Mevinolin (Lovastatin) Inhibits Androstenedione Production by Porcine Ovarian Theca Cells at the Level of the 17α-Hydroxylase:C-17,20-Lyase Complex*†

Abstract

Mevinolin, putatively a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase, was used to assess the contribution of de novo synthesized cholesterol to androgen production by ovarian thecal cells in vitro. Enzymatically dispersed thecal cells from 3- to 6-mm follicles of prepubertal gilts were incubated at 150,000 cells/ml with a maximally effective dose of LH (250 ng/ml) for 24 h. Mevinolin (3-50 microM) caused dose-dependent inhibition of androstenedione production. Addition of 25-hydroxycholesterol (0.025-25 microM) failed to restore androstenedione production to levels seen in the absence of mevinolin, suggesting an additional site of action of mevinolin beyond 3-hydroxy-3-methylglutaryl coenzyme reductase. The site of this inhibitory effect was determined by measuring steroid products formed in the presence of relevant steroid precursors. Mevinolin (12 microM) inhibited the production of 17 alpha-hydroxyprogesterone from progesterone and that of androstenedione from 17 alpha-hydroxyprogesterone, while 25-hydroxycholesterol to progesterone and pregnenolone to progesterone conversions were unimpaired. That mevinolin did not affect 3 beta-hydroxysteroid dehydrogenase:delta 5-delta 4-isomerase reactions was confirmed by demonstrating that conversions of pregnenolone, 17 alpha-hydroxypregnenolone, and dehydroepiandrosterone to progesterone, 17 alpha-hydroxyprogesterone, and androstenedione, respectively, were not affected by 12 microM mevinolin. These results indicate that mevinolin has an additional inhibitory action at the level of the 17 alpha-hydroxylase:C-17,20-lyase complex. The degree of inhibition of androstenedione production was not decreased with increased concentrations of progesterone or 17 alpha-hydroxyprogesterone substrate, suggesting that the inhibition was not competitive in nature. As the dose of mevinolin was increased up to 50 microM, progesterone accumulation was unaffected, but pregnenolone concentrations in medium greatly increased. While the mechanism of this effect is unclear, this finding suggests that preformed intracellular cholesterol, rather than that synthesized de novo, is supplying steroidogenic substrate in these cells.

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

“…In vitro studies have shown that one of the statins, mevastatin, inhibits proliferation and steroidogenesis of rat ovarian theca-interstitial cells in a concentration-dependent fashion [6]. Another statin, lovastatin, induces a dose-dependent inhibition of androstenedione production by porcine theca cells [7]. These actions of statins may have clinical relevance to conditions associated with thecal hyperplasia and hyperandrogenism, such as polycystic ovary syndrome (PCOS), whereby statins may potentially reduce theca-interstitial growth and steroidogenesis.…”

Atorvastatin therapy decreases androstenedione and dehydroepiandrosterone sulphate concentrations in patients with polycystic ovary syndrome: randomized controlled study

“…It has been previously shown in vitro that lovastatin inhibits androstenedione production by porcine ovarian theca cells at the level of the 17a-hydroxylase:C-17,20-lyase complex suggesting that preformed intracellular cholesterol, rather than that synthesized de novo, is supplying steroidogenic substrate in these cells. 23 In this study, there was a 15% reduction in DHEAS concentrations with 12 weeks of atorvastatin. The trend towards reduction in DHEAS related to acquired LDL-C insufficiency was previously reported in chronically ill patients.…”

Statins as Targeted “Magical Pills” for the Conservative Treatment of Endometriosis: May Potential Adverse Effects on Female Fertility Represent the “Dark Side of the Same Coin”? A Systematic Review of Literature

“…[31][32][33][34][35]39,40,41,[44][45][46][47] Similar to the above-mentioned category, many articles evaluating statins effects on ovarian function and fertility focused their attention on the multiple effects of statins. Specifically, 7 articles analyzed statins effects on ovarian cell proliferation and apoptosis [31][32][33][34][35]39,40 ; 6 articles focused on statins' impact on ovarian steroidogenesis, 31,35,39,41,44,46 and finally 3 articles described the possible in vivo effects of statins on human and animal fertility. [45][46][47] Data are summarized in detail in Tables 1 and 2.…”