Habenicht / Aitken Fertility Control

1. Auflage 2010
ISBN: 978-3-642-02062-9
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 198, 263 Seiten

Reihe: Handbook of Experimental Pharmacology

The world's population is growing at an unsustainable rate. From a baseline ?gure of one billion in 1800, global population is predicted to exceed nine billion by 2050 and 87. 8% of this growth will be localized in less developed countries. Such uneven population growth will yield a harvest of poverty, malnutrition, disease and en- ronmental degradation that will affect us all. Amongst the complex mixture of political, social, cultural and technological changes needed to address this issue, the development of improved methods of fertility regulation will be critical. The inadequacy of current contraceptive technologies is indicated by recent data s- gesting that the contraceptive needs of over 120 million couples go unmet every year. As a direct consequence of this de?cit 38% of pregnancies are unplanned and more than 50% end in an abortion, generating a total of 46 million abortions per annum particularly among teenagers. If safe, effective contraceptives were ava- able to every couple experiencing an unmet family planning need, 1. 5 million lives would be saved each year (UNFPA 2003). Progress in contraceptive technology should not only generate more effective methods of regulating fertility, but should also provide a range of methods to meet the changing needs of the world's population. Contraceptive practice was revo- tionized in 1960 in the US and 1961 in Europe by the introduction of the oral contraceptive pill by Gregory Pincus, MC Chang and colleagues, based on fun- mental hormone research conducted in Germany.

Autoren/Hrsg.

Aitken, John

Habenicht, Ursula-F.

Aitken, Robert John

Inhaltsverzeichnis

1;Fertility Control;3
1.1;Preface;5
1.2;References;7
1.3;Contents;9
1.4;Contributors;11
1.5;New Insights into Ovarian Function;16
1.5.1;1 Introduction;17
1.5.2;2 Novel Aspects of Gonadal Development, Primordial Follicle Formation, and Early Follicle Growth;17
1.5.3;3 Transcription Factors That Regulate Early Postnatal Follicle Growth;19
1.5.4;4 Oocyte-Derived Growth Factors That Mediate Somatic Cell Function and Follicle Growth;22
1.5.5;5 Novel Regulatory Mechanisms That Control Follicle Growth and Differentiation;24
1.5.6;6 The TGFbeta Family in Regulation of Granulosa Cell Growth and Differentiation;25
1.5.7;7 New Mediators of Ovulation and Luteinization;28
1.5.8;8 New Regulators of Oocyte Maturation and Meiosis;30
1.5.9;9 Summary;31
1.5.10;References;32
1.6;Estrogen Signaling in the Regulation of Female Reproductive Functions;41
1.6.1;1 Introduction;42
1.6.2;2 Production of Estrogens;42
1.6.3;3 Cellular Mechanisms of Action;43
1.6.4;4 Estrogens and Contraception;44
1.6.4.1;4.1 Regulation of Estrogen Production;45
1.6.4.2;4.2 Regulation of Estrogen Action;45
1.6.5;5 Conclusions;46
1.6.6;References;47
1.7;Progesterone Receptors and Ovulation;48
1.7.1;1 Introduction;49
1.7.2;2 Progesterone Receptors Control LH-Induced FollicularRupture but Not Luteinization;50
1.7.3;3 Molecular Signaling Pathways That Mediate PR-Dependent Follicular Rupture;51
1.7.4;4 Regulation of Cumulus Matrix Components by PRs;51
1.7.5;5 Paracrine Growth Factor Signaling by PRs to Cumulus Cells;52
1.7.6;6 Transcriptional Programs Downstream of PRs;52
1.7.7;References;53
1.8;Contraception Targets in Mammalian Ovarian Development;56
1.8.1;1 Introduction;57
1.8.2;2 Ovarian Folliculogenesis and Exhaustion of the Primordial Follicle Pool;58
1.8.3;3 Early Folliculogenesis: Roles of Cytokines, Chemokines, Hormones and Growth Factors;60
1.8.4;4 Multiple Activator and Repressor Pathways Converge to Regulate Activation of the Primordial Follicle;62
1.8.5;5 Intracellular Signalling in Oocytes and Pregranulosa Cells in Primordial Follicles;62
1.8.6;6 Signal Transduction: The Phosphatidylinositol 3-Kinase (PI3K) and the mTOR Pathways;63
1.8.7;7 Promoting and Regulating Early Follicle Growth and Development;65
1.8.8;8 Conclusions;70
1.8.9;References;71
1.9;Proteomics of Embryonic Implantation;78
1.9.1;1 Introduction;79
1.9.2;2 Proteomic/Secretomics of the Human Embryo;81
1.9.3;3 Proteomics of the Human Endometrium;83
1.9.4;4 Proteomics of Human Endometrial Fluid;85
1.9.5;5 Conclusions;87
1.9.6;References;87
1.10;Evaluation of Plasma Membrane Calcium/Calmodulin-Dependent ATPase Isoform 4 as a Potential Target for Fertility Control;90
1.10.1;1 Introduction;91
1.10.1.1;1.1 The Need for New Safe, Effective, Non-hormonal Contraception;91
1.10.2;2 The Role of PMCA4 in Sperm Motility;93
1.10.3;3 The Plasma Membrane Calcium/Calmodulin-Dependent Calcium ATPases;94
1.10.3.1;3.1 Tissue Distribution of PMCA Isoforms and In vivo Specificity of Function;95
1.10.4;4 PMCA4 as a Suitable Drug Target;96
1.10.4.1;4.1 Suitability of the Structure of PMCA4 to Drug Targeting;96
1.10.4.2;4.2 Drugability of PMCA4;97
1.10.4.3;4.3 Target Validation: Modelling Target Action Using Knockout Mice;98
1.10.5;5 Identification of Hit Compounds;99
1.10.6;6 Specificity of Action of Potential PMCA4 Inhibitor;101
1.10.7;7 Conclusions;103
1.10.8;References;103
1.11;New Insights into Sperm Physiology and Pathology;108
1.11.1;1 Introduction;109
1.11.2;2 Oxidative Stress and Impaired Sperm Function;110
1.11.3;3 Impact of Oxidative Stress on Spermatozoa;111
1.11.3.1;3.1 Motility Loss;111
1.11.3.2;3.2 DNA Damage;111
1.11.4;4 The Physiological Role of ROS;115
1.11.5;5 Conclusions: Oxidative Stress in Infertility and Prospects for Contraception;118
1.11.6;References;120
1.12;The Epididymis as a Target for Male Contraceptive Development;125
1.12.1;1 Introduction;126
1.12.2;2 Infertile Males as a Contraceptive Paradigm;126
1.12.3;3 Transgenic Mice: Epididymal Models of Male Infertility;127
1.12.3.1;3.1 Infertile Male Mice Lacking the Initial Segment and Exhibiting Sperm Flagellar Angulation;127
1.12.3.1.1;3.1.1 c-Ros-Deficient Mice;127
1.12.3.1.2;3.1.2 GPX5Tag2 Transgenic Mice;128
1.12.3.2;3.2 Infertile Mice Lacking the Epididymal Initial Segment;129
1.12.3.3;3.3 Infertile Mice with Angulated Spermatozoa;130
1.12.3.3.1;3.3.1 Foxi1-Deficient Mice;130
1.12.3.3.2;3.3.2 FKBP52-Deficient Mice;131
1.12.3.3.3;3.3.3 Herc4-Deficient Mice;131
1.12.3.3.4;3.3.4 SLO3-Deficient Mice;131
1.12.3.4;3.4 Infertile Male Mice with Flagellar Angulation Combined with Testicular Defects;132
1.12.3.5;3.5 Infertile Male Mice Displaying Other Forms of Sperm Tail Angulation;133
1.12.4;4 Targeting Other Epididymal Proteins;133
1.12.4.1;4.1 Infertility in Mice Involving Blockage of the Efferent Ducts;133
1.12.4.1.1;4.1.1 HE6-Deficient Mice;133
1.12.4.1.2;4.1.2 Pax8-Deficient Mice;134
1.12.4.2;4.2 Infertility After Targeting Epididymal Proteins;134
1.12.4.2.1;4.2.1 Immunological Depletion of P34H;134
1.12.4.2.2;4.2.2 Immunological Depletion of Eppin;135
1.12.4.3;4.3 Persistent Fertility After Targeting Epididymal Proteins;135
1.12.4.3.1;4.3.1 SED1-Deficient Mice;135
1.12.4.3.2;4.3.2 SPAM1-Deficient Mice;136
1.12.4.3.3;4.3.3 CRISP1-Deficient Mice;136
1.12.4.4;4.4 Infertility in Mice Involving Blockage of the Distal Duct;137
1.12.4.4.1;4.4.1 Juvenile Steatosis;137
1.12.4.4.2;4.4.2 RARa-Deficient Mice;137
1.12.5;5 The Blood-Epididymis Barrier as a Hurdle and an Opening to the Administration of Putative Male Contraceptives;138
1.12.5.1;5.1 A Physical Barrier;138
1.12.5.2;5.2 A Physiological Barrier;138
1.12.5.3;5.3 Epithelial Transporters as Targets or Vehicles for Male Contraceptive Development;139
1.12.6;6 Conclusion;139
1.12.7;References;140
1.13;Sperm-Zona Pellucida Interaction: Molecular Mechanisms and the Potential for Contraceptive Intervention;146
1.13.1;1 Introduction;147
1.13.2;2 Sperm-Zona Pellucida Interaction;147
1.13.2.1;2.1 The Zona Pellucida;147
1.13.2.1.1;2.1.1 The Role of O-linked ZP3 Sugars in Mouse Sperm-ZP Interaction;149
1.13.2.1.2;2.1.2 The Role of N-Linked ZP3 Sugars in Sperm-ZP Interaction;155
1.13.2.1.3;2.1.3 Carbohydrate-Independent Models of Sperm-ZP Interaction;155
1.13.2.1.4;2.1.4 Models of ZP3 Independent Sperm-ZP Interaction;157
1.13.2.1.5;2.1.5 The Role of ZP2 in Sperm-ZP Interactions;157
1.13.2.2;2.2 Sperm Receptor Molecules Involved in Zona Pellucida Interaction;158
1.13.2.2.1;2.2.1 Acquisition of the Ability to Engage in Sperm-ZP Interaction;158
1.13.2.2.1.1;Epididymal Maturation;159
1.13.2.2.1.2;Sperm Capacitation;160
1.13.2.2.2;2.2.2 ZP Receptor Candidates;162
1.13.2.2.2.1;Molecular Basis for Multiple Sperm-ZP Receptor Candidates;163
1.13.2.3;2.3 Toward an Integrated Model of Sperm-Zona Interaction;164
1.13.2.3.1;2.3.1 The Role of Molecular Chaperones in Sperm-Zona Pellucida Interaction;164
1.13.2.3.2;2.3.2 The Role of Membrane Rafts in Sperm-Zona Pellucida Interaction;167
1.13.3;3 Potential for Contraceptive Intervention;169
1.13.3.1;3.1 Target Antigens of the Zona Pellucida;170
1.13.3.2;3.2 Target Antigens of Spermatozoa;171
1.13.4;4 Summary;172
1.13.5;References;172
1.14;Mouse Models as Tools in Fertility Research and Male-Based Contraceptive Development;186
1.14.1;1 Mammalian Spermatogenesis;187
1.14.2;2 Mouse Models for Fertility Research and Male-Based Contraceptive Development;188
1.14.3;3 Transgenic Mice: Ectopic Expression Models;189
1.14.4;4 Knockout Mice: Loss of Function Models;191
1.14.5;5 Conventional and Conditional Knockout Mice;193
1.14.6;6 Knockout Generated by Gene Trapping;195
1.14.7;7 Chemical-Induced Point Mutant Mice Generated by Random Whole Genome Mutagenesis;195
1.14.8;8 Conclusions;198
1.14.9;References;198
1.15;Male Hormonal Contraception;203
1.15.1;1 Introduction;204
1.15.1.1;1.1 The Rationale for Hormonal Male Contraception;204
1.15.1.2;1.2 Choices for the Male;204
1.15.2;2 Principle of Hormonal Male Contraception;205
1.15.3;3 Clinical Trials to Date;213
1.15.3.1;3.1 Androgens Alone;213
1.15.3.1.1;3.1.1 Testosterone Enanthate;213
1.15.3.1.2;3.1.2 Testosterone Buciclate;213
1.15.3.1.3;3.1.3 Testosterone Undecanoate;214
1.15.3.1.4;3.1.4 Testosterone Pellets;215
1.15.3.1.5;3.1.5 19-Nortestosterone;215
1.15.3.1.6;3.1.6 7a-Methyl-19-Nortestosterone (MENT);216
1.15.3.2;3.2 Androgens Combined with GnRH Analogs;216
1.15.3.2.1;3.2.1 GnRH Agonists;216
1.15.3.2.2;3.2.2 GnRH Antagonists;216
1.15.3.3;3.3 Androgens Plus Gestagens;217
1.15.3.3.1;3.3.1 Depot Medoxyprogesterone Acetate (DMPA);217
1.15.3.3.2;3.3.2 Levonorgestrel;219
1.15.3.3.3;3.3.3 Norethisterone;219
1.15.3.3.4;3.3.4 Cyproterone Acetate;220
1.15.3.3.5;3.3.5 Desogestrel and Etonogestrel;220
1.15.3.4;3.4 Differences Between Responders and Nonresponders;220
1.15.4;4 Acceptability of Male Contraception;222
1.15.5;5 Responsibility for the Development of Contraceptives;223
1.15.6;References;224
1.16;Family Planning: Today and in the Future;230
1.16.1;1 Background;231
1.16.1.1;1.1 Why Do We Need Them?;231
1.16.1.2;1.2 Who Needs Them?;232
1.16.2;2 Methods of Contraception in the Clinic;233
1.16.2.1;2.1 Female Methods;233
1.16.2.1.1;2.1.1 Steroidal;233
1.16.2.1.2;2.1.2 Nonsteroidal;239
1.16.2.2;2.2 Male Methods;241
1.16.2.3;2.3 Need for Improved Methods;245
1.16.3;3 New Leads in the Preclinical Discovery Phase;246
1.16.3.1;3.1 Potential New Female Methods;247
1.16.3.2;3.2 Potential New Female or Male Methods;249
1.16.4;4 Factors Influencing a Successful Outcome;252
1.16.5;5 Resources to Complete the Translational Process;253
1.16.6;6 Conclusions;254
1.16.7;References;254
1.17;Index;264