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

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 Axis
			40.3.2	 Normal Reproductive Pathway
			40.3.3	 Spermatogenesis
			40.3.4	 Erectile Physiology
		40.4	 Male Infertility
			40.4.1	 Factors Affecting Male Fertility
			40.4.2	 Testicular Factors
			40.4.3	 Genetic Contribution
			40.4.4	 Immune
		40.5	 Effects of Smoking on Male Fertility
			40.5.1	 Adverse Effects on General Homeostasis
			40.5.2	 Adverse Effects on Male Reproductive System as a Whole
			40.5.3	 Mechanism of Smoking Effects on Male Fertility
			40.5.4	 Risks to Spermatogenesis and Sperm Function
			40.5.5	 Sperm Morphology
			40.5.6	 Motility
			40.5.7	 Sperm Concentration and Volume
		40.6	 Impairment of Genetic Environment
			40.6.1	 Gene Methylation
			40.6.2	 DNA Damage
		40.7	 Male Fertility Rescue
			40.7.1	 Does Cessation of Smoking Increase Male Fecundity?
		40.8	 Conclusions
		40.9	 Review Criteria
		References
	41: Recreational Drugs
		41.1	 Introduction
		41.2	 Cigarette Smoking
		41.3	 Alcohol
		41.4	 Marijuana (Cannabis)
		41.5	 Opioids
		41.6	 Cocaine
		41.7	 Methamphetamine and Ecstasy
		41.8	 Conclusion
		41.9	 Review Criteria
		References
Part IV: Nutrition, Life-Style and Antioxidants Role for Male Reproductive Health
	42: Nutritional Pathways to Protect Male Reproductive Health
		42.1	 Introduction
		42.2	 Nutrients and Male Reproductive Health
			42.2.1	 Arginine
			42.2.2	 Zinc
			42.2.3	 Selenium
			42.2.4	 Vitamin C
			42.2.5	 Vitamin E
			42.2.6	 l-Carnitine
		42.3	 Factors Contributing to Subfertility
			42.3.1	 Obesity
			42.3.2	 Alcohol
		42.4	 Conclusion
		42.5	 Review Criteria
		References
	43: Antioxidants and Male Infertility
		43.1	 Introduction
		43.2	 The Role of Reactive Oxygen Species
			43.2.1	 Nonenzymatic Systems
				43.2.1.1	 Carnitine
				43.2.1.2	 Coenzyme Q10
			43.2.2	 Vitamin E
			43.2.3	 Vitamin C
			43.2.4	 Zinc
			43.2.5	 Myo-inositol
			43.2.6	 Herbal Remedy
		43.3	 Perspectives
		43.4	 Conclusion
		43.5	 Review Criteria
		References
	44: Synthetic Antioxidants
		44.1	 Introduction
		44.2	 Synthetic Antioxidants
		44.3	 Reactive Oxygen Species and Antioxidants
		44.4	 Oxidative Damage to Sperm Cells
		44.5	 Synthetic Antioxidants
		44.6	 Mechanisms of Action
			44.6.1	 Vitamin E
			44.6.2	 Vitamin A
			44.6.3	 Vitamin C
		44.7	 Safety, Dosing, and Side Effects of Toxicity
			44.7.1	 Vitamin E
			44.7.2	 Vitamin A
			44.7.3	 Vitamin C: No Updated Data on Toxicity of Vitamin C
		44.8	 Management of Oxidative Stress in Male Infertility
			44.8.1	 Vitamin/Antioxidant Supplementation
		44.9	 Conclusion
		44.10	 Review Criteria
		References
	45: New Developments for the Enhancement of Male Reproductive Health Using Antioxidant Therapy: A Critical Review of the Literature
		45.1	 Introduction
		45.2	 “Taming the Flames”: A Holistic Path to Preventing Sperm Oxidative Stress
		45.3	 Antioxidant Therapy for the Treatment of Male Infertility
		45.4	 Vitamin E
		45.5	 Vitamin C
		45.6	 Combined Vitamin C and Vitamin E Therapy
		45.7	 Coenzyme Q10
		45.8	 Selenium
		45.9	 Glutathione
		45.10	 L-Carnitine
		45.11	 N-Acetyl Cysteine
		45.12	 Miscellaneous Antioxidant Monotherapies
		45.13	 Combination Therapies
		45.14	 Therapies to Reduce Production of ROS Within the Male Reproductive Tract
			45.14.1 Accurately Identify the Presence of Leukocytes in Semen
			45.14.2 Treat Infectious Causes of Leukospermia
			45.14.3 General Anti-inflammatory Agents in the Absence of Active Infection
			45.14.4 Symbiotics: A New Potential Therapy for Male Oxidative Stress
		45.15	 Therapies That Fortify Sperm Against ROS Damage
		45.16	 Conclusion
		45.17	 Review Criteria
		References
	46: In Vitro Studies of Antioxidants for Male Reproductive Health
		46.1	 Introduction
		46.2	 ROS and Male Infertility
		46.3	 Semen Antioxidants and Sperm Function
		46.4	 In Vitro Antioxidants in Male Infertility
		46.5	 Role of In Vitro Antioxidants in Protecting Spermatozoa from Exogenous ROS
		46.6	 Role of In Vitro Antioxidants in Protecting Spermatozoa from Endogenous ROS
		46.7	 Role of In Vitro Antioxidants in Protecting Spermatozoa from Semen Processing
		46.8	 Role of In Vitro Antioxidants in Protecting Spermatozoa from Cryopreservation and Thawing
		46.9	 Conclusion
		46.10	 Review Criteria
		References
	47: Antioxidants Use and Sperm DNA Damage
		47.1	 Introduction
		47.2	 Sperm DNA Damage
			47.2.1	 Pathophysiology and Etiology of SDF
			47.2.2	 Impact of SDF on Male Infertility
			47.2.3	 Impact of Sperm DNA Damage on Semen Parameters
			47.2.4	 Diagnosis and Treatment
		47.3	 Use of Antioxidants for Sperm DNA Damage
			47.3.1	 What Are Antioxidants
				47.3.1.1 Vitamin B12
				47.3.1.2 Vitamin C (Ascorbic Acid)
				47.3.1.3 Vitamin E
				47.3.1.4 Folic Acid
				47.3.1.5 Carotenoids
				47.3.1.6 L-carnitine
				47.3.1.7 Zinc
				47.3.1.8 Coenzyme Q10
				47.3.1.9 Selenium
				47.3.1.10 N-acetyl-L-cysteine (NAC)
			47.3.2	 Role of Antioxidants in Male Infertility: Overview
			47.3.3	 Evidences Regarding Utility of Antioxidants for SDF
		47.4	 Safety of Long-Term Antioxidant Use
		47.5	 Conclusion
		47.6	 Review Criteria
		References
	48: Yoga, Meditation, and Acupuncture for Male Reproductive Health
		48.1	 Introduction
		48.2	 Background
		48.3	 Mind Body Interventions (MBI) and Integrative Health for Male Infertility
		48.4	 Yoga Based Lifestyle Intervention
			48.4.1	 Yoga: The Historic Outlook
			48.4.2	 Physiological and Psychological Effects of Yoga
			48.4.3	 Effect of Yoga on Oxidative Stress, Genomic Integrity, and Telomere Dynamics
		48.5	 Traditional Chinese Medicine: Role of Acupuncture
		48.6	 Physiologic Basis of Acupuncture in Treating Subfertility
		48.7	 Conclusion
		48.8	 Review Criteria
		References
Part V: Assisted Reproductive Technology in Male Fertility
	49: The Role of Interventions to Reduce Oxidative Stress and Improve Sperm DNA Integrity Before ICSI
		49.1	 Introduction
		49.2	 Oxidative Stress, Sperm DNA Fragmentation, and ICSI Outcome
		49.3	 Interventions to Reduce Oxidative Stress and Sperm DNA Fragmentation Before ICSI
			49.3.1	 Short Ejaculatory Abstinence
			49.3.2	 Oral Antioxidant Therapy
			49.3.3	 Varicocele Repair
			49.3.4	 Sperm Processing/Selection Techniques
			49.3.5	 Use of Testicular Sperm
		49.4	 Conclusion
		49.5	 Review Criteria
		References
	50: Sperm Retrieval Techniques
		50.1	 Introduction
		50.2	 Sperm Retrieval Techniques
			50.2.1	 Percutaneous
				50.2.1.1	 Epididymal Sperm Aspiration (PESA)
				50.2.1.2	 Testicular Sperm Aspiration (TESA)
			50.2.2	 Open Non-microsurgical
				50.2.2.1	 Testicular Sperm Extraction (TESE)
			50.2.3	 Open Microsurgical
				50.2.3.1	 Epididymal Sperm Aspiration (MESA)
				50.2.3.2	 Microdissection Testicular Sperm Extraction (Micro-TESE)
		50.3	 Prognostic Factors for Successful Sperm Retrieval
			50.3.1	 Obstructive Azoospermia
			50.3.2	 Nonobstructive Azoospermia
		50.4	 Complications
		50.5	 Assisted Reproductive Technology
			50.5.1	 Role of IVF Laboratory
			50.5.2	 Influence of Type of Azoospermia
			50.5.3	 Sperm Retrieval in Non-azoospermic Men
		50.6	 Health of Offspring
		50.7	 Conclusion
		50.8	 Review Criteria
		References
	51: Microdissection Testicular Sperm Extraction
		51.1	 Introduction
		51.2	 Diagnosis of Non-obstructive Azoospermia
		51.3	 Surgical Approaches
		51.4	 Conventional TESE
		51.5	 Fine-Needle Aspiration/Testicular Mapping
		51.6	 Microdissection TESE
		51.7	 Preoperative Preparation and Optimization Prior to Microdissection TESE
			51.7.1	 Genetics Screening
		51.8	 Karyotype Evaluation
		51.9	 Endocrine Evaluation and Treatment
		51.10	 Microdissection TESE Technique
			51.10.1	 Surgical Approach
		51.11	 Complications and Considerations After Microdissection TESE
		51.12	 Predictors of Microdissection TESE Success
		51.13	 Effect of Prior Biopsy or Conventional TESE Procedure
		51.14	 Testicular Histology on Diagnostic Biopsy
		51.15	 Microdissection TESE in Setting of Elevated FSH Levels
		51.16	 AZF Deletions
		51.17	 Microdissection TESE in Patient Subpopulation
			51.17.1 Klinefelter Syndrome
			51.17.2 Post-Chemotherapy Azoospermia
			51.17.3 NOA Associated with Cryptorchidism
		51.18	 Next Years’ View
		51.19	 Conclusions
		51.20	 Review Criteria
		References
	52: Sperm Processing and Selection
		52.1	 Introduction
		52.2	 Reduction of Semen Viscosity
		52.3	 Conventional Sperm Selection Methods
			52.3.1	 Simple Sperm Wash
			52.3.2	 Swim-Up
			52.3.3	 Density Gradient Centrifugation
		52.4	 Preparation of Assisted Ejaculation Samples
		52.5	 Preparation of Retrograde Ejaculation Samples
		52.6	 Sperm Preparation Techniques for Cryopreserved Semen
		52.7	 Preparation of Epididymal and Testicular Sperm
		52.8	 Advanced Sperm Preparation Methods
			52.8.1	 Zeta Potential and Sperm Birefringence
			52.8.2	 Ultrastructural Sperm Selection
			52.8.3	 Hyaluronic Acid-Mediated Sperm Selection
			52.8.4	 Electrophoretic Sperm Selection
				52.8.4.1	 Microflow Cell
			52.8.5	 Annexin V and MACS Separation
			52.8.6	 Microfluidic Separation of Sperm
		52.9	 Specific Indications of Sperm Selection Techniques: Clinical Implications
		52.10	 Future Directions
		52.11	 Conclusion
		52.12	 Review Criteria
		References
	53: Microfluidic Sperm Selection
		53.1	 Introduction
		53.2	 Sperm Characteristics that Can Be Used as Selection Factors
			53.2.1	 Migration in Space-Constricted Environment
			53.2.2	 Migration Through Viscous Fluids
			53.2.3	 Positive Rheotaxis
			53.2.4	 Thermotaxis
			53.2.5	 Chemotaxis
		53.3	 Current Sperm-Sorting Technologies
		53.4	 Microfluidics
			53.4.1	 Chemotaxis and Thermotaxis
			53.4.2	 Short-Distance Migration
			53.4.3	 Resilience
		53.5	 Future Perspectives
		53.6	 Conclusion
		53.7	 Review Criteria
		References
	54: Antioxidants in Sperm Cryopreservation
		54.1	 Introduction
		54.2	 Oxidative Stress and Male Infertility
		54.3	 Oxidative Stress During Cryopreservation
		54.4	 Effects of Antioxidants on Spermatozoa In Vitro
		54.5	 Reduction of Reactive Oxygen Species Levels
		54.6	 Effects on Sperm Motility
		54.7	 Protection of Sperm DNA Integrity
		54.8	 Conclusion
		54.9	 Review Criteria
		References
	55: Antioxidants in ICSI
		55.1	 Introduction: Male Factor Infertility Relevance and Causes
		55.2	 Oxidative Stress and Male Factor
			55.2.1	 Endogenous Sources of Free Radicals
			55.2.2	 Exogenous Sources of Free Radicals
				55.2.2.1	 Lifestyle Factors and Medical Conditions Affecting ROS in Sperm
				55.2.2.2	 Environmental Sources of ROS
				55.2.2.3	 Laboratory Manipulation
		55.3	 Consequences of OS in Sperm Affecting ICSI Results
			55.3.1	 Epigenetic Alterations
			55.3.2	 DNA Oxidation
			55.3.3	 DNA Fragmentation
			55.3.4	 Apoptosis
		55.4	 The Control of Free Radicals: The Antioxidants
		55.5	 The Use of Antioxidants to Improve Reproductive Results
			55.5.1	 Treating the Male Patient
				55.5.1.1	 Trace Elements
				55.5.1.2	 Alpha-Lipoic Acid
				55.5.1.3	 Docosahexaenoic Acid
				55.5.1.4	 Coenzyme Q10
				55.5.1.5	 Curcumin Nanomicelles
				55.5.1.6	 Myo-Inositol
				55.5.1.7	 Antiestrogens
				55.5.1.8	 Vitamins
				55.5.1.9	 Carnitines
			55.5.2	 Treating the Sample
				55.5.2.1	 Embryo Culture Media
				55.5.2.2	 Sperm Treatment
		55.6	 Conclusions
		55.7	 Review Criteria
		References
	56: Role of Sperm-Hyaluronic Acid Binding in the Evaluation and Treatment of Subfertile Men with ROS-Affected Semen
		56.1	 Introduction
		56.2	 Human Sperm Selection with Hyaluronic Acid-Binding Assay (HBA): The Scientific Rationale Behind a Novel Technology to Select Best Sperm in ART
		56.3	 Clinical Significance of HA-Binding-Mediated ICSI Sperm Selection: An Update
		56.4	 Role of ROS Production in Sperm DNA Damage and Clinical Manifestations in Assisted Reproduction: ROS as a Threat for Male Fertility?
		56.5	 Sperm Properties Associated with ROS-Related DNA Defects, Improved Cellular Attributes of HA-Selected Sperm, and Evaluation of Subfertile Men with ROS-Affected Semen
		56.6	 Markers for Sperm Oxidative Stress
		56.7	 Assessment of ROS in Semen: Where Are We Now?
		56.8	 Conclusions
		56.9	 Review Criteria
		References
	57: Male Gametes In Vivo to In Vitro: Clinical and Laboratory Management of Nonobstructive Azoospermia
		57.1	 Introduction
		57.2	 Definition and Epidemiology
		57.3	 Aetiology of NOA
		57.4	 Testicular Histopathology in NOA
		57.5	 Investigations in NOA
			57.5.1 Hormonal Testing
			57.5.2 Genetic Testing
		57.6	 Varicocele in NOA
		57.7	 Medical Management in NOA
		57.8	 SERM
			57.8.1 Aromatase Inhibitor
			57.8.2 Gonadotropins
		57.9	 Monitoring and Freezing of Ejaculate Sperm in Successfully Treated NOA
		57.10	 TESA in NOA
		57.11	 Micro-TESE Case Selection
		57.12	 Micro-TESE Technique and Tubule Retrieval
		57.13	 Micro-TESE Tissue Processing in IVF Laboratory
			57.13.1 Methods for Selecting Viable Immotile Sperm for ICSI
			57.13.2 Hypoosmotic Swelling (HOS) Test
			57.13.3 Sperm Tail Flexibility Test
			57.13.4 Motility Stimulant Sperm Challenge Using Pentoxifylline
		57.14	 ICSI Dish Preparation and Sperm Fishing
		57.15	 Assisted Oocyte Activation in Testicular Sperm
		57.16	 ICSI Outcome in MTESE
		57.17	 Cryopreservation of MTESE Sample
		57.18	 MTESE in Special Situations
		57.19	 Peri- and Postnatal Outcomes in NOA
		57.20	 Conclusion
		57.21	 Review Criteria
		References
	58: Sperm DNA Damage, ART Outcomes, and Laboratory Methods for Selecting DNA Intact Sperm for ICSI
		58.1	 Introduction
		58.2	 Which Are the Origins of Spermatic DNA Breakage?
		58.3	 How Can We Measure the Different Types of Sperm DNA Damage?
		58.4	 Which Is the SDF Implication in Male Fertility and What Indications Should Be Followed in ART?
		58.5	 Is It Possible to Select a Sperm with the DNA Intact for ICSI?
		58.6	 Conclusions
		58.7	 Review Criteria
		References
	59: Testicular Sperm in Non-azoospermic Infertile Men with Oxidatively Induced High Sperm DNA Damage
		59.1	 Introduction
		59.2	 The Oxidatively Induced Sperm DNA Fragmentation
		59.3	 Clinical Impact of Sperm DNA Fragmentation in ART
		59.4	 Biological Plausibility of Testicular Sperm from Non-azoospermic Men for ICSI
			59.4.1	 SDF Rates in Ejaculated, Epididymal, and Testicular Sperm
			59.4.2	 Aneuploidy Rates in Ejaculated, Epididymal, and Testicular Sperm
		59.5	 ICSI Outcomes Using Testicular Sperm from Non-azoospermic Men with High SDF
		59.6	 Sperm Retrieval Methods in Non-azoospermic Men
		59.7	 Offspring Health
		59.8	 Proposed Algorithm for SDF Testing and Use of Testicular Sperm for ICSI in Non-azoospermic Men
		59.9	 Other Strategies to Reduce Sperm DNA Fragmentation
		59.10	 Conclusions
		59.11	 Review Criteria
		References
	60: Development of Artificial Gametes
		60.1	 General Introduction
		60.2	 Development of Artificial Gametes in Animal Models
			60.2.1	 Artificial Male Germ Cells and Gametes Derived from Embryonic Stem Cells
			60.2.2	 Artificial Male Germ Cells and Gametes Derived from Induced Pluripotent Stem Cells
			60.2.3	 Artificial Male Germ Cells and Gametes Derived from Adult Pluripotent Stem Cells
			60.2.4	 Artificial Female Germ Cells and Gametes Derived from Embryonic Stem Cells
			60.2.5	 Artificial Female Germ Cells and Gametes Derived from Induced Pluripotent Stem Cells
			60.2.6	 Artificial Female Cells and Gametes Derived from Adult Pluripotent Stem Cells
		60.3	 Development of Artificial Gametes in Humans
			60.3.1	 Artificial Male Germ Cells and Gametes Derived from Embryonic Stem Cells
			60.3.2	 Artificial Male Germ Cells and Gametes Derived from Induced Pluripotent Stem Cells
			60.3.3	 Artificial Male Germ Cells and Gametes Derived from Adult and Fetal Pluripotent Stem Cells
			60.3.4	 Artificial Female Germ Cells and Gametes Derived from Embryonic Stem Cells
			60.3.5	 Artificial Female Germ Cells and Gametes Derived from Induced Pluripotent Stem Cells
			60.3.6	 Artificial Female Cells and Gametes Derived from Adult Pluripotent Stem Cells
		60.4	 Biological Progress and Ethical Aspects of Clinical Application of Human Artificial Gametes
		60.5	 Concluding Remarks
		60.6	 Review Criteria
		References
	61: ICSI and Male Infertility: Consequences to Offspring
		61.1	 Introduction
		61.2	 Risks and Sequelae of ICSI to the Health of Offspring
			61.2.1	 Congenital Abnormalities
			61.2.2	 Epigenetic Disorders
			61.2.3	 Chromosome Abnormalities
			61.2.4	 Infertility
			61.2.5	 Cancer
			61.2.6	 Psychological and Neurodevelopment
			61.2.7	 Metabolic and Cardiovascular
		61.3	 Conclusions
		61.4	 Review Criteria
		References
Part VI: Guidelines and Best Practices in Male Infertility and Antioxidants
	62: Best Practice Guidelines for Male Infertility Diagnosis and Management
		62.1	 Introduction
		62.2	 AUA Best Practice Statement: Optimal Evaluation of the Infertile Male
		62.3	 ASRM Guidelines
		62.4	 European Association of Urology Guidelines
		62.5	 An Assessment of the Guidelines for the Evaluation of the Infertile Male
		62.6	 Conclusion
		62.7	 Review Criteria
		References
	63: Best Practice Guidelines for Sperm DNA Fragmentation Testing
		63.1	 Introduction
		63.2	 SDF Testing Methods
			63.2.1	 The TUNEL Assay
			63.2.2	 The Comet Assay
			63.2.3	 The Sperm Chromatin Dispersion Test
			63.2.4	 The Sperm Chromatin Structure Assay
		63.3	 Indication of SDF Testing
			63.3.1	 Men with Clinical Varicoceles
			63.3.2	 Unexplained Infertility, Recurrent Pregnancy Loss, or Intrauterine Insemination Failures
			63.3.3	 In Vitro Fertilization (IVF)/Intracytoplasmic Sperm Injection (ICSI) Failure
			63.3.4	 Patients with Risk Factors
		63.4	 Treatment
			63.4.1	 Conservative and Counseling Methods
			63.4.2	 Antioxidant Treatment
			63.4.3	 Surgical Treatment (Varicocele Ligation)
			63.4.4	 In the Setting of ART
		63.5	 Conclusion
		63.6	 Review Criteria
		References
	64: Antioxidants in the Medical and Surgical Management of Male Infertility
		64.1	 Introduction
		64.2	 Ascorbic Acid (Vitamin C)
		64.3	 α-Tocopherol (Vitamin E)
		64.4	 Ascorbic Acid (Vitamin C) and α-Tocopherol (Vitamin E)
		64.5	 α-Tocopherol (Vitamin E) and Selenium
		64.6	 Glutathione
		64.7	 Carnitines
		64.8	 Coenzyme Q10
		64.9	 Myoinositol
		64.10	 Lycopene
		64.11	 Other Compounds
			64.11.1 N-Acetyl-Cysteine (NAC) or Vitamin A Plus Vitamin E and Essential Fatty Acids
			64.11.2 Pentoxifylline
			64.11.3 Selenium
			64.11.4 Zinc
		64.12	 Conclusion
		64.13	 Review Criteria
		References
Part VII: Special Topics
	65: Fertility Preservation for Boys and Adolescents
		65.1	 Introduction
		65.2	 Physiology of Reproduction in Children and Adolescents
			65.2.1	 Hypothalamic-Pituitary-Gonadal Axis
			65.2.2	 Spermatogenesis
		65.3	 Effect of Cancer on Reproductive Function in Adolescents and Young Boys
			65.3.1	 Effect of Cancer on Fertility
			65.3.2	 Effect of Chemotherapy on Fertility
			65.3.3	 Effect of Radiotherapy on Fertility
			65.3.4	 Effect of Cancer Surgery on Fertility
		65.4	 Fertility Preservation Options
			65.4.1	 Testicular Shielding
			65.4.2	 Sperm Cryopreservation
				65.4.2.1	 Ejaculate
				65.4.2.2	 Testicular Sperm Extraction
			65.4.3	 Testicular Transposition
			65.4.4	 Experimental Methods
				65.4.4.1	 Cryopreservation of Testicular Tissue and Spermatogonial Stem Cells (SSCs)
				65.4.4.2	 Spermatogonial Stem Cell Maturation
				65.4.4.3	 Spermatogonial Stem Cell Transplantation
				65.4.4.4	 Transplantation of Immature Testicular Tissue (ITT)
				65.4.4.5	 In Vitro Gamete Maturation (IVM)
				65.4.4.6	 Artificial Gametes
		65.5	 Challenges in Cryopreservation in Children and Adolescents
			65.5.1	 Patient/Family Related
			65.5.2	 Physician Related
			65.5.3	 System Related
		65.6	 Ethical Considerations
		65.7	 Conclusion
		65.8	 Review Criteria
		References
	66: Novel Home-Based Devices for Male Infertility Screening
		66.1	 Introduction
		66.2	 Conventional Semen Analysis
		66.3	 Home-Based Semen Tests (Fig. 66.1)
			66.3.1	 SpermCheck Fertility
			66.3.2	 SwimCount™ Sperm Quality Test
			66.3.3	 Micra First Step
			66.3.4	 Trak System
		66.4	 Smartphone-Based Semen Testing Devices
			66.4.1	 Yo Home Sperm Test (Fig. 66.2)
		66.5	 Limitations
		66.6	 Conclusion
		66.7	 Review Criteria
		References
	67: Ethical Dimensions of Male Infertility
		67.1	 Introduction
		67.2	 Oncofertility
		67.3	 Posthumous Reproduction/Sperm Retrieval (PHR/PSR)
		67.4	 Advanced Paternal Age
		67.5	 Transgender Fertility (Male to Female)
		67.6	 Economic Disparities
		67.7	 Conclusions
		References
	68: Harmful Effects of Antioxidant Therapy
		68.1	 Introduction
		68.2	 Reactive Oxygen Species
		68.3	 Oxidative Stress
		68.4	 Antioxidants and Male Infertility
		68.5	 Antioxidants: A Double-Edged Sword
			68.5.1	 The “Antioxidant Paradox”
			68.5.2	 Reductive Stress
		68.6	 Clinical Aspects of Antioxidant Treatment
			68.6.1	 Benefits of Antioxidant Treatment
			68.6.2	 Risks of Antioxidant Treatment
			68.6.3	 Risks of Dietary Antioxidants
				68.6.3.1	 Oxalic Acid
				68.6.3.2	 Phytic Acid
				68.6.3.3	 Tannins
				68.6.3.4	 Others
			68.6.4	 Risks of Antioxidant Supplements
		68.7	 Conclusion
		68.8	 Review Criteria
		References
	69: Male Infertility from the Developing Nation Perspective
		69.1	 Introduction
		69.2	 Prevalence of Male Infertility in Developing Countries
		69.3	 Etiology of Male Infertility in Africa
		69.4	 Reproductive Tract Infections
			69.4.1	 Neisseria Gonorrhoeae
			69.4.2	 Chlamydia Trachomatis
			69.4.3	 Human Immunodeficiency Virus Infection
			69.4.4	 Genital Tuberculosis
			69.4.5	 Genitourinary Bilharziasis
			69.4.6	 Lepromatous Leprosy
			69.4.7	 Sickle Cell Disease
			69.4.8	 Mycotoxin and Environmental Toxins
			69.4.9	 Smoking and Alcohol Intake on Male Infertility
			69.4.10 Iatrogenic Causes of Male Infertility in Africa
			69.4.11 Management of Male Infertility in Africa
			69.4.12 Prevention of Male Infertility in Africa
			69.4.13 Male Infertility (the Case of Zambia)
		69.5	 Conclusion
		69.6	 Review Criteria
		References
	70: Diabetes and Male Infertility
		70.1	 Introduction
		70.2	 General Mechanisms
			70.2.1	 Oxidative Stress
			70.2.2	 Hypothalamic-Pituitary-Gonadal Axis
			70.2.3	 Neuropathy
			70.2.4	 Infectious
		70.3	 Steroidogenesis
		70.4	 Spermatogenesis and Sperm Parameters
		70.5	 Sexual Dysfunctions
			70.5.1	 Erectile Dysfunction
			70.5.2	 Ejaculatory Dysfunctions
			70.5.3	 Libido
		70.6	 Conclusions
			70.6.1	 Review Criteria
		References
	71: Empiric Medical Therapy for Idiopathic Male Infertility
		71.1	 Introduction
		71.2	 Hormonal Treatments
			71.2.1	 Gonadotropins
			71.2.2	 Androgens
			71.2.3	 Selective Estrogen Receptor Modulators
			71.2.4	 Aromatase Inhibitors
		71.3	 Antioxidant Treatments
		71.4	 Conclusion
		71.5	 Review Criteria
		References
	72: Testosterone Therapy in Male Infertility
		72.1	 Introduction
		72.2	 HPG Axis and Association with Male Reproduction
		72.3	 Effects of TRT on Male Fertility
			72.3.1	 Transdermal Gels and Patches
			72.3.2	 Long- and Short-Acting Injections
			72.3.3	 Subcutaneous Pellets
			72.3.4	 Intranasal Gels
		72.4	 Treatment Options to Increase Intratesticular Testosterone
			72.4.1	 Gonadotropins: GnRH and hCG
			72.4.2	 Clomiphene Citrate
		72.5	 Aromatase Inhibitors
		72.6	 Lifestyle Modification
		72.7	 Varicocele Repair
		72.8	 Leydig Stem Cells
		72.9	 Conclusion
		72.10	 Review Criteria
		References
Index