The overall goal of this proposal is to investigate mechanisms by which sex hormones favorably alter lipoprotein metabolism to protect women from coronary heart disease. The mechanisms by which estrogen raises triglyceride and HDL levels, and lowers LDL levels, and the mechanisms by which androgenic progestins have the opposite effects will be studied. The effects of sex hormones on VLDL, LDL and HDL metabolism, in vivo, will be determined by endogenous stable isotope labeling of apolipoproteins A-I and B. These studies measure the rates of production, clearance and interconversion of light and dense VLDL subfractions, IDL, and light and dense LDL subfractions, and apo E-containing particles. Multiple potential control points of apo B metabolism may therefore be identified. HDL metabolism will be studied similarly, and will analyze the relationships between immunochemically defined subfractions that contain apo A-I but not apo A-II, apo A-I with apo A-II, and apo E. Lipoprotein metabolism will be assessed during the following three crossover studies. (1) Oral estradiol. Fifteen healthy postmenopausal women will receive oral 17-beta estradiol 2mg daily or placebo. (2) Progestins. Androgenic progestins, such as levonorgestrel, are used in oral contraceptives and with estrogen in postmenopausal hormonal replacement. To distinguish between its androgenic and progestational effects, levonorgestrel will be compared to oral progesterone and to placebo in fifteen healthy postmenopausal women. (3) Induction of hypoestrogenism. Menopause is associated with deleterious effects on plasma triglyceride, LDL and HDL levels. To determine if these effects are caused by hypoestrogenism, per se, rather than by other processes, such as aging, hypoestrogenism will be induced by administering leuprolide, a long- acting gonadotropin-releasing-hormone agonist, or placebo to fifteen women. Taken together, this series of protocols will define estrogenic, androgenic, and progestational effects on specific mechanisms that control the metabolism of apo A-I and B. The findings will also help to define atherogenic and protective mechanisms in lipoprotein metabolism, and the mechanisms that underlie the difference in coronary heart disease rates between women and men. The study also will provide information to guide clinicians in the use of estrogen and progesterone in postmenopausal women.
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