Clinical review 108: The molecular and neuroanatomical basis for estrogen effects in the central nervous system.

Abstract

With increasing life expectancy during the 20th century, women are likely to live a substantial part of their lives in a state of estrogen deficiency. Hot flushes are for many women the most dramatic and noticeable consequence of loss of ovarian hormones. Loss of bone calcium and osteoporosis, developing much more gradually, is another consequence that has led many women to take estrogen replacement therapy (ERT) at the menopause. Likewise, the loss of protection of the coronary arteries, leading postmenopausal women to increased risk for cardiovascular disease, is another result of estrogen deficiency that has reinforced the value of ERT. Yet, it is only quite recently that medical science has recognized that the brain is one of the organs of the body that suffers from the loss of this circulating hormone. This has happened despite studies over more than 30 yr indicating that estrogens target the brain of experimental animals (for summary, see Ref. 1). However, most of the animal studies have focused on estrogen actions on the hypothalamus affecting ovulation and reproductive behavior, and only recently has it become apparent that estrogens exert many actions outside of the reproductive function, including actions on brain areas that are important for learning and memory, emotions and affective state, as well as motor coordination and pain sensitivity. Indeed, some women experience at surgical or natural menopause difficulties in remembering names and other information important for daily life as well as deficits in fine motor coordination and reaction times and feelings of depression and anxiety (2). These effects reflect the actions of estrogens on a large number of brain areas outside of the hypothalamus. The problem in these brain regions has been to recognize the receptors and mechanisms by which estrogens produce their effects. This brief review will focus on two aspects: first, the cellular and molecular mechanisms by which estrogens produce their diverse effects on the brain; and second, the brain regions and cell types in which estrogens produce their effects, emphasizing new knowledge regarding estrogen actions outside of the hypothalamus and pituitary gland. Finally, a brief discussion will summarize the potential clinical applications of this information, particularly in relation to cognitive function and dementia.