do irritable bowel syndrome symptoms vary between men and ...

Alimentary Pharmacology and TherapeuticsMeta-analysis: do irritable bowel syndrome symptoms varybetween men and women?M. A. Adeyemo*, B. M. R. Spiegel & L. Chang**Center for Neurobiology of Stress,Los Angeles, CA 90095, USA.VA Greater Los Angeles HealthcareSystem; Division of Digestive Diseases,David Geffen School of Medicineat UCLA; and UCLA ⁄VA Centerfor Outcomes Research and Education(CORE), Los Angeles, CA 90073,USA.Correspondence to:Dr L. Chang, Center for the Neurobiologyof Stress, CHS 47-122, 10833 LeConte Avenue, Los Angeles, CA90095, USA.E-mail: linchang@ucla.eduPublication dataSubmitted 16 February 2010First decision 5 March 2010Resubmitted 23 June 2010Accepted 23 June 2010SUMMARYBackgroundStudies suggest that sex and gender-related differences exist in irritablebowel syndrome (IBS), but data is often conflicting.AimTo evaluate gender differences and the effect of menstrual cycle and menopausalstatus on IBS symptoms.MethodsWe performed a systematic review of MEDLINE to search for studiescomparing IBS symptoms between gender, menstrual cycle phases andmenopausal states in IBS and ⁄ or healthy individuals. We performed metaanalysesto compare the relative risk (RR) of individual IBS symptomsbetween men and women.ResultsTwenty-two studies measured gender differences in IBS symptoms. Womenwere more likely to report abdominal pain (RR = 1.12, 95% CI: 1.02, 1.22)and constipation-related symptoms (RR = 1.12, 95% CI: 1.02, 1.23) thanmen (all P < 0.05). However, men with IBS were more likely to reportdiarrhoea-related symptoms than women with IBS (RR = 0.84, 95% CI:0.75, 0.94, P < 0.05). A systematic review of 13 studies demonstrated thatboth IBS and healthy women reported increased IBS symptoms duringmenses vs. other phases. There were insufficient data to determine the effectof menopause and hormone supplementation on IBS symptoms.ConclusionsIn the general and IBS populations, gender differences in IBS symptomsexist, although these differences are modest. Studies suggest that female sexhormones influence the severity of IBS symptoms, but more studies areneeded.Aliment Pharmacol Therª 2010 Blackwell Publishing Ltd 1doi:10.1111/j.1365-2036.2010.04409.x

M. A. Adeyemo et al.INTRODUCTIONIrritable bowel syndrome (IBS) is characterized by recurrentabdominal pain or discomfort associated with achange in bowel habits. 1 The prevalence of IBS rangesfrom 6% to 22% in Western countries, although theprevalence in Eastern countries tends to be lower andranges from 2% to 17%. 2 IBS has a female predominancewith a female-to-male ratio of 2–2.5:1 in those who seekhealth care. The female predominance is less apparent inthe general population, which suggests that women withIBS are more likely to seek healthcare for their symptoms.3–7 However, some Asian studies fail to report significantgender differences in the prevalence of IBS,suggesting that cultural differences may also play a rolein IBS symptom reporting. 8, 9Gender differences in IBS are evident by subclassification,nongastrointestinal (GI) symptoms, pathophysiologicalresponses and treatment response. 10 Specifically,female predominance is particularly apparent in the IBSwith constipation (IBS-C) subtype compared with IBSwith diarrhoea (IBS-D) and alternating or mixed pattern(IBS-M). 11 Although gender differences in pathophysiologicalstudies (e.g. GI transit, rectal perception, brainactivation patterns) have been reported in IBS andhealthy controls, 12, 13 there are also conflicting reportsthat failed to identify differences between men andwomen. 14 Response to some IBS treatments, such asserotonergic agents, appears to be more robust in womenthan in men. 12, 15–17 However, these findings may be dueto an inadequate number of men in IBS studies ratherthan a true gender difference in nonstudy populations.In fact, there have been inadequate efforts to enrollsufficient numbers of men in many IBS studies and inadequateattempts to control for menstrual cycle phaseamong women in these trials. 10 In addition, genderdifferences and the effect of female sex hormones havelargely been understudied in IBS. A recent review suggestedthat a strong relationship between menstrual cycleand bowel symptoms exists and that this may be due toeffects of ovarian hormones on visceral pain sensitivityand bowel function. 18It is important to determine whether there are truesymptom differences between genders in IBS because thisinformation can potentially impact our understanding ofthe pathophysiology of IBS and influence research studydesign, drug development and treatment. Two previousreviews assessed gender differences in the diagnosis ofIBS. One review was conducted in developing countries,19 whereas the other was a systematic review ofstudies conducted in community populations. 2 Bothreviews concluded that most Western studies supporteda female predominance of IBS. However, approximatelyhalf of the studies conducted in Eastern countriesreported a female predominance while the other half didnot. Irrespective of whether the studies were conductedin Western or Eastern populations, the female-to-maleratio was dependent on the diagnostic criteria, i.e. agreater female predominance was seen when Manningcriteria were used vs. Rome criteria. 2To understand better the gender differences in IBS,we performed a systematic review and meta-analysis ofthe literature to evaluate gender differences in individualIBS symptoms and the role of menstrual cycle, menopausalstatus and hormone supplementation on thesesymptoms. We hypothesized that the pooled data wouldreveal that women more frequently report abdominalpain and nonpain related symptoms associated with constipationsuch as hard stools, bloating, abdominal distensionand straining than men, and that men more oftenreport symptoms associated with diarrhoea such as loosestools and increased stool frequency. In addition, wehypothesized that the pooled data would reveal a higherprevalence of IBS symptoms at times when ovarian hormonesare low, i.e. at the onset of menses in premenopausalwomen and during menopause, and that thesesymptoms decrease with hormone supplementation.METHODSSearch strategyThe analysis for this study was based on a broadersearch for articles pertaining to dyspepsia and ⁄ or IBS.We conducted a comprehensive search for English languagestudies in MEDLINE published up to June 2010,which examined gender differences in IBS and ⁄ or theeffect of menstrual cycle, menopausal status or hormonesupplement on GI symptoms. The keywords and searchstrings used to perform the search with Reference ManagerSoftware are indicated in Table 1. In addition, weperformed manual searches of reference lists from relevantpapers to identify other manuscripts, which mayhave been missed by the search strategy.Screening strategyWe excluded titles if they did not meet the followinginclusion criteria: (i) written in English; (ii) investigationof humans; (iii) examination of IBS or functional dyspepsiasymptoms; (iv) assessment of IBS or functional2 Aliment Pharmacol Therª 2010 Blackwell Publishing Ltd

M. A. Adeyemo et al.Table 3 | Relative risk of IBS symptoms in women vs. men in both the general and IBS patient populationsGeneral population IBS onlyRR favouring women(95% CI)No.studiesHeterogeneity(P)RR favouring women(95% CI)No.studiesHeterogeneity(P)IBS diagnostic symptomsPain 1.12 (1.02, 1.22)* 5

Meta-analysis: gender variance in irritable bowel syndromeAbdominal painStudyRisk ratio % WeightStudy(95% CI)Zuckerman 31 1.01 (0.94, 1.09) 20.41.09 (1.00, 1.20) 19.3Talley 28Talley 281.08 (1.02, 1.14) 21.9Talley 27Talley 271.08 (1.02, 1.15) 21.6 Taub 29Taub 291.40 (1.24, 1.58) 16.8 Zuckerman 31Abdominal pain associatedwith a change in stool formRisk ratio(95% CI)% Weight1.23 (1.14, 1.33) 24.41.10 (1.03, 1.17) 25.91.19 (1.11, 1.27) 25.60.98 (0.91, 1.06) 24.1Sandler 52 Sandler 52Overall (95% CI)1.12 (1.02, 1.22)0.8 1 2Favors men Favors womenOverall (95% CI)1.12 (1.02, 1.23)0.8 1 2Favors men Favors womenBloatingStudyRisk ratio(95% CI)% WeightStudyShen 58Talley 27Talley 281.21 (1.06, 1.39) 14.41.00 (0.95, 1.05) 18.01.00 (0.89, 1.13) 15.1Schmulson 59Shen 58Talley 27TalleyTan 531.44 (1.33, 1.57) 17.028Tan 53Taub 291.11 (1.06, 1.16) 18.1 Taub 29Zuckerman 31 1.02 (0.95, 1.09) 17.4 Tujeta 30Zuckerman 31Overall (95% CI)1.12 (1.01, 1.25)Overall (95% CI)StrainingRisk ratio % Weight(95% CI)1.10 (1.04, 1.16) 12.31.47 (1.08, 2.01) 4.91.04 (1.00, 1.09) 12.61.07 (0.95, 1.20) 10.61.09 (1.02, 1.17) 12.11.11 (1.02, 1.21) 11.51.43 (1.35, 1.52) 12.31.09 (1.01, 1.17) 11.90.97 (0.89, 1.05) 11.71.12 (1.03, 1.23)0.8 1 2Favors men Favors women0.8 1 2Favors men Favors womenFigure 2 | Forest plots of the risk ratios and 95% confidence intervals for gender differences in general populationstudies evaluating abdominal pain, bloating and straining are shown.Assessment for publication bias. Only two symptomcomparisons surveyed in the general population showeda potential publication bias. Funnel plots suggest a lackof small, positive studies for abdominal pain associatedwith change in stool frequency and a lack of small, negativestudies for frequent stools.Menstrual cycle effect on IBS symptomsTable 4 provides general information on the 13 studiesthat assessed the effect of menstrual cycle on IBS symptoms.32, 37–45, 62, 63 Study methodology varied withregard to study design and determination of menstrualcycle phase with seven studies of good quality and six ofintermediate quality. Six studies assessed symptoms prospectivelyusing daily diaries, two surveyed currentsymptom severity score and the remaining studies usedsymptom recall. Only two studies used ovulation kits todocument menstrual cycle phase.All but three studies stated that women (average 40–60%) reported increased GI symptoms at time of mensescompared with other phases. 32, 37–42, 44, 45, 62 The symptomsfor which most studies showed a significant menstrualcycle effect were (in descending order) loose stools, bloating,abdominal pain, stool frequency and other changes inbowel habit (Figure 4, Table 4). In general, increased diarrhoeawas reported at the time of menses by more womenthan increased constipation. Although menstrual cycleeffects on symptoms were similar in healthy women and IBSwomen, symptom severity was greater in women with IBS.If only the seven higher quality studies were assessed,five reported a menstrual cycle effect on IBS symptomsat time of menses, while two did not. Bloating, gas andbowel habit changes (diarrhoea more than constipation)were reported to increase at time of menses. Only threeof these studies assessed symptoms prospectively andwere from a single centre.Aliment Pharmacol Ther 7ª 2010 Blackwell Publishing Ltd

M. A. Adeyemo et al.Schmulson 59Abdominal distensionAbdominal bloatingStudyRisk ratio % Weight StudyRisk ratio % Weight(95% CI)(95% CI)Lee, OY 32 Lee, OY 321.19 (0.96, 1.48) 19.81.52 (1.27, 1.81) 22.3Celebi 540.94 (0.71, 1.26) 6.0Celebi 540.96 (0.67, 1.37) 8.5Han 91.16 (0.86, 1.58) 4.0Han 91.18 (0.85, 1.64) 9.9Lee, OY 321.17 (1.07, 1.29) 30.5Lee, OY 321.41 (1.16, 1.70) 20.4Lu 33 1.11 (1.04, 1.19) 32.5Lu 33Perveen 56 1.12 (1.04, 1.22) 36.61.06 (0.98, 1.15) 9.3LuMasud 251.00 (0.86, 1.16) 23.4331.15 (1.02, 1.31) 25.5Perveen 56Si 341.32 (0.95, 1.84) 13.61.14 (0.93, 1.41) 20.8Ringel 602.36 (1.50, 3.71) 9.1Smith 35 1.50 (1.17, 1.93) 18.61.47 (1.08, 2.01) 14.5Schmulson 59 1.17 (1.06, 1.29) 17.7Thompson 681.30 (1.12, 1.53) 24.6Thompson 36 1.47 (1.04, 2.06) 14.9Smith 351.50 (1.17, 1.93) 17.5Overall (95% CI)1.29 (1.06, 1.56)Overall (95% CI)1.37 (1.16, 1.61)0.8 1 20.8 1 2Favors men Favors women Favors men Favors womenInfrequent stoolsHard/Lumpy stoolsStudyRisk ratio % WeightStudyRisk ratio(95% CI)(95% CI)% WeightOverall (95% CI)1.13 (1.08, 1.18)Overall (95% CI)1.21 (1.08, 1.36)0.8 1 20.8 1 2Favors men Favors women Favors men Favors womenFigure 3 | Forest plots of the risk ratios and 95% confidence intervals for gender differences in IBS only studies evaluatingbloating, distension, hard ⁄ lumpy stools and infrequent stools are shown.Effect of menopausal status on IBS symptomsThree retrospective and one prospective survey comparedIBS symptoms in premenopausal vs. postmenopausalwomen 32, 37, 46, 55 and were considered to be of high quality.Sample sizes for premenopausal women ranged from 58to 89 subjects and postmenopausal women ranged from 55to 170 subjects. Amongst the three studies restricted toIBS, 32, 37, 55 nausea was the only symptom reported morefrequently by premenopausal women than postmenopausalwomen. 32 In the study by Cain et al., 55 various GI symptomswere reported less frequently by premenopausalwomen than postmenopausal women; however, these differenceswere not significant after adjusting for age.Amongst healthy women, gaseousness and excessive flatulencewere the only GI symptoms that were significantlymore prevalent in postmenopausal women.Effect of hormone supplementation on IBS symptomsTable 5 shows the results from four studies which evaluatedthe effect of hormone supplementation on IBSsymptoms in pre- or postmenopausal women. Two ofthe studies were randomized controlled trials; one evaluatingthe effect of estradiol or progesterone in postmenopausalwomen 50 was of high quality and the otherevaluating a gondotropin-releasing hormone (GnRH)agonist in premenopausal women 49 was of intermediatequality. The other two studies were not randomized controlledtrials. One consisted of a retrospective chartreview 48 and the other was a prospective study, 39 butboth achieved criteria for good quality.Two studies investigated the effect of hormonereplacement therapy (HRT) on IBS symptoms inwomen over the age of 50 who were presumably postmenopausal.48, 50 Ruigomez et al. 48 found that womenwho use HRT are more likely to develop IBS thanwomen who do not; however, the prevalence and severityof IBS symptoms were similar among non-HRTusers and HRT users. Gonenne et al. 50 found that postmenopausalhealthy women who were given estradiol orprogesterone therapy alone for 7 days were more likely8 Aliment Pharmacol Therª 2010 Blackwell Publishing Ltd

Meta-analysis: gender variance in irritable bowel syndromeTable 4 | Evidence table of studies comparing menstrual cycle effect on IBS symptomsStudy Population (N) Study design SettingMenstrualcycle assessmentIBSdiagnosticcriteria Findings QAJackson et al. 41 Healthycontrols (20)Prospective(daily diary)Not specified Menses: day 1–4;follicular: day 8–10;luteal: day 18–20;premenstrual: day24–28N ⁄ A Stool form was significantlylooser at menses comparedto luteal phase; There wasnot a significant phase effecton number of stools per day9Hinds et al. 62 Healthycontrols (25)Retrospective Not specified Recall N ⁄ A 96% reported change in bowelhabit before and duringmenses; 72% reported loosestools during menses; 32%reported constipation theweek prior to menses9Simmons et al. 44 Healthycontrols (7)Prospective(daily diary)Not specified Basal bodytemperatureN ⁄ A No significant phase effect onstool form; 1 of 7 subjectsreported constipation beforeor during menses; 2 of 7subjects reported diarrhoea atthe beginning of menses11Lee et al. 43 GI clinicpatients (193)Cross-sectional(survey)3° care Menstrual: day 0–6;proliferative: day 7–14; secretory: afterday 15Rome II 50.8% of women metdiagnostic criteria for IBS. Nosignificant phase effect forabdominal pain, constipation,diarrhoea, abdominaldistension, tenesmus13Altman et al. 63 IBS (114) Prospective(daily diary)1° care andcommunityMenses: day 1; lutealphase: 7–10 daysprior to onset ofmensesDiagnosismade by health provider;criteria not specifiedNo significant phase effect onabdominal or stomach pain13Chang et al. 37 IBS (380) Retrospective 3° care andcommunityRecall Rome I 40% of bloating patients and43% of bloating + distensionpatients reported thatbloating was related tomenstrual cycle15Aliment Pharmacol Ther 9ª 2010 Blackwell Publishing Ltd

M. A. Adeyemo et al.Table 4 | (Continued)Study Population (N) Study design SettingMenstrualcycle assessmentIBSdiagnosticcriteria Findings QAHoughton et al. 40 IBS (29) Prospective(daily diary)Not specified Menses: day 1–4;follicular: day 8–10;luteal: day 18–20;premenstrual: day24–28Rome I There were significant phaseeffects on abdominal pain,bloating, stool frequency andloose stools11Lee et al. 32 IBS (477) Retrospective 3° care andcommunityRecall Rome Overall 40% of women and50.8% of women

Meta-analysis: gender variance in irritable bowel syndromeTable 4 | (Continued)Study Population (N) Study design SettingMenstrualcycle assessmentIBSdiagnosticcriteria Findings QAHoughton et al. 57 IBS-D (39)Healthycontrols (19)Cross-sectional University clinic,general practices,advertisementLuteal phase (days18–20 of cycle) ortaking OCP wereclassified as highprogesterone ⁄oestrogen; menses(days 2–3) wasclassified as lowprogesterone ⁄oestrogen: menses(days 2–3 of cycle)Rome II No differences in severity ofpain, bloating, urgency oroverall symptoms betweenhigh and low progesterone ⁄oestrogen conditions in IBS-Dwomen or healthy women11Kane et al. 42 IBS (46)Healthycontrols (90)Retrospective 2° care andcommunityRecall Rome Increased diarrhoea wasreported significantly moreoften during premenstrualperiod and menses in IBS vs.controls. Increasedconstipation was less oftenreported than diarrhoea, butwas significantly moreprevalent in IBS vs. controlsduring menses. There was asignificant menstrual cycleeffect on abdominal pain inIBS16Whitehead et al. 45 IBS (72)Healthycontrols (234)Retrospective 1° and 2° care Recall Manning IBS were more likely thancontrols to report mensesrelatedincreases in gas (39–48% vs. 14%), diarrhoea(29–32% vs. 19%) andconstipation (18–24% vs.11%)11QA, quality assessment; GI, gastrointestinal; N ⁄ A, not applicable; 1°, primary; 2°, secondary; 3°, tertiary; OCP, oral-contraceptive pills.Aliment Pharmacol Ther 11ª 2010 Blackwell Publishing Ltd

M. A. Adeyemo et al.Number of studies6420Menstrual cycle effectNo menstrual cycle effectLoose stools Bloating AbdominalpainStoolfrequencyChange inbowel habitFigure 4 | The number of studies that tested for a significanteffect of IBS symptoms on menstrual cycle ispresented. The P-value of significance was specific toeach study. One study was not included in the figurebecause statistical analysis of menstrual cycle effect onbloating was not performed. 37 Another study was notincluded because it did not specifically evaluate a menstrualcycle effect on these symptoms. 45to have looser stools and greater ease of passage thanthose on placebo.Two studies evaluated the effect of hormone supplementationon IBS symptoms in premenopausal women.One study assessed the effect of oral-contraceptive pills(OCP), whereas the other assessed the effect of a GnRHagonist. 38, 49 Heitkemper et al. 38 found that OCP use bywomen with IBS was associated with lower abdominalpain severity compared with non-OCP users, but thisdifference did not maintain significance after correctingfor multiple comparisons. Palomba et al. 49 found thattreatment with a GnRH agonist improved the severity ofIBS symptoms compared with placebo.DISCUSSIONDue to conflicting data in the literature regarding genderdifferences in IBS, we performed a systematic review toinvestigate if there are differences in IBS symptomsbetween genders, and further evaluated the literatureregarding the relationship between IBS symptoms, menstrualcycle phase and menopause. Our study has fourmain findings: (i) women experience a greater prevalenceof IBS symptoms than men, particularly constipationrelatedsymptoms; (ii) women appear to have morefrequent and severe IBS symptoms during menses comparedwith other phases of the menstrual cycle; (iii) theeffect of hormonal therapy on IBS symptoms cannot bedetermined based on limited available data; and (iv)there is a lack of studies comparing IBS symptoms inpre- and postmenopausal women.For the most part, the occurrence and diagnosis of6, 29, 64IBS is more common in women than in men.Female gender is a significant independent risk factor forthe development of IBS, 65 including postinfectious IBS. 66In cross-sectional surveys conducted in the US, 67 Canada68 and Israel, 69 women reported IBS symptoms 1.5 to2 times more commonly than men. Greater health careseeking and referral for IBS in women may in part bedue to increased IBS severity 32, 70, 71 and greater impactof symptoms on health related quality of life in womenwith IBS compared with men. 70, 72, 73 However, populationstudies conducted in Asia suggest that the prevalenceof IBS in men and women is similar. 19, 74–76 Thisdifference may be largely due to cultural reasons. InAsia, men see physicians as much and more often thanwomen possibly for cultural and economic reasons. 76–79Gender differences in IBS symptomsOur meta-analysis reveals that women more frequentlyreport individual IBS symptoms than men. In generalpopulation studies, which included individuals with IBS,women reported a greater prevalence of the IBS diagnostic(i.e. pain-related) symptoms than men. These findingsare consistent with studies which showed an enhancedperception of pain or discomfort to distension in the80, 81colon and rectum in women vs. men.Overall, women had a greater prevalence of constipation-associatedsymptoms, particularly bloating andabdominal distension, than men. Men had a greaterprevalence of diarrhoea-associated symptoms of loose ⁄ -watery stools and increased stool frequency in the IBSonly studies, but not in the general population studies.This is consistent with studies demonstrating a female67, 82, 83predominance in IBS-C and chronic constipation.82, 84 Several studies have found that women haveslower colonic transit than men. 85–87The generally higher IBS symptom reporting in womenthan men may be due to several reasons. Since womenwith IBS tend to have significantly more healthcare visitsthan men, 88 studies which used healthcare-based recruitmentmethods may underestimate the symptom prevalencein men. Another plausible explanation is thatwomen tend to recall their symptoms better than men. 89However, this is not likely to explain why constipationassociatedsymptoms were reported more commonly inwomen than in men, while diarrhoea-associated symptomswere reported more often in men. Gender differenceshave been demonstrated in GI function, including12 Aliment Pharmacol Therª 2010 Blackwell Publishing Ltd

Meta-analysis: gender variance in irritable bowel syndromeTable 5 | Evidence table of studies comparing hormone supplement effect on IBSStudyTreatment groups(N) PopulationMenopausalstatus Study design Age (years) SettingIBSdiagnosticcriteria Symptoms QARuigomez et al. 48 IBS HRT users(405); IBS HRTnever users(255)IBS Not specified Prospective 50–69 1° care Not specified IBS symptoms were similaramong users of HRT and HRTnever users (data notprovided)15Palomba et al. 49 Leuprolide acetatedepot (LAD) plustibolone (36);LAD plus placebo(37); placebo(39)IBS Premenopausal RCT 25.5 (mean) 2° care Rome II There was an improvementfrom baseline and vs. placeboin abdominal discomfort anddistension, nausea, frequencyand consistency, diarrhoea,constipation and bloating forboth treatment groups17Gonenne et al. 50 Placebo (12),progesterone(13), estradiol(12), combinedprogesterone andestradiol (12)Controls Postmenopausal RCT 40–65 Not specified N ⁄ A Treatmenteffect of looser stoolconsistency scores withprogesterone alone, estradiolalone andprogesterone + estradiol;Greater ease of passagescores for estradiol alone; Notreatment effect on stoolfrequency, stool consistencyor sense of incompletepassage24Heitkemper et al. 38 IBS oralcontraceptive(56); IBS non-OCP (93)IBS Premenopausal Prospective 32.5 (mean) GeneralpopulationRome I OCP users reported less severeabdominal pain than non-OCPusers but this difference didnot maintain significance aftermultiple comparisons. Therewere no significantdifferences in other individualGI symptoms16RCT, randomized controlled trial; 1°, primary; 2°, secondary; 3°, tertiary; HRT, hormone replacement therapy; OCP, oral-contraceptive pills; N ⁄ A, not applicable.Aliment Pharmacol Ther 13ª 2010 Blackwell Publishing Ltd

M. A. Adeyemo et al.transit time, visceral perception, brain activation patternsand colonic mucosal mast cell count 12, 13, 81, 90, 91 whichcan conceivably contribute to the greater prevalence ofIBS symptoms in women and the gender differences inbowel habits.Most Western studies reported a higher prevalence ofindividual IBS symptoms in women compared withmen. 26, 27, 29, 30, 35, 36 Similarly, eight of the ten Easternstudies found that more women reported individual IBSsymptoms than men 9, 31, 33, 34, 51, 53, 56, 58 ; however oneof these studies also reported higher prevalences of loosestools and increased stool frequency in men. 33 These studieswere conducted mainly in community and universityclinic populations, although one surveyed secondary clinicpatients. Interestingly, two studies did not find a genderdifference in individual symptoms, but reported a higherratio of women-to-men with Rome positive IBS (1.3–1.8:1). 25, 54 One of these studies was conducted in a ruralcommunity in Bangladesh 25 and the other in an urbancommunity in Turkey. 54 Thus, this meta-analysis supportsa higher overall prevalence of IBS symptoms in womenthan in men in Western and Eastern countries, althoughthe differences are relatively modest. This review overcomesthe limitations of previous epidemiological investigations9, 26–28, 30–36, 47 because data from studiesconducted in both Eastern and Western populations areincluded. However, additional studies are needed to investigatehow the interactions between genetic, environmentaland ⁄ or cultural factors contribute to gender differences inIBS symptoms and may differ across diverse cultures.The relatively small, but significant gender differencesin the prevalence of individual IBS symptoms suggeststhat gender effects may be confounded by other factorsthat significantly influence the presence of IBS symptoms.These include psychological and social factors thatcan affect symptom reporting, health care seeking andglobal outcomes in IBS. 92 For example, studies havereported that a previous history of abuse and other traumaticevents or stressors are associated with more severepain and greater symptom severity in IBS. 93–96Limitations of our meta-analysis include the extensiveheterogeneity of the studies, which may in part explainthe low RR estimates. For example, the diagnostic criteriaused for IBS varied between studies. This is notablebecause gender differences in the prevalence of IBS varyaccording to criteria used. 97 In a population-based,cross-sectional survey study in Olmstead County, Minnesota,there was a greater prevalence of women with IBSif the Manning criteria were used, but a higher prevalenceof men with IBS if the Rome criteria were used. 98Menstrual cycle effect on IBS symptomsOur systematic review found that IBS symptoms areheightened at time of menses. Enhanced visceral perceptionat menses is supported by the finding of decreasedsensory thresholds to rectal distension compared withother phases of the menstrual cycle. 40 One plausiblemechanism that is supported by some animal andhuman studies is that declining or low ovarian hormonelevels at time of menses may underlie the increased GIsymptoms and discomfort across the menstrual cycle. 99A study by Laessle and colleagues 100 showed that progesteronelevels negatively correlated with pain-relatedsymptoms (i.e. back pain and headache) which supportsthat lower levels of female sex hormones are associatedwith greater somatic pain. It is conceivable that womenhave more prevalent and severe IBS symptoms at time ofmenses when progesterone (and oestrogen) decline fromhigh to low levels. There are other possible mechanismsinvolved in GI function to explain these findings. Forexample, gender differences exist in postprandial serotoninlevels in IBS-D 101, 102 and in colonic mucosal mastcell counts in IBS. 91 Both have been found to correlatewith IBS symptoms and potentially have a key role in thepathophysiology of IBS. 103 In addition, mast cell secretionis affected by both oestrogen and progesterone. 104Although more studies reported increased diarrhoea attime of menses than increased constipation, there weretwo retrospective recall studies which found that somewomen reported increased diarrhoea and others reportedincreased constipation (Table 4). 42, 45 It is possible thatan increase in a particular bowel habit would be reportedby IBS patients with that predominant bowel subtype.For example, women with IBS-D may be more likely toreport increased diarrhoea than constipation, while IBS-C patients may be more likely to report increased constipation.However, this information was not availablein the studies to determine if this could explain thesefindings.Despite a relatively adequate number of studies, methodologicallimitations in these studies could have affectedthe results. Half of the studies were based on symptomrecall. As women are likely to report a greater severity ofsymptoms retrospectively than prospectively, 105 the retrospectivestudies may overestimate the effect of menstrualcycle on IBS symptoms and are less accurate thanprospective assessment. In addition, confirmation ofmenstrual cycle phase should be performed using ovulationkits, although this was only done in two of the 12studies. A review of the effect of menstrual cycle phaseon experimental pain response found a lack of standard-14 Aliment Pharmacol Therª 2010 Blackwell Publishing Ltd

Meta-analysis: gender variance in irritable bowel syndromeized operational definitions for identifying menstrualcycle phases. 106 More studies with an optimal studydesign (e.g. use of ovulation kits, prospective daily symptomassessment, sufficient sample sizes) are needed totruly assess the validity of the menstrual cycle effect onIBS symptoms.Menopausal status effect on IBS symptomsDue to the small number of studies that compared GIsymptoms in pre- and postmenopausal women, there isinsufficient evidence to determine the effect of menopausalstatus on IBS symptoms. However, the limiteddata suggest that premenopausal women with IBS aremore likely to experience nausea than postmenopausalwomen with IBS. This finding is supported by studieswhich have shown that nausea and vomiting thatoccurred post-operatively, 107, 108 and during pregnancy,are associated with high levels oestrogen109, 110and ⁄ or progesterone levels.In one study, healthy postmenopausal womenreported gas and excessive flatulence significantly morethan premenopausal women. 46 To our knowledge, therehave been no studies that have compared intestinal gasclearance or colon transit times in pre- and postmenopausalwomen.Effect of hormone supplement on IBS symptomsThe available studies provided limited information andtherefore a conclusion on the effects of hormone supplementationcannot be definitively determined. However,the available evidence suggests that use of OCPs and aGnRH agonist by premenopausal women may be protectiveof IBS symptoms, although further studies areneeded. These medications act differently on the hypothalamic–pituitary–gonadalaxis. OCPs prevent ovulationbecause the progesterone derivative inhibits the release ofGnRH by the hypothalamus thereby decreasing therelease of follicular-stimulating hormone (FSH) andluteinizing hormone (LH) by the anterior pituitary, andoestrogen inhibits follicular development. In contrast,leuprolide, the GnRH agonist, stimulates the release ofFSH and LH, which suppress the secretion of ovarianhormones. Undoubtedly, more studies are needed todetermine conclusively the effect of hormone supplementson IBS symptoms.CONCLUSIONOur study demonstrates that women overall have agreater prevalence of IBS symptoms than men, particularlythose associated with constipation. However,within the IBS patient group, men have more diarrhoeasymptoms than women. There are some limitations inthe quality, methodology and number of studies evaluatingthe effect of menstrual cycle, hormone supplementationand menopausal status on IBS symptoms.Notably, most studies relied on symptom recall. Nonetheless,existing data raise the possibility that there maybe a female sex hormone effect on IBS symptoms aswell as on GI function. It is plausible that this maycontribute to the increased prevalence and greater vulnerabilityto develop IBS, the higher prevalence of constipationsymptoms and the increased severity ofsymptoms at time of menses in women. In addition tothe need for more, well-designed studies, there shouldbe a greater attempt to recruit adequate and comparablenumbers of men and women with and without IBS,and attention should be paid to assessing and controllingfor menstrual cycle phase and menopausal statusin clinical study design as they can potentially affectstudy results.ACKNOWLEDGEMENTSDeclaration of personal interests: The authors thankMelissa Alberto and Teresa Olivas for their assistancein the preparation of the work. Mopelola Adeyemohas nothing to declare. Brennan Spiegel has served asa consultant for Prometheus Laboratories, Astra-Zeneca,TAP, Takeda, Ironwood, and Novartis. He hasreceived research funding from Takeda, Rose, Prometheus,Amgen, Shire, and Novartis. Lin Chang hasserved as a consultant for Prometheus Laboratories,Takeda, Forest, Albireo, McNeil, Rose Pharma, Glaxo-SmithKline, Salix, Ocera and Movetis. She has receivedresearch funding from Takeda, Rose and Prometheus.Declaration of funding interests: This study was fundedby NIH Grants Nos P50 DK64539 and R24AT002681.SUPPORTING INFORMATIONAdditional Supporting Information may be found in theonline version of this article:Appendix S1. Down and Black checklist for measuringstudy quality.Please note: Wiley-Blackwell are not responsible forthe content or functionality of any supporting materialssupplied by the authors. Any queries (other than missingmaterial) should be directed to the corresponding authorfor the article.Aliment Pharmacol Ther 15ª 2010 Blackwell Publishing Ltd

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