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Home , Pelvic pain

Review

Irritable Bowel Syndrome and : 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 (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, , (IBS), myofascial pain, pelvic floor It can be argued that IBS is a constellation of hypertonia, and .2,3 In reality, CPP symptoms that includes , , 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), (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 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. 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 , 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, , 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. studies to date have examined women with IBS and asked how many have endometriosis. While Endometriosis up to a third of endometriosis patients have bowel Endometriosis is an estrogen-dependent, inflam- implants, it remains unknown how many women matory condition affecting women from men- with IBS have endometriosis and how many of arche to menopause.33 It is present in 5%–10% of those have lesions on or near the bowel. the general population but in up to 70% of women Most women with IBS are under- or misdiag- with pelvic pain. Endometriosis is characterized nosed.72 Nasim et al points out that bowel endo- by a constellation of symptoms including pain- metriosis is often not considered or included in ful periods (dysmenorrhea), painful intercourse the differential diagnosis for acute or chronic (), and painful bowel movements abdominal complaints.73 In our practice, we per- (dyschezia). In addition, subtle signs of endome- form routinely for CPP and have triosis have been recognized, and are related to examined a subset of women with complaints a hormonal disturbance known as progesterone specific to IBS. This study is the first to examine resistance, leading to infertility, spotting before women with IBS and perform laparoscopy for menses, and luteal phase defect. Systemic mani- determination of endometriosis. festations of the inflammatory milieu associated with endometriosis are also thought to contrib- As shown in Table 1, the finding of endometrio- ute to more global symptoms including malaise, sis was uniformly positive in these women. In 12 22 chronic fatigue, and IBS. consecutive laparoscopies in women identified with IBS, 12/12 (100%; 95% CI: 75% to 100%) were Endometriosis is defined as the presence of ecto- found to have endometriosis present. The 95% con- pic , composed of glandular and/ fidence interval (CI) reflects an important finding, or stromal elements outside of the uterine cavity. worthy to pursue further investigation. Perhaps This material gets deposited inside the at more important, the stage of disease was generally the time of menstruation, likely from retrograde minimal or mild disease; in all but 1 case, endo- menstruation.61 Genetic predisposition plays a metriosis was found on or near the rectum, in the dominant role in its pathogenesis.62,63 pouch of Douglas (posterior cul-de-sac). We, and others, have documented that the pres- Although these data are preliminary, they suggest ence of this ectopic tissue in the pelvis and else- that endometriosis is a predominant finding in where can generate a significant systemic inflam- women with menstrual cycle-related IBS and may matory response.16,64-66 Inflammatory changes reflect direct irritation of endometriosis on nearby have been shown to improve after treatment, but bowel. As women with IBS have other symptoms as a relapsing disease, a return of inflammation of endometriosis (eg, dysmenorrhea), it would can occur as menstruation resumes. be important to better define this population in Association Between Endometriosis future studies. and IBS This finding of posterior cul-de-sac disease in the Bowel and bladder complaints are common in majority of IBS patients suggests that local inflam- women with endometriosis.67 Up to a third of mation secondary to the endometriotic implant women with endometriosis report gastrointesti- may directly contribute to symptoms of IBS. Only

GHS Proc. June 2017; 2 (1): 43-50 45 Table 1 Findings at laparoscopy and at pathology for women with symptoms of IBS.

Case # Age Parity Operative Findings Pathology Stage On Bowel?

1 28 G0 Endometriosis everywhere but especially on rectum. Confirmed, 3 yes Implants on anterior and posterior cul-du-sac. Normal endometriosis; and bilateral tubes/. proliferative endometrium 2 27 G0 Posterior pelvic sidewalls, none in cul-de-sac. There were Confirmed, 2 no multiple obvious endometriosis implants along the left endometriosis; pelvic side wall. secretory phase endometrium 3 37 G0 Adjacent to rectum on right. Normal appearing bilateral Confirmed, 2 yes fallopian tubes with small endometriosis implant on right endometriosis mesosalpinx.

4 32 G0 Endometriosis adjacent to rectum on left. Uterus: Confirmed, 2 yes enlarged, multinodular. Fibroids: 3.5 cm fundal near left endometriosis; cornual region; 5 cm right anterior subserosal. Left : secretory phase several surface implants of endometriosis with 8 mm endometrium .

5 36 G3P3003 Endometriosis on rectum. Absent right tube and ovary. Confirmed, 1 yes Multiple areas of white stellate scarring consistent with endometriosis; endometriosis on midline posterior cul-de-sac proliferative phase endometrium 6 24 G0 Posterior cul-de-sac and left side wall endometriosis. Confirmed, 1 yes Abnormal with peritoneal window and thickened endometriosis; peritoneum. Left ovary: abnormal adherent to omentum inactive and bowel on left. endometrium 7 25 G1P1 Endometriosis seen on posterior cul-de-sac on rectum. Confirmed, 1 yes Normal uterus; surgically absent left tube and ovary. endometriosis 8 31 G0 Posterior cul-de-sac disease. Anterior cul-de-sac: abnormal Confirmed, 2-3 yes with endometriosis across the bladder. Midline posterior endometriosis; cul-de-sac: abnormal with endometriosis to the right of the benign proliferative rectum and above, near the termination of the uterosacral phase endometrium ligament. Left pelvic sidewall below the area of the ureter. Left ovary: endometriosis.

9 25 G0 Endometriosis on rectum, multiple endometriotic implants Confirmed, 2 yes identified and resected including left and right ovarian endometriosis lesions, a lesion under the ovary on the left, and implants across the left uterosacral.

10 28 G0 Endometriosis on rectum; endometrioma on left ovary, Confirmed, 3 yes endometriosis throughout left pelvic sidewall, posterior cul- endometriosis; early de-sac, right pelvic sidewall, bilateral uterosacral ligaments, secretory phase bilateral ovaries, posterior uterine serosa, and small endometrium endometriosis implant on anterior cul-de-sac.

11 23 G0 Endometriosis with large nodule on rectum; left ovary stuck Confirmed, 4 yes to sidewall. Endometriosis on bladder, left sidewall, cul-de- endometriosis; sac, right side wall, out of the pelvis on the right abdominal proliferative phase wall, and on the right ovary. Endometriosis on appendix, endometrium which was twisted on itself because of endometriosis. 12 36 G2P2002 Nodules on small intestine and colon. Endometriosis of Confirmed, 3 yes the right pelvic sidewall, right ovary, left pelvis, anterior endometriosis abdominal wall left side, 2 areas on the large intestine (sigmoid colon), 1 area on the small intestine at the area of the cecum (terminal ileum).

46 GHS Proc. June 2017; 2 (1): 43-50 IBS AND ENDOMETRIOSIS

1 other study suggests that location of implants A true association between endometriosis and might be critical to symptoms of IBS.74 In that IBS would be supported by reduced symptoms study, it was reported that both mild, superficial after treating endometriosis. Both surgical and disease and deep, infiltrating endometriosis (DIE) medical treatments for endometriosis have been were associated with IBS symptoms. Women with described.81 Drossman identified 13 women with DIE involving the rectum were more likely to IBS who had endometriosis treated surgically by experience cycle-dependent dysmenorrhea, while resection.82 They reported that 83% of participants superficial disease contributed more to painful sex experienced complete relief of symptoms follow- (dyspareunia). Interestingly, women with superfi- ing surgery. cial disease reported cyclic constipation and cyclic dyschezia in 38% and 33% of cases, respectively. Medical therapy has also been reported to improve IBS symptoms. Ferrero treated 6 patients with Studies in rats suggest a mechanism for the associ- colorectal endometriosis with 6 months of nore- ation between endometriosis and bowel dysfunc- thindrone acetate (2.5 mg/d) and the aromatase tion. Li and colleagues showed in the rat model inhibitor Letrozole (2.5 mg/d) and reported that endometriosis caused inflammation with an improvement in 67% of subjects (4/6). Neither increase in immunoreactivity in dor- study included controls, and the number of treated sal root ganglia neurons innervating both uterus subjects was low. Prospective studies are needed to 75 and colon. further study the effect of treating IBS in women with endometriosis. In human endometriosis, Remorgida and col- leagues examined the relationship between gas- Summary and Conclusions trointestinal complaints and histologic findings in women with endometriosis.76 In this import- Recognizing the association between endometri- ant study, 18% of women with endometriosis had osis and IBS represents a great challenge for cli- bowel lesions. They found that women experi- nicians treating women. Endometriosis is rarely enced bowel complaints only when the subserosal included in the differential diagnosis for gas- layer of the bowel was interrupted, damaging the trointestinal complaints, even though evidence interstitial cajal cells. now strongly suggests it may be a primary cause of both IBS and a similar syndrome, interstitial Mast cells have been implicated in IBS.77 Intestinal cystitis. Most female IBS patients are never diag- mast cells are involved in low-grade inflammation nosed with endometriosis, even though a cause- of the bowel and are capable of releasing a variety and-effect relationship exists. Both medical and of factors in response to different stimuli.78 Mast surgical treatments for endometriosis reduce IBS cells can be activated by IgE as well as pro-in- symptoms, and cessation of menses either medi- flammatory cytokines through specific receptors, cally or after menopause decreases symptoms in including TNF-α and IL-6, shown to be elevated both conditions. in rectovaginal endometriotic tissues.79 Mast cells have been shown to be elevated in endometriotic Mechanisms of IBS may reflect local inflamma- tissues.80 tion caused by endometriosis on or near the bowel in affected individuals. This finding is supported In addition, using nanostring technology for by our case study in which 11 of 12 subjects had immune transcriptomic profiling, we recently posterior, rectal endometriotic implants present. reported that several genes involved in mast cell GIs and clinicians treating gastrointestinal com- biology (major basic protein, Fc fragment of IgE plaints should consider endometriosis as a likely high affinity I receptor for alpha peptide, Fc frag- diagnosis in reproductive-aged women with IBS, ment of IgE, high affinity I receptor for gamma especially when symptoms worsen at menses. polypeptide, and sphinogosine-1phosphate recep- tor I) were differentially expressed in endometri- Future studies are planned to prospectively and otic tissues.17 We also recently found that mast cells rigorously define IBS and to determine the prev- were associated with stem cell factor, a growth fac- alence of endometriosis in this group of women. tor critical for mast cell expansion, differentiation, Further, it will be important to study whether and survival (work in progress). These interactions surgical resection or medical treatment of endo- leading to mast cell expansion at sites of endome- metriosis will lessen or eradicate the symptoms of triosis may represent new therapeutic targets for this common condition, given that effective and treating both endometriosis and IBS. long-term cures for IBS remain limited.

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