MECHANISMS OF GALLSTONE FORMATION IN WOMEN - EFFECTS OF EXOGENOUS ESTROGEN (PREMARIN) AND DIETARY-CHOLESTEROL ON HEPATIC LIPID-METABOLISM

Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gall-stones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mu-mol/d) and high (2,021 +/- mu-mol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P < 0.05), increased biliary cholesterol secretion (P < 0.005), lowered chenodeoxycholate (CDCA) pool (P < 0.001) and synthesis (P < 0.05), altered biliary bile acid composition ([CA + DCA]/CDCA up, P < 0.005), stimulated cholesterol esterification (P < 0.03), and enhanced the clearance of chylomicron remnants (P + 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P <0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.