Estradiol produces diverse effects on physiology and behavior, many of which are critical for maintaining the health and well-being of women. However, estradiol also enhances the growth of abnormal cells and increases risk for breast and uterine cancer. Furthermore, loss of estradiol due to medical complications or aging is also associated with a number of adverse outcomes, including increased risk for cardiovascular disease, osteoporosis and dementia. This diverse profile of effect has been linked to differential effectors at receptor sites in tissues throughout in the body, and medications having selective effects at these receptor sites (SERMs) have been forthcoming. Estradiol has clear but subtle effects on cognitive processes and mood. Few studies have evaluate the impact of SERMs on cognition or wood. The overall aim of this application is to compare the effects of estradiol and two SERMs, tamoxifen and raloxifene, on cognition or mood. The overall aim of this application is to compare the effects of estradiol and two SERMs, tamoxifen and raloxifene, on cognition, mood, and brain function in healthy adult women, and to assess whether the behavioral effects of tamoxifen and raloxifene occur through estrogen receptor mechanisms. In the study (women ages 21-35), the effects of estradiol will be determined by comparing behavior measures during testing intervals occurring early and late during the follicular phase of the menstrual cycle in the presence or absence of tamoxifen and raloxifene. The second study with postmenopausal women will examine behavioral measures before initiation of replacement therapy with those taken after 1,6 and 12 months of treatment in matched groups receiving placebo, estradiol or raloxifene. Across these studies, a profile of behavioral effects of estradiol and SERMs will be established. As the mechanisms through with estradiol and estrogen receptor modulators produce their effects become better understood, it is likely that new estrogen receptor modulators will be developed which will have increasingly selective effects at estrogen receptor sites in tissue. It is also likely that pharmacological developments related to other behaviorally active hormones will be forthcoming. A long-term goal of this project is to train young faculty to work with emerging technologies to enhance development of hormonally based medications with beneficial behavioral profiles.
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