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Effects of metformin plus simvastatin on polycysticovary syndrome: a prospective, randomized,double-blind, placebo-controlled study Talieh Kazerooni, M.D.,a Azam Shojaei-Baghini, M.D.,a Sedigheh Dehbashi, M.D.,a Nasrin Asadi, M.D.,aFariborz Ghaffarpasand, M.D.,b and Yasaman Kazeroonic a Department of Obstetrics & Gynecology, Shiraz University of Medical Sciences, Shiraz, and b Student Research Committee,Fasa University of Medical Sciences, Fasa, Iran; and c New Mexico Tech University, Socorro, New Mexico Objective: To evaluate the effect of a combination of simvastatin and metformin on biochemical parameters inwomen with polycystic ovary syndrome (PCOS).
Design: A prospective, randomized, double-blind, placebo-controlled study.
Setting: University hospital.
Patient(s): Eighty-four women with PCOS randomly divided to two study groups.
Intervention(s): Patients were randomly assigned to receive metformin (500 mg three times a day) plus simvastatin(20 mg/day, n ¼ 42; group 1) or metformin (500 mg three times a day) plus placebo (once a day, n ¼ 42; group 2) for12 weeks. Blood samples were obtained before and after treatment.
Main Outcome Measure(s): Testosterone.
Result(s): After 12 weeks of treatment, serum T levels decreased by 25.5% in group 1 and by 16.8% in group 2.
There was a greater decrease of LH (45.5% vs. 6.7%) and a greater decline of the LH/FSH ratio (38.3% decreasedvs. 4.4% increased) in the first group. In group 1 there was a greater decrease of total cholesterol (29.5% vs. 4.2%),low-density lipoprotein (LDL; 18.5% vs. 1.5%), and triglycerides (32% vs. 5.3%). High-density lipoprotein (HDL)increased in the first group by 14%, whereas it decreased by 1% in the second group.
Conclusion(s): This report has demonstrated that the combination of metformin and simvastatin could lead to a bet-ter reduction of T and LH levels and thus reversing the LH:FSH ratio, lipid profile, and insulin resistance in patientswith PCOS and may be an appropriate management option for patients with PCOS. (Fertil Steril� 2010;-:-–-.
�2010 by American Society for Reproductive Medicine.) Key Words: Polycystic ovary syndrome, metformin, simvastatin, testosterone, lipid profile Polycystic ovary syndrome (PCOS) is a common endocrinopathy Treatment for subjects with PCOS typically includes implemen- affecting 6.5%–6.7% of women in reproductive age, and is tation of lifestyle changes, especially weight loss and adjuvant commonly associated with obesity, menstrual irregularity, insulin pharmaceutical intervention including oral contraceptives (OC), resistance, infertility, and clinical hyperandrogenism or hyperandro- antiandrogen therapy, and insulin-lowering drugs (e.g., metformin) genemia (1, 2). The PCOS is also associated with increased risk of (6). Metformin is a biguanide, used extensively in type 2 diabetes.
abnormal lipoproteins and hypertension, as well as cardiovascular or It inhibits hepatic glucose production and increases peripheral insu- cerebrovascular morbidity (3). The lipid and lipoprotein profile in lin sensitivity, but does not cause hypoglycemia. Several studies androgenized women with polycystic ovaries (PCO) is similar to have shown an increase in insulin sensitivity and pregnancy rate the pattern with higher levels of cholesterol, low-density lipoprotein (PR), accompanied by decreased insulin and androgen levels, in (LDL), and lower levels of high-density lipoprotein (HDL), and this patients with PCOS taking metformin (7).
abnormal pattern is independent of body weight (4). Insulin resis- The 3-hydroxy-3-methylglutaryl coenzyme A (hMG-CoA) tance is associated with reproductive abnormalities in women with reductase inhibitors (statins) are the rate-limiting step in cholesterol PCOS. Improving insulin sensitivity through both lifestyle and phar- biosynthesis, and inhibition of this enzyme decreases cholesterol macologic intervention can ameliorate these abnormalities. Insulin synthesis and a compensatory increase in the expression of LDL resistance in women with PCOS is common (up to 50%), both in receptors in the liver. Statins reduce plasma triglycerides in dose-de- obese and nonobese women (5), and disordered insulin action pendent fashion and also have a modest HDL raising effect, which is not dose-dependent (8, 9). Furthermore, statins pose other cardio-protective properties, including antioxidant and anti-inflammatoryactions (10, 11).
Received July 20, 2009; revised November 21, 2009; accepted November Some studies have reported that simvastatin decreases serum androgen levels in women with PCOS (12, 13) by inhibiting prolif- T.K. has nothing to disclose. A.S.-B. has nothing to disclose. S.D. has eration and steroidogenesis of ovarian theca interstitial cells (14).
nothing to disclose. N.A. has nothing to disclose. F.G. has nothing to According to these previous findings, we hypothesized that a combi- disclose. Y.K. has nothing to disclose.
nation therapy with simvastatin and metformin will result in lower Reprint requests: Fariborz Ghaffarpasand, M.D., PO Box: 7173646199, androgen levels and cardiovascular risk factors in women with 987116483561; E-mail: [email protected]).
Fertility and Sterility� Vol. -, No. -, - 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
All hormonal assays were performed in Endocrinology and Metabolism Research Center of Nemazee Hospital. Serum FSH (FSH-IRMA,KIP0264; BIOSOURCE, Nivelles, Belgium), LH (LH-IRMA CT, REF The study was performed at the infertility clinic of Zeinabieh hospital, a ter- KP7CT; RADIM, Rome, Italy), DHEAS (DHEA-S-IRMA, KIP0481; tiary care center affiliated with Shiraz University of Medical Sciences. We BIOSOURCE), and PRL (PRL-IRMA, KIP1406; BIOSOURCE) were mea- screened 92 patients with PCOS ranging in age from 17–29 years between sured by RIA. Serum T levels were measured by RIA (ESTO-RIA-CT, January and March 2008. The review board of Shiraz University of Medical KIP1709; BIOSOURCE). The intra-assay and interassay coefficients of Sciences approved the study and all recruited patients filled the informed variation (CV) were <6% for all assays performed.
Polycystic ovary syndrome was defined according to Rotterdam European Society for Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM) PCOS consensus workshop Thirty-seven patients were required in each group for a study to have 90% (5). All patients had at least two of three following criteria: [1] chronic anov- power to detect significant differences between corresponding variables ulation, [2] clinical or biochemical evidence of androgen excess, and [3] (P¼.05, two-sided). To compensate for possible nonevaluable data, we en- polycystic-appearing ovaries on transvaginal ultrasound (TVUS). Patients rolled 42 participants in each group. The Statistical Package for Social with Cushing’s syndrome, hyperprolactinemia, diabetes mellitus, thyroid Science, SPSS for Windows, version 15.0 (SPSS, Chicago, IL) was used disease, adrenal hyperplasia, and androgen-secreting tumors or other for data analysis. Paired t-tests were used to compare results within groups; endocrinopathies, have been excluded from the study. Patients with adrenal independent t-tests were used to compare results between the groups; c2 tests hyperplasia were excluded by ACTH-stimulated 17a-hydroxyprogesterone were used to compare proportions. Data are reported as means � SD for 95% (17-OHP) levels less than 10 ng/mL (15), and ACTH-stimulated 11-deoxy- confidence interval (CI) with 5% degree of freedom. A two-sided P value cortisol levels less than 21 ng/mL (threefold the 95th percentile (16) of a his- < .05 was considered statistically significant.
toric control group of 60 healthy women controls). Those subjects who hadkidney or liver diseases and those who were smoker or had breast cancer were also excluded from the study. None of the participants received OCs, steroidhormones, or any medications that would interfere with lipid metabolism, All participants finished the study. The baseline characteristics of ovarian, pituitary, and hypothalamic function, or insulin sensitivity in the 3 the two study groups are shown in Table 1. All baseline measure- months before study entry. All patients used barrier methods of contraception ments were comparable. Patients in both treatment groups tolerated during the study regarding the potential teratogenic actions of statins. The the treatments well, and none of them experienced significant side possible teratogenicity of statins was explained to all the participants and effects. In particular, none of the subjects developed symptoms of they were asked to use barrier contraception. This was obeyed by all the par- muscle damage, and liver function tests remained normal through- ticipants. All the patients followed almost the same exercise and diet proto- out the study. Also, none of the patients conceived during the cols during the study period. All subjects were nonsmokers and had normal physical activity, and none drank alcoholic beverages.
Table 2 shows the mean � SD of the variables before and after 12 weeks of treatment and Table 3 represents the changes in the parameters in each study group. The BMI was significantly Patients were given a sealed envelope containing their admission number by decreased by 7.7% in group 1 (P¼.039) and by 7.5% in group 2 a nurse who was blinded to the study and in the order of presentation. This (P¼.041); there was no significant difference between groups admission number became the participant’s medical chart number. Another (P¼.341). Total cholesterol declined after 12 weeks of treatment researcher (a physician) who was blinded to the study opened the envelope by 29.5% in group 1 and by 4.2% in group 2 (P<.001). The and gave the patients a red box if they had odd numbers and a green one if HDL levels increased in group 1 by 14%, whereas it decreased they had even numbers. He did not know the content of the boxes. The par- by 1% in group 2 (P<.001). The LDL levels decreased in group ticipants with odd numbers (n ¼ 42) were assigned to the simvastatin (20 mg/ 1 by 18.5% and by 1.5% in group 2 (P<.001). The TG levels day) plus metformin (500 mg three times a day, n ¼ 42; group 1) group andthose with even numbers (n were also decreased in both groups: 32% in group 1 and 5.3% ¼ 42) were assigned to the placebo (once a day) plus metformin (500 mg three times a day, n ¼ 42; group 2) group.
Serum T level declined by an average of 25.5% (P¼.001) in group 1 and by 16.8% (P¼.002) in group 2; the difference in the treatment effect between groups was significant at P<.001. The On the first day of a spontaneous or P-induced menstrual cycle, after an change in the DHEAS value was also significant between groups overnight fast, blood samples were drawn to determine serum FSH, LH, total (P¼.007); it declined by 3% (P¼.043) and 0.2% (P¼.973) in group T, PRL, DHEAS, fasting blood sugar, fasting insulin, total cholesterol, HDL, 1 and 2, respectively. Serum LH level and LH:FSH ratio were both LDL, and triglycerides (TG). In addition, in a 75-g oral glucose tolerance test significantly decreased in group 1, whereas they remained un- (OGTT), blood samples were drawn at 60 and 120 minutes to determine in-sulin and glucose responses. Insulin sensitivity was assessed by quantitative changed in group 2. The FSH level did not change significantly insulin sensitivity check index defined as 1/[log(fasting insulin) þ log(fasting in either groups. The decline in the LH level (P¼.001) and LH:FSH glucose)] (17). Participants were diagnosed as having insulin resistance when ratio (P¼.009) were significant between groups (Table 3). The the fasting glucose-to-fasting insulin ratio was less than 4.5 (18). Body mass hirsutism score (on the Ferriman–Gallwey scale) declined signifi- index (BMI, as weight in kilograms divided by height in meters squared) was cantly in both groups by 13% and 7 % in group 1 and 2, respec- calculated by a single physician who was blinded to the study groups. Hirsut- tively; the difference between groups was significant at P¼.019.
ism was also scored according to the Ferriman–Gallwey scale by the same Table 4 summarizes the 75-g OGTT results. Fasting insulin level physician (19). All measurements were taken again from all participants after and fasting blood sugar, as well as 60- and 120-minute insulin and 12 weeks of treatment. The participants were instructed to report in a daily glucose levels were significantly decreased after 12 weeks of treat- diary the onset of any adverse experiences (especially muscle pain), specify- ment. However, these changes were not significant between groups.
ing the severity, duration, and a possible cause–effect relationship with drugadministration. To evaluate compliance with the treatment and with the pro- Also, the insulin sensitivity increased in groups 1 and 2 by 3.2% tocol, number of tablets forgotten, changes in diet, physical activity, and (P¼.014) and 2.7% (P¼.029), respectively, but it was not significant weight, as well as the timing of intercourse were also recorded in the diary.
between groups (P¼.084). In the first group, 27 participants (64.2%) Liver function tests were performed at baseline and at 12 weeks.
were insulin resistant at baseline, whereas 11 (26.2%) were on week We tested the hypothesis that combination therapy with metformin Baseline characteristics of two study groups.
and simvastatin in patients with PCOS will have better results inreducing the hyperandrogenism and normalizing other biochemical parameters than using metformin alone, with a possible synergic mechanism. A few studies have assessed the beneficial effect of sim- vastatin in PCOS (12, 13). This study shows that in the presence of simvastatin, metformin is much more effective in reducing the T, DHEAS, clinical hyperandrogenemia (hirsutism), LH, and reversing the LH:FSH ratio in patients with PCOS. Elevated T level and a high LH:FSH ratio are the hallmarks of the hypothalamic-pituitary-ovar- ian dysfunction that is characteristic of PCOS. Metformin alone could not reduce these parameters, except for T level and hirsutism.
Several studies have indicated the beneficial effect of metformin on biochemical and clinical aspects (7, 20–22). Metformin therapy leads to a rapid improvement of hyperandrogenemia and hyperan- drogenism and is effective in reducing insulin resistance in women with high baseline androgen levels similar to PCOS (7, 23).
Three previous randomized controlled trials have shown that sim- vastatin could successfully reduce T and LH levels and the LH:FSH ratio (12, 13, 24). However, none of them could reduce the insulin resistance assessed by insulin indices. Evidence of an association between PCOS and glycometabolic dysfunction has accumulatedduring the past few years, and that a large percentage of women Note: Values are expressed as the mean � SD. Significant difference with this condition have hyperinsulinism and insulin resistance.
BMI ¼ body mass index; FBS ¼ fasting blood glucose; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; QUICKI ¼ quantitative increased androgen production by stimulating ovarian steroidogen- insulin sensitivity check index; TG ¼ triglycerides; WHR ¼ waist-to- esis. At higher concentrations, insulin binds to the insulin-like growth factor (IGF) receptors, transmits its signals to the ovary Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
already in a hyperandrogenic state because of an enzymatic dysregu-lation of cytochrome P450c17-a, and inhibits the synthesis of thehepatic sex hormone-binding globulin (SHBG) (25). We showed 12 of the study (P¼.001). In the second group, 26 participants that combination therapy with simvastatin and metformin not only (61.9%) were insulin resistant at baseline, whereas 12 (28.7%) decreased hyperandrogenemia more effectively but also reduced were at the end of the study (P¼.003).
the number of PCOS patients with insulin resistance and increased Hormonal and metabolic parameters in both groups before and after 12 weeks of treatment.
Note: Values are expressed as the mean � SD. Significant change from baseline in each group (P< .05).
BMI ¼ body mass index; FBS ¼ fasting blood glucose; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein; QUICKI ¼ quantitative insulin sensitivity Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
for the lowering of plasma cholesterol (10). Steroid hormone synthe- sis depends on a supply of cholesterol, which may be derived from Changes in the baseline values of 84 patients with the uptake of plasma lipoproteins or from endogenous synthesis polycystic ovary syndrome after 12 weeks of treatment with metformin plus simvastatin (group 1) and metformin Because of the design of our study we cannot dissociate the effects of statins on the ovary from the effects on the hypothalamus and pituitary. However, it is likely that the primary actions are taking place in the level of the ovary. Several lines of evidence support this concept. First, statins had no effect on serum T level in postmeno-pausal women in whom the main source of androgens is extraovar- ian (26). Second, paravastatin significantly decreased cholesterol level in patients with heterozygous familial hypercholesterolemia in whom delivery of LDL to the adrenal cortex is impaired and thus have demonstrable deficiencies of adrenal steroid production (27). Third, it was shown that statins decrease ovarian theca interstitial proliferation and T production in vitro (14). And the last evidence is that surgical resection or ablation of a portion of the ovary (wedge resection or laparoscopic diathermy, which decreases ovarian androgen production) leads to marked decline of T, LH, and The precise metformin mechanism of action is yet to be eluci- dated. Attia et al. (30) found that metformin directly inhibited andro- gen production in human ovarian thecal cells. It still remains unclear whether metformin improves ovulation by direct inhibition of androgen production or by improving insulin sensitivity, and thus Note: Values are expressed as the mean � SD. Significant change from indirectly lowering serum androgens. The mechanisms of action of simvastatin on inhibition of T levels are likely related to inhibition BMI ¼ body mass index; FBS ¼ fasting blood glucose; HDL ¼ high-den- of the mevalonate pathway. Such an inhibition has a broad range of sity lipoprotein; LDL ¼ low-density lipoprotein; QUICKI ¼ quantita- consequences, including decreased availability of cholesterol tive insulin sensitivity check index; TG ¼ triglycerides.
(a substrate for androgen production), as well as inhibited growth Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
demonstrated previously by in vitro studies (14). Statins mightalso decrease the expression of several key enzymes involved in T the insulin sensitivity, and the 75-g OGTT supported these results.
production: cholesterol side chain cleavage (P450SCC), 17a-hydrox- These effects are attributable to metformin, as they were observed ylase/17,20-lyase (P450c17), and 3b-hydroxysteroid dehydrogenase (3bHSD). Such effects of statins were noted in adrenocortical cells The hMG-CoA reductase inhibitors (statins), the rate-limiting (31, 32). The mechanisms of these actions might be due to the inhib- enzyme in cholesterol synthesis is the most effective agent available itory effects of statins on isoprenylation (33), leading to decreased Fasting insulin and glucose levels and response to 75-g oral glucose tolerance test in 84 women with polycystic ovary syndrome.
Note: Values are given as mean � SD. P< .05 is considered significant.
a No significant differences were observed between the mean of variables in the studied groups before therapy (P>.05).
b No significant difference compared with metformin plus placebo group (P>.05).
Kazerooni. Metformin plus simvastatin in PCOS. Fertil Steril 2010.
function of small guanosine triphosphatases, such as Ras, Rho, and We noted some limitations to our study. First, this study evaluated Rac. Ras might increase expression of P450SCC, P450c17, and only the effects of metformin in the presence of a single dose of a sin- 3bHSD, and statin might abrogate Ras-induced steroidogenesis gle statin. Therefore we cannot attribute the primary and secondary (32). In addition, statin-induced inhibition of proliferation of theca end pints of this study to any of these drugs alone. However, we interstitial cells (14) might reduce T output of the ovary by reducing decided to use this combination to find their synergic effects.
the size of the theca interstitial compartment.
Metformin can reduce insulin resistance, whereas simvastatin can An abnormal lipid profile is a common finding in PCOS and improve the lipid profile, and both reduce the androgen levels in includes elevated total cholesterol, triglycerides, and LDL and patients with PCOS. Therefore combination therapy may result decreased levels of HDL (3, 6). The most characteristic lipid alter- in a better reduction of androgen levels, as well as lipid profile ation in patients with PCOS is decreased levels of HDL (3). It was and insulin resistance. Adding a simvastatin plus placebo group to also shown that patients with PCOS have higher levels of serum a similar study will sheds light on the single effects of these two TG, very LDL, LDL:HDL ratio, and significantly lower levels of drugs. Second, although simvastatin plus metformin can success- HDL compared with the normal population (26). There are several fully reduce hyperandrogenism, insulin resistance, and lipid profile, lines of evidence suggesting that women with PCOS are also at but its clinical significance is yet to be characterized. More long- increased risk of cardiovascular disease due to dyslipidemia, insu- term studies are needed to make this obvious. Third, the course of lin-resistant increased (3–7 times), and markers of abnormal vascu- the study was 3 months, which does not reflect the clinical usage lar function (3, 6). Another finding of our study was improvement of of these drugs that tends to be chronic once initiated. A limitation the lipid profile. Simvastatin significantly reduced TG, total choles- is that we do not know the risk-to-benefit ratio beyond 3 months terol, LDL and increased HDL. These findings are consistent with for women with PCOS. And fourth, we used barrier contraception previous studies regarding the LDL, HDL and cholesterol levels during the study. Regarding the potential teratogenicity of statins, (12, 13). However, the TG levels were unchanged (12) or increased this method of contraception is not ideal and needs strict patient (13) in these two studies that may be due to OC usage in these stud- compliance with constant and perfect use and should be replaced ies. Therefore, reduction of TG in our study may suggest a synergic by other methods when used in practice.
effect of metformin added to simvastatin. Taking all together, In summary, this report demonstrates that the combination of simvastatin and metformin can reduce cardiovascular risk factors metformin and simvastatin could lead to a better reduction of T in patients with PCOS by making beneficial changes in lipid profiles, and LH levels and thus reversing the LH:FSH ratio, lipid profile, direct effect on vascular tissue due to positive impact on vascular and insulin resistance in patients with PCOS and may be an appro- and glomerular nitric oxide production, attenuation of vascular priate management option for patients with PCOS.
inflammation, improvement in insulin sensitivity, and androgen Acknowledgment: The authors acknowledge all the patients and their families who patiently participated in this study.
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