Cloudy Picture – Testosterone-therapy Trials in Older Men Bring Mixed Results

In older men with low testosterone, one year of testosterone treatment improved bone density and corrected anemia of both known and unknown causes, but also increased the volume of coronary artery plaque, according to results reported from the Testosterone Trials (T Trials). Testosterone treatment had no effect on memory or other cognitive function. The results of the trials were reported in two American Medical Assoc. journals last month.

The T Trials were conducted at 12 sites across the country in 790 men age 65 and older with low levels of testosterone and symptoms to which low testosterone might contribute. The studies were funded primarily by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). Other funding came from the National Heart, Lung, and Blood Institute, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all part of NIH. Additional funding, and the study drug and placebo, were provided by AbbVie Pharmaceuticals.

“A number of older men have testosterone levels below those found in healthy younger men,” said NIA Director Dr. Richard Hodes. “In most cases, these low levels are not due to diseases known to affect testosterone levels. Many of these men also have problems that could be related to low testosterone, including impaired cognition, anemia, cardiovascular disease, diminished sexual function, decreased mobility, and fatigue. The T Trials were designed to determine if testosterone treatment might help alleviate these symptoms and conditions while monitoring for adverse effects.”

The findings were reported by principal investigator Dr. Peter Snyder, professor of Medicine in the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, and colleagues at the 12 study sites.

Participants were randomly assigned to receive testosterone gel or a placebo gel applied to the skin daily. Serum testosterone concentration was measured at one, two, three, six, nine, and 12 months. The men were also closely monitored for prostate and cardiovascular problems. In addition to low testosterone, the presence of complaints such as low sexual function, difficulty in walking, or low vitality was required for eligibility to participate in the trials. The results of these outcomes were reported in 2016.

The study also measured testosterone treatment’s effects on additional outcomes in the study population. Effects on anemia and bone density appeared in JAMA Internal Medicine, while the results of the cardiovascular and cognitive function trials appeared in the Journal of the American Medical Association. The results of each are as follows:

Anemia Trial

Of all the men enrolled in the T Trial, 64 had anemia from known causes, and 62 had unexplained anemia. After one year of treatment, 54{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5} of the men with unexplained anemia and 52{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5} of those with anemia from known causes had clinically significant increases in hemoglobin (red blood cell) levels, compared with 15{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5} and 12{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5}, respectively, of those in the placebo group.

These changes may be of clinical significance, as suggested by the magnitude of the changes, the correction of anemia in the majority of men, and the association of the increases with improvements in global impression of change in overall health and energy. Measurement of testosterone might be considered in men age 65 and older who have unexplained anemia and symptoms suggestive of low testosterone levels.

Bone Trial

The goal of this trial was to determine whether testosterone treatment would increase volumetric bone mineral density (vBMD) — the amount of mineral in bone — and estimated bone strength in older men with low testosterone. vBMD, a marker of increased risk for fractures, was measured in hip and spine at baseline and 12 months later. After one year of treatment, older men with low T significantly increased vBMD and estimated bone strength compared to controls, moreso in the spine than in the hip. A larger and longer trial would be needed to determine if testosterone treatment reduces fracture risk.

Cardiovascular Trial

The study assessed the effects of testosterone treatment on the progression of non-calcified coronary artery plaque — a buildup within the walls of the blood vessels in the heart — which is a risk factor for cardiovascular disease. The study found that non-calcified plaque volume increased significantly more in the testosterone-treated group compared to controls, as measured by coronary computerized tomographic arteriography, a special type of heart scan.

The researchers note that, because just 170 men had the scans, the clinical importance is uncertain and may depend on how testosterone affects different components of plaque. A larger and longer trial is needed to establish the clinical significance of these findings.

Cognition Trial

This trial sought to determine if testosterone treatment improved cognition in older men with age-associated memory impairment (AAMI), a mild form of impairment, distinct from dementia. Of the initial participants in the T Trials, 493 met the criteria for AAMI. After one year of treatment, there were no significant differences between the testosterone treatment and the placebo groups.

“The results on diverse outcomes indicate the potential tradeoffs between benefits and risks of testosterone treatment in older men,” said Dr. Evan Hadley, director of NIA’s Division of Geriatrics and Clinical Gerontology. “However, clarifying the effects of testosterone on many major clinical outcomes such as cardiovascular events, fractures, and disability will require longer, larger-scale trials. The results also illustrate that decisions about testosterone treatment need to be individualized, taking into account each patient’s balance of risks for the various conditions that testosterone treatment could affect”