Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment

Abstract

Importance: Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions.

Objective: To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI).

Design, setting, and participants: The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014.

Interventions: Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year.

Main outcomes and measures: The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months.

Results: Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89).

Conclusions and relevance: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions.

Trial registration: clinicaltrials.gov Identifier: NCT00799617.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Resnick reports receiving grants from the National Institute on Aging (NIA), National Institutes of Health (NIH), and AbbVie (formerly Solvay & Abbott Lab) and being an intramural employee of NIA/NIH. Dr Matsumoto reports receiving personal fees from AbbVie, Endo, Lilly, Lipocine, and Clarus Therapeutics. Dr Stephens-Shields reports receiving grants from NIA, NIH, and AbbVie. Dr Ellenberg reports receiving grants from NIH and AbbVie. Dr Gill reports receiving grants from NIH. Dr Bhasin reports receiving grants from NIA, AbbVie, Lilly, and Transition Therapeutics; personal fees from AbbVie, Lilly, and Regeneron; a patent pending for a free testosterone calculator; and holding equity interest in FPC, LLC. Dr Cunningham reports receiving personal fees from AbbVie, Apricus Biosciences, Besins Healthcare, Clarus Therapeutics, Endo, Ferring Pharmaceuticals, Lilly, Pfizer, Repros Therapeutics. Dr Ensrud reports receiving grants from NIA. Dr Farrar reports receiving grants from NIA, NIH, and AbbVie. Dr Lewis reports receiving grants from NIH and AbbVie. Dr Molitch reports receiving grants from NIH and Abbott Laboratories and personal fees from AbbVie, Lilly, and Pfizer. Dr Swerdloff reports receiving grant funding from the Bone Trial of the Testosterone Trial, Clarus Therapeutics, Lipocine, and Antares Pharma and personal fees from Clarus Therapeutics and Antares Pharma. Dr Basaria reports receiving personal fees from Lilly and Takeda. Dr Diem reports receiving grants from NIA. Dr Wang reports receiving grants from Besins Health International, Clarus Therapeutics, and Lipocine and personal fees from Antares, TesoRx, and Besins Health International. Dr Snyder reports receiving grants from NIA, NIH, and AbbVie and personal fees from Watson Laboratories. No other disclosures were reported.

Figures

Figure 1. Screening and Retention of Participants Throughout the Cognitive Function Trial

AAMI indicates age-associated memory impairment. “Allocated to treatment incorrectly” indicates that the individuals were found to be ineligible after they received treatment allocation. a The number analyzed is based on the primary outcome variable for the Cognitive Function Trial (delayed paragraph recall score).

Figure 2. Adjusted Mean Change From Baseline to 6 Months and 12 Months for Men With AAMI by Treatment Group (Testosterone vs Placebo) for Verbal Memory (Delayed Paragraph Recall), Visual Memory, Executive Function, and Spatial Ability

AAMI indicates age-associated memory impairment. Error bars indicate 95% CIs. The score range for the delayed paragraph recall test (Wechsler Memory Scale-Revised Logical Memory II) was 0 to 50. Benton Visual Retention Test scores could range from 0 to 26 but were inverted to −26 to 0 so that higher scores indicated better performance. Possible scores for the Trail-Making Test B minus A range from −290 to 290. The range of possible scores for the Card Rotation Test was −80 to 80. Some participants completed the Delayed Paragraph Recall Test at baseline but not the secondary assessments.