ORAL-CONTRACEPTIVES DECREASE HEPATIC CHOLESTEROL INDEPENDENT OF THE LDL RECEPTOR IN NONHUMAN-PRIMATES

Pharmacological doses of estrogens have been reported to increase hepa tic catabolism of low-density lipoprotein (LDL) by the LDL receptor (L DL-R) pathway and to increase the concentration of mRNA for the LDL re ceptor. The induction of LDL-Rs by large doses of estrogen may not be relevant to the role of estrogens under physiological conditions. Furt hermore, the mechanisms by which oral contraceptives, a combination of synthetic estrogen and progestin, may modulate LDL metabolism remain largely unexplored. Adult female cynomolgus monkeys were given combina tion ethinyl estradiol/norgestrel preparations (n=16) for 16 weeks and were compared with a control group that did not receive exogenous sex hormones (n=7). All animals consumed a diet containing 0.25 mg choles terol/kcal with 40% of calories from saturated fats. After 16 weeks of treatment there was no significant difference in LDL cholesterol (LDL -C) and hepatic LDL-R mRNA concentration between oral contraceptive-tr eated animals (LDL-C, 242+/-113 mg/dL; LDL-R mRNA, 0.60+/-0.31 pg/mug RNA) and control animals (LDL-C, 277+/-100 mg/dL; LDL-R mRNA, 0.51+/-0 .21 pg/mug RNA). In contrast, the hepatic cholesteryl ester concentrat ion was significantly lower in the oral contraceptive-treated animals (7.28+/-3.59 mg/g liver) compared with the control animals (16.07+/-11 .86 mg/g liver, P=.01) with no significant difference in hepatic free cholesterol concentration between the groups. Thus, oral contraceptive s decrease hepatic cholesterol concentration independent of LDL-R expr ession. These data support the hypothesis that the increase in LDL-R m RNA abundance and activity observed with pharmacological doses of estr ogen may be secondary to depletion of hepatic cholesterol.