Estrogens and Antiestrogens I

History of Estrogen Research.- 1 History of Estrogen Research.- A. The Classical Experiments of Extirpation and Reimplantation.- I. Ovarian Extracts.- B. Isolation of Estrogens.- C. Analysis of the Steroid Structure; Nomenclature and Standardization.- D. Partial and Total Synthesis of Estrogens.- E. Localization of the Estrogen Production.- F. Estrogens in Body Fluids and Tissues.- G. Estrogens in Food.- H. Estrogen Determination.- I. Estradiol Effects at the Target Organs.- I. Vagina and Endometrium.- II Breasts.- III. Hypothalamus and Pituitary.- J. Biogenesis and Metabolism of Estrogens.- K. Physiological Effects of Estrogens.- I. Genomic Actions.- II. Non-genomic Actions.- L. Mechanism of Action of Estrogens.- M. Effects on Lipids.- N. Effects on Coagulation.- O. Estrogens in Pregnancy.- P. Fetal Endocrinology.- Q. Estrogens for Treatment.- I. Preparations.- II. Treatment of Cycle Anomalies, Bleeding Disturbances and Dysmenorrhea.- R. Side Effects of Estrogens.- S. Treatment in Pregnancy.- T Treatment of Climacteric Complaints.- U. Estrogens and Carcinogenesis.- V. Estrogens and Life Expectancy.- References.- 1: Chemistry of Estrogens and Antiestrogens.- 2 Steroidal Estrogens.- A. Introduction.- B. Total Synthesis.- C. Partial Synthesis.- I. Ring-A Substitution.- II. Ring-B Substitution..- III. Ring-C Substitution.- IV. Ring-D Substitution.- V. The Periphery.- D. Labeling of Estradiol and its Derivatives.- E. Bioconversions of Estrogens.- References.- 3 Non-steroidal Estrogens.- A. Introduction.- B. Structural Classifications of Non-Steroidal Estrogens.- I. 1,2-Diarylethanes and Ethylenes.- 1. Diethylstilbestrol (DES), hexestrol (HES) and Analogs.- 2. Structure — Activity Relationships.- 3. DES Metabolites.- II. Flavones and Isoflavones.- III. Macrolactones.- IV. Alkylphenols and Arylphenols.- V. Non-Aromatic Estrogens.- VI. Miscellaneous Non-Steriodal Templates.- C. Conclusions.- References.- 4 Antiestrogens and Partial Agonists.- A. Introduction.- B. Triphenylethylene Derivatives.- I. Tamoxifen.- II. Triphenylethylene Derivatives Related to Tamoxifen.- III. Fixed-Ring Analogues of Tamoxifen.- IV. 1,2,3-Triarylpropenone-Derived Antiestrogens.- C. Diphenylethylene Derivatives.- I. 1,1-Diphenylethylene-Derived Agents.- II. 1,2-Diphenylethylene Derivatives.- III. 2-Phenylindoles and Related Heterocycles.- D. Steroidal Compounds.- I. 7?-Substituted Estradiol Derivatives.- II. 11?-Substituted Estradiol Derivatives.- E. Conclusion.- References.- 5 Structure — Activity Relationships.- A. Introduction.- B. Estrogens and Antiestrogens with a Modified Steroid Structure.- I. Modifications of the A Ring.- II. Modifications of the D Ring.- III. Modifications of the B Ring.- IV. Modifications of the C Ring.- V. Conclusion.- C. Non-Steroidal Estrogens and Antiestrogens.- I. Derivatives of Diethylstilbestrol.- II. 2-Phenylindole Derivatives.- III. 2-Phenylbenzo[b]thiophene Derivatives.- IV. Triphenylethylene Derivatives.- V. 2,3-Triphenyl-2H-1-Benzopyrans and Related Structures.- VI. Conclusion.- References.- 2: Molecular Biology of Estrogenic Action.- 6 Structure and Function of the Estrogen Receptor.- A. Introduction.- B. Structure of the Estrogen Receptor.- I. The A/B Domain.- II. The DNA-Binding Domain.- III. The Ligand-Binding Domain.- C. ER Functions and Transcription.- I. ER DNA-Binding Properties.- IL ER Ligand-Independent Activity.- III. Ligand-Dependent Transcriptional Activity.- D. ER Isotype Diversity Generates Specificity.- I. ERa and ER/? Heterodimerization.- II. Tissue Distribution and Ligand Binding.- III. ERa and ER/? Differential Activity.- E. ERa Knock-Out Mouse: A Functional Model.- F. Future Directions.- References.- 7 Estrogen-Regulated Genes.- A. Introduction.- B. Transcriptional Control of Gene Activity by Estrogens.- I. Molecular and Cellular Determinants of Gene Responses to Estrogens.- 1. The Estrogen Receptors.- 2. Estrogen-Reponsive Gene Elements.- a) Estrogen Response Elements and Other Estrogen-Responsive DNA Elements.- b) Target Gene Promoters.- 3. The Target Cell Environment.- C. Non-transcriptional Control of Gene Activity by Estrogens.- I. Post-transcriptional Effects of Estrogens.- II. Extra-Genomic Effects of Estrogens.- References.- 8 Regulation of Constitutive and Inducible Nitric Oxide Synthase by Estrogen.- A. Introduction.- B. Isoenzymes of NOS.- I. Nitric Oxide Synthase-I.- IL Nitric Oxide Synthase-II.- III. Nitric Oxide Synthase-III.- C. Regulation of NOS Isoenzymes by 17?-Estradiol.- I. Inhibition of NOS-II Activity by 17?-Estradiol.- II Upregulation of Endothelial NOS-III Activity by 17?-Estradiol.- 1. Gender Difference and the Effect of 17?-Estradiol on Endothelial Function.- 2. Potential Mechanism of Estrogen-Induced Increased Endothelial NO Production.- a) NOS-III Gene Expression.- b) NOS-III Enzyme Activity.- c) Bioactivity of NO.- 3. Role of the Estrogen Receptor in the Regulation of NOS-III.- 4. Role of Increased Endothelial NO in the Anti-Atherosclerotic Effect of 17?-Estradiol.- D. Summary.- References.- 9 Non-Genomic Effects of Estrogens.- List of Abbreviations.- A. Introduction.- B. Evidence for Fast Estradiol-Evoked Biological Responses.- I. Central Biological Responses.- 1. Fast Estradiol Effects on the Catecholamine System.- 2. Fast Estradiol Effects on the Hippocampus.- 3. Fast Estradiol Effects on Other Areas of the Central Nervous System.- II. Peripheral Biological Responses..- C. Evidence for Specific Estradiol Binding Sites in Cellular Membranes.- I. Central Sites.- II. Peripheral Sites.- D. Evidence for Diverse Protein Estrogen Binders.- I. Estrogen Binders in Plasmalemmal Microsomal Fractions.- II. Estrogen Binders in Mitochondrial Lysosomal Fractions.- III. Estrogen Binders from Other Origins.- E. Diverse Mechanisms in the Fast Actions of Estradiol.- I. Channel Regulator.- 1. Ca2+ Channels.- 2. Others.- II. Transduction Activator.- 1. Cyclic Adenosine Monophosphate (cAMP).- 2. Phospholipase C (PLC).- 3. Mitogen-Activated Protein Kinase (MAPK).- III. Metabolic Regulator.- 1. ATPase/ATP Synthase.- 2. Glyceraldehyde-S-Phosphate Dehydrogenase (G3PD).- 3. Others.- F. Overview and Concluding Remarks.- I. The Continuum Theory.- References.- 10 Molecular Mechanisms of Antiestrogen Action.- A. Introduction.- B. Key Elements in Estrogen-Receptor Signalling Important for Antiestrogen Action.- C. Molecular Actions of Antiestrogens.- I. Effects of Antiestrogens on Binding to the Receptor, Dimerisation and Nuclear Localisation.- II. Effects of Antiestrogens on Estrogen Receptor (ER) — Estrogen Response Element (ERE) Binding and Subsequent Transcriptional Activation.- 1. Altered ER — ERE Binding Efficiency.- 2. Changes in ER Conformation Influence AF-2 Activity.- 3. Effects Enabled by AF-1 and the Phenomenon of AF-1/AF-2 Promoter Dependency.- 4. Effects Enabled by the Cellular Levels of Co-Activators/Co-Repressors.- 5. Effects on Ligand-Independent ERE Transactivation.- 6. Effects Enabled by Promoter Elements and ERE Sequence.- 7. Effects Enabled by ER Sub-Type.- III. Effects on Ap-1- and NF-kB-Mediated Transactivation.- IV. Effects on Antiestrogen-Specific Response Elements.- V. Effects on ER Degradation.- VI. Non-ER Action of Antiestrogens.- D. Modifying Effects of the Normal Cellular Phenotype on Antiestrogen Response.- E. Modifying Effects of the Cancer Cell Phenotype on Antiestrogen Response.- F. Conclusions.- References.- 3: Biosynthesis and Metabolism of Endogenous Estrogens.- 11 Estrogen Transforming Enzymes.- A. Introduction.- B. Metabolism of Estradiol by 17?-Hydroxysteroid Dehydrogenase Type 2 (HSD2).- I. 17?HSD Superfamily.- II. Tissue Distribution.- III. Regulation of 17?HSD2.- C. Cytochrome P450 Mono-Oxygenase Hydroxylation of Estrogens.- I. Cytochrome P450s.- II. C2-and C16?-Hydroxylation of Estrogens.- 1. Effect of 2- or 16?-Hydroxylation on Metabolite Estrogenicity.- 2. Modulation by Thyroid Hormones, Body Weight and Diet.- 3. Effect of Smoking on C2/C16?-Hydroxylation.- 4. C2/C16?-Hydroxylation and Breast Cancer.- 5. Induction of C2-Hydroxylation by Indole-3-Carbinol.- 6. C2/C16?-Hydroxylation in Different Ethnic Groups.- 7. Effect of Pesticides on C2/C16?-Estrogen Hydroxylation.- 8. Inhibition of C2-Hydroxylation.- 9. Estrogen-2-Hydroxylation by Placental Aromatase.- D. Catechol Estrogens and Carcinogenesis.- E. Estrogen Sulphates.- I. Estrogen Sulphate Formation.- II. Biological Role of Estrogen Sulphation.- III. Regulation of Estrogen Sulphation.- F. Estrogen Glucuronides.- G. Lipoidal Estrogens.- H. Conclusions.- References.- 12 Metabolism of Endogenous Estrogens.- A. Introduction.- I. Estradiol Breakdown Mechanisms.- II. Sex Differences in Estradiol Metabolism.- III. Catechol Estrogen Metabolism.- B. Estrogen Metabolism and Disease.- I. Breast Cancer.- II. Endometrial Cancer.- III. Cervical Cancer.- IV. Prostate Cancer.- V. Papilloma of the Larynx.- VI. Liver Disease.- VII. Lupus Erythematosus.- VIII. Disease of the Thyroid.- IX. Weight Changes.- X. Depression.- XL Osteoporosis.- C. Drugs.- D. Lifestyle.- E. Pregnancy.- I. Changes in Metabolism During Pregnancy.- References.- 4: Physiology and Pathophysiology of Estrogens.- 13 Phylogeny of Estrogen Synthesis, Extragenital Distribution of Estrogen Receptors and Their Development Role.- A. Phylogeny of Estrogen Synthesis.- B. Extragenital Distribution of Estrogen Receptors and Their Functional Significance.- I. Breast.- II. Bone.- III. Gastrointestinal Tract.- IV. Cardiovascular System.- V. Immune System.- VI. Pituitary.- VII. Central Nervous System.- VIII. Membrane-Bound ERs.- C. Hormonal Regulation of ER Synthesis.- I. Estrogens.- II. Thyroid Hormones.- III. Progesterone.- IV. Androgens.- V. Glucocorticoids.- VI. Neurotransmitters.- D. Developmental Role of ERs as Exemplified by Hormone-Dependent Brain Differentiation.- References.- 14 Female Reproductive Tract.- A. Embryology of the Reproductive Tract.- B. Sex Differentiation.- I. Genetic Sex.- II. Gonadal Sex.- 1. Male.- 2. Female.- III. Somatic Sex.- 1. Male Sex Differentiation.- 2. Female Sex Differentiation.- 3. Estrogens and Sex Differentiation.- C. Estrogens and Ovary.- D. Fallopian Tubes.- I. Steroidal Regulation.- E. Uterus.- I. Estrogen Regulation.- II. Estrogens and Uterine Pathology.- F Cervix.- I. Estrogen Regulation.- G. Vagina.- I. Estrogens and Vaginal Pathology.- References.- 15 Estrogen and Brain Function: Implications for Aging and Dementia.- List of Abbreviations.- A. Introduction.- B. Current Views on Estrogen’s Mechanism of Action.- C. Non-Reproductive Brain Functions Influenced by Estrogen.- I. Cognition (Learning and Memory).- 1. Basal Forebrain Cholinergic System.- 2. Hippocampal ?-Aminobutyric Acid (GABA) Interneurons.- 3. Hippocampal CA1 Pyramidal Neurons.- II. Psychological Function.- 1. Midbrain Serotonergic Neurons.- III. Sensorimotor Performance.- 1. Nigrostriatal Dopaminergic System.- IV. Non-Neuronal Functions: “Brain Maintenance”.- 1. Glial Cells.- 2. Endothelial Cells of the Blood — Brain Barrier (BBB).- D. Summary.- References.- 16 Cardiovascular System.- A. Introduction.- B. Cardioprotective Mechanism of Estrogens.- I. Indirect Action on the Cardiovascular System by a Change of the Lipid Balance.- 1. Atherogenic Lipoproteins.- 2. High-Density Lipoprotein.- 3. Lipoprotein (a).- 4. Influence of Estrogen Replacement Therapy and HRT on the Lipid Profile.- II. Direct Effect of Estrogens on the Vascular Wall.- C. Influence of Progesterone and Progestagens.- D. Conclusion.- References.- 17 Immune System.- A. Introduction.- B. Effect on Primary Lymphoid Tissue.- I. The Effect of Estrogens.- 1. The Bone Marrow.- 2. The Thymus.- C. Effect on Immune Function.- I. The Effect of Estrogens.- 1. Receptors.- 2. Cytokines.- 3. Humoral Immunity.- 4. Cell-Mediated Immunity.- 5. Inflammation.- II. The Effect of Anti-Estrogens.- 1. Lymphocytes.- 2. Humoral Immunity.- 3. Cell-Mediated Immunity.- 4. Inflammation.- D. Conclusions.- References.- 18 Male Reproductive function.- A. Introduction.- B. Source of Estrogen in the Male.- C. Localization of the Estrogen Receptor in the Male Genital Tract.- D. Function of Estrogens in the Male.- I. Bone Maturation.- II. Testicular Function.- III. Prostate.- IV. Behavior.- E. Conclusions.- References.- 19 The Effect of Estrogens and Antiestrogens on the Urogenital Tract.- A. Introduction.- B. Pathophysiology.- I. Hormonal Influences on the Urogenital Tract.- II. The Effect of Ageing on the Bladder.- C. Estrogen and Urinary Incontinence.- I. Epidemiological Studies.- II. Estrogen and the Continence Mechanism.- III. Estrogens for Stress Incontinence.- IV. Estrogens for Urge Incontinence.- D. Estrogen for Recurrent Urinary-Tract Infections.- E. Estrogen for Vaginal Atrophy.- E Antiestrogens and the Urogenital Tract.- G. Conclusions.- References.- 20 Effects of Estrogens on Various Endocrine Regulations.- A. The Complexity of Estrogen’s Action on Various Tissues.- I. Introduction.- II. Estrogen Receptor-Mediated Tissue Specificity.- III. Sex-Hormone-Binding Globulin-Mediated Estrogenic Action.- B. Estrogens and the Thyroid.- I. Sexual Dimorphism in Thyroid Disease.- II. The Effect of Estrogens in Thyroid Enlargement.- III. Thyroid Dysfunction.- IV Thyroid Hormone-Binding Globulin.- V Thyrotropin Regulation.- C. Estrogens and the Adrenal Glands.- I. Sexual Dimorphism in Adrenal Disease?.- II. Regulation of Adrenal Sex-Steroid Precursors.- III. Anti-toxic Properties of the Adrenal Glands.- IV Corticosteroid-Binding Globulin.- V Corticotropin Regulation.- D. Estrogens and the Phosphocalcic Metabolism.- I. Bone Remodeling and Calcium Kinetics.- II. Parathyroid Hormone.- III. Vitamin D.- References.