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

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References

Paper Citations

1. Bussiere JR, Beer TM, Neiss MB, Janowsky JS. Androgen deprivation impairs memory in older men. Behav Neurosci. 2005 Dec;119(6):1429-37. PubMed.
2. Yaffe K, Lui LY, Zmuda J, Cauley J. Sex hormones and cognitive function in older men. J Am Geriatr Soc. 2002 Apr;50(4):707-12. PubMed.
3. Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, Latendresse S, Craft S. Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology. 2001 Jul 10;57(1):80-8. PubMed.
4. Vaughan C, Goldstein FC, Tenover JL. Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone. J Androl. 2007 Nov-Dec;28(6):875-82. Epub 2007 Jul 3 PubMed.
5. Cherrier MM, Matsumoto AM, Amory JK, Johnson M, Craft S, Peskind ER, Raskind MA. Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men. Psychoneuroendocrinology. 2007 Jan;32(1):72-9. Epub 2006 Dec 4 PubMed.
6. Institute of Medicine (US) Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy, Liverman CT, Blazer DG. Testosterone and Aging: Clinical Research Directions. Washington (DC): National Academies Press (US); 2004.
7. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS, Testosterone Trials Investigators. Effects of Testosterone Treatment in Older Men. N Engl J Med. 2016 Feb 18;374(7):611-24. PubMed.

Further Reading

Papers

1. Hua JT, Hildreth KL, Pelak VS. Effects of Testosterone Therapy on Cognitive Function in Aging: A Systematic Review. Cogn Behav Neurol. 2016 Sep;29(3):122-38. PubMed.

News

1. Estrogen Therapy Could Hold Back Alzheimer’s, Shrink the Brain? 3 Sep 2015
2. Could “Brain-Only” Estrogen Treat Symptoms of Menopause? 5 Aug 2015
3. Just for Her? Study of Women’s Biology Offers New Therapeutic Angle 19 Dec 2014
4. Early Hormone Therapy Does No Cognitive Harm 28 Jun 2013