Abstract
BackgroundTestosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease.MethodsA systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.ResultsOf 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60).ConclusionsThe effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.
Highlights
We carried out a meta-analysis of adverse events from randomized placebo-controlled trials to examine the overall risk of cardiovascular-related events associated with testosterone therapy
Most trials only reported serious adverse events, but a few reported a wider range of events, so we examined the effect of testosterone therapy by seriousness
Given potential lack of clarity as to the selection of the cardiovascular-related adverse events reported, we examined whether the effect of testosterone therapy varied with funding source
Summary
No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, very high levels of androgens are thought to promote cardiovascular disease. Expert advice and reviews, largely based on observational evidence, warn that cardiovascular disease may be increased by androgen deprivation therapy [4] and low testosterone [5,6]. Previous meta-analyses of randomized placebo-controlled trials found that testosterone therapy resulted in a non-significantly higher risk of cardiovascular events, based on adverse events, but only included trials through March 2005 [13,14]. We carried out a meta-analysis of adverse events from randomized placebo-controlled trials to examine the overall risk of cardiovascular-related events associated with testosterone therapy
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