Clinical Andrology EAU/ESAU Course Guidelines - 1st

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Clinical Andrology
EAU/ESAU Course Guidelines

Edited by

Lars Björndahl, MD, PhD

Centre for Andrology and Sexual Medicine
Endocrinology Clinic, Department of Medicine, Huddinge
Karolinska University Hospital and Karolinska Institutet
Stockholm, Sweden

Aleksander Giwercman, MD, PhD

Reproductive Medicine Centre
Skåne University Hospital Malmö
Lund University
Malmö, Sweden

Herman Tournaye, MD, PhD

Centre for Reproductive Medicine
University Hospital of the Dutch-speaking Brussels Free University
Brussels, Belgium

Wolfgang Weidner, MD
Department of Urology, Pediatric Urology and Andrology
University of Giessen
Giessen, Germany

Published in association with the European Academy of Urology

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Foreword

I am very honored to have the opportunity to include a few skills at his/her disposal, and the evaluation of many patients,
words in this edition of Clinical Andrology. At first glance more often than not, will involve a team of experts (reproduc-
one may think “Yet another book on andrology,” albeit a very tive endocrinologist, geneticists, gynecologists, sex therapists,
comprehensive one. But this is, in many ways, a truly unique oncologists, etc.). Also in oncology settings we see reproductive
publication: not only because it provides very comprehensive health problems, including sexual dysfunction and impaired
coverage of this difficult and multidisciplinary field, but also fertility, which should be dealt with in a multidisciplinary set-
because it represents a unique collaboration between a scientific ting.
publisher and top experts from a number of societies operating The ability to coordinate all efforts to ensure centralized man-
in this challenging medical area. Clinical Andrology will be an agement and oversight to guarantee continuity of patient care
important reference publication for our young colleagues tak- requires a high level of competency.
ing part in a joint training program organized by the European We need to set, unify, and raise the standards in all areas
Academy of Andrology (EAA), the European Federation of of care, but andrology will definitely be a field that will be
Endocrine Societies (EFES), the European Society of Human taxed heavily in the years to come. Changing demographics,
Reproduction and Embryology (ESHRE), and the European with the first wave of the Baby Boomer generation approaching
Association of Urology (EAU). Aside from this direct link to 60 years of age will greatly affect the demands on healthcare
a specialization program, Clinical Andrology offers the state of professionals. Additionally, changes in social patterns influence
the art in all aspects covered by what we nowadays consider to the demand on experts with particular andrological expertise:
be in the realm of andrological urology, and it will surely prove delayed parenthood, second marriages, a greater acceptance of
a valuable reference document also for experienced colleagues. diverse family units, and more openness about gender-related
Over the past decennia, a great progress has been made in the problems are just a few factors that will affect practice patterns.
understanding of both the physiology and the pathophysiology The trend of further specialization is visible in most medical
of the male reproductive system, and it is generally recognized fields, and clear division lines between responsibilities relating
now that specialized training in clinical andrology is needed to to patient care seem to fade. Education of young colleagues
keep pace with the emerging techniques for assisted reproduc- should remain a central activity if we, as medical associations,
tion. The curricula of the various medical specialties involved fully commit to optimizing patient care.
have been lagging behind. Sustainable high-quality structures to I cannot commend the editors—Lars Björndahl, Aleksander
train professionals are needed and this first collaborative train- Giwercman, Herman Tournaye, and Wolfgang Weidner—
ing effort is an enormous step forward and all collaborators enough for bringing together this wealth of information and
consider it a solid foundation to further build on. motivate and engage so many eminent experts in this area to
One only needs to look at the table of contents to understand provide high-quality contributions. I take the liberty to speak
the complexity of this field and the range of skills involved also on behalf of the all colleagues directly benefiting from all
to appropriately treat the different patients groups. The most these efforts: it has most certainly paid off—my sincere con-
important attributes for a clinical andrologist would be the gratulations.
ability to take a clinical history and carry out a competent
clinical examination. This may sound straightforward, but it Per-Anders Abrahamsson
clearly is not. A clinical andrologist will need to have a range of Secretary-General, European Association of Urology

v
Preface

You are holding in your hands the first edition of Clinical Androl- The aim of this textbook is to cover all these four fields and to
ogy. As editors, we would shortly explain the intentions behind provide a comprehensive evidence based and clinically oriented
this textbook and also ask for your help in improving the edi- tool for training clinical andrologists. However, it can also be
tions we are expecting to follow the opus one. used in teaching at the pregraduate level as well as an aid in
During the recent years, it has became more and more evident the daily life of more experienced andrologists. According to
that diseases of male reproductive system represent a serious and these quite ambitious goals, we have approached some of the
common health problem. At least 15% of all couples experi- highest ranked experts within the field of clinical andrology
ence infertility problems, the contribution of male-related fac- to contribute to this book. The authors were asked to focus
tors assumed to be as frequent as the female ones. Together on the clinical aspects of andrology basing and documenting
with sexual dysfunction, fertility problems represent one of the their recommendations by stating proper levels of evidence. We
most common disorders in our society. Another issue receiving thank all the authors for their invaluable efforts.
increasing attention is age-related androgen deficiency and the We are aware of the fact that the first edition of a textbook
link between low testosterone levels and the risk of metabolic will not be perfect. However, we hope that the readers, trainees,
and cardiovascular disorders. However, proper and evidence- students will find it valuable in their work with clinical androl-
based management of these conditions is seriously hampered ogy. We would also appreciate constructive feedback—negative
by lack of clinical andrologists—specialists in disorders of male or positive—since this will be an important tool for improving
reproductive system. During the past few years, collaboration the forthcoming editions. Therefore, do not hesitate to let us
between European Academy of Andrology (EAA) and European know your opinion about Clinical Andrology.
Association of Urology (EAU), aiming to establish a joint train-
ing program within the field of clinical andrology, has been Lars Björndahl
established. Four different subareas of this clinical discipline Aleksander Giwercman
have been defined: (a) infertility, (b) hypogonadism, (c) sexual Herman Tournaye
dysfunction, and (d) male accessory sex gland infections. Wolfgang Weidner

vi
Contents

Foreword v
Preface vi
Contributors xi

PART I MALE INFERTILITY

1. Defining male factor infertility 1
Dimitrios A. Adamopoulos, Giorgios Mitios, and Stamatina S. Nicopoulou
2. Clinical investigation of the infertile male 9
Gert R. Dohle
3. The female factor 18
Lynne Robinson and Masoud Afnan
4. Basic semen analysis and laboratory quality for clinicians 28
Lars Björndahl
5. Genetic causes of male infertility and their impact on future generations 39
Csilla Krausz
6. Conventional treatment of the male in infertile couples 49
Herman Tournaye and Aleksander Giwercman
7. Nonsurgical methods for sperm retrieval in patients with anejaculation and
retrograde ejaculation 52
Axel Kamischke
8. Sperm preparation for ART and IUI 65
Kersti Lundin
9. Intrauterine insemination for male subfertility 73
Astrid E. P. Cantineau and Ben J. Cohlen
10. IVF and ICSI for treating male infertility 79
Herman Tournaye
11. Surgery for male infertility: surgical treatment of obstructive azoospermia 85
Laurent Vaucher and Peter N. Schlegel
12. Surgery for male infertility: surgical sperm retrievals 95
Giovanni M. Colpi, Guido Piediferro, Fabrizio I. Scroppo, Elisabetta M. Colpi,
and Patrizia Sulpizio
13. Surgery for male infertility—varicocelectomy and its alternatives 105
Howard H. Kim and Marc Goldstein

vii
 contents
14. Assisted reproduction with surgically retrieved sperm 116
Valérie Vernaeve and Herman Tournaye
15. Therapeutic sperm cryopreservation 124
Mathew Tomlinson
16. Testicular tissue for ICSI 134
Greta Verheyen
17. Donor insemination: Past, present, and future challenges 149
Vanessa J. Kay and Christopher L. R. Barratt
18. Male contraception 159
Ahmed Mahmoud and Guy T’Sjoen
19. Prevention of male infertility: Environmental and systemic disease effects
on male fertility 164
Jens Peter Bonde and Jorma Toppari
20. Infertility and testis cancer 176
Patrick de Geeter and Peter Albers
21. Male aging and reproduction 186
Sabine Kliesch

PART II ANDROLOGICAL ENDOCRINOLOGY

22. Sex steroids in men: Biosynthesis, transport, metabolism, interaction with
receptors, and cellular (Genomic and Nongenomic) and biological actions 193
Jemima Gaytant, Katrien Venken, and Dirk Vanderschueren
23. Gonadotropins and gonadotropin receptors 201
Ilpo Huhtaniemi and Maria Alevizaki
24. Androgen effects in reproductive and nonreproductive organs 216
Michael Zitzmann
25. Clinical aspects of male sex differentiation 226
Johan Svensson and Yvonne Lundberg Giwercman
26. Disturbances in male pubertal development 237
Olle Söder
27. Clinical investigation and laboratory analyses in male hypogonadism 245
Gianni Forti, Giovanni Corona, and Mario Maggi
28. Testosterone deficiency syndrome 260
Stefan Arver
29. Androgen replacement—indications and principles 269
Fotios Dimitriadis, Evlalia Vlachopoulou, Stavros Gratsias, Dimitrios Baltogiannis, Dimitrios Giannakis,
Panagiota Tsounapi, Michael Rimikis, Nikolaos Pardalidis, Takeshi Watanabe, Motoaki Saito,
Ikuo Miyagawa, and Nikolaos Sofikitis
30. Androgen deficiency in cancer-treated men 282
Jakob Eberhard, Patrik Romerius, and Aleksander Giwercman

viii
 contents
31. Gynecomastia 286
Niels Jørgensen, Niels Kroman, Jens-Jørgen Elberg, and Anders Juul

PART III UROGENITAL INFECTION AND STD

32. Male infertility in chronic urogenital infections and inflammation with special
reference to ejaculate findings 293
Wolfgang Weidner, Thorsten Diemer, and Florian M. E. Wagenlehner
33. Inflammatory parameters of the ejaculate 301
Zsolt Kopa and Mihály Berényi
34. Sperm morphology in male urogenital tract infections 309
Roelof Menkveld
35. Immunological aspects of male accessory gland infection 317
Luciano Adorini, Mario Maggi, and Mauro Gacci
36. ROS and DNA integrity—implications of male accessory gland infections 324
Ralf Henkel

PART IV MALE SEXUAL DYSFUNCTION

37. Hematospermia (Hemospermia) 329
Nadja Engel and Hubert John
38. Prostatic disease and male sexual dysfunction 336
Francesco Montorsi
39. Sexual dysfunction and the prostate: andrological implications of PCa, BPH,
and prostatitis 345
Wolfgang Weidner and Richard Berges
40. Psychological abnormalities of male sexual function 351
Emmanuele A. Jannini and Andrea Lenzi
41. Ejaculatory disorders 359
Nancy L. Brackett, Charles M. Lynne, Dana A. Ohl, and Jens Sønksen
42. Diagnostic management of erectile function—clinical andrology 372
Chi-Ying Li, Giulio Garaffa, and David J. Ralph
43. Conservative treatment of erectile dysfunction 380
Thomas C. Stadler, Uwe Hartmann, Armin J. Becker, and Christian G. Stief
44. Surgery for erectile dysfunction 387
Levent Gurkan, Mathew C. Raynor, and Wayne J. G. Hellstrom
45. Peyronie’s disease and penile curvature 396
Ekkehard W. Hauck, Thorsten Diemer, and Wolfgang Weidner

ix
 contents
46A. Female-to-male transsexualism 403
Carlo Bettocchi, Fabrizio Palumbo, and David J. Ralph
46B. Male-to-female transsexualism 409
Vincenzo G. Mirone, Ciro Imbimbo, Paolo Verze, and Davide Arcaniolo
47. Priapism 414
Emre Akkus

Index 423

x
Contributors

Dimitrios A. Adamopoulos Department of Endocrinology, Karolinska University Hospital and Karolinska Institutet,
Diabetes, and Metabolism, Elena Venizelou Hospital, Athens, Stockholm, Sweden
Greece
Jens Peter Bonde Department of Environmental and
Luciano Adorini Bioxell, Milan, Italy Occupational Medicine, Copenhagen University Hospital,
Bispebjerg Hospital, Copenhagen, Denmark
Massoud Afnan Assisted Conception Unit, Birmingham
Women’s Hospital, Birmingham, U.K. Nancy L. Brackett The Miami Project to Cure Paralysis,
University of Miami Miller School of Medicine, Lois Pope Life
Emre Akkus Professor in Urology-Andrology, Cerrahpasa Center, Miami, Florida, U.S.A.
School of Medicine, Istanbul University, Istanbul,
Turkey Astrid E. P. Cantineau Isala Clinics Zwolle, Zwolle, The
Netherlands
Peter Albers Department of Urology,
Heinrich-Heine-University, Düsseldorf, Germany Ben J. Cohlen Isala Clinics Zwolle, Zwolle, The Netherlands
Elisabetta M. Colpi Biogenesi Reproductive Medicine
Maria Alevizaki Endocrinology, Metabolism and Diabetes
Center, Istituti Clinici Zucchi, Monza, Italy
Unit, Evgenidion Hospital, and Department of Medical
Therapeutics, Alexandra Hospital, Athens University School of Giovanni M. Colpi Uro-Andrology and IVF Unit, Ospedale
Medicine, Athens, Greece San Paolo – Polo Universitario, Milano, Italy
Davide Arcaniolo Department of Urology, University Giovanni Corona Endocrinology Unit, Ospedale Maggiore,
Federico II, Naples, Italy Bologna, Italy

Stefan Arver Centre for Andrology and Sexual Medicine, Thorsten Diemer Department of Urology, Pediatric Urology
Department of Endocrinology, Metabolism and Diabetes, and Andrology, University of Giessen, Giessen, Germany
Karolinska University Hospital and Karolinska Institutet, Fotios Dimitriadis Department of Urology, School of
Stockholm, Sweden Medicine, Tottori University, Japan
Dimitrios Baltogiannis Department of Urology, Ioannina Gert R. Dohle Erasmus Medical Centre, Rotterdam, The
University School of Medicine, Ioannina, Greece Netherlands
Christopher L. R. Barratt Assisted Conception Unit and Jakob Eberhard Reproductive Medicine Centre, Skåne
Reproductive & Developmental Biology Group, Division of University Hospital Malmö, Lund University, Malmö, Sweden
Maternal and Child Health Sciences, Ninewells Hospital,
Jens-Jørgen Elberg Department of Plastic Surgery,
University of Dundee, Dundee, Scotland, U.K.
Rigshospitalet, University of Copenhagen, Copenhagen,
Armin J. Becker Department of Urology, University Denmark
Hospital Munich–Grosshadern, Nadja Engel Klinik Hirslanden, Zurich, Switzerland
Ludwig-Maximilians-University, Munich, Germany
Gianni Forti Endocrinology Unit, Department of Clinical
Mihály Berényi National Medical Center, Budapest, Physiopathology, University of Florence, Florence, Italy
Hungary
Mauro Gacci Department of Urology, University of
Richard Berges PAN Klinik, Köln, Germany Florence, Florence, Italy
Carlo Bettocchi Department of Urology, University of Bari, Giulio Garaffa Institute of Urology, University College
Bari, Italy London, London, U.K.
Lars Björndahl Centre for Andrology and Sexual Medicine, Jemima Gaytant Bone Research Unit, Laboratory for
Clinic for Endocrinology, Department of Medicine, Huddinge Experimental Medicine and Endocrinology, Department of

xi
 contributors
Experimental Medicine, Katholieke Universiteit Leuven, Anders Juul Department of Growth and Reproduction,
Leuven, Belgium Rigshospitalet, University of Copenhagen, Copenhagen,
Denmark
Patrick de Geeter Department of Urology, Klinikum Kassel,
Kassel, Germany Axel Kamischke Centre for Reproductive Medicine and
Andrology, University Clinic Münster, Münster, Germany
Dimitrios Giannakis Department of Urology, Ioannina
University School of Medicine, Ioannina, Greece Vanessa J. Kay Assisted Conception Unit & Reproductive &
Developmental Biology Group, Division of Maternal and
Aleksander Giwercman Reproductive Medicine Centre, Child Health Sciences, Ninewells Hospital, University of
Skåne University Hospital Malmö, Lund University, Malmö, Dundee, Dundee, Scotland, U.K.
Sweden
Howard H. Kim Department of Urology and Cornell
Yvonne Lundberg Giwercman Molecular Genetic Institute for Reproductive Medicine, Weill Medical College of
Reproductive Medicine, Department of Clinical Sciences, Cornell University, and The Population Council at Rockefeller
Lund University, Malmö, Sweden University, New York, New York, U.S.A.
Marc Goldstein Department of Urology and Cornell Sabine Kliesch Department of Clinical Andrology, Centre
institute for Reproductive Medicine, Weill Medical College of for Reproductive Medicine and Andrology, University Clinic
Cornell University, and The Population Council at Rockefeller Münster, Münster, Germany
University, New York, New York, U.S.A.
Zsolt Kopa National Medical Centre, Budapest, Hungary
Stavros Gratsias Department of Urology, Ioannina
University School of Medicine, Ioannina Csilla Krausz Department of Clinical Physiopathology,
Andrology Unit, University of Florence, Florence, Italy
Levent Gurkan Department of Urology, Tulane University
School of Medicine, New Orleans, Louisiana, U.S.A. Niels Kroman Department of Breast Surgery, Rigshospitalet,
University of Copenhagen, Copenhagen, Denmark
Uwe Hartmann Department of Urology, University Hospital
Andrea Lenzi Department of Medical Pathophysiology,
Munich–Grosshadern, Ludwig-Maximilians-University,
University of Rome “La Sapienza,” Rome, Italy
Munich, Germany
Chi-Ying Li Institute of Urology, University College London,
Ekkehard W. Hauck Department of Urology,
London, U.K.
Dr.-Otto-Gessler-Krankenhaus, Lindenberg, Germany, and
Department of Urology and Pediatric Urology, University Kersti Lundin Reproductive Medicine, Sahlgrenska
Hospital Giessen and Marburg GmbH, University Hospital, Göteborg, Sweden
Justus-Liebig-University Giessen, Giessen, Germany
Charles M. Lynne Department of Urology, University of
Wayne J. G. Hellstrom Department of Urology, Tulane Miami Miller School of Medicine, Miami, Florida, U.S.A.
University School of Medicine, New Orleans, Louisiana, U.S.A.
Maric Maggi Andrology Unit, Department of Clinical
Ralf Henkel Department of Medical Biosciences, University Physiopathology, University of Florence, Florence, Italy
of the Western Cape, Bellville, South Africa
Ahmed Mahmoud Section of Endocrinology/Andrology,
Ilpo Huhtaniemi Department of Reproductive Biology, Department of Internal Medicine, University Hospital Ghent,
Imperial College London, Hammersmith Campus, London, Ghent, Belgium
U.K. Roelof Menkveld Andrology Laboratory, Department of
Ciro Imbimbo Department of Urology, University Federico Obstetrics and Gynaecology, Tygerberg Academic Hospital
II, Naples, Italy and University of Stellenbosch, Tygerberg, South Africa

Emmanuele A. Jannini School of Sexology, Course of Vincenzo G. Mirone Urology Department, University
Endocrinology and Medical Sexology, University of L’Aquila, Federico II, Naples, Italy
L’Aquila, Italy Giorgios Mitios Department of Endocrinology, Diabetes,
Hubert John Department of Urology, Kantonsspital and Metabolism, Elena Venizelou Hospital, Athens, Greece
Winterthur, Switzerland Ikuo Miyagawa Department of Urology, Tottori University
Niels Jørgensen Department of Growth and Reproduction, School of Medicine, Yonago, Japan
Rigshospitalet, University of Copenhagen, Copenhagen, Francesco Montorsi Division of Urology, Istituto Scientifico
Denmark San Raffaele, Milan, Italy

xii
 contributors
Stamatina S. Nicopoulou Department of Endocrinology, Johan Svensson Department of Pediatrics, University
Diabetes, and Metabolism, Elena Venizelou Hospital, Athens, Hospital MAS, Malmö, Sweden
Greece
Mathew Tomlinson Consultant Scientist in Andrology, and
Dana A. Ohl Department of Urology, University of Honorary Special Lecturer, Nottingham University Hospitals
Michigan, Ann Arbor, Michigan, U.S.A. NHS Trust and University of Nottingham, Nottingham, U.K.
Fabrizio Palumbo Department of Urology, University of Jorma Toppari Departments of Physiology and Pediatrics,
Bari, Bari, Italy University of Turku, Turku, Finland
Nikolaos Pardalidis Department of Urology, Ioannina Herman Tournaye Centre for Reproductive Medicine,
University School of Medicine, Ioannina University Hospital of the Dutch-Speaking Brussels Free
University, Brussels, Belgium
Guido Piediferro Uro-Andrology and IVF Unit, Ospedale
San Paolo — Polo Universitario, Milano, Italy Guy T’Sjoen Section of Endocrinology/Andrology,
Department of Internal Medicine, University Hospital Ghent,
David J. Ralph St. Peter’s Andrology Centre and Institute of
Ghent, Belgium
Urology, University College London, London, U.K.
Panagiota Tsounapi Department of Urology, School of
Mathew C. Raynor Department of Urology, Tulane
Medicine, Tottori University, Japan
University School of Medicine, New Orleans, Louisiana,
U.S.A. Dirk Vanderschueren Bone Research Unit, Laboratory for
Experimental Medicine and Endocrinology, Department of
Michael Rimikis Department of Urology, Ioannina
Experimental Medicine, Katholieke Universiteit Leuven,
University School of Medicine, Ioannina
Leuven, Belgium
Lynne Robinson Assisted Conception Unit, Birmingham
Laurent Vaucher Department of Urology, Weill Cornell
Women’s Hospital, Birmingham, U.K.
Medical College, New York Presbyterian Hospital, New York,
Patrik Romerius Reproductive Medicine Centre, Skåne New York, U.S.A.
University Hospital Malmö, Lund University, Malmö, Sweden
Katrien Venken Bone Research Unit, Laboratory for
Motoaki Saito Division of Molecular Pharmacology, Experimental Medicine and Endocrinology, Department of
Department of Pathophysiological and Therapeutic Science, Experimental Medicine, Katholieke Universiteit Leuven,
School of Medicine, Tottori University, Japan Leuven, Belgium
Peter N. Schlegel Department of Urology, Weill Cornell Greta Verheyen Centre for Reproductive Medicine,
Medical College, New York Presbyterian Hospital, New York, University Hospital of the Dutch-speaking Brussels Free
New York, U.S.A. University, Brussels, Belgium
Fabrizio I. Scroppo Neuro-Andro-Urology Service, Spinal Valérie Vernaeve Clinica EUGIN, Travessera de Les Corts,
Unit, Ospedale Niguarda, Milano, Italy Barcelona, Spain
Olle Söder Paediatric Endocrinology Unit, Department of Paolo Verze Department of Urology, University Federico II,
Women’s and Children’s Health, Karolinska Institutet and Naples, Italy
Karolinska University Hospital, Stockholm, Sweden
Evlalia Vlachopoulou Department of Urology, Ioannina
Nikolaos Sofikitis Department of Urology, Ioannina University School of Medicine, Ioannina
University School of Medicine, Ioannina
Florian M. E. Wagenlehner Department of Urology,
Jens Sønksen Department of Urology, Herlev Hospital, Pediatric Urology and Andrology, University of Giessen,
University of Copenhagen, Herlev, Denmark Giessen, Germany
Thomas C. Stadler Department of Urology, University Takeshi Watanabe Department of Urology, Tottori
Hospital Munich–Grosshadern, University School of Medicine, Yonago, Japan
Ludwig-Maximilian-University, Munich, Germany
Wolfgang Weidner Department of Urology, Pediatric
Christian G. Stief Department of Urology, University Urology and Andrology, University of Giessen, Giessen,
Hospital Munich–Grosshadern, Germany
Ludwig-Maximilians-University, Munich, Germany
Michael Zitzmann Centre of Reproductive Medicine and
Patrizia Sulpizio Obstetrics and Gynecology Clinic, Andrology/Clinical Andrology of the University Clinics,
University of Milano, Milano, Italy Münster, Germany

xiii
1 Defining male factor infertility
Dimitrios A. Adamopoulos, Georgios Mitios, and Stamatina S. Nicopoulou

INTRODUCTION tive and good for classification purposes, but offer no insight
Male factor infertility is defined as a couple’s failure to achieve with regard to the etiology or prognosis.
pregnancy due to problems in the male partner. This condition In this chapter, the terminology proposed by WHO (2) is
has emerged as a serious reproductive health issue during the followed throughout, since it has been the most widely used up
last few decades. As expected, it appeared first in the western to now.
societies and attracted immediate attention of both the relevant
medical specialists and the public. As new evidence has accumu- Diagnostic Categories
lated from epidemiological data and clinical observations cou- The currently used diagnostic categorization for male infer-
pled with original information coming from the emergence of tility is based on the rather simple investigative procedures
assisted reproduction technology (ART) and also from diverse employed originally in the 1970s (1) and later in the 1980s (2)
faculties such as genetics, molecular biology, and environmen- (Table 2). Thus, precise identification of the causative factors
tal toxicology, the interest of the medical community increased leading to male reproductive problems has been unattainable
sharply. and for years remained the ultimate, although elusive, goal in
In this context, special bodies of interest in human repro- Andrology. And, since achieving fully this task is practically
duction not only voiced their concern but also took specific impossible, one may fare for investigation improvements aim-
actions to highlight the problem, to standardize the methodol- ing to reduce the very high incidence of sperm problems of
ogy for evaluation of reproductive function, and, even, to issue unknown etiology known as idiopathic. Indeed, with the stan-
instructions to those of the medical practitioners and scien- dardization and improvement of semen analysis methods, avail-
tists involved in clinical and/or research work in Reproductive ability of additional endocrine markers (e.g., inhibin-B, anti-
Medicine and Andrology. For additional information, the reader Müllerian hormone), introduction of new functional tests (e.g.,
is encouraged to consult some important monographs issued DNA fragmentation), high quality of ultrasound, availabil-
by the World Health Organization (WHO) (1–3). ity of cytological–histological indices, and genetics–molecular
biology techniques (Y chromosome microdeletions, etc.), this
task for more precise classification has to a large extent been
PRESENTING THE PROBLEM achieved. Moreover, improvement of the investigative proce-
Definitions dures has led to the introduction of some novel diagnostic
Before proceeding to definitions related to male fertility capac- categories: major and secondary (Table 2). In this new diag-
ity, it is important to define reproductive health, at large, as nostic classification, single, two, and three or more causative
the condition that is free from disease and disturbances in the factor combinations have been introduced as separate classes.
reproductive system of both sexes. The definitions employed to As single-cause new categories, epididymopathy, environmen-
describe the state of reproductive capacity are either the gen- tally induced (mostly occupational), recreation-related activi-
eral ones, applicable to both sexes, or those specific only for ties (motorbike, bicycle, etc.), and life-style–associated habits
the male (Table 1). Thus, infertility is the broad term used to (tobacco, alcohol, etc.) have emerged as separate entities. Com-
describe a couple’s failure to induce pregnancy within one year binations of new and/or old known causes were also another
of unprotected regular intercourse, whereas primary or sec- important feature of this categorization (4). Thus, the wide
ondary male infertility specifically characterizes a man’s failure range of known diagnostic categories has recently, with the
to impregnate a woman (2). By and large, definitions for a cou- introduction of new investigative tools, been expanded with
ple’s reproductive problem are hindered by difficulties arising result (a) the marked reduction of the unknown etiology cases
from the diversity of the approach followed by different groups (idiopathic), (b) more insight into the physiopathology and
or authors. To date, all the terms describing the problem are used future state of reproductive health in men with the problem,
in the context of fertility outcome, without any reference to the and (c) better prognosis for therapeutic attempts and their
diagnostic steps employed, the duration of the problem, or its outcome.
prognosis. In effect, the established terms refer to reproductive
performance rather than capacity and are used according to Distribution of Causative Factors
whether there is, or not, actual childbearing during a certain Data for the distribution of causative factors are very limited
period of time. In this context, existing definitions are descrip- and come from record analysis of a few referral centers. In this

1
 adamopoulos et al.
Table 1 Definitions for Reproductive Capacitya

Definitions applicable in both sexes

Fecundity the capacity of a man or woman to produce a live baby

Total fertility rate indicates the number of live births a woman will have by the end of her
reproductive life-span (15–49 years of age)
Fertility is the capability to conceive or induce pregnancy in the respective sex
Infertility is a couple’s failure to induce pregnancy within one year of unprotected regular
intercourse
Subfertility signifies a reduced, but not impossible, chance to achieve pregnancy
Sterility is defined as the permanent inability to conceive/induce pregnancy
Primary no pregnancy has ever been achieved
Secondary inability to achieve further desired pregnancies

Definitions specific for male reproductive problems

Primary male infertility characterizes a man’s past and present failure to impregnate a woman
Secondary male infertility is defined as a man’s present inability to impregnate a woman, although he did so
in the past
Dyspermiab a general term referring to any quantitative and/or qualitative sperm aberration
a Ref. 2.
b Not part of WHO definitions.

Table 2 Diagnostic Categories of Male Infertility

A. Data from 1980s a

Sexual/ejaculatory dysfunction Varicocele

Immunological cause Accessory gland infection
No demonstrable cause Endocrine causes
Seminal plasma abnormalities Idiopathic
Iatrogenic cause Oligozoospermiab
Systemic cause Asthenozoospermia
Congenital anomalies Teratozoospermia
Testicular maldescent Cryptozoospermia
Karyotype abnormalities Azoospermia
Epididymal/seminal vesicles agenesis Obstructive
Acquired testicular damage Idiopathic

B. Data from the 1996–2005 c

WHO diagnostic categories, as above (A.) additional:

Single cause
Epididymopathyd , environmental, life-style
Genetic abnormalities (Y microdeletions, CF gene mutations, etc.)
Two-cause combinations
One of single causes plus one of A. causes
Three or more cause combinations
One of single causes plus ≥ 2 of A. causes
a Refs. 1 and 3.
b Oligo- <20 × 106 /mL, astheno- <50% progressively motile, and <25% rapidly progressively motile, terato-
<subnormal (according to the reference level of the laboratory) percentage of normal forms, cryrpo-: no
spermatozoa seen in fresh sample but a few in sediment (3).
c Ref. (4).
d Mostly occupational.

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 defining male factor infertility
Table 3 Frequency Distribution of Male Infertility Diagnostic Table 4 Frequency Distribution of Male Infertility Diagnostic
Categories in Two Periods of Time Classes Based on Recent Data (1996–2005)a

1970sa 1980sb % of each % of total no.

class of cases
% %
Idiopathic infertilityc 39.7 Idiopathic infertility 31.0 1. Single-cause class b
Varicocele 22.8 Varicocele 15.6 Idiopathic OTA syndrome 40.6 15.2
Infections 12.4 Endocrine 8.9 Varicocele 18.7 7.1
hypogonadism Epididymopathy 12.8 4.8
Seminal plasma 6.3 Infections 8.0 Environmentalc 8.0 3.1
abnormalities Genital infections 5.3 1.8
Immunological factors 5.4 Maldescented testes 7.8 Acquired testicular damage 4.8 1.7
Congenital abn/ties 3.0 Sperm deposition 5.9 Congenital anomalies 3.4 1.3
problems Systemic causes 2.4 0.8
Sexual-ejaculatory 2.9 Immunological factors 4.5 Endocrine dysfunction 1.6 0.6
problem Ejaculatory problems 1.5 0.5
Systemic diseases 2.5 Systemic diseases 3.1 Life-style 1.0 0.4
Obstructive azoospermia 1.6 Obstructions 1.7
2. Two-cause classes d
Endocrinopathies 1.2 Remainder (testicular 13.4
Combination of one other factor with
tumors, cryo, etc.)
Epididymopathy 31.3 9.8
Various 2.2
Varicocele 26.5 8.5
a Estimate from 3555 couples with a male factor infertility problem, Environmental 20.6 6.3
Remainder 21.6 6.7
extracted from Table 1 (1).
b Data from a reference reproductive medicine center, adapted from
3. Three or more cause classes e
Table 5.2 (5). Combination of two or more factors with
c Oligo-terato-astheno-necro-zoo-spermia.
Epididymopathy 24.8 7.8
Varicocele 19.2 6.0
Environmental 19.0 6.0
context, the specific nature of the center (endocrinology, urol- Remainder 37.0 11.5
ogy, etc.) might have been interfering with the representative-
ness of the population sample. Another important aspect was a Ref. 4.
b Singleclass, n: 289 (37.3%).
the time-related deviations in the relative incidence of etiologi-
c Mainly occupational.
cal factors for compromised male reproductive capacity. These
d Two-cause classes, n: 242 (31.3%).
have been demonstrated in sets of data assembled in the 1970s e Three- or more-cause classes, n: 243 (31.4%).
or 1980s and observations made over the last decade. It appears
that the main explanation for the differences observed was the
updating of the investigative means available over the years idiopathic oligozoospermia [15.2% as compared to the 39.7%
passed. and 31.0% found in the earlier reports (1,5)]. Another inter-
Thus, in study from the 1970s (1), the highest incidence of esting observation was the emergence of new categories listed
male factor infertility was observed in subgroups of men with as epididymopathy (12.8%), environmentally induced (8.0%),
idiopathic dyspermia, varicocele, and accessory gland infections and life-style–related classes (including use/abuse of alcohol,
(39.7%, 22.8%, and 12.4%, respectively; Table 3). An intermedi- tobacco, motorbike, etc., ∼1.0%). Finally, of particular impor-
ate, time-wise, distribution of diagnostic categories originated tance was the observation that single factor categories accounted
from a single reference center caring for a mid-European pop- for only 37.3% of the total study population, the remaining
ulation showed similar findings, although the clinical material being combinations of 2 (31.3%) and 3 (31.4%) or more fac-
classified was not exclusively infertile (5). This picture has signif- tor categories. This finding makes the relative distribution of
icantly changed as a result of an improved diagnostic approach diagnostic categories presented in the past not relevant today,
applied in recent years. Thus, analysis of a set of data from a because this classification was formulated on the assumption
total of 774 dyspermic men investigated for couple infertility of a single factor etiology for each group. As it is noted, in the
in an andrology clinic in the decade 1996 to 2005, using up- recent categorization, varicocele, as a part of the single-cause
to-date investigative tools, showed marked differences from the category, represents 18.7% of this subgroup, but only 7.1% of
early reports regarding both the number of categories listed and the whole sample (Table 4). However, its total incidence for all
their relative frequency distribution (Table 4). It was of inter- three subgroups was 21.6%. Moreover, two- or multi-cause fac-
est that despite applying sophisticated investigative means, the tor classes were the commonest diagnostic categories (31.3% +
most frequently occurring diagnostic category was still that of 31.4% = 62.7%).

3
 adamopoulos et al.
It is concluded that single-cause etiology of the problem is factor fertility problem (2,5). Another estimate of male factor
present only in approximately one-third of the cases, the great infertility originated from the Society for Assisted Reproduc-
majority being bi- or multifactorial in origin, and this new dis- tive Technology, which listed in its Clinic Summary Report a
tribution of causative factors is the result of improvement in male problem as the only factor in 17% of infertile couples,
the investigative tools employed. Moreover, a clearer picture and a combination of male plus female factor in another 18%
of the distribution of causative factors is mandatory for deci- of ART trials performed for the year 2005 in the United States
sion making both for prevention policies and for therapeutic (17). Moreover, in a recent report, male factor problem was
prognosis. considered to be the cause in one-third of couple infertility
cases, with an equal percentage attributed to a problem of both
TRENDS IN MALE REPRODUCTIVE HEALTH partners (18). However, the gravest piece of news came from
Conflicting data from epidemiological observations and large the annual report of the U.S. Society on ART for the year 2003,
data bases have created a rather blurred picture of the prevail- which showed that an alarming 53% of the couples using in
ing trends in male reproductive capacity, with some extreme vitro fertilization (IVF) and intracytoplasmic sperm injection
estimations ranging from those reporting no change or even (ICSI) were admitted to these procedures because of male factor
improvement to some prophets of the doom, who have made infertility (19).
catastrophic predictions. Some of the main constituents depict-
ing male reproductive capacity trends include: Reproductive Organ Morbidities
During the last decade or so it became apparent, mostly through
Sperm Parameter Changes the pioneering work of Scandinavian workers, that poor semen
Since the 1992 meta-analysis demonstrating a significant decline quality is not a random observation but, indeed, a part of the
of sperm parameters during the last 50 years (6), a number of consequences of a wider assault of the environment on male
reports from different parts of the world, mostly Europe and the reproductive health (13,20). These pathologies were consid-
United States, have either supported or refuted the findings of ered to be different morbidities developing on a common back-
that study (7,8); this topic has been strongly debated in the early ground and were manifested as separate problems including the
1990s (9). To date, it is generally accepted that a deterioration following entities.
of sperm parameters is a frequently observed phenomenon in
certain populations, but there are also some notable exceptions.
Compromised Testicular Function
These differences should be properly analyzed on each partic-
Information regarding a declining trend in sperm parameters
ular case, and, if confirmed, it might be timely to consider a
has been widely reported and published (6,8) and its impact
re-evaluation of normal sperm values as indeed was the case in
on fertility rates has been well documented (11). This phe-
the new WHO update (10) and introduction of new standards
nomenon, although not universal, has been considered as mul-
in specific populations on earth.
tifactorial in origin.
Trends in Male Factor Infertility
Up until the 1980s–1990s, overpopulation was a major global Increased Rate of Testicular Cancer
concern, particularly in high breeding countries in develop- It appears that this malignancy, more common in young to
ment. However, in recent years, this tide has been reversed and middle adult ages, has been on the rise in the West during the
a marked drop in fertility rates has been observed, but most con- second half of the 20th century and was a consistent finding in
vincingly in the developed countries (11,12). This turn of events various Caucasian populations (21). It was thought that fetal
has not only been linked to the prevailing modern life-style but gonads may be the target of various detrimental factors and,
also to the environmental assault on men’s reproductive health in this context, testicular cancer may not be but one of the
(13). In this context, it was of interest that a marked decline deleterious consequences, the other one being sperm problems
of total sperm number and seminal volume occurred over a in adult age (13).
two-decade period in reverse fashion, with an increase of some
important environmental pollutants in a South-European Cap- Congenital Anomalies of Male Genitalia
ital (14), and, most importantly, this change was concomitant Cryptorchidism and hypospadias are two abnormalities for
with other reproductive health-compromising events occurring which an increasing incidence has been observed in recent
in both sexes (15). Moreover, a recent report on declining con- decades in certain populations (22,23). These trends run con-
ception rates in a Northern European population related this currently with the rise of testicular cancer’s incidence in the
finding with an overall compromise of the male reproductive same populations, suggesting a common pathogenetic cause.
health (16). By and large, it appears that a rising tendency in reproduc-
Direct information on the prevalence of male factor infertil- tive organ morbidities occurred during the last few decades. In
ity is difficult to obtain from any source. In an early study, a those compromising male fecundity conditions, one may add
prevalence of about 8% was reported as a couple’s single male the recently described testicular dysgenesis syndrome (20).