Male Infertility : Contemporary Clinical Approaches, Andrology, ART and Antioxidants

A groundbreaking contribution to the literature now in its revised and expanded second edition, this textbook offers a comprehensive review of diagnostic and treatment techniques for male infertility. This state-of-the-art, evidence-based textbook incorporates new multidisciplinary and complementary medicine approaches to create a first-of-its-kind guide to treatment strategies for male infertility and beyond. While this new edition is primarily designed as a reference for students and residents in reproductive medicine and andrology, it will be equally useful as well for professionals in urology, reproductive endocrinology, embryology, and research fields who are interested in the role that antioxidants play in male infertility. World-renowned experts in these areas have been selected to participate in this work. Careful selection of the highest quality content will span the whole range of topics in the area of male infertility, providing a complete review of well-established and current diagnostic and treatment techniques for male infertility. The incorporation of 20 new chapters will enhance the book’s appeal by including the most recent advances brought to the male infertility arena. Additionally, this edition incorporates new features, including bulleted key points, review criteria and select video clips demonstrating some of the most fascinating male infertility treatment modalities. A dedicated new section on current guidelines on male infertility will enlighten readers on how to most optimally manage male infertility clinical scenarios. Covering all aspects of diagnosis and management, ART, lifestyle factors and associated conditions for male infertility, Male Infertility: Contemporary Clinical Approaches, Andrology, ART and Antioxidants will be a readily accessible, high quality reference for medical students and residents, and will be of significant value to professionals working in the various fields treating this condition as well. Foreword Preface About the Editors Contents Contributors Part I: Male Infertility Diagnosis and Management 1: Causes of Male Infertility 1.1 Introduction 1.2 Causes of Male Infertility 1.2.1 Pre-testicular 1.2.1.1 Hypogonadotropic Hypogonadism 1.2.1.2 Elevated Prolactin 1.2.1.3 Pharmacologic 1.2.1.4 Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome 1.2.1.5 Testicular Varicocele Cryptorchidism Testicular Cancer 1.2.1.6 Ionizing Radiation 1.2.1.7 Chemotherapy 1.2.1.8 Genetic Azoospermia/Oligospermia 1.2.1.9 Lifestyle Factors 1.2.1.10 Testicular Injury 1.2.1.11 Primary Ciliary Dyskinesia 1.2.1.12 Antisperm Antibodies 1.2.2 Post-testicular 1.2.2.1 Absence of the Vas Deferens 1.2.2.2 Young’s Syndrome 1.2.2.3 EjDO/Seminal Vesicle Dysfunction 1.2.2.4 Nerve Injury 1.2.2.5 Medications 1.2.2.6 Coital 1.3 Conclusion 1.4 Review Criteria References Notable Suggested Readings from the Last 5 Years 2: Epidemiologic Considerations in Male Infertility 2.1 Introduction 2.2 Epidemiology of Infertility 2.2.1 Incidence and Prevalence of Infertility in Developed Countries 2.2.2 Infertility in the Developing World 2.2.3 Reproduction—a Matter of Chance: The Natural History of Infertility 2.3 Diagnostic Accuracy and Utility of Semen Studies 2.3.1 Relationship Between Semen Parameters and Male Infertility 2.3.2 Do Semen Parameters Prospectively Predict Fertility and Assisted Reproductive Technique Outcomes? 2.3.3 Novel Assays for Diagnosis of Male Infertility 2.4 Are Sperm Counts Declining? 2.5 Health-Care Resource Utilization for Male Infertility 2.5.1 Office Visits and Ambulatory Surgery Cases 2.5.2 Assisted Reproductive Technology 2.5.3 Cost of Treatment for Male Infertility 2.6 Cost Analysis Models for Management of Male Infertility 2.7 Conclusion 2.8 Review Criteria References 3: Laboratory Evidence for Male Infertility 3.1 Introduction 3.2 WHO Guidelines for Assessment of Semen Specimen 3.3 Laboratory Evaluation of Male Factor Infertility 3.3.1 Basic Semen Analysis 3.3.1.1 Collection 3.3.1.2 Volume 3.3.1.3 Liquefaction and Viscosity 3.3.1.4 pH [normal > 7.2] 3.3.1.5 Concentration 3.3.1.6 Motility 3.3.1.7 Morphology 3.3.1.8 Agglutination 3.3.1.9 Leukocytospermia 3.4 Retrograde or Post-Ejaculatory Urinalysis (PEUA) 3.5 Reactive Oxygen Species (ROS) Testing 3.6 Acrosome Reaction Testing 3.7 Antisperm Antibody (ASA) Testing 3.8 Sperm Viability Testing 3.9 Advanced Semen Testing 3.9.1 Sperm DNA Fragmentation (SDF) 3.9.2 Sperm Chromatin Structure Assay (SCSA) 3.9.3 Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) 3.9.4 Single-Cell Gel Electrophoresis Assay (Comet) 3.9.5 Sperm Chromatin Dispersion (SCD) 3.9.6 Endocrine Evaluation 3.9.7 Genetic Evaluation 3.9.8 Conclusion 3.10 Review Criteria References 4: Imaging Modalities in the Management of Male Infertility 4.1 Introduction 4.2 Testicular Tissue Imaging for Guided Sperm Retrieval 4.2.1 Doppler Duplex Flow Imaging 4.2.2 MRI Spectral Imaging 4.2.3 Testicular Artery Mapping During Varicocelectomy 4.3 Management of Testicular Lesions in Infertile Patients 4.3.1 Organ-Sparing Microsurgical Resection of Testicular Tumors in Infertile Patients 4.3.2 Testicular Microlithiasis 4.3.3 Seminal Vesicle and Ejaculatory Duct Imaging 4.4 Conclusion 4.5 Review Criteria References 5: Endocrinopathies 5.1 Introduction 5.2 Hormonal Deficiency 5.2.1 Hypogonadotropic Hypogonadism 5.2.2 Hypergonadotropic Hypogonadism 5.2.3 Hypothyroidism 5.3 Hormonal Excess 5.3.1 Androgen Excess 5.3.2 Estrogen Excess 5.3.3 Thyroid Excess 5.3.4 Prolactin Excess 5.4 Conclusion 5.5 Review Criteria References 6: Oxidative Stress and Its Association with Male Infertility 6.1 Introduction 6.2 Biochemistry of Oxidative Stress 6.3 Sources of ROS in Male Reproductive Tract 6.3.1 Endogenous Sources 6.3.1.1 Leukocytes 6.3.1.2 Immature Spermatozoa 6.3.1.3 Infections, Autoimmune/Inflammatory Conditions Genitourinary Tract Infection Systemic Infection Autoimmune/Inflammatory Condition 6.3.1.4 Varicocele and Cryptorchidism 6.3.1.5 Other Chronic Diseases 6.3.2 Exogenous Sources 6.3.2.1 Radiation 6.3.2.2 Lifestyle Factors 6.3.2.3 Toxins 6.4 Physiological Role of ROS 6.4.1 Capacitation 6.4.2 Hyperactivation 6.4.3 Acrosome Reaction 6.4.4 Fertilization 6.5 Mechanisms of ROS-Mediated Male Infertility 6.5.1 Lipid Peroxidation 6.5.2 Sperm DNA Fragmentation 6.5.3 Apoptosis of Spermatozoa 6.6 ROS in Assisted Reproduction 6.7 Measurement of OS 6.7.1 Assessment of Sperm OS from Routine Semen Analysis 6.7.2 Total Antioxidant Capacity (TAC) 6.7.3 Lipid Peroxidation Markers 6.7.4 Seminal Oxidation-Reduction Potential (ORP) 6.7.5 Direct Laboratory Assessments of OS 6.8 Management of OS-Associated Male Infertility 6.8.1 Lifestyle Management Approach 6.8.2 Vitamin and Antioxidant Supplementation 6.8.3 Surgery 6.9 Conclusion 6.10 Review Criteria References 7: Oxidative Stress Measurement in Semen and Seminal Plasma 7.1 Introduction 7.2 Seminal Reactive Oxygen Species and Antioxidants: Physiological and Pathological Roles 7.2.1 Physiological Roles 7.2.2 Pathological ROS and Oxidative Stress 7.2.3 Oxidative Stress and Male Infertility 7.2.4 Types of Samples for Oxidative Stress Measurement 7.2.5 Markers of Oxidative Stress and their Assessment 7.3 Common Methods to Measure Oxidative Stress 7.3.1 Nitroblue Tetrazolium Test 7.3.2 Chemiluminescence Assay 7.3.3 Factors Affecting the ROS Measurement 7.3.4 Measurement of Intracellular ROS 7.3.5 Measurement of DNA Fragmentation 7.3.6 Sperm Chromatin Structure Assay (SCSA) 7.3.7 Terminal Deoxynucleotidyl Transferees dUTP Nick End Labeling (TUNEL) Assay 7.3.8 Epifluorescence Using Acridine Orange Dye 7.3.9 Comet Assay 7.3.10 Sperm Chromatin Dispersion (SCD) Assay 7.4 Measurement of Total Antioxidant Capacity 7.4.1 Colorimetric Analysis 7.4.2 ROS-TAC Score 7.5 Measurement of Lipid Peroxidation 7.5.1 TBARS Assay 7.5.2 4-Hydroxynonenal-Histidine Adduct ELISA Assay 7.5.3 Isprostane (IsoP) Method 7.6 Measurement of ROS-Induced Post-translational Modifications 7.7 Measurement of ROS-Induced Protein Alterations: Proteomic Analysis 7.8 Limitations of Current Oxidative Stress Markers 7.9 What Is Oxidation Reduction Potential? 7.9.1 Measurement of Oxidation Reduction Potential Using MiOXSYS 7.9.2 Protocol to Measure Oxidation Reduction Potential 7.9.3 Value of ORP in Fresh and Frozen Semen Samples and Seminal Plasma 7.9.4 Assessment of Semen Quality and Fertility Status Using Oxidation Reduction Potential 7.9.5 Oxidative Reduction Potential: Establishing Reference Values 7.9.6 Update on Research on Oxidative Reduction Potential: Multicenter Findings 7.9.7 Clinical Utility of Oxidation Reduction Potential in Male Infertility 7.9.8 Oxidation Reduction Potential: A Test Replacement or a Test in Conjunction with Semen Analysis? 7.9.9 Clinical Relevance of Combination of OS Markers and Other Sperm Function Tests 7.10 Future Directions 7.11 Conclusions 7.12 Review Criteria References 8: Sperm Chromatin Integrity Tests and Indications 8.1 Introduction 8.2 Limitation of Semen Analysis 8.3 Sperm DNA Integrity 8.4 Indications and Importance of Sperm DNA Integrity in Male Infertility 8.5 Clinical Relevance of DNA Integrity with ART Outcomes 8.6 Contemporary Sperm Chromatin Integrity Tests 8.6.1 Aniline Blue Staining 8.6.2 Toluidine Blue Staining 8.6.3 CMA 3 Assay 8.6.4 Acridine Orange 8.6.5 Sperm Chromatin Structure Assay 8.6.6 Measurement of 8-Hydroxy-2-Deoxyguanosine (8-OHdG) 8.6.7 Comet Assay 8.6.8 Sperm Chromatin Dispersion Test (Halosperm Assay) 8.6.9 Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) Assay 8.7 Limitations of Current Protocols 8.8 Controversies of Sperm DNA Fragmentation 8.9 Common Laboratory Protocols for Measuring DNA Fragmentation by TUNEL and Flow Cytometry (Direct and Indirect Methods) 8.10 Challenges Using Indirect Assays to Measure DNA Integrity by TUNEL Assay 8.11 Common Direct Methods to Measure DNA Integrity 8.12 Current Challenges in Sperm Chromatin Integrity Tests 8.13 Future Direction 8.14 Conclusion 8.15 Review Criteria References 9: Proteomic and Metabolomic Fingerprinting in Male Infertility 9.1 Introduction 9.2 Proteomics in Male Infertility 9.2.1 General Approach to Proteomics 9.2.2 Assessment of Sperm and Seminal Plasma: Methods and Tools, Analysis, Bioinformatics 9.2.3 Sperm Proteomics 9.2.4 Seminal Plasma Proteomics 9.3 Metabolomics in Male Infertility 9.3.1 General Approach to Metabolomics 9.3.2 Analysis of the Metabolome 9.3.3 Sperm Metabolomics 9.3.4 Seminal Plasma Metabolomics 9.3.5 Urine Metabolomics 9.3.6 Testicular Tissue Metabolomics 9.4 Potential Biomarkers of Male Infertility 9.5 Current Challenges and Future Outlook 9.6 Conclusion 9.7 Review Criteria References 10: Epigenetics and Male Infertility 10.1 Introduction 10.1.1 Definition of Epigenetics 10.1.2 History of Epigenetics 10.2 Epigenetics Mechanisms 10.2.1 DNA Methylation 10.2.2 Chromatin Remodeling 10.2.3 Histone Modification 10.2.4 Non-coding RNA 10.2.5 Genomic Imprinting 10.3 Sperm Epigenetics 10.3.1 Current Technology Used to Evaluate Sperm Epigenetics 10.3.2 Value of Sperm Epigenetics to the Male Infertility Evaluation 10.3.3 Sperm Epigenetic–Fertility Phenotypes 10.3.3.1 Abnormal Semen Analysis 10.3.3.2 Unexplained Infertility 10.3.3.3 Embryo Development and Miscarriage 10.3.4 Sperm Epigenetics and Paternal Age 10.3.5 Lifestyle and Environmental Influences on Sperm Epigenetics 10.3.6 The Hereditability of Sperm Epigenetics 10.4 Conclusion 10.5 Review Criteria References 11: Genetic Aspects of Male Infertility 11.1 Introduction 11.2 Genomic Regulation of Male Sexual Development 11.2.1 Testicular Development 11.2.2 Testicular Descent 11.2.3 Spermatogenesis 11.2.4 Male Genital Tract Development 11.2.5 Male External Genitalia Development 11.3 Genetic Defects Associated with Male Infertility 11.3.1 Numerical and Structural Chromosomal Abnormalities 11.4 Klinefelter Syndrome 11.5 XYY Syndrome 11.6 XX Male Syndrome 11.7 Mixed Gonadal Dysgenesis 11.8 Translocations and Inversions 11.9 Y Chromosome 11.10 AZF Region 11.10.1 AZFa 11.10.2 AZFb 11.10.3 AZFc 11.11 Yq Microdeletions in Clinical Practice 11.12 Other Y Chromosome Conditions 11.13 X Chromosome 11.13.1 Congenital Bilateral Absence of the Vas Deferens (CBAVD) and Cystic Fibrosis 11.13.2 Genes Involved in Meiotic Recombination 11.13.3 Gene Mutations Associated with Sperm Functional Defects 11.13.4 Copy Number Variations (CNVs) 11.14 Mitochondrial Genetics 11.15 Epigenetic Alterations 11.16 Malignancy Risks Associated with Genetic Perturbations in Infertile Men 11.17 Male Genetic Testing in Clinical Practice 11.18 Gene Therapy for Male Infertility 11.19 Conclusion 11.20 Review Criteria References 12: Surgical Treatment for Male Infertility 12.1 Introduction 12.2 Surgical Treatment 12.2.1 Varicocele Repair 12.2.1.1 Indications 12.2.1.2 Preoperative Planning Patient Evaluation 12.2.1.3 Operative Aspects Anesthesia Techniques 12.2.1.4 Postoperative Care Semen Improvement Results Fertility Results 12.2.2 Reconstructive Surgery of the Vas Deferens and Epididymis 12.2.2.1 Indications 12.2.2.2 Preoperative Planning Patient Evaluation 12.2.2.3 Operative Aspects Anesthesia Incision Approaching the Vas Vasal Fluid Examination Vasovasostomy Techniques Vasoepididymostomy Techniques 12.2.2.4 Postoperative Care Results 12.2.3 Transurethral Resection of the Ejaculatory Duct 12.2.3.1 Indications 12.2.3.2 Preoperative Planning Patient Evaluation 12.2.3.3 Operative Aspects Anesthesia Technique 12.2.3.4 Postoperative Care Results 12.3 Conclusions 12.4 Review Criteria References 13: Microsurgery for Male Infertility 13.1 Introduction 13.2 Etiology and Evaluation 13.2.1 Reconstruction Versus Sperm Retrieval and In Vitro Fertilization/Intracytoplasmic Sperm Injection (IVF/ICSI) 13.3 Microsurgical Procedures 13.4 Vaso-epididymal Anastomosis 13.5 Our Surgical Technique 13.6 Outcomes 13.7 Vasovasal Anastomosis 13.8 Our Surgical Technique 13.9 Outcomes 13.10 Microsurgical Varicocelectomy 13.11 Our Surgical Technique 13.12 Outcomes 13.13 Training and Credentials 13.14 Conclusions 13.15 Review Criteria References 14: Advanced Techniques of Vasoepididymostomy 14.1 Introduction 14.2 Vasoepididymostomy 14.3 End-to-End Anastomosis 14.4 End-to-Side Techniques 14.5 Anastomotic Technique 14.6 Original End-to-Side 14.7 End-to-Side Intussusception Technique 14.8 Two-Stitch Longitudinal Vasoepididymostomy (LIVE Technique) 14.9 Techniques When Vasal Length Is Severely Compromised 14.10 Long-Term Follow-Up Evaluation and Results 14.11 Conclusion 14.12 Review Criteria References 15: Grafting Techniques for Vasectomy Reversal 15.1 Introduction 15.2 Grafting Techniques in Reconstruction of the Male Reproductive Tract 15.2.1 Stents 15.2.2 Conduits 15.2.3 Autografts 15.3 Conclusions 15.4 Review Criteria References 16: Mini-incision Vasectomy Reversal Using the No-Scalpel Vasectomy Instruments and Principles 16.1 Introduction 16.2 History 16.3 Vasectomy Reversal Techniques 16.4 Mini-incision Vasectomy Reversal (MIVR) 16.5 Technique of Mini-incision Vasectomy Reversal 16.6 Outcome of Mini-incision Vasectomy Reversal 16.7 Single Mini-incision Vasectomy Reversal (SMIVR) 16.8 Conclusion References 17: Office-Based Microsurgery Under Local Anesthesia for Male Infertility 17.1 Introduction 17.2 Clinical Setup 17.2.1 Procedure Suite 17.2.2 Pain Control 17.3 Technical Description of Procedures 17.3.1 TESE 17.3.2 MESA 17.3.3 Varicocelectomy 17.3.4 Vasectomy Reversal 17.4 Tips and Tricks to Overcoming the Learning Curve 17.5 Financial Considerations 17.6 Conclusions 17.7 Review Criteria References 18: Robotic Microsurgery for Male Infertility and Chronic Orchialgia 18.1 Introduction 18.2 Novel Equipment 18.3 New Robotic Surgical Platform 18.4 Refined Robotic Doppler Flow Probe 18.5 Enhanced Digital Visual Magnification 18.6 Robotic Microsurgical Procedures 18.6.1 Robotic-Assisted Microscopic Vasectomy Reversal 18.6.2 Robotic-Assisted Microscopic Varicocelectomy 18.6.3 Robotic-Assisted Microscopic Denervation of the Spermatic Cord 18.7 Single Port and Abdominal Robotic Microsurgical Neurolysis 18.8 Conclusion 18.9 Review Criteria References 19: Robotic Vasectomy Reversal: An American Perspective 19.1 Introduction 19.2 History of Robotics in Surgery 19.3 Da Vinci® Robotic System 19.4 Technology Hype (Gartner-Palmer Tech Hype Curve) 19.5 Anatomy 19.6 Preoperative Evaluation/Physical Examination 19.7 Preoperative Laboratory Testing 19.8 Anesthesia 19.9 Positioning the Patient and the Robot 19.10 Incision Approaches 19.11 Vas Deferens Preparation 19.12 Technical Aspects of Anastomosis 19.13 The Da Vinci® Robotic Platform to Assist with Microsurgical Vasectomy Reversal 19.14 Robot-Assisted Vasectomy Reversal 19.15 Robot-Assisted Microsurgical Vasovasostomy 19.16 Robot-Assisted Microsurgical Vasoepididymostomy 19.17 Robot-Assisted Microsurgical Vasectomy Reversal Learning Curve 19.18 Future of Evolution of Robot-Assisted Microsurgical Vasectomy Reversal 19.19 Postoperative Care 19.20 Complications 19.21 Conclusions 19.22 Review Criteria References 20: Robot-Assisted Vasectomy Reversal (Vasovasostomy) 20.1 Introduction 20.2 Robot-Assisted Vasectomy Reversal 20.3 Surgical Technique 20.4 Outcome 20.5 Costs 20.6 Conclusion 20.7 Review Criteria References 21: Robotic-Assisted Varicocelectomy 21.1 Introduction 21.2 Materials and Methods 21.3 Results 21.4 Discussion 21.5 Conclusion 21.6 Review Criteria References 22: Management of Fertility Preservation in Male Cancer Patients 22.1 Introduction 22.2 Incidence of Cancer 22.3 Quality of Life Concerns and Reproductive Aspirations in Men with Cancer 22.4 Cancer in Children and Adolescents 22.5 Impact of Cancer Therapies on Male Fertility Potential 22.5.1 Radiation Therapy 22.5.2 Chemotherapy 22.5.3 Surgery 22.5.4 Immunotherapy and Other Modalities 22.6 Fertility Preservation Counseling for Men, Couples, or Family 22.7 Sperm Parameters and Semen Quality in Men with Cancer 22.8 Semen Collection for Male Cancer Patients 22.9 Techniques for Sperm Cryopreservation 22.9.1 Sperm Preparation Prior to Cryopreservation 22.9.2 Slow Freezing 22.10 Rapid Freezing 22.11 Sperm Vitrification 22.12 Options for Home Banking: An Innovation-Based Approach 22.13 Cryopreservation of Epididymal or Testicular Tissue: Indications and Techniques 22.14 Fertility Preservation in Prepubertal Boys: Experimental Techniques with IRB Guidelines 22.15 Sperm Quality After Cryopreservation 22.16 Procedure for Post-thaw Sperm Preparation 22.17 Number of Ejaculates Stored Prior to Use of Cryopreserved Sperm 22.18 ART Outcomes in Cryopreserved Sperm 22.19 Utilization of Cryopreserved Samples 22.20 Challenges, Barriers, and Safety Issues of Sperm Cryopreservation 22.21 Factors Preventing Individuals from Banking 22.22 Counseling and Ethical Considerations 22.23 Cost-Effectiveness of Fertility Preservation in the ART Era 22.24 Future Research Strategies 22.25 Conclusion 22.26 Review Criteria References 23: Clinical Management of Men with Nonobstructive Azoospermia due to Spermatogenic Failure 23.1 Introduction 23.2 Step 1: Confirm the Diagnosis of NOA due to Spermatogenic Failure 23.2.1 Semen Analysis 23.2.2 Medical History 23.2.3 Physical Examination 23.2.4 Endocrine Profile 23.2.5 Hypogonadotropic Hypogonadism 23.2.6 Testis Biopsy 23.3 Step 2: Define Who Are Possible Candidates for Sperm Retrieval 23.4 Step 3: Define Who Can Benefit from Interventions Before Sperm Retrieval 23.4.1 Medical Therapy 23.4.2 Varicocele Repair 23.5 Step 4: Use the Optimal Method for Harvesting Testicular Sperm 23.6 Step 5: Laboratory Handling of Testicular Sperm 23.7 Outcomes of ICSI 23.8 Complete Aspermatogenesis 23.9 Conclusions 23.10 Review Criteria References 24: Novel Approaches in the Management of Klinefelter Syndrome 24.1 Introduction 24.2 Genetic Background 24.3 Endocrine Function and Spermatogenesis in KS 24.4 Clinical Manifestations 24.5 Diagnosis 24.6 Management 24.6.1 Managing Hypogonadism 24.6.1.1 In Adolescents and Adults 24.6.2 Fertility Management 24.6.2.1 Peripubertal KS Boys 24.6.2.2 Cryopreservation in Adolescents 24.6.2.3 Adult KS Men 24.7 Genetics Risks to Offspring 24.8 Conclusion 24.9 Review Criteria References 25: Assisted Reproductive Technology and Its Impact on Male Infertility Management 25.1 Introduction 25.2 Male Infertility Workup and the Role of Urologists 25.3 Multidisciplinary Clinical Care 25.4 The Techniques and Impact of the ART Laboratory on Male Infertility 25.5 Oxidative Burden and the Use of Antioxidants 25.6 Use of Antioxidant Additives During Fertilization and Embryo Culture 25.7 Selection of Sperm 25.7.1 Centrifugation 25.7.2 Swim-Up 25.7.3 Electrophoresis 25.7.4 Magnetic-Activated Cell Sorting 25.7.5 Microfluidics 25.8 Further Selection for ICSI 25.8.1 Sperm-Hyaluronic Acid Binding 25.8.2 High-Magnification Sperm Selection ICSI 25.9 Additional Sperm Processing 25.9.1 Culture and Supplementation 25.9.2 Cryopreservation 25.10 Use of Testicular Sperm 25.11 Stem Cells 25.12 Conclusions 25.13 Review Criteria References Further Reading Part II: Sperm Physiology and Metabolism 26: Fuel/Energy Sources of Spermatozoa 26.1 Introduction 26.2 Functional Ultrastructure of Sperm: Fuel Machineries 26.2.1 Flagellar Ultrastructure 26.2.2 Spermatozoa ATPases 26.2.3 Unique Properties of Sperm Glycolytic Enzymes 26.2.4 Seminal Plasma Components 26.3 Energy Production in Spermatozoa 26.3.1 ATP Production via Oxidative Phosphorylation 26.3.2 ATP Production via Glycolysis 26.3.3 Metabolic Coordination of Sertoli Cells and Germ Cells in Spermatogenesis 26.4 Energy Utilization by Spermatozoa 26.4.1 Sperm Motility and Flagellar Movements 26.4.2 Sperm Capacitation, Hyperactivation, and Acrosome Reaction 26.5 Consequences of Fuel Depletion in Sperm Functions 26.6 Knowing the Energy Sources of Spermatozoa Contributes Toward Improving: 26.6.1 Handling of Gametes In Vitro: Cryopreservation 26.6.2 Handling of Gametes In Vitro: Ambient Temperature Storage 26.6.3 Non-hormonal Male Contraception 26.7 Conclusion 26.8 Review Criteria References 27: Physiological Role of ROS in Sperm Function 27.1 Introduction 27.2 Reactive Oxygen Species 27.3 Origins of ROS in Male Reproductive Tissues 27.4 Endogenous Sources of ROS in Seminal Plasma 27.4.1 Leukocytes 27.4.2 Immature Spermatozoa 27.4.3 Sertoli Cells 27.4.4 Varicocele 27.5 Exogenous Sources of ROS in Seminal Plasma 27.5.1 Radiation 27.5.2 Lifestyle Factors 27.5.3 Toxins 27.6 Physiological Role of ROS on Different Sperm Functions 27.6.1 Sperm Transformational Stages 27.6.2 Maturation 27.6.3 ROS as Signal Transducers 27.6.4 Motility and Hyperactivation 27.6.5 Capacitation 27.6.6 Acrosome Reaction 27.6.7 Sperm-Oocyte Fusion 27.7 Conclusion 27.8 Review Criteria References 28: Sperm Physiology and Assessment of Spermatogenesis Kinetics In Vivo 28.1 Introduction 28.2 The Testis: Structure and Function 28.2.1 Seminiferous Tubules 28.2.2 Sertoli Cells 28.2.3 Hemato-testicular Barrier 28.2.4 Peritubular Microenvironment 28.2.5 Steroidogenesis 28.2.6 Spermatogenesis 28.2.7 Spermiogenesis and Spermiation 28.3 The Epididymis: Structure and Function 28.3.1 Sperm Maturation 28.3.2 Sperm Transport 28.4 Sperm Function 28.4.1 Hyperactivation 28.4.2 Capacitation 28.4.3 Acrosome Reaction 28.4.4 Sperm-Zona Pellucida Binding and Penetration 28.4.5 Chromatin Condensation/Decondensation and DNA Integrity 28.5 Assessment of Spermatogenesis Kinetics In Vivo 28.5.1 The Past 28.5.2 The Present 28.6 Conclusions 28.7 Review Criteria References 29: Origins of Sperm DNA Damage 29.1 Introduction 29.2 What Is Deoxyribonucleic Acid Damage? 29.3 Spermatogenesis and Chromatin Packaging 29.4 Mechanisms of DNA Damage 29.4.1 Reactive Oxygen Species 29.4.2 Sperm Chromatin Packaging 29.4.3 Apoptosis 29.5 Etiological Factors of DNA Damage 29.5.1 Varicocele and Increased Testicular Heat 29.5.2 Genital Tract Infection and Inflammation 29.5.3 Poor Nutritional Intake 29.5.4 Obesity and Metabolic Syndrome 29.5.5 Diabetes Mellitus 29.5.6 Alcohol and Tobacco 29.5.7 Cancer and Chemotherapy 29.5.8 Pollution and Environmental Toxins 29.5.9 Medications and Recreational Drugs 29.5.10 Aging 29.6 Conclusion 29.7 Review Criteria References 30: Seminal Oxidation-Reduction Potential 30.1 Introduction 30.2 Oxidative Stress 30.3 The MiOXSYS System 30.4 Oxidation-Reduction Potential and Male Infertility 30.4.1 Semen Quality and Oxidation-Reduction Potential 30.4.2 Determining a Cutoff to Diagnose Infertile Men 30.4.3 Global Validation 30.4.4 Oxidation-Reduction Potential and In Vitro Fertilization 30.5 Five-Year Outlook 30.6 Conclusion 30.7 Review Criteria References Part III: Common Conditions and Factors Affecting Male Reproductive Health 31: Varicocele 31.1 Introduction 31.2 Epidemiology 31.3 Pathophysiology 31.4 Infertility 31.5 Diagnosis 31.6 Treatment 31.7 Subclinical Varicocele 31.8 Azoospermia 31.9 Hypogonadism 31.10 Oxidative Stress Markers 31.11 Varicocelectomy, ICSI, or Both? 31.12 Future Diagnostic Approach 31.13 Conclusions 31.14 Review Criteria References 32: Infection in Infertility 32.1 Introduction 32.2 Pathogens Causing Male Genital Tract Infections 32.3 Chlamydia trachomatis 32.4 Mycoplasms 32.5 Ureaplasma urealyticum, U. parvum 32.6 Mycoplasma hominis, M. genitalium 32.7 Neisseria gonorrhoeae 32.8 Escherichia coli 32.9 Viruses 32.10 Protozoa 32.11 Treponema pallidum 32.12 Trypanosoma spp. 32.13 Schistosoma spp. 32.14 Male Genital Tract Infections 32.14.1 Orchitis 32.14.2 Epididymitis 32.14.3 Prostatitis 32.14.4 Urethritis 32.15 Male Accessory Gland Infection 32.16 Consequences of Infections on Sperm Fertilizing Capacity 32.17 Treatment of Infections 32.18 Conclusion 32.19 Review Criteria References 33: Ejaculatory Dysfunction and Vasodynamics 33.1 Introduction 33.2 Physiology of Ejaculation 33.2.1 The Events 33.2.2 Neural Control 33.2.3 Definitions 33.3 Evaluation 33.3.1 History 33.3.2 Physical Examination 33.3.3 Laboratory Evaluation 33.3.4 Genetic Testing 33.4 Management of Ejaculatory Disorders 33.4.1 Anatomic 33.4.1.1 Bladder Neck Incompetence 33.4.1.2 Müllerian Duct Cyst 33.4.1.3 Congenital Bilateral Absence of the Vas Deferens/Cystic Fibrosis 33.4.1.4 Ejaculatory Duct Obstruction 33.4.2 Neuropathic 33.4.2.1 Spinal Cord Injury 33.4.2.2 Diabetes Mellitus 33.4.2.3 Postsurgical 33.4.2.4 Neurologic Disorders 33.4.3 Pharmacologic 33.4.3.1 Antidepressants 33.4.3.2 Alpha-Adrenergic Antagonists 33.4.3.3 Finasteride 33.4.4 Functional 33.4.4.1 Premature or Early Ejaculation 33.4.4.2 Delayed Ejaculation 33.4.4.3 Seminal Megavesicles 33.4.4.4 Retrograde Ejaculation 33.4.4.5 Anejaculation 33.5 Conclusion 33.6 Review Criteria References 34: Environmental Factors 34.1 Introduction 34.2 Metals 34.2.1 Arsenic (As) (Metalloid) 34.2.2 Cadmium (Cd) 34.2.3 Lead (Pb) 34.2.4 Mercury (Hg) 34.2.5 Chromium 34.2.6 Copper 34.3 Endocrine-Disrupting Chemicals (EDCs) 34.4 Environmental Estrogens (Xenoestrogens) 34.5 Pesticides 34.5.1 Atrazine 34.5.2 Carbaryl 34.5.3 Chlordecone (Kepone) 34.5.4 Dioxins 34.5.5 Ethylene Dibromide 34.5.6 Polychlorinated Biphenyls 34.5.7 Vinclozolin 34.6 Synthetic and Industrial Chemical Pollutants 34.6.1 Benzene 34.6.2 Carbon Disulfide 34.6.3 Glycol Ether 34.6.4 Methoxychlor 34.6.5 Phthalates 34.6.6 Bisphenol A 34.7 Radiation 34.7.1 Ionizing Radiation 34.7.1.1 Ultraviolet Radiation 34.7.1.2 X-Rays and Gamma Rays 34.7.2 Nonionizing Radiation 34.7.2.1 Cell Phone Signals, 3G, Wi-Fi, and Microwave 34.8 Tobacco 34.9 Air Pollution 34.10 Conclusion 34.11 Review Criteria References 35: Effect of Exogenous Medications and Anabolic Steroids on Male Reproductive and Sexual Health 35.1 Introduction 35.2 5α-Reductase Inhibitors 35.3 α-Blockers 35.4 Phosphodiesterase 5 Inhibitors 35.5 Psychotropic Medications 35.6 Anti-hypertensive Agents 35.7 Anti-infection Medications 35.8 Anti-inflammatories and Salicylates 35.9 Opioids and Analgesics 35.10 Gastrointestinal Medications 35.11 Dermatological Medications 35.12 Antigout Agents 35.13 Anti-cancer Medications 35.13.1 Chemotherapeutic Agents 35.13.2 Targeted Therapies 35.14 Androgenic Anabolic Steroids 35.14.1 Background 35.15 Anabolism Versus Androgenism 35.16 Anabolic Steroids: Beyond Testosterone 35.16.1 Oral AAS Preparations, or 17α-Alkylated Steroids 35.16.2 Parenteral AAS Preparations or 17β-Esterified Steroids 35.16.3 Side-Effects 35.16.4 Anabolic Steroids Impact on Male Fertility 35.16.4.1 The Classic Reversible AAS-Induced Hypogonadotrophic Hypogonadism 35.16.4.2 Permanent Testicular Damage Histopathlogy Impact on Semen Quality Apoptosis Aneuploidies and Ultrastructural Changes in Spermatozoa 35.16.5 Management Strategies 35.17 Conclusions, Management Policy and Authors’ Recommendations 35.18 Review Criteria References 36: Male Age and Andropause 36.1 Introduction 36.2 Aging 36.2.1 Cellular Changes 36.2.2 Semen Analysis 36.2.3 Assisted Reproductive Technology 36.3 Effects of Aging on Genes of Offspring 36.4 Effects of Aging on Offspring Syndromes 36.5 Effects of Aging on Androgen Levels 36.6 Systemic Effects of Decreased Androgens 36.7 Conclusion 36.8 Review Criteria References 37: Apoptosis and Male Infertility 37.1 Introduction 37.2 Physiological Role of Apoptosis in Male Reproduction 37.3 Extrinsic Pathway 37.4 Intrinsic Pathway 37.5 Fas/FasL 37.6 Caspase and Calpain Families 37.7 Cytochrome c 37.8 Nuclear Factor Kappa B 37.9 Spermatogenesis 37.10 Steroidogenesis 37.11 Effect of Environmental Contaminants 37.12 Oxidative Stress 37.13 Mechanisms Involved in Inducing Apoptosis 37.14 Conclusion 37.15 Review Criteria References 38: Impact of Spinal Cord Injury 38.1 Introduction 38.2 Semen Abnormalities in Men with Spinal Cord Injury 38.3 Role of Hormonal Alterations 38.4 Role of Scrotal Temperature 38.5 Role of Bladder Management 38.6 Role of Ejaculation Frequency 38.7 Studies of Oxidative Stress in Men with Spinal Cord Injury 38.8 Reactive Oxygen Species in Whole Semen Versus Washed Sperm 38.9 Reactive Oxygen Species and Sperm Characteristics 38.10 Effect of Leukocytes 38.11 Effect of Cytokines 38.12 The Inflammasome 38.13 Pannexin-1 38.14 Consequences of Oxidative Stress in Semen of Men with Spinal Cord Injury 38.15 Conclusions 38.16 Review Criteria References 39: Obesity 39.1 Introduction 39.2 Obesity: Metabolic Syndrome and Male Infertility 39.3 Obesity and Semen Quality 39.4 Altered Spermatogenesis in Obese Men 39.5 Obesity and Sperm DNA Integrity 39.6 Obesity and Hormones 39.6.1 Hypothalamic–Pituitary–Gonadal Axis (HPG) and Sex Hormones 39.6.2 Adipose Tissue and Metabolic Hormones 39.7 Obesity-Induced Genetic and Epigenetic Modifications 39.8 Obesity-Related Disorders and Male Infertility 39.8.1 Increased Scrotal Temperature 39.8.2 Erectile Dysfunction 39.8.3 Oxidative Stress 39.8.4 Sleep Apnea 39.9 Consequences of Male Obesity on ART Outcomes 39.9.1 Obesity and Pregnancy Onset from ART 39.9.2 Obesity and Pregnancy Outcome After ART 39.9.3 Paternal Obesity and Infant Development Following ART 39.10 Management of Obesity-Induced Male Infertility 39.10.1 Lifestyle Modifications 39.10.2 Prescription Medicine 39.10.3 Surgical Interventions 39.11 Conclusion 39.12 Review Criteria References 40: Smoking Effects on Male Fertility 40.1 Introduction 40.2 Overview of Smoking 40.3 Overview of Male Reproductive Physiology 40.3.1 Hormonal Due to the success of the first edition of this book in 2012, we decided to work on the secondedition in 2018 with the goal to bring out a medical textbook that can serve as the most reliablesource of accurate information on various aspects of the rapidly developing field of male infertility.This book was an attempt to gather experts from each of these fields and present an integratedmanagement approach with detailed descriptions of topics ranging from the initialclinical diagnosis, management, new treatment options, and scientific rational for the variousapproaches. The book initially focuses on the clinical aspects of male infertility and then divesinto the use of antioxidants as adjunctive therapy and the current state of affairs in antioxidantresearch. In this second edition, which includes 72 chapters in total across 7 parts, over 20 newchapters were added to enhance the book’s appeal by including the most recent advancesbrought to the male infertility arena. Additionally, this edition has new features including videoclips illustrating some of the most fascinating male infertility treatment modalities and a dedicatednew part on current guidelines on male infertility and antioxidants to enlighten readers onhow to most optimally manage male infertility clinical scenarios. The 129 contributing authorshail from leading institutions in 18 countries across 6 continents in an attempt to capture a widerange of techniques and approaches. New to this edition are dedicated sections within eachchapter covering key points and review criteria, carefully bookended by introductory and concludingcontent that sets the stage for and sums up the state of the art in male infertility. We arehoping that this text may serve as a reference guide for specialists across the male infertilityteam to further enhance dialogue, discussion, and refinement in our multidisciplinary approach.