EFFECT OF 17-ALPHA-DIHYDROEQUILIN SULFATE, A CONJUGATED EQUINE ESTROGEN, AND ETHYNYLESTRADIOL ON ATHEROSCLEROSIS IN CHOLESTEROL-FED RABBITS

The effect of 17 alpha-dihydroequilin sulfate (DHES), a water-soluble estrogen of conjugated estrogens (Premarin), and ethynylestradiol (EE) , a commonly used estrogen found in many oral contraceptives, on the d evelopment of atherosclerosis was studied in rabbits fed an atherogeni c diet (0.2% cholesterol) for 24 weeks. Ten animals were given 15 mu g . kg(-1) . d(-1) EE, 10 received 3.8 mg . kg(-1) . d(-1) of DHES, and the remaining 10 sham-ovariectomized and 10 ovariectomized animals se rved as cholesterol-fed controls. These doses were chosen to have simi lar estrogenic potency. Plasma cholesterol concentrations increased to about 900 mg/dL and did not differ among the experimental groups. Aft er 24 weeks, plasma beta-VLDL and HDL cholesterol concentrations were the same for all cholesterol-fed groups, while LDL cholesterol was sig nificantly higher in the two estrogen-treated groups. In spite of this , both EE and DHES significantly reduced atherosclerosis by 35% in the aortic arch and 75% to 80% in the thoracic and abdominal aorta. The r eduction in atherosclerosis was seen in animals with a wide range (400 to 1400 mg/dL) of plasma cholesterol concentrations and was independe nt of lipoprotein profile. beta-VLDL isolated from estrogen-treated an imals was not significantly different from control beta-VLDL in its ab ility to stimulate cholesterol accumulation in THP-1 macrophages in cu lture. This suggests that the protective effect of estrogens on the de velopment of atherosclerosis is not mediated by qualitative difference s in beta-VLDL that affect uptake by macrophages. The results of this study extend our knowledge of the range of estrogens that reduce ather osclerosis. Given the lack of effect on plasma lipid and lipoprotein c oncentrations, these data are consistent with the conclusion that estr ogens exert some of this beneficial effect directly at the level of th e arterial wall by influencing certain key components in the pathogene sis atherosclerosis.