By Kristina Fiore, Staff Writer, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

A new analysis countered recent studies linking the use of testosterone therapy with increased risks of myocardial infarction (MI) and stroke.

Among roughly 20,000 patients treated with testosterone over a 6-year period, the rate of new MIs was 30 per 100,000 and the rate of new strokes was 10 per 100,000, according to Robert Tan, MD, of OPAL Medical Clinic in Houston.

Those rates were significantly lower compared with rates in the Kaiser Permanente and Northern Manhattan Registry databases (P lees then 0.0001 for both MI and stroke), he reported at the American Association of Clinical Endocrinologists meeting in Las Vegas.

"The study suggests a protective effect of testosterone against MI and strokes," Tan said. "Further, there was no evidence of worsening of pre-existing MI or strokes in patients treated with testosterone."

George Grunberger, MD, vice president of AACE, said although the study was retrospective and not the gold standard, randomized controlled trial, it should allay some concerns.

"I think it should take out some of the element of fear," said Grunberger, who was not involved in the study. "The last thing you want is patients who are doing well to stop their treatment because of some headline."

While the results should "assure the public that if you know what you're doing, testosterone doesn't increase cardiovascular risk," he cautioned that "I would leave it there. It's a hypothesis-generating thing. Let's do a real study to show if you can offer cardiovascular protection."

Recent Concerns

Recent studies have flagged concerns about the cardiovascular safety of testosterone. One published in the Journal of the American Medical Association that garnered the most attention was an analysis of Veterans Affairs patients. The researchers found that men who'd undergone testosterone therapy and coronary angiography had a higher risk of cardiovascular complications.

A group of healthcare providers called on JAMA to retract the study, citing two corrections that were subsequently published.

Other recent research has found a potential link between testosterone therapy and heart risks, including one in January in PLoS One, the 2010 randomized controlled TOM trial, and a 2013 meta-analysis in BMC Medicine of randomized trials.

These data prompted the FDA to launch an investigation into the cardiovascular safety of testosterone therapy, which is ongoing.

The testosterone therapy field has also come under fire for its financial relationships with industry. Several articles in the New York Times -- including one on the marketing of the "Low-T Movement," (Nov. 23, 2013) and another on testosterone gels (Oct. 15, 2013) -- have questioned the potential overselling of the therapy.

The Low T Center Experience

Tan and colleagues conducted their retrospective analysis in almost 40,000 patients who were seen at 40 "Low-T Centers" across the U.S. between 2009 and 2014.

About half of these patients met criteria for treatment and were put on testosterone therapy.

To validate the accuracy of their information, Tan and colleagues checked on ICD-9 codes in the electronic health records and conducted interviews with families of patients who'd had a cardiovascular event.

They found that of the treated patients, there were four nonfatal MIs and two fatal MIs during that time period -- calculating a rate of new MI of 30 per 100,000.

There were 46 patients who'd had a heart attack before starting testosterone therapy, and none of these patients had any adverse cardiovascular outcomes after starting treatment, they reported.

As for stroke, there were only two cases among treated patients, for a rate of new stroke at 10 per 100,000.

Of the 12 patients who had a stroke before starting testosterone therapy, none had any further adverse events.

Since there was no comparison group in the database, Tan and colleagues compared their numbers with outcomes in the general population using Kaiser Permanente and Northern Manhattan Registry databases, which showed a rate of 208 per 100,000 and 93 per 100,000, respectively -- suggesting that testosterone may be protective against cardiovascular events, Tan said.

The rate ratio for MI in testosterone patients was 0.14 (95% CI 0.098 to 0.211, P

"This study contradicts the two other studies," Tan said, "instead suggesting a protective effect of testosterone against MI and strokes."

He said his study had some features that could account for a difference in the results, including the fact that the mean testosterone levels were higher than those seen in the JAMA study (543 ng/dL versus 332 ng/dL), and that his patients were followed very closely on a strict protocol.

Tan called for a long-term randomized controlled trial to further clarify the issue, although he said he wasn't sure he'd ever see one in his lifetime.

Yehuda Handelsman, MD, of the Metabolic Institute of America in Tarzana, Calif, and a past president of AACE, agreed that a large trial would still be needed to settle the debate.

"I like this study because it nullifies the other two studies, and tells us we don't really know what's going on," Handelsman told MedPage Today. "Neither the studies that claim damage, nor this study that claims protection, are good enough. At best, they are hypothesis-generating and we need to study them further."

Likelihood of a Large Trial?

But Grunberger expressed a lack of confidence in getting such a trial done because of the high cost and length of time needed to see cardiovascular events.

"When a patient comes to my office, I have to make a decision about what I'm going to do," Grunberger said. "What are you [the patient] going to do if I tell you to come back in 15 years? ... to see cardiovascular events, you have to have a critical mass of people in the same situation exposed to the same thing for a long enough time. It would be decades before we have an answer."

Handelsman said the appropriate study would establish exactly which patients should get testosterone therapy, what level is appropriate to supplement, and track all outcomes.

Grunberger added that "in a strange way, [the negative attention] may be good, because maybe patients [who don't really need testosterone] will think twice. But the last thing we want is to have people who are legitimate, who have low testosterone and need to get help, to get scared or stop taking it."