Norethindrone Acetate Enhances the Antiatherogenic Effect of 17ß-Estradiol

A Secondary Prevention Study of Aortic Atherosclerosis in Ovariectomized Cholesterol-Fed Rabbits

From the Center for Clinical & Basic Research, Ballerup (P.A., J.H., I.S., H.L., C.C.); and Novo Nordisk A/S, Clinical Department, Gynecological Pharmaceuticals, Bagsvaerd (M.S.), Denmark.

Correspondence to Peter Alexandersen, MD, Center for Clinical & Basic Research, Ballerup Byvej 222, DK-2750 Ballerup, Denmark.

Abstract—The influence of progestogens in combination with 17ß-estradiol (E2) on cardiovascular disease remains controversial. This study investigated the effect of norethindrone acetate (NETA) combined with E2 on aortic atherosclerosis. Eighty mature female rabbits were ovariectomized, then fed a cholesterol-rich diet (240 mg/d) for 14 weeks to induce aortic atherosclerosis. They were randomized to four equally large groups for the following 38-week intervention period. One group received placebo, another group oral E2 4 mg daily (E2), and the last two groups oral E2 4 mg daily combined with either NETA 1 mg (E2NETA1) or NETA 3 mg (E2NETA3). The cholesterol intake was reduced to a "maintenance" level of 80 mg/d during the intervention period. Total serum cholesterol and ultracentrifuged lipoproteins were analyzed enzymatically throughout the study. The cholesterol content in the aortic wall was 2.76±0.44 µmol/cm² (mean±SEM) in the E2NETA1 group, 1.77±0.37 µmol/cm² in the E2NETA3 group, 5.46±0.77 µmol/cm² in the E2 group, and 7.20±0.94 µmol/cm² in the placebo group (ANOVA P<0.0001). The difference (in the aortic cholesterol accumulation) between the E2 and each of the combined E2/NETA groups was statistically significant (P<0.01) but could only partly be explained by the differences in serum lipids and lipoproteins. In conclusion, NETA enhances the antiatherogenic effect of E2 in cholesterol-fed rabbits. This effect is only partially mediated through changes in serum lipids and lipoproteins.

Key Words: atherosclerosis • prevention • rabbits • estradiol • NETA

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