Low-Dose Contraceptive Estrogen-Progestin and Coronary Artery Atherosclerosis of Monkeys

In Brief Objective To determine the separate and combined effects of the estrogen and progestin components of a modern triphasic oral contraceptive (OC) formulation on extent of coronary artery atherosclerosis. Methods Female cynomolgus monkeys (n = 81) were fed atherogenic diets for 32 months. After the first 7 months, they were randomized to four groups and treated triphasically for 21 of each 28 days with ethinyl estradiol (E2) (monkey equivalent of 30–40 μg), levonorgestrel (monkey equivalent of 50–125 μg), a combination of the two steroids, or placebo. Results Treatment with estrogen alone reduced coronary artery atherosclerosis extent 67% compared with untreated controls (P < .05). Treatment with progestin alone had no effect (P > .20). While atherosclerosis extent in monkeys treated with the combined OC was reduced 28%, this did not differ statistically from the other groups (P > .20). Conclusion In doses used for oral contraception, E2, like all other estrogens studied to date, has a marked inhibitory effect on atherosclerosis progression. Levonorgestrel, at doses used in modern OC formulations, antagonizes this effect. When considered with other experimental evidence, these findings support the concept that progestins used in OCs and hormone replacement therapy can antagonize estrogen's atheroinhibitory effects. Whether this occurs seems to depend on a relative balance between estrogen and progestin with respect to dose, potency, route, and pattern of administration. However, when considered with evidence from previous studies, the findings also indicate a modest atheroinhibitory influence of combination (estrogenprogestin) OCs. While levonorgestrel partially antagonizes the inhibitory effects of ethinyl estradiol on atherosclerosis, there appears to be a modest atheroinhibitory influence of combination oral contraceptives.