Prefrontal cortex as the site of estrogen's effect on cognition

The hippocampus has long been presumed the primary site of action of estrogens on cognition; and explicit memory is considered the cognitive function most vulnerable to menopausal loss of estrogen. We hypothesize instead that the prefrontal cortex and its neural circuitry are prime mediators of estrogen's role in cognition. We also propose that previously reported menopausal cognitive decline, presumed to be hippocampally mediated, may be secondary to executive dysfunction. We used a cross sectional design to compare the performance of nine menopausal women on hormone replacement therapy (HRT) and 10 menopausal women with no prior exposure to HRT on a battery of neuropsychological tests. The battery was comprised primarily of tests of memory and executive functioning. Executive functioning is mediated by the frontal lobes and encompasses working memory, directed attention, the inhibition of inappropriate responses, cognitive set switching, and behavioral monitoring. Unlike most previous studies, we used a memory measure that yields multiple scores reflecting various problem-solving strategies and error types, thus isolating spared and impaired cognitive processes. Results yielded both qualitative and quantitative evidence for disruption of cognitive processes subserved by the frontal lobes rather than the hippocampus: 1) despite intact free recall on a list-learning task (CVLT), untreated menopausal women were relatively impaired in correctly recognizing words previously learned and distinguishing them from items not on the list (discriminability), 2) untreated women also had difficulty inhibiting inappropriate responses in the form of perseverative errors, and 3) the non-HRT group consistently performed worse on the N-back test of working memory. The prefrontal cortex is critical for intact working memory and estrogen enhances performance on working memory tasks. In conclusion, this study provides preliminary evidence for executive dysfunction in untreated menopausal women as women with HRT outperformed women without HRT on tests requiring directed attention, inhibition of inappropriate responses, and cognitive set switching.