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 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.
AUDIE CORNISH, HOST:
Many men age 65 and up who have low levels of testosterone say their sense of well-being, not to mention their libido, isn't what it used to be. That's why some doctors prescribe testosterone replacement. In the past, studies haven't had clear results about how well replacement works and whether it's safe. Today, there are new findings from five studies, but they don't do much to clear up the confusion. NPR's Patti Neighmond reports.
PATTI NEIGHMOND, BYLINE: The studies, called the TTrials, were conducted at 12 medical centers across the country. Seven-hundred-eighty-eight men with low levels of testosterone took part. About half received testosterone gel. The other half got a placebo. Scientists looked at potential benefits of the hormone gel, including cognition, bone health, heart health and anemia. Researcher Susan Ellenberg says the bottom-line message for patients is mixed.
SUSAN ELLENBERG: It tells them that this is not likely to be a magic bullet for them but that it may lead to some improvements in some areas and probably not in others.
NEIGHMOND: The biggest improvement, she says, was bone health.
ELLENBERG: The volumetric bone density increased much more on testosterone than on placebo. It was a very strong effect in measuring both bone density and bone strength.
NEIGHMOND: Longer-term research is needed, she says, to make sure stronger bones mean fewer fractures as men age. There was some benefit for men with anemia - more on that study in a moment. But when it came to cognition and memory, there were no improvements among the men on testosterone gel. And there was a red flag when it came to plaque buildup in the arteries, a risk factor for heart disease.
ELLENBERG: The volume of plaque increased more on the testosterone arm than on the placebo arm. And that difference was statistically significant.
NEIGHMOND: Again, large long-term studies are needed to see whether testosterone supplements actually increase incidence of heart attack and stroke. A separate study also published today found no increase. The companies that manufacture the supplements are now planning more research. Endocrinologist Shalender Bhasin with Boston's Brigham and Women's Hospital says because there's not enough evidence that testosterone is safe for the cardiovascular system, doctors should be cautious with certain patients.
SHALENDER BHASIN: The frail elderly or people who have preexisting heart disease or have had a recent heart attack or a stroke - I think one should be particularly careful in those individuals.
NEIGHMOND: Decisions about whether to take or not take testosterone, he says, should be made after careful discussion between patients and their doctors.
BHASIN: Physicians should do what physicians always do. They weigh the available evidence and individualize their treatment decisions and have that conversation with their patients about the uncertainty, about the risks and benefits.
NEIGHMOND: Earlier research with this same group of men showed clear improvements in sexual function and libido along with a slight elevation in mood. Patti Neighmond, NPR News. Transcript provided by NPR, Copyright NPR.