Simvastatin reduces steroid hormone production in rat ovarian cells. - GreenMedInfo Summary

Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia and increased androgen production by theca cells. Previously, our group has demonstrated that statins, competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase), a rate limiting step of the mevalonate pathway, reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Since actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, this study also investigated whether steroidogenesis was affected by cell- and mitochondrion- permeable 22-hydroxycholesterol, isoprenylation substrates: farnesyl-pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in Cyp17a1 mRNA levels, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 hours, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation resulting in decreased expression of CYP17A1.