Studies on the mechanism of action of danazol and gestrinone (R2323) in the rat: evidence for a masked estrogen component.

The effects of androgen and estrogen receptor antagonists on the action of danazol and gestrinone (R2323) were investigated. The tropic effect of danazol and gestrinone on sex accessory tissues of castrated, immature male rats was inhibited by the antiandrogen flutamide, whereas the uterotropic action of these steroids in immature female and adult ovariectomized rats was not inhibited by flutamide. In contrast, the uterotropic effect of danazol was reduced by the antiestrogen, LY156758. The estrogen-sensitive endpoints, vaginal keratinization and uterine progesterone receptor concentration, were enhanced by treatment with a combination of flutamide and either danazol or gestrinone. These data indicate that danazol and gestrinone have estrogenic activity that is masked by the androgenic component of these drugs.

Danazol suppression of luteinizing hormone in the rat: evidence for mediation by both androgen and estrogen receptors.

Previous studies had indicated that the effects of danazol on rat peripheral tissues were mediated through both androgen and estrogen receptors. The purpose of this study was to examine the role of androgen and estrogen receptors in danazol suppression of luteinizing hormone (LH) in the rat. The estrogen receptor antagonist, LY 156758, partially antagonized the suppressed levels of LH observed 3-5 hr after administration of danazol to ovariectomized rats. In contrast, the androgen receptor antagonist, flutamide, had no effect on suppressed LH levels 3-5 hr after danazol, but did partially reverse the inhibition of LH 24 hr after danazol administration to ovariectomized rats. Danazol also increased pituitary progesterone receptor levels, an estrogen-sensitive end point. These data indicate that the suppressed levels of LH following danazol treatment resulted from the functional activation of both androgen and estrogen receptors.

Inhibition of ovulation in rats with epostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase.

Epostane (Win 32729), an inhibitor of the 3 beta-hydroxysteroid dehydrogenase enzyme system, inhibited both spontaneous and pregnant mare's serum/human chorionic gonadotropin-induced ovulation in rats. When administered on the morning of proestrus, the drug blocked pregnancy in females that were inseminated that evening. The blockage of pregnancy occurred at a dose of 200 mg/kg but not at 50 mg/kg. Similarly, when administered on the morning of proestrus at a dose of 200 mg/kg, epostane inhibited the appearance of ova in the oviducts the next day. In gonadotropin-primed immature rats, epostane inhibited ovulation in a dose-related fashion with an ED50 between 25 and 50 mg/kg. The drug also decreased plasma progesterone levels in these animals. The inhibitory effect of epostane on gonadotropin-stimulated ovulation was reversed by injections of progesterone at a total daily dose of 6.25 mg/rat or greater. These results support the contention that steroidogenesis, specifically progesterone synthesis, is a prerequisite to ovulation.