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J Clin Endocrinol Metab. Dec 2009; 94(12): 4938–4945.
Published online Nov 4, 2009. doi:  10.1210/jc.2009-1674
PMCID: PMC2795658

Comparison of Simvastatin and Metformin in Treatment of Polycystic Ovary Syndrome: Prospective Randomized Trial

Abstract

Context: Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction and hyperandrogenism; it is also associated with increased cardiovascular risks such as adverse lipid profile and endothelial dysfunction. Metformin and, more recently, statins have been shown to improve endocrine and metabolic aspects of PCOS.

Objective: The aim of the study was to compare effects of simvastatin and metformin on PCOS.

Design: In a prospective trial, women with PCOS (n = 136) were randomized to simvastatin (S), metformin (M), or simvastatin plus metformin (SM) groups. Evaluations were performed at baseline and after 3 months.

Setting: The study was conducted at an academic medical center.

Primary Outcome: The change of serum total testosterone was measured.

Results: The study was completed by 113 subjects. Total testosterone decreased significantly and comparably in all groups: by 17.1, 13.6, and 15.1%, respectively, in the S, M, and SM groups. Significant decreases were also observed in all groups with respect to body mass index, C-reactive protein, and soluble vascular cell adhesion molecule-1. DHEAS declined significantly only in the S group. None of the treatments were associated with significant changes in LH or FSH. Total cholesterol and low-density lipoprotein cholesterol significantly declined only in S and SM groups.

Conclusions: Simvastatin treatment was superior to metformin alone, whereas a combination of simvastatin and metformin was not significantly superior to simvastatin alone.

Polycystic ovary syndrome (PCOS) is a common and heterogeneous syndrome associated with a broad range of clinical, hormonal, and metabolic derangements affecting 5–8% of women of reproductive age (1,2,3). Although the reproductive and cosmetic aspects of PCOS (ovulatory dysfunction, hirsutism, acne) have been appreciated for decades, more recently it has become apparent that this syndrome is also linked to a broad range of cardiovascular risk factors. In particular, women with PCOS are at increased risk for dyslipidemia, hypertension, insulin resistance, gestational and type 2 diabetes, systemic inflammation, endothelial dysfunction, and ultimately, cardiovascular morbidity (4,5,6,7,8,9). It has been estimated that the total cost of evaluating and providing care to reproductive-aged PCOS women in the United States exceeds $4 billion annually (10).

Ideally, long-term treatments of PCOS should address not only endocrine dysfunction but also cardiovascular risks. In recent years, metformin has been commonly used to treat women with PCOS. The proposed and documented effects of metformin include decreased testosterone level, reduction of ovarian volume, greater insulin sensitivity, improvement of lipid profile, and improved endothelial function (11,12,13,14). However, several investigators have failed to detect some of these effects of metformin. Thus, for example, several studies have not detected any significant improvement of lipid profile after metformin therapy (15,16).

Recently, the use of statins emerged as a novel therapeutic approach to PCOS. In the first clinical trial, women with PCOS were randomized to treatment with simvastatin (20 mg daily) plus oral contraceptive pill (OCP) or OCP alone (17). After 12 wk of treatment, women receiving simvastatin had significantly lower total testosterone and a better lipid profile than those taking OCP alone. Subsequent crossover of treatments and follow-up for 24 wk have shown that simvastatin also improved chemical markers of systemic inflammation and endothelial function (18). More recently, in a randomized, placebo-controlled trial, another statin, atorvastatin, induced a significant decrease of testosterone, C-reactive protein, and insulin resistance, as well as improvement of lipid profile (19).

The present study was designed to directly compare effects of metformin and simvastatin as well as to determine whether a combination of these treatments is superior to either monotherapy.

Subjects and Methods

Subjects

PCOS was defined according to modified Rotterdam criteria: 1) the presence of clinical and/or biochemical signs of hyperandrogenism; and 2) at least one of the following: oligo- or anovulation and/or polycystic ovaries (20,21). In all subjects, congenital adrenal hyperplasia was excluded by determination of normal morning follicular phase 17-hydroxyprogesterone (<2 ng/ml), whereas hyperprolactinemia was excluded by determination of normal levels of prolactin. Cushing’s syndrome and androgen-secreting tumors were excluded based on clinical presentation. None of the subjects had thyroid disease or diabetes mellitus. All recruited women had no history of cardiovascular disease and no hypertension. All patients had normal concentrations of bilirubin, aminotransferases, blood urea nitrogen, and creatinine. Polycystic ovaries were identified according to standard ultrasonographic criteria (22). Participants were recruited among patients evaluated for PCOS at Poznan University of Medical Sciences between December 2006 and March 2009; all participants gave informed consent, and the study was approved by the Institutional Review Board at the Poznan University of Medical Sciences and the Institutional Review Board at the University of California Davis. The study was registered at clinicaltrials.gov with identifier NCT00396513.

For at least 3 months before the study, all subjects refrained from the use of any form of oral contraceptives, other steroid hormones, or any other treatments likely to affect ovarian function, insulin sensitivity, or lipid profile.

Procedures

Figure 11 summarizes enrollment, randomization, and follow-up data. The 136 women who consented to the study were randomly assigned to three groups: S group (received simvastatin, 20 mg orally once a day); M group (received metformin, 850 mg orally twice a day); and SM group (received simvastatin, 20 mg orally once a day, and metformin, 850 mg orally twice a day). Simvastatin (Simvachol) was provided by Polfa Grodzisk (Grodzisk Mazowiecki, Poland), whereas metformin (Metformax) was obtained from Polfa Kutno SA (Kutno, Poland). Patients were randomly assigned to three treatment groups with 1:1:1 allocation ratio, using blocks of random size (6, 9, and 12 subjects in a block). Random number tables were used for random patient allocation and block size determination. Subjects were randomized by opening sequentially numbered sealed envelopes. Allocation to study group was concealed until a consent was obtained and inclusion/exclusion criteria were verified. The randomization list was kept locked, and the allocation numbers were generated and sealed in the envelopes by one of the authors (R.Z.S.). Allocation of the patients was performed only by the first author, who was unaware of the randomization schedule. There was no blinding after randomization because commercially available pills were used, and thus investigators and patients could clearly identify the treatment arm. The primary endpoint was change of total testosterone. Baseline parameters describing the subjects and secondary outcomes are listed in Table 11.

Figure 1
Flow diagram of the trial.
Table 1
Baseline parameters in individual study groups at the time of randomization

Study design and assays

Evaluations were performed at baseline and after 3 months of treatment during the follicular phase of a natural menstrual cycle or after medroxyprogesterone-induced menses. Examination included determinations of body mass index (BMI), scoring of hirsutism using Ferriman and Gallwey score (23), and acne score (24). Acne was evaluated using a four-grade scale: 0, no acne; 1, minor acne, face only; 2, moderate acne, face only; 3, severe acne, face and back or chest. Hormonal and metabolic testing was performed after carbohydrate intake of 300 g/d for 3 d to standardize conditions before glucose tolerance test. Venous blood was collected between 0700 and 0800 h after an overnight fast. Tests included a 2-h oral glucose tolerance test with determinations of fasting glucose and insulin as well as glucose and insulin after 75 g glucose load at 30, 60, 90, and 120 min. Glucose was determined using enzyme electrode in the EBIO (enzymatic amperometric principle, enzyme glucose oxidase; Eppendorf-Netheler-Hin, Hamburg, Germany). Insulin, total testosterone, LH, FSH, prolactin, SHBG, and dehydroepiandrosterone sulfate (DHEAS) were determined by specific electrochemiluminescence assays (automated Elecsys 2010 immunoanalyzer; Roche Diagnostics GmbH, Mannheim, Germany). Free testosterone was estimated as described by Vermeulen et al. (25). 17-Hydroxyprogesterone was measured using ELISA assay (DRG Instruments GmBH, Marburg/Lahn, Germany). Insulin and glucose determinations were used to calculate insulin sensitivity index, which was derived from oral glucose tolerance test results and calculated as described by Matsuda and DeFronzo (26); this measure reflects both hepatic and peripheral tissue sensitivity to insulin.

Total cholesterol and triglycerides were determined by enzymatic colorimetric assays (Roche Diagnostics GmbH). High-density lipoprotein (HDL) was separated by precipitating apolipoprotein-B (Roche Diagnostics GmbH). Low-density lipoprotein (LDL) was calculated using the Friedwald formula. High sensitivity C-reactive protein (hs-CRP) was determined using specific electrochemiluminescence assay (automated Elecsys 2010 immunoanalyzer; Roche Diagnostics GmbH). Soluble vascular cell adhesion molecule 1 (sVCAM) was determined using a human Quantikine ELISA kit from R&D Systems (Minneapolis, MN). Serum specimens were stored at −20 C until analysis.

Statistical analysis

Power analysis revealed that 108 patients were needed to detect a significant difference in change of serum testosterone, assuming a decline of 12% after simvastatin treatment, 12% after metformin treatment, and 18% after combined treatment with simvastatin and metformin with the assumption of the coefficient of variation to be 60%, power of 80%, and α error at 0.05 significance level. Anticipating a 20% dropout, 136 subjects were enrolled. Analysis was performed according to the actual treatment received.

Comparisons between groups were performed by ANOVA, and change of values for individual variables (at 3 months compared with baseline) was analyzed by repeat measures ANOVA. Post hoc comparisons of individual pairs included t tests with Bonferroni correction. In the absence of normal distribution (tested by Shapiro-Wilk test), logarithmic transformations or nonparametric testing was carried out.

Results

Among women recruited and randomized, at baseline 107 of 136 (79%) subjects were hirsute (Ferriman and Gallway score ≥8) and 116 of 136 (85%) subjects had oligomenorrhea (≤8 spontaneous menses per year). The 3-month study was completed by 113 subjects. Among those who completed the study, 88 of 113 (78%) women were hirsute, and 96 of 113 (85%) had oligomenorrhea. Total serum testosterone was elevated (>0.6 ng/ml) in 72% of nonhirsute and in 89% of hirsute subjects. BMI was above 25 kg/m2 in 25% of subjects and above 30 kg/m2 in 12% of subjects. Seventy-three percent of women had eight or less spontaneous menses per year. None of the subjects developed symptomatology suggestive of rhabdomyolysis such as muscle pain; liver function tests and renal function tests were normal throughout the study. None of the subjects had other serious adverse events, and three patients receiving metformin (one in M group and two in SM group) complained of minor gastrointestinal side effects that caused no discontinuation of treatment.

Table 11 presents baseline parameters of all subjects who completed the study. Comparisons between the groups reveal that most of the baseline study’s parameters, including primary outcome, total testosterone, were comparable across the groups. Baseline FSH was slightly (by 1.1 IU/liter) lower in subjects assigned to the SM group in comparison to the M group. Baseline HDL cholesterol was higher (by 11 mg/dl) in subjects assigned to simvastatin than those assigned to metformin. Finally, sVCAM was higher in the M group than in the other two groups.

Effects of treatments are summarized in Table 22.. Primary outcome, total testosterone, declined significantly in all three groups (by 13.6–16.3%), and no significant difference between the groups was noted. Similarly, in all treatment groups, there was a significant and comparable decline of free testosterone. These changes were paralleled by a comparable improvement of acne score as well as minimal (and of borderline statistical significance) reduction of hirsutism in all groups. BMI declined after all treatments by 1.6–2.7% with no statistically significant difference between the treatment groups. In all groups, there was also a significant and comparable improvement of markers of systemic inflammation and endothelial function, as manifested by reduction of hs-CRP and sVCAM.

Table 2
Change of parameters at 3 months of treatment in comparison to baseline values

DHEAS and SHBG declined significantly only in the simvastatin group, whereas prolactin declined only after treatment with metformin alone or metformin in combination with simvastatin. Gonadotropins were not significantly affected by any of the treatments.

In contrast, lipid profile improved only in subjects who received simvastatin, either alone or in combination with metformin; this effect consisted of a profound reduction of total cholesterol and LDL cholesterol in the absence of changes in HDL cholesterol. Treatment with simvastatin alone was also associated with a significant decrease of fasting insulin and improvement of insulin sensitivity index, whereas treatment with metformin alone resulted in a modest but statistically significant reduction of fasting glucose.

Discussion

This study presents the results of a first trial comparing effects of statin and metformin on clinical, endocrine, and metabolic aspects of PCOS. We have demonstrated that: 1) simvastatin and metformin exert comparable effects on reduction of testosterone, clinical hyperandrogenism, BMI, and markers of systemic inflammation and endothelial function; 2) only simvastatin significantly improved lipid profile, DHEAS, and insulin sensitivity; and 3) the combination of simvastatin and metformin was not significantly superior to simvastatin alone with regard to any of the studied variables.

The effects of simvastatin on testosterone are consistent with our previous clinical trial on women with PCOS comparing treatment with OCPs alone and OCPs in combination with simvastatin (18). In that trial, reduction of total testosterone level in the presence of simvastatin was 12% greater than that seen in the presence of OCPs alone. Simvastatin, like other statins, is thought to exert its actions primarily by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a rate-limiting step of the mevalonate pathway (27). Inhibition of testosterone production may be due to reduced availability of several products of mevalonate pathway, including decreased level of cholesterol, a substrate for steroid production, as well as decreased availability of substrates for isoprenylation. Decreased isoprenylation may lead to reduction of activities of small GTPases such as Ras, Rho, and Rac, resulting therefore in alterations of mechanisms regulating proliferation and function of ovarian tissues. In particular, statins may reduce activity of MAPK1 and decrease cytoplasmic production of reactive oxygen species by attenuating activity of reduced nicotinamide adenine dinucleotide phosphate oxidase (28,29). It is also possible that, in this trial, reduction of testosterone level may be related to increased likelihood of ovulation and consequent negative feedback effect of steroids produced in the luteal phase on testosterone. However, ovulation was not directly tested in this trial.

Consistent with the concept of direct action of statins on the ovary, in vitro studies have indicated that statin treatment reduces ovarian androgen production by inhibiting proliferation of theca-interstitial cells as well as reducing theca-interstitial cell steroidogenesis (30,31). These actions of statins may address important features of PCOS: ovarian thecal and interstitial cell hyperplasia and excessive androgen production (32,33).

In this study, simvastatin also exerted a broad range of other beneficial effects on women with PCOS, especially improving markers of cardiovascular risks including hs-CRP, sVCAM, and lipid profile. Such effects of statins are well recognized in various at-risk populations, including women with metabolic syndrome, diabetes, and insulin resistance. These observations are of importance, because PCOS is associated with an adverse profile of markers of cardiovascular risks including dyslipidemia, increased thickness of arterial intima and media, as well as elevated markers of systemic inflammation (such as hs-CRP) and endothelial dysfunction (such as sVCAM) (8,34,35,36,37).

In addition, in the present study, simvastatin treatment was associated with reduced fasting insulin and improved insulin sensitivity. Comparable beneficial effects on insulin sensitivity were also reported after a 12-wk course of atorvastatin in women with PCOS (19). However, statin-induced improvement of insulin sensitivity may be a transient phenomenon or may depend on the treated population because in various other clinical trials statins either had no significant effect or even worsened insulin sensitivity (38,39). Another unexpected observation in the present study pertains to reduction of DHEAS and BMI after simvastatin treatment. Such effects of statins were not observed in previous studies evaluating women with PCOS; consequently, these observations should be interpreted with caution and await verification in further studies (18,19).

The present report indicates that metformin improved testosterone level and several other features of PCOS, such as markers of systemic inflammation and endothelial dysfunction, but had no significant effect on lipid profile or insulin sensitivity. A review of previous studies evaluating effects of metformin on women with PCOS indicates that effects of metformin had no consistent beneficial effect on these aspects of PCOS. Specifically, several reports describe a metformin-induced decrease of androgens (11,14,15,40,41), whereas others do not (13,42). Similarly, some, but not all, studies document improvement of lipid profile (12,13,16,43). The variability in the response to metformin may be related to differences in the underlying characteristics of study populations including BMI and insulin sensitivity.

Another important finding of this study is the observation that a combination of simvastatin and metformin did not improve parameters of PCOS beyond the effects obtained by monotherapy using simvastatin. One possible explanation for this observation may be a putative convergence of some mechanisms of action of statins and metformin. Indeed, it is now well recognized that one of the important mechanisms of action of metformin involves activation of AMP kinase (44). AMP kinase has been shown to phosphorylate and hence reduce activity of HMG-CoA reductase (45). Because statins are competitive inhibitors of HMG-CoA reductase, it is possible that actions of metformin and statins converge at that point and both reduce activity of the mevalonate pathway.

This study evaluated women with PCOS who fulfilled the Rotterdam criteria, but in addition were hyperandrogenic (elevated testosterone, hirsutism, and/or acne), as recommended in recent position statements by the Androgen Excess and PCOS Society (20,21). Selection of this particular population, and hence exclusion of normoandrogenic women with polycystic ovarian morphology and oligoamenorrhea, was based on the evidence that hyperandrogenism aids in identifying women with greater risk of metabolic dysfunction (46). Furthermore, participants of the present trial were young and mostly lean; thus, extrapolation of the present observations to other populations of women with PCOS should be avoided.

In summary, this report indicates that statin use may represent a promising novel treatment of many features of PCOS including hyperandrogenism and a broad range of cardiovascular risk factors. However, routine use of statins in the treatment of PCOS cannot be advocated yet. Furthermore, large studies on diverse populations are needed to reevaluate their effectiveness and safety. In addition, statins may be potentially teratogenic (47), and reliable contraception during their use is important.

Footnotes

This work was supported by Polish State Committee for Scientific Research (KBN) Grant Nr 2PO5E 09630 and by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grant RO1 HD050656.

Trial Registration: clinicaltrials.gov Identifier: NCT00396513.

Disclosure Summary: B.B., L.P., and R.Z.S. received grant support from KBN. A.J.D. received grant support from the NICHD (2007 to present).

First Published Online November 4, 2009

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; hs-CRP, high sensitivity C-reactive protein; OCP, oral contraceptive pill; PCOS, polycystic ovary syndrome; sVCAM, soluble vascular cell adhesion molecule.

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