Genetics of Male Infertility: A Case-Based Guide for Clinicians

✍ Scribed by Mohamed Arafa (editor), Haitham Elbardisi (editor), Ahmad Majzoub (editor), Ashok Agarwal (editor)

• Publisher: Springer
• Year: 2020
• Tongue: English
• Leaves: 374
• Category: Library

✦ Synopsis

This unique, case-based guide provides a thoughtful and comprehensive overview of the genetic basis of male infertility for the practicing clinician. In addition to discussing the molecular foundations of sperm production and the consequences of genetic abnormalities on various stages of sperm development, it examines the clinical aspects of acknowledged genetic disorders and their implications on male fertility. In so doing, it offers the necessary tools required by the clinician for the diagnosis and treatment of infertile men with genetic abnormalities. Moreover, it provides essential algorithms that may aid in counseling patients in the clinic.
The text is arranged in four thematic sections for easy reference. The genetic foundation of male reproduction is presented in part 1, including regulation of sperm production, the structure of sperm chromatin, and spermatogenesis. The impact of genetic abnormalities on male infertility is the subject of part 2, covering sperm defects, mitochondrial function and DNA fragmentation. The clinical case material in part 3 illustrates real-world examples of genetic etiologies and the current diagnostic and therapeutic strategies for conditions such as vas asplasia, cryptorchidism, immotile cilia syndrome, sperm aneuploidy and other challenging scenarios. Casting forward, the fourth and final section presents an overview of future possibilities for management of genetic causes of male infertility, including gene editing.
Fully exploring the clinical context of these genetic conditions in a practical manner that appeals to the practicing clinician, Genetics of Male Infertility is an exciting and essential text for reproductive medicine specialists, andrologists, urologists, researchers and all other clinicians treating infertile patients.

✦ Table of Contents

Foreword
Preface
Contents
Author Biographies
Contributors
Part I: The Genetic Basis of Reproduction
Chapter 1: The Molecular Genetics of Testis Determination
Background
Assembly of the Bipotential Gonads
Sex Determination
Sertoli Cell Specification
Sex Differentiation
Partitioning of Testis Cords by Mesonephric Cell Migration, Formation of Peritubular Myoid Cell, and Testis Vascularization
Leydig Cell Specification
Lymphangiogenesis in the Testis
Germ Cell Sex Determination
Antagonism of the Testis and Ovarian Pathways
Summary
References
Chapter 2: Molecular Regulation of Sperm Production Cascade
Introduction
Spermatogonial Stem Cells (SSCs)
Extrinsic Factors
Intrinsic Factors
Spermatogonial Differentiation
Spermatocytes and Meiosis
Spermatids and Spermiogenesis
Axoneme
Manchette Formation and Cytoplasmic Exclusion
Chromatin Remodelling
Conclusion and Future Perspective
References
Chapter 3: Spermatozoal Chromatin Structure: Role in Sperm Functions and Fertilization
Introduction
Chromatin Structure and Organization
Origin and Mechanisms of Chromatin Damage
Sperm Chromatin and Male Infertility
Assays to Evaluate Sperm Chromatin Status
Conclusions
References
Chapter 4: Genetic Basis of Endocrine Regulation of Spermatogenesis
Introduction
The Hypothalamic-Pituitary-Gonadal Axis
Disorders of the Hypothalamic-Pituitary-Gonadal Axis
Androgen Production
Disorders of Androgen Production
Hormonal Influence Within the Germinal Epithelium
Disorders of the Androgen Receptor
The Role of Estrogen in Spermatogenesis
Regulation of the Hypothalamic-Pituitary-Gonadal Axis
Disorders of Hypothalamic-Pituitary-Gonadal Axis Regulation
Conclusion
References
Chapter 5: Epidemiology of Genetic Disorders in Male Infertility
Introduction
Epidemiology of Infertility
General Epidemiology of Genetic Infertility
Epidemiology of Specific Genetic Abnormalities
Klinefelter Syndrome
Y Chromosome Microdeletions
Congenital Bilateral Absence of Vas Deferens
47,XYY
46, XX
Kallmann Syndrome
Translocations
Inversions
Significance and Difficulties in Epidemiological Studies in Genetic Male Infertility
Conclusion
References
Chapter 6: Genetic Evaluation of Male Infertility
Introduction
Genetic Evaluation of Male Infertility
Obstructive Conditions
Quantitative Conditions
Single-Gene Tests
Morphological Abnormalities
Motility Abnormalities
Next-Generation Sequencing Technologies
Successful Application of Next-Generation Sequencing to Male Infertility
Suitability of Male infertility for Next-Generation Sequencing
Advances in Male infertility due to Next-Generation Sequencing by Subtype
Quantitative Anomalies
Morphological Anomalies
Motility Anomalies
CBAVD and Y Chromosome Next-Generation Sequencing Studies
Conclusions
References
Part II: Impact of Genetics on the Sperm Cell
Chapter 7: Genetic Basis of Sperm Morphologic Defects: Head Defects and Body and Tail Defects
Introduction
A Look Into the Basics of Sperm Morphology
Structure and Function of Each Part of a Normal Sperm
Spermatogenesis and Spermiogenesis
Abnormal Sperm Morphology: Teratozoospermia
What Is Teratozoospermia?
Types of Sperm Morphology Defects (Head, Middle Piece and Tail Abnormalities)
General Causes
Diagnosis Criteria
Genetics of Male Infertility: Overview
Molecular and Genetic Basis of Teratozoospermia
Macrozoospermia
Globozoospermia
Multiple Morphological Abnormalities of the Flagella (MMAF)
Acephalic Spermatozoa
Conclusion
References
Chapter 8: Mitochondrial Function and Male Infertility
Introduction
Overview on Mitochondrial Function
Oxidative Phosphorylation
Molecules that Capture and Transfer Electrons: NADH and FADH2 Formation
Mitochondrial DNA and Nucleic DNA
The Fate of mt-DNA
Effects of mt-DNA Mutations on Fertility
Metabolic Substrates for Sperm Mitochondria
Mitochondrial Membrane Potential
Mitochondrial Function in Swim-Up Sperm
Apoptosis: Site for Intrinsic Apoptotic Pathway
Levels of ROS
Effects of Temperature on Mitochondrial Function
Concluding Remarks
References
Chapter 9: Sperm DNA Fragmentation and Male Infertility
Introduction
Etiology of Sperm DNA Damage
Molecular Changes associated with Sperm DNA Fragmentation
Male Infertility Factors/Conditions Associated with SDF
Male Age
Diet, Lifestyle, and Modifiable Risk Factors
Obesity
Environmental Toxicants
Chemo/Radiotherapy
Infections and Testicular Trauma
Techniques Used for SDF Assessment
Sperm Chromatin Maturity Testing
Aniline Blue Staining (AB)
Chromomycin A3 (CMA3)
Sperm DNA Fragmentation Testing
Sperm Chromatin Structure Assay (SCSA)
Sperm Chromatin Dispersion (SCD) Test
Comet Assay/Single-Cell Gel Electrophoresis (SCGE)
Terminal Deoxynucleotidyl Transferase dUTP Nick-End Labeling (TUNEL)
SDF Testing for Male Infertility
Conclusion
References
Chapter 10: The Sperm Epigenome and Potential Implications for the Developing Embryo
Introduction
Epigenetics of the Male Gamete
Sperm Chromatin: Fertility/Embryogenesis
DNA Methylation: Fertility/Embryogenesis/Inheritance
ncRNAs: Fertility/Embryogenesis/Inheritance
Clinical Relevance
References
Part III: Clinical Case Scenarios
Chapter 11: Klinefelter Syndrome
Case Scenarios
Case 1
Case 2
Introduction
Historical Background
Incidence of Klinefelter Syndrome
Genetic Basis of Klinefelter Syndrome
Mechanisms Causing Klinefelter Syndrome
Karyotype Variants of Klinefelter Syndrome
Effects of Klinefelter Syndrome on Spermatogenesis and Hormones
Clinical Presentation of Klinefelter Syndrome
Management
Management of Hypogonadism
Management of Fertility
Genetic Counselling
ICSI Outcomes in Klinefelter Syndrome
Conclusion
References
Chapter 12: Chromosomal Translocations and Inversion in Male Infertility
Case 1
Case 2
Case 3
Introduction and Definition
Types of Chromosomal Anomalies
Incidence
Mechanisms
Clinical Presentations
Management
Preimplantation Genetic Screening (PGS) or Preimplantation Genetic Diagnosis (PGD)
Reproductive Counseling
Conclusion
References
Chapter 13: Genetics of Vas Aplasia
Clinical Scenarios
Case 1
Case 2
Case 3
Vas Aplasia
Genetic Abnormalities in Vas Aplasia
Clinical Diagnosis of Vas Aplasia and Associated Subphenotypes
CBAVD
CUAVD
CBAVD Men Having Renal Anomalies (CBAVD-URA)
Congenital Absence of Seminal Vesicles (CASV) and Ejaculatory Duct Obstruction (BEDO)
CBAVD, Assisted Reproduction, and Genetic Counseling
Future Perspectives
References
Chapter 14: Anomalies of the Y Chromosome
Case Scenario
Case 1
Introduction
Background
Prevalence of Y-Chromosome Anomalies
The Genetic Basis for Investigating Y-Chromosome Anomalies
Clinical Presentation and Diagnosis of Men with Y-Chromosome Anomalies
Genetic Counseling
Management and Prognosis
Conclusion
References
Chapter 15: Infertility and Cryptorchidism
Introduction
Prevalence
Risk Factors
Testicular Descent
Cryptorchidism and Infertility
Cryptorchidism and Cancer
Treatment
References
Chapter 16: Kartagener and Immotile Cilia Syndrome
Case Scenario
Introduction
Historical Background
Physiopathology
Genetic Basis for PCD
Clinical Presentation
Diagnosis
Infertility Management and Prognosis
Conclusion
References
Chapter 17: Persistent Müllerian Duct Syndrome
Introduction
Epidemiology
Embryology
Genetics
Presentation
Clinical Features
Evaluation and Management
Diagnosis
Differential Diagnosis
Fertility
Radiological Studies
Surgical Management
Other Considerations
References
Chapter 18: Disorders of Sex Determination
Introduction
Case Presentation
How the Diagnosis Was Made
Genetic and Epigenetic Pathways of Sex Determination
Clinical Presentation of Nonsyndromic 46, XX Testicular DSD
Management of Nonsyndromic 46, XX Testicular DSD
Conclusions
References
Chapter 19: Endocrine Genetic Defects
Genetic Defects of the Testicular Microenvironment
Genetic Defects of LH and FSH
Prader-Willi Syndrome
Isolated LH Deficiency
Isolated FSH Deficiency
Genetic Defects of GNRH
Isolated GnRH Deficiency
Kallmann Syndrome
Mutations of the Androgen Receptor
Hyperprolactinemia
References
Chapter 20: Sperm Aneuploidy
Case
Introduction
How to Analyze Sperm Aneuploidy: Technical Aspects
Indications for Sperm Aneuploidy Testing
Impact of Sperm Aneuploidy
Reproductive Counseling
References
Part IV: Genetic Infertility: Is There Any Hope?
Chapter 21: Sperm DNA Fragmentation: Treatment Options and Evidence-Based Medicine
Introduction
SDF Testing Methods
TUNEL Method
Single-Cell Gel Electrophoresis (The Comet Assay)
The Sperm Chromatin Dispersion Method (SCD)
Sperm Chromatin Structure Assay (SCSA)
Indications of SDF Testing
Clinical Varicoceles
Unexplained Infertility, Recurrent Pregnancy Loss, or Intrauterine Insemination Failures
Effect on IVF and ICSI
Risk Factors
Treatment
Conservative and Counseling Methods
Medical Treatment: Antioxidants
Surgical Treatment – Varicocele Ligation
Assisted Reproductive Treatment
Sperm Selection Techniques
Sperm Retrieval Techniques
Conclusion
References
Chapter 22: The Potential of CRISPR/Cas Gene Editing to Correct Male Infertility
Introduction
Gaining a Better Understanding of the Genetic Basis of Male Infertility
Challenges in Studying the Genetic Basis of Male Infertility
The Search for Variants Responsible for Male Infertility
Variants Known to Cause Male Infertility
Gene Therapy Candidate Genes
Epigenetic Variation and Male Infertility
Understanding the Biology of Spermatogonial Stem Cells
In Vitro Culture of Spermatogonial Stem Cells
CRISPR Technologies for SSC Gene Editing
Conclusions
References
Index