Background: The hypothalamus plays a key role in mediating the effects of estrogen on many physiological functions, including reproduction, metabolism, and thermoregulation. We have previously observed marked estrogen-dependent gene expression changes within the hypothalamus of rhesus macaques during aging, especially in the KNDy neurons of the arcuate-median eminence (ARC-ME) that produce kisspeptin, neurokinin B, and dynorphin A. Little is known, however, about the mechanisms involved in mediating the feedback from estrogen onto these neurons. Methods: We used quantitative real-time PCR to profile age- and estrogen-dependent gene expression changes in the rhesus macaque hypothalamus. Our focus was on genes that encode steroid receptors (ESR1, ESR2, PGR, and AR) and on enzymes that contribute to the local synthesis of 17β-estradiol (E2; STS, HSD3B1/2, HSD17B5, and CYP19A). In addition, we used RT2 Profiler™ PCR Arrays to profile a larger set of genes that are integral to hypothalamic function. Results: KISS1, KISS1R, TAC3, and NPY2R mRNA levels increased in surgically menopausal (ovariectomized) old females relative to age-matched ovariectomized animals that received E2 hormone therapy. In contrast, PGR, HSD17B, GNRH2, SLC6A3, KISS1, TAC3, and NPY2R mRNA levels increased after E2 supplementation. Conclusion: The rhesus macaque ARC-ME expresses many genes that are responsive to changes in circulating estrogen levels, even during old age, and these may contribute to causing the normal and pathophysiological changes that occur during menopause.

Keywords:
17β-estradiol, Estrogen receptor-α, Estrogen receptor-β, Progestin receptor, Androgen receptor, Aging, Menopause, Hypothalamus
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