Putting the 'T'rouble in Testosterone Therapy?

Charles P. Vega, MD


January 30, 2014

In This Article

Putting It All Together

The VA study is limited by its observational nature, which leaves the analysis open to unknown confounding variables. However, other randomized clinical trials also suggest that testosterone therapy may be dangerous, particularly for older men with multiple cardiovascular risk factors. Specifically, a trial of 209 men with an average age of 74 years was halted early after 23 cardiovascular events were recorded in the testosterone treatment group -- a much higher number than the 5 that occurred in the placebo group.[17]

A systematic review and meta-analysis of placebo-controlled randomized trials found an odds ratio of 1.54 for cardiovascular events associated with testosterone therapy.[18] There was evidence that pharmaceutical funding of trials exerted an influence. The effect of therapy varied with the source of funding, but not with baseline testosterone levels. A higher risk for cardiovascular events was found in trials not funded by the pharmaceutical industry.

These results stand in contrast to some other data that focused on men with cardiovascular risk factors. In a study of 581 men with type 2 diabetes, TD was associated with a 2-fold increase in the risk for mortality.[19] However, testosterone therapy reduced the risk for mortality. Untreated TD was associated with a hazard ratio of 2.3 for mortality compared with testosterone treatment.

What is the practicing clinician to do with this conflicting and highly concerning data? The Endocrine Society produced a practice guideline for the use of testosterone treatment in 2010.[20] This guideline is designed in large part to curb the overuse of exogenous testosterone. Only symptomatic men should be evaluated for possible TD, and TD should not be diagnosed without 2 morning testosterone levels that are unequivocally low. Serum testosterone levels should be reevaluated 3-6 months after the initiation of testosterone treatment, with the goal of achieving serum testosterone levels in the mid-normal range.

These guidelines make sense. They emphasize clinical rigor and personalized care when recommending a medication that still has many questions to answer about its safety. There is certainly a role for testosterone therapy among men with TD. For these men, treatment can improve symptoms as well as metabolic outcomes, and perhaps even mortality.

But the current study, particularly in the context of previous research, makes it clear that testosterone therapy should not be used for every man who is a little tired and not feeling himself. Supraphysiologic levels of testosterone appear to promote a higher risk for death, and patients should understand the potential cardiovascular and mortality risks associated with testosterone therapy as part of pretreatment counseling. In particular, caution is warranted before recommending testosterone therapy to any man at high risk for cardiovascular events. It is our job as physicians to make the "T" about "thinking" and weighing options in this important clinical decision.


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