COGNITIVE AGING: EFFECTS OF ESTRADIOL AND RALOXIFENE

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Estrogens have a multiplicity of effects on a variety of systems and deficiency of these hormones at menopause can increase the risk of developing age-related problems such as osteoporosis, cardiovascular diseases, memory impairments and dementia. Estrogen Replacement Therapy (ERT) is often prescribed to menopausal women to protect against such adverse consequences of estrogen deficiency. ERT, however is associated with a grater risk of developing breast and urine cancers. Non-steroidal estrogens have been developed to mimic the beneficial effects of estrogens on specific systems, yet minimize their proliferative effects on breast and endometrial tissues. These compounds called selective Estrogen Receptor Modulators(SERMs), have a well-documented efficacy in peripheral target tissues, but their effects on cognitive function are not known. Clearly, the effects of SERMs on cognition must be characterized before these agents can be considered as a useful alternative to ERT. We will use a rhesus monkey model of human menopause to examine the effects of estradiol and the SERM raloxifene on female cognition. A preliminary study in aged ovariectomized (OVX) female rhesus monkeys suggested that long-term deprivation of estrogens may exaggerate visual recognition memory deficits, but protect against the development with aging of spatial memory deficits. This project will determine in the same OVX monkeys whether ethinyl estradiol (EE2) is able to reverse this pattern of cognitive performance and whether the SERM raloxifene has similar effects. Monkeys will be repeatedly tested on a battery of three memory tasks, during periods with and without hormonal treatment. Specific Aim 1 will determine whether EE2 enhances visual recognition memory and working memory, while impairing spatial memory in aged OVX female rhesus monkeys; Specific Aim 2 will determine whether the SERM raloxifene acts as an EE2 agonist on memory functions. These data in the rhesus monkey will provide valuable information on the efficacy of EE2 and raloxifene on female cognition and will help evaluating the risks and benefits of using these compounds in hypoestrogenic women, especially after menopause.