MENTORED PATIENT ORIENTED RESEARCH CAREER DEVELOPMENT AW

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PROPOSAL (Adapted from the applicant's abstract): Postmenopausal estrogen replacement therapy (ERT) has become an accepted intervention in aging women. The recent publication of the Heart and Estrogen and Progestin Replacement Study (HERS) has made the difficult decision to initiate postmenopausal ERT even more difficult for clinicians. Both small, dense low density lipoprotein (LDL) and plasminogen activator inhibitor Type 1 (PAI-1) are risk factors for coronary artery disease (CAD) that increase with menopause and may represent markers of future individual CAD risk. The primary objective of the proposed study is to investigate whether women who develop small, dense LDL across the menopause will selectively benefit from transdermal ERT. The mechanisms underlying the changes in LDL size will also be studied by measuring hepatic lipase activity, cholesteryl ester transfer protein (CETP) activity, triglyceride (TG) levels, body fat distribution and the hepatic lipase gene promoter polymorphism, all known to affect LDL size. The investigators will also determine whether women who develop small, dense LDL with menopause also have elevated PAI-1. This is a prospective, randomized non-blinded crossover trial comparing oral and transdermal ERT in two groups of postmenopausal women who have been followed since the premenopausal state. Twenty-three postmenopausal women who have developed small, dense LDL with menopause will be compared to 23 postmenopausal women who remain with large, buoyant LDL. They will be randomized to a six-month course of transdermal or oral ERT followed by a six-month washout period before the start of the second ERT course. This study will determine if there is a preferred method of postmenopausal ERT in the subset of women who develop small, dense LDL after menopause. They will also elucidate the mechanisms that underlie the shifts in LDL size with oral and transdermal ERT.