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Hormone therapy raises risk for gallbladder disease — but does the route of administration matter? In the Million Women Study, U.K. investigators prospectively analyzed self-reported HT use in a cohort of 1.3 million postmenopausal women (age range, 50–69) and their rate of hospital admissions for gallbladder disease or cholecystectomy (determined through linkage to National Health Service data) during a mean follow-up of 6 years.
Among those who used HT, about four times more women used oral estrogens than used transdermal estrogens (77% vs. 18%). Overall, current users of estrogens were 64% more likely to experience gallbladder disease than were never users (relative risk, 1.6). Oral estrogen use raised risk more than did transdermal estrogen use (RR, 1.7 vs. 1.2). Adjustment for confounders (smoking status; alcohol intake; physical activity; previous oral contraceptive use; treatment for hypertension; cholesterol levels; dietary factors; and history of stroke, heart disease, thrombosis, or bilateral oophorectomy) did not substantially change risk estimates. Oral equine estrogen posed a higher risk than did oral estradiol (RR, 1.8 vs. 1.6; P<0.001). A modest risk for gallbladder disease persisted in ever users of estrogen versus never users at 10 years after HT discontinuation (RR, 1.2). RR for gallbladder disease that was associated with oral estrogen use decreased with increasing BMI (RR, 1.9 for BMI <25 vs. 1.5 for BMI ≥35; P<0.001).
Liu B et al. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: Prospective cohort study. BMJ 2008 Jul 10; 337:a386 (http://dx.doi.org/10.1136/bmj.a386)
Comment
The hepatic first-pass metabolism of oral estrogen generates byproducts in bile, which can, in turn, affect the gallbladder; however, transdermal estrogen bypasses the liver. Surprisingly, higher BMI was associated with less excess risk for gallbladder disease in HT users, but whether overweight and obese study participants had undergone cholecystectomies before data collection is unknown. The authors note that over the course of 5 years, transdermal estrogen users would have one fewer hospital admission per 125 women and one fewer cholecystectomy per 140 women than would oral estrogen users. For the 20,000 participants who were hospitalized for gallbladder disease (17,200 of whom underwent cholecystectomies), this translates to 160 fewer hospitalizations and 123 fewer surgeries during 5 years. Transdermal estrogen is more expensive than oral estrogen, but the overall healthcare savings as well as the health benefits to individual women (which also may include a more favorable risk profile for venous thromboembolism) could be considerable.