Testosterone replacement therapy is safe for most men with heart problems who also have been diagnosed with a low testosterone disorder, a new clinical trial has concluded.

The trial found that testosterone replacement did not raise these patients’ incidence of heart attack, stroke or heart-related death in a group of men with both heart problems and hypogonadism — a condition in which low testosterone levels have led to specific health problems.

“For men with heart disease or at risk for heart disease, taking testosterone — when given in appropriate doses and carefully monitored — did not increase the risk of heart-related events like heart attack, stroke or death from heart-related causes,” said senior researcher Dr. Steve Nissen, chair of cardiovascular medicine with the Cleveland Clinic.

However, researchers warn the results are not a green light for “Low-T Centers” to tout testosterone replacement for any healthy man, including those whose levels of the male hormone are declining naturally with age.

“My nightmare really is that we’ll see ads on television that say, ‘Cleveland Clinic says that testosterone is safe. Now, come on in and we’ll give you your testosterone.’ That’s not a good outcome from this study,” Nissen said.

The trial also identified certain health risks with testosterone replacement therapy that should be taken into account before prescribing the treatment, Nissen added.

“There are some people I would not give it to,” Nissen said. “Men that have had a history of atrial arrhythmias [heart rhythm problems] or any kind of clotting problems probably shouldn’t get it.”

The. trial was prompted by the U.S. Food and Drug Administration’s response to the proliferation of “Low-T Centers” throughout the nation. The results were published June 16 in the New England Journal of Medicine.

Prescriptions for testosterone replacement therapy in the United States increased between 1.8- and fourfold during the previous two decades, according to a 2017 meta-analysis in the journal European Urology Focus.

Data presented to an FDA advisory committee in 2014 showed that the number of patients taking testosterone leaped from nearly 1.3 million in 2010 to about 2.3 million in 2013, Nissen noted.

Testosterone can stimulate too much red blood cell production, which can increase a man’s risk of developing a blood clot. Such clots could cause a heart attack, stroke or pulmonary embolism.

In March 2015, the FDA ordered manufacturers of approved testosterone products to conduct clinical trials to determine whether the therapy could increase the risk of heart attacks or strokes.

For this latest trial, Nissen and his colleagues recruited more than 5,200 men 45 to 80 with clinically diagnosed hypogonadism and either an existing heart problem or high risk of heart disease.

The men all had two fasting blood tests which showed low testosterone, as well as one or more symptoms related to hypogonadism. These symptoms included decreased libido, decreased spontaneous erections, fatigue or decreased energy, depressed mood, decreased frequency of shaving or hot flashes.

“We’re dealing with men who could benefit from testosterone,” said Dr. Robert Eckel, a past president of the American Heart Association who was not involved in the study. “Two-thirds of these patients had diabetes. It’s a group of men who are people you have to be hesitant to do anything with that’s not evidence-based.”

The men were randomly assigned to take daily doses of either a testosterone gel or a placebo gel for nearly two years, to see whether testosterone treatment affected their heart health.

After about three years of follow-up, researchers concluded that the number of major heart-related health events were about the same between the testosterone and placebo groups.

Heart attack, stroke, or heart-related death occurred in 182 patients in the testosterone group versus 190 in the placebo group.

However, researchers did notice some serious side effects in the testosterone group.

Men taking testosterone were more likely to develop a heart rhythm problem, kidney damage or a pulmonary embolism:

  • Twice as many men taking testosterone suffered a pulmonary embolism (24 versus 12 for placebo).
  • Arrhythmias developed in 134 testosterone patients versus 87 placebo patients (5.2% versus 3.3%).
  • Acute kidney injury occurred in 60 testosterone patients versus 40 placebo patients (2.3% versus 1.5%).

Nissen and Eckel agreed that doctors prescribing testosterone therapy should screen for these risk factors, and probably not give it to men with arrhythmias, kidney problems or clotting issues.

“That’s a cautionary note, but I think the study has really clarified this issue,” said Eckel, a professor of medicine emeritus with the University of Colorado School of Medicine. “Can we give testosterone safely to hypogonadal men who are proven to be hypogonadal? I think for the most part, the answer is yes.”

But Eckel reiterated Nissen’s point that this shouldn’t open the floodgates for low testosterone treatment.

“A lot of men seek testosterone therapy because of all the advertising, that testosterone gives them more muscle mass, more strength, better sex drive and sex performance,” Eckel said. “This is not what we’re talking about.”

Nissen also warned that the longer-term health impacts from testosterone therapy remain unclear.

“We studied only for 21.7 months. We didn’t study these patients for five years,” Nissen said. “What happens if you take testosterone longer-term? That’s an unanswered question.”

Nissen is skeptical that any follow-up clinical trials will be done to see whether testosterone replacement therapy is safe for average aging men whose male hormone levels are naturally declining.

“I don’t think anybody’s going to do it. All these drugs are now generic. There’s not really any impetus from sponsors to pay for it,” Nissen said. “The NIH could do such a study but frankly, aging is a normal process. I think most men need to accept the fact that some of the things that they could do when they were younger, they can’t do when they’re older.

“Trying to fix aging with a tonic called testosterone is probably not wise,” Nissen noted.

Men concerned with low testosterone would be better off addressing all the other health problems that can contribute to male hormone decline, said Dr. Romit Bhattacharya, associate director of Massachusetts General Hospital’s Cardiac Lifestyle Program in Boston.

“We know that it’s associated with numerous other health indicators, including poor-quality diet, lack of physical activity, obesity and diabetes,” Bhattacharya said. “Low testosterone appears to be a chronic metabolic health condition that is in large part due to this trend of worsening cardio-metabolic health, worsening dietary trends, worsening exercise trends, increasing obesity and increasing insulin resistance and diabetes.

“We have to be thinking about, are we putting a Band-Aid on a much larger problem?” Bhattacharya said. “I would like to see men who have noticed that they have low testosterone, they’re feeling perhaps less energetic, less libido, have erectile dysfunction, to think about what processes led them there.”

The trial was funded by drugmakers AbbVie, Acerus Pharmaceuticals, Endo Pharmaceuticals and Upsher-Smith Laboratories.

More information

The Mayo Clinic has more about the potential benefits and risks of testosterone therapy.

SOURCES: Steven Nissen, MD, chair, cardiovascular medicine, Cleveland Clinic; Robert Eckel, MD, professor of medicine emeritus, University of Colorado School of Medicine, Aurora; Romit Bhattacharya, MD, associate director, Massachusetts General Hospital’s Cardiac Lifestyle Program, Boston; New England Journal of Medicine, June 16, 2023