Studies in experimental animal models provide a convincing rationale for a role for Estrogen Replacement Therapy (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 Central Nervous System that are analogous to those regions of the brain most sensitive to the neurodegenerative changes associated with Alzhiemer's Disease. Furthermore, behavioral studies in these animals establish a correlation between the hormone dependent changes in the neuronal architecture and learning and memory. However, researcher suggested that extrapolation of these studies must be taken with caution because 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 signigicant until 28 weeks after ovariectomy -- the equivalent of approximately 2 decades of human life. Except for the familial forms of the disease, Alzhiemer's Disease 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 Alzheimer's Disease. Thus, the neurodegenerative process of this disease probably procedes by many years the age of onset. Nevertheless, no one knows what factors contribute to the selective neuronal injury which, over time, eventually leads to the neuronal loss and reduced synpatic density that result in the cognitive impairment of Alzhiemer's. At this time, however, studies have speculated as to estrogen's role in modifying this process.

Data from experiemental animal models suggested that estrogen deficiency would selectively increase the vulnerbility 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 impared by estrogen deficiency as suggested by estrogen's ability to restore the synaptic density of lesioned brains of ovariectomized animals. Thus, estrogen deficiency can be considered not a cause of Alzhiemer's disease but one of perhaps several factors modifying the neuronal injury and loss leading to the disease.

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