For years, people taking testosterone replacement therapy were advised that it could be bad for their hearts and lead to troubled tickers down the road.

However, a new study has found that older men who were already at risk for heart problems didn’t have an increased rate of major cardiac events when they took testosterone.

a middle-aged man makes a heart shape with his hands. Image by stockking on FreepikStanding the testosterone of time

For the past ten years, testosterone’s reputation has been going through a bit of a rough patch (or a rough gel, injection or pill, depending on your preferred delivery method).

77 years after it was first synthesised, two studies observed that testosterone was associated with a higher rate of heart attacks, stroke, and death.

Concerned by these reports, the USA’s Food and Drug Administration (FDA) told manufacturers to add a label to the medications warning of these risks. They also restricted the kinds of people and conditions testosterone could be prescribed for, and requested that the drug manufacturers put some work into investigating the risks of their products.

These decisions by the FDA set off a decade of research into testosterone replacement therapy.

A series of studies known as the Testosterone Trials demonstrated that testosterone replacement therapy had enormous benefit for people with low testosterone levels. These government-funded trials recruited 790 men over the age of 65 in multiple locations across America to apply either a testosterone gel or a placebo gel for 12 months. They found that testosterone replacement therapy helped increase sexual desire and ability, physical activity, and mood.

However, these studies were designed to test whether taking testosterone as a medication even worked to address hormone deficiency at all, not whether it was safe to take long term or what the ongoing effects might be.

A middle-aged man with tattoos makes a heart shape with his hands. Image by cookie_studio on Freepik.Putting the test in testosterone

To assess the safety of testosterone, especially its cardiovascular effects, manufacturers and doctors developed TRAVERSE, the Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE study.

Happily, they worked as hard on their study design as they did their acronym, developing a randomised, double-blind, placebo-controlled experiment for a large cohort of 5246 patients. The men recruited for the study were all between the ages 45 to 80 years of age, had testosterone levels lower than normal, reported symptoms of low testosterone, and were at high risk for cardiovascular events.

For the duration they were in the study, (a mean time of 22 months), the men either applied 1.62% testosterone gel or a placebo gel daily. Over time, each person’s dose was adjusted. For the men taking the actual medication, their dose was adjusted to help them achieve normal testosterone levels. The men taking placebo also had their doses adjusted randomly to maintain the double-blind effect.

a middle-aged man in a red shirt makes a heart shape with his hands. Image by stockking on Freepik

Heart warming, not heart warning

In medicine, no news is good news.

The study found that there was no real difference in terms of major cardiac events between the men taking testosterone and placebo. There was also no significant difference between the two groups when it came to death, hospitalisation, urgent visits for heart failure, or need for revascularisation during the trial period.

In Stat News, one of the authors of one of the studies that had initially reported the link between testosterone and heart disease called the TRAVERSE findings “very reassuring” and the data “very conclusive.”

a middle-aged man makes a silly face while also making a heart shape with his hands. Image by stockking on Freepik

Everybody HRTs sometimes

While these results are reassuring, the study authors note that the results shouldn’t be taken as proof that any amount of testosterone would be safe for anyone at any time.

In the general population, testosterone is used with and without a doctor’s prescription for a variety of reasons – to treat a diagnosed hormone deficiency, to get massive gym gains, to treat gender dysphoria, and as a lifestyle drug to try and forestall the changes in sexual function and energy that come with age.

“Men should not use testosterone for anti-aging,” one of the authors of the study stated in the Washington Post, “I don’t want our study to be misused by physicians to prescribe it to men who simply want to feel younger.”

The chairman of the trial’s steering committee added “We do not want our study to be used as a justification for the widespread prescription of testosterone as a tonic for ageing men so that they can try to feel like they were 18 to 25 years of age again. And I’m concerned that there will be misuse … I can see the ads now.”

While a desire to feel young and fun is certainly a good reason to try new things, if the new thing is off-label prescription medication, the authors stress caution.

Firstly, the patients studied had a unique intersection of risk factors – they were middle-aged to elderly cisgender men with a pre-existing risk of heart disease for which they were taking medication. Most of them were white, most of them had a BMI around 35, and a majority also lived with diabetes.

Secondly, while the effects were small, the study also found that testosterone replacement therapy had some negative outcomes. Compared to placebo, the men taking testosterone had slightly higher chances of experiencing blood clots in their lungs (0.9% vs. 0.5%), an irregular heartbeat that required treatment (5.2% vs. 3.3%), atrial fibrillation (3.5% vs. 2.4%), and damage to their kidneys (2.3% vs. 1.5%).

Thirdly, although the men in the study were taking hormone replacement medication for quite a long period, most of them only experienced a modest increase in their testosterone levels. The men had started the trial with a median testosterone level of 227 ng per deciliter, which reached a height of 386 ng per deciliter in the middle of the trial before declining to 326 g per deciliter by the end. Whether the number or type of negative events would have changed if the men had been able to get their testosterone levels higher is a question for further research.

For older men who might have worried about the cardiovascular effects of their hormone replacement therapy though, this result is extremely heartening.