Intramuscular testosterone treatment in elderly men: Evidence of memory decline and altered brain function

Context: Recent clinical trials of im testosterone in eugonadal men suggest positive effects on verbal memory, but other studies find no effect. Objective: Our objective was to determine whether supraphysiological testosterone influences verbal memory and brain function during a verbal memory task in healthy eugonadal older men. Patients, Design, and Setting: Fifteen cognitively normal men, aged 66-86 yr, participated in a randomized, double-blind, placebo-controlled crossover trial involving 9 months of participation per participant at a hospital-based research facility. Intervention: We used testosterone enanthate (200 mg im every other week for 90 d) crossed over with placebo (sesame oil vehicle im) with a 90-d washout between treatments. Main Outcome Measures: Performance was assessed on a standardized verbal memory test, and brain activity (relative glucose metabolic rates) in medial temporal and frontal regions was measured with positron emission tomography during a verbal memory task. Results: Treatment increased total testosterone by 241%. Behavioral results showed a significant decrease in short-delay verbal memory with treatment (P < 0.05, effect size = 0.59 SD) and a nonsignificant decrease on a composite verbal memory measure (P = 0.09, effect size = 0.48 SD). Positron emission tomography scans revealed decreased relative activity in ventromedial temporal cortex (i.e. right amygdala/entorhinal cortex) and increased relative activity in bilateral prefrontal cortex with treatment. Conclusions: Decreased verbal memory and altered relative activity in medial temporal and prefrontal regions suggest possible detrimental effects of supraphysiological testosterone supplementation in elderly men. The results do not rule out potential benefits with other regimens, cognitive tests, or populations.