title: Is there a role for estrogen replacement therapy in the prevention and treatment of dementia?
abstract: Studies in experimental animal models provide a convincing rationale for a role for ERT in the treatment and prevention of dementia. These studies establish the role of estrogen in the regeneration and preservation of neuronal elements within the CNS that are analogous to those regions of the brain most sensitive to the neurodegenerative changes associated with AD. Furthermore, behavioral studies in these animals establish a correlation between the hormone dependent changes in the neuronal architecture and learning and memory. However, extrapolation of these studies to post-menopausal women must be done with caution. Surgical and natural loss of ovarian function does not result in a clinically relevant decline in cognitive function over the short term (1 to 2 decades) or ever in some women. The modest changes that are observed may relate to the hormone's effect on neurotransmitter levels or their receptors. Although Singh et al. noted changes in neurotransmitter concentrations 5 weeks after ovariectomy, changes in cognitive performance in their rat model did not become significant until 28 weeks after ovariectomy--the equivalent of approximately 2 decades of human life. Except for the familial forms of the disease, AD is rarely seen in the first 2 decades after the menopause. However, by the third decade after the menopause, 50% of women can be expected to manifest the histopathological changes of AD. Approximately half of these women are without clinical evidence of disease. Thus, the neurodegenerative process of AD probably precedes by many years the age of onset of the disease. We do not know what factors contribute to the selective neuronal injury which, over time, eventually leads to the neuronal loss and reduced synaptic density that result in the cognitive impairment of AD. At this time we can only speculate as to estrogen's role in modifying this process. Data from experimental animal models suggest that estrogen deficiency would selectively increase the vulnerability of estrogen-responsive neural elements, for example, the cholinergic neurons of the basal forebrain and hippocampus--offulnerability mediated perhaps by the reduced expression of neurotrophic factors, decreased clearance of the amyloid protein, and/or reduced cerebral blood flow that are associated with estrogen deficiency. The brain's ability to adapt to the neuronal loss by stimulating axonal and synaptic regeneration would also be impaired by estrogen deficiency as suggested by estrogen's ability to restore the synaptic density of lesioned brains of ovariectomized animals. Thus, estrogen deficiency, like the apolipoprotein E4 allele, can be considered not a cause of AD but one of perhaps several factors modifying the neuronal injury and loss leading to AD. The limited epidemiologic data and intervention trials currently available are consistent with this interpretation. Because of the urgency and enormity of the problem of dementia in our aging society, there would now appear to be sufficient reason to allocate the resources needed to conduct the appropriate clinical trials to determine estrogen's efficacy in both the treatment and prevention of this devastating condition. These trials are needed so that women and their physicians can adequately weigh the risks and benefits of hormone replacement for the treatment and, more importantly, the prevention of dementia.
authors.affiliation: Division of Geriatrics and Gerontology, Washington University, School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Birge
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D005260:Female; D006801:Humans
chemical_list: D004967:Estrogens; D004958:Estradiol