The combination of an increase in the average life expectancy of women with no recent change in the age of menopause has resulted in a dramatic increase in the number of years of postmenopausal life. Epidemiologic studies have associated increases in cardiovascular disease and osteoporosis with menopause and the loss of gonadal steroids, and undoubtedly there are other important physiologic changes which stem from the loss ovarian function making it critical that efforts be made to understand the process of aging of the reproductive system and to separate those factors which result from changes in the sex steroid environment from those due to aging per se. The broad goals of this project are to determine the hypothalamic and pituitary contributions to aging of the reproductive endocrine system and to differentiate the specific effects of aging from those due to sex steroid deprivation. By using a combination of clinical models, pharmacologic probes and new measurement techniques, we aim to address the hypothesis that ovarian senescence is not the sole mediator of the end of reproductive competence, but that important age-related changes occur in hypothalamic GnRH and pituitary gonadotropin secretion. We hypothesize that neuroendocrine aging and sex steroid changes contribute independently and synergistically to the clinical features of the menopause. The loss of gonadal hormone secretion during the menopause makes it possible to isolate the independent effects of aging and changes in gonadal hormone secretion on the hypothalamic and pituitary components of the reproductive system. We propose to determine: 1) changes in hypothalamic GnRH secretion which occur with aging in the absence of ovarian feedback on the hypothalamus by assessment of the frequency of the hypothalamic GnRH pulse generator, the impact of sleep and circadian rhythms on hypothalamic and pituitary function, and the overall quantity of hypothalamic GnRH secretion using a GnRH antagonist as a probe of endogenous GnRH secretion in the intact human; 2) alterations in the quantitative and differential control of FSH, LH and follistatin secretion by GnRH versus other determinants of secretion as a function of age and ovarian hormonal status by complete blockade of the GnRH receptor; and 3) changes in the qualitative characteristics of pituitary FSH and LH with age and hormonal status by examination of changes in gonadotropin bioactivity and isoform heterogeneity in relation to serum follistatin levels and overall amount of GnRH secreted. The information derived from these studies will provide important insights into the neuroendocrine changes which occur with aging per se and the degree to which these changes can be overcome by gonadal steroid replacement.
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