Norethindrone Acetate Enhances the Antiatherogenic Effect of 17β-Estradiol

Abstract

Abstract —The influence of progestogens in combination with 17β-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/cm 2 (mean±SEM) in the E2NETA1 group, 1.77±0.37 μmol/cm 2 in the E2NETA3 group, 5.46±0.77 μmol/cm 2 in the E2 group, and 7.20±0.94 μmol/cm 2 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.