Should we use statins in treatment of polycystic ovary syndrome?

Finding effective treatments for polycystic ovary syndrome (PCOS) is not an easy challenge. The root causes of PCOS are yet to be understood and most information regarding this condition is descriptive in nature. It is a highly heterogeneous syndrome, characterized by a broad range of clinical, endocrine and metabolic derangements, affecting 5–8% of women of reproductive age [1,2]. The key reproductive aspects of PCOS (hyperandrogenism and anovulation) have been known for decades; however, more recent studies also point to other relevant aspects of this syndrome: the high rate of metabolic problems associated, in particular, with cardiovascular risks. Women with PCOS frequently exhibit evidence of insulin resistance and abnormal insulin secretion, dyslipidemia, endothelial dysfunction, early atherosclerotic changes, increased oxidative stress and systemic inflammation [3,4]. To date, recognized approaches to the management of PCOS have included lifestyle modifications (e.g., diet and exercise), use of antiandrogens, ovulation induction, progestins, oral contraceptive pills and, more recently, metformin. Many of these treatments are effective in addressing hirsutism and anovulation; however, with the exception of lifestyle modifications that are very difficult to accomplish, their impact on the reduction of cardiovascular risks is usually modest.

Conceptually, an effective treatment of PCOS would combine reduction of cardiovascular risks and improvement of ovarian function. At the ovarian level, important features of PCOS include hyperplasia of theca-interstitial cells and excessive androgen production [5,6]. Both proliferation and androgen synthesis by theca-interstitial cells may be, at least in part, induced by hyperinsulinemia and increased oxidative stress associated with PCOS. Indeed, in culture, insulin and moderate oxidative stress promote theca-interstitial cell proliferation and steroidogenesis [7–10]. These observations provide a basis for the search for therapeutic agents that would reduce oxidative stress, decrease intraovarian insulin signaling and, ultimately, decrease growth and androgen production by the ovary.

In view of the above considerations, our group has focused on a novel approach for treatment of PCOS by using statins. In order to better understand the rationale for the use of statins, it may be helpful to briefly review their actions. Statins are inhibitors of the rate-limiting step of the mevalonate pathway: 3-hydroxy-3-methylglutaryl-coenzyme A-reductase (HMG-CoA-R). Inhibition of HMG-CoA-R results not only in reduction of cholesterol synthesis but is also associated with decreased production of several other biologically important products of the mevalonate pathway, including dolichol, geranyl-geranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP).

Decreased cholesterol synthesis may be of obvious benefit to PCOS as it may improve the lipid profile, especially by reducing low-density lipoprotein (LDL) levels. Furthermore, since cholesterol is a substrate for ovarian steroidogenesis, decreased availability of cholesterol may lower androgen production. Dolichol is required for maturation (N-linked glycosylation) of insulin and IGF-1 receptors; hence, reduction of dolichol may protect from the adverse ovarian effects of excessive levels of insulin and free IGF-1, both of which are common in PCOS. It is worth noting that decreased insulin function in other tissues and organs, such as liver, adipocytes and muscle, may have adverse effects related to increased insulin resistance; however, so far, it appears that statins do not reduce insulin sensitivity. Finally, two other important products of the mevalonate pathway, GGPP and FPP are required for prenylation and consequent activation of various key regulatory proteins, including Ras, Rho and Rac [11]. These proteins play an important role in the regulation of proliferation, apoptosis and function of cells, including the modulation of reactive oxygen species generation. Interruption of prenylation may have profound consequences, including decreased tissue growth and reduced oxidative stress. Another potentially beneficial mechanism of action of statins may not be related to inhibition of the mevalonate pathway, but be due to their intrinsic antioxidant properties, including antihydroxyl and antiperoxyl radical activities [12].

Studies on ovarian theca-interstitial cells have demonstrated that statins exert a concentration-dependent inhibitory effect on cell proliferation and androgen production [13]. Effects on proliferation involve reduction of basal and insulin-stimulated activity of the MAPK pathway, possibly by decreasing prenylation of Ras [14]. Inhibition of androgen production by statins may be due to reduction of the expression of key enzymes involved in androgen production: CYP11A1, CYP17 and 3βHSD [15]. Preliminary data also indicate that statins may reduce intraovarian oxidative stress by decreasing expression of NADPH oxidase subunits p22phox and p47phox [16].

The first clinical trial evaluating the effects of statins on PCOS involved 48 young and mostly lean women randomized to two treatment arms: simvastatin (20 mg per os daily) plus oral contraceptive pill (OCP), or OCP alone [17]. After 3 months, the decline of total testosterone was significantly greater in the presence of simvastatin than OCP alone (41 vs 14%, respectively). Subjects taking simvastatin also had greater reduction of luteinizing hormone (LH) and LH to follicle-stimulating hormone (FSH) ratio, as well as a significantly better lipid profile. This trial was followed by a crossover follow-up study for another 3 months, whereby subjects previously taking OCP alone also started simvastatin, while those on simvastatin plus OCP discontinued simvastatin [18]. At the end of the trial, final analysis revealed that the addition of simvastatin to OCP was superior to OCP alone in several outcomes: reduction of total and free testosterone, LH and LH:FSH ratio, hirsutism score, total cholesterol, LDL-cholesterol and triglycerides, as well as decreased measures of systemic inflammation (C-reactive protein) and endothelial function (VCAM1). Simvastatin had no effect on insulin sensitivity as measured by indices using both fasting and 2-h oral glucose tolerance test determinations of insulin and glucose.

In a subsequent clinical trial, Kaya et al. randomized 52 women with PCOS to treatment using atorvastatin (20 mg per os daily) and simvastatin (20 mg per os daily) [19]. After 12 weeks, there was a significant decline of total and free testosterone and homocysteine, and improvement of lipid profile in both groups. In the atorvastatin group, but not the simvastatin group, fasting insulin and a fasting index of insulin resistance (homeostasis model assessment [HOMA]) also declined.

More recently, a randomized, double-blind, placebo-controlled trial evaluated effects of atorvastatin at a dose of 20 mg daily in 40 hyperandrogenemic women with PCOS [20]. Following 12 weeks of treatment, atorvastatin significantly reduced testosterone and C-reactive protein levels, improved insulin sensitivity (measured by HOMA) and lipid profiles. By contrast, worsening of HOMA was observed in the placebo group.

Taken together, both in vitro and clinical studies provide consistent and encouraging data supporting the concept that statins may be useful in the treatment of many facets of PCOS, including reduction of hyperandrogenemia/hyperandrogenism, and various metabolic aspects of this syndrome, including dyslipidemia, systemic inflammation and even improving insulin sensitivity (at least in the absence of OCPs). The effects of statins on anovulation and the potential for carryover of post-treatment effects of statins on subsequent fertility remains unknown. On a cautionary note, statins are considered to be potentially teratogenic; hence, it is usually recommended that their use should be restricted to women who are either not sexually active or using reliable contraception. Interestingly, a recent small, prospective, observational trial on 64 women taking statins during the first trimester of pregnancy was reassuring, and suggested that the risk of statin-induced teratogenicity, if any, is small [21].

At present, in our view, the endorsement of routine use of statins in treatment of PCOS is still premature. It would be prudent to continue evaluating their effects in carefully monitored clinical trials and await results of further, especially long-term, studies to verify their effectiveness and safety.

Financial & competing interests disclosure

This article was supported in part by grant number RO1-HD050656 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Antoni J Duleba). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.