Differential responses of sex steroid target tissues of rats treated with 4-hydroxyandrostenedione.

4-Hydroxyandrostene-3,17-dione (4-OHA) inhibits ovarian aromatase activity and causes regression of carcinogen-induced hormone-dependent mammary tumors in rats. Although estrogen levels were reduced, LH levels did not increase nor did uterine weight decline in 4-OHA-treated animals. These findings are in contrast to those in animals deprived of estrogen by ovariectomy. The possible direct action of 4-OHA on gonadotropin secretion and uterine growth was, therefore, investigated in ovariectomized rats not treated with the carcinogen. Treatment with 4-OHA for 2 weeks prevented regression of the uterus and the increase in gonadotropin secretion in ovariectomized rats in a dose-dependent manner. The effect on gonadotropin secretion of 4-OHA at 50 mg/kg.day was similar to that of dihydrotestosterone at 0.5 mg/kg.day and could be completely antagonized by administration of the antiandrogen flutamide. The stimulation of uterine growth by 4-OHA was also blocked by flutamide, but not by the antiestrogen enclomiphene. The trophic action of 4-OHA at 50 mg/kg.day was equivalent to that of 1.8 mg/kg.day dihydrotestosterone. Furthermore, treatment with 4-OHA caused a reduction in uterine estrogen receptor and progesterone receptor levels. The reduction in uterine estrogen and progesterone receptor levels was also counteracted by the concomitant injection of flutamide, but not by enclomiphene. The results suggest that in the rat 4-OHA has multiple actions on sex steroid target tissues in addition to inhibition of aromatase. The effects appear to be related to the androgenic rather than estrogenic activity of the compound. Inhibition of gonadotropins may help maintain reduced ovarian estrogen secretion and contribute to the antitumor activity of this compound.