REPRODUCTIVE AGING AND THE HUMAN HYPOTHALAMUS

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.