The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause

Menopause is associated with increased neurokinin B (NKB) gene expression a nd decreased proopiomelanocortin (POMC) gene expression in the human hypoth alamus. In the present study, young, ovariectomized cynomolgus monkeys were used in a model of menopause to examine the effects of hormone replacement therapy (HRT) on hypothalamic neuropeptide gene expression. A secondary go al was to determine whether HRT produces signs of estrogen toxicity in the primate hypothalamus by examining POMC neurons and microglial cells. In sit u hybridization was performed using synthetic, radiolabeled, 48-base oligon ucleotide probes. alpha-napthyl butyrate esterase histochemistry was used t o visualize microglial cells. Both estrogen and estrogen plus progesterone treatments produced a marked suppression of the number of infundibular neur ons expressing NKB gene transcripts. In contrast, HRT had no effect on the POMC system of neurons or the number of microglial cells in the infundibula r nucleus. These results provide strong support for the hypothesis that the increased NKB gene expression in the hypothalamus of postmenopausal women is secondary to estrogen withdrawal. Conversely, these data suggest that th e dramatic decline in the numbers of neurons expressing POMC gene transcrip ts in older women is caused by factors other than ovarian failure. Finally, we found no evidence that HRT, in doses designed to mimic currently prescr ibed regimens, produces signs of estrogen toxicity in the primate infundibu lar nucleus.