Estrogens And Antiestrogens Ii: Pharmacology And Clinical Application Of Estrogens And Antiestrogen by Michael OettelEstrogens And Antiestrogens Ii: Pharmacology And Clinical Application Of Estrogens And Antiestrogen by Michael Oettel

Estrogens And Antiestrogens Ii: Pharmacology And Clinical Application Of Estrogens And Antiestrogen

byMichael OettelEditorEkkehard Schillinger

Paperback | January 6, 2012

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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 anti estrogens 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 anti estrogens 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.
Title:Estrogens And Antiestrogens Ii: Pharmacology And Clinical Application Of Estrogens And AntiestrogenFormat:PaperbackDimensions:681 pages, 23.5 × 15.5 × 0.17 inPublished:January 6, 2012Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:3642642616

ISBN - 13:9783642642616

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Table of Contents

5: Pharmacology of Estrogens and Antiestrogens.- In Vitro and In Vivo Models to Characterise Estrogens and Antiestrogens.- A. General Aspects.- I. Physiological Targets of Estrogens.- II. ER Ligands.- III. The Receptors - Mediators of Hormone Action, Targets for Antihormones and Modulators of Gene Expression.- B. In Vitro Methods to Characterise Estrogens and Antiestrogens.- I. Receptor-Binding Assay.- 1. Principle.- 2. Binding of Estrogens and Antiestrogens to Insect- Cell-Produced Human ERa (hERa).- a) Preparation of ER-Containing Cytosol..- b) Competition Experiment.- c) Results.- II. Ligand Effects on DNA Binding of the ER.- III. Transactivation Assays for Detection of Estrogenic and Antiestrogenic Activity.- 1. Principle.- 2. Transactivation Assay with the Vitellogenin A2-ERE-tk-CAT Reporter Gene in HeLa Cells.- a) Comparative Study of the Agonistic Potency of Four Selected Estrogens.- b) Comparative Study of the Antagonistic Potency of Selected Antiestrogens.- 3. Transactivation Assay with MVLN Cell.- 4. Comparative Study of the Transactivational Activity of ERa and ERf3.- 5. Transactivation Assay with an rPR-ERE-tk-CAT Reporter Gene.- IV. Transactivation Assay in Yeast as a Model System to Characterise Estrogenic Compounds.- 1. Principle.- Determination of the Agonistic Activity of Selected Phyto- and Mycoestrogens by Transactivation Assay in Yeast..- The Yeast Strain.- Vector Plasmids.- Recombinant Yeast Strains.- Transactivation Assay.- V. Reporter Assays Based on "Non-Classical" Mechanisms of Gene Activation by the ER.- 1. ER Activation of Genes Through AP-1.- 2. TGF-fJ3 Induction Through a Non-Classical ERE.- a) Study of Raloxifen and ZM182,780 in the TGF-f?Ass.- 3. Repression of the IL-6 Gene Expression by the ER.- VI. Estrogen Effects on Expression of Endogenous Genes in Diverse Cell Lines.- 1. Alkaline Phosphatase and PR Measurement in Ishikawa Endometrial Carcinoma Cells.- 2. The Endometrial Adenocarcinoma Cell Line RUCA-I as an In Vitro/In VivoTumor Model.- 3. Cathepsin D, PS2 and PR Induction in Mammary Cell Lines by Estrogens.- a) Estrogen Effects on the PR Level in MCF-7 Cell.- b) Estrogen Effects on the Cathepsin D and pS2 mRNA Levels and on the PR Protein Level in MCF-7 Cells.- 4. Estrogen Regulation of Prolactin Expression in Pituitary Cell.- 5. Estrogen-Regulated Genes in Liver Hepatoma Cells.- 6. Induction of ERs and Vitellogenin Synthesis in Fish Liver Cells.- VII. Ligand-Induced ER Stabilisation or Destabilisation.- 1. Comparative Study of the Effects of Different Antiestrogens on the ER Level in T47-D Cells.- VIII. Effects of ER Ligands on the Proliferation of ER-Expressing Breast Cancer and Endometrial Cell Lines.- 1. Inhibition of Estrogen-Stimulated Growth of MCF-7 Mammary Carcinoma Cells by Antiestrogens.- Experimental Design.- IX. Antioxidative Activity.- 1. Protection from Amyloid-Induced Neurotoxicity and Prevention of Glutamate-Induced Cell Death in Nerve Cell.- 2. Attenuation of Lipid Peroxidation in Synaptosomal Membranes.- 3. Fe(II) Autoxidation and Fe(III) Reduction Assays.- 4. Oxidation of Low-Density Lipoprotein Cholesterol.- C. In Vivo Test Systems to Characterise Estrogens and Antiestrogens.- I. Allen-Doisy Assay.- 1. Principle.- 2. Study Design.- 3. Scoring Criteria.- 4. Evaluation and Discussion.- II. Vaginal Mitosis and Epithelial Thickness.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- III. Vaginal Tetrazolium Reduction.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- IV. Vaginal Opening.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- V. Vaginotrophic Response.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- VI. Measurement of Sialic Acid.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- VII. Uterine Fluid Inhibition (Astwood Bioassay.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- VIII. Uterine Growth Tes.- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- IX. Regulation of Steroid Hormone Receptors, Proliferation, Differentiation and Protein Expression in the Rodent Uterus.- 1. Principle.- Steroid Hormone Receptors.- Proliferation.- Protooncogenes.- Luminal Epithelial Cell Height.- Uterine Glycogen Deposition.- Peroxidase Activity.- Complement Component C3.- 2. Study Design.- Steroid Hormone Receptors.- Proliferation.- Protooncogenes.- Luminal Epithelial Cell Height.- Uterine Glycogen Deposition.- Peroxidase Activity.- Complement Component C3.- 3. Evaluation and Discussion.- Steroid Hormone Receptors.- Proliferation.- Protooncogenes.- Luminal Epithelial Cell Height.- Uterine Glycogen Deposition.- Peroxidase Activity.- Complement Component C3.- X. Withdrawal Bleeding (Primates).- 1. Principle.- 2. Study Design.- 3. Evaluation and Discussion.- XI. Imaging of the Primate Uterus.- 1. Principle.- 2. Experimental Design.- MRI Evaluation.- Ultrasound Evaluation.- 3. Evaluation and Discussion.- XII. Pituitary Blockade.- Gonadal Growth Methods.- Gonadotropin Methods.- Ovulatory Methods.- D. Transgenic Animals.- I. ERKO Mouse.- Uterus.- Ovary.- Testis.- Mammary Gland.- Behaviour.- II.PR Mutant Mouse.- Uterus.- Ovary.- Mammary Gland.- Behaviour.- References.- Estrogen Receptor ? in the Pharmacology of Estrogens and Antiestrogens.- A. Introduction.- B. Basic Similarities Between ER? and ER?.- C. ER? Isoforms.- D. Role of Ligands in the Tissue-Specific Action of ER?.- E. Tissue Distribution of ER? mRNA and Protein.- F. Multiple Mechanisms of Transcriptional Activation and Repression by ERs.- G. What is the Phenotype of ER? Knockout Mice.- References.- Interrelationship of Estrogens with other Hormones or Endocrine Systems.- A. Introduction.- B. Thyroid Hormone Effects on Estrogen Levels.- C. Estrogen Effects on Thyroid Function.- D. Estrogen Effects on the Gastrointestinal System.- E. Estrogen Effects on the Pancreas.- F. Estrogen Effects on the Parathyroid.- G. Conclusion.- Reference.- Mammary Gland.- A. Pharmacological and Physiological Effects of Estrogens in the Mammary Gland.- I. Introduction.- II. Hormone Action on the Development of the Mammary Gland.- 1. Pregnancy.- III. Proliferation.- 1. Progestogen Effects are Complex.- IV. Apoptosis.- V. Estrogen Action During the Normal Menstrual Cycle.- 1. Estrogen and Progesterone Receptors.- 2. Proliferation.- B. Pharmacological Effects of Exogenous Estrogens and Progestogens in the Mammary Gland.- I. Effects on Proliferation and Sex-Steroid Receptors.- II. Effects on Enzymatic Conversion of Estrogens in Mammary Tissue.- References.- Cardiovascular System.- A. Introduction.- B. Female Cardiovascular Morbidity.- C. Anti-Atherosclerotic Effects.- D. Lipid Metabolism.- E. Haemostatic System.- F. Carbohydrate Metabolism.- G. Blood Pressure.- H. Direct Effects on the Arterial Wall.- I. Antioxidative Effect.- J. Antiestrogens.- References.- Bone.- Bone.- I. Macroscopic Anatom.- II. Microscopic Anatomy.- 1. Matrix and Minerals.- 2. Bone Cells.- 3. Bone Remodeling.- III. Estrogen and Bone.- Reference.- Central Nervous System.- A. Introduction.- B. Estrogens and CNS.- I. Estrogens, Neurotransmitters and Neuropeptides.- II. Estrogen Effects on Neuronal Plasticity.- III. Estrogens and Cognitive Functions.- C. Selective Estrogen Receptor Modulators (SERMs).- I. Introduction.- II. SERMs and CNS.- D. Conclusions.- References.- Liver Inclusive Protein, Lipid and Carbohydrate Metabolism.- A Liver - A Non-Reproductive Target Organ for Estrogens.- I. Regulation of the Hepatic Estrogen Receptor.- II. Exogenous Estrogen.- B. Plasma Proteins.- I. Coagulation Factors.- C. Lipids.- D. Carbohydrates.- References.- Pharmacology of Antiestrogens.- A. Introduction.- B. Reproductive Tract.- C. Breast and Breast Cancer.- D. Bone.- E. Brain.- F. Cardiovascular System.- G. Conclusion.- References.- Oncology.- A. Introduction.- B. Estrogens and Cancer Etiolog.- I. General Considerations.- II. Breast Cancer.- III. Uterine and Cervical Cance.- IV. Ovarian Cancer.- V. Vaginal Adenocarcinoma.- VI. Liver Cancer.- C. Hormones and Cancer Therapy.- I. Hormone-Dependent Neoplasms.- II. Breast Cancer.- 1. Endocrine Ablation.- 2. Antiestrogens.- 3. Aromatase Inhibitors.- 4. Estrogen Receptors.- III.Uterine and Cervical Cancer.- D. Summary.- References.- Hormonal Resistance in Breast Cancer.- A. Introduction.- B. The Estrogen Receptor.- I. The ER's Ligands.- II. ER Structure: Mutants, Variants and Post-Translational Changes.- III. Transcriptional Activity: Co-Activators and Co-Repressor.- IV. EREs and Promoter Elements.- V. Non-estrogen Response Element-Dependent Pathways.- C. Secondary Resistance.- I. Tumour Adaptation to Estrogen Levels.- II. Tamoxifen Stimulation and Withdrawal Responses.- D. Clinical Implications and New Endocrine Agents.- E. Conclusions.- References.- Pharmacology of Inhibitors of Estrogen Biosynthesis.- A. Introduction.- B. Non-Steroidal and Steroidal Aromatase Inhibitors.- C. Inhibition of Intracellular Aromatase.- References.- Pharmacology of Inhibition of Estrogen-Metabolizing Enzymes.- A. Rationale for Development of Steroid Sulphatase and Estradiol 17,?-Hydroxysteroid Dehydrogenase Inhibitors.- B. Steroid Sulphatase Inhibitors.- I. Substrate Analogue Inhibitors.- II. Identification of the Active Pharmacophore Required for Potent Steroid Sulphatase Inhibition.- III. Development of Potent Non-steroidal, Non-estrogenic Steroid Sulphatase Inhibitors.- IV. Pharmacological Effectiveness of Steroid Sulphatase Inhibition.- C. Estradiol 17,?-Hydroxysteroid Dehydrogenase Inhibitor.- I. Substrate Analogue Inhibitors.- II. Irreversible Inhibitors.- III. Fused A- or D-Ring Pyrazole and Isoxazole Inhibitors.- IV. Inhibitors with Antiestrogenic Properties.- V. Flavone and Isoflavone Inhibitors.- D. Future Perspectives.- References.- Pharmacology of Different Administration Routes - Oral vs Transdermal.- A Rationale for Various Routes of Estrogen Delivery.- B. Estrogens Available for Therapy.- I. Artificial Estrogens.- 1. Ethinyl Estradiol.- 2. Mestranol.- 3. Others.- II. Natural Estrogens.- 1. Conjugated Equine Estrogens (CEE).- 2. Estradiol.- 3. Parenteral Estrogens.- 4. Potency of Various Estrogens According to the Route of Administration.- III. Pharmacodynamic Effects of Oral and Non-oral Estrogen.- 1. On the Endometrium.- 2. On Bone.- 3. On Cardiovascular Risk Factors.- a) Acute Effects of Estradiol.- b) Chronic Effects of Estradiol.- C. Conclusion.- References.- 6: Kinetics and Toxicology of Estrogens and Antiestrogens.- Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens.- A. Natural Estrogens.- I. Analytical Methods.- II. Pharmacokinetics in Animals.- 1. Absorption.- 2. Distribution.- 3. Metabolism.- 4. Excretion.- III. Pharmacokinetics in Humans.- 1. Absorption.- 2. Distribution.- 3. Metabolism.- 4. Excretion.- IV. Comparison of Different Routes of Administration.- V. Other Estrogens.- 1. Conjugated Equine Estrogens.- 2. Estriol.- VI. Drug Interactions.- 1. Interaction with Progestins.- 2. Interaction of Estradiol with its Own Metabolism.- 3. Interaction of Estradiol with Other Drugs.- B. Synthetic Estrogens.- I. Analytical Methods.- II. Pharmacokinetics in Animals.- 1. Absorption.- 2. Distribution.- 3. Metabolism.- 4. Excretion.- III. Pharmacokinetics in Humans.- 1. Absorption.- 2. Distribution.- 3. Metabolism.- 4. Excretion.- IV. Comparison of Different Routes of Administration.- V. Drug Interactions.- 1. In Vitro.- a) Interaction with Progestins.- b) Interaction of EE with Its Own Metabolism.- 2. In Vivo.- a) Interaction with Progestins.- b) Interaction of EE with Its Own Metabolism.- c) Drugs Interfering with the Metabolism of EE.- d) Interaction with Anticonvulsant Drugs.- e) Interaction with Rifampicin.- f) Interaction with Antibiotics.- g) Interaction with Paracetamol.- h) Interaction with Grapefruit Juice.- i) Interaction with Ascorbic Acid.- j) Interference of EE with the Metabolism of Other Drugs.- C. Antiestrogens.- I. Analytical Methods.- II. Pharmacokinetics in Animals.- 1. Absorption.- 2. Distribution.- 3. Metabolism.- 4. Excretion.- III. Pharmacokinetics in Humans.- 1. Absorption.- 2. Distribution.- 3. Metabolism.- 4. Excretion.- IV. Special Populations.- 1. Influence of Age.- 2. Influence of Altered Liver and Kidney Function.- V. Drug Interactions.- References.- Toxicology of Estrogens and Antiestrogens.- A. General Aspects.- B. Toxicology of Estrogens.- I. Acute Toxicity.- II. Subchronic and Chronic Toxicity.- III. Genotoxi.- IV. Carcinogenicity.- V. Reproductive Toxicity.- 1. Effects on Fertility and Preimplantational Development.- 2. Embryotoxicity.- 3. Perinatal and Postnatal Effects.- C. Antiestrogens.- I. Acute Toxicity.- II. Subchronic and Chronic Toxicity.- III. Genotoxicity.- IV. Carcinogenicity.- V. Reproductive Toxicity.- References.- Estrogens and Sexually Transmitted Diseases.- A. Introduction.- B. The Impact of Hormonal Contraceptives.- I. Human Immunodeficiency Virus Infection.- II. Human Papilloma virus Infection.- III. Infection with Chlamydia trachomatis, Neisseria gonorrhea and Mycoplasma.- IV. Candida Albicans Infection.- V. Trichomoniasis.- C. The Impact of Hormonal Replacement Therapy.- D. Conclusion.- References.- 7: Clinical Application and Potential of Estrogens and Antiestrogens.- Hormonal Contraception.- A. History.- B. Types of Hormonal Contraceptives.- I. Progestogen-Only Contraceptives.- 1. Mini-pill.- 2. Depot -Progestogens.- II. Estrogen/Progestogen-Containing Contraceptives.- 1. Post -coital Pill.- 2. Ovulation Inhibitors.- C. Pharmacology of Contraceptive Steroids.- I. Pharmacology of Estrogens.- II. Pharmacology of Progestogens.- 1. Nortestosterone Derivatives.- 2. Progesterone Derivatives.- D. Mode of Action of Oral Contraceptives.- E. Pharmacokinetics of Oral Contraceptives.- I. Factors Influencing Efficacy.- II. Interaction of Oral Contraceptives with Drugs.- F. Use of Oral Contraceptives.- I. Choice of Oral Contraceptives.- II. Metabolic Effects of Oral Contraceptives.- III. Beneficial Effects of Oral Contraceptives.- IV. Risks and Side Effects of Oral Contraceptives.- 1. Minor Complaints during Intake of Oral Contraceptives.- 2. Fertility, Pregnancy and Lactation.- 3. Immune System.- 4. Genital Tract Infections.- 5. Respiratory Tract and Gingiva.- 6. Eyes and Ears.- 7. Skin.- 8. Gastrointestinal Tract Disease.- 9. Urinary Tract.- 10. Endocrine Effects.- 11. Neurological Diseases.- 12. Psychiatric Diseases.- 13. Physical Condition and Sports.- 14. Venous Complaints.- 15. Venous Thromboembolic Diseases.- 16. Stroke.- 17. Hyperten.- 18. Myocardial Infarction.- 19. Raynaud's Syndrome.- 20. Diabetes Mellitus.- 21. Liver.- 22. Liver Tumors.- 23. Breast.- 24. Breast Cancer.- 25. Uterine Tumors.- 26. Cervical Neoplasi.- 27. Ovarian Tumors.- 28. Other Cancers.- References.- Hormone Replacement Inclnding Osteoporosis.- A. The Menopause.- I. Climacteric Complaints.- II. Estrogens and the Skeleton.- III. HRT, Serum Lipids and the Risk of Cardiovascular Disease.- IV. Estrogens and Neurodegenerative Diseases.- V. Selective Estrogen Receptor Modulators.- References.- Gynaecological Disorders.- A. Introduction.- B. Primary Amenorrhoea.- C. Secondary Amenorrhoea.- D. Bleeding Problems.- E. Anti-estrogens.- References.- Oncology.- A. Breast Cance.- I. Systemic Hormonal Treatment of Breast Cancer.- II. Tamoxifen.- III. Present Strategies.- 1. Adjuvant Therapy.- 2. Metastatic Therapy.- 3. Prophylaxis.- 4. Male Breast Cancer.- 5. Desmoid Tumours.- IV. Estrogen Hormone Receptors in Breast Cancer.- V. Second-Line Therapy.- 1. Aromatase Inhibitors.- 2. Evolution of Aromatase Inhibitors.- VI. Future Developments.- 1. Tamoxifen Analogue.- 2. Benzothiophene Derivatives.- 3. Steroidal "Pure" Anti-estrogens.- B. Ovarian Cancer.- I. Hormonal Involvement.- 1. Hormone Replacement Therapy.- 2. Oral Contraceptives..- 3. Tamoxifen.- C. Endometrial Cancer.- I. Hormonal Involvement.- 1. Hormone Replacement Therapy.- 2. Tamoxifen.- References.- Cardiology.- A. Introduction.- B. Epidemiological Association Between Oral Contraceptive Use and Thrombosis.- C. Oral Contraceptives and Hemostasis.- I. Oral Contraceptives and the Vessel Wall.- II. Oral Contraceptives and Platelets.- III. Oral Contraceptives and Coagulation.- 1. Clotting System.- 2. Fibrinolytic System.- a) Oral Contraceptives and Fibrinolysis.- IV. Oral Contraceptives and Molecular Markers of Hemostasis Activation.- D. Oral Contraceptives and Thrombophilia.- E. Summary.- References.- Urogenital Ageing and Dermatology.- A. Urogenital Aging.- I. Specific Functional Aspects of the Urogenital System.- II. Functional Changes Due to Age and Menopause.- III. Epidemiology of Urogenital Symptoms.- IV. Clinical Evaluation.- V. Treatment.- VI. Conclusion.- B. Dermatology.- I. Skin Composition.- II. Effects of Age and Estrogen Deficiency on the Skin.- 1. Epidermis.- 2. Dermis.- III. Effects of Estrogen Replacement Therapy.- IV. Conclusion.- References.- Geriatric Neurology and Psychiatry.- A. Introduction.- B. Estrogen and the Brain..- C. Estrogen, Mood, and Behavior.- D. Estrogen and Cognition.- E. Stroke.- F. Dementia.- I. Alzheimer's Disease.- 1. Estrogen Impact on Alzheimer's Disease: Possible Mechanisms.- 2. Estrogen and Alzheimer's Disease Risk.- a) Alzheimer's Risk: Strength of Association.- b) Alzheimer's Risk: Estrogen and Apolipoprotein E.- c) Estrogen and Alzheimer's Risk: Caveats.- 3. Estrogen and Alzheimer's Disease Symptoms..- 4. Indirect Markers of Estrogen Exposure and Alzheimer's Disease.- II. Multi-infarct Dementia.- G. Other Neuropsychiatric Disorders..- I. Migraine Headache.- II. Epilepsy.- III. Parkinson's Disease and Other Movement Disorders.- IV. Multiple Sclerosis.- H. Conclusions.- References.- Estrogens and Antiestrogens in the Male.- A. Introduction.- B. Age-Related Changes of Estrogen Secretion.- C. Metabolism and Pharmacokinetics of the Estrogens in the Male.- D. Genitourinary System.- I. What Can We Learn from the ERa Knock-Out (ERKO) Mice?.- II. Gonads.- III. Epididymis.- IV. Prostate.- E. Mammary Gland.- F. Liver.- I. Estrogens.- II. Antiestrogens.- G. Bone.- H. Cardiovascular System.- I. Central Nervous System.- I. What Do We Know About Gender Differences Concerning Cerebral Blood Flow?.- II. What Do We Know About the Connection between the Serum Levels of Endogenous Estrogen and Certain CNS Functions in Men?.- III. What Do We Know about the Influence of Exogenous Estrogen on CNS Functions in Men?.- J. The Influence of Environmental Estrogens (Xenoestrogens) on the Fertility of Men.- K. Regimens for Estrogen and Antiestrogen Treatment in Men.- I. Treatment of Prostate Cancer with Estrogens.- II. Estrogen Replacement in Men.- III. Male Contraception with Estrogens.- IV. Treatment of Male-to-Female Transsexuals with Estrogens.- L. The Therapeutic Value of Antiestrogens and Aromatase Inhibitors in Men.- M. The Concept of Non-Feminizing Estrogens.- References.- 8: Comparative Endocrinology.- Comparative Aspects of Estrogen Biosynthesis and Metabolism and the Endocrinological Consequences in Different Animal Species.- A. Evolution of Estrogens.- B. Comparative Biochemistry.- I. Estrogen Biosynthesis.- II. Estrogen Receptor and Signal Transduction.- III. Elimination.- C. Evolution of Estrogen Functions.- I. Oviparous Vertebrates.- II. Viviparous Eutherian MammaliaiPlacentalia.- 1. Estrus.- 2. Embryonic Pregnancy Signaling.- 3. Placental Estrogens.- 4. Estrogens in Males.- 5. Metabolic, Anabolic and Other Secondary Features..- References.- Therapeutic Use of Estrogens in Veterinary Medicine.- A. Introduction.- B. Pharmacokin.- C. Undesirable Effects, Interactions, and Toxicity.- D. Indications.- E. Dosage.- F. Antiestrogens.- References.- 9: Estrogens, Antiestrogens, and the Environment.- Environmental Estrogens.- A. Introduction and Perspective.- B. Initial Identification of Environmental Estrogens.- I. Phytoestrogens.- II. Mycoestrogens.- III. Xenoestrogens.- C. Structures and Sources of Major Prototype Environmental Estrogens.- I. Phytoestrogens.- 1. Isoflavones.- 2. Coumestans.- 3. Lignans.- II. Mycoestrogens.- III. Xenoestrogens.- 1. Pesticides and Agricultural Chemicals.- 2. Halogenated Aromatic Hydrocarbons.- 3. Commercially Used Phenols and Related Compounds.- D. Mechanisms of Action.- I. Receptor Interactions.- II. Gene Expression.- 1. Phytoestrogens.- 2. Mycoestrogens.- 3. Xenoestrogens.- III. Cell Growth and Proliferation.- 1. The In Vivo Uterotrophic Response to Environmental Estrogens.- 2. Proliferation of Estrogen-Sensitive Cancer Cell Lines.- 3. Angiogenesis.- IV. Development and Differentiation.- 1. Effects on Female Sexual Differentiation.- 2. Effects on Uterus, Vagina and Ovary.- 3. Effects on Mammary-Gland Differentiation and Carcinogenesis.- 4. Effects in Males.- E. Human Exposures, Epidemiology and Potential Health Effects.- I. Organochlorines and the Incidence of Breast Cancer.- II. Phytoestrogens and Prevention of Breast Cancer.- III. Phytoestrogens and Prostate Cancer.- IV. Cardiovascular Disease and Osteoporosis.- V. Fertility and Reproductive Health.- F. Conclusion.- References.