One of the first endocrine manifestations of reproductive aging in both rats and humans is an increase in the secretion of follicle-stimulating hormone (FSH). Moreover, the anterior pituitary glands (AP) of older rats and humans contain proportionately more acidic FSH isohormones than the AP's of their younger counterparts. Therefore, the major objective of the proposed research is to determine both the causes and consequences of age-related alterations in the secretion and production of FSH by the AP of female rats in hopes of providing valuable information regarding the etiology of hormonal imbalances associated with the human menopause. In view of age-related decrements in ovarian inhibin secretion on estrus, the first series of studies will be designed to evaluate the effects of aging on: 1) ovarian responsiveness to FSH with respect to inhibin production utilizing an in vitro incubation system, 2) ovarian FSH receptors utilizing an ovarian membrane preparation as well as isolated granulosa cells, and 3) the responsiveness of the hypothalamo-pituitary axis to inhibin employing both an in vivo bioassay model and a dispersed pituitary cell monolayer system. A second study will be conducted to determine whether age-related increases in plasma FSH levels during estrus are due to an alteration in the basal (hypothalamic-independent) secretion rate of FSH from the AP as assessed in vitro utilizing cultures of hemipituitary glands. A third and final set of experiments will be designed to explore the possible consequences of an increase in FSH secretion with respect to aging of the reproductive axis. These studies will include an attempt to correlate possible age-related changes in the synthesis and/or secretion of estradiol-17Beta with the initial alterations in FSH secretion and production. Thus, by determining the genesis of increased FSH secretion and altered FSH production, it may be possible to disclose the initial perturbation in the reproductive axis which signals the onset of reproductive senescence in female rats. Moreover, since similar changes in FSH secretion and production are associated with the aging process in humans it is hoped that the results of the proposed experiments will aid the gynecologist in developing a treatment which would effectively regulate the erratic nature of menstrual cycles normally observed during the menopausal transition.
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