Young adult female rats exposed to alcohol in utero exhibit several hormonal abnormalities. One of these is a reduced ability to secrete luteinizing hormone (LH) in response to estrogen (positive feedback), This deficit in positive feedback is similar to that previously described in the middle aged female rat immediately prior to the onset of sterility and suggest that the female rat expose to ethanol in utero may undergo premature reproductive senescence. This grant application will describe some mechanisms which may underlie the reduced positive feedback response of young adult female rats exposed to ethanol in utero. In addition, a strategy is proposed and examined in hopes of ameliorating the deficits in LH secretion in this population of fetal alcohol exposed (FAE) females. The reproductive history of the FAE female will be characterized in terms of 1) onset of puberty, 2) regularity of cyclicity and onset of persistent vaginal estrous, 3) proestrus gonadotropin secretion and gonadotropin response to estrogen and progesterone, 4) reproductive and non-reproductive behaviors. The mechanisms to be examined which might underlie reduced LH secretion in FAE females are: 1) Alterations in estrogen sensitivity as revealed by changes in estrogen receptor (ER). ER concentration and synthesis (determined by in vitro binding assay, solution hybridization and in situ hybridization. 2) Reductions in gonadotropin releasing hormone (GnRH) concentration as determined by RIA, synthesis as determined by in situ hybridization or GnRH secretion as determined using an in vitro perfusion system. Based on our existing knowledge, as therapeutic strategy involving the prepuberal administration of low doses of estrogen will be evaluated to determine its potential in ameliorating the observed reduced LH secretion of FAE females. These studies are important in determining the factors underlying the reduced reproductive potential of FAE females and to determine the efficacy of a therapeutic strategy which can be used clinically to ameliorate reproductive deficits in FAE females.
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