The functional significance of cerebral estrogen synthesis

Evidence that circulating estrogen modulates cognition and the risk of dementia in elderly women is contradictory. On the one hand, many preclinical studies and a few clinical studies show that increasing the levels of circulating estradiol (E2) by hormone therapy can increase synaptic plasticity and neuronal survival in the hippocampus and prefrontal cortex regions of the brain, and that these changes are paralleled by increased cognitive performance and reduced dementia risk. On the other hand, other studies show no such association. There are two sources of E2 with the potential to affect the brain; one is the ovary and the other is the brain itself, but most studies focus on the potential for ovarian E2 to influence cognitive function. This article proposes that the importance of cerebrally synthesized E2 on cognitive function has been overlooked. Based on the small body of evidence that addresses this issue, it appears that cerebrally synthesized E2 could play a major role in maintaining cognitive performance and reducing dementia risk in women. If this were indeed the case, it might help explain some of the contradictory clinical results and guide the design of new therapies aimed at reducing cognitive decline and dementia risk in elderly women.