We sought to evaluate whether exogenous testosterone therapy is associated with increased risk of serious cardiovascular events as compared with other treatments or placebo.
Methods
Study selection included randomized controlled trials (RCTs) and observational studies that enrolled men aged 18 years or older receiving exogenous testosterone for 3 or more days. The primary outcomes were death due to all causes, myocardial infarction, and stroke. Secondary outcomes were other hard clinical outcomes such as heart failure, arrhythmia, and cardiac procedures. Peto odds ratio was used to pool data from RCTs. Risk of bias was assessed using Cochrane Collaboration tool and Newcastle and Ottawa scale, respectively. The strength of evidence was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation Working Group approach.
Results
A total of 39 RCTs and 10 observational studies were included. Meta-analysis was done using data from 30 RCTs. Compared with placebo, exogenous testosterone treatment did not show any significant increase in risk of myocardial infarction (odds ratio [OR] 0.87; 95% CI, 0.39-1.93; 16 RCTs), stroke (OR 2.17; 95% CI, 0.63-7.54; 9 RCTs), or mortality (OR 0.88; 95% CI, 0.55-1.41; 20 RCTs). Observational studies showed marked clinical and methodological heterogeneity. The evidence was rated as very low quality due to the high risk of bias, imprecision, and inconsistency.
Conclusions
We did not find any significant association between exogenous testosterone treatment and myocardial infarction, stroke, or mortality in randomized controlled trials. The very low quality of the evidence precludes definitive conclusion on the cardiovascular effects of testosterone.
Sales of exogenous testosterone products, available since the 1950s, have increased substantially during the past 15 years. For example, the prevalence of commercially insured US men aged 40 years and older receiving androgen replacement therapy tripled over 10 years, from 0.81% in 2001 to 2.9% in 2011.1 These increases have been attributed to factors such as the emergence of more convenient routes of delivery, such as gels and patches, as well as marketing of “low T” to middle-aged and elderly men with symptoms suggestive of hypogonadism.1, 2, 3
Clinical trials evaluating testosterone therapy have demonstrated improvement in certain symptoms such as sexual dysfunction,4 dysthymia,5 and body composition6 among males with low testosterone levels, but these trials have been underpowered to evaluate safety. Early suggestion of potential cardiovascular risks with exogenous testosterone arose from the prematurely terminated Testosterone in Older Men with Mobility Limitations (TOM) trial.7 Since then, use and safety of testosterone has been scrutinized by regulators and researchers alike.8, 9, 10 In September 2014, a US Food and Drug Administration (FDA) advisory committee found insufficient evidence to confirm an association between cardiovascular events and testosterone, while in March 2015, the FDA issued a Drug Safety Communication cautioning that the use of testosterone was not approved for men with age-related low testosterone levels, and should be prescribed only to men with low testosterone levels caused by certain medical conditions after assessing the risk/benefit balance for each patient due to possible cardiovascular side events.11
Since early evidence of potential risk, additional observational studies have given rise to uncertainty about these signals, with some investigations suggesting decreased cardiovascular risk with these products.12, 13 Several systematic reviews and meta-analyses have pooled data from randomized controlled trials to examine these associations.14, 15, 16 The more recently published reviews have shown conflicting results as well, with some16suggesting an increase in cardiovascular risk, while others show no effect.17, 18 We undertook our review to update previous analyses as well as to apply a more comprehensive literature search and more detailed evaluation of the quality of included studies. Also, in contrast to the previous systematic reviews, we used meta-analytic techniques appropriate for rare events and examined the risks of events such as myocardial infarction or stroke separately rather than as a single aggregate outcome representing all cardiovascular events. Thus, this systematic review and meta-analysis assessed whether exogenous testosterone therapy with any formulation, whether injection, oral, or topical, is associated with increased risk of serious cardiovascular events as compared with other treatments or placebo.
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-G. Caleb Alexander, MD, MS, Geetha Iyer, MBBS, Eleanor Lucas, BA, Dora Lin, MHS, Sonal Singh, MD
This article originally appeared in the March 2017 issue of The American Journal of Medicine.
