Many men over 65 with low testosterone levels say their sense of well-being, not to mention sexual function, isn't what it used to be.

That's why some doctors prescribe testosterone replacement. But the effectiveness of testosterone has been controversial. Studies of the risks and benefits have been mixed, and the Food and Drug Administration beefed up its warnings about cardiac side effects of testosterone supplementation in 2015.

And the findings of five studies released Tuesday aren't likely to clear up the confusion. They appear in JAMA, the journal of the American Medical Association and JAMA Internal Medicine.

The studies are collectively called the Testosterone Trials (TTrials) and they compared a testosterone gel, AndroGel, against a placebo. The results are based on 788 men with below normal levels of testosterone studied at 12 sites across the country over a year.

Overall, researchers saw improvements in bone density and bone strength in men who used a testosterone gel, which raised their testosterone to levels seen in younger men.

In men with unexplained anemia, testosterone also improved iron levels in the blood. (A reviewer of the study raised questions about whether it was done ethically.)

But in men using testosterone who had been reporting memory problems at the start of the study, there were no improvements in memory or cognition. And there were worrisome signs of an increase in the risk of cardiovascular problems.

Taken together, says Dr. David Handelsman of the University of Sydney and Concord Hospital in Australia, the TTrials "do not materially change the unfavorable balance of safety and efficacy to initiate testosterone treatment." His comments appear in an editorial in JAMA.

"Low testosterone levels due to obesity" and other aging health problems, Handelsman says, "are better addressed by lifestyle measures" directed at those problems. He also called for strengthened warnings on the drug's packaging to note the cardiovascular risk.

In another accompanying editorial, Eric Orwoll, a professor of medicine at the Oregon Health and Science University, says convincing answers about the effects on cardiovascular health remain "elusive" and will require large, prospective randomized trials.

"At this point, clinicians and their patients should remain aware that the cardiovascular risks and benefits of testosterone replacement ... have not been adequately resolved," he says.

The results

The red flag on cardiovascular risk was raised in the TTrials' Cardiovascular Trial, where researchers found an increase in plaque buildup, a known risk factor for heart disease. The study was based on 73 men using the gel and 65 receiving a placebo. The study was originally done because there had been suggestions that testosterone has heart benefits.

Indeed, another trial published Tuesday, which was not part of the TTrials, showed a lower risk of cardiovascular events, including heart attack or stroke, in men who'd received testosterone, on average, for 3.4 years.

Somewhat more positive results were seen in the TTrials' Bone Trial. Among men using the testosterone gel, there were statistically significant improvements in lumbar spine and hip bone density and bone strength. There was a small and equivalent number of bone fractures in each group. The Bone Trial included 189 of the 790 men in the overall study.

But another TTrial, the Cognitive Function Trial, failed to find improvements in memory and cognitive skills associated with testosterone treatment. This trial studied 493 men who had age-associated memory impairment at the start of the study, as measured by subjective memory complaints and objective memory performance.

The TTrials started out by screening more than 51,000 men 65 and older. To qualify for one of the subtrials, men needed a blood level of testosterone to be below 275 ng/dL, just below the range many doctors consider "normal" for healthy, younger men.

After screening, 788 men were considered to have low testosterone.

Until the first year of TTrials was over, neither the participants nor the researchers knew which men were getting the placebo or the testosterone gel.

The first set of TTrial studies was reported last year in the New England Journal of Medicine. Those looked at sexual function, physical activity and mood and found that sexual function and desire did improve significantly among men using the testosterone gel.

Some mood improvements were also noted although there was not significant improvement in overall vitality or in physical activity.

Final decisions about testosterone treatment for older men will depend on "balancing the results" from the TTrials "with the results from a much larger and longer-term trial designed to assess cardiovascular and prostate risk," says endocrinologist Peter Snyder of the University of Pennsylvania, who headed the studies.

In the meantime, TTrial researcher Susan Ellenberg says decisions about whether to take or not take testosterone should be made between older men and their physicians, taking into account overall health and medical history while weighing potential benefits and risks.

The studies were funded by the National Institute on Aging and other parts of the National Institutes of Health. Additional funding was provided by the maker of AndroGel, AbbVie, which also supplied the drug, which is customary in clinical trials. The company was not otherwise involved in the implementation or analysis of the trial.

Copyright 2017 NPR. To see more, visit http://www.npr.org/.

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