Effects of ethinylestradiol and norethisterone on liver microsomal metabolism of steroids in male and female rats

Abstract

The effects of administration of ethinylestradiol (17α-ethinyl-1,3,5(10)-estratriene-3, 17β-diol), 5 or 500 mg · kg −1 per day, and norethisterone (17β-hydroxy-17α-ethinyl-4-estren-3-one), 0.5 or 50 mg · kg −1 per day, for two weeks on the hepatic microsomal metabolism of 5α-[4- 14C]androstane-3α,17β-diol, 4-[4- 14C] and rostene-3,17-dione, 4-[4- 14C] pregnene-3,20-dione and 7α-hydroxy-4-[6β- 3H] cholesten-3-one and on the fine structure of parenchymal cells were studied in male and female rats. The low dose of ethinylestradiol suppressed most hydroxylase levels and increased 5α-reductase levels in male rats in a manner consistent with a feminizing effect of the drug. Female rats reacted much less to the low dose of ethinylestradiol although 5α-reductase levels were slightly but significantly reduced. The high dose of ethinylestradiol suppressed most enzyme activities both in male and female rats. The low dose of norethisterone stimulated some hydroxylase and oxidoreductase activities in the metabolism of 4-androstene-3,17-dione, 4-pregnene3, 20-dione and 7α-hydroxy-4-cholesten-3-one. In contrast, the high dose reduced these activities in both male and female rats. No alterations in the fine structure of hepatic parenchymal cells were observed following the administration of ethinylestradiol or norethisterone. It is concluded that ethinylestradiol affects hepatic steroid hydroxylation and reduction mainly in male rats and by virtue of its estrogenic, demasculinizing effect, and that it causes a general suppression of the steroid metabolizing enzymes in rats of both sexes when given in the large doses, 500 mg · kg −1, commonly used in previous studies. Norethisterone, like progesterone, increases the activities of a few hydroxylases but generally suppresses