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Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study

BMJ 2008; 337 doi: (Published 10 July 2008) Cite this as: BMJ 2008;337:a386
  1. Bette Liu, clinical epidemiologist1,
  2. Valerie Beral, professor of epidemiology1,
  3. Angela Balkwill, statistical programmer1,
  4. Jane Green, clinical research scientist1,
  5. Siân Sweetland, statisticial epidemiologist1,
  6. Gillian Reeves, statistical epidemiologist1
  7. for the Million Women Study Collaborators
  1. 1Epidemiology Unit, University of Oxford, Oxford OX3 7LF
  1. Correspondence to: B Liu Bette.Liu{at}
  • Accepted 9 May 2008


Objective To determine whether transdermal compared with oral use of hormone replacement therapy reduces the risk of gallbladder disease in postmenopausal women.

Design Prospective cohort study (Million Women Study).

Setting Women registered with the National Health Service (NHS) in England and Scotland.

Participants 1 001 391 postmenopausal women (mean age 56) recruited between 1996 and 2001 from NHS breast screening centres and followed by record linkage to routinely collected NHS hospital admission data for gallbladder disease.

Main outcome measures Adjusted relative risk and standardised incidence rates of hospital admission for gallbladder disease or cholecystectomy according to use of hormone replacement therapy.

Results During follow-up 19 889 women were admitted for gallbladder disease; 17 190 (86%) had a cholecystectomy. Compared with never users of hormone replacement therapy, current users were more likely to be admitted for gallbladder disease (relative risk 1.64, 95% confidence interval 1.58 to 1.69) but risks were substantially lower with transdermal therapy than with oral therapy (relative risk 1.17, 1.10 to 1.24 v 1.74, 1.68 to 1.80; heterogeneity P<0.001). Among women using oral therapy, equine oestrogens were associated with a slightly greater risk of gallbladder disease than estradiol (relative risk 1.79, 1.72 to 1.87 v 1.62, 1.54 to 1.70; heterogeneity P<0.001) and higher doses of oestrogen increased the risk more than lower doses: for equine oestrogens >0.625 mg, 1.91 (1.78 to 2.04) v ≤0.625 mg, 1.76 (1.68 to 1.84); heterogeneity P=0.02; estradiol >1 mg, 1.68 (1.59 to 1.77) v ≤1 mg, 1.44 (1.31 to 1.59); heterogeneity P=0.003. The risk of gallbladder disease decreased with time since stopping therapy (trend P=0.004). Results were similar taking cholecystectomy as the outcome. Standardised hospital admission rates per 100 women over five years for cholecystectomy were 1.1 in never users, 1.3 with transdermal therapy, and 2.0 with oral therapy.

Conclusion Gallbladder disease is common in postmenopausal women and use of hormone replacement therapy increases the risk. Use of transdermal therapy rather than oral therapy over a five year period could avoid one cholecystectomy in every 140 users.


  • We thank the women who participated in the Million Women Study, the study steering committee, coordinating centre staff, and collaborating NHS breast screening centres. We also thank ISD Scotland, the Information Centre for Health and Social Care, and Northgate Solutions for the linkage of hospital records.

  • Contributors: All authors contributed to the design and conduct of the study and read and approved the final manuscript. VB and BL are the guarantors.

  • Funding: This work was supported by Cancer Research UK [grant No C570/A5028], the NHS breast screening programme, and the UK Medical Research Council [grant No G0700474]. The funders had no involvement in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of this manuscript.

  • Competing interests: None declared.

  • Ethical approval: The study has been approved by the Eastern multicentre research ethics committee.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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