Effects of Estrogens on Gallstone Formation in Postmenopausal Women
ABSTRACT & COMMENTARY
Synopsis: Transdermal and oral estrogen given in comparable doses for eight weeks to 97 postmenopausal women altered biochemical markers in favor of gallstone formation to the same extent in both groups.
Source: Uhler ML, et al. J Clin Endocrinol Metab 1998;83:410-414.
It has been hypothesized that nonoral administration of estrogen would reduce gallstone formation because the nonoral route of delivery has less effect upon hepatic function. Prior studies supported this notion. To test the concept in a more rigorous fashion, Uhler and colleagues performed a double-blind, randomized, placebo-controlled trial in 97 postmenopausal women. Transdermal estradiol was given in a twice weekly dose of 0.1 mg. The oral preparation was conjugated equine estrogens 1.25 mg daily. Bioequivalency was confirmed by measuring the decline in LH and FSH. Markers of hepatic function included SHBG and lipoprotein profile. Bile samples were obtained before and after therapy by cholecystokinin-stimulated duodenal drainage. Several outcome parameters were determined, including biliary saturation index and the presence of cholesterol crystals in the bile.
The decline in LH and FSH was comparable in both groups. SHBG rose to a much greater extent in the oral group. Total cholesterol declined to a similar extent in both groups, but the changes in HDL, LDL, and trigly-cerides were much greater in the oral group. None of the 10 parameters used to assess biliary function differed between oral and transdermal groups after therapy. However, cholesterol saturation index increased in both groups. Overall, the effect of both transdermal and oral estrogen use would tend to promote gallstone formation.
COMMENT BY SARAH L. BERGA, MD
I read this article because I knew that there was not enough reliable information regarding the issue as to whether women predisposed to gallstones would fare better on oral or transdermal estrogen. I was surprised by the results of this study, which is the most definitive one yet to be conducted using surrogate indices of gallstone formation. As Uhler et al point out, gallstone formation requires three steps: enhanced saturation of bile with cholesterol, more rapid precipitation of solid crystals, and growth of microscopic crystals into stones. Estrogen use is thought to enhance gallstone formation by increasing cholesterol saturation of bile, altering bile acid composition, and decreasing bile flow. Indeed, the results of this study confirm this notion and show that estrogens increase cholesterol saturation index and promote crystal formation, but the route of administration apparently makes no difference. If a postmenopausal woman finds that estrogen use provokes gallbladder dysfunction or symptoms of gallstones, should she discontinue therapy? Uhler et al suggest that lower doses should have lesser effect. The doses chosen for the study were higher than those commonly used in clinical practice to increase the chances of inducing relevant alterations. Thus, if estrogen use provokes right upper quadrant pain, the first steps include dietary alterations such as discontinuing or reducing alcohol and fatty foods and decreasing the estrogen dose. Interestingly, a greater hepatic effect of oral estrogens was observed in this study, even though this did not result in lesser effect upon parameters of gallstone formation. Therefore, it is still true that, overall, transdermal estradiol use spares the liver. For instance, since the transdermal approach did not elevate trigly-cerides, while oral use provoked at 24% increase, women with elevated triglycerides might fare better on a transdermal preparation. The best estrogen, however, is the one that gives the least bothersome side effects to the patient and is the one that she is most inclined to use.
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