Cholesterol gallstones, a common and costly disease, occurs 2.5 times as frequently in women as in men, and its incidence is doubled again by contraceptive steroids (CS) or postmenopausal estrogen. The major goal of this project is to discover the precise biochemical and physiological mechanisms of action of female sex steroid hormones that predispose to gallstone formation so that strategies for prevention can be devised. Since gallstones occur spontaneously only in humans, women volunteer subjects will be studied. Hepatic secretion of excess biliary cholesterol, especially in relation to bile acid and phospholipid, is essential for gallstone formation. Pregnancy and CS increase cholesterol secretion. The hypothesis proposed to explain the increase is that estrogen increases the hepatic uptake of cholesterol (endogenous and exogenous) and progestin inhibits its esterification, so that cholesterol, which can be stored in the liver only as an ester, is secreted into the bile (and possibly also converted to bile acids). This hypothesis will be tested by in postmenopausal women by measuring: 1) effects of ethinyl estradiol (EE) on plasma clearance of chylomicron remnants, using retinyl palmitate as remnant marker, and on LDL receptors an freshly isolated peripheral blood monocytes using ligand binding, immunoblotting and binding of 125I-LDL to membrane receptors and 2) effects of norethindrone on the activity of acyl-CoA:cholesterol acyltransferase activity and on cholesterol synthesis in the same cells. Plasma apoprotein A-I and B will be measured by ELISA in both studies. An additional hypothesis that dietary cholesterol contributes to the pathogenesis of cholesterol gallstone in some subjects will be tested by measuring the effects of increasing dietary cholesterol on gallbladder bile saturation with cholesterol and on biliary secretion of cholesterol in patients with cholesterol gallstones and matched controls. In this study we shall also measure regulatory responses to dietary cholesterol, such as bile acid synthesis, cholesterol synthesis and esterification and LDL receptors in monocytes, chylamicron remnant clearance, cholesterol absorption and apo A-I and B to help in understanding the metabolic difference between subjects whose biliary cholesterol secretion increases and those it whom it does not.
