Simvastatin Reduces Steroidogenesis by Inhibiting Cyp17a1 Gene Expression in Rat Ovarian Theca-Interstitial Cells

• Published in: Biology of reproduction Vol. 86; no. 1; pp. 1 - 20
• Main Authors: ORTEGA, Israel, CRESS, Amanda B, WONG, Donna H, VILLANUEVA, Jesus A, SOKALSKA, Anna, MOELLER, Ben C, STANLEY, Scott D, DULEBA, Antoni J
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction 2012
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Androgens; Animals; Biological and medical sciences; Cell proliferation; Cells, Cultured; Cholesterol; Enzymes; Farnesyl-diphosphate farnesyltransferase; Farnesyltranstransferase - antagonists & inhibitors; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Enzymologic - drug effects; Geranylgeranyltransferase; Hydroxycholesterols; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hyperplasia; mevalonic acid; Ovary - cytology; polycystic ovary syndrome; Polyisoprenyl Phosphates - metabolism; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; reductase; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sesquiterpenes - metabolism; Simvastatin; Simvastatin - pharmacology; statins; Steroid 17-alpha-Hydroxylase - antagonists & inhibitors; Steroid 17-alpha-Hydroxylase - genetics; Steroid 17-alpha-Hydroxylase - metabolism; Steroidogenesis; Substrate Specificity; Theca; Vertebrates: reproduction; Cell culture; Theca folliculi; Rat; theca cells; Rodentia; androgens/androgen receptor; simvastatin; Steroid hormone receptor; Gene expression; In vitro; ovarian theca-interstitial cells; steroid hormones/ steroid hormone receptors; CYP17A1; Interstitial cell; Ovary; Vertebrata; Reproduction; Mammalia; Animal; Female genital system; Androgen receptor; Steroidogenesis; Ovarian follicle
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod.111.094714

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-coenzyme A 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. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present 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 mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, 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.