Clomiphene and Tamoxifen Inhibit Progesterone Synthesis in Granulosa Cells: Comparison with Estradiol

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Abstract
The actions of clomiphene, tamoxifen, and 17.beta.-estradiol were studied in an isolated avian granulosa cell system during short-term incubations. A dose-dependent inhibition of ovine luteinizing hormone enhanced progesterone production was observed for all 3 compounds, with an IC50 of 3 .times. 10-6 M and maximal inhibition (95%) at 5 .times. 10-5 M. A similar inhibition was found when cells were stimulated by either 8-bromo-cAMP or forskolin. Neither clomiphene nor tamoxifen had an inhibitory effect on the conversion of pregnenolone to progesterone, a step that was blocked by 17.beta.-estradiol and isoxazole, a known inhibitor of 3.beta.-hydroxysteroid dehydrogenase. Cells exposed to clomiphen failed to use [6-3H]25-hydroxycholesterol, while estradiol significantly increased the conversion of labeled substrate to pregnenolone at the expense of progesterone (30% vs. 7% of the total radioactivity). By comparison, in control cells, progesterone represented the major metabolite with 36% of the total radioactivity; pregnenolone had only 2.8%. These triphenylethylene compounds, which are used clinically as antiestrogens, inhibit steroidogenesis at a step before pregnenolone formation, probably at the site of the cholesterol side-chain cleavage enzyme complex, while 17.beta.-estradiol inhibits 3.beta.-hydroxysteroid dehydrogenase.