Further Studies on the Androgenic, Anti-androgenic, and Syiiandrogenic Actions of Progestins*

Abstract

Testosterone increases the activity of specific proteins up to 50-fold in the renal proximal convoluted tubule of the mouse; several progestins modify these effects by mimicking, inhibiting or potentiating androgen action. A series of C-21 and C-18 progestins were examined for their androgenic actions relative to testosterone by using renal .beta.-glucuronidase and alcohol dehydrogenase activities as end points. These steroids were then examined for anti-androgenic and synandrogenic activities by using a fixed dose of testosterone (0.1 mg/day) and varying amounts of progestins (0.05-1.0-mg/day). The androgenic activity of the progesterone derivativies correlated with 6.alpha.-methyl substitution. A 17.alpha.-hydroxyl group inhibited while a 17.alpha.-acetoxy group enhanced the androgenic activity of the 6.alpha.-substituted steroids. All of the C-18 progestins (norethynodrel, d-norgestrel and lynestrenol) were mildly androgenic on mouse kidney. Because few steroids were anti-androgenic, no structure-function correlation was possible. Both C-18 and C-21 progestins potentiated the action of androgens on mouse kidney. All of the synandrogenic steroids with 6.alpha.-substitutions were effective when administered at doses comparable to those of the test androgen (i.e., progestin:androgen ratios of 1:2-2:1). Other progestins without 6.alpha.-substitutions were synandrogenic only when much larger progestin:androgen ratios were used. Androgenic progestins always stimulated both .beta.-glucuronidase and alcohol dehydrogenase. Anti-androgenic steroids inhibited the action of testosterone on both enzymes. The synandrogenic progestins were more selective in that they potentiated the action of testosterone on .beta.-glucuronidase but not on alcohol dehydrogenase. Synandrogenic activity of progestins influenced specific rather than all gene products.