Estradiol: a hormone with diverse and contradictory neuroprotective actions

Abstract

The concept that estrogens exert important neuroprotective actions has gained considerable attention during the past decade. Numerous studies have provided a deep understanding of the seemingly contradictory actions of estrogens. We realize more than ever that the effects of estrogens (with and without simultaneous or sequential progestins) are diverse and sometimes opposite, depending on the use of different estrogenic and progestinic compounds, on different delivery routes, on different concentrations, on treatment sequence, and on the age and health status of the women who receive hormone therapy. During the past few years, we have gained an increasing appreciation of the impact of estrogens on the immune system and on inflammation. In addition, we have learned that estrogens cannot only protect against cell death, but can also stimulate the birth of new neurons. Here we posit the concept that estrogen's modulation of the immune status may be the basic mechanism that underlies its ability to protect against neurodegeneration and its powerful neuroregenerative actions. We hope that this update will encourage even richer dialogues between basic and clinical scientists to ensure that future clinical studies fully consider the information that can be derived from basic science studies. Only then will we have a better understanding of the impact of hormones on the menopausal and postmenopausal period in a woman's life.

Figure 1.. Overview of the brain cell types and neuromodulators influenced by estrogens. The ability of estrogens to exert trophic and protective actions depends upon their ability to alter the birth and death of neurons, synaptogenesis, and neuritogenesis. Estradiol influences neurons, astrocytes, and microglia through altering the expression of a broad profile of neurotransmitters and neuropeptides and their receptors, pro- and anti-inflammatory agents, and factors which influence, birth, survival, growth, and maturation of neurons.

Figure 2.. Estradiol influences the number of newborn neurons. Panel A shows confocal micrographs of newborn neurons dual-labeled with bromodeoxyuridine and doublecortin in vehicle and estradiol-treated mice following stroke injury. Panel B shows the mean of groups of 4 to 6 animals in each experimental group and shows that the differences are statistically significant.

Figure 3.. Estradiol protects the brain only if treatment is initiated immediately after hypoestrogenicity is induced. Estradiol decreases the size of the infarct, induces estrogen receptor (ER) and suppresses inflammation only if it is administered immediately after ovariectomy. We have used ovariectomy to mimic the menopause. These findings strongly suggest that, if estrogen therapy (ET) is initiated after several years of postmenopause, as was the case in the Womens' Health Initiative, that ET will not be effective in protecting the brain against neurodegeneration.