Estrogens in the Pathogenesis and Treatment of Alzheimer's Disease in Postmenopausal Women

Abstract

There have been extensive studies documenting the effects of gonadal hormones on behavior in animals (reviewed elsewhere in this symposium and in McEwen et al. ) Sexual behavior in animals is regulated by both "organizational" and "activational" effects of gonadal hormones on the brain. The organizational effects of gonadal hormones are related to those effects on behavior which are the result of gonadal effects on the prenatal development of the brain. These prenatal organizational effects are permanent and provide the neurobiological basis for adult male and female behavior. It is likely that organizational effects of gonadal hormones also occur in human beings. "Activational effects" relate to the effects of gonadal hormones during adult life on responsive neurons, such as alterations in neurotransmitter activity.2 In addition, during the normal adult estrous cycle and after injury, estrogens may affect neuronal pla~ticity.~ In development and in adult life, estrogens, along with other growth factors, may also be important for survival of neurons which are estrogen responsive.* These observations form the neurobiological basis for the hypothesis that gonadal hormones such as estrogen have effects on behavior in human beings. Although sex-related differences in animal behavior are well established, gonadal hormone-dependent gender-related differences in human behavior are obviously more difficult to discern and establish. Numerous studies have indicated that hormones play an important role in gender-related differences in human b e h a~i o r .~ Indeed, human sexual dimorphism has gained considerable interest r e~e n t l y .~,~ If gender-related differences in human behavior do exist, the biological basis for such differences may be primarily mediated by the neurobiological effects of gonadal hormones. In addition, dysregulation or deficiency of gonadal hormones may have effects on adult human brain function. Furthermore, if critical estrogen sensitive neurons are lost, a process of deafferentiation may be initiated with widespread effects. Thus, estrogen deficiency in postmenopausal women may have profound short-term and long-term effects on brain function as it does on other organ systems, particularly bone and vasculature, with clinically significant expression in pathologic states in old age, including osteoporosis and vascular disease.'Recent studies in women who have undergone surgical menopause have 233 234 ANNALS NEW YORK ACADEMY OF SCIENCEScarefully demonstrated the effects of acute estrogen deficiency on both cognitive and affective function in humans, as described elsewhere by Sherwin in this symposium (pp. 213-231) and in ref. 9. These studes demonstrate that surgical menopause is associated with sub-clinical cognitive and affective dysfunctions which are not related to hot flashes or sleep disorders and appear to be a primary effect of the abrupt menopausal loss of estrogen on human cognitive function. Of further interest has been the finding by Sherwin's group that estrogen replacement therapy and ...

Estrogen–cholinergic interactions: Implications for cognitive aging

“…Both prospective and case-control studies have shown that estradiol use in postmenopausal women may decrease the risk of the development and/or expression of AD (Kawas et al, 1997; Paganini-Hill and Henderson, 1994; Panidis et al, 2001; Tang et al, 1996; Zandi et al, 2002) with an overall odds ratio of 0.66 (LeBlanc et al, 2001). Estradiol treatment alone may improve cognitive functioning in some female AD patients (Fillit, 1994; Ohkura et al, 1994) but large controlled trials of estradiol alone as a therapy for mild to moderate AD have been negative, showing no significant effect on cognitive measures of long-term progression (Henderson et al, 2000; Mulnard et al, 2000), although estradiol appears to enhance the effect of anticholinesterase medication in AD (Schneider et al, 1996). It may be that estradiol alone cannot significantly prevent progression of an already established disease, perhaps due to the progressive deterioration in basal forebrain cholinergic systems (Craig et al, 2011) necessary for estrogen to have salutary effects on cognition.…”

Molecular Mechanisms, Physiological Consequences and Pharmacological Implications of Estrogen Receptor Action

“…[102,103] Furthermore, it has been claimed that users. [104,105] ERα and ERβ are expressed in the brain and their individual distribution in the rat brain has been evaluated through References the use of in situ hybridization. [106,107] The expression of ERβ in…”

Estrogen and Non-Feminizing Estrogen for Alzheimer's Disease

“…Many clinical studies have supported the therapeutic effect of estrogen on AD, since Fillit et al [20] first reported an open trial of estradiol-17b (E 2 ) therapy for AD (Table 2) [20][21][22][23][24][25][26][27][28][29][30][31][32]. However, the therapeutic effect was not established.…”