Impact of Combined Estradiol and Norethindrone Therapy on Visuospatial Working Memory Assessed by Functional Magnetic Resonance Imaging

Abstract

Hormones regulate neuronal function in brain regions critical to cognition; however, the cognitive effects of postmenopausal hormone therapy are controversial. The goal was to evaluate the effect of postmenopausal hormone therapy on neural circuitry involved in spatial working memory. A randomized, double-blind, placebo-controlled crossover study was performed. The study was performed in a tertiary care university medical center. Ten healthy postmenopausal women of average age 56.9 yr were recruited. Volunteers were randomized to the order they received hormone therapy (5 microg 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. The effects of hormone therapy on brain activation patterns were compared with placebo. 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). 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.