Substantial evidence suggests that ovarian hormones might importantly influence the course of normal cognitive aging. Relevant research in women, however, has yielded mixed results. Studies conducted during the current project period used a controlled, prospective design to define the cognitive effects of surgical menopause and unopposed, cyclic estradiol replacement in an established nonhuman primate model of normal aging. The results demonstrate that this clinically approved regimen potently regulates cognitive function, including a near complete reversal of the most well-characterized signature of age-related decline in monkeys. Our revised proposal builds on this background to address several, inter-related aims. Current evidence suggests that aging modulates the cognitive and neurobiological response to estrogen, and studies to be completed early in the coming funding period will be among the first to test this proposal directly in a nonhuman primate model. A second major initiative is to expand our earlier analysis to compare the effects of multiple, clinically relevant replacement strategies on the cognitive outcome of aging: 1) long-term continuous estrogen alone, 2) long-term continuous estrogen plus concurrent micronized progesterone, 3) long-term continuous estrogen plus cyclic progesterone, delivered for 10 consecutive days of each 28 day cycle, and 4) long-term cyclic estrogen plus cyclic progesterone. Ovariectomy and replacement will be implemented following a brief period of pre-operative testing, and monkeys wilt be evaluated subsequently across a neuropsychological battery with established sensitivity to aging and ovarian hormone status. By this approach the project will yield entirely novel data documenting whether progesterone influences the cognitive response to continuous and cyclic estrogen, and whether these effects are dependent on the specific schedule of progesterone administration. Assessment also will include systematic manipulations of interference and distraction, aimed at illuminating the specific information processing functions that mediate the effects of replacement. As with all studies in the project, the behavioral results ultimately will be evaluated in relation to the neurobiological consequences of ovarian hormone manipulation. This integrated approach is expected to realize substantial progress toward the development of safe and effective strategies for optimizing women's neurobiological health after menopause.
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