A mechanism emerges for the critical period hypothesis for estrogen treatment

Abstract

During the past few decades, a significant body of literature has emerged from the basic science community demonstrating neuroprotective effects and synaptic enhancements induced by estrogen in brain regions that mediate memory and cognition, such as the hippocampus (1). A parallel but less consistent literature emerged from clinical studies suggesting that estrogen treatment (ET) is protective against cognitive decline in surgically and naturally menopausal women (2, 3). However, the Women's Health Initiative (WHI) studies published in 2003 not only failed to support such positive effects, but, in contrast, reported an increased risk of cognitive decline and dementia with hormone therapy (HT) (4, 5). Although the WHI results generated great concern in the clinical research and basic science communities, they also galvanized both groups to address conflicting reports on benefits vs. risks of HT and inconsistencies between the preclinical and clinical findings (6). Recent analyses of the clinical literature (2, 3, 7) have supported a hypothesis that was initially proposed by Gibbs based on animal studies (8); ET or HT has to be administered soon after estrogen depletion as a result of a “window of opportunity” during which estrogen could exert positive effects. Currently, there is strong support in both the basic science and clinical research communities for what is now referred to as the critical period hypothesis, which posits that ET or HT must be administered relatively soon after ovarian estrogen is depleted to be neuroprotective and exert positive effects on brain circuitry and cognitive function (7). Although there are extensive data supporting the critical period hypothesis, the cellular mechanism(s) underlying the decreased response to estrogen with time are poorly understood. The report by Brann and colleagues in PNAS (9) offers compelling evidence for a mechanism underlying the critical period that centers on sustaining sufficient levels of estrogen receptor (ER)-α. In addition, Brann and colleagues link the same mechanism to underlying events that occur with natural aging, which further extends the translational relevance of their findings (9).