By Andreea Vorobchevici
Editor’s Note: Inflammatory bowel disease (IBD) encompasses two related but different conditions: Crohn’s disease and ulcerative colitis. Both of these inflammatory conditions cause similar and unique changes within the gastrointestinal (GI) tract, and these differences impact their clinical manifestations, treatment options, and prognosis. While on the FACTS elective in fertility awareness, Andreea Vorobchevici chose to summarize the article by Dr. Hamed Khalili [1] titled, “Risk of Inflammatory Bowel Disease with Oral Contraceptives and Menopausal Hormone Therapy: Current Evidence and Future Directions.” While more research is needed in this area, the article provides data and perspectives to support patients with IBD when making choices about fertility and family planning.
Introduction
The article by Dr. Hamed Khalili [1] analyzed evidence on the association between oral contraceptives (OCPs) and Crohn’s disease and menopausal hormone replacement therapy (HRT) and ulcerative colitis (UC). Although more empirical research needs to be conducted, current theories on the association between exogenous hormones and inflammatory bowel disease (IBD) in women include the effects of these hormones on the permeability of the intestinal wall, endogenous levels of hormones, and the gut microbiome. [1]
Article Summary
Multiple studies have explored the association between exogenous hormones and risk of inflammatory bowel disease such as ulcerative colitis and Crohn’s disease. Although previous studies have identified more than 100 risk loci associated with Crohn’s disease and UC, it is believed that genetic predisposition accounts for only 25% of the risk of developing these chronic conditions. This highlights the importance of other environmental factors in the development of these diseases.
The association between OCPs and Crohn’s disease has been documented since the late 1960s. Multiple case studies, a meta-analysis, and a prospective study found an association of increased rates of Crohn’s disease in patients taking OCPs, but not in patients with ulcerative colitis. One of these studies reported a significant increase in the risk of developing UC with OCP use, but this risk became statistically insignificant once corrected for smoking.
“Multiple case studies, a meta-analysis, and a prospective study found an association of increased rates of Crohn’s disease in patients taking OCPs.”
Regarding HRT use in menopause, there is conflicting evidence on the association between different types of inflammatory bowel disease and HRT. One small study found a positive association between hormone replacement therapy use and Crohn’s disease but not UC; a larger prospective study found the inverse result.
Potential role of exogenous hormones
Although many plausible biological mechanisms could account for increased risk of IBD with exogenous hormone use, the actual mechanism is still unknown. One theory is that estrogen is involved in mucosal immunity and maintenance of the intestinal barrier. Another theory involves OCPs shifting endogenous hormone levels, thereby modifying immune function. Oral contraceptives have been found to be associated with a 50% decrease in testosterone and dehydroepiandrosterone sulfate (DHEA-S), which may play a role in regulating immune function. Testosterone has been implicated in animal studies to moderate the immune system by acting on toll-like receptors on macrophages and modifying cytokine production. One study supports this theory by finding an inverse relationship between testosterone and Crohn’s disease. Some data also suggests hormone levels may affect the gut microbiome, which may affect hormone levels. Studies have shown exogenous estrogen is associated with changes in the vaginal and oral flora, and gut microbes affect circulating levels of testosterone, which could lead to autoimmune disease. These are all possible mechanisms for the development of inflammatory bowel disease from OCP use.
“Oral contraceptives have been found to be associated with a 50% decrease in testosterone and dehydroepiandrosterone sulfate (DHEA-S), which may play a role in regulating immune function.”
Multiple theories exist as to why OCP use is associated with Crohn’s disease while HRT is associated with ulcerative colitis. There are many differences in doses and formulations between OCPs and HRT. Also, there may be different effects of exogenous estrogen acting on younger patients with high baseline levels of estrogen versus postmenopausal patients who are estrogen deficient. Crohn’s disease and UC also have different cytokine profiles in the pathogenesis of the disease, with Crohn’s disease primarily mediated by Th1-related cytokines and UC mediated by Th2-related cytokines.
Due to limitations in study design such as small sample sizes, limited determination of OCP exposure, and retrospective design, more research is needed to support the link between exogenous hormones and IBD and guide future clinical recommendations. [1]
Discussion
Although more research needs to be conducted in this area, the article by Khalili [1] presents key information pertinent to women forming evidence-based decisions about their health and family planning. Patients with known genetic predispositions to IBD may be more likely to pursue fertility awareness-based methods (FABMs) for family planning versus OCPs when given access to all the current information regarding possible benefits and side effects of OCPs.
“Patients with known genetic predispositions to IBD may be more likely to pursue fertility awareness-based methods (FABMs) for family planning versus OCPs when given access to all the current information regarding possible benefits and side effects of OCPs.”
Some of the studies presented are limited by small sample size, confounding variables, retrospective design, and lack of standardization of exposure to exogenous hormones. Still, some studies were prospective with larger sample sizes and provide considerable evidence to support the link between exogenous hormones and the development of IBD. Future research is needed using prospective design, larger sample sizes, and detailed records of forms and dosages of OCPs. Women have higher rates of autoimmune diseases compared to men, with a large body of evidence supporting the role of estrogen in the immune response. [2] Therefore, future research should also include associations between OCPs and HRT and the risk of developing other autoimmune diseases.
References
[1] Khalili H. Risk of Inflammatory Bowel Disease with Oral Contraceptives and Menopausal Hormone Therapy: Current Evidence and Future Directions. Drug Saf. 2016 Mar;39(3):193-7. doi: 10.1007/s40264-015-0372-y. PMID: 26658991; PMCID: PMC4752384.
[2] Moulton VR. Sex Hormones in Acquired Immunity and Autoimmune Disease. Front Immunol. 2018 Oct 4;9:2279. doi: 10.3389/fimmu.2018.02279. PMID: 30337927; PMCID: PMC6180207.
About the Author
Andreea Vorobchevici
Andreea Vorobchevici is a fourth-year medical student at the California University of Science and Medicine in Colton, CA. She completed her undergraduate education at the University of California Los Angeles in Los Angeles, CA. She enrolled in the FACTS elective to gain a better understanding of natural family planning methods and learn a holistic approach to women’s health that focuses on identifying and treating the root cause of symptoms through cycle tracking.
