The broad goal of this project is to examine the neuroendocdne mechanisms that contribute to aging of the female reproductive system in the human. The underlying hypothesis is that there are changes in the physiology of hypothalamic gonadotropin-releasing hormone (GnRH) secretion and pituitary responsiveness in women that are specifically related to aging. In this revised proposal we will continue to concentrate our studies on postmenopausal women in whom the absence of gonadal function makes it possible to investigate the independent effects of aging and gonadal hormones on the brain. Specifically, the age-related changes in pituitary function and the age-related changes in gonadal steroid control of hypothalamic and pituitary function will be explored.
In Aim 1, the pituitary contribution to the decline in gonadotropin secretion with age will be determined in vivo and in vitro, addressing the hypothesis that a decrease in pituitary response to GnRH occurs with aging that is independent of changes in hypothalamic GnRH input. In this aim, pituitary responsiveness to GnRH will be assessed in the presence of GnRH receptor blockade to control for antecedent GnRH stimulation.
This aim will further determine whether the decline in gonadotropin secretion that occurs with aging in postmenopausal women is associated with a decrease in gonadotrope number using human autopsy specimens.
Aim 2 will determine whether the negative feedback of estradiol on gonadotrope responsiveness to GnRH is altered with aging in vivo and whether there are changes in estrogen receptor alpha (ERalpha) in vitro.
Aim 3 will determine the effect of aging on gonadotropin responses to short-term negative and positive feedback effects of gonadal steroids. In these studies, PET scanning will be used to differentiate hypothalamic from pituitary sites of action.
This aim will investigate the hypotheses that negative feedback effects of estradiol are exerted at both the hypothalamic and pituitary levels in postmenopausai women and are maintained with aging and that estrogen positive feedback is exerted primarily at the pituitary level in the human and declines with age in postmenopausal women. The information derived from these studies will provide basic insights into the effects of aging on the brain in women and the degree to which aging affects the hypothalamic and pituitary responses to gonadal steroids. These studies may also have important implications for our understanding of the potential neuroendocrine contributions to reproductive aging and menopause.
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