Different Intracellular Mechanisms Underlie Testosterone's Suppression of Basal and Stimulation of Cyclic Luteinizing Hormone Release in Male and Female Rats*

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Abstract
The aromatase inhibitor 1,4,6-androstatriene- 3,17-dione (ATD), a nonsteroidal antiandrogen (flutamide), testosterone and estradiol were administered by Silastic capsule or injection to ovariectomized female and castrate and intact male rats. The treatments were given separately or in combination to investigate the relative importance of elevations in nuclear estrogen receptor levels in hypothalamic and preoptic area target neurons for the expression of several of testosterone's neuroendocrine actions. These actions include the suppression of basal LH secretion, the stimulation of cyclic LH release, the induction of lordosis behavior, and the regulation of progestin receptor levels. Estrogen receptor levels were measured in purified nuclear pellets from the hypothalamus, preoptic area, and adenohypophysis with an in vitro [3H]estradiol exchange assay. Progestin receptors were quantified in cytosol preparations of these tissues using the synthetic progestin [3H]R5020. When exposed to t stosterone levels of 2–4 ng/ml serum for 48 h, ovariectomized rats displayed increases in cell nuclear estrogen receptor number in the hypothalamus and preoptic area and responded to progesterone administration with lordosis behavior and cyclic LH discharges. These testosterone-induced alterations in neuroendocrine function were not influenced by flutamide. However, each response was inhibited dramatically and, in most instances, completely by ATD, although ATD did not exert similar inhibitory actions in estrogen-treated rats. Testosterone treatment also increased cytosol progestin receptor levels in the hypothalamus and preoptic area, and these responses were inhibited by ATD as well. Although flutamide did not influence the testosterone-induced increase in progestin receptors in the preoptic area, it appeared to do so in the hypothalamus. However, this appeared to be a nonspecific action of the antiandrogen, since a similar net decline in hypothalamic receptors was observed in estrogen-treated rats. Taken together, these pharmacological results suggest that testosterone's induction of neuronal progestin receptor levels, lordosis behavior, and cyclic LH release depends on aromatization and the nuclear translocation of estrogen-receptor complexes in target neurons of the hypothalamus and preoptic area. Such a conclusion for cyclic LH release is underscored by observations that the testosterone treatment did not modify estrogen receptor levels or increase the number of progestin receptors in the pituitary and failed to influence hypophysial responsiveness to gonadotropinreleasing hormone. When administered to castrate male rats, the same testosterone treatment suppressed basal gonadotropin secretion. This negative feedback action was not influenced by ATD, but was inhibited completely by flutamide. ATD also failed to interfere with the feedback actions of testicular androgens in intact male rats despite reducing neuronal estrogen receptor levels to castrate values. In contrast, male rats given flutamide displayed normal levels of neuronal estrogen receptors and postcastrationlike elevations in circulating LH concentrations. Such observations suggest that testosterone-induced elevations in brain cell nuclear estrogen receptor levels are not sufficient, or even necessary, for the expression of the negative feedback action of this steroid on LH release. Rather, in view of flutamide's interactions with androgen receptors, it would appear that this feedback depends on androgen-androgen receptor-mediated interactions within the brain and/or anterior pituitary gland.