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Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones 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 jsmol/d) and high (2,021±262 ,umol/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 (ICA + DCAI/ CDCAt, 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. (J. Clin. Invest. 1991. 87:237-246.)

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A B S T R A C T To study the events that might lead to an increased risk of cholesterol gallstones, we examined biliary lipid composition and secretion and bile acid composition and kinetics at different stages of pregnancy or ovulation in young, nonobese, healthy women.Lipid composition and bile acid distribution were determined in duodenal fluid obtained in percentage of cholic acid. The pool size of each major bile acid increased in the first trimester. Chenodeoxycholic acid and deoxycholic acid pools, but not cholic acid pools, subsequently decreased. The fractional turnover rate of both primary bile acids was slower during pregnancy. The synthesis rate of chenodeoxycholic but not cholic acid decreased in a linear manner during the first 20 wk of pregnancy. The rate of enterohepatic cycling of the bile acid pool was reduced throughout pregnancy.The volume of the fasting gallbladder and the residual volume after a physiologically stimulated contraction were directly correlated with bile acid pool size. The residual volume was also directly related to total bile acid synthesis.

Administration of the synthetic estrogen ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,173diol) decreases hepatic Na+,K+-ATPase (ATP phosphohydrolase; EC 3.6.1.3) activity and bile flow to 50% and alters the composition and structure of surface membrane lipid in rats. Although the content of phospholipids was not changed by treatment, free cholesterol (130%) and cholesterol esters (400%) were increased in liver surface membrane fractions. These observations correlate with changes in membrane viscosity, as shown by electron spin resonance probes. Both rotational correlation time, using the isotropic probe methyl (12-nitroxyl)stearate, and the order parameter, determined by the anisotropic probe 5-nitroxylstearic acid, were significantly increased in liver surface membrane fractions from rats treated with ethinyl estradiol. Administration of Triton WR-1339, a nonionic detergent that corrects hepatic and serum lipid changes caused by ethinyl estradiol treatment, restored toward normal elevated membrane lipids and viscosity as well as Na+,K+-ATPase activity and bile flow. Although restoration of normal liver surface membrane structure and function may be due to reversal of abnormal lipid composition, detergents also may directly alter membrane enzyme activity. Addition of Triton WR-1339 in vitro increased Na+,K+-ATPase activity and reduced membrane viscosity of surface membranes from rats treated with ethinyl estradiol. Triton had no effect on either parameter in normal membrane preparations. Studies of membrane structure and function both in vivo and in vitro suggest that alterations in lipid composition may alter Na+,K+-ATPase function and bile flow. Na+,K+-ATPase (ATP phosphohydrolase, EC 3.6.1.3) is a mammalian surface membrane that is sensitive to the lipid structure of the membrane bilayer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)). An important function of Na+,K+-ATPase in the hepatocyte may be the active secretion of sodium into the bile canaliculus, thus driving water across the canalicular membrane (8,9). This fraction has been called bile salt-independent bile flow, and recent studies have demonstrated a strong correlation between hepatic Na+, K+-ATPase activity and bile flow (10), supporting the hypothesis that this component of bile flow is regulated by the sodium pump. One drug consistently shown to reduce bile salt-independent bile flow is the synthetic estrogen derivative ethinyl estradiol (17a-ethinyl-1,3,5-estratriene-3,17f3-diol) (10)(11)(12)(13).The aim of the present study was to examine whether Na+, K+-ATPase activity is reduced after ethinyl estradiol treatment and, if so, what possible mechanisms might be involved. We recently found that ethinyl estradiol significantly increases hepatic cholesterol ester concentrations by activating hepatic microsomal cholesterol acyl-CoA transferase (14).The possibility that altered membrane lipid composition was involved in the mechanism through which ethinyl estradiolThe publication costs of this article were defrayed in part by page charge payment. Thi...

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We examined changes in cholesterol and bile acid metabolism produced by dietary cholesterol in gallstone subjects and matched controls. Healthy women were recruited and, after confirming the presence or absence of radiolucent gallstones, they were studied on regular diets and again on the same diet supplemented with five eggs daily for 15-18 d. Studies included plasma lipids, lipoproteins and apolipoproteins, dietary records, cholesterol absorption, cholesterol synthesis, plasma clearance of chylomicron remnants, biliary lipid composition, and secretion and bile acid kinetics. On low cholesterol, gallstone subjects absorbed a slightly lower fraction of dietary cholesterol, synthesized more cholesterol, and had smaller bile acid pools and faster fractional turnover rate (FTR) of bile acids. On high cholesterol, the fraction of cholesterol absorbed decreased in both groups and cholesterol synthesis decreased, especially in the gallstone group. Biliary cholesterol secretion increased in the gallstone group only. FrR of bile acids did not change in either group. Bile acid synthesis and pool tended to increase (P = NS) in the controls, but in gallstone subjects, synthesis and pool size decreased. We concluded that in gallstone subjects cholesterol and bile acid homeostasis is significantly altered, and that increasing dietary cholesterol increases biliary cholesterol secretion and decreases bile acid synthesis and pool, changes associated with cholesterol gallstone formation. (J. Clin. Invest. 1994.93:1186-1194