Skip to main content
SpringerLink
Log in

Risk of Inflammatory Bowel Disease with Oral Contraceptives and Menopausal Hormone Therapy: Current Evidence and Future Directions

  • Current Opinion
  • Published:
Drug Safety Aims and scope Submit manuscript

Abstract

Crohn’s disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel diseases, are archetypical inflammatory disorders of the gastrointestinal tract with rising incidence worldwide. Although the role of genetic factors in disease development has been highlighted by genome-wide association studies, environmental risk factors likely play a pivotal role in development of CD and UC. Prior observational studies have suggested a link between exogenous hormone use and risk of CD and UC. Specifically, studies have shown an association between oral contraceptive use and risk of CD and menopausal hormone therapy and risk of UC. Although the exact mechanism of these associations is largely unknown, a number of hypotheses have been proposed. First, oral estrogen has been shown to modify intestinal permeability, a critical step in the pathophysiology of inflammatory bowel disease. Second, exogenous hormone use through its effect on endogenous levels of hormones may enhance the development of Th1- and Th2-mediated inflammatory diseases. Lastly, recent data have linked modification in the gut microbiome to endogenous levels of androgens, which are also known to be altered with exogenous hormone use and influence the development of autoimmune diseases. This supports the intriguing hypothesis that the gut microbiome lies at the crossroads of pathways linking exogenous hormone use with innate and adaptive immunity. Future studies should therefore focus on bridging these epidemiologic findings to disease pathogenesis through comprehensive understanding of the complex interaction between exogenous hormone use, sex steroid biomarkers, genetic risk loci, and alterations in the intestinal microbial environment in the etiology of CD and UC.

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. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43(3):246–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Williams CN. Does the incidence of IBD increase when persons move from a low- to a high-risk area? Inflamm Bowel Dis. 2008;14(Suppl 2):S41–2.

    Article  PubMed  Google Scholar 

  5. Khalili H, Higuchi LM, Ananthakrishnan AN, Manson JE, Feskanich D, Richter JM, et al. Hormone therapy increases risk of ulcerative colitis but not Crohn’s disease. Gastroenterology. 2012;143(5):1199–206.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Khalili H, Higuchi LM, Ananthakrishnan AN, Richter JM, Feskanich D, Fuchs CS, et al. Oral contraceptives, reproductive factors and risk of inflammatory bowel disease. Gut. 2013;62(8):1153–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Berjian RA. Regional enteritis, superior mesenteric vein thrombosis, common iliac thromboembolism: possible association with oral contraceptives. J Am Osteopath Assoc. 1969;69(1):84–6.

    CAS  PubMed  Google Scholar 

  8. Delavierre P, Bourdais JP, Hureau J, Vayre P. Intestinal complications during the use of oral contraceptives. Sem Hop Paris. 1976;52(20):1225–8.

    Google Scholar 

  9. Johnson GK, Geenen JE, Hensley GT, Soergel KH. Small intestinal disease, folate deficiency anemia, and oral contraceptive agents. Am J Dig Dis. 1973;18(3):185–90.

    Article  CAS  PubMed  Google Scholar 

  10. Rhodes JM, Cockel R, Allan RN, Hawker PC, Dawson J, Elias E. Colonic Crohn’s disease and use of oral contraception. Br Med J (Clin Res Ed). 1984;288(6417):595–6.

    Article  CAS  Google Scholar 

  11. Bonfils S, Hervoir P, Girodet J, Le Quintrec Y, Bader JP, Gastard J. Acute spontaneously recovering ulcerating colitis (ARUC). Report of 6 cases. Am J Dig Dis. 1977;22(5):429–36.

    Article  CAS  PubMed  Google Scholar 

  12. Cornish JA, Tan E, Simillis C, Clark SK, Teare J, Tekkis PP. The risk of oral contraceptives in the etiology of inflammatory bowel disease: a meta-analysis. Am J Gastroenterol. 2008;103(9):2394–400.

  13. Garcia Rodriguez LA, Gonzalez-Perez A, Johansson S, Wallander MA. Risk factors for inflammatory bowel disease in the general population. Aliment Pharmacol Ther. 2005;22(4):309–15.

  14. Braniste V, Jouault A, Gaultier E, Polizzi A, Buisson-Brenac C, Leveque M, et al. Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats. Proc Natl Acad Sci. 2010;107(1):448–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Looijer-van Langen M, Hotte N, Dieleman LA, Albert E, Mulder C, Madsen KL. Estrogen receptor-beta signaling modulates epithelial barrier function. Am J Physiol Gastrointest Liver Physiol. 2011;300(4):G621–6.

  16. Coenen CM, Thomas CM, Borm GF, Hollanders JM, Rolland R. Changes in androgens during treatment with four low-dose contraceptives. Contraception. 1996;53(3):171–6.

    Article  CAS  PubMed  Google Scholar 

  17. Wilke TJ, Utley DJ. Total testosterone, free-androgen index, calculated free testosterone, and free testosterone by analog RIA compared in hirsute women and in otherwise-normal women with altered binding of sex-hormone-binding globulin. Clin Chem. 1987;33(8):1372–5.

    CAS  PubMed  Google Scholar 

  18. Rettew JA, Huet-Hudson YM, Marriott I. Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity. Biol Reprod. 2008;78(3):432–7.

    Article  CAS  PubMed  Google Scholar 

  19. Khalili H, Ananthakrishnan AN, Konijeti GG, Higuchi LM, Fuchs CS, Richter JM, et al. Endogenous levels of circulating androgens and risk of Crohn’s disease and ulcerative colitis among women: a nested case-control study from the nurses’ health study cohorts. Inflamm Bowel Dis. 2015;21(6):1378–85.

    PubMed Central  PubMed  Google Scholar 

  20. Devillard E, Burton JP, Hammond JA, Lam D, Reid G. Novel insight into the vaginal microflora in postmenopausal women under hormone replacement therapy as analyzed by PCR-denaturing gradient gel electrophoresis. Eur J Obstet Gynecol Reprod Biol. 2004;117(1):76–81.

    Article  CAS  PubMed  Google Scholar 

  21. Galhardo CL, Soares JM Jr, Simoes RS, Haidar MA, Rodrigues de Lima G, Baracat EC. Estrogen effects on the vaginal pH, flora and cytology in late postmenopause after a long period without hormone therapy. Clin Exp Obstet Gynecol. 2006;33(2):85–9.

    CAS  PubMed  Google Scholar 

  22. Heinemann C, Reid G. Vaginal microbial diversity among postmenopausal women with and without hormone replacement therapy. Can J Microbiol. 2005;51(9):777–81.

    Article  CAS  PubMed  Google Scholar 

  23. Brusca MI, Rosa A, Albaina O, Moragues MD, Verdugo F, Ponton J. The impact of oral contraceptives on women’s periodontal health and the subgingival occurrence of aggressive periodontopathogens and Candida species. J Periodontol. 2010;81(7):1010–8.

    Article  PubMed  Google Scholar 

  24. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–8.

    Article  CAS  PubMed  Google Scholar 

  25. Hatoum OA, Binion DG, Otterson MF, Gutterman DD. Acquired microvascular dysfunction in inflammatory bowel disease: loss of nitric oxide-mediated vasodilation. Gastroenterology. 2003;125(1):58–69.

    Article  CAS  PubMed  Google Scholar 

  26. Ibrahim CB, Aroniadis OC, Brandt LJ. On the role of ischemia in the pathogenesis of IBD: a review. Inflamm Bowel Dis. 2010;16(4):696–702.

    Article  PubMed  Google Scholar 

  27. Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60(12):1739–53.

    Article  CAS  PubMed  Google Scholar 

  28. Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest. 2004;113(10):1490–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn’s disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157(3):1261–70.

    CAS  PubMed  Google Scholar 

  30. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005;129(2):550–64.

    Article  CAS  PubMed  Google Scholar 

  31. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, et al. Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997;112(4):1169–78.

    Article  CAS  PubMed  Google Scholar 

  32. Cutolo M, Capellino S, Straub RH. Oestrogens in rheumatic diseases: friend or foe? Rheumatology (Oxford). 2008;47(Suppl 3):iii2–5.

  33. Gonzalez DA, Diaz BB, Rodriguez Perez Mdel C, Hernandez AG, Chico BN, de Leon AC. Sex hormones and autoimmunity. Immunol Lett. 2010;133(1):6–13.

  34. Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med. 2003;349(6):523–34.

    Article  CAS  PubMed  Google Scholar 

  35. Sutherland LR, Ramcharan S, Bryant H, Fick G. Effect of oral contraceptive use on reoperation following surgery for Crohn’s disease. Dig Dis Sci. 1992;37(9):1377–82.

    Article  CAS  PubMed  Google Scholar 

  36. Timmer A, Sutherland LR, Martin F. Oral contraceptive use and smoking are risk factors for relapse in Crohn’s disease. The Canadian Mesalamine for Remission of Crohn’s Disease Study Group. Gastroenterology. 1998;114(6):1143–50.

    Article  CAS  PubMed  Google Scholar 

  37. Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Gendre JP. Oral contraceptive use and the clinical course of Crohn’s disease: a prospective cohort study. Gut. 1999;45(2):218–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Evans G, Sutton EL. Oral contraception. Med Clin N Am. 2015;99(3):479–503.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Hamed Khalili

  2. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Hamed Khalili

  3. Digestive Healthcare Center—Crohn’s and Colitis Center, Massachusetts General Hospital, 165 Cambridge Street, 9th Floor, Boston, MA, 02114, USA

    Hamed Khalili

Authors
  1. Hamed Khalili
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hamed Khalili.

Ethics declarations

Funding

No sources of funding were used to assist in the preparation of this study.

Grant support

Dr. Khalili is supported by a career development award from the American Gastroenterological Association (AGA) and by the National Institute of Diabetes and Digestive and Kidney Diseases (K23 DK099681).

Conflict of interest

Dr. Khalili has received consulting fees from Abbvie Inc.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khalili, H. Risk of Inflammatory Bowel Disease with Oral Contraceptives and Menopausal Hormone Therapy: Current Evidence and Future Directions. Drug Saf 39, 193–197 (2016). https://doi.org/10.1007/s40264-015-0372-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40264-015-0372-y

Keywords

Search

Navigation