Evidence for statin therapy in polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age group that is associated with increased cardiovascular risk. In addition to its lipid-lowering effects, statin therapy has shown been shown to have beneficial pleiotropic effects that may contribute to their reduction in cardiovascular morbidity and mortality. In this review, the effect of statins on PCOS is discussed with reference to the underlying potential mechanism of action.

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age with a reported prevalence of 5–7% [Ehrmann, 2005; Azziz et al. 2004; Asuncion et al. 2000]. In clinical practice, women with PCOS present with infertility, menstrual irregularity, hyperandrogenism and virilization [Goldzieher and Axelrod, 1963]. The endocrine profile of women with PCOS is characterized by high plasma concentrations of ovarian and adrenal androgens, gonadotropin abnormalities, a relative increase in oestrogen levels derived from conversion of androgens, reduced levels of sex hormone binding globulin (SHBG), and often high levels of insulin [De Leo et al. 2003]. Moreover, PCOS is associated with a broad range of adverse sequelae, including dyslipidemia, hypertension, insulin resistance, hyperandrogenemia, gestational and type 2 diabetes (T2DM), which ultimately increase the risk of cardiovascular morbidity [Lo et al. 2006; Vryonidou et al. 2005; Christian et al. 2003; Son et al. 2001; Talbott et al. 2000; Wild et al. 2000; Pierpoint et al. 1998; Dahlgren et al. 1992a, 1992b].

Theoretically, an effective treatment of PCOS would combine a reduction in cardiovascular risks with an improvement in ovarian function. At the ovarian level, important features of PCOS include hyperplasia of theca-interstitial cells and excessive androgen production [Nelson et al. 1999]. 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 [Duleba et al. 1998; Barbieri et al. 1986]. The recognized approaches for the management of PCOS include lifestyle modifications including weight loss and the use of inter-ventional agents such as insulin-sensitizing agents, contraceptive pills, antiandrogens and ovulation induction agents. However, their impact on the reduction of cardiovascular risk is usually modest [Huber-Buchholz et al. 1999]. There is emerging evidence that HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) are beneficial in patients with PCOS.

Statins have been shown to reduce cardiovascular morbidity and mortality [Shepherd et al. 2006; Pedersen et al. 2005; MRC/BHF, 2003]. They also have other nonlipid-lowering pleiotropic effects, demonstrated by their benefit in hypertensive patients with normal lipids [Sever et al. 2008] as well as their anti-inflammatory effect in patients with rheumatoid arthritis [McCarey et al. 2004]. Other pleiotropic effects of statins include improvement of endothelial dysfunction, normalized vasomotion, increased bioavailability of nitric oxide, antioxidant effects, anti-inflammatory effects, reduction of serum C-reactive protein (CRP), reduction of adhesion molecules, plaque stabilization, stimulation of endothelial progenitor cell recruitment, immunomodulation and inhibition of myocardial hypertrophy [Fuhrman et al. 2002; Gokce et al. 2002; Plenge et al. 2002; Albert et al. 2001; Crisby et al. 2001; Feron et al. 2001; Laurat et al. 2001; Takemoto et al. 2001; Weitz-Schmidt et al. 2001; Lindahl et al. 2000; Romano et al. 2000; Schachinger et al. 2000; Ridker et al. 1998; O'Driscoll et al. 1997; Kobashigawa et al. 1995]. These and several other emergent properties may act in concert with the potent low-density lipoprotein (LDL) cholesterol-lowering effects of statins to exert early and long-lasting cardiovascular protective effects. Understanding the pleiotropic effects of statins is important to optimize their use in the treatment and prevention of cardiovascular disease.

Mechanism of action of statins in PCOS

Statins are inhibitors of the rate-limiting step of the mevalonate pathway: HMG-CoA reductase. Inhibition of HMG-CoA reductase results in both a reduction in cholesterol synthesis and with decreased production of other biologically important products of the mevalonate pathway, including dolichol, geranyl—geranyl pyrophosphate (GGPP) and farnesyl pyrophosphate (FPP). Decreased cholesterol synthesis is clearly of benefit to PCOS patients as it improves the adverse lipid profile, especially by reducing LDL levels. Since cholesterol is a substrate for ovarian steroidogenesis, decreased availability of cholesterol may result in lower androgen production. Dolichol is required for maturation (N-linked glycosylation) of insulin and insulin-like growth factor-1 (IGF-1) receptors; hence, a reduction in dolichol may protect the ovary from the adverse effects of excessive insulin and free IGF-1 levels, both of which are common in PCOS. Finally, two other important products of the mevalonate pathway, GGPP and FPP play an important role in posttranslational modification (e.g. geranylation and farnesylation) of a variety of small GTPase proteins, such as Ras and Rho [Danesh et al. 2002; Kato et al. 1992; Pituitary Adenoma Study Group, 1983]. 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 rather be due to their intrinsic antioxidant properties, including antihydroxyl and antiperoxyl radical activities [Franzoni et al. 2003].

Both Ras and Rho are involved in the regulation of critical cellular processes such as proliferation, apoptosis, and differentiation. An inhibition of HMG-Co (A) and a consequent decrease of the geranylation or farnesylation of Ras and Rho may inactivate important signal transduction pathways regulating mitotic activity. Studies have indicated that statin-induced inhibition of proliferation of mesangial cells was associated with a repression of activation of Rho GTPase/p21 signalling, independent of the cholesterol-lowering actions [Danesh et al. 2002]. Comparable mechanisms may be involved in mevastatin-induced inhibition of theca-interstitial proliferation. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis [Izquierdo et al. 2004]. The ovaries of women with PCOS are typically enlarged with prominent hyperplasia of ovarian theca-interstitial cells and excessive production of androgens by these cells [Wickenheisser et al. 2000; Nelson et al. 1999; Hughesdon, 1982]. The effects of mevastatin on steroidogenesis are most likely related to the inhibition of cholesterol synthesis and a consequent decrease in the availability of the precursors of progesterone and testosterone.

Clinical evidence of the effect of statins in patients with PCOS

There is growing evidence that statins may have beneficial effects in patients with PCOS. In a randomized double-blind placebo-controlled study looking in the effects of atorvastatin on biochemical hyperandrogenemia, insulin resistance and markers of inflammation in PCOS, atorvastatin 20 mg daily improved all of these parameters when given over a 12-week period [Sathyapalan et al. 2009a]. In patients with PCOS, 3 months of treatment with atorvastatin resulted in a significant reduction in inflammatory markers, insulin resistance and hyperandrogenemia, in addition to the expected improvement in the lipid profile. The reduction of the hyperandrogenemia was also independent of the improvement of the lipid profile with atorvastatin.

The improvement in biochemical hyperandrogenemia with atorvastatin in the above study was comparable to established antiandrogen agents [Moghetti et al. 2000; Venturoli et al. 1999]. The reduction in testosterone was similar to the reduction in testosterone by the combined oral contraceptive pill (OCP) (ethinyl oestradiol/levonorgestrel combination) that may reduce testosterone by 27%. However, OCPs are more effective in improving SHBG by up to 100% when given for 3 months [Burkman, 1995; Crook et al. 1993; Wild et al. 1991], leading to a reduction in the free testosterone. Simvastatin 20 mg daily concomitant with an OCP was reported to give a 38% decrease in total testosterone [Banaszewska et al. 2007] compared with a 25% reduction with atorvastatin alone (20 mg daily) in patients with PCOS. These data suggest that there might be a dose-dependent effect or the effects might be due to differences in potency and the class of statins. The ethinyl oestradiol/cyproterone acetate pill has been shown to reduce testosterone by around 42% after a 6-month period [Falsetti et al. 2001]. However, antiandrogens reduce hirsutism not only by reducing hyperandrogenemia, but also by other mechanisms including androgen receptor blockage, effect on luteinizing hormone (LH) secretion and 5α reductase activity [Fruzzetti et al. 1999].

Weight loss of less than 10% of initial body weight has been shown to reduce testosterone levels in women with PCOS [Moran et al. 2003]. There was no weight change with atorvastatin in the study noted above [Sathyapalan et al. 2009a], however, the reduction in testosterone levels was more than that seen with orlistat (17% reduction) and it increased SHBG by 4% after 3 months of treatment. However, it was less than the 33.2% reduction in testosterone achieved with the endocannabinoid blocker rimonabant after 3 months that correlated with weight loss [Sathyapalan et al. 2008]. The statin reduction of testosterone is more comparable to the improvement seen with insulin sensitizers such as metformin that gave a 14% decrease in total testosterone in 3 months [Jayagopal et al. 2005] and thiazolidi-nediones that gave a 6–15% reduction in serum testosterone [Ortega-Gonzalez et al. 2005; Brettenthaler et al. 2004; Azziz et al. 2001]. No improvement in hirsutism with metformin may be seen [Lord et al. 2003].

There was a 25% reduction in high-sensitivity CRP (hsCRP) with atorvastatin in this group of patients with PCOS [Sathyapalan et al. 2009a]. PCOS is associated with increased levels of indices of low-grade chronic inflammation such as CRP [Diamanti-Kandarakis et al. 2006; Kelly et al. 2001] that appears to be a predictor of cardiovascular events in women [Ridker et al. 2002, 2003]. Atorvastatin has been shown to significantly reduce hsCRP with a trend to reducing insulin resistance in patients with the prediabetes category, impaired fasting glucose [Costa et al. 2003].

A reduction in insulin resistance may be central to the improvements seen for hyperandrogenemia and hsCRP. There was a 21% reduction in serum insulin levels and a 20% improvement in homeostasis model assessment—insulin resistance (HOMA-IR) with atorvastatin [Sathyapalan et al. 2009a]. This improvement in insulin resistance (as measured by HOMA-IR) was correlated positively with the degree of reduction in triglyceride levels and is in accord with other studies that have demonstrated a similar link in patients with both the metabolic syndrome and T2DM treated with atorvastatin [Huptas et al. 2006; Paolisso et al. 2000]. Hypothetically, the reduction in triglyceride availability leads to an increased use of glucose as the main intracellular substrate [Paolisso et al. 2000] thereby improving insulin sensitivity.

When the patients who were randomized to atorvastatin or placebo were subsequently switched to 1.5 g of metformin alone, atorvastatin pretreatment both augmented and facilitated the effect of metformin in the improvement of the metabolic parameters, biochemical hyperandrogenemia and inflammatory markers in patients with PCOS [Sathyapalan et al. 2009b]. The improvements of these parameters were independent of the elevation of LDL and total cholesterol following the cessation of atorvastatin. There was a significant reduction in total testosterone with metformin after atorvastatin, over and above the initial changes through atorvastatin treatment. Three months of metformin following 3 months of atorvastatin reduced total testosterone by 31%, free androgen index (FAI) by 41% and increased SHBG by 18%, whilst there were no significant improvements in any of these parameters with 12 weeks of metformin following placebo pretreatment [Sathyapalan et al. 2009b]. Statins have been reported to inhibit ovarian theca-interstitial cell proliferation and steroidogenesis in vitro most likely due to reduced availability of testosterone precursors [Izquierdo et al. 2004; Wickenheisser et al. 2000; Nelson et al. 1999]. In addition, statins have also been shown to rapidly activate AMP-activated protein kinase (AMPK), a protein kinase that modulates metabolic homeostasis and energy balance in individual cells and multiple organs [Zhou et al. 2001], both in vivo and in vitro [Sun et al. 2006]. Interestingly, this is the same mechanism reported for metformin action and this may explain the augmented effects of metformin following atorvastatin treatment.

This study also demonstrated the enhanced improvement of insulin resistance and hsCRP with metformin after atorvastatin pretreatment [Sathyapalan et al. 2009b]. There was a reduction of insulin by 16% and HOMA index by 21% that was not seen in patients who had been placebo pretreated. In total, 12 weeks of atorvastatin followed by 12 weeks of metformin reduced the insulin levels by 33% and HOMA-IR by 35%. There was also a 33% reduction of hsCRP with metformin treatment following atorvastatin. There was a 25% reduction in hsCRP with atorvastatin in this group of patients with PCOS. This may be important for patients with PCOS who have increased levels hsCRP [Diamanti-Kandarakis et al. 2006; Kelly et al. 2001] that is a predictor of cardiovascular events in women [Ridker et al. 2002, 2003].

There were no significant changes in insulin resistance, biochemical hyperandrogenemia and hsCRP in patients who went on to 12 weeks of metformin treatment following placebo compared to atorvastatin group. This is consistent with other studies which shows that metformin may not be effective in all patients with PCOS especially those who are overweight [Tang et al. 2006; Harborne et al. 2005; Maciel et al. 2004]. Since these studies were of short duration, changes in clinical hyperandrogenemia, menstrual irregularities or ovulation was not studied.

In a different study on patients with PCOS, simvastatin, combined with concomitant OCP therapy, has shown to reduce testosterone, LH and markers of systemic inflammation incrementally more than OCP treatment alone. Both regimes (with and without statin treatment) had an adverse effect on glucose metabolism [Banaszewska et al. 2007]. However, the OCP accounted for the majority of the biochemical benefit, which was consistent with other OCP studies showing a reduction in testosterone and improvement in SHBG in PCOS patients [Hardiman et al. 2003; Balen, 2001; Burkman, 1995; Wild et al. 1991].

Others have reported that when patients with PCOS were randomized to simvastatin, metformin or simvastatin plus metformin, simvastatin was superior to metformin alone, whereas a combination of simvastatin and metformin was not significantly superior to simvastatin alone in reducing biochemical hyperandrogenemia and inflammatory markers [Banaszewska et al. 2009]. Total testosterone decreased significantly and comparably in all groups: by 17.1%, 13.6% and 15.1% respectively in the simvastatin, metformin and simvastatin plus metformin groups. Significant decreases were also observed in all groups with respect to CRP and soluble vascular adhesion molecule-1, where as dehydroepian-drosterone sulphate (DHEAS) declined significantly only in the simvastatin group.

Conclusions

Both in-vitro and clinical studies provide consistent and encouraging data supporting the concept that statins may be useful in the treatment of many aspects of PCOS, including reduction of hyperandrogenemia, and various metabolic aspects. 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 small, observational trial on women taking statins during the first trimester of pregnancy was reassuring, and suggested that the risk of statin-induced teratogenicity, if any, is small [Taguchi et al. 2008]. For now, however, first-line therapy in obese women with PCOS should focus on lifestyle and dietary change with additional antiandrogen or ovulatory therapy as indicated. Although additional therapeutic choices such as statin therapy may prove to have substantial benefit this requires further clarification.