Cognition Is Not Modified by Large but Temporary Changes in Sex Hormones in Men

Context: Little is known about the role of testosterone and estradiol on cognition in healthy older men. Objective: The cognitive effects of increasing or lowering testosterone or estradiol were examined. Design: Cognition was assessed before and after 6 wk of double-blind placebo-controlled hormone modification. Setting: The study was conducted at an academic medical center. Participants: Healthy older (ages 60-80 yr) and younger men (ages 25-35 yr) were recruited from the community. Intervention: Men were randomized to one of four treatments: 1) maintain testosterone and estradiol at eugonadal levels for young men (GnRH agonist + testosterone gel); 2) block testosterone's conversion to estradiol(GnRH agonist + testosterone gel + aromatase inhibitor); 3) induce hypogonadism (GnRH agonist alone); and 4) all placebo. Main Outcome Measures: Measures of executive function, memory, and spatial cognition were obtained before and after treatment. Hormone levels were obtained 10 times over the course of the study. Results: Counter to expectations, hormone treatment did not affect cognition (P > 0.10). Free testosterone was positively related to spatial cognition in older men after treatment and controlling for age and estradiol level or exclusion of the hypogonadal men (P = 0.02). Estradiol was negatively associated with working memory controlling for the same variables (P = 0.01). Blinding to treatment assignment was maintained, with the exception of the hypogonadal group. Conclusions: A significant change in sex hormone status, including complete hypogonadism, does not modify cognition in men. These findings, along with studies that show a risk for neurodegenerative disease in those with low testosterone, suggest that sex hormone status may be important for neuroprotection in aging but not modulation of normal day-to-day cognitive function. (J Clin Endocrinol Metab 95: 280-288, 2010)