Effect of estrogen therapy on gallbladder disease.
BACKGROUND
Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than randomized trials.


OBJECTIVE
To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes.


METHODS
Two randomized, double-blind, placebo-controlled trials conducted at 40 US clinical centers. The volunteer sample was 22,579 community-dwelling women aged 50 to 79 years without prior cholecystectomy.


METHODS
Women with hysterectomy were randomized to 0.625 mg/d of conjugated equine estrogens (CEE) or placebo (n = 8376). Women without hysterectomy were randomized to estrogen plus progestin (E + P), given as CEE plus 2.5 mg/d of medroxyprogesterone acetate (n = 14,203).


METHODS
Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures, with events ascertained through medical record review. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) using intention-to-treat and time-to-event methods.


RESULTS
The CEE and the E + P groups were similar to their respective placebo groups at baseline. The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials, respectively. The annual incidence rate for any gallbladder event was 78 events per 10,000 person-years for the CEE group (vs 47/10,000 person-years for placebo) and 55 per 10,000 person-years for E + P (vs 35/10,000 person-years for placebo). Both trials showed greater risk of any gallbladder disease or surgery with estrogen (CEE: HR, 1.67; 95% CI, 1.35-2.06; E + P: HR, 1.59; 95% CI, 1.28-1.97). Both trials indicated a higher risk for cholecystitis (CEE: HR, 1.80; 95% CI, 1.42-2.28; E + P: HR, 1.54; 95% CI 1.22-1.94); and for cholelithiasis (CEE: HR, 1.86; 95% CI, 1.48-2.35; E + P: HR, 1.68; 95% CI, 1.34-2.11) for estrogen users. Also, women undergoing estrogen therapy were more likely to receive cholecystectomy (CEE: HR, 1.93; 95% CI, 1.52-2.44; E + P: HR, 1.67; 95% CI, 1.32-2.11), but not other biliary tract surgery (CEE: HR, 1.18; 95% CI, 0.68-2.04; E + P: HR, 1.49; 95% CI, 0.78-2.84).


CONCLUSIONS
These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy. The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy.
Cirillo
Dominic J
DJ
Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, USA.
Wallace
Robert B
RB
Rodabough
Rebecca J
RJ
Greenland
Philip
P
LaCroix
Andrea Z
AZ
Limacher
Marian C
MC
Larson
Joseph C
JC
D000368:Aged; D002763:Cholecystectomy / Q000706:statistics & numerical data; D002764:Cholecystitis / Q000139:chemically induced / Q000453:epidemiology; D002769:Cholelithiasis / Q000139:chemically induced* / Q000453:epidemiology; D004311:Double-Blind Method; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004966:Estrogens, Conjugated (USP) / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005705:Gallbladder Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000601:surgery; D006801:Humans; D015994:Incidence; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use; D008875:Middle Aged; D017698:Postmenopause; D016016:Proportional Hazards Models; D012307:Risk Factors
D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate