Pro-Opiomelanocortin Messenger RNA in Hypothalamic Neurons Is Increased by Testosterone through Aromatization to Estradiol

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Abstract
We have previously demonstrated that neurons in the rostral arcuate nucleus expressing the messenger RNA (mRNA) for pro-opiomelanocortin (POMC) are responsive to modulation by physiological levels of testosterone. It is uncertain, however, whether testosterone’s action is mediated through direct activation of androgen receptors or through aromatization to estradiol and subsequent binding to estrogen receptors. We examined this question by evaluating the effectiveness of estradiol and dihydrotes-tosterone (DHT), a nonaromatizable androgen, in reversing the castration-induced diminution of POMC mRNA in the arcuate nucleus. Using in situ hybridization, we measured POMC mRNA content within arcuate neurons of intact, castrated, castrated testosterone-replaced, castrated estradiol-replaced, and castrated DHT-replaced male rats. Adult male rats were castrated and implanted (s.c.) with a Silastic capsule filled to one of the following specifications: crystalline testosterone (30 mm; n = 4); 17β-estradiol (E2) diluted 1:1 with cholesterol (5 mm; n = 4); DHT (40 mm; n = 4); or empty (30 mm; n = 4). Control, sham-operated animals (n = 4) were left intact. Analysis of the results showed that following castration, POMC mRNA content was significantly reduced in cells of the arcuate nucleus (intact: 152 ± 3 grains/cell vs. castrate: 110 ± 3 grains/cell). Replacement with physiological levels of testosterone prevented the decline in POMC mRNA levels (castrated testosterone-replaced: 143 ± 6 grains/cell), as did replacement with physiological levels of estrogen (castrated estrogen-replaced: 149 ± 8 grains/cell). Treatment with DHT failed to prevent the postcastration decline in POMC mRNA content (castrated DHT-treated: 118 ± 4 grains/cell). These results show that whereas testosterone and estrogen prevent the postcastration decline in POMC mRNA, the nonaromatizable androgen DHThad no such effect. Based on these observations, we conclude that the ability of testosterone to stimulate POMC gene expression is likely to be mediated through aromatization and subsequent activation of estrogen receptors.

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