Impact of combined estradiol and norethindrone therapy on visuospatial working memory assessed by functional magnetic resonance imaging

Context: Hormones regulate neuronal function in brain regions critical to cognition; however, the cognitive effects of postmenopausal hormone therapy are controversial. Objective: The goal was to evaluate the effect of postmenopausal hormone therapy on neural circuitry involved in spatial working memory. Design: A randomized, double-blind, placebo-controlled crossover study was performed. Setting: The study was performed in a tertiary care university medical center. Participants: Ten healthy postmenopausal women of average age 56.9 yr were recruited. Interventions: Volunteers were randomized to the order they received hormone therapy (5 mu g ethinyl estradiol and 1 mg norethindrone acetate). Subjects received hormone therapy or placebo for 4 wk, followed by a 1-month washout period with no medications, and then received the other treatment for 4 wk. At the end of each 4-wk treatment period, a functional magnetic resonance imaging study was performed using a nonverbal (spatial) working memory task, the Visual Delayed Matching to Sample task. Main Outcome Measure: The effects of hormone therapy on brain activation patterns were compared with placebo. Results: Compared with the placebo condition, hormone therapy was associated with a more pronounced activation in the prefrontal cortex ( BA 44 and 45), bilaterally (P < 0.001). Conclusions: Hormone therapy was associated with more effective activation of a brain region critical in primary visual working memory tasks. The data suggest a functional plasticity of memory systems in older women that can be altered by hormones.