The overall goal of this research is to develop a more complete understanding of the interactions of components of the hypothalamic-pituitary-ovarian axis as they contribute to the aging of the reproductive system. Examination of the interaction of specific organs should provide insight into the basis of reproductive aging and may allow development of means of deferring natural reproductive senescence, as well as understanding the mechanisms involved in the aging of other endocrine-dependent systems. Specifics regarding training in cell and molecular biology are outlined in this proposal. Phase I research will attempt to clarify the respective roles of hypothalamic-pituitary and ovarian factors in the reproductive aging of the female rat. The working hypothesis is that aging of the hypothalamic-pituitary-ovarian axis is an endocrine-dependent process. Assessment of the neuroendocrine and ovarian contributions to aging of the female rat's reproductive system will be done by comparing the results of selective, reversible inhibition of the hypothalamus and ovaries. The intent is to assess concurrently the effects of these interventions in the hypothalamic arcuate nucleus and ovarian follicles, which are critical to preovulatory LH surges and ovarian steroidogenesis, respectively. To test the working hypothesis, two organ-specific questions will be addressed. 1) Is aging of the hypothalamus a function of (ovarian) estrogen exposure? The presence of gonadotrophin positive feedback and morphologic hypothalamic changes in rats given placebo, 17 Beta-estradiol, or the antiestrogen, keoxiphene will be examined. Following discontinuation of each treatment, rats will be examined for the extent of arcuate nucleus gliosis as evidence of synaptic remodeling in addition to an assessment of estradiol-induced daily LH surges and reproductive function. 2) Is aging of the ovary a function of repetitive stimulation by gonadotropins? Whether blocking repetitive stimulation with gonadotropins affects the primordial oocyte pool will be investigated. The number and diameter of ovarian follicles will be assessed in rats given GNRH agonist, GNRH agonist plus 17 Beta-estradiol and compared with placebo-treatment controls. Following discontinuation of each treatment rats will be examined for ovarian follicular depletion, the ability of E2 to induce daily LH surges, arcuate nucleus lesions, and reproductive function. Phase II research will focus upon determining possible genetic markers of aging of the female rat reproductive system as well as the investigation of interventions which affect the expression of such markers.
