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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 2 456-461
Copyright © 2007 by The Endocrine Society

Effects of Simvastatin and Oral Contraceptive Agent on Polycystic Ovary Syndrome: Prospective, Randomized, Crossover Trial

Beata Banaszewska, Leszek Pawelczyk, Robert Z. Spaczynski, James Dziura and Antoni J. Duleba

Department of Gynecology/Obstetrics (B.B., L.P., R.Z.S.), Poznan University of Medical Sciences, 60-535 Poznan, Poland; and Departments of Epidemiology and Public Health (J.D.), and Obstetrics and Gynecology (A.J.D.), Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Antoni J. Duleba, Yale University School of Medicine, Department of Obstetrics and Gynecology, 333 Cedar Street, New Haven, Connecticut 06510. E-mail: antoni.duleba{at}yale.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and cardiovascular risks including dyslipidemia and systemic inflammation. In vitro, statins decrease proliferation and steroidogenesis of ovarian theca-interstitial cells.

Objective: The study objective was to compare effects of two treatments of PCOS: simvastatin plus oral contraceptive pill (OCP) vs. OCP alone.

Design: In a prospective, crossover trial, 48 women with PCOS were randomized to either simvastatin plus OCP for 12 wk followed by OCP alone for an additional 12 wk, or to OCP alone for 12 wk and, subsequently, simvastatin plus OCP for an additional 12 wk. Evaluations were performed at baseline, after 12 wk (crossover), and after 24 wk. Data were analyzed using a random effects model.

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

Primary Outcome: Serum total testosterone was the primary outcome measure.

Results: Total testosterone decreased by 38% after Statin + OCP, whereas OCP alone led to a 26% decrease; the statin-attributable effect was significant (P < 0.004). Free testosterone declined by 58% after Statin + OCP, significantly more than the 35% decline after OCP alone (P = 0.006). Hirsutism decreased by 8.1% after Statin + OCP, a greater effect than the 4.7% decrease after OCP alone (P = 0.02). Statin decreased LH, but not FSH or prolactin. Statin + OCP decreased total and low-density lipoprotein cholesterol by 7.5% and 20%, respectively. OCP alone led to a 5% increase of total cholesterol without effect on low-density lipoprotein cholesterol. Statin prevented OCP induced increase of triglycerides. C-reactive protein decreased by 45% after Statin + OCP, a significantly different effect (P = 0.006) than a 6% increase after OCP alone. Soluble vascular cell adhesion molecule 1 decreased by 18% after Statin + OCP, a greater decline than the 10% decrease after OCP alone (P = 0.01).

Conclusions: Simvastatin improved endocrine/clinical aspects of PCOS and had beneficial effects on lipid profile and markers of systemic inflammation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is one of the most common endocrine disorders in women of reproductive age. Several studies evaluating diverse populations estimate its prevalence at 5–7% (1, 2, 3). Immediate clinical consequences of PCOS include menstrual dysfunction, infertility, and hirsutism. In addition, PCOS is associated with a broad range of adverse sequelae, including dyslipidemia, hypertension, insulin resistance, compensatory hyperinsulinemia, gestational and type 2 diabetes, and ultimately increased risk of cardiovascular morbidity (4, 5, 6, 7, 8, 9, 10, 11, 12). Women with PCOS also have elevated emerging cardiovascular risk factors, including measures of systemic inflammation and endothelial dysfunction (13, 14). The resulting physical, emotional, and economic burden of PCOS is very high (15, 16).

Conceptually, several aspects of PCOS may be alleviated by the use of statins. Growing evidence supports the notion that statins not only improve lipid profile, but also exert a broad range of other cardioprotective effects, including antiinflammatory properties and improved endothelial function (17, 18, 19, 20).

In vitro studies have shown that statins may also reduce ovarian androgen production by inhibiting proliferation and androgen production of theca-interstitial cells (21, 22, 23). We have recently presented preliminary findings of a clinical trial, whereby women with PCOS were prospectively randomized to treatment with simvastatin plus oral contraceptive pill (OCP) or treated with OCP alone (24). We found that after 12 wk of treatment, subjects taking simvastatin had significantly lower total testosterone and LH as well as a better lipid profile than those taking OCP alone. The present report provides new and final findings of this trial after a crossover of treatments and follow-up for 24 wk. For the first time, we demonstrate that simvastatin reduces hirsutism and free testosterone and improves chemical markers of systemic inflammation and endothelial function. We propose that statins may be used in women with PCOS to reduce hyperandrogenism and cardiovascular risks.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

PCOS was defined according to a recent Rotterdam European Society for Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM)-sponsored PCOS Consensus Workshop, i.e. in the presence of at least two of the three criteria: 1) oligo- or anovulation, 2) clinical and/or chemical signs of hyperandrogenism, and/or 3) polycystic ovaries; and exclusion of other etiologies such as congenital adrenal hyperplasia, Cushing’s syndrome, or androgen-secreting tumors (25). In addition, conditions such as thyroid disease, hyperprolactinemia, and diabetes mellitus were excluded. Polycystic ovarian appearance was identified using standard ultrasonographic criteria (26). Ninety-four percent (45/48) of subjects had evidence of hyperandrogenism [hirsutism score (Ferriman-Gallwey) ≥ 8] and/or hyperandrogenemia (total testosterone ≥ 0.6 ng/ml); the remaining three subjects had acne. Seventy-five percent (36/48) of subjects had oligomenorrhea (defined as ≤8 spontaneous menses per year); the remaining 12 subjects had more frequent but irregular menses. Participants were recruited among patients evaluated for PCOS at Poznan University of Medical Sciences between April and September of 2004; all participants gave informed consent, and the study was approved by the Ethics Committee at the Poznan University of Medical Sciences and Yale University School of Medicine. 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 1Go summarizes the study. Forty-eight subjects consented to the study and were randomly assigned to two groups. Group I received first a 12-wk course of simvastatin (20 mg po daily) and OCP (containing 20 µg ethinyl estradiol and 150 µg desogestrelpo) followed by a crossover and an additional 12-wk course of OCP alone; the age of patients in this group was 24 ± 3.5 yr (mean ± SD). Group II received first a 12-wk course of OCP alone followed by a crossover and an additional 12-wk course of simvastatin plus OCP; the age of patients in this group was 23.8 ± 3.7 yr (mean ± SD). Simvastatin was provided by Polfa Grodzisk Mazowiecki (Grodzisk Mazowiecki, Poland), whereas OCP was provided by Organon Polska (Warsaw, Poland). Randomization (open label) was performed in blocks of 10, using sealed envelopes. Primary endpoint was total testosterone. Secondary outcomes are listed in Table 1Go.


Figure 1
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  		FIG. 1. Flow diagram of the trial.

 

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  		TABLE 1. Summary of effects of OCP and simvastatin

 
Study design and assays

Baseline evaluations were performed during the follicular phase of a natural menstrual cycle or after medroxyprogesterone-induced menses. Examination included determinations of body mass index (BMI), waist-to-hip ratio (WHR) and scoring of hirsutism using Ferriman-Gallwey score (27). Endocrine and metabolic tests were performed after carbohydrate intake of 300 g per day for 3 d to standardize conditions before glucose tolerance test. Venous blood collections were carried out between 0700 and 0800 h after an overnight fast. Testing included a 2-h glucose tolerance test with determinations of glucose and insulin before glucose load (fasting), as well as 30, 60, 90, and 120 min after oral glucose load (75 g). Glucose was measured using enzyme electrode in the EBIO (enzymatic amperometric principle, enzyme glucose oxidase; Eppendorf-Netheler-Hin, Hamburg, Germany). Insulin determinations were carried out using a microparticle enzyme immunoassay (AxSYM System; Abbott Diagnostics, Tokyo, Japan). Insulin and glucose determinations were used to calculate insulin area under the curve (AUC) and glucose AUC. A fasting measure of insulin sensitivity, quantitative insulin sensitivity index (QUICKI), was derived as described by Katz et al. (28). Insulin sensitivity index (ISI) was derived from glucose tolerance test results and calculated as described by Matsuda and DeFronzo (29); this measure reflects both hepatic and peripheral tissue sensitivity to insulin.

Total testosterone, LH, FSH, and prolactin were determined by specific chemiluminescence assays (Chiron Diagnostics GmbH, Fernwald, Germany). Free testosterone was measured by direct RIA using Coat-A-Count (Diagnostic Products Corp., Los Angeles, CA). Specific RIAs were used to determine SHBG (Orion Diagnostica, Espoo, Finland) and DHEAS (Diagnostic Products Corp.). Total cholesterol and triglycerides were measured by enzymatic colorimetric assays (Roche Diagnostic GmbH, Mannheim, Germany). High-density lipoprotein (HDL) cholesterol was separated by precipitating apolipoprotein-B (Roche Diagnostic GmbH, Mannheim, Germany). Low-density lipoprotein (LDL) was calculated using the Friedwald formula. High-sensitivity C-reactive protein (hs-CRP) was determined using an enzyme immunoassay kit (Life Diagnostics, Inc., West Chester, PA). Soluble vascular cell adhesion molecule 1 (sVCAM) was determined using a kit from R&D (Minneapolis, MN). Serum specimens were stored at –20 C until analysis.

Identical testing was performed during the last 2 d of a pill-free interval at 12 wk of the trial (before crossover) and at 24 wk (end of the study). At each visit, subjects were asked about possible side-effects of statins and especially about muscle pain. Liver function tests were performed at baseline, at 12 wk, and at 24 wk.

Statistical analysis

Power analysis revealed that 20 patients in each group were needed to test the hypothesis that serum testosterone will decline by 40% after simvastatin + OCP treatment and by 15% after OCP treatment, with the assumption of the coefficient of variation to be 70%. This study had the power of 80% at the 5% significance level. Anticipating a 15–20% dropout, 24 subjects were enrolled in each group. Analysis was performed according to the actual treatment received.

Mixed model analyses were used to make treatment comparisons. In these models, a random subject effect was included along with fixed effects for treatment, period, and the treatment-by-period interaction. Covariate adjustment was also included for the baseline value of the outcome. Where appropriate, log transformations were employed to meet modeling assumptions. Least squares means and 95% confidence intervals are presented.

Role of the funding source

Medications used in this study were obtained by donation from pharmaceutical companies: simvastatin was obtained from Polfa Grodzisk Mazowiecki and OCP was obtained from Organon Polska. Sponsors had no input into the study design, its execution, or interpretation of the findings.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Findings of the study are summarized in Table 1Go. The primary outcome was that total testosterone decreased by 38% after treatment with Statin + OCP, whereas treatment with OCP alone led to a 26% decrease; this difference in the effects of treatments was highly significant (P < 0.004). An even more prominent effect of statin was noted with regard to free testosterone, which declined by 58% after Statin + OCP, significantly more than the 35% decline after OCP alone. The decreased hyperandrogenemia was accompanied by an 8.1% decrease of hirsutism after Statin + OCP treatment, a significantly greater effect than the 4.7% decrease after OCP alone. In contrast to the effects of simvastatin on testosterone, no significant effect of statin was observed with regard to DHEAS, which declined by 28% after treatment with Statin + OCP and by 30% after treatment with OCP alone.

Assessment of pituitary hormones revealed a significant simvastatin-attributable decline of LH, whereas statin had no significant effect on FSH or prolactin. Statin + OCP treatment resulted in a 37% decline of LH and a corresponding 40% decline of LH to FSH ratio. These effects were significantly greater than those of OCP alone.

Statin + OCP also induced a decrease of total cholesterol and LDL cholesterol by 7.5% and 20%, respectively. In contrast, OCP alone induced a modest increase of total cholesterol by 5% without any marked effect on LDL cholesterol. Comparable increases of HDL cholesterol were observed after both treatments. Triglycerides remained virtually unchanged after Statin + OCP treatment, but increased significantly by 20% after OCP alone.

OCP induced a modest, but statistically significant, adverse effect on glucose metabolism; fasting glucose and glucose AUC increased in the range of 4–8% after either treatment, without any significant statin-attributable effect. Fasting insulin also significantly increased after treatment with Statin + OCP and OCP alone, by 11% and 9%, respectively. Increases of insulin AUC (by 18–31%) with no significant statin-attributable effect were even more prominent. In parallel, ISI, a post-glucose challenge measure of insulin sensitivity, declined after treatment with Statin + OCP and OCP alone, by 22% and 15%, respectively; the difference between treatments was not significant.

Finally, statin had a significant effect on the improvement of markers of systemic inflammation and endothelial dysfunction: hs-CRP and sVCAM. Thus, hs-CRP decreased by 45% after Statin + OCP treatment and increased by 6% after OCP treatment. sVCAM decreased by 18% after Statin + OCP, a significantly greater decline than the 10% decrease observed after treatment with OCP alone.

All of the above effects were observed in the absence of significant changes to BMI or WHR. None of the subjects experienced significant side-effects in the course of this trial. In particular, none of the subjects developed symptoms of muscle damage, and liver function tests remained normal throughout the study.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This report presents new evidence demonstrating that simvastatin may exert a broad range of beneficial effects on endocrine and metabolic aspects of PCOS. The primary goal of this study was to determine the effects of simvastatin on hyperandrogenism and hyperandrogenemia. It is apparent that simvastatin-attributable improvement of total and free testosterone was also accompanied by an improvement of hirsutism. Because excessive levels and activity of androgens are the salient features of PCOS, the present findings open new possibilities for the use of statins as a novel and effective treatment for this condition.

The mechanisms of action of simvastatin on inhibition of testosterone levels are likely related to inhibition of the mevalonate pathway; such inhibition has a broad range of consequences, including decreased availability of cholesterol (a substrate for androgen production), as well as inhibited growth of androgen-producing ovarian theca-interstitial cells, as demonstrated previously by in vitro studies (22, 23).

It is possible that a simvastatin-induced decline of androgen levels may lead to improvement of hypothalamo-pituitary function. Patients with PCOS often have altered hypothalamo-pituitary function including increased baseline LH and elevated LH to FSH ratio (30, 31). In the present study, simvastatin treatment resulted in a significant decline of LH and LH to FSH ratio. The mechanism of action of statin on the pituitary remains to be elucidated. It is likely that decline of LH is secondary to lower androgen levels; indeed, similar effects on LH and LH to FSH ratio were noted in women who underwent ovarian wedge resection with a consequent significant decline of testosterone (32). The concept that a decline of LH may be mediated by decreased androgen levels is also supported by a recent study by Eagleson et al. (33), which demonstrated that treatment with an antiandrogen resulted in restoration of the sensitivity of the GnRH pulse generator to estradiol and progesterone, ultimately leading to decreased LH pulse frequency . However, effects of statins on LH may also be due to other mechanisms, such as effects mediated by changes in lipid profile, or even direct actions on the hypothalamus and/or pituitary. Indeed, in rat pituitary tumor cells, statin has been shown to modulate Gs and Gi proteins in the plasma membrane, as well as adenyl cyclase activity (34).

Notably, in the course of this trial, patients did not experience any significant changes in body weight or body mass distribution, as determined by WHR. OCP induced modest worsening of fasting glucose and insulin, as well as a decrease of ISI; however, simvastatin had no significant effect on any of these parameters. Thus, the effects of statin on testosterone and LH cannot be attributed to changes in BMI or modulation of insulin sensitivity.

Another important aspect of PCOS is an increase of a broad range of cardiovascular risk factors. Several studies have demonstrated that this condition is associated with adverse lipid balance, hypertension, and increased cardiovascular morbidity and mortality (7, 8, 9, 10). Women with PCOS typically have elevated plasma levels of total cholesterol, LDL cholesterol, and triglycerides, but decreased levels of HDL cholesterol (8, 35, 36, 37). Furthermore, in these patients, markers of subclinical atherosclerosis, such as increased thickness of arterial intima-media, are elevated (38, 39). There is also growing evidence that PCOS is associated with endothelial dysfunction and increased levels of indices of low-grade chronic inflammation such as hs-CRP (13, 40). Recent studies indicate that hs-CRP is an excellent predictor of cardiovascular events in women, and its predictive power appears to be greater than that of LDL cholesterol (41, 42). VCAM is a protein produced by endothelial cells and, when shed into the circulation as a sVCAM, it is a marker of endothelial activation correlating with atherosclerosis (43, 44).

In view of the above considerations, the present findings provide reassuring evidence that statin treatment significantly reduces cardiovascular risk factors even in this young, but at-risk, population. Indeed, in the present report, we observed that simvastatin significantly improved lipid profile as well as reduced hs-CRP and sVCAM.

Notably, this study evaluated the use of simvastatin during concomitant treatment with OCP. The decision to use OCP in this trial was based on two considerations. First, OCP therapy is considered the mainstay of medical therapy of PCOS in women not attempting pregnancy, resulting in regulation of menstrual cycle, protection from endometrial hyperplasia, and improvement of hyperandrogenism in adults and adolescents (45, 46). Second, statins may have teratogenic effects (47, 48), and therefore reliable contraception is essential.

In summary, the present study provides new evidence demonstrating that the use of simvastatin may substantially improve endocrine and clinical parameters of PCOS while simultaneously decreasing both traditional and emerging cardiovascular risk factors.


   Footnotes
 
Trial registration was conducted at clinicaltrials.gov (identifier: NCT00365638).

This work was supported by Grant R01 HD40207 from the National Institutes of Health (to A.J.D.).

The authors have nothing to disclose.

First Published Online November 14, 2006

Abbreviations: AUC, Area under the curve; BMI, body mass index; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; ISI, insulin sensitivity index; LDL, low-density lipoprotein; OCP, oral contraceptive pill; PCOS, polycystic ovary syndrome; sVCAM, soluble vascular cell adhesion molecule 1; WHR, waist-to-hip ratio.

Received September 10, 2006.

Accepted November 2, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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