Testosterone replacement therapy used to treat "low T" doesn't appear to increase the risk for serious heart problems as some experts had feared, according to research published Friday in The New England Journal of Medicine and presented in Chicago at ENDO 2023, an annual meeting of the Endocrine Society.
The finding comes nearly a decade after the Food and Drug Administration demanded that drugmakers study the potential cardiovascular effects of testosterone replacement therapy.
And it may serve as a welcome relief to men who take it to counter the symptoms of low testosterone — loss of sex drive later in life, usually — as well as the physicians who treat them.
"This is the trial we've been waiting for for a really long time," said Dr. Joshua Halpern, a urologist at Northwestern Medicine in Chicago.
"This has provided the closest thing we have to a definitive answer about cardiovascular risk and testosterone therapy," said Halpern, who studies testosterone therapy but was not involved with the new research.
Testosterone replacement therapy is usually meant for men diagnosed with hypogonadism, which, in men, means low levels of testosterone. It can cause symptoms such as fatigue, decreased libido, depressed mood, hair loss and in some cases, hot flashes much like women get during menopause.
When topical testosterone products hit the market in the early 2000s, "manufacturers picked up on this theme that testosterone was like the fountain of youth," said Dr. Gregory Broderick, a urologist at the Mayo Clinic in Florida who was not involved with the new research.
There was a flood of ads about treating low T, enticing middle-aged and older men with the promise of regaining their 20-something-year-old bodies and once-abundant energy and sexual appetite.
"These are very distressing symptoms to middle-aged and older men who are still in the prime of their life," said Dr. Shalender Bhasin, an endocrinologist at Brigham and Women's Hospital in Boston and one of the authors of the new study. "They motivate men who have never seen a doctor to go to the doctor’s office seeking medical attention."
Sales of the medication skyrocketed. A 2013 study found that from 2001 through 2011, rates of testosterone replacement therapy use increased more than three times among men 40 and older, from 0.81% to 2.91%.
A quarter of those men, that study found, never had blood tests to determine whether there was any true medical reason for the therapy. Bhasin said that because symptoms are not life-threatening and are usually interpreted as normal signs of aging, testosterone levels aren't checked during regular blood draws. Because of this, it's also difficult to measure the true prevalence of the condition, though Bhasin estimated it to be between 2%-4% of middle-aged and older men.
In 2013, another study raised a major safety flag: It suggested that men with previous heart problems who took testosterone replacement therapy had an increased risk for heart attack, stroke and cardiac death.
But that research and others like it were not robust enough to determine true heart risks, experts said. The FDA slapped a warning label about the potential for cardiovascular problems onto testosterone replacement products, and in 2015 the agency "said to the manufacturers of testosterone, 'OK, if you think your drug is safe, prove it,'" said Broderick, who is also a past president of the Sexual Medicine Society of North America.
That's where the latest research comes in.
"Here was this therapy being given to millions of men with no information about its cardiovascular safety," said Dr. Steven Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic and senior author of the paper. "That needed to be addressed, and we did our best to address it."
The trial, called Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men, or TRAVERSE, enrolled 5,198 men who had all been diagnosed with low testosterone levels through two different blood tests and also had symptoms of low T.
They also had at least three risk factors for cardiovascular disease, including high blood pressure, Type 2 diabetes, abnormal levels of fat in the blood or a history of smoking. Participants were ages 45 to 80, but most were in their 60s.
Half applied a standard dose of testosterone gel to their arms once a day, while the other half applied a placebo gel.
After nearly two years of treatment, on average, there was no difference in the rate of heart attacks, strokes or death from any cardiovascular problem between the groups.
However, the trial did find that men taking the testosterone therapy had a higher incidence of irregular heartbeat, kidney problems and blood clots in the legs or lungs when compared to men who had the placebo.
Even so, Nissen said he was relieved by the result. "I've had men come in my clinic who have very severe heart disease, who have gone somewhere and gotten somebody to prescribe testosterone, and they will look me in the eye and they will say, 'Is it safe?' And I've had to tell them, 'We don't know.'"
Our concern here is that this will be interpreted as a justification for a more widespread use of testosterone in men.
Dr. steven nissen, cleveland clinic
While that answer is now more clear, Nissen cautioned against overestimating the positive results.
"Our concern here is that this will be interpreted as a justification for a more widespread use of testosterone in men," he said. "We don't want this used by bodybuilders and athletes and other people to build muscle mass."
Dr. Peter Wilson, a preventive cardiologist and endocrinologist at the Emory University School of Medicine, agreed.
"If you want to lift more weights, if you want to ride the bicycle faster, win the race, I'm sorry, that is not" a reason to use testosterone replacement therapy, he said. "We deal with medical indications, not performance enhancement." Wilson was not involved in the new study.
And testosterone replacement therapy can come with negative side effects not related to heart health.
If men using testosterone replacement therapy have prostate cancer, for example, the treatment can fuel the cancer's growth, Halpern said. Testosterone replacement therapy does not cause prostate cancer, he added. All men taking testosterone must be monitored regularly for any rise in their prostate antigen levels.
The therapy can also decrease sperm production.
"We certainly see men who haven't been counseled appropriately about taking testosterone," Halpern said, "who present to my clinic with significant fertility issues."
There is also a risk that the therapy can cause the body to make too many red blood cells, raising the risk for clotting.
Still, it is possible that the FDA could remove the cardiovascular warning label based on the trial. The agency declined to comment directly on the findings but said in a statement that it would evaluate them "as part of the body of evidence to further our understanding" of testosterone replacement therapy.
There were limitations of the new research. Patients were followed for just about 21 months, so there is no data on the potential for long-term risks. Researchers only looked at the gel form of testosterone, so the findings may not apply to the other forms, which include injections and pills.
And more than half — over 61% of men in each group — stopped taking the medication before the study was completed.
That may be because men were frustrated when neither the placebo nor the actual medicine worked to ease their symptoms.
"I think patients have this perception that it will improve their sexual function, will improve their mood and energy level," Bhasin said. "But that's never been shown in a randomized clinical trial."
That is, there's no scientific proof that testosterone replacement therapy works as intended.
But doctors who treat patients say that in their experience, many patients who truly need the drug can benefit.
"There's no doubt about it. Symptoms, especially low libido, do improve," Wilson said. "This is very reassuring."