Statins Inhibit Growth of Human Theca-Interstitial Cells in PCOS and Non-PCOS Tissues Independently of Cholesterol Availability

Sokalska, Anna; Piotrowski, Piotr; Rzepczynska, Izabela J.; Cress, Amanda B.; Dulęba, Antoni J.

doi:10.1210/jc.2010-0770

Cited by 45 publications

(33 citation statements)

References 20 publications

(23 reference statements)

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“…Our present and previous findings [6,[18][19][20] indicate that statins might alter ovarian steroidogenesis by reducing steroidogenic activity as well as decreasing the growth and, hence, the number of theca-interstitial cells. Our previous studies have shown that statins inhibit the proliferation of both rat and human theca-interstitial cells irrespective of the availability of cholesterol in both normal and PCOS ovaries [6,20]. Furthermore, in clinical trials, statins, including simvastatin, have been shown to decrease ovarian androgen levels in patients with PCOS [21][22][23].…”

Section: Discussionsupporting

confidence: 69%

Simvastatin Reduces Steroidogenesis by Inhibiting Cyp17a1 Gene Expression in Rat Ovarian Theca-Interstitial Cells1

Ortega

Cress

Wong

et al. 2012

Biology of Reproduction

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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.

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Section: Discussionsupporting

confidence: 69%

Simvastatin Reduces Steroidogenesis by Inhibiting Cyp17a1 Gene Expression in Rat Ovarian Theca-Interstitial Cells1

Ortega

Cress

Wong

et al. 2012

Biology of Reproduction

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“…In clinical trials, statins improved the lipid profile, reduced androgen levels, and decreased systemic inflammation in women with PCOS (10,11). In our previous studies, statins reduced theca-interstitial cell growth (12) and androgen production (13).…”

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confidence: 83%

Resveratrol inhibits the mevalonate pathway and potentiates the antiproliferative effects of simvastatin in rat theca-interstitial cells

Wong

Villanueva

Cress

et al. 2011

Fertility and Sterility

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“…We also found that in these cells simvastatin inhibits activity of HMGCR and reduces cholesterol synthesis in a concentration-dependent fashion [6]. The effect of simvastatin on reduction of growth of theca-interstitial cells is not reversed in the presence of the cell-and mitochondrion-permeable forms of cholesterol (22-hydroxycholesterol and 25-hydroxycholesterol) indicating that the inhibition of proliferation of theca-interstitial cells is not due to reduced availability of cholesterol [4,7]. However, the effects of simvastatin on cellular proliferation are partly abrogated in the presence of geranylgeranyl pyrophosphate and farnesyl pyrophosphate, indicating that simvastatin acts by inhibiting isoprenylation [4].…”

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confidence: 67%

Comparison of Effects of Different Statins on Growth and Steroidogenesis of Rat Ovarian Theca-Interstitial Cells1

Sokalska

Stanley

Villanueva

et al. 2014

Biology of Reproduction

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Statins are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting enzyme of the cellular production of cholesterol and other products of the mevalonate pathway. Statins exert hepatic and extrahepatic effects, modulating the function of various tissues and organs, including ovaries. Previously, we have demonstrated that simvastatin inhibited cellular proliferation and reduced androgen production by ovarian theca-interstitial cells. The above actions are of translational relevance to the most common endocrine disorder among women in reproductive age: polycystic ovary syndrome. However, different statins may have distinctly different profiles of effects on cholesterol and androgens. The present study was designed to compare the effects of several statins on growth and steroidogenesis of rat theca-interstitial cells. The cells were incubated in the absence (control) or in the presence of simvastatin, lovastatin, atorvastatin, or pravastatin. Assessment of effects of statins on cell growth was carried out by evaluation of DNA synthesis and by estimation of the number of viable cells. Effects on steroidogenesis were evaluated by quantification of steroid production and expression of mRNA for the key enzyme regulating androgen production: Cyp17a1. Among tested statins, simvastatin exerted the greatest inhibitory effects on all tested parameters. The rank order of the effects of the tested statins is as follows: simvastatin > lovastatin > atorvastatin ≥ pravastatin. While the lipophilicity is likely to play a major role in determining the ability of statins to act on nonhepatic cells, other factors unique to individual cell types are also likely to be relevant.

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Statins Inhibit Growth of Human Theca-Interstitial Cells in PCOS and Non-PCOS Tissues Independently of Cholesterol Availability

Abstract: Statins inhibit proliferation of human theca-interstitial cells irrespective of the availability of cholesterol and independently of leukocytes both in normal and PCOS ovaries.

Cited by 45 publications

References 20 publications

Simvastatin Reduces Steroidogenesis by Inhibiting Cyp17a1 Gene Expression in Rat Ovarian Theca-Interstitial Cells1

Simvastatin Reduces Steroidogenesis by Inhibiting Cyp17a1 Gene Expression in Rat Ovarian Theca-Interstitial Cells1

Resveratrol inhibits the mevalonate pathway and potentiates the antiproliferative effects of simvastatin in rat theca-interstitial cells

Comparison of Effects of Different Statins on Growth and Steroidogenesis of Rat Ovarian Theca-Interstitial Cells1

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