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 cross-over 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 µg ethinyl estradiol and 1 mg norethindrone acetate. Subjects received hormone therapy or placebo for 4 weeks, followed by a one month washout period with no medications, and then received the other treatment for 4 weeks. At the end of each 4 week treatment period a functional magnetic resonance imaging (fMRI) 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.