Drug Safety

, Volume 39, Issue 3, pp 193–197 | Cite as

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

  • Hamed KhaliliEmail author
Current Opinion


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.


Ulcerative Colitis Oral Contraceptive Menopausal Hormone Therapy Exogenous Hormone Intestinal Barrier Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards


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.


  1. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066–78.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.Google Scholar
  13. 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.Google Scholar
  14. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 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.Google Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.PubMedCentralPubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 27.
    Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60(12):1739–53.CrossRefPubMedGoogle Scholar
  28. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 32.
    Cutolo M, Capellino S, Straub RH. Oestrogens in rheumatic diseases: friend or foe? Rheumatology (Oxford). 2008;47(Suppl 3):iii2–5.Google Scholar
  33. 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.Google Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Evans G, Sutton EL. Oral contraception. Med Clin N Am. 2015;99(3):479–503.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Division of GastroenterologyMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  2. 2.Clinical and Translational Epidemiology UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA
  3. 3.Digestive Healthcare Center—Crohn’s and Colitis CenterMassachusetts General HospitalBostonUSA

Personalised recommendations