Unexplained Infertility Glenn L. Schattman • Sandro C. Esteves Ashok Agarwal Editors Unexplained Infertility Pathophysiology, Evaluation and Treatment Editors Glenn L. Schattman Ashok Agarwal Ronald O. Perelman and Claudia Cohen Center Lerner College of Medicine for Reproductive Medicine Case Western Reserve University Weill Cornell Medical College Andrology Center & New York, NY, USA Center for Reproductive Medicine Cleveland Clinic Sandro C. Esteves Cleveland, OH, USA ANDROFERT, Andrology and Human Reproduction Clinic Referral Center for Male Reproduction Campinas, São Paulo, Brazil ISBN 978-1-4939-2139-3 ISBN 978-1-4939-2140-9 (eBook) DOI 10.1007/978-1-4939-2140-9 Library of Congress Control Number: 2014955347 Springer New York Heidelberg Dordrecht London © Springer Science+Business Media, LLC 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface Infertility, or involuntary childlessness, is customarily defined as the failure of a couple to conceive after 12 months of unprotected regular intercourse. It has been estimated that 10–15 % of couples seek medical assistance for fertility evaluation, and the problem is apparently equally shared be- tween male and female partners. However, after extensive evaluation of both partners by routinely used tests and without physical or endocrine abnormalities, up to 30 % of infertile couples remain childless devoid of identifiable causes—leading to a diagnosis of unexplained infertility. Potential etiologies of unexplained infertility include couples’ miscomprehension of the concept of the female fertile window, improper coital techniques, erectile dysfunction, and molecular and functional causes of male and female infertility. Interestingly, contemporary advanced technologies have demonstrated various ultrastructural, molecular and genetic etiol- ogies in male or female partners with unexplained infertility. Men with unexplained infertility typically have normal semen parameters with no demonstrable abnormalities in their history, physical or endocrinological examination. Possible underlying causes of unexplained male infertility include mainly immune, humoral or cellular sensitization against sperm, genetic defects, sperm dysfunction and fertilization incompetence. Even more interestingly, highly intricate testing methods provide a great deal of informa- tion about the potential contribution of female factors in UI. Cervical hostility, endometrial receptivity problems, fallopian tube dysfunction and oocyte quality may all weaken female fertility potential. Further, immunity against sperm, genetic causes, oxidative stress and subtle foci of endometriosis are some of the conditions that need to be evaluated in a patient with unexplained infertility, in order to understand the underlying cause(s) of unexplained infertil- ity. These conditions may serve as a guide in any future research plans to solve the infertility dilemma. This book introduces unexplained infertility, its definition and incidence in both males and females. The current use of the 2010 WHO guidelines in semen analysis has an impact on the diagnosis of unexplained infertility. The pathophysiological factors of this type of infertility include physical, immunological and genetic abnormalities. Factors that cause the develop- ment of oxidative stress and a variety of environmental factors have a role in the etiology of unexplained infertility. The management of unexplained infertility is complex, as its diagnosis was likely made by exclusion of various potential causes of infertility. Unexplained infertility may be managed through medications that may help normalize the endocrine profile or soothe immunological imbalances. Active interventions and the outcomes of each treatment modality are also considered. Couples dealing with a diagnosis of either male or female factor unex- plained infertility very often resort to assisted reproductive technology to achieve conception, and the outcomes of these interventions will be discussed. This textbook, the first of its kind, is intended to provide the reader with a thoughtful and comprehensive review of the clinical and scientific significance of unexplained infertility. We had invited leading, internationally recognized clinicians and basic scientists with exper- tise in male and female infertility to contribute their thoughts on these various aspects of v vi Preface unexplained infertility. The experts from the various sub-specialties have contributed for this textbook. This book puts together information that serves as an invaluable tool both for the basic scientists with an interest in reproductive medicine and for clinicians working in the field of infertility (e.g., urologists, andrologists, gynaecologists and reproductive endocrinologists and embryologists). It is hoped that the topics discussed in this book serves to enlighten the readers regarding unexplained infertility and provide an in-depth perspective of this form of infertility. Glenn L. Schattman Sandro C. Esteves Ashok Agarwal Contents Part I Definitions and Epidemiology 1 Definitions and Relevance of Unexplained Infertility in Reproductive Medicine ............................................................................................... 3 Sandro C. Esteves, Glenn L. Schattman and Ashok Agarwal 2 Definitions and Epidemiology of Unexplained Male Infertility .............................. 7 Ahmet Gudeloglu, Jamin Brahmbhatt and Sijo Parekattil 3 Controversies Surrounding the 2010 World Health Organization Cutoff Values for Human Semen Characteristics and Its Impact on Unexplained Infertility .......................................................................................... 13 Sandro C. Esteves 4 Definitions and Epidemiology of Unexplained Female Infertility .......................... 21 Luciano G. Nardo and Spyridon Chouliaras Part II Pathophysiology: Male 5 Sperm Biology from Production to Ejaculation ....................................................... 29 Damayanthi Durairajanayagam, Anil K. Rengan, Rakesh K. Sharma and Ashok Agarwal 6 Idiopathic Infertility: Survival and Function of Sperm in the Female Reproductive Tract ............................................................................. 43 Michelle van der Linde and Stefan S. du Plessis 7 Potential Male Etiologies of Unexplained Infertility ............................................... 53 Brent M. Hardin and Edward D. Kim 8 Genetic Basis of Unexplained Male Infertility ......................................................... 57 Ricardo Miyaoka and Sandro C. Esteves 9 Role of the Immune System in Unexplained Male Infertility ................................. 71 Rajesh K. Naz and Walter K. H. Krause 10 Oxidative Stress in Unexplained Male Infertility..................................................... 81 Sejal B. Doshi, Rakesh K. Sharma and Ashok Agarwal vii viii Contents 11 Role and Significance of Sperm Function in Men with Unexplained Infertility................................................................................................ 91 Sandro C. Esteves, Sidney Verza Jr., Rakesh K. Sharma, Jaime Gosálvez and Ashok Agarwal 12 R ole of Environmental Factors and Gonadotoxin Exposure in Unexplained Male Infertility ...................................................................................... 121 Pieter Johann Maartens, Yapo Guillaume Aboua and Stefan S. Plessis Part III Pathophysiology: Female 13 Potential Etiologies of Unexplained Infertility in Females ...................................... 141 Daniela Galliano and Antonio Pellicer 14 Oxidative Stress in Unexplained Female Infertility ................................................. 149 Fatma Ferda Verit 15 Role of Environmental Factors and Gonadotoxin Exposure in Unexplained Female Infertility .................................................................................. 161 Victor Y. Fujimoto and Michael S. Bloom 16 Cervical Hostility and Vaginal pH in Females with Unexplained Infertility ......... 175 Fabiana Y. Nakano, Rogério B. F. Leão and Sandro C. Esteves 17 Role of Endometrial Receptivity in Unexplained Infertility ................................... 185 Alfredo Guillén Antón and Juan Antonio García Velasco 18 Fallopian Tube Dysfunction in Unexplained Infertility ........................................... 193 Thalia R. Segal and Avner Hershlag 19 Subtle Endometriosis and Unexplained Infertility .................................................. 203 Paula Andrea de Albuquerque de Salles Navarro, Anderson Sanches de Melo and Rui Alberto Ferriani Part IV Evaluation 20 Evaluation of Women with Unexplained Infertility ................................................. 213 Richard P. Dickey 21 Evaluation of Men with Unexplained Infertility ...................................................... 223 Marcello Cocuzza and Bruno Camargo Tiseo Part V Expectant, Medical and Surgical Treatment 22 T he Role of Expectant Management for Couples with Unexplained Infertility ....................................................................................... 241 N. M. van den Boogaard, Fulco van der Veen and Ben Willem Mol 23 Treatment and Prognosis of Immunological Factors in Unexplained Male Infertility ...................................................................................... 245 Darius Paduch and Ali A. Dabaja Contents ix 24 Medication Strategies for the Male with Unexplained Infertility 255 Christopher L Starks and Edmund S Sabanegh 25 Clomiphene Citrate for Women with Unexplained Infertility  261 Richard P Dickey 26 Aromatase Inhibitors in the Treatment of Unexplained Female Infertility  273 Lucky H Sekhon, Patricia Rekawek and Lawrence Grunfeld 27 Gonadotropins for Women with Unexplained Infertility  283 Anupa Nandi and Roy Homburg Part VI Assisted Reproductive Techniques and Future Perspectives 28 Gonadotropin in Assisted Reproduction: An Evolution Perspective 293 Rogério B F Leão and Sandro C Esteves 29 Intrauterine Insemination in Unexplained Female Infertility  323 Paolo Emanuele Levi Setti, Irene Zerbetto, Alberto Vaiarelli, Marcello Desgro and Pasquale Patrizio 30 Role of In Vitro Fertilization in Unexplained Female Infertility  329 Hassan Sallam, Fathy Ezzeldin and Nooman Sallam 31 Role of Assisted Reproduction Techniques in the Management of Unexplained Male Infertility  335 Bhushan K Gangrade, Zamip Patel and Sejal Dharia Patel 32 Future Perspectives in the Diagnosis and Management of Unexplained Male Infertility  347 Avinash Maganty, Ranjith Ramasamy and Peter N Schlegel Erratum  E1 Index  355 Contributors Yapo Guillaume Aboua Division of Medical Physiology, Department of Biomedical Sci- ences, Stellenbosch University, Cape Town, South Africa Ashok Agarwal Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA Alfredo Guillén Antón Department of Reproductive Medicine IVI Madrid, Rey Juan Carlos University, Madrid, Spain Michael S. Bloom Environmental Health Sciences and Epidemiology and Biostatistics University at Albany, State University of New York School of Public Health, Rm. #157, One University Place, Rensselaer, NY 12144 Jamin Brahmbhatt Department of Urology, University of Florida & Winter Haven Hospital, Winter Haven, FL, USA Spyridon Chouliaras Reproductive Medicine and Gynecology, Gynehealth, Manchester, UK Marcello Cocuzza Department of Urology, University of Sao Paulo (USP), Sao Paulo, SP, Brazil Ali A. Dabaja Department of Urology, Weill Cornell Medical College, New York-Presbyte- rian Hospital, New York, NY, USA Anderson Sanches de Melo Department of Obstetrics and Gynecology, University of São Paulo, Ribeirão Preto, São Paulo, Brazil Marcello Desgro Department of Gynecology and Division of Gynecology and Reproductive Medicine, IRCCS Istituto Clinico Humanitas, Rozzano (Milano), Italy Richard P Dickey The Fertility Institute, Mandeville, LA, USA Sejal B. Doshi Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA Stefan S. du Plessis Division of Medical Physiology, Department of Biomedical Sciences, Stellenbosch University, Parow, Western Cape, South Africa Damayanthi Durairajanayagam Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, USA Sandro C. Esteves ANDROFERT, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Campinas, Sao Paulo, Brazil Fathy Ezzeldin Department of Obstetrics and Gynaecology, Alexandria University, Alexan- dria, Egypt Rogério de Barros Ferreira Leão ANDROFERT, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Campinas, SP, Brazil xi