REPRODUCTIVE AGING AND THE HUMAN HYPOTHALAMUS

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Menopause marks the cessation of a dynamic physiological system regulating the cyclic release of pituitary and ovarian hormones. Due to an irreversible loss of ovarian follicles there is a marked decline in the production of steroids. Serum levels of gonadotropins become elevated, presumably due to the lack of steroid negative feedback on higher centers. The site of this steroid negative feedback in the human is unknown. Our preliminary studies demonstrate hypertrophy of neurons containing estrogen receptor gene transcripts in the infundibular nucleus of postmenopausal women. We hypothesize that postmenopausal neuronal hypertrophy is secondary to the withdrawal of the inhibitory feedback effects of ovarian steroids and not due to aging per se. The proposed studies are designed to test this hypothesis and determine the specificity of neuronal hypertrophy in the infundibular nucleus of postmenopausal females. Morphometric methods and computer microscopy will be used to measure neuronal cross-sectional areas in various, hypothalamic regions of pre- and postmenopausal women. We will also measure neuronal cross-sectional areas in the infundibular nucleus of young ovariectomized women, women with estrogen replacement therapy, and men. In situ hybridization will be used to determine the neurotransmitter content of the hypertrophied neurons. Finally, we will establish an experimental model of postmenopausal neuronal hypertrophy in laboratory rats by removing the ovaries. These studies will provide new information concerning the physiology of postmenopausal females, the control of reproductive function in humans, and the relationship between gonadal and neuroendocrine aging. Moreover, because postmenopausal neuronal hypertrophy represents an early, dramatic age-associated change in the human. brain, these studies will provide new insights into normal human aging and age-associated disease.