Drugs in

Obstetrics and
Gynecology
A Practical Approach
Part II Gynecology
Drugs in
Obstetrics and
Gynecology
A Practical Approach
Part II Gynecology
Ruchika Garg
Fellow Indian Menopause Society FIMS
Professor, Department of Gynecology
SN Medical College, Agra, India
Editor-in-Chief Journal of Midlife Health
Executive Editor Journal of SAFOG

Priya Vora Thakur

DNB, FICOG, FCPS, DFP, DGO, MBBS
Consultant, Department of Gynecology, Saint Elizabeth
Bhatia, Ruxmani and Dr Vora’s Hospitals
Mumbai, India

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 Contributors

Aaishwarya R MBBS MS DNB Archana Bhosale MS DGO FCPS FICOG

Assistant Professor Associate Professor
Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology
Seth GS Medical College and LTMMC and LTMGH, Sion Hospital, Mumbai
Wadia Maternity Hospital, Mumbai
Asha Dalal MD DGO MBBS
Amarjeet Kaur Bava DGO MD Head, Department Obstetrics and Gynecology
Associate Professor Sir HN Reliance Foundation and Research Centre
Department of Obstetrics and Gynecology
Mumbai
LTMMC and LTMGH Sion Hospital, Mumbai
Ashwin Shetty MD DFFP MRCOG CCST FRCOG
Ameya Medhekar MD DTM and H CTropMed
Consultant, Department of Obstetrics and Gynecology
Consultant Physician
Department of Medicine Sir HN Reliance Foundation Hospital and Research
Specialist in Tropical Medicine Centre, Mumbai
Lilavati Hospital and Resem arch Centre, Mumbai Ashwini Hotkar MS DNB ADART FII (Fellowship in infertility
Ameya Purandare MBBS DGO FICOG DNB MD Senior Resident
Consultant Department of Obstetrics and Gynecology
Department of Obstetrics and Gynecology, Bhatia LTMMC and GH, Sion Hospital, Mumbai
Hospital, HN Reliance, Purandare Hospitals
Naigaon Maternity Hospital, Mumbai Asmita Patil MS
Associate Professor and Unit In-charge
Anahita Chauhan MD DGO MBBS Department of Obstetrics and Gynecology
Consultant HBT Medical College and Dr RN Cooper Hospital
Department of Obstetrics and Gynecology Mumbai
Saifee and St. Elizabeth Hospitals Mumbai
Amrita Tandon MS DNB FMAS MRM (London)
Arundhati Tilve DNB DGO
Consultant, Department of Obstetrics and
Assistant Professor
Gynecology, IVF and Endoscopic Surgeon
Department of Obstetrics and Gynecology
Dr Sudha Tandon IVF Maternity and
TNMC and BYL Nair Hospital, Mumbai
Gyn Endoscopy Hospital Chembur and Vashi
Anjaly Raj MBBS MD
Consultant, Department of Gynecology Avir Sarkar MBBS MD
All India Institute of Medical Sciences Senior Resident
New Delhi ESIC Medical College and Hospital NIIT
Faridabad
Anusha Devalla MBBS MS DNB
Assistant Professor Bhavini Shah DGO DNB
Department of Obstetrics and Gynecology Consultant
All India Institute of Medical Sciences, Bibinagar Department of Obstetrics and Gynecology
Private Practitioner Saifee Hospital and Medical Research Centre and
Gayatri Hospital, Ramanthapur, Hyderabad Masina Hospital, Mumbai
vi Drugs in Obstetrics and Gynecology

Bhumika Kotecha Mundhe DGO DNB MNAMs FICOG Jiteeka Thakkar

Consultant MBBS DGO DFP BDRME (Germany) ADRM (Germany)
Department of Obstetrics and Gynecology Consultant
Masina, Saifee, Ruxmani, Wockhardt, Department of Gynecology
St. Elizabeth and NH-SRCC Hospitals, Mumbai Bloom IVF Lilavati Hospital
PPNH Opera House
Charumati V Pekhale MBBS DGO DNB
Infertility Specialist Kairavi H Gokani MBBS DNB MRCOG ICOG
Consultant, Department of Obstetrics and Consultant
Gynecology, NOVA IVF, Nasik Department of Gynecology
Ankur Fertility Clinic
Devika Chopra MBBS DNB MSC (Oxford UK)
Fellowship in Reproductive Medicine Diploma in
Department of Obstetrics and Gynecology
Reproductive Medicine and IVF (Kiel, Germany)
Bhatia, Elizabeth, Wockhardt
Fellowship in Minimal Access Surgery, Mumbai
SRCC Hospitals, Mumbai
Kedar N Ganla MBBS MD DNB FCPS DGO DFP
Danny Laliwala MD FCPS DGO DFP
Consultant
Consultant
Department of Obstetrics and Gynecology
Department of Obstetrics and Gynecology
Jaslok Breach Candy, Saifee, Masina, Wockardt, Family Physician, Ankoor Fertility Clinic, Mahim,
SRCC Hospitals, Mumbai Mumbai

Ganpat Sawant Kinjal Shah MBBS DGO DNB

DNB DICOG DFP FCPS DGO MD Consultant
Department of Obstetrics and Gynecology
Ex-Professor and Head
Department of Obstetrics and Gynecology Bhatia Ruxmani Hospital, Mumbai
DY Patil Medical College, Navi Mumbai Kiran Guleria MBBS MS
Geetha Agarwal CIMP FAMS MD Professor and Director
Department of Obstetrics and Gynecology
Consultant, Department of Obstetrics and
Gynecology, Heritage Hospital, Raipur UCMS and GTB Hospital, Delhi

Geetha Balsarkar MD Komal Chavan

Professor and Head MD DNB MNAMS FCPS DGO FICOG
Department of Obstetrics and Gynecology Diploma in Reproductive Medicine (UK-SH)
Seth GS Medical College, Nowrosjee Wadia Chairperson FOGSI Medical Disorders in Pregnancy
Committee (2019-2022)
Maternity Hospital, Parel, Mumbai
Senior Consultant
Isha Wadhawan Department of Obstetrics and Gynecology
MBBS MD MRCOG Diplomate ABOG DNB Teacher, V N Desai Hospital Mumbai
Consultant
Department of Obstetrics and Gynecology Madhuri Patel MD DGO FICOG
Secretary General, FOGSI
Fortis Escorts Hospital, NIT, Faridabad
Hon. Consultant, Police Hospital
Indra Prasad MBBS MS Visiting Consultant, St. Elizabeth Hospital, Mumbai
Associate Professor
Department of Obstetrics and Gynecology Madhuri Mehendale DNB FCPS DGO
All India Institute of Medical Sciences, Patna Diploma in Advance Laparoscopy and Infertility
Assistant Professor
Jagruti Ghosh MBBS DNB OBGY Department of Obstetrics and Gynecology
Consultant LTMMC and LTMGH Sion Hospital
Department of Obstetrics and Gynecology Consultant, Department of Obstetrics and
JUANA Mother and Child Care Hospital LLP Gynecology
Wockhardt and Family Care Hospital, Mumbai ZYNOVA Multispeciality Hospital, Mumbai
 Contributors vii

Malavika JC MBBS MS Mukta Agarwal MBBS MD FICOG

Associate Professor Additional Professor
Department of Gynecology Department of Obstetrics and Gynecology
SS Institute of Medical Sciences and Research AIIMS, Patna
Centre, Davangere, Karnataka
Neha Kamath MD DNB
Manan Boob MBBS MS (ObGy) Assistant Professor
Consultant Department of Obstetrics and Gynecology,
Department of Obstetrics and Gynecology LTMMC and LTMGH Sion Hospital, Mumbai
Subham Hi Tech Hospital, Amravati
Neha Rajji Matthews MBBS DGO DNB
Mandakini Megh MD DGO FICMCH FICMU FICOG Consultant
Chairperson, ICOG-FOGSI Department of Obstetrics and Gynecology
International Vice President, MWIA Central Asia Mulund Fortis Hospital, Mumbai
Consultant, Department of Obstetrics and
Gynecology, Gynae-O-Care Clinic, Mumbai Niraj Mahajan MBBS MS
Head of Unit
Mansi Medhekar MBBS MS DNB FICOG Department of Obstetrics and Gynecology TNMC
Consultant and BYL Nair Hospital, Mumbai
Department of Obstetrics and Gynecology
Lilavati Hospital and Research Centre Nishita Shah MBBS DGO MD
SL Raheja, Fortis Hospital, Surya Hospital Consultant
Mumbai Department of Obstetrics and Gynecology
St. Elizabeth and Saifee Hosptials, Mumbai
Mamta Gupta MD (Obs. Gynae)
Consultant Gynecologist and Former Head Nidhi Shah DNB DGO IFCPC-IARC Colposcopy
Department of Obstetrics and Gynecology Consultant
Hindu Rao Hospital and associated NDMC Medical Department of Gynecology
College, Delhi, India Jaslok Hospital and Dr Vora’s Hospitals, Mumbai
Mala Arora FRCOG (UK) FICOG DA (UK) D OBST (Ire) Niharika Sethi
Director Senior Resident
Department of Obstetrics and Gynecology Department Obstetrics and Gynecology
Noble IVF Centre, Faridabad VMMC and SJ Hospital, New Delhi
Senior Consultant
Department of Obstetrics and Gynecology Pariskshit Tank
Fortis La Femme GK2, New Delhi MD DNB FCPS DGO DFP MNAMS FICOG FRCOG
Consultant, Department of Obstetrics and
Meenal Sarmalkar MD DGO MBBS Gynecology, Ashwini Maternity and Surgical Hospital
Associate Professor and Jupiter Hospital, Mumbai
Department of Obstetrics and Gynecology
LTMMC and LTMGH, Sion Hospital, Mumbai Pradnya Changede MS FICOG FCPS DGO IBCLC
Associate Professor
Milan Balakrishnan MBBS MD Department Obstetrics and Gynecology
Consultant, Department of Psychiatry LTMMC and LTMGH, Sion Hospital, Mumbai
Bombay Hospital and Medical Research Centre,
Mumbai Priyanka Vora MBBS DGO FCPS DFP (GOLD) BIMIE
Masters In Reproductive Medicine and IVF (UK)
Moushmi Parpillewar Tadrs Diploma in Reproductive Medicine and IVF (Kiel,
MBBS DGO DNB FICOG FMAS Germany)
Associate Professor Associate Consultant
Department of Obstetrics and Gynaecology Department of Gynecology
Government Medical College, Nagpur Ankoor Fertility Clinic, Mahim, Mumbai
viii Drugs in Obstetrics and Gynecology

Priyanka Mathe MBBS MS Rahul Mayekar MD DGO

Assistant Professor Associate Professor and Head of Unit
Department of Obs and Gyn Department Obstetrics and Gynecology
UCMS and GTB Hospital, Delhi LTMMC and LTMGH Sion Hospital, Mumbai
Punit Bhojani MS DNB FICOG FCPS Rajendra Nagarkatti MD FICOG FCPS DGO DFP
Consultant Consultant
Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology and IVF
Bhojani Clinic, Consultant at Surya, SRCC, Somaiya Specialist Ashirwad Maternity and General Hospital
and Masina Hospitals, Mumbai Mira Bhayander, Mumbai
Purnima Satoskar MD DNB FRCOG Rajeshwari L Khyade MBBS DGO DNB FMAS
Consultant Senior Consultant and DNB Teacher
Department Obstetrics and Gynecology Department of Gynecology
Jaslok Hospital KB Bhabha Hospital, Mumbai
Wadia Hospital, Mumbai
Rajshree D Katke MD OBGY FICOG FMAS
Pradnya Supe MS Obs and Gyn, IBCLS Professor
Fellowship in Laparoscopy, Ex-Assistant Professor Department of Obstetrics and Gynecology
Department of Gynecology Grant Government Medical College, Mumbai
LTMMC and LTMGH, Sion, Zen and SRV Hospitals
Mumbai Rana Choudhary
MBBS DNB DGO DFP DCR FCPS FICOG FICMCH MNAMS
Preeti Frank Lewis MD Masters in Reproductive Medicine and IVF (UK)
Associate Professor
Senior Consultant
Department Obstetrics and Gynecology
Department of Obstetrics and Gynecology
GGMC and Sir JJ Group of Hospital, Mumbai
Wockhardt Hospital, Mumbai
Priti Vyas MD DGO FCPS FICOG MSC
Consultant, Department Obstetrics and Gynecology
Rashmi Jalvee MS DGO DNB MRCOG
Assistant Professor
Sangita Maternity Surgical and Diagnostic Centre
Hinduja Hospital, Surya Mother and Child Care Centre Department Obstetrics and Gynecology
HBT Medical College and Dr RN Cooper Hospital,
KLS Memorial Hospital, Mumbai
Mumbai
Priya Vora MBBS DNB FCPS FICOG DGO DFP
Senior Consultant Rashmi Kahar MBBS DGO FICOG FICMCH
Department of Obstetrics and Gynecology Consultant, Department of Gynecology
Dr Vora’s hospital, Saint Elizabeth, Ruxmani, Bhatia, Kharodkar Hospital, Sai Nagar, Amaravti
Wockhardt Hospitals, Mumbai Rashmi Upadhyay MBBS MS
Prabhat Kumar Agrawal Senior Resident, Department of Gynecology
Professor, Department of Medicine GSVM Medical College, Kanpur
SN Medical College, Agra 414/2 Adarsh Nagar, Manduadih, Varanasi

Pratima Verma MBBS MS Reena Wani

Associate Professor MD FRCOG FICOG DNBE DGO DFP FCPS
Department of Gynecology Additonal Professor and Head
GSVM Medical College, Kanpur Department of OBGY, HBT Medical College and Dr
RN Cooper Hospital, Mumbai
Pooja Mishra MS
Senior Resident Reeta Bansiwal
Department of Obstetrics and Gynecology Professor, Department of Obstetrics and Gynecology
KG Medical College, Lucknow VMMC and Safdarjung Hospital, New Delhi
 Contributors ix

Reshma Palep MS DNB MRCS(Ed) Shweta Khade DNB (OBGY) DGO Dip. ART
Consultant Assistant Professor
Department of Gynecology Department Obstetrics and Gynecology
Breast Surgeon, Sir HN Reliance Saifee, Dr Palep’s LTMMC and LTMGH, Sion Hospital, Mumbai
Nursing Home, Mumbai
Shilpa Agrawal DGO FCPS DNB FNB
Ritu Bharadwaj MBBS MS Consultant
Junior Resident, Department Gynecology Department Obstetrics and Gynecology
SN Medical College, Agra High Risk Pregnancy and Fetal Medicine Specialist.
Jaslok Hospital and Research Centre
Rohan Palshetkar MS FRM IVF Specialist ADRM
Dr G Deshmukh Road, Mumbai
(Germany) DRME (Gemany)
Consultant, Department Obstetrics and Shreedevi Tanksale
Gynecology, Palshetkar-Patil Nursing Home Breach DNB DGO DFP Diploma in Reprod. Med.
Candy Hospital, Surya Hospital, Mumbai Little Miracles Fertility Clinic
Roopali Sehgal MBBS MS Consultant, Department of Obstetrics and Gynecology
Resident, Department of Obstetrics and Gynecology Surya Mother and Child Care, Criticare Asia Hospital,
GGMC and Sir JJ Group of Hospital, Mumbai Apollo Spectra, Mumbai

Ruchika Garg Shreya Prabhoo MBBS DNB DGO MNAMS FICOG

Fellow Indian Menopause Society FIMS Consultant
Professor, Department of Gynecology Department of Obstetrics and Gynecology
SN Medical College, Agra, India Mukund Hospital, L&T Healthcare Centre
Editor-in-Chief Journal of Midlife Health Visiting Consultant, Surya Hospital, Mumbai
Executive Editor Journal of SAFOG
Siddesh Iyer MBBS DGO DNB MRCOG (London)
Sangeeta Agrawal MD DNB DGO FRCOG Consultant
Consultant Department Obstetrics and Gynecology
Department of Obstetrics and Gynecology Laparoscopic Surgeon, Director, Saukhyam
Bhatia and Breach Candy hospital, Mumbai Hospital
Ex-Assistant Professor, Cooper and JJ Hospital DNB
Sarita Bhalerao MD DNB FRCOG Consultant BDBA, Mumbai
Senior Consultant
Obstetrics and Gynecology, Reliance HNH, Bhatia, Suchitra N Pandit MBBS FRCOG MD
Saifee, Breach Candy Hospital St. Elizabeth, Wadia Senior Consultant
Maternity Hospital, Mumbai Department of Obstetrics and Gynecology
Surya Hospital, Mumbai
Seema Mehrotra MS
Professor, Department of Obstetrics and Sudha Tandon MD DGO
Gynecology, KGMC, Lucknow Director, Dr Sudha Tandon IVF
Maternity and Gyn Endoscopy Hospital
Shailesh Kore
Chembur and Vashi
MD DNB MNAMS FCPS DGO DFP DICOG
Head, Department Obstetrics and Gynecology Sana Ismail MS
Nair Hospital and TN Medical College, Mumbai Senior Resident
Shaily Agarwal MBBS MS Department of Gynecology
Professor, Department of Gynecology SN Medical College, Agra
GSVM Medical College, Kanpur
Sujata Dalvi MD DGO FCPS FICOG
Shraddha Mevada MS Consultant
Assistant Professor Department of Obstetrics and Gynecologist
Department of Obstetrics and Gynecology Global Saifee, Bhatia, St. Elizabeth Hospitals
HBT Medical College and Hon Clinical Associate–Nowrosjee Wadia
Dr RN Cooper Hospital, Mumbai Jagjivan Ram Hospital, Mumbai
x Drugs in Obstetrics and Gynecology

Sunil Tambvekar Usha Saraiya MD DGO FIAC FRCOG (UK)

MBBS DNB MNAMS DFB FMAS PGDMLS Consultant, Department Obstetrics and Gynecology
Consultant Saifee, Breach Candy and St. Elizabeth Hospitals
Department of Obstetrics and Gynecology Mumbai
Assistant Professor, Department of Obstetrics and
Vandana Walvekar MD DGO DPF FAMS
Gynecology, Nowrosjee Wadia Maternity Hospital
Consultant, Department Obstetrics and Gynecology
Seth GS Medical College, Mumbai Wadia Hospital and Bhatia Breach Candy Hospital
Shalini Bhatija MBBS DNB MS Mumbai
Clinical Associate Vidya Thobi MD MS FICOG
Department of Obstetrics and Gynecology Jaslok Professor, Department Obstetrics and Gynecology
Hospital, Mumbai AL-Ameen Medical College, Bijapur
Tejal Poddar MS DFP Vijaya Babre2
Consultant MS DNB FCPS DGO DFP FICOG MNAMS DHA
Department in Reproductive Medicine Senior Consultant
Little Miracles Fertility Clinic, Saifee, Bhatia Department Obstetrics and Gynecology
Elizabeth, Apollo Spectra, SRCC, Ruxmani DNB Teacher, Khan Bahadur Bhabha Municipal
Hospitals, Mumbai Hospital, Kurla, Mumbai
 Foreword
As the field of obstetrics and gynaecology continues to advance, it is
essential for healthcare professionals to remain up-to-date and well-
informed. The book Drugs in Obstetrics and Gynecology: A Practical
Approach covers a wide range of topics, from the use of drugs during
pregnancy and lactation to the management of common gynecological
conditions, such as endometriosis, polycystic ovary syndrome (PCOS),
and menopause. The discussion on the use of hormonal therapies,
including oral contraceptives and hormone replacement therapy, is
particularly informative and highlights the potential risks and benefits
associated with these drugs.
The book also provides detailed information on the use of drugs in the management of
infertility and assisted reproductive technologies, as well as the management of obstetric
complications, such as pre-eclampsia, gestational diabetes, and postpartum hemorrhage.
Additionally, the book provides information on the use of drugs for the management of
gynecological cancer, such as ovarian, endometrial, and cervical cancer.
One of the unique features of this book is the practical approach in which it is written.
The book provides breadth, depth and expansive research from many medical experts in
the field of reproductive and sexual health. The book honours fact-based information and
provides cutting-edge interpretation of various obstetrics and gynaecology in its both parts.
The book provides up-to-date resources and approach to obstetrics and gynaecology.

Jaydeep Tank
President FOGSI 2024-2025
Mumbai, India
 Foreword

The book Drugs in Obstetrics and Gynecology: A Practical Approach

provides clear and concise information on the indications, dosages, side
effects, and contraindications of commonly used drugs in obstetrics and
gynecology. It also includes case studies, algorithms, and tables to help
readers understand and apply the information presented in the book.
This book is an invaluable resource for healthcare professionals,
including obstetricians, gynecologists, and primary care physicians,
who are involved in the care of women. It is also a useful resource for
medical students and residents who are training in this field.
Prof Ruchika and Dr Priya, the authors, have done an excellent job of providing a
comprehensive and up-to-date guide to the safe and effective use of drugs in obstetrics and
gynecology in a practical approach. I highly recommend this book to anyone involved in
the care of women.

S Shantha Kumari
MD, FRCOG (UK) FRCPI (Ireland)
Hyderabad
President FOGSI 2021–2023
Honorary Treasurer FIGO 2021–2023
 Foreword
Dr Ruchika Garg is a Professor in the Department of Obstetrics and
Gynaecology in SN Medical College, Agra, India. She is Editor-in-
Chief, Journal of South Asian Federation of Obstetrics and Gynecology
(SAFOG), and Associate Editor in Journal Midlife Health and Joint
Editor of Journal of South Asian Federation of Menopause Societies
(SAFOMS). She is President, Agra Chapter of Indian Menopause Society
Agra Society 2023-25.
I am honoured to write the foreword for the book, Drugs in Obstetrics
and Gynecology: A Practical Approach. This book is an essential resource
for healthcare professionals, including obstetricians, gynecologists, and other specialists who
deal with women's health.
The use of drugs in obstetrics and gynaecology is an ever-evolving field, and the correct
use of drugs is crucial for successful outcomes. This book provides an in-depth discussion
of the pharmacological management of various conditions that are encountered in obstetrics
and gynecology. The book is structured in a way that enables healthcare professionals to
quickly and easily access of the information they need to make informed decisions about
the use of drugs.
The authors have provided a comprehensive review of the use of drugs in obstetrics and
gynecology, including information on drug interactions, dosages, and potential side effects.
The book covers a range of topics, including contraception, menstrual disorders, infertility,
preterm labor, and postpartum hemorrhage. The authors have also provided practical advice
on how to manage adverse drug reactions, which is essential in clinical practice.
I highly recommend this book to all healthcare professionals who deal with women's health.
It is a valuable resource that will help clinicians to provide safe and effective pharmacological
management for their patients.
The book is written in a clear and concise style, making it accessible to healthcare
professionals at all levels of training and experience including postgraduate students and
busy practitioners.
This is a well-written and comprehensive guide for the use of drugs in women's health.
I commend the authors for their excellent work and am confident that this
book will become a widely used reference for healthcare professionals in this
field.
JB Sharma
MD FRCOG (London) MFFP FAMS PhD FICOG FIMSA
Professor, Department of Obstetrics and Gynaecology
All India Institute of Medical Sciences
Dr BC Roy Awardee, Labhsetwar Awardee
Chairperson, Urogynaecology FOGSI Society (2020-22)
Co-ordinator Delhi PG Forum
Ansari Nagar, New Delhi
[email protected]
 Foreword
The practice of obstetrics and gynecology requires a deep understanding
of the unique physiological and anatomical features of the female
reproductive system. The use of drugs in this field is equally complex
and requires a thorough understanding of the potential risks and benefits
associated with different medications. This book, Drugs in Obstetrics
and Gynecology: A Practical Approach provides a comprehensive and
practical guide to the safe and effective use of drugs in the management
of conditions specific to women's health.

Prashant Gupta
Principal and Dean
SN Medical College, Agra
 Foreword
As a healthcare professional, it is crucial to have a comprehensive
understanding of drugs and their implications in obstetrics and
gynaecology. The field of obstetrics and gynaecology is constantly
evolving, and staying up-to-date with the latest drug therapies and
their practical applications is essential.
This book, Drugs in Obstetrics and Gynaecology: A Practical Approach,
provides a thorough examination of the drugs commonly used in
obstetrics and gynaecology, and how they can be effectively employed
in clinical practice. The authors have put together a concise yet
comprehensive guide to equip healthcare providers with the knowledge and skills necessary
to provide safe and effective care to their patients.
The book is written in a clear and concise manner, and is organized to provide readers with
a thorough understanding of each drug category. Each chapter includes an overview of the
drug, its mechanism of action, indications, contraindications, and potential side effects. In
addition, practical guidance on dosing, administration, and monitoring is provided, making
this book an invaluable resource for healthcare professionals in their daily practice.
The book is an essential resource for undergraduates, postgraduate students, any healthcare
provider, midwifery, homeopathic and Ayurvedic students looking to expand their knowledge
and stay up-to-date with the latest drug therapies and practical applications in obstetrics
and gynaecology. Dr Ruchika Garg has a teaching experience of 18 years as a undergraduate
and Postgraduate teacher. She is a popular teacher, researcher and surgeon par excellence.
She has provided exhaustive literature in this book. It will be useful to solve MCQs too.
I highly recommend this book to any healthcare provider looking to improve the
understanding and skills in the field of obstetrics and gynaecology.
Jaideep Malhotra
Consultant Rainbow IVF, Agra
Ex-President FOGSI
Ex-President ASPIRE 2014–2016
 Preface
Having the passion for reading can be the biggest sign of a successful clinician. The book
"Drugs in Obstetrics and Gynaecology: A Practical approach” is an exclusive book, unique of
its kind, as it covers practical aspects of prescribing various drugs used and approach to
management of obstetric and gynaecological cases. As postgraduate students and busy
consultants often do not remember pharmacokinetics, common and important side effects
and contraindications of various commonly used drugs and may land up in trouble due to
missed diagnosis.
This book has emphasized on this often forgotten and important points. It covers the latest
evidence-based guidelines to help clinicians keep themselves abreast with the latest advances
in obstetrics and gynaecology. The book will help the readers take rational decisions for
managing different conditions in obstetrics and gynaecology. The addition of various trials
is an icing on the cake. The book has two parts, one covering drugs in obstetrics including
tocolytics, MgSO4 drugs for induction of labour, ectopic pregnancy, etc. The second part
covers gynaecological disorders like premenstrual syndrome, thin endometrium, drugs in
PCOS, ovulation induction, contraception, contraceptive vaginal rings, etc. The book will
be helpful to postgraduate students, busy practitioners as a guide in OPD for tackling tricy
situations and the latest drugs available.
We thank our contributors who are all doyens in the subject. They have penned down
their vast experiences in this book.
Without the love and support of our family members: Husband Dr Prabhat Agrawal, kids
Pratham, Palakshi, parents Dr Anuradha and Dr JK Garg, this hurculine task would not
have seen the light of day. We express our gratitude to the learned faculty of the department
of Obstetrics and Gynaecology SNMC, Agra, with Prof Richa Singh, Prof Nidhi Gupta,
Prof Shikha Singh, for their support and cooperation.
We are indebted to Dr Abhijit Thakur, Arya and Anushka for letting us do the task from
stealing their time. We thank CBS Publishers & Distributors Pvt. Ltd. for their support and
cooperation throughout the publication of this book.
Happy Reading!
Ruchika Garg
Priya Vora Thakur
 Contents
Contributors v
Foreword by Jaydeep Tank x
Foreword by S Shantha Kumari xi
Foreword by JB Sharma xii
Foreword by Prashant Gupta xiii
Foreword by Jaideep Malhotra xiv
Preface xv

PART I OBSTETRICS
1. Anticoagulants in Pregnancy and Postpartum 3
2. Antiepileptic Drugs in Pregnancy 11
3. Hypertensive Disorders of Pregnancy 19
4. Viral infections and Antivirals in Pregnancy 25
5. Drugs in Recurrent Pregnancy Loss: Aspirin and Low Molecular Weight Heparin 36
6. Atosiban 39
7. Augmentation of Labour 46
8. Common Problems in Pregnancy 51
9. Drugs for Induction of Labour 59
10. Bronchial Asthma during Pregnancy 69
11. Lactation Suppression 75
12. Malaria in Pregnancy 79
13. Toxoplasmosis in Pregnancy 89
14. Drugs in Urinary Tract Infection 94
15. Drugs in Gestational Diabetes Mellitus 104
16. Induction of Abortion 120
17. Magnesium Sulphate 125
18. Management of Peripartum Psychiatric Disorders 133
19. Medical Management of Ectopic Pregnancy 146
20. Micronutrient Supplementation in Obstetrics and Gynecology 151
21. Prevention and Treatment of Postpartum Haemorrhage including Carbetocin 159
22. Thyroid Disorders in Pregnancy 172
23. Tocolysis 178
24. Sildenafil in Obstetrics and Gynecology 181
25. Steroids in Obstetrics and Gynecology 189
xviii Drugs in Obstetrics and Gynecology

26. Vaccination in Pregnancy 198

27. Combined Oral Contraceptive Medication 206
28. Progesterone Only Pills and Depot Medroxyprogesterone Acetate 215
29. Emergency Contraception 227
30. Contraceptive Vaginal Ring 233
31. Gestational Trophoblastic Neoplasia 241

Index I-II

PART II GYNECOLOGY
32. Postmenopausal Osteoporosis 247
33. Drugs in Dysmenorrhea 261
34. Drugs in Fibroids 272
35. Drugs in Male Infertility 280
36. Drugs in Pelvic Inflammatory Disease 287
37. Drugs in Urinary Incontinence 303
38. Drugs in Vaginal Discharge 313
39. Drug Therapy in Adolescent Polycystic Ovary Syndrome 322
40. Drugs for Ovulation Induction 333
41. Drugs to Treat Endometrial Hyperplasia 343
42. Drugs to Treat Thin Endometrium 348
43. Ormeloxifene in Mastalgia and Benign Breast Disorders 355
44. Pharmacotherapy In Endometriosis 359
45. Genital Tuberculosis: Medication with Case-Based Approach 378
46. Hyperprolactinemia 381
47. Current Concepts in Hormone Replacement Therapy: Estrogen and Progesterone 384
48. Pelvic Congestion Syndrome 391
49. Premature Ovarian Insufficiency 399
50. Premenstrual Syndrome 409
51. Tamoxifen in Breast Cancer 414
52. Tibolone as Postmenopausal Hormonal Therapy 427
53. Treatment of Abnormal Uterine Bleeding 432

Index I-II
 2

Gynecology
32. Postmenopausal Osteoporosis 44. Pharmacotherapy In Endometriosis
33. Drugs in Dysmenorrhea 45. Genital Tuberculosis: Medication with Case-
34. Drugs in Fibroids Based Approach
35. Drugs in Male Infertility 46. Hyperprolactinemia
36. Drugs in Pelvic Inflammatory Disease 47. Current Concepts in Hormone Replacement
Therapy: Estrogen and Progesterone
37. Drugs in Urinary Incontinence
48. Pelvic Congestion Syndrome
38. Drugs in Vaginal Discharge
49. Premature Ovarian Insufficiency
39. Drug Therapy in Adolescent Polycystic
Ovary Syndrome 50. Premenstrual Syndrome
40. Drugs for Ovulation Induction 51. Tamoxifen in Breast Cancer
41. Drugs to Treat Endometrial Hyperplasia 52. Tibolone as Postmenopausal Hormonal
Therapy
42. Drugs to Treat Thin Endometrium
53. Treatment of Abnormal Uterine Bleeding
43. Ormeloxifene in Mastalgia and Benign
Breast Disorders
 32
Postmenopausal Osteoporosis

• Rajendra Nagarkatti • Jagruti Ghosh

Introduction the diet, bone production and bone tissue

Aging is a non-homogenous process, where may suffer. Thus, the bones may become
progressive and broadly predictable changes weaker, resulting in fragile and brittle
begin and are associated with increased bones that can break easily. Inadequate
susceptibility to many diseases. Genetics, intake of calcium and vitamin D and lack of
lifestyle, and environment play an influential weight-bearing exercise is also associated
role in aging. with age-related bone changes.
Osteoporosis (OP) is a topic neglected by • The leading cause of osteoporosis is a
general population. Merely giving painkillers lack of certain hormones, like oestrogen
and calcium and vitamin D will not suffice in women and androgen in men. Women,
after confirmation of diagnosis of menopause especially those older than 60 years of age,
and osteoporosis. are frequently diagnosed with the disease.
When bone density is reduced, altered bone E2 falls 2 years preceding the final menstrual
architecture and reduced bone production period and is persistently low in the
happens. Osteoporosis affects both males and following 12-month period of amenorrhea,
females also. whilst follicle-stimulating hormone (FSH)
continue to rise. In postmenopausal
It commonly happens after menopause
women, estrone (E1), generated through
due to sudden decrease in oestrogen. Chances
the conversion of androgens (secreted by
of fracture will be there if it has not treated
the adrenal glands and postmenopausal
or prevented. Even small fall or minor knock
ovaries) in the adipose tissue and liver,
will be responsible for fracture.
predominates in the circulation. It is believed
to be the main cause that contributes to bone
CAUSES OF OSTEOPOROSIS loss in this age group.
• Calcium is essential for proper functioning • Overuse of corticosteroids (Cushing
of the heart, brain, and other organs. To syndrome), thyroid problems, lack of
keep those critical organs functioning, the muscle use, bone cancer, certain genetic
body reabsorbs calcium that is stored in disorders, use of certain medications, and
the bones to maintain blood calcium levels. problems such as low calcium in the diet.
If calcium intake is not sufficient or if the • Women who are postmenopausal,
body does not absorb enough calcium from including those who have had early
248 Drugs in Obstetrics and Gynecology

Flowchart 32.1: Menopausal symptoms

or surgically-induced menopause, or the risk of fracture. Bone biopsy may be

abnormal or absence of menstrual periods, indicated in specific situations. Conventional
are at greater risk. radiography is used for the qualitative and
• Cigarette smoking, eating disorders, such as semi-quantitative evaluation of osteoporosis;
anorexia nervosa or bulimia, low amounts morphometry assesses the presence of fractures.
of calcium in the diet, heavy alcohol Quantitative imaging methods commonly
consumption, inactive lifestyle, and use of used are—dual-energy X-ray absorptiometry
certain medications, such as corticosteroids (DXA or DEXA) and quantitative computed
and anticonvulsants, are also risk factors. tomography (QCT) scanning. In the United
• Rheumatoid arthritis itself is a risk factor States, current diagnostic and treatment
for osteoporosis. criteria for osteoporosis are based solely
• History of osteoporosis to parents is a risk on QCT hip and DXA spine or hip T-score
factor for the offspring. measurements.
Two types of devices can carry out a DEXA
Investigations scan:
Workup consists of appropriate laboratory • A central device: A hospital-based scan
studies to establish baseline values and to look measures hip and spine BMD, while the
for potential secondary causes of osteoporosis, patient lies on a table.
along with measurement of bone mineral • A peripheral device: A mobile machine that
density (BMD) to assess bone loss and estimate tests bone in the wrist, heel, or finger.
 Postmenopausal Osteoporosis 249

Bone Mineral Density Screening (Fig. 32.1) compared to estimate the bone density. DEXA
WHO defines osteoporosis as a “systemic screening is fast and exposes the person to
skeletal disease characterized by low bone a low dose of radiation. BMD results are
mass (measured as BMD) and micro- expressed based on standard deviation (SD)
architectural deterioration of bone tissue units from the population mean in young
with a consequent increase in bone fragility adults (T-score) or from the mean in an age
and susceptibility to fracture and involves matched population (Z-score). World Health
the wrist, spine, hip, pelvis, ribs or humerus.” Organisation (WHO) and International
As per American College of Obstetricians Osteoporosis Foundation recommended
and Gynecologists (ACOG), BMD testing is the T-score in post-menopausal women
recommended for diagnosis of osteoporosis. based on the National Health and Nutrition
ACOG recommends BMD testing to be Examination Survey III reference database,
performed based on patients risk factors. conducted in Caucasian women in the
It should be done only if it affects the 20–29 years age group (Fig. 32.2). The T-score
treatment. BMD testing is recommended for is measured at lumbar and two hip sites
all postmenopausal women and age above (femoral neck and total hip). Osteoporosis
65 years. Below the age of 65 years, BMD testing was defined as a T-score ≤–2.5 at any of the
is recommended if patient is postmenopausal three sites. Osteopenia is defined as the T-
and has risk factors. Epidemiological data score between –2.5 to –1 (not inclusive) at
suggests that for women below 60 years, any site.
osteoporosis screening and treatment would The results of the test are given as a DEXA
be inefficient. The frequency of screening T-score or a Z-score.
should not be more than once in 2 years.6 In The Z-score describes the SD variation by
India opportunistic screen is recommended which the BMD in an individual differs from
above 40 years by Indian menopause society. the mean expected for a particular age group
DXA is the gold standard for measuring and sex. This is used in pre-adolescent and
BMD, as it is accurate, precise measures at premenopausal women. Z-score below –2 is
important sites and is not expensive relatively abnormal and is low for age.
and has moderate exposure to radiation. In Other methods for BMD screening like
DEXA, two beams of X-ray are projected on peripheral bone densitometry including
the site. The amount of the X-ray beam that ultrasonography (USG), single energy X-ray
is blocked by the bone and soft tissue are absorptiometry, peripheral DEXA (P-DEXA)
One year later
and peripheral quantitative tomography are
Baseline
cheaper, portable and involve less radiation.
They only assess peripheral skeleton and
cannot replace DEXA.
P-DEXA is a modification of DEXA. It
measures bone density in peripheral bones
like wrist. Radiation dose is low.
Quantitative CT is accurate but involves
higher dose of radiation.
In USG, sound waves bounce off the bone.
It is usually done at the heel. It is quick and
not harmful.
Fig. 32.1: Change in bone in untreated post­ Dual photon absorptiometry is another
menopausal women method that uses a radioactive substance.
250 Drugs in Obstetrics and Gynecology

To collate and consider all factors, WHO mildly elevated in patients with fractures. In
has an absolute fracture prediction algorithm addition, patients with hyperparathyroidism,
(FRAX), which use a computer-based tool Paget disease, or osteomalacia can have
to estimate patients 10 years fracture risk. elevations of BSAP. Serum OC levels, if
It takes into consideration BMD and other high, indicate a high-turnover type of osteo­
personal and family history. Treatment is porosis. Elevation of urinary NTx (>40 nmol
recommended for women with 10 years bone collagen equivalent per mmol urinary
fracture probability of 3% or more. The test creatine) indicates a high turnover state.
is repeated every 2 years, as this allows for Significant controversy exists regarding
comparison between results. the use of these biochemical markers, and
concerns have been raised about intra-assay
Biochemical Markers of Bone Turnover and interassay variability. Further study is
Biochemical markers of bone turnover reflect needed to determine the clinical utility of
bone formation or bone resorption. These these markers in osteoporosis management.
markers (both formation and resorption) may Plain radiography is recommended to assess
be elevated in high-bone turnover states (e.g. overall skeletal integrity. In particular, in the
early postmenopausal osteoporosis) and may workup for osteoporosis, plain radiography
be useful in some patients for monitoring may be indicated if a fracture is already
early response to therapy. suspected or if patients have lost more than
Currently available serum markers of bone 1.5 inches of height.
formation (osteoblast products) include the
following: TREATMENT OF OSTEOPOROSIS
• Bone-specific alkaline phosphatase (BSAP) Treatment aims to:
• Osteocalcin (OC) • Slow or prevent the development of osteo­
• Carboxyterminal propeptide of type I porosis
collagen (PICP) • Maintain healthy bone mineral density
• Aminoterminal propeptide of type I and bone mass
collagen (PINP) • Prevent fractures
Currently available urinary markers of • Reduce pain
bone resorption (osteoclast products) include • Maximize the person’s ability to continue
the following: with their daily life
• Hydroxyproline • Fracture management
• Free and total pyridinolines (Pyd) 1. Relieve pain
• Free and total deoxypyridinolines (Dpd) 2. Stabilise fracture and restore anatomy
• N-telopeptide of collagen cross-links (NTx) 3. Manage co-morbidities
(also available as a serum marker) 4. Restore level of function and mobility
• C-telopeptide of collagen cross-links (CTx) 5. Psychosocial support
(also available as a serum marker) This is done through preventive lifestyle
Currently available serum markers of bone measure and the use of supplements and
resorption include cross-linked ctelopeptide drugs.
of type I collagen (ICTP) and tartrate-resistant
acid phosphatase, as well as NTx and CTx. Of Whom to Treat
all the biochemical markers of bone turnover a. Fragility fractures [clinical, height loss
mentioned above, the ones most commonly of >4 cm, kyphosis or morphometric by
used in clinical practice are BSAP, OC, X-rays or vertebral fractures assessment
urinary NTx, and serum CTx. BSAP can be (VFA) by DXA]
 Postmenopausal Osteoporosis 251

b. BMD T-scores ≤–2.5 at the femoral neck or can reduce the risk of spine fractures in
spine, wrist by DXA women after menopause.
c. Women with low bone mass by DXA with 4. Calcitonin: This helps prevent spinal
one major or two other risk factors or fracture in postmenopausal women, and it
eligible by fracture risk assessment tool can help manage pain if a fracture occurs.
(FRAX). 5. Parathyroid hormone: For example, teri­
paratide—antiresorptive. This is approved
Drug Therapy (Tables 32.1, 32.2 and for people with a high risk of fracture, as
Flowcharts 32.2, 32.3) it stimulates bone formation.
Drugs that can help prevent and treat 6. Receptor activator of nuclear factor kappa-b
osteoporosis include: (NF-kb) ligand [RANK ligand (RANKL)]
• Substrates for bone formation—nutrients inhibitors, such as denosumab: This is an
• Drugs which inhibit bone resorption— immune therapy and a new type of
antiresorptive agents osteoporosis treatment. Other types of
• Drugs which stimulate bone formation— oestrogen and hormone therapy may help.
bone anabolic agents Choice of Medication
Drugs that can help prevent and treat Depends on
osteoporosis include: • Drug-related (risk-benefit)
1. Bisphosphonates—alendronate, rise­ • Patient profile (age, years since menopause,
dronate ibandronate, zoledronate. These symptoms, comorbidities)
are antiresorptive drugs that slow bone • Environment-related factors (economics
loss and reduce fracture risk. and social)
2. Menopausal hormone therapy (MHT) • Patients should be educated in patient
3. Estrogen agonists or antagonists, also management orders (PMO) and its treatment
known as selective estrogen-receptor and empowered to take part in shared
modulators, SERMs), e.g. raloxifene: These decision-making to improve adherence.

Table 32.1: FDA approved drugs for osteoporosis

Drugs Prevention Treatment
Alendronate 5 mg, PO, daily 10 mg, PO, daily
35 mg, PO, weekly 70 mg, PO, weekly
70 mg + D, daily
Risedronate 5 mg, PO, daily 5 mg, PO, daily
35 mg, PO, weekly 35 mg, PO, weekly
150 mg, PO, monthly 150 mg, PO, monthly
Ibandronate 2.5 mg, PO, daily 2.5 mg, PO, daily
150 mg, monthly 150 mg, monthly
3 mg, IV, q3mo
Zoledronic acid 5 mg, IV, q2yrs 5 mg, IV, q1yr
Estrogen Multiple formulations/regimens —
Raloxifene 60 mg, PO, daily 60 mg, PO, daily
Calcitonin — 200 IU, intranasal, OD or 100 IU, SC
Denosumab — 60 mg, SC q6mo
Teriparatide — 20 mg, SC OD for up to 24 mo
252 Drugs in Obstetrics and Gynecology

Flowchart 32.2: Osteoporosis risk analysis

Flowchart 32.3: Management of women with fragility fractures

 Postmenopausal Osteoporosis 253

Table 32.2: Antiresorptive drugs for osteoporosis

Drugs Dose Efficacy Advantages Disadvantages
Estrogen (CEE) 0.625–1.25 Vertebral and non- Physiologic test Need for early use
mg/day vertebral BMD of menopausal (<5 yrs)
↓Vertebral and hip symptoms AEs on endometrium
fractures by 33–50% breast, CVS
Oral 5–10 mg/day Vertebral and non- Once weekly dose Upper GI side effects
bisphosphonates 35–70 mg/wk vertebral BMD 10-yr safety record Precautions
(alendronate) 5–10% Lasting benefits Contraindications
Ibandronate 150 mg/mo ↓Verbebral and non- (up to 2 yrs after (renal failure)
vertebral fractures by withdrawal) Atypical femur
40–50% fractures
↓Vertebral fracture Osteonecrosis of jaw
62% no change in
non-vertebral
IV 5 mg, yearly ↓Vertebral fracture Yearly dose Acute flue-like
bisphosphonate for 3–6 yrs 70% complicance syndrome
SERMs 60 mg/day ↓Vertebral fractures: Bone selective DVT
(raloxifene) 30–50% No endometrial Hot flashes
BMD in spine and effects No effect on non-
femoral neck by 2.5% Anti-mitotic on breast vertebral fractures
Salmon 200 mg nasal 36% ↓vertebral
calcitonin fractures in older PM
women
No effects on non-
vertebral fractures
Denosumab 60 mg twice a ↓Vertebral fractures Only twice a year self Infections
year sc 68% administration Rare atypical femur
↓Hip fracture 40% fractures
↓Non-vertebral Osteonecrosis of jaw
fracture 20%

Table 32.3: BMD response Challenges of Treatment

Medication Spine Hip • Economics
Estrogen ↑↑ ↑ • Long-term compliance
• Side effects.
Alendronate ↑↑↑ ↑↑
Despite major advances in diagnosis and
Risedronate ↑↑↑ ↑↑ therapy, most patients with osteoporosis
Ibandronate ↑↑↑ ↑↑ receive no evaluation or treatment, even
Zoledronic ↑↑↑ ↑↑ patients who have had a fragility fracture.
acid
I. Bisphosphonates
Calcitonin ~ ~
↑
Most widely used drugs. Effect on bone
Raloxifene (↑)
resorption persists after discontinuation
Denosumab ↑↑↑ ↑↑
(unique to bisphosphonate). It should be
Teriparatide ↑↑↑↑ ↑ consumed empty stomach with glass of
BMD: Bone mineral density water. Do not bend for 30 minutes.
254 Drugs in Obstetrics and Gynecology

Safety data available for 10 years. Serum • Concomitant therapy with skeletotropic
calcium and serum creatinine should be drugs
measured before starting therapy. Patient • Inappropriate choice of drugs, or wrong
should be calcium and vitamin D replete choice of monitoring strategies (GRADE
(Figs 32.2, 32.3 and Flowcharts 32.3, 32.4). C). There are no head-to-head trials of the
Side effects: various drugs comparing their effects on
• GI intolerance (oral) fracture rates.
• Hypocalcemia
• Renal dysfunction II. Menopausal Hormone Therapy
• Acute phase reaction—flu-like symptoms Most prolonged and most predictable dose
(myalgia, arthralgia, fever) common in and duration-dependent increase in bone
12–48 hours after IV dosing, lasts usually density with estrogen. Effective in preventing
for 1–2 days, sometimes 1 week. osteoporotic fractures of the hip and spine
• Osteonecrosis of the jaw in a study of low and mixed risk women.
• Atypical fractures. EPT/ET is a cost effective first line therapy
in early postmenopausal women at risk for
Monitoring therapy (Flowchart 32.4)
osteoporosis unless contraindicated (GRADE
• BMD by DEXA—repeat after 1 year of
A). Estrogen progesterone therapy (EPT)/
therapy
estrogen therapy (ET) may be used for
• Bone turnover markers
prevention and treatment of osteoporosis in
• Resorption markers after 3–6 months after the early post‑menopause in symptomatic
treatment initiation women unless there is a contraindication.
• Formation markers—6 months after
ET/EPT prevents all osteoporotic fractures
treatment initiation
even in low-risk population, it increases
Non-responders to therapy: May be due to: lumbar spine BMD up to 7.6% and femoral
• Poor adherence neck BMD up to 4.5% over 3 years. It reduces
• Poor calcium/vitamin-D health the risk of spine, hip, and other osteoporotic
• Untreated secondary osteoporosis fractures by 33–40% (GRADE A).

Fig. 32.2: Bisphosphonates—alendronate, risedronate, ibandronate, zoledronic acid

 Postmenopausal Osteoporosis 255

Flowchart 32.4: Bisphosphonates—algorithm for long-term treatment

Progestogens should be added to ET in • Extended use possibly associated with

women with uterus (GRADE A). increased diagnosis of breast cancer [only
• Hormone therapy (HT) should not be combined hormone replacement therapy
started solely for bone protection after (HRT)]
10 years of menopause. Extended use of • Cessation of therapy unpredictable effect
HT in women with reduced bone mass
is an option after considering the risk– III. Tibolone
benefit analysis compared to the other It has an estrogenic effect on bone, inhibiting
available therapies for osteoporosis. The bone resorption by reducing osteoclastic
bone protective effect is lost after stopping activity. Tibolone is approved in 90 countries to
HT (GRADE B). treat menopausal symptoms. We recommend
• HT is indicated as primary therapy that tibolone is prescribed in a single daily
to prevent bone loss in women with dose of 2.5 mg orally. A lower dose of
premature menopause and secondary 1.25 mg has been found to be equally effective
amenorrhea (GRADE C). for most indications, including osteoporosis
Side effects: (GRADE A).
• Increased risk of deep vein thrombosis
(DVT) IV. Raloxifene
• Not recommended to initiate therapy Acts as an agonist in bone and lipid meta­
above age 60 bolism. And as a Antagonist at uterine
256 Drugs in Obstetrics and Gynecology

endometrium and at breast tissue. Hence, non-vertebral and hip fracture risk. It is well-
used in treatment and prevention of post- tolerated even in patients with creatinine
menopausal osteoporosis. clearance <30 ml/min.
Role of raloxifene is being evaluated in: Dose: SQ injection every 6 months.
• Advanced breast cancer
• Chemoprevention of breast cancer Side effects:
• Cardioprotection. • Hypocalcemia, infection, osteonecrosis
of the jaw (ONJ), atypical femur fracture
Benefit: (AFF) possible
• Prevents vertebral fractures • Cost
• Prevents estrogen receptor positive (ER+) • Discontinuation:
breast – Effect promptly lost
• Has a favorable effect on lipid profile – BMD declines
• Has no effect on risk for coronary events. – Effects reverse with restarting treatment.
Side effect:
VIII. Teriparatide
• Does not prevent non-vertebral fractures
It is indicated in
• DVT risk—increased
• Fatal stroke risk—increased • Women at high risk for fracture, including
those with very low BMD (T-score worse
• Hot flushes
than –3.0)
• Leg cramps.
• With a previous vertebral fracture
V. Tissue Selective Estrogen Complex (TSEC) • Those patients intolerant of or unresponsive
The concept is partnering of a SERM with to antiresorptive therapy
other estrogens to achieve optimal clinical • Glucocorticoid-induced osteoporosis and
results based on their blended tissue selective male osteoporosis
activity profile. The first TSEC in clinical Safety beyond 2 years is not known of
development partners bazedoxifene (BZA), parathyroid hormone (PTH) use.
a SERM with a unique endometrial profile, Current recommendation is to use teri­para­
with conjugated estrogens (CE). tide in low dose 20 mg, daily, subcutaneously.
Monitor serum calcium and serum uric
VI. Calcitonin Nasal Spray
acid levels at 1, 6 and 12 months.
It reduces risk of vertebral fractures, no Adverse effects are headache, hyper­
proven benefit for hip or non-vertebral calcemia; hypercalciuria, renal adverse
fractures. effects, nausea, rhinitis, arthralgia.
Other effects:
• Possible analgesic effect Treatment options: Anabolic PTH
• Occasional nasal irritation, rarely epistaxis Benefits:
• No known drug interactions. • Vertebral fracture reduction
• True anabolic effect.
VII. Denosumab
It is a monoclonal antibody, specifically targets Side effects:
RANKL and is approved for postmenopausal • No non-vertebral data
women with osteoporosis at high risk of • Narrow therapeutic index (18 months)
fracture. It increases both trabecular and • Daily, SC injections
cortical bone strength, reduces vertebral, • Cost.
 Postmenopausal Osteoporosis 257

PREVENTION OF OSTEOPOROSIS improvement in reducing bone loss in

the lumbar spine in postmenopausal
The prevention of osteoporosis begins with women. Moreover, wholebody vibration
optimal bone growth and development can be used as an intervention for fall
in youth. Bones are living tissue, and the prevention. Eight studies were reviewed
skeleton grows continually from birth to and Ma, et al. have concluded that the low-
the end of the teenage years, reaching a magnitude whole-body vibration therapy
maximum strength and size (peak bone mass) is an agreeable alternative for providing
in children and adolescents should: significant effective reduction in bone loss
• Ensure a nutritious diet with adequate in the lumbar spine of postmenopausal
calcium intake women.
• Avoid protein malnutrition and under- 3. Research is underway regarding the
nutrition also particularly the effects relationship between chronic stress and
of severe weight-loss diets and eating osteoporosis. The activation of hypo­
disorders thalamo-pituitary-adrenocortical (HPA)
• Maintain an adequate supply of vitamin D axis leading to inhibition of gonadal
• Participate in regular physical activity hormones, and imbalance of inflammatory
• Avoid the effects of passive smoking cytokines ultimately leading to bone loss,
• Avoid heavy drinking. inhibits bone formation and stimulates
It is estimated a 10% increase of peak bone resorption. These were the findings
bone mass in children reduces the risk of of Azuma, et al. and they have concluded
an osteoporotic fracture during adult life that improvement of psychological status
by 50%. Bone mass acquired during youth of women is in itself an important measure
is an important determinant of the risk of to prevent osteoporosis.
osteoporotic fracture during later life. The 4. Many alternative medicinal methods are
higher the peak bone mass, the lower the risk being studied for the purpose of preven­
of osteoporosis. tion of osteoporosis. A recent review article
Once peak bone mass has been reached, it has reported in detail the effects and
is maintained by a process called remodelling. interactions between contents of Chinese
This is a continuous process in which old medicinal plants and various cytokines
bone is removed (resorption) and new bone involved in bone health. The regulation
is created (formation). The renewal of bone of the cytokine microenvironment by
is responsible for bone strength throughout immune modulation is the main common
life. pathway. Though exact details are still
Any factor, which causes a higher rate of being studied, they can be recommended
bone remodelling, will ultimately lead to a in improving bone health with no major
more rapid loss of bone mass and more fragile side effects. These form a possible basis
bones. The nutritional and lifestyle advice for future research in the subject.
for building strong bones in youth is just as 5. A significant role can be played by doctors
applicable to adults too. of other speciality also. Orthopedicians
and endocrinologists can complement
Other Treatment Options the gynecologists in giving consistent
1. Olive oil and olive polyphenols are being advice for the postmenopausal women. In
considered as nutritional supplements for those with osteoporosis, the ill effects are
the prevention of osteoporosis. compounded by falls. Prevention of falls
2. Low-magnitude whole-body vibration can be helped by appropriate intervention
therapy can provide a significant by opthalmologists, neurologists and
258 Drugs in Obstetrics and Gynecology

cardiologists, to ensure that respective cell therapy is to induce bone formation

systems are working fine. via the proliferation and differentiation of
6. When it is a family physician who is bone progenitor cells. The main hurdle for
attending to the patient, home visits can stem cell-based osteoporosis therapy is the
also be considered. The institutions which uncertainty of stem cell fate following stem
are employing women could consider cell transplantation.
taking some efforts regarding those with Findings published in 2015 suggested that
low physical activity. Making exercise/ growth hormone (GH) taken with calcium
physical activity easy by providing for and vitamin-D supplements could reduce
work-out rooms and the sort can be done the risk of fractures in the long term. Also in
at institutional level with good impact. 2015, researchers in the United Kingdom (UK)
found evidence that a diet containing soy
FUTURE OF OSTEOPOROSIS THERAPY protein and isoflavones may offer protection
from bone loss and osteoporosis during
In future, treatment by stem-cell therapy menopause.
may be included in the management. In Scientists believe that up to 75% of a
2016, researchers found that injecting a person’s bone mineral density is deter­
particular kind of stem cell into mice reversed mined by genetic factors. Researchers are
osteoporosis and bone loss in a way that investigating which genes are responsible for
could, potentially, benefit humans too. bone formation and loss, in the hope that this
In a review by Jeffrey Kiernan, et al. might offer new ways of preventing.
An article makes a strong case for the use
of cell therapy for the treatment of human- Kyphoplasty and vertibroplasty in osteo­
age-related (type II) osteoporosis. The porosis: Vertebroplasty and kyphoplasty have
authors highlight that age-related bone loss is become common surgical techniques for the
associated with the decline of musculoskeletal treatment of vertebral compression fractures.
progenitors, and transplantation of such Vertebroplasty involves the percutaneous
progenitors may alleviate the disease. injection of bone cement into the cancellous
Preclinical animal studies are integrated into bone of a vertebral body with the goals of
the design and, as available, clinical human pain alleviation and preventing further loss of
data into a proof of principal, that cell therapy vertebral body height. Kyphoplasty utilizes
should be explored to treat age-related an inflatable balloon to create a cavity for the
bone loss. Finally, the authors make the cement with the additional potential goals
case for the use of ancillary clinical trials to of restoring height and reducing kyphosis.
collaborate with existing human cell therapy Vertebroplasty and kyphoplasty are effective
trials to maximize the scientific impact these treatment options for the reduction of pain
expensive experimental interventions. associated with vertebral body compression
fractures (Figs 32.3 and 32.4).
In a review by Antebi B, Pelled G, Gazit D.
DOI: 10.1007/s11914-013-0184x} Source:
PubMed: In osteoporosis, the number of bone CONCLUSION
marrow mesenchymal stem cell (MSCs) that DEXA is gold standard for BMD measurement,
can differentiate into osteoblasts and form but needs careful assessment and clinical
bone, is significantly reduced. In addition, correlation. Detailed clinical, biochemical
recent findings suggest an imbalance in evaluation is important before treatment
the differentiation of MSCs in favor of initiation. All OP patient need calcium and
adipogenesis rather than osteogenesis in vitamin supplementation. Choose the drug
osteoporotic patients. The goal of stem- treatment according to severity and indication.
 Postmenopausal Osteoporosis 259

Fig. 32.3: Kyphoplasty

Fig. 32.4: Vertebroplasty

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treatment and monitoring. Attain peak bone 1. Antebi B, Pelled G, Gazit D. DOI: 10.1007/
mass. Prevent first fragility fracture or future s11914-013-0184-x} · Source: PubMed.. Stem cell
fractures if one has already occurred. therapy for osteoporosis.
It is never too early to start prevention of 2. Dunnewind T, Dvortsin EP, Smeets HM, Konijn
osteoporosis. RM, Bos JHJ, de Boer PT, et al. Economic
Consequences and Potentially Preventable Costs
It is never too late to start treatment of
Related to Osteoporosis in the Netherlands.
osteoporosis. Value Heal. 2017 Jun; 20(6):762–8.
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3. Harvey NCW, McCloskey E V, Mitchell PJ, Surg Res [Internet]. 2016 Feb 17 [cited 2018 Dec
Dawson-Hughes B, Pierroz DD, Reginster 4]; 11:24. Available from: http://www.ncbi.nlm.
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perspective on current and future strategies for 7. Meeta, Digumarti L, Agarwal N, Vaze N,
prevention of fragility fractures. Osteoporos Int. Shah R, Malik S. Clinical practice guidelines
2017; 28(5):1507–29. on menopause: *An executive summary and
4. Jeffrey Kiernan; John E Davies; William L recommendations. J Mid-life Health 2013;4:77–106.
Stanford. Concise Review: Musculoskeletal 8. Studd J, Holland EF, Leather AT, Smith RN. The
Stem Cells to Treat Age-Related Osteoporosis. dose response of recutaneous estradiol implants
stemcellsjournals.onlinelibrary.wiley.com/doi/ on the skeletons of postmenopausal women. Br
full/10.1002/sctm.17-0054. J Obstet Gynaecol 1994;101:787–91.
9. Tsuda T. Epidemiology of fragility fractures
5. Kanis JA, Harvey NC, Cooper C, Johansson
and fall prevention in the elderly: a systematic
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review of the literature. Curr Orthop Pract. 2017
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Osteoporosis Guideline Group and the education in the primary prevention of osteo-
International Osteoporosis Foundation. Arch porosis in perimenopausal and postmenopausal
Osteoporos [Internet]. 2016 [cited 2018 Dec women. Menopause Rev. 2014 Mar.
4];11(1):25. Available from: http://www.ncbi. 11. Zhao H, Zhao N, Zheng P, Xu X, Liu M,
nlm.nih.gov/pubmed/27465509 Luo D, et al. Prevention and Treatment of
6. Ma C, Liu A, Sun M, Zhu H, Wu H. Effect of Osteoporosis Using Chinese Medicinal Plants:
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 33
Drugs in Dysmenorrhea

• Archana Bhosale • Shweta Khade

DYSMENORRHEA thighs, myalgia, arthralgia, and swollen legs,

The term dysmenorrhea is defined as painful sweating. The gastrointestinal symptoms
menstruation of sufficient magnitude so include an increase or decrease in appetite,
as to incapacitate day-to-day activities.1,2 nausea, vomiting, and bloating, constipation,
Dysmenorrhea pain may be spasmodic (sharp diarrhea. Psychological symptoms include
pelvic cramps at the start of menstrual flow) anxiety, depression, irritability, and nervous-
or congestive (deep, dull ache). It is commonly ness.4
associated with symptoms, such as lower Pathophysiology: In ovulatory cycles,
backache, vomiting, headache, diarrhea during menses endometrial sloughing causes
and fatigue. Prevalence of dysmenorrhea endometrial cells to release prostaglandins
can vary between 16 to 91% in women of (PGs) PGF2a, PGE2, vasopressin and leuko­
reproductive age with severe pain observed trienes, which stimulates myometrial
in 2 to 29%.3 Despite its high prevalence, contractions and ischemia. Depending upon
there is insufficient evidence to support the levels of prosta­glandin release, the degree
management-seeking practices and their of dysmenorrhea varies. The secretion of
perceived efficacy in females with primary prosta­glandins causes uterine contractions
dysmenorrhea. along with other ailments, such as nausea,
vomiting, headache and tympanites.5,6
TYPES OF DYSMENORRHEA
1. Primary Dysmenorrhea 2. Secondary Dysmenorrhea
Dysmenorrhea occurs in absence of pelvic It is defined as painful menstruation due
pathology. It is more common in adolescents to pelvic pathology or recognised medical
and young adult females and usually starts condition. It is associated with diffused or
1 to 2 days before the onset of menses or just constant pain that does not necessarily occur
after the menses with pain, typically lasting during menstruation.5 It is usually detected in
for 1 to 3 days. It may be associated with females with age more than 24 years with no
systemic, gastrointestinal and psychological history of dysmenorrhea. They have clinical
symptoms. The systemic symptoms include features that distinguish their condition from
headache, lethargy, fatigue, sleepiness/ primary dysmenorrhea, which includes a
sleeplessness, tender breasts, heavy lower large uterus, pain during sexual intercourse,
abdomen, backache, painful knees and inner and resistance to effective treatment.
262 Drugs in Obstetrics and Gynecology

ASSOCIATED RISK FACTORS7 PRIMARY DYSMENORRHEA: PHARMACO­

Various risk factors are associated with it and LOGICAL MANAGEMENT (CASES 1 TO 9)
enlisted below. Indications: Patients who do not have adequate
1. Age (13 to 15 years) relief with non-pharmacological interventions
2. Smoking or who desire immediate pharmacologic
3. Attempts to lose weight therapy.
4. Body mass index (BMI) (less than 17 and Case 1: Adolescent Girl
more than 30) (10 years to 18 years) with Dysmenorrhea
5. Depression or anxiety Most adolescent girls will have primary
6. Earlier age at menarche dysmenorrhea and will respond well to
7. Nulliparity empirical treatment with non-steroidal
8. Longer and heavier menstrual flow anti-inflammatory drugs (NSAIDs) and
9. Family history of dysmenorrhea antispasmodics (Table 33.1) or progesterone
oral hormonal preparation (Table 33.2)
10. Disruption of social network.
or both. Progesterone preparation in the
form of norethisterone acetate or medroxy­
TREATMENT OF DYSMENORRHEA progesterone acetate 5 to 10 mg daily to be
Treatment of dysmenorrhea depends on the used.
type and severity of dysmenorrhea. In this Dose schedule should be individualized
chapter, we will discuss case-based medical depending upon age and symptoms. A
management approach to treat dysmenorrhea. short protocol for the last 10 days before
menses or cyclical 21 days regimen can be
Initial approach: Detailed patient history used. Duration of treatment will be 6 to 9
and clinical examination should be done to months. Resistant cases can be evaluated by
rule out pelvic pathology at the first visit. ultrasonography to rule out pelvic pathology.
Patients should be educated regarding
menstrual cycles, causes and symptoms of Medical management:
dysmenorrhea and reassurance should be 1. NSAIDs and antispasmodics: These drugs
given. Treatment is planned according to age are used as the first line of management
and symptoms. of dysmenorrhea. It should be started
1 or 2 days prior to menses and to be
Non-pharmacological interventions: Pain continued for initial 2–3 days of menses
relief without medication is an important along with antacids. Antispasmodics to
healthcare target and it is safe and inexpensive be started with initiation of symptoms and
and easily accepted by patients. can be given for 3–5 days. NSAIDs and
Acupuncture, heat therapy, psychotherapy, antispasmodics which can be used safely
massage therapy, hypnotherapy, physio­ in adolescent girls are discussed in detail
therapy, transcutaneous electrical nerve in Table 33.1.
stimulation (TENS) are used to reduce the 2. Hormonal management: Progesterone
primary dysmenorrhea immensity. preparations (oral formulations)—patients
whose dysmenorrhea is not curable by
Mechanisms NSAIDs could be given hormone therapy
Increasing pelvic blood supply, inhibiting for at least three menstrual cycles. About
uterine contractions, release of endorphins 75% of patients receiving progestins
and serotonin, and altering the ability to experience reduction in pain. Combined
receive and perceive pain signs.8 estrogen–progesterone pills and depot
 Drugs in Dysmenorrhea 263

Table 33.1: NSAIDs and antispasmodics9

Drugs Mechanism of Dosages Max. dose Side effect Contraindications
action
A. NSAIDs
1. Paracetamol Inhibition of 325 mg to 1 g 4 g per 24 Nausea, Hypersensitivity
(para- two isoforms orally every 4 hours vomiting, to
aminophenol) of cyclo- to 6 hours constipation, acetaminophen,
oxygenase, hypersensitivity severe hepatic
COX-1 and rash, pruritus, impairment, or
COX-2, which hepatotoxicity severe active
are involved in hepatic disease
prostaglandin
(PG) synthesis
2. Ibuprofen Non-selective 200 to 400 mg 3200 mg/ Gastritis, Active GI or
(propionic acid inhibitor orally every day ulceration, cerebrovascular
derivative) of cyclo- 4 hours as hemorrhage, bleeding,
oxygenase needed perforation, uncontrolled
COX-1 and diminished renal heart failure,
COX-2 function, rashes lupus, renal
impairment,
and hepatic
impairment
3. Mefenamic Inhibitor of 250 mg orally Not to z Diarrhea History of asthma,
acid COX-1 and every 6 hours exceed 3 z Nausea, urticaria, or other
(anthranilic COX-2 as needed days stomach allergic-type
acid derivative) bloating reactions after
z Swelling of the aspirin or other
face, fingers NSAIDs
z Feet,
z Lower legs
4. Naproxen Blocks 275 mg every 6 1100 mg/ GI intolerance Hypersensitivity,
(propionic acid arachidonic acid to 8 hourly day liver and renal
derivative) to inhibit COX-1 impairments
and COX-2
B. Antispasmodics
Drotaverine Selective inhib- 80 mg every 240 mg/day Heating Liver and kidney
(smooth muscle itor of phospho- 12 hourly sensation, failure and in
relaxant) diesterase-4 dizziness, severe heart
headache failure and in
(rarely), children under
insomnia 12 years of age
Hyoscine Anticholinergic 2 tablets 160 mg/day Side effects Myasthenia
butyl bromide action—binds (40 mg), taken may include gravis,
(antimuscarinic) to muscarinic 4 times a day sleepiness, mechanical
acetylcholine vision changes, stenosis in the
receptors, dry mouth, gastrointestinal
blocking their rapid heart rate, tract, paralytical
effect triggering of or obstructive
glaucoma, and ileus, megacolon
severe allergies
(Contd...)
264 Drugs in Obstetrics and Gynecology

Table 33.1: NSAIDs and antispasmodics9 (Contd...)

Drugs Mechanism of Dosages Max. dose Side effect Contraindications
action
Dicyclomine Dicyclomine 325 to 650 mg 4 g per day Liver damage or Hypersensitivity
+ Paracetamol is a muscarinic every 4 to allergic reactions to
(antimuscarinic) M1, M3, and 6 hours like swelling of acetaminophen,
M2 receptor the mouth, face, severe hepatic
antagonist as throat, difficulty impairment, or
well as a non- in breathing, severe active
competitive skin rash, or hepatic disease
inhibitor of itching
histamine and
bradykinin
Camylofin + Camylofin 25 mg 4 g per 24 Skin rash, Heart disease,
Paracetamol is a smooth camylofin + hours headache, gran- glaucoma (narrow
muscle relaxant 300 mg PCM ulocytopenia, angle)
with both irregular heart
anticholinergic rate
action

medroxyprogesterme acetate (DMPA) use (Table 33.1) or hormonal suppression or

has been associated with smaller gains both. Progestin (Table 33.2) or combinations
or loss of bone mass during this critical of estrogen and progesterone (low dose or
age period for acquiring bone strength, high dose) can be used depending upon
therefore should be averted. Oral progestin ultrasonography (USG) findings. Duration
formulations are enlisted in Table 33.2. of treatment will be 6 to 9 months. If there is
any pelvic pathology, then treatment is based
Case 2: Young Unmarried Female on the type of pelvic pathology.
(Age ≥18 years) with Dysmenorrhea Hormonal management (oral formulations):
Detailed history, clinical examination, pelvic Progestin preparations or combined estrogen–
ultrasonography and if required magnetic progesterone—patients not responding to
resonance imaging (MRI) is to be done. Drugs NSAIDs, start with hormone therapy for
of choice will be NSAIDs and antispasmodics at least three menstrual cycles. Continuous

Table 33.2: Progestin preparations (oral formulations)10

Progestin preparation Mechanism Oral dosage Side effects
(oral)
Medroxyprogesterone Decidualization and 5 or 10 mg daily for 5 to z Irregular bleeding/
acetate (pregnanes), atrophy of endometrium 10 days starting on day spotting
C-21 progestin 16 or daily for 21days z Mood variability
(cyclical) z Depression
Norethindrone acetate 5 or 10 mg daily for 5 to z Bloating
(estrane) 19-nor- 10 days starting on day z Breast tenderness
testosterone 16 or daily for 21days z Weight gain
(cyclical) z Drowsiness
Dydrogesterone 10–30 mg twice/ thrice
(gonanes) 19-nor- daily for 6 months
testosterone
 Drugs in Dysmenorrhea 265

combined oral pills for 3 months give excellent of menses and continues for 21 days for 6
results. to 9 months or as long as contraception is
required.
Case 3: Married Female with Apart from oral preparation injectables,
Dysmenorrhea Desiring for Contraception vaginal rings, transdermal patches and
After evaluation, if there is no pelvic intrauterine devices are widely available
pathology, different hormonal preparations and can also be used safely in these women.
can be used in the form of oral, injectable, Various available formulations of combined
implants, patches, vaginal rings, intrauterine estrogen–progesterone and progestin are
devices. It should be started on day 1–3 enlisted in Table 33.3.

Table 33.3: Hormonal preparation: Combined estrogen–progesterone and progestin11

Hormonal preparation Formulations Dosage Side effects Contraindications
Combined (estrogen + 1. OC pills: Ethinyl estradiol Nausea Arterial venous
progesterone) Low/ high dose (20 or 30 mg) + LNG vomiting, thrombosis
Mechanism of action: (0.15 mg) weight gain, severe
1. Synthetic progestins 2. Transdermal Ethinyl estradiol venous hypertension,
suppress ovulation and patch (20 mg) + thrombosis DM with
make the endometrium Norelgestromin mastalgia vascular
thin which has small (0.15 mg) complications,
amounts of arachidonic active liver
acid, the substrate for diseases
most prostaglandin breast cancers
synthesis.
2. It reduces both uterine
bleeding flow and
contractions during
menses, which decreases
dysmenorrhea.
3. Vaginal ring Ethinyl estradiol
(15 mg) + Etonogestrel
(0.12 mg)
Progestin mechanism Oral progestin Refer Table 33.2
Progestins cause
endometrial atrophy and
inhibit ovulation

DMPA: Depot Medroxyprogesterone Irregular Unexplained

intramuscular acetate 150 mg every menses, vaginal bleeding,
3 monthly amenorrhea, thromboembolic
loss of BMD diseases,
LNG (IUD): Levonorgestrel, 52 mg Irregular breast cancer,
Intrauterine (20 µg/day) frequent osteoporosis
device menses,
spotting
Norplant Etonogestrel, 68 mg Acne,
mastalgia,
menstrual
irregularities
266 Drugs in Obstetrics and Gynecology

Table 33.4: GnRH agonists and antagonists13

Preparation Mechanism of action Dosages Side effect
GnRH agonist Prolonged activation Menopause-like side
of GnRH receptors effects, high cost, loss of
1. Nafarelin 200 mg intranasal spray
by GnRH leads bone density with long-
twice day
to desensitization term use
2. Leuprolide acetate and consequently 3.75 mg intramuscularly
depot to suppressed every 4 weeks
gonadotrophin secretion

GnRH antagonist It competes with Tab 150–200 mg, OD Hot flushes, night sweat,
GnRH for receptors for 6 months nausea, weight gain,
1. Elagolix
on gonadotroph cell vomiting
membranes, inhibits
GnRH-induced
signal transduction
and consequently
gonadotrophin secretion

Case 4: Patients with Continued Menstrual Case 5: Patients with Persistent Dysmenorrhea
Pain Despite NSAIDs and Hormonal Treatment who Desire to Avoid Surgery (Diagnostic Lap-
Reassess patients by clinical examination and aroscopy)
USG to rule out pelvic pathology. Minimally Empirical treatment with a gonadotropin
invasive techniques, such as transcutaneous hormone-releasing hormone (GnRH) agonist
electrical nerve stimulation can be offered analog or antagonist: Make an endometriosis
to patients who still insist on conservative presumptive diagnosis and suggest empirical
management.12 GnRH agonist or antagonist therapy. With
1. Transcutaneous electrical nerve stimula­ either agonist or antagonist medication, if the
tion: Percutaneous tibial nerve stimulation pain significantly diminishes or goes away,
(PTNS). endometriosis is likely present, however this
is not proven. Details of GnRH agonist or
Mechanism: antagonist are given in Table 33.4.
1. It raises the threshold for pain signals from
uterine hypoxia and hypercontractility Case 6: Patients with Persistent Pain
by sending a volley of afferent impulses and Negative Laparoscopy
through the large diameter sensory fibers If laparoscopy is negative and the patient
of the same nerve root, resulting in lower has previously failed both hormonal
perception of painful uterine signals. contraception and NSAIDs, a 3-month course
2. Peripheral nerves and the spinal cord of a GnRH agonist analog can be tried, since
release endorphins.8 The major limitation endometriosis may have been missed. Even
need for continuous treatment for 12 weeks. in the hands of experienced laparoscopists,
an accurate diagnosis of endometriosis can be
Role of laparoscopy: In absence of pelvic difficult, since the disease is often microscopic
pathology diagnostic laparoscopy can be and presents visually with a variety of
offered. The most common diagnosis is atypical lesions. Calcium supplementation
endometriosis as mild grade of endometriosis 1–2 g daily should be considered with GnRH
can not be detected by USG. agonist.
 Drugs in Dysmenorrhea 267

Refractory dysmenorrhea: (Cases 7, 8, 9). training, exercises, relaxation training). In

Despite the above treatments, a minority of motivated patients, it serves as an adjuvant
patients will continue to have dysmenorrhea to therapeutic exercise and medication.
that limits their function. Treatment options
for refractory dysmenorrhea should be Complementary Medicine15
individualized as per age and future • Acupuncture or acupressure—improve­
childbearing. Cases 7, 8 and 9 are discussed ments were noted in the worst pain
as follows: intensity, number of days with pain,
and proportion of patients using pain
Case 7: Patient with Abnormal Uterine
medication.
Bleeding with Dysmenorrhea
• Diet and vitamins—dietary advice to
Patients who do not desire future childbearing avoid food that causes bloating and water
but want to retain uterus—endometrial retention, e.g. fatty foods, carbonated
ablation can be advised. beverages, caffeine and salty foods. A
variety of dietary changes and vitamin
Case 8: Patients who have Exhausted All
Treatment Options and have Completed their therapies has been reported to reduce the
Childbearing severity of menstrual pain, which includes
1. Low-fat vegetarian diet
Hysterectomy is the definitive treatment.
2. Increased dairy intake
Case 9: Patients with Chronic Midline Pelvic 3. Vitamin E (500 units per day or 200 units
Pain with no Organic Pathology twice per day, beginning 2 days before
Nerve transection procedures like pre-sacral menses and continuing through the first
neurectomy can be done. three days of bleeding)
4. Vitamin B1 (100 mg daily), vitamin B6
Non-pharmacological (200 mg daily), and fish oil supplement,
Supportive Treatment14 vitamin D3
• Exercise: It functions by enhancing pelvic 5. Ginger powder consumption: 750
blood flow and triggering the production to 2000 mg of on days 1 to 3 of the
of endorphins, which serve to reduce pain. menstrual cycle
Increasing physical activity is a sensible 6. Chinese herbs.
strategy to lessen dysmenorrhea due to
its numerous health advantages and a Unproven Treatment16
low risk of injury. Walking, yoga, and • Nerve transection procedures: Laparoscopic
cardiovascular exercises should be done uterosacral nerve ablation (LUNA), pre­
for 30 to 45 minutes. sacral neurectomy (PSN) involve transec­
• Apply heat pack to the lower abdomen. tion of (uterosacral ligaments or pelvis)
It can increase circulation, ease muscle afferent nerve fibers causing interruption
tension, and relax the abdominal muscles to of cervical sensory pain fibers in patients
lessen pain brought on by muscle spasms. with chronic midline pelvic pain associated
The effectiveness of other treatments may with endometriosis.
be increased by heat therapy. • Tocolytics: Nitric oxide, calcium channel
• Behavioral counseling changes how they blockers and nitroglycerin all have tocolytic
perceive their pain (such as desensitization- effects and are under investigation as
based techniques, hypnotherapy, imagery, potential therapies of dysmenorrhea.
and coping mechanisms) and how they react • Magnesium: Phosphodiesterase inhibitors—
to pain (e.g. biofeedback, electromyographic by inhibiting phosphodiesterase, sildenafil
268 Drugs in Obstetrics and Gynecology

Table 33.5: Causes of secondary dysmenorrhea

Causes of secondary Signs: Dysmenorrhea Diagnosis Management
dysmenorrhea with
Gynecological causes
Endometriosis dyspareunia, infertility Clinical examination/ Medical/surgical/
USG/laparoscopy combined
Adenomyosis Abnormal uterine Clinical examination/ Medical/surgical/
bleeding USG/MRI combined
Fibroid Large uterus Clinical examination/USG Medical/ surgical
Endometrial polyp Abnormal uterine Clinical examination/ Polypectomy
bleeding USG/ hysteroscopy
Pelvic inflammatory Vaginal discharge Clinical examination/USG Antibiotics and anti-
syndrome inflammatory drugs
Obstructive mullerian Large uterus Clinical examination/ surgery
anomalies USG/MRI/laparoscopy
Use of IUCD Non-cyclical pain Clinical examination/USG NSAIDs/ removal
Pelvic congestion Non-cyclical pain USG/Doppler NSAIDs
syndrome
Other causes
Gastro-intestinal: Constipation/diarrhea USG/gastrointestinal Medical
Inflammatory and endoscopy
irritable bowel
syndrome
Renal: Ureteropelvic Loin-to-groin pain USG/CT scan Medical/surgical
obstruction
Psychogenic Pain at multiple site Detailed history by Counseling/medical
specialist

enhances the vasodilatory effects of nitric 1. Endometriosis: Among the various

oxide, facilitating myometrial blood flow, gynecological pathologies endometriosis
and thus reducing primary dysmenorrhea. is the commonest benign disorder defined
as the presence of functional endometrium
SECONDARY DYSMENORRHEA outside the uterine mucosa. It is seen
It is defined as dysmenorrhea due to pelvic in around 8–10% of reproductive age
pathology. Along with accompanying group females, affecting 20–50% infertile
pelvic disease, prostaglandin release and population and chronic pain (3–80%). It is
anatomical mechanisms are also responsible usually diagnosed based on symptoms/
for secondary dysmenorrhea. Various causes physical examination and confirmed on
of secondary dysmenorrhea, their diagnosis ultrasonography or laparoscopy, but finally
and management are discussed in Table 33.5. proven by histopathology of the specimen.

Gynecological pathologies: Most common 2. Fibroid uterus: It is the second most

pelvic pathologies which are associated common pelvic pathology. Fibroids vary in
with secondary dysmenorrhea are discussed number, size and location. It gives rise to
below. different types of pain patterns, like dull
 Drugs in Dysmenorrhea 269

to sharp pain, menstrual cramping pelvic the upper genital tract including uterus,
pain, low back pain, abdominal pressure, cervix, ovary and fallopian tube. Outpatient
dyspareunia, rectal and bladder pressure and inpatient management depends upon
(uncomfortable pressure leads to pain). severity of disease. Patients may complain
It can also compress sciatic nerves leading of continuous dull aching lower abdomen
to leg pain. Causes of acute pain in the pain with or without fever.oral or parenteral
abdomen are twisted pedunculated fibroid, antibiotics are required to treat this condition.
submucosal fibroid and red degeneration For chronic pelvic pain the possibility of
of fibroid. Posterior fibroids may cause low tuberculosis should be ruled out.
backache and anterior fibroid can contribute
to anterior pelvic pain, pressure and urinary Treatment for Secondary Dysmenorrhea
complications. It varies depending upon type of pelvic
3. Pelvic inflammatory disease (PID): It pathology, age of patient, severity of
involves infection and inflammation of symptoms and child bearing status. For

Table 33.6: Medical management for secondary dysmenorrhea17,18

Gynecological Drugs used Mechanism of Dosages Side effects
pathology action
Endometriosis/ Dienogest Atrophy of 2 mg one or twice Irregular bleeding
adenomyosis endometrium a day for 3 to 6 spotting
months Mood variability
Androgens: Inhibits 400–800 mg, orally Acne, hirsutism,
1. Danazol steroidogenesis and in 4 divided doses voice changes,
2. Gestrinone atrophy of lesion for 6–9 months diminished breast
1.25/2.5 mg, twice size, decreased
a week for 6–9 libido
months
Progesterone (NEW) Decidualization of 4 mg, once a day for
Drospirenone endometrium 21 days for 3 cycles
Aromatase inhibitor: Reduces estrogen 2.5 mg daily for 6 Headache, nausea,
1. Letrozole synthesis with lesion months vomiting, skin
2. Anastrozole atrophy 1 mg daily for 6 changes, vasomotor
months symptoms,
arthralgia,
osteoporosis
SERMs: Inhibit estrogen 40–60 mg/day for Fatigue, hot flushes,
1. Tamoxifen receptors 6 months night sweats, vaginal
2. Raloxifene discharge, mood
swings
Fibroid SPRMs: Antiproliferative 5 mg /day for Dizziness, hot
1. Ulipristal effects in the 6 months flushes, fatigue,
2. Mifepristone endometrium 25 mg/day for headache, nausea,
3 months vomiting
PID Antibiotics and anti- Cap. doxycycline 100 mg, BD, for Nausea vomiting
inflammatory drugs Tab. metronidazole 14 days
400 mg, TDS, for
7 days
270 Drugs in Obstetrics and Gynecology

Flowchart 33.1: Management of dysmenorrhea

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 34
Drugs in Fibroids

• Rajeshwari L Khyade • Madhuri Patel • Aaishwarya R

Introduction Diagnosis is usually either by pelvic

Uterine leiomyomas better known as uterine ultrasound with Doppler studies or by
fibroids, are most frequent nonmalignant magnetic resonance imaging (MRI).
smooth muscle tumors of the uterus. MRI is preferred because of its greater
They are the most common tumors found ability to demonstrate individual fibroids
in the female reproductive system. and for fibroid mapping, i.e. denote their size,
location, and number within the uterus.2–5
Uterine fibroids are common in 50–60% of
women. The definitive treatment, so far, has been
hysterectomy and sums up to two-thirds of
Most are asymptomatic.
all hysterectomies done in premenopausal
Patients with asymptomatic uterine women.
fibroids and who do not desire of pregnancy
Myomectomy is an option for patients
do not need any intervention except for serial
desiring child-bearing and in women who
ultrasonography (USG) monitoring for the
want to preserve her uterus.
growth of fibroid and their condition.
Uterine artery embolization also is a form
In 30–40% of cases, fibroids cause morbidity of conservative management of myomas, but
due to abnormal uterine bleeding and pelvic carries risk of premature ovarian failure and
pressure. has its own risks, limitations, and availability
This disease is one of the major concern is an issue.
of health expenditure in gynecology field
Medical treatment is given to:
African–American women have a greater
chance of being affected by uterine fibroids,1 1.Reduce the symptoms
due to high follicle-stimulating hormone 2.Preoperatively
(FSH). 3.Correction of anemia
Uterine fibroids can occur at any time 4.Shrinkage of fibroids
between menarche and menopause but are 5.To preserve fertility
mostly seen in 35–49 years of age. 6.To avoid or delay surgery.
They typically resolve after menopause. After evaluating 52 studies came to a
Pathogenesis of fibroids is still unclear, conclusion that proves the efficacy of a
however they are estrogen and progesterone number of agents, as medical alternative to
dependent tumors. surgery.6,7
 Drugs in Fibroids 273

The drugs most commonly used are: They include progesterones made from
1. Gonadotropin-releasing hormone (GnRH) plant and synthetic form, that is bio-identical
agonist and antagonist progesterone. Progesterone was first used in
2. Selective progesterone receptor modulator 1940 to manage fibroids.
(SPRM) Depot medroxyprogestrone acetate
3. Progestogens. (DMPA) inj., intramuscularly, to treat and
GnRH agonist reduces leiomyoma size to prevent increase in the size of fibroids.
about 50% in 3 months, but it is expensive LNG–IUD-containing levonorgestrol,
and has to be given parenteral. 52 mg, releases daily 20 mg, acts locally
Long-term use of GnRH agonists treatment thereby causing thinning of the endometrium
is accompanied by side effects, such as hot and decreases the menstrual blood flow.
flushes, night sweats, bone resorption due It can be safely used for 5 years.
to hypoestrogenic effect, etc. and the need As progestogens temporarily reduce
for add back therapy. Cessation of GnRH the bleeding, cannot be used for long-term
causes regrowth of myoma and recurrence of medical therapy.
symptoms; therefore use of GnRH is limited They exert dual action on myomas.
for only 6 months or prior to surgery. Moravek, et al. concluded that progesterone
GnRH agonist-produced side effect is and progestin play a key role in uterine
overcome with the use of GnRH antagonist fibroid growth, hence it is like adding fuel to
cetrorelix. the fire.
A new kid on the block, in its earlier phase E s t ro g e n – p ro g e s t i n c o m b i n a t i o n s
is orally-active nonpeptitide GnRH-receptor (oral contraceptives), especially low dose
blocker, elagolix. estrogen:
The levonorgestrel intrauterine device 1. Decreases menstrual pain,
(LNG-IUS) is effective in decreasing menstrual 2. Decreases length and severity of bleeding
blood loss, correcting hemoglobin levels, and 3. Regulates menstrual bleeding and
it can be an alternative to surgical treatment.
4. Does not cause the growth of new fibroids.
Although the expulsion rate of levonor­
5. They may have beneficial effect on the size
gestrel intrauterine device is high in patients
of already existing fibroids.
with fibroid uterus.
In May 2021, United States Food and
When the cavity is big, it is ineffective of
Drug Administration approved estradiol
the SPRM, ulipristal and mifepristone.
and norethindrone acetate (MYFEMBREE)
Ulipristal is an expensive option and for the treatment of symptomatic fibroids
should be used with caution because of rare for duration of 2 years in a perimenopausal
occurrence of liver complications. women.
Mifepristone is effective in reducing the This changed the dynamics of treatment of
size of fibroid and is a more cost efficient. fibroids, as there were very few noninvasive
All SPRMs produce unique endometrial methods.
changes that are benign, reversible and have
negative consequences. Selective Progesterone Receptor
Modulators (SPRMs)
Progestogens SPRM are providing a great hope and change
Progestogens produce results similar to as an effective medical therapy for fibroids
natural hormone progesterone in the body, with fewer side effects and beneficial long-
used in medical management of fibroids. term effects.
274 Drugs in Obstetrics and Gynecology

Mifepristone and Ulipristal Acetate Have show the effect of mifepristone.

Mifepristone: Synthetic steroid, code name • When given for 3 months in doses of 10,
RU 486, is the first SPRM to be produced and 25 and 50 mg.
used clinically. • Decreased the size of uterine fibroids and
It is antiestrogen hormone, weak anti­ uterine volume.
progestin, which antagonizes progesterone To obtain amenorrhea, decreased clinical
receptors. symptoms, controlled bleeding and corrected
Though estrogen is major contributor for anemia.
fibroids, many studies show the effect of It even cut short the surgical time, amount
progesterone, which promotes fibroid cell of bleeding and the need for blood transfusion
mitosis, and thus fibroids grow. if surgery was considered later.

MIFEPRISTONE Clinical Approach

It causes: Contraindication: Ectopic pregnancy, hyper­
1. Heavy menstrual bleeding sensitive to prostaglandin, undiagnosed renal
2. Reduction in fibroid size masses, concurrent intrauterine device (IUD)
3. Pain causes allergic disorders and anemia.
4. Improves overall the quality of life.
Side effects: Leg cramps, hot flushes, Abdo­
minal cramping, allergic reaction, diarrhea,
Mechanism of Action dizziness, fainting, fatigue, headache,
Low-dose progesterone blocks by compe­ insomnia, indigestion, nausea and vomiting.
titively binding its intracellular receptors. Neelofer Shaikh, et al. 8 compared the
They inhibit progesterone receptor (PR) efficacy of using 25 mg daily and 50 mg
and EGF mRNA gene expression in the twice weekly for 3 month, the results were
myoma, which are overexpressed in myomas. mifepristone in both dosages is highly
Glutathione pathway also was significantly efficacious in causing amenorrhea, improving
changed, thus causing inhibitory effect on the anemia, and enhancing the quality-of-life,
growth of fibroids. and hence 50 mg biweekly dosage shows
potential for being cost efficient.
Pharmacokinetics Another study by Vidushikulshresthra9
Mifepristone is active orally. dose of 10 versus 25 mg, given daily for
• Bioavailability is only 25%. 3 months, there was greater reduction of
• It is largely metabolized in the liver by myoma size with 25 mg dose, amenorrhea
CYP3A4. was seen in 90–95% of patients, which is
• Excreted in bile. reversible. Symptomatic relief with more than
90% reduction in menstrual blood.
• t1/2 is 20–36 hours.
Some enterohepatic circulations occur. Gil Yerushalmi, et al. 10 did study to
evaluate the efficacy and safety of vaginal
Side effects: Causes endometrial hyperplasia. mifepristone, 10 mg, daily for 3 months
treatment on uterine leiomyoma and related
Dosage symptoms. The results were similar to other
5–10 mg, 25 to 50 mg, daily, once, orally for studies given orally. There were no major side
3–6 months. effects and improved the quality-of-life. There
Many domestic and international clinical was no evidence of endometrial hyperplasia
studies. or atypia.
 Drugs in Fibroids 275

GnRH AGONIST The advantages of the preoperative use of

gonadotropin-releasing hormone agonists
Short peptide analogues of GnRH cause are:
profound down regulation of pituitary, which 1. Reduction in uterine and myoma size
cause inhibition of estrogen and androgen 2. Vascularity
synthesis.
3. Correction of anemia
Leuprolide, goserelin and triptorelin are 4. Potentially improved operative technique
GnRH agonist.
5. Uterine cavity integrity and
Mechanism of Action 6. Abdominal hysterectomies could be
converted to vaginal hysterectomies
GnRH is a decapeptide, synthesized in the
7. Fewer post-operative complications.12
hypothalamus.
Fibroid shrinkage occurs in the initial 8–10
Reaches GnRH receptor of gonadotropin
weeks, highest after 14 weeks of treatment,
cells in the pituitary gland, triggers a domino
after this, steady state of reduction occurs.
effect.
Efficacy of the drug is 90%. And is a
Stimulates the release of luteinizing hormone
suitable alternative to surgical intervention.
(LH) and follicular-stimulating hormone
Efficacy is higher in women under 35 years.
(FSH), which results in the production and
Women with the largest initial uterine or
release of estrogen by the ovaries, that is
fibroid volume were more likely to undergo
stimulates hypothalamic pituitary ovarian
the greatest fibroid shrinkage.
axis.
The lower the serum estradiol levels the
As fibroids are estrogen and progesterone-
greater the tumor shrinkage.13
dependent GnRH causes growth of fibroids.
Gonadotropin-releasing hormone analogues
GnRH is typically produced in a small
are very effective in reversing heavy menstrual
rhythmic burst pulsatile manner, GnRH
bleeding and pain.
agonist changes the pattern of GnRH release.
The fibroids regrow quickly about
GnRH agonists when administered
6 months once medication is discontinued,
cause an initial flare effect, increasing in sex
hormones, but with continued constant flow As effects are temporary.
in a non-pulsatile stimulation, LH and FSH, GnRHa treatment are not recommended
estrogen and progesterone synthesis is halted for long time because of
and ovulation declines. 1. Potential side effects
Thus, prolonged activation of GnRH 2. Complications
receptors by GnRH leads to desensitization 3. High cost
and suppression of gonadotropin secretion, 4. Need for add-back therapy.
Without estrogen, menstruation stops. The course of GnRHa should be used:
Hypo-estrogenic state causes fibroids to 1. Long-term protocol for 6 months in pre­
regress in size and decreasing its fibroid- menopausal women to induce iatrogenic
associated symptoms. climacteric stage and in those waiting to
Finally, GnRHa directly acts on myomatous attain menopause, later shrinks on its own.
cell inducing a suppression of cell proliferation 2. Short-term for 2–3 months, preoperatively,
and apoptosis. prior to surgery.
GnRH analogues are more potent and 3. Intermittent 6-month course is effective
sustained in action. in treating myoma symptoms to limit
The native decapeptide have been used climacteric like state.
extensively in modulation of sex hormone Use of GnRHa for more 6 months warrants
synthesis.11 add-back therapy.
276 Drugs in Obstetrics and Gynecology

Drugs used for add-back therapy are: Side Effects

1. Progestin—MPA, 20 mg/day • Stops production of estrogen and proges­
2. OC pills. terone
3. Tibolone—2.5 mg/day • Hot flushes, mood changes
4. Ipriflavone—reduced bone loss • Vaginal dryness, lower sex drive
5. Raloxifine—60 mg daily in postmenopausal • Transient frontal headache
women. • Arthralgia, myalgia, insomnia, edema,
Pre-surgical GnRHa use indicates a definite emotional liability, depression and
treatment advantage and the use of GnRHa decreased libido.
as adjuncts to surgery are well-established.14 • Hypo-estrogenic state induced by GnRH
causes significant bone loss and osteoporosis
Pharmacokinetics after 6 months of therapy.
• Therefore, they will require add-back
GnRH agonists are derived from native
therapy with oral contraceptive (OC)
GnRH, by substituting a D-amino acid for the
pills or progestin to help mitigate the side
native L-amino acid position 6 of the native
effects of bone loss and hot flushes.
decapeptide.
• Dosage-related long-term metabolic abnor­
This substitution makes the agonist
mali­ties are like weight gain, worsening of
resistant to degradation by endopeptidases,
diabetic and osteoporosis.
resulting in prolonged receptor occupancy.15
Leuprorelin acetate is a synthetic non­ Uses of Various Drugs
apeptide agonist analogue of gonadotropin-
releasing hormone. Clinical approach: Used in endometriosis,
precocious puberty, infertility and uterine
Continued leuprorelin administration
fibroid and other sex hormone-related
causes medical castration.
disorders.
As leuprorelin is a nonapeptide, is orally
inactive and given subcutaneously or
intramuscularly, nasal spray. ULIPRISTAL ACETATE
The hydrophilic leuprorelin is entrapped Ulipristal acetate known as CDB-2914, is a
in biodegradable highly lipophilic synthetic synthetic orally active SPRM, characterized
polymer microspheres. by a tissue-specific partial progesterone
The peptide drug is released from these antagonist effect.17
depot formulations at a constant daily rate
for 4–12 weeks to avoid daily injections. Mechanism of Action
With doses ranging between 3.75 and It reversibly blocks the progesterone receptors.
30 mg.16 1. Hypothalamus,
2. Uterus,
Onset of action: Initial transient flare,
3. Cervix
hormone suppression occurs 2–4 weeks of
continued therapy. 4. Ovaries.
• Protein binding: 43–49% UPA, as a progesterone antagonist:
• Metabolism: It is metabolized to smaller 1. Prevents the proliferation of leiomyoma
inactive peptides that are further catabolized. cells
• Bioavailability: 94% 2. Initiates apoptosis
• Half-life elimination: ~3 hours 3. Increases cleaved caspase-3 expression
• Excretion: Urine. 4. Reducing Bcl-2 expression.18
 Drugs in Fibroids 277

5. Downregulates the expression of angio­ Half-life elimination—32–38 hours. Its

genic growth factors, vascular endothelial monodemethylated metabolite—27 hours.
growth factor (VEGF) and their receptors. Time to peak in serum—1 hour.22
6. Stops neo-vascularization
7. Stops cell proliferation and survival in Side Effects
leiomyoma cells but not in normal myo­ • Headache and hot flushes, vertigo,
metrial cells.19 functional ovarian cyst, nausea, acne,
8. Enhances the expression of matrix muscle pain sweating and tiredness
metalloproteinase (MMPs) and reduces • Rarely changes in liver function seen
the expression of tissue inhibitor of • Bone ­mineral density (BMD) not adversely
metalloproteinase (TIMPs) and collagens affected
in cultured fibroid cells. • Hyperplasia was observed.
9. Ulipristil acetate (UPA) may impair • Dosage: 5 to 10 mg, daily, orally, 12 weekly.
fibroid tissue integrity by decreasing the • For 4 times in a year
deposition of collagen in the extracellular • Within 1 week—70% is bleeding controlled.
spaces.20 • 80% had 25% reduction in volume of
Median fibroid volume after successive fibroid and improvement in pain.
courses of UPA treatment ranged from –63% Uses of Various Drugs
to –72% as compared to the baseline value.
Controls bleeding, and reduction in the size
The significant reduction in fibroid size
of fibroids and increase the quality-of-life.
lasts for at least 6 months after treatment.
Some small studies demonstrated potential
UPA shows several advantages:
endometrial effect inhibiting implantation.23
1. It is faster than leuprolide in reducing the UPA has been shown
fibroid-associated bleeding.
1. To improve quality-of-life,
2. It improves hemoglobin and hematocrit
2. To reduce fibroid volume,
levels in anemic patients.
3. To induce amenorrhea in most of the
3. It brings a significant reduction in the size women treated.
of fibroids, which lasts for at least 6 months
It is now approved for clinical use in both
after the end of the treatment.
Europe and Canada.24
4. UPA is a better tolerated when compared
Ulipristal has successfully completed
to leuprolide.
two-phase III clinical trials (PEARL I and
5. It keeps estradiol levels at mid-follicular II) proving its safety and efficacy for the
phase range. treatment of symptomatic fibroids.
6. Reducing the frequency of hot flushes and Uterine bleeding was controlled in 90% of
has no impact on bone turnover.7 patients receiving 5 mg dose and 98% with
Recommendation: 5–10 mg per day for 10 mg dose while leuprolide acetate was 89%.
3 months as per individual needs.21
GnRH ANTAGONISTS
Pharmacokinetics GnRH antagonists are a class of drugs, which
Good bioavailability and rapid absorption. antagonize the gonadotropin-releasing
Metabolism—extensively in liver by hormone receptor and act immediately to
cyto­chrome (CYP) 3A4 protein-binding— suppress the secretion of FSH and LH by
more than 94% to plasma proteins including blocking pituitary GnRH receptors, so no
albumin, alpha1 acid glycoprotein and high- flare effect seen which inhibit the ovaries from
density lipoprotein. producing estrogen.
278 Drugs in Obstetrics and Gynecology

The subsequent decrease in estradiol levels: – Future research is needed to evaluate

1. Leads to improvement in bleeding patterns the safety and efficacy of new depot
and formulation of GnRH antagonist in
2. A shrinkage in uterine fibroid size as early decreasing the size and symptoms of
as 2 weeks after initiation of treatment.25 fibroids.
And within a shorter time in comparison
Reference
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1. Donnez J, Dolmans MM. Uterine fibroid
of its rapid onset of action, and avoidance of
management: from the present to the future.
gonadotropin flare effect, patients experience Hum Reprod Update. 2016 Nov. 22 (6): 665–686.
faster symptom relief. [Medline].
Further research is needed for dosing and 2. Chapiro J, Duran R, Lin M, Werner JD, Wang
its side effects. Z, Schernthaner R, et al. Three-Dimensional
Relugolix and elagolix is a FDA-approved Quantitative Assessment of Uterine Fibroid
oral tablet and can be given for 2 years to Response after Uterine Artery Embolization
treat in perimenopausal women with heavy Using Contrast-Enhanced MR Imaging. J Vasc
Interv Radiol. 2015 May. 26 (5): 670–678.e2.
menstrual flow, compared to GnRH agonist [Medline].
given intramuscularly and only for short
3. Kong CY, Meng L, Omer ZB, Swan JS, Srouji S,
duration of 6–12 months with add back Gazelle GS, et al. MRI-guided focused ultrasound
therapy. surgery for uterine fibroid treatment: a cost-
effectiveness analysis. AJR Am J Roentgenol.
CONCLUSION 2014 Aug. 203 (2): 361–71. [Medline].
• Fibroids are the most common non- 4. Kirpalani A, Chong J, Yang N, Jenkins SJ,
Nisenbaum R, Prabhudesai V, et al. Diffusion-
malignant tumors of the reproductive age.
weighted imaging properties of uterine fibroids
• As women continue to delay reproductive pre- and post-uterine fibroid embolization. Eur
age. J Radiol. 2014 Sep. 83 (9): 1620–5. [Medline].
• An increasing number of patients will 5. De La Cruz MS, Buchanan EM. Uterine Fibroids:
require conservative or fertility-preserving Diagnosis and Treatment. Am Fam Physician.
treatment methods. 2017 Jan 15. 95 (2): 100–107. [Medline].
• Medical management of uterine fibroids 6. Bartels CB, Cayton KC, Chuong FS, et al.
may provide symptomatic relief of the An evidence-based approach to the medical
management of fibroids: a systematic review.
uterine fibroid-related symptoms like
Clin Obstet Gynecol. 2016; 59 (1): 30–52.
heavy menstrual bleeding, pain along with
7. Uterine fibroids: an update on current and
the opportunity to preserve fertility. emerging medical treatment options Manuela
• Also long-term medical treatment of Farris, Carlo Bastianelli, [...], and Giuseppe
fibroids seems possible today, especially Benagia Ther Clin Risk Manag. 2019; 15: 157–178.
in peri and premenopausal women. 8. Mifepristone in fibroids: Comparative study of
• The most promising drugs belong to two safety and efficacy of biweekly dosage vs. daily
categories: dosage schedule Neelofer Shaikh year 2021, vol:
12 issue: 1, page 39–45.
– Progesterone receptor modulators and
9. Vidusi kulshresthra et al. Indian J Med Res.
orally active GnRH antagonist and
2013 Jun. Low dose mifepristone in medical
GnRH agonist in depot formulations management of uterine leiomyoma. An
with add-back therapy. experience from tertiary care hospital from
– Use of SPRM has emerged as a most north India.
viable option capable of offering women 10. Gil M Yerushulmi et al Fertil Steril 2014 Feb.
effective long-term medical management Vaginal mifepristone for the treatment of
and prevent surgery altogether. symptomatic uterine leiomyomata.
 Drugs in Fibroids 279

11. McGinnis T, Montgomery E. Approach to the 19. Maruo T, Matsuo H, Samoto T, Shimomura Y,
Transgender Adolescent and Specific Health Kurachi O, Gao Z, Wang Y, Spitz IM, Johansson
Considerations. E. Effects of progesterone on uterine leiomyoma
12. Adamson GD. Treatment of uterine fibroids: growth and apoptosis. Steroids. 2000 Oct 1;
Current findings with gonadotropin-releasing 65(10-11): 585–92.
hormone agonists. American journal of obstetrics 20. Spitz IM. Clinical utility of progesterone receptor
and gynecology. 1992 Feb 1; 166(2): 746–51. modulators and their effect on the endometrium.
13. Healy DL, Vollenhoven BJ. The role of GnRH Current Opinion in Obstetrics and Gynecology.
agonists in the treatment of uterine fibroids. 2009 Aug 1; 21(4): 318–24.
BJOG: An International Journal of Obstetrics & 21. Talaulikar VS, Manyonda I. Progesterone
Gynecology. 1992 Feb; 99:23–6. and progesterone receptor modulators in the
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14. Golan A. GnRH analogues in the treatment of
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 35
Drugs in Male Infertility

• Jiteeka Thakkar • Charumati V Pekhale • Rohan Palshetkar

Introduction Antioxidants help in counterbalancing

Around 50% of cases of infertility are due to ROS by maintaining the equilibrium in the
male factors.1,2 Either testis are malfunctioning redox potential desired for optimal sperm
or obliteration of duct. function.6–7
There are several causes of male factor
infertility, however, in most cases, the exact ANTIOXIDANTS IN MALE INFERTILITY
cause remains unknown.1 Seminal fluid is rich Mechanism of action of commonly used
in antioxidants that nourish and protect the antioxidants.
sperm. They exist in two forms—an enzymatic
Antioxidant compound Mechanism of action
and a non-enzymatic antioxidant system.7
Ascorbic acid (vitamin C)
The enzymatic system includes glutathione
peroxidase, superoxide dismutase, and Tocopherol (vitamin E) Neutralises free radicals
catalase. These are naturally occurring Folate (vitamin B9) Scavenges free radicals
enzymes in the sperm cell or seminal plasma Selenium Enhancement of
and originates from the prostate. The non- enzymatic antioxidant
enzymatic system, are consumed through activity
diet or as supplements. Oxidative stress (OS) Zinc Inhibition of
is an important contributor of infertility.3 nicotinamide adenine
Reactive oxygen species (ROS) are pro- dinucleotide phosphate
duced by the sperm cell in small quantities. (NADPH) oxidase
There main functions are initiation of sperm Carnitines Neutralises free radicals
capacitation, regulation of sperm matura- and acts as an energy
tion, and enhancement of cellular-signalling source
pathways.4 CoQ10 In its reduced form,
And thus high levels of ROS have paradoxical scavenges free radicals
effects on sperm function, which results in intermediate in
mitochondrial electron
infertility and deoxyribose nucleic acid (DNA) transport system
damage and lipid peroxidation.5 Causes of
NAC Enhances enzymatic
increased ROS production are immature
antioxidant activity
spermatozoa, leucocytes, varicocele and
exogenous factors like testicular hyperthermia, Lycopene Quenches free radicals
environmental and habitual exposure. NAC: N-acetyl cystein
 Drugs in Male Infertility 281

CLINICAL SCENARIOS AND Advanced sperm

ANTIOXIDANTS PRESCRIBED function
High SDF Vitamin E, vitamin C, zinc,
Clinical Antioxidant selenium and folic acid
circumstance
Vitamin E (1 g) + vitamin C
Basic semen (1 g)
parameters
Vitamin C (400 mg), vitamin E
Oligozoospermia Vitamin E, vitamin C, NAC, (400 mg), b-carotene (18 mg),
carnitines, CoQ10, lycopene, zinc (500 µmol) and selenium
selenium and zinc (1 µmol)
Vitamin E (300 mg)
LC (1500 mg); vitamin C
Vitamin E (180 mg), vitamin (60 mg); CoQ10 (20 mg);
A (30 mg) and essential fatty vitamin E (10 mg); zinc (10 mg);
acids or NAC (600 mg) folic acid (200 μg), selenium
NAC (600 mg) + other (50 μg); vitamin B12 (1 μg)
vitamins/minerals OS Vitamin E, vitamin C, NAC,
LC (2 g) selenium and zinc
CoQ10 (300 mg) Vitamin E (300 mg)
NAC (600 mg) and selenium Vitamin E (180 mg) and
(200 µg) b-carotene (30 mg)
Folic acid (5 mg) + zinc Vitamin E (20 mg), vitamin
(66 mg) C (10 mg) and zinc (400 mg)
Lycopene (2 mg) Vitamin E (400 mg) and
Asthenozoospermia Vitamin E, vitamin C, NAC, selenium (225 g)
carnitines, CoQ10, lycopene, NAC (600 mg)
selenium and zinc
Improving success Vitamin E, vitamin C,
Vitamin E (400 mg) + selenium rate of ART lycopene, CoQ10, folic acid,
(200 μg) selenium, zinc
Zinc (400 mg), vitamin E
Vitamin E (200 mg daily)
(20 mg) and vitamin C (10 mg)
Lycopene (6 mg), vitamin E
LC (2 g) and LAC (1 g)
(400 IU), vitamin C (100 mg),
CoQ10 (300 mg) zinc (25 mg), selenium (26 g),
NAC (600 mg) folate (0.5 mg) and garlic (1 g)
NAC (600 mg) and selenium Vitamin E (600 mg)
(200 µg)
Vitamin C (1 g) + vitamin E (1 g)
Lycopene (2 mg)
Live-birth rate Vitamin E, vitamin C,
Teratozoospermia Vitamin E, NAC, lycopene, carnitines, CoQ10, and zinc
selenium and zinc
CoQ10 (300 mg)
Vitamin E (400 mg) + selenium
(200 μg) Vitamin E (300 mg)

NAC (600 mg) and selenium Zinc (5000 mg)

(200 µg) Vitamin E (1 g) + vitamin C
Zinc (400 mg), vitamin E (1 g)
(20 mg) and vitamin C (10 mg) Carnitines: LC (2 g) + LAC
Lycopene (8 mg) (1 g/day)
282 Drugs in Obstetrics and Gynecology

Vitamin E (α-tocopherol) is an organic N-acetyl cysteine (NAC): An amino acid

fat soluble compound. It reduces lipid that is converted in body tissues to cysteine,
peroxidation initiated by ROS by quenching a precursor of glutathione. The latter is an
free hydroxyl radicals and superoxide anions. important naturally occurring antioxidant
The percentage of motile spermatozoa in capable of neutralising various ROS
semen is directly related to levels of vitamin E preventing their detrimental effects and
in seminal plasma.8 Lower levels of vitamin E reduces OS through scavenging hypochlorous
were observed in the semen of infertile men.9 acid and hydroxyl radicals.19–21
Vitamin C (ascorbic acid): It is present at Selenium: An essential trace element and
concentration 10 times higher in seminal protects sperm DNA against OS damage in a
plasma than in blood serum.10 mechanism that is not very well-understood
It neutralises hydroxyl, superoxide and and augments the function of glutathione.
hydrogen peroxide radicals providing More than 25 selenoproteins exist, such as
protection against endogenous oxidative phospholipid hydroperoxide glutathione
damage. 11 Seminal fluid analyses from peroxidase (PHGPX)22 and sperm capsular
infertile men with asthenozoospermia were selenoprotein glutathione peroxidase,23 which
found to contain lower vitamin C levels and help maintain sperm structural integrity.24
higher ROS levels.12 Selenium deficiency has been most commonly
Carnitines [L-carnitine (LC) and L-acetyl associated with morphological sperm mid-
carnitine (LAC)] are also water-soluble piece abnormalities and impairment of sperm
antioxidants. It helps in sperm metabolism motility.25
and helps increasing parameters like sperm
Zinc: Another essential trace element.26 It
motility.
plays a vital role in the metabolism of RNA and
There are studies where sperm cultured
DNA, signal transduction, gene expression,
in media with carnitines and LAC showed
and regulation of apoptosis. Its antioxidant
better viability and motility.13,14 They have
properties are thought to result from its ability
antioxidant property and act on superoxide
to decrease production of hydrogen peroxide
anions and hydrogen peroxide radicals thereby
and hydroxyl radicals through antagonising
inhibiting lipid peroxidation.15 Infertile men
redox-active transition metals, such as iron
with oligoasthenoteratozoospermia showed
and copper.27 Zinc concentrations of seminal
significantly lower carnitine levels in semen
plasma were found to be significantly higher
sample.16
in fertile men in comparison with subfertile
CoQ10 is a vital antioxidant omnipresent men.28 Zinc is thought to deliver an important
in almost all body tissues. It is particularly protective effect on sperm structure. Sperm
present at high concentrations in sperm flagellar abnormalities, such as hypertrophy
mitochondria involved in cellular respiration and hyperplasia of the fibrous sheath,
and plays an integral role in energy produc­ axonemal disruption, defects of the inner
tion.17 This contribution rationalises its use microtubular dynein arms, and abnormal or
as a pro-motility and antioxidant molecule. absent mid-piece have all be associated with
Furthermore, co-enzyme Q10 (CoQ10) inhibits zinc deficiency.
superoxide formation delivering protection
against OS-induced sperm dysfunction. A Folic acid: Folic acid (vitamin B9) is involved
significant negative correlation between in nucleic acid synthesis and amino acid
CoQ10 levels and hydrogen peroxide and a metabolism.
linear correlation between CoQ10 levels in Free radical scavenger: Folic acid intake was
seminal plasma sperm count and motility associated with an elevation in the reduced
was detected.18 oxidized glutathione ratio.29
 Drugs in Male Infertility 283

Lycopene: Lycopene is a carotenoid found pregnancies in men with adult-onset HH.35,36

in fruits and vegetables. It is known for Secondary causes of HH include, pituitary
its powerful ROS quenching abilities. 30 infiltrative disorders (e.g. hemochromatosis,
Lycopene is found at high concentrations in tuberculosis, sarcoidosis, histiocytosis),
human testes and seminal plasma. Infertile pituitary or suprasellar tumors, exogenous
men tend to have lower levels of lycopene androgen use, other medications (e.g. chronic
compared to fertile men.31 narcotic exposure), prior head trauma,
However, it is important to note that pituitary apoplexy, hyperprolactinemia
the benefits of supplements, including and severe chronic illness.37 The primary
antioxidants and vitamins, in treating male treatment for secondary HH is directed
infertility are of questionable clinical utility. towards addressing the underlying disorder.
Existing data are inadequate to provide Aromatase inhibitors (AIs), human
specific recommendations for the use of these chorionic gonadotropin (hCG), and selective
agents in treating male infertility. Patients estrogen receptor modulators (SERMs) are
need to be counselled regarding the same. medications that work through different
mechanisms to increase endogenous
CONDITIONS AND PROPOSED TREATMENT testosterone production. Each of these agents
Hypogonadotropic hypogonadism (HH), the can be used individually or in combination
underlying cause of the disorder should be to raise serum testosterone levels without
determined before initiating treatment. The negatively affecting spermatogenesis. It is
congenital form idiopathic hypogonadotropic important to note that while hCG is approved
hypogonadism (IHH), also known as isolated by the Food and Drug Administration (FDA)
gonadotropin-releasing hormone (GnRH) for use in men with hypogonadotropic hypo­
deficiency, is a rare genetic disorder associated gonadism (HH), the other medications are
with defects in the production and/or action not approved for this purpose. Additionally,
of GnRH. it should be recognized that the goal of
The usual first-line drug for the treatment optimizing testosterone levels in infertile
of IHH is human chorionic gonadotropin males may focus on alleviating symptoms,
(hCG), which is used to restore testosterone but the symptomatic outcomes and benefits
levels and spermatogenesis. The response to may not be comparable to those achieved
hCG treatment correlates with the size of the with standard exogenous testosterone
testis before initiation of treatment.32–34 Initial replacement therapy.
treatment involves hCG injections (1,500- The conversion of testosterone to estrogen
2,500 IU, twice weekly) followed by follicle occurs peripherally through the enzyme
stimulating hormone (FSH) if indicated, aromatase. AIs are oral medications that
after testosterone levels are normalized with inhibit this conversion, resulting in a relative
hCG. If medical treatment fails to result in a decrease in serum estradiol levels, an increase
pregnancy but some sperm are found in the in luteinizing hormone (LH) secretion by the
ejaculate, referral for assisted reproductive pituitary gland, and a relative increase in
technology (ART) is recommended. serum testosterone concentration. Clinicians
Selective estrogen receptor modulators may consider the use of AIs for men with
(SERMs) have been used off-label as an testosterone deficiency and elevated estradiol
alternative treatment to increase testosterone levels.38,39 hCG which is given by parenteral
and sperm density in men with adult- route acts as an LH analogue, stimulating
onset IHH. However, the evidence for this testosterone production by the Leydig
treatment is limited, with only a small cells. SERMs are oral medications with
number of studies reporting successful centrally antiestrogenic effects that impede
284 Drugs in Obstetrics and Gynecology

the negative feedback of the hypothalamic- A trial compared letrozole, an aromatase

pituitary–testis axis. inhibitor (AI) to placebo in cases of NOA. Not
all NOA cases with letrozole showed sperms
Clomiphene Citrate in ejaculate. There were no sperm recovery
It leads to increase in LH and FSH production in the ejaculate of the placebo group. None
by the pituitary gland. The increased LH of the groups had unassisted pregnancies.42
production, in turn, stimulates Leydig A study compared the effects of hCG before
cell production of testosterone. Clinically, surgical approach to no treatment in cases of
either hCG or SERMs can be considered NOA. There was no statistically significant
for optimization of testosterone in men difference in SSR, pregnancy rate or live birth
with low or normal serum LH levels. rate between the two groups.43
However, men who show elevated LH Another small study compared FSH to no
with primary hypogonadism, may have treatment prior to TESE. Surgical SSR in the
limited testosterone response due to inherent FSH group was 64% as compared to 33% in
testicular dysfunction. the no treatment group.44
Exogenous FSH can be used in the Men suffering with cancers should be
treatment of HH to initiate and maintain encouraged to freeze semen, preferably
spermatogenesis. In some studies, exogenous multiple samples before they begin with
FSH has been used in males without HH chemotherapy or other treatment that may
(baseline FSH in or slightly above the normal affect fertility in men.
values) to improve the fertility chances. The
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19. Gressier B, Cabanis A, Lebegue S, Brunet C, Dine to human chorionic gonadotropin is predicted
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Clin Endocrinol Metab. 1998. of spermatogenesis and fertility during
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Scavenging effect of N-acetyl-L-cysteine against deficient infertile men: Predictors of fertility
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infertility? Andrologia. 1997. patients with hypogonadotropic hypogonadism
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 36
Drugs in Pelvic
Inflammatory Disease
• Priti Vyas • Suchitra N Pandit

Introduction harm reproductive health in addition to

An acute infection of the female upper causing emotional stress.
genital tract tissues, including the uterus, The term ‘silent PID’ refers to a condition
fallopian tubes, and/or ovaries, along with when there are little or no symptoms, yet tubal
or without the surrounding pelvic organs, reasons of infertility and/or serologic proof
is known as pelvic inflammatory disease of prior sexually transmitted diseases (STDs)
(PID).1 It might be mild-to-moderate PID, are present without any prior history of overt
defined as the absence of a tubo-ovarian illness.2 These are particularly the ones that
abscess, or severe illness, characterized require prevention if PID complications and
as the presence of a tubo-ovarian abscess their consequences are to be avoided.
or severe systemic symptoms. Cervicitis,
salpingitis, endometritis parametritis, and India PID incidence: According to National
pelvic peritonitis are just a few of the Family Health Survey (NFHS)2 data, it is
possible long-term effects on fertility that estimated that the prevalence of symptoms
this condition can have. It can also lead to suggestive of sexually transmitted infection
persistent pelvic pain, adhesions, and ectopic (STI)/reproductive tract infection (RTI) in
pregnancies. When compared to women women was in the range of 23–43%, while in
without a history of PID, a woman’s chance of men it is in the range of 4–9% (Table 36.1).3,4
an ectopic pregnancy rises seven times after
only one incident. After a single episode of ETIOLOGY
PID, about 12% of women are infertile; after Microorganisms
two episodes, nearly 25%; and after three • Chlamydia trachomatis and Neisseria gonorrhea
episodes or more, over 50%. • Anaerobic gram-negative rods, Mycoplasma
genitalium and bacterial vaginosis
INCIDENCE • Often polymicrobial infection with
2–8%. It is one of the most frequent but Gardnerella vaginalis, Hemophilus influenza,
harmful infection that affects women who are anaerobes, enteric gram-negative rods.
of reproductive age. 15 to 20% of women with Majority are sexually transmitted and
PID are thought to experience the problems, remaining are caused by E coli, Group-B
which may potentially necessitate surgical streptococci, Bacteroides fragilis and lower
treatment. The effects of PID can seriously genital tract organisms.
288 Drugs in Obstetrics and Gynecology

• Genital tuberculosis is also implicated as • Risk factors associated with STI, such as
a common cause of pelvic inflammation – Multiple sexual partners,
in India.5–9 – Non-usage of barrier contraception,
More details will be with the clinical – Smoking, recreational drugs,
features. – Oral contraceptive (OC) pills
– Young adolescents with risky sexual
Risk Factors behavior
• Previous history of PID – Older women due to menopausal
• Untreated chlamydia or gonococcal changes in vaginal mucosa, etc.
infec­tion, with increased risk with each Abortions, puerperal sepsis, and
subsequent reinfection intrauterine device (IUD) insertions are the
most frequent causes in Indian settings.
Table 36.1: Organism/infection—symptoms3
STI/RTI Pathogen Clinical features
Gonorrhoea ‘drip’ Neisseria gonorrhoea z Vaginal muco-purulent discharge
z Dysuria and urethritis
Trichomoniasis Trichomonas vaginalis z Asymptomatic
z Foul-smelling, foamy, and greenish vaginal discharge
z Foul-smell with itching and burning
z pH >5
Chlamydia Chlamydia trachomatis z Produces minimal symptoms, even when there is an
upper genital tract infection (silent PID).
z An often ‘beefy’ crimson, friable, and purulent cervical
discharge that bleeds readily.
Bacterial vaginosis Overgrowth of z Not necessarily sexually transmitted.
anaerobes like z Vaginal discharge that smells fishy, greyish in colour.
Gardnerella vaginalis z May not have itching or burning.
z pH >4.5
Candidiasis Candida albicans z A white, curd-like vaginal discharge
z Moderate-to-severe vulval or vaginal itching and burning
z No foul smell
z pH <4.5
Presenting with pain in lower abdomen
Pelvic inflammatory z Neisseria gonorrhea z A lowered stomachache
disease (PID) z Chlamydia trachomatis z Vaginal discharge
z Anaerobes z Heavy, irregular vaginal bleeding is a sign of menstrual
abnormalities.
z Dysmenorrhea, pain during sexual activity, or dyspareunia
z Dysuria tenesmus
z Lower back pain
z Discharge from the cervix or vagina
z Congestion or ulcers
z Stiffness in the lower abdomen
z Cervical movement discomfort
z Pelvic mass presence
z Uterine/adnexal soreness
 Drugs in Pelvic Inflammatory Disease 289

PATHOGENESIS OF PID10 complexity of diagnosis and the potential for

serious harm to women’s reproductive health,
• Ascending it is best to have a low threshold for suspicion
• Hematogenous and the clinical diagnosis of PID.
• Local spread
The signs and symptoms may be one or
PID occurs basically in 2 stages for most of more of the following:
the cases:
• Lower abdominal pain with
• Acquiring a sexually transmitted, frequently
• Dyspareunia
asymptomatic vaginal or cervical infection.
These germs directly ascend to the upper • Vaginal and/or cervical discharge-
vaginal canal, infecting and causing yellowish or purulent, positive whiff test,
inflamation of these organs. foul smell, or fishy odor; cervical friability
• Salpingitis with spread to parametrium • Nausea, vomiting and bloating with or
or bowel. The infection may spread without loose motions
through hematogenous or direct purulent • Menorrhagia with irregular menstrual
discharge from the tubes into the pelvic bleeding
cavity causing cute peritonitis or even • Dysmenorrhea
perihepatitis—Fitz-Hugh−Curtis syndrome • Dysuria
• Cervical mucus forms a protective barrier, • Fever with chills
during ovulation and menstruation the • In case of severe infections: Severe pain
hormonal changes decrease the efficacy with high fever, tachycardia, nausea,
of this barrier and vaginal inflammation vomiting and right upper quadrant pain
would do the same. • Lower abdominal pain and tenderness
• When indigenous flora in the lower with or without guarding
genital tract is out of balance due to • Uterine, adnexal and cervical movement
antibiotic therapy, typically nonpathogenic tenderness
organisms might overgrow and ascend.
• Friable cervix, strawberry vaginitis.

CLINICAL FEATURES
DIAGNOSIS (Flowchart 36.1)
PID is often an acute condition with varied
The specificity of the diagnosis is increased
presentation depending on the nature of
when the lower genital tract inflammatory
the causative organism but occasionally can
symptoms listed below are present in addition
be a chronic presentation over weeks. It is
to one of the three minimal requirements.
often a diagnosis of exclusion with no single
diagnostic criteria. The differential diagnosis In addition to the minimum clinical criteria
of ectopic, appendicitis, torsion have to listed below, one or more of the following
be ruled out before coming to a definitive additional criteria may be used to support
diagnosis. the diagnosis of PID:10–12
It can be difficult to diagnose PID, if • Oral temperature >38.3°C (>101°F)
it is mild or asymptomatic since neither • Abnormal cervical mucopurulent discharge
the patient nor the doctor will notice the or cervical friability
clinical signs. Even individuals with mild or • Saline microscopy of vaginal secretions
asymptomatic PID may be at risk for infertility showing plenty of white blood cells
when nonspecific symptoms or indicators • Heightened erythrocyte sedimentation
(such as abnormal bleeding, dyspareunia, and rate
vaginal discharge) are disregarded. Given the • Increased C-reactive protein
290 Drugs in Obstetrics and Gynecology

Flowchart 36.1: Clinical diagnosis of PID

CT: Computed tomography

 Drugs in Pelvic Inflammatory Disease 291

• Nucleic acid amplification test (NAAT) • Secondary prevention—early treatment

evidence of cervical infection with N. gonorr­ and stoppage of spread
hoeae or C. trachomatis Both at local and national level effective STI
control programs have to be implemented.
Other tests specifically can be:
These should include:
• Polymerase chain reaction (PCR) • Medical management
• Chlamydia antibodies: Immunoglobulin G • Education of individuals for adopting
(IgG) and immunoglobulin M (IgM) healthy behaviours
• Test for other infections: Syphilis, human • Screening for STI, especially the at risk
immunodeficiency virus (HIV) and urinary individuals
tract infection (UTI) • Prevention and treatment for both partners.
• Endometrial biopsy is not routinely done
but if done will show histopathologic TREATMENT
evidence of endometritis—acute or chronic
Aims
• Imaging—ultrasonography (USG) and
magnetic resonance imaging (MRI)—will Diagnose and early treatment is important
show thickened tubes or tuboovarian (TO) for:
mass or hydrosalpinx or pelvic vascularity • Eradication of infection
and congestion on doppler, • Relief of symptoms
• Laparoscopic diagnosis. • Preventing spread to partner
• Preventing long-term sequel
There are two main approaches to STI/RTI
diagnosis and management (Tables 36.2 and The type of treatment methods are
36.3): commonly referred to as the ‘six Cs’3
• The etiological approach • Counselling, educating the patient
• The syndromic approach • Contact tracing
However, syndromic approach has its • Condom usage
limitations of missing out on asymptomatic • Compliance check
infections completely (Tables 36.4). • Come back for a follow-up
• Cure the patient.
Clinical diagnosis of PID There are three ways to treat patients with
See Flowchart 36.1.13 PID
Complications of STI • Presumptive treatment
• Etiological treatment
• PID, ectopic pregnancy, infertility and
• Syndromic management
chronic pelvic pain
• Increased chance of contacting other Presumptive treatment: When there is no other
infections known cause of the pelvic or lower abdominal
• Preterm labour, stillbirths, and miscarriages pain other than PID, or if one or more of the
• Neurological, cardiovascular, and other following three minimum clinical criteria
systemic complications are present on pelvic examination: Cervical
motion tenderness, uterine tenderness, or
• Chronic pain.
adnexal tenderness, presumptive treatment
for PID—was frequently used, began. There
PREVENTION is no perfect course of treatment, and it is
The best prevention is14–16 unknown whether subclinical PID patients
• Primary prevention of infection in both who receive early treatment will fare better
sexes in the long run.
292 Drugs in Obstetrics and Gynecology

Table 36.2: Clinical features of common STI3

Clinical feature Pathogens
Unusual vaginal discharge BV, chlamydia, gonorrhoea, trichomonas infection,
vaginal yeast infection
Genital itching BV, trichomonas infection, vaginal yeast infection
Abnormal and/or heavy vaginal bleeding Chlamydia, gonorrhoea and mixed anaerobic
infection.
Gonorrhoea (Note: This symptom is often caused by
factors other than STI)
Post-coital bleeding Chlamydia, gonorrhoea, chancroid, genital herpes
Lower abdominal pain (pain below the belly button; Chlamydia, gonorrhea and chlamydia, gonorrhea
pelvic pain) and mixed anaerobic infection.
Repetitive vaginal candidiasis HIV/AIDS
Painful intercourse
On the mouth, lips, genitals, anus, or adjacent regions, Chancroid, genital herpes, and syphilis
blisters or ulcers (sores)
Dysuria Chlamydia, genital herpes, trichomonas infection,
and gonorrhoea
Itching or tingling sensation Genital herpes, candidiasis
Genital herpes, candidiasis
Jaundice, fever, headache, muscle pain, yellower Hepatitis B, hepatitis C
urine
Genital warts on the anus or nearby places HPV (genital warts)
Mild liver inflammation, fever, exhaustion, headaches, CMV
and other flu-like symptoms
Skin lesions which are small, dimpled lumps that Molluscum contagiosum
are often painless and itchy and are flesh-colored,
however they can also be white, yellow, or pink
Chronic ulcers on the genitals or anus, small, red LGV
lesions or ulcers in the anal or genital region, lymph
node enlargement in the anal or genital region
Anus, genitalia, or mouth-red nodules or eruptions Donovanosis
under the skin that bleed readily, ulcerate, and
become sensitive.

Table 36.3: Comparison between etiologic and syndromic approach

Etiological approach Syndromic approach
Can get exact diagnoses with lab test May go wrong, e.g. gonorrhoea and chlamydia with vaginal discharge
Over treatment avoided Over treatment may happen
Patient has to come back for results, First visit treatment started
hence treatment delayed
Chances of lost to follow-up No loss to follow-up
Cost of lab test Relatively less expensive
 Drugs in Pelvic Inflammatory Disease 293

Table 36.4: Treatment protocols

OPD treatment
Mild-to-moderate infections Drug Duration
I. Third generation cephalosporin Doxy and metronidazole to
ceftizoxime or cefotaxime 1–2 g complete a 2-week course
doxycycline, 100 mg, BD with Third generation cephalosporin
metronidazole, 500 mg, twice daily is less effective on anaerobes,
hence use metronidazole
II. Alternative regimen Ceftraixone, 250 mg, IM, single
dose
Plus azithromycin, 1 g, one dose
every week for 2 weeks
III. Ceftraixone, 250 mg, IM, single Doxy and metronidazole to
dose or cefoxitin 2 g, IM, once complete the 2-week course
Plus doxycycline, 100 mg, BD,
with or without metronidazole
500 mg, BD
In patient therapy or allergy to Tubo-ovarian abscess requires
beta-lactams or severe infections surgical management, if no
including tubo-ovarian abscess or response to medical management
endometritis
I. Clindamycin 900 mg iv 8 hourly After clinical improvement—
with Gentamycin 2 mg/kg loading Clindamycin (450 mg, orally, QID)
dose followed by 1.5 mg /kg 8 hrly or doxycycline (100 mg, orally, BD)
to complete the 2-week course
II. Azithromycin, 2 g stat oral 14 days
Plus levofloxacin, 500 mg, OD
III. Levofloxacin, 500 mg, OD or 14 days
ofloxacin, 400 mg, BD, or plus
metronidazole, 500 mg, BD
Moxifloxacin, 400 mg, BD
IV. Inj. cefotetan, 2 g, BD, or After clinical improvement—
cefoxitin 2 g, IV, 6 hrly, doxy, 100 mg, BD, for 14 days
plus doxy, IV, 100 mg, BD
V. Ampicillin/Sulbactam, 3 g, IV, 6 After clinical improvement—
hrly plus doxycycline, 100 mg, doxy, 100 mg, BD, for 14 days
IV, BD

Etiological treatment: It is based on labora­ needed to diagnose accurately. Precious time

tory diagnosis, smears, and blood work to is lost while the results are awaited for the
document the infection and then specific treatment to start. Sometimes the patient may
treatment is given depending on the diagnosis be lost to follow up while awaiting results.
or pathologic agent identified. This being S y n d ro m i c m a n a g e m e n t : T h e Wo r l d
ideal situation; however, may not always be Health Organization (WHO) created the
available due to paucity of lab supplies or syndromic management strategy for STI/
skilled manpower or specialised equipment RTI management in 1991 to overcome the
294 Drugs in Obstetrics and Gynecology

Flowchart 36.2: Management of vaginal discharge in females3

 Drugs in Pelvic Inflammatory Disease 295

Flowchart 36.3: Management of lower abdominal pain in females3

296 Drugs in Obstetrics and Gynecology

limitations of etiological and presumptive The Antibiotics Given against

diagnosis. The syndromic management flow the Common Pathogens17–19
charts are the gold standard of care in the • Cephalosporins: Gonococcal infection
majority of resource-constrained situations • Azithromycin, doxycycline: Chlamydia
when the etiological diagnosis cannot be trachomatis
made accessible for the therapy to start and • Metronidazole: Anaerobes, gram negative
if laboratory testing is not available or is and positive
difficult to get. Clinical algorithms based on
an STD syndrome, based on clinical signs Inpatient therapy or hospitalization will
and symptoms that the patient presents with, be needed if:
have been made. This approach may land up • Noncompliance or
overtreating the partners, but the treatment • Severe side effects to oral therapy or
is started in time and on the first visit itself. • Fever of more than 38.5°C (101°F) or severe
Based on groups of symptoms and clinical illness with nausea and vomiting
indicators that are simple to recognize, STI • There is need for surgical drainage of
are categorized into syndromes, and the most infection or abscess.
prevalent organisms that cause each syndrome • Pregnancy with PID
are treated. By employing or distributing pre- • Doubtful diagnosis
packaged, color-coded STI/RTI medication • Other diseases, such as appendicitis and
kits, standardized therapy is provided. This ectopic pregnancy can not be ruled out.
method has good cure rates, since it treats • The patient is unable to tolerate or failed
patients right away and involves little to no to respond to outpatient regimen.
laboratory expense. The guidelines mentioned
• Within 3 days of beginning antibiotic
here are developed by National Aids Control
medication, the patient cannot return for
Society, New Delhi, in association with World
a clinical check-up.
Health Organization, include management
of symptomatic infections related to urethral
Efficacy of Treatment Regimens
discharge syndrome, vaginal discharge
syndrome, anorectal infection; genital ulcer Some experts recommend to admit all patients
disease syndrome; and lower abdominal pain with PID to start treatment with parenteral
syndrome.3 antibiotics. But efficacy for outpatient vs
inpatient therapy is similar with similar
Rationale for the Treatment Regimes results and long-term sequel as per the—
The diagnosis for the majority of PID patients pelvic inflammation disease evaluation
is frequently clinical, and prompt initiation clinical health (PEACH) trial.
of a broad-spectrum empirical therapy
is required. Because upper genital tract General Advice, Follow-up and
infection can still occur even if endocervical Partner Treatment
screening for N. gonorrhoeae and C. trachomatis • Monitor the response to treatment in 48–72
is negative, the PID regimens should also be hours—if no improvement—admit and
effective against these pathogens. Women start parental therapy. If response good,
with PID have anaerobic bacteria and BV that call for follow-up at one week, to review
can destroy the tubal and epithelial lining of cure and reports, if any done. Ensure
the vaginal canal. Anaerobic organisms in completion of treatment.
the upper vaginal tract are more successfully • Encourage abstinence from sex until
eliminated when metronidazole is added to treatment is finished and symptoms have
intramuscular (IM) or oral PID treatments.6 subsided.
 Drugs in Pelvic Inflammatory Disease 297

• All sexual partners or from the last 60 days • Flucanozole should not be used orally
should be investigated and treated. when pregnant.
• Counsel: The couple and the patient about • When trichomoniasis or BV are detected,
safe sex practices, so as to prevent repeation metronidazole pessaries or cream should
of episodes, also about genital cancers and be used intravaginally.
barrier contraception—condoms.
• Instruct to avoid douching. In Second and Third Trimesters of Pregnancy
• If PID diagnosed—test for gonorrhoea, Oral metronidazole can be given.
chlamydia, HIV, and syphilis. • Tab. secnidazole, 2 g, orally, single dose or
• Immunisation status—for hepatitis B, metronidazole, 400, TDS, for 5 days or tab.
human papillomavirus (HPV). tinidazole, 500 mg, orally, BD, for 5 days.
• Regardless of whether the spouse has had • Tab. metoclopropramide taken half hour
treatment or not, repeated testing should before tab. metronidazole to prevent
be done 3 months following therapy, if nausea/vomit.
chlamydial or gonococcal PID was diag-
Management of Pregnant Women
nosed.
with Cervicitis
SPECIAL CASES Look for and treat gonococcal as well as
chlamydial infections.
PID in HIV Positive Patients • Cephalosporins to cover gonococcal
Higher risk of tubo-ovarian abscess and infection are safe and effective in pregnancy.
severe disease. Treatment protocols are same – Tab. cefixime, 400 mg, orally, single dose
but in patient therapy may be needed for the or ceftriaxone, 125 mg, by intramuscular
immune suppressed. injection plus
– Tab. erythromycin, 500 mg, orally, four
Pregnancy times a day for 7 days or
PID: High risk of premature birth and maternal • Cap. amoxicillin, 500 mg, orally, three
morbidity. In conjunction with an infectious times a day for 7 days to cover chlamydial
disease expert, the pregnant PID patients infection.
need to be hospitalized and given intravenous • Quinolones (like ofloxacin, ciprofloxacin),
(IV) antibiotics. Avoid using medications doxycycline are contraindicated in pregnant
known to be harmful during pregnancy, such women.
as tetracyclines and quinolones. For PID, a
14-day course of cefotaxime, azithromycin, Postmenopausal Patients
and metronidazole may be prescribed. By Can have similar complaints but keep in
doing a speculum examination, pregnancy mind the differential diagnosis of malignancy
problems, such as abortion and premature while diagnosing tubo-ovarian abscess in this
rupture of membranes should be ruled out in population.
patients with STI, PID, and UTI.
Intrauterine Devices
Treatment for Vaginitis [Trichomonal The risk for PID associated with IUD, was
Vaginitis (TV), Bacterial Vaginosis (BV) higher with the first and second generation
and Candida]11,14 IUD. With the third generation Cu-IUD and
In First Trimester of Pregnancy LNG-IUS use, the risk of PID is primarily
• Only use clotrimazole vaginal pessaries confined to the first 3 weeks after insertion. If an
or cream for localized candidiasis therapy. IUD user receives a diagnosis of PID, the IUD
298 Drugs in Obstetrics and Gynecology

does not need to be removed; full treatment in comparison to the triple combination
according to the local recommendations has group (oral ampicillin, intramuscular genta­
to be given followed by a close follow-up. If micin, and metronidazole tablets/pessaries)
no clinical improvement occurs within 48–72 demonstrated a reduction in pain and
hours of initiating treatment, then should discharge symptoms (p 0.05).
consider removing the IUD.7–9 It is advised that patients who are hospita­
lised with severe PID and/or tubo-ovarian
Tubo-ovarian Abscess abscess be released after completing a 14-day
Seen in around 10% of women with PID, an course of broad-spectrum oral antibiotics. The
inflammatory mass involving fallopian tube, most often suggested methods for getting rid
ovary, and pelvic organ, with pus collection of these organisms are:
and adhesions. Can be a sequel to PID. It can be 1. Amoxicillin and clavulanic acid, 2–3 g/day
potentially life-threatening requiring medical + doxycycline (200 mg/day)
and surgical management. Necrosis within the 2. Amoxicillin and clavulanic acid 2–3 g/ day
mass can result in further increasing infection + ofloxacin (400 mg/day)
and anaerobic growth which can worsen the Table 36.5 shows drugs, pharmacokinetics,
condition and result in sepsis. side effects and contraindications.20–25
Signs and symptoms: Acute abdomen and CONCLUSION
fever with tachycardia and toxic symptoms
and sepsis. 10–15% can result in rupture and PID is a disease which has high implications
would require urgent exploration. for future fertility and well-being. The
The treatment would be as mentioned prevention with safe sexual practices has to
be promoted and emphasized on, however
in the table but with close vigilance for
aggressive primary treatment is a must
deterioration and if no change in status to
to prevent or reduce the sequalae. There
consider surgical drainage.
is a need for treatment that targets the
• Laparoscopy or exploratory laparotomy
broad-spectrum of organisms that may be
be used to drain pelvic abscesses and
responsible for the issue at hand. The World
do adhesiolysis in order to hasten the
Health Organization (WHO) has recognized
disease’s early resolution.
syndromic case management (SCM), a
• Sometimes a less intrusive but as effective, comprehensive strategy for STI/RTI control,
an ultrasound-guided aspiration of pelvic as the cornerstone of STI/RTI management.
fluid collection may be suggested. The treatment techniques include a careful
follow-up program for each patient, contact
β-lactam/β-lactamase inhibitor
tracing, and partner therapy to stop the
Combinations
disease from spreading. The implementation
Although cephalosporins are generally of treatment and prevention methods at
preferred over b-lactam/b-lactamase inhibitor the individual level is just as crucial as it
combinations for treating extended-spectrum- is at the social and governmental levels.
lactamase producers, doing so may prevent Young women must be safeguarded against
the spread of these latter pathogens as well STI/RTI and pregnancy due to the high
as other resistant pathogens like Clostridium prevalence of unprotected sexual activity
difficile and vancomycin-resistant enterococci. among adolescents. Every chance to inform,
Sulbactam is coupled with either cefo­ prevent, and treat STI/RTI should be taken,
perazone or ampicillin. especially when young women are seeking
After 3 days of therapy, more patients abortion treatment, pregnancy care, or
in the amoxycillin/clavulanic acid group assistance with any gynecological disorders.
 Drugs in Pelvic Inflammatory Disease 299

Table 36.5: Drugs for PID with their pharmacokinetics, side effects and contraindications
Name and spectrum of Pharmacokinetics Side effects Contraindications
coverage
Cephalosporins, Third generation— Abdominal pain, Known allergy to the
grouped into five eliminated rapidly, diarrhoea, nausea and cephalosporin group
generations serum half-lives—1 to 2 vomiting, decreased of antibiotics, allergic
Gram-positive and gram- hours. appetite reactions in 10% of
negative bacteria Third generation have to Injection site patients with known
Third Generation be given IV or IM inflammation or skin allergies to penicillins.
z t rash Cephalosporins with
z Cefonicid
1/2 of 4.4 hours
z t Leukopenia, warfarin, combination,
z Cefotetan
1/2 of 3.5 hours
z t Thrombocytopenia correlates with an
z Ceftriaxone
1/2 of 8.5 hours
Eliminated mostly by Swelling of tongue and increased risk of
Others: Cefoparazone,
the kidneys, high biliary throat and difficulty in bleeding.
cefmenoxime,
elimination breathing As a precautionary
ceftriaxone,
Predominant excretion- measure, patients
cefbuperazone, and Serious side effects:
bile/faeces (44% of dose) should avoid alcohol
latamoxef Major hypersensitivity
consumption while on
Bactericidal Drug-induced immune third-generation agents
hemolytic anemia to avert disulfiram-like
(DIIHA) reactions.
Pseudomembranous Pregnancy category
colitis B medications—not
Suppression of gut flora CI in pregnancy and
causing reduction in compatible with
vitamin-K synthesis breastfeeding.
Bleeding
Disulfiram-like reaction
Azithromycin Long half-life—68 Common—vomiting and It comes under
Broad-spectrum hours and a high diarrhoea, reducing its pregnancy category B
macrolide antibiotic degree of tissue absorption further. drug.
Bacteriostatic penetration, additional Serious—major Single high dose or
Haemophilus influenzae, immunomodulatory adverse effects include short course over 3
Moraxella catarrhalis effects17 cardiovascular days is more effective
or Streptococcus 37% is bio available after arrhythmias, with better bacterial
pneumoniae, oral administration and hepatotoxicity and clearance then same
Chlamydophila absorption is not affected caution for patients with total dose over longer
pneumoniae, by food. renal GFR <10 ml/min periods, but side effects
Mycoplasma Predominant excretion— have to be kept in mind
pneumoniae bile/faeces
Chlamydia trachomatis
or Neisseria gonorrhoeae
Haemophilus ducreyi
Metronidazole Orally absorption Primary adverse effects Documented
Antibiotic and almost complete, with of metronidazole hypersensitivity to the
antiprotozoal >90% bioavailability for include confusion, drug or its components,
medication, effective tablets. peripheral neuropathy, avoided in first-trimester
against anaerobic Rectal and intravaginal metallic taste, nausea, pregnancy.
infections absorption are 67 to vomiting, and diarrhoea.
82%, and 20 to 56%.
(Contd...)
300 Drugs in Obstetrics and Gynecology

Table 36.5: Drugs for PID with their pharmacokinetics, side effects and contraindications (Contd...)
Name and spectrum of Pharmacokinetics Side effects Contraindications
coverage
Either alone or with Metabolized Headache, vaginitis and Void consuming alcohol
other antibiotics to treat extensively by liver nausea. Adverse events or products containing
pelvic inflammatory into 5 metabolites— affecting less than 10% of propylene glycol while
disease, endocarditis, and hydroxy metabolite has the population are metallic taking metronidazole
bacterial vaginosis. Also biological activity of 30 taste, dizziness, genital and within 3 days of
giardiasis, trichomoniasis, to 65% and a longer pruritus, abdominal pain, therapy completion.
and amebiasis. elimination half-life than diarrhoea, xerostomia, Metronidazole is
Other members of this the parent compound, dysmenorrhea, urine likewise contraindicated
class include tinidazole, renal and liver abnormality, urinary if there has been recent
ornidazole and diseases lead to a tract infection, bacterial disulfiram use within the
secnidazole. decreased clearance of infection, candidiasis, past 2 weeks.
They have prolonged metronidazole flu-like symptoms, upper
half-lives compared with respiratory tract infection,
metronidazole pharyngitis, and sinusitis.
Rarely, there are reports of
transient leukopenia and
neutropenia as well.19,20
Comes with a black box
warning that it may be
carcinogenic
Prolonged drug courses
can causes severe neuro­
logical disturbances
due to the risk of
cumulative neurotoxicity,
fungal or bacterial
superinfection, including
C. difficile-associated
diarrhea (CDAD) and
pseudomembranous
colitis.
Doxycycline— Completely absorbed Headaches, feeling sick, Alcohol with
tetracyclines wide range with a bioavailability of increased skin sensitive to doxycycline—reduces
of gram-positive and more than 80%20 with the sun including photo- the efficacy of
-negative bacteria an average of ~95% onycholysis. doxycycline, allergic
Bacteriocidal Absorption takes place Oral thrush. reaction
in the duodenum.21 Serious—diarrhea and Kidney or liver
Food has less effect on blood in stools, jaundice, problems, oesophagitis,
absorption. sore throat, ringing or have lupus or
Eliminated unchanged buzzing in the ears, intra- myasthenia gravis.
by both the renal and cranial hypertension, Pregnant or
biliary routes. Bile nose bleeds. breastfeeding—(small
concentrations may be chance that it can
10–25 times those in affect teeth and bone
serum. development—seen
Slowly absorbed orally, more if babies given the
taking 2–3 hours to reach drug directly rather than
peak concentrations. through breastfeeding)
(Contd...)
 Drugs in Pelvic Inflammatory Disease 301

Table 36.5: Drugs for PID with their pharmacokinetics, side effects and contraindications (Contd...)
Name and spectrum of Pharmacokinetics Side effects Contraindications
coverage
The elimination half-life
is long, ranging from
12 to 25
Predominant excretion—
urine (30–65% of dose)
Quinolones Predominant excretion— Generally, very safe Epilepsy, Marfan's
Potent antimicrobial urine (40–50% of dose) antibiotics syndrome, Ehlers-
agents— Gastrointestinal Danlos syndrome, QT
fluoroquinolones, reactions (nausea, prolongation, pre-
namely ofloxacin, dyspepsia, vomiting) and existing CNS lesions,
ciprofloxacin, CNS reactions, such as or CNS inflammation,
norfloxacin, pefloxacin, dizziness, insomnia and or who have had a
levofloxacin, headache. Confusion, stroke. They are best
moxifloxacin weakness, loss of avoided in the athlete
bactericidal effect appetite, tremor or population. Patients
against numerous depression with uncorrected
pathogens including Serious side effects hypokalaemia or
Gram-positives, gram- include tendonitis, hypomagnesaemia
negatives, aerobes and tendon rupture, patients receiving
anaerobes arthralgia, pain antiarrhythmic agents.
Bactericidal in extremities,
gait disturbance,
neuropathies associated
with paraesthesia,
depression, fatigue,
memory impairment,
sleep disorders, and
impaired hearing, vision,
taste and smell, ruptures
or tears in the aorta,
which is the main artery
in the body, significant
drops in blood sugar
levels

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 37
Drugs in Urinary Incontinence

• Preeti Frank Lewis • Roopali Sehgal

History Taking
CLINICAL APPROACH TO URINARY
INCONTINENCE The history further identifies the patient’s
urinary symptoms and severity.11 Classifying
The initial evaluation of urinary incontinence
the type of incontinence helps direct treatment.
includes characterizing and classifying the In a multicenter study of 300 middle-aged
type of incontinence, identifying underlying women with moderate incontinence, the
conditions (e.g. neurologic disorder or 3 incontinence questionnaire (3IQ) had a
malignancy) that may manifest as urinary sensitivity of 0.75 and specificity of 0.77
incontinence, and identifying causes of for identifying urgency incontinence and a
incontinence.1,2 sensitivity of 0.86 and specificity of 0.60 for
Historically, the diagnosis of urinary stress urinary incontinence (SUI) (Fig. 37.1
incontinence required an extensive work- and Table 37.1).12
up. Currently, based on the new American
Urological Association (AUA) and American Urinary Symptoms
College of Obstetricians and Gynecologists Frequency, volume, severity, hesitancy,
(ACOG) guidelines, the work-up of urinary precipitating triggers, nocturia, intermittent
incontinence has become more streamlined.3,4 or slow stream, incomplete emptying,
The urethral Q-tip test has mostly been continuous urine leakage, and straining to
eliminated, and the 7-day bladder diary has void.13
been replaced with a 2- to 3-day diary.5–7 Stress urinary incontinence: Urine loss
Similarly, simpler and shorter forms of with increase in intra-abdominal pressure,
quality-of-life (QOL), bother, and sexual commonly occurs during laughing, coughing,
dysfunction questionnaires, specific to or sneezing. Urine volume lost may be small
urinary incontinence, have been developed or large. There is no urge to urinate prior to
(Figs 37.1–37.2). Cystoscopy is rarely an the leakage.
indication for uncomplicated urinary Urgency urinary incontinence/overactive
incontinence, and urodynamics is no longer bladder: Frequent, small volume voids that
necessary prior to treatment for simple may keep the patient up at night or worsen
urgency urinary incontinence, or prior to after taking a diuretic. The patient has a
surgery for uncomplicated stress urinary strong urge to void but are unable to make it
incontinence.8,9 to the washroom in time.
304 Drugs in Obstetrics and Gynecology

Fig. 37.1: The 3 incontinence questionnaire10

Overflow urinary incontinence due to slow flow, and nocturia. This condition
detrusor muscle underactivity: Loss of urine may be misdiagnosed as mixed urinary
with no warning or triggers. The volume incontinence, in which the evaluation of post-
leaked may be small or large. Loss often void residual (PVR) is important.
occurs with a change in position and/or with Overflow urinary incontinence due to
activity. Symptoms may also be associated urinary outlet obstruction, in patients with
with urinary frequency, urgency, and/or pelvic organ prolapse, fibroids, or pelvic
voiding difficulties, such as urinary hesitancy, surgery, is often associated with stress and/
 Drugs in Urinary Incontinence 305

or urgency urinary incontinence symptoms Systemic symptoms: Evaluate all women

and often an intermittent or slow stream, with incontinence for UTI, with symptoms
hesitancy (difficulty getting urine stream of fever, dysuria, pelvic pain, and hematuria.
started), and a sensation of incomplete Sudden onset of incontinence, women with
emptying. Patients with obstruction often these symptoms should have appropriate
need to strain to pass their urine or may have work-up and evaluation for underlying
pain and cramping with voiding attempts conditions. We should inquire about changes
and usually describe a sense of incomplete in bowel function (e.g. constipation and
emptying (Table 37.2). accidental bowel leakage) and symptoms of
pelvic organ prolapse (something coming out
 Changes in gait or new lower-extremity weakness, per vagina) as these conditions often coexist.14
 Cardiopulmonary or neurologic symptoms (for
example, the combination of overflow urinary Alcohol and caffeine:16 Caffeine exacerbates
incontinence, urinary incontinence due to its smooth muscle
 Perineal anesthesia, and new accidental bowel stimulant and diuretic effects. Although a
leakage suggests cauda equina syndrome), small pilot study demonstrated reductions
 Mental status changes, in urinary urgency and frequency with intake
 Recurrent documented urinary tract infections of decaffeinated compared with caffeinated
(UTIs) (three or more per year), drinks, meta-analyses failed to identify
 Advanced pelvic organ prolapse beyond the
significant associations between caffeine and
hymen,
urinary incontinence.17–19
 Elevated PVR (>1/3 total volume),

 Long-term urinary catheterization, or difficulty Voiding diaries: Can be found online.

passing a urinary catheter. While basic diary records of frequency and
volume are neither sensitive nor specific for

Table 37.2: Drugs causing urinary incontinence15

Drug class Mechanism of incontinence
I. Drugs causing overflow incontinence
a. Anticholinergics
1. Antidepressants Decreased bladder contractions with retention
2. Antipsychotics Decreased bladder contractions with retention
3. Sedative-hypnotics Decreased bladder contractions with retention
4. Antihistamines Decreased bladder contractions with retention
b. Nervous system depressants
1. Narcotics Decreased bladder contractions with retention
2. Alcohol Decreased bladder contractions with retention
3. Calcium channel blockers Decreased bladder contractions with retention
4. Alpha-adrenergic agonists Sphincter contraction with outflow obstruction
5. Beta-adrenergic blockers Sphincter contraction with outflow obstruction
2. Drugs causing stress incontinence
Alpha-adrenergic antagonists—sphincter relaxation with urinary leakage
3. Drugs causing urge incontinence
Diuretics Contractions stimulated by high urine flow
Caffeine Diuretic effect
306 Drugs in Obstetrics and Gynecology

determining the cause of incontinence,20,21 Duloxetine is highly bound (>90%) to

they may be helpful to determine if urinary human plasma proteins, binding primarily
incontinence is associated with high fluid to albumin and α1-acid glycoprotein.
intake. In addition, they provide a measure Duloxetine has an elimination half-life of
of the severity of the problem that can be approximately 12 hours (range 8–17 hours).
followed over time. Voiding diaries also Therefore, steady-state plasma concentrations
identify the maximum bladder capacity and are typically achieved after 3 days of dosing.
time interval that the woman can reasonably Duloxetine is a substrate of CYP1A2 and
wait between voids, a measure used to guide hence, coadministration of CYP1A2 inhibitors
bladder training. like fluvoxamine, cimetidine and quinolone
antimicrobials, such as ciprofloxacin and
DRUGS enoxacin; since these would be expected to
have similar effects on the pharmacokinetics
Stress Urinary Incontinence
of duloxetine, these combinations should
No pharmaco­logic therapies have been be avoided. Contrastingly, duloxetine does
approved by the United States Food and Drug not inhibit or induce CYP1A2 activity and,
Administration (FDA) for treatment of stress accordingly, duloxetine does not affect the
incontinence in women, although multiple metabolism of CYP1A2 substrates such as
medications have been evaluated.22 theophylline.
Duloxetine is both a substrate and
Duloxetine
an inhibitor of CYP2D6. Therefore, co-
Mechanism of action: Duloxetine is a combined administration of duloxetine with other
serotonin/norepinephrine reuptake inhibitor. drugs that are extensively metabolized by
Duloxetine exerts balanced in vivo reuptake CYP2D6, particularly if they have a narrow
inhibition of 5-hydroxytryptamine (5HT) therapeutic index, should be approached with
and norepinephrine (NE) and exhibits no caution. These include certain antidepressants
appreciable binding affinity for receptors of (e.g. tricyclic antidepressants such as
neurotransmitters. The action of duloxetine nortriptyline, amitriptyline and imipramine),
in the treatment of stress urinary incontinence phenothiazines and type 1C antiarrhythmics
is associated with reuptake inhibition (e.g. propafenone and flecainide). Duloxetine
of serotonin and norepinephrine at the should not be combined with monoamine
presynaptic neuron in Onuf’s nucleus of the oxidase inhibitors to avoid occurrence of a
sacral spinal cord. 5-HT syndrome.
Pharmacokinetics: The commercially The commercially available duloxetine
available duloxetine capsules represent a formulation has an enteric coating that resists
delayed-release formulation. Under steady- dissolution until it reaches a segment of the
state conditions, exposure to duloxetine, gastrointestinal tract where pH exceeds 5.5.
judged by its trough plasma concentrations, Finally, it should be considered that
increases linearly with dose in the range from numerous patients with SUI concomitantly
20 mg/day to 40 mg twice daily.23 suffer from urinary urgency, in other words,
Duloxetine is well-absorbed following oral have mixed incontinence. The urgency
administration24 with a median lag time of component of mixed incontinence is mostly
2–3 hours before absorption begins. Maximal treated with muscarinic receptor antagonists,
plasma concentrations (Cmax) of duloxetine such as oxybutynin or tolterodine. Due to
occur after 6 hours when administered in the their differential modes of action, it appears
fasted state and after 10 hours when taken plausible to apply their combination in
with a meal.25–30 patients with mixed incontinence.
 Drugs in Urinary Incontinence 307

Dosage: 20 mg/day to 40 mg twice-daily. compound is highly lipophilic, metabolized

Adverse effects: Duloxetine has a very low in the liver, and eliminated in the urine
anticholinergic side effect profile; adverse (55%) and feces (34%), mainly in unchanged
effects of the cardiovascular, gastrointestinal, form.
central nervous system, such as headaches Dose: Mirabegron is available as extended-
and drowsiness, and fatigue, are more release daily oral tablets in doses of 25 and
common. 50 mg.
Serious adverse effects of duloxetine Monotherapy: Mirabegron is available
include: Suicidality, serotonin syndrome, in 25 and 50 mg extended-release doses.
hepatoxicity, mania, syncope, syndrome of Mirabegron monotherapy is started at
inappropriate antidiuretic hormone secretion 25 mg daily. Although up to 8 weeks may
(SIADH), hyponatremia. be required for full efficacy, the dose can be
Common adverse effects of duloxetine increased to 50 mg daily as quickly as 4 weeks
include: Headache, drowsiness, fatigue, from initiation, if patients are tolerating the
nausea, xerostomia, abdominal pain, weight drug but have inadequate symptom control.
loss, weakness, insomnia, dizziness, change
in libido, diaphoresis, constipation, decreased Vibegron
appetite, tremor, diarrhoea and erectile Pharmacokinetics: Vibegron reaches peak
dysfunction. plasma concentration 1–3 hours after
oral administration, and constant blood
URGENCY URINARY INCONTINENCE/ concentration is achieved in 7 days of once-
OVERACTIVE BLADDER daily administration. It is excreted in feces
Beta-3-adrenergic agonist drugs and and urine as unchanged drug. The plasma
antimuscarinic agents are the main options concentration of the drug increases in people
for treatment of overactive bladder (OAB) >65 years of age and those with moderate–
symptoms. severe renal impairment. It does not induce
Beta-3-adrenergic agonists—mirabegron or inhibit the activity of CYP2D6 and CYP3A4
and vibegron—are beta-3-adrenergic receptor enzymes, and thus drug–drug interactions
agonists used to treat symptoms of OAB with most frequently prescribed agents
(Fig. 37.2). are limited. The elimination half-life is
approximately 70 hours.32
Mechanism of action: They work via the
sympathetic nerve pathway and stimulates Dose: Vibegron is given as a single 75 mg
beta-3 receptors, causing smooth muscle oral dose daily.
relaxation in the bladder. 31 The use of a Adverse effects: Mirabegron is avoided in
beta-3 agonist is specific to the bladder as 97% individuals with poorly controlled hyper­
of the beta-adrenergic receptor subtypes are tension or who develop new hypertension
the beta-3 subtype. while using the medication.
Mirabegron For both mirabegron and vibegron: Urinary
retention is a potential adverse effect of
Pharmacokinetics: Mirabegron is rapidly
antimuscarinic and beta-3-adrenergic
absorbed after oral administration, reaching
agonists.
maximum plasma concentration in 3–5
hours whether taken with or without food. Other side effects: Headache, runny nose,
When administered as a single daily dose of and gastrointestinal upset, dry mouth and
50 mg, steady-state concentrations are constipation which are often mild and rarely
usually achieved within 7 days. The lead to discontinuation.
308 Drugs in Obstetrics and Gynecology

Antimuscarinics: There are seven anti­ Mechanism of action: Anticholinergics

muscarinic agents available in different dampen the amplitude of bladder contractions,
doses and formulations: Darifenacin, improving bladder capacity and reducing
fesoterodine, oxybutynin, solifenacin, involuntary detrusor contractions, urgency,
tolterodine, trospium, and propiverine. and frequency. Selective anticholinergics
The pharmacokinetics and dosage of these have relatively more affinity for M2 and M3
formulations are mentioned in Table 37.3. receptors, which are the most prevalent in
the bladder, reducing side effects in the other
systems.

Table 37.3: Antimuscarinics and their pharmacokinetics with dosage

S.No. Drug Pharmacokinetics Dosage
1. Darifenacin Peak plasma concentrations of darifenacin 7.5–15 mg, orally, once daily
are achieved approximately 7 hours post (extended release)
oral dose.
Metabolized in liver by CYP3A4; maximum
7.5 mg daily with strong CYP3A4 inhibitors
2. Fesoterodine After oral administration , it is well-absorbed. 4–8 mg, orally, once daily
It undergoes rapid and extensive hydrolysis (extended release)
by nonspecific plasma esterases to form
its active metabolite, 5-HMT, which is
responsible for its antimuscarinic activity.
No accumulation occurs after multiple-dose
administration.
3. Oxybutynin
Immediate release 5 mg, orally, twice a day, four
times a day
Extended release 5–30 mg, orally, daily
Transdermal gel Apply 1 sachet /1 pump once
(sachet)/pump daily (each delivers 1 g of gel =
100 mg oxybutynin
Transdermal Apply 1 patch, twice per week
patch (i.e. once every 3 to 4 days)
4. Solifenacin Solifenacin undergoes hepatic metabolism 5–10 mg, orally, once a day
and has a long half-life of 45−68 hours.
5. Tolterodine Tolterodine undergoes hepatic metabolism
following oral ingestion
Extended release 2–4 mg, orally, once a day
Immediate release 1–2 mg, orally, once a day
6. Trospium After oral administration, less than 10%
of the dose is absorbed. Peak plasma
concentrations (Cmax) occur between 5 and
6 hours post-dose.
Extended release 60 mg, orally, once daily
Immediate release 20–40 mg orally, once daily
7. Propiverine 30 mg, orally, daily
 Drugs in Urinary Incontinence 309

Fig. 37.2: History of OAB medications FDA approvals33

Flowchart 37.1: Evaluation of urinary incontinence

310 Drugs in Obstetrics and Gynecology

Flowchart 37.2: Approach to urge incontinence

Adverse Effects of Antimuscarinic Drugs Combination therapy: Options for combina­

Dry mouth with difficulty in swallowing, tion therapy include use of a beta-3 adrenergic
thirst, dilatation of the pupils with difficulty agonist plus an antimuscarinic drug or two
accommodating and sensitivity to light, i.e. antimuscarinic drugs together.
blurred vision, increased intraocular pressure,
Combined antimuscarinic and beta-3-adrenergic
hot, dry and flushed skin, bradycardia
agonist: Combination anti­muscarinic and
followed by tachycardia, palpitations and
beta-3-agonist treatment is helpful for
arrhythmias, difficulty with micturition—
patients with persistent symptoms who
urinary retention and constipation.
are unable to increase the dose of the initial
More rarely: Fever, confusion, mania, hallu­ medication dose secondary to side effects or
cinations and rashes. dose limits.
 Drugs in Urinary Incontinence 311

Dual antimuscarinic therapy: Dual anti­ Recommendations of the International Scientific

muscarinic therapy may be helpful in those Committee: Evaluation and treatment of urinary
patients with OAB who have a partial incontinence, pelvic organ prolapse, and fecal
incontinence. Neurourology and Urodynamics:
but inadequate response to single-agent
Official Journal of the International Continence
treatment and are unable to access beta-3- Society. 2010 Jan;29(1):213–40.
adrenergic agonist medications. 12. Brown JS, Bradley CS, Subak LL, Richter HE,
Kraus SR, Brubaker L, Lin F, Vittinghoff E,
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Q-tip test for urethral mobility measurement: A, Thiagamoorthy G, Cardozo L. Are we
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6. Dmochowski RR, Sanders SW, Appell RA, et al. urinary tract disease? Report from the ICI-RS
Bladder-health diaries: An assessment of 3-day 2015. Neurourology and urodynamics. 2017
vs 7-day entries. BJU Int 2005;96: 1049–1054. Apr;36(4):876–81.
7. Bright E, Cotterill N, Drake M, et al. Developing 17. Sun S, Liu D, Jiao Z. Coffee and caffeine intake
a validated urinary diary: Phase 1. Neurourol and risk of urinary incontinence: a meta-analysis
Urodyn 2012;31:625–633. of observational studies. BMC Urology. 2016
8. Nygaard I. Clinical practice. Idiopathic Dec;16(1):1–7.
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2010;363:1156–1162. SM, Fader MJ. The effect of caffeinated versus
9. Nager CW, Brubaker L, Litman HJ, et al. decaffeinated drinks on overactive bladder: a
Urinary Incontinence Treatment Network. A double-blind, randomized, crossover study.
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2012;24;366:1987–1997. 19. Bradley CS, Erickson BA, Messersmith EE,
10. Brown JS, Bradley CS, Subak LL, et al. The Pelletier-Cameron A, Lai HH, Kreder KJ, Yang
sensitivity and specificity of a simple test to CC, Merion RM, Bavendam TG, Kirkali Z.
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Cardozo L, Chapple C, Cottenden A, Davila W, Straus SE. What type of urinary incontinence
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21. Parsons M, Amundsen CL, Cardozo L, Vella M, 27. Lantz, RJ, Gillespie, TA, Rash, TJ: Metabolism,
Webster GD, Coats AC. Bladder diary patterns excretion, and pharmacokinetics of duloxetine
in detrusor overactivity and urodynamic stress in healthy human subjects. Drug Metab. Dispos.
incontinence. Neurourology and Urodynamics: 2003;31:1142–1150.
Official Journal of the International Continence 28. Skinner, MH, Kuan, HY, Pan, A: Duloxetine is
Society. 2007 Oct;26(6):800–6. both an inhibitor and a substrate of cytochrome
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 38
Drugs in Vaginal Discharge

• Tejal Poddar • Mandakini Megh

Introduction respect to consistency/colour/odour/(e.g.

Vaginal discharge may be a complaint or discoloured or purulent or odorous).
a finding on examination. Patients may Abnormal discharge is often associated
complain of excessive secretions, colored or with pain during intercourse (dyspareunia),
textured discharge. Physiologic discharge or painful or difficult urination (dysuria) or
should be differentiated from abnormal lower abdominal pain or vulval pruritis.
discharge.
CAUSES OF VAGINAL DISCHARGE
Psychosexual problems may present with
recurrent episodes of vaginal discharge and Vaginal discharge may be caused by a number
vulval burning. It needs to be considered if of physiological and pathological conditions
tests for specific infections are negative. Many (Table 38.1).
of the symptoms and signs are non-specific
and allergic and irritant reactions or vulval VAGINITIS
dermatoses should be ruled out. Abnormal vaginal discharge is most often
associated with infection.
Definition Important causes are: Bacterial vaginosis
Abnormal vaginal discharge is defined as (BV), vulvovaginal candidiasis (VVC) or
discharge that is different from normal with trichomoniasis vaginalis (TV).1 BV is one of

Table 38.1: Types of vaginal discharge

Physiological Pathological
Ovulation Vaginitis
Premenstrual phase Sexually transmitted diseases
During and after intercourse Cervical: Erosion, ulcer, polyp and ectropion
During pregnancy Genital prolapse with ulcer
During puerperium Foreign body
Malignancy
Atrophic vaginitis
Pyometra
314 Drugs in Obstetrics and Gynecology

the most common and accounts for up to 50% inflammatory state (e.g. Gardnerella vaginalis,
of all infections.2,3 Bacteroides species, Peptostreptococcus species,
Fusobacterium species, Prevotella species, and
Pathogenesis Atopobium vaginae).5,6
In women of reproductive age, Lactobacillus BV can arise and remit spontaneously.
species is one of the predominant constituents of Although not strictly considered a sexually
normal vaginal flora. Vaginal pH is maintained transmitted infection (STI), it is associated
in the normal range by colonization by these with sexual activity. The exact cause of BV
bacteria (3.8 to 4.2), thereby preventing is still unclear but evidence suggests that
overgrowth of pathogenic bacteria. formation of a biofilm with G. vaginalis is
Factors that predispose to overgrowth of important in the switch from normal vaginal
bacterial vaginal pathogens include: flora to BV (Fig. 38.1).7,8
• Use of antibiotics (may decrease lactobacilli)
• Alkaline vaginal pH due to menstrual Candidiasis
blood or semen Candidiasis is one of the most prevalent
• Vaginal douching form of vaginitis. An estimated three-fourths
• Pregnancy of women will experience at least one
• Diabetes mellitus symptomatic episode during their lifetime
• An intravaginal foreign body (e.g. a and 10% will experience chronic recurrent
forgotten tampon or vaginal pessary) vulvovaginal candidiasis (at least four
episodes per year). Vulvovaginal candidiasis
Etiology and Transmission results from an overgrowth of Candida albicans
Bacterial Vaginosis in 90% of women (remainder with other
Bacterial vaginosis (BV) is the one of the species, e.g. Candida glabrata).9,10
most common causes of abnormal vaginal More than 60% of healthy premenopausal
discharge in woman of childbearing age, women are colonised with Candida, with
but may also be encountered in menopausal higher rates in pregnancy, and lower rates
women, and is rare in children.4 in children and postmenopausal women
BV represents a change in the normal without hormonal replacement therapy.11,12
microbiome of the vagina with an overgrowth Predisposing factors include: Endogenous or
of facultative anaerobic organisms, hence exogenous immunosuppression (including
bacterial vaginosis is not a true infectious or diabetes mellitus and immunosuppressive

Fig. 38.1: Histopathology of bacterial vaginosis

 Drugs in Vaginal Discharge 315

medication) antibiotic therapy, pregnancy, gynecologic surgery; acquisition of sexually

Candida albicans visualized by Gram stain and transmitted diseases, including pelvic
microscopy. inflammatory disease; acquisition and
transmission of human immunodeficiency
Trichomoniasis Vaginalis virus (HIV); and recurrent urinary tract
Trichomonas vaginalis (TV) is a flagellated infections. Screening and treating for bacterial
protozoan that is a parasite of the genital tract. vaginosis prior to elective gynecologic
It is almost exclusively sexually transmitted. procedures are recommended. Trichomoniasis
Due to specificity of site, infections follows has also been associated with preterm birth
intravaginal or intraurethral inoculation of and acquisition and transmission of HIV.
the organism. In women, urethral infection
is present in 90% of episodes, although the Symptoms and Signs
urinary tract is the sole site of infection in There are most common symptoms and signs
5% of cases. of vaginal infections, but these are frequently
Predisposing factors are multiple sexual absent or non-specific.13,14 The diagnosis of
contacts, unhygienic conditions and infected both BV and candidiasis based on clinical
partner (Fig. 38.2). symptoms and signs supported by laboratory
findings, which themselves vary in specificity
Complications and sensitivity. Box 38.1 shows symptoms
Bacterial vaginosis (BV) is a risk factor associated with the common causes of
for preterm birth and low-birth weight. vaginal discharge. Table 38.2 shows the type
However, pros­pective treatment studies have of discharge as per BV, TV, candidiasis and
yielded inconsistent results as to the benefit of genital ulcer.
screening and treating for bacterial vaginosis
in pregnancy. Gynecologic complications Box 38.1: Symptoms associated with the common
include postoperative infections following causes of vaginal discharge15,16
The following findings are the alert signals of
concern:
 Pelvic pain of fever
 Postmenopausal women with bloody discharge
 Fecal discharge (suggesting a fistula, even if not seen)
 Trichomonal vaginitis in children (suggesting
sexual abuse)

Table 38.2: Conditional types of discharge in BV,

TV, candidiasis and genital ulcer
Condition Type of discharge
Normal White or clear, odorless, and
nonirritating
Bacterial Thin, gray discharge with a fishy
vaginosis odour
Trichomoniasis Yellow-green vaginal discharge,
vaginosis often with a fishy odour, frothy
Candidiasis Cottage cheese like white
discharge
Fig. 38.2: Trichomonas vaginalis. May-Grünwald
staining Genital ulcer Bloody or watery discharge
316 Drugs in Obstetrics and Gynecology

Diagnosis (Table 38.3) and bacterial vaginosis. The slide is examined

Testing using a microscope; KOH dissolves most
cellular material except yeast hyphae,
Patients with vaginal itching or discharge
making identification easier. The saline wet
need the following testing:
mount is examined using a microscope as
• Wet mount
soon as possible to look for clue cells and
• pH (Table 38.4)
motile trichomonads, which can become
• Potassium hydroxide (KOH) preparation
immotile and more difficult to recognize
Vaginal secretions are tested using pH
within minutes after slide preparation. If
paper with 0.2 intervals from pH 4.0 to 6.0.
clinical criteria and in-office test results are
Then, a cotton swab is used to place secretions
inconclusive, the discharge may be cultured
on 2 slides; secretions are diluted with 0.9%
for fungi and trichomonads.
sodium chloride on one slide (saline wet
mount) and with 10% KOH on the other
Treatment (Table 38.5, Boxes 38.2 and 38.3)
(KOH preparation).
The KOH preparation is sniffed (whiff Treatment of Vaginal Itching and Discharge
test) for a fishy odor, which results from • Causes of vaginal pruritus and itching—
amines produced in trichomonal vaginitis age dependent.

Table 38.3: Diagnosis of BV, TV and candidiasis13

Criteria Bacterial vaginosis Trichomoniasis Candidiasis
Vaginal pH >4.5 All pH >4.5
Saline microscopy of Clue cells (95% of cases) Pseudohyphae (40–60% Flagellated protozoa
vaginal discharge from cases), blastospores (addi­
lateral vaginal wall tion of KOH to the wet
smear (40–80% cases)
lyses epithelial cells and
may make hyphae more
apparent)
Gram stain of vaginal Spores/pseudohyphae
discharge from lateral (65% or more of
vaginal wall symptomatic cases)
Whiff test—release of Positive Negative Usually positive
fishy odour on adding
alkali (10% KOH)

Table 38.4: Use of vaginal pH in diagnosis13

3.5 4.0 4.5 5.0 5.5 6.0
The normal vaginal pH remains between 3.8 and 4.5. An altered vaginal pH is indicative of vaginal infection.
pH ≤4.5 <4.5 >4.5 ≥5.0
Vaginal +/– + (white, thick, + (white/grey, thin, + (greenish-yellow, frothy
discharge clumpy discharge) clumpy discharge) discharge)
Malodour – – + +
Itching – + – +
Burning – + – –
Normal Candidiasis Bacterial vaginosis Trichomoniasis
 Drugs in Vaginal Discharge 317

• Measure vaginal pH and obtain a sample

Box 38.2: Recommended topical treatment regimens
of secretions for microscopic examination
for vulvovaginal candidiasis20
and testing;
Over-the-counter intravaginal agents
 Clotrimazole, 1% cream, 5 g, intravaginally, daily
• If needed, do testing for sexually trans­
for 7 to 14 days mitted infections.
 Clotrimazole, 2% cream, 5 g, intravaginally, daily • In postmenopausal women, promptly
for 3 days evaluate any vaginal discharge.
 Miconazole, 2% cream, 5 g, intravaginally, daily
Cervicitis may be difficult to diagnose.
for 7 days
When in doubt, offer treatment for cervicitis
 Miconazole, 4% cream, 5 g, intravaginally, daily
for 7 days
to women with vaginal discharge and any of
 Miconazole, 100 mg, vaginal suppository, one
the these risk factors:
suppository daily for 7 days • Urethral discharge in the partner
 Miconazole, 200 mg, vaginal suppository, one • Context of sexual violence or prostitution
suppository daily for 3 days • New partner or more than one partner in
 Miconazole, 1,200 mg, vaginal suppository, one the preceding 3 months.
suppository for 1 day
 Tioconazole, 6.5% ointment, 5 g, intravaginally Methods for Diagnosis of Vaginal pH
in a single application
1. Litmus paper
Prescribed intravaginal agents
2. Gloves.12
 Butoconazole, 2% cream, 5 g, intravaginally in a
single application Differential Diagnosis9
 Terconazole, 0.4% cream, 5 g, intravaginally,
daily for 7 days • Vaginal infection
 Terconazole, 0.8% cream, 5 g, intravaginally, • Bacterial vaginosis
daily for 3 days • Candidiasis
 Terconazole, 80 mg, vaginal suppository, one • Trichomoniasis.
suppository daily for 3 days
 Fenticonazole, 600 mg, single dose vaginally; Bacterial Vaginosis
300 mg, vaginally on day 1 and day 3
The primary treatment of bacterial vaginosis
 ltraconazole, 200 mg, orally, twice a day for 1 day
is oral metronidazole 400 mg given thrice a
day for 7 days.18
The cure rate after treatment with metro­
Box 38.3: Treatment recommendations for vaginal nidazole is up to 95%, but after 4 weeks this
dryness declines to 80% in open-label studies and less
 Topical estrogen therapies reverse these mucosa! than 70% in blinded studies.17
changes and are effective treatments for the
symptoms of atrophic vaginitis.14
A single 2.0 g dose of metronidazole in
 Vaginal moisturizers and lubricants also provide
treating trichomoniasis is less effective and
symptomatic relief for vaginal dryness and is not recommended.19 Vaginal preparations
dyspareunia, respectively.14 containing 0.75% metronidazole gel or 2%
 Probiotics help reduce vaginal discharge, odor clindamycin cream or ovules containing
and prevent bacterial vaginosis and complicated 100 mg, clindamycin; OD are effective and
vulvovaginal candidiasis.16 have few systemic effects.19
 Topical vaginal preparation containing hyaluronic
acid may improve symptoms of vaginal dryness in Trichomoniasis
vulvovaginal atrophy.15
Metronidazole, 2 g, orally, single or divided
 lsoflavone containing vaginal gel may provide
relief of vaginal dryness and dyspareunia.20
dose on the same day or tinidazole, 2 g, orally,
single dose.
318 Drugs in Obstetrics and Gynecology

Table 38.5: Treatment of BV and TV

Initial regimens Alternative Pregnancy Recurrence Treatment of sex
regimens partners
Bacterial vaginosis
Metronidazole, Tinidazole, 2 g, Metronidazole, First recurrence: Routine treatment
400 mg, orally, orally, once daily 400 mg, orally, Retrial of same of sex partners is
thrice for 2 days thrice daily for regimen not recommended
daily for 7 days* or 7 days or
or Tinidazole, 1 g, Trial of alternative
Metronidazole, orally, once daily initial regimen
0.75% gel, one full for 5 days Multiple
applicator (5 g), or recurrences:
intravaginally, Clindamycin, Metronidazole,
daily for 5 days 300 mg, orally, 0.75% gel,
or twice daily for intravaginally,
7 days twice weekly for 4
Clindamycin 2%
or to 6 months
cream, one full
Clindamycin,
applicator (5 g),
100 mg,
intravaginally, at
intravaginally, at
bedtime for 7 days bedtime for 3 days
Trichomoniasis
Metronidazole, 2 g, Metronidazole, Metronidazole, Differentiate Concurrent
orally, single or 400 mg, orally, 2 g, orally, single persistent or treatment of
divided dose on thrice daily for 7 dose in any stage recurrent infection sex partners is
the same day days of pregnancy from reinfection11 recommended
or If metronidazole, Advise refraining
Tinidazole, 2 g, 2 g, single dose from intercourse
orally, single dose fails: until partners
Trial of are treated and
metronidazole symptom-free
400 mg, thrice
daily for 7 days
If metronidazole
400 mg thrice daily
for 7 days fails:
Trial of
metronidazole, 2 g,
daily for 7 days
If above regimens
fail: Consider
susceptibility
testing

In the case of treatment failure: Tinidazole, Vulvovaginal Candidiasis

PO, 500 mg, 2 times daily for 5 days or Clotrimazole (500 mg, vaginal tab.), 1 tablet
metronidazole, PO, 400 to 500 mg, 2 times inserted deep into the vagina at bedtime,
daily for 7 days. single dose.
 Drugs in Vaginal Discharge 319

If the patient has extensive vulvar Antibiotics can break down the overgrowth of
involvement, miconazole, 2% cream (one vaginal anaerobes and formation of biofilm.
application to the vulva, 2 times, daily for Hence, probiotics administered intravaginally
7 days), may be used in combination with will adhere to and colonize vaginal epithelial
the intravaginal treatment above. Miconazole cell surfaces.22
cream may complement, but does not replace, A Cochrane analysis, suggests beneficial
treatment with clotrimazole. outcome of microbiological cure with the
oral metronidazole/probiotic regimen and
Treatment of the Partner the probiotic/estriol preparation.23,24
When the patient is treated for vaginitis
or cervicitis, the partner receives the same Summary
treatment as the patient, whether or not Vaginitis is an overgrowth of anaerobic
symptoms are present. organisms (e.g. Gardnerella vaginalis,
In the case of vulvovaginal candidiasis, Mycoplasma hominis, Mobiluncus spp.) in the
the partner is treated only if symptomatic vagina leading to a replacement of lactobacilli
(itching and redness of the glans/prepuce): and an increase in vaginal pH.
Miconazole, 2% cream, one application,
Signs and Symptoms
2 times daily for 7 days, pessaries PV, twice
daily for 10 days. For bacterial vaginosis: Fishy odor; thin,
off-white homogenous discharge that may
Role of Probiotics worsen after intercourse; pelvic discomfort
Antimicrobial therapy is generally effective, without inflammation.
but there is still a high incidence of recurrence For vulvovaginal candidiasis: White, thick,
and increase of resistance. Thus, it is cheesy, or curdy discharge; vulvar itching or
suggested that administration of probiotics burning; no odor (pruritis dysuria), vulvar
using selected Lactobacillus strains can be erythema and edema.
an effective strategy for preventing vaginal For trichomoniasis: Green or yellow, frothy
infections.20 discharge; foul odor; vaginal pain or soreness
Probiotics: copious, malodorous, yellow-green (or
• Have positive effects on vaginal micro­ discolored) discharge, pruritus vaginal
flora composition by promoting the irritation. No symptoms with inflammation
proliferation of beneficial micro­ and strawberry cervix.
organisms
• Alter the intravaginal microbiota Screening and Diagnosis
composi­tion • Screening of asymptomatic patients for
• Prevent vaginal infections in post­ trichomoniasis is not recommended.
menopausal • Culture for the diagnosis of bacterial
• Reduce the symptoms of vaginal vaginosis not needed because it represents
infections and prevent vaginitis. a polymicrobial infection.
The use of Lactobacillus acidophilus, • Nucleic acid amplification testing is
Lactobacillus rhamnosus GR-1 and Lactobacillus recommended for the diagnosis of
fermentum RC-14 at a dose of at least 10 CFU/ trichomoniasis in symptomatic or high-
day for 2 months is found to be effective.21 risk women.
In a Cochrane analysis, the efficacy and • Elevated vaginal pH in the absence of
safety of probiotics administered intravaginally current vaginal infection is a risk for adverse
combined with antibiotic therapy for the pregnancy outcome that is mediated by
treatment of bacterial vaginosis is established. systemic inflammatory response.
320 Drugs in Obstetrics and Gynecology

Treatment • Vaginally administered probiotics

• It is recommended to screening for containing L. brevis CD2, L. salivarius subsp.
increased vaginal pH during pregnancy, salicinius, L. plantarum can cure bacterial
as it may be useful in reducing preterm infection and reduce vaginal inflammatory
birth rates. response
• Vaginally administered probiotics affects • For non-infectious vaginitis topical vaginal
vaginal microflora composition by estrogen is preferred because of the low
promoting the proliferation of beneficial systemic absorption and reduced risk
microorganisms, alters the intravaginal of adverse effects compared with oral
microbiota composition and prevents therapy. Estrogen-containing creams,
vaginal infections. Probiotics also reduce pessaries, intravaginal tablets and the
the symptoms of vaginal infections such estradiol vaginal ring appear equally
as vaginal discharge, odor, etc. and are effective for the symptoms of atrophic
helpful for the treatment and prevention vaginitis
of bacterial vaginosis and complicated • First-line nonhormonal treatment recom-
vulvovaginal candidiasis. mendations include vaginal lubricants and
• Hyaluronic acid, vaginal gel and estriol moisturizers; continued sexual activity
cream can significantly improve the should be encouraged
clinical symptoms of vaginal dryness. • Antibiotics, such as amoxicillin/clavulanic
• Moisturizers help maintain natural acid, are shown to be effective in women
secretions and coital comfort. The length with anaerobic vaginal isolates
of effectiveness is generally less than • Post-infection vaginal probiotic pessaries
24 hours. for the treatment of bacterial vaginosis is
• Vaginal dryness: Topical estrogen replacement an effective treatment for treating vaginitis
therapies reverse these mucosal changes and • The exogenous strains of lactobacilli
are effective treatments for the symptoms have been suggested as a means of re-
of atrophic vaginitis: establishing a normal healthy vaginal flora
– Vaginal moisturizers and lubricants also • In women with manifest clinical signs
provide symptomatic relief for vaginal of bacterial vaginosis or yeast vaginitis,
dryness and dyspareunia, respectively vaginal probiotics given in combination
– Vaginally administered probiotics help with antibiotic or antimycotic therapy,
reduce vaginal discharge, odor, etc. lowered clinical symptoms and led to
and prevent bacterial vaginosis and lower Nugent scores compared with a
complicated vulvovaginal candidiasis treatment with antibiotics/antimycotics
– Topical vaginal preparation containing alone.
hyaluronic acid, improves vaginal • Vaginal probiotics containing lactobacilli
dryness in vulvovaginal atrophy. enables successfully establish normal
– Isoflavone containing vaginal gel vaginal flora in pregnant women with
provides relief of vaginal dryness and imbalance in vaginal flora.
dyspareunia symptom. • In pregnant women requiring vaginal
• Treatment of uncomplicated vulvovaginal probiotics along with antifungal or
candidiasis involves a short course of antibiotic therapy, attain normal vaginal
antifungals; oral and topical preparations flora and reduces inflammation after 10
are similarly effective days of therapy
• Treatment of complicated vulvovaginal • Vaginal lactobacilli tablet containing
candidiasis involves an intensive, longer at least 1 billion viable lactobacilli
course of antifungals (L. brevis CD2, L. salivarius subsp., salicinius
 Drugs in Vaginal Discharge 321

and L. plantarum) is effective, safe and 12. Sobel JD. Pathogenesis and epidemiology of
well-tolerated in reducing the symptoms vulvova_ginal candidosis. Ann N Y Acad Sci
of vaginal infections and restoring the 1988; 544: 547–557.
13. Wolner-Hanssen P, Kreiger JN, Stevens
vaginal flora to normal. CE, et al. Clinical manifestations of vaginal
trichomoniasis. JAMA 1989;264:571–6.
References 14. Fouts AC, Kraus SJ. Trichomonas vaginalis:
1. Paladine HL, Desai UA. Vaginitis: diagnosis and re-evaluation of its clinical presentation and
treatment. Am Fam Physician 2018; 97:321–9. laboratory diagnosis. J Infect Dis 1980;141:137–
2. NHS Oxfordshire Clinical Commissioning 43.
Group. Investigation and Management of Vaginal 15. US Centers for Disease Control and Prevention.
Discharge in Adult Women [online]. Available Diseases Characterized by Vaginal Discharge. In:
at: https://www.ouh.nhs.uk/ microbiology/ 2015 Sexually Transmitted Diseases Treatment
diagnostic-tests/atoz/documents/discharge. Guidelines. Available at: https://www.cdc.gov/
pdf. Accessed May 13, 2020. std/tg2015/vaginal-discharge. htm. Accessed
3. Neal CM, Kus LH, Eckert LO, Peipert JF. October 13, 2019.
Noncandidal vaginitis: a comprehensive 16. NHS Oxfordshire Clinical Commissioning
approach to diagnosis and management. Am J Group. Investigation and Management of Vaginal
Obstet Gynecol 2020; 222:114–22. Discharge in Adult Women [online]. Available
4. Akinbiyi AA, Watson R, Feyi-Waboso P. at: https://www.ouh.nhs.uk/ microbiology/
Prevalence of Candida albicans and bacterial diagnostic-tests/atoz/documents/discharge.
vaginosis in asymptomatic pregnant women pdf.
in South Yorkshire, United Kingdom. Outcome 17. Hay P. Vaginal Infections. Bacterial vaginosis.
of a prospective study. Arch Gynecol Obstet 2005; Medicine. 33:10; pages: 58–61.
2008;278:463–6. 18. Nayagam AT, Smith MD, Ridgway GL.
5. Powell AM, Nyirjesy P. Recurrent vulvovaginitis. Comparison of ofloxacin and metronidazole for
Best Pract Res Clin Obstet Gynaecol 2014;28:967– the treatment of bacterial vaginosis. International
76. (Level III). Journal of STD & AIDS 1992; 3: 204–07.
19. Mustafa M, Yanggau BB, Lasimbang H.
6. Ness RB, Hillier SL, Richter HE, Soper DE,
Pathogenesis, diagnosis and treatment of
Stamm C, McGregor J, et al. Douching in
vaginitis and cervicitis in clinical practice. IOSR
relation to bacterial vag_inosis, lactobacilli,
Journal of Pharmacy. 2014; 4(8): 7–13.
and facultative bacteria in the vagina. Obstet
20. Santos CM, Pires MC, Leão TL, et al. Selection
Gynecol 2002;100:765–72. (Level II-2).
of Lactobacillus strains as potential probiotics
7. Swidsinski A, Mendling W, Loening-Baucke V, for vaginitis treatment. Microbiology.
et al. Adherent biofilms in bacterial vaginosis. 2016;162(7):1195–207.
Obstet Gynecol 2005; 106: 1013–1023. 21. Homayouni A, Bastani P, Ziyadi S, et al. Effects
8. Donders GG. Definition of a type of abnormal of probiotics on the recurrence of bacterial
vaginal flora that is distinct from bacterial vaginosis: A review. J Low Genit Tract Dis.
vaginosis: aerobic vaginitis. BJOG 2002; 109: 2014;18(1):79–86.
1–10. 22. Ma L, Su J, Su Y, et al. Probiotics administered
9. Fidel PL Jr, Barousse M, Espinosa T, et al. An intra_ intravaginally as a complementary therapy
vaginal live Candida challenge in humans leads combined with antibiotics for the treatment
to new hypotheses for the immunopathogenesis of bacterial vaginosis: A systematic review
of vulvovaginal candidiasis. Infect Immun 2004; protocol. BMJ Open. 2017;7:e019301.
72: 2939–2946. 23. Senok AC, Verstraelen H, Temmerman M,
10. Holland J, Young ML, Lee O, et al. Vulvovaginal Botta GA. Probiotics for the treatment of
car_riage of yeasts other than Candida albicans. bacterial vaginosis. Cochrane Database Syst Rev.
Sex Transm Infect 2003; 79: 249–250. 2009;(4):CD006289.
11. Lindner JG, Plantema FH and Hoogkamp 24. Ya W, Reifer C, Miller LE. Efficacy of vaginal
K. Quantitative studies of the vaginal flora probiotic capsules for recurrent bacterial
of healthy women and of obstetric and vaginosis: A double-blind, randomized,
gynaecological patients. J Med Microbiol 1978; placebo_controlled study. Am J Obstet Gynecol.
11: 233–241. 2010;203:120.
 39
Drug Therapy in Adolescent
Polycystic Ovary Syndrome
• Nidhi Shah • Usha Saraiya

Introduction Micronutrients, especially vitamin D has

Polycystic ovary syndrome (PCOS) is the important role in treating adolescent girls
most common endocrinopathy affecting with PCOS.
women of reproductive age group with a Pharmacotherapy for managing PCOS in
higher prevalence in adolescent girls ranging adolescents includes the following:
from 9% (regular cycles) to 45% (girls with • Inositols
oligomenorrhea).1 • Insulin-sensitizing drugs—metformin
• Combined oral contraceptive pills
Strict criteria have been proposed to • Antiandrogens.
diagnose PCOS in adolescents. 2 Patho­
physiology of PCOS is complex (Fig. 39.1, INOSITIOLS
Flowchart 39.1).
Inositols are a group of natural polyols (sugars).
They are naturally present in food including
TREATMENT fruits, like cantaloupe, grapefruit and citrus
The treatment for PCOS should be individua­ fruits, beans, whole grains and nuts, like
lised as per the clinical picture, need and almonds and walnuts.
preferences of the patient. Inositols form a part of the cell membrane
Aim is to improve the quality of life phospholipids, plasma lipoproteins as well
and long-term health outcome; and may as the phosphate component in the nucleus;
need some parental support as well as and are involved in many cellular processes,
such as signal transduction, osmoregulation
psychological counselling.
and ion channel regulation.
Lifestyle modification by way of diet with In PCOS, inositol administration:
calorie restriction and exercise forms the first • Improves symptoms
line of management of obese/overweight • Regulates the lipid levels
adolescents with PCOS. • Reduces testosterone and androgen levels
A 5–10% reduction in weight is said to • Reduces appetite, fat and body mass index
overcome menstrual irregularities, hirsutism, (BMI) via efficient breakdown of fats
testosterone, sex hormone-binding globulin • Improves insulin sensitivity
(SHBG) resume ovulation and fertility and • Improves ovulation rate and menstrual
regulate insulin resistance.3 cycle.4–6
 Drug Therapy in Adolescent Polycystic Ovary Syndrome 323

Fig. 39.1: Female HPG axis. GnRH: Gonadotropin-releasing hormone; LH: Luteinizing hormone; FSH:
Follicle-stimulating hormone

Flowchart 39.1: Pathophysiology of PCOS. Female hypothalamic–pituitary–gonadal (HPG) axis and

hypothalamic–pituitary–adrenal glands leading to androgen excess and consequently anovulation and/or
metabolic disorders

PCOS: Polycystic ovary syndrome; GnRH: Gonadotropin-releasing hormone; IGF1: Insulin-like growth factor-1; T2DM: Type 2
diabetes mellitus; LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; SHBG: Sex hormone-binding globulin
324 Drugs in Obstetrics and Gynecology

Box 39.1: International evidence-based guideline.

Molecule Structure
BMC Med 2020.2 Myoinositol (MI) constitutes 99% and
1. Irregular cycles defined years post-menarche; D-chiro-inositol (DCI)—the remaining 1% of
>90 days for any one cycle (>1 year post- the total inositol amount.
menarche), cycles <21 or >45 days (>1 to <3 years
Time taken to achieve (Fig. 39.2) maximum
post-menarche); cycles <21 or >35 days (>3 years
post-menarche) and primary amenorrhea by age plasma concentration is about 4 hours.7
15 or >3 years post-menarche.
2. <1 year post-menarche irregular cycles are
Metabolism
normal pubertal transition. Excretion is via the kidneys with an elimina­
3. Hyperandrogenism—hirsutism, severe acne and/ tion half-life of 5.22 hours.8
or biochemical hyperandrogenaemia
4. Sonography not required for diagnosis of PCOS Dosage
within 8 years post-menarche. Combination therapy with an MI/DCI ratio
5. Anti-müllerian hormone not needed for PCOS
of 40:1 is recommended.9
diagnosis; and exclude other disorders that mimic
PCOS. Daily dosage—2 grams before breakfast
6. For adolescents who have features of PCOS and dinner for 3 months.
but do not meet diagnostic criteria, they are
categorized ‘at risk’ and regular re-evaluations. Mechanism of Action
7. Re-evaluate them 3 years post-menarche and Insulin resistance plays a significant role in
where only menstrual irregularity or hyper­ the development of PCOS. MI and DCI are
androgenism are present initially, ultrasound can intracellularly incorporated into inositol
occur after 8 years of menarche.
phosphoglycans (IPGs), which are second

Fig. 39.2: (a) Effects of myoinositol and D-chiro-inositol on glucose metabolism in PCOS. (b) Effects of
myo-inositol (MI) and D-chiro-inositol (DCI) on hormonal synthesis in PCOS.10 FSH: Follicle-stimulating
hormone; LH: Luteinizing hormone
 Drug Therapy in Adolescent Polycystic Ovary Syndrome 325

messengers of insulin, follicle-stimulating leads to MI deficiency in the ovary. A balance

hormone (FSH) and thyroid-stimulating between the two inositols is associated with
hormone (TSH). Some actions of insulin are insulin resistance (IR) and sensitivity.
mediated by these IPGs.
1. Myo-inositol IPG inhibits cyclic adenosine Adverse Effects
monophosphate (AMP)-dependent protein 1. Gastrointestinal effects on consuming
kinase and improves glucose uptake at the higher doses
cellular level. 2. Excessive DCI—↓ estrogen levels and
2. D-chiro-IPG activates pyruvate dehydro­ ↑androgen levels
genase phosphatase and is involved in 3. Acne, hair loss and excessive hair growth.11
glycogen synthesis.
Under physiological conditions, the MI/ Metformin
DCI ratio is between 100:1 in the follicular It is a biguanide anti-hyperglycemic agent.
fluid and 40:1 in plasma.10,11 In PCOS, metformin reduces androgen and
PCOS patients have an increased DCI/MI serum lipid levels; induces ovulation and
ratio (overproduction of DCI). This in turn regularizes the menstrual cycles.

Fig. 39.3: Pharmacokinetics pathway of metformin14

326 Drugs in Obstetrics and Gynecology

Absorption and Bioavailability Adverse Effects

50–60% for a 500 mg tablet taken on an Metformin reduces the hepatic uptake of
empty stomach. Food reduces and delays the lactate, this may increase the blood lactate
absorption of metformin (Fig. 39.3).12 levels and result lactic acidosis.12 Risk factors
for metformin-associated lactic acidosis, thus
Distribution demanding cautious use is as follows:
Metformin is scarcely bound to plasma • Impaired kidneys and liver function
proteins. The plasma elimination half-life • Concomitant use of drugs, like carbonic
is approximately 17.6 hours, suggesting anhydrase inhibitors—topiramate
distribution within the erythrocytes.12 • Elderly, ≥65 years of age
The drug is widely distributed into body • Undergoing procedures—surgery/radio­
tissues including the intestine, liver, and kidney. logical study with contrast
Under routine circumstances (dosage and • Hypoxic conditions, like acute congestive
timing), metformin hydrochloride tablet heart failure
reaches a steady-state plasma concentration • Excessive consumption of alcohol.
within 24–48 hours, which is generally <1 mg/ Combination pills containing inositol and
ml.12 metformin are now available specially to treat
adolescent PCOS.
Metabolism and Elimination
Combined Oral Contraceptives (COCs) Pills
Metformin is not metabolized and 90% is
COCs are the first choice of therapy for
primarily eliminated unchanged through
adolescent girls with PCOS as they not only
the kidneys within the first 24 hours, with a
address symptoms, like menstrual irregularity
half-life of approximately 6.2 hours.12
(amenorrhea, oligomenorrhea, menorrhagia
Dosage and abnormal uterine bleeding) and cutaneous
hyperandrogenemia, but also serve as
Metformin hydrochloride is available as
contraception in sexually-active adolescent
500 mg, 850 mg and 1000 mg extended
girls.17
release tablets. Start with a dose of 500 mg
and gradually increase by 500 mg every 1 Composition
to 2 weeks until a maximum dose of 2500/
Estrogen component: Ethinyl estradiol,
2550 mg per day is reached based on the need
estradiol or estetrol.
and tolerance of the patient.13
Progesterone component: With varying
Mechanism of Action degrees of androgenic and progestogenic
Metformin differs from other oral anti­ potential (Table 39.1).
hyperglycemic agents; it lowers both basal • First generation progestin: Norethindrone
and post-prandial glucose levels. It reduces acetate, ethynodiol acetate, lynestrenol and
hepatic glucose production by reducing norethynodrel.
gluconeogenesis, decreases intestinal • Second generation progestin: Levonorgestrel,
absorption of glucose, reduces the synthesis dl-norgestrel.
of fatty acid and triglycerides, increases • Third generation progestin: Norgestimate,
fatty acid β-oxidation and improves insulin gestodene, desogestrel.
sensitivity by increasing peripheral glucose • Fourth generation progestin: Drospirenone
uptake and utilization (Fig. 39.4).15,16 and cyproterone acetate.
 Drug Therapy in Adolescent Polycystic Ovary Syndrome 327

Fig. 39.4: Pharmacodynamics pathway of metformin14

Table 39.1: Hormonal effects produced by 4 generations of progestin18–20

Generation Progestin Estrogenic Progestational Androgenic
First Norethindrone ++ ++ ++
Elhynodiol diacetate ++ +++ +
Norgestrel – +++ +++
Norethindrone acetate ++ ++ ++
Second Levonoroestrel – ++++ ++++
Third Norgestimate – ++ ++
Desogestrel +/– ++++ ++
Fourth Drosplrenone – +/- –
+/– indicates low to no activity.
– indicates no activity.
328 Drugs in Obstetrics and Gynecology

Selection of the right combination depends Dosage

on the dose required, desired effect as well as COC should be taken at a fixed time daily,
the undesirable side effects of the progestin delay of >24 hours should be avoided to
component.21 ensure maximum efficacy.
COC can be prescribed as follows:
Absorption, Bioavailability and Distribution
• Cyclic: Hormonal pills for 21–24 days,
COCs are absorbed from the small intestine followed by 7–4 days of hormone-free pills
reaching a peak plasma level within 1–4 hours
• Extended cycle: 3 months—hormone pills,
with individual variation. While levonor­
followed by 1 week—placebo
gestrel does not undergo first pass metabolism
• Continuous use: Daily usage of hormonal
and has 100% bioavailability, norethisterone
pills up to a maximum of 1 year.
has an average of 70% whereas ethinyl
estradiol has a mean bioavailability of 40 to Phases of COC
45%.21
Monophasic: Start on day 1 of the cycle for
COCs are bound to plasma proteins.
21 days—estrogen and progestin in equal
97–98% of ethinyl estradiol is bound to plasma
proportion.
albumin. The progestins are bound mainly
to SHBG and to lesser extent to albumin Biphasic: The estrogen level remains constant
(levonorgestrel 93 to 95%; norethisterone throughout the cycle with 2 different progestin
79 to 80%).21 levels that changes mid-cycle.
Triphasic: Varying levels of both estrogen and
Metabolism
progestin throughout the 21 days of the cycle.
COCs are metabolized in the liver by cyto­ Monophasic is generally what is used in
chrome p450 enzymes either unchanged or our daily practice as biphasic and triphasic
by conjugation with glucuronide or sulphate; pills are not well-tolerated or as effective.
thus, drugs that induce cytochrome p450 may
increase COC metabolism. Missed doses: If a patient misses a tablet,
she should take the missed pill as soon as
Mechanism of Action she remembers and then take her next tablet
COC reduces the androgen levels through at the usual time. If she misses 2 pills in a
different mechanisms: row, she should take 2 tablets the minute she
1. COC suppress the endogenous hypo­ remembers as well as 2 pills the next day and
thalamic–pituitary–ovarian (HPO) axis then resume her routine of a pill a day.22
resulting in a ↓ pituitary gonadotropins Duration of treatment with COC is not
thereby interfering with folliculogenesis yet well-defined. Improvement in menstrual
and reducing ovarian androgen production pattern is seen within 2 to 3 months. Hyper­
2. COC reduces adrenal androgen secretion androgenemia is also shown to improve after
and inhibits the peripheral conversion the third month of therapy.21,23
of testosterone to dihydrotestosterone as
well as binding of dihydrotestosterone to Adverse Effects22
androgen receptors Most side effects are mild and will disappear
3. COC ↑ SHBG, thereby further reducing the with either continued use or by switching
free androgen index. over to another formulation.
In addition, the progesterone component Most common: Breakthrough bleeding and
of the COC prevents unopposed action of spotting.
estrogen, thereby preventing endometrial Others: Nausea (overcome by taking the
hyperplasia and menstrual irregularities. pill at bedtime), headache, abdominal cramps,
 Drug Therapy in Adolescent Polycystic Ovary Syndrome 329

breast tenderness, ↑ vaginal discharge or • History of bariatric surgeries

libido. • Adolescents on some antiseizure medicine.
Long-term serious side effects, like an ↑ in A thorough hematological evaluation is
blood pressure, venous thromboembolism advisable before starting COC, as menstrual
and breast cancer, not generally seen in irregularities may be due to thrombophilia
adolescents. and not hormonal imbalance.
COC does not provide protection against Girls on COC should have an annual visit
sexually transmitted infections. with their doctor for weight, BMI, blood
pressure and routine medical care.
Progestin-only Pills (POPs, Minipill)
Progestins may be used to induce a withdrawal ANTIANDROGENS
bleed in adolescents with amenorrhea/
Antiandrogens are a group of drugs, such as
oligomenorrhea.
spironolactone, cyproterone acetate (CPA), or
Some progestin compounds have more
flutamide that act as competitive inhibitors
potent antiandrogenic properties and are
of androgen-binding receptors or reduce
more effective androgenic symptoms of
androgen production.24 They may be used
PCOS—hirsutism and acne.
as the first line of management for cutaneous
Dosage hyperandro­genemia—acne and hirsutism.
• Micronized progesterone (100–200 mg However, these drugs have teratogenic
daily) potential and may result in feminization of
• Medroxyprogesterone acetate (5 mg/day) the male fetus and hence, they should be
• Norethindrone acetate (2.5 or 5 mg/day) administered in combination with adequate
for 5–10 days. contraception in sexually active adolescent
girls. In view of toxicity frequent monitoring
Contraindications22 of liver and kidney function is necessary
Centers for Disease Control and Prevention when on antiandrogens.
(CDC) and World Health Organisation
(WHO) have set criteria for women who want CYPROTERONE ACETATE
to initiate COC or POP; some absolute and
CPA is a progestational antiandrogen. It is
relative contraindications in adolescent girls
used along with estrogen for treating acne
are as follows:
and hirsutism.
• Cigarette smokers (>15 cigarettes/day)
>35 years of age. Absorption, Bioavailability and Distribution
• Adolescents with thrombogenic mutations, When taken orally, CPA is completely
like prothrombin mutation, factor V Leiden, absorbed with an absolute bioavailability of
protein C, protein S and antithrombin almost 88%.
deficiencies Cyproterone acetate has a special affinity
• Migraines with auras for plasma albumin with just 3.5–4%,
• History of venous thromboembolism remaining unbound.
(VTE), stroke
• Valvular heart disease Metabolism and Elimination
• Acute liver disease/hepatocellular adenoma. CPA is metabolised in the liver by the
CYP3A4 enzyme and forms the active
Progesterone Only Pill metabolite 15-beta-hydroxy cyproterone
• Pregnancy acetate, a metabolite with antiandrogenic
• Undiagnosed abnormal uterine bleeding activity but progestational activity.
330 Drugs in Obstetrics and Gynecology

60% is excreted in the bile and 33% through Mechanism of Action

the kidney with a plasma half-life of 38 hours 1. In large doses, it is a non-selective competitive
after oral intake.25 inhibitor of androgen and progesterone
receptors
Mechanism of Action
2. It can also inhibit 5α-reductase activity.
• CPA competitively inhibits testosterone
and its potent metabolite 5a-dihydro­
Dosage
testosterone (DHT) from binding to the
androgen receptor. Spironolactone is available as 25 mg, 50 mg,
• CPA may also inhibit 5a-reductase activity, or 100 mg tablets and the dose recommended
decreasing the availability of the more for treating acne/hirsutism is 100–200 mg
potent androgen, dihydrotestosterone. daily.27
• It suppresses luteinizing hormone thereby
Adverse Reactions
reducing testosterone levels.25
Generally, well-tolerated, can occasionally
Dosage and Follow-up cause breast discomfort, hyperkalemia,
Dose: 50 to 100 mg, orally, after meals for first fatigue, postural hypotension, dizziness,
10 days after a period (reverse sequence) or gastrointestinal complaints and menstrual
lower dose in combination with 20–50 μg of irregularities at high doses.
ethinyl estradiol.
It takes at least 6 months of treatment to FLUTAMIDE
notice any improvement in hirsutism with It is a nonsteroidal, selective antiandrogen
maximum effect seen after 9 to 12 months. without progestogenic effect. It is very
effective in treating hirsutism and male
Adverse Effects
pattern hair loss. The effective dose ranges
CPA is generally well-tolerated, but patients from 125–500 mg daily. However, it is rarely
may complain of headache, nausea, weight used, as it is expensive and causes severe
gain, breast tenderness, and loss of libido. hepatotoxicity.28
Rarely one may experience hepatic toxicity,
benign or malignant hepatic tumours
CONCLUSION
leading to intra-abdominal haemorrhage
and thromboembolic episodes. PCOS is a heterogeneous endocrinopathy
affecting adolescent girls. The exact etiology
Contraindications is unknown; however, hyperinsulinemia and
• Hepatic disease/tumours hyperandrogenism form the main pathological
• Patient with history of a VTE episode basis of this syndrome. In adolescents, it may
• Sickle cell anaemia be difficult to differentiate irregular cycles of
PCOS from physiologic anovulation. However,
• Severe chronic depression
persistence of menstrual irregularity for
• Past or present history of meningioma.
>2 years post-menarche is a strong predictor
of long-term ovulatory dysfunction. COC pills
SPIRONOLACTONE are the first line of medical management for
Spironolactone is an aldosterone antagonist menstrual disturbances and acne, metformin
with moderate antiandrogenic effects when for weight reduction and dysglycemia and
taken in large doses, hence it is used along a combination of both in addition with
with COC to treat hirsutism, female pattern other treatment modalities for treatment of
hair loss, and adult acne vulgaris.26 hirsutism.
 Drug Therapy in Adolescent Polycystic Ovary Syndrome 331

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and pharmacokinetics of multiple dose myo-
1. van Hooff MH, Voorhorst FJ, Kaptein MB,
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Aug;80(2):209–17. doi: 10.1038/pr.2016.97. Epub
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9. Nordio M, Basciani S, Camajani E. The 40: 1 myo-
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2. Ref: Sultan C, Paris F. Clinical expression of with other ratios. Eur Rev Med Pharmacol
polycystic ovary syndrome in adolescent girls. Sci. 2019;23(12):5512–21. doi:10.26355/eurrev_
Fertil Steril 2006; 86(Suppl 1): S6. 201906_18223.
3. Kiddy DS, Hamilton-Fairley D, Bush A, et al. 10. Unfer V; Carlomagno G; Papaleo E; Vailati S;
Improvement in endocrine and ovarian function Candiani M; Baillargeon J-P. Hyperinsulinemia
during dietary treatment of obese women with Alters Myoinositol to d-chiroinositol Ratio in the
polycystic ovary syndrome. Clin Endocrinol Follicular Fluid of Patients With PCOS. Reprod.
(Oxf) 1992; 36(1): 105–11. Sci. 2014, 21, 854–858.
4. Zacche MM, Caputo L, Filippis S, Zacche G, 11. Facchinetti F; Dante G; Neri I. The Ratio of MI to
DCI and Its Impact in the Treatment of Polycystic
Dindelli M, Ferrari A: Efficacy of myo-inositol
Ovary Syndrome: Experimental and Literature
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Evidences. Front. Gynecol. Endocrinol. 2016, 3,
young women with polycystic ovary syndrome.
103–109.
Gynecol Endocrinol. 2009 Aug;25(8):508-13.
12. FDA Approved Drug Products: Riomet
doi: 10.1080/09513590903015544. (PubMed ID
(metformin hydrochloride) oral solution.
19551544).
13. FDA Approved Drug Products: Glumetza
5. Gerli S, Papaleo E, Ferrari A, Di Renzo GC: (metformin hydrochloride) extended-release
Randomized, double blind placebo-controlled tablets for oral use.
trial: effects of myo-inositol on ovarian 14. Metformin pathways: pharmacokinetics and
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PCOS. Eur Rev Med Pharmacol Sci. 2007 Sep- genomics. 2012. Gong Li, Goswami Srijib,
Oct;11(5):347–54. (PubMed ID 18074942). Giacomini Kathleen M, Altman Russ B and Klein
6. Gerli S, Mignosa M, Di Renzo GC: Effects of Teri E. PMID:22722338 (PMCID:PMC3651676
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factors in women with PCOS: a randomized 15. Lashen H. Role of metformin in the management
double-blind placebo-controlled trial. Eur Rev of polycystic ovary syndrome. Ther Adv
Med Pharmacol Sci. 2003 Nov-Dec;7(6):151-9. Endocrinol Metab. 2010 Jun;1(3):117–28. doi:
(PubMed ID 15206484) Nordio M, Basciani S, 10.1177/2042018810380215. PMID: 23148156;
Camajani E. The 40: 1 myo-inositol/D-chiro- PMCID: PMC3475283.
inositol plasma ratio is able to restore ovulation 16. Hundal RS, Krssak M, Dufour S, Laurent D,
in PCOS patients: comparison with other ratios. Lebon V, Chandramouli V, et al. Mechanism by
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17. Legro RS, Arslanian SA, Ehrmann DA, et al.
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Hallman M, Frantz ID 3rd, Faix RG, Zaterka- 5:1445–1461.
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2000;1(2):89–99. 252.
 40
Drugs for Ovulation Induction

• Sudha Tandon • Amrita Tandon

GENERAL PHYSIOLOGY The primordial follicle develops into the

primary follicle, which then becomes the
Ovulatory dysfunction makes-up about 25% secondary follicle which is surrounded by
of infertility in females. For a mature oocyte granulosa cells containing follicle-stimulating
to develop, it needs coordination between the hormone (FSH) receptors and theca cells. This
hypothalamus, anterior pituitary and ovaries stage of folliculogenesis is not dependent on
(hypothalamic-pitutiary axis) along with gonadotropins (Fig. 40.1). The majority of
factors produced by the ovaries locally. Any these preantral follicles undergo atresia. The
disruption of this feedback mechanism can granulosa and theca cells then proliferate and
cause ovulatory dysfunction and infertility.1 form a fluid-filled cavity called the antrum.
About one million oocytes are present in Follicles beyond this stage are referred to
the ovary at birth, and about 400–500 ovulate as antral or pre-ovulatory follicles which
during the reproductive years. A single layer are now dependent on FSH for further
of granulosa cells surrounds the primordial development.2
follicles, and these are arrested in meiosis 1 Once, the FSH threshold level is reached,
until menarche. a set cohort of preovulatory follicles is

Fig. 40.1: Neural control of ovulation

334 Drugs in Obstetrics and Gynecology

Table 40.1: WHO classification of ovulatory disorders4

WHO Group I: 5–10% of anovulatory Low/low-normal serum Women with hypothalamic
Hypogonadotropic women follicle-stimulating amenorrhea related to
hypogonadal hormone (FSH) and low physical, nutritional, or
anovulation serum estradiol levels emotional stress; weight loss;
excessive exercise; anorexia
nervosa and its variants;
Kallmann syndrome; and
isolated gonadotropin
deficiency.

WHO Group II: 75–85% of anovulatory Normal serum FSH and Polycystic ovary syndrome
Normogonadotropic women e s t r a d i o l l e v e l s a n d (PCOS)
normoestrogenic normal or elevated LH
anovulation concentrations
WHO Group III: 10–20% of anovulatory Elevated serum Premature ovarian
Hypergonadotropic women FSH and low AMH insufficiency
anovulation concentrations, and
most have amenorrhea
Hyperprolactinemic 5–10% of anovulatory Serum FSH concentrations
anovulation women are low or low-normal,
and serum estradiol levels
are usually low

recruited. These follicles can now respond • A basic hormonal profile which includes
to the increasing FSH/luteinizing hormone thyroid profile (TSH), hyperprolactinemia
LH levels, secrete estrogen, and grow. The (serum prolactin) and anti-müllerian
dominant follicle responds more aggressively, hormone (AMH).
and via aromatase, there is higher estrogen • Husband semen analysis
levels in the follicle’s microenvironment, and • Transvaginal ultrasound
large number of FSH receptors leading to • Tubal patency test in the form of hystero­­­
follicular growth. The rest of the preovulatory salpingography, saline infusion sonosalp-
follicles become atretic due to the falling FSH ingography or Hycosy should ideally be
levels (Fig. 40.1). offered prior to ovulation induction.
The theca cells produce steroids in • For PCOS patients with a BMI more than
following the LH stimulation, which then 25 kg/m2, lifestyle management for weight
produce estrogen via aromatization. When loss is recommended. A weight loss of
estrogen levels peak in the circulating blood, 5–10% of body weight, may even lead
the hypothalamus is stimulated, leading to an to resumption of spontaneous ovulatory
LH surge and thus ovulation.3 cycles in obese anovulatory women with
PCOS.
PRETREATMENT EVALUATION OF INFERTILITY
AND OVULATORY DISORDERS4,5 MONITORING OF OVULATION
A complete work up for infertility and INDUCTION (OI) CYCLES
endocrine dysfunction should be done in the Ultrasound: Transvaginal ultrasound is
couple before starting treatment for ovulation always used to visualize the number and
induction (Table 40.1). size of recruited follicles in stimulated cycles
Table 40.2: Treatment of ovulatory disorders
Drug Mechanism of action Dosage Results Side effects Risks
Clomiphene citrate It is a selective estrogen 50–150 mg, orally, for When patient selection Mild symptoms, like Multiple pregnancy—
(CC) receptor modulator 5 days, starting from is appropriate, CC transient hot flashes 7–10%9
(SERM), comprises day 2–5 of menses. The achieves ovulation in (10–20%), headache, OHSS 0.5–2.5% but
of 2 stereoisomers starting dose is 50 mg 70–80% women.6 Live pelvic pressure or pain, these are mild-to
zuclomifene and and it can be stepped birth rates are between breast tenderness, and -moderate OHSS. Risk
enclomiphene, of which
up in the next few 15% and 20%. nausea (2–5%) of severe OHSS is
enclomiphene is the
more potent isomer. It cycles until the patient CC when combined remote.
competetitively blocks ovulates. Maximum with IUI, for
hypothalamus and dose—250 mg/day.7 unexplained infertility
pituitary gland receptors CC Resistance is is very effective, in an
and thus competes when patients fail to effort to increase the
with endogenous, respond to CC at doses numbers of both ova
and interfering with of 250 mg/day or do and sperm.8
the negative feedback not ovulate after six
signalling of natural
cycles . They require re-
estrogen. CC binds
in the hypothalamus evaluation and alternate
for a longer time treatments for ovulation
compared to natural induction.
estrogen, thus prevents
the replenishment of
estrogen receptors. This
causes a hypoestrogenic
state in the body which
causes GnRH and
FSH to be released.
CC administration
requires an intact
HPO axis to have an
adequate action. The
high levels of FSH cause
hyperstimulation of the
ovary and the potential
for m ulti -f ol lic ular
development.6
Drugs for Ovulation Induction 335

(Contd...)
Table 40.2: Treatment of ovulatory disorders (Contd...)
Drug Mechanism of action Dosage Results Side effects Risks
Letrozole Competitive 2.5 mg /day for 5 days Letrozole is the Common minor Risk of multiple
aromatase inhibitor. starting from day 2–5 of drug of choice for side effects include pregnancy—3–7%.12
Aromatase catalyzes menses. ovulation induction in headaches, cramps, Risk of severe OHSS—
the rate-limiting Maximum dose—7.5 anovulatory women fatigue (20%) and negligible.
step of conversion mg/day with PCOS due to dizziness (12%).11
of testosterone to Extended letrozole higher live birth rates
estrogen. Letrozole protocol—2.5–5 mg/ compared to CC. It
blocks estrogen day for 10 days from is also efficacious for
production in the day 2–5 of menses. ovulation induction
peri­phery and in anovulatory CC
brain, and leads resistant women.10
to a compensatory
336 Drugs in Obstetrics and Gynecology

increase in pituitary
gonadotropin
secretion which causes
ovarian follicular
development.
Similar to clomiphene,
letrozole does not work
in women a abonormal
HPO axis, and those
with hypogonadotropic
hypogonadism.10
Metformin Metformin is an oral Initial: 500 mg/day A 2017 meta-analysis Abdominal pain As a sole therapy,
insulin-sensitizing Increase 500 mg/day evaluated the benefit Nausea it does not increase
biguanide, that acts every week and safety of metformin Vomiting the risk of OHSS or
by reducing hepatic Max. dose 2500 mg in improving fertility Diarrhoea multiple pregnancy.
gluconeogenesis and day.14 outcomes for women Rare lactic acidosis
secondarily decreases with PCOS undergoing
intestinal glucose ovulation induction.
absorption and
increases its uptake in
the periphery.
(Contd...)
Table 40.2: Treatment of ovulatory disorders (Contd...)
Drug Mechanism of action Dosage Results Side effects Risks
This reduces insulin It concluded that
resistance and androgen metformin leads to
concentrations, and significantly higher
helps achieve ovulation ovulation rates, clinical
in some PCOS women.13 pregnancy, and live
birth rates compared
to placebo or no
treatment. This meta-
analysis also concluded
that combination
of metformin and
clomiphene achieves
higher ovulation rate (OR
= 1.57, CI = 1.28–1.92)
and pregnancy rates (OR
= 1.59, CI = 1.27–1.99),
compared to treatment
with clomiphene
alone.15
CC + Metformin Metformin 1500 mg/ Combined treatment
day for 6–8 weeks. with metformin and
Initiate CC 100 mg daily clomiphene is useful
for 5 days from day 2–5 in women with
of menses. clomiphene resistant.
Letrozole + Metformin Metformin 1500 mg/ A recent study
day for 6–8 weeks. concluded that
Letrozole as per in PCOS with
normal protocol clomiphene-failure,
2.5 mg × 5 d metformin + letrozole
together results in
higher pregnancy
rates and less abortion
than metformin-
clomiphene.16
Drugs for Ovulation Induction 337

(Contd...)
Table 40.2: Treatment of ovulatory disorders (Contd...)
Drug Mechanism of action Dosage Results Side effects Risks
Gonadotropins In type-1 WHO classifi- Regimens: In women with The multiple pregnancy
cation system, women Recombinant FSH or hypo­gonadotropic rate is approximately
are ideal candidates hMG hypogonadism, 15%.
for gonadotropin (Gn) 1. ‘Step-up’ cycle fecundity is The overall incidence of
therapy as they do not treatment regimen approximately 25%, spontaneous miscarriage
have an intact HPO in both women with equal to or even greater in gonadotropin-
axis. These patients hypogonadotropic than that observed in induced conception
require exogenous hypogonadism (WHO normal fertile women; cycles is approximately
Gn to overcome the Group I) and those cumulative pregnancy 20–25%,moderately
HPO axis inability to with oral antiestrogen- rates after up to six higher than generally
produce FSH, to directly resistant anovulation cycles of gonadotropin observed (15%). 23
stimulate follicular (WHO Group II), stimulation approach Risk factors for OHSS
338 Drugs in Obstetrics and Gynecology

growth and ovulation.17 initially, to induce 90%.22 By comparison, include young age,
Gn treatment is also ovulation , begin cycle fecundity is low body weight,
second-line treatment with a low daily dose significantly lower high ovarian reserve
for anovulatory or PCOS (75 IU, daily) in a in clomiphene- as indicated by high
women who have failed ‘step-up’ treatment resistant anovulatory serum AMH levels or
first-line oral ovulogens, regimen. After 4–7 women. Overall, antral follicle count,
as the FSH had not days, a transvaginal cycle fecundity ranges PCOS, higher doses
reached threshold level ultrasonography, between 5% and of gonadotropins, and
required to generate a provides the first idea 15%, and cumulative previous history of
dominant follicle with of follicular response. conception rates hyperstimulation. Risk
oral agents.18 Subsequently, the range between 30% increases with serum
dose of gonadotropins and 60%; within the estradiol levels and the
may be maintained or group, those with number of developing
increased, as seen by hyperandrogenic ovarian follicles and
the response. chronic anovulation when supplemental
have the poorest doses of hCG are
prognosis.19 administered after
ovulation for luteal
phase support.24

(Contd...)
Table 40.2: Treatment of ovulatory disorders (Contd...)
Drug Mechanism of action Dosage Results Side effects Risks
2. ‘Low-slow’ treatment
regimen—low doses
(37.5–75 IU daily), small
increments, and a longer
duration of stimulation
are given for ovulation
induction20
3. ‘Step-down’
treatment regimen
is designed to more
closely approximate
the pattern of serum
FSH concentrations
observed in
spontaneous ovulatory
cycles. The cycle
begins with a higher
dose (150–225 IU daily)
and thereafter decreases
gradually in an effort
to allow continued
development of only
the dominant follicle
and withdrawing
support from the
less sensitive smaller
follicles in the cohort.21

(Contd...)
Drugs for Ovulation Induction 339
Table 40.2: Treatment of ovulatory disorders (Contd...)
Drug Mechanism of action Dosage Results Side effects Risks
4. Sequential regimen:
Sequential treatment
with clomiphene and
gonadotropins can
help some clomiphene-
resistant anovulatory
women. The cycle
involves the usual
course of clomiphene
treatment (50–100 mg
daily), followed by low-
dose FSH or hMG (75 IU
340 Drugs in Obstetrics and Gynecology

daily) beginning on the

last day of clomiphene
therapy or the next day;
treatment is followed
up and monitored
subsequently just as
gonadotropin-stimulated
cycles. The advantage
of this treatment was
decreasing significantly,
(50% or more), the
dose and duration of
gonadotropin therapy
and the associated costs
of monitoring.
 Drugs for Ovulation Induction 341

and especially in gonadotropin cycles. The women with clomiphene citrate-resistant

endometrial thickness can also be measured. polycystic ovarian syndrome: a randomized
Typically, when the mean diameter of the controlled trial. Hum Fertil (Camb) 2017;20(1):37–
42. doi: 10.1080/14647273.2016.1242783.
dominant follicle reaches 18–20 mm, human
8. Imani B, Eijkemans MJ, te Velde ER, Habbema
chorionic gonadotropin (hCG) is given
JD, Fauser BC, A nomogram to predict the
to trigger ovum release; ovulation can be probability of live birth after clomiphene citrate
expected to occur around 36–48 hours later induction of ovulation in normogonadotropic
and this helps to decide the correct timing oligoamenorrheic infertility,Fertil Steril 77:91,
of intrauterine inseminisation (IUI) or timed 2002.
intercourse. 9. Schenker JG, Yarkoni S, Granat M, Multiple
pregnancies following induction of ovulation,
Serum estradiol: In a natural ovulatory cycle,
Fertil Steriln 35:105, 1981.
there is a peak in serum estradiol levels
10. Franik S, Eltrop SM, Kremer JA, Kiesel L,
between 200 and 400 pg/ml just before the Farquhar C, Aromatase inhibitors (letrozole)
LH surge. Serum estradiol (E2) levels are for subfertile women with polycystic ovary
expected to rise in a similar way in medically syndrome, Cochrane Database Syst Rev
stimulated cycles, for each mature follicle (5):CD010287, 2018
observed. Usually, serum E2 levels are not 11. Legro RS, Brzyski RG, Diamond MP, Coutifaris
routinely used for monitoring. With the C, Schlaff WD, Casson P, Christman GM, Huang
current gonadotropin stimulation regimens, H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT,
it has been observed that positive results are Bates GW, Usadi R, Lucidi S, Baker V, Trussell
JC, Krawetz SA, Snyder P, Ohl D, Santoro N,
obtained when estradiol concentrations peak Eisenberg E, Zhang H; NICHD Reproductive
between 500 and 1,500 pg/ml; and it has also Medicine Network, Letrozole versus clomiphene
been seen that pregnancies are not common for infertility in the polycystic ovary syndrome,
at levels below 200 pg/m.4 N Engl J Med 371:119,2014.
12. Warraich G, Vause TD, First reported case of
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ovulation. In: Falcone T, Hurd WW, editors. 14. Lashen H. Role of metformin in the management
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practical guide. 2. London: Springer; 2013. Endocrinol Metab. 2010;1(3):117–128. doi: 10.
3. Mesiano S, Jones EE. Chapter 55: The female 1177/2042018810380215
reproductive system. In: Boron WF, Boulpaep 15. Morley LC, Tang T, Yasmin E, Norman RJ, Balen
EL, editors. Medical physiology. 3. Philadelphia: AH, Insulin-sensitising drugs (metformin,
Elsevier; 2017. rosiglitazone, pioglitazone, D-chiro-inositol)
4. Speroff L, Fritz M, editors. Clinical gynecologic for women with polycystic ovary syndrome,
endocrinology and infertility. 9. Philadelphia: oligo amenorrhoea and subfertility, Cochrane
Lippincott, WIlliams & Wilkins; 2020. Database Syst Rev (11):CD003053, 2017.
5. Lindsay TJ, Vitrikas KR. Evaluation and 16. Davar R, Javedani M, Fallahzadeh MH. Metformin-
treatment of infertility. Am Fam Physician. letrozole in comparison with Metformin-
2015;91(5):308–314. clomiphene citrate in clomiphene-resistance
6. Homburg R. Clomiphene citrate – end of an era? PCOS patients undergoing IUI. Iran J Reprod
A mini-review Hum Reprod. 2005;20:2043–2051. Med. 2011;9(1):31–36.
7. Hassan A, Shehata N, Wahba A. Cost effectiveness 17. Melo AS, Ferriani RA, Navarro PA. Treatment
of letrozole and purified urinary FSH in treating of infertility in women with polycystic ovary
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syndrome: approach to clinical practice. Clinics 21. Practice Committee of American Society for
(Sao Paulo) 2015;70(11):765–769. doi: 10.6061/ Reproductive Medicine Use of exogenous
clinics/2015(11)09. gonadotropins in anovulatory women: a
18. Thessaloniki ESHRE/ASRM-Sponsored PCOS technical bulletin. Fertil Steril. 2008;90(5
Consensus Workshop Group Consensus on Suppl):S7–S12.
infertility treatment related to polycystic ovary 22. FlukerMR, UrmanB, MackinnonM, BarrowSR,
syndrome. Hum Reprod. 2008;23(3):462–477. PrideSM, YuenBH, Exogenous gonadotropin
doi: 10.1093/humrep/dem426 therapy in World Health Organization groups
19. Cumulative conception and live birth rates I and II ovulatory disorders, Obstet Gynecol
after the treatment of anovulatory infertility: 83:189, 1994.
safety and efficacy of ovulation induction in 200 23. Martin JA, Hamilton BE, Osterman MJK, Driscoll
patients, Hum Reprod 9:1563, 1994. AK, Drake P, Births: final data for2016, Natl Vital
20. Homburg R, Levy T, Ben-Rafael Z, A comparative Stat Rep 67:1, 2018.
prospective study of conventional regimen with 24. Ashrafi M, Bahmanabadi A, Akhond MR,
chronic low-dose administration of follicle- Arabipoor A, Predictive factors of early moderate/
stimulating hormone for anovulation associated severe ovarian hyperstimulation syndrome in non-
with polycystic ovary syndrome, Fertil Steril polycystic ovarian syndrome patients: a statistical
63:729, 1995. model, Arch Gynecol Obstet 292:1145, 2015.
 41
Drugs to Treat
Endometrial Hyperplasia
• Kinjal Shah • Sangeeta Agrawal

Introduction apoptosis is maintained by a number of

Estrogen helps the epithelial cell proliferation factors like hormonal balance, molecular
which results in thickening of the uterus, mechanisms, environment, age, and is prone
while progesterone helps the epithelial cell to various disturbances leading to different
differentiation in the secretory phase of the endometrial abnormalities (Flowchart 41.1).
endometrial cycle. The fine equilibrium Endometrial hyperplasia (EH) is a pre-
between endometrial proliferation and cancerous, non-physiological, non-invasive

Flowchart 41.1: The investigation and management of endometrial hyperplasia

CCHRT: Continuous combined hormone replacement therapy

344 Drugs in Obstetrics and Gynecology

proliferation of the endometrium that results treatment has been highly successful in
in increased volume of endometrial tissue reversing EH with or without atypia in
with alterations of glandular architecture (size patients on estrogen-alone replacement
and shape) and endometrial gland to stroma therapy, and was found to reduce EH in 61%
ratio of greater than 1:1. The majority of cases of patients with atypical hyperplasia.
of EH are due to chronic exposure to estrogen, The mode and duration of progestin
unopposed by progesterone, such as in earlier treatment is assessed on its success to reduce
forms of hormone replacement therapy. The EH. EH usually shows a response after 10-
most common symptom of EH is abnormal week of dosing, but significant responses
uterine bleeding which includes menorrhagia, are commonly observed after 3-months of
intermenstrual bleeding, postmenopausal progestin therapy, with the median time to
bleeding, and irregular bleeding when on resolution being 6 months. Progestin therapy
hormone replacement therapy or tamoxifen. may be continued further or hysterectomy
Currently, the treatment approaches for EH is been advised in cases of no response
are limited, such as hysterectomy or hormone (Table 41.1).
therapy. EH without atypia is generally
treated with progestins while EH with atypia MEDROXYPROGESTERONE ACETATE
are advised hysterectomy. Medroxyprogesterone acetate (MPA) is
a synthetic steroidal progestin (synthetic
PROGESTIN THERAPY steroid hormone progesterone), used to treat
Progestins are synthetic progestogens with patients with absent or irregular menstrual
similar effects as progesterone. Progestins periods, or with abnormal uterine bleeding.
are ideally used to induce EH regression MPA is used to prevent thickening of the
in women with EH without atypia or those endometrial lining in postmenopausal
who wish to retain fertility. Progestins can women receiving estrogen hormone therapy
provide hormonal contraception either and decreases the risk of endometrial
alone or with estrogen, and prevent EH carcinoma. MPA is commonly administered
development associated with unopposed at 10 mg per day, orally and continuously for
estrogen. Progestins decrease the glandular 6 weeks, or cyclically for 3 months (2 weeks
cellularity by inducing apoptosis and to of each month). Cyclic MPA is safer and more
inhibit angiogenesis in the myometrium acceptable therapy than continuous MPA.
immediately underlying the complex EH.
The different routes available to administer MEGESTROL ACETATE
progestins are oral, intramuscular, micronized Megestrol acetate (MA) is a steroidal progestin
vaginal cream, or intrauterine devices. This (specifically, 17-hydroxylated progesterone)

Table 41.1: Common dose of various progestins for treatment of endometrial hyperplasia
Progestin type Commonly available as Benign/simple Atypical hyperplasia or
hyperplasia EIN
Progesterone Progestasert, crinone, 300 mg, PO × 14 day/mo 300 mg/day, PO
endometrin
Medroxyprogesterone Depo-provera 10 mg, PO × 14 day/mo 100 mg PO, or 1000 mg/
acetate (injection), provera (oral) wk, IM
Megestrol acetate Megace 80 mg, PO × 14 day/mo 160 mg/day, PO
Levonorgestrel IUD Mirena, orplant 20 mg/day × 6 mo to 2 yrs
EIN: Endometrial intraepithelial neoplasia; IUD: Intrauterine device
 Drugs to Treat Endometrial Hyperplasia 345

with predominantly progestational and THERAPIES OTHER THAN PROGESTINS

antigonadotropic effects. It has been shown
to have the potential to inhibit proliferation in 1. Danazol
the uterus and treat EH. MA at doses ranging Danazol is a synthetic androgen, which
from 160 to 320 mg/day has been reported is a derivative of 17α-ethinyl testosterone
to be an effective method of treatment for which is commonly used in the management
endometrial pathologies without causing of endometriosis. Danazol can induce a
harmful effects on serum lipid profiles or hypoestrogenic, as well as, a hypoandrogenic
glucose levels. state in the uterus, resulting in atrophy of the
endometrium. Danazol is an effective and safe
LEVONORGESTREL alternative to progesterone for management
of EH. However, some studies have shown
Levonorgestrel (LNG) is a second-generation that danazol can increase the risk of ovarian
progestin (synthetic progestogen) commonly cancer in women with endometriosis.
used as hormonal contraceptives. The LNG- Other side effects associated with danazol
impregnated intrauterine device (LNG-IUD) include weight gain, muscle cramps, acne,
is commonly used in the management of seborrhea, decreased breast size, hirsutism,
endometrial hyperplasia. It contains 52 mg and deepening of the voice, which are all
of levonorgestrel and release at a rate of strongly related to androgenic action.
approximately 20 mg/day over a period of
5 years. Common side effects associated 2. Genistein
with levonorgestrel are headache, acne,
Genistein is an isoflavonoid extracted from
breast tenderness, irregular bleeding, mood
soy products which acts as an inhibitor of
changes, cramping or pelvic pain.
protein-tyrosine kinases and topoisomerase-II.
Genistein suppresses estrogen-induced genes,
NORETHINDRONE ACETATE OR such as c-fos and c-jun, as well as the internal
NORETHISTERONE ACETATE cytokines interleukin-1a (IL-1α) and tumor
Norethisterone (or norethindrone) is a necrosis factor-a (TNF-α) through cytokine-
synthetic, orally active steroidal progestin and ER-mediated pathways. Treatment with
with antiandrogen and antiestrogen effects. genistein aglycone (54 mg/day, n = 19) for 6
Various studies have been performed on the months has shown a 42% positive response
use of norethisterone to reduce the incidence rate in premenopausal women with non-
of EH in postmenopausal women treated atypical EH.
with estradiol and has been found to be
very effective. There are some common side 3. Metformin
effects like dizziness, headache, nausea, Metformin (N,N-dimethylbiguanide) belong-
abdominal pain, uterine pain, delay of ing to a class biguanides is commonly used
menstruation, heavy menstruation, uterine for the treatment of type-2 diabetes mellitus
bleeding, fatigue, diarrhea, vomiting, and polycystic ovary syndrome (PCOS),
and painful menstruation associated with especially in over-weight and obese indi-
norethisterone. viduals, or in cases when insulin resistance
Failure of progestin treatment depends on may be an important factor. Since insulin
multiple factors such as patient’s age, health, resistance is associated with the occurrence
other diseases, and hyperplasia grade or type. of atypical EH and metformin was shown
Hence, precautions, such as routine checkups to have anti-proliferative, anti-invasive, and
and biopsies are recommended for patients anti-metastatic effects in multiple cancers,
while on progestin therapy. use of metformin is a logical approach for the
346 Drugs in Obstetrics and Gynecology

treatment of EH. Metformin was shown to in- SURGICAL MODALITIES

duce progesterone receptor (PR) expression in
endometrial cancer cells, which may enhance Since EH can progress to endometrial
progestin therapy efficiency or overcome the carcinoma, surgery is advised in most
progestin resistance caused by PR depletion women with complex EH with atypia if
in long-term progestin therapy. the childbearing is completed and do not
desire preservation of their fertility or did
4. Gonadotropin-releasing not respond to hormone therapy. Several
Hormone Therapy surgical options have been widely reported
The endometrium contains gonadotropin- as common treatments of atypical EH, such
releasing hormone (GnRH) receptors and as thermal balloon ablation, laser therapy or
GnRH agonists which downregulate GnRH resectoscopic surgery. Hysterectomy might
receptors upon prolonged exposure. GnRH be considered a first-choice treatment for
analogues suppress the hypothalamic EH. Resectoscopic surgery is an effective
pituitary–ovarian (HPO) axis, thereby treatment for EH without atypia, especially
resulting in inhibition of estrogen production. for those at high risk for medical therapy
Thus, GnRH analogues have a direct anti- or hysterectomy. It is also recommended
proliferative action on endometrial cells. that postmenopausal women with atypical
The ideal dose administered of GnRH is EH undergo hysterectomy with bilateral
1 ampule/3.75 mg, intramuscularly, every 28 s a l p i n g o - o o p h o re c t o m y r a t h e r t h a n
days for 6 months to treat women with EH, with hysterectomy alone.
or without atypia. Further studies are needed to Currently, the recommended treatment
determine the usefulness of GnRH analogues in approach for EH includes the following,
patients with atypical endometrial hyperplasia. cyclic progestin therapy, GnRH therapy, and
hysterectomy. Progestins continue to be an
5. Aromatase Inhibitors effective option, especially for patients with
Aromatase inhibitors can inhibit estrogen low-grade estrogen receptor (ER) and/or
production and thus reduce estrogen PR/positive disease, some of whom achieve
levels. Examples of aromatase inhibitors prolonged remission. The disadvantages of
include letrozole (Femara; Novartis, Basel, GnRH therapy include high cost, menopausal
Switzerland), anastrozole [Arimidex, symptoms and bone demineralization
AstraZeneca, London, United Kingdom (UK)], associated with prolonged therapy. Fat tissues
and exemestane [Aromasin, Pfizer, New York, are the most common site for conversion of
NY, United States of America (USA)], which androgen to estrogen.
are commonly used to treat breast cancer, and
also thought to be helpful in the treatment of CONCLUSIONS
endometrial cancer. Anastrozole or letrozole Endometrial hyperplasia being a precursor of
were shown to reduce endometrial thickness endometrial cancer is of clinical importance.
in patients with EH. Recent studies have Available therapeutic options for EH, are
established letrozole as good therapeutic progestin, danazol, genistein, metformin
option for simple EH without atypia. and GnRH therapy or surgery which is
Anastrozole was also found to be a new indicated in women with restricted efficacy
modality for the management of EH in obese due to high cost, side effects and drug
postmenopausal women. Side effects of resistance. Endometrial hyperplasia still
aromatase inhibitor may include joint and remains a challenge in patients who wish
muscle pain as well as hot flashes, bones to retain their fertility. As a novel approach,
weakening and occasionally osteoporosis. the antiestrogens, aromatase inhibitors and
 Drugs to Treat Endometrial Hyperplasia 347

cytokines might give optimistic outcome for 8. Vollmer G. Endometrial cancer: experimental
EH; however, clinical trials are needed to models useful for studies on molecular aspects
prove their efficacy. Future investigations and of endometrial cancer and carcinogenesis.
Endocr Relat Cancer 2003;10:23–42.
clinical trials with these novel compounds
9. Portman DJ, Symons JP, Wilborn W, Kempfert
in combination with known established EH
NJ. A randomized, double-blind, placebo-
therapies are required to achieve precise controlled, multicenter study that assessed the
management of EH. Further research endometrial effects of norethindrone acetate
on the cellular signaling pathways that plus ethinyl estradiol versus ethinyl estradiol
control endometrial cell proliferation and alone. Am J Obstet Gynecol 2003;188:334–42.
development of EH, as well as targeting 10. Cottreau CM, Ness RB, Modugno F, Allen GO,
various mutations and single nuleotide Goodman MT. Endometriosis and its treatment
polymorphisms (SNP) in pathobiology of EH with danazol or lupron in relation to ovarian
will help to identify novel targeted therapeutic cancer. Clin Cancer Res 2003;9:5142–4.
agents to improve the management of EH. 11. Fatima I, Chandra V, Saxena R, Manohar M,
Sanghani Y, Hajela K, et al. 2,3-Diaryl-2H-1-
References benzopyran derivatives interfere with classical
and non-classical estrogen receptor signaling
1. Medh RD, Thompson EB. Hormonal regulation
pathways, inhibit Akt activation and induce
of physiological cell turnover and apoptosis. Cell
apoptosis in human endometrial cancer cells.
Tissue Res 2000;301:101–24.
Mol Cell Endocrinol 2012;348:198–210.
2. Horne FM, Blithe DL. Progesterone receptor
modulators and the endometrium: Changes 12. Zagouri F, Bozas G, Kafantari E, Tsiatas M,
and consequences. Hum Reprod Update Nikitas N, Dimopoulos MA, et al. Endometrial
2007;13:567–80. cancer: what is new in adjuvant and molecularly
3. Trimble CL, Method M, Leitao M, Lu K, Ioffe O, targeted therapy? Obstet Gynecol Int 2010;2010
Hampton M, et al. Management of endometrial :749579.
precancers. Obstet Gynecol 2012;120:1160–75. 13. Barker LC, Brand IR, Crawford SM. Sustained
4. Reed SD, Voigt LF, Newton KM, Garcia RH, effect of the aromatase inhibitors anastrozole
Allison HK, Epplein M, et al. Progestin therapy and letrozole on endometrial thickness in
of complex endometrial hyperplasia with and patients with endometrial hyperplasia and
without atypia. Obstet Gynecol 2009;113:655–62. endometrial carcinoma. Curr Med Res Opin
5. Emarh M. Cyclic versus continuous medroxy­ 2009;25:1105–9.
proges­terone acetate for treatment of endometrial 14. Emarh M. Cyclic versus continuous medroxy­
hyperplasia without atypia: a 2-year observational p ro ge s te ro ne ac e tate fo r tre atme nt of
study. Arch Gynecol Obstet 2015;292:1339–43. endometrial hyperplasia without atypia: a
6. Reifenstein EC. The treatment of advanced 2-year observational study. Arch Gynecol Obstet
endometrial cancer with hydroxyprogesterone 2015;292:133–43.
caproate. Gynecol Oncol 1974;2:377–414. 15. Figueroa-Casas PR, Ettinger B, Delgado E, Javkin
7. Saegusa M, Okayasu I. Progesterone therapy for A, Vieder C. Reversal by medical treatment of
endometrial carcinoma reduces cell proliferation endometrial hyperplasia caused by estrogen
but does not alter apoptosis. Cancer 1998;83:111– replacement therapy. Menopause 2001;8:
21. 420–3.
 42
Drugs to Treat Thin Endometrium
• Devika Chopra • Priya Vora • Manan Boob

Introduction physiology of thin endometrium. These

The uterine endometrium serves as the include intrauterine adhesions, ovarian
receptive ground for the implantation of an stimulation using clomiphene citrate (CC),
embryo during the mid-luteal phase of the and prolonged use of progesterone and
menstrual cycle. It undergoes intricate changes combined oral contraceptive pills (COCPs).3
in response to estrogen and progesterone, As a result, several treatment options have
preparing it for implantation. These changes been proposed to enhance endometrial
occur at the morphological, biochemical, and thickness and subsequent endometrial
molecular levels, and any disturbance at these receptivity for patients with this condition.
levels can lead to unsuccessful implantation.1
Various ultrasound markers, including HOW TO MEASURE ENDOMETRIAL THICKNESS
endometrial thickness (EMT), endometrial To minimize inter-operator variation, it is
blood flow, and uterine volume, have been crucial to adopt a consistent method for
studied to detect a receptive endometrium. measuring EMT. The recommended approach
However, their specificity and positive involves using a transvaginal probe with
predictive value have been found to be low. an empty bladder, as this brings the probe
A triple-line endometrium observed on closer to the endometrium, resulting in
ultrasonography on the day of the human higher-frequency waves compared to the
chorionic gonadotropin (hCG) trigger, has transabdominal probe. 4 When measuring
been linked to successful implantation. EMT, it is best to do so in the sagittal plane
Although a minimum endometrial thickness or long axis. The measurement should be
of 6 mm has been considered important taken from the thickest echogenic area,
for achieving implantation in assisted starting from one stratum basalis endometrial
reproductive technologies (ART), there interface across the endometrial canal to the
have been documented cases of successful other stratum basalis interface (Fig. 42.1).
pregnancies with a minimum EMT of 4 mm.2 The surrounding inner myometrial lucency
Many ART centres have their cut-off value for should not be included in this measurement.
EMT ranging from 7–10 mm, below which the This standardized method ensures more
success of the ART cycle is reduced. accurate and consistent EMT assessments
Numerous mechanisms have been across different operators.4 This measurement
suggested to elucidate the underlying patho­ is usually found within 1 cm of the fundal tip.5
 Drugs to Treat Thin Endometrium 349

differences observed between the two groups

regarding EMT, pregnancy rate, or live birth
rates.8 Based on a Cochrane study, low-dose
aspirin has no substantial positive effect on
pregnancy and endometrial thickness.9

Luteal Estradiol
The endometrium is a hormone-dependent
tissue, and its growth and development
are regulated by estrogen. Estrogen plays a
crucial role in supporting the proliferation
of the endometrial tissue. It achieves this by
Fig. 42.1: Measurement of endometrial thickness5 causing contraction of the spiral arteries and
reducing the oxygen tension in the functional
TREATMENT OF THIN ENDOMETRIUM layer of the endometrium. These changes
A thin endometrium is a complex condition create a favorable environment for embryo
influenced by various factors, and its manage­ implantation to occur successfully.10
ment should be targeted at addressing the Both oral estrogen in the form of micro­
underlying causes. The primary objective of nized estradiol and estradiol valerate have
treatment is to enhance endometrial recepti­ similar effectiveness. Estrogen can also be
vity and facilitate successful implantation. administered vaginally, and this route is
Nonetheless, managing patients with thin associated with the highest levels of serum
endometrium poses considerable challenges, and endometrial estradiol. In cases where oral
leading to the exploration of multiple administration proves ineffective, the vaginal
treatment regimens in the existing scientific route is preferred.
literature (Fig. 42.2).6 A study compared the effects of oral and
vaginal administration of estradiol in donor–
Aspirin egg recipients. The results indicated that
According to the hypothesis, the administra­ women who did not achieve an acceptable
tion of low-dose aspirin (at 75 mg) is believed endometrial thickness after oral estradiol
to enhance endometrial blood flow by administration experienced an increase in
reducing uterine artery impedance. Studies endometrial thickness and an improved
have shown that low-dose aspirin can lead ongoing pregnancy rate when switched
to a decrease in the pulsatility index of the to vaginal estradiol administration for 4–6
uterine artery, ultimately contributing to an weeks. This suggests that the vaginal route
improvement in pregnancy rates.7 can be more effective in certain cases, where
A single, non-blinded randomized the oral route was not successful in achieving
controlled trial (RCT) has investigated the the desired EMT.11
application of low-dose aspirin in patients Research has demonstrated that the
with thin endometrium. This study enrolled prolonged administration of estradiol valerate
28 recipients of donor oocytes who had during controlled ovarian hyperstimulation
previously experienced an endometrial (COH) cycles leads to notable improvements in
thickness of less than 8 mm in a prior mean endometrial thickness. The endometrial
cycle. The participants were randomly thickness increased from an average of
assigned to receive either aspirin treatment 6.7 mm to 8.6 mm. Pregnancy rates increased
or no intervention. The results of the study to 38.5% in the extended administration
indicated that there were no significant group, while they were only 4.3% in the group
350 Drugs in Obstetrics and Gynecology

Fig. 42.2: Vascular therapeutic options for thin endometrium before an embryo transfer. Blue background with
frozen flake identifies the frozen embryo transfer (FET) cycle. Timing for treatment introduction and ending
are specified (D, day; S, stimulation day; i.e. D1, first day of the menstrual cycle). The administration route
is represented: Vaginal in red, oral in dark yellow, and electrostimulation in orange. ET: Embryo transfer;
hCG: Human chorionic gonadotropin; GnRH: Gonadotropin-releasing hormone

with conventional administration. These endometrial receptivity, making it more

findings suggest that the extended use of favorable for embryo implantation.13
estradiol valerate can have a positive impact In a pilot study conducted by Papanikolaou
on endometrial thickness and significantly et al., a group of 17 patients with a resistant
improve the likelihood of achieving successful thin endometrium (measuring <7 mm) was
pregnancies during COH cycles.12 enrolled during fresh or frozen donor-embryo
cycles. To address the thin endometrium,
hCG Priming in the Follicular Phase the patients received daily doses of 150 IUs
Human chorionic gonadotropin plays a of hCG for 7 days, beginning on either day
crucial local paracrine role in the regulation of 8 or day 9 of estrogen administration. The
endometrial differentiation and receptivity. It study revealed that the mean EMT increased
exerts its effects by stimulating the release of significantly from an average of 5.18 mm
various cytokines and growth factors within to 6.01 mm (P = 0.008) following the hCG
the endometrium. This complex signaling treatment. However, it is worth noting that
process contributes to the enhancement of approximately 29.4% of the patients (5 out of
 Drugs to Treat Thin Endometrium 351

17), did not experience any improvement in muscles. Studies have shown that sildenafil
EMT despite the intervention. citrate administration can also increase
After the treatment, the overall pregnancy uterine blood flow. This effect is achieved
rate among the patients was 52.9%, with through increased p53 activity and elevated
9 out of 17 patients achieving successful levels of endometrial vascular endothelial
pregnancies.14 growth factor (VEGF).
When combined with estrogen, sildenafil
GnRH Agonist in Luteal Phase
citrate may facilitate the estrogen-induced
Gonadotropin-releasing hormone agonists proliferation of the endometrial lining. This
are synthetic peptides designed to mimic the combination treatment could potentially
structure of natural GnRH, which is released improve endometrial receptivity and support
in a pulsatile manner by the hypothalamus. successful embryo implantation in certain
When given in a chronic manner, these cases, especially for patients with thin
agonists suppress normal pituitary–gonadal endometrium or inadequate blood flow to
function and lead to downregulation of the the uterus.17
pituitary axis. The potential benefits of GnRH An RCT reported enhanced EMT with
agonists on embryonic development have triple-line endometrial pattern in 77.5% of
led to the investigation of their impact when patients in the sildenafil group versus 30% in
administered as a single dose during the luteal the control group (p < 0.001). In addition, the
phase in oocyte recipients. This study aimed chemical pregnancy rate was higher in the
to explore whether a single administration sildenafil group.18
of GnRH agonist at the time of implantation
could enhance the developmental potential GRANULOCYTE COLONY-
of the embryos in these recipients.15 In this STIMULATING FACTOR
study, GnRH administration improved both Granulocyte colony-stimulating factor
the implantation rate as well as the live birth (G-CSF) is a glycoprotein with various
rate.15 In a study involving 120 women with roles, including promoting hematopoiesis
thin endometrium who were undergoing and aiding in endometrial growth. In 2011,
in vitro fertilization (IVF), two groups were Gleicher, et al. first reported the successful
formed. The case group received triptorelin use of G-CSF intrauterine infusion. They
(0.1 mg) on the day of ovum pickup, on the day found that patients who had previously
of embryo transfer, and for 3 days afterward. been resistant to conventional treatments
The control group was given a placebo. The experienced EMT expansion to at least 7 mm
results showed that the treatment with GnRH within 48 hours after the G-CSF intrauterine
agonist (GnRHa) led to a significant increase infusion. This indicates that G-CSF treatment
in EMT, implantation rate, and pregnancy rate can be effective in improving endometrial
compared to the control group. This suggests growth in cases, where standard therapies
that the use of GnRHa can be beneficial in were not successful.19
improving the outcomes of IVF in patients Barad, et al. (2014)24 conducted a double-
with thin endometrium.16 blinded study, randomizing patients to
receive either G-CSF intrauterine infusion or
Sildenafil a placebo. The study found that there were no
Sildenafil citrate is an inhibitor of the (cGMP) significant differences in clinical pregnancy
specific phosphodiesterase type-5 (PDE5) rate and mean endometrial thickness between
enzyme. By inhibiting PDE5, it prevents the the G-CSF group and the control group.
breakdown of cGMP, leading to increased Similarly, Xu, et al. prospectively randomized
effects of nitric oxide on vascular smooth 30 patients with EMT <7 mm during frozen-
352 Drugs in Obstetrics and Gynecology

thawed embryo transfer cycles to receive and cytokines, has gained popularity in
either intrauterine G-CSF or G-CSF with various clinical settings. However, its
endometrial scratch, while 52 patients application to improve EMT has not been
served as the control group. The study extensively studied.
showed a significant increase in EMT after Chang, et al. introduced intrauterine
treatment (D 3.9 ± 2.0 mm, P <0.001) with infusion of PRP as a novel approach for
no difference between the two subgroups treating thin endometrium. They prepared
(G-CSF vs. G-CSF + scratch). Moreover, both PRP from autologous blood through
treatment subgroups had significantly higher centrifugation and administered 0.5–1 ml of
implantation and clinical pregnancy rates PRP on the tenth day of the ART cycle. If EMT
compared to the control group (31.5% vs. did not improve 72 hours later, additional PRP
13.9%, P <0.01, and 48.1% vs. 25.0%, P = 0.038, infusions were given in each cycle. Embryo
respectively).20 transfer was carried out, once the endometrial
thickness reached more than 7 mm. The study
PLATELET-RICH PLASMA reported successful endometrial growth
Platelet-rich plasma (PRP) prepared from and pregnancies in all patients after PRP
fresh whole blood containing growth factors infusion.21

Fig. 42.3: Summary of proposed strategies in case of thin endometrium. The left side shows interventions
in fresh cycles and the right side shows interventions in frozen cycles. In dark purple, treatments with low-
to-moderate evidence. In light purple with a dotted border, strategies with unclear effects. In pale purple
without border, interventions with no evidence of benefit.23 NMES: Neuromuscular electrical stimulation
 Drugs to Treat Thin Endometrium 353

In another study, 10 patients undergoing 6. The thin endometrium in assisted reproductive

frozen embryo transfer (FET) received technology: An ongoing challenge. Eftekhar M,
intrauterine infusion of PRP. The results Tabibnejad N and Tabatabaie A. 2018, Middle
East Fertility Society Journal, Vol. 23, pp. 1–7.
showed that the endometrial thickness
7. The benefits of low-dose aspirin therapy in
increased following the PRP infusion, and
women with impaired uterine perfusion during
50% of the patients achieved pregnancy. assisted conception. Wada I, et al. 10, 1994,
These findings suggest that PRP may have Human Reprod, Vol. 9, pp. 1954–1957.
a positive impact on endometrial growth 8. Endometrial growth and uterine blood flow: a
and can potentially improve the chances of pilot study for improving endometrial thickness
successful pregnancy in patients undergoing in the patients with a thin endometrium.
FET.22 Weckstein L, et al. 5, 1997, Louis N. Weckstein,
Arnold Jacobson, Donald Galen, Kim Hampton,
Janine Hammel, Vol. 68, pp. 927–930.
CONCLUSION
9. Endometrial preparation for women undergoing
In conclusion, the endometrium’s receptivity embryo transfer with frozen embryos or
is vital for successful embryo implantation, embryos derived from donor oocytes.
and proper endometrial growth is crucial D Glujovsky, R Pesce, G Fiszbajn, C Sueldo,
in this process. While poor endometrial RJ Hart, A. Ciapponi. 2010, Cochrane Database
development is linked to reduced pregnancy Syst. Rev., Vol. 1, p. CD006359.
chances, it is not the sole predictor, and the 10. Oestrogen and progesterone action on
endometrium: a translational approach to
endometrial pattern may be more significant.
understanding endometrial receptivity. Young
Vaginal sildenafil during the stimulation cycle SL 5, 2013, Reprod. Biomed. Online, Vol. 27, pp.
seems like a reasonable first-line treatment 497–505.
option, and intrauterine G-CSF infusion 11. Endocrine and clinical effects of micronized
before ovulation trigger could be considered estradiol administered vaginally or orally.
as a second-line option. However, larger Tourgeman D, et al. 1, 2001, Fertil Steril , Vol.
randomized studies evaluating outcomes 75, pp. 200–202.
and optimal timing and dosage for G-CSF 12. Extended estrogen administration for women
administration are needed to further assess with thin endometrium in frozen-thawed in-
its efficacy. vitro fertilization programs. Chen M, et al.
7-8, 2006, J. Assist. Reprod. Genet., Vol. 23, pp.
References 337–342.
13. Effect of adding human chorionic gonadotropin
1. Modern management of thin lining. Mouhayar
to the endometrial preparation protocol in
Y and Sharara F: Middle East Fertility Society
frozen embryo transfer cycles. Eftekhar M,
Journal, 2017, Vol. 22, pp. 1–12.
Rahmani E and Eftekhar T. 3, 2012, Int J Fertil.
2. The use of vaginal ultrasound for monitoring
Steril, Vol. 6, pp. 175–178.
endometrial preparation in a donor oocyte
program. Shapiro H, Cowell C and Casper R: 14. Follicular HCG endometrium priming for
Fertil Steril, 1993, Vol. 59, pp. 1055–1058. IVF patients experiencing resisting thin endo­
3. It’s time to pay attention to the endometrium. metrium. A proof of concept study. Papanikolaou
Casper, RF. 3, 2011, Fertil Steril, Vol. 96, pp. E, et al. 2013, J Assist Reprod Genet, Vol. 30, pp.
519–521. 1341–1345.
4. Ultrasonographic assessment of endometrial 15. Enhancement of embryo developmental
thickness—a review. Persadie RJ. 2002, J potential by a single administration of
Obstetric Gynaecol Canada, Vol. 24, pp. 131–136. GnRH agonist at the time of implantation.
5. Management of thin endometrium in assisted Tesarik, J, Hazout, A and Mendoza, C. 2004,
reproduction: A clinical practice guideline from Human Reproduction, Vol. 19, pp. 1176–
the Canadian Fertility and Andrology Society. 1180.
Liu K, Hartman M and Hartman A. 1, 2019, 16. Luteal phase support with GnRH-a improves
RBMO, Vol. 39, pp. 49–62. implantation and pregnancy rates in IVF cycles
354 Drugs in Obstetrics and Gynecology

with endometrium of < or = 7 mm on day of egg 21. Autologous platelet-rich plasma promotes
retrieval. Qublan, H, et al. 1, 2008, Hum Fertility, endometrial growth and improves pregnancy
Vol. 11, pp. 43–47. outcome during in vitro fertilization. Chang Y,
17. Effect of vaginal sildenafil on the outcome et al. 1, 2015, Int. J. Clin. Exp. Med., Vol. 8, pp.
of in vitro fertilization (IVF) after multiple 1286–1290.
IVF failures attributed to poor endometrial 22. Tre a t m e n t o f t h i n e n d o m e t r i u m w i t h
development. Sher, G. and Fisch, JD. 5, 2002, autologous platelet-rich plasma: A pilot study.
Fertil Steril, Vol. 78, pp. 1073–1076. Zadehmodarres S, et al. 1, 2017, JBRA Assist.
18. Effect of sildenafil citrate on endometrial Reprod, Vol. 21, pp. 54–56.
preparation and outcome of frozen-thawed 23. Embryo transfer strategy and therapeutic options
embryo transfer cycles: a randomized clinical in infertile patients with thin endometrium:
trial. Firouzabadi R, et al. 2013, Iran J Reprod a systematic review. Ranisavljevic N, Raad J,
Med., Vol. 11, pp. 151–158. Anahory T, Grynberg M, Sonigo C. 11, 2019, J
19. Successful treatment of unresponsive thin Assist Reprod Genet., Vol. 36, pp 2217–2231.
endometrium. Gleicher N, Vidali A and Barad 24. David H. Barad, Yao Yu, Vitaly A. Kushnir, Aya
DH. 2011, Fertil Steril , Vol. 95, pp. 13–17. Shohat-Tal, Emanuela Lazzaroni, Ho-Joon Lee,
20. Two protocols to treat thin endometrium with Norbert Gleicher. A randomized clinical trial of
granulocyte colony-stimulating factor during endometrial perfusion with granulocyte colony-
frozen embryo transfer cycles. Xu B, et al. stimulating factor in vitro fertilization cycles:
4, 2015, Reprod Biomed Online, Vol. 30, pp. impact on endometrial thickness and clinical
349–358. pregnancy rates, Fertil Steril. 2014;101(3):710–5.
 43
Ormeloxifene in Mastalgia and
Benign Breast Disorders
• Reshma Jaydeep Palep

Introduction 60 mg oral dose showed a maximum serum

Ormeloxifene has shown a very good role in concentration (Cmax) varying from 117 to
the regression of fibroadenomas instead of 129 ng/ml after 4 hours of the drug being
the most commonly used medicine evening ingested.6 In patients who were given 30 mg
primrose oil (EPO) or surgical removal of tablets, it was shown that Cmax was 30.45 to
lumps, especially in young girls where cosmesis 78.41 ng/ml after 3 to 8 hours.
and damage to lactiferous glands which is a big
concern. It is a safe non-steroidal drug to treat DOSAGE
mastalgia, particularly in comparison to other Patients are given ormeloxifene 30 mg
medicines used at the moment. on alternate days for 3 months for fibro­
adenomas and are called for check-up at
MECHANISM OF ACTION 3 months and 6 months.7
Ormeloxifene (centchroman—C30H35NO3), is For mastalgia, the patients are given
a unique drug first discovered and developed oral ormeloxifene 30 mg twice a week for
by our own Central Drug Research Institute, 3 months.8
Lucknow, India. 1 It is a non-hormonal,
non-steroidal oral contraceptive pill.2 It is a SIDE EFFECTS
selective estrogen receptor modulator (SERM),
Common side effects are nausea, headache,
the mechanism of action is through the
rise in blood pressure, weight gain and
estrogen receptor3,4 with a weak agonist action
delayed or prolonged menstrual period.
on the endometrium and a strong antagonist
In most of the studies for ormeloxifene
action on the breast ductolobular epithelium.5
given for breast lesions, major side effects
Hence, it acts on breast lumps, via the estrogen
requiring the patient to withdraw from the
receptor to cause a regression in the size.2 It
study were not seen. The common side effect
is not Food and Drug Administration (FDA)
was menstrual abnormality, in which the
approved, used only in India, presently.
patients reported missing their menstrual
periods. In some patients, the duration of
PHARMACOKINETICS cycle was also extended, but these normalised
Oral intake is the only route of administration after stopping the medication within 12 weeks
for this drug. Absorption of the drug after a and hence were not a huge concern.9
356 Drugs in Obstetrics and Gynecology

Ormeloxifene does affect the endocrine, side effects, especially ovarian cyst formation
hepatic systems or lipid function. It does in the patients who were put on ormeloxifene
not pose any serious complications like was a bit worrisome.13
thrombosis heart attack or stroke.6,10 In comparison to danazol in the treatment of
It does not affect ovulation, and so there mastalgia, ormeloxifene scores over danazol
is no effect on fertility which can be a major in ameliorating the pain score, reduction was
concern of the patients in the reproductive age seen after 24 weeks of treatment (p = 0.019)
group.11 However it acts as a contraceptive and was hence considered a better, safer and
due to its effect on the endometrium which less expensive solution to danazol devoid of
is reversible.4 major side effects in order to treat patients
with mastalgia.14
CLINICAL APPROACH
Fibroadenomas
Mastalgia
In a randomized controlled trial of 48 patients
The role of ormeloxifene in regression of and 48 controls which was conducted,
mastalgia with or without fibroadenomas it showed that there is regression of
has also been scrutinised in various studies fibroadenoma in 60% of women receiving
so far. Several medicines have been tried ormeloxifene and 30% in the control arm.11
for mastalgia and benign breast disorders. Ultrasound breast was used to measure
There are two categories of medicines which fibroadenoma volume and also estrogen-
can be used for these problems and can be receptor studies were done which showed
classified into hormonal and non-hormonal. that the receptor positivity was 40%. It
Hormonal formulations which have been was also observed that patients who are
used are danazol, tamoxifen, bromocriptine, receptor-negative status also responded to
progesterone, oral contraceptive pills, ormeloxifene. The reason for the response
luteinizing hormone-releasing hormone of the receptor-negative lesions is difficult to
(LHRH) analogue or goserelin. The non- ascertain. It is presumed that the drug may
hormonal formulations include analgesics, be acting through some unknown pathway.11
EPO and gamma linolenic acid (GLA).
In a study conducted at the All India Mastalgia and Fibroadenomas
Institute of Medical Sciences, New Delhi, Ormeloxifene is a good drug to bring about
India it was found that after 3 months of an effective reduction in pain (mastalgia)
treatment with ormeloxifene, 90% patients as well regression in the size of the of
were free of pain.11 Results like these have fibroadenomas. A study that has looked at
made the usage of this drug a big boon to both parameters has found that the visual
young girls, seeking relief from pain. analogue scores (VASs) in mastalgia patients
The drug was found to be more efficacious were decreased to ≤3. They also have noted a
with faster response in patients who had a complete response in 34%, partial dissolution
cyclic pattern of mastalgia. Total relief of pain in 46% and no response in 17%.7
was found in 66% of cyclic mastalgia and 40% A large prospective study of 100 women in
of non-cyclic mastalgia patients after 1 week the reproductive age group (up to 35 years)
of treatment.12 found that ormeloxifene is a unique non-
Another study which compared the steroidal drug and considered to be the
effectiveness of ormeloxifene and tamoxifen pride molecule for India. It has been found
in bringing about pain relief in patients of to be effective in reducing the symptoms
mastalgia, found the results to be similar in of mastalgia as well as helping in reducing
both groups. However, a higher incidence of the size of fibroadenoma within 3 months.
 Ormeloxifene in Mastalgia and Benign Breast Disorders 357

97.6 to 100% of women in mastalgia group were reduced and there was a good response
were found to have complete relief of pain to the treatment.7
which is a tremendous response and 28% of The drug has been found to be of great
fibroadenoma patients reported complete benefit not only in mastalgia, but also in
regression after 3 months of treatment.15 regression of fibroadenomas and fibrocystic
Another prospective clinical study of 142 conditions as well.17
patients over 6 months in all, comprised of
patients who came with the complaints of ANTI-CANCER AGENT
breast symptoms of a lump or pain who The role of ormeloxifene as an anti-cancer
were below 30 years of age. At the end of agent has been established in breast and
3 months, 19 (43.1%) patients had a decrease uterine cancer18,19 due to its strong estrogen
in lump size in the ormeloxifene group antagonistic action.2 Apart from this, similar
whereas in 4 patients (12.5%), a decrement to many SERMs, ormeloxifene also has an
was seen in the placebo group. At the end effect on modulation of other signalling
of 6 months, 23 (52.2%) patients had a pathways which are not dependent on ER
reduction in the size of the lump whereas in expression to regulate the growth of cancer
only 7 (21.8%) patients in the placebo arm cells. This drug has also been studied for
showed a decrease in size. 14 (31.8%) patients its suppressive role in other cancers, like
had complete regression of the lump, as chronic myeloid leukaemia and head and
compared to only 5 (15.6%) patients on the neck squamous cell carcinoma.19 The anti-
placebo arm. Due to a similarity in etiology, cancer activity of ormeloxifene can be further
i.e. hyper responsiveness of the breast tissue improved by encapsulation using hyaluronic
to estrogen, ormeloxifene is considered acid (HA), which improves targeted delivery
to be the best drug in the conservative to a large extent.20
management of benign breast disorders. They
cause a significant reduction in the size of References
the fibroadenoma, nodularity, to the extent 1. Dhar A, Srivastava A. Role of centchroman
that they may regress completely and also in regression of mastalgia and fibroadenoma.
World J Surg. 2007 Jun;31(6):1178–84. doi:
cause amelioration of pain with minimal side
10.1007/s00268-007-9040-4. PMID: 17431715.
effects. It also reduces the risk of surgery and 2. Lal J. Clinical pharmacokinetics and interaction
anaesthesia, avoids bad cosmesis due to scar of centchroman—A mini review. Contraception.
contracture or any damage to the lactiferous 2010;81(4):275–80.
glands. There is no hospitalisation required 3. Lal J, Nitynand S, Asthana OP, Nagaraja NV,
in the treatment.16 Gupta RC. Optimization of contraceptive
In conclusion, ormeloxifene is found to be dosage regimen of Centchroman. Contraception.
2001;63(1):47–51.
better that the drug therapies presently being
4. Makker A, Tandon I, Goel MM, Singh M,
used since it is a nonsteroidal molecule and Singh MM. Effect of ormeloxifene, a selective
hence does not have the steroidal side effects estrogen receptor modulator, on biomarkers
even if used for long-term therapy. It is easy of endometrial receptivity and pinopode
to administer, as long as patients remember to development and its relation to fertility and
take it on alternate days for breast problems infertility in Indian subjects. Fertil Steril. 2009;
and shows good patient compliance. The 91(6):2298–307.
5. N i t y a n a n d S , C h a n d r a w a t i X , S i n g h L ,
significant relief of symptoms in the young
Srivastava JS, Kamboj YR. Clinical evaluation of
patients who are anxious and distressed Centchroman: a new oral contraceptive. In: Puri
due to pain and lumps results in higher CP, Vanlook PF A, editors. Hormone antagonists
satisfaction as well. After 6 months, it was for fertility regulation. Bombay: Indian Soc Study
found that the patients who needed surgeries Reprod Fert, India; 1998. pp. 223–30.
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6. Paliwal JK, Gupta RC, Grover PK, Asthana OP, regression of mastalgia: a randomized controlled
Srivastava JS, Nityanand S. High-performance trial. Int J Surg. 2015 Mar;15:11-6. doi: 10.1016/j.
liquid chromatography (HPLC) determination of ijsu.2014.12.033. Epub 2015 Jan 22. PMID:
centchroman in human serum, and application 25619124.
to single-dose pharmacokinetics. Pharm Res 14. Tejwani PL, Srivastava A, Nerkar H, Dhar
1989;6:1048–51. A, Hari S, Thulkar S, Chumber S, Kumar S.
7. Brahmachari S, Bhagat V, Patil P, Vasuniya V. Centchroman regresses mastalgia: a randomized
Evaluating the Effect of Ormeloxifene on Multiple comparison with danazol. Indian J Surg. 2011
Fibroadenomas and Mastalgia. J Pharm Bioallied Jun;73(3):199-205. doi: 10.1007/s12262-010-
Sci. 2021 Nov;13(Suppl 2):S1386-S1389. doi: 0216-z. Epub 2010 Nov 30. PMID: 22654331;
10.4103/jpbs.jpbs_222_21. Epub 2021 Nov 10. PMCID: PMC3087062.
PMID: 35017994; PMCID: PMC8686955. 15. Gupta N, Malhotra J. A prospective study to
8. Bansal V, Bansal A, Bansal AK. Efficacy of SEVISTA study the efficacy and side effects of ormeloxifene
(Ormeloxifene) in treatment of mastalgia and in regression of mastalgia and fibroadenoma: Is
fibrocystic breast disease. Int J Reprod Contracept it the ideal drug? J SAFOG. 2016;8:48–56.
Obstet Gynecol 2015;4:1057-60. 16. Girish TU et al. Role of ormeloxifene in
9. Santen RJ, Mansel R. Benign breast disorders. N regression of benign breast diseases Int Surg J.
Engl J Med. 2005;353:275–85. 2020 March;7(3):743–750.
10. Sharma B, Narayan S, Sharma N, Parmar A. 17. Kumari V, Rohatgi R. Effect of Ormeloxifene
Centchroman regress mastalgia and fibro­ on Mastalgia and Fibrocystic breast diseases.
adenoma: An institutional study. JMSC. JMSCR Vol 07 Feb;2:981–984.
2016;4:11334–9. 18. Mishra R, Tiwari A, Bhadauria S, Mishra J,
11. Tejwani PL, Nerkar H, Dhar A, Kataria K, Murthy PK, Murthy PS. Therapeutic effect of
Hari S, Thulkar S, Chumber S, Kumar S, centchroman alone and in combination with
Srivastava A. Regression of Fibroadenomas with glycine soya on 7,12-dimethylbenz[alpha]
Centchroman: a Randomized Controlled Trial. anthracene-induced breast tumor in rat. Food
Indian J Surg. 2015 Dec;77(Suppl 2):484-9. doi: Chem Toxicol. 2010;48(6):1587–1591.
10.1007/s12262-013-0886-4. Epub 2013 Feb 21. 19. Gara RK, Sundram V, Chauhan SC, Jaggi
PMID: 26730050; PMCID: PMC4692841. M. Anti-cancer potential of a novel SERM
12. Rathi J, Chawla I, Singh K, Chawla A. ormeloxifene. Curr Med Chem. 2013;20(33):4177-
Centchroman as First-line Treatment for 84. doi: 10.2174/09298673113209990197. PMID:
Mastalgia: Results of an Open-label, Single-arm 23895678; PMCID: PMC4030721.
Trial. Breast J. 2016 Jul;22(4):407-12. doi: 10.1111/ 20. Kumar A, Lakshmi S, Rosemary MJ. Ormelo­
tbj.12593. Epub 2016 Apr 5. PMID: 27059808.. xifene-Hyaluronic acid microfibers for breast
13. Jain BK, Bansal A, Choudhary D, Garg PK, cancer therapy. Materials Today: Vol 45;
Mohanty D. Centchroman vs tamoxifen for 3;2021,3800–3804.
 44
Pharmacotherapy in
Endometriosis
• Mamta Gupta

Introduction Pain usually precedes the onset of menses

Growth of endometrial tissue outside the and lasts for the duration of the cycle. Other
uterus is termed endometriosis. The condition symptoms include fatigue, infertility and heavy
is estrogen-dependent and about 10% of menstrual bleeding. Non-gynaecological cyclic
females of reproductive age are affected.1 symptoms can occur, including dyschezia,
Endometriosis is diagnosed in 21–47% in dysuria, urinary frequency, abdominal
women with subfertility and 71–87% of women bloating, nausea, and vomiting and inguinal
with chronic pelvic pain. 2 Endometriosis pain. One-third women will have no symptoms
occurs rarely in postmeno­pausal women.3 (asymptomatic).1
It is considered a benign disorder, yet, Diagnosis of endometriosis is predomi­
endometriosis can affect the patient’s quality- nantly clinical, but the definite diagnosis is
of-life. Sampson hypothesized retrograde usually confirmed by surgery and suspicious
flow of sloughed endometrial cells into the lesions biopsied for histology.
pelvic cavity from the fallopian tubes and There is currently no cure for endometriosis.
subsequent implantation onto the peritoneum, The goals of endometriosis treatment may
results in the growth of endometriotic lesions. include symptom relief and/or enhancement
These lesions have the same steroid receptors of fertility by medications and/or surgery
as normal endometrium. Microscopic internal depending on the following:
bleeding, inflammation, neovascularization, • Age
and fibrosis also do occur.4 These ectopic • Current symptoms and their severity
implants are located in the pelvis, i.e. ovaries, • Severity of the disease
fallopian tubes, vagina, cervix, or uterosacral • Desire for children
ligaments or rectovaginal septum. More • Tolerance to various medications, proce-
unusual implantation sites are scars, pleura, dures and therapies
spleen, gallbladder, spinal canal, stomach, Long-term and repeated treatment is
etc.5,6 required in most of the cases. Also, symptoms
of endometriosis may return after the
Symptoms treatment is stopped or, in the case of surgery,
Pelvic pain in the form of dysmenorrhea, as more time passes after the procedure.
deep dyspareunia, non-cyclical chronic pelvic Treatment is not required in women with
pain, lower abdominal pain and back pain.7 no fertility problems without or with minimal
360 Drugs in Obstetrics and Gynecology

symptoms. However, during follow-up, if (and possibly diclofenac, tolfenamic acid

symptoms arise or get worsen appropriate and fenbufen) which undergoes hydrolysis
treatment is required. to form salicylic acid. NSAIDs, if given
with food or antacids may lead to delayed
Rationale of Conventional or reduced absorption. Immediate-release
Pharmacotherapy in Endometriosis tablets (such as diclofenac potassium), are
Endometriosis depends on the woman’s cyclic more rapidly absorbed compared with
production of menstrual cycle hormones extended-release formulations. NSAIDs are
and provides the basis for medical therapy. highly bound to plasma proteins (mainly
Thus, combined oral contraceptive pills albumin), with low levels of distribution
(COCPs), danazol, progestational agents, and in the extracellular spaces. The elimination
gonadotropin-releasing hormone (GnRH) of these drugs depends largely on hepatic
analogues, androgens hormones interrupt metabolism; renal excretion of unchanged
the normal cyclic production of reproductive drugs is usually small.
hormones and form the mainstay of
treatment. Aromatase inhibitors can be used Mechanism of Action
for refractory or recurrent endometriosis. The main mechanism of action of NSAID is
Medical treatment of minimal or mild the inhibition of the enzyme cyclooxygenase-1
endometriosis has not been shown to increase (COX-1) and/or cyclo-oxygenase-2 (COX-2)
pregnancy rates8 and no benefit is derived required to convert arachidonic acid into
from ovulation suppression in subfertile prostaglandins (PGs).10 PGs decrease the
women with endometriosis who wish to threshold to noxious stimuli. In soft tissues,
conceive. Moderate-to-severe endometriosis prostaglandin E2 (PGE2) causes pain and
should be treated surgically.9 inflammation.
Medical treatment is indicated for relief COX-1 is expressed in all tissues and
of pain, to slow the growth of endometriosis ensures gastric mucosal integrity. COX-2 is
lesions, to stop recurrence of disease. not expressed in tissues; but its expression is
Various options for medical management induced during an inflammatory response.
of endometriosis include non-steroidal anti NSAIDs are inhibitors of COX-activity
inflammatory drugs (NSAIDs), hormones, and either selectively inhibit the COX-2
gonadotropin analogues and aromatase enzymes or nonselectively inhibit both the
inhibitors. Some newer drugs which are COX-1 and the COX-2 enzymes, making
still under trial, might contribute to the the nonselective NSAIDs a higher risk for
management of endometriosis. ulcerogenic and other adverse effects. 11
Most commonly used NSAIDs inhibit both
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS COX-1 and COX-2. However, COX-2
NSAIDs, such as ibuprofen or naproxen selective NSAIDs (e.g. celecoxib) only target
sodium to help relieve pelvic pain and COX-2 and provide anti-inflammatory
menstrual cramping. No effect on endometrial relief without compromising the gastric
implants or progression of endometriosis has mucosa.11
been observed with NSAIDs. NSAIDs have a favourable effect in women
NSAIDs are used as first line of drugs with with primary dysmenorrhea. Although
or without oral contraceptives or progestins. endometriosis is a condition of secondary
dysmenorrhea, it seems reasonable to
Pharmacokinetics consider NSAIDs as a first-line treatment
NSAIDs are well-absorbed from the gastro­ in women with suspected endometriosis-
intestinal tract, with the exception of aspirin associated pain.12
 Pharmacotherapy in Endometriosis 361

Dosage (Table 44.1) • Gastric adverse effects are more likely

Start before the start of menstruation in order in a patient that has a prior history of
to block the endometriosis-associated PG peptic ulcers. Since it is COX-1 specific,
formation that leads to pain and swelling. COX-2 selective NSAID is an alternative.15
Because of the variability in interindividual NSAIDs should be administered with
response, if the first NSAID is not effective, plenty of water and on a full stomach to
another NSAID should be tried. No NSAID protect the gastrointestinal tract from the
has been found to be superior to another. loss of cytoprotective PGE2. Women having
If they are effective in controlling the pain, history of gastric irritation, ulceration, and
no other procedure or medical treatment is bleeding should avoid COX-1 inhibitors.
• Renal adverse effects does not pose a large
needed. If not, then NSAID may be combined
problem, in a patient with normal renal
with a hormonal preparation.
function. However, in a patient with renal
dysfunction or when give on chronic
Adverse Effects of NSAIDs basis, renal injury can occur. This can
NSAIDs may have different safety profile lead to acute renal dysfunction, fluid and
according to inhibition of COX-1 or 2 or both. electrolyte disorders.16 NSAIDs should not
COX-1 inhibition may cause gastric ulcer and be administered on a chronic basis as renal
gastrointestinal (GI) bleeding. COX-1 and 2 injury can result.
inhibition may cause Na and K retention, • Cardiovascular adverse effects can be increased
hypertension and hemodynamic kidney with NSAID use; these include myocardial
injury. COX-2 > COX-1 inhibition may cause infarction (MI), thromboembolic events,
myocardial infarction and stroke because of and atrial fibrillation. Diclofenac seems to
increased risk due to platelet aggregation and be the NSAID with the highest reported
vasoconstriction. increase in adverse cardiovascular events.17

Table 44.1: Commonly used NSAIDs used and their dosage13,14

Drug COX-2 selectivity Tablet amount Dose and Upper daily limit
frequency
Ibuprofen Moderate 200 mg 1 tab, 4–6 hrly 1200 mg
Ketoprofen Low 50 mg 1 tab, 6 hrly 300 mg
Naproxen Low 220 mg 1 tab, 8–12 hrly 660 mg
Aspirin (acetyl salicylic acid), Low 80 mg 4–6 tab, 4000 mg
low dose 4–6 hrly
Aspirin, regular strength Low 325 mg 1–2 tabs, 4 hrly 4000 mg
Aspirin, extra strength Low 500 mg 1–2 tabs, 6 hrly 4000 mg
Acetaminophen (paracetamol), High 325 mg 2 tabs, 4–6 hrly 4000 mg
regular strength
Acetaminophen, extra strength High 500 mg 1–2 tab, 6hrly 4000 mg
Acetaminophen, extended High 650 mg 1–2 tabs, 8hrly 4000 mg
release
Diclofenac High 50 mg 1 tab, 8 hrly 200 mg
Diclofenac High 100 mg 1 tab, 12 hrly 200 mg
Celexocib High 200 mg 1 tab, daily 400 mg
362 Drugs in Obstetrics and Gynecology

• Hepatic adverse effects are less common; on fetal kidney. They are also linked with
Among the various NSAIDs, diclofenac premature births and miscarriage.
has a higher rate of hepatotoxic effects.18 Aspirin, together with heparin is used
• Hematologic adverse effects can occur, in pregnant woman with antiphospholipid
particularly with nonselective NSAIDs syndrome. Indomethacin is used in
due to their antiplatelet activity. This polyhydramnios as it reduces fetal urine
effect poses a problem if the patient production due to inhibition of fetal kidney
has history of GI ulcers, diseases that blood flow. Paracetamol (acetaminophen) is
impair platelet activity (hemophilia, safe and well-tolerated during pregnancy.
thrombocytopenia, von Willebrand, etc.),
and in some perioperative cases.19 ORAL CONTRACEPTIVE PILLS
• Other minor adverse effects include There are epidemiological evidence that
anaphylactoid reactions that involve the women using of combined oral contraceptives
skin and pulmonary systems, like urticaria (COCs) have reduced incidence of endo­
and aspirin-exacerbated respiratory metriosis.23 COCs have been shown to be
disease.20,21 NSAIDs may inhibit ovulation effective in treating pain in women with
which is reversible after stopping its endometriosis.24 They can be used as first-line
use. This may be of concern in a woman therapy for endometriosis with or without
wanting to conceive. The inhibition is more NSAIDs.
with diclofenac and less for naproxen.22
Mechanism of Action
Contraindications They reduce menstrual flow and cause
NSAID hypersensitivity or salicylate hyper­ decidualisation of endometriotic implants.
sensitivity, peptic ulcer/GI bleed, kidney They decrease cell proliferation and increase
disease, inflammatory bowel disease, apoptosis leading to decreased pain and
congestive heart failure, brain stroke (except scarring associated with endometriosis.
aspirin), myocardial infarction (except aspirin), Empirical treatment, with COC, without first
coronary artery disease, who have undergone performing a diagnostic laparoscopy can be
gastric by-pass surgery or coronary artery by- given to treat pain symptoms suggestive of
pass graft surgery. endometriosis.25
They can be taken for long-term during
Drug interactions: NSAIDs decrease efficacy
reproductive life and are generally safe, well-
of diuretics, and inhibit elimination of lithium
tolerated and acceptable by most women. It
and methotrexate, increases risk of bleeding
also decreases the number of bleeding days
with warfarin. NSAIDs may aggravate
and dysmenorrhea.
hypertension and antagonizes the effect of
Low-dose, monophasic combined oral
antihypertensives, i.e. angiotensin-converting
contraceptive pills (COCPs) are often used in
enzyme (ACE) inhibitors. NSAIDs, when
clinical practice. COCs that use high-dose of
used in combination with selective serotonin
progestin are the most effective for alleviating
reuptake inhibitors (SSRIs), reduce efficacy
the symptoms of endometriosis.
of SSRIs and increase the risk of adverse GI
effects. COC Regimes for Endometriosis
Use in pregnancy: NSAIDs are not recommended COCs can be used in a cyclic, long cyclic or
in pregnancy, especially in third trimester. continuous manner. Previously, cyclic use
Though NSAIDs are not direct teratogens, of COCs as for contraception was common.
they may cause premature closure of fetal However, COCs in extended regimes (long-
ductus arteriosus and have adverse effect cycle, continuous) are one of the safest,
 Pharmacotherapy in Endometriosis 363

cheapest, most practical and recommended • History of thromboembolism or pulmonary

methods to suppress menstruation, alleviate embolism,
endometriosis-related symptoms and • Cerebrovascular accident,
probably avoid endometriosis progression.26 • Familial factor V Leiden,
Studies have shown that 3 out of 4 women • History of migraine with aura, women
with endometriosis have reduced pain after who smoke, age >35 years, advanced
COCs.27 A trial of cyclic or long-cyclic COC diabetes,
should be administered for 3 months. If pain • Liver tumors,
is relieved, the treatment is continued for • Hepatic adenoma or severe cirrhosis of
6–12 months. the liver,
Other Routes for Administration of • Suspected breast cancer,
Combined Hormones • Endometrial cancer,
Estrogen–progestin hormones can also be • Unexplained uterine bleeding.
delivered by a vaginal contraceptive ring
Pregnancy
(Nuvaring) or a skin patch (Ortho Evra)
that lasts for a week. Vaginal ring releasing Postpartum breastfeeding women are also
15 mg of ethinyl estradiol (EE) and 120 mg of advised not to start COCPs until 4 weeks.
etonogestrel, was compared with patch which
Interactions
released 20 mg EE and 150 mg norelgestromin
daily. When used continuously both were After absorption, EE undergoes metabolism
associated with poor control of bleeding. in the liver by CYP enzyme, as it metabolizes
Regarding pain symptoms ring was found many drugs.
to be better than patch.28 CYP inhibitors: CYP inhibition occurs
within 48 hours and can increase drug
Postoperative Use of COCs concentrations and vascular complications
It can be effective in prevention of recurrence with increased EE levels. Macrolides except
after conservative surgery for endometriosis. azithromycin, azoles, potentially increase the
Continuous and cyclic oral-contraceptive pills risk of adverse effects of EE, such as vascular
both have comparable effects. The protective disease complications because of increased
effect, however, seems to be associated with EE plasma concentration. CYP inducers may
the duration of treatment.29 take up to 3 weeks, resulting in decreased
In women with infertility with minimal to drug concentrations. Hence, short-term use of
mild endometriosis suppression of ovarian CYP inducers generally will not have clinical
function by COCs is not effective and should significance. After the discontinuation of a
not be given for this indication alone.30 CYP inducer, the induction may take several
Breakthrough bleeding: The most frequently weeks to subside, e.g. antimycobacterials,
encountered problem is unscheduled anti­r etrovirals, anticonvulsants (except
‘breakthrough’ bleeding or spotting, which lamotrigine). These drugs may cause break-
usually becomes less frequent, the longer the through bleeding and increased risk of
hormone treatment is taken. Taking the pill pregnancy. Hence, women need a backup
at same time a day and avoiding missed pills method of contraception for 6 weeks after
will help to prevent breakthrough bleeding. discontinuing rifampin.31

Contraindications PROGESTOGENS
• Hypertension, They are appropriate for patients who do not
• Pre-existing cardiovascular disease, respond to COCs or have a contraindication
364 Drugs in Obstetrics and Gynecology

to use estrogen–progestin contraceptives. Routes of Administration

Progestins are used as a first-line hormonal Progestogens can be used to treat endo­metriosis
therapy for endometriosis-related pain, by various routes, including oral, injections,
effects of progestins are comparable to other subdermal implants and intrauterine system.
treatment options. Choice of progestogen-medroxy­proges­
terone acetate (provera), norethindrone
Mechanism of Action
acetate, and norgestrel acetate, are more
The suggested mechanisms of progestins potent progestins and are recommended in
in resolving endometriosis-related pain are endometriosis management.
summarized as:32,33
Dienogest (DNG), a newer progestin has
• Ovarian suppression. gain popularity in medical management of
• Effects on endometrial morphology endometriosis. Long-acting progestin-only
(decidualization, atrophy and alteration in contraceptive methods, may also be useful
steroid-receptor–ligand binding). in treating endometriosis, i.e. injectable
• Local modulation of immune reaction medroxyprogesterone (Depo-provera) and
[suppression of interleukin (IL) 8 produc­ levonorgestrel intrauterine device (mirena).
tion, increase of nitric oxide production,
reduction of tumor necrosis factor-a Dose
(TNF-a) induced nuclear factor-χ-β].
• Suppression of the matrix metallo­ Refer Table 44.2 for dosages. Treatment
proteinases, which enable the implantation should be continuous and therefore, the dose
and progression of ectopic endometriotic has to be adapted individually in such a way
implants. that amenorrhea is acheived. This is essential
• Inhibition of the proliferation of endo­ for elimination of pain symptoms, and also
metrial stromal cells. to prevent progression of endometriosis and
presumably to attain regression.
• Angiogenesis [suppression of transcription
of basic fimbroblast growth factor (bFGF), Medroxyprogesterone acetate: It is effective
suppression of vascular endothelial growth in endometriosis-related pain suppression
factor (VEGF) and cysteine rich angio­genic in both the oral and injectable depot
inducer (CYR61)]. preparations. Breakthrough bleeding can
• Progesterone receptor expression and occur with prolonged use.
progesterone resistance.
Depot medroxyprogesterone acetate (DMPA)
• Direct effect on nerve fibers. Progestins and
reduces endometriosis-associated pain as
COCs were found to decrease nerve fiber
effectively as leuprolide with significantly
density and nerve growth factor receptor
less bone-mineral density (BMD) decline.35
p75 expression in peritoneal endometriotic
Time for resumption of ovulation is longer.
lesions.34
Common indications of DMPA is residual
When taken for a long-term continuously,
endometrosis after hysterectomy when future
progestogens tend to thin the endometrium
fertility and irregular bleeding are not the
causing amenorrhoea and has similar activity
concerns. When used long-term DMPA is
against endometriosis lesions, resulting in
detrimental to BMD.
their regression. Amenorrhoea induced by
high doses of progestins can last many months Norethindrone (norethisterone) acetate is a
after stopping therapy, hence, these drugs commonly used C-19 nortesterone derivative.
are not recommended for women planning It should be continued for 6 to 9 months
pregnancy immediately following cessation or until the occurrence of breakthrough
of therapy. bleeding.
 Pharmacotherapy in Endometriosis 365

Table 44.2: Various progestogens used in endometriosis

S. No. Name of progestin Route of Dosage Comment
administration
1. Norethindrone acetate Oral 2.5–5 mg, daily Approved by US-FDA for
(2.5 mg) endometriosis
2. Medroxyprogesterone Oral 10–40 mg, daily
acetate
3. Megestrol acetate Oral 40 mg, daily
4. Cyproterone acetate Oral 10–12.5 mg, daily Side effects limit its use
5. Depot medroxy- Intramuscular 150 mg, 3 monthly
progesterone acetate
6. Depot mdroxy- Subcutaneous 104 mg, 3 monthly Approved by US-FDA
progesterone acetate for endometriosis
7. LNG intrauterine device Intrauterine device 52 mg, releases 20 μg Effective for 5 years
LNG daily
8. Etonogestrel Subdermal implant 68 mg in single rod Effective for 3 years
9. Dienogest Oral 2 mg, daily Approved by
European union
LNG: Levonorgestrel; US-FDA: United States Food and Drug Administration

Megestrol acetate has been also used with Safety profile of DNG: DNG, 2 mg is well-
similar good results.36 tolerated, with a favorable safety profile
even after administration of dienogest for
Cyproterone acetate (CPA) is a C-21-
up to 5 years. A progressive decrease in
progestogen derivative. It is an anti-androgen
adverse effects and bleeding irregularities
with weak progestational activity. Continuous
occur with low discontinuation rates. The
administration has been found comparable
most commonly reported adverse events
to oral contraceptive (desogestrel and
are headache, breast discomfort, depressed
ethinyl estradiol) when used for 6 months in
mood, and acne, each occurring in <10%
treatment of endometriosis in terms of pain
of patients, which were generally mild-to-
and quality-of-life.37 The main drawback
moderate in intensity.
depression, decreased libido, hot flushes and
• BMD: A small decrease of 0.5% to 2.7%
vaginal dryness limits its generalized use.
BMD in the lumbar spine after 1 year of
DNG is a C-19-nortestosterone progestogen DNG use has been observed in 20–75% of
derivative. It has an antiandro­genic and a weak study populations with partially recovery
antigonadotropic action. It also has a local by 6 months after stopping treatment.
antiproliferative and anti-inflammatory effect Changes in BMD should not prevent
on endometriotic lesions. It is well- tolerated. long-term use of dienogest in women
A favorable efficacy and safety profile has with endometriosis. Women already
been observed with long-term dienogest use, predisposed to osteoporosis, i.e. chronic
in terms of progressive decreases in pain steroid use, previous fragility fractures,
and bleeding. The decrease of pelvic pain smoking, and malabsorption conditions
persists for at least 24 weeks after stopping should be advised about the risks of
treatment.38 decreased BMD.
366 Drugs in Obstetrics and Gynecology

• Bleeding irregularities: Treatment with formulations because there is no repeated

dienogest, 2 mg, as with other progestins, administration.
leads to endometrial regression and Adverse effects of progestogens include
bleeding irregularities. Initial bleeding weight gain, fluid retention, breast tenderness,
during the first 3 months occurs in 80% depression, and breakthrough bleeding.
patients,39 typically lasting for 8–10 days, Irregular or unscheduled ‘breakthrough’
with decrease in intensity and frequency bleeding usually becomes less frequent the
over time. In addition, spotting can occur longer the medication is used.
with long-term dienogest treatment. Because a chronic disease needs a long-
Patients should be counselled for possible term or intermittently repeated medication
bleeding. clinicians should take the different side-effect
Initial irregular bleeding may be reduced profiles of progestagens into account when
by a regimen involving gonadotropin- prescribing these drugs.
releasing hormone followed by long-term Further studies are necessary to clarify
dienogest therapy. Furthermore, initiation the length of treatment, type of progestin,
of dienogest 2 mg at the onset of menses dosage used, intermittent medication and
may also decrease initial bleeding. Bleeding combinations with other drugs, effective in
that occurs during long-term treatment the reduction of endometriosis.
is typically spotting. If the sonographic
endometrium thickness is low, management GnRH AGONISTS
can include a treatment break of 5–7 days Mechanism of Action
to allow for the recovery of the atrophic
The GnRH analogues cause constant
endometrium, or a short-term use of 1 mg
stimulation of the pituitary receptors, leading
oral or transdermal estradiol (5–7 days). If
to downregulation and eventual suspension
abnormal uterine bleeding persists, further
of follicle-stimulating hormone (FSH) and
investigations are required for other uterine
luteinizing hormone (LH) secretion and
pathologies beyond endometriosis.
hypoestrogenic state. Because endometrial
Subdermal implants: Etonogestrel contra­ implants are dependent on estrogen
ceptive implant/implanon—68 mg in single stimulation, they regress. GnRH agonists
rod with a life span of 3 years, have been also enhance apoptosis and decrease cellular
found to be equally effective compared with proliferation in the endometrial cells.
DMPA in pain relief in 12 months use.40 It The initial surge of LH and FSH may
is a safe, well-tolerated for the treatment exacerbate endometriosis pain because of the
of endometriosis and achieving long-term ovarian stimulation. However, 2 weeks after
contraception. initiation of therapy, an estrogen-deficient
Levonorgestrel-releasing intrauterine state occurs. Women should be counselled
system (LNG-IUS) has been shown to about ‘flare up’ of symptoms and irregular
reduce endometriosis-associated pain. Main bleeding shortly after they receive their first
advantages of the vaginal route include dose of medication. Later, low estrogen levels
avoidance of the hepatic-first pass metabolic may contribute to hot flashes and cessation of
effect, use of lower therapeutic doses and periods and other symptoms. GnRH therapy
reduced systemic side effects compared to offers high rates of pain relief in 85–100% of
oral administration. When inserted at the time women and longer symptom-free period for
of laparoscopic surgery, it has been found up to 12 months.41 Combined with surgery
to reduce the recurrence of dysmenorrhea (given perioperatively), a higher cure rate
by 35%. This device has improved patient and lower rate of recurrence is seen. Though
compliance over the once-daily oral progestin fertility rates may show no improvement.
 Pharmacotherapy in Endometriosis 367

Table 44.3: Dosage of GnRH agonists used for endometriosis

Name of GnRH agonist Dose Route
Leuprolide acetate 3.75 mg, monthly Injectable SC/IM
11.75 mg, every 3 months Injectable SC/IM
Goserelin 3.6 mg, every 28 days SC Injectable implant
10.8 mg, every 3 months SC injectable implant
Triptorelin 3.75 mg, every 4 weeks Intramuscular
Buserelin 2 sprays in each nostril
8 hourly (total 900 mg daily)
Nasal spray 1 mg/ml
200–500 mg daily Subcutaneous injection
Nafarelin One spray into one nostril in morning, and one spray Nasal spray as 2 mg/ml
into other nostril in evening daily (total 400 mg daily).
May increase to 1 spray in each nostril, twice daily
SC: Subcutaneous; IM: Intramuscular

Dosage low-dose estrogen or a combination of

For dosage of commonly used GnRH agonists estrogen and progestin have also been used.47
refer to Table 44.3. The combination of GnRH agonists and
norethindrone acetate use is approved only
Adverse Effects for 12 months.
Secondary to hypoestrogenism, like bone
Limitation
loss, vaginal atrophy and dryness, hot
flashes and abnormalities in lipid profile are GnRH-agonist therapy can be used only for 6
encountered.42 Accelerated bone loss can months or 12 months with add-back therapy.
occur in patients treated long-term with these As they suppress ovulation, therefore,
agents. Six-months duration is the maximum GnRHa cannot be used in women desiring
duration. Loss of trabecular bone density fertility.
caused by GnRH is restored by 2 years after
cessation of therapy.43 Careful consideration GnRH ANTAGONISTS
in young women and adolescents, since these GnRH antagonists are being studied as
women may not have reached maximum possible management option for endo­
bone density. metriosis. These drugs differ from GnRH
agonists in that instead of downregulation,
Add-back Therapy there is a competitive blockade at the
Prevents osteoporosis and hypoestrogenic pituitary GnRH receptor. Gonadotropins
symptoms. Hormone replacement therapy are suppressed without the initial flare of
preparations, progestins, tibolone maleate, estrogen.48 This suppression of gonadotropins
and bisphosphonates have all been shown and estrogens is dose-dependent. This inhibits
to be effective.44–46 It prevents loss of bone endometriotic cell proliferation and invasion
density and helps to reduce vasomotor while maintaining sufficient circulating
symptoms without reducing the efficacy of estradiol levels to avoid vasomotor symptoms,
GnRH. Norethindrone acetate, a progestin vaginal atrophy, and bone demineralization.
is the only Food and Drug Administration GnRH antagonists are available as injectables
(FDA) approved add-back therapy, but (ganirelix, cetrorelix) and increasingly as oral
368 Drugs in Obstetrics and Gynecology

nonpeptide forms (elagolix, abarelix, ozarelix, Cetrorelix: Administration of 3 mg weekly

TAK-385). dose of cetrorelix for 8 weeks can be a feasible
Elagolix is an oral GnRH-receptor anta­ medical option for endometriotic pain. In a
gonist, approved by the FDA in July 2018 study, it was reported that all women (100%)
for management of moderate-to-severe had pain-free period during treatment with
pain associated with endometriosis. A dose- cetrorelix.48
dependent improvement of dysmenorrhea is
reported. Improvement in noncyclic pelvic Adverse Effects
pain was also found to be significant.49 GnRH antagonists—hypoestrogenic adverse
Elagolix may be considered for pre­meno­ effects include hot flushes, elevated serum
pausal women with very severe endometriosis lipids. Decreases in bone mineral density
associated pain and/or severe endometriosis- is more compared to placebo treatment but
related dyspareunia, who have not responded less compared to GnRH agonists. Frequency
to or have intolerable side effects with first-line of hot flushes with elagolix was found to be
treatments (e.g. NSAIDs, combined hormonal lower than that with leuprolide acetate.
contraceptives, and progestins), and in whom
other causes of pelvic pain have been ruled AROMATASE INHIBITORS (AIs)
out. It may also be an appropriate first-line
A more current approach to the treatment of
therapy for those with a history of side effect endometriosis has involved the administration
from contraceptive agents.50 of drugs known as aromatase inhibitors, e.g.
Treatment with elagolix should be initiated anastrozole and letrozole.
at the lowest effective dose starting from
150 mg once daily. Elagolix 200 mg twice Mechanism of Action
daily is recommended for patients in whom
Estrogen is the major biochemical driving
dyspareunia is the main symptom and may
force for endometriotic implant growth.
be considered for patients with severe non-
Besides ovaries, evidences indicate the
menstrual pelvic pain. Subsequent transition
expression of P450 aromatase enzyme
to 150 mg once-daily dose can be done.
by endometriotic implants which are an
intracrine source of estrogen.51 This enzyme is
Contraindications involved in the conversion of androstenedione
Elagolix is not recommended for patients with to estrone and testosterone to estradiol (E2).
a history of nonresponse to GnRH agonists or As a result, emphasis has been placed upon
antagonists, and is contraindicated in women the use of aromatase inhibitors (AIs) to curtail
who are pregnant, have known osteoporosis, production of estrogen by endometriotic
or have severe hepatic impairment. implants and subsequent implant growth.
Advantages for elagolix are convenient These drugs act by inhibiting local estrogen
oral therapy, immediate suppression of formation within the endometriosis implants.
pituitary gonadotrophs, avoiding the initial They also inhibit estrogen production within
1–2 week flare-up effect of GnRH agonists, the ovary and adipose tissue.
dosage can be individualized according to The most potent, selective, and reversible
symptom severity. Vasomotor symptoms are the third-generation AIs, which are
are mild-to-moderate and not as severe as commonly used, e.g. letrozole and anastrozole.
seen with GnRH-agonist treatment. Further The third-generation AIs decrease serum
studies are needed to determine if add-back 17β-estradiol by 97–99% as early as 24 hours
therapy might help to alleviate mild-to- after dosing. They also increase FSH levels in
moderate hypoestrogenic side effects. premenopausal women.
 Pharmacotherapy in Endometriosis 369

AIs in Pre-menopausal Endometriosis been used in recurrent severe endometriosis

Standard management, such as GnRH after hysterectomy and bilateral salpingo-
analogues, which effectively downregulates oophorectomy, resulting in a significant
ovarian E 2 (estradiol) biosynthesis, has reduction in pelvic pain and lesion size.
little impact on extraovarian E2 production.
However, AIs downregulate extraovarian E2 Aromatase Inhibitors in the Treatment of
synthesis, which in turn stimulates ovarian Infertility Caused by Endometriosis
E2 production through initiation of the FSH In infertility caused by endometriosis,
surge. Accordingly, AIs are combined with medical treatment with hormones is not
standard regimes to suppress both ovarian effective and not indicated. It has been
and extraovarian E2. observed that intrauterine insemination (IUI)
AIs have been beneficial and effective ther- with controlled ovarian stimulation (without
apy for premenopausal patients with chronic surgery or within 6 months of surgery) may
pelvic pain, after prior conservative surgery, be effective in patients with mild-to-moderate
used for 3 to 6 months whether given alone endometriosis.54,55 Letrozole is administered
or in combination with oral contracep­tives/ at a dose of 2.5–7.5 mg/day on days 3–7 of
progestins/GnRH. It has also been used in the menstrual cycle for ovulation induction.
ovarian endometriosis, i.e. bladder endome- Compared to clomiphene, letrozole inhibits
triosis, colorectal endometriosis with good re- oestradiol synthesis rather than its oestrogenic
sults. Use of postoperative AIs with GnRHa for activity and has no anti-oestrogenic effect on
6 months reduced the risk of recurrence of cervical mucus or endometrium.
endometriosis when compared with GnRHa
alone.52 Dosage: Letrozole—2.5 mg/day for 3–6
AIs should only be administered to patients months; anastrozole—1 mg/day for 3–6
who failed to respond to conventional months.
therapies (such as progestins and/or oral Side effects of the third-generation
contra­ceptives) and do not want surgical AIs include vaginal dryness, hot flushes,
removal of disease. headache, back pain, numbness in lower
extremities, and arthralgia, irregular
AIs in Postmenopausal Endometriosis bleeding.56 Its long-term use is associated with
Aromatase inhibitors (AI) are being considered increased risks of osteoporosis and fracture
as potential treatments for postmenopausal rate owing to diminished BMD.57 For these
endometriosis as most of the body’s estrogen is reasons, aromatase inhibitors and may be
produced outside the ovaries after menopause given concurrently with combined estrogen-
which is suppressed by AIs. progestin contraceptives or progestins for
The incidence rate of endometriosis is management of endometriosis. Also, vitamin
2–5% in postmenopausal women. Surgery is D or bisphosphonates are sometimes added
preferred over non-surgical treatment in these to AI therapy.
patients due to the risk of cancer development. Long-term monotherapy with aromatase
However, recurrence of endometriosis even inhibitors when given to reproductive-age
after surgery can occur. Moreover, all older women will cause increased FSH levels and
patients are not eligible for surgery. In these subsequent superovulation, resulting in
women with endometriosis, treatment with ovarian cyst development due to the initial
letrozole and anastrozole for 4–15 months FSH rise.
reduced pain.53 Letrozole also decreased Treatment of endometriosis by AIs is
urinary and gastrointestinal tract symptoms reserved for severe, intractable endometriosis-
associated with endometriosis. AIs have associated pain in combination therapy with
370 Drugs in Obstetrics and Gynecology

Table 44.4: Medical options priority-wise for various symptoms related to endometriosis
Medication Indication Priority Adverse effects
NSAIDs Dysmenorrhea First Nausea, vomiting, GI irritation, vertigo
COCs
COCs Dysmenorrhea First Nausea, weight gain, water retention,
cyclic depression, breast tenderness, headache,
intercyclic bleeding, decreased menstrual
bleeding
COCs Dysmenorrhea, non-cyclic First or Nausea, weight gain, water retention,
continuous chronic pelvic pain second breast tenderness, headache, amenorrhea,
breakthrough bleeding
Progestins
MPA, NETA Dysmenorrhea, non-cyclic First or Nausea, weight gain, water retention,
DNG, CPA chronic pelvic pain second breast tenderness, headache, amenorrhea,
breakthrough bleeding, delay in regulation
of menstrual pattern
LNG-IUS Dysmenorrhea, dysparunia, Second or Bloating, weight gain, headache, breast
recto-vaginal endometriosis third tenderness
GnRH Dysmenorrhea, dysparunia, Second or Hypoestrogenism (hot flushes, vaginal
agonists third dryness, irritability), decreased BMD
*Aromatase Dysmenorrhea, non-cyclic Third Hypoestrogenism (hot flushes, vaginal
inhibitors chronic pelvic pain dryness, irritability), ovulation induction
Danazol Dysmenorrhea, non-cyclic Second or Hyperandrogenism (acne, edema, decrease
chronic pelvic pain third in breast size)
*Aromatase inhibitors should be combined with COCs or GnRHa.

oral contraceptive pills, progestins, and is lipophilic and hence has the potential to
GnRH analogues. penetrate deep tissue compartments. Danazol
is extensively metabolized in the liver to
DANAZOL 2-hydroxymethyl ethisterone. It is mainly
This agent is a synthetic androgen with excreted in the urine, and a small amount is
minimal estrogen or progesterone potential. excreted in the feces.The half-life of danazol
has been reported to be at a mean of 9.7 hours.
Mechanism of Action It is quite extensively studied agent used
Drug acts by inhibiting gonadotropin for endometriosis. Pain relief and shrinkage
secretion and inhibiting steroidogenic of endometriosis implants occur in 80%
enzymes in ovary, preventing midcycle FSH women using danazol.
and LH surge and interfering with ovulation
and ovarian production of estrogen.58 Dose
Danazol is administered orally in divided
Pharmacokinetics doses ranging from 400 mg to 800 mg daily
Danazol is well-absorbed from the gastro­ for 6 to 9 months in mild cases; severe cases
intestinal system. Peak plasma concentration may require 800 mg per day in two divided
of danazol is reached within 2 to 8 hours post- doses. However, smaller doses have been
oral administration of 400 mg tablet. Danazol used with success.59,60 In a small study of
 Pharmacotherapy in Endometriosis 371

Flowchart 44.1: Algorithm for management of endometriosis

21 patients, vaginal danazol (200 mg/d) Pregnancy: Danazol should not be used in
was successful in relieving endometriosis- pregnancy. While on danazol therapy, due to
associated pain.61 possibility of virilizing changes in a female
fetus, additional barrier contraception must
Side Effects
be used (Flowchart 44.1).
Up to 75% of women develop significant side
effects from the drug. These include androgenic Limitations
and hypoestrogenic manifestations: Side The increase in liver injury, androgenic
effects include weight gain, edema (swelling), adverse effects, such as acne, hirsutism,
breast shrinkage, acne, oily skin, facial and male pattern baldness and risk of
hirsutism, deepening of the voice, headache, thromboembolism limits the use of danazol
hot flashes, emotional lability, changes in for endometriosis treatment. The drug has
libido, mood alterations etc. All of these
several US-FDA boxed warnings, including
side effects are reversible with exception of
the risk of thrombosis and teratogenicity.
voice changes. It may take many months for
resolution of the side effects.
NEWER THERAPIES
Contraindications Endometriosis is a chronic medical condition
Women with liver, kidney, or heart conditions and requires long-term therapy. Various
should not take danazol. treatment options available, have varying
372 Drugs in Obstetrics and Gynecology

degrees of success in symptom control. Many The feasibility, effectiveness of benzedoxifene

are limited by long-term use, side effects of acetate (BZA) is yet to be evaluated.
prolonged hypoestrogenism and high rates of Anti-angiogenesis factors: Angiogenesis
recurrence after therapy is discontinued. Also, is crucial for growth and survival of
endometriosis predominantly is a disease of endometriotic lesions. Studies have shown
young reproductive-age women and most that these lesions secrete angiogenic factors
of the commonly available therapeutic like VEGF. Therefore, anti-angiogenic factors
agents interfere with fertility. Due to these could stop growth of new lesions and regress
drawbacks there is a constant search for older ones. This forms the basis of use of
newer therapies that could offer cure and anti-angiogenic factors in the treatment
which can be safely used with fewer side of endometriosis. These are still in early
effects. development phase. TNP-470, endostatin,
anginex and anti-VEGF antibody (Avastin)
Selective Progesterone Modulators (SPRMs)
have been successful in decreasing the size
SPRM can have a variable effect from of endometriotic lesions in animal models,
different tissues from pure agonist to mixed however, no data is available in humans.
agonist and antagonist to pure antagonist. Dopamine-receptor-2 agonists, cabergoline
Mifepristone have shown to have dose and quinagolide reduce angiogenesis by
dependent inhibitory effect on endometriotic dephosphorylation of VEGF2. Cabergoline
implants. It was shown to have positive- has shown better results compared to
effects on endometriosis-related pain. It LHRH-agonist, in reducing the size of
induced amenorrhoea without causing endometrioma. It has no major side effects,
hypoestrogenism. easy to administer, and cheaper than LHRH
Ulipristal acetate and asoprisnil also have agonists.64 In a study comparing cabergoline
shown to cause regression of endometriotic and medroxyprogesterone acetate, both were
lesions. However, in the endometrium, found to be equally effective in decreasing
SPRM-associated changes, closely mimicked chronic pelvic pain due to endometriosis.
hyperplasia which developed after less than Cabergoline had a better acceptance and
3 months of treatment, and resolved after compliance due to lesser side effects and less
discontinuation of ulipristal and induction frequent dosing. It can be a better alternative
of withdrawal bleed. Feasibility of SPRMs is to medroxyprogesterone acetate,65 though
yet to be determined.62 enough data is not available to recommend
its routine use.
Selective Estrogen Receptor Modulators
These have different effects in different tissue Peroxisome Proliferator-activated
types, make them interesting agents for Receptor Gamma Ligands (PPAR-γ)
further endometriosis research, e.g. blocking These PPARs are ligand-activated nuclear
estrogen-mediated growth of endometriotic receptors. PPAR-γ ligands have anti-
lesions and at the same time supporting bone- inflammatory properties and reduce estrogen
mass remediation. production by inhibiting aromatase enzyme.
Bazedoxifene (BZD), a third generation In experimental models, they have been
SERM, approved for use in menopausal shown to inhibit cell proliferation, increase
symptoms, has demonstrated to regress apoptosis and inhibit the growth of the
endometriotic lesions. Combined with endometriotic lesions through angiogenic
conjugated estrogens has better tolerability factor VEGF. In animal models, rosiglitazone
and reduced side-effect profile.63 It represents and pioglitazone reduce the volume, weight
a potential treatment option for endometriosis. and size of the endometriotic lesions. Human
 Pharmacotherapy in Endometriosis 373

studies are underway, however there are treatments that can only target developing
concerns about the possible cardiovascular angiogenesis, romidepsin eliminates pre-
risk.66 existing pathologic vessels. Consequently,
romidepsin could serve as a novel, fertility-
TNFα Blockers preserving, and effective treatment for
It is a pro-inflammatory cytokine and its endometriosis.69
levels have been found to be elevated in the
peritoneal fluid of women with endometriosis Pentoxyphylline
with a direct correlation with the stage of the It is a methylxanthine with anti-inflammatory
disease. Infliximab, a monoclonal antibody property, acting as a phosphodiesterase
against TNFa, has shown to reduce the size inhibitor, that has been proposed for treating
and number of the endometriotic implants endometriosis. In a prospective RCT designed
and decrease in the levels of inflammatory to test the effect of oral pentoxifylline
cytokines in animal models. In a study combined with laparoscopic surgery on
on infliximab vs placebo in women with pelvic pain, reduction in pain scores was
endometriosis, no improvement was reported documented most significantly.70
in the severity of pain.67 There is lack of
evidence in humans regarding the efficacy Nanotechnology
of these agents. Some fundamental principles of cancer
nanomedicine can potentially be used for
Statins the development of novel nanoparticle-
These drugs, e.g. atorvastin, simvastin, based strategies for treatment and imaging
lovastin, etc. lower cholesterol levels by of endometriosis. Finding of nanoparticles
blocking the conversion of 3-hydroxy-3- that can predominantly accumulate in
methylglutaryl- coenzyme-A into mevalonate, endometriotic lesions without toxic effect on
which is a precursor of cholesterol. Their anti- the body, while preserving their imaging and
inflammatory, antiangiogenic and antioxidant heating properties is a challenge. The heat
properties have provoked interest in their use generated ablates the endometrial lesions
for endometriosis. Only lipid-soluble statins completely within a day or two. Strategy
were effective in inhibition of growth and can eventually shift the current paradigm
invasiveness of human endometrial cells in for endometriosis detection and treatment.71
a in vitro study. Though evidence support
statins as the potential therapeutic agent for SUMMARY
conservative treatment of endometriosis, For the treatment of endometriosis, diverse
yet, the uncertainties regarding their impact therapeutic approaches, including no
on gonadal function may deter its use as treatment, medical treatment, surgical
an appropriate therapy for all young fertile treatment, and a combination of medical and
women.68 surgical treatment, have been used. Medical
treatment consists of hormonal therapy
Romidepsin that most commonly includes combined
An anticancer drug used in cutaneous T-cell oral contraceptives, high-dose progestins,
lymphoma, targets VEGF at transcriptional danazol, and GnRH agonists. The basis of
level, which cause reduction in secretion of pharmacologic therapy is that endometriosis
VEGF from human immortalized epithelial implants are capable of responding to
cells. Therefore, romidepsin may be a potential hormones. NSAIDs may be considered in
therapeutic agent against angiogenesis in patients with mild symptoms and can be
endometriosis. Unlike other antiangiogenic combined with hormonal therapy. However,
374 Drugs in Obstetrics and Gynecology

none of these treatments eradicates the with endometriosis. J Reprod Med. 1988 Sep.
disease, they are associated with side effects. 33(9):757–60. [Medline].
Sometimes, endometriosis-related symptoms 9. Marcoux S, Maheux R, Bérubé S. Laparoscopic
surgery in infertile women with minimal or mild
reappear after therapy is discontinued. GnRH
endometriosis. Canadian Collaborative Group
analogues, danazol, and depot progestagens on Endometriosis. N Engl J Med. 1997 Jul 24.
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adverse events. Hormonal management 10. Vane JR. Inhibition of prostaglandin synthesis as
is not suitable for woman suffering from a mechanism of action for aspirin-like drugs. Nat
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severe symptoms or severe disease (stage III, 11. Chaiamnuay S, Allison JJ, Curtis JR. Risks
IV). AIs can be given in intractable cases along versus benefits of cyclooxygenase-2-selective
nonsteroidal antiinflammatory drugs. Am J
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drug. 2010:CD001751.
13. Blondell R; Azadfard M; and Wisniewski AM.
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 45
Genital Tuberculosis: Medication
with Case-Based Approach
• Sujata Dalvi

Introduction (DOTS) strategy. DOTS has 70% detection

Female genital tuberculosis is an important and 85 % successful treatment rates.
cause of infertility. Its incidence in India varies
from 3 to 16%. The fallopian tubes are involved MEDICAL THERAPY
in 90–100%, endometrium 50–80%, ovaries National Institute of Clinical Excellence
20–30% and cervix 5–15% of cases.1 It occurs (NICE)/American Thoracic Society/British
secondary to pulmonary or extrapulmonary Thoracic Society guidelines recommend
TB, like gastrointestinal (GI) tract because of first choice of treatment to be ‘standard
hematogenous/lymphatic spread. Diagnosis recommended regime’ using daily dosing
is made by actual visualization of lesions- schedule with combination tablets. Those
adhesions on laparoscopy/hysteroscopy who can adhere to treatment, DOTS is not
followed by biopsy of suspicious lesions. necessary. However, DOTS is recommended
Histopathology report of endometrial tissue/ by WHO.
lesion, positive culture for acid-fast bacillus
(AFB) or positive Mycotracterium tuberculosis- WHO Recommendation
polymerase chain reaction (TB-PCR) test are
also methods of diagnosis. However, high Daily therapy of rifampicin (R), isoniazid
degree of suspicion is required. (H), pyrazinamide (Z) and ethambutol (E) for
2 months followed by daily rifampicin (R)
There is increased incidence of tuberculosis
and isoniazid (H) for 4 months
in developing countries and it may be co-
existent with human immunodeficiency virus • Weight <45 kg (2 HRZE—300/450/1250/
(HIV). 800)
Antituberculosis drug regime is 3 or 4 • Weight >45 kg (2 HRZE—300/600/1750/
drug combination [antitubercular treatment 1200)
(ATT)]. Duration of therapy will be for 9 to Or
12–18 months. Multidrug resistant (MDR) • 2 months intense therapy of RHZE daily,
or extreme drug-resistant TB (XDR) are of followed by alternate days combination of
concern because of poor drug management. RH for 4 months.
World Health Organization (WHO) declared Or
TB a global emergency in 1993 and promoted • 3 times a week dose of (2 RHZE)/(4RH)
directly observed treatment short course throughout therapy, provided patient
 Genital Tuberculosis: Medication with Case-Based Approach 379

is under direct observation and is HIV Continuation phase daily (18 months):
negative. • Weight <45 kg—levofloxacin (O) 500/
Or ethionamide (O) 500/cycloserine (O) 500/
• Continuation phase daily (4 months)— ethambutol (O) 800
3-drug-fixed-dose combination after • Weight >45 kg—levofloxacin (O) 750/
intense therapy of 2 months ethionamide (O) 750/cycloserine (O) 750/
• Weight <45 kg (4 HRE—300/450/800) ethambutol (O) 1200
• Moxifloxacin to be given—resistant to
• Weight >45 kg (4 HRE—300/600/1200)
levofloxacin
• 4-Drug fixed dose combination (FDC)—
Treatment of chronic and multidrug
HRZE (75/150/400/275)
resistant (MDR) FGTB is similar to that for
Therapy is given after categorizing patient pulmonary MDR with second-line drugs for
to one of the treatment regimes. Genital TB is 18–24 months.
classified as category 1, as seriously ill extra-
pulmonary disease. To ensure adequate dose Pregnancy:
with quality control, 6-month course pack box For latent tuberculous infection (LTBI)—
is booked in DOTS center with fixed-drug isoniazid 300 mg with pyridoxine 25 mg,
combipacks (FDC) of isoniazid, rifampicin, daily for 6 to 9 months. HIV positive—to start
pyrazinamide and ethambutol, three times immediate treatment. Those on antiretro­
a week for first 2 months (intensive phase) viral therapy (ART)/HIV negative—defer
followed by combination pack of isoniazid treatment till postpartum if no risk factors.
and rifampicin, three times a week for next 4 Rifampicin, isoniazid, pyrizinamide are
months (continuation phase). safe during pregnancy.
Female genital tuberculosis (FGTB) cases Active TB during pregnancy—INH,
with relapse or failure are included into RIF, pyrizinamide and ethambutol (EMB)
category II. The regime has streptomycin given for 2 months followed by INH, RIF
injections, intramuscular, three times a week for next 4 to 7 months daily with pyridoxine
for 2 months with other four drugs (SRHZE) supplementation. Monitoring of hepatic
of category I, followed by four drugs (RHZE), function is recommended. Newborn to
three times a week for 1 month (intensive receive INH for 6 months followed by bacillus
phase) then continuation phase with three calmette-Guerin (BCG) vaccine after ruling
drugs isoniazid (H), rifampicin (R) and out active TB. Vitamin K to be given to
ethambutol (E), three times a week for next newborn if mother is on rifampicin.
5 months.
Non-DOTS Treatment
Multidrug Resistant/Probable Patients not opting for DOTS, should take
Multidrug Resistant RHZE daily for 2 months (intensive phase)
followed by RH for 4 months (continuation
Intensive phase, daily (6–9 months): phase). Combipacks are available at reasonable
• Body weight <45 kg—kanamycin (IM) 500/ cost.
levofloxacin (O)—500/ethionamide (O)
500 / cycloserine (O) 500/pyrazinamide Monitoring
(O) 1250/ ethambutol (O) 800 Counselling is necessary for the importance
• Body weight >45 kg—kanamycin (IM) of taking AKT regularly with good/nutritious
750/levofloxacin (O) 750/ethionamide (O) diet and reporting any side effects. Liver
750 /cycloserine (O) 750/pyrazinamide function tests to be done only for symptoms
(O) 1750/ethambutol (O) 1200 of hepatic toxicity. Pyridoxine should be
380 Drugs in Obstetrics and Gynecology

prescribed with AKT only with symptoms • Defer antiretroviral therapy until end of
of peripheral neuropathy with isoniazid. initial phase of treatment and usage of
Occasionally, hepatitis is seen with isoniazid, ethambutol and isoniazid in continuation
rifampicin and pyrazinamide, optic neuritis phase
by ethambutol and auditory/vestibular • To treat TB with rifampicin-containing
toxicity by streptomycin. In these cases, regimen with efavirenz and 2 nucleoside
modified form of AKT can be restarted after reverse transcriptase inhibitors (NRTIs)
expert opinion. • Treat TB with rifampicin-containing
Adverse effects: First-line medications are regimen with 2 NRTIs and then change
safe. There are minor side effects. Rarely, to maximally suppressive highly active
serious ones like hepatitis can occur. The side antiretroviral therapy (HAART) regimen
effects are as follows: on completion of TB treatment.
• Isoniazid—peripheral neuropathy,
seizures, erythema, hepatitis, lethargy NEW TB RESEARCH
Rifampicin—hepatitis, skin reaction, Globally, there is renewed interest in research
arthritis, thrombocytopenic purpura. in TB. Improvised new BCG vaccines are
• Pyrazinamide—hepatitis, GI irritation, being developed. Newer drugs, effective
nausea, vomiting against resistant strains and requiring
• Ethambutol—optic neuritis shorter treatment are being developed.
Reserve drugs: WHO recommends Xpert MTB/RIF rapid
• Streptomycin/kanamycin—ototoxicity, screening test for resistant strains with
renal problems, vertigo simultaneous detection of TB (<2 hours),
• Quinolone derivatives/ethionamide—GI where culture takes 3 to 6 weeks. Injection-
irritation, abdominal pain, vomiting free regimen using bedaquiline and
delamanid have been recommended by WHO
• Cycloserine—neurological like dizziness,
Consolidated Guidelines on Drug-Resistant
seizures, headache, tremors
Tuberculosis Treatment (2019).2 WHO rapid
Treatment of FGTB in HIV-Positive Women communication has recommended injection-
free regimens for all types of TB, including
HIV has serious impact to control TB and
MDR and rifampicin-resistant (RR) TB... By
is leading cause of HIV-related morbidity
controlling TB, FGTB can be under control to
and mortality. In India, Revised National
prevent complications.
Tuberculosis Control Program (RNTCP)
and National AIDS Control Organization
References
(NACO) together have devised protocol for
1. JB Sharma: Current Diagnosis and Management
proper management of this dual epidemic.
of Female Genital Tuberculosis:J Obstet Gynecol
The options for antiretroviral therapy in TB India: 2015 Dec: 65(6):362–71.
patients are: 2. JB Sharma: Female Genital Tuberculosis:
• Defer antiretroviral therapy until comple­ Revisited: Indian Journal of Medical
tion of TB treatment Research:2018 Dec:148(1):S71–S83.
 46
Hyperprolactinemia

• Ritu Bharadwaj • Ruchika Garg

Introduction Symptoms of hyperprolactinemia depend

Serum prolactin (PRL) concentration in upon the magnitude of prolactin elevation as
normal adult males and females is less than • Serum prolactin greater than 100 ng/dl
14 mg/L and 24 mg/L, respectively (PRL will have overt hypogonadism with the
conversion units: 1 mg/L = 21.2 mU/L). presentation of amenorrhea, hot flashes,
The reported reference ranges for total PRL and vaginal dryness.
on the Abbott Architect assay is 2.7–19.7 • Serum prolactin between 50 ng/dl to
mg/L for males and 3.0–26.4 mg/L for 100 ng/dl may cause amenorrhea or
females. Serum PRL is unaffected by food oligomenorrhea.
and a fasting sample is not necessary. • Serum prolactin 20 to 50 ng/dl may
Hyperprolactinemia causes galactorrhea- only shorten the luteal phase because of
amenorrhea-infertility syndrome in women. insufficient progesterone secretion.
Prolactin causes inhibition of gonadotropin- There are physiologic causes for a rise in
releasing hormone (GnRH) which leads PRL, such as pregnancy, lactation, physical
to inhibition of luteinizing hormone (LH) exertion or stress. During pregnancy, PRL
and follicle-stimulating hormone (FSH) increases in response to increasing estradiol
secretion. ranging from 35–600 mg/L. PRL is not
increased in non-lactating women and men
SIGN AND SYMPTOMS OF after nipple stimulation or breast imaging and
HYPERPROLACTINEMIA breast examination.
• Menstrual disturbances like oligo­ The causes of hyperprolactinemia are
menorrhea, amenorrhea, menorrhagia prolactin-secreting tumours which may be
• Infertility micro or macroprolactinoma.
• Galactorrhea and as hypogonadotropic A microadenoma is described as having
hypogonadism like decreased libido, a maximum diameter of up to 10 mm (the
impotence, infertility, oligospermia or maximal diameter of the normal pituitary
gynecomastia, erectile dysfunction or gland) while a macroadenoma has a diameter
galactorrhea (rare) in men. larger than 10 mm. Giant adenomas are
• Sign and symptoms caused by mass effect defined as the presence of the largest
are headache, visual field defect or external diameter of the tumor being larger than 4
ophthalmoplegic. cm.18 A microadenoma is often visualized
382 Drugs in Obstetrics and Gynecology

using magnetic resonance imaging (MRI). its relationship to the optic chiasm and
Usually, the serum prolactin level is below cavernous sinuses. Cisternal herniation is
200 ng/ml (4000 mU/L) in patients with also readily seen. If MRI is not available,
microadenomas. A macroadenoma that computed tomography (CT) scanning is
secretes prolactin is usually associated also helpful, but the resolution is less good
with a serum prolactin level of more than and it is less satisfactory for delineating the
200 ng/ml (4000 mU/L). If the patient has relationship of the diaphragm sellae with the
a macroadenoma and a serum prolactin optic chiasm. There is little place for routine
level of less than 200 ng/ml (4000 mU/L), skull X-ray other than for delineating bony
possibility of a nonfunctioning pituitary structures.26
adenoma (pseudo-prolactinoma), resulting
from deprivation of some lactotrophs of PROLACTIN INHIBITORS USED IN
dopaminergic inhibition is there. TREATMENT OF HYPERPROLACTENEMIA
Other causes include hypothalamic
1. Bromocriptine
disorders, like craniopharyngioma, suprasellar
pituitary mass extension, meningioma, Bromocriptine is a synthetic ergot derivative
dysgerminoma, hypothalamic metastases which is a potent dopamine agonist. It has its
weakening its inhibitory control over pituitary. greater action on D2 receptors and it decreases
prolactin release from pituitary, while at certain
dopamine sites in the brain, it acts as a partial
DRUGS CAUSING HYPERPROLACTINEMIA
agonist or antagonist of D1 receptor. It is also
A n t i p s y c h o t i c ( d o p a m i n e re c e p t o r- a weak a-adrenergic blocker. Bromocriptine is
blocking agents) risperidone, haloperidol, preferred during pregnancy because of more
fluphenazine, etc. antiemetic (dopamine favorable data than cabergoline.
receptor-blocking agents), metoclopramide,
Side effects: Nausea, vomiting, constipation.
domperidone and prochlorperazine.
Postural hypotension may be marked at
initiation of therapy. Syncope may occur if
MEDICAL CONDITIONS CAUSING starting dose is high. Hypotension is more
INCREASED PROLACTIN likely in patients taking antihypertensive, etc.
Chronic Renal Failure Behavioural alterations, mental confusion,
hallucinations, psychosis, etc. are other rare
Polycystic ovarian disease (PCOD), liver
side effects.
cirrhosis, pseudocyesis, primary hypothyroi­
dism, ectopic production in bronchogenic Pharmacokinetics:
carcinoma and hypernephromas and may Bioavailability—28% of oral dose absorbed
be idiopathic. Metabolism—extensively liver-mediated
Prolactin is under predominant inhibitory Elimination—half-life 12–14 hours
control of hypothalamus through prolactin Excretion—85% bile (feces), 2.5–5.5% urine.
release-inhibiting hormone (PRIH) which is
Dosage: For initiation of therapy, dosage
dopamine that acts on pituitary lactotrophs
is 1.25–2.5 mg, once a day. Dosage may be
D2 receptor. Thus, dopaminergic agonist,
increased up to a dosage of 15 mg, once a day,
such as bromocriptine, cabergoline decrease
according to the patient’s serum prolactin level.
plasma prolactin.
2. Cabergoline
DIAGNOSIS OF PROLACTINOMA BY IMAGING Cabergoline is D2 agonist more potent more
MRI allows accurate measurement of the selective for pituitary lactotrope D2 receptors.
size of the pituitary and of any tumor, and It is the first-choice drug for treatment of
 Hyperprolactinemia 383

hyper­prolactinemia. Serum prolactin levels Cabergoline and pergolide are associated

fall to the normal range in 2–4 weeks and in with a higher risk of cardiac valvopathy in
many women it is found that they conceive patients with Parkinson’s disease.
within a year.
Note:
Side effects: Same as bromocriptine but
incidence is lower. • Before initiating treatment for hyper­
prolactinemia, cardiovascular evaluation
Pharmacokinetics: should be performed and echocardiography
Bioavailability—first-pass effect seen; absolute should be considered to assess for valvular
bioavailability unknown. disease.
Protein binding—moderately bound (40–42%),
• Dosage increase should not occur more
concentration, independent.
rapidly than every 4 weeks, so that the
Metabolism—hepatic, predominately via
physician can assess the patient’s response
hydrolysis of the acylurea bond.
to each dosage level.
Elimination—Half-life 63–69 hours (estimated),
thus cabergoline is longer-acting than • If the patient does not respond adequately
bromocriptine. and no additional benefit is observed with
Excretion—Urine (22%), feces (60%). higher doses, the lowest dose that achieved
maximal response should be used and
Dosage: For initiation of therapy, dosage
other therapeutic approaches considered.
is 0.25 mg, twice a week. Dosage may be
increased up to a dosage of 1 mg, twice • Patients receiving long-term treatment
a week, according to the patient’s serum should undergo periodic assessment of
prolactin level. The dose can be reduced from their cardiac status and echocardiography
the typical dose of 0.25 mg, twice a week to should be get done.
0.25 mg once a week and then to 0.25 mg • DA therapy is effective not only in patients
every other week before discontinuation. with microadenomas, but also in the
Side effects of dopamine agonist (DA) majority of patients with large prolactin-
therapy, usually occur at the start of treatment secreting tumors in reducing tumor size.
and frequently disappear with continued Moreover, emerging evidence point to the
therapy. If treatment is started with full possibility of drug withdrawal after long-
doses or increased too quickly, dizziness, term treatment.
nausea, and postural hypotension may occur.
To avoid such effects, DA must always be Bibliography
taken during a meal. Administration should 1. McKenna TJ. Should macroprolactin be
be started at night, with a snack, when the measured in all hyperprolactinaemic sera?
patient retires to bed. Doses can be gradually Clin Endocrinol (Oxf) 2009;71:466–9. [PubMed]
increased afterwards. [Google Scholar].
 47
Current Concepts in Hormone
Replacement Therapy:
Estrogen and Progesterone
• Priya Vora • Rana Choudhary

Introduction heart diseases, stroke and clotting tendencies.

Menopause is an important transition However, there was no agent/drug which
phase that brings in many changes that could replace estrogen in terms of providing
can affect the quality of life in a woman.1 beneficial effect over various organs and
The reproductive morbidity and mortality systems as was seen with use of estrogen.
increase as aging progresses and leads to However, over these years the fear of using
menopause. 1 Due to gradual decrease in HRT has not reduced among women and
estrogen and progesterone from these aging clinicians which has resulted in unnecessary
ovaries, hormone replacement therapy can anguish. Unfortunately, after the WHI, till date
be used in the form of synthetic progesterone several clinicians do not feel safe prescribing
and estrogen to replace a woman’s depleting HRT neither are they trained in this. There
hormone levels, thus alleviating symptoms are many papers which demonstrate the
of menopause and preventing long-term protective effect of HRT in reducing risk
adverse effects on bone, cardiovascular of coronary disease, osteoporosis, and
system, and urogenital system. dementias when it was started within
Hormone replacement therapy underwent 10 years of menopause.
dramatic swings during the last 50 years.
It was extremely popular before the WHI NEED FOR HRT
study. The enthusiasm for HRT was smashed
in 2002, after the WHI trial on health costs South Korea is predicted to be the number
and benefits of hormonal therapy. Age of one in the world (by 2030) in terms of life
the women at starting HRT is extremely expectancy of women. This is reaching
important in the beneficial effects of HRT, as 90.82 years. In a recent study, it is estimated
it determines its effectiveness as well as side worldwide that 1 billion women by 20202
effects. The use of HRT reduced significantly and by 2050 1.6 billion women will reach
after the results of WHI study (2002). This menopause or be postmenopausal.3 Indian
has lead the scientists and caregivers to look women have a life expectancy of 72.3 years,4
for alternative options in management of with an average age for attaining menopause
perimenopausal and menopausal symptoms. around 47–49 years. Hence, maintaining a
According to this study, postmenopausal on positive post reproductive phase, preventing
HRT had an increased risk for breast cancer, non-communicable disease, reducing
 Current Concepts in Hormone Replacement Therapy:Estrogen and Progesterone 385

mortality, and better quality-of-life after break in between two cycles. In these cases,
menopause is crucial. oestrogen can be used continuously with
Most menopausal Indian women progestogen added in between.
complain of instability in vasomotor
system presenting in the form of hot flashes, MECHANISM OF ACTION
sweating and palpitations. Urogenital
symptoms, like urinary frequency, urgency, Estrogen (steroid hormone) has an important
vaginal dryness, soreness and dyspareunia role in the functioning of reproductive
are common. Psychological symptoms, such system. It acts basically on the uterus and
as mood changes, insomnia, depression and vagina. It changes the transcription of genes
anxiety make day-to-day activities difficult. in these tissues. This is through the action on
Long-term effects are osteoporosis and certain receptors, like nuclear transcription
cardiovascular disease and Alzheimer ’s factors. These nuclear transcription factors
disease. HRT ma rkedly reduces the regulate the genes by getting attached to
symptoms of menopause, like vasomotor, the promoter regions in specific genes of the
vaginal and vulvar dryness, risk of fractures uterus and vagina.
due to osteoporosis and improves quality- Oestrogen has an important effect on the
of-life. vaginal pH. This typically ranges between
4.5 and 6.0, in years preceding menopause.
WORK-UP BEFORE HRT Estrogen is responsible for decreasing the
pH by its mechanism on the vaginal and
• History taking and a proper physical ectocervix epithelial cells and increases
examination are imperative. secretion of proton. After menopause, due to
• Blood pressure needs to be recorded before reduction in estrogen, there is alkalinization
giving HRT. and increase in pH up to 7.0. The risk of
• Haemoglobin including complete blood vaginal infections, urinary tract infections
count (CBC), sugar levels, liver function (UTIs) dryness, pruritus and dyspareunia
tests, lipid profile, and thyroid profile increases when pH is above 6.5. Even
are the investigations needed to be malignancies of cervix are associated with
performed. high vaginal pH.
• Pelvic ultrasonography, mammography,
bone mineral density (BMD) test, Pap ROUTE OF ADMINISTRATION
smear screening, and endometrial biopsy
are also helpful. Estrogen therapy can be given in various
forms like:
TYPES OF HRT • Oral pills, e.g. esterified estrogens, conju­
gated equine estrogens, ethinyl estradiol,
• Hormonal HRT—many women are 17-beta-estradiol.
given a combination of oestrogen and
• Transdermal—patches
progestogen hormones. However, women
who have undergone hysterectomy can • Local—creams
take only estrogen without any need for • Vaginal—suppositories.
progesterone supplementation. • The local estrogen is available as 17 beta-
• These preparations are available in various estradiol.
forms, like tablets, gels, vaginal creams, • All forms of therapy are equally equipped
pessaries or rings and skin patches. to help in menopausal symptom.
• These medicines used as HRT medicine • However, most women use oral estrogen
can be taken continuously or with a small therapy. But the problem with this route
386 Drugs in Obstetrics and Gynecology

is the higher-dose requirement because • Minimal systemic side effects with vaginal
of increased first-pass metabolism in the preparations.
liver. • Progesterone is not needed as there is no
endometrial stimulation.
Estrogen in Menopausal Hormone Therapy • Estriol cream conjugated equine estrogens
• Conjugated equine estrogen, 0.3 mg/0.625 (CEE) creams are available.
mg, estradiol valerate 1/2 mg, or 17-beta • Ultra-low-dose estriol 0.03 mg/day and
oestradiol, 1 mg, are present in the most standard dose 0.5 mg/day for 2 weeks
oral preparations. followed by maintenance dose can be
• Routes—transdermal patches, sprays, gels, continued for a long time.
topical emulsion and vaginal. • Safety data beyond 1 year is unavailable
• During its passage through the liver, currently.
oral estrogens increases the production
of many inflammatory markers along Progesterone
with coagulation factors. Because of this, • In women, who still have their uterus,
the risk of venous thromboembolism is progestogen is needed to prevent the
increased. Also these women may have increased risk of endometrial cancer
increased triglycerides and gallstones in when these women take oral estrogen
future. supplementation. This unopposed action of
• Transdermal and local estrogen applications oral estrogen makes the endometrial lining
bypass first-pass metabolism and have the thick and increases risk of endometrial
advantage of safety and accurate dosing. cancer if there is no cyclic withdrawal
• These are preferred in women intolerant bleed.
to oral therapy. • There are various preparations of
• Transdermal estrogen sprays are also proges­terone available in the market,
recently available. Once applied, these e.g. micronized progesterone, synthetic
sprays reached maximum levels estradiol progestins, e.g. medroxyprogesterone
in serum after 18–20 hours and reached a acetate (MPA) or norethindrone.
stable concentration by 1 week of initiating • Micronized progesterone is better as it
their use. is similar to endogenously produced
progesterone. It has a good absorption
Estrogen in Vaginal Form rate after taking orally as well as when
• The United States Food and Drug used vaginally.
Administration (US/FDA) has approved • Synthetic progestins have much better
the use of low-dose vaginal estrogen in activity than natural ones (10 to 100-fold)
treatment of moderate-to-severe vaginal and hence are cheaper alternative.
dryness and dyspareunia. These are • R e c e n t l y, c o m b i n e d p re p a r a t i o n s
commonly seen in women approaching containing micronized progesterone or
menopause (genitourinary syndrome). dydrogesterone are available.
• Vaginal forms of estrogen HRT—cream, • A woman who already has levonorgestrel-
ring, tablet or capsule. releasing intrauterine system (LNG-IUS)
• These primarily act on the local tissue and can be given oral or transdermal estrogens.
help in treating the vulvovaginal dryness LNG-IUS will give protection to the
also. endometrium.
 Current Concepts in Hormone Replacement Therapy:Estrogen and Progesterone 387

FORMULATIONS OF MENOPAUSAL HORMONE Available Packages of Estradiol and

THERAPY AVAILABLE IN INDIA Dydro­gesterone Tablets
• Combipack of estradiol and estradiol and
Systemic Therapy
dydrogesterone
Oestrogen • Other options have estradiol (as hemi-
• Oral CEE, 0.3 mg/0.625 mg; 17-beta- hydrate) in 1 mg, 2 mg or 0.5 mg with
oestradiol, 1 mg/2 mg; oestradiol valerate, different dosage of dydrogesterone (10 mg,
1 mg/2 mg 5 mg or 2.5 mg)
• Transdermal oestrogen gel, 0.125 mg per Estradiol (as hemihydrate) 1 mg with
2.5 g of gel. dydrogesterone 5 mg or 10 mg as it has
progesterone component, it can be used in
Progesterone postmenopausal women with uterus. It helps
• Dydrogesterone 10 mg; micronized in prevention of osteoporosis also. In this
progesterone, 100, 200, 300, 400 mg combination, estrogen is given continuously
• Levonorgesterol intrauterine device with dydrogesterone given in the last 2 weeks
52 mg–release 20 mg/day of the 4-week cycle (Table 47.1).
Estradiol (as hemihydrate) 2 mg and
Combination of Oestrogen and Progesterone dydrogesterone 10 mg, can be used in
Combined sequential—17-beta-oestradiol peri- and post-menopausal women with
1 mg and 10 mg with dydrogesterone symptoms of estrogen deficiency. This can
Continuous combined—17-beta-oestradiol be as a result of natural menopause or after
and dydrogesterone 5 mg, daily. removal of ovaries. As with other similar
combination, it helps in post-menopausal
Estrogen Therapy for Genitourinary Syndrome osteoporosis prevention. This is also given
Estriol cream, 0.5 mg/0.5 g of cream; oral in similar fashion.
estriol, 0.5 mg Estradiol (as hemihydrate) 0.5 mg and
Conjugated equine estrogen, 0.625 mg/ dydrogesterone 2.5 mg, this combination can
1 g of cream. be used as HRT. This preparation is given

Table 47.1: Important points to consider in HRT therapy

S. No. Points to consider in HRT therapy
1 Before starting MHT, the symptoms can be reduced by lifestyle modifications, like reduction in
weight, decreasing stress, Yoga, meditation, hypnotherapy and cognitive behavioural therapy (CBT).
2 Medications, like vitamin E, omega-3 fatty acids, isoflavones, and soya beans may be useful, as MHT
comes with its own risk and contraindications and should be given only when the benefits outweigh
the risk. Therefore, MHT has to be started with a very low dose and for a minimum duration.13
3 Vasomotor symptoms (VMS) normally appear within a couple of years from the last day of
menstruation and generally continue for 5 years.
4 A lower dose than the routine dose of MHT is more effective for treating VMS14
5 Women who were under 52 years and presenting with peri- or post-menopuasl symptoms had
associated comorbidities, like depression, anxiety, osteoporosis and insomnia15
6 There was a 40 to 65% improvement in symptoms with use of non-hormonal agents, like selective
serotonin receptor inhibitors (SSRIs) and selective norepinephrine receptor inhibitors (SNRIs). The
vasomotor symptoms improved by 50% after using gabapentin (900 mg/day) and 65% with use of
pregabalin (150 mg/day)16,17
388 Drugs in Obstetrics and Gynecology

daily without interruption. Each packet is for The following symptoms need immediate
28 days. stoppage of the HRT:
• Jaundice or Increase in liver enzymes
CONTRAINDICATIONS FOR HRT23 • Rise in blood pressure
• Any history or suspicion of cancer breast • New onset of migraine-type headache
• Pregnancy.
• Any history or suspicion of estrogen-based
cancer like uterine malignancy
LITERATURE REVIEW AND GUIDELINES
• History of thrombosis or deep vein
thrombosis (DVT) or pulmonary embolism National Institute for Health and
(PE) or any active lesion Care Excellence Guidelines18
• Any blood clotting abnormalities, e.g. • HRT should be discussed with menopausal
factor V Leiden mutation carriers and perimenopausal women suffereing
• History of thrombotic diseases of arteries, with vasomotor symptoms (VMS), like hot
like myocardial infarction or cardiovascular flushes and night sweats.
illness, like stroke • HRT should be considered in mood
changes and anxiety along with cognitive
• Chronic liver disease or hepatitis
behavior therapy (CBT).
• Severe headache/migraine with aura
• Oestrogen alone does not lead to significant
• Any abnormal and undiagnosed bleeding increase in risk of breast cancer. Although
from genitals estrogen and progesterone are associated
• Unknown hyperplasia of endometrium with an increase in the risk of breast cancer,
• Protein C, protein S or antithrombin this risk reduces after HRT is stopped.
deficiency or any other thrombophilic HRT, if started before 60 years does not
disorders. increase the risk of cardiovascular diseases.
However, vaginal estrogen route can be • Refer these woman to a menopause
used in these cases as the concentration of specialist if no improvement.
estrogen in blood after vaginal route is quite
low. International Menopause
Society Guidelines19
MONITORING • MHT is among the most effective therapy
management of menopausal symptoms.
Measurement of serum estradiol and proges­
• For vasomotor symptoms, a combination
terone is not required to test the effectiveness
of CEE and bazedoxifine (BZA) is the most
of therapy. Relief from menopausal symptoms
effective.
and absence of adverse effects is a measure
• HRT can be started in menopausal women
of the effectiveness of therapy and response
who are at risk of fracture or osteoporosis
to treatment.23
even before they reach the age of 60 or
within 10 years of attaining menopause
SIDE EFFECTS OF HRT (Table 47.2).
• Abnormal uterine bleeding
• Accumulation of fluids in third space CONCLUSION
• Tenderness of breast • Estrogen-containing products are widely
• Headaches used therapies for vasomotor symptoms
• Mood swings and irritability and vaginal and vulvar atrophy.
 Current Concepts in Hormone Replacement Therapy:Estrogen and Progesterone 389

Table 47.2: Different formulations—estrogen and progestins

Oral estrogen Conjugated equine estrogen (CEE) 0.3 mg/ 0.625 mg
17β-estradiol 1 mg /2 mg, body-identical
Transdermal 17β-estradiol 0.125 mg per 2.5 mg of gel, avoid
Estrogen gel first-pass metabolism
Oral progestrone Norethindrone acetate Indicated for AUB
Micronized progesterone 100, 200, 300, 400 mg
Body-identical
Medroxyprogesterone acetate (MPA) Strong action on the endometrium
Dydrogestrone 10 mg
Intrauterine Levonorgesterel 52 mg releases 20 mg/day
Combination of E 17-Beta estradiol + Dydrogestrone 1 mg
and P
Continuous sequential 17-Beta estradiol + Dydrogestrone 10 mg
AUB: Abnormal urine bleeding

• They are good in preventing osteoporosis, endometriosis, endometrial ablation and

cardiovascular disease, and dementia supracervical hysterectomy.
but they pose a serious risk of thrombo­
embolism. Post-menopause
• HRT should be started and maintained at 1. Continuous combined—continuous
the lowest dose and for the shorter duration estrogen continuous progesterone
necessary to relieve the symptoms. 2. Tibolone.
• Dose and duration should be tailor-
made according to the patient’s need and Premature Ovarian Insufficiency
reviewed periodically.
1. Standard/high-dose estrogen and
• Risk of serious side effects is least with the cyclical or continuous progesterone (not
low-dose regimens of HRT. a contraceptive)
• HRT must not be used for the primary or
2. Oral contraceptive pill, if not contra­
secondary prevention of coronary artery
indicated.
diseases.

Transition and Menopause <1 year Local Therapy for Genitourinary Syndrome of
Menopause (GSM)
1. Sequential combined regime—continuous
estrogen and cyclic progesterone 12–14 1. For correction of deficiency: Estriol cream
days/month, (not a contraceptive) 0.5 mg/day of vaginal application or tab.
2. Low-dose contraceptive pill, if not estriol, 1–8 mg/day, single dose before a
contraindicated. meal OR
2. Conjugated equine estrogen: 0.3–1.25 mg/
In Women without Uterus day of vaginal application for 15 days
1. Continuous estrogen alone 3. For maintenance therapy: Tab. estriol 1 mg/
2. Tibolone day or estriol cream, 0.5 mg or conjugated
3. Progesterone is added along with estrogen equine estrogen, 0.3 mg—twice weekly for
in hysterectomised women in cases of 2 months to 1 year.
390 Drugs in Obstetrics and Gynecology

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 48
Pelvic Congestion Syndrome

• Asmita Patil • Shraddha Mevada

Introduction varicosities. The resultant stasis produces

Pelvic congestion syndrome (PCS) is chronic congestion and pelvic pain.2
pelvic pain in women who have varicose
b. Sexual Dysfunction
veins in or near the ovaries and is a common
cause of chronic pelvic pain in women Vasocongestion in the pelvic viscera may
of reproductive age. Pelvic congestion cause some pain in the female when she is
syndrome is caused by varicosity and sexually stimulated.
venous insufficiency of the ovarian veins
c. Hormonal Disorders
and is usually asymptomatic. Most women
with pelvic congestion syndrome are aged There is a higher incidence of polycystic
between 18 to 45 years and have a history ovaries, bulky uterus, and thickened
of multiple pregnancies. Understanding the endometrium, which all may be hormonally
pathophysiology and possible causal factors induced in these patients.
will help us to give focused treatment. As the pelvic congestion syndrome is
rarely known in the postmenopausal female,
Taylor and Beard proposed that this condition
ETIOLOGY
might be related to hormonal sensitivity.3
Various etiological factors have been described
so far. El-Minawi 1 has classified various d. Iatrogenic
etiologies as follows: The use of intrauterine devices and tubal
ligation surgeries have been found to be
a. Anatomical Causes associated with this condition by some
• Parity is one of the risk factors in the develop­ studies. However, this is not proven.
ment of pelvic congestion syndrome.
• Pregnancy increases the capacity of the PATHOPHYSIOLOGY
pelvic veins by 60%. Anatomy of pelvic venous plexuses: It consists
• Malposition of the gravid uterus, along of various veins, like ovarian, para-ovarian,
with venous kinking, leads to venous uterine, vesical, rectal, and vulvar veins. The
stagnation, flow reversal, and varicosities. vulvar and uterine veins, normally drain into
• Incompetent venous valvular system the internal iliac vessels. The left ovarian
under the effect of gravity results in pelvic vein drains into the left renal vein, and the
392 Drugs in Obstetrics and Gynecology

Fig. 48.1: Anatomy of pelvic venous plexuses

right ovarian vein drains into the vena cava vasopressin, have been found to play a
directly (Fig. 48.1). possible role.6,7
Vascular connections between the vesical d. Calcitonin gene-related peptides and nitric
and rectal venous complexes are interlaced oxide have also been implicated.8
into each other as well as the upper thigh.
These channels are relatively valveless and SYMPTOMS
are gravity and vascular-tone sensitive.
1. Pain: Pain is the most common symptom
a. Complete resolution of symptoms after
of PCS. It is usually intermittent and dull
menopause also indicates the influence
aching in character with intermittent
of hormone levels on this syndrome.
aggravation by activities which cause
Estrogen acts as a venous dilator and can
venous stagnation, such as standing,
thus produce the venous dilatation which
walking, prolonged sitting, sexual
is involved in the pathophysiology of the
intercourse, and vigorous exercises.
PCS.4
2. Dyspareunia and postcoital pain can also
b. In PCS, the vessels are not only enlarged
present in cases of PCS.
but the flow through them is slowed
down. Reginald 5 showed that these 3. Menorrhagia and menometrorrhagia.
changes could be reversed for a short time 4. Congestive dysmenorrhea, which may
with intra­venous dihydroergotamine; by mimic endometriosis.
documenting pelvic venography, which 5. Gastrointestinal symptoms, e.g. bloating,
offers a reduction of symptoms before and nausea, and abdominal pain
after injection. 6. Frequency and urgency of urination can be
c. Neurotransmitters produced by these present in some cases, which may be due
abnormal vessels, like adenosine-5'- to the peri-vesicle and rectal space edema
triphosphate, substance P, endothelin, and due to venous congestion.
 Pelvic Congestion Syndrome 393

7. Headache, fatigue, and insomnia may be

due to a general autonomic dysfunction.
8. Psychiatric manifestations can occur in
a wide range of symptoms. Anxiety and
depression are the most common.

PHYSICAL EXAMINATION
1. On per abdominal examination, tenderness
is present over the bilateral iliac regions.
Especially on the spine-umbilical line at
the junction of the upper and middle third.
At the level of the ovarian vein crossing
into the bony pelvis, and on compression,
it increases the venous pressure, which
causes the ovarian tenderness.
2. Superficial varicosities may be present in
some rare cases.
3. Vulvodynia may be present, the cervix may
reveal cyanosis and an increase in cervical
Fig. 48.2: Pelvic venogram in a patient with pelvic
secretions.
congestion syndrome
4. Tenderness is present on the uterus,
ovaries, posterior parametrium and
the uterosacral ligaments on bimanual (transuterine) approach. It can measure
examination. the maximum diameter of the veins and
the time required for the dye to clear. The
DIAGNOSTIC TESTS transuterine scoring system is available
(Fig. 48.2).9
a. A diagnostic study that can measure
both the criteria of enlarged veins and
TREATMENT
reduced circulation can be used for the
diagnosis of pelvic congestion syndrome. Treatment should include elimination
Ultrasonography, computerized tomo­ of the microcirculatory disorders and
graphy, magnetic resonance imaging, and vascular inflammation, increased venous
radio-nuclear studies have not yet been tone, improved lymphatic drainage and
proven to make an accurate diagnosis. symptomatic pain relief.10
b. Laparoscopy can give a false negative
impression, and chances of missing Psychological Approach
the diagnosis are there as it is usually Neuropeptides, like substance P, neurokinin
done in the Trendelenburg position with A, and neurokinin B are released in pelvic
increased intra-abdominal pressure, which congestion syndrome.They play an integral
leads to venous collapse. Just reverse the role in the regulation of emotion pathway;
head down position and decrease the they act as a modulator for pain perception
insufflation pressure so that an accurate and are also involved in mental stress.11
diagnosis can be made.9 Psychotropic drugs, like gabapentin and
c. Pelvic venography can be the choice as amitriptyline have proven to be effective in
a diagnostic test. It can be performed treating chronic pelvic pain. After long-term
using an intravenous or transcervical therapy, analgesia was significantly better in
394 Drugs in Obstetrics and Gynecology

patients receiving gabapentin either alone day for 8 weeks, and the pain was reduced
or in combination with amitriptyline than in by week 8 of treatment, and at 14 weeks,
patients receiving amitriptyline alone.12 complete relief of symptoms was achieved
and persisted for a long time with suppression
Pain Relief in the progression of the disease. Emission
Analgesics are used very commonly to reduce computed tomography showed improvement
the pain. in the pelvic circulation.
Daflon ® is an oral micronized purified
Dihydroergotamine pleiotropic drug containing 90% diosmin and
Dihydroergotamine has systemic vaso­ 10% hesperidin, which belongs to the flavonoid
constrictor properties, due to which it can family. It improves venous tone and lymphatic
be used in the treatment of pelvic congestion drainage and reduces capillary permeability
syndrome; however, due to its narrow by protecting the microcirculation from
therapeutic margin of safety, it should be inflammatory process.27
used cautiously.13 Mechanism of action: MPFF (daflon, 500 mg)
reduces oedema by inhibiting endothelial
Nonsteroidal Anti-inflammatory Drugs activation. It blocks prostaglandins and
Nonsteroidal anti-inflammatory drugs are thromboxane A2 which further prevents
widely accepted as first-line treatment. They the inflammatory cascade resulting from
can be used as stop-gap therapy to offer the leukocyte-endothelium interaction
pain relief while further investigations are delaying the reflux and inhibits the process
performed, or more definitive treatment is of the vicious circle ending in raised venous
found. pressure. Rheological disturbances also play
a major role in these disorders as increased
Suppression of Ovarian Function venous pressure causes leakage from the
Estrogen is known to cause vasodilatation. vessels and capillaries exhibiting increased
Pelvic congestion syndrome is not common vascular permeability, leading to increase in
after menopause, suggesting that hypo­ hydrostatic pressure, and overloading of the
estrogenic states would result in symptom lymphatic network, leading to exudation of
resolution.11 plasma and oedema.28
Venoactive drugs containing the bio­
Venoactive Drugs flavonoids, diosmin and hesperidin have
Venoactive drugs containing the bio­ been proven effective in the medical therapy
flavonoids, like diosmin and hesperidin of PCS. Some research studies have shown
[micronized purified flavonoid fraction that by improving venous tone, MPFF
(MPFF)] have been studied for the treatment may restore pelvic circulation and provide
of PCS.23,24 relief from chronic pelvic pain and various
These drugs reduce venous stasis by symptoms of pelvic congestion syndrome.29
increasing venous tone, reduce capillary Side effects when taken orally—it is
hyperpermeability and improve lymphatic possibly safe for most people when used for
drainage. MPFF has been used effectively in short term. However, it can cause some side
the treatment of symptomatic patients with effects, such as gastritis, diarrhoea, dizziness,
PCS.25,26 headache, skin redness and hives, muscle
pains, altered heart rate.
A. MPFF Contraindicated in bleeding disorders, its
Gavrilov, et al. studied 85 women and found safety during pregnancy and breastfeeding
that MPFF, when given at 1000 mg per is not known.
 Pelvic Congestion Syndrome 395

Drug interactions with MPFF: When taken significant improvements in PCS, reduced
along with chlorzoxazone, it may increase anxiety levels and better sexual satisfaction.
the bioavailability of chlorzoxazone. Similar A side effect of GnRH analogues—
interactions are observed with diclofenac. symptoms of menopause, e.g. hot flushes,
Drugs that are metabolised by the osteoporosis, etc.
cytochrome P450 pathway interact with
diosmin. It delays the process of metabolism E. Danazol
of these drugs in the liver). Danazol, a 17-ethinyl-testosterone derivative,
is an anti-gonadotropic agent used for the
B. Medroxyprogesterone Acetate14
treatment of pelvic endometriosis. It has been
According to the study done by Farquhar CM, used as a treatment option for chronic pelvic
et al., medroxyprogesterone acetate (MPA) pain associated with endometriosis. It is given
along with psychotherapy, is effective in the a dose of 600 mg/day for endometriosis-
relief of symptoms in 60% of the patients, associated chronic pelvic pain of PCS. 19
and only MPA has shown symptomatic Side effects include acne, hirsutism, vaginal
improvement in 40% of the patients.15 dryness, etc.
Another study showed that when patients
with PCS were given 30 mg MPA for 6 F. Contraceptive Implant
months, pelvic congestion was reduced, as The synthetic etonogestrel (3-keto-desogestrel)
shown by venography (17 out of 22 patients), steroid implanon.
and in 16 women, the pain relief was
It is a single-rod, nonbiodegradable implant.
associated with prolonged amenorrhea. So,
It is a progestin that is used to suppress ovarian
successful ovarian suppression is an essential
function and steroid production, thereby
constituent in the treatment of PCS.16
producing a state of hypoestrogenism and
Side effects: Weight gain and bloating.
thus helps in treatment of PCS.20
C. Depot Medroxyprogesterone Acetate Implanon is a potent alternative for long-
term treatment of patients with pure PCS-
Depot medroxyprogesterone acetate (DMPA)
related pelvic pain.21
is a low-dose MPA that is injected at 150 mg/
ml, and it has better efficacy, safety, and rapid It has an advantage over MPA is that the
onset of action. In a 12-month trial, DMPA patients get back their fertility by spontaneous
depot (150 mg every 3 months) had effects ovulation soon after discontinuation.22
equivalent to GnRH agonists.17 However,
DMPA has remarkable hypoestrogenic Effectiveness of
side effects (hot flushes, bleeding and Long-term Medical Treatment
osteoporosis). There is insufficient literature evidence
regarding the long-term usefulness of
D. Gonadotropin-releasing Hormone Agonists medical therapy in controlling the symptoms
Gonadotropin-releasing hormone (GnRH) of PCS patients. GnRH agonists alone may
agonists downregulate GnRH receptors be used for 6 months or a maximum of up
which in turn reduces the synthesis of ovarian to 2 years, along with hormone replacement
hormones. therapy to avoid osteoporosis.
A randomized controlled trial showed that The limitations of using GnRH agonists for
when 47 patients diagnosed with PCS were more extended periods were its menopausal
treated with either goserelin acetate alone side effects and costs.
without the hormone replacement therapy Of all the options of medical treatment
or MPA for 6 months.18 Both drugs showed described above, implanon was found to
396 Drugs in Obstetrics and Gynecology

provide good results in pelvic pain relief or occluded blood vessels. Depending on the
with tolerable side effects in patients with morphology of the treated vessels and the
symptomatic and pure PCS.15,16,22 extent of the lesions, the diameter and length
of the stents can be selected, self-expandable
Surgical Management of stents are also available.
Pelvic Congestion Syndrome30 Complications can be hematoma at the
Patients who are resistant to medical procedure site, perforation of the vein,
management should be considered for migration of the stent, and fistula formation
surgical treatment. It includes options with adjacent structures.
like stenting, ligation, embolization or
sclerotherapy of the ovarian veins. Ligation Complications of Surgical Management of
of the ovarian veins can be done through Pelvic Congestion Syndrome
a McBurney’s incision or laparoscopically. a. Persistent pelvic pain (20%) or residual
In patients with a retroverted uterus and pain (33%) is observed even after surgical
deep thrust dyspareunia, uterine suspension administration of PCS.
should be performed laparoscopically. Very b. There can be aesthetic damage and longer
rarely, hysterectomy with bilateral salpingo- hospitalization.30
oophorectomy has been done in a few c. Ovarian failure is the known complication
cases. of ovarian vein ligation and oophorectomy
A. Embolotherapy: The principle of emboliza­ for which hormone replacement therapy
tion procedure is to occlude insufficient veins can be considered.31
as close as possible to the origin of the damage
by the lodgement of artificial material. CONCLUSION
In pelvic venous disorders, these vessels Pelvic congestion syndrome should be kept as
will be the gonadal veins, pelvic varicose a diagnosis in mind in a patient with chronic
veins, or sometimes tributary branches pelvic pain when no visible, identifiable
of the internal iliac veins. Embolization is pathology at laparoscopy is found. Detail
typically performed on outpatient or daycare history or physical examination should be
basis. This procedure is performed using done in patients with chronic pelvic pain not
metallic devices with 2% ethoxisclerol foam responding to conventional therapy. Pelvic
(sclerosing agent). venography can be performed to confirm
The embolization is performed 5 cm the diagnosis.
proximal to the origin of the gonadal Medical therapy with medroxyprogesterone
(ovarian) veins of the left renal vein or acetate should be tried as first line of manage­
inferior vena cava, taking care to close all ment for at least 3 months before surgical
the potential collateral veins in the pelvis. treatment is considered. Laparoscopic venous
After embolization of the ovarian veins, ligation of ovarian and various pelvic veins
internal iliac veins should be investigated, or embolotherapy should be selected for
and embolization should be performed in those patients not responding to medical
selective cases. management.
B. Stenting: Venous compression syndromes References
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and which may result in PCS. In such congestion syndrome. In: Howard FM, Perry
patients, a permanent intravascular stent CP, Carter JE, El-Minawi AM. eds. Pelvic Pain:
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2. Capasso P, Simons C, Trotteur G, Dondelinger 14. Schindler AE, Campagnoli C, Druckmann R,

RF, Henroteaux D, Gaspard U. Treatment of Mathias CJ, Samarage SU, Sutherland IA et al.
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3. Taylor HC. Vascular congestion and hyperemia, S, Wadsworth J, Beard RW. A randomized
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Gynecol. 1949:57: 637–53. congestion. Br J Obstet Gynaecol.
4. Raffetto JD, Qiao X, Beauregard KG, Khalil RA. 16. Reginald PW, Beard RW, Kooner JS, Mathias CJ,
Estrogen receptor-mediated enhancement of Samarage SU, Sutherland IA et al. Intravenous
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Surg. 2010 Apr;51(4):972–81. 17. Barthel W, Venous tonus-modifying effect,
5. Reginald PW, Adams J, Franks S, Wadsworth pharmacokinetics and undesired effects of
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congestion. Br J Obstet Gynaecol. 1989; 96:1148–
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6. Stones RW, Vials A, Milner P, Beard RW, medroxyprogesterone acetate in the treatment
Burnstock G. Release of vasoactive agents from of pelvic congestion. Hum Reprod.
the isolated perfused human ovary. Eur J Obstet
19. Telimaa S, Puolakka J, Rönnberg L, Kauppila A.
Gynecol Reprod Biol. 1996; 67:191–6.
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peptide but not vasoactive intestinal peptide
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10. Bush R, Comerota A, Meissner M, Raffetto JD, combined etonogestrel/ethinyl estradiol
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3–19. doi: 10.1177/0268355517692221. on pelvic pain in women with laparoscopically
11. Nicholson T, Basile A. Pelvic congestion diagnosed pelvic congestion syndrome: A
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12. Sator-Katzenschlager SM, Scharbert G, Kress 24. Gavrilov SG, Karalkin AV, Moskalenko EP,
HG, Frickey N, Ellend A, Gleiss A, et al. Chronic Beliaeva ES, Ianina AM, Kirienko AI. Micronized
pelvic pain treated with gabapentin and purified flavonoid fraction in treatment of
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 49
Premature Ovarian Insufficiency

• Shaily Agarwal • Rashmi Upadhyay

Introduction 40 years of age.1,2 In POI, the menopause

In premature ovarian insufficiency (POI) occurs at an age more than two standard
ovarian functions decrease irrevocably deviations below the mean age for that
below 40 years of age. It can have a range of specific reference population. POI affects
symptoms including bothersome menopausal medical, psychological, and reproductive
symptoms to devastating infertility. Long- aspects of women’s health.
term consequences of POI can be in the Diagnostic criteria: Oligo/amenorrhea
form of cardiovascular disorders, cognitive for at least 4 months and elevated follicle-
decline, and osteoporosis. There is substantial stimulating hormone (FSH) levels >25
evidence that these women have increased mIU/ml on two occasions >4 weeks apart.
risk of mortality. Early diagnosis is necessary [European Society of Human Reproduction
to prevent long-term implications as well and Embryology (ESHRE)].
as to minimize the effects of POI on the
quality of life. Recent advances have opened Incidence: 1 in 10,000 women by age 20; 1in
new hopes for the patients seeking fertility 1000 women by age 30; 1 in 100 women by
treatment, however the success rates are not age 40.3 Familial form of premature ovarian
that high. failure (POF) represents 4 to 31% of all POF
This chapter summarizes the current cases.4–6
issues related to etiology, diagnosis as well
as treatment of POI. ETIOLOGY
In most cases, etiology is heterogeneous and
DEFINITION OF PREMATURE unknown.
OVARIAN INSUFFICIENCY • Familial trait is recognized in 4 to 31%
POI means diminution of functions of ovaries cases.7–10
well in advance the time intended for an • Mutations in more than 50 genes have
average female. Primary amenorrhea due been reported as etiological cause of POI,
to ovarian defect presents as main feature significant.11–13
of premature ovarian failure or it may • Forkhead Box L2 (FOXL2) mutation—POI,
present as secondary amenorrhea due to in the form of blephorophimosis-ptosis-
untimely diminution of ovarian follicles/ epicanthus inversus syndrome (BPES)
arrested follicular development in less than type 1.
400 Drugs in Obstetrics and Gynecology

Table 49.1: Etiology of POI

z Bilateral oophorectomy, bilateral ovarian cystectomies
z Chemotherapy by alkylating agents and anthracyclines
Idiopathic Iatrogenic z Radiation-external beam or intracavitary
z Environmental toxins
z Pelvic vessel embolization
z Turner syndrome (45XO) or mosaic Turner (45X/46XX)
Chromosome-X defects
z Fragile X permutation
z Glycosylation disorders
Syndromic defects z Galactosemia
z Pseudohypoparathyroidism
Genetic z Follicle-stimulating hormone receptor mutations (FSHR), (recessive)
z Luteinizing hormone receptor mutations (LHR), (recessive)
Isolated defects
z FOXL2 (transcription factor involved in BPES) mutations (female-
limited defect, dominant)
z Bone morphogenetic protein 15 (BMP15) mutations (female-limited
defect, heterozygous mutation)
z Mumps oophoritis
z TB
Systemic z Malaria
Infections
defects z CMV
z Varicella
z Shigella

• Follicle-stimulating hormone receptor The most severe forms of hypergonado-

(FSHR) gene mutation-primary amenorrhea tropic ovarian failure present with absence
and truncated follicle growth, as seen in the of pubertal development and primary
Finnish population.14 amenorrhea. 16,17 Post-pubertal onset of
• The fragile X mental retardation gene ovarian failure is characterized by secondary
(FMR1)-linked with POI.15 amenorrhea which may be of sudden onset or
Ovarian surgeries constitute 64% of preceded by menstrual cycle changes (oligo­
the iatrogenic POI cases (i.e. not including menorrhea or polymenorrhea). 18 Female
bilateral oophorectomy) (Table 49.1). infertility is an irrevocable outcome of POF
which is due to the decline in ovarian reserve.
POI patients may develop diabetes due to
CLINICAL FEATURES deficiency of endogenous estrogens which
In POI, symptoms are highly variable; from seems to have protection of functioning of
features of hypoestrogenism, like vasomotor pancreatic beta-cells and increases insulin
symptoms to symptoms reflecting signs of sensitivity. Women with POI are prone for
the underlying causative disorder. Symptoms the development of cardiovascular disease
may develop suddenly or it may develop due to endothelial dysfunction, autonomic
over a longer period of time. It is also dysfunction, abnormal lipid profile, insulin
known as premature ovarian failure but the resistance and metabolic syndrome.19 These
term ‘primary ovarian insufficiency’ more women have shorter life expectancy as
accurately represents the spectrum of ovarian blood vessels and bones age early due to
dysfunction in affected women. estrogen deficiency.20–24 Alzheimer’s disease,
 Premature Ovarian Insufficiency 401

FSH value >30 U/L is indicative of ovarian

Box 49.1: Clinical features of POI
failure.
Menstrual abnormalities
The investigations should aim to establish
 Prolonged cycles, irregular cycles
the diagnosis; once the diagnosis is made,
 Primary or Secondary amenorrhea
etiology should be determined after which
Infertility/Subfertility complications should be ruled out (Table 49.2).
Menopausal symptoms: Vasomotor symptoms,
dryness of vagina, dyspareunia, sleep disorders MANAGEMENT
Cardiovascular disease
Treatment should be individualized according
Diabetes mellitus type 2
to health issues of patient. Hormone
Autoimmune: Vitiligo, hyperpigmentation
replacement therapy (HRT) is the main
Osteopenia/osteoporosis
stay of treatment. HRT must be continued
Hair loss till the normal age of menopause until
Goiter contraindicated to mitigate long-term health
Fatigue risks.
Anxiety/Depression
Alzheimer’s disease Hormone Therapy (Table 49.3)
POI: Premature ovary insufficiency Menopausal Symptom
The vasomotor symptoms are due to
hypercholesterolemia is also seen in these hypo­e strogenemia for which adequate
women. Early onset of osteopenia and systemic estrogen replacement is required.
osteoporosis is also common which have Local estrogen therapy may relieve focal
been attributed to the hypoestrogenism and symptoms. For addressing decreased libido,
hypoandrogenism (Box 49.1). testosterone supplementation along with
estrogen therapy may be useful but evidence
DIAGNOSIS about long-term safety and efficacy of
4–6 months of amenorrhea under the age androgens in menopause treatment are very
of 40 years with raised gonadotropins and few (Tables 49.4 and 49.5).
decreased estradiol is essential to make For genitourinary syndrome, options
diagnosis of POI. The hormonal levels must available are estrogen containing vaginal
be checked on two occasions 4 weeks apart. creams, nonhormonal vaginal moisturizers,

Table 49.2: Investigations of POI

Lab investigations Tests for Reason for conducting the test
Human chorionic gonadotropins To rule out pregnancy
Follicle-stimulating hormone To evaluate HPO axis
Estradiol dysfunction
Hormonal tests Anti-mullerian hormone To assess ovarian reserve
Thyroid-stimulating hormone (TSH) To assess thyroid function and
Thyroid peroxidase (TPO) antibody adrenal function
21-hydroxylase antibody
Karyotype To rule out genetic causes
Genetic studies
Fragile X mental retardation-1 (FMR1) premutation
Transvaginal ultrasound To measure antral follicle count
Imaging studies
DEXA scan To measure bone density
402 Drugs in Obstetrics and Gynecology

Table 49.3: Bioequivalent hormonal dosages for hormone therapy for primary ovarian insufficiency
Estrogen Progesterone continuous Progesterone sequential
Micronized 17-beta-estradiol Medroxyprogesterone acetate 10 mg medroxyprogesterone
(oral), 1–2 mg daily (oral) 2.5–5 mg acetate daily (oral) for 12 days
17-beta estradiol (transdermal), Micronized progesterone daily 200 mg micronized progesterone
100 mg (oral) 100 mg daily (oral) for 12 days each month
Conjugated equine estrogen
(oral), 0.625–1.25 mg
Note: Select one of the estrogen options to be combined with one of the progesterone options.

Table 49.4: Estrogen for managing vasomotor symptoms

Oral Dose (mg)
Conjugated equine estrogen 0.3, 0.45, 0.625, 0.9, 1.25 (per day)
17-beta-estradiol 0.5, 1.0, 2.0 (per day)
Ethinyl estradiol 0.005
Transdermal
17-beta-estradiol patch 0.025, 0.05, 0.075, 0.1 (twice per week)
17-beta-estradiol gel 1.5/2 metered doses
Vaginal
Conjugated equine estrogen 0.3125
17-beta-estradiol 0.25, 0.5, 1.0 (per day)
Transdermal spray
Estradiol 0.53 per spray (start with 1 spray per day, adjust up to 3 sprays per day
based on response)

Table 49.5: Combined estrogen/progestogen for treating vasomotor symptoms

Oral Dose (mg)
Estradiol/Norethindrone acetate 0.5/0.1, 1.0/0.5 (per day)
Estradiol/Drospirenone 0.5/0.25, 1.0/0.5 (per day)
Conjugated equine estrogen/Bazedoxifene 0.45/20.0 (per day)
Estradiol/Norethindrone acetate 2.5 mg/0.5 mg (per day)
Estradiol/Norgestimate 1.0/0.09 (per day; estrogen alone for 3 days followed by
estrogen/progestogen for 3 days, then repeat)
Conjugated estrogen/medroxyprogesterone 0.625/5.0 (per day; estrogen alone for days 1 to 14
then add progestogen for days 15 to 28)
Transdermal
Estradiol/Levonorgestrel 0.45/0.015 (once per week)
Estradiol/Norethindrone acetate 0.05/0.14, 0.05/0.25 (twice per week)
 Premature Ovarian Insufficiency 403

Table 49.6: Treatment for genitourinary syndrome function which leads to atherosclerosis,
ultimately leading to decreased life expectancy
Drugs Dosages
(Fig. 49.1)
Estradiol, 0.01% 2 to 4 g applied daily for
Since estrogen deficiency is the main
1–2 weeks, then 1 g applied
one to three times/week reason for cardiovascular disease (CVD),
(maintenance therapy) HRT should be initiated timely in early
Estradiol vaginal ring 2 mg released at 7.5 mg per
stages to achieve optimal cardiovascular
day over 3 months protection.26–29
Ospemifene 60 mg/day oral with food
Studies favors use of micronized natural
progesterone in HRT, as it is lipid friendly,
Conjugated estrogen 0.625 mg of conjugated
associated with reduced risk of breast cancer
vaginal cream equine estrogen per g; usual
dosage: 0.5 to 2 g applied and effectively protects the endometrial
daily for 21 days then off for lining of uterus.30,31
7 days, 1–3 times/week for Furthermore, it is very essential for these
(maintenance therapy) women to opt for therapeutic life-style
Vaginal moisturizer 10 mg applied once daily for modification.
2 weeks, then twice weekly
Bone Health
and the newer oral systemic estrogen agonist– Estrogen has important role in bone formation
antagonist ospemifene. Ospemifene is and maintaining bone health. In POI, there
approved by Food and Drug Administration is increased chance of osteopenia, osteoporosis
(FDA) as a non-hormonal therapy for and fracture which can be reduced by HRT.32–37
menopausal atrophy and dyspareunia. Emphasis should be given to lifestyle
Ospemifene is contraindicated in women with modifications, like regular exercise, balanced
history of breast cancer or thromboembolic diet, optimal calcium intake (1200 mg,
disease. Creams can be applied both in elemental calcium) and vitamin D (1000–2000
intravaginal and vulvar areas. Vaginal tablets IU/day). Avoidance of smoking is advised to
containing estradiol or the vaginal rings optimize bone health. Bone mineral density
with low-dose estradiol provide continuous (BMD) should be considered with patients
therapy for 3 months (Table 49.6). of POI.
Since bisphosphonates have very long
Cardiovascular Morbidity half-life, it should be used with caution in
Cardiovascular morbidity in patients with patients who opt for in vitro fertilization (IVF)
POI is due to decreased vascular endothelial by donor egg to achieve a pregnancy.38

Fig. 49.1: Factors associated with cardiovascular disease

404 Drugs in Obstetrics and Gynecology

Cognition are rapidly metabolized in the gut and the

In POI, risk of neurological dysfunction, liver before reaching the general circulation
cognitive impairment, and dementia is through first pass effect resulting in higher
increased.39–41 The cognitive decline is more estrone levels than estradiol because estradiol
rapid with earlier age of surgical POI.42,43 It is metabolized by mucosa of intestine.
has been suggested that early initiation of Synthetic estrogens are degraded very slowly
HRT may have protective effects on cognitive in the liver and other tissues leading to their
functions. high potency.
Half-life of various estrogens
Infertility • Conjugated equine estrogen (CEE): 10–25
Despite newer approaches and treatment hours
options in infertility management, there are • Estradiol: 16 hours (oral) and 4–8 hours
limited options from these patients as they do transdermaly.
not respond to traditional treatment options. The oral administration of EE, estriol
Their options include donor egg, or donor and other progesterone characterized by
embryo using IVF. Preconception counselling rapid rise, up to a maximum of 1–3 hours
to understand the risks of chromosomal followed by rapid decline, the level of
aberrations (balanced translocations or estradiol remains elevated for up to 12 hours
Turner mosaicism single-gene disorders- and decrease slowly during the following
FMR1 permutation carrier state) should time. Important factors in the regulation of
be offered to these patients. The risk of the pharmacokinetics are the conversion of
transmission of particular genetic mutations estrone and the formation and hydrolysis of
can be minimized by use of IVF with conjugates which are catalyzed by intestinal
preconception genetic diagnosing. Oocytes, and liver enzymes. Interindividual variations
embryos, or ovarian tissue cryopreservation mainly due to genetic or acquired differences
is a strategy that can be used to preserve in the intestinal and hepatic metabolism,
fertility in selected women. It should be while the intraindividual variations from
noted that some women having POI may day-to-day may be due to diet, alcohol, or
spontaneously ovulate (25%), and may drug consumption.
conceive and deliver (5–10%).44,45 Therefore, Non-oral administration: Estrogens are
contraception methods must be suggested to well-absorbed through the skin mucous
patients who do not want pregnancy. membranes, subcutaneous fat, transdermal
If any young woman is planned for pelvic and topical administrations produce
irradiation therapy to manage underlying therapeutic plasma levels of estradiol with
disease, surgical transposition of the ovaries lower circulating levels of estrone and
out of the pelvis should be offered to preserve estrange conjugates and require smaller dose
her reproductive potential. Ovarian function in comparison to oral route.
suppression by gonadotropin-releasing For women with POI, facts favor
hormone analogs is commonly employed in transdermal or transvaginal estradiol therapy
women anticipating chemotherapy with use as the first-line HRT. Compared to transdermal
of agents which can be gonadotoxic.46 route, the risk of thromboembolism is more
in oral routes.47–50 This risk is more increased
PHARMACOKINETICS in obese women and in presence of clotting
Estrogens (Table 49.7) disorders.49
Oral administration: All orally administered, Progestins: In women with POI, cyclic progestin
naturally occurring estrogens and their esters is recommended. Medroxyprogesterone
 Premature Ovarian Insufficiency 405

Box 49.2: Contraindications of MHT Box 49.3: Relative contraindications of MHT

 Undiagnosed vaginal bleeding  Hypertriglyceridemia
 History of endometrial and other hormone-  Active gallbladder disease
dependent gynecological cancers, active cancer  Obesity
of breast, high risk for breast cancer  Smokers
 Established CVD or increased risk of CVD
 Migraine with aura
 Previous personal or family history of venous
 Uterine fibroids, endometriosis
thromboembolism
 Moderate risk of breast cancer
 Systemic lupus erythematosus
 Severe liver disease, impaired/abnormal liver
function test known or suspected pregnancy.

Table 49.7: Comparative effects of oral versus transdermal estrogens

Effect Oral estrogen Transdermal estrogen
Pharmacokinetics Serum level peaks and troughs Serum level relatively constant
Inflammatory markers (CRP) Increased No effect
Lipid profile Triglycerides—increased Triglycerides—decreased
HDL—increased HDL/LDL—no effect
LDL—decreased
BP Increased Decreased
Insulin-like growth factor-1 (ILGF-1) Decreased No effect
SHBG Markedly increased Minimally increased
Synthesis of clotting protein Increased No effect
Source: Good man MP. Are all estrogens equal? A review of oral vs transdermal therapy. J women health (Larchmt). 2012;
21(2):161–9.

acetate (MPA) fully induces secretory DRUG INTERACTIONS

endometrium in conjunction with full
Majority of menopausal hormone therapy
replacement dose of estrogen unlike oral
(MHT) products undergo liver metabolism
micronized progesterone.51, 52 mediated by the CYP450 system. Drugs
Women who are on oral micronized like rifampicin, barbiturates increase the
progesterone, should be screened for metabolism of MHT. Hormone therapy
endometrial suppression on yearly basis. enhances effects of imipramine, phenytoin,
There are no substantial studies showing carbamazepine, reduces the effects of
difference in association of development anticoagulants, hypoglycemic agents. MHT
of breast cancer in users of MPA and oral increases the levels of thyroid-binding
micronized progesterone but some studies globulin and may increase T4 requirements.
have shown that oral micronized progesterone
may be superior in improving high-density SUMMARY
lipoprotein (HDL) levels as compared to POI is associated with long-term adverse
MPA.53 impact on woman’s health. HRT is needed
406 Drugs in Obstetrics and Gynecology

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 50
Premenstrual Syndrome

• Pradnya Supe • Shailesh Kore

Introduction releasing hormone (GnRH) analogues

Premenstrual syndrome (PMS) is defined supports this theory.7
as a condition with emotional, physical • Serotonin receptors are sensitive to estrogen
and behavioural symptoms that increase and progesterone. Progesterone increases
in severity during the luteal phase of the monoamine oxidase, which makes an
menstrual cycle, and resolve by the end of individual susceptible to depression, while
menstruation. By definition, there must be a estrogen has an antidepressant effect.
symptom-free interval after menstruation and Therefore, low estrogen levels and high
before ovulation.1,2 According to American progesterone levels in luteal phase are
College of Obstetricians and Gynecologists responsible for depression.
(ACOG), it occurs approximately 5 days • Allopregnanolone, which is the metabolite
before menstruation and ends few days after of progesterone, regulates the level of
menstruation starts and is accompanied by gamma-aminobutyric acid (GABA in the
physical and psychological symptoms as blood. GABA receptors are less susceptible
PMS.3 to allopregnanolone, since they are exposed
Symptoms normally start 14 days before to high concentrations of allopregnanolone
menses, causing mental instability, amongst prior to the luteal phase. Low concentration
which anger and irritability are the most of allopregnanolone in luteal phase causes
prominent symptoms. 4,5 Approximately, anxiety, depression and aggression.
3–8% of menstruating women are affected • PMS is more likely to develop in women
by PMS, and 15–20% of women suffer from whose mothers have had severe PMS and
subclinical PMS.6 in monozygotic twins. PMS may have a
genetic component.8
• BMI, exercise and diet also have a role in
PATHOPHYSIOLOGY
the pathophysiology of PMS.9
The causes of PMS are multifactorial and are
still unclear.7,8 Symptoms
• PMS is associated mainly with ovarian PMS is most common in women of child-
hormones. PMS is absent before puberty, bearing age; more common in women
during pregnancy, after menopause and between late 20s and mid-40s. Symptoms
during treatment with gonanotropin- usually start up to a week or so before the due
410 Drugs in Obstetrics and Gynecology

date of menstruation and disappear when the or work performance.3 PMS does not have a
bleeding starts, or a few days after. Symptoms gold standard test for diagnosis.3
vary from month to month. Laboratory diagnostic testing is not a
must but can be used. For instance, blood
Related to Water Retention count can be recommended to screen for
• Abdominal bloating anemia, and thyroid function to detect
• Breast tenderness hypothyroidism and hyperthyroidism.
• Swelling of the extremeties Prospective questionnaires, such as the
• Weight gain. daily record of severity of problems (DRSP),
calendar of premenstrual experiences (COPE)
Neuropsychiatric Symptoms among others are the most valid and reliable
• Irritability, depression, mood swings tools for diagnosis of PMS. However, these
• Forgetfulness, restlessness, tearfulness methods are difficult and time consuming as
patients have to notedown their symptoms
• Increased appetite
daily for at least two menstrual cycles.
• Anxiety, tension, confusion, headache.

Behavioural Symptoms TREATMENT10

• Fatigue Pharmacological intervention is the best
• Dyspareunia management for treatment of women with
• Tiredness PMS (Flowchart 50.1). Since premenstrual
symptoms are a normal body phenomenon,
• Loss of interest in sex, decreased libido
treatment of PMS mainly concentrates on
relief physical and psychiatric symptoms.
DIAGNOSIS Medications used mainly affect the hormonal
The ACOG has defined PMS as a condition activity through suppression of ovulation,
in which a woman experiences at least one while others affect neurotransmitter levels
affective symptom and one somatic symptom in the brain.11 Therapy for PMS should be
that cause dysfunction in social, academic, strictly modified based on patient tolerance.

Flowchart 50.1: Management of PMS

 Premenstrual Syndrome 411

1. First Step • Six small meals at frequent intervals per

Raising awareness: Majority of women are day should be preferred
unaware of PMS and do not visit a doctor • Decreased fat, sugar, alcohol consumption
for its treatment. Women in many regions do and increased fibre, vegetables and fruit
not think that PMS can be treated and they consumption are recommended
hesitate to talk to others about it. • To reduce caffeine (tea, coffee, cola) intake
Self screening: Educate them about changes and salt consumption in the diet.
occurring on ovaries and uterus every • Whole grain bread, barley, brown rice,
month to create awareness of menstrual beans and lentils should be included and
cycle. Advice them to keep a PMS diary so also foods with high level of protein and
that she can recognize the symptoms she complex carbohydrates.
has experienced and determine the type and • Iron rich food should be consumed along
severity of symptoms, when and how they with sources rich in vitamin C.
occur. • Omega-3 rich foods such as walnuts, chia
Lifestyle changes: 12 Exercise at least 30 seeds, flax seeds and fatty fishes should be
minutes a day. Aerobic exercises, including also included in the diet.
walking, running, cycling, and swimming • Calcium-rich foods, such as yoghurt and
elevate endorphins levels, and depressive green leafy vegetables are recommended.
mood is relieved.
• Adequate (at least 8 hours a day) sleep 2. Second Step
is recommended to reduce fatigue and (Non-pharmacological Treatment)
depressive mood. Cognitive behavioural therapy can be
• Smoking is recommended to be stopped, useful, it helps in decreasing all symptoms
because nicotine is known to worsen and depression. It provides relaxation,
premenstrual symptoms. management of stress and improves
• In case of general edema, clothing which is assertiveness.
loose should be preferred; in case of pedal Complementary and alternative treatments
edema , comfortable and supportive shoes are also found to be useful.
should be worn; and if edema is in breasts, • Commonest and most convincing of
supportive bras and elastic waist band are them is calcium plus vitamin D. Daily
recommended. average 1000 mg calcium supplements
Coping with stress: are recommended to improve nearly all
Measures that can be tried also are: symptoms.13,14
• Breathing exercises, • Daily 400 g magnesium intake improves
• Relaxation exercises (meditation and premenstrual symptoms associated with
yoga), depressive mood and fluid retention.
The combination of magnesium + B6 is
• Having a bath, adequate sleep,
also recommended in the management
• Finding and supporting a hobby,
of PMS.14
• Massage,
• Other treatments, e.g. vitamin E, vitex
• Biofeedback,
agnus castus, saffron, ginkgo biloba,
• Autohypnoses and evening primrose oil, lemon grass (lemon
• Acupressure. balm), curcumin, wheat seed, isoflavones,
Diet regulation: PMS is more prevalent in multivitamins, refloxology and acupuncture
women with a higher body mass index (BMI). are effective in the management of PMS,
Therefore, regulation of diet is very important. but there is insufficient evidence.15
412 Drugs in Obstetrics and Gynecology

3. Third Stage (Pharmacological Treatment) hot flashes, night sweats, insomnia and
A. Non-hormonal treatment: Selective depressive mood and long-term effects are
serotonin receptor inhibitors (SSRI) are the vaginal atrophy, increased cardiovascular
first-line treatment of choice in PMS. They disease and osteoporosis risk. All these are
increase the serotonin activity in the brain.16 due to the hypoestrogenic environment
They are quite effective in reducing the caused by GnRH analogues. Therefore,
symptoms of PMS. they should not be used for longer than
Side effects are: Nausea, insomnia, drowsi­ 6 months and if given beyond that period,
ness, fatigue and decreased libido with bone mineral density (BMI) should be
continuous use. For reduction of side effects, evaluated regularly.7
SSRIs can be used intermittently. If done so, C. Symptomatic treatment
they should be started before symptoms start Non-steroidal anti-inflammatory drugs
and should be continued throughout the (NSAIDs): These have analgesic and
luteal phase along with an antianxiety drug.7 anti-inflammatory actions that inhibit
B. Hormonal treatment: Hormonal therapy prostaglandin synthesis, which improve the
can improve physical symptoms by sup- symptoms of PMS. They also help in reducing
pressing ovulation and reducing hormonal cramps, headaches, back pain and sensitivity
fluctuations.7 in the breasts.
• Estrogen: Oral contraceptives containing • Diuretics: Diuretics help in treating the
drospirenone are the first choice among fluid retention. However, they should be
hormonal interventions. The use of hormone carefully used with other drugs, such as
pills for 24 days and inactive pills for NSAIDs as may cause renal injury.
4 days has improved significantly in PMS. D. Fourth stage (surgical treatment)
However, estrogen alone can cause breast Oophorectomy: Oophorectomy treats PMS,
and endometrial tissue hyperplasia and but estrogen replacement is necessary after
also can cause thrombosis, so it should be surgery. Along with this, progesterone
given with progesterone. Since synthetic treatment is needed to prevent endometrial
progestin causes PMS-like symptoms, it hyperplasia.
should be given in minimal doses (the
dose should not exceed the maximum Total hysterectomy with bilateral salphingo-
amount produced from corpus luteum). oophorectomy: This may be abdominal or
Alternatively, progesterone can be given laparoscopic. It is successful by preventing
directly in the form of levonorgeterol ovulation completely. However, since this
containing device.7 treatment method is permanent and serious,
• Danazol: Low-dose danazol therapy it should be preferred only if:
during luteal phase is effective in reducing 1. Pharmacological treatment fails,
the sensitivity of the breasts. 2. Long-term use of GnRH analogues is
Side effects: Irreversible virilism. Also, the required
woman should be told about the importance 3. There is an associated different gynecological
of using a reliable contraceptive method as condition requiring surgery.
danazol can cause virilism in the fetus as This treatment method should be decided
well. considering the anesthetic risks, surgical
• GnRH: GnRH analogues are most effective complications, infertility and the development
in the treatment of severe PMS. However, of surgical menopause. Hormone replacement
they are not recommended for routine use. therapy (HRT) is recommended for women
The short-term effects of these drugs are under 45 years of age after the surgery.
 Premenstrual Syndrome 413

SUMMARY 7. Green LJ, O’Brien PMS, Panay N, Craig M; on

behalf of the Royal College of Obstetricians and
PMS is a common problem and the treatment Gynaecologists. Management of premenstrual
should be tailored as per age, desired fertility syndrome. BJOG 2017;124:73–105.
and the severity of patient symptoms. The 8. European Medicines Agency, 2011. Guideline
treatment of PMS should be focused on on the treatment of premenstrual dysphoric
improving the quality-of-life of the patient. disorder (PMDD). Available from: URL: http://
www.ema.europa.eu/docs/en_GB/document_
It is important to create an awareness
l i b r a r y / S c i e n t i f i c _ g u i d e l i n e / 2 0 11 / 0 8 /
among the woman population regarding WC500110103.pdf (11.12.2017)
premenstrual syndrome. 9. Khajehei M. Aetiology, diagnosis and
management of premenstrual syndrome. J Pain
References Relief 2015;4:1–4
1. O’Brien PMS, BCackstrCom T, Brown C, 10. Halime Abay, Sena Kaplan. Current Approaches
Dennerstein L, Endicott J, Epperson CN, in Premenstrual Syndrome Management,
et al. Towards a consensus on diagnostic Bezmialem Science 2019;7(2):150–6. DOI:
criteria, measurement and trial design of the 10.14235/bas.galenos.2018.2358
premenstrual disorders: the ISPMD Montreal 11. Marjoribanks J, Brown J, O’Brien PM, Wyatt
c o n s e n s u s . Arc h Wo m e n s Me nt He alth K. Selective serotonin reuptake inhibitors for
2011;14:13–21. premenstrual syndrome. Cochrane Database
2 . Yonkers KA, O’Brien PM, Eriksson E. Syst Rev 2013; 6: CD001396.
Premenstrual syndrome. Lancet 2008;371:1200– 12. Women’s Health Concern. 2012. Premenstrual
10. syndrome (PMS). Available from: URL: https://
3. The American College Of Obstetricians And www.womens-health-concern. org/_wpress/
Gynecologists. 2015. Premenstrual syndrome wp-content/uploads/2015/02/WHC_FS_PMS.
(PMS). Available from: URL: https://www.acog. pdf
org/-/media/For-Patients/faq057. pdf?dmc= 13. Hofmeister S, Bodden S. Premenstrual syndrome
1&ts=20171211T1813370296 (11.12.2017) and premenstrual dysphoric disorder. Am Fam
4. Dhingra V, O’Brien SPM. Quantification of Physician 2016;94:236–40.
premenstrual syndrome and premenstrual 14. Daugherty JE. Treatment Strategies for
dysphoric disorder. In: O’Brien PMS, Rapkin Premenstrual Syndrome. Am Fam Physician
A, Schmidt P, editors. The Premenstrual 2017;58:183–92.
Syndromes: PMS and PMDD. London: Informa 15. Jang SH, Kim DI, Choi MS. Effects and treatment
Healthcare; 2007. p. 27–36. methods of acupuncture and herbal medicine
5. Pearlstein T, Yonkers KA, Fayyad R, Gillespie JA. for premenstrual syndrome/ premenstrual
Pretreatment pattern of symptom expression in dysphoric disorder: systematic review. BMC
premenstrual dysphoric disorder. J Affect Disord Complement Altern Med 2014;14:1–13.
2005;85:275–82. 16. Marjoribanks J, Brown J, O’Brien PMS, Wyatt
6. O’Brien S, Rapkin A, Dennerstein L, Nevatte T. K. Selective serotonin reuptake inhibitors for
Diagnosis and management of premenstrual premenstrual syndrome. Cochrane Database
disorders. BMJ 2011;342:d2994. Syst Rev 2013;6:1–159.
 51
Tamoxifen in Breast Cancer
• Meenal Sarmalkar • Ashwini Hotkar

BREAST CANCER: AN INTRODUCTION Epidemiology

International Breast Cancer
Cancers of the breast are a category of diseases
Burden (Worldwide)
that are physiologically and molecularly
diverse and that have various outcomes and Breast cancer is the most frequent type of
treatment implications.1 cancer in women. Every year, almost 1 in 2
Roughly 10% of breast cancers can be persons and 1 in 11 women are diagnosed
traced back to a direct ancestor.2 with cancer. In 2020, new cases were reported
in 24.5% of the world’s countries. One in four
women may develop breast cancer in her
lifetime (Fig. 51.1).3

Fig. 51.1: Estimated number of new cases in 2020, worldwide, females, all ages
 Tamoxifen in Breast Cancer 415

In India, National Breast Cancer Burden DIAGNOSIS OF BREAST CANCER

As per the Globocan data 2020, breast cancer
Until the symptoms have subsided or a
accounted for 13.5% (178361) of all cancer
benign-malignant state has been established,
cases and 10.6% (90408) of all deaths with a
a detailed medical history should be taken,
cumulative risk of 2.81.4
with special attention paid to any and all
breast cancer risk factors.
RISK FACTORS ASSOCIATED WITH Any suspicion in any one of the three
BREAST CANCER5 tests [clinical examination, imaging (often
Non-modifiable Risk Factors mammography and/or ultrasonography),
• Increasing age and needle biopsy], should prompt an open
• Female sex surgical biopsy to confirm a diagnosis of
• Menstrual factors breast cancer.6,7
• Early age at menarche (onset of menses Important prognostic and therapeutic
before the age of 12 years) implications stem from the histological and
molecular characteristics; hence, multiple
• Older age at menopause (onset beyond the
classifications based on these features have
age of 55 years)
been proposed.
• Nulliparity
• Family history of breast cancer Histological Classification8–10
• Genetic predisposition BReast CAncer Based on criteria of pathological features and
gene 1 (BRCA1) and BReast CAncer gene invasiveness, common breast cancers can
2 (BRCA2) mutation carriers] be divided into three major groups: Non-
• Personal history of breast cancer invasive (or in situ), invasive, and metastatic
• Race, ethnicity (white women have increased breast cancers.
risk compared with women of other races)
• History of radiation exposure. Non-invasive (or In Situ) Breast Cancer
Ductal carcinoma in situ (DCIS).
Modifiable Risk Factors
• Reproductive factors Invasive or Infiltrating Breast Cancer
• Age at first live birth (full-term pregnancy Invasive breast cancers have cancer cells that
after the age of 30 years) invade and spread outside of the normal
• Parity breast lobules and ducts, growing into the
• Lack of breastfeeding surrounding breast stromal tissue. Together,
• Obesity 90–95% of all breast cancer cases fall into
invasive subcategories.
• Alcohol consumption
• Invasive ductal carcinoma (IDC): IDC is
• Tobacco smoking
the most common type of breast cancer
• Use of hormone replacement therapy
with about 80% of all breast cancers.
• Decreased physical activity Most common being tubular carcinoma,
• Shift work (night shifts). medullary carcinoma, mucinous carcinoma,
papillary carcinoma, and cribriform
Histologic Risk Factors
carcinoma.
• Proliferative breast disease • Invasive lobular carcinoma (ILC): ILC is
• Atypical ductal hyperplasia the second most common type of breast
• Atypical lobular hyperplasia cancers and accounts for approximately
• Lobular carcinoma in situ. 10–15% of all breast cancers.
416 Drugs in Obstetrics and Gynecology

Table 51.1: Surrogate definitions of intrinsic subtypes of breast cancer (adapted from the 2013 St Gallen
Consensus)12
Intrinsic subtype definition Clinico-pathologic surrogate Type of therapy
Luminal A Luminal A-like all of: Endocrine therapy
ER and PgR positive
HER2 negative
Ki-67 ‘low’ (<14%)
Recurrence risk ‘low’ based on multi-
gene-expression assay (if available)
Luminal B Luminal B-like (HER2 negative): Endocrine therapy for all
ER positive patients, cytotoxic therapy
HER2 negative for most
and at least one of:
Ki-67 ‘high’
PgR ‘negative or low’
Recurrence risk ‘high’ based on multi-
gene-expression assay (if available)
Luminal B Luminal B-like (HER2 positive): Cytotoxics + Anti-HER2 +
ER positive Endocrine therapy
HER2 over-expressed or amplified
Any Ki-67
Any PgR
HER2 overexpression HER2 positive (non-luminal): Cytotoxics + Anti-HER2
HER2 over-expressed or amplified
ER and PgR absent
Basal-like Triple negative (ductal): Cytotoxics
ER and PgR absent
HER2 negative
Special histological types: Endocrine therapy
A. Endocrine responsive (cribriform, Cytotoxics
tubular and mucinous)
B. Endocrine non-responsive
(apocrine, medullary, adenoid
cystic and metaplastic

Metastatic Breast Cancers receptor (ER), progesterone receptor (PR),

Breast cancers that have migrated to other human epidermal growth factor receptor
parts of the body are considered to be in their (HER2) and cells proliferation regulator Ki-67
late stages, or stage IV. Lymph nodes under were identified which play a crucial role in
the arm are a common site for metastatic molecular subtyping.11
breast cancer, but other organs like the lung, Surgery, radiotherapy, chemotherapy,
liver, bone, and brain can also be affected. hormone treatment, and targeted therapies
are frequently used in tandem to treat breast
Molecular Classification (Table 51.1) cancer.12 Overexpression of ER and/or PR
Using classical immunohistochemistry promotes the development of breast cancer
(IHC) surrogate markers such as estrogen in the vast majority of people with breast
 Tamoxifen in Breast Cancer 417

cancer.13,14 Tamoxifen is the most important proliferation and a halt in the G1 phase of the
anti-estrogen chemo drug, and has been for cell cycle. The tumor’s growth and death rates
the past 40 years (Figs 51.2 and 51.3). may eventually reach a new equilibrium,
causing the tumour to shrink.17
TAMOXIFEN
Agonistic Action
Introduction Organs displaying agonist effects of
Initiated as an oral contraceptive, tamoxifen tamoxifen include the uterine endometrium
was later found to promote ovulation (endometrial hypertrophy, vaginal bleeding,
and have antiproliferative properties on and endometrial cancer); the coagulation
estrogen-dependent breast cancer cell lines. system (thromboembolism); bone metabolism
Its synthesis occurred in 1966. V. Craig [increase in bone mineral density (BMD),
Jordan is widely regarded as the ‘father of which can slow development of osteoporosis];
tamoxifen.’ Repurposing a ‘failed morning- and liver (tamoxifen lowers total serum
after contraceptive’ into the ‘gold standard’ cholesterol, low-density lipoprotein
for treating breast cancer is one of his many cholesterol, and lipoproteins (Fig. 51.2).18
accomplishments.
Structure
Drug Information Similar to diethylstilbestrol (DES), tamoxifen
As a selective oestrogen receptor modulator has both estrogenic and antiestrogenic
(SERM), tamoxifen citrate is used to treat properties, since it is a trans-isomer of the
breast cancer. Depending on the organ in triphenylethylene ring. The antiestrogenic
question, they bind to ER and produce properties of the trans conformations are
estrogenic or anti-estrogenic actions. In breast more common than those of the cis ones.18
cancer cells and blood vessels, tamoxifen
functions as a powerful oestrogen antagonist Pharmacodynamics and Pharmacokinetics
by competing with estradiol for oestrogen Absorption: Tamoxifen is readily absorbed
receptor, hence preventing estrogen- following oral administration, with peak
stimulated tumour growth. In the uterus, concentrations measurable after 3–7 hours
bone, liver, and pituitary, it plays a partial and steady-state levels reached at 4–6
agonist role.15 weeks.18
Metabolism: Several primary and secondary
Mechanism of Action
metabolites, including 4-hydroxytamoxifen,
Antagonistic Action N-desmethyl tamoxifen, and endoxifen
Tamoxifen blocks estrogen’s ability to promote (4-hydroxy-N-desmethyl tamoxifen), are
growth of human breast cancer by competing produced during the extensive cytochrome
with oestrogens (such as 17-estradiol) P450 (CYP)-mediated metabolism of
for binding to the ER. Competition with tamoxifen.21 Endoxifen, a highly effective
oestrogen for binding to ER16 is assumed to secondary metabolite, is produced primarily
be the mechanism through which tamoxifen via the 4-hydroxylation and N-demethylation
exerts its anticancer actions. This means that pathways during tamoxifen metabolism.
tamoxifen can block the growth-promoting The CYP2D6-catalyzed 4-hydroxylation of
effects of autocrine and paracrine tumour tamoxifen to 4-hydroxytamoxifen accounts
growth-promoting substances, such as for only about 7% of tamoxifen metabolism,
growth factors and angiogenic factors, by while the N-demethylation of tamoxifen
reducing the expression of estrogen-regulated to N-desmethyltamoxifen accounts for
genes. The end result is a slowdown in cell around 92%. The most major tamoxifen
418 Drugs in Obstetrics and Gynecology

Fig. 51.2: The different mechanisms of action of tamoxifen in relation to estrogen and its receptor19

Fig. 51.3: Simplistic representation of the biotransformation of tamoxifen and its metabolites20. SULT:
Sulfotransferase isoenzyme; UGT: UDP-glucuronosyltransferare
 Tamoxifen in Breast Cancer 419

metabolite, endoxifen, is produced from studies comparing tamoxifen to a placebo for

N-desmethyltamoxifen through additional preventing invasive breast cancer in high-risk
oxidation. women have been reported.
Even while 4-hydroxytamoxifen and Breast cancer prevention trial [National
endoxifen are about the same in terms of Surgical Adjuvant Breast and Bowel Project
antiestrogenic efficacy, endoxifen plasma (NSABP P-01)] was the largest trial, randomly
concentrations in patients taking tamoxifen assigning over 13,000 women with a 5-year
therapy are, on average, about 10-fold higher Gail relative risk of breast cancer of 1.66%
than those reported with 4-hydroxytamoxifen, or greater, or LCIS, to receive tamoxifen
with considerable inter-patient variability.22 or placebo. Breast cancer incidence was
reduced by 49% in the tamoxifen group after
Biological half-life: Terminal half-life is (t1/2)
a mean of 4 years of follow-up. The reduction
is 7 days. The elimination is biphasic, with
was seen exclusively in ER-positive breast
an initial half-life of around 7 hours and a
malignancies, while ER-negative tumours
terminal half-life of 7–11 days.18 Due to the
showed no discernible change.18
prolonged t1/2, 3–4 weeks of treatment are
Three separate trials—the Italian Tamoxifen
required to reach steady-state plasma levels.
Prevention Trial25, the International Breast
Excretion: After enterohepatic circulation, Cancer Intervention Study I (IBIS-I) study,
glucuronides and other metabolites are and the Royal Marsden Hospital Tamoxifen
excreted in the stool; excretion in the urine Chemoprevention Trial 24 —found that
is minimal. tamoxifen significantly reduced ER-positive
breast cancers compared with placebo. There
Distribution: Tamoxifen is more than 99%
was no impact on mortality, but the trials
protein-bound in serum, predominantly to
did not have enough participants to reliably
albumin.23
measure deaths from breast cancer or other
Dosage and Route of Administration causes. All four randomised trials found that
tamoxifen caused similar adverse effects,
20 mg once daily, orally.18
such as an increased incidence of endometrial
Indications18 cancer, thromboembolic events, cataract
development, and vasomotor abnormalities.
a. Treatment of advanced or metastatic ER(+)
Women with a Gail relative risk of 1.66%
breast cancer in pre- and postmenopausal
or greater, those aged 35 to 59, those aged 60
women.
and over, and those diagnosed with LCIS or
b. Following primary excision of an ER(+)
atypical ductal or lobular hyperplasia are the
tumor as an adjuvant treatment for
only groups for whom tamoxifen medication
pre-menopausal for 5–10 years and
is now indicated. Women who use tamoxifen
postmenopausal women for 2–5 years
also have an increased risk of developing
to decrease the risk of cancer in the
deep vein thrombosis (DVT) (1.6 times),
contralateral breast.
pulmonary embolism pulmonary embolism
c. Breast cancer prevention in pre- and (PE) (three times), and endometrial cancer
postmenopausal women with high-risk (EC) (2.5 times). Postmenopausal women
factors for 5 years. only face an elevated risk for endometrial
cancer in its first stages.
CHEMOPREVENTION Recurrence rates in ER-positive early
The first medicine to successfully reduce the breast cancer are reduced by about half
risk of breast cancer in otherwise healthy during treatment and about one-third in the
women was tamoxifen. Four prospective subsequent 5 years when treated with the
420 Drugs in Obstetrics and Gynecology

selective ER modulator tamoxifen, and breast premenopausal or perimenopausal. If the

cancer mortality is reduced by almost one- patient is still premenopausal after 5 years
third over the first 15 years when tamoxifen of treatment with tamoxifen, she should
is used.26 Extending tamoxifen treatment to be offered a further 5 years of treatment
10 years reduces breast cancer mortality even (Flowchart 51.1 and Table 51.2).
further in years 10–14.27,28
Contraindications
Optimal Duration of Therapy • Pregnancy
Results from the two largest studies with the • Lactation
longest follow-up were released, exploring • History of DVT or PE
the effects of tamoxifen treatment for longer
• Hypersensitivity to tamoxifen.
than 5 years. Women who took tamoxifen for
10 years rather than 5 years experienced a 25%
Drug Interactions
reduction in recurrence and a 3% reduction in
mortality risk, with the advantage becoming Anti-depressants
more obvious after year 1027, according to the Recent research has found no evidence
adjuvant tamoxifen: Longer against shorter for a clinically relevant effect of using
(ATLAS) experiment. The results of the antidepressants that suppress CYP2D6
aTTom (adjuvant Tamoxifen—To offer more?) activity, like selective serotonin reuptake
experiment, in which patients were randomly inhibitors (SSRIs), on tamoxifen’s activity
allocated to receive tamoxifen for either 5 against breast cancer. Due to their low potency
or 10 years, corroborated these findings. as CYP2D6 inhibitors, the antidepressants
Breast cancer recurrence and mortality rates venlafaxine and desvenlafaxine are not
were both reduced in those who received contraindicated here. However, caution
treatment for longer.28 These data prompted should be exercised when mixing SSRIs with
the American Society for Clinical Oncology CYP-metabolized medicines. It is important
(ASCO) to revise its recommendations for to use caution while dosing SSRIs like
using endocrine therapy as part of adjuvant escitalopram and citalopram in the elderly
treatment. It is suggested that women take due to a decrease in CYP2C19 metabolism
tamoxifen for a period of 5 years if they are that occurs with age.

Flowchart 51.1: Algorithm for choice of endocrine therapy in the adjuvant setting

OS: Ovarian suppression; Tam: Tamoxifen; AI: Aromatase inhibitor (letrozole, anastrozole, exemestane)30
 Tamoxifen in Breast Cancer 421

Rifampicin • Irregular menses

Strong CYP3A4 inducers should not be used • Ocular toxicity
with tamoxifen. Strong CYP3A4 inducers (e.g. • Thromboembolic events
rifampin) reduce tamoxifen efficacy.31 • Thrombocytopenia or leukopenia
• Endometrial cancer (low grade) endo­
Adverse Effects metrial hyperplasia and polyps.
Tamoxifen is extremely well-tolerated by
most patients with breast cancer. In early Menopausal Symptoms
trials of tamoxifen for adjuvant therapy, fewer Menopausal symptoms are the most common
than 5% of patients withdrew from therapy side effect of tamoxifen, and they occur more
because of toxicity. frequently in premenopausal women than in
• Menopausal symptoms postmenopausal women. Up to 80% of people
• Hot flashes on tamoxifen report experiencing hot flashes
• Atrophic vaginitis throughout treatment (Fig. 51.4).31

Table 51.2: Tamoxifen therapy in adjuvant setting; benefits and adverse effects and their management29

Therapeutic Benefit Adverse effects

agent
Tamoxifen Type Prevalence Management
When used for 5–10 years in the adjuvant setting, is associated with a 9.2% ± 1%, absolute
reduction in breast cancer mortality over 15 years
Hot flashes 40–80% z Lifestyle changes in dressing, bedding

z For severe symptoms try SSRI, SNRI

(venlafaxine, citalopram, escitalopram,
sertraline)
z Avoid paroxetine, fluoxetine

Venous thrombo- Relative increase z Use caution in patients with factor V Leiden
embolism (VTE) in VTE by a hetero or homozygosity, recent fracture,
factor of 2–3 recent surgery, immobilization, prior history
Pulmonary of VTE
embolism: 0.2% z Treat VTE per guidelines
over 5 years
Endometrial Relative increase z No routine surveillance for standard-risk
cancer by a factor of patients
2.7 (1.2/1000 z Premenopausal patients: Any irregular

patient-years) vaginal bleeding to be investigated with

endometrial biopsy
z Postmenopausal patients: All vaginal
bleeding to be investigated with endometrial
biopsy; otherwise, only normal routine
gynecologic exam per standard guidelines.
Ocular Cataract: 3.7% z Consider yearly eye examination
pathologies of patients
Fatty Iiver disease Up to 33% of z No routine screening recommended

patients z If fatty liver documented, obtain liver

enzymes every 3–6 months

z Stop tamoxifen if liver enzymes exceed

twice the upper limit of normal

422 Drugs in Obstetrics and Gynecology

Venous Thromboembolism Fatty Liver Disease

In older women, tamoxifen increases the Overall, tamoxifen has a favourable effect
incidence of venous thromboembolism by a on lipid profile.39 However, it was recently
factor of two to three.32,33 Extending therapy discovered that one-third of tamoxifen patients
in the adjuvant situation from 5 to 10 years develop fatty liver as a side effect, as detected
appears to increase the risk. Surgery, fracture, by ultrasonography. Because steatohepatitis
immobilisation, and heterozygous factor V rarely has serious consequences, frequent
Leiden carrier status, all increase the likelihood screening is unnecessary. You can keep
of complications. For women younger than taking tamoxifen unless your liver enzymes
54 years of age, however, extending tamoxifen are twice as high as normal. Liver function
use to 10 years (0.2%) does not appear to raise tests should be performed on patients with
the risk of fatal pulmonary embolism.32,34 diagnosed fatty liver disease every 3–6
Therefore, individuals undergoing surgery months.29
must abstain from taking tamoxifen for
4 weeks before to the procedure.35 BENEFITS OF TAMOXIFEN31
Endometrial Cancer • Slows development of osteoporosis in
Although the absolute annual risk of endo­ postmenopausal women.
metrial cancer remains low at 1.2 per 1000 • Lowers total serum cholesterol, low density
patient-years, tamoxifen has been linked to lipoprotein cholesterol and lipoprotein and
a risk that is enhanced by a factor of 2.7 for raises A-I levels, potentially decreasing the
both endometrial cancer and uterine sarcoma. risk of myocardial infarction.
While taking tamoxifen, a patient has an
increased risk of cancer, which gradually TAMOXIFEN AND CHEMOTHERAPY
decreases once treatment is stopped.37 According to the results of the Southwest
Guidelines for monitoring uterine cancer Oncology Group Intergroup Trial S8814 (INT-
in tamoxifen users are as follows:36 0100), tamoxifen is currently administered
• A hysteroscopy or endometrial biopsy sequentially after chemotherapy rather
(or both) should be performed on pre­ than concurrently. In this trial, 1,477 post­­-
menopausal women who experience menopausal women who tested positive for
a b n o r m a l b l e e d i n g . Wo m e n p a s t receptors and lymph nodes were randomly
menopause who experience unexpected assigned to receive either tamoxifen
vaginal bleeding, should follow the same monotherapy, tamoxifen plus cyclophospha­
advice. mide, doxorubicin and fluorouracil (CAF),
• Routine age-appropriate screening is or CAF followed by tamoxifen. Eight-year
advised for postmenopausal women disease-free survival (DFS) estimates were
without vaginal bleeding. 67% for sequential CAF followed by tamoxifen
Ocular Pathologies
and 62% for concurrent CAF + tamoxifen (p =
0.045), demonstrating somewhat lower DFS
An increased risk of cataracts (3.7%), corneal and OS (overall survival) for the concurrent
pigmentation (reversible), and retinal deposits arm.40
(irreversible) in combination with macular
edoema and vision loss (38%) have all been
linked to tamoxifen exposure. Although these TAMOXIFEN RESISTANCE
problems are less common, it is nevertheless De novo or acquired resistance may occur
suggested that everyone get an annual eye after treatment, limiting the effectiveness of
examination.38 tamoxifen in many patients.
 Tamoxifen in Breast Cancer 423

Types of Tamoxifen Resistance resistant tumours retain ER expression, and

a. Loss of ER (ER isoform) expression and ER many of these tumours shrink in response to
gene alterations, such as deletion and point second-line hormone therapy.41
mutation, are hallmarks of de novo (at the Patients with ER-positive breast cancer,
onset of treatment) disease. Patients with and notably those with metastatic disease,
cytochrome P4502D6 (CYP2D6) deficiency typically benefit most from endocrine
are resistant to tamoxifen because they lack therapy. There is evidence that some breast
the enzyme necessary to convert the drug tumours, despite expressing ER, are more
into its active metabolite, endoxifen. resistant to endocrine therapy than others.
b. Resistance to endocrine therapy was Molecular profiling studies performed over
acquired by nearly all metastatic patients the past decade have provided evidence for
following treatment. this theory by allowing the classification of
Although ER is present in many tumours, ER-positive tumours into the luminal A and
some of them become hormone-independent luminal B subtypes. While luminal A is more
on their own, and some tumours that are placid and endocrine-responsive, luminal B
originally ER-positive, eventually become is more aggressive and endocrine-resistant
ER-negative. At least 66% of tamoxifen (Fig. 51.4).41

Fig. 51.4: Scheme showing the different mechanisms of tamoxifen resistance42

424 Drugs in Obstetrics and Gynecology

Causes of Tamoxifen Resistance42 the P-2 study, but raloxifene was linked to
1. Loss of ERα expression and function lead fewer side effects. New research shows that
to disappearance of the molecular target raloxifene is just as effective as tamoxifen in
for tamoxifen preventing invasive breast cancer, with less
2. Altered expression of coactivators or side effects. Long-term tamoxifen use was
coregulators that plays a critical role in associated with a considerably increased
ER-mediated gene transcription chance of developing endometrial cancer.43
3. Ligand-independent growth factor • Aromatase inhibitors trial: Aromatase
signaling cascades that activate kinases inhibitors dramatically lower oestrogen
and ER-phosphorylation concentrations, blocking the activation of
4. Altered availability of active tamoxifen ER-positive breast cancer cells, but only in
metabolites regulated by drug-metabolizing postmenopausal women. Recurrence rates
enzymes, such as CYP2D6 are decreased more by aromatase inhibitors
when taken for 5 years compared to when
5. Regulation of autophagy and/or apoptosis
taken for 5 years following 2–3 years of
6. ER-negative cancer stem cells that differen­
tamoxifen.44
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 52
Tibolone as Postmenopausal
Hormonal Therapy
• Seema Mehrotra • Pooja Mishra

Introduction condition characterized by weakened

Menopause is a natural biological process bones that are more prone to fractures.
that occurs in women, typically between
the ages of 45 and 55 years. This hormonal TIBOLONE
change can lead to various physical and Tibolone is a synthetic steroid that has been
psychological symptoms that can impact a used in hormone replacement therapy
woman’s quality-of-life. (HRT) for menopausal women. It has a
Some of the symptoms associated with unique pharmacological profile due to its
menopause include: conversion into three active metabolites:
• Musculoskeletal pain: Fluctuations in hor- 3α-hydroxytibolone, 3β-hydroxytibolone,
mone levels, especially estrogen, can lead and ∆4-isomer. Each of these metabolites
to joint and muscle discomfort in some has specific effects on different tissues and
women. organs, contributing to tibolone’s therapeutic
actions.
• Insomnia: Changes in hormone levels and
T h e 3 α - h y d ro x y t i b o l o n e a n d 3 β -
hot flushes can disrupt sleep patterns,
hydroxytibolone metabolites provide
leading to insomnia or difficulty in falling
estrogenic effects in tissues like the vagina,
and staying asleep.
brain, and bone, while having minimal
• Forgetfulness: Some women may experience effects on the endometrium. This is beneficial
cognitive changes, such as forgetfulness or because it reduces the risk of endometrial
difficulty with memory during menopause. proliferation and associated issues, like
• Hot flushes: Hot flushes or night sweats are vaginal bleeding. These metabolites also
common symptoms of menopause, caused interact with estrogen receptors, leading to
by hormonal fluctuations. improved bone mineral density and reduced
• Sexual dysfunction: Decreased estrogen bone turnover, like traditional hormone
levels can lead to changes in vaginal replacement therapy.
tissues, reduced lubrication, and decreased Tibolone’s effects on the breast are unique.
sexual desire in some women. The hydroxymetabolites inhibit the action
• Osteoporosis: After menopause, the decline of sulfatase, which reduces the conversion
in estrogen levels can result in bone loss of estrone to estradiol, resulting in lower
and increase the risk of osteoporosis, a estrogenic stimulation. The ∆4-isomer has
428 Drugs in Obstetrics and Gynecology

progestagenic and androgenic properties, half-lives. Tibolone is mainly eliminated in

binding to progesterone and androgen the form of sulfated metabolites through
receptors. The progestational activity helps the feces, with some excretion via the urine.
reduce endometrial proliferation, which Renal function does not significantly affect
means that additional progestins are not the elimination of tibolone.
required for therapy. The androgenic effects
can affect sex hormone-binding globulin Effects of tibolone on various tissues: Effects on
levels and lead to increased levels of unbound bone—tibolone stimulates estrogen receptors
testosterone. in bones, leading to decreased osteoclast
In hepatic tissue, the ∆4-isomer affects lipid activity and restoration of the balance between
levels, reducing high-density lipoproteins bone resorption and formation. This therapy
(HDL) and triglycerides, while leaving is commonly used for the prevention and
low-density lipoproteins (LDL) relatively treatment of osteoporosis. Unlike traditional
unchanged. HRT, which requires continuous use for
osteoporosis protection, tibolone has shown
Pharmacokinetics positive effects on bone density even after
Absorption and distribution: Tibolone is withdrawal.
rapidly and extensively absorbed after oral Effects on the breast: Tibolone exhibits
administration. However, due to extensive effects on breast tissue that differ from those
metabolism, the plasma concentrations of of estrogen. Its metabolites inhibit enzymes
the parent compound (tibolone itself) remain involved in converting estrone sulfate to
very low. Instead, plasma concentrations of estradiol, leading to reduced estrogenic
the metabolites (3a-OH-tibolone, 3β-OH- activity in breast tissue. Observational
tibolone, and delta-4-isomer of tibolone) are studies suggest that tibolone may have a
higher and appear within 30 minutes, peaking lower incidence of breast tenderness and pain
around 1–1.5 hours after administration. compared to traditional HRT. While some
Food does not significantly affect the extent studies have indicated a potential increased
of absorption. risk of breast cancer with estrogen-containing
Metabolism: Tibolone undergoes metabolism HRT, data on tibolone’s impact on breast
through multiple pathways in the GI tract cancer risk are still inconclusive and require
and liver. The metabolites include estrogenic further investigation.
(3α-OH-tibolone and 3β-OH-tibolone) and
Effects on cardiovascular parameters:
progestogenic/androgenic (D-4-isomer)
Historically, HRT was believed to provide
compounds. The activity of tibolone on
cardiovascular protection in postmenopausal
different tissues depends on the activity of the
women, but recent studies have raised doubts
enzyme sulfatase, which converts tibolone to
about its benefits. Tibolone affects various
its active metabolites. Tibolone differs from
parameters related to cardiovascular health.
estrogens in that sulfatase activity is inhibited
It has been shown to reduce triglyceride,
in breast tissue, resulting in reduced estradiol
total cholesterol, and lipoprotein levels,
formation in the breast.
but it may transiently lower high-density
Elimination: The elimination half-life lipoprotein cholesterol (HDL-C). Tibolone also
of the 3α- and 3β-hydroxymetabolites impacts the fibrinolytic system, potentially
is approximately 6–8 hours. The parent explaining its lack of association with venous
compound (tibolone) and the ∆4-isomer do thromboembolic events. However, its long-
not reach appreciable plasma levels, making term effects on cardiovascular outcomes
it difficult to determine their elimination require further research.
 Tibolone as Postmenopausal hormonal Therapy 429

Thromboembolic events: Clinical trials • Menopausal symptom relief: Tibolone

have not demonstrated an increased risk is effective in alleviating menopausal
of venous thromboembolic events with symptoms, such as hot flashes, night
tibolone use. Tibolone may be discontinued sweats, vaginal dryness, and mood
temporarily before elective surgery that swings. By activating estrogen receptors,
involves prolonged immobilization. it helps restore hormonal balance in
Additional considerations: Tibolone is not menopausal women, reducing discomfort
recommended for patients with liver disease and improving their overall quality-of-life.
or a history of hepatotoxicity. Vaginal bleeding • Bone health: During menopause, women
or spotting may occur in some women during are at an increased risk of osteoporosis
the initial months of therapy. Monitoring of due to declining estrogen levels. Tibolone
fluid retention and cardiovascular parameters can help prevent bone loss and reduce the
is essential in patients who may be prone to risk of fractures by enhancing bone density
changes in fluid status. Tibolone does not and strength.
have significant drug interactions and is • Vaginal health: As estrogen levels decrease,
not dependent on renal function for dosage vaginal tissues may become thinner and
adjustments. Routine physical examinations, drier, leading to discomfort and pain during
including family medical history, blood intercourse. Tibolone’s estrogenic effects
pressure checks, and pelvic examinations, help restore vaginal health by promoting
are recommended during tibolone therapy. vaginal lubrication and increasing the
The women’s health initiative (WHI) trial thickness of the vaginal lining.
results suggest that HRT, including tibolone, • Cardiovascular protection: Estrogen has a
should be prescribed at the lowest effective protective effect on the cardiovascular
dose and for the shortest duration necessary system by maintaining healthy blood
to address menopausal symptoms while vessels and regulating cholesterol
balancing potential risks. levels. Tibolone’s estrogenic activity
Dose: Oral formulation in tablet form. can provide cardiovascular benefits for
postmenopausal women, reducing the risk
Tibella: 2.5 mg, daily. of heart disease and stroke.
Oral: Swallow the tablet whole with water/ • Mood enhancement: Menopausal women
fluid irrespective of meal, daily at same time. often experience mood swings and
If doses are missed may be taken as soon emotional disturbances due to hormonal
as they are remembered within 12 hours of fluctuations. Tibolone’s effects on neuro­
the usual time. If ≥12 hours have elapsed, the transmitter systems, including serotonin
missed dose should be skipped and the next and dopamine, may help stabilize mood
dose taken at the usual time. and improve emotional well-being.
Clinical uses: Tibolone is prescribed • Libido improvement: Tibolone’s androgenic
for short-term treatment of vasomotor properties can boost sexual desire in some
symptoms associated with menopause women by stimulating the androgen
in postmenopausal women. It may offer receptors responsible for sexual function.
advantages over traditional HRT in certain • Prevention of endometrial hyperplasia:
aspects, but further studies are needed to Tibolone’s progestogenic activity can
fully understand its long-term effects on help protect the endometrial lining of the
various tissues and disease outcomes. Here uterus from excessive growth, reducing
are some of the main uses and benefits of the risk of endometrial hyperplasia and
tibolone: potential cancer.
430 Drugs in Obstetrics and Gynecology

• Tibolone is not intended for contraceptive manifest as hives, swelling, difficulty

use and should only be administered to breathing, or severe skin reactions.
patients with an intact uterus. It is crucial to note that the list above is
not exhaustive, and other side effects may
Adverse Reactions occur. Additionally, some women may not
While tibolone is generally well-tolerated experience any adverse reactions while
by most women, like any medication, it can taking tibolone.
cause adverse reactions in some individuals.
The severity and occurrence of these side Contraindications
effects can vary from person to person. Some 1. Hormone-sensitive cancers: Such as breast
of the potential adverse reactions of tibolone cancer or endometrial cancer. Since tibolone
may include: has estrogenic effects, it could potentially
• Breast discomfort: Some women may stimulate the growth of hormone-sensitive
experience breast tenderness or enlarge­ tumors.
ment while taking tibolone. 2. Undiagnosed vaginal bleeding
• Vaginal bleeding: Irregular vaginal bleeding 3. Previous blood clotting disorders
or spotting may occur, especially during 4. Hypersensitivity to tibolone
the first few months of tibolone treatment. 5. Pregnancy and breastfeeding
This may be a reason to seek medical
6. Porphyria.
advice to ensure there are no underlying
It is crucial to inform your healthcare
issues.
provider about your complete medical
• Headaches: Headaches can be a side effect
history, including any underlying health
of tibolone use, although they are usually
conditions or medications you are taking,
mild and temporary.
before starting tibolone or any other hormone
• Gastrointestinal disturbances: Tibolone may
replacement therapy.
cause gastrointestinal symptoms, such
as nausea, abdominal pain, bloating, or
Dosage Forms Specific Issues
indigestion.
• Weight changes: Some individuals may Tibolone may contain lactose and should
experience weight fluctuations while on not be used in individuals with galactose
tibolone therapy. intolerance, congenital lactase deficiency, or
• Mood changes: While tibolone can improve glucose-galactose malabsorption syndromes.
mood in some women, it may cause mood
swings or changes in others. In some cases, Other Warnings/Precautions
it can lead to depressive symptoms. • Tibolone should be administered only to
• Skin reactions: Rarely, tibolone can cause patients with an intact uterus. It should not
skin reactions, such as rash or itching. be used for combined hormone therapy,
• Hair changes: Some women may experience and a separate progestogen should not be
changes in hair growth patterns or hair added to tibolone therapy. The treatment
loss. should be reserved for symptoms affecting
• Cholelithiasis: There is a small increased risk the quality-of-life.
of developing gallstones (cholelithiasis) • The risks vs benefits of tibolone therapy
while taking tibolone. should be carefully considered. Tibolone
• Fluid retention: Tibolone may cause mild treatment should continue only as long as
fluid retention in some individuals. the benefits outweigh the risks.
• Allergic reactions: In rare cases, tibolone • In surgery patients, tibolone therapy
can trigger allergic reactions, which may should be interrupted 4 to 6 weeks before
 Tibolone as Postmenopausal hormonal Therapy 431

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 53
Treatment of
Abnormal Uterine Bleeding
• Ruchika Garg • Rajshree Katke

Introduction PALM-COEIN classification proposed by

Abnormal uterine bleeding (AUB) describes the Menstrual Disorders Working Group of
any disturbance in volume, regularity, FIGO in 2011, allows for the standardization
frequency, or duration of menstrual flow. of terminology for clinicians. Etiologies of
This terminology was standardized by the AUB are classified as being either related
International Federation of Gynecology or unrelated to uterine. The etiologies
and Obstetrics (FIGO) in 2009 and replaced unrelated to structural abnormalities are
the previously used ‘dysfunctional uterine further subdivided into categories following
bl eed i n g ( DUB) . ’ AUB i n cl u d e s t h e the acronym COEIN: Coagulation disorders,
subgroups of heavy menstrual bleeding ovulatory disorders, endometrial disorders,
(HMB), intermenstrual bleeding (IMB), iatrogenic causes, and not otherwise classified
and prolonged menstrual bleeding.3 HMB causes. This classification is now widely
has replaced the term ‘menorrhagia’ and is accepted in obstetrics and gynecology.
defined as excessive menstrual blood loss, Abnormalities—the acronym PALM: Polyps.
which interferes with a woman’s physical, Adenomyosis, Leiomyoma, and evaluation
social, emotional, and/or material quality- of acute AUB should begin with a rapid
of-life and which can occur alone or in assessment of the patient’s clinical status,
combination with symptoms. 4 IMB has especially hemodynamic stability and
replaced the term ‘metrorrhagia’ and refers volume status. Orthostatic vital signs can be
to any bleeding that occurs between clearly helpful to further evaluate a patient’s volume
defined and predictable menstrual cycles status, even when she is asymptomatic and
(i.e. typically every 21 to 35 days).5 The term vitally stable at rest. Some patients may
acute AUB describes an episode of bleeding present with an acute worsening of chronic
that, in a clinician’s opinion, is of sufficient HMB, or after a prolonged bleed, and so
quantity to require immediate intervention manifest acute symptoms of hypovolemia or
to prevent further blood loss. Chronic AUB anemia. Young, otherwise healthy patients
refers to abnormality in menstruation over with acute AUB and those with chronic
the majority of the past 6 months.3 AUB may compensate for the blood loss
The evaluation and management of AUB and therefore may not manifest symptoms
will be most effective when the most likely or aberrations in vital signs at the time of
etiology of bleeding is considered. The presentation. Continued bleeding in this
 Treatment of Abnormal Uterine Bleeding 433

setting can lead to acute decompensation pads or tampons per hour an at increased
requiring rapid resuscitation. Patients risk for acute decompensation and need
with hemodynamic instability should be for resuscitation, questions about timing of
resuscitated as any trauma patient would bleeding should include whether the IMB
be. Two large bore IVs, canulas should or postcoital bleeding. Eliciting associated
be placed, even if the patient does not symptoms of pain with endocrinologic
require immediate resuscitation given the or other symptoms may suggest systemic
impending risk of acute decompensation. etiology. Elicit a detailed family history,
Resuscitation should begin with isotonic ask about systemic conditions, infections,
fluids, with transition to cross-matched medications and coagulation.
blood when available. It is not necessary Pelvic examinations should be performed
to await laboratory results to begin blood in a private room with a chaperone present.
transfusion in the setting of hemodynamic Ensure that all supplies are present prior to
instability. O-negative blood can be used in beginning including a stretcher with stirrups,
the absence of a type and screen. Vital signs along with gloves, a speculum, adequate
should be monitored frequently during and lighting, and several large and small cotton
after resuscitation efforts. If the patient has swabs. Whereas bleeding that does not pool
not stabilized after three units of blood, or is not actively coming out of the os on or
especially if she is becoming increasingly is dark red is likely non-acute. Visualization
unstable, massive transfusion protocol of the cervix can optionally be technically
should be started in accordance with hospital difficult, if there are many or large fibroids
operating procedure to ensure replacement distorting the orientation of the uterus. In
of clotting factors and platelets as well as these situations, it may be more helpful
blood. Extensive research has been done to to begin with a bimanual examination to
best quantify how much menstrual blood evaluate the orientation, size, and regularity
loss a patient is experiencing. Previously, of the cervix uterus and then proceed to
quantitative measurements were used and speculum examination.
HMB was defined as more than 80 ml per
cycle. LABORATORY AND DIAGNOSTIC TESTING
Subjective pictorial blood loss charts have Do urine pregnancy test upon presentation
not correlated well with actual blood lose and and all patients presenting with AUB
also do not account for the impact AUB has should have a complete blood count (CBC)
on a patient’s life. Instead, the focus should performed to evaluate for anemia. The CBC
be on the frequency, regularity, duration, should be evaluated in conjunction with a
and volume of bleeding, as well as how this patient’s clinical picture and not be used alone
impacts the patient’s lifestyle.6 A patient to dictate management, specifically need for
should be asked if cycles are frequent, normal, transfusion. A patient with acute AUB may
infrequent, or absent, with either regular or have a normal hemoglobin, if her body has not
irregular intervals, if the duration of bleeding yet equilibrated, and similarly a patient with
is prolonged, normal, or shortened, and chronic AUB may not report any symptoms
if the flow is heavy, normal, or light.5 In but be severely anemic. In the acute setting,
regard to HMB, common questions include a blood type and cross should be ordered in
the number of menstrual products used on case the patient requires transfusion. Pelvic
the heaviest day, size and number of blood ultrasound, including transvaginal and
clots, and the need for simultaneous use of transabdominal approach, as the first-line
menstrual products. 6 Anecdotes patients imaging modality. But diagnosing genital
who report soaking one or more menstrual pathology, pelvic ultrasound, specifically
434 Drugs in Obstetrics and Gynecology

transvaginal sonography (TVS) is usually the for venous thromboembolism (VTE) and
best way to evaluate the endometrial lining. cost associated with its use. Intravenous or
Structure abnormalities, such as submucosal oral tranexamic acid can also be used as an
leiomyoma and endometrial polyps may also adjuvant to hormonal therapies to slow or
be visualized on TVS; however, saline infusion stop acute AUB. A study of trauma patients
sonohysterogram (SIS) is ultimately superior showed a statistically significant reduction in
for this evaluation. Computed tomography death from bleeding and all cause mortality
(CT) is indicated when malignancy or non with the early use of tranexamic acid. 10
gynecologic etiology are suspected. Magnetic Moreover, there was no significant increase
resonance imaging (MRI) can better delineate in vascular occlusive events. Studies in cases
uterine leiomyomata, but are typically not of postpartum hemorrhage have also shown
required for acute or first-line diagnosis. that early administration of tranexamic
acid reduces blood loss, bleeding-related
ACUTE MANAGEMENT mortality, and requirements for blood
Ultimately, management of AUB must transfusion.
account for multiple factors including In concert with medical treatment, if AUB
the patient’s age, reproductive life goals, is very severe, hemostasis can be attempted
medical history, and ability to access health with mechanical tamponade to temporize
care. In the acute setting, the patient’s bleeding and allow sufficient time for
hemodynamic stability and severity of bleed medications and blood transfusion to achieve
guide immediate management. Any further their full benefit. The vagina can be packed
management of AUB should be tailored to the with long continuous sterile gauze. This is
most suspected etiology whenever possible. especially useful if bleeding is deemed to be
First-line treatment for acute AUB is medical vaginal or cervical in nature. If brisk uterine
management. However, there is limited data bleeding is suspected, balloon tamponade
on the success rates of various regimens. Two may be more beneficial. Depending on the
small studies of women treated with high- estimated size of the uterus, a Foley catheter,
dose progestin for acute AUB found high rectal balloon, or Bakri balloon can be placed
rates of rapid decrease in bleeding and 76% to within the uterus, ensuring the balloon is
100% cessation of bleeding within 3 to 5 days. proximal to the internal os and inflated to 40
High-dose progestin was administered as to 60 ml in size. It is important to note that
oral medroxyprogesterone acetate (provera) distension of the vagina with sterile gauze
20 mg, TID, for 3 to 7 days +/– 20 mg daily for packing can kink the ureter causing urinary
21 days or as intramuscular depot medroxy- retention. It is advised that Foley catheter
progesterone acetate (DMPA) 150 mg once.8,9 be placed in the bladder prior to placement
Acute AUB can also be controlled with high- of vaginal packing or balloon tamponade.
dose oral estrogen, which is as effective as Moreover, precise urine output is helpful
high-dose progestin, when provided as a in judging a patient’s volume status and
combined oral contraceptive (COC), TID for adequacy of resuscitation efforts. If a patient
7 days followed by daily for 21 days.8 For can be stabilized and bleeding temporized,
patients with contraindications to estrogen uterine artery embolization (UAE) by
use, like pre-existing cardiovascular risk interventional radiology may be considered.
factors or known or suspected malignancy, Several studies have illustrated the
high-dose progestin is first-line therapy. successful use of levonorgestrel-releasing
High-dose intravenous estrogen has little intrauterine system (LNG-IUS) in treating the
data to support its efficacy and is not ultrasound imaging bleeding symptoms of
recommended because of the higher risk adenomyosis.24–28 A randominzed controlled
 Treatment of Abnormal Uterine Bleeding 435

trial (RCT) comparing LNG-IUD showed fibroids given its high sensitivity.30 Fibroids
equivalent outcomes for bleeding at short- can be classified as pedunculated, subserosal,
term follow-up the minor superiority of myometrial and submucosal.
LNG-IUS in some aspects of quality-of-life.
Long-term use showed satisfaction rates of Leiomyomas
72% with the levonorgestrel-intrauterine In asymptomatic patients, expectant
disease (LNG-IUD) with symptomatic management is encouraged. In patients
decrease in uterine volume, and the who are pregnant at the time of diagnosis,
option for future fertility. Other hormonal it is important to counsel them regarding
contraceptive methods may also be effective the possibility of myomal degeneration and
in decreasing adenomyosis-mediated HMB pain as the pregnancy progresses and the
and dysmenorrhea. Hysterectomy remains growing uterus requires increased blood flow
the definitive treatment to patients who no to support the growing fetus. Anticipatory
longer desire fertility. guidance can also be provided regarding
Uterine fibroids are benign smooth muscle the possible symptomatology of uterine
tumors. Their growth is dependent on fibroids so that a patient may follow-up for
endogenous estrogen and progesterone, gynecologic care if she becomes symptomatic
although they also contain aromatase allow and desires treatment in the future.
for endogenous production of estrogen Medical management allows for the
to stimulate their own growth. Fibroids improvement of symptoms without the risks
are very common, occurring in up to 80% of surgery and allows for fertility preservation.
of women by age 50. 30 They occur most The adverse side effects of some medications
often during the reproductive years, when limit their use, and patients may outgrow
estrogen and progesterone levels are highest, the therapeutic effects of medical treatment
and usually decrease in size following eventually requiring surgical management.
menopause. Nearly, 50% of patients with Non-hormonal medical treatments include
fibroids are asymptomatic: However, fibroids non-steroidal anti-inflammatory drugs
can cause significant symptoms. Symptoms (NSAIDS) and tranexamic acid. NSAID can
are characterized as bleeding symptoms improve dysmenorrhea and HMB associated
or bulk symptoms. Bleeding symptoms with fibroids by blocking prostaglandin
most commonly are HMB and prolonged synthesis.
menstrual bleeding and are attributed to A 2013 Cochrane review found a 30%
increased endometrial surface, increased decrease in menstrual bleeding with NSAID
uterine vasculature, and changes in uterine use compared to placebo. Tranexamic acid
contractility, as well as possible abnormalities is also helpful to decrease HMB associated
in endometrial angiogenesis and hemostasis. with fibroids. Additionally, tranexamic acid is
Bulk symptoms accur when the uterine size thought to lead to possible reduction in fibroid
and shape is distorted by fibroids causing size via ischemia. This may cause increased
compression of the ureters, bowel, bladder, pain as well.38 Some medical treatments work
or other surrounding structures, leading to by blocking the stimulatory effects of fibroid
urinary retention or incontinence, bowel growth and size and/or to decrease HMB,
dysfunction, dyspareunia, back pain and even but are not consistently useful in stopping
hydronephrosis. Fibroids may be diagnosed or decreasing fibroid size gonadotropin-
on pelvic exam, on pelvic ultrasound, or releasing hormone (GnRH) agonists work
incidentally on abdominal/pelvic imaging at the level of the hypothalamus to suppress
for a different indication. Ultrasonography the hypothalamic–pituitary–ovarian (HPO).
is the preferred initial imaging modality for In the first 3 to 6 months of treatment,
436 Drugs in Obstetrics and Gynecology

women may have improvement and a 30 to Malignancy

50% reduction in fibroid volume primarily AUB may be the first presenting symptom of
because of their mechanism of action, GnRH several different gynecologic malignancies.
agonists cause decreased bone mineralization Discussion of gynecologic malignancies in
from hypoestrogenism reason, their use is the pediatric and adolescent population is
limited to 6 months without hormone add- beyond the scope of this chapter, however,
hack therapy. GnRH agonist administration bleeding may be the presenting symptom
prior to hysterectomy or myomectomy for young patients with vaginal or cervical
led to a significant reduction in uterine sarcomas or malignant germ cell or sex cord-
volume, fibroid volume, duration of stay, stromal ovarian tumors.51 The reproductive-
and pre- and postoperative hemoglobin aged and older patient may present with
levels. GnRH agonists are given prior to postcoital bleeding, IMB, or postmenopausal
hysteroscopic myomectomy, resulting in bleeding. Cervical cancer and cervical
decreased operative times absorption, and intraepithelial neoplasia (CIN) anecdotally
ease of procedure. are most associated with postcoital bleeding.
Surgical management of fibroids in One study found that 11% of women with
patients who desire future fertility is cervical cancer presented with postcoital
myomectomy and runs the risk of fibroid bleeding. Cervical cancer is the fourth most
recurrence. Myomectomy can be performed common cancer diagnosed in women. About
hysteroscopically in the case of submucous two-thirds of cervical can cer cases are
fibroids, vaginally prolapsing fibroids, or squamous cell carcinoma and are associated
abdominally for large or numerous fibroids. with exposure to human papillomavirus
Laparoscopy myomectomy can also be (HPV), whereas the remaining one-third are
performed, although minilaparotomy, adenocarcinoma.
morcellation in an endocatch bag or posterior Postcoital bleeding can also be caused
by surface vaginal lesions from vaginal
colpotomy may be required to remove
intraepithelial neoplasia (VAIN) or vaginal
fibroids from the peritoneal cavity safely.
cancer. 53 Primary vaginal cancer is rare,
Definitive surgical management for fibroids
but the majority of cases are squamous cell
is via hysterectomy. It is recommended that
carcinoma and caused by HPV.51 A thorough
the least invasive approach of hysterectomy
examination of the vagina and cervix can help
be performed to minimize recovery time,
to determine the source of bleeding in the case
blood loss, and complications.
of macroscopic lesions. It is important to note
Patients who desire uterine preservation but that macroscopic lesions can cause torrential
do not desire future fertility can pursue a UAE bleeding following sexual intercourse to the
performed by interventional radiologists. highly vascularized tumor.
UAE causes devascularization and involution Women with persistent postcoital bleeding
of fibroids. It has been compared to both may benefit from colposcopy to allow for
myomectomy and hysterectomy and found thorough evaluation of the vagina and
to result in less postoperative pain and cervix.54 Endometrial cancer is the fourth
faster recovery but with increased minor most common gynecologic cancer, and
complications and hospital readmissions. its instance is steadily increasing. Type-1
Although, UAE has been shown to have a endometrial cancer is endometrioid adeno-
reoperation rate ranging from 20 to 33% for carcinoma, which is estrogen-dependent.
persistent or new fibroids, it can be a safe It is estimated that nearly 50% of type-1
option for the patient who is not a good uterine cancer are secondary to obesity
surgical candidate. alone.55 Type-2 endometrial cancers are either
 Treatment of Abnormal Uterine Bleeding 437

clear cell or serous carcinoma of the uterus cycles are more common and vWF is at
and are much less common. Endometrial its nadir.61 If von Willebrand’s disease is
cancer, especially type 1 most commonly suspected, additional laboratory testing
present with AUB, including HMB, IMB, should include vWF ristocetin cofactor
or postmenopausal bleeding. Endometrial activity, vWF antigen, and factor VIII. 60
biopsy should be performed as a first-line Inherited or Acquired platelet disorders
evaluation for any patient above the age of include abnormalities of platelet aggregation
45 who presents with AUB to evaluate for and adhesion, platelet secretion, and signal
endometrial intraepithelial neoplasia (EIN, transduction. Alone, inherited bleeding
previously endometrial hypertrophy) or disorders most commonly lead to prolonged
anyone below the age of 45 with prolonged menstrual bleeding and HMB, but can also
estrogen exposure, such as morbid obesity or worsen symptoms caused by structural
anovulatory cycles from polycystic ovarian etiologies of AUB (PALM). Unlike with
syndrome (POS). 3 Ultrasound imaging other etiologies of AUB, non-steroidal anti-
for evaluation of endometrial thickness inflammatory diseases (NSAIDs) should
is helpful in the postmenopausal patient be avoided with abnormal uterine bleeding
when trying to differentiate uterine atrophy related to coagulopathy (AUB-C) given their
from hyperplasia as the cause for bleeding. irreversible effects on platelets: However,
In the case of EIN or a patient’s desire for cyclo-oxygenase-2 (COX-2) inhibitors may
fertility-sparing management, high-dose oral be used.63 Tranexamic acid is commonly used
progestins and the ING-IUD have been used in bleeding disorders and has been shown to
to avoid or postpone surgery. have utilized for patients with blood loss.
AUB-M is used for patients with AUB Desmopressin (DDAVP) is used to
that are diagnosed with malignancy or increase plasma factor VIII and the release
premalignancy (CIN, VAIN, EIN). These of endogenous VWF to improve hemostasis.
lesions should still be classified according to
the appropriate WHO or FIGO system. Surgical interventions in patients with
AUB-C can prevent further blood loss:
Coagulopathies However, they are associated with a higher
It is estimated that up to 13% of women with risk of postoperative hemorrhage, including
HMB have some variant of Willebrand’s delayed bleeding up to 10 days of surgery.
disease, and up to 20% of women may Patients require an adequate bleeding
have an underlying coagulation disorder.58 risk assessment and plan for hemostatic
Platelet dysfunction has been reported coverage. Given the risk of hemorrhage
in approximately 50% of women with with hysterectomy, patients with HMB
unexplained HMB.59,60 It is important to from AUB-C can benefit from less invasive
screen for underlying disorders of hemostasis. options such as endometrial ablation. Second
If a patient’s screen is positive, laboratory generation endometrial ablation techniques,
testing should be ordered including CBC with which do not rely on hysteroscopy, have
platelets, prothrombin time (PT) and partial been shown to be safer than first-generation
thromboplastin time (PTT). techniques because of less risk of blood
Von Willebrand’s disease results from loss. Major procedures in patients with
either a decreased quantity or quality of high risk of bleeding will require clotting
von Willebrand factor (vWF) resulting most factor replacement. It is also important to
commonly in increased mucocutaneous note that these patients should have factor
bleeding. The condition usually presents levels monitored for up to 10 days post-
at the time of menarche when anovulatory operatively.
438 Drugs in Obstetrics and Gynecology

Ovulatory from peripheral conversion. Several studies

Regular, monthly cycles result from ovulatory have shown a return to ovulatory cycles
function, which produces ovarian steroids with sustained weight reduction in patient
and corpus luteum to release progesterone. with PCOS. Because of chronic anovulation,
Exposure of the endometrium initially it is very important to evaluate EIN and
to estrogen alone causes endometrial endometrial malignancy in these patients.
proliferation, followed by exposure to Endometrial ablation is not recommended
estrogen and progesterone which causes given the need for accurate endometrial
secretory changes, and then withdrawal surveillance in the context of increased risk
of both hormones as the corpus luteum for uterine pathology with tamoxifen use.91, 92
involutes and results in shedding of the Hysterectomy may be performed if fertility
lining. Ovulatory dysfunction generally is not desired and AUB symptoms are not
causes irregular bleeding and HMB because manageable.
of the effects of unopposed estrogen on the COCs are typically contraindicated in
endometrium. Ovulatory dysfunction can patients with a history of ischemic cardiac
be physiologic, such as during adolescence, or neurologic event or venous thrombosis
perimenopause, or lactation or it can be or pulmonary embolism. Thus, treatment
pathologic, caused by aberrations at any for AUB in this population typically relies
level in the HPA axis can also be caused by on progestin-only-based methods. LNG-
other endocrine disorders that affect the IUS is the superior method to treat AUB
HPO axis, such as thyroid disorders and in these patients. DMPA can also be used,
hyperprolactinemia. In adolescents, the and studies have shown that there is no
HPO axis is immature and does not have the significantly increased risk of patients
hormonal feedback necessary for ovulation. developing a hematoma at the injection site of
This resolves in 60 to 80% of adolescents within DMPA.95 If surgical intervention is required,
3 years of menarche. In perimenopause, the endometrial ablation has been shown to
ovaries are producing estrogen, and there are have high satisfaction rates in patients taking
fewer follicles to release an egg and develop anticoagulants.96,97 Finally, hysterectomy by
into a corpus luteum, leading to anovulatory the least invasive method may be performed.
cycles. Hypothalamic hypogonadotropic Classified for those pathologies that are
amenorrhoea caused by stress or malnutrition rare, are poorly defined, or do not fit. These
blunts the pattern of GnRH-releasing hormone diagnoses include uterine arteriovenous
from the hypothalamus, thus disrupting the malformations (AVM), endometrial pseudo­
HPO axis preventing ovulation. aneurysms, myometrial cesarean scar defects,
Polycystic ovary syndrome (PCOS) is the and chronic endometritis.
most common cause of ovulatory dysfunction- The appropriate treatment for both endo­
associated AUB (AUB-O) in reproductive- metrial hypertrophy and cesarean scar defects
aged women. According to the Rotterdam requires additional study, but studies have
criteria, the diagnosis of PCOS is made when shown hysteroscopic repair, laparoscopic
patient has two of the following findings: repair, or vaginal repair to have success rates
Oligomenorrhea, hyperandrogenism, and of 59%, 86%, and 89%, respectively. Lastly,
cystic ovaries on ultrasound. It is unclear what chronic endometritis that is noninfectious
causes PCOS: it is likely several etiologies in etiology is sometimes seen in DMPA or
can lead to the clinical syndrome. However, IUD users. AUB resulting from endometritis
the condition is chronic anovulation. It is because of DMPA or IUD use is considered
often associated with insulin resistance and iatrogenic, whereas idiopathic chronic
obesity leading to increased levels of estrogen endometritis in nonusers is categorized as
 Treatment of Abnormal Uterine Bleeding 439

AUB-N. Chronic endometritis is generally Conjugated Equine Estrogen (Premarin)

successfully treated with a 2-week course Women in perimenopause generally are
of doxycycline after which AUB symptoms estrogen deficient and might experience
should improve. bouts of estrogen withdrawal bleeding. Many
of these patients will recover regular menses
Conclusion and develop an improved sense of well-being
AUB is a common complaint among patients with the initiation of hormonal replacement
presenting for gynecologic care. Using therapy, including estrogen and a progestin.
updated terminology for the description of
Side effects: Abdominal pain, back pain, breast
AUB enables clinicians to more accurately
enlargement, breast tenderness, headache,
describe patient complaints and determine
arthralgia pharyngitis, sinusitis, diarrhea.
their impact on quality-of-life. The PALM-
COEIN classification facilitates the correct Progestins
diagnosis and management of AUB based
on most likely etiology. Most cases of AUB, Progestins inhibit estrogen-receptor
even in acute situations or when etiology replenishment and activate 17-hydroxysteroid
is uncertain, can be managed effectively dehydrogenase in endometrial cells,
with available, safe medical regimens. converting estradiol to the less active estrone.
The evaluation of AUB can be initiated at Medroxyprogesterone acetate (provera) is
the patient’s first presentation and need the most commonly used progestin in this
not preclude short-term management. country, but other types, including norethin­
Depending on the etiology, long-term drone acetate and norethindrone (micronor),
management may require surgery or are equally efficacious. In some patients in
consultation with the interdisciplinary which systemic progestins are intolerable
healthcare teams. due to side effects, a progestin-secreting IUD
(mirena) may be considered.
Synthetic progestins have an antimitotic
HORMONE THERAPY effect, allowing the endometrium to become
Estrogens atrophic if administered continuously.
Effective in controlling acute, profuse bleed- These drugs are very effective in cases of
ing. Exerts a vasospastic action on capillary endometrial hyperplasia. In patients with
bleeding by affecting the level of fibrinogen, chronic eugonadal anovulation who do
factor IV, and factor X in blood, as well as not desire pregnancy, treatment with a
platelet aggregation and capillary perme- progestin for 10–12 days/month will allow
ability. Estrogen also induces formation of for controlled, predictable menses and will
progesterone receptors, making subsequent protect the patient against the development
treatment with progestins more effective. of endometrial hyperplasia.
Most AUB is secondary to anovulation.
In these patients, endometrium continues to Progestin Therapy
proliferate with asynchronous development. • Most commonly used hormonal therapy
As blood supply is outgrown, irregular given during luteal phase.
shedding occurs. Bleeding might be controlled • Norethisterone is the most commonly used
acutely with high-dose estrogen for a short oral progestogen in the treatment of AUB
period of time. Several hours are required Progestins modulate the effect of estrogen
to induce mitotic activity, so most regimens on target cells and metabolism of estrogen,
require 48 hours of therapy before continued the endometrium is maintained in a state of
bleeding is ruled a treatment failure. antimitosis and antigrowth.
440 Drugs in Obstetrics and Gynecology

Medroxyprogesterone Acetate (Provera) • These should be avoided in women with

Short-acting synthetic progestin. Drug of thrombosis or a family history of idiopathic
choice for patients with anovulatory AUB. venous thromboembolism.
After acute bleeding episode is controlled, • The most common side-effects include
can be used alone in patients with adequate weight gain, abdominal discomfort, and
amounts of endogenous estrogen to cause mid-cycle breakthrough bleeding.
endometrial growth. Progestin therapy Not suitable in patients desiring pregnancy,
in adolescents produces regular cyclic adverse effects are edema, weakness,
withdrawal bleeding until positive feedback amenorrhea, breakthrough bleeding, change
system matures. in menstrual flow, spotting, anorexia, deep
Stops endometrial cell proliferation, vein thrombosis (DVT), thrombophlebitis,
allowing organized sloughing of cells after depression, dizziness, abdominal pain,
withdrawal. Typically, does not stop acute change in weight, cholestatic jaundice.
bleeding episode but produces a normal
bleeding episode following withdrawal. Androgens
Provera only indicated for abnormal Certain androgenic preparations have been
uterine bleeding due to hormonal imbalance used historically to treat mild to moderate
in the absence of organic pathology, such as bleeding, particularly in ovulatory patients
fibroids or uterine cancer, 5 or 10 mg, PO for with AUB. Use of androgens might stimulate
5–10 days; begin day 16 or 21 of the menstrual erythropoiesis and clotting efficiency.
cycle. Progestin withdrawal bleeding usually Androgens alter endometrial tissue so that
occurs within 3–7 days after discontinuing it becomes inactive and atrophic.
medroxyprogesterone. Danazol (isoxazole derivative of 12-alpha-
ethinyl testosterone), 200 mg daily for 3–4
Combination Oral Contraceptives cycles is recommended.
Contraceptive pills containing estrogen
and progestin have been advocated for Side Effects
women with AUB who desire contraception. Acne, hirsutism, weight gain, reduced high
Apparently takes longer to induce density lipoprotein.
endometrial proliferation when progestin is
present. In long-term management of AUB, Nonsteroidal Anti-inflammatory Drugs
COCs are very effective. Ethinyl estradiol Blocks formation of prostacyclin, an antagonist
and a progestin derivative (ovral, lo-ovral, of thromboxane, which is a substance that
ortho-novum, ovcon, genora, orthocyclen, accelerates platelet aggregation and initiates
and others) reduce secretion of luteinizing coagulation. Prostacyclin is produced
hormone (LH) and follicle-stimulating in increased amounts in menorrhagic
hormone (FSH) from pituitary by decreasing endometrium. Because NSAIDs inhibit blood
amount of GnRH. prostacyclin formation, they might effectively
decrease uterine blood flow. NSAIDs have
Oral Contraceptive been shown to treat menorrhagia in ovulatory
• Action is probably mediated through cycle.
endometrial atrophy. Oral contraceptive • NSAIDs reduce blood loss by 25–30%, but
pills (OCPs) suppress pituitary gonado­ not all women respond similarly.
tropin release, thus inhibiting ovulation. • Commonly used are mefenamic acid
• High doses of estrogen are associated with and naproxen but are less effective than
an increased risk of thromboembolism. tranexamic acid.
 Treatment of Abnormal Uterine Bleeding 441

• NSAIDs have shown only minimal effect • Studies have demonstrated excellent
in anovulatory menorrhagia. efficacy, with an amenorrhea rate of up to
• Side-effects include minor gastrointestinal 90% with GnRH agonist use.
disturbance, headaches and enervation • Danazol is not frequently used because of
may occur. its androgenic and long-term lipid profile
side-effects.
Tranexamic Acid Depot leuprolide acetate (lupron) suppresses
• Reduces blood loss by 50% ovarian steroidogenesis by decreasing LH and
• However, many women remain menorr­ FSH levels.
hagic and many are non-compliant due Injection-site reactions include abscess,
to daily dosing emotional lability, acne/seborrhea vaginitis,
• Large doses of tranexamic acid are required vaginal bleeding or discharge, rash including
• Incidence of GI side-effects, intermenstrual erythema multiforme, headache.
bleeding are relatively high
• Risk of thrombogenic disorders is a SELECTIVE ESTROGEN RECEPTOR
concern. MODULATORS (SERMs)
They are a non-hormonal non-steroidal class
GnRH Agonists of drugs that act on the estrogen receptor (ER).
Work by reducing concentration of GnRH They selectively bind with high affinity to
receptors in the pituitary via receptor down estrogen receptors in various tissues, but act
regulation and induction of postreceptor as estrogen antagonist in others. So, it causes
effects, which suppress gonadotropin endometrial suppression. Ormeloxifene (also
release. After an initial gonadotropin release known as centchroman) is a selective estrogen
associated with rising estradiol levels, receptor modulator.4 It is a widely used oral
gonadotropin levels fall to castrate levels, contraceptive. It acts by high-affinity interaction
with resultant hypogonadism. This form with ER, antagonizes the effect of estrogen
of medical castration is very effective on uterine and breast tissue and stimulates
in inducing amenorrhea, thus breaking the effect on vagina, bone, cardiovascular
ongoing cycle of abnormal bleeding in many system and central nervous system. It is also
anovulatory patients. Because prolonged effective against advanced breast cancer. In
therapy with this form of medical castration AUB, the treatment of the standard dosage is
is associated with osteoporosis and other 60 mg, orally, twice weekly for a period of
postmenopausal side effects, its use is 12 weeks followed by weekly once in the next
often limited in duration and add-back 12 weeks. It sometimes lengthen the follicular
therapy with a form of low-dose hormonal phase and delays mensturation, can cause
replacement is given. dyspepsia, headache and weight gain.

Indications of GnRH Agonist Surgical Management

• Utility should really for short-term use. The role of surgery in the treatment of
• Particularly useful in the treatment of AUB requires a thorough evaluation of the
leiomyoma, which can reduce considerably underlying pathology and patient factors.
in size when ovarian hormone levels are The medical treatment of heavy menstrual
suppressed. bleeding is effective for many women,
• May be used prior to surgical intervention and treatment with the LNG-IUS may be
in women with fibroids, or for those in comparable to surgical options for improving
whom surgery is not suitable or desirable quality-of-life.
442 Drugs in Obstetrics and Gynecology

The indications for surgery for women Radiofrequency-induced Thermal Ablation

with AUB include: It uses radiofrequency electromagnetic
• Failure to respond to medical therapy, thermal energy which destroys endometrium
inability to utilize medical therapies (i.e. at 66°C. A 0.66 mm metallic probe is inserted
side effects, contraindications), transcervically under general anaesthesia
• Significant anemia, impact on quality-of- and rotated over 360° for 20 minutes. About
life, and concomitant uterine pathology 85% get cured and 30% develop amenorrhea
(large uterine fibroids, endometrial by end of one year, an occasional uterine
hyperplasia). Improvement in quality-of- perforation or vesicovaginal fistula may occur.
life, is the ultimate goal of treatment and
may occur through achieving eumenorrhea Microwave Endometrial Ablation (MEA)
or amenorrhea. Microwave energy of 9.2 GHz is generated
Surgical options for managing AUB depend in a magnetron and is applicated by a
on several factors including the patient’s probe within the endometrial cavity. It is
expectations and uterine pathology. Surgical an outpatient department (OPD) procedure
options include: done under local anaesthesia. Temperature of
80°C is used for 3 minutes. There is no need
• Dilation and uterine curettage,
of preoperative endometria thinning.
• Dilation and uterine curettage,
• Hysteroscopic polypectomy, Balloon Ablation
• Endometrial ablation, Singer, et al. reported preliminary experience
• Myomectomy, and with a thermal ablation system incorporating
a latex intrauterine balloon to treat women
• Hysterectomy.
with intractable menorrhagia. The balloon
Dilatation and curettage, except in cases of is filled with a solution of sterile dextrose
severe acute bleeding refractory to medical and water, and then heated to 83°C for 5
therapy, should be relegated to a diagnostic minutes over pressure of 160–180 mm Hg
technique when endometrial sampling or to exert a tamponade effect. About 6 mm of
hysteroscopic evaluation is not possible. endometrium gets destroyed.
Endometrial ablation is a minimally
invasive surgical option for heavy menstrual Unipolar Electrodes
bleeding. It may be considered in women The Vesta NHEA system comprises an
who have failed medical treatment, have inflatable balloon that is covered with 12
completed childbearing, or who may thermocoupled electrodes. The cervix is
not be candidate for major surgery. Two dilated to approximately 9 mm, the probe is
methods of endometrial ablation may be inserted into the endometrial cavity, and the
offered at the present time. The first method balloon is inflated allowing the electrodes
involves hysteroscopic resection and/or to make intimate contact with endometrial
ablation. Previously termed ‘first generation’ surface. Activation of electrodes results in
endometrial ablation, hysteroscopic-guided a controlled endometrial ablation using a
endometrial ablation has a significant combination of desiccation and coagulation.
number of years of reported experience and
effective results. Bipolar Electrodes
Non-hysteroscopic techniques, or ‘second The NovaSure device is a bipolar instrument
generation’ technologies, include a number designed for performance of NHEA using a
of varying modalities that all destroy the combination of electrosurgical vaporization
endometrium without direct visualization. and desiccation/coagulation. The electrodes
 Treatment of Abnormal Uterine Bleeding 443

are incorporated into the instrument in a • Delayed complications, like vault prolapse,
way that allows propagation of current sexual dysfunction, chronic abdominal
and resultant rapid vaporization. Suction is pain due to postoperative adhesions,
required to remove the steam and carbonized urinary and bowel symptoms due to ideal
vapor from the endometrial cavity. The NSAID, would be a selective inhibitor
instrument is placed into the cavity after of vasodilating prostaglandins (PGs)
dilating the cervix to 8 mm and the electrodes permitting the vasoconstrictor PGs to
are deployed, and then both suction and inhibit the excessive menstrual blood
electrosurgical energy, the latter from a loss.
specially designed and computer-controlled
electrosurgical generator. Bibliography
Risks of endometrial ablation techniques 1. Clinical Guideline 44; Heavy menstrual bleeding
include uterine perforation, infection, 2007.
hemorrhage, and bowel or bladder injury. 2. Curtis KM. Hillis SD, Kieke BA Jr. Brett KM.
Marchbanks PA. Peterson HB. Visits to emer-
Post-ablation syndrome is a condition
geney departments for gynecologic disorders
associated with concomitant or previous in the United States, 1992–1994. Chest Gynecol.
tubal ligation and ablation and is a condition 1998: 91(6):1007–1012.
of hematometra resulting in cyclical pain 3. Fraser IS, Critchley HO, Munro MG. Abnormal
with or without hematosalpinx. Risks specific uterine bleeding straight. Curr Opin Obstet
to hysteroscopic techniques include fluid Gynecol. 2007;19(6):591–5.
overload, especially with the use of hypotonic 4. Matteson KA, Munro MG. Fraser IS. The
solutions (e.g. 1.5% glycine), and resulting structured menstrual history: develop getting
our terminology tool to facilitate diagnosis and
hyponatremia and its sequelae.
aid in symptom management Semin Reprod Mei
2011:29(5):423–35.
HYSTERECTOMY 5. Maheux-Lacroix S, Li F. Laberge P. Abbott J.
Its effectiveness in improving AUB Imaging for polyps and lion in wornen with
symptoms, being curative and definitive is abnormal uterine bleeding a systematic review.
Obstet GHE 2016.128(6):1425–36.
well-recognized.
6. Munro MG. Critchley HO, Broder MS, Fraser IS:
Hysterectomy is required: FWGOM Disorders FIGO classification system
• If medical management fails or menorr­ (PALM-COEIN) for causes of abnormal uterine
hagia recurs. bleeding in nongravid women dreproductive
• In older women more than 40 years not age. Int Gynaecol Obstet. 2011:113(1):3–13.
desirous of pregnancy. 7. Munro MG. Mainor N. Basu R, Brisinger M,
Barreda L Oral medroxyprogesterone ac and
Laproscopic vaginal hysterectomy has
combination oral contraceptives for acute
quicker recovery, less pain, less abdominal uterine bleeding randomized controlled trial.
adhesions and evidance of abdominal scar. Obstet Gynecol, 2006:108(4)924–29.
Lately, vaginal hysterectomy is done for 8. Spencer CP. Whitehead ML Endometrial
undescended uterus which may even be assessment re-visited. Br J Obstet Gynaecol,
enlarged. 1999,106(7):623–32.
 Index
A Congestive dysmenorrhea 392 Etonogestrel 365
Allopregnanolone 409 Conjugated equine estrogen 386, Extreme drug-resistant TB 378
Amenorrhoea 364 439
F
Amitriptyline 393 Controlled ovarian
hyperstimulation 349 Fatty liver disease 422
Anastrozole 368
Cyclooxygenase 360 Follicle-stimulating hormone 366
Androstenedione 368
Cyproterone acetate 365 Frozen embryo transfer (FET) 353
Angiogenesis 364
FSH levels 369
Antiandrogen 345 D
Anti-angiogenic factors 372 D2 agonist 382 G
Antiestrogen 345 Danazol 345, 370 Gabapentin 393
Antituberculosis drug 378 Delamanid 380 Galactorrhea 381
Aromatase inhibitors 346 Depot medroxy-progesterone Ganirelix 367
Asoprisnil 372 acetate 365 Genistein 345
Aspirin 349, 360 DES 417 Genital tuberculosis 378
Assisted reproductive Desmopressin 437 GnRH
technologies (ART) 348 Dienogest 365 agonists 346
Atorvastin 373 Dihydroergotamine 392 antagonists 367
Atypical EH 345 Dopamine-receptor-2 agonists 372 receptors 346
Dopaminergic agonist 382 Goserelin 367
B
DOTS 378 Granulocyte colony-stimulating
Bakri balloon 434
Drospirenone 412 factor 351
Balloon ablation 442
Basal-like breast cancer 416 Ductal carcinoma in situ 415 H
Bazedoxifene (BZD) 372 Dydrogesterone 386, 387 Hematoma 396
Bedaquiline 380 Dysfunctional uterine bleeding 432 HER2 overexpression 416
Biguanides 345 Dyspareunia 386 Hirsutism 371
Bilateral salpingo-oophorectomy E Hormonal contraceptives 345
346, 369 Hormone replacement therapy 344
E2 (estradiol) 369
Bipolar electrodes 442 Hot flushes 388
EE 363
Bisphosphonates 367 Human chorionic gonadotropin 350
Elagolix 368
BMD 365 Hyperprolactinemia 381
Electrosurgical vaporization 442
Breast cancer 346, 388, 414 Hypoestrogenism 367, 372
Embolotherapy 396
prevention trial 419 Hypogonadism 381
Endometrial
Bromocriptine 382 Hypogonadotropic
carcinoma 344
Buserelin 367 hypogonadism 381
hyperplasia (EH) 343
Hypothalamic–pituitary–ovarian
C thickness (EMT) 348
(HPO) 435
Cabergoline 372, 382 Endometriosis 345
Hysterectomy 346, 369
Cetrorelix 367, 368 implants 368
Hysteroscopic myomectomy 436
Chlorzoxazone 395 Estradiol 349
Chronic pelvic pain 391 vaginal ring 403 I
Clomiphene citrate (CC) 348, 369 Estrogen-dependent breast cancer Immunohistochemistry 416
Colposcopy 436 417 Implanon 395
Combined oral contraceptive pills Estrogens 404 Infertility 404
348, 362 Estrone 368 Infliximab 373
II Drugs in Obstetrics and Gynecology

Insomnia 427 Nonfunctioning pituitary R

Insulin resistance 345 adenoma 382 Radiofrequency-induced thermal
Intrauterine insemination (IUI) 369 Non-steroidal anti-inflammatory ablation 442
Invasive drugs 360 RNTCP 380
breast cancers 415 Norethindrone acetate 365 Romidepsin 373
ductal carcinoma 415 Norethisterone 345 Rosiglitazone 372
lobular carcinoma 415 Nuvaring 363 Rotterdam criteria 438
In vitro fertilization (IVF) 351 O S
L Oophorectomy 412 Saline infusion sonohysterogram
Leiomyomas 435 Ortho Evra 363 434
Letrozole 368, 369 Ospemifene 403 Selective estrogen receptor
Leuprolide 364 Osteoporosis 346, 365 modulators 372
Ovarian Selective progesterone
acetate 367
cancer 345 modulators 372
Levonorgestrel (LNG) 345
cyst 369 Sildenafil 351
LNG intrauterine device 365
tissue cryopreservation 404 Simvastin 373
Lovastin 373
SSRI 412
Luminal A 416 P Statins 373
Luminal B 416 PALM-COEIN classification 432 Steroidal progestin 344
Luteal phase 409 PCOS 345 Steroidogenic enzymes 370
Luteinizing hormone 366 Pelvic Synthetic androgen 345
M congestion syndrome (PCS) 391
T
Macroadenoma 381 irradiation 404
Tamoxifen 417
Malignancies 385 varicosities 391
Tibolone 427
McBurney’s incision 396 venous plexuses 391
maleate 367
Medroxyprogesterone acetate Pentoxyphylline 373
TNFa blockers 373
344, 365 PGE2 361
Triptorelin 367
Megestrol acetate (MA) 344, 365 PGs 360
Menometrorrhagia 392 Pioglitazone 372 U
Menopause 384 Platelet-rich plasma 352 Ulipristal acetate 372
Menorrhagia 392, 432 Polycystic ovary syndrome Unipolar electrodes 442
Metformin 345 (PCOS) 438 Uterine artery
Microadenoma 381 Postcoital bleeding 433 embolization 434
Microwave endometrial PPAR-g 372 impedance 349
ablation 442 Preconception counselling 404
V
Mid-luteal phase 348 Premature ovarian insufficiency
Vaginal
Mifepristone 372 399
estrogen 386
MPFF 394 Premenstrual syndrome (PMS) 409
pH 385
Multidrug resistant (MDR) 378 Progestins 344
ring 363
Prolactin 381, 382
N Varicose veins 391
Provera 364
Nafarelin 367 Virilism 412
Pseudo-prolactinoma 382
Nanotechnology 373 Virilizing changes 371
National AIDS Control Q von Willebrand factor (vWF) 437
Organization (NACO) 380 Quinagolide 372 Vulvodynia 393