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Hormone Replacement Therapy, Oral Contraceptives May Increase Risk of Microscopic Colitis

Key findings

  • In two large prospective cohorts of U.S. women, the use of menopausal hormone replacement therapy (HRT) was associated with an increased risk of microscopic colitis
  • The association was stronger with estrogen-containing HRT than with other formulations
  • The risk of microscopic colitis significantly increased as duration of HRT increased
  • Women who had used oral contraceptives were at a significantly increased risk of microscopic colitis compared with non-users

The incidence of microscopic colitis, a chronic inflammatory disorder of the large intestine, appears to be highest in postmenopausal women. This implies that hormonal factors may have a crucial pathogenic role. Kristen E. Burke, MD, research fellow in the Department of Medicine, and Hamed Khalili, MD, MPH, gastroenterologist, and colleagues found an association between microscopic colitis and the use of exogenous hormones. Their research is published in Gastroenterology.

Researchers analyzed two large cohorts of U.S. women: participants in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII). Together, these studies provided more than 20 years of data. The NHS (N=121,706) began in 1976 and the NHSII (N=116,684) began in 1989. In both studies, participants complete a health questionnaire every two years.

Biopsy specimens for diagnosis of microscopic colitis did not become standard practice until the late 1980s, so the researchers restricted their analysis to the 1988–2014 questionnaires for the NHS and the 1989–2015 questionnaires for the NHSII. At the midpoint of the follow-up, the average age of participants was 64 years in the NHS cohort, with about 94% of women having reached menopause, and 45 years in the NHSII cohort, with about 25% of women having reached menopause.

Among 227,766 women, the researchers identified 275 incident cases of microscopic colitis over the 26 years (5,147,282 person-years) of follow-up. The incidence increased with age, and 239 cases occurred in postmenopausal women. Over the entire study period, the average age at diagnosis of microscopic colitis was 65.

Risk Factors in Postmenopausal Women

When the researchers pooled data on menopausal women in both cohorts, both past and current users of menopausal hormone replacement therapy (HRT) were at significantly increased risk of microscopic colitis. Compared with nonusers, the adjusted hazard ratio was 1.95 (95% CI, 1.37–2.78) for past users and 2.64 (95%, CI 1.78–3.90) for current users.

The association was stronger for estrogen-containing HRT than for other types of hormone preparations. The adjusted hazard ratio for microscopic colitis was 2.33 (95% CI, 1.54–3.52) for estrogen-only HRT, 2.12 (95% CI, 1.43–3.12) for combined estrogen and progestin preparations and 1.42 (95% CI, 0.34–5.89) for progestin-only HRT.

Other notable findings were that the risk of microscopic colitis significantly increased with as duration of HRT increased; longer time since discontinuation of HRT was tied to a significantly decreased risk of microscopic colitis.

Reproductive Risk Factors

According to another pooled analysis of NHS and NHSII, women who had used oral contraceptives were at a significantly increased risk of microscopic colitis, compared with nonusers (adjusted hazard ratio, 1.57; 95% CI, 1.16–2.13).

Biological Plausibility of the Findings

Because there are many other reasons for women to minimize the use of HRT, these results may not have important clinical implications. They do, however, confirm that biological pathways related to sex hormones, particularly estrogen, play a critical role in the pathogenesis of chronic inflammatory disorders of the gastrointestinal tract.

Exogenous estrogen has been linked to the development and progression of systemic lupus erythematosus, Crohn's disease and ulcerative colitis. Estrogen is thought to modify colonic epithelial permeability and mucosal immunity in these disorders. Epithelial barrier function also seems to be impaired in microscopic colitis, leading to an inflammatory response to fecal microbiota.

Moreover, estrogen receptors are found on immune cells and might regulate the immune response to gut flora. Estrogen exposure through oral contraceptives or HRT could lead to changes in mucosal immunity, heightening the abnormal inflammatory response to commensal bacteria seen in microscopic colitis.

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