This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Coronary heart disease (CHD) is the leading cause of death among women in developed countries and menopause appears to result in an acceleration of CHD risk. The objectives of the proposed study are to further characterize the menopausal changes in lipid metabolism and to investigate the mechanisms underlying these lipid changes. The Midlife Cholesterol Study is a prospective, longitudinal study (n=120) designed to investigate the effects of 1) estrogen deficiency (observational arm) and 2) estrogen replacement therapy (ERT) (interventional arm) on lipid metabolism. Women who remain premenopausal will act as control subjects, allowing us to separate the effects of aging from estrogen deficiency on lipid metabolism. In the interventional arm, women who transitioned from pre- to postmenopause (n=48) were randomized to a cross-over study comparing the effects of short-term oral and transdermal estrogen on lipid metabolism. We will 1) establish the contribution of proteins of lipid metabolism (CETP and PLTP) and androgens to the menopausal emergence of an atherogenic lipid profile, 2) determine whether menopause leads to an atherogenic shift in HDL particle subclass profile and 3) assess the influence of central fat accumulation on menopausal changes in insulin sensitivity. Furthermore, the interventional arm will allow us to confirm the mechanisms underlying the changes in lipid metabolism, by reversing the lipid abnormalities with short-term transdermal and oral ERT. This study is uniquely designed to answer questions about menopausal changes in lipid metabolism, estrogen action and cardiovascular risk in women.
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