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Testosterone Study Results are Reassuring, but Come with Caveats

Will the findings be used to further push the unjustified use of testosterone in men who do not need it?

This article was originally posted in the Montreal Gazette.

For the past decade, whenever someone asked about testosterone therapy, we had to be cautious. We worried that testosterone could increase the risk of heart attack and the medical community was awaiting the results of the TRAVERSE trial. Those results are finally in.

The TRAVERSE trial, a randomized controlled trial designed specifically to assess the cardiovascular safety of testosterone gel, has shown no increased cardiovascular risk and confirmed the drug’s relative safety. But that is only half the story.

This worry about cardiac safety dates back to 2010, when the TOM trial was stopped early because an interim analysis found more cardiovascular events in men given testosterone rather than the placebo. This was followed in 2013 by an analysis of Veterans Affairs data that suggested the same risk. But the TOM trial was not designed to evaluate cardiovascular events and was terminated early, once the safety signal appeared. And while the Veterans Affairs data added credence to the concern, it was non-randomized observational data and therefore not definitive. Also, not all analyses agreed with the risk assessment.

Hence, the anticipation of the TRAVERSE trial. The surface-level results provided the reassurance that people were looking for. The rate of cardiovascular events was around seven per cent in both testosterone and placebo groups; overall adverse events were the same in both groups as well. Some of the sub-analyses suggested an increased risk of arrhythmias like atrial fibrillation, as well as an increased risk of kidney injury and blood clots in the lung. But the differences were small and might have been random associations.

Overall, the results of TRAVERSE are reassuring that this medication can be used safely. Some caveats are in order, though. More than 60 per cent of patients in both groups stopped taking the medication before the study ended. Whether this was because of side effects or a perceived lack of benefit is unclear. This limited the amount of data that was available for analysis. The average duration of use was less than two years, though average follow-up persisted for three. So while short-term use seems to be safe, some residual doubt might remain about longer term use. Overall though, this is a reassuring trial and the FDA’s warning about testosterone might be revised as a result.

The worry I have is that these results are going to be used to further push the unjustified use of testosterone in men who do not need it. While cardiovascular safety now seems more certain, there are other potential risks with testosterone therapy. The biggest worry is prostate cancer, which is partly testosterone-dependent. Many prostate treatments are about blocking testosterone for that reason. The current data has not shown an increased risk of prostate cancer in men given testosterone therapy. However, these studies usually excluded high-risk men and were short-term studies with relatively small numbers of people. Given the lack of clear data, most experts urge caution and close follow-up.

But the real problem is that many men prescribed testosterone replacement do not actually need it. Off-label testosterone prescriptions skyrocketed in the early 2000s, driven largely by direct-to-consumer marketing. The “lowT” campaign convinced many men to seek out testosterone replacement when many didn’t need it. One analysis found that during this period, only six per cent of men who were prescribed testosterone between 1997 and 2022 had a confirmed diagnosis, while another found that one in four men who started taking it didn’t even have a testosterone test.

Hypogonadism, true testosterone deficiency, can be treated with testosterone therapy and may result in improvements in sexual function, bone density and muscle strength. Its effect on mood, memory and physical function are less certain. We can now be more certain about its cardiovascular safety for the men who need it. We still shouldn’t prescribe it to those who don’t.


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