Endocrinology

Volume 1

Series EditorAndrea LenziChair of EndocrinologyDepartment of Experimental Medicine,Section of Medical PathophysiologyFood Science and EndocrinologySapienza University of RomeRome, Italy

Series Co-EditorEmmanuele A. JanniniChair of Endocrinology & Medical Sexology (ENDOSEX)Department of Systems MedicineUniversity of Rome Tor VergataRome, Italy

Within the health sciences, Endocrinology has a unique and pivotal role. This old,but continuously new science is the study of the various hormones and their actionsand disorders in the body. The matter of Endocrinology are the glands, i.e., theorgans that produce hormones, active on the metabolism, reproduction, food absorp-tion and utilization, growth and development, behavior control, and several othercomplex functions of the organisms. Since hormones interact, affect, regulate, andcontrol virtually all body functions, Endocrinology not only is a very complexscience, multidisciplinary in nature, but is one with the highest scientific turnover.Knowledge in the Endocrinological sciences is continuously changing and growing.In fact, the field of Endocrinology and Metabolism is one where the highest numberof scientific publications continuously flourishes. The number of scientific journalsdealing with hormones and the regulation of body chemistry is dramatically high.Furthermore, Endocrinology is directly related to genetics, neurology, immunology,rheumatology, gastroenterology, nephrology, orthopedics, cardiology, oncology,gland surgery, sexology and sexual medicine, psychology, psychiatry, internal med-icine, and basic sciences. All these fields are interested in updates in Endocrinology.The aim of the MRW in Endocrinology is to update the Endocrinological matterusing the knowledge of the best experts in each section of Endocrinology: basicendocrinology, neuroendocrinology, endocrinological oncology, pancreas with dia-betes and other metabolic disorders, thyroid, parathyroid and bone metabolism,adrenals and endocrine hypertension, sexuality, reproduction, and behavior.

More information about this series at http://www.springer.com/series/14021

Manuela Simoni • Ilpo T. HuhtaniemiEditors

Endocrinology of theTestis and MaleReproduction

With 127 Figures and 73 Tables

EditorsManuela SimoniUnit of EndocrinologyDepartment of BiomedicalMetabolic and Neural SciencesUniversity of Modena and Reggio EmiliaModena, Italy

Ilpo T. HuhtaniemiFaculty of MedicineDepartment of Surgery and CancerImperial College LondonLondon, UK

ISBN 978-3-319-44440-6 ISBN 978-3-319-44441-3 (eBook)ISBN 978-3-319-44442-0 (print and electronic bundle)https://doi.org/10.1007/978-3-319-44441-3

Library of Congress Control Number: 2017948013

# Springer International Publishing AG 2017This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of thematerial is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,broadcasting, reproduction on microfilms or in any other physical way, and transmission or informationstorage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodologynow known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoes not imply, even in the absence of a specific statement, that such names are exempt from the relevantprotective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in this bookare believed to be true and accurate at the date of publication. Neither the publisher nor the authors or theeditors give a warranty, express or implied, with respect to the material contained herein or for any errorsor omissions that may have been made. The publisher remains neutral with regard to jurisdictional claimsin published maps and institutional affiliations.

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Series Preface

Is there an unmet need for a new MRW series in Endocrinology and Metabolism? Itmight not seem so! The vast number of existing textbooks, monographs, andscientific journals suggest that the field of hormones (from genetic, molecular,biochemical, and translational to physiological, behavioral, and clinical aspects) isone of the largest in biomedicine, producing a simply huge scientific output.However, we are sure that this new series will be of interest for scientists, academics,students, physicians, and specialists alike.

The knowledge in Endocrinology and Metabolism limited to the two main (froman epidemiological perspective) diseases, namely hypo/hyperthyroidism and diabe-tes mellitus, now seems outdated and perhaps closer to the practical interests ofthe general practitioner than to those of the specialist. This has led to endocrinologyand metabolism being increasingly considered as a subsection of internalmedicine rather than an autonomous specialization. But endocrinology is muchmore than this.

We are proposing this series as the manifesto for Endocrinology 2.0, embracingthe fields of medicine in which hormones play a major part but which, for varioushistorical and cultural reasons, have thus far been “ignored” by endocrinologists.Hence, this MRW comprises “traditional” (but no less important or investigated)topics: from the molecular actions of hormones to the pathophysiology and man-agement of pituitary, thyroid, adrenal, pancreatic, and gonadal diseases, as well asless usual and common arguments. Endocrinology 2.0 is, in fact, the science ofhormones, but it is also the medicine of sexuality and reproduction, the medicine ofgender differences, and the medicine of well-being. These aspects of Endocrinologyhave to date been considered of little interest, as they are young and relativelyunexplored sciences. But this is no longer the case. The large scientific productionin these fields coupled with the impressive social interest of patients in these topics isstimulating a new and fascinating challenge for Endocrinology.

The aim of the MRW in Endocrinology is thus to update the subject with theknowledge of the best experts in each field: basic endocrinology, neuroendocrinol-ogy, endocrinological oncology, pancreatic disorders, diabetes and other metabolicdisorders, thyroid, parathyroid and bone metabolism, adrenal and endocrine

v

hypertension, sexuality, reproduction, and behavior. We are sure that this ambitiousaim, covering for the first time the whole spectrum of Endocrinology 2.0, will befulfilled in this vast Springer MRW in Endocrinology Series.

Andrea LenziEmmanuele A. Jannini

vi Series Preface

Volume Preface

Generally speaking, the ultimate scope of life is maintenance of the species, which isensured by reproduction. Reproduction depends on exquisite endocrine signals,which start during fetal life, are dormant during childhood, mature and attain fullfunction at the end of puberty, and variably decline thereafter in a gender-dependentfashion. Therefore, if hormones are essential for life of individuals, reproductivehormones are in addition essential for the maintenance of species. Turned in anotherway, if some hormonal defects are deadly for the individual, reproductive failuremay be deadly for the species. This book illustrates what hormones do for malereproduction, in which way they govern the pathophysiology of the hypothalamo-pituitary-gonadal axis, and, more generally, how they are implicated in the mainte-nance of the human species.

The book has been compiled by the world experts of the field, both in basic andclinical science. It aims at providing a comprehensive view of the current knowledgeranging from molecular, genetic, and cellular mechanisms to clinical manifestationsof male reproductive physiology and its disorders to therapeutic perspectives. Malereproduction is a sensitive issue, with wide socioeconomical and ethical implica-tions, which has been covered as well.

Each chapter of this book is meant to stand on itself as a reference work in itsfield. It has been written with human male reproduction in mind, but it also coversthe animal research relevant to understand the clinical problems andrologists andmale reproductive endocrinologists may encounter in their everyday practice.

We are grateful to all distinguished colleagues who generously contributed to thiswork with their knowledge and experience. We are confident that the readership willfind clear answers to their curiosity, to improve their clinical skills and to stimulatethem to more creative research in this fascinating field.

Manuela SimoniIlpo T. Huhtaniemi

vii

Contents

Volume 1

Part I Physiology of the Hypothalamus-Pituitary-Gonadal Axis,the Testis, and Testicular Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1 Control of GnRH Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Marco Bonomi, Valeria Vezzoli, and Anna Cariboni

2 GnRH Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35Kathryn L. Garner, Krasimira Tsaneva-Atanasova, andCraig A. McArdle

3 Gonadotropins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71Alfredo Ulloa-Aguirre, James A. Dias, and George R. Bousfield

4 Gonadotropin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123Livio Casarini, Ilpo T. Huhtaniemi, Manuela Simoni, andAdolfo Rivero-Müller

5 Sex Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169Sarah J. Potter, Deepti Lava Kumar, and Tony DeFalco

6 Male Sexual Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217Catherine H. Sterling, Dagmar Wilhelm, and Stefan Bagheri-Fam

7 Endocrinology of the Fetal Testis . . . . . . . . . . . . . . . . . . . . . . . . . . 245Richard Ivell, Ravinder Anand-Ivell, and Steven D. Morley

8 Testis Development and Descent . . . . . . . . . . . . . . . . . . . . . . . . . . . 273Girolamo Mattioli, Pietro Lazzeroni, Irene Paraboschi,Natascia Di Iorgi, Flavia Napoli, and Mohamad Maghnie

9 Functional Anatomy and Histology of the Testis . . . . . . . . . . . . . . 313D. Fietz and M. Bergmann

10 Testicular Steroidogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343Christa E. Flück and Amit V. Pandey

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11 Anabolic and Metabolic Effects of Testosterone andOther Androgens: Direct Effects and Role of TestosteroneMetabolic Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373Jonas Čeponis, Christina Wang, Ronald S. Swerdloff, and Peter Y. Liu

12 Androgen Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395Päivi Sutinen, Marjo Malinen, and Jorma J. Palvimo

13 Spermatogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417Juho-Antti Mäkelä and Jorma Toppari

14 Epididymal Sperm Transport and Fertilization . . . . . . . . . . . . . . . 457S. Marchiani, L. Tamburrino, M. Muratori, and E. Baldi

Part II Clinical Approach to the Disorders ofMale Reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479

15 Anamnesis and Physical Examination . . . . . . . . . . . . . . . . . . . . . . 481Francesco Lombardo, Francesco Pallotti, Francesco Cargnelutti, andAndrea Lenzi

16 Hormonal Laboratory Examination . . . . . . . . . . . . . . . . . . . . . . . . 495Uberto Pagotto, Flaminia Fanelli, and Antonio Raffaele Granata

17 Genetic Analysis in Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . 517Csilla Krausz

18 The Semen Analysis: The Investigation of theHuman Ejaculate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535Lars Björndahl and Rebecka Holmberg

19 Color-Doppler Ultrasound and New Imaging Techniquesin Andrological Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555Francesco Lotti and Mario Maggi

20 Histopathological Evaluation of Testicular Biopsy . . . . . . . . . . . . . 623Ewa Rajpert-De Meyts, Kenneth M. Grigor, and Niels E. Skakkebaek

Volume 2

Part III Disorders of Sexual Development andMale Hypogonadism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

21 Classification and Epidemiology of Hypogonadism . . . . . . . . . . . . 645George A. Kanakis and Dimitrios G. Goulis

x Contents

22 Clinical Manifestation and Diagnosis of Androgen Deficiency . . . . 669Agnieszka Swiecicka and Frederick Wu

23 Primary and Secondary Hypogonadism . . . . . . . . . . . . . . . . . . . . . 687Daniele Santi and Giovanni Corona

24 Delayed Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749Nanna Kolby, Alexander S. Busch, and Anders Juul

25 Androgen Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773Jarmo Jääskeläinen

26 Estrogen Deficiency in Men . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797Vincenzo Rochira and Cesare Carani

27 Hypogonadism in Systemic Diseases . . . . . . . . . . . . . . . . . . . . . . . . 829Vincenzo Rochira

28 Effect of Cancer Treatments on Testicular Function . . . . . . . . . . . 881Aleksander Giwercman

29 Gynecomastia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899Marco Zavattaro, Giovanna Motta, Stefano Allasia, andFabio Lanfranco

30 Late-Onset Hypogonadism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921Giulia Rastrelli and Gianni Forti

31 Treatment of Hypogonadism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945Giulia Rastrelli and Mario Maggi

Part IV Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 979

32 Pre-Testicular, Testicular, and Post-Testicular Causes of MaleInfertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981Fotios Dimitriadis, George Adonakis, Apostolos Kaponis, CharalamposMamoulakis, Atsushi Takenaka, and Nikolaos Sofikitis

33 Genetics of Male Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029Frank Tüttelmann and Albrecht Röpke

34 Infectious and Immunological Aspects of Male Infertility . . . . . . . 1051Qian Jiang and Daishu Han

35 Hormonal Treatment of Male Infertility:Gonadotropins and Beyond . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071Andrea M. Isidori, Andrea Sansone, and Daniele Gianfrilli

Contents xi

36 Nonhormonal Medical Treatment of Male Infertility . . . . . . . . . . . 1091Aldo E. Calogero, Rosita A. Condorelli, and Sandro La Vignera

37 Varicocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115M.W. Ragab and S. Kliesch

38 Assisted Reproduction for Male Infertility . . . . . . . . . . . . . . . . . . . 1145Biljana Popovic-Todorovic and Herman Tournaye

39 Intratesticular Sperm Extraction . . . . . . . . . . . . . . . . . . . . . . . . . . 1177Davide Oreggia, Eugenio Ventimiglia, and Andrea Salonia

40 Therapy with Antiandrogens in Gender DysphoricNatal Males . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199Giulia Gava, Renato Seracchioli, and Maria Cristina Meriggiola

Part V Miscellaneous Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1211

41 Male Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213Bradley D. Anawalt and Stephanie T. Page

42 Cryopreservation of Spermatozoa . . . . . . . . . . . . . . . . . . . . . . . . . 1235Loredana Gandini, Francesco Pallotti, Donatella Paoli, andAndrea Lenzi

43 Use, Misuse, and Abuse of Androgens . . . . . . . . . . . . . . . . . . . . . . 1251David J. Handelsman

44 Psychological Aspects of Infertility Among Men . . . . . . . . . . . . . . 1287Jane Fisher and Karin Hammarberg

45 Ethical Aspects of Male Reproductive Disordersand Their Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1319Maurizio Mori

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1351

xii Contents

About the Editors

Manuela Simoni, M.D., Ph.D., trained as a clinicalendocrinologist at the Unit of Endocrinology of the Uni-versity of Modena, Italy, between 1982 and 1990 and,thereafter, as molecular endocrinologist at the Institute ofReproductive Medicine of the University of Münster,Germany, where she was Professor for Endocrinologyand Molecular Biology of Reproduction from 1998to 2008.

Since 2008, she is Full Professor of Endocrinology atthe University of Modena and Reggio Emilia, Italy.

Currently, she holds the following positions: Directorof the Clinical Unit of Endocrinology at the Ospedale

Civile of Modena, Director of the School of Specialization in Endocrinology andMetabolism, Deputy Director of the Department of Biomedical, Metabolic andNeural Sciences, and Director of the Center for Genomic Research of the Universityof Modena and Reggio Emilia.

Her research interests are gonadotropin and androgen action, testicular function,male infertility, endocrinology, and pathophysiology of reproduction.

She is member of several societies, including the European Academy of Androl-ogy (EAA) and the European Society of Endocrinology (ESE, serving as theSecretary), and is active in the editorial boards of several journals in the fields ofendocrinology and reproduction. Since January 2017, she is Co-Editor-in-Chief ofANDROLOGY, the official journal of the European Academy of Andrology and theAmerican Society of Andrology.

xiii

Ilpo T. Huhtaniemi received his M.D. and Ph.D. fromthe University of Helsinki, Finland, did postdoctoraltraining in USA (UC San Francisco and NIH, Bethesda),and has been on sabbatical leave in Germany, USA, andScotland. From 1986 to 2002, he held the post of Pro-fessor and Chairman of Physiology at University ofTurku, Finland. He moved in 2002 to UK as a Chair inReproductive Endocrinology at Imperial CollegeLondon, from which post he retired in 2015. He hasreceived several national and international honors,among them a Fellowship of the Academy of MedicalSciences (UK) and a Doctor Honoris Causa of the Med-

ical University Lodz, Poland, and University of Szeged, Hungary. He has been theChief Managing Editor of Mol Cell Endocrinol (1999–2017), has served in theEditorial Board of Endocrinology and Endocr Rev, and is/has been the Editor orEditorial Board Member of several other scientific journals (e.g., Eur J Endocrinol,Clin Endocrinol, Hum Reprod Update, J Endocrinol, Mol Hum Reprod, Reproduc-tion, Asian J Androl, J Endocr Soc). He has held positions of trust in manyinternational scientific organizations (e.g., Past President of International Societyof Andrology; Executive Committee of European Society of Endocrinology). Hisresearch interests include clinical and basic reproductive endocrinology, in particularthe function of gonadotrophins and male reproductive endocrinology. He also haslong-term interests in male contraception, hormone-dependent cancer, and the endo-crinology of aging.

xiv About the Editors

Contributors

George Adonakis Department of Ob/Gyn, School of Medicine, Patras University,Patras, Greece

Stefano Allasia Department of Medical Sciences, Division of Endocrinology,Diabetology and Metabolism, University of Torino, Torino, Italy

Ravinder Anand-Ivell School of Biosciences, University of Nottingham, Notting-ham, UK

Bradley D. Anawalt Department of Medicine- Metabolism, Endocrinology andNutrition, University of Washington, Seattle, WA, USA

Stefan Bagheri-Fam Department of Anatomy and Neuroscience, The Universityof Melbourne, Melbourne, VIC, Australia

E. Baldi Dipartimento di Medicina Sperimentale e Clinica, University of Florence,Florence, Italy

M. Bergmann Institute for Veterinary Anatomy, Histology and Embryology, JustusLiebig University Giessen, Giessen, Germany

Lars Björndahl ANOVA – Andrology, Sexual Medicine and Transgender Medi-cine, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden

Marco Bonomi Department of Clinical Sciences and Community Health, Univer-sity of Milan, Milan, Italy

Division of Endocrine and Metabolic Diseases and Laboratory of Endocrine andMetabolic Research, IRCCS Istituto Auxologico Italiano, Ospedale San Luca,Milan, Italy

George R. Bousfield Department of Biology, Wichita State University, Wichita,KS, USA

Alexander S. Busch Department of Growth and Reproduction, Rigshospitalet,University of Copenhagen, Copenhagen Ø, Denmark

International Research and Research Training Centre in Endocrine Disruption ofMale Reproduction and Child Health (EDMaRC), Rigshospitalet, University ofCopenhagen, Copenhagen Ø, Denmark

xv

Aldo E. Calogero Department of Clinical and Experimental Medicine, Universityof Catania, Catania, Italy

Cesare Carani Department of Biomedical, Metabolic and Neural Sciences, Uni-versity of Modena and Reggio Emilia, Modena, Italy

Francesco Cargnelutti Department of Experimental Medicine, University ofRome “La Sapienza”, Rome, Italy

Anna Cariboni Department of Pharmacological and Biomolecular Sciences, Uni-versity of Milan, Milan, Italy

Livio Casarini Unit of Endocrinology, Department of Biomedical, Metabolic andNeural Sciences, University of Modena and Reggio Emilia, Modena, Italy

Jonas Čeponis Los Angles Biomedical Research Institute at Harbor-UCLA Med-ical Center, Torrance, CA, USA

Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas,Lithuania

Rosita A. Condorelli Department of Clinical and Experimental Medicine, Univer-sity of Catania, Catania, Italy

Giovanni Corona Endocrinology Unit, Medical Department, Azienda USL Bolo-gna Maggiore-Bellaria Hospital, Bologna, Italy

Tony DeFalco Division of Reproductive Sciences, Cincinnati Children’s HospitalMedical Center, Cincinnati, OH, USA

Natascia Di Iorgi Department of Pediatrics, Istituto Giannina Gaslini, Universityof Genova, Genova, Italy

James A. Dias Department of Biomedical Sciences, State University of New Yorkat Albany, Albany, NY, USA

Fotios Dimitriadis Department of Urology, School of Medicine, Aristotle Univer-sity, Thessaloniki, Greece

Flaminia Fanelli Endocrinology Unit and Center for Applied BiomedicalResearch, Department of Medical and Surgical Sciences, University of Bologna –S. Orsola-Malpighi Hospital, Bologna, Italy

D. Fietz Institute for Veterinary Anatomy, Histology and Embryology, JustusLiebig University Giessen, Giessen, Germany

Jane Fisher Jean Hailes Research Unit, School of Public Health and PreventiveMedicine, Monash University, Melbourne, VIC, Australia

Christa E. Flück Pediatric Endocrinology and Diabetology Department of Pediat-rics, Bern University Hospital, and Department of Clinical Research, University ofBern, Bern, Switzerland

xvi Contributors

Gianni Forti Endocrinology Unit, Department of Experimental and Clinical Bio-medical Sciences, University of Florence, Florence, Italy

Loredana Gandini Department of Experimental Medicine, Laboratory of Semi-nology-Sperm Bank, University of Rome “La Sapienza”, Rome, Italy

Kathryn L. Garner Laboratories for Integrative Neuroscience and Endocrinology,School of Clinical Sciences, University of Bristol, Bristol, UK

Giulia Gava Gynecology and Physiopathology of Human Reproduction, S.Orsola-Malpighi Hospital, Department of Medical and Surgical Science, Universityof Bologna, Bologna, Italy

Daniele Gianfrilli Department of Experimental Medicine, Section of MedicalPathophysiology, Food Science and Endocrinology, Sapienza University of Rome,Rome, Italy

Aleksander Giwercman Translational Medicine, Lund University, Malmö,Sweden

Molecular Reproductive Medicine, Department of Translational Medicine, LundUniversity, Malmö, Sweden

Dimitrios G. Goulis Unit of Reproductive Endocrinology, First Department ofObstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki,Thessaloniki, Greece

Antonio Raffaele Granata Endocrinology Unit, Department of Internal Medicine,Endocrinology, Metabolism and Geriatry, Azienda Ospedaliero Universitaria,Modena, Italy

Kenneth M. Grigor Department of Pathology, University of Edinburgh, Edin-burgh, Scotland, UK

Karin Hammarberg Jean Hailes Research Unit, School of Public Health andPreventive Medicine, Monash University, Melbourne, VIC, Australia

Daishu Han Department of Cell Biology, Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences, School of Basic Medicine, Peking UnionMedical College, Beijing, China

David J. Handelsman ANZAC Research Institute, University of Sydney, Sydney,Australia

Andrology Department, Concord Hospital, Sydney, Australia

Rebecka Holmberg ANOVA – Andrology, Sexual Medicine and TransgenderMedicine, Karolinska University Hospital and Karolinska Institute, Stockholm,Sweden

Loredana Gandini: deceased.

Contributors xvii

Ilpo T. Huhtaniemi Faculty of Medicine, Department of Surgery and Cancer,Imperial College London, London, UK

Andrea M. Isidori Department of Experimental Medicine, Section of MedicalPathophysiology, Food Science and Endocrinology, Sapienza University of Rome,Rome, Italy

Richard Ivell School of Biosciences and School of Veterinary Medicine andScience, University of Nottingham, Nottingham, UK

Jarmo Jääskeläinen Institute of Clinical Medicine, Department of Pediatrics,Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland

Qian Jiang Department of Cell Biology, Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences, School of Basic Medicine, Peking UnionMedical College, Beijing, China

Anders Juul Department of Growth and Reproduction, Rigshospitalet, Universityof Copenhagen, Copenhagen Ø, Denmark

International Research and Research Training Centre in Endocrine Disruption ofMale Reproduction and Child Health (EDMaRC), Rigshospitalet, University ofCopenhagen, Copenhagen Ø, Denmark

George A. Kanakis Unit of Reproductive Endocrinology, First Department ofObstetrics and Gynaecology, Medical School, Aristotle University of Thessaloniki,Thessaloniki, Greece

Apostolos Kaponis Department of Ob/Gyn, School of Medicine, Patras University,Patras, Greece

S. Kliesch Department of Clinical and Surgical Andrology, Center of ReproductiveMedicine and Andrology, University Hospital, Münster, Germany

WHO Collaborating Center, EAATraining Center, Münster, Germany

Nanna Kolby Department of Growth and Reproduction, Rigshospitalet, Universityof Copenhagen, Copenhagen Ø, Denmark

International Research and Research Training Centre in Endocrine Disruption ofMale Reproduction and Child Health (EDMaRC), Rigshospitalet, University ofCopenhagen, Copenhagen Ø, Denmark

Csilla Krausz Department of Experimental and Clinical Biomedical Sciences“Mario Serio”, University of Florence, Florence, Italy

Sandro La Vignera Department of Clinical and Experimental Medicine, Univer-sity of Catania, Catania, Italy

Deepti Lava Kumar Division of Reproductive Sciences, Cincinnati Children’sHospital Medical Center, Cincinnati, OH, USA

xviii Contributors

Fabio Lanfranco Department of Medical Sciences, Division of Endocrinology,Diabetology and Metabolism, University of Torino, Torino, Italy

Pietro Lazzeroni Department of Pediatrics, Istituto Giannina Gaslini, University ofGenova, Genova, Italy

Andrea Lenzi Department of Experimental Medicine, Laboratory of Seminology-Sperm Bank, University of Rome “La Sapienza”, Rome, Italy

Peter Y. Liu Los Angles Biomedical Research Institute at Harbor-UCLA MedicalCenter, Torrance, CA, USA

David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, Tor-rance, CA, USA

Francesco Lombardo Department of Experimental Medicine, University of Rome“La Sapienza”, Rome, Italy

Francesco Lotti Sexual Medicine and Andrology Unit, Department of Experimen-tal and Clinical Biomedical Sciences, University of Florence, Florence, Italy

Mario Maggi Sexual Medicine and Andrology Unit, Department of Experimentaland Clinical Biomedical Sciences, University of Florence, Florence, Italy

Mohamad Maghnie Department of Pediatrics, Istituto Giannina Gaslini, Univer-sity of Genova, Genova, Italy

Juho-Antti Mäkelä Department of Physiology, Institute of Biomedicine, Univer-sity of Turku, Turku, Finland

Marjo Malinen Institute of Biomedicine, University of Eastern Finland, Kuopio,Finland

Charalampos Mamoulakis Department of Urology, School of Medicine, Univer-sity of Crete, Heraklion, Crete, Greece

S. Marchiani Dipartimento di Scienze Biomediche, Sperimentali e Cliniche,Università di Firenze, Florence, Italy

Girolamo Mattioli Department of Surgery, Istituto Giannina Gaslini, University ofGenova, Genova, Italy

Craig A. McArdle Laboratories for Integrative Neuroscience and Endocrinology,School of Clinical Sciences, University of Bristol, Bristol, UK

Maria Cristina Meriggiola Gynecology and Physiopathology of Human Repro-duction, S. Orsola-Malpighi Hospital, Department of Medical and Surgical Science,University of Bologna, Bologna, Italy

Maurizio Mori Università di Torino, Consulta di Bioetica Onlus, Turin, Italy

Steven D. Morley Division of Health Sciences, University of Edinburgh MedicalSchool, Edinburgh, UK

Contributors xix

Giovanna Motta Department of Medical Sciences, Division of Endocrinology,Diabetology and Metabolism, University of Torino, Torino, Italy

M. Muratori Dipartimento di Scienze Biomediche, Sperimentali e Cliniche,Università di Firenze, Florence, Italy

Flavia Napoli Department of Pediatrics, Istituto Giannina Gaslini, University ofGenova, Genova, Italy

Davide Oreggia University Vita-Salute San Raffaele, Milan, Italy

Division of Experimental Oncology/Unit of Urology, URI-Urological ResearchInstitute, IRCCS Ospedale San Raffaele, Milan, Italy

Stephanie T. Page Department of Medicine- Metabolism, Endocrinology andNutrition, University of Washington, Seattle, WA, USA

Uberto Pagotto Endocrinology Unit and Center for Applied Biomedical Research,Department of Medical and Surgical Sciences, University of Bologna – S. Orsola-Malpighi Hospital, Bologna, Italy

Francesco Pallotti Department of Experimental Medicine, Laboratory of Semi-nology-Sperm Bank, University of Rome “La Sapienza”, Rome, Italy

Jorma J. Palvimo Institute of Biomedicine, University of Eastern Finland, Kuopio,Finland

Amit V. Pandey Pediatric Endocrinology and Diabetology Department of Pediat-rics, Bern University Hospital, and Department of Clinical Research, University ofBern, Bern, Switzerland

Donatella Paoli Department of Experimental Medicine, Laboratory of Semi-nology-Sperm Bank, University of Rome “La Sapienza”, Rome, Italy

Irene Paraboschi Department of Surgery, Istituto Giannina Gaslini, University ofGenova, Genova, Italy

Biljana Popovic-Todorovic Centre for Reproductive Medicine, UZ Brussel, Brus-sel, Belgium

Sarah J. Potter Division of Reproductive Sciences, Cincinnati Children’s HospitalMedical Center, Cincinnati, OH, USA

M. W. Ragab Department of Clinical and Surgical Andrology, Center of Repro-ductive Medicine and Andrology, University Hospital, Münster, Germany

Department of Andrology, Faculty of Medicine, Cairo University, Cairo, Egypt

Ewa Rajpert-De Meyts Department of Growth and Reproduction, Rigshospitalet,University of Copenhagen and EDMaRC, Copenhagen, Denmark

Giulia Rastrelli Sexual Medicine and Andrology Unit, Department of Experimen-tal and Clinical Biomedical Sciences, University of Florence, Florence, Italy

xx Contributors

Adolfo Rivero-Müller Department of Physiology, Institute of Biomedicine, Uni-versity of Turku, Turku, Finland

Vincenzo Rochira Department of Biomedical, Metabolic and Neural Sciences,University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria diModena, Ospedale Civile di Baggiovara, Modena, Italy

Albrecht Röpke Institute of Human Genetics, University of Münster, Münster,Germany

Andrea Salonia University Vita-Salute San Raffaele, Milan, Italy

Division of Experimental Oncology/Unit of Urology, URI-Urological ResearchInstitute, IRCCS Ospedale San Raffaele, Milan, Italy

Andrea Sansone Department of Experimental Medicine, Section of Medical Path-ophysiology, Food Science and Endocrinology, Sapienza University of Rome,Rome, Italy

Daniele Santi Unit of Endocrinology, Department of Biomedical, Metabolic andNeural Sciences, University of Modena and Reggio Emilia, Modena, Italy

Renato Seracchioli Gynecology and Physiopathology of Human Reproduction, S.Orsola-Malpighi Hospital, Department of Medical and Surgical Science, Universityof Bologna, Bologna, Italy

Manuela Simoni Unit of Endocrinology, Department of Biomedical, Metabolicand Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

Niels E. Skakkebaek Department of Growth and Reproduction, Rigshospitalet,University of Copenhagen and EDMaRC, Copenhagen, Denmark

Nikolaos Sofikitis Department of Urology, School of Medicine, Ioannina Univer-sity, Ioannina, Greece

Catherine H. Sterling Department of Anatomy and Neuroscience, The Universityof Melbourne, Melbourne, VIC, Australia

Päivi Sutinen Institute of Biomedicine, University of Eastern Finland, Kuopio,Finland

FinVector Vision Therapies Oy, Kuopio, Finland

Ronald S. Swerdloff Los Angles Biomedical Research Institute at Harbor-UCLAMedical Center, Torrance, CA, USA

David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, Tor-rance, CA, USA

Agnieszka Swiecicka Andrology Research Unit, Faculty of Biology, Medicine andHealth, The University of Manchester, Manchester, UK

Atsushi Takenaka Department of Urology, School of Medicine, Tottori University,Yonago, Japan

Contributors xxi

L. Tamburrino Dipartimento di Scienze Biomediche, Sperimentali e Cliniche,Università di Firenze, Florence, Italy

Jorma Toppari Department of Pediatrics, Turku University Hospital, Turku,Finland

Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland

Herman Tournaye Centre for Reproductive Medicine, UZ Brussel, Brussel,Belgium

Krasimira Tsaneva-Atanasova Department of Mathematics, College of Engineer-ing, Mathematics and Physical Sciences, University of Exeter, Exeter, UK

EPSRC Centre for Predictive Modelling in Healthcare, University of Exeter, Exeter,UK

Frank Tüttelmann Institute of Human Genetics, University of Münster, Münster,Germany

Alfredo Ulloa-Aguirre Red de Apoyo a la Investigación, Coordinación de laInvestigación Científica, Universidad Nacional Autónoma de México (UNAM),Mexico City, Mexico

Red de Apoyo a la Investigación, Instituto Nacional de Ciencias Médicas yNutrición SZ, Mexico City, Mexico

Eugenio Ventimiglia University Vita-Salute San Raffaele, Milan, Italy

Division of Experimental Oncology/Unit of Urology, URI-Urological ResearchInstitute, IRCCS Ospedale San Raffaele, Milan, Italy

Valeria Vezzoli Laboratory of Endocrine and Metabolic Research, IRCCS IstitutoAuxologico Italiano, Cusano Milanino, Milan, Italy

Christina Wang Los Angles Biomedical Research Institute at Harbor-UCLAMedical Center, Torrance, CA, USA

David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, Tor-rance, CA, USA

Dagmar Wilhelm Department of Anatomy and Neuroscience, The University ofMelbourne, Melbourne, VIC, Australia

Frederick Wu Andrology Research Unit, Faculty of Biology, Medicine andHealth, The University of Manchester, Manchester, UK

Marco Zavattaro Department of Translational Medicine, Division of Endocrinol-ogy, University of Eastern Piedmont, Novara, Italy

xxii Contributors