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As direct targets of pharmaceuticals, estrogen receptors represent an attractive biological system for the discovery of potent, selective and specific drugs to control the evolution of selected disorders. In addition, their endogenous ligands, estrogens, were proved to faithfully fulfill the denomination of endocrine agents: the recent past featured a boost of novel physiological targets outside the hypothalamic-pituitary-ovary axis, the system where the action of sex hormones was believed to be restricted. To date, it appears that almost any tissue and cell in the human body is attracted by the fascinating power of estrogen, particularly the brain. A large body of studies points to a potential beneficial role of estrogens in different brain pathologies, as proved by epidemiological, experimental and animal model data after the natural or surgical ablation of estrogen synthesis. The role of estrogens in depression has been hypothesized for quite a long time based on the observation that decreased plasma levels of these molecules during the menstrual phase, after parturition or at menopause are often associated with mood disorders. Epidemiological studies have also suggested the involvement of hormonal factors in multiple sclerosis (MS): increased levels of sex hormones during pregnancy have been shown to associate with significant reduced severity of MS, whereas clinical symptoms often exacerbate postpartum, when sex hormone levels are remarkably reduced. Similarly, post-menopausal administration of estrogens may delay the onset of Alzheimer’s disease (AD) in elderly women and ameliorate Parkinson’s tremors. More recently, the comparison of the different age profile in the manifestation of psychotic episodes in the two sexes with the levels of circulating estradiol in normal and schizophrenic patients led to hypothesize a role for this hormone also in this CNS disorder. Because of the diverse etiology of these diseases, the comprehension of the mechanism underlying estrogen beneficial action is puzzling. This issue is even more complex if we consider that hormone positively affects other pathophysiologic processes, such as osteoporosis, atherosclerosis and stroke. Is there a common mechanistic denominator in all of these diseases which might underlie the widespread favorable effect of estrogens?

Estrogen and inflammation: hormone generous action spreads to the brain