Genome and hormones: Gender differences in physiology - Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms

Besides their well-established actions on reproductive functions, estrogens exert a variety of actions on many regions of the nervous system that infl uence higher cognitive function, pain mechanisms, fine motor skills, mood, and susceptibility to seizures; they also appear to have neuroprotective ac tions in relation to stroke damage and Alzheimer's disease. Estrogen action s are now recognized to occur via two different intracellular estrogen rece ptors, ER-alpha and ER-beta, that reside in the cell nuclei of some nerve c ells, as well as by some less well-characterized mechanisms. In the hippoca mpus, such nerve cells are sparse in number and yet appear to exert a power ful influence on synapse formation by neurons that do not have high levels of nuclear estrogen receptors. However, we also find nonnuclear estrogen re ceptors outside of the cell nuclei in dendrites, presynaptic terminals, and glial cells, where estrogen receptors may couple to second messenger syste ms to regulate a variety of cellular events and signal to the nuclear via t ranscriptional regulators such as CREB. Sex differences exist in many of th e actions of estrogens in the brain, and the process of sexual differentiat ion appears to affect many brain regions outside of the traditional brain a reas involved in reproductive functions. Finally, the aging brain is respon sive to actions of estrogens, which have neuroprotective effects both in vi vo and in vitro. However, in an animal model, the actions of estrogens on t he hippocampus appear to be somewhat attenuated with age. In the future, es trogen actions over puberty and in pregnancy and lactation should be furthe r explored and should be studied in both the hypothalamus and the extrahypo thalamic regions.