Clinical Question: Does estrogen therapy increase the risk of gallbladder disease among postmenopausal women?

Setting: Outpatient (any)

Study Design: Randomized controlled trial (double-blinded)

Allocation: Concealed

Synopsis: As part of the Women’s Health Initiative postmenopausal hormone trial, investigators gathered more rigorous evidence to assess the risk of gallbladder disease with the use of estrogen therapy. Women with hysterectomy were randomized to receive conjugated equine estrogen in a dosage of 0.625 mg per day or matched placebo. Women without hysterectomy were randomized to receive estrogen plus progestin, given as 2.5 mg per day of medroxyprogesterone acetate or matched placebo. Participants were blinded to treatment group assignment and self-reported hospitalizations for gallbladder disease and related procedures.

These events were judged by medical record acquisition. The mean follow-up times were 7.1 and 5.6 years for the estrogen-only and estrogen-plus-progestin trials, respectively.

Using intention-to-treat analysis, the annual incidence of any gallbladder event (e.g., cholecystitis, cholelithiasis, cholecystectomy) in the estrogen-only trial was 78 per 10,000 person-years in the active treatment group compared with 47 per 10,000 person-years in the placebo group (number needed to treat to harm [NNTH] in one year = 323). For the estrogen-plus-progestin trial, the annual incidence of any gallbladder event was 55 per 10,000 person-years in the active treatment group compared with 35 per 10,000 person-years in the placebo group (NNTH in one year = 500). Both of these differences were statistically significant.

Bottom Line: Evidence from the Women’s Health Initiative, the largest randomized trial available, confirms an increase in gallbladder disease and related procedures among post-menopausal women treated with supplemental estrogen. This is one more risk to consider when helping each patient weigh the risks and benefits of estrogen therapy. (Level of Evidence: 1b)