This application is a supplement to a recently funded clinical trial, Biologic Response of Menopausal Women to 17B-Estradiol (R01-AG024154) that assesses effects of 17B-estradiol on subclinical carotid atherosclerosis progression in two groups of women without evidence of cardiovascular disease: younger women within 6 years of menopause and older women 10+ years after menopause. This supplement focuses on cognitive effects of estradiol in these two groups. The parent study is a randomized, double-blind, placebo-controlled trial to test the hypothesis that estradiol effects on atherosclerosis progression vary by time since menopause. After results of the Women's Health Initiative became widely known, hormone therapy use declined substantially, but almost 10 million Americans still use hormones, primarily younger women for menopausal symptoms. The Women's Health Initiative Memory Study (WHIMS) assessed cognitive outcomes for hormone therapy initiation after age 64, but no long-term clinical trial data address cognitive outcomes in younger hormone users. Given discrepant results between many observational studies (hormone exposure primarily in early postmenopause, suggestion of benefit, prone to bias) and WHIMS (hormone exposure in late postmenopause, harm or no benefit, methodologically more rigorous), it is important to determine cognitive outcomes for younger women. The design, duration and size of the parent trial make it an ideal platform for this purpose. Since the central portion of the trial is funded, a robust database will be obtained at considerable savings. The present objective is to investigate estradiol effects on cognition in 504 postmenopausal women in a two year randomized controlled trial. To address the main study hypothesis, the primary analysis will consist of a comparison of treatment effects between the two strata of time since menopause. Longitudinal changes in cognitive function (particularly episodic verbal memory) will be assessed in a 2 x 2 factorial design, with randomization on treatment assignment as the first factor and time since menopause as the second. We will also assess associations between memory and other cognitive changes and carotid atherosclerosis progression, reproductive factors (e.g., menopausal symptoms, prior exposure to hormone therapy, hysterectomy status), and other variables that might confound or modify associations between treatment assignment and cognitive outcomes. ? ? ? ? ? ?
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