Dose dependent effects of ethinyloestradiol, diethylstilboestrol and oestradiol on the metabolism of 4 androstene 3,17 dione in rat liver microsomes

The effects of administration of ethinyloestradiol (EtE₂), 0.1, 0.5 or 1 μg per day, diethylstilboestrol, 5, 100 or 500 μg per day, and oestradiol, 1 or 100 μg per day, for 12 days, on the hepatic microsomal metabolism of 4 [4 ¹⁴C]androstene 3,17 dione were studied in castrated male and female rats. When rats were given EtE₂ in daily doses of 0.1 and 0.5 μg, the activities of the 3α and 17β hydroxysteroid oxidoreductases increased in both male and female rats. A similar tendency was noted for the 5α reductase in female rats. On the other hand, the activities of the 3β hydroxysteroid oxidoreductase and 7α hydroxylase enzyme systems were suppressed in both male and female rats already after administration of 0.1 μg of EtE₂. Diethylstilboestrol, administered in doses of 100 and 500 μg, and oestradiol, given in a dose of 100 μg, suppressed the microsomal enzyme activities whereas the lower doses of 5 μg of diethylstilboestrol and 1 μg of oestradiol were without effects. The results indicate that oestrogenic compounds given in doses higher than the physiological one have a suppressing effect on microsomal steroid metabolizing enzyme activities. Ethinyloestradiol has a stimulating effect on certain microsomal enzyme activities and an inhibiting effect on others when administered in an amount of 0.5 μg/kg^-1 per day. The findings are discussed in relation to recent reports on impaired drug metabolism in women taking contraceptives.