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Key findings

Testosterone therapy: Is the verdict now in?

March 23, 2017

By Mike Richman
VA Research Communications

Testosterone was given to participants in the Testosterone Trials via a topical gel, but it can also be administered through injections, patches, or implants. (Photo by Michael Moody)

Testosterone was given to participants in the Testosterone Trials via a topical gel, but it can also be administered through injections, patches, or implants. (Photo by Michael Moody)

Testosterone treatment is a billion-dollar industry. But here's the million-dollar question: Is it worth the risk?

Studies have reached myriad conclusions on the pros and cons of testosterone therapy. It's used mostly by aging men with low testosterone levels—a condition called hypogonadism—but is exploited by others looking to stop the normal testosterone decline that's part of male aging and, in a sense, to relive their youth. Testosterone is a key male hormone that affects sex drive, bone mass, the production of red blood cells, and muscle size and strength.

Now, a landmark seven-part series funded by the U.S. National Institute on Aging called the Testosterone Trials (TTrials) has produced mixed results. It found that testosterone treatment increased bone density and corrected anemia, a condition that develops when one's blood lacks enough healthy red blood cells, or hemoglobin.

"As in all therapeutic decisions, the decision to treat should be based on the balance of benefits versus risks of therapy."

But the treatment also failed to improve memory in men with age-associated memory problems, and it increased the volume of non-calcified plaque in blood vessels supplying the heart, or coronary arteries. Plaque buildup can cause arteries to narrow, leading to heart disease, heart attack, or stroke.

The TTrials were published in five separate papers. One of the papers, which included results from three of the studies, appeared in the New England Journal of Medicine in February 2016. The other four papers appeared in either the Journal of the American Medical Association (JAMA) or JAMA Internal Medicine in February 2017.

The TTrials amounted to the largest study ever of testosterone treatment in older men, based on the number who participated (788). The placebo-controlled study was designed to provide definitive answers about the short-term benefits and risks of testosterone treatment, while addressing the limitations of prior studies. Those limitations included small numbers of men studied, the inclusion of men with normal testosterone levels, the use of too little or too much testosterone, a short treatment period, and non-validated outcome measurements.

New answers on short-term benefits

TTrials co-author Dr. Alvin Matsumoto, an endocrinologist and geriatrician in the Geriatric Research, Education, and Clinical Center at the VA Puget Sound Healthcare System in Seattle, acknowledges the mixed results. But he says the research still provides new and more definitive answers on the short-term or lack of benefits of testosterone treatment in older men. The studies included 788 symptomatic men age 65 and older with clearly and consistently low testosterone levels for no apparent reason other than age.

"The TTrials was a landmark study," he says. "But it was too small a study, and the duration of the testosterone treatment was too short to provide answers regarding longer-term clinical benefits and risks related to, for instance, bone fractures, prostate cancer, or cardiovascular events such as heart attack and stroke. A larger and longer study is needed to know the impact of testosterone treatment on those health issues."

Dr. Rajat Barua, director of cardiovascular research at the Kansas City VA Medical Center, says he finds nothing surprising in the results of the TTrials. He agrees that larger, long-term studies are needed to reach definitive answers on the risks of testosterone therapy. Barua did not participate in the TTrials. But he's the author of past studies on testosterone treatment in relation to Veterans and is also involved in ongoing research on the topic.

"Plaque growth alone is not an indication or heart attacks and stroke," he says. "Plaque growth may cause symptoms of angina [severe chest pain caused by an inadequate blood supply to the heart], but not necessarily events such as heart attacks that lead to death."

According to Matsumoto, the TTrials were the culmination of about 20 years of work that began with a proposal put forth by him and Dr. Glenn Cunningham, a former VA researcher and co-author of the TTrials, for a six-year randomized, controlled trial involving 6,000 men at least 65 years old. The proposal was part of a collaboration between the VA Cooperative Studies Program, which is responsible for planning and conducting large clinical trials and epidemiological studies in VA, and the National Institute on Aging.

But the Efficacy and Safety of Testosterone in Elderly Men (ESTEEM) trial, which was to examine the potential effects of testosterone treatment mainly on bone fractures, but also sexual function, memory, vitality, prostate cancer, and cardiovascular events, never took off because of a lack of funding. Subsequently, the Institute of Medicine (now called the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine), a non-governmental group that provides research and recommendations on public health and science policy, called for a coordinated set of studies with the belief that the short-term benefits of testosterone needed to be set before researchers pursued long-term studies, hence the TTrials.

Participants in the TTrials received a testosterone gel or placebo gel on the skin daily for one year. Levels of testosterone were measured at one, two, three, six, nine, and 12 months, with an extra year of follow-up. In addition to signs of androgen deficiency, or lower levels of male sex hormones, particularly testosterone, the presence of complaints such as reduced sexual desire, difficulty in walking, or low energy were a prerequisite for participation.

"This was not an overly healthy group of individuals," Matsumoto says. "But I can't say they were high-risk, either. They were chosen with low prostate cancer risk, but I can't say they had high cardiovascular risk."

Plaque increase in participants 'concerning'

The researchers studied blood counts, bone density, plaque levels in the coronary arteries, and memory. The participants were also monitored for risk of prostate cancer, with the testosterone group showing more men with a PSA, the measurement used to assess the risk of prostate cancer, greater than 1.0. "That reading triggered a urology referral," Matsumoto says. "But a one-year study can't answer the question of prostate cancer risk."

Those in the testosterone group saw improvements in sexual function, mood and depression symptoms, bone mineral density and strength, and anemia. The bone improvements were in the trabecular bone, tissue found at the ends of long bones and in the pelvic bones, ribs, skull, and vertebrae in the spinal column. The treatment helped correct anemia, whether caused by low iron or an unidentifiable factor. The anemia "increases may be of clinical value...but the overall health benefits remain to be established," the researchers write.

But the drug didn't improve energy, walking distance, or cognitive function in men with age-related memory loss, and it increased the amount of non-calcified plaque in blood vessels supplying the heart. None of the men in the testosterone group or the placebo group were reported to have a major cardiovascular event. "The plaque increase in concerning," Matsomoto says, "but the clinical importance of this finding is unknown and may depend on different types of plaque in the coronary arteries."


Matsumoto has treated younger men with low testosterone levels due to disorders of the testicles, pituitary gland, or brain, a form of hypogonadism. They have improved in many of the outcomes measured in the TTrials when treated with testosterone, he says.

For that reason, he wasn't too surprised to see the improvements in sexual function, mood, depression, bone density, and anemia in the TTrials, but he says it's a bit surprising the treatment didn't improve energy. However, he notes, the signs of low testosterone among the participants were "non-specific" and can be caused by other chronic conditions related to aging, such as obesity and diabetes, that don't improve with testosterone treatment.

Mixed results in VA studies on cardiovascular impact

In relation to the Veteran community, which likely has higher levels of chronic illness and obesity and uses more medications that can lower male testosterone levels, compared with the general population, Matsumoto says, two prior VA studies produced mixed results.

A 2013 study found that men with heart problems may be at greater risk of heart attack, stroke, or even death if they receive testosterone therapy. More than 1,200 Veterans took the therapy through gels, patches, or injections. At three years and after the researchers adjusted for many naturally associated medical conditions, 26 percent of the men had died or suffered a heart attack or stroke, compared with 20 percent who didn't receive the therapy. Before adjustment, there were fewer cardiovascular events in testosterone-treated men.

A 2015 database study led by Barua of more than 83,000 patients found that men whose low testosterone was restored to normal through gels, patches, or injections had a lower risk of heart attack, stroke, or death from any cause, versus similar men who were not treated. The study excluded men with a history of heart attacks or strokes, but it included those with existing heart disease.

Matsumoto cautions that those were "observational studies that only provide clues to the presence or absence of safety signals," instead of more definitive studies like the TTrials. " In contrast to a randomized, controlled trial, observational types of studies are susceptible to confounding influences, so you can't be sure that men treated with testosterone are similar to those not treated with testosterone, for instance, with regard to cardiovascular risk. There have been plenty of suggestions that observational studies are very, very useful in hypothesis generation and figuring out what you want to study and how you want to study it. But by and large, they can't be [relied upon alone] to practice medicine."

Based in part on available evidence from published studies, the U.S. Food and Drug Administration (FDA) concluded there is a possible increased cardiovascular risk linked to testosterone use. As a result, the watchdog agency mandated pharmaceutical companies to pursue a randomized, controlled clinical study to more clearly address the question of whether testosterone users are at increased risk of heart attack or stroke. The trial is expected to start sometime in the coming months. The FDA also required drug makers to include warnings on labels about a possible increased risk of heart attack and stroke in men taking testosterone.

Testosterone is FDA-approved as a replacement therapy only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain.

Meanwhile, with the full verdict not in yet, what's a man to do? How should men who could potentially benefit from testosterone treatment weigh its plusses and minuses?

"As in all therapeutic decisions, the decision to treat should be based on the balance of benefits versus risks of therapy," Matsumoto says. "Because long-term benefits and risks of testosterone therapy in older men are not known, the decision to treat with testosterone should be preceded by an informed-consent-like discussion of short-term benefits and risks, all of which were addressed in the TTrials, and the absence of information about the long-term benefits and risks. The discussion should consider patient-centered goals, the presence and treatment of associated chronic medical conditions, and medications that could contribute to symptoms and low testosterone levels."

Barua also sees it as a patient-based decision. "The risks and benefits of testosterone therapy depend on the risk profiling of the patient, rather than on the therapy itself," he says.

"Currently, there is a need for appropriate screening, selection, dosing, and follow-up of patients to maximize the benefit of this therapy. Knowledge of medicine and science is constantly evolving, so the need for screening, dosing, and follow-up will have to evolve with new and robust data."

According to Matsumoto, older men should not hesitate to consider testosterone therapy if they have alarming signs of androgen deficiency. The treatment is also fine, he says, if patients have severe and consistent low testosterone levels with no active prostate or breast cancer, and no drugs or treatable or reversible medical conditions causing those levels.

"Potential short-term benefits are likely to outweigh short-term risks in these men," he says.

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