The goal of this research proposal is to increase our understanding of the effects of aging on the reproductive system of normal women. While women eventually experience complete loss of their reproductive potential (menopause), this proposal focuses on women age 40-45 who have retained regular ovulatory menstrual cycles. These """"""""older"""""""" women who have retained menstrual function have lost 33-50% of their prior fertility potential. current demographic data indicates there is an increase in the female population age 27-40 (baby boomers) who, as a group, tend to defer marriage and childbearing. Loss of reproductive efficiency with age has become a pertinent clinical issue. These proposed studies focus on the hypothalamic-pituitary-ovarian axis as the probable sites of reproductive aging. We and others, have identified a monotropic FSH rise as the initial hormonal change in older women. We have two hypotheses for the monotropic FSH rise: 1) it is a primary neuroendocrine change that leads to follicular depletion, or 2) follicular depletion is the primary change in reproductive aging which leads to a decrease in ovarian feedback hormones. In Section I we will explore in depth various aspects of the monotropic FSH rise including investigation of possible changes in other hormones (i.e. inhibin), FSH bioactivity, GnRH pulse patterns, and control of the intercycle FSH rise. The studies in Section I should clarify the primary site of reproductive aging. Since depletion of ovarian follicles is the final common pathway of reproductive aging in primate species, we hypothesize that women experience compromised folliculogenesis prior to disruption of their cycles (indicative of follicle depletion below a critical threshold). In our ovarian studies (Section II) we propose to monitor follicle development, perform sonographic follicle aspirations, and study: follicular fluid hormone concentrations, granulosa cell function in tissue culture, and examine the cytoskeleton (actin, tubulin) of oocytes. Direct benefits are anticipated from an increased understanding of aging effects on the female reproductive system: 1) predictors can be developed, which, in turn, would dictate specific therapies (or no therapy); 2) lead to improved counseling regarding delayed childbearing, and 3) perhaps interventions could be identified to delay the aging process.
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