Testosterone Regulates Pro-Opiomelanocortin Gene Expression in the Primate Brain*

Abstract

Endogenous opioid peptides such as beta-endorphin, derived from proopiomelanocortin (POMC), have been widely implicated as serving an important role in the neuroendocrine regulation of the primate reproductive axis. In both human and nonhuman primates, POMC neurons are thought to mediate, at least in part, the negative feedback action of sex steroids on GnRH. Sex steroids, such as testosterone, are thought to inhibit GnRH secretion by enhancing the inhibitory activity of beta-endorphin; however, the cellular mechanisms by which steroid hormones regulate the activity of POMC neurons in the primate brain are unknown. In this study, we tested the hypothesis that testosterone stimulates POMC gene expression within the primate brain and that this regulation occurs within a specific subset of POMC neurons residing in the arcuate nucleus of the hypothalamus. We used in situ hybridization to compare cellular levels of POMC messenger RNA in intact (n = 4), castrated (n = 4), and castrated/testosterone-treated (n = 4) monkeys. We report that after castration of the male macaque (Macaca fascicularis), cellular POMC messenger RNA levels decline significantly (P less than 0.05) in neurons within the arcuate nucleus and that this decline is prevented by replacement with physiological doses of testosterone. Moreover, we found that this testosterone-dependent modulation of POMC gene expression is restricted to a small fraction of the numerous POMC neurons located within the most anterior region of the arcuate nucleus in the brain of this primate species. These observations provide evidence that sex steroids regulate expression of the POMC gene in the primate brain.