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Comparison of the Impact of Transdermal Versus Oral Estrogens on Biliary Markers of Gallstone Formation in Postmenopausal Women¹

Department of Obstetrics and Gynecology (M.L.U., B.J.V., H.L.J.) and Internal Medicine (J.W.M.), Cedars-Sinai Medical Center and the University of California School of Medicine, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Howard L. Judd, M.D., Department of Obstetrics and Gynecology, Olive View-University of California-Los Angeles Medical Center, 14445 Olive View Drive, Room 2B163, Sylmar, California 91342-1495.

This prospective, randomized, double blind, parallel study was undertaken to elucidate further the potential mechanisms through which estrogens could promote the formation of cholesterol gallstones and to compare the impact of nonoral (transdermal) and oral estrogens on serum, hepatic, and biliary markers of estrogen action. Ninety-seven postmenopausal women were randomized to receive either transdermal estradiol (E₂; 0.1 mg every 3.5 days; n = 48) or oral conjugated equine estrogens (1.25 mg every day; n = 49) for 8 weeks. Blood samples were drawn, and bile samples were obtained by cholecystokinin-stimulated duodenal drainage before and after 8 weeks of estrogen administration. The main outcome measures included serum FSH, LH, E₂, estrone, estrone sulfate, sex hormone-binding globulin, lipid profiles, biliary cholesterol saturation index, cholesterol nucleation time, presence of cholesterol crystals in bile, as well as biliary arachidonate, PGE₂, and mucous glycoproteins. Estrogens administered by both routes increased circulating estrogens and resulted in similar suppression of both gonadotropins. Sex hormone-binding globulin was clearly increased, and the changes in serum lipids were more pronounced with oral conjugated equine estrogens than with transdermal E₂. The biliary cholesterol saturation index was significantly increased compared to the baseline values with both transdermal E₂ (1.08 ± 0.04 vs. 1.00 ± 0.03; mean change, 8%) and oral conjugated equine estrogens (1.04 ± 0.03 vs. 0.99 ± 0.03; mean change, 6%); however, there was no difference between the treatments. The number of patients with cholesterol crystals detected in bile was similar after both estrogen regimens. Transdermal and oral estrogens decreased nucleation time in vitro, increased arachidonate and PGE₂ levels, and minimally raised total glycoprotein concentrations. In conclusion, transdermal and oral estrogens exerted comparable nonhepatic effects, as evidenced by similar reductions of gonadotropin levels, but oral therapy exhibited substantially greater actions on hepatic markers of estrogen action. Both transdermal E₂ and oral conjugated equine estrogens significantly elevated the biliary cholesterol saturation index and reduced the nucleation time. These results suggest that estrogens at the doses studied could promote gallstone formation by alteration of biliary lipids and cholesterol nucleation time that have been incriminated in this process.

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