Pharmacological doses of estrogens have been reported to increase hepatic catabolism of low-density lipoprotein (LDL) by the LDL receptor (LDL-R) pathway and to increase the concentration of mRNA for the LDL receptor. The induction of LDL-Rs by large doses of estrogen may not be relevant to the role of estrogens under physiological conditions. Furthermore, 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 combination 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 cholesterol/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-treated animals (LDL-C, 242±113 mg/dL; LDL-R mRNA, 0.60+0.31 pg//ig RNA) and control animals (LDL-C, 277±100 mg/dL; LDL-R mRNA, 0.51±0.21 pg/fig RNA). In contrast, the hepatic cholesteryl ester concentration 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 contraceptives decrease hepatic cholesterol concentration independent of LDL-R expression. These data support the hypothesis that the increase in LDL-R mRNA abundance and activity observed with pharmacological doses of estrogen may be secondary to depletion of hepatic cholesterol.