Female Sex Steroids

I. Introduction.- 1. Historical Aspects of Steroid Hormone Action.- 2. General Consideration of the Steroid Receptor Concept.- II. Steroid Receptor Characterization and Measurement.- 1. Receptor Criteria.- a) Finite Binding Capacity.- b) High Affinity.- c) Steroid Specificity.- d) Tissue Specificity.- e) Correlation with Biologic Response.- 2. Receptor Parameters: Theory and Practice.- a) Receptor Measurement when Nonspecific Binding is Large.- b) Interpretation of Saturation Parameters by Scatchard Analysis.- 1) Estimates of Receptor Number in the Presence of Nonspecific Binding.- 2) Two Specific Sites with Different Affinities.- c) Resolving Mixed Binding Systems.- d) Receptor Determination when the Concentration of Receptor Greatly Exceeds the Dissociation Constant of the Reaction.- e) Steroid Binding Specificity.- 1) Competitive vs. Noncompetitive Interactions.- 2) Competitive Binding Analysis: Problems and Interpretations.- f) Hooks and Curves in Scatchard Plots.- 1) High Concentration of Ligand or Receptor Sites.- 2) Nonequilibrium Conditions.- 3) Instability of Ligand or Receptor Sites.- 4) Dilution of Radioactivity.- 5) Interacting Species.- 3. Receptor States and 3H-Steroid Exchange.- a) Exchange Techniques in Theory and Practice.- b) Time and Temperature of Steroid Exchange.- c) Determination of the Binding State of Receptor Sites.- 4. Methods of Receptor Assay.- a) Cytoplasmic Receptors.- 1) Charcoal Adsorption Procedure.- 2) Hydroxylapatite Procedure.- 3) Protamine Sulfate Precipitation Method.- 4) DEAE Filter Method.- b) Nuclear Receptors.- 1) 3H-Estradiol Exchange of Nuclear Receptor-Estrogen Complexes.- 2) Modifications of 3H-Steroid Exchange Assay.- 3) Nuclear Binding and Retention of Receptor-Hormone Complexes.- III. Cellular Compartments and Translocation of Receptor-Steroid Complexes.- 1. Cytoplasmic or Nuclear Localization of Receptors.- 2. Evidence for Nuclear Preference.- 3. Are Cytoplasmic Receptors Necessary?.- 4. Mechanisms for Steroid Accumulation not Involving Receptors.- IV. Characteristics of Cytoplasmic and Nuclear Receptor Forms.- 1. Cytoplasmic Forms of Estrogen and Progesterone Receptors.- a) Sucrose Density Gradient Analysis.- b) Chromatographic and Electrophoretic Analysis.- c) Type II Binding Sites in Uterine Cytosol.- 2. Nuclear Binding of Estrogen and Progesterone Receptors.- a) Receptor Forms and Nuclear Binding.- b) Two Types of Estrogen Binding Sites in Uterine Nuclei.- 3. Nuclear Acceptor Sites and Nuclear Binding.- V. Nuclear Binding and Biologic Response.- 1. Nuclear Occupancy and Response.- a) Nuclear Retention of the Estrogen Receptor.- b) Early Uterotropic Responses and the Retention of Nuclear Estrogen Receptor.- c) Late Uterotropic Responses and the Retention of RnE Complexes.- 2. Nuclear Acceptors and Long-Term Nuclear Retention.- 3. Uterotropic Response and Nuclear Retention of the Estrogen Receptor.- 4. Nuclear Receptor Binding and the Control of Transcriptional Events in the Uterus.- a) RNA Polymerase Activity.- b) RNA Polymerase Initiation Sites in the Uterus.- 5. Interrelationships Between Early and Late Uterotropic Responses.- 6. Nuclear Binding and RNA Transcription in the Chick Oviduct.- 7. Nuclear Binding and the Control of RNA and Protein Synthesis in the Chicken Liver.- a) Binding of Estrogen by Chick Liver Nuclei.- b) Relationship Between Nuclear Binding, RNA Polymerase Activity, and Polymerase Initiation Sites.- c) Relationship Between Nuclear Estrogen Receptor and the Synthesis of VLDL and Plasma Triglycerides.- VI. Control of Steroid Receptor Levels and Steroid Antagonism.- 1. Control of Estrogen Receptor Concentrations.- 2. The Relationship of Cytoplasmic Replenishment of the Estrogen Receptor to Biologic Response.- 3. Control of the Progesterone Receptor by Estrogen.- 4. Effects of Progesterone on the Control of Progesterone Receptor.- 5. Control of Estrogen Receptor Levels by Progesterone and Its Relationship to Estrogen Antagonism.- a) Receptor Replenishment.- b) Nuclear Accumulation and Retention of the Receptor-Estrogen Complex.- c) Antagonism of Estrogen Receptor by Progesterone in the Adult Rat Uterus.- 6. Estradiol Antagonism by Estriol and Other Short-Acting Estrogens.- a) Effects of Estriol on Replenishment of the Cytoplasmic Estrogen Receptor.- b) Estriol Effects on RnE2 Retention and Uterine Growth.- 7. Triphenylethylene Derivatives and Estrogen Antagonism.- a) Effects of Triphenylethylene Derivatives on Uterine Growth.- b) Effects of Anti-Estrogens on Cytoplasmic Replenishment and Nuclear Retention of Estrogen Receptors.- c) Triphenylethylene Derivatives and Differential Cell Stimulation.- 8. General Considerations of Steroid Antagonism and Hormone Potency.- a) Classification of Estrogen Agonists and Antagonists.- b) Biologic Implications of Short- and Long-Acting Estrogen Agonists and Antagonists.- c) Dose Response Curves, Estrogen Potency, and Receptor Occupancy.- VII. Steroid Hormones and Neoplasia.- 1. Estrogens and Cancer.- 2. Triphenylethylene Derivatives, Hyperestrogenization, and Reproductive-Tract Cancer.- 3. Hyperestrogenization and Nuclear Body Formation.- 4. Steroid Receptors and Neoplasia.- a) Estrogen-Dependent Growth.- b) Interactions of Estrogen and Progesterone Receptors.- c) Estrogen-Independent Growth.- VIII. Physiologic Relationships and Steroid Receptor Binding.- 1. Blood Binding and Metabolism of Steroids.- 2. Steroid Receptors During Development.- a) Estrogen Receptors and Uterine Development.- b) Estrogen Receptors During Avian Oviduct Development.- 3. Steroid Receptor Binding During the Reproductive Cycle.- a) Receptor Binding in the Ovary.- b) Steroid Receptors in the Uterus and Pituitary.- 1) Estrogen Receptor.- 2) Progesterone Receptor.- c) Steroid Receptor Binding During Pregnancy and Lactation.- 1) Uterus.- 2) Ovary.- 3) Mammary Gland.- 4) Placenta and Fetus.- IX. Gonadal Steroids and Brain Function.- 1. Distribution of Targets Within the Central Nervous System.- a) In Vivo Uptake and Retention of 3H-Steroid.- b) Autoradiographic Localization of Estrogen and Progesterone Receptive Sites.- 2. Cytoplasmic Receptors for Estrogens and Progestins in the Central Nervous System.- 3. Translocation of Estrogen Receptors to Nuclear Compartments.- 4. Age- and Sex-Related Differences in Receptor Content or Function.- 5. Gonadal Steroids and Nervous System Function.- a) Estrogens and Hypothalamic RNA Polymerases.- b) Hypothalamic Control of Gonadotropin Secretion.- X. Speculations and Conclusions.- 1. Interplay of Low-and High-Affinity Steroid Receptive Sites.- 2. Spare Receptors and Hormone-Induced Responses.- 3. Nuclear Acceptors and Salt-Insoluble Receptors.- 4. Nuclear Processing of the Receptor-Estrogen Complex.- 5. Homeostatic vs. Growth-Regulating Steroid Hormones.- 6. Conclusions.- a) Hormone Delivery to Target Cells.- b) Hormone Binding to Receptors in the Cytoplasm.- c) Nuclear Binding of Receptor-Hormone Complexes and Hormone-Stimulated Events.- d) Antagonism of Hormone Action.- e) Neoplasia and Estrogens.- 7. Epilogue.- References.