The Genetic Basis of Male Infertility

Clinical Aspects of Male Infertility.- 1 Introduction.- 1.1 Definition of Couple and Male Infertility.- 1.2 Assisted Reproduction and Clinical Andrology.- 2 The Elements of Standard Medical Workup.- 2.1 Medical and Familial History.- 2.2 Physical Examination.- 2.3 Diagnostic Tests.- 3 Aetiology of Male Infertility.- 3.1 Infertility Due to Antispermatogenic Agents.- 3.2 Infertility Due to Endocrine Disorders (Hypogonadotrophic Hypogonadism).- 3.3 Infertility Due to Impairment of Sperm Transport and/or Accessory Gland Infections.- 3.4 Autoimmune Infertility.- 3.5 Infertility and Varicocele.- 3.6 Infertility Due to Coital Disorders.- 3.7 Infertility and Cryptorchidism.- 4 Infertility Due to Genetic Disorders.- 4.1 Chromosomal Abnormalities.- 4.2 Klinefelter Syndrome.- 4.3 Other Chromosomal Abnormalities.- 4.4 Male Infertility from Defect in Meiosis.- 5 Monogenic Diseases.- 5.1 The Kartagener Syndrome or Immotile Cilia Syndrome.- 5.2 Androgen Insensitivity Syndromes.- 5.3 The Infertile Male Syndrome.- 5.4 X-Linked Spinal and Bulbar Muscular Atrophy (Kennedy Disease).- 5.5 Persistent Mullerian Duct Syndrome.- 5.6 Inactivating FSH Receptor Mutation.- 6 Clinical Considerations of Genetic Abnormalities.- 7 Treatment of the Infertile Male.- References.- The Cell Biology and Molecular Genetics of Testis Determination.- 1 Introduction.- 2 Human Sex Determination is Chromosomally Based.- 2.1 Sex Reversal.- 3 Gonadal Sex Differentiation.- 3.1 Testicular and Ovarian Morphogenesis in Human Embryos.- 3.2 The Importance of the Supporting Cell Lineage.- 3.3 The Contribution of the Mesonephros.- 3.4 Genes Involved in Formation of the Gonadal Primordium.- 4 The Testis-Determining Factor (TDF).- 4.1 SRY is TDF.- 4.2 The SRY Protein and Its Targets.- 4.3 Is SRY a Negative Regulator?.- 5 The SOX9 Gene and Testis Determination.- 5.1 Campomelic Dysplasia, Sex Reversal and SOX9.- 5.2 Embryonic Expression of Sox9.- 5.3 Where is SOX9 Placed in the Testis-determining Cascade?.- 6 Orphan Nuclear Receptors and Sex Determination.- 6.1 Steroidogenic Factor 1 (SF1).- 6.2 DAX1 and Gonadal Differentiation.- 7 Summary: A Genetic Cascade for Testis Determination.- References.- The Sertoli Cell-Germ Cell Interactions and the Seminiferous Tubule Interleukin-1 and Interleukin-6 System.- 1 Organisation of the Testis.- 1.1 Spermatogenesis.- 1.2 The Sertoli Cell.- 1.3 The Interstitial Tissue.- 2 Endocrine Regulation of Testicular Function.- 3 Paracrine Regulation of Testicular Function.- 3.1 The Place of the IL-1/IL-6 System in the Sertoli Cell-Germ Cell Communication Network.- 3.1.1 IL-1 and IL-6.- 3.2 Sertoli Cell-Germ Cell Interactions.- 3.2.1 The Role of the Sertoli Cell.- 3.2.2 The Action of Germ Cells.- 3.3 Sources of Seminiferous-Tubule IL-1 and IL-6.- 3.3.1 Tubular IL-1.- 3.3.2 Sertoli Cell IL-6.- 3.4 Testicular IL-1 and IL-6 Receptors.- 3.5 Testicular Effects of IL-1 and IL-6.- 3.6 The Regulation of Sertoli Cell IL-1 and IL-6 by Germ Cells and the Synchronisation of the Seminiferous Epithelium Cycle.- 3.6.1 Residual Bodies and Production of Sertoli Cell IL-1 and IL-6.- 3.6.2 Control of Sertoli Cell IL-1 and IL-6 Production by Germ Cell Cytokines.- 4 Conclusion.- References.- Leydig Cell Function and Its Regulation.- 1 Introduction.- 2 Leydig Cell Morphology and Endocrine Function.- 2.1 Morphology of the Leydig Cell.- 2.2 The Hypothalamo-Pituitary-Leydig Cell Axis.- 2.2.1 Hypothalamo-Pituitary Activity and Androgen Secretion.- 2.2.2 The Role of the Testicular Vasculature.- 2.2.3 Androgen Metabolism, Action and Negative Feedback Regulation.- 2.3 Leydig Cell Steroidogenesis.- 2.4 Non-Steroidal Products of the Leydig Cell.- 3 Leydig Cell Development.- 3.1 Species Variation in Leydig Cell Development.- 3.2 Fetal, Perinatal and Prepubertal Development of the Leydig Cell in the Human.- 3.3 Pubertal Development of the Leydig Cell.- 3.4 The Ethane Dimethane Sulfonate Recovery Model.- 3.5 Hormonal Regulation of Adult Leydig Cell Development.- 3.6 Local Factors and Leydig Cell Development.- 4 Molecular Regulation of the Leydig Cell.- 4.1 Luteinizing Hormone and the LH Receptor.- 4.2 Intracellular Signalling Events and cAMP.- 4.3 Cholesterol Mobilization.- 4.3.1 Cholesterol Transport Proteins.- 4.3.2 Steroidogenic Acute Regulatory Protein.- 4.3.3 The Role of the Cytoskeleton.- 4.4 Regulation of the Steroidogenic Enzymes.- 4.4.1 Chronic Regulation of the Steroidogenic Machinery.- 4.4.2 Transcriptional Regulation of Steroidogenesis.- 4.5 Other Transducing Mechanisms.- 4.5.1 Calcium.- 4.5.2 Chloride.- 4.5.3 Protein Kinase C.- 4.5.4 Arachidonic Acid and Its Metabolites.- 5 Extrinsic Regulation of the Leydig Cell by Factors Other than LH.- 5.1 Anterior Pituitary Hormones: FSH, Prolactin, and Growth Hormone.- 5.2 Regulation by the Seminiferous Tubules.- 5.3 Cytokines and Growth Factors.- 5.4 Autocrine Regulation.- 5.4.1 Androgen-Mediated Autoregulation.- 5.4.2 Leydig Cell Desensitization.- 5.5 Glucocorticoids.- 5.6 Neuropeptides.- 5.7 Other Factors.- 6 Leydig Cell Function and Infertility.- References.- Post-Transcriptional Control and Male Infertility.- 1 Introduction.- 2 The Need for Translational Control.- 3 Regulatory Elements in Untranslated Sequences.- 4 The Protamine mRNA Is Stored in a Ribonucleoprotein Particle.- 5 Sequence-Specific RNA Binding Proteins.- 6 Premature Translation of Prm1 mRNA.- 7 Activation of Translationally Repressed mRNAs.- 8 Orphan RNA Binding Proteins.- 9 Perspectives.- References.- An Integration of Old and New Perspectives of Mammalian Meiotic Sterility.- 1 Introduction.- 1.1 The Meiotic Cell Division.- 1.2 Meiotic-Specific Structures.- 1.3 Identified Protein Components of Meiotic-Specific Structures.- 1.3.1 Components of the Synaptonemal Complex.- 1.3.2 Meiotic Nodules.- 2 Sterility from a “Process-Oriented” Perspective.- 2.1 Errors in Synapsis.- 2.1.1 The Asynaptic Phenotype and Sterility.- 2.1.2 Theoretical Links Between Asynapsis and Sterility.- 2.1.2.3 Mismatch Repair and Mammalian Meiotic Sterility.- 2.2 Errors in the Meiotic Divisions (Metaphase I Through Anaphase II).- 3 Sterility from the Perspective of Cell Cycle Checkpoint Control.- 4 Summary and Conclusions.- References.- Mutations of the Cystic Fibrosis Gene and Congenital Absence of the Vas Deferens.- 1 Introduction.- 2 CF and CBAVD: A Common Genetic Background.- 2.1 Mutation Analysis Results and the 5T-Tract Variant.- 3 Pathogenesis of CBAVD.- 4 Spermatogenesis and Epididymal Length.- 5 Remaining Questions.- 6 Conclusions.- References.- Mitochondrial Function and Male Infertility.- 1 Introduction.- 2 Mitochondrial Diseases.- 3 Mitochondrial Function and Aging.- 4 Mitochondrial Biogenesis During Spermatogenesis.- 5 Mitochondrial Organization in the Spermatozoon.- 6 Regulation of Oxidative Phosphorylation in Mitochondria.- 7 Abnormal Mitochondria and Infertility.- 8 Mitochondrial Respiratory Chain, mtDNA and Infertility.- 9 Reactive Oxygen Species Generation and Human Spermatozoa.- 10 ATP Concentration, Creatine Kinase Activity and Infertility.- 11 Mitochondrial Inheritance.- 12 Conclusion.- References.- The Human Y Chromosome and Male Infertility.- 1 Structure of the Human Y Chromosome.- 1.1 Pseudoautosomal Regions.- 1.2 Non-Recombining Region.- 2 Functions Associated with the Non-Recombining Region of the Human Y chromosome.- 2.1 Sex Determination.- 2.2 Turner Syndrome.- 2.3 Histocompatibility Y Antigen (H–Y).- 2.4 Gonadoblastoma.- 2.5 Male Infertility.- 3 Yq-Specific Genes and Gene Families.- 4 Function of Y-Specific Genes in Spermatogenesis.- 4.1 RBMY.- 4.2 DAZ.- 5 Which Genes Underlie the AZF Phenotypes?.- 6 Frequency of Yq Micro deletions.- 7 Microdeletions and Genotype/Phenotype Relationships.- 8 Mechanism of Y Chromosome Microdeletions.- 9 Y Chromosome Susceptibility Haplotypes.- 10 Perspectives.- References.- Spermatogenesis and the Mouse Y Chromosome: Specialisation Out of Decay.- 1 The Unique Y Chromosome.- 2 The Functions of the Mouse Y Chromosome.- 2.1 Somatic Functions of the Mouse Y Chromosome.- 2.2 Germ Cell Functions.- 3 The Molecular Genetics of the Mouse Y Chromosome.- 3.1 Overview.- 3.2 The Long Arm.- 3.2.1 Molecular Structure.- 3.2.2 Deletion of the Long Arm.- 3.3 The Pericentric Region.- 3.3.1 Molecular Structure.- 3.3.2 Deletion of the Pericentric Region.- 3.3.3 Deletion of the Long Arm and the Pericentric Region.- 3.4 The Short Arm.- 3.4.1 Molecular Structure.- 3.4.2 Deletion of the Short Arm.- 3.4.3 Genes in the Sxrb Deletion Interval.- 3.5 The Mouse Y Chromosome in Spermatogenesis — Conclusions.- 4 Comparison of the Mouse and Human Y Chromosome Maps.- 4.1 Distinct Gene Organisation.- 4.2 A Block of Syntenic Homology.- 4.3 Implications for Spermatogenesis.- 5 Evolution of the Y Chromosome.- 5.1 Sex Chromosome Evolution Theory.- 5.1.1 The Origin of the Non-Recombining Y Chromosome (NRY).- 5.1.2 The Decay of Genes on the Non-Recombining Y Chromosome (NRY).- 5.1.3 Accumulation of Male-Enhancing Mutations.- 5.2 Evolution of Y Genes and Spermatogenesis.- 5.2.1 X–Y Homologous Genes.- 5.2.1.1 The Ubiquitin Activating Enzyme.- 5.2.1.2 Dosage Compensation.- 5.2.1.3 Restriction of Expression to the Germ Line.- 5.2.2 Y-Autosomal Genes.- 5.2.2.1 DAZ.- 5.2.2.2 RBMY.- 5.2.3 Genes of Unknown Origin.- 5.2.3.1 TSPY.- 5.2.3.2 Ssty.- 5.2.4 Y Chromosome Gene Evolution and Function.- 6 General Conclusions.- 7 The Future.- References.- The Comparative Genetics of Human Spermatogenesis: Clues from Flies and Other Model Organisms.- 1 Introduction.- 2 Model Organisms for Studying the Genetic Causes of Subfertility in Man.- 2.1 Mendelian Genetics and Male Subfertility.- 2.2 Spermatogenesis: An Ancient, Conserved Process of Cellular and Subcellular Differentiation.- 2.3 Model Organisms.- 2.3.1 Yeast.- 2.3.2 Chlamydomonas.- 2.3.3 Caenorhabditis elegans.- 2.3.4 Mouse.- 2.3.5 Zebra Fish.- 2.3.6 Drosophila.- 2.3.6.1 In Flies, the Y Chromosome Carries Only a Few Genes Essential for Spermatogenesis.- 2.3.6.2 Hundreds of Genes on the X Chromosome and Autosomes Are Involved in Spermatogenesis of Drosophila.- 2.3.6.3 Phenotypic Analysis of Sterile Male Flies Suggests That Most of These Genes Are Expressed in the Male Germ Cells.- 2.2.6.4 Sperm Components Differentiate by Independent Programs in Drosophila.- 2.3.6.5 Genetic Switches Operating During Male Germ Cell Development in Drosophila.- 2.3.6.6 Many Male Sterile Mutations in Flies Are Pleiotropic.- 3 The Comparative Genetics of Male Germ Cell Differentiation in Flies and Man.- 3.1 How Many Male Fertility Genes Exist in Man?.- 3.2 Why Does Such a Large Fraction of All Genes Participate in Spermatogenesis?.- 4 Population Studies and Mutations Affecting Male Fertility in Flies and Man.- 5 Concluding Remarks.- References.