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

Department of Obstetrics and Gynecology (Y.R.S., A.T.), Department of Psychiatry (T.L., C.C.P., J.-K.Z.), Molecular and Behavioral Neuroscience Institute (T.L., J.-K.Z.), Medical School, and Department of Biostatistics (T.E.N.), School of Public Health, University of Michigan, Ann Arbor, Michigan 48109-0276

Address all correspondence and requests for reprints to: Yolanda R. Smith, M.D., M.S., Department of Obstetrics and Gynecology, University of Michigan Health Systems, 1500 East Medical Center Drive, Room L4224, Women’s Hospital, Ann Arbor, Michigan 48109-0276. E-mail: ysmith{at}umich.edu.

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 µg 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.