This meta-analysis of placebo-controlled randomized trials suggests statins reduce testosterone. Among men the evidence was homogeneous and largely related to typical doses for the target group using statins for the prevention of cardiovascular disease, where statins potentially lowering testosterone has always been a concern [11, 12, 14–16]. Among women less concern has existed . Very few trials have examined testosterone among women using statins for the prevention of cardiovascular disease, and our findings were less robust for women than men. Nevertheless, statins have recently been discovered as an effective anti-androgen treatment for polycystic ovary syndrome [25, 35]. A recent meta-analysis of statin therapy for women with polycystic ovary syndrome concluded that statins reduced testosterone based on the same literature .
To the best of our knowledge no previous meta-analysis of placebo-controlled randomized trials has assessed the effect of statins on testosterone among men. Two trials comparing simvastatin 80 mg/day with 40 mg/day among in total 640 men found median testosterone lower by 10.3% and 7.5% respectively after 48 weeks , consistent with the 3.4% reduction here among men mainly using simvastatin 20 mg/day, suggesting a possible dose response of statins on testosterone.
The clinical significance of this reduction in testosterone with statins is difficult to gauge. The normal range of testosterone is wide  and sexual function similar across the range . Erectile dysfunction is a rare side effect of statins , perhaps because statins' have beneficial effects on cardiovascular function that would counteract changes of this magnitude in testosterone. However, large changes in testosterone (and libido) can occasionally occur with statin use , which are reversible by statin withdrawal . The impact on population health may be more germane, where statins causing diabetes could be another side effect. We are not aware of any study examining whether lowering testosterone mediates the effect of statins on diabetes, as this possibility has not, to the best of our knowledge, been considered before, and remains speculative. Moreover, observational studies suggest serum testosterone has sex-specific physiological effects on diabetes, negative among men , but positive among women , when statins increase diabetes in both sexes [4, 5, 42]. We could not identify any RCT confirming testosterone therapy increases diabetes incidence among women. In postmenopausal women, RCTs of testosterone therapy indicate little effect on glucose metabolism . In younger women, some RCTs indicate that low doses of testosterone may improve glucose metabolism [44, 45]; female to male transsexuals given high doses of testosterone have improved glucose metabolism . Nevertheless, distinct effects of testosterone on diabetes may occur by dose, sex and age with the reduction in testosterone with statin treatment insufficient to modulate diabetes risk consistently. This meta-analysis also raises the question as to whether lowering testosterone is a side effect of statin therapy or contributes to statins' mode of action, which could inform new treatments and prevention policies. Observationally testosterone is inversely associated with cardiovascular mortality ; whether testosterone is causal or a marker of health is unknown . No RCT has shown testosterone therapy reduces cardiovascular events; two RCTs of testosterone therapy were halted because of adverse, mainly cardiovascular events, among men allocated to testosterone [48, 49]. Natural experiments suggest lower testosterone protects against specifically ischemic heart disease mortality, with a relatively lower risk in men legally castrated  or with Klinefelter's syndrome . Physiologically lowering testosterone may reduce thromboxane and platelet activation , specifically relevant to reducing ischemic cardiovascular disease but not to diabetes. However, whether lowering testosterone with statin treatment modulates cardiovascular disease, via these or other pathways, has not been examined.
Despite providing a meta-analysis of all known placebo-controlled randomized trials, limitations exist. First, given when they were conducted, not all the trials had high quality scores. However, they had the expected effects on lipids. Second, not all the trials were intended to assess the effects of statins on testosterone. However, the trial, largely designed for this purpose , is influential, and alone found statins reduced testosterone . Third, testosterone was not assayed in the same way in all trials (Table 1). Testosterone is difficult to measure, particularly among women. Heterogeneity for women could be due to differing, possibly suboptimal, testosterone assay techniques, for which we compensated by using a random effects model. Imprecision in the assays also reduces power but would not bias a comparison between statin and placebo groups unless statins interfered with the testosterone assay. Steroids can cause assay interference. We could find no evidence that statins cause assay interference. Fourth, too few trials existed to assess dose-response effects or compare hydrophilic (fluvastatin, rosuvastatin, and pravastatin) to lipophilic (atorvastatin, lovastatin, and simvastatin) statins. However, atorvastatin, pravastatin or simvastatin do not differ substantially in their effects on cardiovascular disease . Fifth, other RCTs may have assessed but not reported the effects of statins on testosterone. Given, the concern that statins lower testosterone [11, 12, 14–16], these might perhaps be trials where statins reduced testosterone among men. Sixth, RCTs are not always tagged as such and could be missed. To check we searched using 'trial' as a search term instead of restricting the search to RCTs, which gave the same selection (data not shown). Seventh, evidence concerning the effect of statins on testosterone in post-menopausal women is lacking. Eighth, considering the effects of statins on testosterone for men and women together may be invalid, hence results stratified and pooled by sex. Ninth, the effect of statins on testosterone in different ethnic groups is lacking. Effects might differ in settings, such as China, where peak testosterone [37, 54], androgen related parameters [55, 56] and ischemic heart diseases mortality rates  are all lower than in western populations. Finally, cross-sectional studies were not included, because these provide evidence from which it is difficult to assess causality. The larger cross sectional studies only considered men and generally observed lower testosterone among statin users than non-users [58–60].