Testosterone rules the physiology of men, not just by regulating sex drive, aggression, muscle mass and bone strength but also by influencing the risks of obesity, prostate cancer and cardiovascular disease. So when the levels of this hormone begin to decline with age, some significant health problems could arise.
Some advocates have touted testosterone supplementation as a fountain of youth, a magic elixir that can cure almost any ailment afflicting men of any age. Yet there is little short-term data to back up such claims and virtually none on longer-term use.
A landmark series of seven ongoing interlocking studies is, however,  providing some answers. The $50-million program, backed by the National Institutes of Health, treated men 65 or older who had significant testosterone deficiency with supplementation in a rigorous trial. This was the group deemed most likely to benefit from such treatment. The researchers discovered, however, that although the participants’ health did improve, the effect was so modest and the entry criteria so restrictive that it was difficult to extend the findings beyond that small slice of the study population to other men.
They enrolled 790 men at an average age of 74 who had a serum testosterone concentration less than 275 nanograms per deciliter (ng/dL). The participants exhibited symptoms associated with low testosterone and were considered to exhibit low risk for prostate cancer, cardiovascular disease and other conditions. Only 15 percent of the 51,085 who volunteered had levels of testosterone low enough to enter the study.
Participants received either a placebo or a testosterone gel to apply, but did not know which their bottle contained. The men were monitored quarterly for a year and the amount of testosterone in their gel was adjusted upward to achieve and maintain a blood level of testosterone that was within the normal range for young men ages 19 to 40, who typically show a total serum testoterone range between 240 ng/dL and 950 ng/dL.
The results from three of the seven trials showed for the first time that raising the blood testosterone levels “improved their sexual function, mood and depressive symptoms, and perhaps walking,” says Peter Snyder, an endocrinologist at the University of Pennsylvania Perelman School of Medicine and lead author of the study recently published in The New England Journal of Medicine. He hopes that results from the other four studies in the matrix—evaluating the impact of supplementation on cognition, bone, coronary artery plaque formation and anemia—will be published within a year.
The safety profile was similar in men who received testosterone or a placebo. Snyder cautions that the findings only apply to the low-risk men enrolled in their study, and only for a single year of supplementation. It could be that men at elevated risk for prostate cancer may respond differently. Additional, longer studies are needed to better determine risks.
“This study makes it difficult to be overly optimistic that testosterone replacement is going to be a panacea,” says Eric Orwoll, an endocrinologist at the Oregon Health & Science University who did not participate in the research but did write an editorial published in theNEJM with the study. “If you interpret this study appropriately, you have to apply the findings only to the men that were studied…. We can’t just apply it to other populations.”
The results do, however, provide a foundation for discussion between doctors and patients on the potential benefits of testosterone replacement. “If there are no contraindications, if the testosterone is low, there are symptoms that might be related to testosterone, [then] there may be no good way to know whether testosterone is going to be beneficial other than to try it,” Orwoll says.
It is reassuring that the study found no strong signal of adverse events over one year, which reinforces what other smaller studies have found. But Orwoll notes that many potential risks such as prostate cancer and cardiovascular issues from using testosterone are slow to develop and would not appear for several years.
The improvement in sexual function “is not a surprise, but a nice finding,” says Edward Schneider, emeritus dean of the Leonard Davis School of Gerontology at the University of Southern California who did not participate in the study. “What would have been outstanding is if it added something to walking or some evidence that it improved functionality.”
Schneider supports supplementing testosterone in younger persons who are deficient and show symptoms of hypogonadism but not as a way to stop the aging process by increasing to higher than normal levels. “If you want to stop aging by adding testosterone, I’m not so sure there is an ounce of data that it will do any good—and potentially it could do some harm,” he says.
There is “no rationale for increasing the testosterone level to higher than normal,” Snyder adds. “In school being average is not considered being very good, but with hormones average is optimal; too high produces disease and too low produces disease. Normal is just right, and that is not just with testosterone, that is with any hormone.”
Schneider believes the studies provide a baseline to focus on those he feels really need the hormone, mostly frail persons, often in their 80s. “Frailty is what kills older people,” he says, “They have totally normal brains and they just can’t move. Theoretically, testosterone should be the perfect drug.” In shorter studies testosterone has shown to improve lean body mass, reduce body fat and reduce the risk of osteoporosis. Schneider would like to see how this plays out over a study lasting at least five years.
“Effects of Testosterone Treatment in Older Men.” Snyder et al; N Engl J Med 2016; 374:611–624.http://www.nejm.org/doi/full/10.1056/NEJMoa1506119
“Establishing a Framework—Does Testosterone Supplementation Help Older Men?” Orwoll E.; N Engl J Med 2016; 374:682–683.http://www.nejm.org/doi/full/10.1056/NEJMe1600196