Premenopausal women have a lower incidence of coronary heart disease than do males. This sex differential in atherosclerosis and coronary heart disease may, in part, be mediated by the effect of sex steroid hormones on lipoprotein levels in the plasma. The present studies are therefore proposed with the major objective to determine the mechanisms by which female sex steroid hormones regulate plasma lipoprotein metabolism and, in turn, influence atherosclerosis. Ovariectomized, adult baboons will be used to determine the effects of treatment with estrogen, progesterone, or a combination of estrogen and progesterone on the production and catabolism of lipoproteins and apoproteins. Simultaneous turnover studies of very low density (VLDL) and low density (LDL) lipoprotein apoprotein (apo) will be conducted by radiolabeling VLDL and LDL with different isotopes of iodine to determine the effect of hormonal treatment on the synthesis and catabolism of apo-B. To determine the effect of estrogens and progesterone on LDL removal pathways, turnover studies of modified LDL (cyclohexanedione treated LDL labeled with I131) and unmodified LDL (labeled with I125) will be conducted. Similarly, to determine the effect of treatment with female sex hormones on the synthesis and removal of apo-E and apo-A-I, turnover studies will conducted after iodinating isolated apoproteins and incorporating them into lipoproteins (VLDL and HDL). The kinetic data will be analyzed by modeling. The effect of sex steroid hormones will also be studied on postheparin plasma lipoprotein lipase and hepatic triglyceride lipase activities and triglyceride secretion. We will further determine if changes in lipoprotein metabolic parameters are mediated by hepatic estrogen receptors by measuring hepatic estrogen receptors in treated and untreated animals. Finally, the effect of lipoprotein pattern altered by estrogen, progesterone, or a combination, on the development of atherogenesis will be studied. Animals will be maintained on hormonal treatment for 18 months, after which they will be necropsied and arterial lesions will be measured.
