Female sex steroids: receptors and function.

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.