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Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial

2010; Elsevier BV; Volume: 95; Issue: 5 Linguagem: Inglês

10.1016/j.fertnstert.2010.11.040

ISSN

1556-5653

Autores

Nazia Raja‐Khan, Allen R. Kunselman, Cynthia S. Hogeman, Christy Stetter, Laurence M. Demers, Richard S. Legro,

Tópico(s)

Ovarian cancer diagnosis and treatment

Resumo

To determine the effects of statins on vascular function, inflammation, and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had low-density lipoprotein cholesterol levels >100 mg/dL to atorvastatin (40 mg/day) or placebo for 6 weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure; increased insulin levels and brachial artery conductance during reactive hyperemia; and failed to improve brachial artery flow–mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment. To determine the effects of statins on vascular function, inflammation, and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had low-density lipoprotein cholesterol levels >100 mg/dL to atorvastatin (40 mg/day) or placebo for 6 weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure; increased insulin levels and brachial artery conductance during reactive hyperemia; and failed to improve brachial artery flow–mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment. As low-density lipoprotein (LDL) cholesterol is the primary precursor for sex steroid biosynthesis, dyslipidemia may play a central role in the pathogenesis of polycystic ovary syndrome (PCOS), contributing to hyperandrogenemia and increased cardiovascular risk. Although many women with PCOS have dyslipidemia (1Legro R.S. Kunselman A.R. Dodson W.C. Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome.Am J Med. 2001; 111: 607-613Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, 2Diamanti-Kandarakis E. Papavassiliou A.G. Kandarakis S.A. Chrousos G.P. Pathophysiology and types of dyslipidemia in PCOS.Trends Endocrinol Metab. 2007; 18: 280-285Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar), they usually do not meet the National Cholesterol Education Program (NCEP) indications for statin therapy (3Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report.Circulation. 2002; 106: 3143-3421Crossref PubMed Scopus (206) Google Scholar). Beyond their LDL-lowering effects, statins inhibit ovarian theca-interstitial cell proliferation and steroidogenesis in vitro (4Izquierdo D. Foyouzi N. Kwintkiewicz J. Duleba A.J. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis.Fertil Steril. 2004; 82: 1193-1197Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 5Rzepczynska I.J. Piotrowski P.C. Wong D.H. Cress A.B. Villanueva J. Duleba A.J. Role of isoprenylation in simvastatin-induced inhibition of ovarian theca-interstitial growth in the rat.Biol Reprod. 2009; 81: 850-855Crossref PubMed Scopus (34) Google Scholar) and reduce T levels in women with PCOS (6Kazerooni T. Shojaei-Baghini A. Dehbashi S. Asadi N. Ghaffarpasand F. Kazerooni Y. Effects of metformin plus simvastatin on polycystic ovary syndrome: a prospective, randomized, double-blind, placebo-controlled study.Fertil Steril. 2010; 94: 2208-2213Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 7Banaszewska B. Pawelczyk L. Spaczynski R.Z. Duleba A.J. Comparison of simvastatin and metformin in treatment of polycystic ovary syndrome: prospective randomized trial.J Clin Endocrinol Metab. 2009; 94: 4938-4945Crossref PubMed Scopus (77) Google Scholar, 8Kaya C. Cengiz S.D. Berker B. Demirtas S. Cesur M. Erdogan G. Comparative effects of atorvastatin and simvastatin on the plasma total homocysteine levels in women with polycystic ovary syndrome: a prospective randomized study.Fertil Steril. 2009; 92: 635-642Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 9Sathyapalan T. Kilpatrick E.S. Coady A.M. Atkin S.L. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study.J Clin Endocrinol Metab. 2009; 94: 103-108Crossref PubMed Scopus (108) Google Scholar, 10Duleba A.J. Banaszewska B. Spaczynski R.Z. Pawelczyk L. Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial.Fertil Steril. 2006; 85: 996-1001Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). In non-PCOS populations, statins have been shown to reduce inflammation and cardiovascular events (11Shepherd J. Barter P. Carmena R. Deedwania P. Fruchart J.C. Haffner S. et al.Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes: the Treating to New Targets (TNT) study.Diabetes Care. 2006; 29: 1220-1226Crossref PubMed Scopus (446) Google Scholar, 12Davignon J. Beneficial cardiovascular pleiotropic effects of statins.Circulation. 2004; 109: III39-III43PubMed Google Scholar, 13Collins R. Armitage J. Parish S. Sleigh P. Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.Lancet. 2003; 361: 2005-2016Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In normocholesterolemic middle-aged men and patients with hypercholesterolemia, statins improve flow-mediated dilation (FMD), a noninvasive measure of endothelial function and early indicator of atherosclerosis (14Simons L.A. Sullivan D. Simons J. Celermajer D.S. Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelial function in patients with severe primary hypercholesterolaemia.Atherosclerosis. 1998; 137: 197-203Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 15O’Driscoll G. Green D. Taylor R.R. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.Circulation. 1997; 95: 1126-1131Crossref PubMed Scopus (940) Google Scholar, 16Vogel R.A. Corretti M.C. Plotnick G.D. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men.Am J Cardiol. 1996; 77: 37-40Abstract Full Text PDF PubMed Scopus (176) Google Scholar). However, the effects of statins on FMD and other parameters of vascular function have not been investigated in PCOS. Our double-blind, randomized placebo-controlled trial determined whether atorvastatin improves brachial artery FMD and conductance, inflammation, and hyperandrogenemia in PCOS. Brachial artery FMD, the percentage change in brachial artery diameter after release of transient occlusion, was selected as the primary outcome because it is the most widely used research tool for evaluating the effects of interventions on endothelial function (17Corretti M.C. Anderson T.J. Benjamin E.J. Celermajer D. Charbonneau F. Creager M.A. et al.Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.J Am Coll Cardiol. 2002; 39: 257-265Abstract Full Text Full Text PDF PubMed Scopus (3825) Google Scholar, 18Al-Qaisi M. Kharbanda R.K. Mittal T.K. Donald A.E. Measurement of endothelial function and its clinical utility for cardiovascular risk.Vasc Health Risk Manag. 2008; 4: 647-652PubMed Google Scholar). Although FMD is currently not suitable for use in clinical practice due to lack of standardization and normative data (18Al-Qaisi M. Kharbanda R.K. Mittal T.K. Donald A.E. Measurement of endothelial function and its clinical utility for cardiovascular risk.Vasc Health Risk Manag. 2008; 4: 647-652PubMed Google Scholar, 19Bots M.L. Westerink J. Rabelink T.J. de Koning E.J. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response.Eur Heart J. 2005; 26: 363-368Crossref PubMed Scopus (195) Google Scholar), FMD has been shown to predict long-term cardiovascular events, even in patients with no apparent heart disease (20Gokce N. Keaney Jr., J.F. Hunter L.M. Watkins M.T. Nedeljkovic Z.S. Menzoian J.O. et al.Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease.J Am Coll Cardiol. 2003; 41: 1769-1775Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar, 21Hirsch L, Shechter A, Feinberg MS, Koren-Morag N, Shechter M. The impact of early compared to late morning hours on brachial endothelial function and long-term cardiovascular events in healthy subjects with no apparent coronary heart disease. Int J Cardiol 2010 [Epub ahead of print].Google Scholar, 22Inaba Y. Chen J.A. Bergmann S.R. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis.Int J Cardiovasc Imaging. 2010; 26: 631-640Crossref PubMed Scopus (518) Google Scholar). The institutional review board of Pennsylvania State University approved the study. Written informed consent was obtained from all participants. Participants were recruited through the clinics of the departments of Medicine and Obstetrics and Gynecology at Penn State Hershey Medical Center from October 20, 2006, to September 8, 2008. Women with PCOS and LDL-cholesterol >100 mg/dL were eligible to participate in the study. This LDL cutoff was selected because NCEP guidelines recommend LDL reduction to <100 mg/dL in high-risk patients (3Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report.Circulation. 2002; 106: 3143-3421Crossref PubMed Scopus (206) Google Scholar). We defined PCOS using the 1990 National Institutes of Health criteria (23Zawadski J.K. Dunaif A. Diagnostic criteria for polycystic ovary syndrome.in: Givens J.H.F. Merriman G. The polycystic ovary syndrome. Blackwell Scientific, Cambridge, MA1992: 377-384Google Scholar). Evaluation for secondary causes of hyperandrogenism and anovulation were carried out, including measurement of thyroid-stimulating hormone (TSH), prolactin (PRL), and 17-hydroxyprogesterone. Participants presented for their baseline evaluation in a 12-hour fasting state and had abstained from caffeine and chocolate for at least 24 hours. Blood pressure (BP), pulse, anthropometrics, and modified Ferriman-Gallwey hirsutism scores were recorded (24Hatch R. Rosenfield R.L. Kim M.H. Tredway D. Hirsutism: implications, etiology, and management.Am J Obstet Gynecol. 1981; 140: 815-830Abstract Full Text PDF PubMed Scopus (824) Google Scholar). Pelvic ultrasound was performed using the 6.5-MHz probe of an ATL 400 machine to characterize ovarian size and morphologic characteristics. The participants were placed supine in a quiet, dimly lit room. Electrocardiogram electrodes were attached to the chest to continuously monitor heart rate and rhythm. Blood pressure was measured beat-by-beat by finger photoplethysmography of the nonexperimental arm using a Finapres device (Ohmeda, Madison, WI), and the data were collected electronically using a MacLab system (ADInstruments, Castle Hill, New South Wales, Australia). Pneumatic cuffs were positioned on the upper arm and wrist of the experimental arm. The brachial artery was imaged using an ATL Doppler ultrasound probe (5–12 MHz linear array scanhead, HDI 5000; Advanced Technology Laboratories, Bothell, WA). Mean blood flow velocity (MBV) and brachial artery diameter (BAD) were recorded at baseline. Then the wrist cuff was inflated to 200–250 mm Hg. After a minute with the wrist cuff still inflated, the arm cuff was inflated to 200–250 mm Hg. After 10 minutes, the arm cuff was released. Upon release of the arm cuff, we continuously measured BP, heart rate, and MBV, and intermittently measured BAD in the experimental arm. Brachial artery conductance (BAC) was calculated as MBV/MAP, and FMD was calculated as the percentage change in BAD from baseline. Some of the baseline data was used as part of a case-control study (25Raja-Khan N, Shuja SA, Kunselman AR, Hogeman CS, Demers LM, Gnatuk CL, et al. Brachial artery conductance during reactive hyperemia is increased inwomen with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. Published online November 16, 2010.Google Scholar). Fasting blood was obtained to measure hormone and metabolic parameters. A 75 g oral glucose tolerance test (OGTT) was performed with blood draws at 0, 30, 60, 90, and 120 minutes. All blood samples were analyzed in either the General Clinical Research Center or Core Endocrine Laboratory at the Penn State Hershey Medical Center using validated assays. After the baseline evaluation, the participants were randomized in a double-blind fashion to receive either atorvastatin 40 mg or placebo once daily for 6 weeks. At the end of the 6 weeks, measurements were repeated to assess change from baseline. Randomization was performed according to Consolidated Standard of Reporting Trials (CONSORT) guidelines. The biostatistician generated a permuted block randomization scheme for the allocation sequence and provided it to the pharmacist. The atorvastatin and placebo were overencapsulated by the pharmacist so that the participants, research coordinator who administered the intervention, and investigators who assessed the outcomes were blinded to group assignment. Whether overencapsulation of atorvastatin affects absorption has not been reported. Overencapsulation is a standard practice for blinding medication and does not affect absorption of the antibiotic moxifloxacin (26Mason J.W. Florian Jr., J.A. Garnett C.E. Moon T.E. Selness D.S. Spaulding R.R. Pharmacokinetics and pharmacodynamics of three moxifloxacin dosage forms: implications for blinding in active-controlled cardiac repolarization studies.J Clin Pharmacol. 2010; 50: 1249-1259Crossref PubMed Scopus (23) Google Scholar). This study was initiated as a pilot study with the goal of enrolling 19 women in each group, which we hypothesized would provide 80% power to detect an absolute difference in the change in FMD between the two groups of 3.75%, assuming a common standard deviation of 4%, using a two-sided, two-sample t test with α = 0.05. Recruitment was slow due to strict inclusion/exclusion criteria, so we analyzed our data after the first 20 women completed the study. This analysis revealed that the required sample size was 235 subjects per group for 80% power to detect an absolute 2% increase in FMD with atorvastatin compared with placebo. A 2% increase in FMD is the minimum improvement required to detect a treatment benefit in clinical trials (17Corretti M.C. Anderson T.J. Benjamin E.J. Celermajer D. Charbonneau F. Creager M.A. et al.Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force.J Am Coll Cardiol. 2002; 39: 257-265Abstract Full Text Full Text PDF PubMed Scopus (3825) Google Scholar, 27Moens A.L. Goovaerts I. Claeys M.J. Vrints C.J. Flow-mediated vasodilation: a diagnostic instrument, or an experimental tool?.Chest. 2005; 127: 2254-2263Crossref PubMed Scopus (241) Google Scholar, 28Sorensen K.E. Celermajer D.S. Spiegelhalter D.J. Georgakopoulos D. Robinson J. Thomas O. et al.Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility.Br Heart J. 1995; 74: 247-253Crossref PubMed Scopus (637) Google Scholar). We stopped the trial early because we had insufficient funds for the required sample size. Linear mixed-effects models, extensions of regression that account for within-subject correlation inherent in pre-post designs, were fit to continuous outcomes to assess the change from baseline to 6 weeks within and between treatment groups. All hypotheses tests were two-sided. All analyses were performed by intention-to-treat using SAS software, version 9.1 (SAS Institute Inc., Cary, NC). Twenty eligible women were randomized and started the allocated treatment. Eighteen women completed their treatment. One woman was on oral contraceptives during the study. She was randomized to the placebo group. The remaining women were instructed to use nonhormonal contraception during the study. Two women, one in each group, were on antihypertensives. None of the women were on metformin or any other medications known to affect any of the outcomes. At baseline, the two groups were similar in age, BMI, and other cardiometabolic and reproductive characteristics (Table 1). Compared with placebo, atorvastatin statistically significantly reduced diastolic BP, and total and LDL-cholesterol, triglycerides, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) levels (see Table 1). Atorvastatin appeared to worsen FMD by reducing it by 1.5% whereas in the placebo group FMD increased by 0.4%. These differences were not statistically significant in the within or between-group comparisons. Compared with baseline, the peak BAC during reactive hyperemia and area under the curve (AUC) for insulin during OGTT were statistically significantly increased, and systolic BP and high sensitive C-reactive protein (hsCRP) were statistically significantly decreased after atorvastatin but not after placebo; these differences did not reach statistical significance in the between-group comparisons. There were no differences in AUC for glucose, fasting glucose, or insulin, homeostatic model assessment of insulin resistance (HOMA-IR), testosterone (T), estradiol (E2,), estrone, or progesterone (P) levels.Table 1Cardiometabolic and reproductive profiles of both groups before and after treatment.Atorvastatin (n = 9)Placebo (n = 11)Atorvastatin vs. placeboProfileBeforeaValues are mean (standard deviation).AfteraValues are mean (standard deviation).Within groupbValues are mean difference (95% confidence interval).P valueBeforeaValues are mean (standard deviation).AfteraValues are mean (standard deviation).Within groupbValues are mean difference (95% confidence interval).P valueBetween groupbValues are mean difference (95% confidence interval).P valueCardiometabolic Age (y)33.8 (4.3)——29.4 (5.8)——— BMI (kg/m2)40.1 (11.8)38.2 (8.4)0.2 (−0.4, 0.9).4336.0 (10.4)35.8 (10.8)0.05 (−0.47, 0.56).850.2 (−0.6, 1.0).63 Systolic BP (mm Hg)119.8 (15.8)112.0 (13.2)−8.5 (−16.6, −0.4)0.04114.5 (14.4)111.4 (8.8)−2.5 (−9.9, 4.8).47−5.9 (−16.9, 5.0).27 Diastolic BP (mm Hg)70.8 (14.8)64.3 (12.3)−6.7 (−12.7, −0.8).0364.6 (8.0)65.4 (8.1)1.1 (−4.2, 6.4).67−7.8 (−15.8, 0.1).05 Total cholesterol (mg/dL)215.8 (39.0)132.0 (19.7)−82.5 (−100.7, −64.4)<.001202.8 (28.3)192.1 (33.6)−11.7 (−28.0, 4.6).15−70.8 (−95.2, −46.4)<.001 HDL cholesterol (mg/dL)44.4 (14.6)47.8 (11.8)3.2 (−1.4, 7.7).1646.5 (8.6)46.8 (8.4)−0.2 (−4.3, 3.9).923.4 (−2.7, 9.5).26 LDL cholesterol (mg/dL)140.7 (24.6)68.5 (19.3)−70.2 (−86.3, −54.0)<.001131.3 (21.6)118.8 (26.8)−12.6 (−27.1, 1.9).08−57.6 (−79.3, −35.9)<.001 Triglycerides (mg/dL)153.3 (84.9)78.5 (24.8)−77.1 (−109.8, −44.5)<.001125.5 (54.2)132.5 (45.7)5.0 (−24.5, 34.5).72−82.2 (−126.2, −38.1)<.001 hsCRP (mg/L)8.0 (9.6)4.3 (5.4)−3.6 (−6.5, −0.6).027.2 (7.7)6.0 (7.3)−1.1 (−3.8, 1.5).39−2.4 (−6.4, 1.5).21 Fasting glucose (mg/dL)87.7 (9.0)87.8 (8.5)0.2 (−6.5, 7.0).9485.3 (8.0)88.9 (10.7)3.6 (−2.5, 9.6).23−3.3 (−12.4, 5.8).45 Fasting insulin (μU/mL)18.6 (10.1)21.0 (11.8)1.4 (−2.6, 5.4).4716.8 (9.5)15.9 (6.7)−1.1 (−4.7, 2.4).512.5 (−2.8, 7.9).33 AUC glucose15,693 (2,162)16,136 (2,569)709 (−1,044, 2,462).4015,309 (3,692)15,448 (3,165)123 (−1,513, 1,758).88586 (−1,811, 2,983).61 AUC insulin12,738 (10,010)17,479 (11,929)3,074 (387, 5,762).039,338 (5,208)9,132 (4,466)−311 (−2,812, 2,191).793,385 (−287, 7,056).07 Peak BAC (mL/s/mm Hg)5.4 (2.9)6.9 (2.8)1.2 (0.0, 2.4).053.6 (3.0)4.3 (3.3)0.5 (−0.5, 1.6).300.7 (−0.9, 2.3).39 FMD (%)12.0 (7.3)10.4 (4.6)−1.5 (−7.0, 3.9).569.8 (5.8)10.2 (2.9)0.4 (−4.5, 5.3).85−2.0 (−9.3, 5.3).58Reproductive Ferriman-Gallwey hirsutism score14.4 (6.2)——15.7 (6.5)——— Free T (ng/dL)18.1 (4.9)——20.2 (8.7)——— Total T (ng/dL)61.3 (16.9)47.1 (21.4)−14.9 (−34.2, 4.4).1292.3 (49.8)75.7 (43.6)−16.7 (−34.0, 0.6).061.8 (−24.1, 27.8).88 Androstenedione (ng/mL)3.4 (0.8)2.5 (0.9)−0.9 (−1.3, −0.5)<.0013.8 (1.2)4.1 (1.2)0.2 (−0.2, 0.5).36−1.1 (−1.6, −0.5)<.001 DHEAS (ng/mL)1,630.0 (873.1)1,326.4 (854.3)−296.5 (−513.5, −79.5).011,701.5 (681.3)1,739.5 (781.8)67.8 (−126.2, 261.7).47−364.3 (−655.3, −73.2).02 Mean ovarian volume (mm3)15.1 (8.8)19.2 (7.0)0.9 (−7.2, 9.1).8125.4 (13.7)25.2 (9.9)−2.5 (−8.8, 3.7).393.5 (−6.8, 13.7).48Note: AUC = area under the curve; BAC = brachial artery conductance; BMI = body mass index; BP = blood pressure; DHEAS = dehydroepiandrosterone sulfate; FMD = flow-mediated dilation; HDL = high-density lipoprotein; hsCRP = high sensitive C-reactive protein; LDL = low-density lipoprotein; T = testosterone.a Values are mean (standard deviation).b Values are mean difference (95% confidence interval). Open table in a new tab Note: AUC = area under the curve; BAC = brachial artery conductance; BMI = body mass index; BP = blood pressure; DHEAS = dehydroepiandrosterone sulfate; FMD = flow-mediated dilation; HDL = high-density lipoprotein; hsCRP = high sensitive C-reactive protein; LDL = low-density lipoprotein; T = testosterone. In the present study we have demonstrated that atorvastatin statistically significantly reduces BP, androstenedione, and DHEAS and may increase BAC during reactive hyperemia. These are novel effects that to the best of our knowledge have not been previously reported. Our finding that atorvastatin may reduce hsCRP in PCOS confirms the findings of an earlier study (9Sathyapalan T. Kilpatrick E.S. Coady A.M. Atkin S.L. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study.J Clin Endocrinol Metab. 2009; 94: 103-108Crossref PubMed Scopus (108) Google Scholar). Our finding of worsening hyperinsulinemia in atorvastatin-treated PCOS women is consistent with the JUPITER study and two meta-analyses demonstrating a small increased risk of diabetes with statin therapy (29Rajpathak S.N. Kumbhani D.J. Crandall J. Barzilai N. Alderman M. Ridker P.M. Statin therapy and risk of developing type 2 diabetes: a meta-analysis.Diabetes Care. 2009; 32: 1924-1929Crossref PubMed Scopus (346) Google Scholar, 30Sattar N. Preiss D. Murray H.M. Welsh P. Buckley B.M. de Craen A.J. et al.Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.Lancet. 2010; 375: 735-742Abstract Full Text Full Text PDF PubMed Scopus (1823) Google Scholar, 31Everett B.M. Glynn R.J. MacFadyen J.G. Ridker P.M. Rosuvastatin in the prevention of stroke among men and women with elevated levels of C-reactive protein: justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER).Circulation. 2010; 121: 143-150Crossref PubMed Scopus (132) Google Scholar). We found no difference in T levels, although previous studies have demonstrated that statins reduce T in women with PCOS (6Kazerooni T. Shojaei-Baghini A. Dehbashi S. Asadi N. Ghaffarpasand F. Kazerooni Y. Effects of metformin plus simvastatin on polycystic ovary syndrome: a prospective, randomized, double-blind, placebo-controlled study.Fertil Steril. 2010; 94: 2208-2213Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 7Banaszewska B. Pawelczyk L. Spaczynski R.Z. Duleba A.J. Comparison of simvastatin and metformin in treatment of polycystic ovary syndrome: prospective randomized trial.J Clin Endocrinol Metab. 2009; 94: 4938-4945Crossref PubMed Scopus (77) Google Scholar, 8Kaya C. Cengiz S.D. Berker B. Demirtas S. Cesur M. Erdogan G. Comparative effects of atorvastatin and simvastatin on the plasma total homocysteine levels in women with polycystic ovary syndrome: a prospective randomized study.Fertil Steril. 2009; 92: 635-642Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 9Sathyapalan T. Kilpatrick E.S. Coady A.M. Atkin S.L. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study.J Clin Endocrinol Metab. 2009; 94: 103-108Crossref PubMed Scopus (108) Google Scholar, 10Duleba A.J. Banaszewska B. Spaczynski R.Z. Pawelczyk L. Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial.Fertil Steril. 2006; 85: 996-1001Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Because in vitro studies demonstrate that statins inhibit ovarian theca-interstitial cell proliferation (4Izquierdo D. Foyouzi N. Kwintkiewicz J. Duleba A.J. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis.Fertil Steril. 2004; 82: 1193-1197Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 5Rzepczynska I.J. Piotrowski P.C. Wong D.H. Cress A.B. Villanueva J. Duleba A.J. Role of isoprenylation in simvastatin-induced inhibition of ovarian theca-interstitial growth in the rat.Biol Reprod. 2009; 81: 850-855Crossref PubMed Scopus (34) Google Scholar), we hypothesized that statins might reduce ovarian volume in PCOS. However, we found no statistically significant effects of atorvastatin on ovarian volume. The nonsignificant weight loss observed in both groups might be due to the women behaving differently while participating in a trial. Lifestyle modification was not part of the study. Conclusions for these secondary outcomes are exploratory in nature as they were not formally powered. Although statins have been shown to improve FMD in other patient populations (14Simons L.A. Sullivan D. Simons J. Celermajer D.S. Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelial function in patients with severe primary hypercholesterolaemia.Atherosclerosis. 1998; 137: 197-203Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 15O’Driscoll G. Green D. Taylor R.R. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month.Circulation. 1997; 95: 1126-1131Crossref PubMed Scopus (940) Google Scholar, 16Vogel R.A. Corretti M.C. Plotnick G.D. Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle-aged men.Am J Cardiol. 1996; 77: 37-40Abstract Full Text PDF PubMed Scopus (176) Google Scholar), our study suggests that atorvastatin does not statistically significantly affect FMD in women with PCOS. We acknowledge that our study is underpowered, and a small difference in FMD might be present. Despite this, we believe our study adds to the existing literature as it is the first study, to the best of our knowledge, to explore the effect of a statin on FMD in women with PCOS. Until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment (32Wild R.A. Carmina E. Diamanti-Kandarakis E. Dokras A. Escobar-Morreale H.F. Futterweit W. et al.Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society.J Clin Endocrinol Metab. 2010; 95: 2038-2049Crossref PubMed Scopus (705) Google Scholar). Appropriate contraception is required when statins are used in women with PCOS who have reproductive potential.

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