Estrogens and Antiestrogens I

For many years, Springer has been publishing an impressive series of textbooks of pharmacology which have set standards in medical science. Surprisingly, an extensive overview of the current state of the art in research on estrogens and anti estrogens was still lacking. The present two volumes on estrogens and antiestrogens provide a comprehensive review of a field of research in which remarkable progress has been made over the past few years. New insights into the mechanisms of steroid hormone action resulted in a tremendous number of publications from which new principles of preventive and therapeutic appli­ cations of estrogens and antiestrogens emerged. Although various electronic data bases provide easy access to this copious information, there was a clear necessity for a monograph-style textbook which assesses and summarizes current knowledge in this rapidly expanding field of research. It should be noted, however, that, due to this dynamic development, it is barely possible to comprehensively update every aspect of basic and clinical knowledge on estro­ gens and antiestrogens. Thus, the intention of the editors was to provide the reader with an overview of the "classic" and most recently explored areas of research and stimulate future interests in basic and applied endocrinology. Estrogens were among the first steroid hormones described in the scientific literature. Since they were first isolated, since the chemical, synthesic and pharmacological characterization of naturally occurring estrogens and, later on, of orally active derivatives, estrogen research has produced continu­ ously hallmark results in reproductive endocrinology worldwide.

Contenu

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-…