Postmenopausal Hormone Therapy and Gallbladder Disease

Abstract & Commentary

Synopsis: Postmenopausal hormone therapy is associated with about a 2-fold increased risk of gallbladder disease.

Source: Cirillo DJ, et al. JAMA. 2005;293:330-339.

The mechanism for a possible adverse effect of hormone therapy on the biliary system is believed to be estrogen-induced increases in cholesterol saturation in the bile and progestin inhibition of gallbladder contraction, leading to gallstone formation. The Women’s Health Initiative (WHI) reported the incidence of gallbladder disease in the 2 canceled arms of the trial, the combined estrogen-progestin arm and the estrogen alone arm. The results were as follows:

  Estrogen Alone Estrogen-Progestin
Annual incidence 31 additional cases per 10,000 per year 20 additional cases per 10,000 per year
Gallbladder disease or surgery 1.67 (1.35-2.06) 1.59 (1.28-1.97)
Cholecystitis 1.86 (1.42-2.28) 1.54 (1.22-1.94)
Cholelithiasis 1.86 (1.48-2.35) 1.68 (1.34-2.11)

Surprisingly, no interactions could be documented with BMI (known to be associated with risk of gallstone formation), prior hormone use, or use of aspirin and statins at baseline. In contrast to previous reports from the WHI, the adjustment for having multiple end points (the Bonferroni correction) continued to show statistical significance. The increase in risk was demonstrable in the first year of use and was maintained throughout the period of follow-up.

Comment by Leon Speroff, MD

Once again the WHI agrees with previous reports in the literature. More and more, clinicians are reaching the logical conclusion that the WHI results do not disagree with 20 years of research. But I can’t help pointing out something I call selective reporting. In the introduction, Cirillo and colleagues report that the HERS data revealed a 38% increase risk for biliary tract surgery, but fail to also say that this conclusion did not achieve statistical significance.1,2 This common practice among epidemiologists of being less than accurate is a disservice for clinicians and patients.

It is now well-recognized that the participants in the WHI were older than the general population usually prescribed hormone therapy. The strongest argument that prevents restricting this risk to older postmenopausal women is the fact that case-control and cohort studies have reported similar risks in younger populations. The Nurses’ Health Study indicated that oral estrogen therapy carries a 1.5-2.0-fold increased risk of gallbladder disease.3 The risk of cholecystectomy appeared to increase with dose and duration of use and to persist for 5 or more years after stopping treatment. Others have also reported increased risks of cholecystectomy in past and current users of estrogen.4-6 But at least 2 case-control studies concluded that estrogen use is not a risk factor for gallstone disease in postmenopausal women, although the statistical power was limited by small numbers.7,8 A cross-sectional study of gallstone disease could detect no association with postmenopausal hormone treatment.9

Thus far, the available evidence does not allow clinicians to identify which women receiving hormone therapy might be at greater risk for gallbladder disease. The routine, periodic use of blood chemistries is not cost-effective, and careful monitoring for the appearance of the symptoms and signs of biliary tract disease suffices. It is not certain that this potential problem is limited to oral therapy. Transdermal routes of estrogen administration have been reported to both increase and not increase biliary cholesterol saturation (a lithogenic response).10,11


1. Hulley S, et al. JAMA. 1998;280:605-618.

2. Simon JA, et al. Ann Intern Med. 2001;135:493-501.

3. Grodstein F, et al. Obstet Gynecol. 1994;83:5-11.

4. Petitti D, et al. Gastroenterolgoy. 1988;94:91-95.

5. La Vecchia C, et al. J Epidemiol Community Health. 1992;46:234-236.

6. Hulley S, et al. JAMA. 2002;288:58-66.

7. Scragg RK, et al. Br Med J. 1984;288:1795-1799.

8. Kakar F, et al. Am J Public Health. 1988;78:564-566.

9. Jorgensen T. Gut. 1988;29:433-439.

10. Van Erpecum KJ, et al. Gasteroenterology. 1991;100: 482-488.

11. Uhler ML, et al. J Clin Endocrinol Metab. 1998;83: 410-414.

Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland is Editor for OB/GYN Clinical Alert.