W.-B. Schill · F. H. Comhaire · T. B. Hargreave (Eds.) Andrology for the Clinician

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W.-B.Schill·F.H.Comhaire·T.B.Hargreave(Eds.) Andrology for the Clinician W.-B. Schill · F.H.Comhaire · T. B. Hargreave (Eds.) Andrology for the Clinician

With 225 Figures in 300 Parts and 120 Tables Prof. em. Dr. Dr. Wolf-Bernhard Schill Center of Dermatology and Andrology, Justus Liebig University Giessen Gaffystraße 14 35385 Giessen, Germany Prof. em. Dr. Frank Comhaire Center for Medical and Urological Andrology and Reproductive Endocrinology, University Hospital Ghent 6K12IE De Pintelaan 185 9000 Ghent, Belgium Prof. Dr. TimothyB.Hargreave Department of Oncology, University of Edinburgh Human Genetics Building, Western General Hospital Edinburgh EH4 2XU Scotland UK

ISBN 3-540-23171-4 Springer-Verlag Berlin Heidelberg New York

Library of Congress Control Number: 2005935881 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media http://www.springer.com ˇ Springer-Verlag Berlin Heidelberg 2006 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Marion Philipp Desk Editor: Ellen Blasig Production Editor: Joachim W. Schmidt Cover design: eStudio Calamar, Spain Typesetting: FotoSatz Pfeifer GmbH, D-82166 Gräfelfing Printedonacid-freepaper–24/3151–543210 Foreword

Andrology in its widest sense is a fast growing medical discipline with special em- phasis on the disturbances of male reproductive function including erectile dysfunction and problems of the ageing male. There is a great need to educate both the spe- cialists who practise as andrologists, such as endocrinologists, urologists and dermatologists, as well as the general practitioner, who is often involved in the management of these patients. Three international scientists from different medical disciplines (dermatology, endocrinology and urology) have created an alternative to a classical textbook by providing a new format in this book to facilitate the review of informationinthefieldprovidedbyalargenumberofinternationalexperts. This textbook is written in two parts. Part I provides easily accessible, brief, problem-oriented information about modern andrology including male factor infertility, male contraception, male genital tract infection and tumours. The book is intended to be of use to the busy clinician and to provide quick access to didactic information about current practice. Part II is subject-oriented and provides the background scientific information for the recommendations in Part I. The three editors are recog- nized experts in the field and have invited key international scientists to write vari- oussectionsofthisbookbut,bytheirextensivesub-editing,havecreatedahomoge- neousconcept.Thekeyfeaturesofthisbookaretheclearrecommendationsabout current practice and easy access to the underlying science. I have no doubt that this textbook will be an asset to the clinical andrologist by facilitating information on to the rapidly increasing scientific data in the fast growing field of andrology. It is the aim of this textbook to reach doctors working in the field of andrology all over the world but should be of particular value in European countries. The book will be valuable for urologists, andrologists, dermatologists, endocrinologists, gynaecologists, reproductive biologists, general practitioners, gerontologists, psycholo- gists, psychiatrists, paediatricians and paramedicals including all professions allied to medicine as well as pharmaceutical companies working in the field of andrology. Iamsurethatthebookwillbeagreatsuccessandwillbeofgreatvaluetoitsreaders. DaviddeKretser Monash Institute of Medical Research Monash University, Melbourne Preface

Andrology is the medical practice of disorders that afflict men. These include congenital and acquired abnormalities of the male reproductive system as well as disorders of the male endocrine system. As these may be treated by different disciplines including endocrinology, dermatology, urological surgery, plastic surgery, oncology, venereology, and sexual medicine, it is difficult for doctors in these various special- ties to have a holistic view of andrology. We hope that this book will be a source of reference to the broad spectrum of andrological conditions and that it will promote a holistic view of andrology and catalyse interdisciplinary co-operation in the management of andrological disorders. The book is written in two parts: Part I presents current clinical practice, whereas PartII provides the reader with more detail on the theoretical background. The reader will find chapters on the diagnosis and treatment of disorders of male fertility, disorders of male sexual function, sexually transmitted infections, disorders of androgen status, including ageing changes, and chapters on benign and malignant growths of the male reproductive organs. In addition, we have included chapters on phytotherapeutics and aesthetic dermatology and medical cosmetics because in practice many men seek these treatments and the competent andrologist needs to understand alternative as well as traditional approaches. Our contributors are from many different countries and each is an acknowledged expert. Wherever possible, reference has been made to the results of randomized clinical trials and it has been our intention that the information in this book should be evidence-based. All contributors were asked to present a comprehensive review of their field as well as their own work. In previous years, andrological problems have been relatively ignored but this is changing because of the development of effective treatments such as phosphodies- terase inhibitors for erectile dysfunction and 5- [ -reductase inhibitors for prostatic enlargement, and as a result, greater media coverage of andrological disorders. Therefore, more men seek treatment and increasingly men expect their clinician to be well informed about all aspects of andrology. We hope that this book will help ad- vance towards that objective. Wolf-Bernhard Schill, Frank Comhaire, Timothy Hargreave Giessen – Ghent – Edinburgh, February 2006 Contents

List of Contributors ...... XXI I.1.1.5 Prognosis ...... 22 References...... 22 Introduction I.1.2 Disorders of Sexual Differentiation Andrology: Definition, Clinical Issues G.G.R. T’Sjoen ...... 23 and Prevalence I.1.2.1 Definition ...... 23 W.-B. Schill, F. Comhaire, T.B. Hargreave .... 1 I.1.2.2 AetiologyandPathogenesis...... 23 References...... 3 I.1.2.3 ClassificationofIntersex...... 23 I.1.2.4 Clinical Findings ...... 24 Layout and How to Use the Book I.1.2.5 Management...... 24 F. Comhaire ...... 4 I.1.2.6 Prevention...... 25 References...... 25 General Considerations Evidence-Based Medicine in Reproductive Medicine I.2 Problem: Abnormal Pubertal Development and Andrology S.A. Wudy ...... 27 F. Comhaire, A. Mahmoud ...... 5 I.2.1 Physiology ...... 27 References...... 6 I.2.2 Precocious Puberty ...... 27 Economic Cost and Cost-Effectiveness F. Comhaire, A. Mahmoud ...... 7 I.2.3 Delayed Puberty ...... 28 References...... 9 References...... 28 Ethics of Reproductive Research and Treatment I.3 Male Factor Fertility Problems T.B. Hargreave ...... 9 Introduction ...... 9 I.3.1 Consensus-Based Approach to Standardized Basic Principles Underlying Ethical Considerations 10 Diagnosis and Management Consent ...... 10 of the Infertile Male Applying the Principles to Reproductive Medicine 11 F. Comhaire, A. Mahmoud ...... 29 Conclusion...... 13 References...... 30 References...... 13 I.3.2 WHO Recommended Diagnostic HumanTissueforResearch Flow Chart T.B. Hargreave ...... 14 F. Comhaire, A. Mahmoud ...... 31 I.3.3 Implications of Multifactorial Aetiology in the Diagnosis and Management I Diagnosing and Solving Clinical Problems of Male Infertility F. Comhaire, A. Mahmoud ...... 33 I.1 Problem: Gender Dysphoria and Disorders References...... 35 of Sexual Differentiation I.3.4 Sexual Dysfunction and Male Fertility I.1.1 Gender Dysphoria T.B. Hargreave ...... 35 G.G.R. T’Sjoen ...... 19 I.3.4.1 DefinitionoftheDisease...... 35 I.1.1.1 Definition ...... 19 I.3.4.2 AetiologyandPathogenesis...... 35 I.1.1.2 AetiologyandPathogenesis...... 19 I.3.4.3 Clinical Findings: History, Physical I.1.1.3 Clinical Findings ...... 19 Examination, Technical Investigations, I.1.1.4 Treatment...... 20 LaboratoryFindings ...... 36 X Contents

I.3.4.4 DifferentialDiagnosis...... 37 I.3.10 Congenital Disorders and Male Infertility I.3.4.5 Treatment...... 37 T.B. Hargreave ...... 63 I.3.4.6 ResultsofTreatment...... 37 I.3.10.1 DefinitionoftheDisease...... 63 I.3.4.7 Prevention...... 39 I.3.10.2 Aetiology and Pathogenesis ...... 63 References...... I.3.10.3 Clinical Findings: History, Physical Examination, Technical Investigations, I.3.5 Reference Values of Semen Variables LaboratoryFindings ...... 63 and Their Interpretation I.3.10.4 DifferentialDiagnosis...... 64 F. Comhaire, A. Mahmoud ...... 40 I.3.10.5 Treatment...... 64 References...... 43 I.3.10.6 ResultsofTreatment ...... 65 I.3.6 Normal Spermatozoa and Isolated I.3.10.7 Prevention...... 66 Abnormalities of Seminal Plasma I.3.11 Acquired Testicular Damage F. Comhaire, A. Mahmoud ...... 44 G. Haidl ...... 66 I.3.6.1 Definition ...... 44 I.3.11.1 Definition ...... 66 I.3.6.2 AetiologyandPathogenesis...... 44 I.3.11.2 Aetiology and Pathogenesis ...... 66 I.3.6.3 Clinical and Laboratory Findings ...... 45 I.3.11.3 Clinical and Laboratory Findings ...... 67 I.3.6.4 DifferentialDiagnosis...... 45 I.3.11.4 DifferentialDiagnosis...... 67 I.3.6.5 Treatment...... 45 I.3.11.5 Treatment...... 67 I.3.6.6 ResultsofTreatment...... 46 I.3.11.6 ResultsofTreatment ...... 67 I.3.6.7 Prognosis ...... 46 I.3.11.7 Prognosis...... 67 I.3.6.8 Prevention...... 46 I.3.11.8 Prevention...... 68 I.3.6.9 Other...... 46 I.3.11.9 Other...... 68 References...... 46 References...... 68 I.3.7 Immunological Causes I.3.12 Cause: Varicocele A. Mahmoud, F. Comhaire ...... 47 F. Comhaire, A. Mahmoud ...... 68 I.3.7.1 Introduction...... 47 I.3.12.1 Definition ...... 68 I.3.7.2 Mechanisms of Male Immunity to I.3.12.2 Aetiology and Pathogenesis ...... 68 Spermatozoa...... 47 I.3.12.3 Clinical Findings, Technical Investigations I.3.7.3 DetectionofAntispermAntibodies...... 48 and Laboratory Findings ...... 69 I.3.7.4 Antisperm Antibodies in Male I.3.12.4 DifferentialDiagnosis...... 70 Infertility 49 I.3.12.5 Treatment...... 70 I.3.7.5 Clinical Aspects of Men with Antisperm I.3.12.6 ResultsofTreatment ...... 70 Antibodies...... 50 I.3.12.7 Prognosis...... 70 I.3.7.6 Perspectives ...... 50 I.3.12.8 Prevention...... 71 References...... 51 I.3.12.9 Other...... 71 I.3.8 Iatrogenic Causes of Abnormal Spermatozoa References...... 71 G. Haidl ...... 53 I.3.13 Infection/Inflammation of the Accessory I.3.8.1 Definition ...... 53 Sex Glands I.3.8.2 AetiologyandPathogenesis...... 53 F. Comhaire, A. Mahmoud ...... 72 I.3.8.3 Clinical and Laboratory Findings ...... 55 I.3.13.1 Definition ...... 72 I.3.8.4 DifferentialDiagnosis...... 55 I.3.13.2 AetiologyandPhysiopathology...... 72 I.3.8.5 Treatment...... 55 I.3.13.3 Clinical and Laboratory Findings ...... 72 I.3.8.6 ResultsofTreatment...... 55 I.3.13.4 DiagnosisandDifferentialDiagnosis .... 73 I.3.8.7 Prognosis ...... 55 I.3.13.5 Treatment...... 73 I.3.8.8 Prevention...... 56 I.3.13.6 ResultsofTreatment ...... 73 I.3.8.9 Other...... 56 I.3.13.7 Prognosis...... 74 References...... 56 I.3.13.8 Prevention...... 74 I.3.9 Systemic Causes of Male Infertility References...... 74 A. Mahmoud, F. Comhaire ...... 57 I.3.14 Endocrine Factors I.3.9.1 Introduction...... 57 R. Weber ...... 75 I.3.9.2 SystemicCauses...... 57 I.3.14.1 Definition ...... 75 References...... 61 I.3.14.2 Aetiology and Pathogenesis ...... 75 I.3.14.3 Clinical Findings ...... 76 Contents XI

I.3.14.4 Treatment...... 77 I.4.3 Ejaculatory Dysfunction. Premature References...... 77 Ejaculation, Delayed Ejaculation, Anejaculation, Low-Volume Ejaculation, I.3.15 Oligo-Astheno-Teratozoospermia with no Retrograde Ejaculation and Painful Demonstrable Cause (Idiopathic O-A-T) Ejaculation F. Comhaire, A. Mahmoud ...... 77 T.B. Hargreave ...... 99 I.3.15.1 DefinitionoftheDisease...... 77 I.4.3.1 DefinitionoftheDisease...... 99 I.3.15.2 Aetiology and Pathogenesis ...... 78 I.4.3.2 AetiologyandPathogenesis...... 100 I.3.15.3 Clinical Findings: History, Physical Exam- I.4.3.3 Clinical Findings: History, Physical ination, Technical Investigations, Laboratory Examination, Technical Investigations, Findings ...... 78 LaboratoryFindings ...... 101 I.3.15.4 DifferentialDiagnosis...... 78 I.4.3.4 Treatment...... 102 I.3.15.5 Treatment...... 79 I.4.3.5 Prognosis ...... 103 I.3.15.6 ResultsofTreatment ...... 79 I.4.3.6 Prevention...... 103 I.3.15.7 Prognosis...... 79 References I.3.15.8 Prevention...... 79 I.3.15.9 Other...... 79 I.4.4 Orgasm Dysfunction ...... 105 References...... 80 T.B. Hargreave ...... 105 I.4.4.1 DefinitionoftheDisease...... 105 I.3.16 Azoospermia I.4.4.2 AetiologyandPathogenesis...... G.R. Dohle ...... 81 I.4.4.3 Clinical Findings: History, Physical Exam- I.3.16.1 Definition ...... 81 ination, Technical Investigations, Laboratory I.3.16.2 Introduction...... 81 Findings ...... 106 I.3.16.3 Investigations...... 82 I.4.4.4 Treatment...... 106 References...... 84 References...... 107 I.4 Problem: Sexual Dysfunction I.4.5 Abnormal Libido B. Brosig ...... 107 I.4.1 Erectile Dysfunction I.4.5.1 Definition ...... 107 T.B. Hargreave ...... 85 I.4.5.2 Epidemiology...... 108 I.4.1.1 DefinitionoftheDisease...... 85 I.4.5.3 AetiologyandPathogenesis...... 108 I.4.1.2 AetiologyandPathogenesis...... 85 I.4.5.4 Clinical Findings ...... 109 I.4.1.3 Clinical Findings: History, Physical Exam- I.4.5.5 Therapy...... 109 ination, Technical Investigations, Laboratory I.4.5.6 Prognosis ...... 110 Findings ...... 87 References...... 110 I.4.1.4 Treatment...... 88 I.4.1.5 ResultsofTreatment ...... 91 I.4.6 Sexual Deviation and Paraphilias I.4.1.6 Prevention...... 92 M. Beutel ...... 111 References...... 92 I.4.6.1 Definition ...... 111 I.4.6.2 AetiologyandPathogenesis...... 111 I.4.2 Erectile Deformity, Including Peyronie’s I.4.6.3 Paedophilia as an Example of Paraphilia 112 Disease I.4.6.4 DiagnosisandTreatment ...... 112 T.B. Hargreave ...... 93 References...... 113 I.4.2.1 DefinitionoftheDisease...... 93 I.4.2.2 AetiologyandPathogenesis...... 93 I.5 Problem: Male Contraception I.4.2.3 Clinical Findings: History, Physical Exam- ination, Technical Investigations, Laboratory I.5.1 Controversies Regarding Post-Vasectomy Findings ...... 94 Management I.4.2.4 Treatment...... 95 J. Shah, H. Fisch ...... 114 I.4.2.5 ResultsofTreatment ...... 97 I.5.1.1 Introduction...... 114 I.4.2.6 Prevention...... 98 I.5.1.2 Definition ...... 114 References...... 98 I.5.1.3 Prevalence...... 114 I.5.1.4 Treatment...... 115 I.5.1.5 ResultsofTreatment...... 115 I.5.1.6 Conclusion...... 117 References...... 117 XII Contents

I.5.2 Vasectomy Reversal I.7 Problem: Emergencies in Andrology A. Belker ...... 119 I.7.1 Testicular Torsion I.5.2.1 Indications...... 119 C.F. Heyns, A.J. Visser ...... 134 I.5.2.2 Contraindications ...... 119 I.7.1.1 Definition ...... 134 I.5.2.3 VasectomyReversalTechniques...... 119 I.7.1.2 AetiologyandPathogenesis...... 136 I.5.2.4 PostoperativeCare...... 120 I.7.1.3 Clinical Findings ...... 138 I.5.2.5 Complications ...... 120 I.7.1.4 DifferentialDiagnosis...... 145 I.5.2.6 Results...... 120 I.7.1.5 Treatment...... 146 I.5.2.7 Conclusions ...... 120 I.7.1.6 ResultsofTreatment ...... 150 References...... 121 I.7.1.7 Prognosis...... 151 I.5.3 Male Contraception I.7.1.8 Prevention...... 155 D. Handelsman, G. Waites ...... 121 I.7.1.9 Conclusions...... 156 I.5.3.1 Introduction...... 121 References...... 156 I.5.3.2 HormonalMethods...... 121 I.7.2 Blunt Testicular Trauma I.5.3.3 NonhormonalMethods...... 121 J. Vale ...... 162 I.5.3.4 Vaccines...... 121 I.7.2.1 Definition ...... 162 I.5.3.5 Conclusions ...... 122 I.7.2.2 AetiologyandPathogenesis...... 162 References...... 122 I.7.2.3 Diagnosis...... 162 I.5.4 Traditional Methods I.7.2.4 Treatment – Conservative Versus Surgical 163 D. Handelsman, G. Waites ...... 122 I.7.2.5 PostoperativeFollow-up...... 163 I.5.4.1 Introduction...... 122 References...... 163 I.5.4.2 Conclusions ...... 124 I.7.3 Penile Fractures References...... 124 W.D. Aiken ...... 164 I.7.3.1 DefinitionoftheDisease...... 164 I.6 Problem: Reproductive Tract Infections I.7.3.2 AetiologyandPathogenesis...... 164 I.6.1 Reproductive Tract Infections/Sexually I.7.3.3 Clinical Findings ...... 164 Transmitted Diseases I.7.3.4 PhysicalExamination ...... 165 F.R. Ochsend orf ...... 125 I.7.3.5 Investigations...... 165 I.6.1.1 DefinitionoftheDisease...... 125 I.7.3.6 DifferentialDiagnosis...... 165 I.6.1.2 AetiologyandPathogenesis...... 125 I.7.3.7 Treatment...... 165 I.6.1.3 Clinical Findings: History, Physical Exam- I.7.3.8 ResultsofTreatment ...... 166 ination, Technical Investigations, Laboratory I.7.3.9 Prognosis...... 166 Findings ...... 126 I.7.3.10 Prevention...... 166 I.6.1.4 DifferentialDiagnosis...... 129 References...... 166 I.6.1.5 Treatment...... 129 I.7.4 Priapism I.6.1.6 ResultsofTreatment...... 129 P. Kum ar , D. J. R a lph ...... 166 I.6.1.7 Prognosis ...... 129 I.7.4.1 Definition ...... 166 I.6.1.8 Prevention...... 129 I.7.4.2 AetiologyandPathogenesis...... 166 I.6.1.9 Other...... 129 I.7.4.3 Clinical Findings, Technical Investigations References...... 130 and Laboratory Findings ...... 167 I.6.2 HIV Infection I.7.4.4 Treatment...... 168 F.R. Ochsend orf ...... 131 I.7.4.5 Conclusion ...... 169 I.6.2.1 DefinitionoftheDisease...... 131 References...... 169 I.6.2.2 AetiologyandPathogenesis...... 131 I.7.5 Testicular Pain and Related Pain I.6.2.3 Clinical Findings: History, Physical Exam- Syndromes ination, Technical Investigations, Laboratory T.B. Hargreave, L. Turner-Stokes ... 170 Findings ...... 131 I.7.5.1 DefinitionoftheDisease...... 170 I.6.2.4 Treatment...... 131 I.7.5.2 AetiologyandPathogenesis...... 170 I.6.2.5 ResultsofTreatment...... 132 I.7.5.3 Clinical Findings: History, Physical Exam- I.6.2.6 Prognosis ...... 132 ination, Technical Investigations, Laboratory I.6.2.7 Prevention...... 132 Findings ...... 173 I.6.2.8 Other...... 132 I.7.5.4 DifferentialDiagnosis...... 174 References...... 132 I.7.5.5 Treatment...... 174 Contents XIII

I.7.5.6 ResultsofTreatment ...... 176 I.8.5 Circumcision I.7.5.7 Prognosis...... 177 C.F. Heyns, J.N. Krieger ...... 203 I.7.5.8 Conclusion ...... 177 I.8.5.1 Introduction...... 204 References...... 177 I.8.5.2 EpidemiologyofCircumcision...... 204 I.8.5.3 Embryology and Function of the Foreskin 204 I.8 Benign Lesions and Malignant Tumours I.8.5.4 IndicationsforCircumcision...... 205 oftheMaleGenitalTract I.8.5.5 Contraindications for Circumcision . . . . 206 I.8.5.6 ComplicationsofCircumcision...... 207 I.8.1 Scrotal Benign Lesions, Epididymal I.8.5.7 Current Controversies About Cysts, Epididymal Tumours Circumcision ...... 208 K. Turner ...... 179 I.8.5.8 AlternativestoCircumcision ...... 210 I.8.1.1 Hydrocele ...... 179 I.8.5.9 Conclusions...... 210 I.8.1.2 EpididymalCysts...... 181 References...... 211 I.8.1.3 EpididymalTumours...... 181 I.8.1.4 Other Benign Epididymal Lesions: Sperm I.9 Problem: Diseases of the Prostate (Infection, Granuloma ...... 182 Benign Prostatic Hyperplasia, Cancer) I.8.1.5 Other Benign Epididymal Lesions: TuberculosisoftheEpididymis ...... 182 I.9.1 Benign Prostatic Hyperplasia and References...... 182 Prostatic Cancer S.A. McNeill, S.K.W. Leung ...... 213 I.8.2 Testicular Cancer, CIS, Microcalcifications, I.9.1.1 Introduction...... 213 TNM Classification O. Ståhl, J. Eberhard, A. Giwercman 183 I.9.1.2 AetiologyandPathogenesis...... 213 I.9.1.3 ProstateCancer...... 214 I.8.2.1 TesticularCancer...... 183 I.9.1.4 Symptoms, Diagnosis and Treatment . . . 214 I.8.2.2 Carcinoma-in-SituoftheTestis...... 187 References...... 216 References...... 188 I.9.2 Prostatitis I.8.3 Penile Inflammations M.C. Bishop ...... 217 F.-M. Köhn ...... 190 I.9.2.1 Introduction...... 217 I.8.3.1 Introduction...... 190 I.9.2.2 DiagnosisofProstatitis...... 218 I.8.3.2 PearlyPenilePapules...... 190 I.9.2.3 AetiologyofChronicProstatitis...... 220 I.8.3.3 Sclerosing Lymphangitis of the Penis . . . 191 I.9.2.4 Treatment...... 221 I.8.3.4 BalanitisandBalanoposthitis...... 191 References...... 223 I.8.3.5 LichenSclerosusetAtrophicus...... 193 I.8.3.6 Balanitis Circumscripta Plasmacellularis I.10 Problem: Male Breast Disorder (Zoon’sBalanitis)...... 193 I.8.3.7 BalanitisCircinata...... 194 I.10.1 Gynaecomastia and Benign Breast I.8.3.8 PsoriasisVulgaris...... 195 Hyperplasia Including Iatrogenic Causes I.8.3.9 LichenPlanus...... 196 W. Krause ...... 225 I.8.3.10 FixedDrugEruption...... 197 I.10.1.1 Definition, Epidemiology ...... 225 I.8.3.11 Other Drug-Induced Lesions of the Penis 198 I.10.1.2 AetiologyandPathogenesis ...... 226 I.8.3.12 Allergic and Irritant Contact Dermatitis I.10.1.3 ClinicalFeatures...... 227 ofthePenis...... 198 I.10.1.4 Histopathology...... 227 I.8.3.13 AtopicDermatitis...... 199 I.10.1.5 GeneticRiskFactors ...... 228 I.8.3.14 SeborrhoeicDermatitis...... 199 I.10.1.6 DiagnosticProcedures...... 228 References...... 200 I.10.1.7 Prevention and Treatment ...... 230 References...... 231 I.8.4 Penile Cancer I.D.C. Mitchell ...... 201 I.10.2 SkinDiseasesoftheMaleNipple I.8.4.1 Definition ...... 201 W. Krause ...... 232 I.8.4.2 AetiologyandPathogenesis...... 201 I.10.2.1 General Skin Diseases ...... 232 I.8.4.3 Clinical Findings ...... 201 I.10.2.2 Localized Inflammatory Diseases ...... 232 I.8.4.4 DifferentialDiagnosis...... 202 I.10.2.3 Tumours ...... 233 I.8.4.5 Treatment...... 202 I.10.2.4 Malformations...... 235 I.8.4.6 ResultsofTreatment ...... 203 I.10.2.5 SurgicalInterventions...... 236 I.8.4.7 Prognosis...... 203 References...... 236 I.8.4.8 Prevention...... 203 I.8.4.9 Other...... 203 XIV Contents

I.10.3 Male Breast Cancer II.1.1.1 TestisandScrotum...... 259 P.S.H. Soon, J.M. Dixon ...... 237 II.1.1.2 Epididymis...... 260 I.10.3.1 Incidence...... 237 II.1.1.3 Spermatic Cord and Ductus Deferens . . 261 I.10.3.2 RiskFactors ...... 237 II.1.1.4 Prostate ...... 262 I.10.3.3 Pathology ...... 238 II.1.1.5 Seminal Vesicle, Bulbourethral Gland . . 263 I.10.3.4 Presentation...... 238 II.1.1.6 PenisandUrethra...... 263 I.10.3.5 Investigation...... 239 Suggested Reading ...... 266 I.10.3.6 Management of Early Breast Cancer . . . . 239 II.1.2 Sexual Differentiation and Development I.10.3.7 Management of Metastatic Breast Cancer . 240 Y.L. Giwercman, A. Nordenskjöld ... 266 I.10.3.8 Follow-up ...... 240 II.1.2.1 Introduction ...... 266 I.10.3.9 Conclusion ...... 240 II.1.2.2 Genes Involved in Male Sex References...... 240 Differentiation...... 268 II.1.2.3 DiagnosisofSexualAmbiguity...... 271 I.11 Problem: Male Ageing References...... 271 I.11.1 Neuroendocrine Regulation of Testicular II.1.3 Physiology of Spermatogenesis Function M. Bergmann ...... 272 J.M. Kaufman ...... 241 II.1.3.1 Spermatogenesis...... 272 I.11.1.1 Definition ...... 241 II.1.3.2 SeminiferousTubules...... 272 I.11.1.2 AetiologyandPathogenesis ...... 241 II.1.3.3 Spermatogonia ...... 274 I.11.1.3 Clinical Findings, Technical Investigations II.1.3.4 Spermatocytes/Meiosis ...... 274 and Laboratory Findings ...... 246 II.1.3.5 Spermatids/Spermiogenesis ...... 274 I.11.1.4 DifferentialDiagnosis...... 246 II.1.3.6 Spermatozoon...... 276 I.11.1.5 Treatment...... 246 II.1.3.7 SertoliCell...... 276 I.11.1.6 ResultsofTreatment ...... 246 II.1.3.8 ApoptosisandSpermatogenesis...... 278 I.11.1.7 SummaryandConclusions...... 246 II.1.3.9 KineticsofSpermatogenesis...... 278 References...... 246 II.1.3.10 Pathophysiology of Spermatogenesis I.11.2 Male Ageing: Wear and Tear andInfertility ...... 279 F. Comhaire, A. Mahmoud ...... 249 References...... 280 I.11.2.1 DefinitionandPathogenesis...... 249 II.1.4 Physiology of Sexual Function I.11.2.2 Clinical Findings: History, Physical O. Baldo, I. Eardley ...... 281 Examination, Technical Investigations, II.1.4.1 PenileErection ...... 282 LaboratoryFindings ...... 249 II.1.4.2 EjaculationandOrgasm...... 285 I.11.2.3 TreatmentandPrevention...... 250 References...... 288 I.11.2.4 Other...... 250 References...... 250 II.1.5 Endocrine Regulation F. Comhaire, A. Mahmoud ...... 288 I.11.3 Organ Failure and Common Disease II.1.5.1 Hypothalamo–Pituitary–Testicular of the Ageing Male Axis...... 288 E.J.H. Meuleman, F. Comhaire ...... 251 References...... 290 I.11.3.1 Introduction and Definition of the Disease...... 251 II.1.6 Immunology of the Testis and Excurrent I.11.3.2 AetiologyandPathogenesis ...... 251 Ducts I.11.3.3 Clinical Findings: History, Physical H.-C. Schuppe, A. Meinhardt ...... 292 Examinations and Laboratory Findings 253 II.1.6.1 ImmunePrivilegeoftheTestis...... 292 I.11.3.4 DifferentialDiagnosis...... 254 II.1.6.2 ImmuneCellsintheTestis...... 292 I.11.3.5 Treatment...... 254 II.1.6.3 Blood–TestisBarrier...... 293 I.11.3.6 Prevention...... 255 II.1.6.4 Mechanisms of Immune Tolerance References...... 255 intheTestis...... 294 II.1.6.5 Local Factors of Testicular Immuno- II Rationale regulation – The Dual Role of Cytokines 294 II.1.6.6 InflammationoftheTestis...... 296 II.1 Understanding Normal Anatomy and Function II.1.6.7 Immunobiology and Pathology of the ExcurrentDucts ...... 297 II.1.1 Anatomy and Histology of the Male References...... 298 Genital Tract A. Meinhardt ...... 259 Contents XV

II.1.7 Male Contributions to the Biology II.2.5.1 Erectile Dysfunction and Vascular of Conception and Fertilization Disease...... 339 H.J. Tournaye ...... 300 II.2.5.2 Varicocele...... 340 II.1.7.1 TheForeplay...... 300 II.2.5.3 TesticularTorsion...... 342 II.1.7.2 Paternal Contributions to Conception . . . 301 II.2.5.4 UndescendedTestis...... 343 II.1.7.3 OtherSpermatozoalAttributes...... 303 References...... 345 References...... 303 II.2.6 Effects of Lifestyle and Toxicants J. P. Bonde ...... 348 II.2 Mechanisms of Dysfunction and Pathology II.2.6.1 Introduction...... 348 II.2.1 Disorders of Prenatal Sexual Development II.2.6.2 LifestyleFactors...... 349 P. Wieacker ...... 305 II.2.6.3 WorkplaceFactors...... 350 II.2.1.1 Introduction...... 305 II.2.6.4 EnvironmentalExposures...... 354 II.2.1.2 Primary Disorders of Gonadal II.2.6.5 Male-Mediated Developmental Toxicity 354 Development...... 305 II.2.6.6 Conclusion ...... 354 II.2.1.3 Disorders of Steroid Hormone References...... 355 Biosynthesis...... 309 II.2.7 Influence of Systemic Diseases and Iatrogenic II.2.1.4 AndrogenInsensitivity...... 310 Factors on Sexual and Reproductive Functions II.2.1.5 DisordersofAMHAction...... 311 R. Bornman ...... 358 II.2.1.6 Disorders of the Hypothalamic – Pituitary – II.2.7.1 Introduction...... 358 GonadalAxis ...... 311 II.2.7.2 SexualandReproductiveFunction ..... 358 II.2.1.7 Hypospadia and Undescended Testis . . . . 311 II.2.7.3 SystemicDiseasesandFertility ...... 362 References...... 311 References...... 362 II.2.2 Endocrine Disorders and the Role II.2.8 Mechanisms of Pathogenesis of of Hormone Disrupters Uro-Genital Cancers A. Mahmoud, Frank Comhaire ...... 313 T.F.’Aho,D.E.Neal ...... 362 II.2.2.1 Introduction...... 313 II.2.8.1 Pathogenesis of Cancer in General ...... 362 II.2.2.2 EndocrineDisorders...... 313 II.2.8.2 PathogenesisofProstateCancer...... 366 II.2.2.3 TheRoleofHormoneDisrupters...... 315 II.2.8.3 PathogenesisofTestisCancer...... 368 References...... 319 II.2.8.4 PathogenesisofPenileCancer ...... 369 II.2.3 Infection/Inflammation of the Male Genital II.2.8.5 Future ...... 370 Tract as Cause of Abnormal Spermatozoa References...... 370 C. Depuydt, A. Mahmoud, K. Everaert ...... 322 II.3 Diagnostic Tools II.2.3.1 Introduction...... 322 II.3.1 History and Examination for Andrological II.2.3.2 Causal Factors and the Role of Cytokines 323 Problems II.2.3.3 White Blood Cells and Reactive Oxygen T.B. Hargreave ...... 371 Species...... 325 II.3.1.1 HistoryTaking...... 371 II.2.3.4 Obstruction of Sperm Transport and II.3.1.2 SchemeforHistoryTaking...... 371 Anti-spermAntibodies...... 325 II.3.1.3 Problem-Specific Special History Taking 372 References...... 326 II.3.1.4 Clinical Examination for Andrological II.2.4 Urethritis, Sexually Transmitted Diseases Conditions ...... 376 (STD), Acquired Immunodeficiency References...... 380 Syndrome (AIDS) II.3.2 Semen Analysis and Sperm Function Tests F.R. Ochsend orf ...... 327 F. Comhaire, A. Mahmoud ...... 381 II.2.4.1 Introduction...... 327 II.3.2.1 Introduction...... 381 II.2.4.2 Urethritis...... 328 II.3.2.2 SampleCollectionandDelivery...... 381 II.2.4.3 STD ...... 331 II.3.2.3 InitialMacroscopicExamination...... 382 II.2.4.4 HIV ...... 331 II.3.2.4 InitialMicroscopicInvestigation...... 382 References...... 334 II.3.2.5 Evaluation of Morphological II.2.5 Disorders of Blood Flow: Arterial and Characteristics...... 385 Venous/Sexual Dysfunction and Varicocele II.3.2.6 Testing for Antibody-Coated G.M. Colpi, M. Mancini, G. Piediferro, Spermatozoa ...... 386 F.I. Scroppo ...... 338 II.3.2.7 CountingofSpermatozoa...... 387 XVI Contents

II.3.2.8 SemenCulture...... 388 II.3.6.2 Markers for Prostatic Carcinoma: II.3.2.9 SummaryofBasicTesting...... 388 Prostate-specific Antigen (PSA) II.3.2.10 Advanced Assessment of Basic Sperm andOthers ...... 415 Characteristics...... 388 II.3.6.3 Markers for Testicular Carcinoma: II.3.2.11SpermFunctionTests...... 389 [ -Fetoprotein, Human Chorionic II.3.2.12 Biological and Biochemical Tests GonadotrophinandOthers...... 418 onSemen...... 390 References...... 421 References...... 392 II.3.7 Technical Investigations Including II.3.3 Cytomorphological Semen Analysis Imaging Procedures: Doppler, MRI, PET, G. Haidl, H.-C. Schuppe ...... 395 Echo for Tumours E.L.F. Nijs, R.H. Oyen II.3.3.1 Introduction ...... 395 ...... 425 II.3.3.2 MethodologicalAspects...... 395 II.3.7.1 Ultrasound(US)...... 425 II.3.3.3 Predictive Value of Sperm Morphology II.3.7.2 Doppler...... 437 InVivoandInVitro...... 397 II.3.7.3 MRI (Magnetic Resonance Imaging) . . . . 439 II.3.3.4 Clinical Relevance of Cytomorphological II.3.7.4 PET (Positron Emission Tomography) . . 441 SemenAnalysis...... 398 II.3.7.5 EmergenciesinAndrology...... 442 II.3.3.5 SpermMorphologyandICSI...... 399 II.3.7.6 Tumours ...... 445 References...... 399 References...... 446 II.3.8 Technical Investigations Including II.3.4 Clinical Microbiology Imaging Procedures: Colour Flow Doppler H.G. Schiefer, A. von Graevenitz ... 401 and Thermography for the Detection II.3.4.1 Normal Flora of the Male Urogenital of Reflux in Varicocele Tract...... 401 Y. Gat, M. Gornish ...... 447 II.3.4.2 Diagnosis of Pathogens in the Male II.3.8.1 Introduction on the Bilaterality UrogenitalTract ...... 401 oftheDisease...... 447 II.3.4.3 Microbiological Examinations in the II.3.8.2 How to Use Contact Scrotal Diagnosis of Male Urogenital Infections 404 Thermograph...... 448 References...... 407 II.3.8.3 Medical Importance of the Complete and II.3.5 Hormonal Evaluation in Infertility and AccurateDiagnosisofVaricocele...... 449 Sexual Dysfunction II.3.8.4 Is There a Relationship Between Varicocele D. Klingmüller, N. Bliesener, andMaleInfertility?...... 450 G. Haidl ...... 408 II.3.8.5 Is Subclinical Varicocele Relevant to II.3.5.1 Introduction ...... 408 Male Infertility and Does it Require II.3.5.2 TotalTestosterone...... 409 Treatment?...... 450 II.3.5.3 FreeTestosterone ...... 409 II.3.8.6 Is Ultrasonography a Better Diagnostic II.3.5.4 Luteinizing Hormone (LH) and Follicle- Tool Because Venography is Subject to StimulatingHormone(FSH)...... 409 TechnicalVariations?...... 451 II.3.5.5 InhibinB ...... 410 II.3.8.7 WhyRightVaricoceleCouldNotbe II.3.5.6 Anti-MüllerianHormone...... 410 Detected ...... 451 II.3.5.7 Oestradiol ...... 410 II.3.8.8 Goren-Gat Technique for Detection and II.3.5.8 Sex Hormone Binding Globulin (SHBG) 411 Treatment of Right and Left Varicocele 451 II.3.5.9 Prolactin...... 411 II.3.8.9 “Recurrent” Varicocele After Left High II.3.5.10Dihydrotestosterone...... 411 Ligation is Actually “Survived” Varicocele 452 II.3.5.11 Hormonal Evaluation of Sexual References...... 453 Dysfunction...... 411 II.3.9 Evaluation of Testicular Biopsy Samples II.3.5.12 Human Chorionic Gonadotrophin (hCG) from the Clinical Perspective StimulationTest ...... 412 M. Bergmann ...... 454 II.3.5.13 Gonadotrophin Releasing-Hormone II.3.9.1 Indication...... 454 (GnRH)StimulationTest...... 412 II.3.9.2 Preparation...... 455 II.3.5.14StimulationTests...... 413 II.3.9.3 Evaluation...... 455 References...... 413 References...... 461 II.3.6 Tumour Markers in Andrology II.3.10 Genetics and Male Infertility M. E. Bracke ...... 415 T.B. Hargreave, D.J. Elliott ...... 462 II.3.6.1 Introduction ...... 415 II.3.10.1Introduction...... 462 Contents XVII

II.3.10.2 Basic Information about the Human II.4.4.7 Complications...... 508 GeneticCode...... 462 II.4.4.8 Results...... 508 II.3.10.3 Chromosomal Abnormalities and Male II.4.4.9 Conclusions...... 509 Fertility...... 463 References...... 509 II.3.10.4 Genetic Defects and Male Fertility . . . . 465 II.4.5 Nonsurgical Cure of Varicocele by II.3.10.5 DNA Methylation and Gene Imprinting Transcatheter Embolization of the Internal andAgeingChanges...... 473 Spermatic Vein(s) with a Tissue Adhesive II.3.10.6 MitochondrialAbnormalities...... 473 J. Kunnen, M. Kunnen ...... 510 II.3.10.7 Inherited Cytoplasmic Disorders and II.4.5.1 Introduction...... 510 MaleFertility...... 473 II.4.5.2 DiagnosticVenography...... 510 II.3.10.8 Chromosomal and DNA Abnormalities II.4.5.3 TreatmentbyEmbolization...... 510 inSperm...... 474 II.4.5.4 GeneralInformation...... 510 II.3.10.9 Chromosomal Abnormalities in Sperm 474 II.4.5.5 Specific Information on Superselective, Co- II.3.10.10 Risks of Intracytoplasmic Sperm axial Catheterization and Embolization . . 512 Injection...... 475 II.4.5.6 Data on Tissue Adhesives and Sclerosing II.3.10.11 Ethical Considerations, Genetic Counselling Agents...... 514 and Intracytoplasmic Sperm Injection . . 475 II.4.5.7 Results in 3043 Consecutive Patients . . . . 514 II.3.10.12Conclusion...... 475 II.4.5.8 Effect on Semen and Pregnancies ...... 515 References...... 476 II.4.5.9 Conclusion ...... 515 II.3.11 Tumour Genetics (Prostate/Testis/Penis) References...... 515 O. Tatarov, D. Kirk ...... 481 II.4.6 Hormonal Treatment of Infertility II.3.11.1 Genetic Aspects of Prostate Cancer . . . 481 F. Comhaire, A. Mahmoud II.3.11.2 GeneticsofTesticularCancer ...... 481 ...... 516 II.3.11.3 GeneticsofPenileCancer...... 482 II.4.6.1 Introduction...... 516 II.3.11.4 GeneticTesting...... 482 II.4.6.2 Androgens...... 516 References...... 482 II.4.6.3 Gonadotrophins...... 517 II.4.6.4 Luteinizing Hormone Releasing Hormone II.4 Therapeutic Options (LHRH)...... 517 II.4.6.5 Treatments Interfering with Oestradiol . . 517 II.4.1 Introduction to Surgical Section ..... 484 II.4.6.6 Conclusion ...... 519 II.4.2 Surgical Procedures in Andrology References...... 519 C. Evans ...... 484 II.4.7 Hormonal Male Contraception II.4.2.1 Scrotal Surgery ...... 484 D.J. Handelsman, G.M.H. Waites ..... 520 II.4.2.2 Anaesthesia for Scrotal, Inguinoscrotal II.4.7.1 Introduction...... 520 and Penile Surgery ...... 485 II.4.7.2 Androgens Alone as Hormonal II.4.2.3 Surgical Procedures on the Scrotum . . . 485 Contraceptives...... 521 II.4.2.4 SurgeryforAdultHydrocele...... 486 II.4.7.3 PharmacokineticConsiderations...... 521 II.4.2.5 Excision of Epididymal Cyst/ II.4.7.4 Safety...... 521 Spermatocele...... 487 II.4.7.5 Combination Regimens as Hormonal II.4.2.6 UndescendedTestisintheAdult...... 488 Contraceptives...... 521 II.4.2.7 CircumcisioninAdults...... 489 II.4.7.6 Efficacy of Combination Regimens . . . . . 522 II.4.2.8 InsertionofPenileProsthesis ...... 491 II.4.7.7 Gonadotrophin Blockade: GnRH Suggested Reading ...... 494 Analogues...... 522 References...... 494 II.4.7.8 Immunoneutralization as a Contraceptive II.4.3 Vasec tomy Technique Approach...... 522 T.B. Hargreave ...... 495 References...... 522 II.4.4 Vasovasostomy and Vasoepididymostomy II.4.8 Treatment of Gender Dysphoria A.M. Belker ...... 500 L.J.G. Gooren ...... 524 II.4.4.1 Indications...... 501 II.4.8.1 RealLifeTest...... 524 II.4.4.2 Contraindications...... 501 II.4.8.2 HormonalSexReassignment...... 525 II.4.4.3 AlternativeProcedures...... 501 II.4.8.3 Side-Effects of Hormonal Sex II.4.4.4 Factors That Influence Choice of Vaso- Reassignment...... 526 vasostomy or Vasoepididymostomy . . . 501 II.4.8.4 JuvenileGenderDysphoria...... 527 II.4.4.5 SurgicalTechniques ...... 502 References...... 527 II.4.4.6 PostoperativeCare ...... 508 XVIII Contents

II.4.9 Treatment of Sexual Dysfunction II.4.13 Exotic Hormones L.J.G. Gooren ...... 528 F. Comhaire, A. Mahmoud ...... 561 II.4.9.1 ErectileDysfunction...... 528 II.4.13.1Introduction ...... 561 II.4.9.2 RetardedEjaculation ...... 531 II.4.13.2HormonalChangesinAgeingMen..... 561 II.4.9.3 RapidEjaculation...... 531 II.4.13.3TreatmentOptions...... 562 II.4.9.4 TestosteroneTreatment ...... 531 II.4.13.4Conclusion...... 563 II.4.9.5 PubertalDevelopment...... 532 References...... 563 II.4.9.6 SexualFunctionandAgeing...... 532 II.4.14 Anti-Ageing Nutrition and Food II.4.9.7 Hyperprolactinaemia...... 532 Supplements II.4.9.8 Paraphilias and their Pharmacologic F. Comhaire, A. Mahmoud ...... 565 Treatment...... 533 II.4.14.1Introduction ...... 565 References...... 533 II.4.14.2ComponentsofNutriceuticals...... 565 II.4.10 Therapeutic Options for Benign Prostate References...... 569 Hyperplasia (BPH) and Prostatic Cancer II.4.15 Nutriceuticals and Food Supplements S.K.W. Leung, S.A. Mc Neill ...... 535 in the Treatment of the Infertile Man II.4.10.1 Diagnosis...... 536 F. Comhaire, A. Mahmoud ...... 572 II.4.10.2 ManagementofBPH...... 539 II.4.15.1Introduction ...... 572 II.4.10.3 WatchfulWaiting...... 539 II.4.15.2 Role of Life Style and Nutritional Factors 572 II.4.10.4 PharmacologicTherapy...... 539 II.4.15.3PivotalRoleofInhibinB ...... 573 II.4.10.5 Minimally Invasive Therapies ...... 541 II.4.15.4FoodSupplementation...... 573 II.4.10.6 SurgicalTreatment...... 542 II.4.15.5Conclusions...... 575 II.4.10.7 Complications of Surgical Treatments 542 References...... 576 II.4.10.8 Therapeutic Options for Prostate Cancer ...... 543 II.4.16 Assisted Reproductive Techniques II.4.10.9 Management of Localized Prostate W. Ombelet ...... 578 Cancer ...... 544 II.4.16.1IUIandMaleInfertility...... 579 II.4.10.10 Management of Locally Advanced Prostate II.4.16.2 Male Infertility: IUI Versus IVF/ICSI . . . 579 Cancer and Metastatic Disease ...... 546 II.4.16.3IVFandICSI...... 581 II.4.10.11 Treatment of Hormone Relapsed II.4.16.4 Azoospermia: MESA, PESA, TESE ProstateCancer...... 547 andTESA...... 581 References...... 548 II.4.16.5 ART: Prevention of Multiple Pregnancies 583 II.4.16.6Conclusion...... 583 II.4.11 Partial Androgen Deficiency of the References...... 584 Ageing Male (PADAM) and Testosterone Supplementation: Use, Misuse or Abuse? II.4.17 Cryopreservation of Spermatozoa and D. Vanderschueren ...... 551 Testicular Tissue Including Autotrans- II.4.11.1 Introduction ...... 551 plantation of Germinal Epithelium II.4.11.2 Who is to Benefit from T Replacement? F.-M. Köhn ...... 585 WhatistheTargetPopulation?...... 551 II.4.17.1Introduction ...... 586 II.4.11.3 What is the Expected Benefit from T II.4.17.2BasicPrinciplesofCryobiology ...... 586 ReplacementinElderlyMen?...... 552 II.4.17.3 Indications for Human Sperm II.4.11.4 What are the Risks/Side-Effects Cryopreservation ...... 586 ofTReplacement?...... 553 II.4.17.4 Sperm Preparation Techniques Before II.4.11.5 What Type of T Replacement Should be Cryopreservation ...... 587 UsedinElderlyMen? ...... 554 II.4.17.5 Effects of Freezing on Sperm Quality . . . 588 II.4.11.6 How Long Should we Administer T in the II.4.17.6 Fertilization Rates with Cryopreserved Elderly?...... 554 Spermatozoa...... 588 II.4.11.7 Conclusions and Research Agenda . . . . 554 II.4.17.7 Cryobanking of Semen for Fertility References...... 554 Protection From Radiation or Cytotoxic Treatment...... 588 II.4.12 Abuse of Androgens H.-C.Schuppe,A.Jung,W.-B.Schill 555 II.4.17.8 Autotransplantation of Germinal Epithelium...... 589 II.4.12.1 Introduction ...... 555 References...... 589 II.4.12.2 Anabolic-AndrogenicSteroids ...... 555 II.4.12.3 PatternsofAbuse ...... 557 References...... 559 Contents XIX

II.4.18 Current Research and Future Prospects II.4.20.3OocyteDonation...... 610 for Gene Therapy in Andrology II.4.20.4EmbryoDonation...... 612 Y. Kojima, S. Sasaki, K. Kohri ...... 592 II.4.20.5 Informing the Children of their Origin 613 II.4.18.1Introduction ...... 592 II.4.20.6LookingtotheFuture...... 614 II.4.18.2EthicalIssueinGeneTherapy...... 593 References...... 614 II.4.18.3GeneTransferVectors ...... 593 II.4.21 Aesthetic Andrology: Surgical II.4.18.4 Gene Therapy for Prostate Cancer . . . . . 593 Interventions II.4.18.5 Gene Therapy for Male Infertility ...... 595 R. Ponchietti ...... 617 II.4.18.6 Gene Transfer for Treatment of Erectile II.4.21.1 Normal Size Measurements of the Penis 617 Dysfunction 596 II.4.21.2 Indications and Contraindications for II.4.18.7Conclusions...... 597 PenisEnlargementSurgery...... 618 References...... 597 II.4.21.3 Preferred Techniques of Penis Enlargement II.4.19 Behavioural Therapy and Counselling Surgery...... 618 E.A. Jannini, A. Lenzi, G. Wagner .... 598 II.4.21.4Phalloplasty...... 619 II.4.19.1FertilityProblemCounselling...... 598 II.4.21.5TesticularProsthesis...... 619 II.4.19.2SexualDysfunction...... 599 II.4.21.6ScrotalSkinRedundancy...... 620 II.4.19.3GeneticCounselling...... 602 References...... 620 II.4.19.4CancerCounselling...... 603 II.4.22 AestheticAndrology:SkinCareforMen– II.4.19.5GenderDysphoria...... 605 Male Cosmetics and Cosmetic Dermato- References...... 605 logic Procedures C. Müller, W.B. Schill ...... 621 II.4.20 Donor Insemination, Egg and Embryo II.4.22.1TrendsinMaleSkinCare...... 621 Donation G.T.Kovacs,A.Trounson, II.4.22.2 Basic Concepts of Male Skin Science . . . 622 II.4.22.3 Cosmetic Dermatologic Procedures . . . . 624 K. Dawson ...... 607 References...... 632 II.4.20.1Introduction ...... 607 II.4.20.2DonorInsemination...... 607 Subject Index ...... 635 List of Contributors

Wolf-Bernhard Schill, Co-ordinating Editor Jens Peter Bonde Centre of Dermatology and Andrology, Justus Liebig Department of Occupational Medicine, Arhus˚ University Giessen, Gaffystr. 14, 35385 Giessen, Ger- University Hospital, Nørrebrogade 44, Building 2 C, many (e-mail: wb@prof_schill.de/www.prof-schill.de) 8000 Arhus˚ C, Denmark (e-mail: [email protected]) Tev ita F. ’Aho Riana Bornman Addenbrooke’s NHS Foundation Trust, Department of Department of Urology, Faculty of Health Sciences, Urology, Box 43, Hills Rd, Cambridge CB2 2QQ, UK University of Pretoria, PO Box 169 Pretoria 0001, (e-mail: [email protected] South Africa (e-mail: [email protected]) William Derval Aiken Marc E. Bracke Department of Surgery, University of the West Indies Laboratory of Experimental Cancerology, Department Mona, Kingston 7, Jamaica of Radiotherapy and Nuclear Medicine, University (e-mail: [email protected]) Hospital, De Pintelaan 185, 9000 Ghent, Belgium, Laboratory Nuytinck, Reibroekstraat 13, 9940 Evergem, Omer Baldo Belgium (e-mail: [email protected]) Pyrah Department of Urology, St. James University Hospital, Beckett Street, Leeds LS9 7TF, UK Burkhard Brosig Centre of Psychosomatic Medicine, Clinic for Arnold M. Belker PsychosomaticsandPsychotherapy,Ludwigstr.76, University of Louisville School of Medicine, Depart- 35392 Giessen, Germany (e-mail: Burkhard.Brosig@ ment of Urology, Louisville, Kentucky 40292, USA, psycho.med.uni-giessen.de) 250 E. Liberty St., Suite 602, Louisville, KY 40202 USA (e-mail: [email protected]) Giovanni M. Colpi Unit`a di Andrologia, Ospedale San Paolo, Polo Martin Bergmann Universitario, Milano, Italy Institute of Veterinary Anatomy, Histology and Em- (e-mail: [email protected]) bryology, Justus Liebig University, Frankfurterstr. 98, 35392 Giessen, Germany Frank Comhaire (e-mail: martin. [email protected]) Centre for Medical and Urological Andrology and Reproductive Endocrinology, University Hospital Manfred Beutel Ghent 6K12IE, De Pintelaan 185, 9000 Ghent, Belgium Clinic and Policlinic for Psychosomatic Medicine and (e-mail: [email protected]) Psychotherapy, Johannes Gutenberg University, Untere Zahlbacher Str. 8, 55131 Mainz, Germany K. Dawson (e-mail: [email protected]) Monash Immunology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton, M.C. Bishop Victoria, 3800, Australia Department of Urology, Nottingham City Hospital NHS Trust, Nottingham, NG5 1 PB, UK Christophe Depuydt (e-mail: [email protected]) Laboratory for Clinical Pathology, Amerikalei 62–64, 2000 Antwerp, Belgium N. Bliesener (e-mail: [email protected]) Institute for Clinical Biochemistry, Endocrinology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany XXII List of Contributors

J. Michael Dixon Michael Gornish Edinburgh Breast Unit, Western General Hospital, Department of Radiology and the Interventional and Crewe Road South, Edinburgh EH4 2XU, UK Vascular Unit, Rabin Medical Center, Beilinson (e-mail: [email protected]) Campus, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Gert R. Dohle Department of Urology, Erasmus Medisch Centrum Alexander von Graevenitz Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Department of Medical Microbiology, University of Netherlands (e-mail: [email protected]) Zürich, Gloriastrasse 32, 8028 Zürich, Switzerland (e-mail: [email protected]) Ian Eardley Pyrah Department of Urology, St. James University Gerhard Haidl Hospital, Beckett Street, Leeds LS9 7TF, UK Department of Dermatology/Andrology Unit, (e-mail: [email protected]) University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany (e-mail: [email protected]) Jakob Eberhard Department of Oncology, Lund University Hospital, David J. Handelsman Lund, Sweden (e-mail: [email protected]) ANZAC, Research Institute & Department of Andrology, Concord Hospital, University of Sydney, David J. Elliott Sydney NSW 2139, Australia (e-mail: [email protected]) Institute of Human Genetics, International Centre for Life, University of Newcastle-upon-Tyne, Central Timothy B. Hargreave Parkway, Newcastle NE1 3BZ, UK Department of Oncology, Edinburgh University, (e-mail: [email protected]) Human Genetics Building, Western General Hospital, Edinburgh EH4 2XU, UK Christine Mary Evans (e-mail: [email protected]) Smithy Cottage, Llanarmon-yn-ial, Mold, CH74QXN, Wales, UK Christiaan Frederik Heyns (e-mail: [email protected]) Department of Urology, Faculty of Health Sciences, University of Stellenbosch and Tygerberg Hospital, K. Everaert PO Box 19063, Tygerberg 7505, South Africa Department of Urology, Ghent University Hospital, (e-mail: [email protected]) De Pintelaan 185, 9000 Ghent, Belgium (e-mail: [email protected], Tel.: + 32-92-402276) Emmanuele A. Jannini Course of Medical Sexology and Endocrinology, Harry Fisch Dept. of Experimental Medicine, University of L’Aquila Clinical Urology Department of Urology, Columbia Coppito, Bldg. 2, Room A2/54. Via Vetoio, University, Columbia University Medical Center of 67100L’Aquila,Italy(e-mail:[email protected]) New York, Presbyterian Hospital, 944 Park Avenue, New York, NY, USA (e-mail: [email protected]) Andreas Jung Justus Liebig University Giessen, Yigal Gat Gaffkystr. 14, 35385 Giessen, Germany Andrology Unit, Department of Obstetrics and (e-mail: [email protected]) Gynecology, Rabin Medical Center, Beilinson Campus, Petah Tiqva and Sackler Faculty of Medicine, Tel Aviv Jean M. Kaufman University, Tel Aviv, Israel (e-mail: [email protected]) Department of Endocrinology, Laboratory of Hormo- nology and Unit for Osteoporosis and Metabolic Bone Aleksander Giwercman Diseases, Ghent University Hospital, De Pintelaan 185, Fertility Centre, Malmö University Hospital, 20502 9000 Ghent, Belgium (e-mail: [email protected]) Malmö, Sweden (e-mail: [email protected]) David Kirk Urology Department, Gartnavel General Hospital, Louis J.G. Gooren 1053 Great Western Road, Glasgow G12 0YN, UK Department of Endocrinology, Andrology section, (e-mail: [email protected]) Vrije Universiteit Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands Dietrich Klingmüller (e-mail: [email protected]) Institute for Clinical Biochemistry, Endocrinology, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany (e-mail: [email protected]) List of Contributors XXIII

Frank-Michael Köhn Yvonne Lundberg Giwercman Department of Dermatology and Allergology, Technical Department of Urology, Wallenberg Laboratory, University, Biedersteiner Str. 29, 80802 Munich, Malmö University Hospital, 20502 Malmö, Sweden Germany (e-mail: [email protected]) (e-mail: [email protected]) Kenjiro Kohri Ahmed Mahmoud Department of Nephro-urology, Nagoya City Center for Medical and Urological Andrology and University Graduate School of Medical Sciences, Reproductive Endocrinology, University Hospital 1 Kawasumi, Mizuho-cho, Mizuho-ku, Ghent 6K12IE, De Pintelaan 185, 9000 Ghent, Belgium Nagoya 467–8601, Japan (e-mail: [email protected]) (e-mail: [email protected]) Mario Mancini Yoshiyuki Kojima Unit`a di Andrologia, Ospedale San Paolo, Department of Nephro-urology, Nagoya City Polo Universitario, Milano, Italy University Graduate School of Medical Sciences, S. Alan McNeill 1 Kawasumi, Mizuho-cho, Mizuho-ku, Department of Urology, Western General Hospital, Nagoya 467–8601, Japan Crewe Road, Edinburgh, EH4 2XU, UK (e-mail: [email protected]) (e-mail: [email protected]) Gabor Thomas Kovacs Andreas Meinhardt Monash University, Department of Obstetrics and Department of Anatomy and Cell Biology, Justus- Gynaecology, Box Hill Hospital, Victoria, Australia Liebig University Giessen, Aulweg 123, 35385 Giessen, (e-mail: [email protected]) Germany (e-mail: Andreas.Meinhardt@anatomie. Walter Krause med.uni-giessen.de) Department of Andrology and Venerology, University E.J.H. Meuleman Hospital, Philipp University, 35033 Marburg, Germany Free University of Amsterdam, Medical Centre (e-mail: [email protected]) Department of Urology, de Boelelaan 1117, John N. Krieger 1081 HV Amsterdam, The Netherlands Department of Urology, University of Washington Ian David Cumming Mitchell School of Medicine, Box 356510, Seattle, WA 98195, Department of Urology, Queen Margaret Hospital, USA (e-mail: [email protected]) Whitefield Road Dunfermline, Fife KY12 0SU, UK Pardeep Kumar (e-mail: [email protected]) The St Peter’s Andrology Centre and Institute of Christina Müller Urology, 48 Riding House St, London W1P 7PN, UK Centre of Dermatology and Andrology, Justus Liebig (e-mail: [email protected]) University, Gaffkystr. 14, 35385, Giessen, Germany Jan Kunnen (e-mail: [email protected] giessen.de) Department of Radiology and Medical Imaging, ZNA David Edgar Neal Middelheim Hospital, Lindendreef 1, 2020 Antwerp, Department of Urology, Addenbrooke’s NHS Belgium (e-mail: [email protected]) Foundation Trust, Department of Oncology, Oncology Marc Kunnen Centre, Box 193, Addenbrooke’s Site, Hills Road, Department of Radiology and Medical Imaging, Cambridge CB2 2QQ, UK (e-mail: [email protected]) University Hospital Ghent, De Pintelaan 185, Els L.F. Nijs 9000 Ghent, Belgium Department of Radiology, University Hospitals Gast- Andrea Lenzi huisberg, Katholieke Universiteit Leuven, Herestraat Chair of Clinical Pathology, Department of Medical 49, 3000 Leuven, Belgium Physiopathology, University of Rome „La Sapienza“ (e-mail: [email protected]) Policlinico Umberto I, 00161 Rome, Italy Agneta Nordenskjöld (e-mail: [email protected]) Department of Molecular Medicine, CMM 02, Steve Ken Wing Leung Karolinska Hospital, 17176 Stockholm, Sweden Prostate Research Group, School of Molecular and (e-mail: [email protected]) Clinical Medicine, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK (e-mail: [email protected]) XXIV List of Contributors

F.R. Ochsendorf P. S. H. S o on Centre of Dermatology and Venerology, J.W. Goethe Edinburgh Breast Unit, Western General Hospital, University, Theodor-Stern-Kai 7, 60590-Frankfurt/M, Crewe Road South, Edinburgh EH4 2XU, UK Germany (e-mail: [email protected]) Olof Ståhl Willem Ombelet Department of Oncology, Lund University Hospital, Genk Institute for Fertility Technology, Lund, Sweden (e-mail: [email protected]) Schiepse Bos 6, 3600 Genk, Belgium Oleg Tatarov (e-mail: [email protected]) Urology Department, Gartnavel General Hospital, Raymond H. Oyen 1053 Great Western Road, Glasgow G12 0YN, UK Department of Radiology, University Hospitals (e-mail: [email protected]) Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium Herman J. Tournaye (e-mail: [email protected]) Centre for Reproductive Medicine, Dutch-speaking Brussels Free University Hospital, 101, Laarbeeklaan, Guido Piediferro 1090 Brussels, Belgium (e-mail: [email protected]) Unit`a di Andrologia, Ospedale San Paolo, Polo Universitario, Milano, Italy Alan Trounson Monash Immunology and Stem Cell Laboratories, Roberto Ponchietti Monash University, Wellington Road, Clayton, University of Siena, Cattedra di Urologia, Policlinico Victoria, 3800, Australia S., Maria alle Scotte, Viale Bracci 13, 53110 Siena, Italy (e-mail: [email protected]) (e-mail: [email protected]) Guy G.R. T’Sjoen David J. Ralph Department of Endocrinology, University Hospital, The St Peter’s Andrology Centre and Institute of Belgium 9K12IE, De Pintelaan 185, 9000 Ghent, Urology, 48 Riding House St, London W1P 7PN, UK Belgium (e-mail: [email protected]) (e-mail: [email protected]) Kevin James Turner Shoichi Sasaki Department of Urology, Western General Hospital, Department of Nephro-urology, Nagoya City Edinburgh, EH4 2XU, UK University Graduate School of Medical Sciences, (e-mail: [email protected]) 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467–8601, Japan (e-mail: [email protected]) Lynne Turner-Stokes Regional Rehabilitation Unit, Northwick Park Hans Gerd Schiefer Hospital,WatfordRoadHarrow,MiddlesexHA13UJ, Department of Medical Microbiology, Justus Liebig UK University Giessen, Schubertstr. 1, 35392 Giessen, Germany (e-mail: [email protected] Justin Alastair Vale giessen.de) Consultant Urological Surgeon, St Mary’s Hospital, Praed Street, London W2 1NY, UK Frank Schoonjans (e-mail: [email protected]) Centre for Medical and Urological Andrology and Reproductive Endocrinology, University Hospital Dirk Vanderschueren Ghent, 6K12IE, De Pintelaan 185, 9000 Ghent, Laboratory for Experimental Medicine and Belgium (e-mail: [email protected]) Endocrinology, Katholieke Universiteit Leuven, Campus Gasthuisberg, Onderwijs & Navorsing, Hans-Christian Schuppe Herestraat 49, 3000 Leuven, Belgium Centre of Dermatology and Andrology, Justus Liebig (e-mail: [email protected]) University, Gaffkystr. 14, 35385 Giessen, Germany (e-mail: [email protected] A.J. Visser giessen.de) Garden City Hospital, Johannesburg, South Africa Fabrizio I. Scroppo Gorm Wagner Unit`a di Andrologia, Ospedale San Paolo, Dept. Medical Physiology, University of Copenhagen, Polo Universitario, Milano, Italy Blegdamsvej 3, 2200 Copenhagen N, Denmark (e-mail: [email protected]) Jay B. Shah Squier Urological Clinic, Columbia University Medical Center, 161 Fort Washington Avenue, New York, NY 10032, USA (e-mail: [email protected]) List of Contributors XXV

Geoffrey Malcolm Hasting Waites (deceased) Peter F. Wieacker ANZAC, Research Institute & Department of Institute for Human Genetics, Otto-von-Guericke Andrology, Concord Hospital, University of Sydney, University of Magdeburg, Leipziger Strasse 44, Sydney NSW 2139, Australia 39120 Magdeburg, Germany (e-mail: [email protected]) R.F.A. Weber Department of Andrology Erasmus MC, Stefan A. Wudy Dr. Molewaterplein, 40 3015 GD Rotterdam, The Centre of Child and Adolescent Medicine, Justus Netherlands (e-mail: [email protected]) Liebig University, Feulgenstr. 12, 35392 Giessen, Germany (e-mail: [email protected]) Introduction

Andrology: Definition, Clinical Issues and Prevalence W.-B. Schill, F. Comhaire, T.B. Hargreave

Andrology is a young interdisciplinary medical special- 1. Male fertility and infertility ty derived linguistically from the Greek word “andros”, 2. Erectile dysfunction and sexual disturbances whichdealswiththemalewithspecialemphasisofthe 3. Ageing male and hormone replacement therapy physiology and pathophysiology of male reproductive 4. Male reproductive tract inflammation and functions. Therefore, primarily, its clinical focus is the infection diagnosis and therapy of male fertility disturbances. 5. Testicle problems (testicular tumours) Thus,andrologyisthemaleequivalentofgynaecology 6. Prostate disorders (BPH, carcinoma) and deals with the disorders of the male reproductive 7. Primary and secondary hypogonadism organs. In some parts of the world, andrology is closely 8. Delayed puberty connected or even an integral part of in vitro fertiliza- 9. Prevention and rehabilitation tion centres. According to the definition of the World 10. Adverse drug side effects Health Organization (WHO), andrology is engaged in 11. Environmental pollutants all aspects of male reproductive health. 12. Cryopreservation of semen and testicular tissue In addition, andrology is concerned with problems of 13. Forensic paternity problems erectile dysfunction. Approximately 10% to 15% of an- 14. Family planning drology patients consult for disturbed sexual dysfunc- 15. Male contraception tions. The diagnosis and management of penis problems 16. Basic andrological research includes lack of firmness of penis erection or bending and deformity of the erect penis (Peyronie’s disease). Re- Historically, the term “andrology” was introduced in cently, treating the ageing male has become another im- Germany in 1951 by the gynaecologist Harald Siebke portant issue. Because of dramatic changes in the demo- from the university of Bonn, who considered androlo- graphicdevelopmentoftheagepyramid,therewillbea gy as a counterpart to gynaecology (Schirren 1985). tremendous change of the ratio old to young men within Thereafter, andrology developed within the field of the next 20 years. Therefore, consultations on the part of dermatovenereology (as in Egypt), where it was associ- older men will greatly increase, particularly in terms of ated with names such as Döpfmer, Heinke, Adam, Mey- health prevention and hormone dysfunction. höfer, and Schirren (Adam 1986; Schirren 1989). The Further areas of andrological activities are the diag- importance of andrology was acknowledged in 1958 nosis and management of testicle problems and pros- when the newly established German Society for the tate disorders, for example prostate enlargement, in- Study of Fertility and Sterility considered andrology as flammation or cancer (the latter being mostly a genu- a main part of its activities. In 1970, the Comit´eInter- ine problem of urology) prevention and rehabilitation, national de Androlog´ıa (CIDA) was founded in Barce- primary and secondary hypogonadism, delayed puber- lona,followedin1973bytheNordicAssociationofAn- ty, adverse drug side effects and environmental pollut- drology, in 1974 by the American Association of An- ants with regard to fertility, cryopreservation of semen drology, and in 1975 by the German Society of Andro- and testicular tissue, forensic paternity problems, fam- logy. In 1976, the American Society of Andrology was ily planning, male contraception and basic andrologi- established, followed in 1981 by the formation of the cal research. All these issues are of increasing impor- International Society of Andrology (www.androlo- tance for the further development of clinical andrology. gy.org), which in 2005 was made up of 41 national In summary, the following subjects are within the member societies with more than 10,000 members. In field of responsibility of andrology: 1992, the European Academy of Andrology was found- 2Introduction

ed with the formation of andrology training centres on dermatology have training facilities and departments a European level (European Academy of Andrology, in andrology. In addition, during the last 50 years an- 2001). Today more than 16 training centres in Europe drologywassubstantiallyinfluencedbyurology(Mac- (Belgium, Denmark, Germany, Italy, the Netherlands, leod 1951; Macleod and Gold 1951a–c; Macleod et al. Poland, and Spain) have been appointed after a strin- 1964; Tulloch 1953; Amelar et al. 1977; Kelami 1980; gent international reviewing process by the European Whitfield et al. 1998) endocrinology (Hellinga 1950, Academy of Andrology. Andrological activities have al- 1957, 1976; Rosemberg and Paulsen 1970; Steinberger so been strengthened by ESHRE and other internation- 1970, 1971; Comhaire 1996; Nieschlag and Behre 2000), al societies involved in reproductive medicine. Dra- immunology (Rümke and Hellinga 1959; Rümke 1965, matic changes have occurred after the availability of in 1970), and gynaecology (Schoysman 1961, 1964, 1968; vitro fertilization in the years after 1978, followed by in- Insler and Lunenfeld 1986). For example, andrology tracytoplasmic sperm injection in the early 1990s. It is has been firmly integrated into the graduation rules for particularly remarkable that apart from infertility urologists, where important surgical procedures to treatment, the spectrum of diseases treated is expand- overcome a severe male factor had been established. ing via erection and ejaculation disorders to problems Historically, the term “andrology” as a medical subspe- of the ageing male as well as to urological issues con- cialty officially has been used in Italy since 1989, in cerning inflammatory and neoplastic diseases of the France since 1993, in Poland since 1995, and in the testes, epididymides, and the prostate. Netherlands since 2003. Also, the European Dermatol- The international development of andrology shows ogy Forum (EDF) is using the term “andrology”. that the field is mainly represented by clinicians from Therefore, the activities of the European Academy of urology, endocrinology, dermatology, and gynaecology, Andrology (EAA) are of particular importance for the depending on history and scientific activities. Thus the proclamation of andrology to receive more attention rapid development of andrology over the past 25 years and awareness by the European health politicians. The (Prins and Bremner 2004) is reflected by the fact that in most recent progress is the acceptance of andrology as addition to several national andrological journals there a medical specialty by the medical associations of Indo- are presently five international andrological periodicals nesia (2002), and Germany (2003). In the latter, the ac- available (Andrologia as the first international journal quisition of an additional skill in andrology may be ac- founded by Carl Schirren in 1969, Journal of Andrology, quired by dermatologists, endocrinologists, and urolo- International Journal of Andrology, Asian Journal of An- gists, but not by gynaecologists. A medical qualifica- drology, Archives of Andrology)andatleasttenjournals tion officially certified by the medical association al- that are exclusively concerned with scientific questions lows the identification of the specialist by the patient, of reproductive medicine and reproductive biology. guarantees quality control and efficiency assurance, Curiously, the term “andrology” was first anecdotal- and attracts more medical professionals to the field. ly used as early as 1891, when JAMA published an edi- The diagnosis and treatment of childless couples re- torial entitled “Andrology as a speciality” (Niemi 1987). quire a particularly close cooperation between andro- This editorial was soon forgotten but contained pas- logy and gynaecology, which has been conducted to the sagesthatarestillvalidtoday,aftermorethan formation of centres of reproductive medicine in many 110 years, and can therefore be considered a milestone places throughout the world. The causes of barren mar- of reproductive medicine. Later, in 1902, the first sur- riagestemequallyfromthefemaleandthemale,butin geon to treat the problem of obstructive azoospermia some cases may be compensated by the high fertility of successfully was Edward Martin (1859–1938), who as a the other partner. If there is coincidentally a sterility clinician already pointed out the need for accurate di- factor in both partners, a compensation is no longer agnosis in the treatment of male infertility and thus possible, leading to a severe infertility problem. The was recently considered as the founding father of mod- definition of infertility commonly used is that more ern clinical andrology (Jequier 1991). than 12 months are required to conceive. However, in- Remarkably, from the historical point of view, one of fertility shows considerable geographic variation. In the first books on human semen came from Joel (1953), general, the male factor contributes one-third to one- Thaddeus Mann (1964, 1981) and Rune Eliasson half of all factors that contribute to a couple’s problem (1971), the two latter particularly on seminal plasma with conception (Hull et al. 1985). The prevalence of biochemistry.In1960,twoGermanbookswerepub- primary and secondary infertility is estimated to be lished on the subject of andrology: Male Fertility Dis- 15% or more of all couples in their reproductive age turbances,withmorethan880pageseditedbytheder- (Bruckert 1991). Thus, the percentage of couples seek- matologists Schuermann and Döpfmer, and The Male ing medical advice and treatment for infertility is in the Gonad by the anatomist Tonutti in collaboration with rangeof5%to17%.Lastly,3%to4%ofallcouplesre- colleagues from internal medicine and dermatology. main involuntarily childless at the end of their repro- Thus today most of the German university clinics of ductive life phase (Templeton 1992). Andrology: Definition, Clinical Issues and Prevalence 3

Concerning the prevalence of male factor infertility, logic diagnosis of seminal pathology (Dutch). Ned Tijdschr it is estimated to be in the range of 7% of all men, under Verloskd Gynaecol 50:267–284 the assumption that a male factor is responsible in Hellinga G (1976) Clinical andrology. William Heinemann Medical, London about half of the involuntarily childless couples. This Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, Hinton incidenceisabovetheprevalenceofdiabetesmellitus RA, Coulson C, Lambert PA, Watt EM, Desai KM (1985) Pop- (Nieschlag and Behre 2000). In contrast to earlier re- ulation study of causes, treatment and outcome of infertility. ports that the male’s age does not influence the couple’s Br Med J 291:1693–1697 Insler V,Lunenfeld B (1986) Infertility: male and female. Chur- fertility, new data suggest that in addition to the female chill Livingstone, Edinburgh age factor, the age of the male should not be neglected Jequier AM(1991) Edward Martin (1859–1938).The founding (Dunson et al. 2004). father of modern clinical andrology. Int J Androl 14:1–10 Besides a careful medical history, physical examina- Jequier AM (2004) Clinical andrology- still a major problem in tion, and at least two spermiograms, andrological diag- the treatment of infertility. Hum Reprod 19:1245–1249 Joel CA (1953) Studies an human semen (in German). Schwa- nosis comprises the enlarged semen analysis, including be, Bale biochemical parameters and sperm function tests, hor- Kelami A (1980) Atlas of operative andrology. Selected opera- monal diagnosis, immunological and microbiological tions on male genitalia and their accessory glands. Walter de examinations, cytogenetic analysis and, if necessary, Gruyter, Berlin testicular biopsies. Further diagnostic and therapeutic Macleod J (1951) Semen quality in 1000 men of known fertility and in 800 cases of infertile marriage. Fertil Steril 2:115–139 procedures may be required in interdisciplinary coop- Macleod J, Gold RZ (1951a) The male factor in fertility and infer- eration with urology, gynaecology, endocrinology, ra- tility. II. Spermatozoon counts in 1000 men of known fertility diotherapy, sexology, psychosomatic medicine, neurol- and in 1000 cases of infertile marriage. J Urol 66:436–449 ogy, psychiatry, and cytogenetics. Macleod J, Gold RZ (1951b) The male factor in fertility and infertility. III. An analysis of motile activity in the spermato- Both history taking and clinical examination of the zoa of 1000 fertile men and 1000 men in infertile marriage. malepatientareessentialfortheandrologicalworkup Fertil Steril 2:187–207 and the diagnosis of a male factor in the case of infertil- Macleod J, Gold RZ (1951c) The male factor in fertility and in- ity. Often only the clinical examination of the patient fertility. VI. Sperm morphology in fertile and infertile mar- allows the correct interpretation of the semen parame- riage. Fertil Steril 2:394–414 Macleod J, Pazianos A, Ray BS (1964) Restoration of human ters, leading to an aetiopathologically orientated thera- spermatogenesis by menopausal gonadotrophins. Lancet py. Therefore, to improve the management of androlo- 1:1196 gical problems, formal training and training courses in Mann T (1964) The biochemistry of semen and of the male re- clinical andrology are urgently required (Jequier 2004). productive tract. Methuen, London Mann T, Lutwak-Mann C (1981) Male reproductive function This is underscored by the fact that presently only a few and semen. Springer, Berlin Heidelberg New York textbooks and WHO guidelines on the subject of an- Niemi M (1987) Andrology as a speciality – its origin. J Androl drology are available (Rowe et al. 1993, 2000; WHO 8:201–202 1999; Nieschlag and Behre 2000), together with some Nieschlag E, Behre HM (2000) Andrology. Male reproductive international congress proceedings (Waites et al. 1997; health and dysfunction 2nd edn. Springer, Berlin Heidelberg New York Robaire et al. 2001). In conclusion, further training and Prins GS, Bremner W (2004) The 25th volume: President’s mes- education in all aspects of clinical andrology is urgently sage: Andrology in the 20th century: a commentary on our needed. progress during the past 25 years. J Androl 25:435–440 Robaire B, Chemes H, Morales CR (2001) Andrology in the 21st century.ProceedingsoftheVIIthInternationalCongressof References Andrology, Montreal, Canada. Medimond, Englewood, N.J. Rosemberg E, Paulsen CA (1970) The human testis. Plenum, Adam W (1986) Where stands andrology today? Retrospection New York and perspectives (in German) Hautarzt 37:472–475 Rowe PJ, Comhaire FH, Hargreave TB, Mellows HJ (1993, 2000) Amelar RD, Dubin L, Walsh PC (1977) Male infertility. Saun- WHO manual for the standardized investigation and diag- ders, Philadelphia, Pa. nosis of the infertile couple. Cambridge University Press, Bruckert E (1991) How frequent is unintentional childlessness Cambridge in Germany? Andrologia 23:245–250 Rümke P (1965) Autospermagglutinins: a cause of infertility in Comhaire FH (1996) Male infertility. Clinical investigations, men. Ann N Y Acad Sci 1234:696–701 cause evaluation and treatment. Chapman and Hall Medical, Rümke P (1970) Sperm antibodies and their action upon hu- London man spermatozoa. Ann Inst Pasteur (Paris) 118:525–528 Dunson DB, Baird DD, Colombo B ( 2004) Increased infertility Rümke P, Hellinga G (1959) Autoantibodies against spermato- with age in men and women. Obstet Gynecol 103:51–56 zoa in sterile men. Am J Clin Pathol 32:357–363 Eliasson R (1971) Standards for investigation of human semen. Schirren C (1985) Andrology: origin and development of a Andrologie 3:49–64 special discipline in medicine. Andrologia 17:117–125 European Academy of Andrology (2001) Membership list Schirren C (1989) History of andrology within dermatology 2001, statutes, andrology centres. Int J Androl 24, Suppl 1 (in German). Andrologia 21 [Suppl 1] Hellinga G (1957) Classification of male hypogonadism. Acta Schoysman R (1961) Exploration and physiological treatment Endocrinol 31:148 of a case of male infertility (in French). Bull Soc R Belge Gy- Hellinga G (1959) Analysis of the seminal picture in the etio- necol Obstet 31:445–450 4Introduction

Schoysman R (1964) Preliminary studies of the treatment of Tonutti E, Weller O, Schuchardt E, Heinke E (1960) The male average oligospermia by human gonadotropins extracted gonad-structure, function, clinic – main features of andro- from the urine of menopausal women (H.M.G.) (in French). logy (in German). Georg Thieme, Stuttgart Bull Soc R Belge Gynecol Obstet 34:399–407 Tulloch WS (1953) Testicular biopsy: indications and tech- Schoysman R (1968) Creation of an artificial spermatocele in nique. Proc R Soc Med 46:838–839 agenesis of the deferent duct (in French). Bull Soc R Belge Waites GMH, Frick J Baker GWH (1997) Current advances in Gynecol Obstet 38:307–317 andrology. Proceedings of the VI International Congress of Schuermann H, Doepfmer R (1960) Fertility disturbances in Andrology, Salzburg, Austria. Monduzzi Editore, Bologna, man (in German) In: Jadassohn J (ed) Handbook of skin and Italy venereal diseases. Supplementum VI/3. Springer, Berlin Whitfield HN, Hendry WF, Kirby RS, Duckett JW (1998) Text- Heidelberg New York book of genitourinary surgery, 2nd edn, vol 1, 2. Blackwell, Steinberger A, Steinberger E (1970) In vitro growth and devel- Oxford opment of mammalian testes. In: Johnson AD, Gomes WR, World Health Organization (1999) WHO laboratory manual Vandemark NL (eds) The testis, vol II. Academic, New York, for the examination of human semen and sperm-cervical pp 363–391 mucus interaction, 4th edn. Cambridge University Press, Steinberger E (1971) Hormonal control of mammalian sper- Cambridge matogenesis. Physiol Rev 51:1 Templeton AA (1992) The epidemiology of infertility. In: Tem- pleton AA, Drife JO (eds) Infertility. Springer, Berlin Heidel- berg New York, pp 23–32

Layout and How to Use the Book F. Comhaire

In everyday practice, the clinician is faced with patients The second part of the book includes more extended consulting for different problems related to the broader anddetailedinformationgivingtherationale,scientific field of andrology. background, and literature references and is organized The first concern will be to rapidly gain information into four major sections: that is immediately applicable for the management of 1. Understanding normal anatomy and function the patient. 2. Mechanisms of dysfunction and pathogenesis The first part of the present book aims at providing 3. Diagnostic tools this “express” information in a condensed manner and 4. Therapeutic options using a systematic sequence. Under the heading “Prob- lem:...,”thefollowingitemsareaddressedinsequence: Whenever required or desired, the clinician can cross- reference from Part I to Part II in order to discover or 1. Definition of the disease ascertain the consensus-based and current knowledge 2. Aetiology and pathogenesis supporting the guidelines that are summarized in 3. History taking, physical examination, technical Part I. and laboratory findings Although this book can perfectly serve as a teaching 4. Differential diagnosis (when applicable) instrument,thisisnotitsprimarypurpose.Theeditors 5. Treatment have instead aimed at creating a working instrument 6. Expected treatment results for the everyday practice of the busy clinician. Neither 7. Prognosis the choice of the topics nor the contents of the book fo- 8. Prevention (when applicable) cus on completeness or considerations which are most- 9. Complementary considerations ly irrelevant for clinical practice. General Considerations

Evidence-Based Medicine in Reproductive Medicine and Andrology F. Comhaire, A. Mahmoud

In modern, rational and scientific medicine, the pres- infertility (WHO 1987). Therefore, some trials rely on sure of society on practitioners is continuously increas- an intermediate end-point to estimate the effect of treating. Good health is considered a right, rather than a ment, namely sperm quality. However, the relation be- privilege, and the population expects diseases to be tween semen characteristics and men’s fertility is com- overcome promptly and efficiently. This applies to all plicated, and techniques of sperm analysis are often diseases, including infertility. poorly reproducible. So far, there is no single test on se- More than before, it is emphasized that diagnosis men that can confidently predict the fertilizing poten- and treatment must be based on the current best evi- tial. Treatment by means of in vitro fertilization (IVF) dence that is acquired by high-standard scientific re- with or without ICSI hold an increased risk for congeni- search and is applied judiciously and conscientiously. tal malformations (In’t Veld et al. 1995; Sutcliffe et al. Good clinicians have always relied on their personal 1999; Koudstaal et al. 2000; Wennerholm et al. 2000; experience and judgment to decide on the treatment Hansen et al. 2002) or impaired development of the off- strategy for individual patients, which may sometimes spring (Strömberg et al. 2002), and must be used with differ from current evidence (Kirk-Smith and Stretch extreme restraint. Such techniques should be reserved 2001). The approach based on personal experience is as an ultimate option when other solutions are excluded sometimes questioned and even rejected as “authority- or have turned out to be ineffective (Mitchell 2002). based” and, therefore, unscientific. The seeming differ- Otherwise “children may become the nameless, face- ence between experience and evidence may result in less, voiceless victims of reproductive technology, be- conflicting views on, for example, the treatment of the cause they do not have standing to oppose the use of infertile male with far-reaching ethical and economic those new technologies” (Berry 2002). consequences. The problem is complicated by the fact In the second place, the quality of current best evi- that different therapeutic strategies affect not only the dence must be questioned and put through serious consulting couple, but also the health and happiness of scrutiny. Evidence-based medicine attaches the highest the future child. value to evidence gained from double-blind random- First of all, there may be problems in defining the out- ized prospective trials (Ellis and Adams 1997). The comesoftreatment,e.g.ofinfertility.Intheheterosexual crossover method should, however, be avoided in trials couple, it is not just the dichotomy between whether or of reproductive medicine (Khan et al. 1996). Meta-anal- not there is a successful delivery, but several nuances ysis of selected trials is also considered highly valuable; must be considered. The time needed to reach the de- whereas prospective (open label) cohort trials score sired pregnancy, the physical and emotional invasive- much lower as to their scientific reliability. The lowest ness of treatment and its economic impact on society levelisawardedtoretrospectivecohortstudiesand and the couple, possible adverse effects of the treatment case studies. The reliability of meta-analysis is, howev- for the mother, and the health of the offspring must be er, highly questionable (Editorial 1997). It has indeed included in the decision-making process. been documented that the correspondence between the Men can only prove their fertility through the inter- conclusions of meta-analysis as compared to those of mediate of their female partner (Steinberger et al. 1981), (subsequent) large-scale randomized trials is only 67% and the potential fertility of the latter is suboptimal in (LeLorier et al. 1997), so hardly better than by chance approximately half of the couples consulting for male (50%). Hence, selecting treatment based on the evi- 6 General Considerations

dence of meta-analyses may be incorrect in as many as correct. Evidencing the effect of a particular treatment one-third of patients! We should not bestow too much that results in relatively minor improvement (e.g. from confidence to the conclusions of meta-analyses, particu- 15% to 25% success) requires a large number of cases in larly if these contradict medical experience or results of the treated and the control groups in order to reach a either prospective or retrospective cohort studies. This reasonable power of confidence. Any trial not reaching is particularly true if the trials on which the meta-analy- this number of participants will suffer from a type 2 or sis is based yield highly divergent outcomes (Comhaire beta error, and the conclusions are invalid. Large trials and Mahmoud 2004; Evers and Collins 2004). commonly require a multi-centre effort, which intro- In addition, concern has risen about the reliability of duces additional confounders such as the diagnostic ad- the published randomized trials. Many of these are co- equacy (Kassirer and Kopelman 1989) and the therapeu- ordinated and financed (“sponsored”) by companies tic (surgical) expertise of the clinicians (Nilsson et al. (Miller and Shorr 2002) that have direct interest in a fa- 1979; Olive 1996), the quality of the laboratory (Cle- vourable outcome of the trial (Smith 1998; Stelfox et al. ments et al. 1995; Neuwinger et al. 1990), etc. 1998),whereastheresultsoftrialsnotgeneratingthe Finally, randomized trials are subjected to ethical expected positive outcome may never be published, concerns when the implementation of a reasonably val- disclosed or cited (Kjaergard and Gluud 2002). Similar- idated treatment comes into conflict with the require- ly, centres that dispose of particular techniques have a ments of trial protocol (Hope 1995). From the philo- commercial interest in claiming high success rates sophical point of view, evidence suggests that some- (Teris 1998; Van Steirteghem 1998; Wilson 2002), and it thing is scientifically proven, and therefore the obser- may take years or even decades before the statistical vations are in agreement with the “truth” (Kaptchuk manipulations are unveiled. For example, recent publi- 2001). Whether the truth always corresponds to the cations report the “real” effective success rate of assist- “good” is another question (Hope 1995). ed reproductive techniques such as IVF and ICSI to be Progress in medicine depends on high-quality scien- more than 40% lower than those claimed or extrapolat- tific research and on the evidence gained from this. But ed from theoretical models (Schroder et al. 2004). the outcome of trials and meta-analyses must be con- There are many pitfalls that are inherent to the proper fronted with the knowledge on, for example, pathogene- methodology of randomized trials (Cleophas 1996; sis and epidemiology, as well as the experience from in- Schulz and Grimes 2002). In correctly performed trials, dividual and cohort observations, which may all con- the “blind” assignment to patients to groups is done by tribute valuable indirect evidence. Furthermore, the an external and independent body (Kiene 1996a, b; Fer- quality of current practice must continuously be con- gusson et al. 2004), and not by the clinician or the centre trolled by means of auditing. The judicious amalgam- directly involved in patient care. Furthermore, inevita- ationoftheso-calledharddirectevidencewithmore bly an unintentional bias in selecting cases will take soft indirect evidence, well-balanced and validated by a placeassoonaspatientsmustconsenttoparticipateina groupofexperts,willproducethebestpossibleevidence placebo-controlled trial, since a particular type of per- by consensus. It is this consensus-based evidence that is son may refuse to do so, or indeed accept recruitment implemented in the present book. because of perceived opportunistic self-interest. It is usually accepted as self-evident that results obtained in randomized trials may confidently be extra- References polated to the general population. However, partici- Berry JJ (2002) Congenital anomalies after IVF/ICSI. Tulane pantsofsuchtrialsarerecruitedonthebasisofwell- Law Review 72:248–256 defined inclusion and exclusion criteria, and the select- Clements S, Cooke ID, Barratt CL (1995) Implementing com- ed “cases” may not be representative of the real-life pa- prehensive quality control in the andrology laboratory. tient population seen by clinicians. In the case of infer- Hum Reprod 10:2096–2106 Cleophas TJ (1996) Clinical trials: design flaws associated with tility treatment, many different factors can coincide in use of a placebo. Am J Ther 3:529–534 each particular couple and the implementation of rec- Comhaire FH, Mahmoud AM (2004) Editorial commentary. ommendations gained from another (trial) population J Androl 25:771–772 to individual couples may be unwarranted (Ellis and Editorial (1997) Meta-analysis under scrutiny. Lancet 350:675 Adams 1997). Examples of confusing factors that are Ellis SJ, Adams RF (1997) The cult of the double-blind placebo- controlled trial. Br J Clin Pract 51:36–39 usually not considered are lifestyle (tobacco, alcohol, Evers J, Collins J (2004) Surgery or embolisation for varicocele sedentary lifestyle, stress), educational and social sta- in subfertile men. Cochrane Database Syst Rev 3:CD000479 tus, exposure to environmental or professional agents, FergussonD,GlassKC,WaringD,ShapiroS(2004)Turninga ethnic background, genetic constitution, etc. blind eye: the success of blinding reported in a random sam- ple of randomised, placebo controlled trials. BMJ 328:432 Too often, no (statistical) evidence of effect is inter- Hansen M, Kurinczuk JJ, Bower C, Webb S (2002) The risk of preted as evidence of no effect. Whereas the latter may major birth defects after intracytoplasmic sperm injection be true, there are many reasons why it may in fact not be and in vitro fertilization. N Engl J Med 346:725–730 Economic Cost and Cost-Effectiveness 7

Hope T (1995) Evidence based medicine and ethics. J Med Eth- Nilsson S, Edvinsson A, Nilsson B (1979) Improvement of se- ics 21:259–260 men and pregnancy rate after ligation and division of the in- In’t Veld P, Brandenburg H, Verhoeff A, Dhont M, Los F (1995) ternal spermatic vein: fact or fiction? Br J Urol 51:591–596 Sex chromosomal abnormalities and intracytoplasmic Olive DL (1996) Evidence based medicine and the surgical pro- sperm injection. Lancet 346:773 cedure. Course on evidence based medicine: contemporary Kaptchuk TJ (2001) The double-blind, randomized, placebo- mode of practice. Am Soc Reprod Med 1–65 controlled trial: gold standard or golden calf? J Clin Epide- Schroder AK, Katalinic A, Diedrich K, Ludwig M (2004) Cumu- miol 54:541–549 lative pregnancy rates and drop-out rates in a German IVF Kassirer JP, Kopelman RI (1989) Cognitive errors in diagnosis: programme: 4102 cycles in 2130 patients. Reprod Biomed instantiation, classification, and consequences. Am J Med Online 8:600–606 86:433–441 Schulz KF, Grimes DA (2002) Blinding in randomised trials: KhanKS,DayaS,CollinsJA,WalterSD(1996)Empiricalevi- hiding who got what. Lancet 359:696–700 dence of bias in infertility research: overestimation of treat- Smith R (1998) Beyond conflict of interest. Transparency is the ment effect in crossover trials using pregnancy as the out- key. BMJ 317:291–292 come measure. Fertil Steril 65:939–945 Steinberger E, Rodriguez-Rigau LJ, Smith KD (1981) The inter- Kiene H (1996a) A critique of the double-blind clinical trial. action between the fertility potentials of the two members of Part 1. Altern Ther Health Med 2:74–80 an infertile couple. In: Frajese G, Hafez ES, Conti C, Fabbrini Kiene H (1996b) A critique of the double-blind clinical trial. A (eds) Oligozoospermia: recent progress in andrology. Part 2. Altern Ther Health Med 2:59–64 Raven, New York, pp 9–19 Kirk-Smith MD, Stretch DD (2001) Evidence-based medicine Stelfox HT, Chua G, O’Rourke K, Detsky AS (1998) Conflict of and randomized double-blind clinical trials: a study of fla- interest in the debate over calcium-channel antagonists. wed implementation. J Eval Clin Pract 7:119–123 N Engl J Med 338:101–106 Kjaergard LL, Gluud C (2002) Citation bias of hepato-biliary Strömberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M, randomized clinical trials. J Clin Epidemiol 55:407–410 Stjernqvist K (2002) Neurological sequelae in children born Koudstaal J, Bruinse HW, Helmerhorst FM, Vermeiden JP,Wil- after in-vitro fertilisation: a population-based study. Lancet lemsen WN, Visser GH (2000) Obstetric outcome of twin 359:461–465 pregnancies after in-vitro fertilization: a matched control SutcliffeAG,TaylorB,LiJ,ThorntonS,GrudzinskasJG,Lieber- study in four Dutch University hospitals. Hum Reprod 15: man BA (1999) Children born after intracytoplasmic sperm 935–940 injection: population control study. Br Med J 318:704–705 LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F Teris B.(ed) (1998) Recombinant FSH: a collection of previous- (1997) Discrepancies between meta-analyses and subse- ly published papers. Fertil Steril 69 (Suppl 2) quent large randomized, controlled trials. N Engl J Med Van Steirteghem A (1998) Outcome of assisted reproductive 337:536–542 technology. N Engl J Med 338:194–195 Miller FG, Shorr AF (2002) Ethical assessment of industry-spon- Wennerholm U, Bergh C, Hamberger L, Lundin K, Nilsson L, sored clinical trials: a case analysis. Chest 121:1337–1342 Wikland M, Kallen B (2000) Incidence of congenital malfor- Mitchell AA (2002) Infertility treatment–more risks and chal- mations in children born after ICSI. Hum Reprod 15: 944–948 lenges. N Engl J Med 346:769–770 WHO (1987) Towards more objectivity in diagnosis and man- Neuwinger J, Behre HM, Nieschlag E (1990) External quality agement of male infertility. Int J Androl Suppl 7 control in the andrology laboratory: an experimental multi- Wilson AM (2002) Press communication. The Independent, 22 center trial. Fertil Steril 54:308–314 October 2002

Economic Cost and Cost-Effectiveness F. Comhaire, A. Mahmoud

Optimal health care is a universal human right. Alas, Therefore it is mandatory and, in fact, part of the de- this right can be claimed by only a fraction of the ontological obligation of all clinicians to make the best world’s population, and many persons in large areas are possible use of financial means, both public and private deprived of this right. On the other hand, the financial money, by selecting the most cost-effective modalities cost to implement this right in both poor and wealthier for diagnosing and treating the patient. Also, the cost- partsoftheworldisenormous.Inaddition,providing effectiveness of methods for the prevention and/or adequate health care to the population seems to be a early detection of diseases, or of impaired health and rather low priority in certain countries where greater function must be assessed. financial means are being invested in other projects For the majority of problems in the field of clinical (e.g. waging wars). In so-called developed and wealthi- andrology, there are several possible options with re- er countries, the care for an increasing proportion of gard to investigation and management. Aside from the ageing persons, the enhanced prevalence of certain dis- fact that internal and external auditing is required to eases related to the modern lifestyle, unsuitable nutri- assess the good quality of the care delivered, medical tion and environmental contamination, for example, strategies must continuously be evaluated as to their and the availability of new but commonly expensive cost-effectiveness and the optimal approach. modalities of treatment make the cost of medical care In the field of surgery, the endoscopic approach may for the entire population hardly bearable. sometimes be as effective but less expensive compared 8 General Considerations

to open surgery, by shortening the duration of hospital stay and the time needed to recover and to resume eco- nomically rewarding work, for example. Also, in vasectomized patients surgical reversal is more cost-effective than IVF with ICSI (Pavlovich and Schlegel 1997). Another example relates to the systematic and peri- odic measurement of prostate-specific antigen (PSA) in thebloodofmenoveracertainage,inviewoftheearly detection and more effective treatment of cancer of the prostate. With respect to the management of reproductive disorders, the World Health Organization and the United NationsPopulationFundhavesetthegoaltouniversal access to reproductive health care no later than 2015, including the prevention and appropriate treatment of infertility (WHO 2003). Considering the enormity of this task and its massive financial consequences (Collins et Fig. 1. Cost per delivery in euros. [1 First cycle, 2 second cycle, al. 1997), methods for the diagnosis and management of 3 third cycle, ICSI in vitro fertilization plus intracytoplasmic the infertile male in particular should be scrupulously sperm injection (first cycle), IUI intrauterine insemination, evaluated for their cost-effectiveness (Comhaire 1995). IVF in vitro fertilization (first cycle), TAM treatment with ta- Cost not only refers to expenses carried by the public moxifen, TLC tender loving care, or treatment-independent pregnancies, VA R varicocele treatment] healthcare systems and insurance, but also by the patients involved (Collins 2002; Pratt 2004). In doing so, it is the cost per delivery of a healthy singleton that must cost-effectiveness is, in order: tamoxifen treatment, be the end-point, but the effective cumulative pregnan- one or two cycles of IUI (Goverde et al. 2000; Philips et cy rate and the time needed to attain the desired preg- al. 2000), and varicocele treatment (Schlegel 1997; Pen- nancy are also important (Comhaire et al. 1996). son et al. 2002). Since the spontaneous pregnancy rate Calculation of the direct cost per delivery is rather during counselling (also referred to as treatment-inde- simple and can be done by dividing the cost per treat- pendent pregnancy rate or tender loving care) is rela- mentbytherateofsuccessintermsoftheprobabilityof tively low, the cost-effectiveness of this approach is a healthy singleton will result from that particular treat- poor, particularly in couples with longer duration of ment. A clear-cut example of this calculation is the cost infertility (Mol et al. 2000). Also, the cost per delivery per delivery after in vitro fertilization in case of couple of IUI is high in the 3rd and 4th cycles of IUI, because infertility due to oligozoospermia (Neumann et al. of the decreasing conception rates. There is prelimi- 1994). The net cost per treatment cycle, including medi- nary evidence that complementing established treat- cation for ovarian hyperstimulation, cycle monitoring, ment modalities by food supplementation may de- pick-up and laboratory expenses amounts to a mini- crease the time to pregnancy, reducing the cost per mum of 2,500 c. The take-baby-home rate per treatment delivery. The cost per delivery of IVF for male subfer- cycle is approximately 20%, so the direct cost per deliv- tility is highest, even more when used in older women ery is between at least 12,500 c. Other estimations result (Legro et al. 1997), while ICSI may be slightly better in a cost per successful outcome in the first treatment from this point of view because of the higher immedi- cycle of US $60,000 (Griffin and Panak 1998). This cost ate success rate. It is a matter of debate whether or not increases with the increasing number of treatment cy- insemination with donor semen should also be includ- cles (Trad et al. 1995), reaching approximately US ed in the comparison of cost-effectiveness (Granberg $114,000 in the 6th cycle (Neumann et al. 1994). Estima- et al. 1996). tions do not include indirect costs and economic fac- Knowing the frequency of particular aetiological tors, such as time away from work, cost for postnatal andrological diagnoses in the patient population visit- care of the newborn which is approximately five times ing infertility clinics, the effective cumulative pregnan- higher than after natural conception (Callahan et al. cy rates and cost per successful outcome of various 1994; Wolner-Hanssen and Rydhstroem 1998), and treatment modalities, it is estimated that no more than complementary expenses for the treatment of congeni- 80 deliveries can be obtained with an investment of 1 tal defects or problems during development. million c when IVF is used as primary treatment, as Using this approach, it is possible to estimate the cost compared to approximately 300 deliveries when treat- per successful delivery for different modes of treatment ing the subfertile men in agreement with the WHO of the infertile male (Fig. 1; Comhaire 1995). The best guidelines (Comhaire 1995). Therefore, the latter ap- Ethics of Reproductive Research and Treatment 9 proach must be taken as part of good medical practice comparing the outcome and cost of in vitro fertilization (Collins 1994; Karande et al. 1999). with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril 71:468–475 Legro RS, Shackleford DP, Moessner JM, Gnatuk CL, Dodson WC (1997) ART in women 40 and over. Is the cost worth it? References J Reprod Med 42:76–82 Callahan TL, Hall JE, Ettner SL, Christiansen CL, Greene MF, MolBW,BonselGJ,CollinsJA,WiegerinckMA,vand,V,Bos- Crowley WF Jr (1994) The economic impact of multiple-gesta- suyt PM (2000) Cost-effectiveness of in vitro fertilization tion pregnancies and the contribution of assisted-reproduc- and embryo transfer. Fertil Steril 73:748–745 tion techniques to their incidence. N Engl J Med 331:244–249 Neumann PJ, Gharib SD, Weinstein MC (1994) The cost of a Collins J (2002) An international survey of the health econom- successful delivery with in vitro fertilization. N Engl J Med ics of IVF and ICSI. Hum Reprod Update 8:265–277 331:239–243 Collins JA (1994) Reproductive technology – the price of pro- Pavlovich CP, Schlegel PN (1997) Fertility options after vasec- gress. N Engl J Med 331:270–271 tomy: a cost-effectiveness analysis. Fertil Steril 67:133–141 Collins JA, Feeny D, Gunby J (1997) The cost of infertility diag- Penson DF, Paltiel AD, Krumholz HM, Palter S (2002) The cost- nosis and treatment in Canada in 1995. Hum Reprod 12: effectiveness of treatment for varicocele related infertility. 951–958 J Urol 168:2490–2494 Comhaire F (1995) Economic strategies in modern male sub- Philips Z, Barraza-Llorens M, Posnett J (2000) Evaluation of fertility treatment. 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Ethics of Reproductive Research and Treatment T.B. Hargreave

Key Messages Introduction ■ Three ethical principles underpinning all medical ethics are respect for autonomy, Any clinician involved in clinical practice or clinical re- beneficence and justice. search will face ethical problems; this is particularly ■ Consideration of these principles has to be relevant for those engaged in fertility clinic work. Each balanced between the individual, the couple, the clinician, both individually and in the context of guid- future child, the family and society as a whole. ance from regional and national ethical committees, ■ In general, consideration of the interests of the must formulate his or her own ideas. No one person has future child takes precedence over consider- the competence to pronounce on ethical issues because ation of other parties. these depend on culture, religion and national and in- ■ Consent is a process of giving the individual all ternational law. There are different perspectives in dif- the information necessary for that individual ferent countries. The purpose of the following text is to to make a free choice. help the clinician think about the ethical issues. ■ Consent is not just signing a piece of paper. ■ Reproductive advances such as intracytoplasmic sperm injection (ICSI), sex selection, cloning and germ-line genetic repair pose particular ethical problems.