Testosterone supplements have grown into a $2 billion market, with millions of men of a certain age taking it for low energy, low libido, low mood — what marketers call "low T" — even though that's not an approved use.
Now, the first study to rigorously test whether the quintessential male hormone can fight the toll of aging shows it isn't much of a youth elixir.
A year of testosterone treatment was no better than a placebo for memory and thinking, and it increased fatty plaque in coronary arteries, a risk factor for heart disease. The hormone helped anemia and low bone density in the minority of men with those conditions, which can be treated with other, proven therapies.
The results, published Tuesday in the Journal of the American Medical Association and JAMA Internal Medicine, add to findings from a year ago: Testosterone did not improve fatigue or walking speed, and its modest benefits on sexual function faded by the end of the study.
"The hopes for testosterone-led rejuvenation for older men are dimmed and disappointed if not yet finally dashed," University of Sydney professor of medicine David J. Handelsman concluded in an editorial accompanying the latest results.
University of Pennsylvania endocrinologist Peter Snyder, who led the complicated, government-funded clinical trials involving 788 senior men at 12 medical centers, disagreed.
"It shows for the first time that treatment of older men with low testosterone has certain benefits, including bone density and anemia," Snyder said. "I would say the effects on bone and anemia were striking."
He added a caveat. Even though the $50 million "T Trials" are the most conclusive studies ever done on the hormone, researchers didn't follow enough men long enough to tell whether testosterone increases risks such as heart attacks, stroke, or prostate cancer.
AbbVie, which donated its leading brand, Androgel, to the trials, said in a statement that the company is "committed to our patients and is proud of our continuous support of research that advances science for the benefit of hypogonadism patients."
Actually, hypogonadism occurs when the body doesn't produce enough of the hormone due to disease, injury, or chemotherapy. It's the condition for which testosterone-replacement therapy is approved.
Prescribing testosterone for age-related deficiency — which is only vaguely defined — took off in 2000. The trend was driven not by solid scientific evidence, but by the introduction of convenient, rub-on testosterone products, the first being Androgel. Many men are put on testosterone with no tests of their levels or despite tests showing normal levels, a study of Medicare claims found.
Two years ago, the U.S. Food and Drug Administration cracked down on this overprescribing. It ordered drugmakers to revise product labeling to stress the approved use, and to warn that the drug may increase the risk of heart attacks and stroke. Another order — that manufacturers conduct a clinical trial to clarify the heart risks — is "under discussion," the FDA said Friday.
Concerns about testosterone use also led the National Institute on Aging to fund the T Trials, which began enrolling men over age 64 in 2009.
T Trials researchers had to screen more than 50,000 men to find 788 with confirmed abnormally low testosterone levels along with one or more age-related symptom that the hormone might help. More than 60 percent of the men were also obese, a condition that can depress testosterone levels.
Now, with a clearer scorecard on benefits, Snyder would like to see the government fund a study to tease out the risks — an effort that would take 5,000 men, five years of treatment, and $500 million.
Other experts see no point in defining the downsides of a therapy with weak upsides.
"The improvements in outcomes in the T Trials were minimal," said Deborah Grady, a professor of medicine at the University of California, San Francisco, and an editor of JAMA Internal Medicine.
Grady was a leader of the Women's Health Initiative, the mammoth government study that in 2002 shattered the deeply held belief that menopausal hormone therapy protected women's hearts. The National Institutes of Health agreed to fund the initiative because estrogen, unlike testosterone, had decades of circumstantial evidence of cardiac benefits.
Testosterone's cardiac effects are still unsettled. Some studies that mine medical records — including one in Tuesday's JAMA Internal Medicine — have found men taking it have fewer heart problems.
The T Trials' anemia findings add to the complexity.
Testosterone is known to increase production of red blood cells, which carry hemoglobin, a protein that ferries oxygen. In 126 men with mild anemia — a deficiency of red blood cells or hemoglobin that can cause fatigue — testosterone was better than a placebo at boosting hemoglobin. The hormone corrected anemia that had no apparent cause, as well as anemia caused by iron deficiency or inflammation.
However, in six men, the hormone triggered an oversupply of red blood cells. Testosterone labeling warns about this because the blood can become too thick, a risk for dangerous blood clots or stroke.
Like all participants in the trials, the six men were closely monitored, so the problem was detected, their testosterone dose was reduced, and their red blood cell counts returned to normal, Snyder said.
"The results illustrate that decisions about testosterone treatment need to be individualized," said Evan Hadley , director of the National Institute on Aging's geriatrics division.