Modulation of hepatic cholesterol metabolism by ethinyl estradiol and norgestrel

Previous investigators reported that certain combination oral contraceptives are associated with significant alterations in serum lipid concentrations, namely a decrease in high density lipoprotein and increase in low density lipoprotein fractions. The mechanism(s) responsible for these changes remain unclear. In the present study we sought to determine the effect of the oral contraceptive components, ethinyl estradiol (EE) and norgestrel (N) on hepatic cholesterol metabolism, specifically on 3-hydroxy-3-methylglutaryl coenzyme A (HMG) reductase. Forty-eight cycling female Sprague-Dawley rats were divided into six groups and treated daily with either 0.1 mg or 1.0 mg EE daily, 1.0 mg or 10.0 mg N daily, or 0.1/1.0 mg or 1.0/10.0 mg EE/N in combination daily. Twelve age- and weight-matched animals served as controls. No significant changes in hepatic HMG reductase activity were observed between those groups treated with either EE or N alone and the control group. However, hepatic HMG reductase activity was increased significantly in both EE/N combination-treated groups when compared to controls, the EE-treated groups and the N-treated groups. These results are suggestive that the changes in serum lipids noted clinically in association with oral contraceptive use may be related to the induction specifically of hepatic HMG reductase activity and subsequent changes in cellular cholesterol synthesis or metabolism.