Estrogen is more than just a "sex hormone": Novel sites for estrogen action in the hippocampus and cerebral cortex - Commentary

For decades estrogen was thought of only as a "sex hormone," as it plays a fundamental role in regulating behavioral and physiological events essentia l for successful procreation. In recent years, estrogen has been shown to e xert effects on the structure and function of the hippocampus and cortex. T he discovery of a new estrogen receptor (ER-beta) and localization of ER-al pha and ER-beta mRNAs in the pyramidal cells of the rat hippocampus and ER- beta mRNA in rat cortex have provided new insight into how estrogen may dir ectly modulate the structure and function of these neurons. Moreover, recen t in vivo I-125-estrogen binding studies have shown that nuclear estrogen b inding sites are widely distributed in the pyramidal cells throughout CA1-3 of the hippocampus and laminae II-VI of the isocortex, demonstrating that ER mRNAs are translated into biologically active protein. The functional im pact of estrogen receptor localization in the cortex and hippocampus may pr ove relevant to the emerging role for estrogen as a protective factor in ne urodegenerative injury. This potential role is further highlighted by the r ecent findings that the expression of ER-alpha and ER-beta changes followin g ischemic brain injury and that these changes correlate with the hormonal modulation of protective factors. These data provide the first evidence tha t the expression of ERs in the adult cortex is not static, but instead, res ponsive to neuronal injury and perhaps additional factors that influence th e cortical environment and status of these neurons. Together, these data in dicate that estrogen has a far greater effect on the hippocampus and isocor tex than previously thought. Furthermore, these new findings challenge our current thinking about steroid hormones and their mechanism(s) of action in regions associated with learning and memory and affected by the neurodegen erative conditions of aging. KEY WORDS: estrogen receptor; ER-alpha; ER-bet a; Alzheimer's disease; cognition; neuroprotection; stroke; ischemia. (C) 2 000 Academic Press.