Reproductive aging in female rats is characterized by a cessation of regular estrous cyclity. During middle age, just prior to the loss in regular cyclicity, discernible decreases in the amplitude and a time delay in the onset of the proestrous LH surge can be identified. These observations implicate that age-related changes in the hypothalamic-pituitary axis may initiate the collapse in reproductive function. The purpose of this proposal is to determine whether there are decreases in hypothalamic GnRH release and/or functional declines in the ability of the pituitary to release LH in response to GnRH stimulation which are associated with the attenuated proestrous LH surges of middle-aged rats. Since some middle-aged females display normal proestrous LH surges and continue to cycle regularly for many months beyond that of similar aged rats with attenuated surges, longitudinal investigations on individual animals are essential. Using an established in vitro perifusion system, hypothalamic GnRH release and pituitary LH responses to GnRH stimulation will be quantitated on proestrus in the same individual females and compared to their previous proestrous LH surge profiles. Similar comparisons also will be made between in vivo pituitary LH responses to GnRH infusions on proestrus and the previous proestrous LH surge profiles. These systematic approaches are designed to identify whether changes in hypothalamic or pituitary function are associated with decreases in the proestrous LH surge profiles of middle-aged rats. Further studies are designed to identify whether middle-aged females with attenuated proestrous LH surges also have decreased LH surge responses to the positive feedback effects of estrogen administration. These studies will identify whether the attenuated proestrous LH surges of middle- aged female rats are associated with a functional inability of the hypothalamic-pituitary axis to respond to estrogen stimulation. The information gained from these proposed studies may provide evidence to suggest that changes in hypothalamic and/or pituitary function may be causally related to the loss of reproductive cyclicity in aging female rats and provide clues to the mechanisms by which this loss may occur. Although human female menopause appears to be primarily due to ovarian failure, the biological mechanisms studied in this proposal may be relevant to understanding other aspects of the human aging process.
