sex at birth: FTM (n = 104) MTF (n = 20) BMI Median BMI (kg/m², range), P < .001:
gender-affirming hormonal o AMAB: n = 20 Cross-sectional: exposures/ o FTM: 23.1 (17.2 to 39.0)
Adolescent gynecology
treatment (N = 124) outcomes were measured at the
clinic in o AFAB: n = 104 o MTF: 19.5 (16.4 to 29.9)
Eligibility: Adolescents diagnosed beginning of the identity
Median age at the first contact with diagnostic process Proportion of participants classified as overweight (BMI ≥ 25
(Finland) with GD, referred to gender identity
gender identity services (yr, range; kg/m², but ≤ 30 kg/m²; n, %), P = NS
services at Helsinki University
N = 124): o FTM: 22 (25.3)
Hospital before 18 years of age for
GD symptoms, and further referred o 16.7 (12.1 to 18.0) o MTF: 3 (15.8)
to the adolescent gynecology clinic Median age at GD diagnosis (yr, Proportion of participants classified as obese (BMI > 30
for gender-affirming hormonal range; N = 124): kg/m²; n, %), P = NS
assessment
o 18.1 (14.8 to 20.1) o FTM: 10 (11.5)
Sampling method: Referred by
Median age at the time of assessment o MTF: 0 (0)
gender identity services
at the adolescent gynecology clinic
Subset definition: Comparisons (yr, range; N = 124):
were made between MTF (n = 20) o 17.7 (14.6 to 19.8)
and FTM (n = 104) transgender
adolescents

Willemsen (2023)127 N = 146 FTM treated with GnRH Pubertal group: n = 61 Pubertal group: BA of 14 years Postpubertal group: BA older Height and weight were Height (cm): The pubertal group was significantly taller at the
analogs and testosterone that o Mean age was 12.7 ± 1.0 years at or less than 14 years assessed every 3-6 months start of PS and at adulthood.
reached adult height the start of PS. from the start of PS
at start of PS: 8.0 (95% CI = 5.5, 10.6)
Eligibility: FTM individuals were o BA was 12.4 ± 1.0 years at the start Height SDS was calculated
at start of CSHT: 0.6 (95% CI = -1.7, 2.9)
eligible if they started PS before of PS. according to Dutch reference
16 years of age, received data for females at adulthood (adult height): 3.0 (95% CI = 0.7, 5.2)
o Height at start of PS: 157.3 ± 8.5
testosterone therapy for at least Midparental height was Female height SDS: While there was no difference at start of PS
cm
6 months, and had reached the calculated using (paternal or CSHT, the pubertal group did have a higher SDS at adulthood
age of 18 at the time that the o PAH at start of PS: 168.1 ± 6.2 cm
height + maternal height)/2 - compared to the pubertal group
study was conducted. They Postpubertal group: n = 85 6.5 at start of PS: 0.1 (95% CI = -0.3, 0.6)
were excluded if they had not
o Mean age was 15.1 ± 0.9 years at BA was determined by
reached adult height (defined as at start of CSHT: 0.0 (95% CI = -0.3, 0.4)
the start of PS. evaluating X-rays of the left
skeletal age of 14 years or older, at adulthood (adult height): 0.5 (95% CI = 0.1, 0.8)
or had a growth velocity of less o BA was 15.7 ± 1.1 years at the start hand
than 2 centimeters per year). of PS. Cohort: Outcomes were PAH (cm) at start of CSHT: 3.5 (95% CI = 0.0, 7.0)
o Height at start of PS: 166.4 ± 6.7 measured after exposure at start Adult height - PAH (cm): While not significant and start of PS, at
Sampling Method: Data was
of PS, at start of CSHT and at start of CSHT, the pubertal group had a larger difference
retrospectively collected as part o PAH at start of PS: 167.3 ± 6.8
adulthood. between adult height and PAH
of the Amsterdam Cohort of
Gender Dysphoria (ACOG)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
730

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
study, and includes the at start of PS: 1.2 (95% CI = -0.1, 2.4)
complete population of patients
at start of CSHT: 1.2 (95% CI = 0.2, 2.1)
seen at the clinic. It was
gathered from 1972 - December Adult height - midparental height (cm): The difference between
2018. adult height and midparental height was not significantly
different between the groups
Subset Definition: Participants
were divided into two groups 0.9 (95% CI = -1.0, 2.9)
based on growth potential, BA -CA (cm): There was a significant difference between the
based on bone age (BA). comparison of BA to CA comparing the pubertal and post
o Pubertal group: Participants pubertal group
had a BA of 14 years or less at
at start of PS: 1.2 (95% CI = 0.8, 1.6)
the start of PS, or had
menarche for less than 1 year at start of CSHT: 2.4 (95% CI = 1.8, 2.9)
before the start of PS.
o Post pubertal group:
Participants had a BA of older
than 14 years or menarche
for 1 year or more before the
start of PS.
N = 61 FTM treated with GnRH Mean age was 12.7 ± 1.0 years at the FTM with BA over 12 years FTM with BA 12 years or less Height SDS:
analogs and CSHT with growth start of PS.
Transgender boys with BA > 12 years at start PS declined
potential (BA of 14 or less; or
BA was 12.4 ± 1.0 years at the start of more in height SDS during PS compared with transgender
menarche for less than 1 year
PS. boys with BA ≤ 12 years (difference between groups −0.6;
before start of PS)
Height at start of PS: 157.3 ± 8.5 cm 95% CI, −0.7 to −0.4), but height SDS at start of CSHT did not
Setting, eligibility, and sampling differ between the groups (difference 0.3; 95% CI, −0.3 to
method: same as above BA was 12.4 ± 1.0 years at the start of 0.9).
PS.
Subset Definition: Pubertal youth BA - CA (years):
who had a bone age < 12 were
At the beginning of PS, comparing BA to CA, there was a
compared with pubertal youth who
difference among those with BA ≤ 12 at start PS compared
had a bone age > 12
with those with BA > 12 years (difference, 0.7 years; 95% CI,
0.2-1.2).
Same as above. Mean age was 12.7 ± 1.0 years at the FTM that reached adult dose FTM that reached adult dose of Adult height (cm): Adult height did not differ between the 2
start of PS. of testosterone within 1 year testosterone after 1 year dosing regimens
Subset Definition: Participants
were split into two groups BA was 12.4 ± 1.0 years at the start of 0.8 (95% CI = -3.0, 4.6)
depending on length of time it took PS.
Height SDS at adulthood (adult height): no difference (statistics
for them to reach the adult not listed)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
731

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Table I.J.3. Clinical studies with between-TGNB-group comparisons examining body change outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P, if Exposure/intervention Comparator Results
timing
and study setting reported
testosterone dose (125 mg every 2 Adult dose within 1 year: median 10.8 Adult height - PAH:
weeks or 250 mg every 3-4 weeks). (IQR = 9.5, 11.6) months to reach
at start of PS: no difference (statistics not listed)
Youth who reached adult dose adult dose.
within 1 year (n = 21) were at start of CSHT: no difference (statistics not listed)
Adult dose after 1 year: median 13.6
compared to youth who reached Mean testosterone levels in first year of CSHT (nmol/L): Levels
(IQR = 12.8, 15.9) months to reach
adult dose after 1 year (n = 39 were not significantly higher in subjects who reached adult dose
adult dose.
within 12 months compared with > 12 months (95% CI = -18.2,
18.5)
IGF levels during CSHT: no difference (statistics not listed)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ADHD, attention deficit hyperactivity disorder; AFAB, assigned female at birth; AMAB, assigned male at birth; BA, bone age; BMI, body mass index; cm, centimeter; CA, chronological age; DFAB, designated female at birth; dL, deciliter;
DMAB, designated male at birth; DXA, dual-energy radiograph absorptiometry; FTM, female transitioning to male; FSH, follicle stimulating hormone; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone
analog/analog; kg, kilogram; LBM, lean body mass; LH, luteinizing hormone; m, meters; mIU, milli-international units; mL, milliliter; ng, nanograms; MTF, male transitioning to female; N/R, not reported; N/S, not significant; PAH, predicted adult height; pg,
picograms; SD, standard deviation; SDS, standard deviation score; SWLS, Satisfaction With Life Scale; TBF, total body fat; TGNB, transgender/nonbinary TF, transgender female; TM, transgender male; ; ug, microgram; WHO-QOL-Brief, World Health
Organization Quality of Life Brief Version; WHR, waist hip ratio
732

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Avila (2019)101 TGNB patients who completed the Gender identity: Treated participants who Participants who were EDE-Q scores EDE-Q scores:
EDE-Q survey (N = 106) o Transmasculine: 64 (61) received hormonal treatments untreated at the time of the o There was no significant difference between treated and
Academic Intentional weight
at the time of the survey survey (n = 72) untreated participants (P value NS) who had elevated
multidisciplinary Eligibility: Transgender males, o Transfeminine: 30 (28) manipulation behaviors for
(n = 34)a: global EDE-Q scores (n = 16). Effect size: N/R
gender clinic transgender females, and the purposes of aligning with
o Nonbinary: 12 (11)
nonbinary patients ages 13 to 22 Unspecified GnRH analogs: their preferred gender Intentional weight manipulation:
presenting at the clinic for Mean age (yr, SD): n=5 Cross-sectional: o Out of the 101 participants that answered the question, 64
transgender care between January o Transmasculine: 16.3 (1.9) exposures/outcomes were
Testosterone: n = 24 (63%) reported intentional weight manipulation for the
2018 to January 2019 measured at the same time
o Transfeminine: 16.9 (2.2) Estrogen: n = 8 purposes of aligning their body with their gender identity;
Sampling method: Patients were o Nonbinary: 16.5 (2.3) no difference was observed based on hormonal therapy
invited to complete the survey status (P value NS). Effect size: N/R
during their clinic visit. Out of 107 Mean percentage of mBMI based on
invited participants, 106 agreed assigned sex at birth (SD):
o Transmasculine: 125.7 (31.9)
Subset definition: N/A
o Transfeminine: 109.9 (32.2)
o Nonbinary: 113.4 (35.7)
Taking hormonal treatment:
o Transmasculine:
 GnRH analogs: 4 (6)
 Testosterone: 22 (34)
 Estrogen: 0 (0)
o Transfeminine:
 GnRH analogs: 1 (3)
 Testosterone: 0 (0)
 Estrogen: 8 (27)
o Nonbinary:
 GnRH analogs: 0 (0)
 Testosterone: 2 (17)
 Estrogen: 0 (0)
TGNB survey respondents who N/R Treated participants who Participants who did NOT
answered the question about the received GnRH analogs, receive GnRH analogs,
frequency of intentional weight testosterone, or estrogen at testosterone, or estrogen (n,
manipulation (n = 101) the time of the survey (n, N/R) N/R)
Eligibility: same as above
Sampling method: same as above

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
733

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Subset definition: Out of all 106
survey respondents that agreed to
participation, 101 answered this
item (95%)

Becker (2018)103 N = 202 TGNB participants (82 FTM adolescents: (n = 62) TGNB Adolescent (N = 120) TGNB Adult (N = 82) Body image was assessed Body Image:
adolescents, 120 adults) using the FBeK.
Four specialized Mean age (SD) was 16.9 (1.96). There were no significant differences in any body image scale
departments in Setting: Adult sample came from a Cross-sectional: between TGNB adolescents and TGNB adults
34 (54.8%) had not had any medical
Germany serving TGNB multicenter study of German exposures/outcomes were
interventions FBeK Scale 1: Attractiveness/Self-Confidence, Mean (SD)
people. transgender clinics led by the Max measured at the same time
Planck Institute of Psychiatry in 16 (25.8%) had taken hormones TGNB adolescents had a non-significantly lower T score of
Adolescent sample (either GnRH analogs or CSHT)
Munich. 29.48 (7.94) vs 38.23 (11.91) in the TGNB adult cohort.
came from
12 (19.4%) had taken hormones and (F = 0.40, P = NS)
Recruited between September 2013
had surgery. FBeK Scale 2: Accentuation of Body Appearance, Mean (SD)
- December 2015.
MTF adolescents: (n = 20) TGNB adolescents had a non-significantly lower T-score of
Eligibility: Patients were 14 years
old or older, had to fulfill the Mean age (SD) was 16.55 (1.79). 45.89 (9.99) vs. 55.15(9.84) in the TGNB adult cohort,
diagnostic criteria for gender (F = 2.66, P = NS)
10 (50%) had not had any medical
dysphoria/gender identity disorder interventions FBeK Scale 3: Insecurity/Concern
according to the ICD-10 in all TGNB adolescents had a non-significantly higher T-score of
8 (40%) had taken hormones (either
centers and the DSM-5 according to 55.30 (9.66) vs. 52.29 (9.42) in the TGNB adult cohort
GnRH analogs or CSHT)
specialized clinicians, must have F = 0.45, P = NS
had a current or former application 2 (10%) had taken hormones and had
for any type of mental health surgery. FBeK Scale 4: Sexual-Physical Discomfort
service, medical intervention, or FTM adults: (n = 50) TGNB adolescents had a non-significantly higher T-score of
counseling for gender problems at 59.55 (9.30) vs. 58.62(11.10) in the TGNB adult cohort
Mean age (SD) was 35.36 (10.72).
one of the participating F = 3.70, P = NS
departments, and must be of 6 (12%) had not had any medical
German nationality. interventions
Sampling Method: Participation 21 (42%) had taken hormones (either
was a voluntary part of the GnRH analogs or CSHT)
diagnostic assessment of TGNB 23 (46%) had taken hormones and
applying for gender-affirming care. had surgery
Subset Definition: Comparisons MTF adults: (n = 70)
between TGNB adolescents (N = 82)
Mean age (SD) was 43.91 (11.91).
vs. TGNB adults (N = 120), were
made using FBeK scores. 9 (12.9%) had not had any medical
interventions
34 (48.6%) had taken hormones
(either GnRH analogs or CSHT)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
734

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
27 (38.6%) had taken hormones and
had surgery.
Chen (2021)104 Adolescents seeking GnRH analog Mean age (yr, SD), P = .002: AFAB patients seeking GnRH AMAB patients seeking GnRH Self-reported measures: Mean BES score (n = 91; SD), P = NS:
therapy (N = 95) o AFAB: 10.76 (1.43) analog therapy (n = 46) analog therapy (n = 49) o There was no significant difference between the AFAB
Four pediatric BES
academic medical Eligibility: Patients aged 8 to 20 o AMAB: 11.65 (1.36) score of 45.53 (11.74), and the AMAB score of: 46.01
Cross-sectional:
centers in the US years old, diagnosed with GD, (9.97)
Gender identity, P = .000: exposures/outcomes were
eligible to start GnRH analogs or measured at the same time
CSH as deemed by the primary Transmasculine/Male:
treatment team, proficient in o AFAB: 40 (87)
English, and seeking care at one of
o AMAB: 1 (2)
the study clinic locations
Transfeminine/Female:
Sampling method: Patients
presenting at one of the four o AFAB: 1 (2.2)
medical centers between July 2016 o AMAB: 44 (89.8)
and September 2018, desiring to
Non-binary:
start GnRH analogs or CSH
treatment for GD o AFAB: 5 (10.9)

Subset definition: Comparisons o AMAB: 4 (8.2)

were made between AFAB (n = 46)
and AMAB (n = 49)

Adolescents seeking CSH therapy Mean age (yr, SD), P = NS AFAB patients seeking CSH AMAB patients seeking CSH Self-reported measures: There were no significant differences in BES and TCS scores
(ie, testosterone or estrogen) o AFAB: 15.87 (1.76) therapy (n = 205) therapy (n = 111) by designated sex at birth, but there were significant
BES
(N = 316) differences on some BIS and GMSR-A subscales. Specifically,
o AMAB: 16.23 (2.08) BIS youth designated male at birth were significantly more
Eligibility: same as above
Gender identity, P = 0.000: TCS dissatisfied with "neutral" body parts compared to youth
Sampling method: same as above designated female at birth, P = .001.
Transmasculine/Male: GMSR-A
Subset definition: Comparisons o AFAB: 191 (93.72) Youth designated female at birth experienced more non-
Cross-sectional: exposures/
were made between AFAB affirmation of gender identity compared to youth designated
o AMAB: 0 (0) outcomes were measured at the
(n = 205) and AMAB (n = 111) male at birth, P = .02.
same time
Transfeminine/Female: Regarding resilience, youth designated male at birth
o AFAB: 1 (0.5) expressed more identity-related pride than youth designated
o AMAB: 105 (94.6) female at birth, P = .002. There were no differences in overall
satisfaction with primary or secondary sexual characteristics,
Non-binary: internalized transphobia, negative expectations for the
o AFAB: 13 (6.3) future or community connectedness by designated sex at
o AMAB: 6 (5.4) birth.
Mean BES score (n, N/R; SD), P = NS:
o AFAB: 35.88 (8.19)
a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
735

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o AMAB: 36.23 (10.71)
Mean BIS (n, N/R; SD):
Total scale score, P = NS:
o AFAB: 3.19 (0.72)
o AMAB: 3.33 (0.93)
Primary sexual characteristics, P = NS:
o AFAB: 4.39 (0.72)
o AMAB: 4.53 (0.74)
Secondary sexual characteristics, P = NS:
o AFAB: 3.09 (0.77)
o AMAB: 3.12 (0.97)
Neutral (hormonally unresponsive), P = .001:
o AFAB: 2.60 (0.70)
o AMAB: 2.93 (0.90)
Mean TCS (n, N/R; SD):
Total scale score, P = NS:
o AFAB: 2.85 (0.68)
o AMAB: 2.78 (0.85)
Appearance congruence subscale, P = NS:
o AFAB: 2.42 (0.78)
o AMAB: 2.27 (1.03)
Identity acceptance subscale, P = NS:
o AFAB: 4.14 (0.87)
o AMAB: 4.30 (0.85)
Mean GMSR-A (n, N/R: SD):
Non-affirmation of gender identity, P = .020:
o AFAB: 15.78 (5.86)
o AMAB: 14.07 (6.60)
Internalized transphobia, P = NS:
o AFAB: 13.49 (8.23)
o AMAB: 12.77 (8.97)
Negative expectations for the future, P = NS
a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
736

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o AFAB: 19.41 (8.09)
o AMAB: 18.49 (8.98)
Non-disclosure, P = .000:
o AFAB: 14.66 (4.51)
o AMAB: 11.97 (5.41)
Pride, P value = 0.002:
o AFAB: 16.43 (8.05)
o AMAB: 19.43 (7.72)
Community connectedness, P = NS:
o AFAB: 13.58 (3.93)
o AMAB: 13.39 (4.12)
Chen (2023 )67 TGNB adolescents (N = 315) participants were 12 to 20 years of TGNB youth starting GAH in TGNB youth starting GAH in Appearance congruence was Appearance congruence: mean (SD)
age (mean [ ±SD], 16 ±1.9 years.) early puberty (Tanner stages later puberty (Tanner stages 4- captured through the 9-item
USA gender clinics at Eligibility: Participants were Those that had initiated GAH in early puberty had a
1-3) (n = 24) 5) (n = 291) appearance congruence subscale
the recruited from the gender clinics Higher percentage of those significantly higher score of 3.08 (0.95) compared to 2.31
of the Transgender Congruence
from July 2016-June 2019. This designated female at birth (64.8%) (0.85) for those who initiated GAH in later puberty at
Scale.
cohort was initiating GAH as part of then male. baseline, P < .001
their clinical care. For minors, Mostly Non-Latinx or non-Latin white Cohort: outcomes were
Youth initiating GAH in later puberty had greater
parental consent was required to (58.1%) measured at baseline, 6, 12, 18
improvements in appearance congruence over 24 months
initiate treatment. and 24 months of GAH treatment
than those initiating GAH in early puberty with a time-
Sampling Method: Youth were Tanner stage at GAH ini a on: no (%) invariant effect on slope of -0.42, 95% CI (-0.66 to -0.19)
from July 2016 Early n = 24
recruited from 4 different sites at
through June 2019 TGNB youth DFAB (n = 204) TGNB youth DMAB (n = 111) Appearance congruence: mean difference (SD)
the start of GAH therapy. They were o Stage 1: 2 (0.6)
enrolled if they met inclusion There was no significant difference in scores between those
o Stage 2: 14 (14.1)
criteria DFAB and those DMAB: 0.03, 95% CI (-0.09-0.15)
o Stage 3: 9 (2.9)
Subset defini on:
Late n = 291
Comparisons were made
o Stage 4: 29 (9.2)
between those designated
female at birth(n = 204) and o Stage 5: 262 (83.2)
those designated male at birth
(n = 111)
Comparisons were made
between those who started
GAH in early puberty (n = 24)
and those who started in later
puberty (n = 291)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
737

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Costa (2015)77 Adolescents with GD (N = 201) Mean age at baseline (yr, SD), P = NS Natal males Natal females Self-reported measures: Mean UGDS score (SD), P < .001
Eligibility: Diagnosis of GD o Natal males: 15.61 (1.70) UGDS questionnaire Natal females scored significantly higher than natal males
Sampling method: Participants o Natal females: 15.46 (1.22) Cross-sectional: o Natal males (n = 50): 51.6 (9.7)
United exposures/outcomes were
were referred to the Gender Mean age at start of GnRH analogs o Natal females (n = 110): 56.1 (4.3)
Kingdom) measured at the same time
Identity Development Service (yr, SD), P = NS
between 2010 and 2014 and
o Natal males: 16.64 (1.22)
completed the 6-month diagnostic
evaluation o Natal females: 16.39 (1.28)

Subset definition: Comparisons Living in the role of the desired

were made between natal males gender:
(n = N/R) and natal females Completely, P < .001:
(n = N/R) adolescents for puberty o Natal males: 29 (42.6)
suppression
o Natal females: 88 (73.9)
de Vries (2010)78 N = 27 TGNB adolescents Full cohort (N = 27): MTF TGNB adolescents FTM TGNB adolescents Body satisfaction was Body satisfaction:
measured with the BIS
Eligibility: not clearly stated Age, mean (SD) There were no significant gender differences on overall body
Gender Dysphoria was satisfaction scores either Pre-treatment or Post treatment
Sampling method: 140 of 196 o assessment of pre-treatment: 13.5
measured using the UGDS (P = NS).
consecutively referred (1.8) with a range of 11.2–17.0.
adolescents were considered Cohort: participants are followed The gender effect F(df) of the BIS primary sex characteristics,
o start of GnRH analogs: 14.6 (1.7)
eligible for medical intervention over time to monitor the secondary sex characteristics and neutral body
with a range of 11.5–17.9.
between 2000 and 2008 at the exposure status and the characteristics were 0.9 (1,20), 0.2 (1,20) and 4.2 (1,20).
o start of CSH: 16.6 (1.1) with a range development of the outcome of
clinic. Of this cohort, 29 There were significant interaction effects between gender
of 13.9–18.6. interest (prospective review).
adolescents who were age 16 and the changes of BIS between Pre-treatment and Post
years or older were prescribed o assessment of post treatment: 20.9 Measured pre-treatment and
treatment (F(df)) of primary sex characteristics, secondary
CSH only, and 111 adolescents (1.0) with a range of 19.7–22.8. post-treatment, at least one year
sex characteristics and neutral body characteristics were 14.0
were prescribed GnRH analogs after gender reassignment
The mean (SD) full-scale intelligence (1,20), 6.0 (1,20) and 13.9 (1,20), respectively;
to suppress puberty. surgery.
was 98.2 (15.0) with a range of 70–
Subsequently, 70 of the 111 MTFs showed more improvement in their satisfaction with
131.
started CSH treatment between primary (P < 0.001) and secondary sex characteristics
MTFs group (N = 11): (P < 0.05) compared to FTMs.
the years 2003 and 2009. The
first 30 young adults who had Age, mean (SD) With their neutral body characteristics, MTFs became more
become age 18 and had GRS satisfied whereas FTMs became less satisfied between Pre-
o assessment of pre-treatment: 13.9
between 2004 and 2009 were treatment and Post treatment (P < 0.001).
(.8).
invited to participate at least
o start of GnRH analogs: 15.0 (0.6). Gender dysphoria:
one year after their last
operation. GRS was vaginoplasty o start of CSH: 16.7 (1.4). There were no significant gender differences on the gender
for MTFs and hysterectomy for dysphoria either Pre-treatment or Post treatment (P = NS).
o assessment of post treatment: 21.3
FTMs, because after these (1.1). The gender effect (F(df)) of the UGDS score was 4.2 (1,19).
surgeries transsexuals can
legally change their gender. One
a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
738

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
person (MTF) refused to The mean (SD) full-scale intelligence The interaction effects between gender and the changes of
participate and two (one FTM was 94.4(12.3). gender dysphoria between Pre-treatment and post
and one MTF) failed to send FTMs group (N = 16): treatment was not statistically significant (P = NS).
back their questionnaires. This
resulted in 27 participants, 11 Age, mean (SD) age
MTFs and 16 FTMs. o assessment of pre-treatment: 13.2
Subset definition: Comparisons (1.8).
were made between MTF o start of GnRH analogs: 14.4 (0.3).
adolescents (n = 11) and FTM
o start of CSH: 16.6 (0.9).
adolescents (n = 16)
o assessment of post treatment was
20.7 (0.8).
The mean (SD) full-scale intelligence
was 103.5 (15.2).
de Vries (2011)57 Transgender adolescents (N = 70) Mean age at assessment (yr, SD), Natal males (n = 33) Natal females (n = 37) Self-reported measures: Body image scores
P = .028 Compared with natal males, natal females reported
Eligibility: N/R UGDS questionnaire
o Natal males: 13.14 (1.55) significantly more gender dysphoria and were more
Sampling method: First 70 BIS
o Natal females: 14.10 (1.99) dissatisfied with their primary and secondary sex
transgender adolescents who were Cohort: outcomes were characteristics both at T0 and T1. There was a significant
referred for medical treatment (ie, Mean age at start of GnRH analogs measured before (T0) and while interaction effect between natal sex and the changes of
puberty suppression) between 2000 (yr, SD), P = .036 on puberty suppression, before gender dysphoria between T0 and T1; natal females became
and 2008 CSH (T1)
o Natal males: 14.25 (1.79) more dissatisfied with their secondary (F[1,55] = 14.59,
Subset definition: Comparisons o Natal females: 15.21 (1.95) P < 0.001) and neutral (F[1,55] = 15.26, P < 0.001) sex
were made between natal males characteristics compared with natal males.
(n = 33) and natal females (n = 37) Mean age at start of CSH (yr, SD),
P = .008 Mean UGDS score (SD; N = 41):
o Natal males: 16.24 (1.21) Before starting puberty suppression (T0):
o Natal females: 16.99 (1.07) o Natal males: 47.95 (9.70)
Mean time between start of GnRH o Natal females: 56.57 (3.89)
analogs and CSH (yr, SD), P = .NS While taking puberty suppression (T1):
o Natal males: 1.99 (0.94) o Natal males: 49.67 (9.47)
o Natal females: 1.78 (1.16) o Natal females: 56.62 (4.00)
Between-sex significance: 15.98, P < .001
Mean BIS score (SD; N = 57):
Primary sex characteristics:
o Before starting puberty suppression (T0):
 Natal males: 4.02 (0.61)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
739

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
 Natal females: 4.16 (0.52)
o While taking puberty suppression (T1):
 Natal males: 3.74 (0.78)
 Natal females: 4.17 (0.58)
o Between-sex significance: 4.11, P = .047
Secondary sex characteristics:
o Before starting puberty suppression (T0):
 Natal males: 2.66 (0.50)
 Natal females: 2.81 (0.76)
o While taking puberty suppression (T1):
 Natal males: 2.39 (0.69)
 Natal females: 3.18 (0.42)
o Between-sex significance: 11.57, P = .001
Neutral characteristics:
o Before starting puberty suppression (T0):
 Natal males: 2.60 (0.58)
 Natal females: 2.24 (0.62)
o While taking puberty suppression (T1):
 Natal males: 2.32 (0.59)
 Natal females: 2.61 (0.50)
o Between-sex significance: 0.081, P = NS
de Vries (2014)79 Transgender adults who had Mean age at assessment before Transgender women who had Transgender men who had Self-reported measures: Body satisfaction: Trans women reported more satisfaction over
received puberty suppression treatment is started (yr, SD): received puberty suppression received puberty suppression time with primary sex characteristics than trans men and a
UGDS questionnaire
during adolescence, and completed o Transgender women: 13.6 (1.8) during adolescence, and during adolescence, and continuous improvement in satisfaction with secondary and
gender reassignment surgery completed gender completed gender BIS neutral sex characteristics. Trans men reported more
(N = 55) o Transgender men: 13.7 (2.0) reassignment surgery (n = 22) reassignment surgery (n = 33) dissatisfaction with secondary and neutral sex characteristics at
Cohort: outcomes were
Mean age at start of GnRH analogs measured before the start of T1 than T0, but improvement in both from T1 to T2.
the Eligibility: Prescribed puberty
(yr, SD): puberty suppression (pre-
Netherlands) suppression at the clinic as an Mean UGDS score (SD):
adolescent with GD, and received o Transgender women: 14.8 (2.0) treatment; T0), at the start of
CSH (T1), and at least 1 year after o At the start of CSH (T1):
gender reassignment surgery o Transgender men: 14.9 (1.9)
between 2004 and 2011 gender reassignment surgery (T2)  Transgender women: 48.95 (10.80)
Mean age at start of CSH (yr, SD):
 Transgender men: 57.11 (3.40)
Sampling method: This group of
o Transgender women: 16.5 (1.3)
adolescents belonged to a larger o At least 1 year after gender reassignment surgery (T2):
group of adolescents (n = 196) who o Transgender men: 16.8 (1.0)
 Transgender women: 17.27 (2.57)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
740

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
were referred for treatment Mean age at gender reassignment  Transgender men: 15.08 (2.64)
between 2000 and 2008. surgery (yr, SD): Mean BIS score (SD):
Participants were recruited for the o Transgender women: 19.6 (0.9)
study between 2008 and 2012, at o Primary sex characteristics at the start of CSH (T1):
least 1 year post gender o Transgender men: 19.0 (0.8)  Transgender women: 3.82 (0.56)
reassignment surgery Mean age at assessment after gender  Transgender men: 4.13 (0.60)
reassignment surgery (yr, SD):
Subset definition: Comparisons o Primary sex characteristics at least 1 year after gender
were made between transgender o Transgender women: 21.0 (1.1) reassignment surgery (T2):
women (n = 22) and transgender o Transgender men: 20.5 (0.8)  Transgender women: 2.07 (0.74)
men (n = 33)
Mean pre-treatment UGDS (SD):  Transgender men: 2.89 (0.71)
o Transgender women (n = 11): o Secondary sex characteristics at the start of CSH (T1):
47.07 (11.05)
 Transgender women: 2.34 (0.68)
o Transgender men (n = 22): 56.74
 Transgender men: 3.18 (0.43)
(3.74)
o Secondary sex characteristics at least 1 year after gender
Mean pre-treatment BIS (SD):
reassignment surgery (T2):
Primary sex characteristics:
 Transgender women: 1.93 (0.63)
o Transgender women (n = 17): 4.03
 Transgender men: 2.48 (0.40)
(0.68)
o Neutral body characteristics at the start of CSH (T1):
o Transgender men (n = 28): 4.18
(0.53)  Transgender women: 2.29 (0.50)
Secondary sex characteristics:  Transgender men: 2.61 (0.52)
o Transgender women (n = 17): 2.63 o Neutral body characteristics at least 1 year after gender
(0.60) reassignment surgery (T2):
o Transgender men (n = 28): 2.80  Transgender women: 2.09 (0.56)
(0.72)  Transgender men: 2.32 (0.44)
Neutral body characteristics:
o Transgender women (n = 17): 2.57
(0.70)
o Transgender men (n = 28): 2.21
(0.64)
Grannis (2021)110 FTM adolescents (N = 42) Mean age (yr, SD), P < .01: Received intramuscular Did not receive intramuscular Self-reported measures: Participants who received testosterone cypionate reported
o Treated FTM: 17.0 (1.2) testosterone cypionate testosterone cypionate (n = 23) significantly lower body image dissatisfaction compared to
A gender Eligibility: Diagnosis of GD, 9 to 21 BIS
(n = 19) those who did not receive testosterone cypionate (P < .01,
developmental clinic at yrs of age, and able to participate in o Untreated FTM: 15.8 (1.5) Cross-sectional: η² = 0.21)
a children's hospital MRI-based research exposures/outcomes were
History of anxiolytics/anti-depressant Mean composite score (SD):
Sampling method: Study sample use: measured at the same time
was drawn from a larger study of o Treated FTM: 91.16 (19.67)
a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
741

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Table I.J.4. Clinical studies with between-TGNB-group comparisons examining body image outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
transgender youth receiving gender o Treated FTM: 10 (52.6) o Untreated FTM: 108.09 (13.32)
affirming medical care (both PBs o Untreated FTM: 18 (78.3) There was a significant direct relationship between self-
and CSH). All participants were reported body image dissatisfaction and depression (P
receiving gender affirming Birth control use:
value < 0.01) and suicidality within the previous year (P
behavioral support and had not o Treated FTM: 15 (79.0) value < 0.10). The relationship between testosterone and
been prescribed PBs previously. o Untreated FTM: 15 (65.2) depression and suicidality was non-significant after
Subset definition: Comparisons Mean duration of testosterone use controlling for body image dissatisfaction
were made between treated (months, SD): No direct effects were found between body image
(n = 19) and untreated (n = 23) FTM dissatisfaction and anxiety
o Treated FTM: 13.1 (10.3)
adolescents
Mean testosterone dosage (mg, SD):
o Treated FTM: 242.1 (82.3)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CHS, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog/analog; mBMI,
median body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s)
742

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Carmichael (2021)73 N = 44 TGNB adolescents Full cohort: All participants had normal TGNB youth registered male TGNB youth registered female Bone mineral density (BMD) in BMD at lumbar spine:
endocrinology, karyotype, imaging and at birth starting GnRH analogs at birth starting GnRH analogs the lumbar (L1-L4) spine and hip
UK Eligibility Criteria: Patients TGNB youth DFAB showed no significant difference in
clinical phenotype on physical exam for (n = 25) (n = 19) was measured by dual energy X-
recruited from those referred to outcome at 12 months compared to TGNB youth DMAB with a
birth-registered sex and normal full blood ray absorptiometry (DEXA) scans.
GIDS who were between 12-15 difference of -0.02, 95% CI (-0.05,0.01) P = NS
count and liver and renal function. All
years and had commenced GnRH Cohort study-data was compared
patients left study following their 16th TGNB participants who were TGNB participants who were BMD at lumbar spine:
analog treatment. from baseline to 12 months on
birthday when they chose whether to Tanner stage 4 at baseline Tanner stage 3 (n = 19) or 5
treatment Participants starting at Tanner stage 3 at baseline showed a
Had been seen for at least 6 pursue cross-sex hormone therapy. (n = 16) (n = 9) at baseline
difference of 0.008, 95% CI (-0.03,0.04), P = NS compared to
months and attended at least 4
Median age was 13.6. those starting at Tanner stage 4.
interviews.
Tanner stage: Participants starting at Tanner stage 5 at baseline showed a
Psychological stability to
o n = 19 (43%) stage 3 difference of -0.009, 95% CI (-0.05,0.03), P = NS compared to
withstand the stresses of
those starting at Tanner stage 4.
medical treatment and o n = 16 (36%) stage 4
Pubertal stage at baseline showed no significant effect on
Displayed severe and persistent o n = 9 (21%), stage 5
outcome at 12 months.
GD and actively requesting
spent a median of 31 months in study
pubertal suppression
with a median age of 16.1 at end of
Able to give informed consent pathway.
Met physical/medical criteria of 89% of patients were of white
being in established puberty ethnicity.
and having normal endocrine
Birth registered male:
function and karyotype
consistent with birth registered o Median age 13.4
sex. o spent a median 37 months in study
Exclusions: Inability to fully Birth registered female:
participate, BMI < 2nd percentile,
o Median age 13.9
serious psychiatric conditions,
Inability to give consent, low spine o spent a median 29 months in study
or hip BMD
Sampling Method: Patients
attending GIDS were provided with
information and those wishing to
find out more discussed with their
clinician. Those likely deemed
eligible were given detailed
information and invited to a
medical clinic for discussion. Young
people needed to commit to
regular medical and psychosocial
follow up. Informed consent was
obtained. 48 young people
attended the clinics and 44 wished
to participate. 8 young people were

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
743

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
not yet eligible, but were able to
enter the study when sufficiently
advanced in puberty.
Subset Definition:
Comparisons between birth
registered male (n = 25) and
birth registered female (n = 19)
adolescents.
Comparisons between TGNB
participants who were Tanner
stage 4 at baseline (n = 16) and
TGNB participants who were
Tanner stage 3 (n = 19) or 5
(n = 9) at baseline
Karakilic Ozturan TGNB adolescents (N = 28) Baseline characteristics are only given for TGNB youth with low BMI TGNB youth with normal - L1-L4 bone mineral density BMD z-score: The median L1-L4 spine BMD z-score was lower in
(2023)112 the entire screened cohort (N = 53). receiving medical high BMI receiving medical (BMD) z-scores: This value those with low BMI, P = .0006, R2 = .4
Eligibility: Participants must have
interventions interventions compares bone density to the
A tertiary pediatric been diagnosed with GD based on FTM: Median age was 16.4 years In MTF subjects, there was a stronger correlation between
average values for
endocrinology clinic in DSM-5 diagnostic criteria by a (IQR = 1.74) at the time of referral to BMD z-score and low BMI, P = .0135, R2 = .5
participants' age and natal
Turkey. mental health professional after at the clinic adolescents.
sex. It was measured using In FTM subjects, the correlation was weaker, P = .02, R2 = .4
least six months of psychiatric
MTF: Median age was 16.3 years dual-energy X-ray The basal median L1-L4 spine BMD z-score of MTF and FTM
follow-up, and must have been
(IQR = 1.53) at the time of referral absorptiometry. adolescents was -1.1 (IQR 3.4) and 0.4 (IQR 1.9), respectively,
referred to the GD outpatient clinic.
They could not start hormone Cross sectional: Outcomes and no statistical difference was detected (P = NS)
treatment without informed measures were measured at the
consent from both themselves and same time.
their legal guardians. They must
have stayed below the age of 18
during the follow-up period of the
study (3-6 months).
Sampling Method: Authors
retrospectively examined the
medical records of all adolescents
diagnosed with GD after at least 6
months of psychiatric follow-up and
that were referred to their GD
outpatient clinic between 2016 and
2022.
Subset Definition: BMD z-scores
were compared between the entire
cohort, between MTF individuals

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
744

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
(n = 13), and between FTM (n = 15)
individuals.

Subset Definition: Comparisons Age, median (IQR), years: MTF adolescents that started FTM adolescents that started L1-L4 bone mineral density 25-hydroxyvitamine, Median (IQR):
were made between MTF starting GnRH analogs (n = 9) GnRH analogs (n = 13) (BMD) z-scores: This value
MTF starting GnRH analogs: 16.7 (1.2) Levels were significantly higher in the MTF cohort at 26.8
GnRH analogs (n = 6) vs FTM compares bone density to the
FTM starting GnRH analogs: 16.7 (1.0) (10.6) ng/mL vs. 15.7 (6.9) ng/mL in the FTM cohort, P = .009
starting GnRH analogs (n = 13) average values for
P = NS participants' age and natal L1-L4 bone mineral density (BMD) z-score, Median (IQR):
sex. It was measured using There was no significant difference in the BMD z-score
dual-energy X-ray between the MTF cohort at -1.0 (3.3) vs. 0.4 (1.9) in the FTM
absorptiometry. cohort, P = NS
25-hydroxyvitamine levels
were collected at the third
and sixth month of treatment
and every 6 months
thereafter.
Cross Sectional: Exposures/
Outcomes were measured at
one point in time at the onset of
GnRH analogs
Subset Definition: Comparisons Age, median (IQR), years: MTF adolescents that used MTF adolescents that used L1-L4 bone mineral density 25-hydroxyvitamine, Median (IQR)
were made between MTF who took GnRH analogs before starting combined androgen receptor (BMD) z-scores: This value
MTF with GnRH analog treatment: There was no significant difference in levels between the
GnRH analogs and then started CSH CSH (n = 6) blockers before starting CSH compares bone density to the
17.3 (1.1) GnRH analog cohort at 16.7 (3.4) ng/mL vs. 15.9 (2.3) ng/mL in
(n = 6) vs MTF who took combined (n = 6) average values for
MTF with combined androgen the combined androgen receptor blocker cohort, P = NS
androgen receptor blocker and participants' age and natal
then started CSH (n = 6) receptor blocker treatment 17.5 (1.3) sex. It was measured using L1-L4 bone mineral density (BMD) z-score, Median (IQR)
P = NS dual-energy X-ray There was no significant difference in BMD z-score between
absorptiometry. the GnRH analog cohort at -0.91 (3.1) vs. -1.2 (2.3) in the
25-hydroxyvitamine levels combined androgen receptor blocker cohort, P = NS
were collected at the third
and sixth month of treatment
and every 6 months
thereafter.
Cross-sectional: exposures/
outcomes were measured at the
same time before participants
started CSH

Subset Definition: Comparisons Age, median (IQR), years: MTF adolescents that used FTM adolescents that used L1-L4 bone mineral density 25-hydroxyvitamine, Median (IQR)
were made between MTF either GnRH analogs or GnRH analogs before starting (BMD) z-scores: This value
MTF with GnRH analog treatment: There was no significant difference between the MTF cohort
participants who were starting CSH combined androgen receptor CSH (n = 9) compares bone density to the
17.3 (1.1) at 16.7 (3.4) ng/mL and 15.9 (2.3) ng/mL vs. 21.9 (17.9) ng/mL
(combined group whose previous blockers before starting CSH average values for
in the FTM cohort, P = NS
treatment was GnRH analogs and (n = 12) participants' age and natal

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
745

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
combined androgen receptor MTF with combined androgen sex. It was measured using L1-L4 bone mineral density (BMD) z-score, Median (IQR)
blocker) (n = 12) vs. FTM starting receptor blocker treatment: 17.5 (1.3) dual-energy X-ray
There was no significant difference between the BMD z-scores
CSH (n = 9) absorptiometry.
FTM: 17.8 (0.4) in the MTF cohort at -0.91 (3.1) and -1.2 (2.3) vs. -0.9 (1.0) in
25-hydroxyvitamine levels the FTM cohort, P = NS
P = NS
were collected at the third
and sixth month of treatment
and every 6 months
thereafter.
Cross-sectional: exposures/
outcomes were measured at the
same time at the start of CSH

Lee (2020)85 N = 63 early pubertal TGNB youth Assigned gender at birth: TGNB youth with normal BMD TGNB youth with low BMD aBMD and vBMD were Age at GnRH analog start, mean (SD)
initiating GnRH analogs o 33 (52.4%) male (n = 49) (n = 14) assessed by DXA and
Four Children's There was no significant difference between those with
quantitative computed
hospitals Eligibility: Tanner stage 2-3, o 30 (47.6%) female normal BMD: 12.0 (1.7), compared to those with low BMD:
tomography measuring TBLH,
initiation GnRH analogs 11.5 (1.4), P = NS
Gender identity LS, TH and FN.
Sampling method: those Tanner stage, mean (SD)
o 58 (92.1%) Binary Physical activity was assessed
meeting criteria with a DXA at
o 5 (7.9%) Non binary using the PAQ-C There was no significant difference between those with
an appropriate time
normal BMD: 2.43 (0.50), compared to those with low BMD:
Mostly non-Hispanic white (55.6%) Serum 25-hydroxyvitamin D
Subset: 2.30 (0.47), P = NS
and Hispanic (19.1%) was measured by standard
o Comparisons were made clinical assays PAQ-C, mean (SD)
between TGNB youth with Tanner Stage
Cross-sectional: exposures/ Those with normal BMD had a significantly lower PAQ-C of
low BMD, (n = 14) vs TGNB o 40 (63.5%) stage 2 outcomes were measured at the 2.32 (0.71) vs. 2.76 (0.61) of those with low BMD, P = .01
youth with normal BMD,
o 23 (36.5%) stage 3 same time
(n = 49) Serum 25-hydroxyvitamin D, mean (SD)
o Comparisons were made There was no significant difference between those with
between TGNB natal males normal BMD: 28.7 (0.8) compared to those with low BMD:
(n = 33) and natal females 28.8 (9.3), P = NS
(n = 30)
Daily calcium intake, mean (SD)
o Comparisons were made
using the following There was no significant difference between those with
predictors: normal BMD: 520 (106) compared to those with low BMD:
637 (334)), P = NS
1. Natal female
BMI Z-score, mean (SD),
2. PAQ-C score
There was no significant difference between those with
3. BMI Z-score
normal BMD: 0.08 (1.57) compared to those with low BMD:
4. Tanner stage 0.40 (0.99), P = NS
5. Age at blocker placement Height Z-score, mean (SD)

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
746

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
6. Daily calcium intake There was no significant difference between those with
7. Serum 25-OH D normal BMD: -0.27 (1.02) compared to those with low BMD:
0.22 (1.12), P = NS
TGNB natal male (n = 33) TGNB natal female (n = 30) Frequency of low vs normal BMD, percent (95% CI)
o A low aBMD or vBMD Z-score, defined as < -2, was
observed in more natal males: 30% (10/33, 95% confidence
interval [CI], 15.6-48.7) compared to natal females: 13%
(4/30, 95% CI, 3.8-30.7), P = NS
Areal BMD measurements
o Natal males had significantly lower TH BMD scores than
natal females, no other significant differences were
observed
TBLH BMD Z-score, mean (SD), P = NS
o Natal male (n = 18): -0.96 (1.10)
o Natal female (n = 18): -0.65 (1.22)
LS BMD Z-score, mean (SD), P = NS
o Natal male (n = 23): -0.37 (1.02)
o Natal female (n = 21): -0.12 (1.25)
TH BMD Z-score, mean (SD), P = .003
o Natal male (n = 14): -0.69 (0.71)
o Natal female (n = 10): 0.55 (1.10)
FN BMD Z-score, mean (SD), P = .01
o Natal male (n = 13): -0.78 (0.93)
o Natal female (n = 9): 0.30 (0.92)
Volumetric BMD measurements
o Natal males had significantly lower Cortical BMD z-scores
than natal females. There was no significant difference in
trabecular BMD z-scores
Trabecular BMD Z-score, mean (SD), P = NS
o Natal male (n = 8): -0.95 (1.38)
o Natal female (n = 7): -0.49 (0.84)
Cortical BMD Z-score, mean (SD), P = .047
o Natal male (n = 8): -1.80 (1.42)
o Natal female (n = 7): -0.42 (0.92)
Selected determinants of bone health

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
747

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
o The only significant determinate of bone health was age at
blocker placement.
Age at blocker placement, mean (SD), P = .002
o Natal female: 11.0 (1.4)
o Natal male: 12.1 (1.3)
Tanner stage, mean (SD), P = NS
o Natal female: 2.43 (0.50)
o Natal male: 2.30 (0.47)
PAQ-C, mean (SD), P = .04
o Natal female: 2.83 (0.57)
o Natal male: 2.50 (0.69)
Serum 25-hydroxyvitamin, mean (SD), P = NS
o Natal female: 30.8 (7.3)
o Natal male: 26.9 (11.0)
Daily calcium intake, mean (SD), P = NS
o Natal female: 540 (269)
o Natal male: 676 (393)
BMI Z-score, mean (SD), P = NS
o Natal female: 0.28 (1.05)
o Natal male: 0.38 (1.22)
Height Z-score, mean (SD), P = NS
o Natal female: -0.03 (1.17)
o Natal male: 0.25 (1.05)
TGNB youth were compared TGNB youth were compared Predictor: Natal Female
by a list of predictors to by a list of predictors that did
TBLH BMD, beta, (95% CI): 0.4 (-0.3, 1.0), P = NS
predictors that predicted not predict change in BMD
change in BMD scores scores LS BMD, beta, (95% CI): 0.07 (-0.7, 0.9), P = NS
TH BMD, beta, (95% CI): 0.9 (0.03, 1.7), P = NS
FN BMD, beta, (95% CI): 0.6 (-0.3, 1.5), P = NS
TBD BMD, beta, (95% CI): -0.2 (-6.6, 6.1), P = NS
CBD BMD, beta, (95% CI): 2.0 (-4.4, 8.3), P = NS
Predictor: PAQ-C score
TBLH BMD, beta, (95% CI): 0.3 (-0.3, 0.9), P = NS
LS BMD, beta, (95% CI): 0.002 (-0.7, 0.7), P = NS

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
748

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
TH BMD, beta, (95% CI): -0.05 (-0.7, 0.6), P = NS
FN BMD, beta, (95% CI): 0.2 (-0.5, 0.8), P = NS
TBD BMD, beta, (95% CI): 0.1 (-4.1, 4.4), P = NS
CBD BMD, beta, (95% CI): 0.2 (-4.1, 4.5), P = NS
Predictor: BMI Z-score
BMI z-score was significantly associated with an increase in
TBLH BMD z-scores
TBLH BMD, beta, (95% CI): 0.7 (0.4, 1.1), P = < .0001
LS BMD, beta, (95% CI): 0.3 (-0.05, 0.7), P = NS
TH BMD, beta, (95% CI): -0.2 (-0.2, 0.6), P = NS
FN BMD, beta, (95% CI): 0.2 (-0.2, 0.6), P = NS
TBD BMD, beta, (95% CI): -0.5 (-3.1, 2.1), P = NS
CBD BMD, beta, (95% CI): -0.06 (-2.7, 2.6), P = NS
Predictor: Tanner stage
TBLH BMD, beta, (95% CI): -0.2 (-1.0, 0.6), P = NS
LS BMD, beta, (95% CI): 0.4 (-0.5, 1.3), P = NS
TH BMD, beta, (95% CI): 0.3 (-0.7, 1.2), P = NS
FN BMD, beta, (95% CI): 0.3 (-0.7, 1.4), P = NS
TBD BMD, beta, (95% CI): 1.2 (-4.0, 6.5), P = NS
CBD BMD, beta, (95% CI): 0.8 (-4.5 to 6.0), P = NS
Predictor: Age at blocker placement
Age at blocker placement was significantly associated with a
decrease in TH and FN BMD z-scores, but no other scores
TBLH BMD, beta, (95% CI): 0.06 (-0.3 to 0.4), P = NS
LS BMD, beta, (95% CI): -0.1 (-0.5, 0.3), P = NS
TH BMD, beta, (95% CI): -0.5 (-0.9, 0.002), P = .049
FN BMD, beta, (95% CI): -0.6 (-1.1, -0.1), P = .02
TBD BMD, beta, (95% CI): -0.06 (-1.4, 1.2), P = NS
CBD BMD, beta, (95% CI): -0.2 -1.5 to 1.1), P = NS
Predictor: Daily calcium Intake
TBLH BMD, beta, (95% CI): 0.0003 (-0.0008, 0.001), P = NS
LS BMD, beta, (95% CI): -0.00003 (-0.001, 0.001), P = NS
TH BMD, beta, (95% CI): -0.001 (-0.003, 0.0006), P = NS

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
749

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
FN BMD, beta, (95% CI): -0.0009 (-0.003, 0.0008), P = NS
TBD BMD, beta, (95% CI): -0.001 (-0.005, 0.003), P = NS
CBD BMD, beta, (95% CI): -0.0009 (-0.004, 0.003), P = NS
Predictor: Serum 25-OH D
Serum 25-OH D levels were significantly associated with an
increase in TH BMD z-scores
TBLH BMD, beta, (95% CI): -0.0007 (-0.04, 0.03), P = NS
LS BMD, beta, (95% CI): 0.001 (-0.02, 0.05), P = NS
TH BMD, beta, (95% CI): 0.04 (0.0006, 0.08), P = .048
FN BMD, beta, (95% CI): -0.0009 (-0.008, 0.08), P = NS
TBD BMD, beta, (95% CI): -0.04 (-0.4, 0.3), P = NS
CBD BMD, beta, (95% CI): -0.06 (-0.4, 0.3), P = NS
Marwa (2022)87 N = 119 TGNB adolescents Age: The mean age ( ± SD) was 14.7 TGNB AMAB adolescents with TGNB AFAB adolescents LS BMD Z-score LS BMD
±2.6 years for AMAB and 15.0 ±2.6 Puberty suppression and/or Puberty suppression and/or Cohort: outcomes are measured
a multidisciplinary Eligibility: Transgender youth ages AMAB patients had a statistically significant lower adjusted LS
years for AFAB gender-affirming hormone gender-affirming hormone after the exposure has been
gender-affirming clinic 9-21 years who had a dual X-ray mean BMD Z-score (-0.605 ± 1.42) compared with AFAB
therapy (estrogen) (n = 46) therapy (testosterone; n = 73) measured (retrospective review
in Texas, absorptiometry (DXA) scan of the Medical condition: Vitamin D patients (0.043 ± 1.09) when using the gender assigned at
between June 2014 and lumbar spine (LS) before or within deficiency was found in 30.4% of of electronic medical records) birth reference database, P = .01.
June 2019 180 days of starting puberty AMAB and in 32.4% of AFAB
The mean difference between genders was magnified when
suppression and/or gender- Tanner stages: Advanced puberty was using the affirmed gender reference database (AMAB -1.753 ±
affirming hormone therapy present in 73.9% of AMAB and in 1.62, AFAB 1.045 ± 1.06, P < .001).
(estrogen or testosterone). DXA 91.3% in AFAB
scans of the LS are performed at The difference between groups was not evident in patients in
baseline and every 1–2 years as BMI z-score: AFABs had a slightly early puberty (AMAB -0.051 ± 1.32, AFAB 0.038 ± 0.89, P = NS)
part of standard of care guidelines higher mean BMI z-score of 0.576 -
The difference between groups was evident in patients in
in all patients being started on 0.976 compared with 0.056 - 1.69 in
advanced puberty (AMAB -0.800 ± 1.42, AFAB 0.001 ± 1.12,
puberty suppression and/or the AMAB; however, the difference
P = .006).
gender-affirming hormone therapy was not statistically significant
In multivariate model, AMAB gender was a determinants of
Race: White participants were 87.0%
Sampling method: 314 patient lower LS BMD z-score using the gender assigned at birth
of AMAB and 93.2% of AFAB
electronic records were reference database [R2 = 0.206, regression F(3,109) = 9.4,
retrospectively reviewed, 170 Ethnicity: Non-Hispanic were 89.1% P < .001 ]
patients had lumbar spine BMD of AMAB and 86.3% of AFAB
measurements done. Of 170, 51
patients were excluded (40 patients
had a BMD measurement after 180
days of starting puberty
suppression or cross-sex hormone
therapy and 11 patient had BMD
measurements but reports did not

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
750

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
specify the device used for
measurements)
Subset definition: BMD outcome
was compared between n = 46
patients (38.7%) AMAB and n = 73
patients (61.3%) AFAB (both
univariate analysis and multivariate
analysis). Tanner stage (coded as a
binary variable with Tanner stages II
and III (for breasts or testicular size)
being defined as "early puberty"
and stages IV or V as "advanced
puberty")

Navabi (2021)92 Transgender youth with GD Mean aBMD z-score at lumbar spine Transgender males (n = 119) Transgender females (n = 51) Demographic characteristics Transgender females had significantly lower z-scores at
(N = 170) (SD), P < .001: for baseline bone mineral lumbar spine aBMD and BMAD, and left total hip aBMD, and
Endocrine diversity
o Transgender males: 0.04 (1.10) density BMC compared to transgender males
clinic Eligibility: Patients < 18 yrs of age
with a clinic visit between January o Transgender females: −0.9 (−1.8 to Cross-sectional: exposures/
Ontario 2006 to April 2017, and at least 1 0.00) outcomes were measured at the
DXA measurement same time
Mean BMAD z-score at lumbar spine
Sampling method: Reviewed 198 (SD), P < .001
medical records, with 172 meeting
o Transgender males: −0.10 (1.00)
eligibility criteria
o Transgender females: −0.22 (1.41)
Subset definition: Comparisons
were made between transgender Mean aBMD z-score at left total hip
males (n = 119) and transgender (SD), P < .001
females (n = 51) o Transgender males: 0.10 (1.06)
o Transgender females: −0.44 (1.39)
Mean BMC z-score (SD) P = .001
o Transgender males: 0.05 (1.30)
o Transgender females: −0.66 (1.35)
Population, eligibility, and sampling N/R Baseline BMI percentile below Baseline BMI percentile above GnRH analog-induced bone Mean change in BMC z-score (SD):
method is the same as above. the obesity risk threshold the obesity risk threshold mineral content changes o BMI ≤ 85 percentile: −0.26 (0.49)
( ≤ 85; n = 71) ( > 85; n = 47) Cross-sectional: exposures/
Subset definition: Comparisons o BMI > 85 percentile: −0.37 (0.49)
were made between patients with a outcomes were measured at the
same time Difference (95% CI): 0.11 (−0.07 to 0.30), P = NS
BMI ≤ 85 percentile (n = 71) and
those with a BMI > 85 percentile
(n = 47)

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
751

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Schagen (2020)94 Adolescents diagnosed with GD, Mean age at the start of GnRH Transgender females starting Transgender males starting Demographic characteristics Transgender males were significantly older at the start of CSH
eligible for hormonal treatment analogs (yrs, SD), P = NS: GnRH analogs (n = 51) GnRH analogs (n = 70) Cross-sectional: compared to transgender females
Setting: N/R
(N = 121) o Transgender females: 14.1 (1.7) exposures/outcomes were
Eligibility: Diagnosed with GD (per o Transgender males: 14.5 (2.0) measured at the same time
DSM-IV-TR), eligible for treatment
Mean age at the start of CSH (yrs, SD),
according to guidelines, had DXA
P value = 0.005
scans available at the start of GnRH
analog treatment, and were seen o Transgender females: 16.2 (1.2)
from 1998 to 2009 o Transgender males: 16.9 (1.1)
Sampling method: N/R Duration of GnRH analogs use before
Subset definition: Comparisons starting CSH (yrs, SD), P = NS:
were made between transgender o Transgender females: 2.0 (0.94)
females (n = 51) and transgender o Transgender males: 1.8 (1.11)
males (n = 70)

Population, eligibility, and sampling Mean BMAD z-score at the lumbar Early pubertal transgender Late-pubertal transgender BMD z-scores Numerically, pubertal and late-pubertal transgender males
method is the same as above. spine in transgender females at the subjects: subjects: had higher BMAD z-scores at the lumbar spine and hip than
Serum bone markers (P1NP,
start of GnRH analogs: P3NP, 1CTP, osteocalcin) pubertal and late-pubertal transgender females at the start of
Subset definition: Comparisons Early pubertal transgender Late-pubertal transgender
o Early pubertal (n = 15): −0.33 (0.33) GnRH analog treatment
were made between early pubertal females (n = 15) females (n = 36) Cohort: outcomes were
transgender females (n = 15) and o Late pubertal (n = 36): −0.65 (0.20) At baseline, there were no significant difference between any
Early pubertal transgender Late-pubertal transgender measured at baseline, 12 months,
males (n = 14), and late-pubertal 24 months, and 36 months of the bone markers of early and late transgender females
Mean BMAD z-score at the hip in males (n = 14) males (n = 56)
transgender females (n = 36) and At baseline, early pubertal transgender males had significantly
transgender females at the start of
males (n = 56) higher P1NP, P3NP, 1CTP, and osteocalcin than late-pubertal
GnRH analogs:
transgender males
o Early pubertal (n = 15): −0.94 (0.27)
Early pubertal transgender females and males were on GnRH
o Late pubertal (n = 36): −1.01 (0.17)
analogs for a significantly longer time than late-pubertal
Mean BMAD z-score at the lumbar transgender and males (P < .001)
spine in transgender males at the o Early pubertal transgender females: 2.5 yrs
start of GnRH analogs: o Early pubertal transgender males: 4.0 yrs
o Early puberty (n = 14): −0.15 (0.29) o Late-pubertal transgender females: 1.5 yrs
o Late puberty (n = 56): 0.33 (0.14) o Late-pubertal transgender males: 1.7 yrs
Mean BMAD z-score at the hip in Before starting CSH, early pubertal transgender females had
transgender males at the start of significantly higher levels of P1NP, P3NP, and 1CTP compared
GnRH analogs: to late-pubertal transgender girls
o Early puberty (n = 14): −0.23 (0.25) Early pubertal transgender males had significantly higher
o Late puberty (n = 56): 0.04 (0.12) levels of P1NP and P3NP prior to starting CSH compared to
late-pubertal transgender males

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
752

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Vlot (2017)99 Adolescents with diagnosed gender All were treated with GnRH analog Treated TGNB patient Treated TGNB patient BTMs: The formation markers P1NP: median (range), mg/L
dysphoria (N = 70) triptorelin and CSHT (estrogen for trans comparisons were made comparisons were made P1NP and osteocalcin and the
At baseline, young trans men showed higher concentrations
women and testosterone for trans men) between the following groups: between the following groups: resorption marker ICTP were
Eligibility: Adolescents with of P1NP compared to the old trans men (783 (516–1090) vs.
was added in incremental doses from the measured in non-fasting
diagnosed gender dysphoria, a Trans men Trans men 110 (38–471), P = .02)
age of 16 years. state.
serum BTM measurement of P1NP, o Young trans men (n = 7) o Young trans men (n = 7) At baseline, young trans women showed higher
the osteocalcin or carboxy terminal Median ages in years (range) in trans BMAD: A DXA-scan was used
o Old trans men (n = 15) o Old trans men (n = 15) concentrations of P1NP compared to old trans women (935
Netherlands between cross linked telopeptide of type I men at start of GnRH analogs, at start to measure BMD in g/cm² of
(617–1348) vs. 191 (96–792), P = .03)
2001 and 2011. collagen (ICTP) within 90 days of CSHT, and 24 months after Trans women Trans women the LS and FN of the non-
before or after time point D0, C0 initiation of CSHT were 15.1 (11.7- dominant hip. To correct for Old trans women showed borderline higher concentrations of
o Young trans women o Young trans women
and C24, and/or a DXA-scan of the 18.6), 16.3 (15.9–19.5) and 18.3 height and height gain the P1NP at baseline than old trans men (191 (96–792 vs. 110
(n = 9) (n = 9)
lumbar spine (LS) and/or femoral (17.9–21.5), respectively volumetric bone mineral (38–471), P = 0.05)
neck (FN) performed within 90 days o Old trans women (n = 6) o Old trans women (n = 6) apparent density (BMAD) in Osteocalcin median (range), mg/L
Median ages in years (range) in trans
before or after time point D0, C0 g/cm3 for both LS and FN was
women, were 13.5 (11.5–18.3), 16.0 At baseline, young trans men showed higher concentrations
and C24. calculated. BMAD Z-scores
(14.0–18.9) and 18.0 (16.0–20.9), of osteocalcin compared to the old trans men (5 (2.2–11.7) vs.
were calculated for sex
Sampling method: Adolescents respectively. 2.4 (0.4–4.6), P = .02)
assigned at birth using an UK
diagnosed with gender dysphoria Median bone ages in years (range) in reference population. At baseline, young trans women showed higher
who were treated with GnRH trans men at start of GnRH analogs, at
Cohort Study: exposures/ concentrations of osteocalcin compared to old trans women
analogs and CSHT were recruited at start of CSHT, and 24 months after
outcomes were measured at 3 (4.8 (2.6–21.9) vs. 2.29 (0.8–11), P = .03)
their clinic; data and records were initiation of CSHT were 15 (12–17), 16
retrospectively reviewed. moments in time: At the start of No difference between trans men and trans women was
(12–17) and 17 (14–17), respectively
GnRH analog treatment, at the found.
Subset: Comparisons were made Median bone ages in years (range) in start of CSHT and 24 months after 1CTP: median (range), mg/L
between trans women (n = 28) and trans women, were 13.5 (10–17), 14 the start of CSHT
trans men (n = 42). Participants (13–17) and 16.75 (14.5–17), At baseline, young trans men showed higher concentrations
were categorized into young and respectively. of ICTP compared to the old trans men (24 (17–29.9) vs. 7
old pubertal group, based on their (5.2–15), P = .02).
bone age at beginning of treatment.
No significant difference between young trans women and old
Young trans men (n = 7), old trans
trans women was found (23 (15–34) vs. 12 (6.9–21), P = NS).
men (n = 15), young trans women
(n = 9) and old trans women (n = 6) Trans men and trans women did not differ regarding ICTP
were all compared to each other. concentrations at baseline.
BMAD FN: median (range), g/cm³
BMAD FN did not differ at baseline between young and old
trans men (0.31 (0.26–0.36) vs. 0.33 (0.25–0.39), P = NS).
BMAD FN did not differ at baseline between young and old
trans women (0.29 (0.20–0.33) vs. 0.30 (0.26–0.36), P = NS)
was found.
trans men and trans women did not differ regarding their
BMAD FN at baseline.
BMAD FN Z-scores: median (range)

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
753

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Table I.J.5. Clinical studies with between-TGNB-group comparisons examining bone health outcomes
Study first author Select baseline characteristics
Exposure/intervention/ Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Comparator Results
risk factor timing
and study setting value, if reported
Young trans women group showed a lower BMAD-Z score
compared to young trans men at C24 (−1.3 (−3.51–0.92) vs. -
0.37 (−2.03–0.85), P = .02).
BMAD LS, median (range), g/cm³
At baseline, the young trans women had a lower BMAD LS
than the young trans men (0.21 (0.17–0.25) vs. 0.26 (0.21–
0.29), P = .003).
At baseline, there was no difference between young and old
trans men, young and old trans women, or between old trans
men and old trans women.
BMAD LS Z-scores: median (range)
At baseline, young trans men showed a lower Z-score
compared to old trans men (−0.05 (−0.78–2.94) vs. 0.27 (−1.6–
1.8), P = .02)

Table abbreviations: aBMD, areal bone mineral density; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; BMI, body mass index; cm, centimeters; CBD, Cortical BMD; DSM-IV-TR, Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, text revision; DXA, dual-energy radiograph absorptiometry; FN, femoral neck; GAH, gender-affirming hormones; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analog/analog; kg, kilogram; m, meter; LS, lumbar
spine; N/R, not reported; N/S, not significant; TGNB, transgender/nonbinary; yr(s), year(s); PAQ-C, Physical Activity Questionnaire for Older-Children; TBD, Trabecular BMD; TBLH, total body less head; TH, total hip
754

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Chiniara 201876 TGNB participants (N = 203) Age: Mean age ± standard deviation AFAB on testosterone AMAB on estradiol (n = 47) Laboratory data: The baseline Hemoglobin levels
in the assigned female group was (n = 156) blood tests were performed
Eligibility: Age 12–18 years, Significantly increased in AFAB on testosterone, P = 0.002,
16.3 ±1.63 and in the assigned male according to the initial 2009
presence of gender dysphoria, highest value 166 g/L
group was 16.1 ±1.70, with between Endocrine Society guidelines. In a
desire for pubertal suppression or
groups P value of 0.606. subset of individuals, blood Significantly decreased in AMAB on estradiol, P = 0.019,
cross-gender hormone
testing was repeated while lowest value 132 g/L
between January 2014 administration, ability to read and Tanner stage: Mean Tanner stage ±
receiving gender-affirming Statistically significant sex hormone-associated differences,
and June 2016 comprehend English, and deemed standard deviation in the assigned
hormones (after 6–12 months) P < .05
appropriate by TYC staff to fill out female group was 4.42 ±0.76 and in
according to the initial 2009
baseline and follow-up mental the assigned male group was 4.03 Hemoglobin levels stayed within normal limits
Endocrine Society guidelines
health questionnaires (i.e., youth ±1.1, with between groups P value of
including Red blood cell count
with extreme anxiety or learning 0.040. The majority of assigned
disability were excluded). Youth females N = 61 (54.5%) were on Total cholesterol Significantly increased in AFAB, highest value 5.38 × 1012
who exhibited discomfort in their Tanner stage 5 and the majority of Significantly decreased in AMAB, lowest 4.34 × 1012
High-density lipoprotein
assigned gender less than 6 months assigned males N = 14 (45.2%) were
were also included as they were on Tanner stage 5 as well. Low-density lipoprotein Statistically significant sex hormone-associated differences,
deemed likely to benefit from P = 0.001
Bone age: Mean bone age ± standard Triglycerides
puberty suppression. deviation in the assigned female Lipid levels
Hemoglobin
Sampling method: Adolescents group was 15.9 ±1.3 and in the No significant change from baseline following therapy in
Red blood cell count
who did not follow up at the clinic assigned male group was 15.8 ±2.2, either AFAB nor AMAB, but this could be due to the limited
after the first visit were excluded with between groups P value of Cohort Study: outcomes are number of repeat lipid profile tests (AFAB, n = 8; AMAB,
(n = 12). Three adolescents had 0.991. measured after the exposure has n = 4).
their initial visit for gender been measured (retrospective
Height: Mean height ± standard
dysphoria at another center and chart review)
deviation, in cm, in the assigned
were excluded from this analysis female group was 162.8 ±7.1 and in
because of missing data. the assigned male group was 167.2
Subset definition: Comparisons ±11.5. Mean height Z score ±
were made between N = 156 standard deviation in the assigned
(76.8%) AFAB individuals and N = 47 female group was 0.11 ±1.02 and in
(23.2%) AMAB individuals the assigned male group was –0.50
±1.06, with between groups P value
During the study period, 115 of 0.002.
individuals were treated with GnRH
Weight: Mean weight ± standard
analog therapy.
deviation, in kg, in the assigned
female group was 64.7 ±15.8 and in
the assigned male group was 64.7
±19.3. Mean weight Z score ±
standard deviation in the assigned
female group was 0.75 ±1.20 and in
the assigned male group was 0.19
±1.37, with between groups P value
of 0.020.
a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
755

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
BMI: Mean BMI ± standard deviation
in the assigned female group was
24.2 ±5.4 and in the assigned male
group was 23.0 ±5.8. Mean BMI Z
score ± standard deviation in the
assigned female group was 0.78 ±1.21
and in the assigned male group was
0.49 ±1.40, with between groups P
value of 0.238.
Ethnicity: In this cohort, youth of
Caucasian descent were
overrepresented, whereas visible
minorities were under-represented,
except for First Nations youth. There
was no statistically significant
difference in the ethnicity profile
between assigned females and
assigned males.
Comorbidities: In this cohort,
assigned females had more mood
disorders than assigned males. There
was a statistically significant
difference when comparing
comorbidities between the assigned
female and assigned male group
(P = 0.008, Pearson's chi-squared)
Karakilic Ozturan TGNB adolescents (N = 28) Age, median (IQR), years: MTF adolescents that started FTM adolescents that started Physical examination done by BMI, median (IQR)
(2023)112 GnRH analogs (N = 9) GnRH analogs (N = 13) the same examiner each visit.
Eligibility: Participants must MTF starting GnRH analogs: 16.7 (1.2) There was no significant difference in the BMI of the MTF
Blood pressure was taken,
A tertiary pediatric have been diagnosed with GD cohort of 24.8 (5.8) kg/m² vs. 23.1 (4.5) kg/m²) in the FTM
FTM starting GnRH analogs: 16.7 (1.0) height and weight were
endocrinology clinic in based on DSM-5 diagnostic cohort, P = NS
P = NS measured, and BMI
Turkey. criteria by a mental health BMI SDS, median (IQR)
calculated.
professional after at least six
months of psychiatric follow-up Standard deviation scores There was no significant difference in the BMI SDS of the
and must have been referred to (SDS) were calculated MTF cohort of 0.7 (1.5) vs. 0.7 (1.5) in the FTM cohort, P = NS
the GD outpatient clinic. They according to age and natal sex Systolic BP, median (IQR)
could not start hormone Complete blood count,
treatment without informed There was no significant difference in the systolic BP of the
glucose and lipid profile was
consent from both themselves MTF cohort of 110 (20) mmHg vs. 107.5 (11) mmHg in the
performed at the third and
and their legal guardians. They FTM cohort, P = NS
sixth month of treatment and
must have stayed below the age every 6 months thereafter. Diastolic BP, median (IQR)

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
756

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
of 18 during the follow-up Cross Sectional: Exposures/ The MTF cohort had a significantly higher diastolic BP of 80
period of the study (3-6 Outcomes were measured at one (10) mmHg vs. 69 (8.8) mmHg in the FTM cohort, P = .023
months). point in time at the initiation of PRL, median (IQR)
Sampling Method: Authors GnRH analogs
There was no significant difference in the PRL levels of the
retrospectively examined the
MTF cohort of 8.4 (10.8) ng/mL vs. 15.2 (4.1) ng/mL in the
medical records of all
FTM cohort, P = NS
adolescents diagnosed with GD
after at least 6 months of Glucose, median (IQR)
psychiatric follow-up and that There was no significant difference in the glucose levels of
were referred to their GD the MTF cohort of 86.5 (5.1) mg/dL vs. 86 (10.5) mg/dL in the
outpatient clinic between 2016 FTM cohort, P = NS
and 2022.
Insulin, median (IQR)
Subset Definition: There were
n = 13 MTF participants and There was no significant difference in the insulin levels of the
n = 15 FTM participants. From MTF cohort of 13.3 (16.6) ug/mL vs. 9.0 (4.4) ug/mL in the
this group, comparisons were FTM cohort, P = NS
made between: HbA1c, median (IQR)
o MTF starting GnRH analogs There was no significant difference in the HbA1c % of the
(n = 6) vs FTM starting GnRH MTF cohort of 5.4 (0.4) % vs. 5.0 (0.2) %in the FTM cohort,
analogs (n = 13) P = NS
o MTF who took GnRH analogs Total cholesterol, median (IQR)
and then started CSH (n = 6)
vs MTF who took combined There was no significant difference in the total cholesterol
androgen receptor blocker levels of the MTF cohort of 183 (54.9) mg/dL vs. 157.7 (47.5)
and then started CSH (n = 6) mg/dL in the FTM cohort, P = NS
o MTF participants who were Triglycerides, median (IQR)
starting CSH (combined group The MTF cohort had significantly higher triglyceride levels of
whose previous treatment 115 (26.8) mg/dL vs. 63 (13.9) mg/dL in the FTM cohort,
was GnRH analogs and P = .005
combined androgen receptor
blocker) (n = 12) vs. FTM HDL, median (IQR)
starting CSH (n = 9) The MTF cohort had significantly lower HDL levels of 40 (1.9)
mg/dL vs. 55 (4.7) mg/dL in the FTM cohort, P < .001
LDL, median (IQR)
There was no significant difference in the LDL levels of the
MTF cohort of 130 (48.5) mg/dL vs. 91.5 (50.3) mg/dL in the
FTM cohort, P = NS

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
757

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Age, median (IQR), years: MTF adolescents that used MTF adolescents that used Physical examination done by BMI, median (IQR)
GnRH analogs before starting combined androgen receptor the same examiner each visit.
MTF with GnRH analog treatment: There was no significant difference in the BMI of the GnRH
CSH (N = 6) blockers before starting CSH Blood pressure was taken,
17.3 (1.1) analog group of 20.1 (0.7) kg/m² vs. 19.8 (5.9) kg/m² in the
(N = 6) height and weight were
MTF with combined androgen combined androgen receptor blocker group, P = NS
measured, and BMI
receptor blocker treatment: 17.5 (1.3) calculated. BMI SDS, median (IQR)
P = NS Standard deviation scores There was no significant difference in the BMI SDS of the
(SDS) were calculated GnRH analog group of -1.2 (0.7) vs. -0.9 (2.1) in the combined
according to age and natal sex androgen receptor blocker group, P = NS
Complete blood count, Systolic BP, median (IQR)
glucose and lipid profile was
There was no significant difference in the systolic BP of the
performed at the third and
GnRH analog group of 105 (10) mmHg vs. 105 (15) mmHg in
sixth month of treatment and
the combined androgen receptor blocker group, P = NS
every 6 months thereafter.
Diastolic BP, median (IQR)
Cross-sectional: Outcomes were
measured at one point of time There was no significant difference in the diastolic BP of the
before participants started CSH GnRH analog group of 67.5 (6.3) mmHg vs. 62.5 (8.8) mmHg
in the combined androgen receptor blocker group, P = NS
PRL, median (IQR)
There was no significant difference in the PRL levels of the
GnRH analog group of 16.1 (3.8) ng/mL vs. 12.3 (4.0) ng/mL
in the combined androgen receptor blocker group, P = NS
Glucose, median (IQR)
There was no significant difference in the glucose levels of
the GnRH analog group of 90 (5.0) mg/mL vs. 93.5 (7.8)
mg/mL in the combined androgen receptor blocker group,
P = NS
Insulin, median (IQR)
There was no significant difference in the insulin levels of the
GnRH analog group of 9.7 (3.2) ug/mL vs. 9.1 (2.3) ug/mL in
the combined androgen receptor blocker group, P = NS
HbA1c, median (IQR)
There was no significant difference in the HbA1c % of the
GnRH analog group of 5.6 (0) % vs. 5.1 (0.5) % in the
combined androgen receptor blocker group, P = NS
Total cholesterol, median (IQR)

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
758

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
There was no significant difference in the total cholesterol
levels of the GnRH analog group of 167.8 (45.3) mg/dL vs.
166.3 (14.1) mg/dL in the combined androgen receptor
blocker group, P = NS
Triglycerides, median (IQR)
There was no significant difference in triglyceride levels of
the GnRH analog group of 87.5 (59.4) mg/dL vs. 74.6 (31.4)
mg/dL in the combined androgen receptor blocker group,
P = NS
HDL, median (IQR)
There was no significant difference in HDL levels of the GnRH
analog group of 59.1 (19.3) mg/dL vs. 55.5 (16.1) mg/dL in
the combined androgen receptor blocker group, P = NS
LDL, median (IQR)
There was no significant difference in LDL levels of the GnRH
analog group of 95.3 (20.8) mg/dL vs. 90 (17.3) mg/dL in the
combined androgen receptor blocker group, P = NS
Age, median (IQR), years: MTF adolescents that used FTM adolescents that used Physical examination done by BMI, median (IQR)
either GnRH analogs or GnRH analogs before starting the same examiner each visit.
MTF with GnRH analog treatment: There was a no significant difference in the BMI of the MTF
combined androgen receptor CSH (N = 9) Blood pressure was taken,
17.3 (1.1) cohort [20.1 (0.7) kg/m² and 19.8 (5.9) kg/m²] compared to
blockers before starting CSH height and weight were
MTF with combined androgen the FTM cohort at 24.5 (6.9) kg/m², P = NS
(N = 12) measured, and BMI
receptor blocker treatment 17.5 (1.3) calculated. BMI SDS, Median, IQR
FTM: 17.8 (0.4) Standard deviation scores There was a no significant difference in the BMI SDS of the
P = NS (SDS) were calculated MTF cohort [1.2 (0.7) and -0.9 (2.1)] compared to the FTM
according to age and natal sex cohort at 1.1 (2.9), P = NS
Complete blood count, Systolic BP, median (IQR)
glucose and lipid profile was
There was no significant difference in the systolic BP of the
performed at the third and
MTF cohort of 105 (10) mmHg and 105 (15) mmHg vs. 110
sixth month of treatment and
(14) in the FTM cohort, P = NS
every 6 months thereafter.
Diastolic BP, median (IQR)
Cross-sectional: Outcomes and
measures were taken at one There was no significant difference in the diastolic BP of the
point of time at the start of CSH MTF cohort of 67.5 (6.3) mmHg and 62.5 (8.8) mmHg vs. 70
(7.5) mmHg in the FTM cohort, P = NS
PRL, median (IQR)

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
759

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
There was no significant difference in the PRL levels of the
MTF cohort of 16.1 (3.8) ng/mL and 12.3 (4.0) ng/mL vs. 12.7
(5.1) ng/mL in the FTM cohort, P = NS
Glucose, median (IQR)
There was no significant difference in the glucose levels of
the MTF cohort of 90 (5.0) mg/mL and 93.5 (7.8) mg/mL vs.
89 (4.0) mg/dL in the FTM cohort, P = NS
Insulin, median (IQR)
There was no significant difference in the insulin levels of the
MTF cohort of 9.7 (3.2) ug/mL and 9.1 (2.3) ug/mL vs. 12.6
(3.2) in the FTM cohort, P = NS
HbA1c, median (IQR)
There was no significant difference in the HbA1c % of the
MTF cohort of 5.6 (0) % and 5.1 (0.5) % vs. 5.2 (0.1) % in the
FTM cohort, P = NS
Total cholesterol, median (IQR)
There was no significant difference in the total cholesterol
levels of the MTF cohort of 183 (54.9) mg/dL and 157.7
(47.5) mg/dL vs. 158 (46) mg/dL in the FTM cohort, P = NS
Triglycerides, median (IQR)
There was no significant difference in the triglyceride levels
of the MTF cohort of 87.5 (59.4) mg/dL and 74.6 (31.4)
mg/dL vs. 57 (14.1) in the FTM cohort, P = NS
HDL, median (IQR)
There was no significant difference in the HDL levels of the
MTF cohort of 59.1 (19.3) mg/dL and 55.5 (16.1) mg/dL vs.
52.3 (16.1) mg/dL in the FTM cohort, P = NS
LDL, median (IQR)
There was no significant difference in the LDL levels of the
MTF cohort of 95.3 (20.8) mg/dL and 90 (17.3) mg/dL vs. 94.5
(42.5) mg/dL in the FTM cohort, P = NS
Martinez-Martin TGNB subjects (N = 302) Mean age (yrs, SD): Transgender women taking Transgender women taking 5-yr follow-up of baseline Mean weight change at 5-yr follow-up (kg, SD), P < .05:
(2023)86 estradiol + spironolactone estradiol + an LHRH analog characteristics
Eligibility: Subjects who started Spironolactone: 17.1 (4.1) Spironolactone: 5.3 (3.2)
(n = 54) (n = 26)
Outpatient gender CSHT at the clinic since it opened in Incidence of HTN
LHRH analog: 16.2 (1.1) LHRH analog: 8.4 (6.5)
identity clinic, March 2000 and < 30 years of age,

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
760

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
with at least 5 years of follow-up. Mean weight (kg, SD): Cohort: outcomes are measured Mean glucose change at 5-yr follow-up (mmol/L, SD), P = NS:
(Spain) Patients were excluded if they were at the 5-yr follow-up
Spironolactone: 68.5 (11.6) Spironolactone: 0.3 (0.3)
only treated with LHRH analogs,
discontinued hormonal therapy or LHRH analog: 65.6 (10.1) LHRH analog: 0.5 (0.4)
switched to androgen blockers due Mean glucose (mmol/L, SD): Mean cLDL change at 5-yr follow-up (mmol/L, SD), P = NS:
to having pre-existing HTN, or
refused to give informed consent Spironolactone: 5.2 (0.6) Spironolactone: 0.4 (0.3)
LHRH analog: 4.9 (0.4) LHRH analog: 0.5 (0.4)
Sampling method: 811 medical
records were reviewed. After Mean cLDL (mmol/L, SD): Mean triglyceride change at 5-yr follow-up (mmol/L, SD), P = NS:
excluding 509 patients, 302 were
Spironolactone: 2.4 (0.6) Spironolactone: 0.4 (0.2)
included in the study
LHRH analog: 2.3 (0.7) LHRH analog: 0.6 (0.4)
Subset definition: Comparisons
were made between transgender Mean triglycerides (mmol/L, SD): Mean SBP change at 5-yr follow-up (mmHg, SD), P < .05:
women taking estradiol + Spironolactone: 1.6 (0.8) Spironolactone: 2 (1)
spironolactone (n = 54) and
LHRH analog: 1.5 (0.9) LHRH analog: 6 (2)
transgender women taking
estradiol + an LHRH analog (n = 26) Mean SBP (mmHg, SD): Those who had HTN at the 5-yr follow-up (n, %), P = NS:
Spironolactone: 121 (12) Spironolactone: 1 (1.8)
LHRH analog: 119 (13) LHRH analog: 2 (7.7%)
Yearly incidence of HTN (%, 95% CI), P = NS:
Spironolactone: 0.37 (0.00 to 0.74)
LHRH analog: 1.54 (0.45 to 2.63)
Spironolactone and LHRH analog use were nonsignificant
predictors for the development of HTN
Spironolactone was shown to have a marginally protective effect
(OR: 0.632, P = NS), but LHRH analog use did not (OR: 1.103,
P = NS)

Maru (2021)128 Patients with GD, with or without Mean age at first gender clinic visit (yrs, TGD patients with GD who TGD patients with GD and Demographic characteristics There were no significant differences between TGD patients and
T1DM (N = 1,114) SD), P < .05: presented to the clinic T1DM who presented to the those with T1DM for race, designated sex, affirmed gender, or
Cross-sectional: exposures/
between January 2007 and clinic between January 2007 proportion receiving hormonal treatment (ie, GnRH analogs or
Eligibility: Patients with GD TGD: 13 (3.7) outcomes were measured at the
December 2018 (N = 1,114) and December 2018 (n = 11) CSHT)
presenting to the clinic between same time
TGD + T1DM: 16 (2.7)
January 1, 2007 and December 31, Patients with T1DM had their first gender clinic visit at a
2018. Race, P = NS: significantly older age than the overall clinic population
White: (P = .007)
Sampling method: Patients with GD
and T1DM were identified by o TGD: 806 (72)
diagnostic ICD-9 or -10 codes o TGD + T1DM: 8 (72)

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
761

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Subset definition: Comparisons Hispanic/Latino:
were made between TGD patients o TGD: 61 (5.5)
(N = 1,114) and TGD patients with
T1DM (n = 11) o TGD + T1DM: 1 (9)
African American:
o TGD: 30 (2.7)
o TGD + T1DM: 2 (18)
American Indian or Alaskan Native:
o TGD: 6 (0.5)
o TGD + T1DM: 0 (0)
Asian:
o TGD: 27 (2.4)
o TGD + T1DM: 0 (0)
Other/unknown:
o TGD: 184 (17)
o TGD + T1DM: 0 (0)
Designated sex, P = NS:
Male:
o TGD: 390 (35)
o TGD + T1DM: 2 (18)
Female:
o TGD: 724 (65)
o TGD + T1DM: 9 (82)
Affirmed gender, P = NS:
Male:
o TGD: 663 (60)
o TGD + T1DM: 8 (73)
Female:
o TGD: 353 (32)
o TGD + T1DM: 2 (18)
Nonbinary:
o TGD: 98 (8.8)
o TGD + T1DM: 1 (0.09)
a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
762

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Received GnRH analogs, P = NS:
TGD: 177 (16)
TGD + T1DM: 2 (18)
Received CSHT, P = NS:
TGD: 482 (43)
TGD + T1DM: 9 (82)
Millington (2019)88 N = 85 TGNB participants Age: Mean (SD) age at spironolactone Spironolactone (100-200 Spironolactone ( < 100 mg/d) Potassium measurements: Association between dose of spironolactone and hyperkalemia:
start, in years, in all subjects was 16.6 mg/d, > 200 mg/d) Potassium measurements
Subjects with hyperkalemia: For spironolactone < 100 mg/d, number of potassium
(1.7), in subjects without were available for up to 7
n=6 measurements > 5.0 mmol/L/total number of potassium
hyperkalemia group was 16.7 (1.7), years of spironolactone
Subjects without hyperkalemia: measurements (%) was 2/17 (11.8%).
and in subjects with hyperkalemia therapy. Hyperkalemia was
from 2007 to
n = 79 group was 16.0 (1.4). defined as a serum potassium For spironolactone 100-200 mg/d, number of potassium
2017
Eligibility: Gender-diverse youth of concentration > 5.0 mmol/L. measurements > 5.0 mmol/L/total number of potassium
Gender identity: Female gender
any age seen in the hospital from measurements (%) was 2/74 (2.7%).
identity, n (%), in all subjects was 82 Cohort Study: outcomes are
2007 to 2017 and subjects who (96%), in subjects without measured after the exposure has For spironolactone > 200 mg/d, number of potassium
were prescribed spironolactone for hyperkalemia group was 76 (96%), been measured (retrospective measurements > 5.0 mmol/L/total number of potassium
the purposes of gender transition and in subjects with hyperkalemia chart review measurements (%) was 3/98 (3.1%).
were included in the analysis. group was 6 (100%). Compared to spironolactone < 100 mg/d, the relative risk
Sampling method: By retrospective Race: For race, n (%), majority in all (95% CI) of hyperkalemia for spironolactone 100-200 mg/d
chart review, N = 90 gender-diverse subjects was white 59 (69%), in was 0.23 (0.03–1.52), P = NS.
adolescents were prescribed subjects without hyperkalemia group Compared to spironolactone < 100 mg/d, the relative risk
spironolactone during the study was white 54 (68%), and in subjects (95% CI) of hyperkalemia for spironolactone > 200 mg/d was
period. N = 2 patients were with hyperkalemia group was white 5 0.26 (0.05–1.44), P = NS
prescribed spironolactone for (83%).
indications other than gender There was no increased risk of hyperkalemia with a higher
GnRH analog: 19 (22%), 18 (23%), and spironolactone dose.
transition and were excluded. N = 3
1 (17%) in all subjects, in subjects
patients were excluded because Serum Potassium concentrations vs dose/treatment length
without hyperkalemia group, and in
there were no potassium
subjects with hyperkalemia group, Serum potassium concentration is not correlated with
measurements recorded after
respectively, were using GnRH analog. spironolactone dose (P = NS)
spironolactone was initiated. As a
result, N = 85 subjects were Estrogen: 73 (86%), 68 (86%), and 5 There is a significant trend toward lower serum potassium
included in the analysis. (83%) in all subjects, in subjects concentration with longer duration of treatment.
without hyperkalemia group, and in
When the potassium measurements > 5.0 mmol/L were
subjects with hyperkalemia group, excluded, there was no correlation between serum
respectively, were using estrogen. potassium concentration and duration of spironolactone
Potassium measurements: Median exposure.
(range) number of potassium Incidence of hyperkalemia:
measurements per subject in all
subjects was 3 (1–10), in subjects
a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
763

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
without hyperkalemia group was 3 Eight potassium measurements in six subjects exceeded 5.0
(1–10), and in subjects with mmol/L. When these measurements were excluded, the rate
hyperkalemia group was 4.5 (1–8). of hyperkalemia was 2.2%.
Baseline potassium measurement: There were no cases of hyperkalemia in the baseline
Baseline potassium measurement measurements.
available, n (%), in all subjects was 70
All cases of hyperkalemia occurred early in the treatment
(82%), in subjects without
course ( < 6 months after starting spironolactone).
hyperkalemia group was 65 (82%),
and in subjects with hyperkalemia There were no potassium measurements > 6.0 mmol/L.
group was 5 (83%).
Serum potassium: Mean (SD) serum
potassium, in mmol/L, in all subjects
was 4.25 (0.4), in all subjects without
hyperkalemia group was 4.20 (0.3),
and in subjects with hyperkalemia
group was 4.65 (0.5).
Spironolactone dose: Mean (SD)
spironolactone dose, in mg/d, in all
subjects was 105 (42), in all subjects
without hyperkalemia group was 105
(42), and in subjects with
hyperkalemia group was 108 (49).
Millington (2021)89 N = 269 TGNB adolescents Baseline HDL-C levels (mean, SD, 95%C!), Obese DMAB Non-obese DMAB Laboratory and HDL-C level, mean (SD)
P = .01 anthropometric data were
Eligibility: no prior GnRH analog Participants who were DMAB with obesity had lower HDL-C
collected as part of clinical
use, starting CSH Non-obese: 46.1 mg/dL (8.8), 95% CI levels at baseline than participants who were DMAB without
care at baseline and at 6 and
(43.8 to 48.4) obesity, P = .01
Sampling method: recruited (not 12 months after beginning
more detail provided) Obese: 36.0 mg/dL (1.0), 95% CI (35.2 CSH. Obesity was defined as a Participants who were DMAB with obesity showed no
to 36.8) baseline body mass index significant change in HDL-C levels after 6 months of estradiol
Subset definition: Comparisons
more than the 95th percentile treatment from 36.0 [1.0] mg/dL to 41.3 [4.0] mg/dL; 95% CI,
between July were made between obese and
for designated sex. 35.2-36.8 vs 37.6-45.0; P = NS, compared to all participants
2016 and September non-obese TGNB adolescents
who were DMAB, HDL-C levels increased by 11.2 (8.8) mg/dL
2018 DMAB receiving testosterone Cohort Study: Outcomes were
(95% CI, 8.6-13.8; P < .001)
(n = 83) measured at baseline and then 6
months after treatment with CSH Obesity attenuated the benefit of estradiol treatment on
HDL-C levels after 6 months
N = 269 TGNB adolescents Baseline HDL-C levels (mean, SD, 95%C!), Obese DFAB Non-obese DFAB Laboratory and HDL-C level, mean (SD)
P = NS anthropometric data were
Eligibility: no prior GnRH analog For participants who were DFAB, baseline HDL-C levels were
collected as part of clinical
use, starting CSH Non-obese: 53.5 mg/dL (12.4), 95% CI not significantly different between participants with and
care at baseline and at 6 and
(51.3 to 55.0) without obesity, P = NS
12 months after beginning
a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
764

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Sampling method: recruited (not Obese: 48.9 mg/dL (12.2), 95% CI CSH. Obesity was defined as a The fall in HDL-C levels of DFAB participants with
more detail provided) (44.8 to 53.0) baseline body mass index testosterone was significantly more pronounced in
more than the 95th percentile participants with obesity than without obesity (−12.1 [9.9]
Subset definition: Comparisons
for designated sex. mg/dL vs −5.5 [9.7] mg/dL; 95% CI, −16.3 to −7.9 vs −7.7 to
were made between obese and
Cohort Study: Outcomes were −3.4; P = .004)
non-obese TGNB adolescents DFAB
receiving testosterone (n = 186) measured at baseline and then 6 Obesity exacerbated the negative association of testosterone
months after treatment with CSH treatment outcomes after 6 months, with the decrease in
HDL-C levels being more pronounced.
Millington (2022)90 N = 286 TGNB patients DMAB: DFAB- testosterone- average DMAB at baseline Serum Creatinine (SCr) levels DFAB has similar SCr to DMAB at baseline after 12 months of
SQ dose was 40 mg/week, were compared at one point testosterone treatment (0.82 vs 0.83) (P = NS)
Four large hospitals- Eligibility: clinician diagnosed Age: 17.3 years
average transdermal dose was in time-baseline of the DMAB
gender therapy with gender
Gender: 40.5 mg/day after 12 months group and 12 months of
affirming therapy deemed
o 51 identified as trans female of treatment treatment for the DFAB group
appropriate, received care at the
clinic, age 8-20 and reads and o 36 as female SCr was then adjusted by age
understands English. Those who and gender to calculate SCr/Q
o 1 as gender fluid
, previously used CSH were enrolled male and SCr/Q female
that were taking part in in the puberty blocker cohort or o 4 as non-binary
Cross sectional: Exposure and
the Trans Youth Care had severe psychiatric symptoms CSHT: outcome are measured at a single
United States Study were excluded o 77 were taking oral estrogen point in time. Baseline (DMAB)
Sampling method: patients were and 12 mo. post intervention
o 12 were taking transdermal
selected from clinic if they met (DFAB) levels were being
estrogen
inclusion criteria. compared.
o 3 were taking IM estrogen.
Subset definition: DMAB (n = 92) o 58 used spironolactone
and DFAB (n = 194) measured at
baseline and 6 mo increments DFAB:
Age: 16.2 years
Gender: 78 identified as male
o 103 as transgender male
o 2 as gender fluid
o 1 as gender queer
o 10 as non-binary
CSHT:
o 189 were taking testosterone SQ
o 5 were taking testosterone gel.
o 1 used spironolactone

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
765

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Same as above Same as above DMAB- estrogen, average oral DFAB at baseline Same outcomes 12 months of estradiol treatment decreased SCr, but not to the
dose 4 mg/day, average level of DFAB at baseline (0.76 mg/Dl vs 0.68 mg/dL, P = .0003)
Cross sectional: Exposure at
transdermal dose 0,5 mg/day,
outcome are measured at a single
average IM dose was 15
point in time. Baseline (DFAB)
mg/week after 12 months of
and 12 mo. post intervention
treatment
(DMAB) levels were being
compared.

Same as above Same as above DMAB- taking spironolactone DMAB not taking Same outcomes No difference in baseline SCr or SCr/Q between groups.
at baseline spironolactone at baseline
Cross sectional: Exposure at SCr: 0.83 vs 0.79, P = NS
outcome are measured at a single
SCr/Q: 1.0 vs 1.0, P = NS
point in time at baseline

Mullins (2021)91 TGNB adolescents (N = 611) Age at presentation, mean (IQR) TGM on testosterone TGF on estrogen treatment Charts were evaluated for No individual in either cohort developed a VTE or arterial
treatment (n = 429) (estradiol) (n = 182) development of thrombosis thrombosis (including stroke) while on CSHT
Eligibility Inclusion criteria: Total cohort: 17 (15-19) years
Cohort: Outcomes were These data suggest that CSHT in youth, titrated within
initiation of CSHT before March TGM: 17 [15–19] years
measured after a median of 574 physiologic range, does not carry a significant risk of
24, 2019 TGW: 18 [15.5–20] years days of treatment. thrombosis in the short-term, even with the presence of
age 13 to 24 years at initiation TGM were slightly younger at first preexisting thrombosis risk factors.
of CSHT. presentation compared with TGM,
The exclusion criterion was age- P = .0019).
participant had to be 13 years at Sex, n (%)
CSHT start.
428 (70%) subjects were assigned
Sampling Method: Charts were
female at birth
reviewed for inclusion criteria.
Among 1406 individual patients 183 (30%) were assigned male at
seen in the CCHMC Transgender birth.
Health Clinic, 611 subjects were Affirmed Gender, n (%)
eligible for inclusion in the study
cohort. 176 (28.8%) individuals identified as
female
Subset: Comparisons were made
416 (68.1%) as male
between TGF (n = 429) and TGM
(n = 182) participants who were 19 (3.1%) as nonbinary or gender
taking CSHT nonconforming.
Race, n (%)
White (n = 544; 89%)
African American (n = 50; 8.2%);
Hispanic. (n = 14;2.3%)

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
766

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
CSHT treatment
182(29.8%) TGW initiated estrogen
429 (70.2%) TGM initiated
testosterone
Median duration of treatment (IQR)
Total cohort: 574 days (283-962)
TGW: 554 days (283-1037)
TGM: 577 days (283-923)
Treatment initiation age, yr, (IQR)
TGM: 17 (15-19)
TGW: 18 (15.5-20)
The TGM cohort was slightly younger
at initiation of CSHT compared with
the TGW cohort, P = .004
Risk factors for thrombosis, n (%)
BMI 25-30 -Overweight: 148 (24.2)
BMI > 30- Obesity: 211 (34.5)
Tobacco use: 94 (15.4)
Migraine with aura (documented): 28
(2.6)
Family history of
thrombosis(documented): 49 (8.0)
Family history of risk factors for
thrombosis(documented): 5 (0.8)
Inflammatory bowel disease: 3(0.5)
Juvenile rheumatoid arthritis: 1 (0.2)
Previous hormonal use
(documented): 328 (53.7)
Thrombosis before CSHT: 3 (0.5)
Treated with anticoagulation: 3
Referred to hematology for
evaluation: 17 (2.8)

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
767

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
Valentine (2022)98 Transgender youth (N = 4172) Age at first visit, y: median (25th-75th TGNB youth with diagnosis of TGNB youth with diagnosis of Cardiometabolic outcomes were Testosterone (without GnRH analogs) vs. no GAHT
percentile): GD prescribed GAHT GD not prescribed GAHT obtained from electronic health
PEDSNet, a Pediatric Eligibility: TGNB youth subjects had In the adjusted analysis, there was an increased odds of
(N = 1412) (N = 2760) records including:
Learning Health System a diagnosis of gender dysphoria or 10.0 (4.4-14.6), being overweight/ having obesity (1.8; 95% CI, 1.5-2.1;
Network related diagnosis. Age at last visit, y: median (25th-75th N = 267 with a prescription Weight (whether overweight P < .0001), in those taking testosterone compared to those
percentile): for GnRH analogs alone or obese) not on GAHT.
Sampling Method: Clinical data
available from electronic health N = 832 with a prescription Dyslipidemia In the adjusted analysisa, there was an increased odds of
16.7 (14.6-18.3)
care records from the health for testosterone without Liver dysfunction having dyslipidemia (1.7; 95% CI, 1.1-1.9; P ≤ .01), in those
system from 2009 onward for GnRH analogs taking testosterone compared to those not on GAHT
patients with in-person encounters Hypertension
N = 349 with a prescription In the adjusted analysisa, hypertension (1.6; 95% CI, 1.2-2.2;
with a provider were reviewed for for estrogen without GnRH Dysglycemia P < .01) in those taking testosterone compared to those not
inclusion. The data for all TGNB analogs PCOS on GAHT.
patients and at least one outpatient
visit from 2009-2019 was extracted N = 106 with a prescription There was no statistically significant increase in the
from the PEDSnet database on Nov for testosterone with Cohort: Outcomes were unadjusted analysis in odds for liver dysfunction, PCOS, or
2019. GnRH analogs measured after exposures dysglycemia for those on testosterone compared to those
N = 125 with a prescription not on GAHT.
Subset: Comparisons were made
for estrogen with GnRH Testosterone + GnRH analogs vs. no GAHT
between TGNB youth taking GAHT
analogs
vs. TGNB youth not taking GAHT. In the adjusted analysisa, there was an increased odds of
having dyslipidemia (3.7; 95% CI, 2.0-6.7; P < .0001), in those
on testosterone + GnRH analogs compared to those who are
not taking GAHT
In the adjusted analysisa, there was an increased odds of
having liver dysfunction (2.5; 95% CI, 1.4-4.3; P < .01) in
those on testosterone + GnRH analogs compared to those
who are not taking GAHT.
There was no statistically significant increase in odds in the
unadjusted analysis for overweight/obesity, dysglycemia,
hypertension, or PCOS for those on testosterone + GnRH
analogs compared to those not on GAHT.
GnRH analogs vs. no GAHT
In both the adjusteda and the non-adjusted analyses, there
was no statistically significant increase in odds for
cardiometabolic outcomes (overweight/obesity, liver
dysfunction, dyslipidemia, dysglycemia, hypertension, or
PCOS) for those on a GnRH analog compared to those not on
GAHT.
Estradiol + GnRH analogs vs. no GAHT

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
768

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
In the adjusted analysis, there was no statistically significant
increase in odds for cardiometabolic outcomes
(overweight/obesity, liver dysfunction, dyslipidemia,
dysglycemia, hypertension, or PCOS) for those on estradiol +
GnRH analogs compared to those not on GAHT.
In the unadjusted analysis, there was an increased odds of
having liver dysfunction (2.1; 95% CI, 1.3-3.4; P < .01), in
those prescribed both estradiol and GnRH analogs compared
to those not prescribed GAHT.
In the unadjusted analysis, there was an increased odds of
having hypertension (2.1; 95% CI, 1.2-3.6; P < .01), in those
prescribed both estradiol and GnRH analogs compared to
those not prescribed GAHT.
Estradiol (no GnRH analogs) vs. no GAHT
In the adjusted analysesa, there was no statistically
significant increase in odds for cardiometabolic outcomes
(overweight/obesity, liver dysfunction, dyslipidemia,
dysglycemia, hypertension, or PCOS) for those on estradiol
compared to those not on GAHT.
In the unadjusted analysisa, compared to those not
prescribed GAHT, individuals prescribed estradiol had higher
odds of dyslipidemia (1.9; 95% CI, 1.3-2.7; P = .001),
In the unadjusted analysis, compared to those not prescribed
GAHT, individuals prescribed estradiol had higher odds of
liver dysfunction (1.6; 95% CI, 1.2-2.3; P < .01)
In the unadjusted analysis, compared to those not prescribed
GAHT, individuals prescribed estradiol had higher odds of
hypertension (2.3; 95% CI, 1.7-3.2; P < .0001).
Vehmas (2022)125 Transgender adolescents desiring Assigned sex at birth: FTM (n = 104) MTF (n = 20) Blood pressure Mean systolic blood pressure (mmHg, SD), P = .003
gender-affirming hormonal Cross-sectional: exposures/
AMAB: n = 20 FTM: 128.7 (10.5)
treatment (N = 124) outcomes were measured at the
AFAB: n = 104 MTF: 137.9 (12.7)
Eligibility: Adolescents diagnosed same time
(Finland) with GD, referred to gender identity Median age at the first contact with Mean diastolic blood pressure (mmHg, SD), P = NS
services at Helsinki University gender identity services (yr, range;
FTM: 76.8 (8.1)
Hospital before 18 years of age for N = 124):
GD symptoms, and further referred MTF: 75.8 (8.5)
16.7 (12.1 to 18.0)
to the adolescent gynecology clinic
Median age at GD diagnosis (yr, range;
N = 124):

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
769

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Table I.J.6. Clinical studies with between-TGNB-group comparisons examining cardiovascular outcomes
Study first author Select baseline characteristics
Outcome measures and
(publication year) Population n (%, unless otherwise noted), P Exposure/intervention Comparator Results
timing
and study setting value, if reported
for gender-affirming hormonal 18.1 (14.8 to 20.1)
assessment Median age at the time of assessment at
Sampling method: Referred by the adolescent gynecology clinic (yr,
gender identity services range; N = 124):
Subset definition: Comparisons 17.7 (14.6 to 19.8)
were made between MTF (n = 20)
and FTM (n = 104) transgender
adolescents

a
Analysis was adjusted for overweight/obesity, depression, and a prescription for an antipsychotic (Valentine 2022).
Table abbreviations: CI, confidence interval; cLDL, low-density lipoprotein cholesterol; FTM, female-to-male; GAHT, gender-affirming hormone therapy; GnRHa, gonadotropin-releasing hormone analog/analog; Hg, mercury; HTN, hypertension; ICD,
International Classification of Disease; kg, kilogram; L, liter; LHRH, luteinizing hormone-releasing hormone; mm, millimeters; mmol, millimole; MTF, male-to-female; N/S, not significant; PRL, prolactin; SBP, systolic blood pressure; SD, standard deviation; T1DM,
type 1 diabetes mellitus; TGD, transgender/gender diverse; TGF, transgender female; TGNB, transgender, non-binary, gender diverse; TGM, transgender male; yr(s), year(s)
770

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APPENDIX I.K: DATA EXTRACTED FROM STUDIES COMPARING TGNB
PATIENTS TO THEIR CISGENDER PEERS, ORGANIZED BY OUTCOME

771

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Table I.K.1. Clinical studies comparing TGNB to cisgender peers regarding mental health outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Durwood (2017)109 Population: N = 164 Transgender group: Transgender Transgender group: n = 62 Cisgender group: Mental health outcomes: Depression: Mean (SD)
children came from 23 US states and 1 (One child who had no Children reported on anxiety
Part of Trans Youth Transgender: n = 63 children Control group (matched by T score on self-reported depression
Canadian province. medical intervention but who and depression symptoms
Project - a national, age) n = 63 o No statistically significant difference in self-reported
Cisgender: n = 63 age- and was experiencing puberty is using the pediatric short form
longitudinal study of n = 33 children in this group were depressive symptoms across the 3 groups (F = 1.18,
gender-matched controls excluded from this part) Sibling group n = 38 of the National Institutes of
socially transitioned assigned boys, n = 30 assigned girls. P = NS).
Siblings: n = 38, aged 9-14 years Health's Patient Reported
transgender children Cross-sex hormones: N = 5
Mean age (SD) in years = 10.8 (1.3) Outcomes Measurement o Transgender adolescents: 48.7 (9.4)
(no description about Eligibility criteria: To be included as
Majority white, non-Hispanic N = 37 Hormone blockers: N = 18 Information System (PROMIS)
the location) a transgender participant in the o Cisgender controls: 46.4 (8.0)
No medical interventions: scale, and parents completed
study, children needed to identify Cisgender group, Control group: o Cisgender siblings: 47.9 (7.9)
N = 39 the proxy versions of the
as the gender opposite their natal
n = 33 participants in this group were anxiety and depression T score on parent-reported depression
sex in everyday life, to have socially
assigned boys, n = 30 assigned girls PROMIS scales. Participants'
transitioned by using the pronoun o No statistically significant difference in parent-reported
scores across items were
associated with their asserted mean age (SD) in years = 10.9 (1.4) depressive symptoms across the 3 groups (F = 0.32,
summed and then converted
gender in all contexts, and be Majority white, non-Hispanic n = 41. P = NS).
to a standardized T score. T
enrolled in the study from March o Transgender adolescents: 50.2 (8.8)
Cisgender group, Siblings group: scores are normed such that a
2015 to February 2016 (when the
score of 50 represents the o Cisgender controls: 49.4 (7.8)
present measurements were n = 21 participants in this group were
national average for children, o Cisgender siblings 48.9 (7.1)
included). assigned boys, n = 17 assigned girls with 10 points representing a
Sampling method: mean age (SD) in years = 10.6 (1.2) standard deviation and a Anxiety: Mean (SD)

majority white, non-Hispanic n = 25. score of at least 63 indicating T score on self-reported anxiety
Transgender group: No related
clinically significant anxiety or
description o No statistically significant difference in self-reported
depression (top 10% of all
Cisgender group: The siblings anxiety symptoms across the 3 study groups (F = 2.62,
children).
were recruited through the P = NS).
Cross sectional: outcomes and
same methods as the o Transgender adolescents: 52.0 (9.6)
measurements were measured at
transgender group and the o Cisgender controls: 49.0 (7.7)
the same time
matched controls were
recruited through a university o Cisgender siblings: 52.8 (10.5)
database of families interested T score on parent-reported anxiety
in participating in child o Statistically significant difference in parent-reported
development research. anxiety symptoms across the 3 study groups (F = 6.22,
P = .002).
o Transgender adolescents: 54.9 (9.0)
o Cisgender controls: 49.6 (8.6)
o Cisgender siblings: 51.0 (8.2)
López de Lara (2020)62 N=53 adolescents Transgender adolescents: Transgender cohort Cisgender cohort Depression: assessed with Anxiety, mean (SD)
At baseline before treatment BDI-II
n=23 TGNB youth mean age: 16 years (range 14-18)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CSH, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog; mBMI, median
body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s); GAH, gender-
affirming hormone; GD, gender dysphoria; PROMIS, Patient Reported Outcomes Measurement Information System; SD, standard deviation; TGNB, transgender, nonbinary, gender-diverse; YSR, youth self-report
772

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Table I.K.1. Clinical studies comparing TGNB to cisgender peers regarding mental health outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Spain: Pediatric n=30 matched cisgender assigned sex at birth: Anxiety: assessed with STAI-S o At baseline, TGNB youth had significantly higher STAI-S
endocrinology clinic controls (matched for age, o 69% female and STAI-T anxiety scores at 33.3 (9.1) compared to cisgender peers
ethnicity and socioeconomic o 31% male at 11.8 (9.1), P < 0.001
status.) 91% Caucasian and Spanish descent Outcomes and measurements o At baseline, TGNB youth had significantly higher STAI-T
Eligibility: adolescents aged 14 52% parents with a university were measured at the same time anxiety scores at 33 (7.2) compared to cisgender peers at
to 18 yo, absence of psychiatric education before transgender cohort had 14.2 (4.8), P < 0.001
comorbidity, Tanner state 2 or 30.4% had previously used mental received hormone treatment Depression, mean (SD)
higher, understanding of risks health services o At baseline, TGNB youth had significantly higher BDI-II
and benefits of CSH sexual orientation scores at 19.3 (5.5) compared to cisgender peers at 7.2
Sampling method: requested o 65% heterosexual, (3.9), P < 0.001
volunteers o 13% homosexual
Transgender cohort Cisgender cohort Depression: assessed with Anxiety, mean (SD)
o 21% bisexual
After one year of CSHT (oral BDI-II o After 12 months of hormone therapy, there was no
Cisgender adolescents:
estradiol or intramuscular Anxiety: assessed with STAI-S significant difference in STAI-S anxiety scores between
mean age:16 years (range 14-18) and STAI-T TGNB adolescents at 16.8 (8.1), and cisgender
testosterone)
assigned sex at birth Outcomes and measurements adolescents at 12.3 (3.8), P = NS
o 60% female were measured at the same time o After 12 months of hormone therapy, there was no
o 40% male after transgender cohort had significant difference in STAI-T anxiety scores between
100% are of Caucasian and Spanish received hormone treatment for TGNB adolescents at 18.5 (8.4), and cisgender
descent one year adolescents at 14.2 (4.8), P = NS
40% had parents with a university Depression, mean (SD)
education After 12 months of hormone therapy, while the BDI-II
30% had previously used mental depression scores decreased in TGNB youth and they were
health services much closer to the scores of their cisgender peers, they were
sexual orientation, still slightly significantly higher at 9.7 (3.9) compared to 7.4
(3.6), P = 0.034
o 90% were heterosexual
o 10% were homosexual
0% were bisexual
van der Miesen N = 1101 adolescents Transgender subjects who did not started Transgender cohort: on Cisgender cohort (n = 651) Psychological functioning Suicidality:
(2020)124 any affirmative medical treatment yet: puberty suppression and outcomes:
Eligibility criteria: Analyses comparing the transgender group at referral, the
about to start CSH treatment
Mean age (SD) in years = 14.47 (2.18); The Dutch version of the YSR transgender group using puberty blockers, and the cisgender
Not clearly stated (not specified) (n = 178)
116 assigned boys at birth and 156 was used. sample show that groups differed from each other on
Sampling method: assigned girls at birth suicidality. (P < .001)
Self-harm/suicidality was
Transgender cohort: Transgender subjects receiving examined by two YSR items, Post hoc analyses showed no differences found between
the Adolescents who just started affirmative care and about to start CSH item 18 and 91. adolescents using puberty suppression and the comparison
Netherlands, between the diagnostic procedure were treatment:
Effect sizes Cohen's d: .80 or group on self-harm/suicidality.
2012 and 2015 assessed during their first
higher is a large effect size, Mean scores (SD) on the Youth Self-Report for suicidality for
sessions at the VUmc.
.50-.79 a medium effect size, transgender adolescents receiving affirmative care was 0.17
a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CSH, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog; mBMI, median
body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s); GAH, gender-
affirming hormone; GD, gender dysphoria; PROMIS, Patient Reported Outcomes Measurement Information System; SD, standard deviation; TGNB, transgender, nonbinary, gender-diverse; YSR, youth self-report
773

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Table I.K.1. Clinical studies comparing TGNB to cisgender peers regarding mental health outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Adolescents diagnosed with GD Mean age (SD) in years = 16.75 (1.24); .20-.49 small, and effect (0.52) vs. 0.19 (0.60) for cisgender adolescents. Effect sizes
were assessed before the start 68 assigned boys at birth and 110 sizes < .20 are negligible Cohen's d of GP vs. T1 was 0.04.
of CSH. During both assigned girls at birth Cross-sectional: All measures
assessments, parents and Cisgender adolescents: were taken on the same day.
children completed several
questionnaires. During 2012 to Mean age (SD) in years = 15.39 (1.36);
2015, 504 adolescents were 346 assigned boys at birth and 305
seen in their gender identity assigned girls at birth
service. 53 participants did not
complete the assessment
process and therefore, did not
participate in this study. The
reason for dropout was failure
to complete the questionnaire
or alternation of symptoms of
GD. Of the adolescents
diagnosed with GD, 179 were
about to start CSH treatment.
One participant did not
complete the questionnaire and
was thus excluded.
Cisgender cohort: Data from the
comparison group of cisgender
adolescents from the general
population were recruited by
means of the help of different
secondary schools in different
provinces in the Netherlands.
After consent of the parents,
the adolescents completed a
paper-pencil survey during
regular class times.
Subsets:
n = 272 transgender adolescents
referred to a specialized gender
identity clinic. (Data not extract
for this cohort for outcomes
since they did not yet receive
any affirmative medical
treatment.)

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CSH, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog; mBMI, median
body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s); GAH, gender-
affirming hormone; GD, gender dysphoria; PROMIS, Patient Reported Outcomes Measurement Information System; SD, standard deviation; TGNB, transgender, nonbinary, gender-diverse; YSR, youth self-report
774

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Table I.K.1. Clinical studies comparing TGNB to cisgender peers regarding mental health outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
n = 178 Transgender
adolescents receiving
affirmative care and about to
start CSH treatment
n = 651 cisgender adolescents:
Dutch high school adolescents
from the general population.

a The author-reported number of participants on any treatment was 34; however, when adding the number of participants taking a GnRH analog, testosterone, or estrogen, the total number equals 37 (Avila 2019)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: AFAB, assigned female at birth; AMAB, assigned male at birth; BES, Body Esteem Scale for Adolescents and Adults; BIS, Body Image Scale; CSH, cross-sex hormones; EDE-Q, Eating Disorders Examination Questionnaire; FBeK, "Fragebofen zur
Beurteilung des eisenen Körpers" (Body image assessment questionnaire); FTM, female-to-male; GD, gender dysphoria; GMSR-A, Gender Minority Stress and Resilience Measure for Adolescents; GnRHa, gonadotropin-releasing hormone analog; mBMI, median
body mass index; MRI, magnetic resonance imaging; N/A, not applicable; N/R, not reported; SD, standard deviation; TCS, Transgender Congruence Scale; TGNB, transgender/nonbinary; UGDS, Utrecht Gender Dysphoria Scale; yr(s), year(s); GAH, gender-
affirming hormone; GD, gender dysphoria; PROMIS, Patient Reported Outcomes Measurement Information System; SD, standard deviation; TGNB, transgender, nonbinary, gender-diverse; YSR, youth self-report
775

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Table I.K.2. Clinical studies comparing TGNB to cisgender peers regarding psychosocial outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Costa (2015)77 Population: N = 201 GD adolescents Full cohort: TGNB adolescents Children/adolescents without CGAS was used to assess CGAS, mean (SD)
seeking treatment (including observed psychological/ participants psychosocial
mean (SD) baseline age was 15.52 n = 201 at baseline seeking Baseline
immediately eligible and delayed psychiatric symptoms not functioning.
years (1.41), treatment o GD adolescents scores of 57.7 (2.3) at baseline were
eligible) taking puberty suppression
Cohort: Measurements were significantly lower than scores found in
mean (SD) age at the start of GnRH n = 101 immediately treatment.
Of 101 immediately eligible taken at several points in time children/adolescents without observed
analog was 16.48 years (1.26) eligible GD-who had 18
group, n = 35 at 18 months and compared. psychological/psychiatric symptoms, 67.1 (12), t = 7.4,
months of psychological
n = 169 Children/adolescents support and 12 months of P < .001
without observed puberty suppression After 18 months of psychological support/12 months of
psychological/psychiatric treatment puberty suppression
symptoms
o GD adolescents had a mean score of 67.40 (13.93), which
Eligibility criteria: referred to the was not significantly different from the score of 67.1 (12)
GIDS, completed the diagnostic in children/adolescents without observed
procedure, invited for follow-up psychological/psychiatric symptoms, t = 0.01, P = NS
Sampling method: consecutive
enrollment between 2010 to 2014;
100% agreed to participate (page 2)

Durwood (2017)109 Population: N = 310 Transgender group: Transgender group: Of 63 TG Cisgender group: Self-worth scores were Self-worth: Transgender children did not differ from age-and
youth age 9-14 that also reported using the Global gender-matched controls or siblings in self-worth. No
Part of Trans Youth Transgender: n = 116 children Transgender children came from 23 Control group (matched by
completed depression and Self-Worth Subscale from the statistically significant effect of condition (F = 1.96, P = .142), a
Project - a national, US states and 1 Canadian province. age) n = 122
Cisgender: n = 122 age- and anxiety screening, treatment Harter Self-Perception Profile marginal effect of age group (F = 2.66, P = .072), and no
longitudinal study of
gender-matched controls n = 48 children in this group were data was collected: Sibling group n = 72 for Children significant interaction (F = 0.18, P = .949) was found.
socially transitioned
Siblings: n = 72, aged 6-14 years assigned boys, n = 68 assigned girls.
transgender children Cross-sex hormones: n = 5 Cross-sectional: Children in all groups reported self-worth that was higher than
(no description about Eligibility criteria: To be included as Mean age (SD) in years = 9.3 (2.0) Exposures/Outcomes measured the midpoint (2.5) of the scale, indicating high self-worth overall
Hormone blockers: n = 18
the location) a transgender participant in the Majority white, non-Hispanic N = 75 at the same time
transgender, P < .001
study, children needed to identify Cisgender group, Control group:
as the gender opposite their natal controls, P < .001
sex in everyday life, to have socially N = 49 participants in this group were siblings, P < .001
transitioned by using the pronoun assigned boys, N = 73 assigned girls
6-8 years age group: mean (SD). One-sample t test for these
associated with their asserted mean age (SD) in years = 9.2 (2.0) three values indicates high self-esteem (P < .001).
gender in all contexts, and be
enrolled in the study from March Majority white, non-Hispanic N = 79. transgender: 3.50 (0.54)
2015 to February 2016 (when the Cisgender group, Siblings group: controls: 3.62 (0.39)
present measurements were
N = 40 participants in this group were siblings: 3.62 (0.40)
included).
assigned boys, N = 32 assigned girls
9-11 years age group: mean (SD). One-sample t test for these
Sampling method: mean age (SD) in years = 9.1 (1.8) three values indicates high self-esteem (P < .001).
Transgender group: No related majority white, non-Hispanic N = 45. transgender: 3.47 (0.55)
description
No significant difference in gender, controls: 3.68 (0.35)
Cisgender group: The siblings race or age between groups (P = NS)
were recruited through the siblings: 3.64 (0.47)
same methods as the

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: CGAS, children's global assessment scale; fMRI, functional magnetic resonance imaging; FTM, female to male; GD, gender dysphoria; MTF, male to female; SD, standard deviation; TG, transgender; TGNB: transgender, non-binary, gender
diverse; TOL, Tower of London task; YSR, youth self-report
776

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Table I.K.2. Clinical studies comparing TGNB to cisgender peers regarding psychosocial outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
transgender group and the 12-14 years age group: mean (SD). One-sample t test for
matched controls were transgender youth and cisgender controls indicates high self-
recruited through a university esteem (P < .001) and for cisgender siblings, high self-esteem
database of families interested (P = 0.023).
in participating in child
transgender: 3.30 (0.51)
development research.
controls: 3.37 (0.64),
siblings: 3.43 (0.59)
López de Lara (2020)62 N=53 adolescents Transgender adolescents: Transgender group Cisgender group Behavior problems: assessed Behavioral problems, mean (SD)
Spain: Pediatric At baseline before treatment with SDQ o Strength and Difficulties Questionnaire: At baseline, TGNB
n=23 TGNB youth mean age: 16 years (range 14-18)
endocrinology clinic assigned sex at birth: Outcomes and measurements youth had significantly more emotional symptoms, peer
n=30 matched cisgender
were measured at the same problems and total difficulties compared to cisgender
controls (matched for age, o 69% female
time before transgender peers.
ethnicity and socioeconomic o 31% male
cohort had received hormone o Total difficulties, mean (SD), P < 0.001
status.) 91% Caucasian and Spanish descent
treatment Transgender: 14.7 (3.3)
Eligibility: adolescents aged 14 52% parents with a university
education Cisgender: 11.3 (2.3)
to 18 yo, absence of psychiatric
comorbidity, Tanner state 2 or 30.4% had previously used mental  Prosocial, mean (SD), P= NS
higher, understanding of risks health services Transgender: 8 (1.6)
and benefits of CSH sexual orientation Cisgender: 7.7 (1.2)
Sampling method: requested o 65% heterosexual,  Emotional symptoms, mean (SD), P < 0.001
volunteers o 13% homosexual Transgender: 5.2 (1.6)
o 21% bisexual Cisgender: 3.7 (1)
Cisgender adolescents:  Conduct problems, mean (SD), P= NS
Transgender: 2.7 (0.8)
mean age:16 years (range 14-18)
Cisgender: 2.3 (1.2)
assigned sex at birth
 Hyperactivity, mean (SD), P= NS
o 60% female
Transgender: 4 (1.9)
o 40% male
Cisgender: 3.8 (0.9)
100% are of Caucasian and Spanish Peer problems, mean (SD), P < 0.001
descent Transgender: 2.6 (1.3)
40% had parents with a university Cisgender: 1.3 (0.4)
education
30% had previously used mental Transgender cohort Cisgender cohort Behavior problems: assessed Behavioral problems, mean (SD)
health services After one year of CSHT (oral with SDQ o Strength and Difficulties Questionnaire: After 12 months
sexual orientation, estradiol or intramuscular Outcomes and measurements of hormone therapy, TGNB youth still had significantly
testosterone) were measured at the same more peer problems compared to cisgender peers, but
o 90% were heterosexual
time after transgender cohort otherwise had comparable strengths and difficulties.
o 10% were homosexual
had received hormone o Total difficulties, mean (SD), P= NS
0% were bisexual treatment for one year Transgender: 10.3 (2.9)
Cisgender: 11.3 (2.3)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: CGAS, children's global assessment scale; fMRI, functional magnetic resonance imaging; FTM, female to male; GD, gender dysphoria; MTF, male to female; SD, standard deviation; TG, transgender; TGNB: transgender, non-binary, gender
diverse; TOL, Tower of London task; YSR, youth self-report
777

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Table I.K.2. Clinical studies comparing TGNB to cisgender peers regarding psychosocial outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
 Prosocial, mean (SD), P < 0.001
Transgender: 9 (1.2)
Cisgender: 7.5 (1.2)
 Emotional symptoms, mean (SD), P= NS
Transgender: 3.4 (1.2)
Cisgender: 3.7 (1)
 Conduct problems, mean (SD), P= NS
Transgender: 1.8 (1)
Cisgender: 2.6 (1.6)
 Hyperactivity, mean (SD), P = 0.002
Transgender: 2.6 (1.8)
Cisgender: 3.9 (0.8)
Peer problems, mean (SD), P < 0.001
Transgender: 2.3 (0.8)
Cisgender: 1 (0.2)

Staphorsius (2015)119 Population: N = 65 adolescents Mean age (yr, SD): Puberty suppression using a Control group of adolescent TOL performance, an TOL performance: Mean percentage of correct trials (accuracy)
o Treated MTF: 15.4 (0.7) GnRH analog (SubQ or IV peers executive functioning task,(SD): Post hoc analysis showed that treated MTF had a
Subset groups:
triptorelin 3.75 mg every 4 and brain activation using significantly lower accuracy score than the control groups
n = 8 treated MTF o Treated FTM: 16.1 (1.7) weeks) fMRI (P = 0.02) compared to control boys and (P = .04) compared to
the Netherlands)
n = 12 treated FTM o Control M: 14.9 (1.5) Cross-sectional: exposures/ control girls. No other accuracy significant differences was found
MTF: n = 8
n = 21 control M
o Control F: 14.4 (1.8) outcomes were measured at the between groups.
FTM: n = 12
Mean IQ (SD): same time Treated MTF: 73.9 (9.1)
n = 24 control F
o Treated MTF: 94.0 (10.3) Treated FTM:85.7 (10.5)
Eligibility:
o Treated FTM: 95.8 (15.6) Control M:88.5 (6.8)
Treated group: Diagnosed with
GD (per DSM-IV-TR), and o Control M : 110.7 (15.)1 Control F: 87.2 (11.9)
adolescent age. To receive a o Control F: 103.0 (17.3) Mean reaction time in seconds (SD): No significant differences
GnRH analog, patients must be Mean Tanner stage (SD): existed between groups.
at least 12 years of age, and
o Treated MTF: 4.1 (1.0) Treated MTF: 10.9 (4.1)
have breast development of
Tanner stage B2 (natal girls) or o Treated FTM: 4.1 (1.1) Treated FTM: 9.9 (3.1)
genital development of Tanner o Control M: 4.2 (1.2) Control M: 9.6 (2.5)
stage G2 to G3 (natal boys).
o Control F: 4.3 (0.9) Control F: 9.0 (1.8)
Control group: No inclusion
Mean duration of triptorelin Brain activation:
criteria noted, except being an
adolescent. Group exclusion (Decapeptyl-CR) use (yr, SD):
Treated MTF showed greater activation compared to their
criteria still applied and could o Treated MTF: 1.8 (0.8) experienced gender (F) in bilateral DLPFC, left RLPFC, left
also not be receiving any o Treated FTM: 1.4 (1.1) precuneus and right precuneus (trend)
puberty delaying medication or
Treated MTFs also showed greater left RLPFC activation
any form of hormones besides
relative to their natal sex (M)
oral contraceptives.

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: CGAS, children's global assessment scale; fMRI, functional magnetic resonance imaging; FTM, female to male; GD, gender dysphoria; MTF, male to female; SD, standard deviation; TG, transgender; TGNB: transgender, non-binary, gender
diverse; TOL, Tower of London task; YSR, youth self-report
778

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Table I.K.2. Clinical studies comparing TGNB to cisgender peers regarding psychosocial outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Exclusion criteria: included Treated FTMs differed from their experienced gender (M) by
uncontrolled endocrine showing less bilateral precuneus activation, corresponding
disorders, neurological or with the activation differences between the control groups.
psychiatric conditions that could Treated FTMs also showed lower activation of the right
alter study results, precuneus activation than girls (F)
contraindication for MRI scan,
psychotropic medication use,
lack sufficient communication of
Dutch language
Sampling method: Participants
were recruited from the VU
University Medical Center in
Amsterdam. Relatives and
friends of the participants were
asked to participate to serve as
age-matched controls. 3 siblings
participated, but the majority
were friends.
van der Miesen Population: N = 1101 adolescents Transgender subjects who did not started Transgender cohort: on Cisgender cohort: no related Psychological functioning Psychological functioning:
(2020)124 any affirmative medical treatment yet: puberty suppression and description outcomes:
Subset: Analyses comparing the transgender group at referral, the
about to start CSH treatment
Mean age (SD) in years = 14.47 (2.18); The Dutch version of the YSR transgender group using puberty blockers, and the cisgender
n = 272 transgender adolescents (not specify in the article)
116 assigned boys at birth and 156 was used to assess sample show that groups differed from each other on
referred to a specialized gender
assigned girls at birth internalizing and externalizing internalizing, and poor peer relations (P < .001) but not on
identity clinic. (data not extract
Transgender subjects receiving problem behavior, self- externalizing (P = NS).
for this cohort for outcomes
the harm/suicidality, and poor
since they did not yet receive affirmative care and about to start CSH Post hoc analyses show that the transgender adolescents
Netherlands, between treatment: peer relations.
any affirmative medical using puberty suppression scored significantly lower on
2012 and 2015
treatment) Peer Relations scale was internalizing problems but higher on peer relations
Mean age (SD) in years = 16.75 (1.24);
created from three YSR items: compared with the comparison group.
n = 178 transgender adolescents 68 assigned boys at birth and 110
"I don't get along with other Internalizing:
receiving affirmative care and assigned girls at birth
kids" (Item 25), "I get teased a
about to start CSH treatment Cisgender adolescents: Mean scores (SD) on the Youth Self-Report for internalizing
lot" (Item 38), and "I am not
n = 651 cisgender adolescents: liked by other kids" (Item 48). for transgender adolescents receiving affirmative care was
Mean age (SD) in years = 15.39 (1.36);
Dutch high school adolescents 7.76 (6.68) vs. 9.71 (7.73) for cisgender adolescents. Effect
346 assigned boys at birth and 305 Effect sizes Cohen's d: .80 or
from the general population. sizes Cohen's d of GP vs. T1 was 0.30.
assigned girls at birth higher is a large effect size,
Eligibility criteria: Not clearly stated .50-.79 a medium effect size, Externalizing:
Sampling method: .20-.49 small, and effect Mean scores (SD) on the Youth Self-Report for externalizing
sizes < .20 are negligible for transgender adolescents receiving affirmative care was
Transgender cohort:
Cross-sectional: Exposures/ 9.82 (5.79) vs. 10.25 (6.10) for cisgender adolescents. Effect
Adolescents who just started
outcome measures were taken sizes Cohen's d of GP vs. T1 was 0.07.
the diagnostic procedure were
on the same day. Peer relations:
assessed during their first
sessions at the VUmc.
Adolescents diagnosed with GD
See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: CGAS, children's global assessment scale; fMRI, functional magnetic resonance imaging; FTM, female to male; GD, gender dysphoria; MTF, male to female; SD, standard deviation; TG, transgender; TGNB: transgender, non-binary, gender
diverse; TOL, Tower of London task; YSR, youth self-report
779

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Table I.K.2. Clinical studies comparing TGNB to cisgender peers regarding psychosocial outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
were assessed before the start Mean scores (SD) on the Youth Self-Report for peer relations
of CSH. During both for transgender adolescents receiving affirmative care was
assessments, parents and 0.70 (1.06) vs. 0.41 (0.81) for cisgender adolescents. Effect
children completed several sizes Cohen's d of GP vs. T1 was -0.31.
questionnaires. During 2012 to
2015, 504 adolescents were
seen in their gender identity
service. 53 participants did not
complete the assessment
process and therefore, did not
participate in this study. The
reason for dropout was failure
to complete the questionnaire
or alternation of symptoms of
GD. Of the adolescents
diagnosed with GD, 179 were
about to start CSH treatment.
One participant did not
complete the questionnaire and
was thus excluded.
Cisgender cohort: Data from the
comparison group of cisgender
adolescents from the general
population were recruited by
means of the help of different
secondary schools in different
provinces in the Netherlands.
After consent of the parents, the
adolescents completed a paper-
pencil survey during regular class
times.

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: CGAS, children's global assessment scale; fMRI, functional magnetic resonance imaging; FTM, female to male; GD, gender dysphoria; MTF, male to female; SD, standard deviation; TG, transgender; TGNB: transgender, non-binary, gender
diverse; TOL, Tower of London task; YSR, youth self-report
780

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
Alvares (2022)132 N = 42 Transgender women: Transgender women on Cisgender women on estrogen Laboratory blood tests: Total Mean BMI: No significant difference in BMI found between
estrogen treatment: n = 15 treatment: n = 3 testosterone transgender women vs cisgender women or men
A gender specialty Transgender women: n = 15 Age at start of study: mean 34.2 (SD
(100%) (electrochemiluminometric)
endocrine clinic patients 5.2) years Ethinyl estradiol: 25.5 (SD 2.8) for transgender women vs 23.1 (range 19.4-
was analyzed in blood
Cisgender women: n = 13 Age at start of hormone therapy: Estradiol valerate: o n = 1 patient at 0.030 34.9) for cisgender women (P = NS))
samples after same-day
healthy and asymptomatic median 17 years o n = 1 patient at 1 mg/day collection, immediately 25.5 (SD 2.8) for transgender women vs 26.3 (SD 3.2) for
subjects Cisgender women: mg/day o n = 2 patients at 0.035 before bioimpedance, cisgender men (P = NS)
Cisgender men: n = 14 healthy o n = 4 patients at 2 mg/day ergospirometry and strength Mean total testosterone: Transgender women had significantly
Brazil Age at start of study: mean 35.6 (SD
and asymptomatic subjects mg/day tests. lower testosterone levels than cisgender men, but no significant
4.1) years Antiandrogen treatment:
Eligibility criteria: Conjugated estrogens: n=2 Anthropometric measures: difference from cisgender women
Cisgender men: evaluated by using the
Transgender women: DSM o n = 4 patients at 0.625 Cyproterone acetate: n = 2 18.0 ng/dL (range 12.0-637.0) in transgender women vs 19.0
Age at start of study: mean 36.7 (SD following parameters: height, (range 12.0-40.1) in cisgender women (P = NS))
diagnosis for GD, started mg/day patients at 2 mg/day
3.8) years body weight and body mass
androgen blockade after age 12, o n = 3 patients at 1.25 Progestin treatment: n = 1 index (BMI, weight/(height)2; 18.0 ng/dL (range 12.0-637.0) in transgender women vs
regular estrogen use in the last mg/day (kg/m²)." 524.3 (SD 169.0) in cisgender men (P < .0001)
Drospirenone: n = 1 patient
year, age 25-45, BMI 18-34.9, no
current or prior illness that
17-beta estradiol gel: at 3 mg/day Body composition outcomes: Mean skeletal muscle mass: Transgender women had a
significantly higher skeletal muscle mass than cisgender women,
could affect strength/aerobic o n = 1 patient at 0.5 Cisgender men: None o Assessed by an InBody 720 but a significantly lower mass vs cisgender men
tests, chronic disease or chronic mg/day device (Biospace, Korea)
medication use o n = 1 patient at 1 with an 8-point reading 30.7 kg (SD 3.3) for transgender women vs 21.9 kg (SD 2.4)
mg/day through a tactile electrode. for cisgender women (P < .0001)
Cisgender peers: Age 25-45
years, BMI 18-34.9, no history of o n = 1 patient at 1.5 The parameters evaluated 30.7 kg (SD 3.3) for transgender women vs 36.0 kg (SD 3.2)
sexual differentiation disorder mg/day were weight, BMI, total for cisgender men (P < .0001)
or hormonal disorders, no body fat mass (FM),
Antiandrogen treatment: Baumgartner index: Transgender women had a significantly
current or prior illness that percentage of body fat
n = 11 (73.3%) higher index than cisgender women, but a significantly lower
could affect strength/aerobic mass (%FM), skeletal
index than cisgender men.
tests, no chronic disease or Cyproterone acetate: muscle mass (SMM) and
chronic medication use n = 11 patients at 50 fat-free mass (FFM). 12.6 kg/m² (SD 0.9) for transgender women vs 10.8 kg/m²
mg/day o The Baumgartner Index (SD 1.7) for cisgender women (P < .01)
Sampling method: No information
was given about how transgender Prior gonadectomy: n = 4 (appendicular skeletal 12.6 kg/m² (SD 0.9) for transgender women vs 14.6 kg/m²
or cisgender subjects were patients muscle mass (ASM) (SD 0.8) for cisgender men (P < .01)
selected/recruited. Cisgender peers adjusted by height FFM/height²: Transgender women had a significantly lower ratio
Average duration of CSHT:
were matched to transgender squared), fat mass/height2 than cisgender men, but no significant difference from cisgender
14.4 (SD3.5) years
women on age and physical activity (FM/Hgt2) and fat-free women
level (per the IPAQ [ie, International mass/height2 (FFM/Hgt2)
were calculated to 18.3 kg/m² (range 15.9-23.4) for transgender women vs 15.8
Physical Activity Questionnaire])
eliminate height as a kg/m² (range 12.9-22.4) for cisgender women (P = NS)
determinant factor in fat 18.3 kg/m² (range 15.9-23.4) for transgender women vs 20.5
body mass and muscle kg/m² (SD 1.2) for cisgender men (P < .05)
mass."
% FM: Transgender women had a significantly higher % FM than
Cross-sectional: cisgender men, but no significant difference from cisgender
Exposures/Outcomes measured women
at same time.

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
781

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
29.5% (SD 5.7) for transgender women vs 32.9 (SD 5.7) for
cisgender women (P = NS)
29.5% (SD 5.7) for transgender women vs 20.2 (SD 5.7) for
cisgender men (P < .01)
Beking (2020)129 Population: N = 62 Mean age: Transgender boys Cisgender male adolescents fMRI data was collected as Functional Amygdala Lateralization
participants engaged in a
transgender boys, N = 21 Transgender boys: 16.1 years, Session 1 (baseline): had Cisgender female adolescents Session 1:
face-matching task that has
cisgender boys: N = 20 SD = 0.7 received 3.75 mg o LI did not differ significantly between any of the groups,
been shown to engage the
Cisgender boys: 15.9, SD = 0.6 Triptorelin (Decapeptyl- P = NS.
cisgender girls N = 21 amygdala.
CR®) subcutaneously or
Cisgender girls: 16.4, SD = 1.0 intramuscularly every 4 Cohort: Measurements were o Transgender boys tended to be less lateralized in
Eligibility criteria: received puberty
weeks (mean taken at 2 points in time, one at amygdala activation than cis boys: t (57) = 1.82, P = NS;
suppression and testosterone, no Handedness. Handedness per group
duration = 1.6 years, baseline, and one after and cis girls: t(57) = 1.92, P = NS
continuous psychotropic (mean, SD, range):
medication use, no psychiatric or SD = 1.0) intervention. Session 2:
Cisgender boys (8.59, 2.07, 4 to 10)
neurologic disorder Session 2 (follow-up): had o LI did not differ significantly between any of the groups (F
Cisgender girls (8.56, 2.40, 3 to 10) (2,54) = 0.19, P = NS).
Sampling method: Trans boys were been receiving
recruited from the center of Transgender boys (5.67, 5.90, -9 to testosterone treatment ∆ between Session 1 and Session 2:
Expertise on Gender Dysphoria and 10) since session 1 (mean
duration = 9.8 months, o LI differences between session 1 and 2 did not differ
age-matched cisgender boys and Distribution of handedness did not
SD = 2.9, range 5.6–14.8 significantly between any of the groups, P = NS.
girls were recruited via secondary differ between the groups (all
schools and by inviting friends of Kolmogorov-Smirnoff Z < 0.93, P months) o Transgender boys tended to have larger LI difference
the trans boys. value > .358) scores than cis boys: t(52) = 1.84, P = NS; and cis girls:
(t(52) = 1.96, P = NS
Brain Regions Showing a Significant Main Effect of the
Emotional Face Matching Tasks (Between Groups) (through
fMRI) (P < .05)
Session 1:
o Location, T-Values (Note: some are point values, some are
ranges because there are multiple location coordinates)
o Inferior occipital gyrus (both hemispheres), 15.86-16.54
o Cerebellum (hemispheric lobule VI, left hemisphere),
14.86
o Inferior frontal gyrus (triangular part, both hemispheres),
9.05-11.59
o Middle frontal gyrus (right hemisphere), 7.73
o Amygdala (left hemisphere), 10.82
o Hippocampus (left hemisphere), 7.95
o Temporal pole (superior temporal gyrus, left hemisphere),
6.59
o Middle temporal gyrus (right hemisphere), 7.33-8.07

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
782

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
o Supplementary motor area (right hemisphere), 7.09
o Middle temporal gyrus (left hemisphere), 6.63
Session 2:
o Location, T-Values (Note: some are point values, some are
ranges because there are multiple location coordinates)
o Middle occipital gyrus (right hemisphere), 19.02-19.73
o Inferior occipital gyrus (right hemisphere), 18.73
o Inferior frontal gyrus (triangular part, both hemispheres),
9.69-11.58
o Middle frontal gyrus (right hemisphere), 8.66
o Inferior frontal gyrus (orbital part, left hemisphere), 6.52
o Superior temporal gyrus (right hemisphere), 8.02
o Middle temporal gyrus (right hemisphere), 6.05-7.29
o Supplementary motor area (right hemisphere), 7.93
o Precuneus, 8.66
Burke (2015)133 Population: N = 79 The mean ( ± SD) ages were: TGNB Adolescent girls and Control group of adolescent Hypothalamic activation when Hypothalamic activation when smelling androstadienone
boys with GD treated with .75 boys and girls. Female smelling androstadienone was
AFAB TGNB adolescents with 21 girls with GD (16.1 ± 0.8) AFAB:
mg of Triptorelin (Decapeptyl- adolescent controls were ascertained by fMRI using the
GD: N = 21 17 boys with GD (15.3 ± 1.2) o Compared to adolescent girls (AFAB) with GD, control girls
CR®, Ferring, Hoofddorp, The tested randomly according to following methods:
the Netherlands showed a significantly stronger hypothalamic response to
AMAB TGNB adolescents with 21 control girls (16.3 ± 0.9) Netherlands), a GnRH analog, their menstrual cycle, and 11 of
Normal olfactory function for
GD: N = 17 by injection for on average 24 21 control girls reported using androstadienone over time. Thus the comparison of
20 control boys (15.0 ± 0.6) subjects was ascertained. For
months (range 2–48 months), hormonal contraception. adolescent control girls to girls diagnosed with GD
control girls: N = 21 the olfactory stimulation in
resulting in complete revealed a significant effect of gender (control girls > girls
control boys: N = 20 the MRI, androstadienone
suppression of gonadal with GD), which was mainly explained by the effect of the
was diluted and delivered to
Eligibility: All subjects were hormone production. TM regressor (t = 4.3; P = .002).
the subjects' nostrils by
adolescents. All subjects in group o The activation in adolescent girls (AFAB) with GD was very
means of an air-dilution
with GD adolescent group had been similar to that in adolescent control boys, remaining stable
olfactometer. With a total air
treated with GnRH analogs. No over the course of stimulation.
flow of about 1 L per minute
other eligibility requirements or
during the "ON" periods the AMAB:
details were given.
odor was delivered every 2s
o When adolescent boys (AMAB) with GD were compared to
Sampling Method: All subjects with for 1s, whereas during the
adolescent control boys, a significant effect of condition
GD were recruited via the Venter of "OFF" periods, subjects
(ON > OFF) was observed. (P < .05)
Expertise on Gender Dysphoria at received odorless air. The MRI
the Medical Center. The control scans were performed on a o Adolescent boys (AMAB) with GD showed a significantly
participants were recruited via 3.0 T GE Signa HDxt scanner. stronger, thus sex-atypical response, to androstadienone
several primary and secondary A scanning session consisted compared to control boys, irrespective of the factor time.
schools in The Netherlands and by of six alternating ON-OFF (P < .05)
inviting friends and relatives of the lasting 3.6 min. For co- o Adolescent boys (AMAB) with GD showed female-typical
participants with GD. All subjects registration with the hypothalamic responses upon smelling androstadienone
functional images, a T1- without any effects due to sensitization.

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
783

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
and their legal guardians gave their weighted scan was obtained.
informed consent. Individual image data were
analyzed using boxcar
regressors convolved with a
synthetic hemodynamic
response function and a first-
order time modulation (TM)
regressor to test for possible
effects of
adaptatioNSensitization to
androstadienone.
Cross-sectional:
Exposures/outcomes measured
at the same time

Burke (2016)130 Population: N = 62 Mean (SD) age Transgender boys (natal girls Control girls and boys: matched Subjects underwent fMRI while % correct (mean ± SD)
with GD) who had puberty by age. performing a mental rotation task
Transgender boys: Trans boys: Session 1
suppressed, and then started (MRT).
o Session 1: N = 21 o Session 1: 16.1 ± 0.8 CSH. o F = 0.5
MRT: Participants were
o Session 2: N = 21 o Session 2: 17.1 ± 0.7 Session 1 (baseline): presented with 3D drawing o No significant difference between groups (P = NS)
Control girls: Control girls: Transgender boys had from the mental rotation o Transgender boys: 66.7 ± 15.9
o Session 1: N = 21 o Session 1: 16.3 ± 1.0 been treated monthly with stimulus library and could o Control girls: 67.0 ± 11.6
3.75 mg of triptorelin rotate the shape. Between 2
o Session 2: N = 20 (1 dropped o Session 2 17.6 ± 0.8 o Control boys: 70.2 ± 10.7
(Decapeptyl- CR, Ferring) presented shapes,
out) Control boys: by injection for on average participants had to indicate Session 2
Control boys o Session 1: 15.9 ± 0.6 24 (range 2–48) months, whether the 2 shapes were o F = 0.5
o Session 1: N = 20 resulting in complete identical or mirror images.
o Session 2: 17.2 ± 0.7 o No significant difference between groups (P = NS)
suppression of gonadal Outcome parameters were
o Session 2: N = 16 (4 dropped No significant difference between hormone production. the percentage of trials o Transgender boys: 74.2 ± 9.0
out) groups Session 1, P = 0.34, or session correctly identified and mean
Session 2: Transgender o Control girls: 71.7 ± 8.2
Eligibility: Transgender boys were 2, P = 0.16 reaction time per trial
boys had been receiving o Control boys: 71.6 ± 10.3
recruited if they had been GD since IQ (RT/trial).
testosterone treatment for
childhood and were taking GnRH RT/trial (seconds) (mean ± SD)
on average 10 (range 6– fMRI data was used to
analogs and would be taking Trans boys: 100.5 ± 12.7
15) months. All natal girls identify brain activation Session 1:
testosterone. No other inclusion Control girls: 110.3 ± 14.7 with GD either received a differences between groups. o F = 0.04
criteria given. Exclusion criteria for
Control boys: 113.4 ±14.5 testosterone ester mixture Cohort: Measurements were
participation in the study were any o No significant difference between groups (P = NS)
every 2 weeks or taken at 2 points in time, after
form of neurologic or psychiatric There was a significant difference
testosterone undecanoate intervention o Transgender boys: 8.0 ± 2.2
disorder and continuous between groups (P = 0.009), so a one-
every 12 weeks. o Control girls: 8.2 ± 1.5
psychotropic medication use. way ANOVA corrected from group
differences in IQ o Control boys: 8.1 ± 1.6
Sampling Method: Adolescent girls
with GD who had been gender Sexual orientation Session 2:
dysphoric since childhood were Trans boys: 100% gynephilic F = 1.0
recruited via the Center of Expertise

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
784

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
on Gender Dysphoria. Age-matched Control girls: 100% androphilic No significant difference between groups (P = NS)
controls were recruited via several o Transgender boys: 6.7 ± 2.1
Control boys: 100% gynephilic
secondary schools in the
Netherlands and by inviting friends Pubertal stage: There were no significant o Control girls: 6.8 ± 1.7
of the participants with GD. All differences in puberty stages between o Control boys: 7.5 ± 2.0 0.35
participants and their legal the groups-all were in pubertal stage 4 or
Differences in brain activation during mental rotation
guardians gave their informed higher.
consent. Session 1 (baseline)
o Control girls had higher brain activation than transgender
boys in the Frontal R Precentral/inferior frontal operculum
activation region of the brain (P = 0.034) similar to the sex
difference observed between the male and female control
groups.
o No other between-group differences were found
Session 2:
o Transgender boys had higher brain activation than control
girls in the following areas:
o Parietal R Superior parietal/inferior parietal region of the
brain (P = 0.06, authors noted as significant)
o Parietal L Cuneus/superior occipital region of the brain
(P = .002)
o No other significant interaction effects were found
between transgender boys and the control groups
Nokoff (2020)131 Population: N = 143 Mean age (SD) years TM vs CF Body composition measurements TM vs CF
were collected:
Transgender men: n = 21 Transgender women (n = 14): 16 (1.4) TGNB male cohort (TM) with Matched cisgender female Body Composition measurements (estimated from graph):
patients Matched cis females (n = 23): 15.9 testosterone therapy for at cohort (CF) matched by BMI-calculated from weight
and height measured twice to Lean mass (%): TM had a significantly higher lean mass
o TG men (n = 19) matched (1.4) least 3 months. puberty stage (Tanner stage 5)
Colorado calculate BMI. (P = .039) and percent lean tissue than CF (68% vs 64%,
with 19 cisgender men and BMI ± 6%
Matched cis males (n = 24): 15.7 (1.4) The average dose of P = .002)
(n = 19) testosterone was 217 (88) fat mass and percentage
Transgender men (n = 21): 17 (1.4) Body fat (%): TM had significantly lower fat mass (P = 0.029)
o TG men (n = 19) matched mcg/month for the average lean mass and percentage
Matched cis females (n = 42): 15.2 and % body fat compared to CF (28.75% vs 32.81%, P = .002)
with cisgender women duration of 11.2 (5.9) months.
leptin Leptin (ng/mL): TM had significantly lower leptin levels than CF:
(n = 42) Matched cis males (n = 19): 15.3 (1.6) 12 were taking IM injections,
9 were using SQ. 1 participant hormone levels were (13.75 vs 18.5 P = .0018)
o 17 TG men in both
had recently discontinued calculated from fasting blood
comparisons Hormone Levels:
taking GnRH analogs and 3 samples
Transgender women: n = 14 had used them in the past Total estradiol (pg/mL) mean (SD): There was no significant
total estradiol
patients difference in levels between TM and CF: 43 (23) vs 63 (40),
total testosterone P = NS
o TG women (n = 11) matched
with Cisgender women SHBG Total testosterone (ng/dL) mean (SD): The TM cohort had
(n = 23) free androgen index significantly higher levels than the CF cohort: 363 (220) vs 39
(13) P < .001

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
785

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
o TG women (n = 13) matched Cross sectional: transgender SHBG (nmol/L) mean (SD): The TM cohort had significantly
with cisgender men (n = 24) patients had their measurements lower levels than the CF cohort: 24 (11) vs 47 (25) P < .001
o 10 TG women are in both taken on the same day while
Free androgen index mean (SD): The TM cohort had
comparisons cisgender patients were taken
significantly higher levels than the CF cohort: 65 (47) vs 4 (2)
from previous research
Eligibility criteria: P < .001

Transgender patients: had been TM vs CM TM vs CM

taking testosterone or estradiol
TGNB male cohort (TM) with Matched cisgender male Body Composition measurements (estimated from graph):
for the last 3 months. Patients
testosterone therapy for at cohort (CM) matched by
were excluded if they had Lean mass (%): TM had a lower and lean mass (P < .001) and
least 3 months. puberty stage (Tanner stage 5)
significant medical or psychiatric lean mass % compared to CM: (69% vs 73%, P = .029)
and BMI ± 6%
comorbidities The average dose of
Body fat (%): TM had a higher % body fat compared to CM:
Cisgender peers: Controls taken testosterone was 217 (88)
(27.8% vs 24.4%, P = .047)
from the RESISTANT and HIP mcg/month for the average
duration of 11.2 (5.9) months. Leptin (ng/mL): The TM cohort had non-significantly higher
study. The RESISTANT study leptin levels than the CM cohort: 12.5 vs 8.25, P = NS
selected individuals between 12 12 were taking IM injections,
and 19 that were > 1 Tanner 9 were using SQ. 1 participant Hormone Levels
stage, sedentary and were had recently discontinued
taking GnRH analogs and 3 Total estradiol (pg/mL) mean (SD): The TM cohort had
excluded if they had significantly higher levels than the CM cohort: 46 (22) vs 24
hypertension, hemoglobin < 9 had used them in the past
(11), P = .004
mg/dL, serum creatinine > 1.5
mg/dL, had medication Total testosterone (ng/dL) mean (SD): There was no
dependent asthma or another significant difference in levels between the TM and CM
condition that would cause cohort: 378 (219) vs 445 (152), P = NS
insulin resistance. The HIP study SHBG (nmol/L) mean (SD): There was no significant
selected adolescents in early difference in levels between the TM and CM cohort: 26 (11)
puberty that were Tanner Stage vs 36 (13), P = NS
2-3 who were normal weight or
Free androgen index mean (SD): There was no significant
obese through pediatric
difference in the index between the TM and CM cohort: 64
practices during 2009 to 2015.
(47) vs 48 (16), P = NS
Diabetes, prediabetes or
another condition that affected TF vs CF TF vs CF
glucose metabolism was reason
for exclusion. TGNB female cohort (TF) with Matched cisgender female Body Composition measurements (estimated from graph):
estrogen therapy for at least 3 cohort (CF) matched by age
Sampling method: Lean mass (%): TF had a significantly higher lean mass
months (within a year) and BMI
(P = .004) and percent lean tissue than CF (66% vs 62%,
Transgender patient were percentile ± 12.5%
Taking an average dose of P = .032).
recruited from the TRUE Center estradiol of 1.5 (1) mg/day
for Gender Diversity at Body fat (%): TF had significantly lower % body fat compared
with an average treatment
Children's Hospital Colorado to CF (31% vs 35%, P = .033)
duration of 12.3 (9.9) months.
Cisgender patients' data were Four trans females were on a Leptin (ng/mL): TM had non-significantly lower leptin than CF
used from previous studies- the GnRH analog and 6 had been (17.75 vs 19, P = NS)
HIP and RESISTANT study. CM on them in the past. 7 TF were Hormone Levels
on spironolactone and 1 was

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
786

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
and CF matched with TM were on IM medroxyprogesterone Total estradiol (pg/mL) mean (SD): There was no significant
matched based on pubertal acetate difference in levels between TF and CF: 98 (135) vs 96 (127),
stage and BMI. CM and CF P = NS
matched to TF were matched
Total testosterone (ng/dL) mean (SD): The TF cohort had
based on age and BMI.
significantly higher levels than the CF cohort: 224 (182) vs 43
(10) P = .012
SHBG (nmol/L) mean (SD): There was no significant
difference in levels between the TM cohort and the CF
cohort: 49 (36) vs 50 (30), P = NS
Free androgen index, mean (SD): The TF cohort had a
significantly higher index than the CF cohort: 33 (36) vs 5 (3)
P < .01
TF vs CM TF vs CM

TGNB female cohort (TF) with Matched cisgender male Body Composition measurements (estimated from graph):
estrogen therapy for at least 3 cohort (CM) matched by age
Lean mass (%): TF had lower percent lean tissue than CF
months (within a year) and BMI
(69% vs 77%, P = 0.001)
percentile ± 12.5%
Taking an average dose of
Body fat (%): TF had a higher fat mass (P = 0.004) and % body
estradiol of 1.5 (1) mg/day
fat compared to CM: (28% vs 20%, P = .001)
with an average treatment
duration of 12.3 (9.9) months. Leptin (ng/mL): TF had significantly higher leptin levels
Four trans females were on a compared to CM: (13.75 vs 6.25, P < .001)
GnRH analog and 6 had been Hormone Levels
on them in the past. 7 TF were
on spironolactone and 1 was Total estradiol (pg/mL) mean (SD): The TF cohort had
on IM medroxyprogesterone significantly higher levels than the CM cohort: 124 (162) vs
acetate 23 (9) P = .005
Total testosterone (ng/dL) mean (SD): The TF cohort had
significantly lower levels than the CM cohort: 252 (214) vs
412 (168) P = .012
SHBG (nmol/L) mean (SD): There is no significant difference
in levels between TF and CM: 50 (48) vs 40 (16), P = NS
Free androgen index mean (SD): There is no significant
difference in the index between TF and CM: 36 (34) vs 37
(16), P = NS
Nokoff (2021)131 Population: N = 48 Transgender males: Transgender males and Cisgender males and females: Body composition: fat-free mass Body composition: (mean ± SD)
females had been on a GnRH Matched on sex assigned at and fat mass was measured by
Transgender males: n = 9 mean age (SD) in years = 13.8 (1.7) Transgender males had a higher percent body fat (36 ± 7 vs.
analogs for at least 3 months birth, age, and BMI dual-energy X-ray absorptiometry
patients who had been on a mean age (SD) at initiation of GnRH 32 ± 5%, P = .042) and lower total lean mass (32.3 ± 5.2 vs.
GnRH analog for ≥ 3 months Hormone level. Serum/plasma 36.4 ± 7.8 kg, P = .009), but not percent lean mass than
analogs in years = 12.1 (1.9)
Colorado (before initiation of fasted blood samples were cisgender females.
testosterone or estradiol) assayed for:

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
787

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
between 2016 and Transgender females: n = 8 mean GnRH analog duration (SD) in Estradiol Transgender females had higher percent body fat (31 ± 9 vs.
2019 patients who had been on a months = 20.9 (19.8) 24 ± 10%, P = .002) and lower percent lean mass (66 ± 8 vs.
Testosterone
GnRH analog for ≥ 3 months majority white n = 6 (67%) with 74 ± 10%, P < .001) than cisgender males.
(before initiation of SHBL
Hispanic/Latino n = 4 (44%) Hormone levels: (mean ± SD)
testosterone or estradiol) Cross-sectional study: Outcomes
depression at baseline n = 2 (22%) and measures taken at the same Total Estradiol (pg/mL):
Cisgender males: n = 17
anxiety at baseline n = 1 (11%) time. o Transgender males had significantly lower estradiol (15 ±
Cisgender females: n = 14
most N = 3 (33%) were at pubic hair 5) than cisgender females (58 ± 45), P < .05
Eligibility criteria:
Tanner stage 4, most n = 3 (33%) o Transgender female levels (12 ± 3) were not significantly
Transgender cohort: were at breast/testicular Tanner different from the levels of cisgender males (14 ± 5),
Transgender youth who had stage 3. P = NS
been on a GnRH analog for ≥ 3 n = 5 (63%) had hypertension Total Testosterone (ng/dL)
months were recruited between
n = 5 (63%) hypercholesterolemia o Transgender male levels (29 ± 12) showed no significant
2016 and 2019 from the
n = 4 (50%) had type 2 diabetes. difference from cisgender female levels (38 ± 12), P = NS
hospital; youth were excluded if
they had significant medical or Transgender females: o Transgender females had significantly lower testosterone
psychiatric comorbidities (50 ± 52) than cisgender males (231 ± 153), P ≤ .001
(including diabetes or Mean age (SD) in years = 13.7 (1.2)
SHBL (nmol/L)
antipsychotic treatment), or mean age (SD) at initiation of GnRH
o Transgender male levels (53 ± 34) were not significantly
were using hormones not analogs in years = 12.8 (1.3)
different from cisgender females (47 ± 19), P = NS
prescribed by a physician
mean GnRH analog duration (SD) in o Transgender female levels (50 ± 24) were not significantly
Cisgender cohort: Healthy months = 11.3 (7) different from cisgender males (54 ± 26), P = NS
cisgender controls were
majority white n = 7 (88%) with half
obtained from two studies
of Hispanic/Latino n = 4 (50%) and
performed at our institution:
half of not Hispanic/Latino n = 4
the RESistance to InSulin in Type
(50%)
1 ANd Type 2 diabetes
(RESISTANT) study and the depression at baseline, n = 3 (38%)
Health Influences in Puberty anxiety at baseline, n = 1 (12%)
(HIP) study
most n = 3 (38%) were at pubic hair
Sampling method: Tanner stage 2, most n = 5 (63%)
Transgender cohort: All were at breast/testicular Tanner
transgender females and five stage 2.
transgender males were n = 5 (63%) had hypertension
recruited from the same cross-
n = 3 (38%) hypercholesterolemia
sectional study. An additional
four transgender males were n = 1 (13%) had type 2 diabetes.
recruited from a separate Cisgender males:
longitudinal study, and data
from their baseline visit are mean age (SD) in years = 13.9 (0.9)
included here, when they were majority white n = 13 (76%) with not
on a GnRH analog alone. None Hispanic/Latino n = 13 (76%),
of the participants were

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
788

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
receiving testosterone or most n = 5 (29%) were at pubic hair
estradiol treatment at the time Tanner stage 2, most n = 7 (41%)
of this study. were at breast/testicular Tanner
Cisgender cohort: Transgender stage 2.
males (assigned female sex at n = 9 (75%) had hypertension
birth, male gender identity)
n = 8 (67%) hypercholesterolemia
were matched to cisgender
females and transgender n = 4 (33%) had type 2 diabetes.
females (assigned male sex at Cisgender females:
birth, female gender identity)
were matched to cisgender mean age (SD) in years = 13.9 (1.7)
males. majority white n = 10 (71%) with not
Hispanic/Latino n = 9 (64%)
most n = 4 (29%) were at pubic hair
Tanner stage 4, most n = 9 (64%)
were at breast/testicular Tanner
stage 5.
n = 6 (75%) had hypertension
n = 7 (88%) hypercholesterolemia
n = 7 (64%) had type 2 diabetes.
Schulmeister (2022)95 N = 281 youth Transgender cohort: Transgender cohort: GnRH BMDCS cohort: no hormonal Anthropometric data: Height velocity:
analog treatment intervention
Four academic medical TGNB cohort: n = 55 subjects 26 (47%) were DMAB and 29 (53%) Collected in the course of The median (IQR) HV for transgender cohort after starting
centers with were DFAB. clinical care were abstracted GnRH analogs was 5.1 (3.7–5.6) cm/year. Compared to
BMDCS cohort [cisgender]:
multidisciplinary clinics from the medical record and prepubertal, presumed cisgender youth in the BMDCS,
n = 226 subjects Mean age (range) in years at GnRH
analog initiation = 11.5 (9.0 to 14.5). recorded prior to the transgender youth treated with GnRH analogs had similar HV
Eligibility criteria: TGD youth participant beginning GnRH when controlled for mid-age (P = NS).
initiating GnRH analog treatment Most individuals in the cohort started analogs (baseline) and at 6-
for puberty suppression were GnRH analogs in early puberty When stratified by Tanner stage and controlled for mid-age,
and 12-month follow-up TGNB youth who started on a GnRH analogs at Tanner stage
recruited between July 2016 and (Tanner stage II or III). visits.
September 2018. Participants were II or stage III had HV comparable to prepubertal youth in
Of those participants DMAB, most Annualized HV was calculated BMDCS (5.3 (4.1–5.6) cm/year vs. 6.1 (4.3–6.5) cm/year,
included in the analysis if they had
were Tanner stage II at the initiation as the difference between the P = NS and 4.4 (3.3–6.0) cm/year vs. 6.1 (4.3–6.5) cm/year,
been treated with a GnRH analogs
of GnRH analogs (21 individuals, baseline and the 12-month P = NS).
for at least 10 months and no more
81%), 3 (12%) were Tanner III, and 2 visit heights (expressed in
than 14 months. Individuals taking Individuals starting on GnRH analogs at Tanner stage IV had
(8%) were Tanner IV. centimeters), divided by the
stimulant medication for treatment significantly lower HV compared to pre-pubertal youth in the
of ADHD were included in the Of those participants DFAB, 13 (45%) time between the two visits BMDCS (1.6 (1.5–2.9) cm/year vs. 6.1 (4.3–6.5) cm/year,
analysis. Participants were excluded were Tanner II at initiation of GnRH (expressed as a fraction of P = .006).
analogs, 13 (45%) were Tanner III, and one year).
between July 2016 and from the study if they had
previously undergone GnRH analog 3 (10%) were Tanner IV. Tanner stages data: Tanner
September 2018
treatment, had a diagnosis of Cisgender cohort: stages were assigned by the
precocious puberty, had serious participant's clinician in the
psychiatric symptoms, or could not course of clinical care using the

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
789

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Table I.K.3. Clinical studies comparing TGNB to cisgender peers regarding body change outcomes
Study first author Population Select baseline characteristics Exposure/intervention Comparator Outcome measures and Results
(publication year) timing
and study setting
read or understand English. 118 (52%) were DMAB and 108 (48%) standards of Marshall and
Participants were excluded from were DFAB. Tanner.
analysis if they initiated treatment
The BMDCS cohort was younger than Cohort: Outcomes were
with cross-sex hormones (CSH;
the TGD cohort (11.0 ± 2.8 years vs. measured after the exposures
estradiol or testosterone) prior to
11.9 ± 1.2 years, P = 0.01). had been measured (clinical
their 12-month follow-up visit.
All participants in BMDCS were records review).
Sampling method: Participants prepubertal (Tanner I) at baseline.
were recruited prior to GnRH
analog initiation from four gender
specialty clinics in the United
States. A comparison group of
prepubertal, presumed cisgender
youth not receiving hormonal
intervention was drawn from
BMDCS.

Table abbreviations: AMAB, assigned male at birth; AFAB, assigned female at birth; BMDCS, Bone Mineral Density in Childhood Study; BMI, body mass index; DFAB, defined female at birth; DHEAS, dehydroepiandrosterone sulfate; DMAB, defined male at birth;
FFM, fat free mass; FM, fat mass; fMRI, functional magnetic resonance imaging; GAHT, gender affirming hormone therapy; GnRHa, gonadotropin releasing hormone analog; HV, height velocity; IQR, interquartile range; LI, lateralization index; MRT, mental
rotation task; RT, reaction time; SD, standard deviation; SHBG, sex hormone-binding globulin; SMM, skeletal muscle mass; TGD, transgender; TGNB, Transgender, non-binary; TM, time modulation
790

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Millington (2022)90 N= 286 TGNB patients DMAB: DFAB: testosterone, average Comparison group was taken Serum Creatinine (SCr) SCr Z-score, mean ± SD
SQ dose was 40 mg/week, from participants of the measured in Z-score adjusted
Four large hospitals- N=1188 NHANES study Participants Age: 17.3 years At baseline, DFAB participants had a higher baseline SCr than
average transdermal dose was NHANES study, matched by age for age and gender
Gender: female NHANES participants (+0.3 ± 1.0, P = .002).
Eligibility: 40.5 mg/day and sex Cohort: Outcome was measured
o 51 identified as trans female At 12 months this difference was more pronounced (+1.4 ±
TGNB cohort: clinician after exposure, measurements
1.0, P < .0001 compared to baseline).
diagnosed gender therapy with o 36 as female taken at baseline and 12 months.
CSHT deemed appropriate, At 12 months, the DFAB participants' Z score was more
o 1 as gender fluid
received care at the clinic, age similar to that of male NHANES participants (-0.3 ± 0.8) than
that were taking part in 8-20 and reads and understands o 4 as non-binary that of female NHANES participants
the Trans Youth Care English. Those that previously CSHT: DMAB: estrogen, average oral Comparison group was taken SCr Z-score, mean ± SD
United States Study used CSH, were enrolled in the o 77 were taking oral estrogen dose 4 mg/day, average from participants of the
puberty blocker cohort or had At baseline, DMAB SCr did not differ from reference group of
o 12 were taking transdermal transdermal dose 0,5 mg/day, NHANES study, matched by age
severe psychiatric symptoms male NHANES participants (-0.2 ± 0.9, P = NS).
estrogen average IM dose was 15 and sex
were excluded. mg/week After 12 months of treatment with estrogen, the difference
Cisgender cohort came from the o 3 were taking IM estrogen. between the reference group were more pronounced (-1.1 ±
NHANES study participants and o 58 used spironolactone 0.9, P < .0001 compared to baseline).
were matched by age and sex. DFAB: After 12 months, their values were closer to female NHANES
NHANES study participants were participants (-0.6 ± 1.0) than male NHANES participants.
nonpregnant, age 12-22. Age: 16.2 years
Sampling method: patients were Gender
selected from clinic if they met o 78 identified as male
inclusion criteria. No information on
o 103 as transgender male
NHANES participants.
o 2 as gender fluid
Subset definition:
o 1 as gender queer
TGNB cohort (N=286): DMAB
o 10 as non-binary
(n=92) and DFAB (n=194)
measured at baseline and 6 mo CSHT
increments o 189 were taking testosterone SQ
NHANES cohort (N=1188): o 5 were taking testosterone gel.
female (n=584) and male o 1 used spironolactone
(n=604)
NHANES participants
Age: 12-22
Nokoff (2020)131 Population: N = 143 Mean age (SD) TM vs CF Cardiometabolic markers TM vs CF
collected:
Transgender women: N = 14 Transgender women (n = 14): 16 (1.4) TGNB male cohort with Matched cisgender female There were significant differences in HDL levels between the
patients years. testosterone therapy for at cohort matched by puberty trans male and cis female cohorts. All other differences were
least 3 months non-significant.

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
791

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
o TG women (n = 11) matched Matched cis females (n = 23): 15.9 Average dose of testosterone stage (tanner stage 5) and BMI BMI-calculated from weight BMI (%) mean (SD): There was no significant difference
Colorado with Cisgender women (1.4) years was 217 (88) mcg/month for ± 6% and height measured twice to between trans male and the cis female cohort: 71 (22) vs. 71
(n = 23) the average duration of 11.2 calculate BMI. (21), P = NS
Matched cis males (n = 24): 15.7 (1.4)
o TG women (n = 13) matched (5.9) months. 12 were taking
years Diastolic and systolic blood Diastolic BP (mm HG) mean (SD): There was no significant
with cisgender men (n = 24) IM injections, 9 were using
Transgender men (n = 21): 17 (1.4) pressure-measured with difference between trans male and the cis female cohort: 70
SQ. 1 participant had recently
o 10 TG women are in both years. appropriate cuff after sitting (7) vs. 66 (6), P = NS
discontinued taking GnRH
comparisons for 5 min. Systolic BP (mm HG ) mean (SD): There was no significant
Matched cis females (n = 42): 15.2 analogs and 3 had used them
Transgender men: N = 21 in the past Fasting blood samples were used difference between the trans male and the cis female cohort:
(1.9)
patients to collect: 108 (9) vs. 111 (8), P = NS
Matched cis males (n = 19): 15.3 (1.6)
o TG men (n = 19) matched years Inverse of fasting insulin-used Inverse of fasting insulin (mL/mU) mean (SD): There was no
with 19 cisgender men to measure insulin sensitivity. significant difference between the trans male and the cis
(n = 19) female cohort: 0.08 (0.028) vs 0.097 (0.052), P = NS
HOMA-IR-calculated as
o TG men (n = 19) matched (glucose x insulin)/405 HOMA-IR mean (SD): There was no significant difference
with cisgender women between the trans male and the cis female cohort: 3.3 (2) vs
Fasting glucose
(n = 42) 3.2 (1.5), P = NS
Hemoglobin A1c
o 17 TG men in both Fasting glucose (mg/dL) mean (SD): There was no significant
comparisons AST difference between the trans male and the cis female cohort:
ALT 89 (5) vs 85 (6), P = NS
Eligibility criteria:
Total cholesterol Hemoglobin A1c (%) mean (SD): There was no significant
Transgender patients: had been
difference between the trans male and the cis female cohort:
taking testosterone or estradiol TG
5.3 (0.2) vs 5.2 (0.2), P = NS
for the last 3 months. Patients HDL
were excluded if they had AST (U/L) mean (SD):
significant medical or psychiatric LDL-calculated using the o trans male cohort had significantly higher AST levels than
comorbidities Friedewald formula the cis female cohort: 39 (5) vs 29 (8) P = .001
Cisgender peers: Controls taken Cross sectional: transgender o trans female and the cis male cohort: 37 (4) vs 34 (18),
from the RESISTANT and HIP patients had their measurements P = NS
study. The RESISTANT study taken on the same day while
cisgender patients were taken ALT (U/L) mean (SD): There was no significant difference
selected individuals between 12
from previous research between the trans male and the cis female cohort: 26 (5) vs
and 19 that were > 1 Tanner
26 (7), P = NS
stage, sedentary and were
excluded if they had Total Cholesterol (mg/dL) mean (SD): There was no
hypertension, hemoglobin < 9 significant difference between the trans male and the cis
mg/dL, serum creatinine > 1.5 female cohort: 147 (16) vs 153 (29), P = NS
mg/dL, had medication TG (mg/dL) mean (SD): There was no significant difference
dependent asthma or another between the trans male and the cis female cohort: 75 (21) vs
condition that would cause 100 (45), P = NS

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
792

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
insulin resistance. The HIP study HDL (mg/dL) mean (SD): The trans male cohort had
selected adolescents in early significantly lower HDL than the cis female cohort: 40 (5) vs
puberty that were Tanner Stage 46 (7), P = .043
2-3 who were normal weight or
LDL (mg/dL) mean (SD): There was no significant difference
obese through pediatric
between the trans male and the cis female cohort: 92 (16) vs
practices during 2009 to 2015.
87 (22), P = NS
Diabetes, prediabetes or
another condition that affected TM vs CM TM vs CM
glucose metabolism was reason
for exclusion. TGNB male cohort with Matched cisgender male There were significant differences in systolic BP and ALT levels
testosterone therapy for at cohort matched by puberty between the trans male and cis male cohort. All others
Sampling method: least 3 months. stage (tanner stage 5) and BMI comparisons were non-significant.
Transgender patients were ± 6%
Average dose of testosterone BMI (%) mean (SD): There was no significant difference
recruited from the TRUE Center was 217 (88) mcg/month for between trans male and the cis male cohort: 63 (28) vs. 64
for Gender Diversity at the average duration of 11.2 (28), P = NS
Children's Hospital Colorado (5.9) months. 12 were taking
Diastolic BP (mm HG) mean (SD): There was no significant
Cisgender patients' data were IM injections, 9 were using
difference between the trans male and the cis male cohort:
used from previous studies- the SQ. 1 participant had recently
69 (8) vs. 67 (10), P = NS
HIP and RESISTANT study. CM discontinued taking GnRH
and CF matched with TM were analogs and 3 had used them Systolic BP (mm HG ) mean (SD): The trans male cohort had a
matched based on pubertal in the past significantly lower mean systolic BP than the cis male cohort:
stage and BMI. CM and CF 108 (9) vs. 115 (13), P = .005
matched to TF were matched Inverse of fasting insulin (mL/mU) mean (SD): There was no
based on age and BMI. significant difference between the trans male and the cis
male cohort: 0.088 (0.023) vs 0.145 (0.1.09), P = NS
HOMA-IR mean (SD): There was no significant difference
between the trans male and the cis male cohort: 2.7 (0.8) vs
2.2 (1.4), P = NS
Fasting glucose (mg/dL) mean (SD): There was no significant
difference between the trans male and the cis male cohort:
88 (5) vs 86 (10), P = NS
Hemoglobin A1c (%) mean (SD): There was no significant
difference between the trans male and the cis male cohort:
5.3 (0.3) vs 5.3 (0.3), P = NS
AST (U/L) mean (SD): There was no significant difference
between the trans male and the cis male cohort: 39 (4) vs 36
(16), P = NS

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
793

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
ALT (U/L) mean (SD): The trans male cohort had significantly
lower levels of ALT than the cis female cohort: 25 (6) vs 34
(17), P < .001
Total Cholesterol (mg/dL) mean (SD): There was no
significant difference between the trans male and the cis
male cohort: 143 (19) vs 146 (22), P = NS
TG (mg/dL) mean (SD): There was no significant difference
between the trans male and the cis male cohort: 76 (23) vs
91 (30), P = NS
HDL (mg/dL) mean (SD): There was no significant difference
between the trans male and the cis male cohort: 41 (5) vs 46
(9), P = NS
LDL (mg/dL) mean (SD): There was no significant difference
between the trans male and the cis male cohort: 87 (19) vs
82 (19), P = NS
TF vs CF TF vs CF

TGNB female cohort with Matched cisgender female There was a significant difference in AST levels between the
estrogen therapy for at least 3 cohort matched by age (within trans female and cis female cohort. All other comparisons were
months a year) and BMI percentile ± non-significant.
12.5%
Average dose of estradiol of BMI (%) mean (SD): There was no significant difference
1.5 (1) mg/day with an between trans female and the cis female cohort: 55 (34) vs.
average treatment duration of 58 (30), P = NS
12.3 (9.9) months. Four trans
Diastolic BP (mm HG) mean (SD): There was no significant
females were on a GnRH
difference between trans female and the cis female cohort:
analog and 6 had been on
70(7) vs 66 (7) P = NS
them in the past. 7 TF were on
spironolactone and 1 was on Systolic BP (mm HG ) mean (SD): There was no significant
IM medroxyprogesterone difference between the trans female and the cis female
acetate cohort: 107 (12) vs 113 (7), P = NS
Inverse of fasting insulin (mL/mU) mean (SD): There was no
significant difference between trans female and the cis
female cohort: - 0.066 (0.02) vs 0.098 (0.045), P = NS
HOMA-IR mean (SD): There was no significant difference
between trans female and the cis female cohort: 3.8 (2.1) vs
2.8 (1.4), P = NS

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
794

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Fasting glucose (mg/dL) mean (SD): There was no significant
difference between trans female and the cis female cohort:
89 (5) vs 82 (12), P = NS
Hemoglobin A1c (%) mean (SD): There was no significant
difference between trans female and the cis female cohort:
5.2 (0.4) vs 5.0 (0.2), P = NS
AST (U/L) mean (SD): The trans female cohort had
significantly higher AST levels than the cis female cohort: 37
(4) vs 23 (6), P < .001
ALT (U/L) mean (SD): There was no significant difference
between trans female and the cis female cohort: 25.5 (5) vs
26.6 (6), P = NS
Total Cholesterol (mg/dL) mean (SD): There was no
significant difference between trans female and the cis
female cohort: 148 (23) vs 145 (20), P = NS
TG (mg/dL) mean (SD): There was no significant difference
between trans female and the cis female cohort: 77 (34) vs
74 (21), P = NS
HDL (mg/dL) mean (SD): There was no significant difference
between trans female and the cis female cohort: 49 (10) vs
46 (10), P = NS
LDL (mg/dL) mean (SD): There was no significant difference
between trans female and the cis female cohort: 83 (20) vs
84 (20), P = NS
TF vs CM TF vs CM

TGNB female cohort with Matched cisgender male There were significant differences in systolic BP, inverse of
estrogen therapy for at least 3 cohort matched by age (within fasting glucose, HOMA-IR and HDL measurements between the
months a year) and BMI percentile ± trans female and cis male cohort. All other comparisons were
12.5% non- significant.
Average dose of estradiol of
1.5 (1) mg/day with an BMI (%) mean (SD): There was no significant difference
average treatment duration of between trans female and the cis male cohort: 46 (37) vs 45
12.3 (9.9) months. Four trans (36), P = NS
females were on a GnRH
Diastolic BP (mm HG) mean (SD): There was no significant
analog and 6 had been on
difference between trans female and the cis female cohort:
them in the past. 7 TF were on
70 (6) vs 67 (5), P = NS
spironolactone and 1 was on

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
795

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
IM medroxyprogesterone Systolic BP (mm HG ) mean (SD): The trans female cohort had
acetate a significantly lower mean systolic BP than the cis male
cohort: 106 (11) vs 116 (8) P = .007
Inverse of fasting insulin (mL/mU) mean (SD): The trans
female cohort had significantly lower inverse fasting of
insulin compared to cis males: 0.078 (0.025) vs 0.142 (0.064)
P = .011
HOMA-IR mean (SD): The trans female cohort had a
significantly higher HOMA-IR compared to the cis male
cohort: 3.4 (2.2) vs 2.1 (1.2), P = .012
Fasting glucose (mg/dL) mean (SD): There was no significant
difference between trans female and the cis male cohort: 90
(4) vs 86 (6), P = NS
Hemoglobin A1c (%) mean (SD): There was no significant
difference between trans female and the cis male cohort: 5.2
(0.4) vs 5.1 (0.3), P = NS
AST (U/L) mean (SD): There was no significant difference
between trans female and the cis male cohort: 37 (4) vs 34
(18), P = NS
ALT (U/L) mean (SD): There was no significant difference
between trans female and the cis male cohort: 24 (5) vs 32
(18), P = NS
Total Cholesterol (mg/dL) mean (SD): There was no
significant difference between trans female and the cis male
cohort: 152 (22) vs 136 (25), P = NS
TG (mg/dL) mean (SD): There was no significant difference
between trans female and the cis male cohort: 81 (34) vs 97
(30), P = NS
HDL (mg/dL) mean (SD): The trans female cohort had
significantly higher HDL levels than the cis male cohort: 50
(10) vs 43 (6), P = .023
LDL (mg/dL) mean (SD): There was no significant difference
between trans female and the cis male cohort: 85 (20) vs 74
(22), P = NS
Nokoff (2021)134 Population: N = 48 AFAB Cardiovascular outcomes: AFAB

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
796

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Transgender males: n = 9 Transgender males: Transgender males: had been Cisgender females: Matched on Weight- measured twice and BMI (percentile):
patients who had been on a on a GnRH analog for at least sex assigned at birth, age, and averaged. The 2000 Centers
mean age (SD) in years = 13.8 (1.7) the comparison is not statistically significant (P = NS).
GnRH analog for ≥ 3 months 3 months BMI for Disease Control and
Colorado (before initiation of mean age (SD) at initiation of GnRH Prevention Growth Charts transgender males had mean ± SD BMI in percentile of 62 ±
between 2016 and testosterone or estradiol) analogs in years = 12.1 (1.9) were used to calculate BMI 32
2019 mean GnRH analog duration (SD) in percentiles using sex assigned cisgender females had mean ± SD BMI in percentile of 67 ±
Transgender females: N = 8
patients who had been on a months = 20.9 (19.8) at birth 29
GnRH analog for ≥ 3 months majority white n = 6 (67%) with Blood pressure was measured Blood pressure: no significant differences between cohorts
(before initiation of Hispanic/Latino n = 4 (44%) after ~5 min of seated rest,
testosterone or estradiol) with an age- and size- SBP:
depression at baseline n = 2 (22%) appropriate manual cuff.
Cisgender males: N = 17 o transgender males had mean ± SD SBP in mmHg of 104 ±
anxiety at baseline n = 1 (11%) Measured twice and 13
Cisgender females: N = 14 averaged.
most n = 3 (33%) were at pubic hair o cisgender females had mean ± SD SBP in mmHg of 114 ±
Eligibility criteria: Tanner stage 4 Fasting blood samples were used 11
Transgender cohort: to collect: o comparison not statistically significant (P = NS)
most n = 3 (33%) were at
Transgender youth who had breast/testicular Tanner stage 3. HbA1c o transgender males had mean ± SD SBP in percentile of 41
been on a GnRH analog for ≥ 3
n = 5 (63%) had hypertension Inverse of the fasting insulin ± 32
months were recruited between
2016 and 2019 from the n = 5 (63%) hypercholesterolemia concentration (1/[fasting o cisgender females had mean ± SD SBP in percentile of 68 ±
hospital; youth were excluded if insulin])-used to calculate 24
n = 4 (50%) had type 2 diabetes insulin sensitivity
they had significant medical or o comparison not statistically significant (P = NS).
Cisgender females:
psychiatric comorbidities HOMA-IR.
DBP
(including diabetes or mean age (SD) in years = 13.9 (1.7) Total cholesterol
antipsychotic treatment), or o transgender males had mean ± SD DBP in mmHg of 67 ± 5
majority white n = 10 (71%) with not Triglycerides
were using hormones not o cisgender females had mean ± SD SBP in mmHg of 65 ± 9
Hispanic/Latino n = 9 (64%)
prescribed by a physician HDL cholesterol d
most n = 4 (29%) were at pubic hair o comparison not statistically significant (P = NS)
Cisgender cohort: Healthy LDL cholesterol was o transgender males had mean ± SD SBP in percentile of 59
Tanner stage 4
cisgender controls were calculated using the ± 20
obtained from two studies most n = 9 (64%) were at Friedewald formula (for units
performed at our institution: breast/testicular Tanner stage 5. in mg/dL). o cisgender females had mean ± SD DBP in percentile of 55 ±
the RESistance to InSulin in Type 25
n = 6 (75%) had hypertension Body composition: fat-free mass
1 ANd Type 2 diabetes
and fat mass) was measured by o comparison not statistically significant (P = NS)
n = 7 (88%) hypercholesterolemia
(RESISTANT) study and the
dual-energy X-ray absorptiometry Fasting glucose:
Health Influences in Puberty n = 7 (64%) had type 2 diabetes.
(HIP) study Hormone levels. Serum/plasma transgender males had a significantly higher fasting glucose
fasted blood samples were than cisgender females. (P < .05).
Sampling method:
assayed for: transgender males had mean ±SD fasting glucose in mg/dL of
89 ± 4

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
797

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Transgender cohort: All AST cisgender females had mean ±SD fasting glucose in mg/dL of
transgender females and five ALT 79 ±13
transgender males were Insulin sensitivity:
recruited from the same cross- Cross-sectional study:
sectional study. An additional Exposures/outcomes measured transgender males had a significantly lower insulin sensitivity
four transgender males were at the same time compared to cisgender females (P < .05).
recruited from a separate transgender males had mean ± SD inverse of fasting insulin in
longitudinal study, and data mL/lU of 0.067 ± 0.020
from their baseline visit are
cisgender females had mean ± SD inverse of fasting insulin in
included here, when they were
mL/lU of 0.103 ± 0.049
on a GnRH analog alone. None
of the participants were HOMA-IR:
receiving testosterone or
transgender males had significantly higher HOMA-IR when
estradiol treatment at the time
compared to cisgender females (P ≤ .01).
of this study.
transgender males had mean ± SD HOMA-IR of 3.7 ± 1.7
Cisgender cohort: Transgender
males (assigned female sex at cisgender females had mean ± SD HOMA-IR of 2.3 ± 1.1
birth, male gender identity) Hemoglobin A1C:
were matched to cisgender
transgender males had a significantly higher HbA1c % then
females and transgender
cisgender females (P ≤ .05).
females (assigned male sex at
birth, female gender identity) transgender males had mean ± SD Hemoglobin A1C of 5.4% ±
were matched to cisgender 0.2
males. cisgender females had mean ± SD Hemoglobin A1C of 5.2% ±
0.2
Total cholesterol:
the comparison is not statistically significant (P = NS).
transgender males had mean ± SD total cholesterol in mg/dL
of 158 ± 21
cisgender females had mean ± SD total cholesterol in mg/dL
of 152 ± 27
Triglycerides:
the comparison is not statistically significant (P = NS).
transgender males had mean ± SD triglycerides in mg/dL of
87 ± 43
cisgender females had mean ± SD triglycerides in mg/dL of 89
± 24

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
798

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
HDL:
the comparison is not statistically significant (P = NS).
transgender males had mean ± SD HDL in mg/dL of 53 ± 16
cisgender females had mean ± SD HDL in mg/dL of 48 ± 13
LDL:
the comparison is not statistically significant (P = NS).
transgender males had mean ± SD LDL in mg/dL of 88 ± 14
cisgender females had mean ± SD LDL in mg/dL of 86 ± 23
Liver Enzymes:
AST
o transgender males had a significantly higher AST level
compared to cisgender females (P < 0.05)
o transgender males had mean ± SD in U/L of 42 ± 11
o cisgender females had mean ± SD in U/L of 31 ± 10
ALT
o the comparison is not statistically significant (P = NS)
o transgender males had mean ± SD in U/L of 28 ± 13
o cisgender females had mean ± SD in U/L of 24 ± 9
AMAB AMAB

Transgender females: Transgender female: had been Cisgender male: Matched on BMI (percentile):
on a GnRH analog for at least sex assigned at birth, age, and
mean age (SD) in years = 13.7 (1.2) the comparison is not statistically significant (P = NS).
3 months BMI
mean age (SD) at initiation of GnRH transgender females had mean ± SD BMI in percentile of 44 ±
analogs in years = 12.8 (1.3) 39
mean GnRH analog duration (SD) in cisgender males had mean ± SD BMI in percentile of 45 ± 38
months = 11.3 (7) Blood pressure:
majority white n = 7 (88%) with half
SBP:
of Hispanic/Latino n = 4 (50%) and
half of not Hispanic/Latino n = 4 o transgender females had mean ± SD SBP in mmHg of 97 ±
(50%) 6
depression at baseline, n = 3 (38%) o cisgender males had mean ± SD SBP in mmHg of 108 ± 7

anxiety at baseline, n = 1 (12%) o transgender females had significantly lower SBP than
cisgender males (P ≤ .01)

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
799

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
most n = 3 (38%) were at pubic hair o transgender females had mean ± SD SBP in percentile of
Tanner stage 2, 15 ± 12
most n = 5 (63%) were at o cisgender males had mean ± SD SBP in percentile of 52 ±
breast/testicular Tanner stage 2. 21
n = 5 (63%) had hypertension o transgender females had significantly lower SBP
percentiles than cisgender males (P ≤ .001).
n = 3 (38%) hypercholesterolemia
DBP
n = 1 (13%) had type 2 diabetes.
o transgender females had mean ± SD DBP in mmHg of 65 ±
Cisgender males:
11
mean age (SD) in years = 13.9 (0.9) o cisgender males had mean ± SD DBP in mmHg of 65 ± 3
majority white n = 13 (76%) with not o comparison not statistically significant (P = NS)
Hispanic/Latino n = 13 (76%),
o transgender females had mean ± SD DBP in percentile of
most n = 5 (29%) were at pubic hair 55 ± 28
Tanner stage 2, most n = 7 (41%)
o cisgender males had mean ± SD DBP in percentile of 57 ± 9
were at breast/testicular Tanner
stage 2. o comparison not statistically significant (P = NS).
n = 9 (75%) had hypertension Fasting glucose:
n = 8 (67%) hypercholesterolemia the comparison is not statistically significant (P = NS).
n = 4 (33%) had type 2 diabetes. transgender females had mean ± SD fasting glucose in mg/dL
of 88 ± 7 and
cisgender males had mean ± SD fasting glucose in mg/dL of
84 ± 5,
Insulin sensitivity:
transgender females had a significantly lower insulin
sensitivity compared to cisgender males (P < .05).
transgender females had mean ± SD inverse of fasting insulin
in mL/lU of 0.076 ± 0.029
cisgender males had mean ± SD inverse of fasting insulin in
mL/lU of 0.135 ± 0.049
HOMA-IR:
transgender females had significantly higher HOMA-IR when
compared to cisgender males (P < 005).
transgender females had mean ± SD HOMA-IR of 3.5 ± 1.4
cisgender males had mean ± SD HOMA-IR of 2.2 ± 1.3

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
800

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Hemoglobin A1C:
transgender females had a significantly higher HbA1c % then
cisgender males (P ≤ .01).
transgender females had mean ± SD Hemoglobin A1C of 5.4%
± 0.1
cisgender males had mean ± SD Hemoglobin A1C of 5.1% ±
0.2
Total cholesterol:
the comparison is not statistically significant (P = NS).
transgender females had mean ± SD total cholesterol in
mg/dL of 143 ± 16
cisgender males had mean ± SD total cholesterol in mg/dL of
151 ± 35
Triglycerides:
the comparison is not statistically significant (P = NS).
transgender females had mean ± SD triglycerides in mg/dL of
78 ± 28
cisgender males had mean ± SD triglycerides in mg/dL of 117
± 115
HDL:
the comparison is not statistically significant (P = NS).
transgender females had mean ± SD HDL in mg/dL of 51 ± 6
cisgender males had mean ± SD HDL in mg/dL of 54 ± 13,
LDL:
the comparison is not statistically significant (P = NS)
transgender females had mean ± SD LDL in mg/dL of 76 ± 14
cisgender males had mean ± SD LDL in mg/dL of 74 ± 17
Liver Enzymes:
AST
o transgender females had a significantly higher AST level
compared to cisgender males (P ≤ .01)
o transgender females had mean ± SD in U/L of 43 ± 9

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
801

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
o cisgender males had mean ± SD in U/L of 31 ± 5
ALT
o the comparison is not statistically significant (P = NS)
o transgender females had mean ± SD in U/L of 34 ± 17
o cisgender males had mean ± SD in U/L of 24 ± 6
Valentine (2021)97 Population: N = 124 Transgender males: Transgender male cohort: Cisgender cohort: not on BMI was calculated using age, There was a significant increase in BMI percentiles and z-scores
At a large Midwestern Transgender males: N = 42 o mean age (range) in years = 16.6 Testosterone cypionate testosterone treatment, sex assigned at birth, height in the transgender males after starting testosterone as
years (14–19 years) dosing started at 50mg matched to the pre- and weight at time of visit, compared with BMI-matched cis-gender females for both the
pediatric academic patients receiving testosterone
intramuscularly (IM) monthly testosterone BMI's of and is presented as a short- and long-term follow-up periods.
center with a therapy o majority white, with bi-/multiracial and subsequently increased to transgender male cohort percentile. The 2000 CDC
multidisciplinary subjects being the second most BMI (percentile):
Cisgender females: N = 82 BMI- 50–150 mg IM every other Growth Charts were used to
program serving common race represented
matched cisgender female week. calculate percentiles. Mean The transgender group had a significant increase in BMI of +
transgender and
adolescents o total cholesterol, LDL, HDL, and values with standard 1.28 percentiles from visit to visit, and of + 3.29 percentiles
gender-diverse youth
Eligibility criteria: triglycerides, in mg/dL, at baseline deviations were calculated to from baseline through final follow-up.
were 156 ± 30, 87 ± 29, 45 (39, 59) evaluate change in BMI of The cisgender group showed an opposite trend of a
Transgender cohort: 14-21 years and 90 (69, 111), respectively. transgender male adolescents
old and taking testosterone significant decrease in BMI of -0.70 percentiles from visit to
o time (range) between visits was an while on testosterone, as well visit and of -1.77 percentiles from baseline through final
from 2014–2018 were eligible as change in BMI for a similar
average of 4.9 months (0.5–17.7). follow-up.
Cisgender cohort: seen in their time interval of the cisgender
o average total follow-up time BMI (z-score):
13 primary care centers, females.
(range) was 10.8 months (2.6–
without any chronic conditions Both short- and long-term In the transgender group, there was a significant increase in
25.7).
such as attention deficit follow-ups were evaluated, BMI z-score of + 0.08 from visit to visit, and of + 0.20 through
hyperactivity disorder, asthma, Cisgender females: the entire follow-up period.
with short-term follow-up
or conditions managed by our o mean age (range) in years = 15.5 assessing changes in BMI In the cisgender group, there was a BMI z-score decrease of -
subspecialty clinics years (14–21 years) between each clinic visit, and 0.01 from visit to visit, and of -0.05 through the entire follow-
Sampling method: o majority black/African American, long-term follow-up assessing up period.
with white subjects as the second changes in BMI between first
Transgender cohort: Follow-up:
most common racial group and final follow-up clinic
Transgender males (14–21 In transgender group: short-term follow-up, P = 0.004 and
visits.
years) taking testosterone from o total cholesterol, LDL, HDL, and long-term follow-up, P = .002
2014–2018 were identified (no triglycerides, in mg/dL, at baseline Cohort study: Outcomes are
other description about the were 166 ± 30, 97 ± 26, 44 (38, 54) measured after the exposure has In cisgender group, short term follow up, P = 0.004 and long
sampling method). and 92 (63, 170), respectively. been measured (retrospective term follow up, P = .001.
review).
Cisgender cohort: Initial BMIs of o time (range) between visits was an
cisgender females were average of 5.0 months (0.8–21.0).
matched to the pre- o average total follow-up time
testosterone BMIs of the (range) was 12.7 months (1.0–27.1)
transgender male cohort, and a
random number generator used

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
802

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
these matched patients to There was no significant difference in
create a 2:1 match of cisgender lipids between the cohorts
females to the transgender
There was a significant difference in
males.
age (P = .003) between the cohorts
There was a significant difference in
ethnicity (P = .0001) between the
cohorts
There was no significant difference in
the BMI percentiles and z-scores at
baseline between the cohorts (P = NS)
Valentine (2022)98 Population: N = 20,625 Age at first visit, y: median (25th-75th TGNB youth with diagnosis of Matched control group of Electronic health records were Overweight/obese: # (%)
percentile) GD peers: reviewed using SNOMED concept
PEDSNet, a Pediatric TGNB youth: n = 4172 TGNB youth had higher unadjusted odds than controls of
codes and were defined as having
Learning Health System
TGNB female: n = 2766 (66.3%) TGNB: 10.0 (4.4-14.6), n = 1412 with a CSHT Cases and controls were having the diagnosis of overweight/obesity (odds ratioa 1.5;
either a diagnosis or 2 abnormal
Network, USA prescription matched on the predicted 95% CI, 1.4-1.7; P < .0001)
TGNB male: n = 1407 (33.7%) Control group: 9.8 (4.1-14.3) measurements to capture data
n = 267 with a prescription probability of having the In the adjusted modelb, TGNB youth still had higher odds
Age at last visit, y: median (25th-75th for the following metrics:
Control youth: n = 16,453 for GnRH analogs alone diagnosis of GD. than controls of having the diagnosis of overweight/obesity
percentile) Overweight/obese
Control female: n = 11,130 n = 832 with a prescription A priori covariates used for (odds ratioa 1.1; 95% CI, 1.1-1.2; P < .0001)
(66.9%) TGNB group: 16.7 (14.6-18.3) matching include: year of Dyslipidemia
for testosterone without TGNB with female EHR sex had higher odds of overweight/
Control group: 16.6 (14.3-18.4) GnRH analogs birth, age at last visit, sex Liver dysfunction obesity than female controls (odds ratio 1.8; 95% CI, 1.7-2.0;
Control male: n = 5518 (33.1%)
listed in chart, race, P < .0001)
Eligibility: Groups were matched and were mostly n = 349 with a prescription Dysglycemia
ethnicity, insurance status,
white (72.5%,) and non-Hispanic (84.8%) for estrogen without GnRH TGNB youth: 1764 (42.3)
TGNB youth subjects had a duration in database and Hypertension
analogs site. Control youth: 5263 (32.0)
diagnosis of gender dysphoria or PCOS
related diagnosis. n = 106 with a prescription Dyslipidemia: # (%)
for testosterone with EHRs were reviewed for the
Control youth patients were following lab and anthropometric TGNB youth had higher unadjusted odds than controls of
GnRH analogs
seen within the same time data: having the diagnosis of dyslipidemia (odds ratioa 1.8; 95% CI,
frame. No specific eligibility n = 125 with a prescription
BP 1.5-2.1; P < .0001)
criteria listed. for estrogen with GnRH
analogs BMI In the adjusted modelb, there was no difference in odds
Sampling Method: Clinical data between TGNB and control youth subjects (odds ratioa 1.2;
available from electronic health Liver enzymes 95% CI 1.0-1.4, P = NS)
care records from the health
Lipids TGNB youth: 351 (8.4)
system from 2009 onward for
patients with in-person encounters TG Control youth: 806 (4.9)
with a provider were reviewed for HbA1C Liver dysfunction: # (%)
inclusion. The data for all TGNB
Cross-sectional study:
patients and at least one outpatient TGNB youth had higher unadjusted odds than controls of
Exposures/outcomes measured
visit from 2009-2019 was extracted having the diagnosis of liver dysfunction (odds ratioa 1.4; 95%
at the same time
from the PEDSnet database on Nov CI, 1.2-1.5; P < .0001)
a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
803

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
2019. A random sample of 197,039 In the adjusted modelb, TGNB youth had lower odds than
patients with at least one out- controls of having the diagnosis of liver dysfunction (odds
patient visit during the same time ratioa 0.8; 95% CI, 0.7-0.9; P = .003)
period who did not have a diagnosis
TGNB youth: 460 (11.0)
of GD were used as a pool of
controls. Controls were evaluated Control youth: 1360 (8.3)
for the prevalence of well- Dysglycemia: # (%)
characterized pediatric diagnoses
There was no difference in odds between TGNB and control
and the prevalence in the control
pool was similar to PEDSnet as a youth subjects (odds ratioa 0.9; 95% CI, 0.8-1.2, P = NS)
whole. Propensity scores were used In the adjusted modelb, TGNB youth had lower odds than
to match control to cases controls of having the diagnosis of dysglycemia (odds ratioa
(approximately 4:1.) A priori 0.6; 95% CI, 0.5-0.8; P < .001)
covariates used for matching TGNB with a male EHR sex had lower odds of dysglycemia
include: year of birth, age at last than male controls (odds ratio 0.6, 95% CI, 0.4-0.9, P = .01)
visit, sex listed in chart, race,
ethnicity, insurance status, duration TGNB youth: 90 (2.2)
in database and site. Cases and Control youth: 375 (2.3)
controls were matched on the Hypertension: # (%)
predicted probability of having the
diagnosis of GD using a greedy TGNB youth had higher unadjusted odds than controls of
match algorithm. having the diagnosis of hypertension (odds ratioa 1.2; 95% CI,
1.1-1.4; P < .0001)
In the adjusted modelb, there was no difference in odds
between TGNB and control youth subjects (odds ratioa 0.9;
95% CI 0.8-1.1, P = NS)
TGNB youth: 373 (8.9)
Control youth: 1214 (7.4)
PCOS: # (%)
Among those with female EHR sex, TGNB youth had higher
unadjusted odds of having a PCOS diagnosis compared to
controls (odds ratioa 1.7; 95% CI, 1.2-2.6; P < .01)
In the adjusted modelb, there was no difference in odds
between TGNB and control youth female EHR subjects (odds
ratioa 0.9; 95% CI 0.8-1.5, P = NS)
TGNB youth: 42 (1.5)
Control youth: 96 (0.9)
Lab and anthropometric data median (25th-75th percentile)

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
804

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
Systolic BP, mm Hg:
o Statistically but not a clinically significant difference
between groups (P < .0001)
o TGNB youth (n = 1701): 116 (108-124)
o Control youth (n = 6026): 114 (106-121)
Diastolic BP, mm Hg
o Statistically but not a clinically significant difference
between groups (P < .0001)
o TGNB youth (n = 1701): 67 (62-73)
o Control youth (n = 6026): 66 (60-72)
BMI
o Statistically but not a clinically significant difference
between groups (P < .0001)
o TGNB youth (n = 3829): 23 (20-28)
o Control youth (n = 14,633): 22 (19-26)
BMI, %
o Statistically but not a clinically significant difference
between groups (P < .0001)
o TGNB youth (n = 3829): 77 (41-95)
o Control youth (n = 14,633): 69 (39-90)
ALT, IU/L
o No significant difference between groups (P = NS)
o TGNB youth (n = 1627): 24 (17-31)
o Control youth (n = 3940): 24 (16-32)
AST, IU/L
o Statistically but not a clinically significant difference
between groups (P < .0001)
o TGNB youth (n = 1449): 25 (20-32)
o Control youth (n = 3798): 27 (21-36)
Total cholesterol, mg/dL
o No significant difference between groups (P = NS)
o TGNB youth (n = 1633): 156 (138-178)

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
805

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Table I.K.4. Clinical studies comparing TGNB to cisgender peers regarding cardiovascular outcomes
Study first author
Outcome measures and
(publication year) Population Select baseline characteristics Exposure/intervention Comparator Results
timing
and study setting
o Control youth (n = 1907): 156 (137-180)
HDL, mg/dL
o No significant difference between groups (P = NS)
o TGNB youth (n = 1618): 46 (39-55)
o Control youth (n = 1837): 47 (39-56)
LDL, mg/dL
o No significant difference between groups (P = NS)
o TGNB youth (n = 1142): 87 (70-106)
o Control youth (n = 1266): 86 (70-104)
Triglycerides, mg/dL
o No significant difference between groups (P = NS)
o TGNB youth (n = 1633): 93 (67-135)
o Control youth (n = 2021): 91 (66-132)
HbA1c, %
o Statistically but not a clinically significant difference
between groups (P < .0001)
o TGNB youth (n = 532): 5.3 (5.1, 5.5)
o Control youth (n = 959): 5.4 (5.2-6.7)

a odds
were extracted from figure 1 in study. Unadjusted and adjusted ORs were calculated in propensity matched cohorts. A priori covariates used for matching include: year of birth, age at last visit, sex listed in chart, race, ethnicity, insurance status, duration in
database and site. Cases and controls were matched on the predicted probability of having the diagnosis of GD using a greedy match algorithm. (Valentine, 2022)
b odds were further adjusted for overweight/obesity, depression, and antipsychotic prescription (Valentine, 2022)
Abbreviations: AFAB, assigned female at birth; ALT, alanine aminotransferase; AMAB, assigned male at birth; AST, aspartate aminotransferase ; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; EHR, electronic health record; HbA1c,
Hemoglobin A1C; HDL, high-density lipoprotein; HOMA-IR, homeostatic model of insulin resistance; LDL, low-density lipoprotein; NHANES, National Health and Nutrition Examination Survey; N/S, not significant; PCOS, Polycystic ovary syndrome; SBP, systolic
blood pressure; SCr, serum creatinine; SD, standard deviation; TC, total cholesterol; TG, triglyceride; TGNB, transgender, non-binary or gender-diverse
806

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APPENDIX I.L: DATA EXTRACTED FROM STUDIES COMPARING TGNB
PATIENTS BEFORE AND AFTER (PRE-POST) INTERVENTION,
ORGANIZED BY OUTCOME

807

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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Achille (2021)55 TGNB Adolescents (N = 50) Full cohort: Mean (SD) age was 16.2 (2.2); Up to 12-months of endocrine Outcomes were measured Depression:
64% were depressed in the prior year; 10% treatment including: upon referral to the pediatric
A US NY) Eligibility: Participants were CESD-R: Mean baseline CESD-R score was 21.4 at baseline and decreased to 13.9
reported suicidality; 90% were seeing a endocrine department for GD
pediatric endocrine recruited at the clinic, and a vast puberty blockers (N = 23, 46%), at 12 months (P < 0.001). Mean score at 12 months indicates an absence of
therapist; 34% were on psychiatric and after approximately 12
gender dysphoria clinic majority consented/assented. CSHT (N = 35, 70%), clinical depression (ie, < 16) in the average patient.
medications months of treatment.
This study was limited to the both (N = 11, 22%), or PHQ-9: Mean depression scores by the PHQ-9 decreased over time as well
subset of all patients who MTF: Mean (SD) age was 15.5 (1.6); 70.6% Depression and suicide
neither (N = 3, 6%) (P < 0.001) [Extracted scores were 8.86 at baseline and 5.29 at follow-up]
completed 3 rounds of were depressed in the prior year; 11.8% ideation measured using:
questionnaires at 6-month reported suicidality; 94.1% were seeing a Suicide ideation: (from PHQ-9 questionnaire)
o CESD-R
intervals. Patients were therapist; 29.4% were on psychiatric Overall: Suicide ideation was 10% (N = 5) at baseline versus 6% (N = 3) at 12
medications o PHQ-9
excluded if they had sex months (P = NS )
chromosome abnormalities or FTM: Mean (SD) age was 16.6 (2.5); 60.6% FTM: Suicide ideation was 9.1% (N = 3) at baseline, versus 6.1% (N = 2) at 12
disorders of sexual were depressed in the prior year; 9.1% months (P = NS )
differentiation. reported suicidality; 87.9% were seeing a
therapist; 36.4% were on psychiatric MTF: Suicide ideation was 11.8% (N = 2) at baseline, versus 5.9% (N = 1) at 12
Sampling method: Patients
medications months (P = NS )
must have completed 3 waves
of questionnaires at 6-month
intervals, for a total of
approximately 12 months of
observation. A "vast majority"
of 116 patients gave
consent/assent.
Subset definition: N = 50 TGNB
adolescents, including MTF
(N = 17) and FTM (N = 33)
adolescents.
Allen (2019)56 N = 47 TGNB adolescents The age of the participants ranged from CSH treatment Suicidality was measured using Suicidality:
13.73 to 19.04 years (mean = 16.59, the ASQ
Eligibility: Adolescents and Participants showed a decrease in the estimated adjusted mean (standard error)
SD = 1.19).
young adults (age range 13–20 of ASQ scores from 1.11 (.22) at T0 to .27 (.12) at T1.
years) who received services for The range of treatment length was 113-
The main effect was significant, meaning suicidality scores were significantly
GD at the clinic. Participants 1016 days (mean = 349, SD = 193).
lower at T1 after CSH, F(1, 44) = 15.09, P < .001, partial η2 = .26, demonstrating a
were included if they had For most of the sample (90%), the duration large effect size.
pretest and final assessment of treatment was at, or under, 600 days.
data points and were treated The duration of treatment was not significantly related to participants' ASQ
with CSH for at least 3 months Assigned female at birth was n = 33 (70.2%) scores, F(1, 44) = .09, P = .77, partial η2 = .002.
and assigned male at birth was n = 14
Sampling method: A total of 47 (29.8).
eligible participants had pretest
and final assessment data. The The majority of participants were white
pretest for 23 participants n = 39 (83%).
occurred at their first contact

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
808

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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
with the clinic (the other Of the 47 participants, n = 8 were
participants' pretest assessment administered GnRH analogs prior to
was completed at a subsequent beginning CSH (GnRH analogs + CSH
visits to clinic but prior to subgroup) and n = 39 were not received
starting CSH). Thirteen of the GnRH analogs prior to being administered
participants first presented to CSH (CSH-only subgroup).
our clinic in 2015; 19 in 2016; 14
in 2017; and one in 2018.
Patients are administered
questionnaires and screeners at
the beginning of their clinic visit,
either at the time of the
diagnostic evaluation or during
a follow-up appointment with
the multidisciplinary team.
Responses are reviewed by the
mental health professional prior
to meeting with the patient.
Cantu (2020)74 N = 80 TGNB adolescents Full cohort: Mean (SD) age was 15.1 (1.8); At the initial visit or first follow-up Participants were evaluated at PHQ-9 (n = 80) mean (SD)
affirmed male gender, n (%), was 58 (72.5); appointment, participants were their initial visit and then at o There was a nonsignificant decrease from a score of 10.5 (6.5) at the initial visit
An academic medical Eligibility: Youth were included
distance in miles, mean (SD), range was receiving: their first follow-up to 10 (6.4) at follow-up, P = NS
center in the in the current study if they (1)
36.2 (39.9); follow-up time in weeks, mean appointment (recommended 3-
Northwestern United were between the ages of 11 hormone blocker only GAD-7 (n = 78 mean (SD)
(SD) was 20.4 (10.2) 4 months after initial visit)
States between and 18 years, (2) had attended HT only o There was a non-significant decrease from a score of 9.1 (6.1) at the initial visit
September 2017 and both an initial visit and one Only N = 1 (1.3%) individual initiated HT Depression measured using
before the initial visit, and 28 youth both, or PQH-9 and GAD-7 to 8.8 (5.7) at follow-up, P = NS
June 2019 follow-up appointment, and (3)
completed measures assessing initiated HT between initial visit and first neither
acute distress (PHQ-9 and GAD- follow-up.
7) at both visits Of those 28 youth, 6 were started on
Sampling method: All youth feminizing hormones and 22 were started
ages 11 and older complete on masculinizing.
anxiety and depression A total of 17 youth initiated hormone
screeners at every visit blockers between their initial visit and first
regardless of mental health follow-up, 4 of which also initiated HT.
diagnoses or symptom severity.
Second visit is recommended 3– N = 77 (96.2%) received neither HT nor
4 months after the initial visit. hormone blockers at initial visit

Subset definition: All N = 38 (47.5%) received neither HT nor

adolescents (N = 80) completed hormone blockers at follow up
PHQ-9 screeners at both time appointment.
points and n = 78 youth

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
809

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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
completed GAD-7 screeners at
both time points)
Carmichael (2021)73 N = 44 TGNB adolescents Total sample median age at baseline was Suppression of puberty using Patients were measured at Self-harm Index Mean (95% CI)
13.6 (12.8,14.6), 89% white, all beyond GnRH analog triptorelin together study entry, and then re-
UK Eligibility Criteria: There was no significant change in CBCL or YSR self-harm index scores from
stage 3 pubertal status. with psychosocial support and evaluated yearly at 12,24 and
o Patients recruited from those baseline to any data collection point
therapy, from study entry until the 36 month until they turned 16.
Median age at end of study was 16.1
referred to GIDS who were end of the GnRH analog Parent report CBCL
(16.0,16.4). Measures of Psychological
between 12-15 years and had monotherapy pathway at age 16 o 12 month
Birth registered males started at a median or older. 3.75 mg by IM injection functioning were measured
commenced GnRH analog
treatment. age of 13.4 (12.7,14.1) and birth registered given every 28 days during using the CBCL (parent report)  There was no significant change from the baseline score of those that
females at 13.9 (13.5, 14.7) all participants treatment period. 2 participants and YSR (self-report.) followed up: 0(0,1) to the score at 12 months: 0(0, 1), P = NS
o Had been seen for at least 6
months and attended at least had normal endocrinology, karyotype, given 11.25 mg every 10 weeks. Reference data from both o 24 month
4 interviews. imaging and clinical phenotype on physical Australia and the Netherlands  There was no significant change from the baseline score of those that
examination for birth-registered sex and were used to calculate z- followed up: 0(0,1) to the score at 24 months: 0(0, 1), P = NS
o Psychological stability to normal full blood count and liver and renal scores.
withstand the stresses of function. o 36 month
medical treatment and Self-harm index: assessed
No participants had evidence of disorders through two questions in each  There was no significant change from the baseline score of those that
o Displayed severe and of sexual differentiation. of the CBCL and YSR: Item 18 followed up: 0(0,1) to the score at 36 months: 0(0, 1), P = NS
persistent GD and actively Self-report YSR Mean (95% CI)
requesting pubertal
suppression o 12 months

o Able to give informed  There was no significant change from the baseline score of those that
consent followed up: 0(0,1) to the score at 12 months: 0(0, 2), P = NS

o Met physical/medical criteria o 24 months

of being in established  There was no significant change from the baseline score of those that
puberty and having normal followed up: 0(0,0) to the score at 24 months: 0(0, 0), P = NS
endocrine function and
karyotype consistent with
birth registered sex.
Exclusions: Inability to fully
participate, BMI < 2nd
percentile, serious psychiatric
conditions, Inability to give
consent, low spine or hip BMD
Sampling Method: Patients
attending GIDS were provided
with information and those
wishing to find out more
discussed with their clinician.
Those likely deemed eligible

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
were given detailed information
and invited to a medical clinic
for discussion. Young people
needed to commit to regular
medical and psychosocial follow
up. Informed consent was
obtained. 48 young people
attended the clinics and 44
wished to participate. 8 young
people were not yet eligible, but
were able to enter the study
when sufficiently advanced in
puberty.
Subset Definition: N = 44 TGNB
adolescents age 12-15, including
birth registered male (N = 25)
and birth registered female
(N = 19) adolescents.
Chen (2023)75 N = 315 Participants were 12 to 20 years of age (mean [ CSH therapy Outcomes were measured at Depression: Slope mean (95% CI)
±SD], 16 ±1.9 years.) Higher percentage of initiation of therapy, and then o There was a significant decline in depression scores showing an annual change
USA- Gender clinics Eligibility: Participants were
those designated female at birth (64.8%) then at 6,12,18 and 24 months. on a 63-point scale of −1.27 points (−1.98 to −0.57) (unconditional model); -
recruited from the gender
male. Mostly non-Latinx or non-Latin white 0.92 points (-3.82 to -0.06) (conditional model) after a period of 2 years of CSH
clinics from July 2016-June Depression symptoms were
(58.1%) treatment from baseline.
2019. This cohort was initiating assessed using the 21-item
CSH as part of their clinical care. BDI-II. o Depression scores range from 0 to 63 (ranges of severity, minimal, 0 to 13;
For minors, parental consent Anxiety symptoms were mild, 14 to 19; moderate, 20 to 28; and severe, 29 to 63). The model had an
was required to initiate assessed by the RCMAS2 intercept (baseline mean) of 15.46 and estimated slope (change per year) of
treatment. −1.27. Thus, on average, depression started in the mild range and decreased to
from July 2016 the subclinical level by 24 months.
Sampling Method: Youth were
through June 2019
recruited from 4 different sites o Of 27 participants with depression scores in the severe range at baseline, 18
at the start of CSH therapy. They (67%) reported a depression score in the minimal or moderate ranges at 24
were enrolled if they met months. (chi-square statistic with 9 degrees of freedom, 49.85; P < .001)
inclusion criteria.
o Of 33 with depression scores in the moderate range at baseline, 21 (64%)
Subset definition: N = 315 TGNB reported a depression score in the minimal or moderate ranges at 24 months
adolescents, including: (chi-square statistic with 9 degrees of freedom, 49.85; P < .001)
o FTM (n = 190,) MTF (n = 106) Anxiety: Slope mean (95% CI)
and NB (n = 19,) adolescents
o There was a significant decrease in T scores for anxiety showing an annual
o Analytical sample n = 291 due change on a 100-point scale of −1.46 points (−2.13 to −0.79) (unconditional
to missing key variables at
follow-up

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
811

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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
o Designated female at birth model); -1.95 (-3.81 to -0.09) (conditional model) after a period of 2 years of
(n = 204,) and designated CSH treatment from baseline.
male at birth (n = 111) o Of 122 participants with baseline scores in the clinical range (T scores, > 60) 47
o Had early gender-affirming participants (38.5%) decreased to the non- clinical range at 24 months (chi-
care-previously using GnRH square statistic with 1 degree of freedom, 22.05; P < .001)
analog (n = 24)
 youth designated female
at birth with early gender-
affirming care (n = 4)
 youth designated male at
birth with early gender-
affirming care (n = 20)
o analytic sample (n = 291)
de Vries (2011)57 N = 70 TGNB youth Full cohort: mean (SD) age at baseline was GnRH analogs (full cohort), N = 29 Participant data was collected BDI (n = 41), mean (SD)
13.65 years (1.85); mean (SD) age at the also started CSH before and after starting GnRH
Eligibility: adolescents with There was a significant decrease in depressive symptoms in full cohort from 8.31
start of GnRH analogs was 14.75 years analogs
gender dysphoria eligible for (7.12), at baseline to 4.95 (6.72) at follow-up, P = .004
(1.92); mean (SD) age at the start of CSH
medical intervention BDI used to assess depressive o Full cohort: T0- 8.31 (7.12), T1- 4.95 (6.72)
was 16.64 years (1.90); mean (SD) time
Sampling method: first 70 symptoms
between the start of GnRH analogs and o Female at birth: T0- 10.34 (8.24), T1- 6.09 (7.93)
patients consecutively enrolled CSH was 1.88 years (1.05); mean (SD) TPI administered to assess the
o Male at birth: T0- 5.71 (4.31), T1- 3.50 (4.58)
from 2000 to 2008 parental full-scale IQ was 98.2 (15.0); for tendency to respond with
parental marital status, 62.9% had both anger to a threatening or TPI (n = 41), mean (SD)
Subset: N = 70 TGNB youth,
including N-37 natal females parents, 37.1% was other; for parents' annoying situation. (Scale
There was a nonsignificant decrease in anger from 18.29 (5.54), at baseline to
and N = 33 natal males education status, 10.6% had high, 66.7% ranges from 1-4)
17.88 (5.24) at follow-up, P = NS
had medium, 22.7% had low; for sexual STAI administered to assess the o Full cohort: T0- 18.29 (5.54), T1- 17.88 (5.24)
attraction, 88.6% were attracted to their tendency to respond with
own natal sex, 8.6% were attracted to both anxiety to a threatening or o Female at birth: T0- 6.43 (2.78), T1- 6.39 (2.59)
sexes; 2.8% were attracted to other annoying situation. (Scale o Male at birth: T0- 5.22 (2.76), T1- 5.00 (3.07)
Natal male (47%): mean (SD) age at ranges from 1-4) STAI (n = 41), mean (SD)
baseline was 13.14 years (1.55); mean (SD)
age at the start of GnRH analogs was 14.25 There was a nonsignificant decrease in anxiety from 39.43 (10.07), at baseline to
years (1.79); mean (SD) age at the start of 37.95 (9.38) at follow-up, P = NS
CSH was 16.24 years (1.21); mean (SD) time o Full cohort: T0- 39.43 (10.07), T1- 37.95 (9.38)
between the start of GnRH analogs and o Female at birth: T0- 7.00 (2.36), T1- 6.17 (2.62)
CSH was 1.99 years (0.94); mean (SD)
parental full-scale IQ was 97.1 (13.3); for o Male at birth: T0- 4.33 (2.68), T1- 4.39 (2.64)
parental marital status, 69.7% had both
parents, 30.3% had other; for parents'
education status, 3.3% had high, 76.7% had

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
812

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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
medium, 20.0% had low; for sexual
attraction, 87.9% were attracted to their
own natal sex, 6.1% were attracted to both
sexes; 6.0% were attracted to other
Natal female (53%): mean (SD) age at
baseline was 14.10 years (1.99); mean (SD)
age at the start of GnRH analogs was 15.21
years (1.95); mean (SD) age at the start of
CSH was 16.99 years (1.07); mean (SD) time
between the start of GnRH analogs and
CSH was 1.78 years (1.16); mean (SD)
parental full-scale IQ was 99.2 (15.2); for
parental marital status, 56.8% had both
parents, 43.2% had other; for parents'
education status, 16.7% had high, 58.3%
had medium, 25.0% had low; for sexual
attraction, 89.2% were attracted to their
own natal sex, 10.8% were attracted to
both sexes; 0% were attracted to other
de Vries (2014)79 N = 55 TGNB youth Full cohort: the mean age (SD) at assessment CSH and GRS Participants were assessed 3 BDI (depression) (n = 32), mean (SD)
pretreatment was 13.6 (1.9) (range: 11.1– times: pre-treatment (T0, at o Scores showed a nonsignificant decrease from 7.89 (7.52) at intake to 5.44
Eligibility: adolescents with GD
17.0), the mean age (SD) at the start of GnRH intake), during treatment (T1, at (8.40) at post treatment, P = NS
prescribed puberty suppression
analogs was 14.8 (1.8) (range: 11.5–18.5), the initiation of CSH), and post
between 2004 and 2011 o T0- 7.89 (7.52), T1- 4.10 (6.17), T2- 5.44 (8.40)
mean age (SD) at the start of CSH was 16.7 treatment (T2, 1 year after GRS)
Sampling method: first 70, and (1.1) (range: 13.9–19.0), the mean age (SD) at o Linear effect (time) P = .23, Significant quadratic effect (time) P = .04
then filtered to those who were the start of GRS was 19.2 (0.9) (range: 18.0– BDI used to assess depressive
symptoms TPI (Anger) (n = 32), mean (SD)
prescribed puberty suppression 21.3), the mean age (SD) at assessment post
and continued with GRS treatment was 20.7 (1.0) (range: 19.5–22.8); TPI administered to assess the o Scores showed a nonsignificant decrease from 17.55 (5.72) at intake to 16.01
between 2004 and 2011 the mean full scale intelligence (SD) was 99.0 tendency to respond with (5.28) at post treatment, P = .20
Subset: N = 55 TGNB (14.3) (range: 70–128) anger to a threatening or o T0- 17.55 (5.72), T1- 17.22 (5.61), T2- 16.01 (5.28)
adolescents, with n = 22 MTF annoying situation. (Scale
o linear effect (time) P = NS, quadratic effect (time) P = NS
and n = 33 FTM) ranges from 1-4)
STAI (Anxiety) (n = 32), mean (SD)
STAI administered to assess the
tendency to respond with o Scores showed a nonsignificant decrease from 39.57 (10.53) at intake to 37.61
anxiety to a threatening or (10.39) at post treatment, P = NS
annoying situation. (Scale o T0- 39.57 (10.53), T1- 37.52 (9.87), T2- 37.61 (10.39)
ranges from 1-4) o linear effect (time) P = NS, quadratic effect (time) P = NS
General linear models examined  effect (time) P = NS
the repeated measures with an
analysis of variance-based model. Externalizing T-Score, mean (SD)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
A linear effect signifies an overall o Scores showed a significant decrease from 57.85 (13.73) at intake to 47.85
change across T0 to T2. Quadratic (8.59) at post treatment, P < .001
effect signifies change was not o T0- 57.85 (13.73), T1- 53.85 (12.77), T2- 47.85 (8.59)
continuous.
o Significant linear effect (time) P < .001, quadratic effect (time) P = NS
N = 22 MTF TGNB youth MTF: for ages, the mean age (SD) at CSH and GRS BDI (depression) MTF (n = 12), mean (SD)
assessment pretreatment was 13.6 (1.8), the o Scores showed a nonsignificant decrease from 4.73 (4.20) at intake to 3.38
Eligibility: adolescents with GD
mean age (SD) at the start of GnRH analogs (4.40) at post treatment, P = NS.
prescribed puberty suppression
was 14.8 (2.0), the mean age (SD) at the start
between 2004 and 2011 o T0- 4.73 (4.20), T1- 2.25 (3.54), T2-3.38 (4.40)
of CSH was 16.5 (1.3), the mean age (SD) at the
Sampling method: first 70, and start of GRS was 19.6 (0.9), the mean age (SD) TPI (Anger) MTF (n = 12), mean (SD)
then filtered to those who were at assessment post treatment was 21.0 (1.1);
o Scores showed a nonsignificant decrease from 14.17 (3.01) at intake to 5.58
prescribed puberty suppression the mean full scale intelligence (SD) was 97.8
(3.92) at post treatment, P = NS
and continued with GRS (14.2)
between 2004 and 2011 o T0- 14.17 (3.01), T1- 14.00 (3.36), T2- 5.58 (3.92)
STAI (Anxiety) MTF (n = 12), mean (SD)
o Scores showed a nonsignificant decrease from 31.87 (7.42), at intake to 35.83
(10.22) at post treatment, P = NS
o T0- 31.87 (7.42), T1- 31.71 (8.36), T2- 35.83 (10.22)
Externalizing T-Score, mean (SD)
o Scores showed a nonsignificant decrease from 46.00 (11.58), at intake to 50.24
(11.18)]at post treatment, P = NS
o T0- 46.00 (11.58), T1- 44.71 (9.53), T2- 50.24 (11.18)
N = 33 FTM TGNB youth FTM: for ages, the mean age (SD) at CSH and GRS BDI (depression) FTM (n = 17), mean (SD)
assessment pretreatment was 13.7 (2.0), the o Scores showed a nonsignificant decrease from 10.09 (8.34), at intake to 36.95
Eligibility: adolescents with GD
mean age (SD) at the start of GnRH analogs (9.83) at post treatment, P = NS
prescribed puberty suppression
was 14.9 (1.9), the mean age (SD) at the start
between 2004 and 2011 o T0- 10.09 (8.34), T1- 5.05 (7.08), T2- 6.95 (9.83)
of CSH was 16.8 (1.0), the mean age (SD) at the
Sampling method: first 70, and start of GRS was 19.0 (0.8), the mean age (SD) TPI (Anger) FTM (n = 17), mean (SD)
then filtered to those who were at assessment post treatment was 20.5 (0.8);
o Scores showed a significant decrease from 19.55 (5.96), at intake to 16.56
prescribed puberty suppression the mean full scale intelligence (SD) was 100.4
(6.06) at post treatment with a P value of 0.05
and continued with GRS (14.3)
between 2004 and 2011 o T0-19.55 (5.96), T1- 19.25 (5.69), T2- 16.56 (6.06)
STAI (Anxiety) FTM (n = 17), mean (SD)
o Scores showed a nonsignificant decrease from 44.41 (9.06), at intake to 39.20
(10.53) at post treatment, P = NS
o T0- 44.41 (9.06), T1- 41.59 (9.03), T2- 39.20 (10.53)

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Kaltiala (2020)138 N = 52 Mean age of 18.1 (1.1) years at diagnosis, CSH Participants were assessed at Need for Psychiatric Treatment
range 15.2-19.9 years an initial gender identity
Finland Eligibility Criteria: The study There was a nonsignificant decline in the proportion of participants needing
assessment appointment
comprises a retrospective chart overall psychiatric treatment from initial assessment to 12 month follow up from
before starting hormone
review of adolescents referred 50% (26/52) to 46% (24/51), P = NS
therapy, and then about a year
to one of the two gender o Of those not needing psychiatric treatment before or during the assessment
after treatment (called the
identity service facilities (26/52), 73% (19/26) did not need any during the real-life phase but in 27%
"real-life phase")
between 2011-2017, before age (7/26), a need had emerged. Of those who had needed (25/51) psychiatric
18, who had been diagnosed Need for psychiatric treatment
treatment during or before the assessment, 68% (17/25) still needed it during
with transsexualism and data for adolescent
the follow-up but 32% (8/25) did not. (P = .004 using cross tabulations with chi
proceeded to cross-sex development were collected
square statistics)
hormonal treatments and who retrospectivity from charts
had completed a follow-up of with specific criteria There was a significant decline in the proportion of participants needing
approximately a year after treatment due to depression from the initial assessment to the 12 month follow
starting on cross-sex hormones up from 54% (28/52) to 15% (8/52), P < .001
(real-life phase). There was a significant decline in the proportion of participants needing
Sampling Method: Between treatment due to anxiety from the initial assessment to the 12 month follow up
2011 and 2017, 57 adolescents from 48% (25/52) to 15% (8/52), P < .001
at the gender identity facility There was a significant decline in the proportion of participants needing
had been diagnosed with F64.0, treatment due to suicidality/self-harm from the initial assessment to the 12
transsexualism, and had been month follow up from 35% (18/52) to 4% (2/52), P = .001
offered an opportunity to start
There was a nonsignificant decline in the proportion of participants needing
hormonal sex reassignment.
treatment due to conduct problems/antisocial behavior from the initial
One of them did not want any
assessment to the 12 month follow up from 14% (7/52) to 6% (3/52), P = NS
treatment, two withdrew and
two had started hormonal There was a nonsignificant increase in the proportion of participants needing
treatments but had not yet treatment due to psychotic symptoms/psychosis from the initial assessment to
completed the real-life phase at the 12 month follow up from 2% (1/52) to 4% (2/52), P = NS
the end of 2017. Thus, 52 There was a nonsignificant decrease in the proportion of participants needing
patients were included in the treatment due to substance abuse from the initial assessment to the 12 month
study. follow up from 4% (2/52) to 2% (1/52), P = NS
Subset definition: N = 52 There was a nonsignificant decrease in the proportion of participants needing
patients in study. N = 11 birth treatment due to autism from the initial assessment to the 12 month follow up
assigned males. N = 41 birth from 12% (6/52) to 6% (3/52), P = NS
assigned females
There was a nonsignificant decrease in the proportion of participants needing
treatment due to ADHD from the initial assessment to the 12 month follow up
from 10% (5/52) to 2% (1/52), P = NS
There was no significant change in the proportion of participants needing
treatment due to eating disorders from the initial assessment to the 12 month
follow up staying at 2% (1/52), P = NS

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Kuper (2020)141 N = 148 TGNB adolescents Full cohort (N = 148): Most participants are Patients were receiving: Participants were assessed at SCARED: Mean (SD)
white N = 137 (95%); at the initial assessment, initial visit and at a yearly
At a multidisciplinary Eligibility: Youth who received puberty suppression only From baseline to the follow-up period, there were significant in generalized
patients ranged in age from 9 to 18 years assessment visit (range 11-18
program in gender-affirming hormone (n = 25, 17%), [9.7(5.2) to 8.7 (5.1)], separation [4.0(3.4) to 3.3 (2.7)], and school-related
(mean 15.4; SD 2.0); Participants who started months) The mean length of time
Texas, US initial therapy at the clinic [2.6(2.2) to 2.0(2.1)] anxiety symptoms, P < .05. Cohen's d effect sizes were small
puberty suppression only did so at a mean age masculinizing or femininizing receiving treatment before follow-
assessments occurred for change in SCARED total scores (0.27).
Sampling method: Before of 13.7 years (range 9.8–14.9; SD 1.5), and therapy only (n = 93, 63%), or up was 10.9 months (range 11–18;
between August 2014 QIDS: Mean (SD)
initiating care, participants and participants started feminizing or masculinizing both (n = 30, 20%) SD 3.3) mean (SD) number of
and March 2018
their families participated in an hormone therapy at a mean age of 16.2 years months between initial Within the full sample, a significant decrease in total anxiety symptoms was
initial assessment with the (range 13.2–18.6; SD 1.2) assessment and reassessments observed from 32.4 (16.3) at baseline to 28.6 (16.1) at follow-up with a change of
program's psychologist, was 14.9 (2.1) 3.8(CI 1.05 to 6.70), and a P < .001
psychiatrist, and/or clinical
therapist after parents Anxiety and depressive Within the full sample, a significant decrease in self-reported depressive
completed a phone intake symptoms assessed using symptoms was observed from 9.4 (5.3) at baseline to 7.3 (4.6) at follow-up with a
survey and provided a referral SCARED and QIDS change of 2.1(CI 1.24 to 2.97), P < .001
letter from a licensed therapist Suicidal ideation, suicide o A significant change was found in self-reported depressive symptom categories
or counselor documenting the attempts, and NSSI assessed by (P < .001) but not in clinician-reported categories. Cohen's d effect sizes were
presence of gender dysphoria. clinicians using QIDS small to moderate for change in QIDS self-report scores (0.44).
Approximately 1 year after this Body dissatisfaction was Suicidal ideation, suicide attempts, and NSSI n (%)
initial assessment, all patients measured using the BIS
were asked to participate in a 105 (81) participants had a lifetime history of suicide ideation. 1 month before
yearly reassessment visit. assessment, 33 (25) experienced this and in the follow-up period, 51 (38)
Participants were experienced it.
readministered self-report o Of those who experienced suicidal ideation during the follow-up period, 94%
measures and clinicians again had a lifetime history.
completed a report of
depressive symptoms and 20 (15) participants had a lifetime history of a suicide attempt. Within 3 months
documented information about of initial assessment, there were 3(2) suicide attempts, and there were 6(5)
suicidal ideation, suicide attempts during the follow-up period.
attempts, NSSI, and mental o Of those who had a suicide attempt during the follow-up period, 67% had a
health treatment. lifetime history
Subset definition: Assigned 68 (52) participants had a lifetime history of NSSI. Within 3 months of initial
male at birth n = 55 (37%) and assessment, 13 (10) participants had a NSSI and 23 (17) participants had a NSSI
Assigned female at birth n = 94 during the follow-up period.
(63%) o Of those who had a NSSI during the follow-up period, 87% had a lifetime
history.
Lavender (2023)142 N = 38 TGNB adolescents Full cohort (N = 38): Most of participants GnRH analogs and CSH Baseline was assessed at point Self-harm and suicidality:
are white (N = 29); mean (SD) age at first of referral to endocrinology. o Of the young people and their caregivers who completed the statements
Eligibility: younger than 15
endocrine clinic was 13.47 (0.94); mean Assessed after approximately 1 regarding self-harm behaviors and suicidality on the YSR or CBCL at baseline, 1
UK between 2014 years and at Tanner stage 2+,
(SD) age at starting GnRH analogs was year on GnRH analogs, and year after GnRH analogs, and 1 year after CSH (n = 11), improvements were
and 2018 referred by the GIDS for GnRH
14.01 (0.81); mean (SD) age at starting CSH
analog treatment and CSH

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
treatment at 16 years (and with was 16.10 (0.29); mean (SD) time between then after approximately 1 noted in self-harm and suicidality statements from baseline to GnRH analogs,
a minimum of around 1 year on first endocrine clinic and GnRH analogs was year on CSH and further improvements with CSH.
GnRH analogs) 0.57 (0.38); mean (SD) time between start General Linear Models o There was a reduction in percentage of patients answering "very true" to
Sampling method: Young GnRH analogs and CSH was 2.09 (0.85) examined the repeated suicidality and self-harm questions from YSR: 9% at baseline to 0% at 1 year
people referred to Assigned female young people group measures with an analysis of after GnRH analogs and 0% 1 year after CSH and from CBCL: 9% at baseline to
endocrinology were sent (n = 28): Most are white (N = 22); mean variance-based model, 0% at 1 year after GnRH analogs and 0% 1 year after CSH
questionnaires at baseline, after (SD) age at first endocrine clinic was 13.74 incorporating continuous and o There was a reduction in percentage of patients answering "somewhat or
1 year on GnRH analogs, and (0.68); mean (SD) age at starting GnRH categorical predictors, and sometimes true" to suicidality and self-harm questions from YSR: 55% at
after 1 year on CSH treatment. analogs was 14.19 (0.66); mean (SD) age at correcting for the unbalanced baseline to 27% at 1 year after GnRH analogs and 9% 1 year after CSH and from
Before August 2020, starting CSH was 16.06 (0.22); mean (SD) cell sizes. A linear effect CBCL: 36% at baseline to 18% at 1 year after GnRH analogs and 0% 1 year after
questionnaires were sent by time between first endocrine clinic and signifies an overall change CSH.
post to the young people and GnRH analogs was 0.55 (0.36); mean (SD) across T0 to T2. A quadratic
o There was an increase in percentage of patients answering "not true" to
their caregivers, including a time between start GnRH analogs and CSH effect signifies that the change
suicidality and self-harm questions from YSR:36% at baseline to 73% at 1 year
cover letter detailing the was 2.03 (0.79) was not continuous with time
after GnRH analogs and 91% 1 year after CSH and from CBCL: 55% at baseline
purpose of questionnaires and Assigned male young people group as within-subject factor.
to 82% at 1 year after GnRH analogs and 100% 1 year after CSH.
the right to opt out. From (n = 10): Most are white (N = 7); mean (SD) Self-harm and suicidality were
August 2020, questionnaire SRS-2: Mean (95%CI)
age at first endocrine clinic was 12.74 assessed using questions on
administration moved to an (1.20); mean (SD) age at starting GnRH the YSR: "I think about killing o SRS-2 T-scores all lay within the "normal range" and showed non-significant
online platform with email links analogs was 13.51 (0.99); mean (SD) age at myself" and "I deliberately try changes from baseline to 1 year on CSH.
sent to young people and starting CSH was 16.25 (0.42); mean (SD) to hurt or kill myself." o A significant increase in social motivation T-scores was noted from 9.39 (6.02-
caregivers (Qualtrics, Provo, time between first endocrine clinic and Autistic traits and social 12.75) baseline to 12.56 (8.95-16.18) at 1 year on CSH, P = .04.
UT). GnRH analogs was 0.57 (0.38); mean (SD) motivation were measured
Subset definition: Assigned time between start GnRH analogs and CSH using the SRS2
female at birth n = 28 and was 2.10 (0.86)
Assigned male at birth n = 10
López de Lara (2020)62 N=23 TGNB youth Transgender adolescents: CSH (oral estradiol, intramuscular Participants were assessed at Anxiety, mean (SD)
testosterone) baseline and 1 year after CSHT o STAI-S: There was a significant decrease in state anxiety scores from 33.3 (9.1)
Spain: Pediatric Eligibility: adolescents aged 14 mean age: 16 years (range 14-18)
at baseline to 16.8 (8.1) at one year, P < 0.001
endocrinology clinic to 18 yo, absence of psychiatric assigned sex at birth: Anxiety: assessed using STAI-S
comorbidity, Tanner state 2 or and STAI-T o STAI-T: There was a significant decrease in trait anxiety scores from 33 (7.2) at
o 69% female
higher, understanding of risks baseline to 18.5 (8.4) at one year., P < 0.001
o 31% male Depression: assessed using BDI-
and benefits of CSH II Depression, mean (SD)
91% Caucasian and Spanish descent
Sampling method: requested o BDI-II: There was a significant decrease in depression scores from 19.3 (5.5) at
52% parents with a university education baseline to 9.7 (3.9) at one year, P < 0.001
volunteers
30.4% had previously used mental health There was an increase of normal BDI-II scores (0-9) from 0% at baseline to 69.5%
services at one year, a decrease of milk scores (10-18) from 60.8% to 26.0%, decrease on
sexual orientation moderate scores (19-29) from 34.7% to 4.3% and a decrease in sever scores (>30)
o 65% heterosexual, from 4.3% to 0%.
o 13% homosexual
o 21% bisexual

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
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Table I.L.1. Longitudinal pre-post studies evaluating mental health outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Tordoff (2022)96 N = 104 TGNB subjects The final sample included 104 youths ages 13 PB, CSH, or both Participants were assessed at Depression:
to 20 years (mean [SD] age, 15.8 [1.6] years). baseline, 3 6 and 12 months o There were no statistically significant temporal trends in the bivariate model or
Eligibility: TGNB adolescents
N = 84 (80.8%), 84 (80.8%), and 65 (62.5%) model 1. However, among all participants, odds of moderate to severe
Urban and young adults seeking Depression: assessed using
completed surveys at 3, 6, and 12 months, depression increased at 3 months of follow-up relative to baseline (aOR, 2.12;
multidisciplinary gender-affirming care PHQ-9; dichotomized PHQ-9
respectively. 63 transmasculine youths 95%CI, 0.98-4.60), which was not a significant increase (P = NS), and returned
gender clinic from scores into measures of
Sampling method: After a (60.6%), 27 transfeminine youths (26.0%), 10
August 2017 to June moderate or severe depression to baseline levels at months 6 and 12 prior to adjusting for receipt of PBs or
referral is placed or a patient nonbinary or gender fluid youths (9.6%), and 4
2018 (ie, scores ≥ 10) CSHs.
self-refers, new patients, their youths who responded "I don't know" or did
caregivers, or patients with their not respond to the gender identity question on Generalized anxiety: assessed Generalized anxiety:
caregivers are scheduled for a 1- all completed questionnaires (3.8%). using GAD-7; dichotomized o There were no statistically significant temporal trends in the bivariate model or
hour phone intake with a care GAD-7 scores into measures of model 1. Among all participants, the odds of moderate to severe anxiety
navigator who is a licensed moderate or severe anxiety (ie, increased at 3 months of follow-up relative to baseline (aOR, 1.50; 95%CI, 0.71-
clinical social worker. Patients scores ≥ 10) 3.15), which was not a significant increase (P = NS), and decreased at months 6
are then scheduled for an Suicidality: assessed using and 12.
appointment at the clinic with a PHQ-9 question 9 Suicidality:
medical provider. All patients
who completed the phone o There were no statistically significant temporal trends in the bivariate model or
intake and in-person model 1. The odds of having any self-harm or suicidal thoughts increased at 6
appointment between August months of follow-up relative to baseline (aOR, 1.22; 95%CI, 0.63-2.36), which
2017 and June 2018 were was not a significant increase (P = NS), and decreased at months 12.
recruited for this study.
Participants completed baseline
surveys within 24 hours of their
first appointment and were
invited to complete follow-up
surveys at 3, 6, and 12 months.

See Appendix I.H for a complete description of referenced mental health assessment tools.
Table abbreviations: ASQ, Ask Suicide-Screening Questions; BDI-II, Beck Depression Inventory; CESD-R, Center for Epidemiologic Studies Depression Scale; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CI, confidence interval; FTM, assigned female
at birth transitioning to male; GAD-7, General Anxiety Disorder-7th edition; GAH, gender-affirming hormone; GD, gender dysphoria; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; ITS, interrupted time series; MTF,
assigned male at birth transitioning to female; N/A, not applicable; N/R, not reported; NSSI, non-suicidal self-injury; PB, puberty blockers; PHQ-9, Patient Health Questionnaire Modified for Teens; QID, quick inventory of depressive symptoms; RCMAS2, Revised
Children's Manifest Anxiety Scale, Second Edition; SCARED, Screen for Child Anxiety Related Emotional Disorder; SD, standard deviation; SRS-2, Social Responsiveness Scale-2nd edition; STAI, Spielberger's Trait Anxiety Scale; TPI, Spielberger's Trait Anger Scale;
TGNB, transgender, non-binary, or gender-diverse
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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Achille (2021)55 TGNB Adolescents (N = 50) Full cohort: Mean (SD) age was 16.2 (2.2); Up to 12-months of endocrine Outcomes were measured Quality of Life:
64% were depressed in the prior year; 10% treatment including: upon referral to the pediatric
A US NY) Eligibility: Participants were QLES-Q-SF: Scores improved but did not reach statistical significance (P = NS)
reported suicidality; 90% were seeing a endocrine department for GD
pediatric endocrine recruited at the clinic, and a vast puberty blockers (N = 23, 46%), [Extracted scores were 61.3% at baseline and 72.0% at 12 months]
therapist; 34% were on psychiatric and after approximately 12
gender dysphoria clinic majority consented/assented. CSHT (N = 35, 70%),
medications months of treatment.
This study was limited to the both (N = 11, 22%), or
subset of all patients who MTF: Mean (SD) age was 15.5 (1.6); 70.6% Quality of life measured using:
completed 3 rounds of were depressed in the prior year; 11.8% neither (N = 3, 6%)
o QLES-Q-SF
questionnaires at 6-month reported suicidality; 94.1% were seeing a
intervals. Patients were therapist; 29.4% were on psychiatric
excluded if they had sex medications
chromosome abnormalities or FTM: Mean (SD) age was 16.6 (2.5); 60.6%
disorders of sexual were depressed in the prior year; 9.1%
differentiation. reported suicidality; 87.9% were seeing a
Sampling method: Patients therapist; 36.4% were on psychiatric
must have completed 3 waves medications
of questionnaires at 6-month
intervals, for a total of
approximately 12 months of
observation. A "vast majority"
of 116 patients gave
consent/assent.
Subset definition: N = 50 TGNB
adolescents, including MTF
(N = 17) and FTM (N = 33)
adolescents.
Allen (2019)56 N = 47 TGNB adolescents The age of the participants ranged from CSH treatment Psychological well-being was Psychological well-being:
13.73 to 19.04 years (mean = 16.59, measured using the GWBS of
Eligibility: Adolescents and Participants showed an increase in estimated adjusted mean (standard error) of
SD = 1.19). the Pediatric Quality of Life
young adults (age range 13–20 GWBS scores from 61.7 (2.43) at T0 to 70.23 (2.15) at T1.
The range of treatment length was 113- Inventory
years) who received services for
The main effect was significant, meaning GWBS were significantly higher at T1
GD at the clinic. Participants 1016 days (mean = 349, SD = 193).
after CSH, F(1, 44) = 11.39, P < .002, partial η2 = .21, demonstrating a large effect
were included if they had For most of the sample (90%), the duration size.
pretest and final assessment of treatment was at, or under, 600 days.
data points and were treated Duration of treatment was not significantly related to participants' general well-
with CSH for at least 3 months Assigned female at birth was n = 33 (70.2%) being scores, F(1, 44) = .37, P = .54, partial η2 = .01, showing a small effect size.
and assigned male at birth was n = 14
Sampling method: A total of 47 (29.8).
eligible participants had pretest
and final assessment data. The The majority of participants were white
pretest for 23 participants n = 39 (83%).
occurred at their first contact
a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
819

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
with the clinic (the other Of the 47 participants, n = 8 were
participants' pretest assessment administered GnRH analogs prior to
was completed at a subsequent beginning CSH (GnRH analogs + CSH
visits to clinic but prior to subgroup) and n = 39 were not received
starting CSH). Thirteen of the GnRH analogs prior to being administered
participants first presented to CSH (CSH-only subgroup).
our clinic in 2015; 19 in 2016; 14
in 2017; and one in 2018.
Patients are administered
questionnaires and screeners at
the beginning of their clinic visit,
either at the time of the
diagnostic evaluation or during
a follow-up appointment with
the multidisciplinary team.
Responses are reviewed by the
mental health professional prior
to meeting with the patient.
Arnoldussen (2022)135 Population: N = 70 adolescents Gender, N (%) PS, CSH and gender-affirming The SPPA was used to Multilevel modeling (adjusted for gender, age at pretreatment and post treatment
o Trans men: 49 (70.0%) surgery examines self-perception on assessment, use of puberty suppression at pretreatment assessment, full-scale IQ
Eligibility: Adolescents who
seven different domains: and living situation) revealed that the domains of physical appearance (P < .001)
were referred between 2000 o Trans women: 21 (30.0%) Scholastic competence, social and global self-worth (P < 0.001) improved significantly over time. For the
and 2013, who met the criteria
Age at assessment in years, M (SD) acceptance, athletic domains of scholastic competence, social acceptance, athletic competence, and
for a "Gender Identity Dis-
o Pre-irreversible gender-affirming competence, physical close friendship, no significant change over time was found (no significant
order" diagnosis according to
treatment (pretreatment assessment): appearance, behavioral increase nor decrease, all P > .05). Only for the domain of behavioral conduct, an
the DSM-IV-TR27 (because that
14.65 (2.08), range 11.23–19.74 conduct, close friendship, and interaction effect for gender was found; a significant improvement was only
Netherlands was the DSM used during these
global self-worth at pre- observed for trans men (P = .003).
years), who received puberty o Post-irreversible gender-affirming treatment assessment, before Self-Perception Descriptive Scores for total sample, mean (95% CI)
suppression and subsequent treatment (post treatment assessment): any CSHT, and at least 6
gender-affirming hormone 20.70 (1.49), range 18.97–26.28 o Scholastic competence (N = 70),
months after gender-affirming
treatment, and were at least 6
Age at gender-affirming surgery in years: surgeries.  Pre-irreversible gender-affirming treatment: 14.26 (13.54–14.98)
months post gender- affirming
19.23 (1.27), range 17.98–24.75  Post- irreversible gender-affirming treatment: 14.96 (14.22–15.69)
surgery could be included in the
larger evaluation study. There Post-surgical years at post treatment  Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
were no exclusion criteria. assessment: 1.47 (0.67), range 0.69–4.79 ±SE) Without and With Adjustment for Possible Confounders:
Adolescents were included in Living situation of the adolescent at the  Intercept: Unadjusted 13.56 (0.64), P < .05; Adjusted 7.14 (5.26), P = NS
the current study if their pretreatment assessment, N(%)
pretreatment data on self-  Time: Unadjusted 0.70 (0.38), P = NS; Adjusted 0.71 (0.39), P = NS
o Living with both biological parents: 43
perception were available. o Social acceptance (N = 70), P = NS
(61.4%)
Sampling Method: Between  Pre-irreversible gender-affirming treatment: 14.81 (14.05–15.58)
o Other: 27 (38.6%)
2000 and 2013, 513 adolescents

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
820

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
were referred consecutively to Full-scale IQ, M (SD): 99.63 (14.23), range  Post- irreversible gender-affirming treatment: 15.23 (14.48–15.98)
the CEGD. Of these 513 72–135  Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
adolescents, a total of 179 were ±SE) Without and With Adjustment for Possible Confounders:
eligible for the larger evaluation
study, among whom 107  Intercept: Unadjusted 14.40 (0.76), P < .05; Adjusted 22.34 (5.10), P < .05
participated. Of the 107 people  Time: Unadjusted 0.41 (0.46), P = NS; Adjusted 0.43 (0.48), P = NS
who participated in the larger o Athletic competence (N = 69), P = NS
evaluation study, pretreatment
 Pre-irreversible gender-affirming treatment: 12.86 (11.87–13.84)
data on self-perception were
available for 70 of them and  Post- irreversible gender-affirming treatment: 12.54 (11.62–13.46)
they were therefore included in  Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
the current study. As 70 ±SE) Without and With Adjustment for Possible Confounders:
individuals of the 179 eligible
 Intercept: Unadjusted 13.16 (0.73), P < .05; Adjusted 12.98 (7.54), P = NS
were eventually included in this
study, the participation rate was  Time: Unadjusted -0.31 (0.39), P = NS; Adjusted -0.25 (0.40), P = NS
39.1%. o Physical appearance (N = 69), P < .001
Subset definition: n = 49 trans  Pre-irreversible gender-affirming treatment: 10.16 (9.37–10.95)
men and n = 21 trans women
 Post- irreversible gender-affirming treatment: 12.81 (11.92–13.70)
 Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
±SE) Without and With Adjustment for Possible Confounders:
 Intercept: Unadjusted 7.48 (0.72), P < .05; Adjusted 21.57 (5.20), P < .05
 Time: Unadjusted 2.66 (0.42), P < .05; Adjusted 2.65 (0.42), P < .05
o Behavioral conduct (N = 70), P = NS
 Pre-irreversible gender-affirming treatment: 15.81 (15.17–16.46)
 Post- irreversible gender-affirming treatment: 16.83 (16.23–17.43)
o Close friendship (N = 70), P = NS
 Pre-irreversible gender-affirming treatment: 16.87 (16.18–17.57)
 Post- irreversible gender-affirming treatment: 17.30 (16.57–18.03)
 Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
±SE) Without and With Adjustment for Possible Confounders:
 Intercept: Unadjusted 16.44 (0.66), P < .05; Adjusted 21.39 (4.97), P < .05
 Time: Unadjusted 0.43 (0.40), P = NS; Adjusted 0.49 (0.41), P = NS
o Global self-worth (N = 68), P < .001
 Pre-irreversible gender-affirming treatment: 12.01 (11.13–12.90)
 Post- irreversible gender-affirming treatment: 14.19 (13.32–15.06)

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
821

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
 Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
±SE) Without and With Adjustment for Possible Confounders:
 Intercept: Unadjusted 9.71 (0.87), P < .05; Adjusted 14.24 (5.53), P < .05
 Time: Unadjusted 2.23 (0.54), P < .05; Adjusted 2.27 (0.55), P = NS
Self-perception descriptive scores for trans women, mean (95% CI)
o Scholastic competence (N = 21), P = NS
 Pre-irreversible gender-affirming treatment: 14.29 (13.06–15.51)
 Post- irreversible gender-affirming treatment: 15.95 (14.61–17.29)
o Social acceptance (N = 21), P = NS
 Pre-irreversible gender-affirming treatment: 14.91 (13.66–16.15)
 Post- irreversible gender-affirming treatment: 15.71 (14.64–16.79)
o Athletic competence (N = 21), P = NS
 Pre-irreversible gender-affirming treatment: 11.91 (10.32–13.49)
 Post- irreversible gender-affirming treatment: 11.19 (9.41–12.97)
o Physical appearance (N = 21), P < .05
 Pre-irreversible gender-affirming treatment: 12.29 (10.65–13.92)
 Post- irreversible gender-affirming treatment: 14.95 (13.48–16.42)
o Behavioral conduct (N = 21), P = NS
 Pre-irreversible gender-affirming treatment: 16.86 (16.04–17.68)
 Post- irreversible gender-affirming treatment: 16.71 (15.71–17.72)
 Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
±SE) Without and With Adjustment for Possible Confounders:
 Intercept: Unadjusted 17.00 (0.85), P < .05; Adjusted 17.51 (7.99), P < .05
 Time: Unadjusted -0.14 (0.52), P = NS; Adjusted -0.05 (0.57), P = NS
o Close friendship (N = 21), P = NS
 Pre-irreversible gender-affirming treatment: 17.48 (16.46–18.49)
 Post- irreversible gender-affirming treatment: 17.67 (16.07–19.27)
o Global self-worth (N = 21), P < .05
 Pre-irreversible gender-affirming treatment: 13.57 (11.63–15.51)
 Post- irreversible gender-affirming treatment: 15.33 (13.99–16.68)
Self-Perception Descriptive Scores for Trans men, mean (95% CI)
o Scholastic competence (N = 49), P = NS

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
822

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
 Pre-irreversible gender-affirming treatment: 14.25 (13.33–15.16)
 Post- irreversible gender-affirming treatment: 14.53 (13.65–15.41)
o Social acceptance (N = 49), P = NS
 Pre-irreversible gender-affirming treatment: 14.78 (13.80–15.75)
 Post- irreversible gender-affirming treatment: 15.02 (14.03–16.01
o Athletic competence (N = 48), P = NS
 Pre-irreversible gender-affirming treatment: 13.27 (12.01–14.53)
 Post- irreversible gender-affirming treatment: 13.13 (12.06–14.19)
o Physical appearance (N = 48), P < .05
 Pre-irreversible gender-affirming treatment: 9.23 (8.44–10.02)
 Post- irreversible gender-affirming treatment: 11.88 (10.85–12.90
o Behavioral conduct (N = 49), P = .003
 Pre-irreversible gender-affirming treatment: 15.37 (14.53–16.20)
 Post- irreversible gender-affirming treatment: 16.88 (16.11–17.64)
 Estimates of Multilevel Model Fixed Effect and Random Effects Variances (
±SE) Without and With Adjustment for Possible Confounders:
 Intercept: Unadjusted 13.86 (0.80), P < .05; Adjusted 6.16 (5.06), P = NS
 Time: Unadjusted 1.51 (0.49), P < .05; Adjusted 1.51 (0.49), P < .05
o Close friendship (N = 49), P = NS
 Pre-irreversible gender-affirming treatment: 16.61 (15.71–17.51)
 Post- irreversible gender-affirming treatment: 17.14 (16.32–17.97)
o Global self-worth (N = 47), P < .05
 Pre-irreversible gender-affirming treatment: 11.32 (10.39–12.24)
 Post- irreversible gender-affirming treatment: 13.68 (12.58–14.78)
Beckler-Hebly (2021)72 Cohort 1: GnRH analogs (n = 11) Outcomes were compared Cohort 1: GnRH analogs (n = 11)
from intake appointment and
N = 11 TGNB adolescents GnRH analogs (n = 11): for mean (SD) age, GnRH analogs then at follow up (6 months Psychological functioning
baseline was 15.56 years (1.85), follow-up age after the first referral and up to
Eligibility: baseline age of at T YSR/ASR total problem score; mean (SD), 95% CI
was 16.57 years (2.02), age at the time of the 4 years-average of 2 years.)
least 11 YO, persistent GD, o Decreased from 62.27 (8.96), 95% CI (56.26, 68.29) at baseline to 61.91 (10.55),
last medical treatment was 15.97 years (1.84);
Germany request for gender-affirming Psychological functioning 95% CI (54.82, 69.00) at follow-up, P = NS
mean (SD) time since the last referral was
intervention in the absence of measured using YSR/ASR and
12.64 months (4.78); for onset, 91% were early T YSR/ASR internalizing problems score; mean (SD), 95% CI
severe psychiatric issues CGAS
onset, 9% were late onset; for gender, 72.7%
were trans-male, 27.3% were trans-female; for

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
823

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Sampling method: response additional psychotherapy, 91% had additional Health related quality of life o Decreased from 63.64 (10.97), 95% CI (56.87, 70.40) at baseline to 61.55
rate 37% for all psychotherapy, 9% did not. assessed using Kidscreen-27 (12.72), 95% CI (53.00, 70.09) at follow-up, P = NS
T YSR/ASR externalizing problem score; mean (SD), 95% CI
o Decreased from 57.73 (10.05), 95% CI (50.98, 64.48) at baseline to 54.82
(11.37), 95% CI (47.18, 62.45) at follow-up, P = NS
CGAS global functioning score; mean (SD), 95% CI
o Increased significantly from 67.27 (11.91), 95% CI (59.27, 75.27) at baseline to
81.82 (7.51), 95% CI (76.77, 86.86) at follow up. P < .05 a
Health-related quality of life
T Kidscreen-27/SF-8 mental dimension; mean (SD), 95% CI
o Increased from 39.04 (9.25), 95% CI (32.82, 45.25) at baseline to 43.17 (10.20),
95% CI (36.31, 50.01) at follow up, P = NS
T Kidscreen-27/SF-8 physical dimension; mean (SD), 95% CI
o Increased from 43.43 (8.61), 95% CI (37.65, 49.22) at baseline to 49.57 (11.64),
95% CI (41.75, 57.39) at follow-up, P = NS

Cohort 2: CSH and GnRH analogs (n = 32) Cohort 2: CSH and GnRH analogs (n = 32)
N = 32 TGNB adolescents CSH and GnRH analogs (n = 32): for mean (SD) GnRH analogs and CSH Psychological functioning
age, baseline was 15.47 years (1.04), follow-up
Eligibility: baseline age of at T YSR/ASR total problem score; mean (SD), 95% CI
age was 17.51 years (1.24), age at the time of
least 11 YO, persistent GD, o There was a decrease from 61.56 (9.17), 95% CI (58.26, 64.87) at baseline to
the last medical treatment was 16.74 years
request for gender-affirming 60.09 (9.67), 95% CI (56.61, 63.58) at follow-up, P = NS
(1.16); for onset, 84% were early onset, 16%
intervention in the absence of
were late onset; mean (SD) time since the last T YSR/ASR internalizing problems score; mean (SD), 95% CI
severe psychiatric issues
referral was 23.50 months (10.34); for gender,
Sampling method: response o There was a significant decrease from 64.94 (11.18), 95% CI (60.91, 68.97) at
87.5% were trans-male, 12.5% were trans-
rate 37% for all baseline to 59.56 (10.34), 95% CI (55.83, 63.29) at follow-up. P < .05 a
female; for additional psychotherapy, 81% had
additional psychotherapy, 19% did not. T YSR/ASR externalizing problem score; mean (SD), 95% CI
o There was a decrease from 54.13 (7.17), 95% CI (51.54, 56.71) at baseline to
52.03 (8.43), 95% CI (48.99, 55.07) at follow-up, P = NS
CGAS global functioning score; mean (SD), 95% CI
o There was a significant increase from 73.13 (10.91), 95% CI (69.19, 77.06) at
baseline to 85.63 (9.14), 95% CI (82.33, 88.92) at follow-up. P < .05 a
Health-related quality of life
T Kidscreen-27/SF-8 mental dimension; mean (SD), 95% CI
o There was a significant increase from 36.16 (6.78), 95% CI (33.72, 38.60) at
baseline to 42.07 (10.74), 95% CI (8.20, 45.94) at follow-up. P < .05 a

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
824

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
T Kidscreen-27/SF-8 physical dimension; mean (SD), 95% CI
o There was a significant increase from 39.12 (7.10), 95% CI (36.56, 41.68) at
baseline to 49.36 (9.81), 95% CI (45.82, 52.90) at follow-up. P < .05 a

Cohort 3: CSH and GA surgery (n = 11) Cohort 3: CSH and GA surgery (n = 11)
N = 11 TGNB adolescents GA surgery and CSH (n = 11): for mean (SD) CSH and one operation Psychological functioning
age, baseline was 15.96 years (1.02), follow-up
Eligibility: baseline age of at T YSR/ASR total problem score; mean (SD), 95% CI
age was 19.17 years (1.48), age at the time of
least 11 YO, persistent GD, o There was a decrease from 62.18 (8.78), 95% CI (56.28, 68.08) at baseline to
the last medical treatment was 18.03 years
request for gender-affirming 58.27 (8.72), 95% CI (52.42, 64.13) at follow-up, P = NS
(1.13); mean (SD) time since the last referral
intervention in the absence of
was 38.00 months (11.21); for onset, 91% were T YSR/ASR internalizing problems score; mean (SD), 95% CI
severe psychiatric issues
early onset, 9% were late onset; for gender,
Sampling method: response o There was a significant decrease from 65.73 (9.55), 95% CI (59.31, 72.14) at
90.9% were trans-male, 9.1% were trans-
rate 37% for all baseline to 55.36 (8.74), 95% CI (49.49, 61.24) at follow-up. P < .05 a
female; for additional psychotherapy, 73% had
additional psychotherapy, 27% did not T YSR/ASR externalizing problem score; mean (SD), 95% CI
o There was a significant decrease from 54.09 (7.80), 95% CI (48.85, 59.33) at
baseline to 45.27 (10.87), 95% CI (37.97, 52.58) at follow-up. P < .05 a
CGAS global functioning score; mean (SD), 95% CI
o There was a significant increase from 66.36 (14.33), 95% CI (56.73, 75.99) at
baseline to 83.64 (8.09), 95% CI (78.20, 89.07) at follow-up. P < .05 a
Health-related quality of life
T Kidscreen-27/SF-8 mental dimension; mean (SD), 95% CI
o Increased from 37.88 (6.53), 95% CI (33.49, 42.27) at baseline to 43.44 (9.57),
95% CI (37.01, 49.87) at follow-up, P = NS
T Kidscreen-27/SF-8 physical dimension; mean (SD), 95% CI
o Increased significantly from 39.88 (8.49), 95% CI (34.17, 45.59) at baseline to
53.87 (6.15), 95% CI (49.74, 58.00) at follow-up. P < .05 a
Carmichael (2021)73 N = 44 TGNB adolescents Total sample median age at baseline was 13.6 Suppression of puberty using Patients were measured at CBCL (parent report) and YSR
(12.8,14.6), 89% white, all beyond stage 3 GnRH analog triptorelin together study entry, and then re-
UK Eligibility Criteria: 12 months scores mean (95%CI)
pubertal status. Median age at end of study with psychosocial support and evaluated yearly at 12,24 and
o Patients recruited from those was 16.1 (16.0,16.4). Birth registered males therapy, from study entry until the 36 month until they turned 16. o Parent report CBCL
referred to GIDS who were started at a median age of 13.4 (12.7,14.1) and end of the GnRH analog  Total Problems t-score showed a nonsignificant increase from 61.5(58.2,
Measures of Psychological
between 12-15 years and had birth registered females at 13.9 (13.5, 14.7) all monotherapy pathway at age 16 64.7) at baseline for those followed up to 61.8(58.4, 65.1) at 12 months with
functioning were measured
commenced GnRH analog participants had normal endocrinology, or older. 3.75mg by IM injection a change of 0.3(-2.0, 2.6), P = NS
using the CBCL (parent report)
treatment. karyotype, imaging and clinical phenotype on given every 28 days during
and YSR (self-report.)  Externalizing problems t-score showed a nonsignificant decrease from
physical examination for birth-registered sex treatment period. 2 Participants
Reference data from both 55.7(52.1, 59.3) at baseline for those followed up to 55.4(51.8, 59.0) at 12
and normal full blood count and liver and renal given 11.25 mg every 10 weeks.
Australia and the Netherlands months, P = NS

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
825

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
o Had been seen for at least 6 function. No participants had evidence of were used to calculate z-  Internalizing problems t-scores showed a nonsignificant increase from
months and attended at least disorders of sexual differentiation. scores. 61.8(58.3, 65.3) at baseline for those followed up to 62.9(59.5, 66.3) at 12
4 interviews. months, P = NS
o Psychological stability to o Self-report YSR
withstand the stresses of  Total problems t-score showed a nonsignificant increase from baseline for
medical treatment and those followed up from 57.6(54.5, 60.6) to 58.4(54.6, 62.2) at 12 months
o Displayed severe and with a change of 0.8(-3.1, 4.8), P = NS
persistent GD and actively  Total problems z-score (ref: Netherlands) showed a nonsignificant increase
requesting pubertal from 0.97(0.62, 1.33) at baseline for those followed up to 0.99(0.55, 1.42) at
suppression 12 months, P = NS
o Able to give informed  Total problems z-score (ref: Australia) showed no statistical change from
consent 0.68(0.32, 1.03) at baseline for those followed up to 0.68(0.24, 1.12) at 12
o Met physical/medical criteria months P = NS
of being in established  Externalizing problems t-score showed a nonsignificant increase from
puberty and having normal 52.3(49.2, 55.4) at baseline for those followed up to 52.5(48.7, 56.3) at 12
endocrine function and months P = NS
karyotype consistent with
birth registered sex.  Internalizing problems t-score showed a nonsignificant increase from
57.7(54.3, 61.0) at baseline for those followed up to 60.1(55.9, 64.3) at 12
Exclusions: Inability to fully months P = NS
participate, BMI < 2nd
percentile, serious psychiatric 24 month scores mean (95% CI)
conditions, Inability to give o Parent report CBCL
consent, low spine or hip BMD  Total Problems t-score showed a nonsignificant decrease from 61.2(56.5,
Sampling Method: Patients 65.8) at baseline for those followed up to 60.2(54.6, 65.8) at 24 months with
attending GIDS were provided a change of -1.0(-4.0, 2.1), P = NS
with information and those  Externalizing problems t-score showed a nonsignificant increase from
wishing to find out more 55.4(49.9, 60.9) at baseline for those followed up to 55.2(48.9, 61.5) at 24
discussed with their clinician. months, P = NS
Those likely deemed eligible
 Internalizing problems t-score showed a nonsignificant decrease from
were given detailed information
60.4(55.7, 65.1) at baseline for those followed up to 60.1(54.6, 65.6) at 24
and invited to a medical clinic
months, P = NS
for discussion. Young people
needed to commit to regular o Self-report YSR
medical and psychosocial follow  Total problems t-score showed a nonsignificant increase from 55.1(50.9,
up. Informed consent was 59.2) at baseline for those followed up to 56.5(50.6, 62.5) at 24 months with
obtained. 48 young people a change of 1.5(-3.4, 6.3) P = NS
attended the clinics and 44
 Total problems z-score (ref: Netherlands) showed a nonsignificant decrease
wished to participate. 8 young
from 0.66(0.17,1.15) at baseline for those followed up to 0.65(-0.05, 1.36) at
people were not yet eligible, but
24 months. P = NS
a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
826

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
were able to enter the study  Total problems z-score (ref: Australia) showed a nonsignificant decrease
when sufficiently advanced in from 0.39(-0.11,0.89) at baseline for those followed up to 0.37(-0.32, 1.07) at
puberty. 24 months. P = NS
Subset Definition: N = 44 TGNB  Externalizing problems t-score showed a nonsignificant decrease from
adolescents age 12-15, including 53.1(48.5, 57.6) at baseline for those followed up to 52.3(45.3, 59.4) at 24
birth registered male (n = 25) months. P = NS
and birth registered female  Internalizing problems t-score showed a nonsignificant increase from
(n = 19) adolescents. 53.9(49.9, 58.0) at baseline for those followed up to 55.9(50.8, 61.1) at 24
months. P = NS
36 month scores mean (95%CI)
o Parent Report CBCL
 Total problems t-score showed a nonsignificant decrease from 62.4(55.1,
69.6) at baseline for those followed up to 61.1(52.3, 69.9) at 36 months with
a change of -1.3(-6.6, 4.0). P = NS
 Externalizing problems t-score showed a nonsignificant decrease from
56.8(48.0, 65.6) at baseline for those followed up to 56.2(48.3, 64.1) at 36
months. P = NS
 Internalizing problems t-score showed a nonsignificant increase from
60.4(53.5, 67.2) at baseline for those followed up to 62.5(53.6, 71.5) at 36
months, P = NS
There was no significant change in CBCL or YSR scores from baseline to any data
collection point.
Chen (2023)75 N = 315 Participants were 12 to 20 years of age (mean [ CSH therapy Outcomes were measured at Positive Effect: Slope mean (95% CI)
±SD], 16 ±1.9 years.) Higher percentage of initiation of therapy, and then o There was a significant increase in T scores for positive affect showing an
USA- Gender clinics Eligibility: Participants were
those designated female at birth (64.8%) then at 6,12,18 and 24 months. annual increase on a 100-point scale of 0.80 points (0.08 to 1.54)
recruited from the gender
male. Mostly non-Latinx or non-Latin white (unconditional model); 1.79 (0.14-3.43) (conditional model) after a period of 2
clinics from July 2016-June Positive Effect and Life
(58.1%) years of CSH treatment from baseline.
2019. This cohort was initiating Satisfaction were assessed
CSH as part of their clinical care. using measure from the NIH Life Satisfaction: Slope mean (95% CI)
For minors, parental consent Toolbox—Emotion Battery.
o There was a significant increase in T scores for life satisfaction showing an
was required to initiate
annual increase on a 100-point scale of 2.32 points (1.64 to 3.00)
treatment.
(unconditional model); 4.54 (2.66 to 6.43) (conditional model) after a period of
from July 2016
Sampling Method: Youth were 2 years of CSH treatment from baseline.
through June 2019
recruited from 4 different sites
at the start of CSH therapy. They
were enrolled if they met
inclusion criteria.

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
827

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Subset definition: N = 315 TGNB
adolescents, including:
o FTM (n = 190,) MTF (n = 106)
and NB (n = 19,) adolescents
o Analytical sample n = 291 due
to missing key variables at
follow-up
o Designated female at birth
(n = 204,) and designated
male at birth (n = 111)
o Had early gender-affirming
care-previously using GnRH
analog (n = 24)
 youth designated female
at birth with early gender-
affirming care (n = 4)
 youth designated male at
birth with early gender-
affirming care (n = 20)
o analytic sample (n = 291)
Costa (2015)77 N = 201 TGNB adolescents Full cohort: mean (SD) baseline age was 15.52 Puberty suppression and Outcomes were assessed at CGAS Scores for immediately eligible adolescents, Mean (SD)
years (1.41), mean (SD) age at the start of psychological support baseline, then at:
Eligibility: diagnosed with There was a non-significant increase in scores between 58.72 (11.38) at baseline and
GnRH analogs was 16.48 years (1.26); for living
gender dysphoria Time 1: 6 months of 60.89 (12.17) at 6-month follow-up, P = NS
arrangement, 38.8% lived with both parents,
Sampling method: all patients 49.8% lived with one parent, 5.0% lived with psychological support for
There was a significant increase in scores between baseline and 64.70 (12.17) at
referred from 2010 and 2014 to other, 6.5% had no details; for education, immediately eligible GD
12- month follow-up, P = .003
the GIDS who completed adolescents
83.6% were in education, 9.5% were not in There was a significant increase in scores between baseline and 67.40 (13.93) at
diagnostic testing education, 7.0% had no details regarding Time 2: 12 months of
18- month follow-up, P < .001
Subsets: Of n = 201 of total education; for living in role, 58.2% completely psychological support with 6
months of puberty suppression There was a non-significant increase in scores from 6 to 12 months, P = NS
population, n = 100 had delayed did, 13.4% partly did; 21.4% did not, 7.0% had
eligibility and only received no details; for changing name, 53.2% did, for immediately eligible GD There was a significant increase in scores from 6 month to 18 months, P = .001
psychological therapy, and 39.3% did not, 7.5% had no details adolescents
There was a non-significant increase in scores between 12 to 18 months, P = NS
n = 101 were immediately Time 3: 18 months of
o Time 0 (baseline) CGAS, mean (SD)
eligible for hormone therapy psychological support with 12
months of puberty suppression  Immediately eligible GD adolescents (n = 101): 58.72 (11.38)
Out of 101 immediately eligible
population: for immediately eligible GD o Time 1 (6 months) CGAS, mean (SD)
adolescents
o n = 101 at 6 months,  Immediately eligible GD adolescents (n = 101): 60.89 (12.17)

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
828

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
o n = 60 at 12 months CGAS used to assess adolescent's o Time 2 (12 months) CGAS, mean (SD)
o n = 35 at 18 months psychosocial functioning.  Immediately eligible GD adolescents (n = 60): 64.70 (13.34)
o Time 3 (18 months) CGAS, mean (SD)
 Immediately eligible GD adolescents (n = 35): 67.40 (13.93)
de Vries (2011)57 N = 70 TGNB youth Full cohort: mean (SD) age at baseline was GnRH analogs (full cohort), N = 29 Participant data was collected CBCL (n = 54)
13.65 years (1.85); mean (SD) age at the also started CSH before and after starting GnRH
Eligibility: adolescents with Total T-Score, mean (SD)
start of GnRH analogs was 14.75 years analogs
gender dysphoria eligible for o There was a significant decrease in scores from 60.70 (12.76) at baseline to
(1.92); mean (SD) age at the start of CSH
medical intervention CGAS used to assess 54.46 (11.23) at follow-up, P < .001
was 16.64 years (1.90); mean (SD) time
Sampling method: first 70 Psychosocial functioning
between the start of GnRH analogs and o Full cohort: T0- 60.70 (12.76), T1- 54.46 (11.23)
patients consecutively enrolled CSH was 1.88 years (1.05); mean (SD) annoying situation. (Scale
o Female at birth: T0- 61.73 (13.60), T1- 57.73 (10.82)
from 2000 to 2008 parental full-scale IQ was 98.2 (15.0); for ranges from 1-4)
parental marital status, 62.9% had both o Male at birth: T0- 60.00 (9.51), T1- 52.17 (9.81)
Subset: N = 70 TGNB youth, CBCL/ABCL and YSR/ASR used
including N-37 natal females parents, 37.1% was other; for parents' to assess behavioral and Internalizing T-Score, mean (SD)
and N = 33 natal males education status, 10.6% had high, 66.7% emotional problems using the o There was a significant decrease in scores from 61.00 (12.21) at baseline to
had medium, 22.7% had low; for sexual total, internalizing and 54.46 (10.22) at follow-up, P < .001
attraction, 88.6% were attracted to their externalizing T scores as well as
own natal sex, 8.6% were attracted to both o Full cohort: T0- 61.00 (12.21), T1- 54.46 (10.22)
the clinical range scores for the
sexes; 2.8% were attracted to other indices (T score > 63) o Female at birth: T0- 61.80 (14.12), T1- 56.30 (10.33)
Natal male (47%): mean (SD) age at o Male at birth: T0- 60.00 (9.51), T1- 52.17 (9.81)
baseline was 13.14 years (1.55); mean (SD) Externalizing T-Score, mean (SD)
age at the start of GnRH analogs was 14.25
years (1.79); mean (SD) age at the start of o There was a significant decrease in scores from 58.04 (12.99) at baseline to
CSH was 16.24 years (1.21); mean (SD) time 53.81 (11.86) at follow-up, P < .001
between the start of GnRH analogs and o Full cohort: T0- 58.04 (12.99), T1- 53.81 (11.86)
CSH was 1.99 years (0.94); mean (SD) o Female at birth: T0- 60.70 (12.64) , T1- 57.87 (11.66)
parental full-scale IQ was 97.1 (13.3); for
parental marital status, 69.7% had both o Male at birth: T0- 54.71 (12.91), T1- 48.75 (10.22)
parents, 30.3% had other; for parents' YSR (n = 54)
education status, 3.3% had high, 76.7% had
Total T-Score, mean (SD)
medium, 20.0% had low; for sexual
attraction, 87.9% were attracted to their o There was a significant decrease in scores from 55.46 (11.56), at baseline to
own natal sex, 6.1% were attracted to both 50.00 (10.56) at follow-up, P < .001
sexes; 6.0% were attracted to other o Full cohort: T0- 55.46 (11.56), T1- 50.00 (10.56)
Natal female (53%): mean (SD) age at o Female at birth: T0- 57.10 (10.87), T1- 51.86 (10.11)
baseline was 14.10 years (1.99); mean (SD)
o Male at birth: T0- 53.56 (12.26), T1- 47.84 (10.86)
age at the start of GnRH analogs was 15.21
years (1.95); mean (SD) age at the start of Internalizing T-Score, mean (SD)
CSH was 16.99 years (1.07); mean (SD) time

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
829

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
between the start of GnRH analogs and o There was a significant decrease in scores from 56.04 (12.49) at baseline to
CSH was 1.78 years (1.16); mean (SD) 49.78 (11.63) at follow-up, P < .001
parental full-scale IQ was 99.2 (15.2); for o Full cohort: T0- 56.04 (12.49), T1- 49.78 (11.63)
parental marital status, 56.8% had both
parents, 43.2% had other; for parents' o Female at birth: T0- 56.17 (13.25), T1- 50.24 (11.28)
education status, 16.7% had high, 58.3% o Male at birth: T0- 55.88 (11.81), T1- 49.24 (12.24)
had medium, 25.0% had low; for sexual Externalizing T-Score, mean (SD); P-Value (for T0-T1) = 0.009
attraction, 89.2% were attracted to their
own natal sex, 10.8% were attracted to o There was a significant decrease in scores from 53.30 (11.87) at baseline to
both sexes; 0% were attracted to other 49.98 (9.35) at follow-up, P = .009
o Full cohort: T0- 53.30 (11.87), T1- 49.98 (9.35)
o Female at birth: T0- 57.24 (10.59), T1- 52.97 (8.51)
o Male at birth: T0- 48.72 (11.83), T1- 46.52 (9.23)
CGAS (n = 41), mean (SD)
There was a significant decrease in scores from 70.24 (10.12) at baseline to 73.90
(9.63) at follow-up, P = .005
Full cohort: T0- 70.24 (10.12), T1- 73.90 (9.63)
Female at birth: T0- 67.25 (11.06), T1- 70.30 (9.44)
Male at birth: T0-73.10 (8.44), T1- 77.33 (8.69)
de Vries (2014)79 N = 55 TGNB youth Full cohort: the mean age (SD) at assessment CSH and GRS Participants were assessed 3 CGAS (Psychosocial functioning) (n = 32), mean (SD)
pretreatment was 13.6 (1.9) (range: 11.1– times: pre-treatment (T0, at o Scores significantly increased from 71.13 (10.46) at intake to 79.94 (11.56) at
Eligibility: adolescents with GD
17.0), the mean age (SD) at the start of GnRH intake), during treatment (T1, at post treatment, P < .001
prescribed puberty suppression
analogs was 14.8 (1.8) (range: 11.5–18.5), the initiation of CSH), and post
between 2004 and 2011 o T0- 71.13 (10.46), T1- 74.81 (9.86), T2- 79.94 (11.56)
mean age (SD) at the start of CSH was 16.7 treatment (T2, 1 year after GRS)
Sampling method: first 70, and (1.1) (range: 13.9–19.0), the mean age (SD) at o Significant linear effect (time) P < 0.001, Quadratic effect (time) P = NS
then filtered to those who were CGAS used to assess
the start of GRS was 19.2 (0.9) (range: 18.0– CBCL /ABCL (Behavioral and emotional problems) (n = 40)
prescribed puberty suppression Psychosocial functioning
21.3), the mean age (SD) at assessment post
and continued with GRS treatment was 20.7 (1.0) (range: 19.5–22.8); CBCL/ABCL and YSR/ASR used o Total T-Score, mean (SD)
between 2004 and 2011 the mean full scale intelligence (SD) was 99.0 to assess behavioral and  Scores showed a significant decrease from 60.20 (12.66) at intake to 48.10
Subset: N = 55 TGNB (14.3) (range: 70–128) emotional problems using the (9.30) at post treatment, P < .001
total, internalizing and
adolescents, with N = 22 MTF  T0- 60.20 (12.66), T1- 54.70 (11.58), T2- 48.10 (9.30)
and N = 33 FTM) externalizing T scores as well as
the clinical range scores for the  Significant linear effect (time) P < .001, quadratic effect (time) P = NS
indices (T score > 63) o Internalizing T-Score, mean (SD)
General linear models examined  Scores showed a significant decrease from 60.83 (12.36) at intake to 50.45
the repeated measures with an (10.04) at post treatment, P < .001
analysis of variance-based model.  T0- 60.83 (12.36), T1- 54.42 (10.58), T2- 50.45 (10.04)]

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
830

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
A linear effect signifies an overall  Significant linear effect (time) P < 0.001, quadratic effect (time) P = 0.42
change across T0 to T2. Quadratic o Externalizing T-Score, mean (SD)
effect signifies change was not
continuous.  Scores showed a significant decrease from 57.85 (13.73) at intake to 47.85
(8.59) at post treatment, P < .001
 T0- 57.85 (13.73), T1- 53.85 (12.77), T2- 47.85 (8.59)
 Significant linear effect (time) P < .001, quadratic effect (time) P = NS
YSR/ ASR (Behavior and emotional problems) (n = 43)
o Total T-Score, mean (SD)
 Scores showed a significant decrease from 54.72 (12.08) at intake to 48.53
(9.46) at post treatment, P < .005
 T0- 54.72 (12.08), T1- 49.16 (11.16), T2- 48.53 (9.46)
 Significant linear effect (time) P < .005, quadratic effect (time) P = NS
o Internalizing T-Score, mean (SD);
 Scores showed a significant decrease from 55.47 (13.08) at intake to 50.07
(11.15) at post treatment, P < .03
 T0- 55.47 (13.08), T1- 48.65 (12.33), T2- 50.07 (11.15)
 Significant linear effect (time) P < .03, Significant quadratic effect (time)
P < .008
o Externalizing T-Score, mean (SD)
 Scores showed a nonsignificant decrease from 52.77 (12.47) at intake to
49.44 (9.37) at post treatment with a P value of 0.14
 T0- 52.77 (12.47), T1- 49.44 (9.59), T2- 49.44 (9.37)
 linear effect (time) P = NS, quadratic effect (time) P = NS
N = 22 MTF TGNB youth MTF: for ages, the mean age (SD) at CSH and GRS CGAS (Psychosocial functioning) MTF (n = 12), mean (SD)
assessment pretreatment was 13.6 (1.8), the o Scores significantly increased from 74.33 (7.53) at intake to 82.40 (8.28) at post
Eligibility: adolescents with GD
mean age (SD) at the start of GnRH analogs treatment, P < .001
prescribed puberty suppression
was 14.8 (2.0), the mean age (SD) at the start
between 2004 and 2011 o T0-74.33 (7.53), T1- 78.20 (9.56), T2- 82.40 (8.28)
of CSH was 16.5 (1.3), the mean age (SD) at the
Sampling method: first 70, and start of GRS was 19.6 (0.9), the mean age (SD) CBCL /ABCL (Behavior and emotional problems) MTF (n = 15)
then filtered to those who were at assessment post treatment was 21.0 (1.1); o Total T-Score, mean (SD)
prescribed puberty suppression the mean full scale intelligence (SD) was 97.8
and continued with GRS (14.2)  Scores showed a significant decrease from 57.40 (12.76), at intake to 48.13
between 2004 and 2011 (12.58) at post treatment P < .002
 T0- 57.40 (12.76), T1- 49.67 (12.29), T2- 48.13 (12.58)
o Internalizing T-Score, mean (SD)

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
831

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
 Scores showed a significant decrease from 59.40 (10.03), at intake to T2-
48.73 (12.61)]at post treatment ,P < .001
 T0- 59.40 (10.03), T1- 50.93 (11.15), T2- 48.73 (12.61)
o Externalizing T-Score, mean (SD)
 Scores showed a nonsignificant decrease from 52.53 (14.11), at intake to
46.33 (10.95) at post treatment, P = NS
 T0- 52.53 (14.11), T1- 47.87 (12.07), T2- 46.33 (10.95)
YSR/ ASR (Behavior and emotional problems) MTF (n = 17)
o Total T-Score, mean (SD)
 Scores showed a nonsignificant decrease from 50.65 (12.19), at intake to
47.24 (12.28) at post treatment, P = NS
 T0- 50.65 (12.19), T1- 45.94 (12.24), T2- 47.24 (12.28)
o Internalizing T-Score, mean (SD)
 Scores showed a significant decrease from 54.00 (12.31), at intake to 48.12
(12.54) at post treatment, P < .04
 T0- 54.00 (12.31), T1- 47.59 (14.26), T2- 48.12 (12.54)
o Externalizing T-Score, mean (SD)
 Scores showed a nonsignificant decrease from 46.00 (11.58), at intake to
50.24 (11.18)]at post treatment, P = NS
 T0- 46.00 (11.58), T1- 44.71 (9.53), T2- 50.24 (11.18)
N = 33 FTM TGNB youth FTM: for ages, the mean age (SD) at CSH and GRS CGAS (Psychosocial functioning) FTM (n = 17), mean (SD)
assessment pretreatment was 13.7 (2.0), the o Scores significantly increased from 67.65 (11.87), at intake to 76.29 (14.48)]at
Eligibility: adolescents with GD
mean age (SD) at the start of GnRH analogs post treatment, P < .02
prescribed puberty suppression
was 14.9 (1.9), the mean age (SD) at the start
between 2004 and 2011 o T0- 67.65 (11.87), T1- 70.65 (9.89), T2- 76.29 (14.48)
of CSH was 16.8 (1.0), the mean age (SD) at the
Sampling method: first 70, and start of GRS was 19.0 (0.8), the mean age (SD) CBCL /ABCL (Behavior and emotional problems) FTM (n = 25)
then filtered to those who were at assessment post treatment was 20.5 (0.8); o Total T-Score, mean (SD)
prescribed puberty suppression the mean full scale intelligence (SD) was 100.4
and continued with GRS (14.3)  Scores showed a significant decrease from 61.88 (12.56), at intake to 48.08
between 2004 and 2011 (6.95)]at post treatment, P < .001
 T0- 61.88 (12.56), T1- 57.72 (10.23), T2- 48.08 (6.95)
o Internalizing T-Score, mean (SD)
 Scores showed a significant decrease from 61.68 (13.70), at intake to T2-
51.48 (8.25) at post treatment, P < .001
 T0- 61.68 (13.70), T1- 56.52 (9.86), T2- 51.48 (8.25)

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
832

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
o Externalizing T-Score, mean (SD)
 Scores showed a significant decrease from 61.04 (12.71), at intake to 48.76
(6.89) at post treatment, P < .001
 T0- 61.04 (12.71), T1-57.44 (12.01), T2- 48.76 (6.89)
YSR/ ASR (Behavior and emotional problems) FTM (n = 26)
o Total T-Score, mean (SD)
 Scores showed a significant decrease from 57.38 (11.47), at intake to 49.38
(7.21) at post treatment, P < .01
 T0- 57.38 (11.47), T1- 51.27 (10.08), T2- 49.38 (7.21)
o Internalizing T-Score, mean (SD)
 Scores showed a nonsignificant decrease from 56.42 (13.86), at intake to
51.35 (10.19)at post treatment, P = NS
 T0- 56.42 (13.86), T1- 49.35 (11.13), T2- 51.35 (10.19)
o Externalizing T-Score, mean (SD)
 Scores showed a nonsignificant decrease from 57.16 (11.14), at intake to
48.92 (8.18) at post treatment, P = NS
 T0- 57.16 (11.14), T1- 52.54 (8.43), T2- 48.92 (8.18)
Kaltiala (2020)138 N = 52 Mean age of 18.1 (1.1) years at diagnosis, CSH Participants were assessed at Psychosocial indicators of adolescent development:
range 15.2-19.9 years an initial gender identity
Finland Eligibility Criteria: The study There was a significant decline in the proportion of participants living with
assessment appointment
comprises a retrospective chart parent(s)/guardians from initial assessment to 12 month follow up appointment
before starting hormone
review of adolescents referred from 73% (38/52) to 40% (21/50), P < .001
therapy, and then about a year
to one of the two gender There was a significant decline in the proportion of those functioning age-
after treatment (called the
identity service facilities appropriately in peer relationships from initial assessment to 12 month follow up
"real-life phase")
between 2011-2017, before age appointment from 89% (46/52) to 81% (42/52), P < .001
18, who had been diagnosed Psychosocial indicators data for
with transsexualism and adolescent development were o Of those adolescents with age-appropriate peer contacts during assessment
proceeded to cross-sex collected retrospectivity from (46/52), 91% (42/46) continued to have age-appropriate peer contacts during
hormonal treatments and who charts with specific criteria the real-life phase while 9% (4/46) no longer had these.
had completed a follow-up of o Of those with difficulties in peer contacts (6/52), all continued to have
approximately a year after difficulties in this field. (P < .001, using cross tabulations with chi square
starting on cross-sex hormones statistics/Fisher's exact test)
(real-life phase). There was a nonsignificant decline in the proportion of participants progressing
Sampling Method: Between normatively in school/ work from initial assessment to 12 month follow up
2011 and 2017, 57 adolescents appointment from 64% (33/52) to 60% (31/52), P = NS
at the gender identity facility o Of those who progressed age-appropriately at school/working life during
had been diagnosed with F64.0, assessment (33/52), 85% (28/33) continued to do so during the real-life phase,
a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
833

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
transsexualism, and had been but 15% (5/33) did not. Of those with problems at school (work) (19/52), 84%
offered an opportunity to start (16/19) continued to have problems, but 16% (3/19) ceased to have problems
hormonal sex reassignment. in this field. (P < .001 using cross tabulations with chi square statistics/Fisher's
One of them did not want any exact test)
treatment, two withdrew and There was a nonsignificant decline in the proportion of participants that had been
two had started hormonal dating or had steady relationships from initial assessment to 12 month follow up
treatments but had not yet appointment from 62% (32/50) to 58% (30/52), P = NS
completed the real-life phase at
the end of 2017. Thus, 52 o Of those who had experiences of dating/steady relationships during the
patients were included in the assessment (32/50), 66% (21/32) had dating/ steady relationships during the
study. real-life phase, and 34% (11/32) did not. Of those who had not had any
dating/steady relationships by the end of the gender identity assessment, 44%
Subset definition: N = 52 (8/18) had and 56% (10/18) did not have these during the real-life phase.
patients in study. N = 11 birth (P = NS using cross tabulations with chi square statistics/Fisher's exact test)
assigned males. N = 41 birth
assigned females There was no significant change in the proportion of participants who were age-
appropriately able to dealt with matters outside of the home from initial
assessment to 12 month follow up appointment staying at 81% (42/52, P = NS)
o Of those who had had age-appropriate skills in dealing with matters outside
home (42/52), 88% (37/42) continued to be able to do so but 12% (5/42)
functioned below the age-appropriate level during the real-life phase. Of those
who had had difficulties in dealing with matters outside home (10/52), half
(5/10) continued to do so, but half (5/10) no longer had problems in this field
(P < .02 using cross tabulations with chi square statistics/Fisher's exact test).
Lavender (2023)142 N = 38 TGNB adolescents Full cohort (N = 38): Most of participants GnRH analogs and CSH Baseline was assessed at point YSR: Mean (95% CI)
are white (N = 29); mean (SD) age at first of referral to endocrinology. o There was no significant difference in total and internalizing YSR scores across
At an endocrine clinic in Eligibility: younger than 15
endocrine clinic was 13.47 (0.94); mean Assessed after approximately 1 time points, although a general improvement over time was evident, except for
the UK between 2014 years and at Tanner stage 2+,
(SD) age at starting GnRH analogs was year on GnRH analogs, and a significant decrease in Externalizing problem T-scores from 53.91 (48.26-
and 2018 referred by the GIDS for GnRH
14.01 (0.81); mean (SD) age at starting CSH then after approximately 1 59.56) at baseline to 49.38 (44.96-53.79) 1 year after CSH, P < .04
analog treatment and CSH
was 16.10 (0.29); mean (SD) time between year on CSH
treatment at *16 years (and CBCL: Mean (95% CI)
first endocrine clinic and GnRH analogs was General Linear Models
with a minimum of around 1
0.57 (0.38); mean (SD) time between start examined the repeated o Internalizing T-scores demonstrated a significant reduction across time F (1.27,
year on GnRH analogs)
GnRH analogs and CSH was 2.09 (0.85) measures with an analysis of 20.31) = 4.45, P < .04. Specifically, there was a reduction in mean internalizing
Sampling method: Young scores from 62.77 (55.87-69.71) at baseline to 41.89 (23.19-60.59) at 1 year
Assigned female young people group variance-based model,
people referred to after GnRH analogs that was statistically significant (F(1, 16) = 5.50, P = 0.03).
(N = 28): Most are white (N = 22); mean incorporating continuous and
endocrinology were sent There was a non-significant increase after 1 year on CSH relative to baseline.
(SD) age at first endocrine clinic was 13.74 categorical predictors, and
questionnaires at baseline, after
(0.68); mean (SD) age at starting GnRH correcting for the unbalanced o Externalizing T-scores also reduced over time, with reductions approaching
1 year on GnRH analogs, and
analogs was 14.19 (0.66); mean (SD) age at cell sizes. A linear effect significance. Mean scores indicated a general reduction after 1 year on GnRH
after 1 year on CSH treatment.
starting CSH was 16.06 (0.22); mean (SD) signifies an overall change analogs with a slight increase in reported externalizing behaviors after 1 year
Before August 2020,
time between first endocrine clinic and across T0 to T2. A quadratic on CSH in the CBCL caregiver reports.
questionnaires were sent by
GnRH analogs was 0.55 (0.36); mean (SD) effect signifies that the change
post to the young people and
a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
834

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Table I.L.2. Longitudinal pre-post studies evaluating psychosocial outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
their caregivers, including a time between start GnRH analogs and CSH was not continuous with time
cover letter detailing the was 2.03 (0.79) as within-subject factor.
purpose of questionnaires and Assigned male young people group Psychological and behavioral
the right to opt out. From (N = 10): Most are white (N = 7); mean (SD) functions were measured using
August 2020, questionnaire age at first endocrine clinic was 12.74 the YSR and CBCL
administration moved to an (1.20); mean (SD) age at starting GnRH
online platform with email links analogs was 13.51 (0.99); mean (SD) age at
sent to young people and starting CSH was 16.25 (0.42); mean (SD)
caregivers (Qualtrics, Provo, time between first endocrine clinic and
UT). GnRH analogs was 0.57 (0.38); mean (SD)
Subset definition: Assigned time between start GnRH analogs and CSH
female at birth N = 28 and was 2.10 (0.86)
Assigned male at birth N = 10
López de Lara (2020)62 N=23 TGNB youth Transgender adolescents: CSH (oral estradiol, intramuscular Participants were assessed at Behavior Problems, mean (SD)
testosterone) baseline and 1 year after CSHT o Strengths and Difficulties Questionnaire (SDQ): There was a significant decrease
Spain: Pediatric Eligibility: adolescents aged 14 mean age: 16 years (range 14-18)
in prosocial, emotional symptoms, conduct problems, peer problems and total
endocrinology clinic to 18 yo, absence of psychiatric assigned sex at birth: Behavior problems: assessed
difficulties scores from baseline to one year, P < 0.001
comorbidity, Tanner state 2 or o 69% female using SDQ
higher, understanding of risks o Total difficulties, mean (SD), P < 0.001
o 31% male T0: 14.7 (3.3)
and benefits of CSH
91% Caucasian and Spanish descent T1: 10.3 (2.9)
Sampling method: requested
52% parents with a university education  Prosocial, mean (SD), P < 0.001
volunteers
30.4% had previously used mental health T0: 8 (1.6)
services T1: 9 (1.2)
sexual orientation  Emotional symptoms, mean (SD), P < 0.001
o 65% heterosexual, T0: 5.2 (1.6)
o 13% homosexual T1: 3.4 (1.2)
21% bisexual  Conduct problems, mean (SD), P < 0.001
T0: 2.7 (0.8)
T1: 1.8 (1)
 Hyperactivity, mean (SD), P < 0.001
T0: 4 (1.9)
T1: 2.6 (1.8)
 Peer problems, mean (SD), P = NS
T0: 2.6 (1.3)
T1: 2.3 (0.8)
There was an increase in normal (0-15 points) SDQ scores from baseline (n=14;
61%) to one year (n=22; 95.6%), decrease in borderline scores (16-19 points) from
baseline (n=8; 34.7%) to one year (n=1; 4.3%) and a decrease from abnormal
scores (20-40 scores) from n=1 (4.3%) at baseline to none (0%) at one year.

a P values are implicit from 95% confidence intervals. We considered it significant at an alpha of 0.05 by contrasting 95% CIs, but authors did not do a hypothesis test. (Becker-Hebly 2021)
See Appendix I.H for a complete description of referenced mental health assessment tools.
Abbreviations: ABCL, Adult Behavior Checklist; ASR, adult self-report; CBCL, Children's behavior checklist; CSH, cross-sex hormones; CSHT, cross-sex hormone therapy; CGAS, Children's Global Assessment Scale; CI, confidence interval; FTM, assigned female at
birth transitioning to male; GAH, gender-affirming hormone; GD, gender dysphoria; ; GnRHa, gonadotropin-releasing hormone analogs; GRS, gender reassignment surgery; GWBS, General Well-being Scale; ITS, interrupted time series; MTF, assigned male at
birth transitioning to female; N/A, not applicable; N/R, not reported; PB, puberty blockers; QLES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire; SD, standard deviation; SHS, Subjective Happiness Scale; SWLS, Satisfaction With Life Scale; TGNB,
transgender, non-binary, or gender-diverse; YSR, youth self-report
835

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Alvares (2022)132 N = 15 TGNB women 11/15 TGNB women were non- Estrogen treatment: n=15 (100%) Testosterone levels were Total testosterone (TT):
gonadectomized and taking estrogen and measured using
Eligibility Criteria: Women were Estradiol valerate: There was no difference in testosterone levels between the measurements 12
cyproterone acetate electrochemoimmunoassay 12
included if they met the criteria for o n=1 patient at 1 mg/day months before the study and at the time of the study, P = NS
4/15 TGNB women were gonadectomized months before the start of the
a gender dysphoria diagnosis
and taking estrogen only. o n=4 patients at 2 mg/day study and at the time of the
according to the DSM-IV and V
study
and/or ICD-10 guidelines, began None of them used GnRH analogs at any Conjugated estrogens:
androgen blockade after 12 years of time. Blood test collected on the day
o n=4 patients at 0.625
age, regularly used estrogen in the of the study, immediately
Average (SD) age at time of study: 34.2 mg/day
last year, were between 25-45 before bioimpedance,
years old, and had a BMI of 18.0- (5.2) years o n=3 patients at 1.25 mg/day ergospirometry, and strength
34.9 kg/m². They were excluded if Median age at start of CSHT: 17 (range 12- 17-beta estradiol gel: tests
they had current or previous 35) years o n=1 patient at 0.5 mg/day Investigators used median TT of
illnesses that could interfere with Average (SD) duration of CSHT: 14.4 (3.5) the past 12 months to determine
strength or aerobic tests, or had o n=1 patient at 1 mg/day
years values at T0
chronic disease or chronic use of o n=1 patient at 1.5 mg/day
medications. Antiandrogen treatment: n=11
Sampling Method: All participants (73.3%)
were patients at the above setting. Cyproterone acetate:
No additional information is given.
o n=11 patients at 50 mg/day
Prior gonadectomy: n=4 patients
Average duration of CSHT: 14.4
(SD3.5) years

Beking (2020)129 N = 21 transgender boys Mean age = 16.1 years, SD = 0.7 Session 1 (baseline): had fMRI data was collected as Testosterone and change in lateralization were not significantly associated.
received 3.75 mg Triptorelin participants engaged in a face- Changes between session 1 and 2:
Eligibility criteria: received
(Decapeptyl-CR®) matching task that has been
puberty suppression and o ∆ in left amygdala activation: increase, t = 5.3, pFWE = .024
subcutaneously or shown to engage the amygdala
testosterone, no continuous
intramuscularly every 4 weeks at baseline and a follow-up o ∆ in right cerebellar activation: decrease, pFWE < .05
psychotropic medication use, no
(mean duration = 1.6 years, appointment (mean 9.8 ± 2.9 o ∆ in bilateral fusiform gyrus activation: increase, pFWE < .05
psychiatric or neurologic
SD = 1.0) months.)
disorder o ∆ in emotional face processing: no change, pFWE > .05
Session 2 (follow-up): had
Sampling method:
been receiving testosterone
recruitment/invitation
treatment since session 1
(mean duration = 9.8 months,
SD = 2.9, range 5.6–14.8
months)
Boogers (2022)66 N = 161 TGNB girls Median age at start of puberty Puberty suppression: Height and weight were Puberty Suppression only
suppression (yr, range): Triptorelin (Decapeptyl-CR evaluated at the start of PS and
Eligibility: initiated GnRH analog Overall: Growth and bone maturation decelerate during PS, but accelerate again
o Regular dose: 13.5 (13.2 to 14.5) (Ferring) 3.75 mg every 4 then every 3-6 months.
treatment before age 18 years, when starting CSHT
weeks or Pamorelin (Ipsen)
o High dose: 13.1 (12.1 to 13.6) Growth Velocity

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
836

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
received estrogen therapy, and had o Ethinyl estradiol: 12.4 (12.1 to 14.0) 11.25 mg every 10-12 weeks) Bone age was determined at start o There was a significant ∆ between year 1 and year 2 (mean, 95% CI): -1.9 cm,
reached adult height o Post-pubertal: 16.8 (16.1 to 17.3) to suppress puberty. g PS and CSHT and repeated yearly 95% CI (-2.4 cm, -1.4 cm)
Sampling method: 176 from the Mean height at start of puberty From age 15 to 16 years, CSHT to every 2 years until (near) adult o Year 1 (mean ± SD): 5.3 cm/year ± 2.2
was initiated height was reached
5350 birth-assigned males in the suppression (cm, SD): o Year 2 (mean ± SD): 3.5 cm/year ± 1.3
ACOG database met inclusion Measures included:
o Regular dose: 165.8 (8.4) Height SDS
criteria; 15 were excluded due to
o High dose: 163.4 (7.2) Growth velocity o Significant ∆ in height SDS per year (mean, 95% CI): -0.37/year, 95% CI (-0.47, -
missing data and temporary
treatment continuation; 88 of the o Ethinyl estradiol: 160.8 (6.3) Adult height 0.27)
remaining had growth potential and Height SDS was calculated Bone Age
o Post-pubertal: 176.7 (6.9)
were considered as part of the according to Dutch Male
Mean duration of puberty suppression: 2.4 o Significant ∆ BA per year (mean, 95% CI): -0.5 years/year, 95% CI (-0.8, -0.2)
pubertal group; reference data.
(0.8) o Significant ∆ BA (mean ± SD) at the start of PS (baseline) vs. start of CSHT: -1.6
Subset: of N = 161 TGNB girls: Bone age was determined years ± 0.8 (implicit)
Pubertal group (N = 88) through X-rays of the left hand
PAH
o N = 47 regular dose estradiol o Significant ∆ in PAH (mean, 95% CI) at the start of CSHT vs start of PS: 1.5 cm,
treatment 95% CI (0.5 cm, 2.6 cm)
o N = 22 high dose estradiol
Regular dose 17β-estradiol: Height
treatment
starting dose of 5 μg/kg/d, which o Significant ∆ in height (cm) from the start of CSHT to adult height (mean, 95%
o N = 11 ethinyl estradiol was increased every 6 months by 5 CI): 5.9 cm, 95% CI (5.7 cm, 6.2 cm)
treatment μg/kg/d up to an adult dose of 2
mg/d o Significant ∆ in height (SDS) from the start of CSHT to adult height (mean, 95%
o N = 8 combined treatment
CI): 0.17 cm, 95% CI (0.04 cm, 0.29 cm)
N = 73 post-pubertal
High dose, growth reductive 17β- Height
estradiol: dose increased up to 6 o Significant ∆ in height (cm) from the start of CSHT to adult height (mean, 95%
mg per day for 10 weeks CI): 9.9 cm, 95% CI (9.6 cm, 10.2 cm)
o Significant ∆ in height (SDS) from the start of CSHT to adult height (mean, 95%
CI): 0.30 cm, 95% CI (0.01 cm, 0.58 cm)
o Subgroup: those with a BA ≤ 14 years at the start of CSHT (n = 17)
 Non-significant growth reduction (mean, 95% CI) from the start of CSHT to
adult height: 0.7 cm, 95% CI (-1.7 cm, 3.2 cm)
o Subgroup: those with a PAH ≥ 180 cm at the start of CSHT (n = 15)
 Non-significant growth reduction (mean, 95% CI) from the start of CSHT to
adult height: 0.9 cm, 95% CI (-1.4 cm, 3.2 cm)
Growth reductive Ethinyl estradiol: Height
100 or 200 ug per day o Significant ∆ in height (cm) from the start of CSHT to adult height (mean, 95%
CI): 7.6 cm, 95% CI (7.1 cm, 8.0 cm)
o Non-significant ∆ in height (SDS) from the start of CSHT to adult height (mean,
95% CI): 0.05 cm, 95% CI, –0.23 cm to 0.33 cm)
o Subgroup: those with a BA ≤ 14 years at the start of CSHT (n = 6)

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
837

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
 Non-significant growth reduction (mean, 95% CI) from the start of CSHT to
adult height: 2.7 cm, 95% CI (-0.7, 6.2 cm)
o Subgroup: those with a PAH ≥ 180 cm at the start of CSHT (n = 5
 Non- significant growth reduction (mean, 95% CI) from the start of CSHT to
adult height: 0.9 cm, 95% CI (-1.4 cm, 3.2 cm)
Post-pubertal group Height (n = 34)
o ∆ between adult height and PAH at the start of PS (mean ± SD): 0.5 ± 1.0 cm
Ghelani (2020)58 N = 36 TGNB adolescents The mean age for full cohort was 16.5 (15.8– GnRH analog treatment: Patients were measured at Lean mass:
17.2) years. The mean age for transgender Triptorelin (Gonapeptyl Depot baseline and then at 6months and o The fall in lean mass SDS from baseline to 12 months is significant in
Eligibility: not clearly stated
boys was 16.6 years (1 SD = ±0.69 years) and 3.75 mg or Decapeptyl SR 11.25 12 months of GnRH analog transgender girls (P < .002).
Sampling method: Patients for transgender girls was 16.4 years (1 mg) was administered treatment
were verified to be SD = ±0.66 years), P value = 0.50. The mean subcutaneously for at least 1 year o Although lean mass SDS was decreasing from baseline to 12 months for full
between 2013 and Body composition (lean mass, cohort, it is not statistically significant (P = NS).
phenotypically and age of menarche in the transgender boys was
2015 height, weight, BMI): Data was
chromosomally normal through 11.9 years (1 SD = ±1.10 years). All transgender Height:
physical examination and taken from this routine clinic
girls were in late puberty (Tanner stages G4 o The fall in height SDS from baseline to 12 months is significant in transgender
karyotype analysis. 36 subjects and 5). There was no significant difference in monitoring of patients and
subsequently anonymized. girls (P = .012).
whose data were complete age, weight and BMI between the two sexes.
were included in this study. Whole-body impedance at 50 o Although height SDS was decreasing from baseline to 12 months for full cohort,
Transgender girls were significantly taller than
Others were only excluded if kHz (Z, in Ω) was measured it is not statistically significant (P = NS).
transgender boys as expected for a late
they had an incomplete set of pubertal cohort, 167.7 (161.8–173.6) cm vs. using a Tanita Body
Weight:
body composition data or if any 162.8 (156.4–169.2) cm, P value = 0.03. Composition Analyzer, Model
type/Number BC-418MA III. o Changes in weight SDS in both transgender girls and transgender boys were not
other confounding factor was
The conventional whole-body statistically significant, P = NS.
identified from routine clinic
questioning about lifestyle that impedance index (height2/Z) BMI:
could affect the results (n = 4). was calculated and used as an
o Over the whole 12-month treatment period, the average BMI SDS in
Examples included patients that indicator of lean mass.
transgender girls decreased by 0.07.
had excessive weight gain due Standard deviation scores
(SDSs) for lean mass were o In the transgender boys there was a fall in BMI SDS between 0 and 6 months
to body-building activities and
calculated using recent UK but overall by 12 months there was an increase of 0.1 indicating a small but
excessive weight loss when
body composition reference insignificant upward trend.
diagnosed with anorexia.
data. Height, weight and BMI o Changes in BMI SDS in both transgender girls and transgender boys were not
Subset definition: 11 SDS were derived from UK90 statistically significant, P = NS.
transgender girls (birth- data.
registered males identifying as
female) and 25 transgender
boys (birth-registered females
identifying as male)
Hannema (2017)59 N = 28 TGNB girls Average age was 16 with a range from 13.9 Initial treatment was IM triptorelin Data was collected before Tanner Breast Stage:
to 18.9. 3.75 mg every 4 weeks. Oral treatment as a baseline, then o At baseline, there was no breast development.
Eligibility: gender dysphoric
estradiol was added around the at 1 year of treatment. The
adolescents seen at clinic. GD 28 participants completed one year of o Breast development began in all participants within 1 year, with 15 of 18
age of 16 years. Two were treated whole cohort participated in
was diagnosed using DSM-IV, treatment. 21 completed 2 years, and 16 individuals starting within 3 months of treatment.
with 200 ug ethinyestradiol and the one year follow-up,
completed 3 years. All were trans girls
measurements were then o After 1 year on treatment, the median Tanner stage was 3 (range 2-5)

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
838

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
had been treat with four were treated with 6 mg taken at years 2 and 3 with o After 2 years on treatment, the median Tanner stage was 4 (range 2-5)
estrogen > 12 months estradiol. dropout occurring. o At 3 years, 1 individual had tanner stage 2, 1 had stage 3, 3 had stage 4, and 9
Sampling method: adolescents Pubertal development was had stage 5 breast development, with those at stage 2 and 3 taking the longest
at the clinic were invited to measured in several ways: to reach the adult dose of medication.
participant in study. Tanner stage, waist Waist circumference (cm): Mean ± SD
circumference, hip
circumference and waist/hip o There were no significant changes to waist circumference from baseline (T0) to
ratio and testicular volume. measurements at 1 (T1), 2 (T2) or 3 (T3) years
Tanner stage is a scoring o T0: 73.9 ±7.3; T1: 73.1 ± 9.0; T2: 72.8 ± 8.1; T3: 73.7 ±9.5
system used to measure o WC SDS compared to Female: Mean ± SD
pubertal development, in this
 There was a significant decrease from 0.72 ± 0.89 at baseline to 0.42 ± 1.10
case for breast development
after 1 year, P < .05
and testicular volume.
Standard deviation scores were  There was a nonsignificant decrease from baseline to 0.27 ± 1.04 after 2
measured using Dutch years
reference data.  There was a nonsignificant decrease from 0.67 at baseline to 0.22 ± 1.29
Bone age, which is a after 3 years (P = NS)
measurement of skeletal and o WC SDS compared to male:
biological maturity, was
 There was a significant decrease from 0.07 ± 1.10 at baseline to 0.42 ± 1.41
determined via a radiograph of
after 1 year (P < .01)
the left hand.
 There was a significant decrease from baseline to -0.75 ±1.38 after 2 years
Height, height SDS, sitting
(P < .01)
height and sitting height SDS
were measured. SDS values  There was a significant decrease from baseline to -0.9 ±1.70 after 3 years
were calculated using Dutch (P < .01)
reference data Hip circumference (cm): Mean ± SD
Anthropometric data was used o There was a nonsignificant increase from 93.9 ± 7.8 cm at baseline to 95.1 ±
to determine BMI, 8.8cm at year 1 (P = NS)
Fat mass, fat percentage and o There was a significant increase from 93.5 ± 8.2 cm at baseline to 97.5 ± 9.0 cm
lean body mass percentages at year 2 (P = 0.003)
were measured using dual o There was a significant increase from baseline to 97.4 ± 7.9 cm at year 3
energy X-ray absorptiometry (P < .05 )
o HC SDS compared to Female:
 There was no significant change from 0.38 ± 0.96 at baseline to 0.37 ±1.07 at
year 1, 0.51 ± 1.09 at year 2 or, 0.42 ± 0.98 at year 3.
o HC SDS compared to male:
 There was no significant change from 0.60 ± 1.16 at baseline to 0.54 ± 1.30
at year 1, 0.70 ± 1.34 at year 2 or 0.64 ± 1.26 at year 3
Waist to Hip ratio: Mean ± SD

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
839

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
o There was a significant decrease in WHR from 0.79 ± 0.04 at baseline, to 0.76 ±
0.05 after one year. (P < .001)
o There was a significant decrease in WHR ratio from baseline, to 0.75 ± 0.05
after 2 years. (P < .001)
o There was a significant decrease in WHR ratio from baseline, to 0.75 ± 0.06
after 3 years. (P < .001)
o WHR SDS compared to Female:
 There was a significant decrease from 0.49 ± 0.68 at baseline to 0.18 ± 0.85
at year 1. (P < .01)
 There was a significant decrease from baseline to -0.16 ± 0.86 at year 2
(P < .001)
 There was a significant decrease from baseline to -0.04 ±1.01 at year 3
(P = .002)
o WHR SDS compared to Male:
 There was a significant decrease from -0.74 ± 0.86 at baseline to -1.19 ± 1.09
at year 1. (P < .01)
 There was a significant decrease from baseline to -1.71 ± 1.06 at year 2
(P < .001)
 There was a significant decrease from baseline to -1.48 ± 1.29 at year 3
(P < .001)
Testicular volume (mL): Mean ± SD
o Testicular volume slightly decreased during the first year of treatment (P = .02),
and did not significantly change thereafter.
o T0: 8 (3-25), T1: 8 (3-23), T2: 10 (3-18), T3: 6.5 (4-11)
Bone age:
o Bone age advances by a median of 1 year during the first year of treatment, 1.5
during the second year and 1 year during the third year. 25 participants in the
study reached a bone age > 15 years, indicating they were near or at their adult
height.
o T0: 14.3 (13-18), T1: 15.5 (13.5-18), T2: 17 (15-19), T3: 18 (16-19)
Sitting Height/Height: Mean ± SD
o There was no significant change in height from baseline: 0.509 ±0.013, to year
1: 0.509 ± 0.014, year 2: 0.513 ± 0.016 or year 3: 0.518 ± 0.158
o Sitting Height/Height SDS Female comparison:
 There was no significant change from baseline: -0.91 ± 0.82 to year 1: -0.98 ±
0.92, year 2: -0.75 ± 1.0, pr year 3: -0.68 ± 0.99
o Sitting Height/Height SDS Male comparison:

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
840

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
 There was no significant change from baseline: 0.15 ± 0.89, to year 1: -0.27 ±
0.94, year 2: -0.07 ± 1.06, or year 3: 0.21 ± 1.12
Height (cm): Mean ± SD
o There was a significant increase in height from 178 ± 6.9 cm at baseline to
181.3 ± 7.1 cm at year 1 (P < .001),
o There was a significant increase in height from baseline to 181.8 ± 8.4 at year 2
(P < .001)
o There was a significant increase in height from baseline to 180.0 ± 9.4 (P < .01)
o Height SDS Female:
 There was a significant increase from 1.48 ±1.11at baseline to 1.85 1.14 at
year 1 (P < .001)
 There was a significant increase from baseline to 1.84 ± 1.32 at year 2
(P < .001)
 There was a significant increase from baseline to 1.53 ± 1.50 (P < .05 )
o Height SDS Male:
 There was a significant increase from -0.08 ±1.15 at baseline to 0.05 ±1.12 at
year 1 (P < .05 ),
 There was no significant change from baseline to year 2 (-0.12 ± 1.24) or year
3 (-0.49 ± 1.36)
BMI: Mean ± SD
o There was no significant change from 20.8 ± 3.0 kg/m² at baseline to 21.0 ± 3.3
kg/m² at year 1 or 21.3 ± 3.7 kg/m² at year 2.
o There was a significant increase from baseline, 21.5 ± 3.2 kg/m² to 21.5 ± 3.3
kg/m² at year 3 (P = .01)
o BMI SDS Female:
 There were no significant change from baseline to any measurement period
 T0: 0.16 ± 1.21, T1: 0.05 ± 1.28, T2: 0.02 ± 1.35, T3: -0.00 ± 1.35
o BMI SDS Male:
 There was a nonsignificant decline from baseline to all measurement periods
 T0: 0.34 ±1.32, T1: 0.12 ±1.40, T2: -0.03 ± 1.44, T: -0.14 ± 1.47
Fat Mass
o There was no significant change from baseline to year 1 or 2, but there was a
significant increase from 17.2 ± 8.1 kg at baseline to 20.5 ± 9.1 kg at year 3
(P = .007)
Lean Body mass %:
o There was no significant change from baseline to any measurement period

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
841

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
o T0: 71 ± 6.5, T1: 72.8 ± 8.2, T2: 72.7 ± 8.9, T3: 70.9 ± 7.6
Fat Percentage:
o There was no significant change from baseline to any measurement period
o T0: 26 ± 7.0, T1:24 ± 8.7, T2: 24 ± 9.3, T3: 25.9 ± 8.1
Jarin (2017)136 N = 116 TGNB adolescents The mean age of the affirmed male and Affirmed male subjects taking Data was collected at baseline BMI:
female subjects was 16 and 18 years, testosterone and affirmed female (or immediately before
Preexisting databases Eligibility: Outpatient data from For affirmed male subjects, testosterone therapy was associated with significantly
respectively. subjects taking estrogen with or initiation of therapy,) at 1-3
adolescents aged 14 to 25 years increasing BMI, changing from a mean baseline BMI of 26.0 kg/m² to 27.3 kg/m²
without testosterone blockers (ie, months after initiation, at 4-6
diagnosed with GD Depression was the most common medical after 6 months (P < .0001).
spironolactone) months after initiation, and at
(International Classification of comorbidity, with 35 subjects (30%)
6 months and beyond. For affirmed female cohort, mean baseline BMI was 23.7 kg/m² and remained
Diseases, Ninth Revision codes reportedly undergoing treatment for
stable during treatment.
302.85 and 302.50) and depression during hormone use. Anthropometric
receiving cross-sex hormone Ten (23%) affirmed female subjects were measurements height/weight,
therapy from 2008 to 2014 were undergoing medical therapy for HIV; no BMI were compared.
included concurrent HIV was reported among the
Sampling method: Clinic and affirmed male subjects.
outpatient records were The longest follow-up time noted was 35
retrospectively reviewed months. Baseline BMI, blood pressure, and
Subset definition: 72 affirmed metabolic values were within normal limits
male subjects and 44 affirmed for all participants.
female subjects Seven affirmed male subjects reported
undergoing puberty suppression with
gonadotropin releasing hormone analogs
before treatment, and 2 reported hormone
use outside the practice of their medical
providers (ie, street hormones). In affirmed
male cohort, mean baseline total
cholesterol levels were within normal limits
at 151 mg/dL, with a corresponding
baseline LDL level of 84 mg/dL.
Previous puberty suppression with
gonadotropin-releasing hormone analogs
was noted in 2 affirmed female subjects,
whereas 5 subjects reported exogenous
street hormone use.
Klaver (2018)83 N = 192 TGNB adolescents Baseline Characteristics: The treatment protocol, referred Participants were assessed at MTF subset findings: mean (95% CI)
to as the Dutch protocol, was the start of GnRH analog
Eligibility Criteria: All persons MTF participants started GnRH analogs at a Waist circumference showed a significant increase from 71 cm (69-73) at start of
followed. therapy, after the addition of
who started hormonal mean age of 14.5 + 1.8 yrs. and CHT at a GnRH to 76 cm (71-82) at 22 yo follow-up, with a change of 8 cm (5-10) ,P < .001
CHT therapy, and at an
treatment before 18 years of mean age of 16.4 + 1.1 yrs. They were At a minimum age of 12 years Hip circumference showed a significant increase from 89 cm (87-91) at start of
appointment near 22 years of
age, started the Dutch mostly Caucasian. and stage B2 (breast) for girls GnRH to 106 cm (102-110) at 22 yo follow-up, with a change of 17 cm (13-21),
age (range 20.5-23.5)
treatment protocol, had and Tanner stage G3 (genital) P < .001

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
842

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
undergone whole-body dual- FTM participants started GnRH analogs at a for boys, subcutaneous GnRH Whole-body and regional body Waist to hip ratio showed a significant decline from 0.81 (0.79-0.82) at start of
energy x-ray absorptiometry mean age of 15.3 + 2.0 yrs. and CHT at a analogs 3.75 mg for 4 weeks fat, LBM, and total mass were GnRH to 0.77 (0.75-0.79) at 22 yo follow-up, with a change of -0.04 (-0.05 to -
(DXA) during treatment, and mean age of 16.9 + 0.9 yrs. was started. measured using DXA. 0.02), P < .001
according to their age had their From 16 years of age, CHT was There was a decrease of the WHR of 0.02 during GnRH analogs alone and a
medical checkups in young added with increasing doses to further decrease of 0.02 after the addition of CHT.
adulthood ( > 20.5 years) were initiate pubertal development.
eligible for this study. The percentage of body fat in the android region significantly increased from 23%
o Transgender women were (21-25) at start of GnRH to 32% (28-36) with a change of 9% (6-12), P < .001
Sampling method: Medical prescribed oral 17b-
records were retrospectively The percentage of body fat in the gynoid region significantly increased from 29%
estradiol starting at 5 mg
reviewed for all adolescents (27-30) at start of GnRH to 40% (38-42) with a change of 11% (9-12), P < .001
per kilogram of body weight
diagnosed with gender per day, which was The percentage of total body fat significantly increased from 25% (23-26) at start
dysphoria from 1998 until increased by 5 mg/kg per of GnRH to 34% (32-36) with a change of 9% (8-11), P < .001
December 2015. All patients day every 6 months until the There was an increase of percentage of total body fat of 6% (4-7) during GnRH
who met criteria were included maintenance dose of 2 analogs alone and a further increase of 3% (1-5) after the addition of CHT.
in the study. Despite missing mg/day was reached.
data, selection bias was not The percentage of Lean body mass significantly decreased from 75% (74-77) at
found. o Transgender men used start of GnRH to 66% (64-68) with a change of -9% (8-11), P < .001
initially mixed testosterone
Subset definition: N = 192 TGNB There was a decrease of the percentage of lean body mass of 6% during GnRH
esters (Sustanon; Organon
adolescents, MTF (N = 71) and analogs alone and an additional decrease of 3% after the addition of CHT.
Pharmaceuticals, Oss, The
FTM (N = 121) adolescents Netherlands) WHR and body composition changed towards the affirmed sex
intramuscularly starting at FTM subset Findings: Mean (95% CI)
25 mg per square meter of
body surface area every 2 Waist circumference showed a significant increase from 71 cm (69-73) at start of
weeks, which was increased GnRH to 77 cm (75-79) at 22 yo follow-up, with a change of 6 cm (4-8), P < .001
by 25 mg/m² every 6 Hip circumference showed a significant increase from 92 cm (90-93) at start of
months until the GnRH to 96 cm (94-99) with a change of 5 cm (2-7) at 22 yo follow-up, P < .001
maintenance dose of 250
Waist to hip ratio showed a significant increase from 0.77 (0.76-0.78) at start of
mg every 3 to 4 weeks was
GnRH to 0.80 (0.78-0.82) with a change of 0.03 (0.01 to 0.04) at 22 yo follow-up,
achieved.
P < .001
When GnRH analog was
There was a decrease in the WHR of 0.01 (-0.02-0) on GnRH analogs alone, and an
started after 16 years of age,
increase of 0.04 (0.02-0.05) after the addition of CHT
CHT was added after 3 to 6
months with a start dosage of The percentage of body fat in the android region showed no significant change
17b-estradiol 1 mg/day or from 29% (27-30) at start of GnRH to 30% (28-32) with a change of 1% (0-3),
intramuscular Sustanon 75 P = .18
mg/week. After 6 months, this The percentage of body fat in the gynoid region significantly decreased from 36%
was increased to 17b-estradiol (35-37) at start of GnRH to 31% (30-33) with a change of -5% (-6 to -3), P < .001)
2 mg/day in transgender
The percentage of total body fat significantly decreased from 30% (29-31) at start
women and Sustanon 250 mg
of GnRH to 27% (26-28) with a change of -3% (-4 to -2), P < .001
every 3 to 4 weeks in
transgender men. There was an increase of total body fat percentage of 3% (2-4) on GnRH analogs
alone, and a decrease of 6% (-8 to-4) after the addition of CHT
From 18 years, patients were
eligible for gonadectomy, after

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
843

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
which treatment with GnRH The percentage of Lean body mass significantly increased from 70% (69-71) at
analogs ceased. start of GnRH to 73% (72-74) with a change of 3% (2-4), P < .001
There was a decrease of lean body mass percentage of 3% (-4 to -2) on GnRH
analogs alone, and an increase of 6% (4-8) after the addition of CHT
WHR and body composition changed towards the affirmed sex
Klaver (2020)139 N = 192 TGNB subjects All transgender subjects started GnRH GnRH analog treatment with a Measurements were taken at BMI
analog treatment at a mean age of 15 and subsequent addition of CSHs. the start of GnRH analog
Eligibility: subjects were Trans women
CSH treatment at a mean age of 17. The Dutch protocol was treatment, and then followed
the included (1) if they had started o There was a significant increase in BMI during GnRH analog treatment alone.
White participants accounts for 98% of followed. up at the addition of CSH and
Netherlands) from treatment with GnRH analogs The mean change (95% CI) was +1.1 kg/m² (0.7 to 1.5), P < .001
subjects in trans women group and 94% of again at age 22y (range 20.5-
1998 to December before the age of 18, (2) if
subjects in trans men group. 23.5) o There was a significant increase in BMI between start of CSH treatment and 22
2015 whole body dual-energy
radiograph absorptiometry was BMI: Calculated as weight in y. Mean change (95% CI) was +1.9 kg/m² (0.6 to 3.2), P < .005.
In trans women group, duration of GnRH
performed at least once during analogs monotherapy [median (IQR)] = 2.1 kilograms divided by height in Trans men
treatment (4 months before or (1.0–2.7), duration of GnRH analogs + CSH meters squared.
o There was a significant increase in BMI during GnRH analog treatment alone.
after the start of GnRH analogs [median (IQR)] = 3.1 (2.5–3.6) and duration The mean change (95% CI) was +0.9 kg/m² (0.5 to 1.3), P < .001;
or CSH treatment or within 1.5 CSH monotherapy [median (IQR)] = 2.2
years before or after the 22nd o There was a significant increase in BMI between start of CSH treatment and 22
(1.1–3.1); y. The mean change (95% CI) was +1.4 kg/m² (0.8 to 2.0), P < .001.
birthday), and (3) if, on the basis
of their age, they were likely to In trans men group, duration of GnRH
analog monotherapy [median (IQR)] = 1.0
have had at least 1 medical
consultation in young adulthood (0.5–2.9), duration of GnRH analogs + CSH
( > 20.5 years [median (IQR)] = 2.3 (1.8–2.8) and duration
CSH monotherapy [median (IQR)] = 2.9
Sampling method: Medical (1.7–3.4
records of all adolescents
diagnosed with gender
dysphoria at this medical center
were retrospectively reviewed.
Subset: n = 71 trans women and
n = 121 trans men
Klink (2015)140 N = 34 TGNB adolescents Median age of trans women was 14.9 ± 1.9 GnRH analog monotherapy Baseline Data was collected at Trans women (n = 15)
at start of GnRH analogs, 16.6 ± 1.4 at start (median duration in natal boys start of GnRH analogs, start of
Unspecified tertiary Eligibility Criteria: Study Height
of CSH and 22.1 ± 0.9 at 22 year follow up with GD [trans women] and CSH therapy and at follow-up
referral center in subjects were included when o There was a significant increase in height, from 174.6 ± 8.9 cm at start of GnRH
Median age for trans men was 15.0 ± 2.0 at natal girls with GD [trans men] near age 22
the they were at least 21 years of analogs to 179.9 [17.1]cm at start of CSH, P = 0.01, and from 179.9 [17.1]cm at
start of GnRH analogs, 16.4 (2.3) at start of 1.3 and 1.5 y, respectively) Height (in cm) and weight (in
Netherlands age, gonadectomy had taken start of CSH to 181.0 ±9.3 cm at age 22y, P = .001
CSH and 21.9 ± 0.5 at 22 year follow up followed by CSH (median kg) were taken and BMI
place in the period from June
duration in trans women and calculated o There was a significant decrease in height SDS from 0.14 ± 1.3 at start of GnRH
1998 to August 2012, and data Median duration of GnRH analog trans men, 5.8 and 5.4 y, analogs to -0.97 ± 1.3 at start of CSH, P = .001. There was a nonsignificant
on BMD at start of GnRH analog monotherapy in trans women and trans respectively) with increase from start of CSH to -0.42 ±1.3 at age 22y
treatment, at start of CSH men was 1.3 years (range, 0.5–3.8) and 1.5 discontinuation of GnRH
therapy, and at the age of 22 years (range, 0.25–5.2), respectively. Weight
analogs after gonadectomy.
years were available. The 34
eligible subjects and their

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
844

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
parents or legal representatives Median duration of CSH therapy was 5.8 Treatment protocol: Triptorelin o There was a significant increase in weight, from 64.8 ± 10.4kg at start of GnRH
gave written consent for follow- years (range, 3.0–8.0) and 5.4 years (range, (Decapeptyl-CR, Fer- ring) 3.75 analogs to 67.0 ± 10.2kg at start of CSH, P = .004 and from start of CSH to 74.6 ±
up at start of treatment. 2.8–7.8), respectively. mg every 4 weeks s.c. was 14.5 kg at age 22y, P = 0.01
Sampling Method: Patients that The median duration of combined GnRH started in patients diagnosed BMI
met criteria were included analog and CSH therapies was 3.1 years with gender identity disorder
(DMS IV-TR) in the age range o There was a significant increase in BMI, from 20.3 ± 2.3 kg/m² at start of GnRH
Subset: of the total population (range, 2.1– 4.5) and 2.2 years (range, 1.4 – analogs to 21.2 ± 2.8 kg/m² at start of CSH, P = .01. There was a nonsignificant
3.1), respectively. from 11.4 –18.3 years. In the
(N = 34) there were (n = 15) age range from 15.6 –19 years increase to 22.7 ± 4.4 kg/m² at age 22y
trans women and (n = 19) trans trans- women were prescribed o There was a nonsignificant decrease in BMI-SD from 0.17 ± 0.90 at start of
men incremental dosing of 17- GnRH analogs to 0.07 ± 1.11 at CSH and from start of CSH to 0.62 ± 2.1 at age
estradiol orally and trans men 22y.
were given in mixed T esters Trans men (n = 19)
(Sustanon 250 mg/ml, MSD)
every 2–4 weeks in Height
incremental dosages. At a o There was a significant increase in height from 165.2 ± 9.1 cm at start of GnRH
minimum age of 18 years, after analogs to 168.4 ± 8.3 cm at start of CSH, P = .03 and from start of CSH to 170.6
gonadectomy, GnRH analog ± 7.9cm, P = .0001
treatment was terminated and
o There was no significant change in height-SDS from -0.06 ±1.2 at start of GnRH
CSH therapy continued. During
analogs to -0.1 ±1.3 at start of CSH and -0.1 ±1.2 at 22y.
the entire treatment patients
were advised on calcium intake Weight
and weight- bearing physical o There was a significant increase in weight from 57.6 ±12.1 kg at start of GnRH
exercise analog therapy to 64.1 ± 11.5 kg at start of CSH, P = 0.01.
o There was a nonsignificant increase to 68.2 ± 9.8kg at age 22y from start of CSH
BMI
o There was a significant increase in BMI, from 20.9 ± 3.2 kg/m² at start of GnRH
analogs to 22.9 ± 3.7 kg/m² at start of CSH.
o There was a non-significant increase to 23.4 ±2.6 at 22y from start of CSH.
o There was a non-significant increase in BMI-SDS from 0.3 ±1.0 at start of GnRH
analogs to 0.5 ± 1.2 at start of CSH and from start of CSH to 0.96 ± 1.2 at age
22y
Laurenzano (2021)84 N = 119 TGNB individuals assigned Average age at presentation to clinic was 16 Subcutaneous testosterone Patients were assessed before BMI (mean scores)
female at birth years. Average age of starting SC-T was 16.5 injections starting at 50 to 100 starting testosterone as a baseline, o BMI significantly increased from baseline 24.85 to 25.71 kg/m² at follow
A US gender/endocrine
years. 110 patients were transgender males, 3 mg/month in two injections. and then followed up at most (P < 0.001)
(doesn't specify) clinic Eligibility: Younger than 21
were nonbinary, 6 patients were classified as recent testosterone lab check
years when starting T and o There was no significant change of BMI z-score (baseline was 0.56, follow up z-
"other." 99 patients had no menstrual
received T for a minimum of 6 Body mass index (BMI), which score was 0.5, P = NS)
suppression before starting T, 12 used GnRH
California months, assessed by mental is a value derived from the
analogs and 8 used contraceptive. Average  BMI z-score at follow up was only available for 95 patients, as 24 patients
health professional to make height and mass of each
BMI was 24. aged out. The baseline BMI z score given is for the 95 patients.
sure they were ready to start T patient was calculated. BMI z-
and met diagnostic criteria for score, which compares BMI to Overall change in free and total T and estradiol: (mean levels)
GD. a person of similar age and o There was a significant increase in Total T from 31.6 to 432.2 dg/dL (P < .001),
gender. Values for the z-score

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
845

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
Sampling method: Patients were taken from the CDC for o There was a significant increase Free T from 3.7 to 86.2 pg/mL (P < .001),
were selected if they met age 2-20 cisgender females. o There was a significant decrease in Estradiol from 78.9 to 49.1 pg/mL (P < .001)
criteria and were a patient of Hormone levels were assessed
the clinic. Change in free and total T: significant in each dosing group
for total and free testosterone
and estradiol o SC-T < 160 mg:
 Total T: 29.2 baseline to 328.8 ng/dL (P < .001)
 Free T 3.8 to 53.9 pg/mL (P < .001)
 Estradiol: 81.3 to 52.9 pg/mL (P = NS )
o SC-T 160 to 240 mg:
 Total T: 31.6 to 456.8 ng/dL (P < .001)
 Free T: 3.6 to 91.9 pg/mL (P < .001)
 Estradiol: 79.6 to 48.4 pg/mL (P < .001)
o SC-T > 240 mg:
 Total T 37.8 to 522.6 ng/dL (P < .001)
 Free T 4.5 to 124.6 pg/mL (P < .001)
 Estradiol 68.6 to 47.3 pg/mL (P = NS)
Navabi (2021)92 N = 119 transgender males (for this Mean LBM z-score (SD) being -1.03 (1.22); GnRH analogs Participants were assessed at Body composition changes, (n = 80) Mean (95% CI)
subset) mean TBF (SD) was 37.14% (10.46) with the GnRH analog initiation and
Endocrine diversity significant increase in BMI with a mean post-pre difference of 1.36 kg/m² (0.75 to
mean TBF z-score (SD) being 1.68 (0.96); mean then at a follow-up
clinic Eligibility: patients < 18 years 1.97), P < .001
BMI (SD) was 24.04 kg/m² (5.17) with the appointment at least 18
old starting/on GnRH analog non-significant increase in the BMI z-score, with a mean post-pre difference of
mean BMI z-score (SD) being 0.89 (1.25) months after start of therapy.
from treatment with one baseline 0.15 (0.01 to 0.29), P = NS
January 2006 to April DEXA measurement Anthropometrics were
2017 retrieved from medical records no change in TT-FMR, mean post-pre difference: 0.00 (-0.01 to 0.01), P = NS
Sampling method: all patients
and z scores calculated from no change in LT-FMR, mean post-pre difference: 0.00 (-0.01 to 0.00), P = NS
from January 2006 to April 2017
2014 WHO growth charts for
were reviewed, and about no change in ET-FMR, mean post-pre difference: 0.00 (-0.02 to 0.02), P = NS
Canada
86.9% were included as they
significant increase in Android fat %, with a mean post-pre difference: 2.75% (1.21
had a baseline DEXA
to 4.28), P < .001
measurement
significant increase in Gynoid fat % with a mean post-pre difference: 1.83% (0.77
to 2.88), P < .001
significant increase in TBF in kg with a mean post-pre difference: 2.19 (0.75 to
3.63), P = .001
significant increase in TBF in %, with a mean post-pre difference: 2.21 (0.99 to
3.43), P < .001
non-significant increase in TBF z-score in %, with mean post-pre difference: 0.13
(0.00 to 0.25), P = NS
significant increase in LBM in kg, with a mean post-pre difference: 1.05 (0.45 to
1.64), P < .001

Abbreviations: BA, bone age; BMI, body mass index; BP, blood pressure; CI, confidence interval; DXA, dual-energy radiograph absorptiometry; ET-FMR, extremities/trunk fat mass ratio; GAHT, gender-affirming hormone therapy; GD, gender dysphoria; LBM, lean
body mass; LT-FMR, legs/total fat mass ratio; N/A, not applicable; N/R, not reported; PAH, predicted adult height; PS, puberty suppression; SD, standard deviation; T, testosterone; TBF, total body fat; TGNB, transgender, non-binary, or gender-diverse; TT-FMR,
Trunk/total fat mass ratio
846

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Table I.L.3. Longitudinal pre-post studies evaluating body change outcomes in TGNB patients
First author
(publication year) Population Select baseline characteristics Exposure/intervention Outcome measures and timing Results
and study setting
non-significant decrease in LBM z-score, with a mean post-pre difference: -0.02 (-
0.16 to 0.12), P = NS
N = 51 transgender females (for Mean LBM (SD) was 45.74 kg (9.98) with the GnRH analogs Participants were assessed at Body composition changes
this subset) mean LBM z-score (SD) being -1.19 (1.45); GnRH analog initiation and
non-significant increase in BMI, with a mean post-pre difference: 0.57 kg/m² (-
mean TBF (SD) was 24.45% (12.48) with the then at a follow-up
Eligibility: patients < 18 years 0.46 to 1.60), P = NS
mean TBF z-score (SD) being 1.42 (1.02); mean appointment at least 18
old starting/on GnRH analog non-significant decrease in BMI z-score, with a mean post-pre difference: -0.10 (-
BMI (SD) was 23.22 kg/m² (6.33) with the months after start of therapy.
treatment with one baseline 0.38 to 0.17), P = NS
mean BMI z-score (SD) being 0.62 (1.67)
DEXA measurement Anthropometrics were
retrieved from medical records non-significant decrease in TT-FMR, with a mean post-pre difference: -0.02 (-0.03
Sampling method: all patients to 0.00), P = .010
and z scores calculated from
from January 2006 to April 2017
2014 WHO growth charts for significant increase in LT-FMR, with a mean post-pre difference: 0.01 (0.00 to
were reviewed, and about
Canada. 0.02), P = .013
86.9% were included as they
had a baseline DEXA significant increase in ET-FMR, with a mean post-pre difference: 0.08 (0.02 to
measurement 0.13), P = .004
significant increase in Android fat %, with a mean post-pre difference: 4.18 (1.09