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Testosterone supplementation greatly increases cardiovascular events

Clinical Question:
Is testosterone supplementation safe in frail older men?

Bottom Line:
This study found serious risks to testosterone supplementation in frail older men. Although there may be men for whom the risk:benefit ratio is acceptable, we should not screen for and treat "low T" in older men until we have more data. We don't know whether the results will be similar in younger or less frail men. (LOE = 1b)

Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363(2):109-122.  [PMID:20592293]

Study Design:
Randomized controlled trial (double-blinded)



Outpatient (any)

Sometimes the title of a study just says it all. These researchers identified men 65 years and older with limited mobility (difficulty walking 2 blocks on the level or 10 steps climbing, plus a low to moderate score on a physical performance score) who also had a low testosterone level. Low as defined as a free testosterone level of less than 50 pg/mL (173 pmol/L) or a total testosterone level of between 100 ng/dL and 350 ng/dL (3.5 - 12.1 nmol/L). Exclusion criteria included uncontrolled hypertension, unstable cardiovascular disease, cancer, sleep apnea, steroid use, a glycohemoglobin level of less than 8.5%, or morbid obesity. At baseline, the mean age was 74 years, the mean blood pressure was 137/76, and 25% of patients had diabetes. Patients were randomly assigned to receive testosterone in a transdermal gel (100 mg; Testim 1%) applied once daily for 6 months or matching placebo gel. Two weeks after randomization, the dose was adjusted to half the dose if the testosterone level was too high or twice the dose if it was still too low. Groups were similar at baseline, and analysis was by intention to treat for safety and by modified intention to treat of those with at least one postrandomization evaluation for efficacy. Although the researchers intended to enroll 252 men in the study, by the time 209 were enrolled a safety monitoring board concluded that the risk was too great for men in the intervention group, and recruitment was terminated. Men in the testosterone group were much more likely to experience serious adverse events than those in the placebo group, including adverse cardiac events (10 vs 1), more atherosclerotic events (7 vs 1), and more cardiovascular events in general (23 vs 5). There was a dose-response relationship between testosterone levels and cardiovascular risk (hazard ratio = 2.4 for highest quartile vs other 3 quartiles; P = .05). The adjusted odds ratio for cardiovascular adverse events was 5.8 (95% CI, 2.0 - 16.8), although this combined outcome was admittedly quite diverse and included things like edema and ectopy on electrocardiogram. On the bright side, those men not felled by heart attack or stroke did have better results on the tests of leg strength, stair climbing, and gait speed.


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