Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.
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.


CONCLUSIONS
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.
Haddad
Rudy M
RM
Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.
Kennedy
Cassie C
CC
Caples
Sean M
SM
Tracz
Michal J
MJ
Boloña
Enrique R
ER
Sideras
Kostandinos
K
Uraga
Maria V
MV
Erwin
Patricia J
PJ
Montori
Victor M
VM
D000728:Androgens / Q000009:adverse effects* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D016032:Randomized Controlled Trials as Topic; D013739:Testosterone / Q000009:adverse effects* / Q000172:deficiency* / Q000627:therapeutic use
D000728:Androgens; D001786:Blood Glucose; D008055:Lipids; D013739:Testosterone