Fertility Control (eBook)

Fertility Control 3
Preface 5
References 7
Contents 9
Contributors 11
New Insights into Ovarian Function 16
1 Introduction 17
2 Novel Aspects of Gonadal Development, Primordial Follicle Formation, and Early Follicle Growth 17
3 Transcription Factors That Regulate Early Postnatal Follicle Growth 19
4 Oocyte-Derived Growth Factors That Mediate Somatic Cell Function and Follicle Growth 22
5 Novel Regulatory Mechanisms That Control Follicle Growth and Differentiation 24
6 The TGFbeta Family in Regulation of Granulosa Cell Growth and Differentiation 25
7 New Mediators of Ovulation and Luteinization 28
8 New Regulators of Oocyte Maturation and Meiosis 30
9 Summary 31
References 32
Estrogen Signaling in the Regulation of Female Reproductive Functions 41
1 Introduction 42
2 Production of Estrogens 42
3 Cellular Mechanisms of Action 43
4 Estrogens and Contraception 44
4.1 Regulation of Estrogen Production 45
4.2 Regulation of Estrogen Action 45
5 Conclusions 46
References 47
Progesterone Receptors and Ovulation 48
1 Introduction 49
2 Progesterone Receptors Control LH-Induced FollicularRupture but Not Luteinization 50
3 Molecular Signaling Pathways That Mediate PR-Dependent Follicular Rupture 51
4 Regulation of Cumulus Matrix Components by PRs 51
5 Paracrine Growth Factor Signaling by PRs to Cumulus Cells 52
6 Transcriptional Programs Downstream of PRs 52
References 53
Contraception Targets in Mammalian Ovarian Development 56
1 Introduction 57
2 Ovarian Folliculogenesis and Exhaustion of the Primordial Follicle Pool 58
3 Early Folliculogenesis: Roles of Cytokines, Chemokines, Hormones and Growth Factors 60
4 Multiple Activator and Repressor Pathways Converge to Regulate Activation of the Primordial Follicle 62
5 Intracellular Signalling in Oocytes and Pregranulosa Cells in Primordial Follicles 62
6 Signal Transduction: The Phosphatidylinositol 3-Kinase (PI3K) and the mTOR Pathways 63
7 Promoting and Regulating Early Follicle Growth and Development 65
8 Conclusions 70
References 71
Proteomics of Embryonic Implantation 78
1 Introduction 79
2 Proteomic/Secretomics of the Human Embryo 81
3 Proteomics of the Human Endometrium 83
4 Proteomics of Human Endometrial Fluid 85
5 Conclusions 87
References 87
Evaluation of Plasma Membrane Calcium/Calmodulin-Dependent ATPase Isoform 4 as a Potential Target for Fertility Control 90
1 Introduction 91
1.1 The Need for New Safe, Effective, Non-hormonal Contraception 91
2 The Role of PMCA4 in Sperm Motility 93
3 The Plasma Membrane Calcium/Calmodulin-Dependent Calcium ATPases 94
3.1 Tissue Distribution of PMCA Isoforms and In vivo Specificity of Function 95
4 PMCA4 as a Suitable Drug Target 96
4.1 Suitability of the Structure of PMCA4 to Drug Targeting 96
4.2 Drugability of PMCA4 97
4.3 Target Validation: Modelling Target Action Using Knockout Mice 98
5 Identification of Hit Compounds 99
6 Specificity of Action of Potential PMCA4 Inhibitor 101
7 Conclusions 103
References 103
New Insights into Sperm Physiology and Pathology 108
1 Introduction 109
2 Oxidative Stress and Impaired Sperm Function 110
3 Impact of Oxidative Stress on Spermatozoa 111
3.1 Motility Loss 111
3.2 DNA Damage 111
4 The Physiological Role of ROS 115
5 Conclusions: Oxidative Stress in Infertility and Prospects for Contraception 118
References 120
The Epididymis as a Target for Male Contraceptive Development 125
1 Introduction 126
2 Infertile Males as a Contraceptive Paradigm 126
3 Transgenic Mice: Epididymal Models of Male Infertility 127
3.1 Infertile Male Mice Lacking the Initial Segment and Exhibiting Sperm Flagellar Angulation 127
3.1.1 c-Ros-Deficient Mice 127
3.1.2 GPX5Tag2 Transgenic Mice 128
3.2 Infertile Mice Lacking the Epididymal Initial Segment 129
3.3 Infertile Mice with Angulated Spermatozoa 130
3.3.1 Foxi1-Deficient Mice 130
3.3.2 FKBP52-Deficient Mice 131
3.3.3 Herc4-Deficient Mice 131
3.3.4 SLO3-Deficient Mice 131
3.4 Infertile Male Mice with Flagellar Angulation Combined with Testicular Defects 132
3.5 Infertile Male Mice Displaying Other Forms of Sperm Tail Angulation 133
4 Targeting Other Epididymal Proteins 133
4.1 Infertility in Mice Involving Blockage of the Efferent Ducts 133
4.1.1 HE6-Deficient Mice 133
4.1.2 Pax8-Deficient Mice 134
4.2 Infertility After Targeting Epididymal Proteins 134
4.2.1 Immunological Depletion of P34H 134
4.2.2 Immunological Depletion of Eppin 135
4.3 Persistent Fertility After Targeting Epididymal Proteins 135
4.3.1 SED1-Deficient Mice 135
4.3.2 SPAM1-Deficient Mice 136
4.3.3 CRISP1-Deficient Mice 136
4.4 Infertility in Mice Involving Blockage of the Distal Duct 137
4.4.1 Juvenile Steatosis 137
4.4.2 RARa-Deficient Mice 137
5 The Blood-Epididymis Barrier as a Hurdle and an Opening to the Administration of Putative Male Contraceptives 138
5.1 A Physical Barrier 138
5.2 A Physiological Barrier 138
5.3 Epithelial Transporters as Targets or Vehicles for Male Contraceptive Development 139
6 Conclusion 139
References 140
Sperm-Zona Pellucida Interaction: Molecular Mechanisms and the Potential for Contraceptive Intervention 146
1 Introduction 147
2 Sperm-Zona Pellucida Interaction 147
2.1 The Zona Pellucida 147
2.1.1 The Role of O-linked ZP3 Sugars in Mouse Sperm-ZP Interaction 149
2.1.2 The Role of N-Linked ZP3 Sugars in Sperm-ZP Interaction 155
2.1.3 Carbohydrate-Independent Models of Sperm-ZP Interaction 155
2.1.4 Models of ZP3 Independent Sperm-ZP Interaction 157
2.1.5 The Role of ZP2 in Sperm-ZP Interactions 157
2.2 Sperm Receptor Molecules Involved in Zona Pellucida Interaction 158
2.2.1 Acquisition of the Ability to Engage in Sperm-ZP Interaction 158
Epididymal Maturation 159
Sperm Capacitation 160
2.2.2 ZP Receptor Candidates 162
Molecular Basis for Multiple Sperm-ZP Receptor Candidates 163
2.3 Toward an Integrated Model of Sperm-Zona Interaction 164
2.3.1 The Role of Molecular Chaperones in Sperm-Zona Pellucida Interaction 164
2.3.2 The Role of Membrane Rafts in Sperm-Zona Pellucida Interaction 167
3 Potential for Contraceptive Intervention 169
3.1 Target Antigens of the Zona Pellucida 170
3.2 Target Antigens of Spermatozoa 171
4 Summary 172
References 172
Mouse Models as Tools in Fertility Research and Male-Based Contraceptive Development 186
1 Mammalian Spermatogenesis 187
2 Mouse Models for Fertility Research and Male-Based Contraceptive Development 188
3 Transgenic Mice: Ectopic Expression Models 189
4 Knockout Mice: Loss of Function Models 191
5 Conventional and Conditional Knockout Mice 193
6 Knockout Generated by Gene Trapping 195
7 Chemical-Induced Point Mutant Mice Generated by Random Whole Genome Mutagenesis 195
8 Conclusions 198
References 198
Male Hormonal Contraception 203
1 Introduction 204
1.1 The Rationale for Hormonal Male Contraception 204
1.2 Choices for the Male 204
2 Principle of Hormonal Male Contraception 205
3 Clinical Trials to Date 213
3.1 Androgens Alone 213
3.1.1 Testosterone Enanthate 213
3.1.2 Testosterone Buciclate 213
3.1.3 Testosterone Undecanoate 214
3.1.4 Testosterone Pellets 215
3.1.5 19-Nortestosterone 215
3.1.6 7a-Methyl-19-Nortestosterone (MENT) 216
3.2 Androgens Combined with GnRH Analogs 216
3.2.1 GnRH Agonists 216
3.2.2 GnRH Antagonists 216
3.3 Androgens Plus Gestagens 217
3.3.1 Depot Medoxyprogesterone Acetate (DMPA) 217
3.3.2 Levonorgestrel 219
3.3.3 Norethisterone 219
3.3.4 Cyproterone Acetate 220
3.3.5 Desogestrel and Etonogestrel 220
3.4 Differences Between Responders and Nonresponders 220
4 Acceptability of Male Contraception 222
5 Responsibility for the Development of Contraceptives 223
References 224
Family Planning: Today and in the Future 230
1 Background 231
1.1 Why Do We Need Them? 231
1.2 Who Needs Them? 232
2 Methods of Contraception in the Clinic 233
2.1 Female Methods 233
2.1.1 Steroidal 233
2.1.2 Nonsteroidal 239
2.2 Male Methods 241
2.3 Need for Improved Methods 245
3 New Leads in the Preclinical Discovery Phase 246
3.1 Potential New Female Methods 247
3.2 Potential New Female or Male Methods 249
4 Factors Influencing a Successful Outcome 252
5 Resources to Complete the Translational Process 253
6 Conclusions 254
References 254
Index 264