Male Infertility

Contemporary Clinical Approaches, Andrology, ART & Antioxidants wwwwwwwwwwwww Sijo J. Parekattil ● Ashok Agarwal Editors

Male Infertility

Contemporary Clinical Approaches, Andrology, ART & Antioxidants Editors Sijo J. Parekattil Ashok Agarwal Director of Urology, Winter Haven Hospital Director, Center for Reproductive Medicine University of Florida Cleveland Clinic Winter Haven, Florida, USA Cleveland, Ohio, USA

ISBN 978-1-4614-3334-7 ISBN 978-1-4614-3335-4 (eBook) DOI 10.1007/978-1-4614-3335-4 Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2012938258

© Springer Science+Business Media, LLC 2012 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identiﬁ ed as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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Springer is part of Springer Science+Business Media (www.springer.com) Foreword

Drs. Parekattil (University of Florida) and Agarwal (Cleveland Clinic) have combined their expertise in the clinical and laboratory science, respectively, of male reproduction to create a novel and valuable textbook. Dr. Parekattil’s urologic fellowships at the Cleveland Clinic in both male infertility/microsurgery and laparoscopic/robotic surgery added considerably to his vision of the ﬁ eld of male fertility. He has pioneered the area of robotic microsurgical procedures for correction of obstructions in the male reproductive tract, varicocelectomy, neurolysis of the spermatic cord for relief from scrotal and groin pain, and for other procedures. Dr. Agarwal is a recognized authority in the study of the effect of reactive oxygen species (ROS) in the semen and their impact on sperm function. The compilation of a textbook that contains chapters that are written by so many international experts in both clinical and laboratory areas of male reproduction is a prodigious undertaking and the editors are to be congratulated for their efforts to create this book. Drs. Wiser, Sandlow, and Köhler (University of Wisconsin at Milwaukee) offer an encyclopedic discussion on a wide variety of causes of male infertility. They consider genetic, ana- tomic, endocrine, environmental, coital, immunologic, and surgically correctable factors that may affect a man’s fertility potential, and options for treatment other than in vitro fertilization (IVF)/ICSI of many of these conditions. Drs. Haywood, Laborde, and Brannigan (Northwestern University) offer a detailed discussion of various endocrinopathies that may cause male infertility. Drs. Agarwal and du Plessis (Tygerberg, South Africa) offer a chapter concerning the impact of obesity on male fertility. Drs. Mori and Sabanegh (Cleveland Clinic) present a detailed consideration of laboratory tests that are used for the diagnosis of male infertility. Dr. Claudio Teloken and associates (Brazil) discuss various environmental factors that may cause male infertility. The effects of various malignancies and of irradiation therapy and chemotherapy used to treat these malignancies on spermatogenesis are reviewed by Daniel Williams, IV (University of Wisconsin), who also discusses the use of sperm that were cryo- preserved before treatment for assisted reproductive technologies when spermatogenesis does not resume after chemotherapy. Drs. Faasse and Niederberger (University of Illinois at Chicago) present a detailed discussion of the epidemiological considerations of male infertility, including considerations about the incidence and prevalence of infertility in developed countries and in the developing world. They consider the relationship between semen parameters and male infertility and whether or not semen parameters predict fertility and assisted reproductive technology (ART) outcomes. Their chapter also concerns novel assays for the evaluation of male infertility and whether or not male semen quality is declining, as well as health care resource utilization for male infertility in the USA. Dr. Henkel (Bellville, South Africa) gives a thorough discussion of infections of the male genitourinary tract according to the etiologic agent and the location of the infection within the genitourinary tract.

v vi Foreword

Drs. Inci and Gunay (Turkey) discuss medications and other exogenous agents that may decrease the male fertility potential. Drs. Cohen and Moseley (University of Florida) present four fascinating cases of ethical issues that may arise and create problems to both physicians and patients when making decisions about the management of fertility problems. Dr. Vaithinathan et al. (Puducherry, India) consider the various causes of apoptosis that may affect a man’s fertility status, while Drs. Misro and Ramya (New Delhi, India) offer an elegant view of fuel energy sources for spermatozoa. Drs. Hsieh and Shin (Georgetown University) discuss nutritional pathways to protect male reproductive health. Their chapter primarily concerns the use of various antioxidants for infertile men and the impact of obesity on men’s fertility potential. Dr. Pasqualotto et al. (Brazil) discuss the effect of the aging process on male fertility status and the effect of increased DNA abnormalities that occur with increasing age on the genomic pattern of the offspring of aged men. Dr. Kumar (New Delhi, India) discusses various causes of azoospermia in India, some of which are rarely, if ever, seen in the USA. He also presents his techniques for microsurgical vasoepididymostomy and for microsurgical varicocelectomy. Drs. Cassidy, Jarvi, Grober, and Lo (Toronto, Canada) discuss their use of a “mini-incision” to perform vasectomy reversal using no-scalpel techniques. Drs. Hsiao and Goldstein (Cornell Weill School of Medicine) discuss the historical devel- opment of microsurgical vasoepididymostomy. The latter author’s extensive experience with that procedure and the evolution of his anastomotic technique are described in detail. Drs. Stember and Schlegel (also at Cornell Weill) review Schlegel’s extensive experience with microsurgical dissection for testicular sperm extraction (microTESE). All aspects of dealing with patients who have non-obstructive azoospermia, including genetic fi ndings, testicular histology and hormonal values in these patients are considered. The details of the microTESE procedure, including sperm processing methods and results, are clearly described. Various discussions of the use of robotic microsurgery are contained in this book. Drs. Brahmbhatt and Parekattil discuss robotic microsurgery to perform vasovasostomy, varicocelectomy, as well as to perform spermatic cord denervation and robotic single port neurolysis to relieve scrotal and groin pain caused by various etiologies. They describe newly available and prototype instrumentation for robotic microsurgery. Drs. Shu and Wang (Houston, Texas) discuss their method of robotic microsurgical varicocelectomy. They deliver the spermatic cord externally in the normal operative manner, but then use the DaVinci robot to perform dissection within the cord. They found a short learning curve to perform this procedure and now prefer this method for performing varicocelectomy due to the complete lack of tremor and the ease of identi fi cation of the various structures within the spermatic cord. Dr. De Wil et al. (Belgium and Switzerland) present interesting arguments that robotic vasovasostomy is useful to reduce tremor and to enhance dexterity when this procedure is performed. They also discuss the background of robotic surgery and describe the details of their method of robotic vasovasostomy. While many may question the value of robots for urologic microsurgical procedures, the total elimination of tremor when the robot is used certainly should improve the results of microsurgical procedures. The question that will need to be answered in the future is whether or not cost/benefi t considerations support the use of robots for urologic microsurgery except for the unusual situation in which repair of vasal obstruction deep within the pelvis may be required. Drs. Rosevear and Wald (University of Iowa) review experimental procedures to develop vas deferens allografts to bridge the gap when the distance between the two ends of the vas is too long for reconstruction to be performed with microsurgical vasovasostomy. A chapter by Drs. Ignatov and Turek (San Francisco) concerns the diagnosis and management of various types of ejaculatory dysfunction, as well as the surgical treatment of ejaculatory duct obstruction. Drs. Cocuzza (Sao Paulo, Brazil) and Parekattil discuss the various uses of radiology in the diagnosis and treatment of male infertility. There are detailed discussions about IVF and intracytoplasmic sperm injection (ICSI) in the treatment of male infertility. Drs. Rhoton-Vlasak and Drury (University of Florida) discuss Foreword vii

their institution’s multidisciplinary clinic for the evaluation of couples as potential candidates for ART and describe in great detail the laboratory aspects of ARTs, including the indications for, and use of, antioxidants in vitro during ART procedures. Dr. Antinori (Italy) discusses motile sperm organellar morphology examination (MSOME) to reach a fi nal video magnifi cation of 6,600×. This allows the detection of subcellular abnormalities of sperm. The author assumes that certain subcellular microscopic changes in sperm are a result of exposure to reactive oxygen species. Subsequently, the intracytoplasmic mor- phologically selected sperm injection (IMSI) procedure is described as a new method of sperm selection to treat couples with previously failed ICSI cycles. This technology currently is so expensive that it falls into the category of experimental therapy, but it offers promise for the future. Drs. Grunewald and Paasch (Leipzig, Germany) also elaborate on subcellular and other methods of sperm selection for ICSI. The discussions about the effect of ROS on sperm quality and male fertility and on the use of antioxidants to treat male infertility are virtually encyclopedic in nature. Dr. Lampiao et al. review oxidative stress, the physiologic role of ROS in normal sperm physiology, the patho- logic effects of ROS on sperm function, and the prevention of, and therapy for, impaired fertility due to seminal fl uid ROS. Dr. Balercia et al. from Italy discuss the role of coenzyme Q10 and l-carnitine in the treatment of ROS damage to sperm, and Drs. Iremashvili, Brackett, and Lynne (University of Miami) discuss the sources, consequences, and possibility for therapy of ROS in the semen of spinal cord injured men. Drs. Said (Toronto, Canada) and Agarwal con- tribute information about the use of antioxidants in sperm cryopreservation. Dr. Lanzafame et al. (Syracuse and Catania, Italy) present detailed information about the use and value of a host of antioxidants to treat ROS-induced sperm damage. As a balance to these considerations of antioxidant therapy, the harmful effects and risks of antioxidant therapy are discussed by Drs. Stewart and Kim (University of Tennessee). Dr. Garrido et al. (Valencia, Spain) discuss the role of antioxidants in ICSI. Drs. Celik-Ozenci (Antalya, Turkey) and Huszar (Yale University) add other aspects of oxidative stress on sperm and mention the fact that medical therapy for this problem has not proved to be signifi cantly successful. They show the benefi ts of the sperm–hyaluronic acid binding assay and hyaluronic acid-mediated selection of single sperm without DNA chain fragmentation in order to select sperm for ICSI. Drs. Hwang and Lamb (Baylor at Houston) offer an explanation for the molecular mechanisms of antioxidants in male infertility. Dr. Tremellen (Australia) contributes a critical review of the literature concerning the effective- ness of antioxidant therapy for the enhancement of male reproductive health. The author should be congratulated on presenting an overview of the common methodological weaknesses in antioxidant trials. Dr. Ko and others (Cleveland Clinic) conclude that there is a need for randomized controlled trials regarding the value of medical treatment of infertility due to ROS. Dr. Alvarez (Barcelona) discusses the effects on sperm function after thawing that are caused by the loss of intracellular antioxidant enzyme activity during cryopreservation. Dr. Varghese et al. (Montreal, Canada and Cleveland Clinic) discuss the use of antioxidants during embryo culture and during embryo cryopreservation to prevent lipid peroxidation of the cell membrane of the developing embryo. A unique feature of the book is the inclusion of a section of “Expert Commentary” at the end of many of the chapters. This treatise contains discussions of virtually all areas of the diagnosis and treatment of male infertility and also contains information about newer evolving therapies to treat male infertility. The chapters on ethical considerations in male infertility and on the management of chronic inguinal and scrotal pain are welcome additions that are not usually found in textbooks concerning male infertility. The addition of the various laboratory considerations of male infertility makes the book valuable for the libraries of not only clini- cians, but also of laboratory scientists.

Louisville , KY Arnold Belker, MD wwwwwwwwwwwww Preface

The fi eld of male infertility truly illustrates the need for a multispecialty approach to the effective diagnosis and management of such conditions. From the initial referral possibly from a reproductive endocrinology gynecologist and embryologist to the male infertility urologist, andrologist, nurses, researchers, and alternative medicine specialists, this multidisciplinary team needs to work as a cohesive unit to provide our patients with the most effective and high- est quality care. This book was an attempt to gather experts from each of these fi elds and present an inte- grated management approach with detailed descriptions of topics ranging from the initial clinical diagnosis, management, new treatment options, and scienti fi c rational for the various approaches. The book initially focuses on the clinical aspects of male infertility and then dives into the use of antioxidants as adjunctive therapy and the current state of affairs in antioxidant research. The authors come from leading institutions from around the globe in an attempt to capture a wide range of techniques and approaches. We are hoping that this text may serve as a reference guide for specialists across this team to further enhance dialogue, discussion, and re finement in our multidisciplinary approach. We would like to thank the authors for their contributions and our families for their patience in allowing us to put together this project. We would like to acknowledge the Glickman Urological Institute at the Cleveland Clinic Foundation and the Department of Urology at University of Florida for institutional support for this endeavor as well. We are grateful to Richard Lansing, executive editor, for his support and advice, and to Margaret Burns, developmental editor, for her tireless efforts in reviewing and editing each of the manuscripts. We hope that this book will provide a concise, consolidated reference for antioxidants and male infertility.

Winter Haven , FL , USA Sijo J. Parekattil Cleveland, OH, USA Ashok Agarwal

ix wwwwwwwwwwwww Contents

Part I Male Infertility Diagnosis and Management

1 Causes of Male Infertility ...... 3 Herbert J. Wiser, Jay Sandlow, and Tobias S. Köhler 2 Laboratory Evaluation for Male Infertility ...... 15 Ryan Mori and Edmund Sabanegh Jr. 3 Imaging Modalities in the Management of Male Infertility ...... 27 Marcello Cocuzza and Sijo J. Parekattil 4 Endocrinopathies ...... 37 Sam Haywood, Eric L. Laborde, and Robert E. Brannigan 5 Molecular Mechanisms of Antioxidants in Male Infertility ...... 45 Kathleen Hwang and Dolores J. Lamb 6 Surgical Treatment for Male Infertility ...... 55 Sandro C. Esteves and Ricardo Miyaoka 7 Microsurgery for Male Infertility: The AIIMS Experience ...... 79 Rajeev Kumar 8 Advanced Techniques of Vasoepididymostomy ...... 89 Wayland Hsiao and Marc Goldstein 9 Grafting Techniques for Vasectomy Reversal ...... 99 Henry M. Rosevear and Moshe Wald 10 Mini-Incision Vasectomy Reversal Using the No-Scalpel Vasectomy Instruments and Principles ...... 107 Darby J. Cassidy, Keith Jarvi, Ethan D. Grober, and Kirk C. Lo 11 Robotic Microsurgery for Male Infertility and Chronic Orchialgia ...... 115 Jamin V. Brahmbhatt and Sijo J. Parekattil 12 Robot-Assisted Vasectomy Reversal ...... 123 Peter Frank De Wil, Vincenzo Ficarra, George A. de Boccard, and Alexandre Mottrie 13 Robotic-Assisted Varicocelectomy ...... 127 Tung Shu and Run Wang 14 Epidemiological Considerations in Male Infertility...... 131 Mark A. Faasse and Craig S. Niederberger

xi xii Contents

15 Male Infertility from the Developing Nation Perspective ...... 143 Kasonde Bowa and John S. Kachimba 16 Ethical Dimensions of Urology: Four Case Studies ...... 151 Marc S. Cohen and Ray E. Moseley 17 Management of Fertility in Male Cancer Patients ...... 157 Daniel H. Williams IV 18 Genetic Aspects of Male Infertility ...... 171 Orhan Bukulmez 19 Novel Approaches in the Management of Klinefelter Syndrome ...... 191 Fnu Deepinder 20 ART and Its Impact on Male Infertility Management ...... 197 Alice Rhoton-Vlasak and Kenneth C. Drury

Part II Spermatozoa Metabolism

21 Fuel/Energy Sources of Spermatozoa ...... 209 M.M. Misro and T. Ramya 22 Oxidative Stress ...... 225 Fanuel Lampiao, C.J. Opperman, Ashok Agarwal, and Stefan S. du Plessis 23 Loss of Intracellular Antioxidant Enzyme Activity During Sperm Cryopreservation: Effects on Sperm Function After Thawing ...... 237 Juan G. Alvarez

Part III Common Male Infertility Disorders

24 Varicocele ...... 247 Sandro C. Esteves 25 Infection in Infertility ...... 261 Ralf Henkel 26 Ejaculatory Dysfunction and Vasodynamics ...... 273 Aleksey P. Ignatov and Paul J. Turek 27 Environmental Factors ...... 283 Claudio Telöken, Samuel Juncal, and Túlio M. Graziottin 28 Exogenous Medication or Substance-Induced Factors...... 297 Kubilay Inci and Levent Mert Gunay 29 Sperm DNA Damage and Antioxidant Use: Roles in Male Fertility ...... 307 Ashok Agarwal and Aspinder Singh 30 Common Male Infertility Disorders: Aging ...... 317 Fabio Pasqualotto, Edson Borges Jr., and Eleonora Pasqualotto 31 Apoptosis and Male Infertility ...... 329 S. Vaithinathan, Shereen Cynthia D’Cruz, and P.P. Mathur 32 Impact of Spinal Cord Injury ...... 337 Viacheslav Iremashvili, Nancy L. Brackett, and Charles M. Lynne 33 Obesity and Male Fertility ...... 349 Stephanie Cabler, Ashok Agarwal, and Stefan S. du Plessis Contents xiii

Part IV Nutrition and Antioxidants Role for Male Reproductive Health

34 Nutritional Pathways to Protect Male Reproductive Health ...... 363 Tung-Chin Hsieh and Paul Shin 35 Natural Antioxidants ...... 369 Giancarlo Balercia, Antonio Mancini, and Gian Paolo Littarru 36 Synthetic Antioxidants...... 381 Edmund Y. Ko, John C. Kefer, Ashok Agarwal, and Edmund Sabanegh 37 Antioxidant Therapy for the Enhancement of Male Reproductive Health: A Critical Review of the Literature ...... 389 Kelton Tremellen 38 In Vitro Studies of Antioxidants for Male Reproductive Health ...... 401 Armand Zini and Maria San Gabriel

Part V Assisted Reproductive Technologies in Male Fertility

39 Micro-testicular Sperm Extraction ...... 411 Doron Sol Stember and Peter Schlegel 40 Sperm Processing and Selection ...... 423 Sonja Grunewald and Uwe Paasch 41 Antioxidants in Sperm Cryopreservation ...... 431 Tamer Said and Ashok Agarwal 42 Antioxidants in ICSI ...... 439 Nicolas Garrido, Sandra García-Herrero, Laura Romany, José Remohí, Antonio Pellicer, and Marcos Meseguer 43 Antioxidants in IMSI ...... 449 Monica Antinori 44 Role of Sperm–Hyaluronic Acid Binding in the Evaluation and Treatment of Subfertile Men with ROS-Affected Semen: Assessment of Sperm with Oxidative Damage and HA-Mediated ICSI Sperm Selection ...... 459 Ciler Celik-Ozenci and Gabor Huszar 45 Extended Embryo Culture Supplementation ...... 471 Alex C. Varghese, Eulalia Pozo-Guisado, Ignacio S. Alvarez, and Francisco Javier Martin-Romero

Part VI Special Topics

46 Best Practice Guidelines for the Use of Antioxidants ...... 487 Francesco Lanzafame, Sandro La Vignera, and Aldo E. Calogero 47 Harmful Effects of Antioxidant Therapy ...... 499 Adam F. Stewart and Edward D. Kim Index ...... 507 wwwwwwwwwwwww Contributors

Ashok Agarwal , Ph.D. Center for Reproductive Medicine , Glickman Urological and Kidney Institute, Cleveland Clinic Foundation , Cleveland , OH , USA Ignacio S. Alvarez , Ph.D. Department of Cell Biology , School of Life Sciences, University of Extremadura , Badajoz , Spain Juan G. Alvarez , M.D., Ph.D. Centro de Infertilidad Masculina Androgen , La Coruña , Harvard Medical School, Boston, Spain Monica Antinori , M.D. Department of Infertility , RAPRUI Day Surgery , Rome , Italy Giancarlo Balercia , M.D. Andrology Unit, Endocrinology, Department of Internal Medicine and Applied Biotechnologies, Umberto I Hospital, School of Medicine, Italy Department of Clinical and Molecular Sciences, Marche Polytechnic University , Italy Edson Borges Jr., M.D. Department of Fertility , Center for Assisted Fertilization , Sao Paulo , Brazil Kasonde Bowa , M.Sc., M.Med., F.R.C.S., F.A.C.S., F.C.S. Department of Surgery , University Teaching Hospital , Lusaka , Zambia and Ndola Central Hospital, Zambia Nancy L. Brackett , Ph.D., H.C.L.D. The Miami Project to Cure Paralysis , University of Miami Miller School of Medicine , Lois Pope Life Center, Miami , FL , USA Jamin V. Brahmbhatt , M.D. Department of Urology , University of Tennessee Health Science Center , Memphis , TN , USA Robert E. Brannigan , M.D. Department of Urology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA Orhan Bukulmez , M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology , University of Texas Southwestern Medical Center , Dallas , TX , USA Stephanie Cabler , B.Sc. Center for Reproductive Medicine, Glickman Urological and Kidney Institute , Cleveland Clinic Foundation , Cleveland , OH , USA Aldo E. Calogero , M.D. Department of Medical and Pediatrics Sciences , University of Catania , Catania , Italy Darby J. Cassidy , M.D. Department of Urology , University Hospital of Northern British Columbia, Prince George , BC , Canada Ciler Celik-Ozenci , D.D.S., Ph.D. Department of Histology and Embryology School of Medicine , Akdeniz University, Campus , Antalya , Turkey

xv xvi Contributors

Marcello Cocuzza , M.D. Department of Urology , University of Sao Paulo , Sao Paulo , Brazil Marc S. Cohen , M.D. Department of Urology , Shands at the University of Florida , Gainesville , FL , USA George A. de Boccard , M.D. Clinique Generale Beaulieu, Robot Assisted Laparoscopy Surgery Center , Geneva , Switzerland Shereen Cynthia D’Cruz , M.Phil. Department of Biochemistry and Molecular Biology , Pondicherry University , Kalapet , Pondicherry , India Peter Frank De Wil , M.D. Urological Department , Kliniek Sint Jan , Brussels , Belgium Fnu Deepinder , M.D. Department of Endocrinology, Diabetes, and Metabolism , Cedars Sinai Medical Center , Los Angeles , CA , USA Kenneth C. Drury , Ph.D. In Vitro Fertilization and Andrology Laboratory, Department of Obstetrics and Gynecology , University of Florida College of Medicine , Gainesville , FL , USA Stefan S. du Plessis , Ph.D., M.B.A. Department of Medical Physiology, Faculty of Health Sciences , Stellenbosch University , Tygerberg, Western Cape , South Africa Sandro C. Esteves , M.D., Ph.D. ANDROFERT, Andrology and Human Reproduction Clinic, Center for Male Reproduction, Campinas , SP , Brazil Mark A. Faasse , M.D. Department of Urology , University of Illinois at Chicago , Chicago , IL , USA Vincenzo Ficarra , M.D., Ph.D. Department of Oncological and Surgical Sciences , Urology Clinic, University of Padua, Padua , Italy Sandra García-Herrero , Ph.D. IVIOMICS , Valencia , Spain Nicolas Garrido , Ph.D. Andrology Laboratory and Sperm Bank , Instituto Universitario IVI Valencia , Valencia, Spain Marc Goldstein , M.D. Cornell Institute for Reproductive Medicine , New York Presbyterian Hospital/Weill Cornell Medical Center, Weill Cornell Medical College of Cornell University , New York , NY , USA Túlio M. Graziottin , M.D., Ph.D. Andrology Section of Fertilitat – Human Reproduction Center, Department of Urology , Santa Casa Hospital and Federal University of Health Sciences , Porto Alegre , RS, Brazil Ethan D. Grober , M.D., M.Ed. Department of Surgery, Division of Urology , University of Toronto, Mount Sinai Hospital , Toronto , ON , Canada Sonja Grunewald , M.D. Department of Dermatology, Venerology and Allergology, European Training Center of Andrology , University of Leipzig , Leipzig , Germany Levent Mert Gunay , M.D. Department of Urology , Hacettepe University School of Medicine , Ankara , Turkey Sam Haywood , B.A. Department of Urology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA Ralf Henkel , B.Ed., Ph.D. Department of Medical Biosciences , University of the Western Cape , Bellville , South Africa Wayland Hsiao , M.D. Assistant Professor in Urology, Emory University , Department of Urology , Atlanta , GA , USA Contributors xvii

Tung-Chin Hsieh , M.D. Department of Urology , Baylor College of Medicine , Houston , TX , USA Gabor Huszar , M.D. Sperm Physiology Laboratory , Yale School of Medicine , New Haven, CT , USA Kathleen Hwang , M.D. Department of surgery (Urology) , Brown University, Providence, RI , TX , USA Aleksey P. Ignatov , B.S. The Turek Clinic , San Francisco , CA , USA Kubilay Inci , M.D. Department of Urology , Hacettepe University School of Medicine , Ankara , Turkey Viacheslav Iremashvili , M.D., Ph.D. Department of Urology , University of Miami Miller School of Medicine , Miami , FL , USA Keith Jarvi , M.D. Department of Surgery, Division of Urology , University of Toronto , Mount Sinai Hospital, Toronto , ON , Canada Samuel Juncal , M.S., M.D. Andrology Section of Fertilitat – Human Reproduction Center , Federal University of Health Sciences , Porto Alegre , RS, Brazil John S. Kachimba , M.Med, FCS, FCS(Urol) Department of Surgery , University Teaching Hospital, Levy Mwanawasa General Hospital , Lusaka , Zambia John C. Kefer , M.D., Ph.D. Alpine Urology , Boulder , CO , USA Edward D. Kim , M.D. Division of Urology, Department of Surgery , Center for Reproductive Medicine, University of Tennessee Medical Center , Knoxville , TN , USA Edmund Y. Ko , M.D. Section of Male Infertility, Department of Urology , Glickman Urological and Kidney Institute, Cleveland Clinic , Cleveland , OH , USA Tobias S. Köhler , M.D., M.Ph. Division of Urology , Southern Illinois University , Spring ﬁ eld , IL , USA Rajeev Kumar , M.Ch. Department of Urology , All India Institute of Medical Sciences , New Delhi , India Sandro La Vignera , M.D. Department of Medical and Pediatrics Sciences , University of Catania , Catania , Italy Eric L. Laborde , M.D. Department of Urology , Northwestern University Feinberg School of Medicine , Chicago , IL , USA Dolores J. Lamb , Ph.D. Scott Department of Urology , Baylor College of Medicine , Houston , TX , USA Fanuel Lampiao , Ph.D. Department of Medical Physiology , Faculty of Health Sciences, Stellenbosch University , Tygerberg, Western Cape , South Africa Francesco Lanzafame , M.D. Centro Territoriale de Andrologia , Siracusa , Italy Gian Paolo Littarru , M.D. Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche , Universita Politecnica delle Marche , Ancona , Italy Kirk C. Lo , M.D., C.M. Division of Urology, Department of Surgery , University of Toronto, Mount Sinai Hospital , Toronto , ON , Canada Charles M. Lynne , M.D. Department of Urology , University of Miami Miller School of Medicine , Miami , FL , USA xviii Contributors

Antonio Mancini , M.D. Department of Internal Medicine , Division of Endocrinology, The Catholic University of the Sacred Heart , Rome , Italy Francisco Javier Martin-Romero , Ph.D. Department of Biochemistry and Molecular Biology , School of Life Sciences, University of Extremadura , Badajoz , Spain P. P. Mathur , Ph.D. Department of Biochemistry & Molecular Biology and Center for Bioinformatics, School of Life Sciences, Pondicherry University , Kalapet , Pondicherry , India Marcos Meseguer , Ph.D. Clinical Embryology Laboratory, Instituto Universitario IVI Valencia , Valencia , Spain M. M. Misro , Ph.D. Department of Reproductive Biomedicine , National Institute of Health and Family Welfare , New Delhi , India Ricardo Miyaoka , M.D. ANDROFERT, Andrology & Human Reproduction Clinic, Center for Male Reproduction, Campinas, SP, Brazil Ryan Mori , M.D., M.S. Cleveland Clinic Lerner College of Medicine and Glickman Urological and Kidney Institute , Cleveland clinic Foundation, Cleveland , OH , USA Ray E. Moseley , Ph.D. Department of Community Health and Family Medicine , University of Florida Health Science Center , Gainesville , FL , USA Alexandre Mottrie , M.D., Ph.D. Department of Urology , O.L.V. Clinic Aalst , Aalst , Belgium Craig S. Niederberger , M.D. F.A.C.S. Department of Urology , University of Illinois at Chicago College of Medicine and Department of Bioengineering , University of Illinois at Chicago College of Engineering , Chicago , IL , USA C. J. Opperman , B.Sc. Department of Medical Physiology, Faculty of Health Sciences , Stellenbosch University , Tygerberg , South Africa Uwe Paasch , M.D., Ph.D. Division of Dermatopathology, Division of Aesthetics and Laserdermatology, Department of Dermatology, Venerology and Allergology, European Training Center of Andrology , Univeristy of Leipzig , Leipzig , Germany Sijo J. Parekattil , M.D. Division of Urology, Winter Haven Hospital , University of Florida, Winter Haven, FL , USA Eleonora Pasqualotto , M.D., Ph.D. CONCEPTION—Center for Human Reproduction , Caxias do Sul , RS , Brazil Department of Clinical Medicine, Center of Health Science, University of Caxias do Sul, Caxias do Sul, RS, Brazil Fabio Pasqualotto , M.D., Ph.D. Department of Anatomy and Urology , Institute of Biotechnology, University of Caxias do Sul , Caxias do Sul , RS , Brazil CONCEPTION—Center for Human Reproduction , Caxias do Sul , RS , Brazil Antonio Pellicer , M.D. Department of Gynecology and Obstetrics , School of Medicine, Universidad de Valencia , Assisted Reproduction Unit, Instituto Universitario IVI Valencia, Valencia , Spain Eulalia Pozo-Guisado , Ph.D. Department of Biochemistry and Molecular Biology , School of Life Sciences, University of Extremadura , Badajoz , Spain T. Ramya , M.Sc. Department of Reproductive Biomedicine , National Institute of Health and Family Welfare , New Delhi , India José Remohí , M.D. Department of Gynecology and Obstetrics, School of Medicine, Universidad de Valencia, Assisted Reproduction Unit, Instituto Universitario IVI Valencia, Valencia, Spain Contributors xix

Alice Rhoton-Vlasak , M.D. Department of Obstetrics and Gynecology , Shands Hospital , Gainesville , FL , USA Laura Romany , M.D. Clinical Embryology Laboratory , Instituto Universitario IVI Valencia , Valencia, Spain Henry M. Rosevear , M.D. Department of Urology , University of Iowa , Iowa City , IA , USA Edmund Sabanegh, M.D. Department of Urology , Glickman Urological and Kidney Institute, Center for Reproductive Medicine, Cleveland Clinic , Cleveland , OH , USA Tamer Said , M.D., Ph.D. Andrology Laboratory and Reproductive Tissue Bank , The Toronoto Institute for Reproductive Medicine , Toronto , ON , Canada Jay Sandlow , M.D. Department of Urology , Medical College of Wisconsin , Milwaukee , WI , USA Maria San Gabriel , Ph.D. Division of Urology, Department of Surgery , Royal Victoria Hospital, McGill University , Montreal , QC , Canada Peter Schlegel , M.D. Department of Urology , Weill Cornell Medical College , New York , NY , USA Paul Shin , M.D. Urologic Surgeons of Washington , Washington , DC , USA Tung Shu , M.D. Clinical Assistant Professor of Urology, Baylor College of Medicine , Center for Kidney Health at the Vanguard Urologic Institute , TX , USA Aspinder Singh , B.S. Center for Reproductive Medicine , Glickman Urological and Kidney Institute, Cleveland Clinic Foundation , Cleveland , OH , USA Doron Sol Stember , M.D. Division of Urology, Department of Surgery , Memorial Sloan-Kettering Cancer Center , New York , NY , USA Adam F. Stewart , M.D. Division of Urology, Department of Surgery , University of Tennessee Medical Center , Knoxville , TN , USA Claudio Telöken , M.D., Ph.D. Andrology Section of Fertilitat – Human Reproduction Center, Department of Urology , Santa Casa Hospital and Federal University of Health Sciences , Porto Alegre , RS , Brazil Kelton Tremellen , M.B.B.S. (Hons.), Ph.D., F.R.A.N.Z.C.O.G., C.R.E.I. School of Pharmacy and Medical Sciences , University of South Australia , Dulwich, SA, Australia Paul J. Turek , M.D., F.A.C.S., F.R.S.M. The Turek Clinic , San Francisco , CA , USA S. Vaithinathan , Ph.D. Department of Biochemistry and Molecular Biology , Pondicherry University , Kalapet , Pondicherry , India Alex C. Varghese , Ph.D. Montreal Reproductive Centre , Montreal , QC , Canada Moshe Wald , M.D. Department of Urology , University of Iowa , Iowa City , IA , USA Run Wang , M.D., F.A.C.S. Department of Urology , University of Texas Medical School at Houston and MD Anderson Cancer Center , Houston , TX , USA MD Anderson Cancer Center , Houston , TX , USA Daniel H. Williams IV, M.D. Department of Urology , University of Wisconsin Hospital and Clinics , Madison , WI , USA Herbert J. Wiser , M.D. Division of Urology , Southern Illinois University, Spring ﬁ eld , IL , USA Armand Zini , M.D. Department of Surgery , St. Mary’s Hospital , Montreal , QC , Canada wwwwwwwwwwwww