Direct inhibitory effect of estrogen on LH-stimulated androgen synthesis by ovarian cells cultured in defined medium.

The direct inhibitory effect of estrogen on ovarian androgen synthesis was investigated. When primary cultures of rat ovarian theca-interstitial cells were grown in defined medium with LH there was a marked increase in androgen synthesis of which 98% was androsterone (control = 11 +/- 2 ng; LH = 1219 +/- 217 ng/ml/10(6) cells). Diethylstilbestrol (DES), estrone (E1), estradiol (E2), and estriol (E3) inhibited LH-stimulated androsterone synthesis by 81%, 81%, 81%, and 47%, respectively. The ED50's of the estrogens were: DES = 4.2 +/- 2.1 X 10(-9) M; E1 = E2 = 9.5 +/- 2.4 X 10(-8) M; and E3 = 3.8 +/- 2.6 X 10(-7) M. The estrogen effect was very rapid (t1/2 = 10 min) and long-lasting. Metabolic studies revealed that estrogen inhibited androsterone, androstenedione, 5 alpha-androstane-3 alpha, 17 beta-diol, and testosterone accumulation by 80%, dehydroepiandrosterone and 17 alpha-hydroxypregnenolone by 40%, 17 alpha-hydroxyprogesterone by 30%, while pregnenolone and progesterone were unchanged. These results prove, for the first time, that estrogen can directly inhibit LH-stimulated androgen production in ovarian theca-interstitial cells and suggest that mechanism involves, at least in part, a rapid selective inhibition of the 17 alpha-hydroxylase/C17-20 desmolase activities.