Transdermal Rather Than Oral Hormone Therapy May Help Avoid Cholecystectomy

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Transdermal Rather Than Oral Hormone Therapy May Help Avoid Cholecystectomy

News Author: Laurie Barclay, MDCME Author: Laurie Barclay, MD Disclosures

Laurie Barclay, MDDisclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

Brande Disclosure: Brande has disclosed no relevant financial information.

July 16, 2008 — Gallbladder disease is common in postmenopausal women, and use of hormone replacement therapy (HRT) increases the risk. Use of transdermal hormone therapy rather than oral therapy in a 5-year period could avoid 1 cholecystectomy in every 140 users, according to the results of a prospective cohort study reported in the July 11 Online First issue of the BMJ.

"Randomised controlled trials and observational studies have shown a clear increase in the risk of gallbladder disease (cholelithiasis, cholecystitis, or cholecystectomy as outcomes) with use of hormone replacement therapy by postmenopausal women," write Bette Liu, from the University of Oxford, United Kingdom, and colleagues from the Million Women Study Collaborators. "We examined the relation between method of administration and type of hormone replacement therapy and the incidence of gallbladder disease in a large cohort of postmenopausal women in the United Kingdom."

In the Million Women Study, 1,001,391 postmenopausal women registered with the National Health Service (NHS) in England and Scotland were recruited between 1996 and 2001 from NHS breast screening centers and observed by record linkage to routinely collected NHS hospital admission data for gallbladder disease. Mean age at enrollment was 56 years. Primary endpoints were adjusted relative risk (RR) and standardized incidence rates of hospitalization for gallbladder disease or for cholecystectomy on the basis of use of HRT.

Of 19,889 women admitted for gallbladder disease during follow-up, 17,190 (86%) had a cholecystectomy. Current HRT users were more likely than never-users of HRT to be admitted for gallbladder disease (RR, 1.64; 95% confidence interval [CI], 1.58 - 1.69). However, risks were lower with transdermal vs oral therapy (RR, 1.17; 95% CI, 1.10 - 1.24 vs RR, 1.74; 95% CI, 1.68 - 1.80; P for heterogeneity < .001).

For women using oral HRT, the risk for gallbladder disease was slightly greater with use of equine estrogens vs estradiol (RR, 1.79; 95% CI, 1.72 - 1.87 vs RR, 1.62; 95% CI, 1.54 - 1.70; P for heterogeneity < .001). Higher vs lower doses also increased the risk. For equine estrogens of more than 0.625 mg, RR was 1.91 (95% CI, 1.78 - 2.04) vs 0.625 mg or less (RR, 1.76; 95% CI, 1.68 - 1.84; P for heterogeneity = .02). For estradiol of more than 1 mg, RR was 1.68 (95% CI, 1.59 - 1.77) vs 1 mg or less (RR, 1.44; 95% CI, 1.31 - 1.59; P for heterogeneity = .003).

With time since stopping HRT, the risk for gallbladder disease decreased (P for trend = .004). When cholecystectomy was considered as the outcome, findings were similar. Standardized hospital admission rates for cholecystectomy per 100 women during 5 years were 1.1 in never-users of HRT, 1.3 with transdermal HRT, and 2.0 with oral HRT.

Limitations of this study include some changes in HRT use occurring during follow-up, potential confounding factors, and some non–NHS-funded admissions not included in the follow-up,

"Gallbladder disease is common in postmenopausal women and use of [hrT] increases the risk," the study authors write. "Use of transdermal therapy rather than oral therapy over a five year period could avoid one cholecystectomy in every 140 users."

Cancer Research United Kingdom, the NHS breast screening programme, and the UK Medical Research Council supported this study. The study authors have disclosed no relevant financial relationships.

BMJ. Published online July 11, 2008.

Clinical Context

Use of HRT in postmenopausal women has been linked to an increased risk for gallbladder disease on the basis of randomized controlled trials and observational studies to date. Orally administered estrogen is metabolized by the liver before entering the systemic circulation, whereas estrogen administered transdermally avoids this first-pass metabolism.

Use of transdermal HRT may therefore have a lesser effect on gallbladder disease vs orally administered estrogen. This study looked at the association between the method of HRT administration and other factors regarding HRT use and the incidence of gallbladder disease in a large cohort of postmenopausal women in the United Kingdom.

Study Highlights

The cohort prospectively followed up for this study consisted of 1,001,391 postmenopausal women enrolled in the Million Women Study. Between 1996 and 2001, participants registered with the NHS in England and Scotland were recruited from NHS breast screening centers and observed by record linkage to routinely collected NHS hospital admission data for gallbladder disease. At enrollment, mean age was 56 years. Women with a record of admission for gallbladder disease before recruitment were excluded from the analyses. Other exclusion criteria were premenopausal or perimenopausal status, cancer other than nonmelanoma skin cancers at baseline, and unknown HRT use. Main outcome measures were RRs and standardized incidence rates of hospitalization for gallbladder disease or cholecystectomy on the basis of use of HRT. RRs were adjusted for a history of hysterectomy and bilateral oophorectomy, socioeconomic status, body mass index, and other medical history. During follow-up, 19,889 women were admitted for gallbladder disease, of whom 17,190 (86%) underwent cholecystectomy. Admissions for gallbladder disease occurred at a mean of 3.3 years after recruitment. Compared with never-users of HRT, current HRT users were more likely to be admitted for gallbladder disease (RR, 1.64; 95% CI, 1.58 - 1.69). Risks for admission for gallbladder disease were lower for transdermal vs oral HRT (RR, 1.17; 95% CI, 1.10 - 1.24 vs RR, 1.74; 95% CI, 1.68 - 1.80; P for heterogeneity < .001). For users of oral HRT, risk for gallbladder disease was slightly greater with use of equine estrogens vs estradiol (RR, 1.79; 95% CI, 1.72 - 1.87 vs RR, 1.62; 95% CI, 1.54 - 1.70; P for heterogeneity < .001). Among users of oral HRT, the RR, but not the absolute risk, for gallbladder disease associated with HRT decreased with increasing body mass index. Higher vs lower doses of HRT were associated with greater risk for gallbladder disease. For equine estrogens of 0.625 mg or more, RR was 1.91 (95% CI, 1.78 - 2.04) vs 0.625 mg or less (RR, 1.76; 95% CI, 1.68 - 1.84; P for heterogeneity = .02). For estradiol of 1 mg or more, RR was 1.68 (95% CI, 1.59 - 1.77) vs 1 mg or less (RR, 1.44; 95% CI, 1.31 - 1.59; P for heterogeneity = .003). Risk for gallbladder disease decreased with time since stopping HRT (P for trend = .004). Findings were similar with use of cholecystectomy as the outcome measures. Standardized hospital admission rates for cholecystectomy per 100 women in 5 years were 1.1 in never-users of HRT, 1.3 with transdermal HRT, and 2.0 with oral HRT. Limitations of this study include some changes in HRT use occurring during follow-up, potential confounders, and failure to include some non–NHS-funded admissions in the follow-up. The investigators concluded that gallbladder disease is common in postmenopausal women, that use of HRT increases the risk, and that use of transdermal vs oral therapy in a 5-year period could avoid 1 cholecystectomy in every 140 users.

Pearls for Practice

The Million Women Study showed that gallbladder disease is common in postmenopausal women and that use of HRT increases the risk. Of women admitted for gallbladder disease, 86% underwent cholecystectomy. Risks for hospital admission for gallbladder disease were lower for transdermal vs oral HRT. For users of oral HRT, the risk for gallbladder disease was slightly greater with use of equine estrogens vs estradiol, and higher vs lower doses of HRT were associated with greater risk for gallbladder disease.

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