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 are known to modify these effects by mimicking, inhibiting, or potentiating androgen action. In the present study, a series of C-21 and C-18 progestins were examined for their androgenic actions relative to testosterone by using renal β-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 derivatives correlated with 6α-methyl substitution. However, a 17α-hydroxyl group inhibited while a 17α-acetoxy group enhanced the androgenic activity of the Go-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 6α-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 6α-substitutions were synandrogenic only when much larger progestin:androgen ratios were used. It was significant that androgenic progestins always stimulated both β-glucuronidase and alcohol dehydrogenase. Similarly, anti-androgenic steroids inhibited the action of testosterone on both enzymes. By contrast, the synandrogenic progestins were more selective in that they potentiated the action of testosterone on β- glucuronidase but not on alcohol dehydrogenase. These observations suggested that synandrogenic activity of progestins influenced specific rather than all gene products. (Endocrinology120: 736, 1978)