Symptomatology of irritable bowel syndrome and inflammatory bowel disease during the menstrual cycle.

The role of the menstrual cycle in the symptomatology of IBD patients is complex and not completely understood. The literature has shown that there are cyclical changes in GI symptoms in IBD patients during the menstrual cycle [ 55 , 62 ]. The exact etiology of the fluctuations in bowel pattern in relation to ovarian hormones remains to be defined; however, a possible role of PGs has been hypothesized. PGs are important components of inflammation in IBD and they are released by the endometrium during menses, which can exacerbate GI symptoms [ 62 ]. To date, only a few studies have investigated the relationship between GI symptoms in IBD and the menstrual cycle [ 11 , 52 , 62 , 63 ] ( Table 3 ); according to these, the majority of IBD patients reported worsening of GI symptoms during premenstrual and menstrual phases [ 11 ]. Most of these studies involved questionnaires and small sample sizes, with large inter-individual variability. Despite these limitations, it appears that the IBD patients experienced worsening of GI symptoms during the premenstrual and menstrual phases. Table 3. Published studies on IBD and the menstrual cycle Study Study design No. studied, UC/CD/control Age (range in years) Menstrual phase Methods Findings Kane et al. [ 52 ] 1998 Retrospective 49/49/90 20–48 Pre- and during menses Questionnaire 1) IBD group reported a cyclical pattern to menstrual cycle more often than controls 2) Diarrhea: most common symptom reported Parlak et al. [ 62 ] 2003 Prospective 38/21/38 30–47 Menstrual cycle Diary 1) UC and control groups reported more GI symptoms during menses 2) CD symptoms worse pre-, and during menses compared to postmenses Bernstein et al. [ 63 ] 2012 Retrospective 87/151/156 18–65 Pre-, and during menses Questionnaire 1) CD and UC groups more likely to experience diarrhea during menses 2) Premenstrual phase- CD patients more likely to report worsening of their IBD symptoms than UC and control Lim et al. [ 11 ] 2013 Prospective 27/13/44 33–43 Menstrual cycle Questionnaire GI symptomatology worse during menses in IBD and control groups CD = Crohn’s disease; IBD = inflammatory bowel disease; UC = ulcerative colitis Published studies on IBD and the menstrual cycle CD = Crohn’s disease; IBD = inflammatory bowel disease; UC = ulcerative colitis The effect of menopause on IBD disease activity is unclear. In 1989, Lichtarowicz et al. surveyed women with Crohn’s disease (CD) for details of their menstrual cycles, ages at menopause and smoking habits [ 64 ]. Of the 146 patients with CD who responded, 48 (34%) had undergone menopause at a mean age of 47.6 years, compared with 49.6 years in the control group. The investigators concluded that CD was associated with premature menopause [ 58 ]. In contrast, a retrospective study by Kane et al. reported no difference between the IBD and control groups in the age of onset of menopause [ 65 ]. Additionally, there was no significant correlation between having a flare in the pre- and post-menopausal states; however, the use of HRT appeared to confer a protective effect in on disease activity [ 65 ]. Compared with those not using HRT, women with IBD who used HRT were 82% less likely to have a flare in the first 2 years of menopause. Moreover, those on HRT who did have a flare appeared to have a less-severe disease course [ 53 ]. Limited data are available on the variability of GI symptomatology during the menstrual cycle in patients with restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). One study, which included 123 patients with IPAA, reported increased abdominal pain, diarrhea, and urgency during menses compared with pre-menses. Also, painful menses was significantly associated with increased GI symptomatology in those patients (odds ratio 5.67; 95% confidence interval 1.41–22.88; P =  0.015) [ 66 ]. The association between the use of oral contraceptive pills (OCP) and development of disease activity in IBD has been extensively investigated. Cornish et al. summarized data from 14 studies and found that female patients exposed to the OCP have a pooled relative risk (RR) of 1.46 of developing CD with current exposure to the OCP, even after adjusting for smoking [ 67 ]. The role of OCPs in the disease activity of IBD is less clear, although limited evidence suggests that there is no greater risk of relapse or increase in disease activity score with the use of OCP [ 68 , 69 ].

There are gender-related physiological differences in gastrointestinal (GI) symptomatology [ 1 ]. Many healthy women experience variations in GI symptoms during the menstrual cycle [ 2 ]. The phenomenon may be attributed to the fact that there are sex hormone receptors along the GI tract [ 3 ]. In addition, the effect of progesterone on the gut motility during pregnancy—resulting in constipation, increased reflux and biliary dysfunction—suggests a connection between menstrual cycle and the GI symptomatology [ 4 , 5 ]. GI transit has been extensively studied in healthy women throughout the menstrual cycle; however, the results of both prospective and retrospective studies have been inconclusive. Some studies have shown an increased transit time during the luteal phase [ 2 , 3 ], whereas others have shown no changes [ 6 , 7 ]. Possible explanations of the reported discrepancy include differences between study populations, study designs and the markers used to measure GI transit time. The investigation of an association between GI motility and menstruation in patients with irritable bowel syndrome (IBS) is rather more conclusive [ 8 ]. There may be a role of an increased perception of visceral somatic stimuli, resulting in nausea, abdominal distension, and pain, particularly during the first day of menses, probably due to the elevated prostaglandin (PG) levels during menstruation [ 9 , 10 ]. Recent studies have also shown the variability of GI symptomatology in patients with inflammatory bowel disease (IBD) during the menstrual cycle [ 11 ]. There is a general perception that women with IBD experience worsened GI symptoms during menses [ 11 ], but there is disagreement over whether this is a physiological exacerbation or a disease flare. In most studies, diarrhea is the most common GI symptom reported during menses, irrespective of the underlying disease. In this article, we discuss the association between the menstrual cycle and GI symptoms in healthy individuals and in women with IBS or IBD.

Based on this review, we conclude that hormone fluctuations in women of reproductive age influence the GI function, particularly in patients with IBS or IBD. There are several common events in women’s lives that result in dramatic changes in sex hormone levels, including the use of OCPs, pregnancy, lactation, surgical removal of the ovaries, and HRT. Additionally, gonadal hormones influence pain sensitivity via a variety of mediators including serotonin, which is ubiquitous in the GI tract and causes smooth muscle hypersensitivity associated with IBS. Notably, few studies have observed increased GI transit time during the luteal phase; however, these studies have been limited by sample size, study design, differences between the GI markers used, and wide inter-individual variability. Research on the effects of ovarian hormones on IBS and IBD has been more conclusive. Premenstrual and menstrual worsening of GI symptoms has been reported more frequently by patients with IBS or IBD than by controls. Additionally, both disease groups report a cyclical pattern to their bowel habits. Knowledge of cyclical changes in GI symptoms during the menstrual cycle may help us quantify the true exacerbation. A carefully recorded menstrual history may be helpful before considering major changes in therapeutic intervention in patients with IBD or IBS. In women with IBS or IBD, in addition to a good menstrual history, clinicians should give a special consideration to gender-related issues such as contraception, cervical screening and HRT. Further, osteoporosis is a problem that must be considered in patients with IBD, irrespective of their postmenopausal state. Since most studies have limitations—including retrospective design, small sample sizes, non-standardized self-report of symptoms and large inter-individual variability—future avenues of research should include prospective recording of symptoms with respect to different phases of the menstrual cycle. Also, the phase of the menstrual cycle should be validated by serum- or urine analysis of sex hormones. Further, simultaneous measurement of inflammatory markers during symptom flare-up would help to distinguish between acute exacerbation and normal physiological response. An important next step is to determine whether sex or hormone status affects the efficacy of current therapeutic approaches. Additionally, medications such as NSAID and oral contraceptives used for dysmenorrhea and menstrual migraine have rarely been controlled for, in the previous studies, which might have contributed to further bias. Categorization and selection of patients on IBS subtypes may also be needed. Furthermore, the value of sex hormones (e.g. OCP and HRT) in the management of patients with IBS or IBD remains to be clearly defined. Finally, the role of behavioral and psychological interventions for women with IBS or IBD during different phases of menstrual cycle could also be an area of further research. Conflict of interest statement : none declared.

Many characteristics of both IBS and IBD have a significant impact on various aspects of a patient’s quality of life; in addition, female patients can be affected by fluctuations in hormones from menarche to menopause [ 69 , 70 ]. When providing care to women with IBD, physicians should be aware of these gender-specific issues, including symptom fluctuations during the menstrual cycle, body image, sexuality, contraception, cervical cancer screening, fertility and pregnancy and lactation, as well as matters related to the menopause and HRT [ 70 , 71 ]. Marri et al. reported a higher rate of voluntary childlessness in women with IBD than in controls [ 72 ]. The use of OCPs to prevent pregnancy is also common in patients with IBD [ 71 ]. Furthermore, OCPs are frequently prescribed for patients who have a combination of dysmenorrhea and menstrual migraine [ 73 , 74 ]. Additionally, due to poor absorption, there is always a risk of OCPs being ineffective in active disease and in patients with multiple surgeries [ 75 ]. Osteoporosis following menopause is another concern [ 76 ]. The use of HRT in patients with IBD may help reduce risk of flare-up and prevent bone loss but, due to the estrogen effect, there is a small risk of breast cancer, coronary artery disease, stroke, and venous thromboembolism [ 69 ]. Dysmenorrhea and menstrual migraine are problems commonly experienced by women of reproductive age [ 72 , 73 ]. Dysmenorrhea is linked to the excess or imbalance in PG’s and arachidonic acid metabolites released from the endometrium during menstruation, leading to uterine cramping and pain. In addition, these may gain access to the systemic circulation and GI tract, causing abdominal pain and diarrhea. Few studies have investigated the prevalence of dysmenorrhea in patients with IBS and IBD. One, which compared IBS patients with healthy controls, found a higher incidence of dysmenorrhea in patients with IBS [ 77 ]. Also another study, which used daily diaries to record symptoms, found a higher pain score in the late luteal and menstrual phases in patients diagnosed with simultaneous IBS and dysmenorrhea than in patients with IBS alone [ 78 ]. Similarly, one study found an increased prevalence of dysmenorrhea in patients with CD [ 79 ]. In conclusion, dysmenorrhea is highly prevalent in patients with IBS and IBD. Further, in patients with IBS- or IBD comorbid dysmenorrhea, it may be difficult, due to the co-existence of the conditions, to distinguish between an active flare and increased symptom scores during the menstrual phase. Very few studies have investigated the association between endometriosis, polycystic ovarian disease (PCOS) and IBS or IBD. A questionnaire study comparing 50 women with IBS and 30 with endometriosis showed a considerable overlap of reported symptoms between the two groups [ 80 ]. Also, a case-control study of women aged 15–55 years showed that women with endometriosis were more likely to be diagnosed with IBS [ 81 ]. The authors of these studies speculated that there was a significant overlap of symptomatology between the two diseases. In patients with IBD, a population study of 37 661 women with endometriosis showed a 50% increase in their risk of IBD [ 82 ]; the reason stated was the shared immunological pathogenesis of the two diseases. There is a paucity of data on PCOS with IBS or IBD. A questionnaire study which compared patients with PCOS with healthy controls found an increased prevalence of IBS in patients with PCOS [ 83 ]. In conclusion, although few studies have reported increased prevalence of endometriosis and PCOS in patients with IBS or IBD, there could be a component of misclassification bias due to overlap of the symptoms between these groups. After significant exposure to estrogen at the onset of menses, a decline in estrogen concentration is a trigger for migraine in some women. There has been concern about frequent use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with dysmenorrhea and migraine and underlying IBD. While a recent review did not support NSAIDs as an etiological agent in IBD, a weak association between use of NSAIDs and IBD flares was reported [ 84 ]. Recent research has focused on the influences of stress and psychological health on disease activity in patients with IBS and IBD. A large, national, population-based study found that individuals with IBD were more likely to report poor general health, while people with IBS were more likely to report poor mental health [ 85 ]. Anxiety and depression are common mood symptoms experienced by both IBS and IBD patients [ 86 ]. Hypnosis, biofeedback and psychotherapy help to reduce anxiety [ 87 ]. A recent meta-analysis demonstrated a significant benefit from antidepressants in patients with IBS, which was less in those with IBD [ 88 ]. Behavioral intervention was able to prolong remission in IBD patients more than a year [ 89 ]. The general effects of psychotherapy on the disease course of IBD have been mixed, but are nevertheless promising [ 90 ]. The value of behavioral and psychological interventions for women with IBD during different phases of menstrual cycle has not been studied. Ideally, there is a need for a multi-specialty approach to the care of women with IBD, which includes gastroenterologists, gynecologists and psychologists.

The menstrual cycle lasts for 28 ± 4 days and is divided into the follicular, luteal and menstrual phases. Estrogen level peaks in the middle of the follicular phase and drops after ovulation, followed by a rise in both estrogen and progesterone levels in the early luteal phase [ 12 ]. A sudden drop in both of these hormone levels in the late luteal phase leads to menses. It is generally believed that some healthy women experience perimenstrual alterations in bowel habits [ 13 ]. The rate at which food and digestive products transit through the GI tract reflects the integrated activity of intestinal smooth muscle and the influence of factors such as sex hormones [ 14 ]. The assumption is that fluctuations in these hormones produce variations in GI symptoms through sex steroid receptors that are present in the GI tract [ 8 ]. A number of human and animal studies have evaluated the effects of sex hormones on GI motility [ 15–17 ]. The effect of sex steroids on GI motility is more convincing in animals than in humans; in one study, male rats chronically treated with estradiol and progesterone had a slower intestinal transit than controls [ 15 ]. Also, a separate study reported an increased gastric emptying during the late luteal phase, in which the estrogen levels were at their lowest [ 18 ]. Additionally, another study of the dose-dependent response of progesterone on GI transit reported that a low dose of progesterone retarded intestinal transit, while a high dose reduced the transit time [ 19 ]. In addition, colonic transit in rats was shown to be hastened by ovariectomy [ 20 ]. In humans, the majority of the studies in healthy women have been inconclusive, with few suggesting an increased GI transit during the luteal phase [ 16 , 17 ]. There are no published studies comparing gender differences on GI transit in patients with IBS or IBD. At the molecular level, estrogen enhances GI motility through both estrogen receptor-dependent and -independent mechanisms [ 21 , 22 ]. Estrogen receptor-independent mechanisms include direct activation of K + channels and direct inhibition of voltage-dependent Ca 2+ channels. On the other hand, progesterone acts via the progesterone receptors regulating intracellular G proteins that mediate smooth muscle relaxation [ 23 ]. Estrogen alters pain perception through a number of mechanisms involving the afferent sensory system, opiatergic and serotonergic systems, and stress responses [ 24–27 ]. In the afferent sensory system, estrogen modulates sensations of pain through a glutamatergic mechanism or by an increased synthesis of neurotrophins [ 24 , 25 ]. Also, estrogen enhances opioid receptor-mediated neurotransmission in the thalamus, nucleus accumbens, and amygdala [ 26 ]. Additionally, estrogen enhances serotonergic response in the central nervous system (CNS) by increasing synthesis, decreasing uptake and reduced degradation, and by enhancing post-synaptic responsiveness [ 27 ]. Estrogen is also known to modulate pain through the autonomic nervous system and hypothalamic-pituitary axis [ 28 , 29 ]. Studies have shown an increase in sympathetic tone in the mid- to late luteal phase when serum estrogen and progesterone concentrations are at their highest levels [ 28 ]. Finally, progesterone and its metabolites have also been found to modulate afferent sensory pathways, which are major inhibitory receptors in the CNS [ 30 ], through their effect on the γ-aminobutyric acidergic system. Ovarian hormones influence visceral sensitivity and inflammation through serotonergic pathways, mast cell regulation and modulation in stress response. During late luteal phase, decreased serum estrogen and progesterone levels are associated with increased colonic 5-hydroxytryptamine-3 (5-HT) receptor expression, leading to increased GI symptomatology and visceral sensitivity [ 31 ]. Additionally, estrogen may cause mast cell degranulation, with release of inflammatory mediators and an increase in visceral sensitivity [ 32 ]. Further, estrogen modulates cortisol receptors within the enteric neuron during stress response, resulting in increased visceral sensitivity [ 33 ]. In addition, ovarian hormones modulate visceral sensitivity by activation or inhibition of NK1 receptors in the colon [ 34 ]. Finally, estrogen and progesterone can produce both proceptive and antinociceptive effects, depending on the pathways being modulated, their serum concentrations, phase of menstrual cycle, and their net effect. The onset of menstruation is associated with an increase in uterine PGs, particularly PGF2α and prostacyclin, which have a powerful stimulatory effect on the motor activity of the gut [ 35 ]. It is unclear whether PGs released from the uterine muscle gain access to the systemic circulation or whether corresponding changes in intestinal PGs cause these changes. A higher frequency of defecation during the menstrual phase is also thought to be related to the release of PGs [ 36 ]. Also, PGs and their metabolites are implicated in the inflammatory process in patients with IBD [ 37 ]. In contrast, there is speculation that estrogen has anti-inflammatory properties. Estrogen receptors are expressed in the CD4+ and CD8+ T cells, B cells, monocytes, and macrophages. Those receptors are involved in the inhibition of leukocyte recruitment, the increase of epithelial cell proliferation, and a decrease in apoptosis and cellular adhesion molecules [ 38 , 39 ].