Taking testosterone doesn't increase heart disease risk. Why researchers are still wary.

Boosting testosterone in middle-aged and older men with low levels doesn't seem to increase heart attack risk, a new study shows. But researchers were quick to note their finding shouldn't be a license for men to seek out the therapy.

The study looked specifically at men with low levels, known as hypogonadism, as well as symptoms such as anemia, fatigue, loss of pubic hair, hot flashes and low sexual function.

"What we were able to do was to rule out a high level of cardiovascular risk (for that group)," said Cleveland Clinic Cardiologist Dr. Steven Nissen, who led the research.

Testosterone levels naturally fall with age, and many men take the hormone hoping to restore their sexual function.

But many are oversold on its benefits, Nissen said, particularly by shopping mall clinics that end up prescribing testosterone to half the men who walk in the door.

"Men who are getting testosterone are expecting a lot more than they're likely to get. You can't turn back the clock," Nissen said.

Why the research was needed

In 2015, concerned about the common use of testosterone and lack of safety data, the Food and Drug Administration required manufacturers to conduct a clinical trial "to more clearly address the question of whether an increased risk of heart attack or stroke exists” for those taking testosterone.

This study, funded by drugmakers, is the result of that requirement. (Several co-authors are employed by AbbVie or, like Nissen, have received research grants from AbbVie and other companies that make testosterone.)

"This is the data that a lot of doctors are waiting for and hoping to see," said Frederick Wu, an endocrinologist at the University of Manchester in England, who was not involved in the study. "A lot of weight and a lot of attention will be drawn to these disease results."

Studies like this are hard to conduct and extremely expensive, so would only have been funded by the companies, Wu said.

Previous research, published in 2018, showed a year of testosterone treatment among older men with low levels could improve sexual function, slightly improve mood, correct mild anemia and increase bone density.

That trial wasn't large or long-lasting enough to provide definitive information about the risks of treatment, but the new study fills that gap.

"The uncertainty made it impossible to weigh the risks," said co-author Dr. Shalender Bhasin, a men's health expert at Brigham and Women's Hospital and Harvard Medical School. "People can now weigh the benefits in the context of better information on the risks."

The new study also examined possible benefits from testosterone therapy, which will be the subject of future publications, Bhasin said.

Another future paper will examine prostate cancer risk from supplementating testosterone, but this study suggested there was not an increased risk in the research group. The study only included men who were not at high risk for prostate cancer.

The study did not look at people who are "misusing" hormones for body building or athletics, Bhasin said. They typically use much higher doses than was tested in this study, so "these safety data don't apply," he said.

What the study found

The study involved 5,246 volunteers, ages 45 to 80 years old, with pre-existing or a high risk of heart disease, symptoms of low testosterone and a low level of the hormone in their blood when measured twice on an empty stomach first thing in the morning. Half received a daily gel of 1.62% testosterone and half were given a placebo.

If their testosterone levels remained low, despite the treatment, their dose was increased and if it went above the accepted upper limit, it was decreased. Changes also were made to the gel received by patients in the placebo group so neither doctor nor participant knew which one they were getting.

The men were treated for about two years and followed for an additional nearly three years.

Those receiving the active gel had about the same rate of heart attack and stroke as those receiving the placebo, the study found.

"If testosterone caused a lot of cardiovascular events, that might have been the end of testosterone treatment," said Dr. Alvin Matsumoto, an endocrinologist and emeritus professor at the University of Washington in Seattle, who was not directly involved in the research. "That's why it was important to answer this question."

Nissen still worries about the safety of those who take testosterone for many years, which has not been proven safe, and he emphasized the findings only cover men who are symptomatic and shown through testing to have low levels of the hormone.

"With all those caveats, I do think it is reassuring for men that want to try testosterone to relieve symptoms," he said. "We were able to rule out a high level of cardiovascular risk."

Keep in mind

Like all studies, this one has some limitations, which men and their doctors should keep in mind when considering whether to choose prescription testosterone, several experts said.

It still leaves open questions about testosterone in middle-aged and older men, Matsumoto said. The study was not designed to conclude whether testosterone might decrease fracture risk in men with osteoporosis, the risk for major depression or the incidence of diabetes, he said.

Because most of the men in the trial likely had mild testosterone deficiency, it's not clear whether the benefit of therapy outweighs the risks for those men, though "I don't think there's any question that individuals with severe hypogonadism derive benefit more than risk," Matsumoto said.

Nissen warned the findings are limited by the relatively short duration of the trial and the number of men who stopped taking the hormone, presumably because they saw no change either from the placebo or active gel. More than 60% of the participants stopped the study drug and more than 20% left the trial completely.

Symptomatic patients "expect to feel better and if they don't, they stop their study drug and they may even leave the trial," Nissen said. "Those are flaws in the study that tend to undermine the conclusions."

Many men may stopped or left because they were being under-dosed, Wu said. While the study aimed to get all men to a blood testosterone level of between 350 nanograms per deciliter and 750 ng/dl, most remained below 350 and some even below the levels of men receiving placebos.

Wu said he believes this probably was because the trial relied on testosterone gel, rather than injections. Injections sometimes lead to high spikes in hormone levels, while gels can lead to underdosing and require frequent dosing adjustments.

Because the trial relied on a gel and kept levels relatively low, the findings may not apply to men who take injectable testosterone or whose dose leads to a much higher blood level of the hormone, he said.

"I still think this is an extremely important study," Wu said. "We need to take the information very seriously."

Contact Karen Weintraub at kweintraub@usatoday.com.

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