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Irritable Bowel Syndrome and Endometriosis: Twins in Disguise

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Irritable Bowel Syndrome and Endometriosis: Twins in Disguise Review Irritable Bowel Syndrome and Endometriosis: Twins in Disguise Meredith Aragon, MD, MPH, and Bruce A. Lessey, MD, PhD From the Department of OB/GYN, Greenville Health System, Greenville, SC (M.A., B.A.L.) hronic pelvic pain (CPP) is a debilitating, IBS patients incur higher annual healthcare costs lifelong struggle for some individuals. compared to those without IBS,11 with spending C The diagnosis and treatment of CPP also ranging from $1562 to $7547 per year for the contribute to significant annual healthcare costs average IBS patient. Annually, IBS is estimated in the United States (US).1 The most common to result in $1.6 billion in direct costs and $19.2 diagnoses associated with CPP include endo- billion in indirect costs in the US alone. metriosis, interstitial cystitis, irritable bowel syndrome (IBS), myofascial pain, pelvic floor It can be argued that IBS is a constellation of hypertonia, and dysmenorrhea.2,3 In reality, CPP symptoms that includes bloating, diarrhea, con- in women often represents undiagnosed endo- stipation, and varied other bowel complaints, metriosis that may contribute to these other rather than a defined disease.12,13 In general, associated pain syndromes. Since a diagnosis of gastroenterologists (GIs) and others specializ- endometriosis requires surgery, there is a delay ing in gastroenterology complaints are largely in the diagnosis of endometriosis of greater than unaware of the strong links between IBS and 11 years in the US.4,5 endometriosis; therefore, it is rarely included in the differential diagnosis for bowel complaints. For some practitioners, symptoms including This fact may contribute to the poor satisfac- bowel, bladder, and pelvic complaints are recog- tion of patients with current IBS treatments. In nized manifestations of endometriosis. For other a recent survey, IBS caused daily symptoms in healthcare providers, the diagnosis of endome- 43% of patients; under 20% were satisfied with triosis is rarely considered. A lack of appreciation treatments they had received.14 A better under- for the morbidity associated with endometriosis standing of the pathophysiology of this disorder may be the primary reason for our failure to would likely lead to more effective treatments diagnose the majority of patients who present and earlier resolution of symptoms. with CPP.6 The pathophysiology of IBS includes immune Irritable bowel syndrome is a common func- activation, increased gut permeability, and vis- tional gastrointestinal disorder associated with ceral hypersensitivity.12 Endometriosis is also diarrhea (IBS-D), constipation (IBS-C), or both a highly inflammatory and immune-regulated (IBS-M). IBS is diagnosed on the basis of a char- disorder,15 raising the possibility that IBS could acteristic cluster of symptoms—recurring bouts well be a response to local or systemic inflam- of abdominal discomfort or pain relieved by matory changes associated with this disease.16,17 defecation and associated with a change in the C-reactive protein (CRP) has been used to differ- frequency and/or consistency of stools—in the entiate IBS from irritable bowel disease (IBD).18 absence of structural or biochemical abnormal- CRP has also been shown to be systemically ities. Diagnostic criteria are often loosely applied elevated in women with endometriosis.19 Auto- in the clinical setting, and the underlying cause immune dysfunction is common in endometri- 7 is never defined in many individuals. Diet and osis,20-22 but autoimmunity has been reported in 8,9 changes in the bowel microbiome have been patients with IBS as well.23 implicated in the etiology of IBS. Bile acid mal- absorption has also been documented in up to a In population studies, the majority of patients third of individuals with IBS-D.10 with IBS are women.24,25 Female sex is the single GHS Proc. June 2017; 2 (1): 43-50 43 greatest risk factor for development of IBS.12 Over Dysmenorrhea results in large part to prostaglan- 50% of women report cycle-dependent worsening din release,45 and women with IBS are more likely of IBS during menses. All of these associations to experience dysmenorrhea than women with- suggest that endometriosis may be a major con- out IBS.46 In women with IBS, estrogen and pro- tributor to IBS in women. In this review, we will gesterone may have an impact on visceral pain address these questions and provide a case series thresholds, and prostaglandins released during in support of this hypothesis. menstruation might influence those thresholds. Effect of Female Sex and Hormones The menstrual cycle has been shown to have an on IBS impact on bowel function in other ways. Gastro- enterology transit time is prolonged in the luteal Menstrual Cycles and IBS phase of the menstrual cycle47 and reduced when IBS has been noted to be highly related to female estrogen and progesterone levels fall right before 26 sex and to age, but not to race. There is a 2:1 menses. Stools tend to become loose during men- 27 ratio of women to men with IBS, and symptoms ses in women with IBS,28,31 suggesting faster gastro- of IBS are frequently related to the menstrual intestinal transit may be related to this symptom. cycle.28 Women with IBS report significantly more abdominal pain, bloating, intestinal gas, Bharadwaj and colleagues suggested that pros- constipation, and diarrhea at the time of menses taglandins, which are higher during menses, compared to controls.29-31 primarily contribute to IBS symptoms including abdominal pain, bloating, and diarrhea.47 Crow- Whitehead and colleagues found that 50% of ell and colleagues reported that women with female IBS patients compared to 34% of non-IBS dysmenorrhea had greater menstrual-related patients reported worsening bowel symptoms variation in pain sensitivity. The higher levels of 31 during menses. Heitkemper and colleagues prostaglandins in menstrual fluid is associated reported prospective data confirming that IBS with a greater risk of having endometriosis.37 The patients report worse stomach pain, nausea, and inflammation associated with endometriosis pro- diarrhea during menses compared to healthy motes cyclooxygenase-2 expression and prosta- controls.32 The worsening of IBS symptoms with glandin production.48,49 IBS symptoms at menses menses is analogous to symptoms reported by may, therefore, be exaggerated specifically in the women with endometriosis, who report increas- setting of endometriosis, raising the question of ing dysmenorrhea at the time of menses.33-35 whether IBS is merely gastrointestinal reaction to having endometriosis. This association also raises The link between endometriosis and IBS is the question of whether endometriotic implants strengthened further by the observation that dys- on or near the bowel is required for the symptoms 36,37 menorrhea itself is associated with IBS. Treat- of menstrual-related IBS. ment with GnRH agonist therapy to suppress endometriosis and cause cessation of menses Menopause 38 improves symptoms in both IBS and endometri- The influence of sex hormones on IBS is sup- 39,40 osis sufferers. Symptoms of IBS are improved ported by data from women in menopause. Prev- 27 after menopause, similar to what is reported for alence of IBS in women decreases markedly after endometriosis. menopause.26 In a survey of 5430 households in the US, frequency of IBS decreased after age 45 Menstrual Cycle Effects on Pain in women while remaining unchanged in men.50 The menstrual cycle affects pain sensitivity, with Similar trends have been reported in the United distinct differences in somatic compared to vis- Kingdom (UK)51 and Germany52 that document ceral pain. In the rat model, which has a 4-day an age-related decrease in IBS in women after estrus cycle, heightened somatic sensitivity to age 50–65, although symptoms may worsen in skin stimulation occurs during proestrus and the perimenopause before improving later after estrus phases (high estrogen), while visceral menopause.53 pain sensitivity was higher during metestrus and diestrus phases,41 comparable to perimenstrual Mathias and colleagues have demonstrated that or menstrual phase in women. The relationship artificial menopause induced with GnRH agonist between pain sensitivity and phase of the men- leuprolide decreased IBS symptoms.54-57 Con- strual cycle, while variable in women, follows versely, a cohort study in the UK reported an a similar pattern with somatic pain sensitivity increase in IBS symptoms in hormone replace- greatest in mid-cycle42 and visceral pain sensitiv- ment therapy (HRT) users compared to non-us- ity greatest at menses, at least in IBS patients.43,44 ers.58 Fillingim and Edwards showed a decrease 44 GHS Proc. June 2017; 2 (1): 43-50 IBS AND ENDOMETRIOSIS in somatic pain thresholds (increased pain sensi- nal changes at the time of menses—over 50% of tivity) in postmenopausal women receiving hor- women with IBS note cycle-specific worsening of mone therapy.59 symptoms.68 Compared to controls, women with endometriosis are 3.5 times more likely to have Pregnancy an IBS diagnosis.69 Implants of endometriosis Sex hormone levels are high during late preg- on the bowel have been reported in 3.8%–37% of nancy. Early survey data from the University of women diagnosed with endometriosis.70 North Carolina found that a majority of women with IBS reported a reduction in symptoms Essentially all studies exploring the association during pregnancy,60 which may reflect lack of between endometriosis and IBS have focused on hormone fluctuations and absence of menses women first diagnosed with endometriosis. Wu during the 9 months of pregnancy. Pregnant et al studied 6076 subjects with endometriosis 71 women have a higher likelihood of being con- and found that 15% had IBS. Hansen compared stipated, perhaps because of the smooth muscle endometriosis patients to controls and reported 67 relaxation effect of progesterone or the compres- that 22% had symptoms of IBS. Surprisingly, no sion of the bowel by the growing fetus.
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