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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD013587-07
Application #
3312239
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1980-09-30
Project End
1989-08-31
Budget Start
1986-09-16
Budget End
1987-08-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Naftolin, Frederick; Malaspina, Dolores (2007) Estrogen, estrogen treatment and the post-reproductive woman's brain. Maturitas 57:23-6
Naftolin, F; Horvath, T L; Balthazart, J (2001) Estrogen synthetase (aromatase) immunohistochemistry reveals concordance between avian and rodent limbic systems and hypothalami. Exp Biol Med (Maywood) 226:717-25
Keefe, D L; Watson, R; Naftolin, F (1999) Hormone replacement therapy may alleviate sleep apnea in menopausal women: a pilot study. Menopause 6:196-200
Horvath, T L; Garcia-Segura, L M; Naftolin, F (1997) Lack of gonadotropin-positive feedback in the male rat is associated with lack of estrogen-induced synaptic plasticity in the arcuate nucleus. Neuroendocrinology 65:136-40
Diano, S; Naftolin, F; Horvath, T L (1997) Gonadal steroids target AMPA glutamate receptor-containing neurons in the rat hypothalamus, septum and amygdala: a morphological and biochemical study. Endocrinology 138:778-89
Horvath, T L; Roa-Pena, L; Jakab, R L et al. (1997) Aromatase in axonal processes of early postnatal hypothalamic and limbic areas including the cingulate cortex. J Steroid Biochem Mol Biol 61:349-57
Fernandez-Galaz, M C; Morschl, E; Chowen, J A et al. (1997) Role of astroglia and insulin-like growth factor-I in gonadal hormone-dependent synaptic plasticity. Brain Res Bull 44:525-31
Parducz, A; Szilagyi, T; Hoyk, S et al. (1996) Neuroplastic changes in the hypothalamic arcuate nucleus: the estradiol effect is accompanied by increased exoendocytotic activity of neuronal membranes. Cell Mol Neurobiol 16:259-69
Garcia-Segura, L M; Chowen, J A; Duenas, M et al. (1996) Gonadal steroids and astroglial plasticity. Cell Mol Neurobiol 16:225-37
Duenas, M; Torres-Aleman, I; Naftolin, F et al. (1996) Interaction of insulin-like growth factor-I and estradiol signaling pathways on hypothalamic neuronal differentiation. Neuroscience 74:531-9

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