Objective: Any role for sex steroids in modulating cognition in men remains uncertain. We used an experimental paradigm that allowed effects of estradiol (E2) on cognition in older men to be investigated, in the absence of testosterone.
Design: Randomised, placebo-controlled trial of E2 for 6 months, hypothesising that men randomised to E2 would have improved verbal learning, verbal memory and spatial problem solving over time, compared to placebo.
Methods: Participants receiving androgen deprivation therapy for prostate cancer were randomised to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Cognition was assessed by a tablet-based cognitive battery at baseline, month 1, month 3, and month 6. Cognitive tests were: International Shopping List (ISL) (verbal learning and memory); Groton Maze Learning (GML) (spatial problem solving); Detection (processing speed, visual attention, psychomotor function); Identification (attention, psychomotor function, information processing speed); One Card Learning (visual memory); and One Back Task (memory and attention). Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale inventory.
Results: 78 participants were randomised. Serum E2 increased in the E2 group over 6 months compared to the placebo group, mean adjusted difference (MAD) 56.5 pg/mL (95% CI 33.6 – 79.4), p<0.001. There was no significant difference in performance over time between the E2 group and the placebo group for the ISL test, MAD 0.7 (95% CI -1.2 – 2.5), p=0.36, or for the GML test, MAD -3.2 (95% CI -12.0 – 5.6), p=0.53. There was no significant difference between groups in performance on any of the other cognitive tests or in depression or anxiety scores.
Conclusion: We found no major effects of E2 on cognition. Although cognitive effects of ADT are debated, this study suggests that any such effects, are unlikely to be prevented by administration of E2.