Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort studyBMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a386 (Published 10 July 2008) Cite this as: BMJ 2008;337:a386
All rapid responses
The article of Liu and MWS Collaborators confirms a higher risk of gallbladder disease and cholecystectomies in association with hormone replacement therapy (HRT), as already reported from the Nurses' Health Study, HERS and the WHI. The authors' calculations of absolute differences in risk reveals that one extra case of cholecystectomy in 500 users of transdermal HRT has to be expected over 5 years in comparison to one extra case in 111 users of oral HRT over 5 years. It seems that the risk of gallbladder disease with HRT is of secondary importance and may well be balanced by HRT benefits.
Prior MWS analyses focused on breast, endometrial and ovarian cancer at the risk lever of the balance as well as on fractures at the benefit lever. In each of their publications on risks the MWS collaborators carved out absolute differences and extrapolations to the population level.
However, given the ubiquitous effects of HRT, to get the right perspective and the true net impact it is necessary to investigate the most relevant issues for the health of peri- and postmenopausal women, i.e. overall, total cancer-related and cardiovascular mortality as well as cardiovascular and total cancer morbidity. From the publication of Liu et al. (cf. table 1) it seems, that the information to analyze these topics is available.
Before exploring secondary effects it is necessary to show the objective data of primary importance.
Employee of a pharmaceutical company selling HRT products
Competing interests: No competing interests
We read with interest the article by Liu et al.1 comparing
transdermal and oral hormone replacement therapy (HRT) in gallstone
The benefit of HRT in ameliorating vasomotor and urogenital symptoms of
menopause and menopause-related osteoporosis cannot be undermined.
However, numerous studies have indicated that besides the adverse
cardiovascular side-effects following oral administration of oestrogens,2
the possibility of developing gallstone disease was real. 3,4 This
obviously led to considerable uncertainty in the minds of users and
prescribers of HRT resulting in narrowing down the indications for HRT use
in postmenopausal women. While this study has confirmed the existence of
‘the problem’ of the adverse effect of oestrogen-containing HRT on
gallstone disease it has also provided in part - a ‘solution’. The lowered
risk of gallstone disease in postmenopausal women using transdermal
patches based on the outcomes of this large-scale cohort study proves a
shot in the arm for prescribers of transdermal patches. By highlighting
the beneficial effect of transdermal patches on reducing the rate of
cholecystectomies, the authors have indirectly steered clear of the
criticism against previous studies that failed to differentiate the impact
of oestrogen-containing HRT on symptomatic gallstones and the rate of
conversion of asymptomatic to symptomatic gallstones.
The influence of oestrogen dose on gallstone formation (higher doses
associated with higher risk) was also shown. The high incidence of
gallstones in patients with implants seems to cast serious doubts on first
pass metabolism as causative for gallstones.
While we do believe that the development of gallstone disease is just one
side effect of HRT, this study does provide further evidence to support
the use of transdermal patches in the management algorithm of women
requiring oestrogen replacement therapy.
1) Liu B, Beral V, Balkwill A, Green J, Sweetland S, Reeves G and for the
Million Women Study Collaborators. Gallbladder disease and use of
transdermal versus oral hormone replacement therapy in postmenopausal
women: prospective cohort study. BMJ 2008;337:a386.
2) Rossouw JE, Anderson GL, Prentice RL, La-Croix AZ, Kooperberg C,
Stefanick ML, et al. Risks and benefits of estrogen plus progestin in
healthy postmenopausal women: principal results from the Women’s Health
Initiative randomized controlled trial. JAMA 2002;288:321–33.
3) Simon JA, Hunninghake DB, Agarwal SK, Lin F, Cauley JA, Ireland CC,
Pickar JH: Effect of estrogen plus progestin on risk for biliary tract
surgery in postmenopausal women with coronary artery disease: the Heart
and Estrogen/Progestin Replacement Study. Ann Intern Med 2001;135:493–501.
4) Cirillo DJ, Wallace RB, Rodabough RJ, Greenland P, LaCroix AZ, Limacher
MC, Larson JC: Effect of estrogen therapy on gallbladder disease. JAMA
Competing interests: No competing interests