MENOPAUSAL HORMONE THERAPY AND ATHEROSCLEROTIC RISK

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Postmenopausal hormone replacement is of great public health significance because there are over 40 million postmenopausal women in the United States today. Increasing numbers of women will be offered hormonal replacement in the future because it is the treatment of choice for the prevention of osteoporosis and because the addition of progestogens to estrogen regimens greatly decreases the risk of endometrial cancer associated with unopposed estrogen. Decisions regarding the proper formulation of hormonal regimens can not be limited to its effects on bone and the uterus. Estrogen replacement is associated with decreased risk of coronary artery disease, possibly due to the effect on HDL-C. Progestogens, however, adversely affect the beneficial effects of estrogen and thus, may have profound effects on postmenopausal morbidity and mortality. We will examine the effects of estrogen alone and estrogen supplemented with three progestogens on known or suspected CAD risk factors. Changes in the levels and compositions of VLDL, LDL and HDL, as well as in the HDL2 and HDL3 subfractions and apolipoproteins A-I, A-II, B and E will be determined. The nature of the mechanisms responsible for changes in VLDL and HDL levels will be examined by determination of post-heparin hepatic and extrahepatic lipoprotein lipase and of changes in the distribution of VLDL apoC and apoE proteins. Determinations of the above parameters will assist in evaluating the results of experiments designed to examine whether hormone-induced changes in lipoproteins cause changes in the functional roles of HDL and VLDL. We will determine whether expected compositional changes in HDL cause changes in the lecithin: cholesterol acyltransferase-independent transfer of cholesterol from HDL to VLDL and LDL. We will further determine whether steroidal hormone administration changes the uptake of VLDL remnants and subsequent inhibition of fatty acid synthesis in isolated rat hepatocytes and if the removal of VLDL remnant apoC proteins by HDL is altered. Changes in the above parameters will be correlated with changes in levels of sex hormone binding globulin as an indicator of gonadal steroid modified estrogenicity. Similarly this proposal will study various parameters of coagulation and the possible beneficial effects of estrogen replacement.