Although estrogen replacement therapy (ERT) in postmenopausal women has numerous beneficial effects, adverse effects such as an increased incidence of gallbladder disease have been reported. Gallstone formation is also increased in pregnancy, with oral contraceptive use and in men who are treated with estrogen. Gallbladder disease presumably results from the influence of estrogen on hepatic lipid metabolism. Estrogen increases the amount of cholesterol relative to bile salts and lecithin in bile, increasing the saturation of bile with cholesterol, which leads to cholesterol crystal formation. Estrogen also alters bile acid composition, increasing the chance of gallstone formation. Uhler and associates performed a systematic review of all studies that addressed the association between ERT and gallbladder disease to determine if estrogen is an etiologic agent in gallstone formation.

Seven observational studies, two clinical trials, two case studies, one nonrandomized and three randomized trials were available for review. The majority of study groups consisted of postmenopausal women who had a history of gallbladder disease and who had taken ERT compared with a control group matched for age.

Three of the five retrospective observational studies found an increase in gallbladder disease in postmenopausal women taking ERT. In the large nurses' health study, cholecystectomy was reported by 1,750 of the 55,000 postmenopausal women in the trial during eight years of follow-up. In the first randomized trial investigating ERT and cholelithiasis in 84 matched pairs of postmenopausal women, the ERT-treated group had a higher incidence of cholelithiasis compared with the control group, although this difference was not statistically significant. The problems with observational studies are well documented.

There were only two randomized trials of estrogen use in postmenopausal women in which gallbladder disease was reported. The Postmenopausal Estrogen/Progestin Interventions Trial reported gallbladder disease in nine women (two women in the estrogen group, five women in the combination estrogen and progestin group, and two in the placebo group). Because the numbers were so low, it was not possible to determine a statistical difference in gallstone formation among the study groups. In the Heart and Estrogen/Progestin Replacement Study, an increased rate of gallbladder disease was reported in the women in the combination estrogen and progestin group compared with the women in the placebo group during an average follow-up period of four years.

There are few studies in the literature of gall-bladder bile after administration of transdermal or oral estrogens. The only randomized trial that compared the impact of transdermal and oral estrogen on bile found that oral and nonoral administration of estrogens altered the bile acid composition in ways that would promote gallstone formation, such as altering biliary lipids and nucleation of cholesterol. Oral conjugated equine estrogens induced greater changes in hepatic markers (such as levels of globulin and lipids) than transdermal estradiol.

The authors conclude that estrogens increase the lithogenic index of bile and alter biliary acid composition, increasing the likelihood of gallstone formation. Oral and non-oral administration of estrogens altered bile in comparable ways that would be expected to promote gallstone development. Thus ERT should be administered with caution in post-menopausal women who have gallstones or a history of gallbladder disease.