Gonadal steroids, reproductive aging and the primate hypothalamus

Abstract

The gonadal steroid withdrawal of menopause is associated with neuronal hypertrophy and increased tachykinin gene expression in the hypothalamic infundibular nucleus. Previous studies have shown that secretion of hypothalamic b -endorphin is modified by gonadal steroids, and there are consistent age-related changes in b -endorphin neurons in rodents. Therefore, in situ hybridization was used to determine if the expression of POMC mRNA, the precursor for b -endorphin, is altered in the hypothalamus of postmenopausal women. The number of POMC mRNA-containing neurons/section in the infundibular nucleus was reduced by 65% in postmenopausal women. In contrast, there was no significant difference in the number of neurons expressing POMC gene transcripts in the retrochiasmatic region. Our findings support the hypothesis that the activity of hypothalamic POMC neurons is decreased in the infundibular nucleus of postmenopausal women. In a second study, we examined the effects of hormone replacement therapy (HRT) on the hypothalamus of young, ovariectomized cynomolgus monkeys. HRT dramatically suppressed tachykinin gene expression while having no detectable effects on POMC neurons. These results provide strong support for the hypothesis that alterations in tachykinin neurons in postmenopausal women are secondary to estrogen withdrawal. Conversely, postmenopausal changes in POMC gene expression may reflect hypothalamic aging. Finally, we found no evidence that HRT, in doses designed to mimic currently prescribed regimens, produces signs of estrogen toxicity in the primate infundibular nucleus. Degenerative changes, including neuron loss, have been reported in the arcuate nucleus of aging rodents, and hypothalamic aging has been shown to contribute to reproductive decline in these species. In addition, in the infundibular nucleus of postmenopausal women, there is an age-associated decline in proopiomelanocortin gene expression. To evaluate the possibility of neuron loss associated with reproductive aging, unbiased stereological methods were used to compare the total number of infundibular neurons between groups of premenopausal and postmenopausal women. The mean neuronal volume was increased by 40% in postmenopausal women but there was no change in the total number of neurons. These data suggest that the neuronal hypertrophy observed in the postmenopausal human hypothalamus is not a pathological process secondary to degeneration of adjacent infundibular neurons.