The biological actions and metabolism of 6α-methylprogesterone: A progestin that mimics and modifies the effects of testosterone

6α-methylprogesterone (6MP), like other synthetic progestins, such as medroxyprogesterone acetate and cyproterone acetate, can mimic or modify the action of androgens. In the present study, 6MP administration increased prostateseminal vesicle weights of C57BL/6J mice but was much less potent than testosterone (T). The effect of T (0.1 mg/day) on prostate-seminal vesicle weight was potentiated by low doses of 6MP (0.05-0.10 mg/day) and inhibited by high doses (1-3 mg/day). 6MP also had a weak androgenic activity on mouse kidney, evidenced by increases of β-glucuronidase and alcohol dehydrogenase activities. Low doses of 6MP (0.05-0.5 mg/day) either produced no change or inhibited, and high doses were additive with the action of T on β-glucuronidase but not on alcohol dehydrogenase activity. These observations indicate that 6MP modifies the action of T on renal β-glucuronidase in C57BL/6J mice (with the Gus-r^b allele) in a manner that is quite diffrent from its previously reported effect on BALB/cJ mice (Gus-r^a). In order to understand the action of a progestin that modifies the action of T, [³H]6MP (57 Ci/mmol) was synthesized, and its tissue uptake and metabolism were compared with those of [³H] T. The in vivo distribution of [³H]T and [³H]6MP differed after sc administration. T levels were 10- and 100-fold higher than those of 6MP in plasma and prostate-seminal vesicle nuclei, respectively; whereas in kidney nuclei, the concentrations of these two steroids were similar. By contrast, after iv injections, plasma levels of 6MP and T were similar, whereas progestinconcentrations were 10 times and 1/2 those of T in kidney and prostate-seminal vesicle nuclei, respectively. After [³H]T administration greater than 94% of the steroid in kidney nuclei was [³H]T, and in prostate-seminal vesicle nuclei, 50-60% and 40-50% were [³H]T and [³H]dihydrotestosterone, respectively. After iv injection of [³H]6MP, only 30% of the steroid in kidney nuclei was the parent compound and the remaining 70% was a hydroxylated metabolite of 6MP, tentatively identified as 20α-hydroxy-6α-methyl-4-pregnene-3-one by multiple chromatographies and derivative formation. In prostate-seminal vesicle nuclei, 80% of the ³H-labeled steroid was 6MP and 20% metabolite. These results suggest that different enzymes and binding proteins determine the metabolism and nuclear uptake of 6MP in kidney and male reproductive tract of mice.