Received June 20, 2005; Accepted July 13, 2005. Author to whom all correspondence and reprint requests should be addressed: Dr. Jan-Åke Gustafsson, Department of Medical Nutrition and Biosci- ences, Karolinska Institutet, SE-141 57 Huddinge, Sweden. E-mail: jan-ake. gustafsson@mednut.ki.se Estrogen Action in Mood and Neurodegenerative Disorders Estrogenic Compounds with Selective Properties—The Next Generation of Therapeutics Marie K. Österlund, 1 Michael-Robin Witt, 1 and Jan-Åke Gustafsson 2 1 Karo Bio AB, Novum, S-141 57 Huddinge, Sweden; and 2 Department of Medical Nutrition and Biosciences, Karolinska Institutet, SE-141 57, Huddinge, Sweden Endocrine, vol. 28, no. 3, 235–241, December 2005 0969–711X/05/28:235–241/$30.00 © 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 235 In this review, estrogenic effects in depression, anxiety, and neurodegenerative disorders are summarized. Moreover, preclinical findings from in vitro and animal models are discussed. There is a correlation between decreased estrogen levels (e.g., premenstrually, during the postpartum period, and perimenopausally) and increased anxiety and depressive symptoms. Several studies show beneficial effects of estrogen treatment in women with anxiety and depressive symptoms. Recent data indicate that the estrogen receptor (ER)  appears to be a major mediator of estrogenic effects in depres- sion and anxiety. Additionally, both preclinical and clin- ical findings suggest that activation of estrogen recep- tors have an important role in neuroprotective and neurodegenerative processes in the mammalian cen- tral nervous system (CNS). Key Words: Estrogen receptor; depression; anxiety; Alz- heimer’s disease; neuroprotection; affective disorders; 17-estradiol. Introduction In 1996, Kuiper et al. described the discovery of a second estrogen receptor ER (1). Since then, it has become appar- ent that ER has many important physiological roles; for instance, it is antiproliferative in the ventral prostate of rodents (2), it is important in follicular development in the ovary (3), and it is important for normal development of the CNS (4–6). This review addresses some of the properties of ER in the CNS and how ER might be targeted phar- maceutically in attempts to treat diseases of the CNS. The Role of Estrogen in Affective and Anxiety Disorders Clinical Observations For more than a century, gonadal hormones have been reported to affect mood and neuropsychiatric disorders. How- ever, how and when these hormones act appears to be com- plex and is not fully understood. In psychotic disorders, such as schizophrenia, estrogens overall appear to have a protective role. For example, with respect to this particular disease, women have been shown to have a higher age of onset, a milder symptomatology, and a better outcome than men (7–9). In the case of anxiety and affective disorders, the role of estrogens is more ambiguous. Major depression is nearly twice as common in women as in men, with a life- time prevalence of 21% in women as compared to 12.7% in men and the lifetime prevalence for any anxiety disorder is reported to be 30.5% in women versus 19.2% in men (10, 11). Evidence is accumulating that hormonal fluctuations and drastic drops in estrogen levels increase the risk for ex- periencing anxiety and depressive symptoms and that some women appear to be more vulnerable to these changes than others. Premenstrual dysphoric disorders are clearly linked to the radical fall in estrogen levels in the late-luteal pre- menstrual phase of the menstrual cycle and women with pre- menstrual dysphoric disorders show high comorbidity with other mood disorders (12). Another time-period when there is a strong connection between hormonal fluctuations, including a drastic estro- gen drop, and mood symptoms is in the postpartum period (13). Milder mood lability is very common within a few days after delivery, the postpartum “blues” (14). Postpartum depression, a subtype of major depression, is more severe than the “blues” and affects approx 10% of child-bearing women with an onset within a month after delivery; within a year, up to 20% are affected (13,15,16). Moreover, preg- nancy and postpartum influences on anxiety have also been described (17). Several items point toward the fact that there is a subgroup in the female population that is more vulner- able to normal hormonal fluctuations than others. As in pre- menstrual dysphoric disorders, mood disorders are more common in women who experience postpartum depressive symptoms, and these symptoms are more common in women with a history of mood disorder (18,19). Furthermore, women who have experienced postpartum depression have an increased risk of relapse during the postpartum period of future pregnancies (20,21). Another female life event that includes declining estro- gen levels is in the transition to menopause, which occurs