Our overall objective is to characterize and understand the events that occur in the human central nervous system in response to the ovarian failure of menopause. In the previous funding period, significant progress was made in describing dramatic changes in the hypothalamus of postmenopausal women. There is increased hypothalamic tachykinin gene expression in postmenopausal women, accompanied by cellular hypertrophy. In addition, cellular levels of LHRH mRNA are increased within a subpoplation of neurons within the medial basal hypothalamus. We have hypothesized that these changes are secondary to ovarian failure and not due to age per se. The present proposal tests this hypothesis by determining the effects of hormone withdrawal and replacement on neuropeptide gene expression in the primate hypothalamus. In the first specific aim, we will determine if ovariectomy of young cynomolgus monkeys mimics the increase in LHRH and tachykinin gene expression that occurs in postmenopausal women. If so, this would provide compelling evidence that the changes we have observed in postmenopausal women are due to ovarian failure. In specific aims 2 and 3, we will examine the hypothalamus of young ovariectomized monkeys that have received steroid replacement therapy in treatment regimens designed to duplicate those prescribed to humans. In specific aim 4, we will examine the hypothalamus of postmenopausal women treated with hormone replacement therapy. In situ hybridization will be used to determine if hormone replacement reduces LHRH and tachykinin gene expression in the monkey and human hypothalamus as predicted from our previous studies. We will also determine if long-term continuous estrogen replacement produces signs of neurotoxicity in the human and monkey arcuate nucleus. These studies will provide a firm foundation for understanding the important events that occur in the hypothalamus of postmenopausal women and provide the first information on the neuroanatomic effects of hormone replacement therapy in the primate hypothalamus. Millions of women are currently receiving hormone replacement but little is known about the effects of these treatments on the central nervous system.