As men advance in age, their levels of testosterone naturally start to decrease. To avoid some of the adverse health effects that come with the loss of this sex hormone, some men choose to have it replaced artificially. New research investigates the side effects of testosterone replacement therapy.

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Four clinical trials examine the effect of testosterone therapy in men aged 65 and older.

JAMA and JAMA Internal Medicine recently published a group of five papers investigating the role of testosterone treatment on various health aspects.

Four of the studies document the effects of testosterone treatment on bone density, anemia, cognitive function, and the buildup of coronary plaque. The fifth study is observational and examines the links between testosterone treatment and overall cardiovascular health.

Researchers from the Perelman School of Medicine at the University of Pennsylvania, together with 12 medical centers across the United States, have conducted seven clinical trials in partnership with the National Institute on Aging. The Testosterone Trials (TTrials) examined the effect of testosterone treatment on men aged 65 and over who had shown decreased levels of the sex hormone.

The results of the first three of the seven trials showed an improvement in all the aspects of sexual function and overall mood, and were published last year. The recently published JAMA studies conclude the research.

The TTrials analyzed a total of 51,085 men and selected 790 participants whose age-related testosterone levels were low enough to qualify for the studies.

The participants were then randomly divided into two groups: one group took a daily dose of testosterone in the form of a gel for a year, while the other group took placebo for the same period of time. The testosterone dosage was adjusted to maintain normal levels for young men.

Researchers then tested the efficacy of the treatment every 3 months. The trials were double-blinded, meaning neither the experimenters nor the participants knew which group was a placebo and which received the treatment.

For the bone density and strength study, researchers used quantitative computed tomography to assess spine and hip bone mineral density at baseline and a year later.

To test cognition, researchers administerd a delayed paragraph recall test. They also assessed the visual memory, executive function, and spatial ability of the participants.

To determine coronary artery plaque volume, researchers used a coronary computed tomographic angiography.

The cardiovascular health study was observational, using Cox proportional hazard models to study associations between testosterone treatment and various cardiovascular health outcomes. These included acute myocardial infarction, angina, stroke, transient ischemic attack, as well as sudden cardiac death.

The trials showed that testosterone treatment improves bone mineral density and estimated bone strength, although a larger-scale, longer trial is needed to assess if the treatment also lowers the risk of fractures.

The treatment also improved hemoglobin levels in participants who had anemia, whether its causes were known or not. The trial reported an almost 40 percent higher increase in hemoglobin levels in participants who had taken testosterone, compared with the placebo group.

Testosterone corrected both unexplained anemia, as well as anemia induced by an iron deficiency. However, testosterone did not seem to benefit memory or improve any other aspect of cognitive functioning.

Lastly, the trial for cardiovascular health revealed more coronary artery plaque buildup in testosterone-treated men compared with the placebo group. Those treated had a greater increase in the volume of noncalcified plaque than the control group.

However, researchers note that larger studies are needed to fully understand the clinical significance of these studies. Additionally, the cardiovascular health observational study found that the risk of negative cardiovascular events was lower among the testosterone-treated group, compared with the control group, over a median follow-up period of 3.4 years.

Dr. Peter J. Snyder, a professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism at the University of Pennsylvania, cautions that the findings suggest the treatment may pose a cardiovascular risk.

However, he also notes that “treating 788 men for 1 year is far too few to draw conclusions about the clinical significance of the increase in coronary artery plaque volume and the cardiovascular risk of testosterone treatment.” The total number of major cardiovascular negative health outcomes in testosterone-treated men was comparable with those observed in the control group.

The paper reporting the results of the first three trials published last year was the first to show there were advantages to giving testosterone treatment to older men with low testosterone levels, and the bone and anemia trial results further support a benefit. However, the increase of plaque buildup in the coronary artery shows that this treatment may also have some risk.”

Dr. Peter J. Snyder

Dr. Snyder also suggests future testosterone treatments should balance the health benefits with the risks.

“Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer-term trial designed to assess cardiovascular and prostate risk in the future,” he says.

Learn how testosterone treatment may cause blood clots.