• Ting Xiong, Eloise Fraison, Eleni Kolibianaki, Michael F Costello, Christos Venetis, and Elena B Kostova.
• Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
• Cochrane Db Syst Rev. 2023 Jul 18; 7 (7): CD008565CD008565.

BackgroundStatins are lipid-lowering agents with pleiotropic actions. Experts have proposed that in addition to improving the dyslipidaemia associated with polycystic ovary syndrome (PCOS), statins may also exert other beneficial metabolic and endocrine effects, such as reducing testosterone levels. This is an update of a Cochrane Review first published in 2011.ObjectivesTo assess the efficacy and safety of statin therapy in women with PCOS who are not actively trying to conceive.Search MethodsWe searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHLs, and four ongoing trials registers on 7 November 2022. We also handsearched relevant conference proceedings and the reference lists of relevant trials for any additional studies, and we contacted experts in the field for any further ongoing studies.Selection CriteriaWe included randomised controlled trials (RCTs) that evaluated the effects of statin therapy in women with PCOS not actively trying to conceive. Eligible comparisons were statin versus placebo or no treatment, statin plus another agent versus the other agent alone, and statin versus another agent. We performed statistical analysis using Review Manager 5, and we assessed the certainty of the evidence using GRADE methods.Data Collection And AnalysisWe used standard Cochrane methodology. Our primary outcomes were resumption of menstrual regularity and resumption of spontaneous ovulation. Our secondary outcomes were clinical and physiological measures including hirsutism, acne severity, testosterone levels, and adverse events.Main ResultsSix RCTs fulfilled the criteria for inclusion. They included 396 women with PCOS who received six weeks, three months, or six months of treatment; 374 women completed the studies. Three studies evaluated the effects of simvastatin and three studies evaluated the effects of atorvastatin. We summarised the results of the studies under the following comparisons. Statins versus placebo (3 RCTs) One trial measured resumption of menstrual regularity as menstrual cycle length in days. We are uncertain if statins compared with placebo shorten the mean length of the menstrual cycle (mean difference (MD) -2.00 days, 95% confidence interval (CI) -24.86 to 20.86; 37 participants; very low-certainty evidence). No studies reported resumption of spontaneous ovulation, improvement in hirsutism, or improvement in acne. We are uncertain if statins compared with placebo reduce testosterone levels after six weeks (MD 0.06, 95% CI -0.72 to 0.84; 1 RCT, 20 participants; very low-certainty evidence), after 3 months (MD -0.53, 95% CI -1.61 to 0.54; 2 RCTs, 64 participants; very low-certainty evidence), or after 6 months (MD 0.10, 95% CI -0.43 to 0.63; 1 RCT, 28 participants; very low-certainty evidence) Two studies recorded adverse events, and neither reported significant differences between the groups. Statins plus metformin versus metformin alone (1 RCT) The single RCT included in this comparison measured resumption of menstrual regularity as the number of spontaneous menses per six months. We are uncertain if statins plus metformin compared with metformin improves resumption of menstrual regularity (MD 0.60 menses, 95% CI 0.08 to 1.12; 69 participants; very low-certainty evidence). The study did not report resumption of spontaneous ovulation. We are uncertain if statins plus metformin compared with metformin alone improves hirsutism measured using the Ferriman-Gallwey score (MD -0.16, 95% CI -0.91 to 0.59; 69 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.31, 95% CI -0.67 to 0.05; 69 participants; very low-certainty evidence), or testosterone levels (MD -0.03, 95% CI -0.37 to 0.31; 69 participants; very low-certainty evidence). The study reported that no significant adverse events occurred. Statins plus oral contraceptive pill versus oral contraceptive pill alone (1 RCT) The single RCT included in this comparison did not report resumption of menstrual regularity or spontaneous ovulation. We are uncertain if statins plus the oral contraceptive pill (OCP) improves hirsutism compared with OCP alone (MD -0.12, 95% CI -0.41 to 0.17; 48 participants; very low-certainty evidence). The study did not report improvement in acne severity. We are also uncertain if statins plus OCP compared with OCP alone reduces testosterone levels, because the certainty of the evidence was very low (MD -0.82, 95% CI -1.38 to -0.26; 48 participants). The study reported that no participants experienced significant side effects. Statins versus metformin (2 RCTs) We are uncertain if statins improve menstrual regularity compared with metformin (number of spontaneous menses per six months) compared to metformin (MD 0.50 menses, 95% CI -0.05 to 1.05; 1 RCT, 61 participants, very low-certainty evidence). No studies reported resumption of spontaneous ovulation. We are uncertain if statins compared with metformin reduce hirsutism measured using the Ferriman-Gallwey score (MD -0.26, 95% CI -0.97 to 0.45; 1 RCT, 61 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.18, 95% CI -0.53 to 0.17; 1 RCT, 61 participants; very low-certainty evidence), or testosterone levels (MD -0.24, 95% CI -0.58 to 0.10; 1 RCT, 61 participants; very low-certainty evidence). Both trials reported that no significant adverse events had occurred. Statins versus oral contraceptive pill plus flutamide (1 RCT) According to the study report, no participants experienced any significant side effects. There were no available data for any other main outcomes.Authors' ConclusionsThe evidence for all main outcomes of this review was of very low certainty. Due to the limited evidence, we are uncertain if statins compared with placebo, or statins plus metformin compared with metformin alone, improve resumption of menstrual regularity. The trial evaluating statin plus OCP versus OCP alone reported neither of our primary outcomes. No other studies reported resumption of spontaneous ovulation. We are uncertain if statins improve hirsutism, acne severity, or testosterone. All trials that measured adverse events reported no significant differences between the groups.Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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