Estrogens are critical to the development and maintenance of reproduction. We study their action in health and disease. I. Estrogen control of LHRH release. Our studies have indicated that the biochemical effects of estrogens on the hypothalamus and preoptic area are accompanied by ultrastructural changes in the connections between hypothalamic neurons, their organelles and secretory products, and neuronal cell membranes. We will continue to study estrogen effects on catecholamine metabolizing enzymes and catecholamines to assess the permanence of estrogen-induced neurotransmitter changes and their relationship to estrogen-induced hypothalamic damage. Thin section electron microscopy will be used with and without immunohistochemistry for specific hormone and neurotransmitter antigens. Estrogen effects upon endogenous opioid and catecholamine receptors in the arcuate nucleus and preoptic area will be studied using in vitro autoradiographic techniques. Long-term effects of estrogens on arcuate nucleus neuronal membranes will be studied by thin section electron microscopy and morphometry to assess synapses and intracellular membranous structures. Freeze fracture will also be used to study the effects of estrogen upon the protein and lipid domains of arcuate nucleus neuronal membranes. Previous observations on sex differences in membrane composition will be extended and the effects of the estrus cycle and gonadal ablation/replacement will be examined. Acute effects of estrogens on neuronal membranes will be studied by organ culture followed by freeze fracture evaluation of membrane composition and endo/exocytotic activity. In order to resolve the question of direct versus indirect effects of estrogen upon neuronal cells, SV-40 transformed hypothalamic cell lines will be identified which are estrogen receptor positive or negative and tested for effects of estrogens using thin section and freeze fracture electron microscopy. II. Prior studies indicate that catechol estrogens (CE) may be local hormones, acting in and around the tissues which produce them from circulating monophenolic estrogens. There is evidence for a role for CE in the female reproductive tract. We will determine estrogen 2/4 hydroxylase activity in ovary, early placenta and endometrium and measure CE and metabolites in the reproductive tract. We will test for CE actions upon ovarian metabolism, steroidogenesis and implantation of the trophoblast.
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