Effects of Contraceptive Estrogen and Progestin on the Atherogenic Potential of Plasma LDLs in Cynomolgus Monkeys

This study was designed to determine the effect of oral contraceptive treatment (estrogen and progestin), alone or in combination, on LDL composition and atherogenic potential in cynomolgus monkeys fed an atherogenic diet. Groups (n = 8 each) of monkeys were untreated (control) or treated with ethinyl estradiol (EE), levonorgestrel (LNG), or triphasic oral contraceptive (EE + LNG) for 1.5 years before plasma LDLs were isolated for characterization. Total plasma cholesterol concentrations were unaffected by the treatments. LDL particle size (measured as LDL molecular weight, g/micro mol) was significantly smaller in the EE (4.61 +/- 0.09) and EE + LNG (4.43 +/- 0.09) treatment groups compared with the control (4.99 +/- 0.09) or LNG (5.29 +/- 0.17) groups and contained fewer molecules of free and esterified cholesterol. Both the EE and EE + LNG groups had significantly less cholesterol and apolipoprotein B distributed in the d = 1.015 to 1.025 g/mL subfraction and correspondingly more in the d = 1.025 to 1.035 g/mL subfraction of LDL compared with the control and LNG groups. The apolipoprotein E content (molecules/particle) of LDL was significantly less in the EE (0.35 +/- 0.1) and EE + LNG (0.28 +/- 0.1) groups compared with the control (0.86 +/- 0.2) and LNG (0.99 +/- 0.2) groups, and this trend was apparent in all three LDL subfractions. The atherogenic potential of LDL was tested using an in vitro binding assay to arterial proteoglycans. Twice as much LDL bound to arterial proteoglycans in the LNG group (11.3 +/- 1.8% of total LDL cholesterol in the incubation) compared with the control (6.4 +/- 1.9%), EE (5.5 +/- 1.5%), or EE + LNG (5.2 +/- 1.2%) groups. We conclude that EE and EE + LNG treatment alters the composition of LDL toward a less atherogenic particle that is smaller and more dense, contains less cholesterol and less apolipoprotein E, and is less reactive with arterial proteoglycans compared with LNG treatment. The inclusion of EE in the triphasic oral contraceptive treatment was sufficient to negate the potentially atherogenic effects of LNG on LDL composition. (Arterioscler Thromb Vasc Biol. 1997;17:1216-1223.)