ORIGINAL ARTICLE
Testosterone and Cardiovascular Risk in Men: A Systematic Review and Meta-analysis of Randomized Placebo-Controlled Trials

https://doi.org/10.4065/82.1.29Get rights and content

OBJECTIVE

To conduct a systematic review and meta-analysis of randomized trials that assessed the effect of testosterone use on cardiovascular events and risk factors in men with different degrees of androgen deficiency.

METHODS

Librarian-designed search strategies were used to search the MEDLINE (1966 to October 2004), EMBASE (1988 to October 2004), and Cochrane CENTRAL (inception to October 2004) databases. The database search was performed again in March 2005. We also reviewed reference lists from included studies and content expert files. Eligible studies were randomized trials that compared any formulation of commercially available testosterone with placebo and that assessed cardiovascular risk factors (lipid fractions, blood pressure, blood glucose), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, angina or claudication, revascularization, stroke), and cardiovascular surrogate end points (ie, laboratory tests indicative of cardiac or vascular disease). Using a standardized data extraction form, we collected data on participants, testosterone administration, and outcome measures. We assessed study quality with attention to allocation concealment, blinding, and loss to follow-up.

RESULTS

The 30 trials included 1642 men, 808 of whom were treated with testosterone. Overall, the trials had limited reporting of methodological features that prevent biased results (only 6 trials reported allocation concealment), enrolled few patients, and were of brief duration (only 4 trials followed up patients for >1 year). The median loss to follow-up across all 30 trials was 9%. Testosterone use in men with low testosterone levels led to inconsequential changes in blood pressure and glycemia and in all lipid fractions (total cholesterol: odds ratio [OR], -0.22; 95% confidence interval [CI], -0.71 to 0.27; high-density lipoprotein cholesterol: OR, -0.04; 95% CI, -0.39 to 0.30; low-density lipoprotein cholesterol: OR, 0.06; 95% CI, -0.30 to 0.42; and triglycerides: OR, -0.27; 95% CI, -0.61 to 0.08); results were similar in patients with low-normal to normal testosterone levels. The OR between testosterone use and any cardiovascular event pooled across trials that reported these events (n=6) was 1.82 (95% CI, 0.78 to 4.23). Several trials failed to report data on measured outcomes. For reasons we could not explain statistically, the results were inconsistent across trials.

CONCLUSION

Currently available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects. Patients and clinicians need large randomized trials of men at risk for cardiovascular disease to better inform the safety of long-term testosterone use.

Section snippets

METHODS

We developed a systematic review protocol (available by request) in collaboration with the members of the Endocrine Society Task Force on Testosterone in Men with Androgen Deficiency. This report adheres to the Quality of Reporting of Meta-analyses standards for reporting systematic reviews of randomized trials.3

Study Characteristics

Figure 1 shows the results of our systematic search. We found 30 eligible trials that enrolled 1642 men, 808 of whom were treated with testosterone.

Methodological Quality

Table 1 provides the methodological characteristics of the included trials. Overall, the included trials had limited reporting of methodological features that protect trials from the introduction of bias. All but 6 trials (20%)9, 12, 17, 19, 24, 26 inadequately reported allocation concealment; 2 had inadequate blinding.25, 37 The median loss to

Principal Findings

The best available evidence suggests small and clinically negligible effects of testosterone use on lipid fractions, blood pressure, and glycemic control in men with different degrees of androgen deficiency. On the basis of the width of the 95% CI, the pooled data are consistent with both a 1-fold decrease and a 4-fold increase in the odds of cardiac events in patients using testosterone.

Limitations and Strengths

A key limitation of this review refers to the extent to which authors did not explicitly report on all

CONCLUSION

Currently available evidence weakly supports the inference that testosterone use in men is not associated with important cardiovascular effects. Large randomized trials that enroll men with and without cardiovascular disease and measure cardiovascular end points are needed to better inform the decision to use long-term testosterone for other indications.

Acknowledgments

We thank Gunjan Y. Gandhi, MD, Theophilus E. Owan, MD, and Laura I. Pelaez, MD, for their assistance with study selection, data collection, and author contact. We are grateful for the ongoing input and advice from the Endocrine Society Task Force on Testosterone in Men with Androgen Deficiency. We extend our gratitude to the research team at the Knowledge and Encounter Research Unit at Mayo Clinic College of Medicine.

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    This work was funded by a Mayo Foundation scholarship to Dr Montori and supported by the Department of Medicine, Mayo Clinic College of Medicine.

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