Effects of Long Term Androgen and Estradiol Exposure on the Hypothalamus*

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Abstract
Evidence has accumulated indicating that estradiol induces degeneration in the hypothalamic arcuate nucleus of the rat. In contrast, testosterone appears to be relatively inert in this regard. The relative inability of testosterone to induce hypothalamic damage may account for the lack of effect of orchidectomy on senescent degeneration in the arcuate nucleus, whereas oophorectomy greatly suppresses this process. Since the hypothalamus has the enzyme system to aromatize testosterone to estradiol as well as that which reduces testosterone to 5α-dihydrotestosterone (DHT), it was decided to examine the effects and possible interaction of these two testosterone metabolites at the hypothalamic level. A system was designed in which the hypothalamus would receive long term exposure to estradiol, testosterone, or DHT alone or to estradiol combined with either testosterone or DHT. This was accomplished by implanting oophorectomized rats with sustained release capsules containing these steroids. Hypothalamic degeneration after the exposure was assessed by measuring microglial and astrocytic activity in the arcuate nucleus. Estradiol-implanted animals showed significant increases in both glial indices compared to blankimplanted controls, whereas testosterone-implanted animals showed a slight increase in microglial activity and no increase in astrocytic activity. DHT-implanted animals exhibited control levels of glial activity. Surprisingly, however, the combined treatment of DHT and estradiol also showed control levels of glial activity. These results indicate that constant low levels of estradiol are pathogenic to the arcuate nucleus and that 5α-reduced androgens may exert a potent and direct inhibitory effect on the neuropathogenic action of estradiol at the hypothalamic level. The antagonism between these two classes of testosterone metabolites may explain the relative nonpathogenicity of testosterone and the lack of participation of the testis in aging of the hypothalamic arcuate nucleus.