Testosterone Benefits Older Men With 'Low T' in Trials

Miriam E Tucker

February 17, 2016

A year's worth of testosterone treatment in older men may help improve sexual function, mood, depressive symptoms, and possibly walking distance, but it doesn't seem to improve vitality, suggests three coordinated trials encompassing 790 men aged at least 65 years.

The new findings are from the first three of seven placebo-controlled, multicenter Testosterone Trials: the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The trials stem from a 2004 Institute of Medicine (IOM) call for trials to assess whether testosterone benefits older men who have low testosterone levels for no known reason other than age, along with clinical symptoms to which low testosterone might contribute.

The current three Testosterone Trials were published in the February 18 issue of the New England Journal of Medicine by Peter J Snyder, MD, professor of medicine at the University of Pennsylvania, Philadelphia, and colleagues.

Because the IOM advised that trials be done to "establish a clear benefit before assessing long-term risks," the Testosterone Trials don't address potential risks of testosterone treatment. They include the possibility of heart attack and stroke raised recently by the US Food and Drug Administration and reflected in labeling changes.

Also last year, the FDA moved to clarify that the products are approved to treat only men with low testosterone due to specific medical conditions and not simply aging. The agency issued a call "encouraging companies to work together on a single trial" to assess cardiovascular risk.

Dr Snyder told Medscape Medical News in an interview, "We now have the first part of the answer about benefit. When we have the results of the other four trials, we'll have a pretty good idea about benefit. But even then we won't have an idea about risk. A trial to assess risk would require many, many more men followed for a longer period of time."

The trials represent "a landmark study in the field of men's health," according to an accompanying editorial from Eric S Orwoll, MD, professor of medicine and director of the Bone and Mineral Clinic and the Bone Density Lab at Oregon Health and Science University, Portland. "The findings begin to provide a basis for more rational clinical decisions about testosterone use as well as for additional research."

Orwoll also writes, "The results show that testosterone therapy did yield certain benefits, but at this point their clinical importance is uncertain. Therapy was not a panacea, and the findings alone might be insufficient to support a decision to initiate testosterone therapy in symptomatic older men."

Moreover, he notes, "There is considerable controversy about possible adverse effects of testosterone therapy in older men, and these studies do not resolve this controversy."

Sexual Function, Physical Function, and Vitality

In the three current Testosterone Trials, 790 men 65 years or older with serum testosterone concentration less than 275 ng/dL and symptoms suggesting hypoandrogenism were randomized to receive either testosterone gel or placebo gel for 1 year and were followed for an additional year. Each man participated in one or more of the three trials.

Men recruited for each of the individual trials — focusing on sexual function, physical function, and vitality, respectively — all had shortfalls in those areas. In addition, about two-thirds were obese, 72% had hypertension, and 15% had a history of myocardial infarction. Any with prostate cancer, high cardiovascular risk, and severe depression had been excluded.

Of the original 790 men, 705 completed the 12 months of study treatment. A total of 91% assigned to testosterone maintained a mean concentration above the lower limit of the normal range for men 19 to 40 years of age, the group reported.

Averaged over all follow-up visits, sexual activity as determined by the Psychosexual Daily Questionnaire score increased more with testosterone than with placebo, both among men in the Sexual Function Trial (P < .001) and among all Testosterone Trials participants (P < .001).

Testosterone treatment was also associated with significant increases in measures of sexual desire (P < .001) and erectile function (P < .001). Men in the testosterone group were more likely than those in the placebo group to report that their sexual desire had improved since the beginning of the trial (P < .001).

In the Physical Function Trial, there were no significant differences between the testosterone group and the placebo group in the primary outcome of percentage of men whose 6-minute-walk distance increased by at least 50 m (P < .20) or in other measures, including change from baseline in the 6-minute-walk distance (mean difference, 4.09 m; P < .28) or the percentage of men whose physical function-10 score increased by at least 8 points (P = .15).

However, when men from all the Testosterone Trials were combined, there was a significant between-group difference in four physical function measures, including the percentage whose 6-minute walking distance increased by at least 50 m (P = .003).

Testosterone had no significant benefit on vitality as measured by an increase of at least 4 points on the Functional Assessment of Chronic Illness Therapy–Fatigue scale (P = .30). But men who received testosterone reported slightly better mood and lower severity of depressive symptoms than did those who received placebo.

In the Vitality Trial, there were significant differences between the testosterone group and the placebo group in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality score (P = .03), the Positive and Negative Affect Schedule (PANAS) scales positive affect score (P = .04), the PANAS negative affect score (P < .001), and the Patient Health Questionnaire 9 depression score (P = .004).

No Major-Adverse Event Signals

Although more men assigned to testosterone than those assigned to placebo showed an increase in prostate-specific antigen of 1.0 ng/mL or more during the treatment period (23 vs eight), only one man (in the testosterone group) was diagnosed with prostate cancer during that time. Also, two men in the testosterone group and one in the placebo group received that diagnosis during the subsequent year.

Seven men in each group were adjudicated to have had major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes) during the treatment period. Two from the testosterone group and nine in the placebo group were adjudicated to have had major cardiovascular events during the subsequent year. There was no pattern of a difference in risk with respect to the other cardiovascular adverse events.

Next Steps

Dr Snyder told Medscape Medical News that results from the other four Testosterone Trials — the Cognitive Function Trial, Anemia Trial, Bone Trial, and Cardiovascular Trial (assessing coronary artery plaque volume) could be available within 9 to 12 months but that results from a subsequent safety trial would likely take years.

"We need to wait for the results of the other four trials to know all the possible benefits of testosterone in older men with low testosterone but will need to wait even longer to know about the possible risks," he noted.

Indeed, Dr Orwoll says, like the Women's Health Initiative findings on estrogen-replacement therapy, "the report by Snyder et al is likely to stimulate controversy and to engender additional research questions."

The Testosterone Trials were supported by a grant from the National Institute on Aging, with additional funding from the National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) provided funding and donated Andro-Gel and placebo gel. Dr Snyder reports receiving consulting fees from Watson Laboratories; disclosures for the coauthors are listed in the article. Dr Orwoll reports grant support from Eli Lilly and grant support and personal fees from Merck and Amgen outside the submitted work.

N Engl J Med. 2016;374:611-624, 682-683. Article, Editorial

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