24 Feb 2017

The results are in and they leave little doubt—a year of testosterone therapy does not enhance cognitive function in older men who produce low levels of the hormone. Thus concludes an NIA/NIH–sponsored trial that aimed to test whether testosterone therapy was all it was cracked up to be. In the cognitive arm of this trial, testosterone gave men no edge on any cognitive domain tested, whether or not they started out with mild memory impairments, report scientists led by Peter Snyder, University of Pennsylvania, Philadelphia, in the February 21 JAMA. Though some sub-studies noted mild benefits, others reported potential harm.

“These convincing, unequivocal findings affirm that testosterone treatment does not improve cognitive function in older men,” wrote David Handelsman, University of Sydney and Concord Hospital, Australia, in an accompanying editorial. “The hopes for testosterone-led rejuvenation for older men are dimmed and disappointed, if not yet finally dashed.”

In many men, testosterone levels wane with age. Supplement use to restore hormone levels is on the rise, partly driven by marketing strategies that may exaggerate the benefits, experts say. Is it helpful? Prior epidemiological studies suggested an association between low testosterone levels and cognitive impairment (Bussiere et al., 2005; Yaffe et al., 2002). A few small clinical trials on the cognitive benefits of testosterone supplementation came to conflicting results (Cherrier et al., 2001; Vaughan et al., 2007; Cherrier et al., 2007). In 2004, an Institute of Medicine panel ruled there wasn’t enough evidence to justify the growing use of testosterone supplementation, and called for clinical trials to settle the question (Liverman and Blazer, eds., 2004).

In response, Snyder and colleagues undertook the Testosterone Trials (TTrials), a series of seven coordinated studies that involved 12 academic medical centers. Between 2010 and 2014, researchers recruited 788 men 65 years and older who had testosterone levels below 275 ng/dL. For a year, half applied a gel every day that returned levels to a normal range of 500 to 800 ng/dL. The rest applied a placebo gel. Together, the studies tested whether treatment had any benefit on physical or sexual function, vitality, bone health, anemia, cardiovascular health, or cognition. A prior paper on three TTrial sub-studies reported a temporary increase in sexual function, but no improvements in physical function or vitality, as measured by level of fatigue (Snyder et al., 2016).

First authors Susan Resnick of the National Institute on Aging in Baltimore and Alvin Matsumoto of the University of Washington School of Medicine, Seattle, headed the cognitive sub-study. They tested every participant, but their initial analysis focused on 493 men who had age-associated memory impairment (AAMI). That meant they had subjective cognitive complaints and performed one standard deviation below young adults on measures of objective memory testing. The primary outcome for this sub-study was change from baseline on the delayed paragraph recall. Prior epidemiological studies and small clinical trials suggested testosterone might modify performance on this test, said Resnick. Secondary outcomes tested visual memory, executive function, and spatial coordination, for example the ability to mentally rotate an image. The authors also looked at cognitive changes in the group as a whole.

No matter how they parsed the data, the authors found no difference in scores between the treatment and placebo groups. Both improved on the cognitive tests due to practice effects, and the changes were equal in size. This was true for the subgroup of men with AAMI, and for all 788 men in the trials, and for primary and secondary outcomes. The authors also checked for any difference on global cognition or subjective memory complaints, but found none. A dose-response analysis of achieved plasma testosterone levels versus cognitive performance also found no correlation.

Resnick was confident that if some subtle effect was there, these tests would have been sensitive enough to detect it. The epidemiological signals that pointed to a cognitive benefit of testosterone might have come from a different age-related factor that co-varies with the hormone, she suggested. She speculated that a different testosterone formulation, perhaps an injectable form that spikes levels rather than releasing a steady dose, as does the gel, might have transient effects on memory.

Craig Atwood at the University of Wisconsin-Madison believes hormones could still benefit cognition, but that it would require adjusting multiple hormones. "Giving back one sex steroid may not be sufficient," he told Alzforum. "It's a bit like pumping up one tire on a car with four flats." Cells in the body and brain are regulated by a milieu of hormones, with upwards of 50 becoming dysregulated during menopause or andropause, he said; "Studies should focus on attempting to rebalance all sex hormones.”

Snyder was corresponding author on three other TTrial reports published on February 21. Two JAMA Internal Medicine papers suggest increased hemoglobin levels and reduced anemia in testosterone-treated men, and increased density and strength in spine and hip bones, whereas a JAMA paper reports increased non-calcified plaques in the coronary artery. These plaques are associated with adverse cardiovascular events, although none occurred during the study.—Gwyneth Dickey Zakaib