Skip to main content
SpringerLink
Log in

Postmenopausal Estrogen Therapy and Risk of Gallstone Disease: A Population-Based Case–Control Study

  • Original Research Article
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Background

Female gender and increasing age are key risk factors for gallstone disease; therefore, postmenopausal women are at high risk. Estrogen increases cholesterol saturation of bile and may further increase gallstone risk, but population-based evidence is sparse.

Objective

Our objective was to examine the association between postmenopausal estrogen therapy and risk of gallstone disease and the impact of duration of treatment and use of opposing progestin.

Study Design

We conducted a population-based case–control study. Cases were postmenopausal women (defined as aged ≥45 years) with gallstone disease identified in the period 1996–2010. For each case, we selected ten population controls matched to cases by age and sex. We defined exposure as any use of estrogen (opposed and unopposed by progestin). Cases/controls were categorized as current estrogen users if their last prescription was redeemed <90 days before gallstone diagnosis (or corresponding date for controls); all other users were categorized as former users. The reference group consisted of cases/controls with no/rare estrogen use.

Setting

Medical databases covering the population of Northern Denmark (2.4 million inhabitants through the period 1996–2010).

Main Outcome Measure

We used conditional logistic regression to compute adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) of gallstone disease in women treated with estrogen. The ORs were adjusted for relevant comorbidity, other drugs known to influence gallstone risk, and parity.

Results

We identified 16,386 cases with gallstone disease and 163,860 controls. A total of 1,425 cases (8.7 %) and 8,930 controls (5.4 %) were current estrogen users, yielding an adjusted OR for gallstone disease of 1.74 (95 % CI 1.64–1.85) compared with non-users. The corresponding adjusted OR for former users was 1.35 (95 % CI 1.28–1.42). The results suggested a duration response for current users. Use of unopposed estrogen was associated with higher adjusted ORs than estrogen opposed by progestin.

Conclusion

Postmenopausal estrogen therapy was associated with increased risk of gallstone disease in current and former estrogen users. Use of unopposed estrogen was associated with higher risk than use of estrogen opposed by progestin; this finding needs to be confirmed and explored further in future studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Jørgensen T. Gall stones in a Danish population: fertility period, pregnancies, and exogenous female sex hormones. Gut. 1988;29(4):433–9.

    Article  PubMed  Google Scholar 

  2. Stinton LM, Myers RP, Shaffer EA. Epidemiology of gallstones. Gastroenterol Clin N Am. 2010;39(2):157–69, vii.

    Google Scholar 

  3. Yoo EH, Lee SY. The prevalence and risk factors for gallstone disease. Clin Chem Lab Med. 2009;47(7):795–807.

    Article  CAS  PubMed  Google Scholar 

  4. Uhler ML, Marks JW, Judd HL. Estrogen replacement therapy and gallbladder disease in postmenopausal women. Menopause. 2000;7(3):162–7.

    Article  CAS  PubMed  Google Scholar 

  5. Everson GT, McKinley C, Kern F Jr. Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Investig. 1991;87(1):237–46.

    Article  CAS  PubMed  Google Scholar 

  6. Dowling RH. Review: pathogenesis of gallstones. Aliment Pharmacol Ther. 2000;14(Suppl 2):39–47.

    Article  PubMed  Google Scholar 

  7. Jørgensen T. Prevalence of gallstones in a Danish population. Am J Epidemiol. 1987;126(5):912–21.

    PubMed  Google Scholar 

  8. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease? Expert Opin Drug Saf. 2006;5(1):117–29.

    Article  CAS  PubMed  Google Scholar 

  9. Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and cholecystectomy in a large prospective study. Obstet Gynecol. 1994;83(1):5–11.

    CAS  PubMed  Google Scholar 

  10. Simon JA, Hunninghake DB, Agarwal SK, Lin F, Cauley JA, Ireland CC, et al. 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(7):493–501.

    Article  CAS  PubMed  Google Scholar 

  11. Cirillo DJ, Wallace RB, Rodabough RJ, Greenland P, LaCroix AZ, Limacher MC, et al. Effect of estrogen therapy on gallbladder disease. JAMA. 2005;293(3):330–9.

    Article  CAS  PubMed  Google Scholar 

  12. Hart AR, Luben R, Welch A, Bingham S, Khaw KT. Hormone replacement therapy and symptomatic gallstones—a prospective population study in the EPIC-Norfolk cohort. Digestion. 2008;77(1):4–9.

    Article  CAS  PubMed  Google Scholar 

  13. Gonzalez-Perez A, Garcia Rodriguez LA. Gallbladder disease in the general population: association with cardiovascular morbidity and therapy. Pharmacoepidemiol Drug Saf. 2007;16(5):524–31.

    Article  PubMed  Google Scholar 

  14. Grodstein F, Colditz GA, Stampfer MJ. Postmenopausal hormone use and cholecystectomy in a large prospective study. Obstet Gynecol. 1994;83(1):5–11.

    CAS  PubMed  Google Scholar 

  15. Rothman K, Greenland S, Lash T, editors. Modern epidemiology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

    Google Scholar 

  16. Schwarz S, Volzke H, Baumeister SE, Hampe J, Doren M. Menopausal hormone therapy and gallbladder disease: the Study of Health in Pomerania (SHIP). Clin Endocrinol (Oxf). 2007;67(1):51–9.

    Article  CAS  Google Scholar 

  17. Shaffer EA, Taylor PJ, Logan K, Gadomski S, Corenblum B. The effect of a progestin on gallbladder function in young women. Am J Obstet Gynecol. 1984;148(5):504–7.

    Article  CAS  PubMed  Google Scholar 

  18. StatBank Denmark. Population and elections. Table FOLK1. Copenhagen: Statistics Denmark; 2012. http://www.statistikbanken.dk/statbank5a/default.asp?w=1613.

  19. Frank L. Epidemiology. When an entire country is a cohort. Science. 2000;287(5462):2398–9.

    Article  CAS  PubMed  Google Scholar 

  20. Andersen TF, Madsen M, Jørgensen J, Mellemkjær L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46(3):263–8.

    CAS  PubMed  Google Scholar 

  21. Ehrenstein V, Antonsen S, Pedersen L. Existing data sources for clinical epidemiology: Aarhus University Prescription Database. Clin Epidemiol. 2010;2(2):273–9.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Nielsen GL, Sørensen HT, Zhou W, Steffensen FH, Olsen J. The Pharmacoepidemiologic Prescription Database of North Jutland—a valid tool in pharmacoepidemiological research. Int J Risk Saf Med. 1997;10(3):203–5.

    CAS  PubMed  Google Scholar 

  23. Gaist D, Sørensen HT, Hallas J. The Danish prescription registries. Dan Med Bull. 1997;44(4):445–8.

    CAS  PubMed  Google Scholar 

  24. Eugster-Hausmann M, Waitzinger J, Lehnick D. Minimized estradiol absorption with ultra-low-dose 10 microg 17beta-estradiol vaginal tablets. Climacteric. 2010;13(3):219–27.

    Article  CAS  PubMed  Google Scholar 

  25. Notelovitz M, Funk S, Nanavati N, Mazzeo M. Estradiol absorption from vaginal tablets in postmenopausal women. Obstet Gynecol. 2002;99(4):556–62.

    Article  CAS  PubMed  Google Scholar 

  26. Attili AF, Capocaccia R, Carulli N, Festi D, Roda E, Barbara L, et al. Factors associated with gallstone disease in the MICOL experience. Multicenter Italian Study on Epidemiology of Cholelithiasis. Hepatology. 1997;26(4):809–18.

    Article  CAS  PubMed  Google Scholar 

  27. Reshetnyak VI. Concept of the pathogenesis and treatment of cholelithiasis. World J Hepatol. 2012;4(2):18–34.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Erichsen R, Frøslev T, Lash TL, Pedersen L, Sørensen HT. Long-term statin use and the risk of gallstone disease: a population-based case–control study. Am J Epidemiol. 2011;173(2):162–70.

    Article  PubMed  Google Scholar 

  29. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull. 1998;45(3):320–3.

    CAS  PubMed  Google Scholar 

  30. Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol. 2003;158(9):915–20.

    Article  PubMed  Google Scholar 

  31. Boland LL, Folsom AR, Rosamond WD, Atherosclerosis Risk in Communities (ARIC) Study Investigators. Hyperinsulinemia, dyslipidemia, and obesity as risk factors for hospitalized gallbladder disease. A prospective study. Ann Epidemiol. 2002;12(2):131–40.

    Article  PubMed  Google Scholar 

  32. Rossouw JE, Anderson GL, Prentice RL, LaCroix 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(3):321–33.

    Article  CAS  PubMed  Google Scholar 

  33. Mamdani MM, Tu K, van Walraven C, Austin PC, Naylor CD. Postmenopausal estrogen replacement therapy and increased rates of cholecystectomy and appendectomy. CMAJ. 2000;162(10):1421–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Nielsen LH, Løkkegaard E, Andreasen AH, Hundrup YA, Keiding N. Estimating the effect of current, previous and never use of drugs in studies based on prescription registries. Pharmacoepidemiol Drug Saf. 2009;18(2):147–53.

    Article  PubMed  Google Scholar 

  35. Mosbech J, Jørgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen TD. The national patient registry. Evaluation of data quality. Ugeskr Laeger. 1995;157(26):3741–5.

    CAS  PubMed  Google Scholar 

  36. Nickelsen TN. Data validity and coverage in the Danish National Health Registry. A literature review. Ugeskr Laeger. 2001;164(1):33–7.

    CAS  PubMed  Google Scholar 

  37. Løkkegaard EL, Johnsen SP, Heitmann BL, Stahlberg C, Pedersen AT, Obel EB, et al. The validity of self-reported use of hormone replacement therapy among Danish nurses. Acta Obstet Gynecol Scand. 2004;83(5):476–81.

    PubMed  Google Scholar 

  38. Bakken K, Eggen AE, Lund E. Hormone replacement therapy in Norwegian women, 1996–1997. Maturitas. 2001;40(2):131–41.

    Article  CAS  PubMed  Google Scholar 

  39. Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med. 2002;137(4):273–84.

    Article  CAS  PubMed  Google Scholar 

  40. Johannes CB, Crawford SL, Posner JG, McKinlay SM. Longitudinal patterns and correlates of hormone replacement therapy use in middle-aged women. Am J Epidemiol. 1994;140(5):439–52.

    CAS  PubMed  Google Scholar 

  41. Progetto Menopausa Italia Study Group. Determinants of body mass index in women around menopause attending menopause clinics in Italy. Climacteric. 2003;6(1):67–74.

    Google Scholar 

Download references

Acknowledgments

This work was supported by the Clinical Epidemiology Research Foundation, Aarhus University Hospital, Aarhus, Denmark. The Department of Clinical Epidemiology is involved in studies with funding from various companies as research grants to (and administered by) Aarhus University. None of these studies have any relation to the present study.

Conflict of interest

Maja Hellfritzsch Simonsen, Rune Erichsen, Tine Frøslev, Jørgen Rungby, and Henrik Toft Sørensen have no conflict of interests that are directly relevant to the content of this manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Epidemiology, Aarhus University Hospital, Oluf Palmes Allé 43-45, 8200, Aarhus N, Denmark

    Maja Hellfritzsch Simonsen, Rune Erichsen, Trine Frøslev & Henrik Toft Sørensen

  2. Department of Clinical Pharmacology, Aarhus University Hospital, 8000, Aarhus C, Denmark

    Maja Hellfritzsch Simonsen & Jørgen Rungby

Authors
  1. Maja Hellfritzsch Simonsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rune Erichsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Trine Frøslev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jørgen Rungby
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Henrik Toft Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maja Hellfritzsch Simonsen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Tables (DOCX 30 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simonsen, M.H., Erichsen, R., Frøslev, T. et al. Postmenopausal Estrogen Therapy and Risk of Gallstone Disease: A Population-Based Case–Control Study. Drug Saf 36, 1189–1197 (2013). https://doi.org/10.1007/s40264-013-0118-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-013-0118-7

Keywords

Search

Navigation