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PRACTICAL GASTROENTEROLOGY MAY 200562

IBS: CLINICAL SYMPTOMS

IBS is a disorder in which abdominal pain or dis-comfort is a primary symptom. It is accompanied bya change in bowel habit and abnormal stool fre-

quency (defined as >3 bowel movements per day[diarrhea] or


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the only physician they ever see. IBS accounts for 12%of diagnoses in the primary care setting (5) and isresponsible for 30% to 50% of referrals to gastroen-terologists (9).

Coexistence of IBS and Other GI Disorders

IBS often coexists with other GI disorders, both func-tional (e.g., dyspepsia, chronic constipation) andorganic (e.g., celiac disease, gastroesophageal refluxdisease, inflammatory bowel disease [IBD]) (10). Fur-thermore, many patients with IBD are diagnosed ini-tially with IBS (11,12). However, once a diagnosis of

IBD is established, comorbid IBS tends to be under-diagnosed and undertreated. Studies have shown thatmore than 40% to 57% of Crohns disease patients andone third of ulcerative colitis patients who were inremission had comorbid IBS (11,13). IBS can con-tribute to symptoms of IBD, especially in quiescentdisease, if the symptoms of IBS are mistaken for anIBD flare. This results in IBD overtreatment and IBSundertreatment.

IBS: IMPACT

IBS symptoms affect the lives of patients and theirfamilies. Several studies have reported negative effectson quality of life (1416), as well as on work-relatedand social activities (1720). The direct costs associ-ated with IBS are estimated to be as high as $10 billionper year, and indirect costs as high as $20 billion annu-ally (excluding prescription and over-the-counter drugcosts) (21,22).

IBS: A ROLE FOR HORMONES?

A variety of observations support the hypothesis that

female sex hormones, and fluctuations thereof, mayhave an impact on IBS, including the simple fact thatmore women than men experience IBS. Men with IBShave lower serum luteinizing hormone (LH) than menwithout IBS, suggesting a potential protective effect ofthis hormone (23).

Additional evidence comes from reports of men-strual cycle-related symptom fluctuations. Manywomen with IBS report that symptoms fluctuate with

their menstrual cycles and that flares occur in the per-imenstrual and perimenopausal phases (2426). Alter-ations in rectal sensitivity (27) (increased duringmenses) and GI transit, which is increased during thefollicular phase compared with the luteal phase(28,29), also have been reported. Other studies showedthat menses (a time of declining/minimal ovarian hor-mone levels) was associated with looser stools com-pared with the follicular and luteal phases (30,31). Fur-thermore, IBS is diagnosed more often in women withdysmenorrhea than in those who cycle normally (32).It also has been proposed that hormonal disparities andfluctuations may be responsible, at least in part, for

differences in prevalence and symptom presentationamong women and between women and men (23,33).

Changes in hormone status associated with preg-nancy or menopause also may influence symptoms.During pregnancy, a time during which estrogen andprogesterone levels are high, GI symptoms increaseand intestinal transit decreases (28). Reports ofabdominal bloating increase after menopause, primar-ily among women who are not receiving hormonereplacement therapy (HRT) (34).

These thoughts are all intriguing, but exactly howhormonal factors influence IBS remains unclear. There

also exists the question as to whether hormone differ-ences are associated with specific symptoms (e.g.,bloating) or with the wider spectrum of IBS symptoms.

Cycling Female Sex Hormones

During the reproductive years in women, the normalmenstrual cycle is characterized by predictable andcyclic changes in estrogen and progesterone levels(Figure 1) that may influence bowel activity. In the fol-licular phase, or immediate postmenstrual phase, estro-gen predominates and progesterone levels are low.

Responding to follicle-stimulating hormone (FSH)secretion from the pituitary gland, the granulose cellsof the ovarian follicles secrete gradually increasing lev-els of estradiol, which peak around day 13, inducing thepituitary LH surge that heralds ovulation. The intra-ovarian events leading to ovulation involve estrogen-induced production of prostaglandins, primarilyprostaglandin F2 (PGF2), PGE2, and prostacyclin,all of which are measurable in follicular fluid. The

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Hormonal Influences on the Gastrointestinal Tract and IBS


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release of this prostaglandin-rich fluid is thought tocause the pain that sometimes occurs with ovulation.

After ovulation, the corpus luteum secretes bothestrogen and progesterone. Progesterone levels peak 8 to9 days after ovulation. Rising luteal phase estrogen levelsare thought to induce luteolysis, mediated by PGF2 viaendoethelin-1 and tumor necrosis factor-alpha (TNF-)in the corpus luteum. With the decline of the corpusluteum, estrogen and progesterone levels drop, triggeringthe events in the uterine endometrium that lead to men-struation. These events involve complex interplay of

prostaglandins, cytokines, and other lytic enzymes.The endometrium also produces prostaglandins,

the predominant one being PGF2, with lower levelsof PGE2 also produced. PGF2 release leads tosmooth muscle contraction, ischemia, and sensitiza-tion of nerve endings; PGE2 is a smooth muscle relax-ant. Other molecules produced include endothelin-1,metalloproteinases, TNF-, and cytokines. Endome-trial prostaglandin levels are three times higher in theluteal than in the follicular phase. Levels are highest



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Figure 1. Hormonal, ovarian, endometrial, and basal body temperature changes and relationships throughout the normal men-strual cycle. (Reprinted with permission from Carr BR, Bradshaw KD. Disorders of the ovary and female reproductive tract. In:Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrisons Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill;2001:2154-2172.) P = progesterone; E2 = estrogen; LH = luteinizing hormone; FSH = follicle-stimulating hormone.


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during menstruation, when most PGF2 release from

the endometrium occurs. Women who experience dys-menorrhea have greater endometrial prostaglandin lev-els than do asymptomatic women, and they havehigher levels of PGF2 in their menstrual fluid (35).Prostaglandin production has been thought to influ-ence diarrhea associated with menses by inhibitingtransepithelial ion transport in the small intestine.

The perimenopausal transition is characterized byits unpredictability and by wide fluctuations in estrogenlevels throughout the cycle. Levels of estradiol may bemarkedly increased because of ovarian follicularresponse to elevated FSH levels. There may be a rela-

tive progesterone deficiency due to lack of ovulation orluteal phase deficiencies as the quality of the ovarianfollicles diminish. This estrogen-dominant environ-ment can occur even in the presence of hot flushes, andleads to irritability, breast tenderness, and bloating.Bloating can occur when estrogen induces nitric oxidesynthetase, which relaxes the smooth muscle in the gut.This nitrogen oxide synthetase induced smooth musclerelaxation clinically results in bloating.

Potential Hormonal Influences on the GI Tract

Estrogen, TNF-, endothelin, and prostaglandins alsoexert effects on the GI tract. Estrogen receptors arefound throughout the GI tract (36) in components ofthe pelvic floor (37) and in sensory neurons of the dor-sal root ganglia (38), suggesting that female sex hor-mones may play a role in IBS symptomatology. Stud-ies have shown that estrogen and progesterone exertmany effects on the GI tract (36). These hormoneshave a relaxing effect on the lower esophageal sphinc-ter and decrease colonic transit. TNF- inducesinflammation, delays gastric emptying, increasescolonic transit time, and induces flow of fluid into GI

tissues. Endothelin has potent effects on GI smoothmuscle, leading to contraction of the esophagus, stom-ach, and intestines, and has a modulatory effect on GImotility (39). It also is a potent stimulator of gallblad-der motility, stimulates sphincter of Oddi motility, anddecreases trans-sphincteric flow (39).

Prostaglandins are a diverse set of moleculesderived from the modification of essential fatty acids.When present at the proper time, place, and amount,

these local chemical messengers play a vital role innumerous functions, maintaining homeostasis. In thegut, prostaglandins, particularly those of the E type,are implicated in the proper maintenance of mucosalblood flow, stimulation of the mucous secretion liningthe gut surface, stimulation of GI motility, and secre-tion of bicarbonate to help neutralize acids (40).Altered prostaglandin levels can result in abdominalpain, colonic contractions, and diarrhea.

In women who experience dysmenorrhea, there isa significant increase in the uterine expression ofPGF2 (41), which is the likely explanation for theincreased pain associated with their menstruation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) arethe most common treatment modality; however, use ofthese agents can lead to GI depletion of prostaglandins(42). Medications to reduce acid production, neutralizethe acid, or coat the lining of the GI tract often are usedas adjunctive therapies in patients taking NSAIDs forchronic conditions. Misoprostol (Cytotec) is a syn-thetic PGE1 analog that stimulates secretion of gastricmucus and production of bicarbonate; prostaglandinsprovide a protective effect for patients taking medica-tions that inhibit GI COX enzymes. However, miso-prostol also invokes prostaglandin effects in the uterus

(uterine muscle contractions) that can lead to compli-cations in pregnancy, including premature labor andabortion (Pfizer, data on file). Therefore, misoprostolshould not be used in women known or thought to bepregnant. Alternatively, medications that inhibit pro-duction of gastric acid or coat the lining of the GI tractcan provide protection to patients on long-termNSAID therapy.

Clinical Evidence LinkingFemale Hormones to Bowel Function

It has been postulated that cycling female sex hormonesare related to changes in bowel habits. In the 1980s,alterations in GI transit (increased during the follicularphase compared with the luteal phase) (28,29) werereported. Heitkemper and colleagues (1988) reportedthat menses (a time of declining/minimal ovarian hor-mone levels) was associated with looser stools com-pared with the follicular and luteal phases (30). In con-trast, high levels of estradiol and progesterone during




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the luteal phase were reported to be associated withdelayed GI transit (28), which may account for firmerstools during this phase of the menstrual cycle. Healthywomen describe changes in bowel habits during theirmenstrual cycle, and women with IBD experience aneven higher prevalence of GI symptomrelated fluctu-ations. A suggestive physiologic mechanism may bethe increased intestinal prostaglandin production thatcauses contraction of colonic smooth muscle or theincreased intestinal secretions related to variation inprogesterone levels (43).

Whereas other early clinical studies failed to showa relationship between female hormones and bowel

function, a growing body of evidence suggests thatsuch a relationship exists. Kamm and colleagues(1989) reported that, under normal physiologic condi-tions, sex hormones have no major effect on bowelfunction (44). They based this conclusion on theirobservation that mean transit times (whole gut transit)and stool weights were not significantly different dur-ing the follicular versus the luteal phase of the men-strual cycle in 18 healthy women. Furthermore, self-reported bowel frequency and stool consistency werenot significantly different during the menstrual, follic-ular, or luteal phase.

However, Wald and colleagues (1981) describeddifferent findings in a more recent report of their studyof hormone levels and GI transit times in 15 normallymenstruating women (28). They measured serumestradiol and progesterone levels and GI transit timesat 2 points during the menstrual cycle, once in the fol-licular phase (days 810) when progesterone levels arelow, and once in the luteal phase (days 1820) whenprogesterone levels are elevated. GI transit was deter-mined via monitoring of breath hydrogen levels at10-minute intervals after the ingestion of lactulose (todetermine time from ingestion until delivery to the

cecum). The authors reported that progesterone levelsdid increase during the luteal phase, as expected, andthat GI transit time was significantly (P < 0.01) pro-longed during this phase as compared with the follicu-lar phase. Based on these findings, they concluded thatthe menstrual cycle plays a role in determining GItransit time in normally menstruating women.

Jackson and colleagues (1994) reported that,although the phase of the menstrual cycle may affect

transit, it did not appear to affect rectal motility or sen-sitivity in 20 healthy women (31). However, in theirlater study of 29 female patients with IBS, they foundthat, in contrast to healthy women, women with IBShad increasing levels of rectal sensitivity at the time ofmenses compared with all other phases of the men-strual cycle (27). This increase in rectal sensitivity wasnot related to changes in rectal compliance or wall ten-sion. The authors considered the possibility that,because acute episodes of diarrhea are associated withincreases in rectal sensitivity in women (but not men)and IBS patients are more susceptible to sensitizingevents, this may be an explanation for the increased

rectal sensitivity noted in IBS patients at menses. Theauthors also posed a second explanationthatprostaglandin release during menses may play a role inrectal sensitivity. Because the GI system of IBSpatients may already be sensitive, the release ofprostaglandins, known to induce afferent nerve sensiti-zation, may be enough to trigger a further increase inthis sensitivity. The authors also noted that anxiety anddepression remained unaltered throughout the men-strual cyclea finding that was consistent with paststudies demonstrating that psychological traits are notassociated with perimenstrual bowel-related symp-

toms (25,45). Similar to past studies, Houghton, et al(2002) reported a significant worsening of abdominalpain and bloating and more frequent bowel movementsduring menses (27). They also reported firmer consis-tency of the stool during the luteal phase. Houghtonand colleagues concluded that women with IBS arepredisposed to fluctuations in visceral sensitivity asso-ciated with the menstrual cycle.

Further evidence for a role of female hormones inbowel function comes from studies conducted inwomen in the perimenopausal and postmenopausalstates. Triadafilopoulos and colleagues (1998)

prospectively studied 228 women (170 post-menopausal and 58 premenopausal) who presented forevaluation at a primary care practice facility; investi-gators used a previously validated GI symptom ques-tionnaire designed to evaluate symptoms consistentwith IBS (46). (At the time of their participation in thestudy, none of these women presented for evaluationof abdominal or genitourinary symptoms.) The authors





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found that 38% of postmenopausal women reportedaltered bowel function, as opposed to 14% of pre-menopausal women (P < 0.001). However, the twogroups did not differ in occurrence of abdominal pain,diarrhea, and constipation, which are symptoms sug-gestive of IBS. The prevalence of IBS-type complaintspeaked at a high of 36% among the 40- to 49-year-oldage group. Laxative usage, gaseousness/excessive flat-ulence, and heartburn/acid regurgitation were alsomore common among postmenopausal women thanpremenopausal women, with prevalence rates of 9.4%vs 3.4%, 48% vs 27%, and 34% vs 18%, respectively.Interestingly, estrogen use did not affect GI symptoms

in either group. The authors concluded that there is ahigh prevalence of altered bowel function and IBS-likeGI complaints among women in the perimenopausaland postmenopausal periods.

Copas and colleagues (2001) attempted to explainvarious pelvic floor disorders, including fecal inconti-nence, by evaluating hormone receptor expression in thelevator ani muscle and fascia, which make up the pelvicfloor (37). The study looked at 55 women undergoingsurgery for asymptomatic gynecological (n = 10) orsymptomatic urogynecological (n = 45) conditions.Twenty-four of the women, all of whom were sympto-

matic, were receiving HRT. Estrogen receptor (ER)expression in the levator ani fascia was increasedsignificantly (P < 0.03) in symptomatic women notreceiving HRT when compared with asymptomatic,age-matched women, but was significantly lower(P < 0.001) in symptomatic women receiving long-termHRT when compared with age-matched women withoutHRT. The authors concluded that ER expression is sig-nificantly higher in symptomatic women when com-pared with asymptomatic women of the same age, butthat long-term use of estrogen leads to a significantdecrease in ER expression. This may explain why long-

term HRT does not appear to favorably impact pelvicfloor disorders and suggests that down-regulation ofreceptors or relative tissue dominance of the progestincomponent of therapy is the cause.

Crowell and colleagues (1994) noted an overlap indiagnoses of dysmenorrhea and functional bowel dis-orders (FBDs) in their 12-month evaluation of 383women (aged 20 to 40 years) who presented to a sin-gle Planned Parenthood clinic (32). Dysmenorrhea, as

identified via history and physical examination, waspresent in 19.8% of patients. Functional bowel disor-der, defined as abdominal pain with altered bowelfunction, was diagnosed in 61% of patients with dys-menorrhea compared with 20% of patients withoutdysmenorrhea (P < 0.05). A relationship betweenbowel symptoms (bowel symptom inventory [25]) andmenstrual symptoms (Moos Menstrual Distress Ques-tionnaire [47]) was evident throughout the study andwas independent of psychological differences (i.e.,neuroticism, as measured using the NEO PersonalityInventory [48]). Prostaglandin levels were measured invaginal dialysate on the first day of menses in a subset

of subjects (n = 44) and were elevated in women withdysmenorrhea regardless of bowel symptoms. Theauthors concluded that the observed relationshipbetween menstrual and bowel symptoms and the over-lap in diagnoses of dysmenorrhea and functionalbowel disease were evidence of a common physiologicbasis for many of the symptoms characteristic of thesedisorders.

Data from an earlier study conducted by Heitkem-per and colleagues (1992) also suggested a relationshipbetween symptoms and the menstrual cycle in womenwith FBD. In this study, patterns of GI symptoms and

select mood and somatic symptoms were evaluatedacross two menstrual cycles in a group of 19 womenwith and 39 women without FBD (45). Each day,women rated their GI, perimenstrual, and other symp-toms and recorded stool frequency and consistency.Serum estrogen and progesterone concentrations weremeasured during menses and during the follicular andluteal phases. The group with FBD rated stomach pain,nausea, and diarrhea higher at menses than did thegroup without FBD. Stomach pain was higher duringthe remaining days as well. The group with FBD alsoreported higher levels of perimenstrual symptoms on

six of the eight Menstrual Distress Questionnaire-Tsubscales (P < 0.01). Interestingly, the authors reportedno significant group differences in ovarian hormonelevels or stool consistency/frequency scores. This is inagreement with what is known about premenstrual syn-dromethose who suffer from this condition do notexhibit differences in ovarian hormone levels comparedwith healthy individuals; rather, they differ in their






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responses to normal hormonal fluctuations, in this case,in the central nervous system and other target organs.

GI symptoms also appear to be influenced by themenstrual cycle in women with IBS. Whitehead, et al(1990) assessed differences in GI complaints betweenfemale patients at a family planning clinic and womenwith IBS or FBD who were referred to a gastroen-terology clinic (25). (Criteria for diagnosis of IBSwere abdominal pain plus altered bowel habits, butrestrictive criteria for IBS were not satisfied.) Allpatients were asked whether gas, diarrhea, or constipa-tion occurred during menstruation. One third ofpatients who denied symptoms of IBS or FBD reported

that menstruation was associated with one or morebowel symptoms; however, patients with IBS weresignificantly more likely to experience exacerbationsof each of these bowel symptoms, especially increasedbowel gas. The authors noted also that reports ofbowel symptoms during menstruation were not associ-ated with psychological traits or with menses-relatedchanges in mood.

Similarly, Heitkemper, et al (2003) reported inanother study that women with IBS had higher symp-tom severity, in terms of somatic, psychological, andGI symptoms, than did women in a control group (49).

Compared with controls, women with IBS had signifi-cantly more severe GI symptoms, including abdominalpain, gas, and bloating, and also reported a higher per-centage of days with hard and with loose stools. GIsymptoms were significantly affected by the menstrualcycle phase, with complaints worse during menses.Among women with IBS, oral contraceptive usersreported fewer symptoms of abdominal pain than didnonusers; however, there were no significant differ-ences between the two groups with respect to gas,bloating, constipation, and diarrhea. In a subsequentstudy of women with IBS, Heitkemper and colleagues

(2004) described a specific relationship between bloat-ing and menses-associated symptoms such as uterinecramping and breast tenderness (50).

In a study of 477 female patients with IBS, Lee, et al(2001) reported that 40% of all female patients with IBSreported menstrual cycle-related worsening of symptoms(8). Of women younger than age 45, 50.8% reportedexperiencing menstrual cycle-related worsening ofsymptoms. However, based on two findings, the authors

argued against a significant role for menstrual cycle-related hormone fluctuations in causing symptom differ-ences. First, when premenopausal women with IBS werecompared with postmenopausal women, there was nosignificant difference in bowel habit predominance (i.e.,constipation, diarrhea, or alternating constipation anddiarrhea). Furthermore, when postmenopausal womenwere compared with a group of age-matched men, thesame difference as in the total male and female sampleswas observed, highlighting the concept that menstrualstatus does not affect bowel habit predominance. Theauthors did report, however, that premenstrual womenwere two times more likely to complain of nausea than

were postmenopausal women with IBS.

Hormonal Influences on Serotonin Activity?

Serotonin (5-hydroxtryptamine [5-HT]), which is pro-duced mainly by and stored in enterochromaffin cells inthe GI tract, is vital to normal gut function. It is respon-sible for initiating and maintaining peristalsis, mediat-ing secretion in the GI tract, and modulating the sensa-tion of pain (51,52). Recent research has uncovered apotential role for abnormal serotonin expression and/orsignaling in IBS and other GI disorders (53). The

potential effect of sex hormones such as estrogen andprogesterone on serotonin remains to be elucidated.However, the importance of serotonin and its receptors,as well as serotonin polymorphisms, in predictingresponse to treatment is an area of interest. A recentstudy has shown that estrogen and progesterone influ-ence the level of 5-HT type 3 (5-HT3) receptor mRNA(54). In ovariectomized rats, lower levels of PGE2 andprogesterone resulted in significantly higher amountsof 5-HT3 receptor mRNA. When ovariectomized ani-mals were treated with estradiol and progesterone,5-HT3 receptor transcript levels returned to normal.

Additional studies highlight the importance of theserotonin reuptake transporter in IBS as polymor-phisms in this gene resulted in a differential responseto alosetron, a 5-HT3 receptor antagonist that is used totreat diarrhea-predominant IBS (55,56). Collectively,these results suggest that 5-HT3 receptor activity,which is a target of pharmacologic intervention inpatients with diarrhea-predominant IBS, also is regu-lated by female sex hormones.



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IBS SYMPTOMS IN PATIENTS

USING ORAL CONTRACEPTIVESOral contraceptive use should be investigated amongpatients seeking relief from GI symptoms. Becauseestrogen excess can cause nausea, bloating, and cyclicweight gain, patients taking preparations high in estro-gen may benefit from switching to low-estrogen for-mulations (i.e., those containing only 20 g of estro-gen such as Loestrin 1/20, Mircette, or Alesse).After switching to low-estrogen formulations, patientsexperience less bloating and less weight gain. Prepara-tions with increased progestin content (e.g., Demulin1/35) also may be beneficial, especially in patients

with functional nausea who are also thin. Drospirenone,a C21 progestin derivative of spironolactone that hasboth progestational and mineralocorticoid effects, isthe primary component of the recently introduced oralcontraceptive Yasmin. It produces mild diuresis (sim-ilar to spironolactone 25 mg). Recipients typically loseweight initially (34 pounds) but return to baselineweight after 6 months. Patients taking Yasmin shouldavoid potassium supplementation or other medicationsthat affect potassium levels, such as chronic dailyNSAIDs or angiotensin-converting enzyme inhibitors.The effects of various types of HRT on the GI tract arenot yet understood. Whether natural progestins willoffer any advantage is not known.

SUMMARY

There now exists a considerable body of evidence sup-porting a role for sex hormones in the development ofIBS symptoms. Sex differences in prevalence andsymptom presentation, as well as differences and fluc-tuations based on hormone status, have beendescribed. An important next step is to determine

whether sex or hormone status affects the efficacy ofstandard management approaches. To this end, catego-rization and selection of patients for clinical trial par-ticipation should not focus solely on IBS subtypes, asthey currently do (i.e., constipation, diarrhea, andalternators); they should also focus on sex and hor-mone status. Furthermore, the role of sex hormones(e.g., oral contraceptives, HRT) in the management ofpatients with IBS symptoms remains to be defined. I

Acknowledgment

The authors would like to acknowledge the editorialassistance of Maribeth Bogush, PhD, in preparation ofthis manuscript.

References1. Thompson WG, Longstreth GF, Drossman DA, Heaton KW,

Irvine EJ, Muller-Lissner SA. Functional bowel disorders andfunctional abdominal pain. Gut, 1999; 45 Suppl 2:II43-II47.

2. Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic reviewon the management of irritable bowel syndrome in North Amer-ica.Am J Gastroenterol, 2002; 97(11 Suppl):S7-S26.

3. Mayer EA, Naliboff B, Lee O, Munakata J, Chang L. Reviewarticle: gender-related differences in functional gastrointestinaldisorders. Aliment Pharmacol Ther, 1999; 13 Suppl 2:65-69.

4. American College of Gastroenterology Functional Gastrointesti-

nal Disorders Task Force. Evidence-based position statement onthe management of irritable bowel syndrome in North America.

Am J Gastroenterol, 2002; 97(11 Suppl):S1-S5.5. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syn-

drome: a technical review for practice guideline development.Gastroenterology, 1997; 112(6):2120-2137.

6. Zaman A. Irritable bowel syndrome. Clin Cornerstone, 2002;4(4):22-33.

7. Camilleri M. Management of the irritable bowel syndrome. Gas-troenterology, 2001; 120(3):652-668.

8. Lee OY, Mayer EA, Schmulson M, Chang L, Naliboff B. Gen-der-related differences in IBS symptoms. Am J Gastroenterol,2001; 96(7):2184-2193.

9. Sykes MA, Blanchard EB, Lackner J, Keefer L, Krasner S. Psy-chopathology in irritable bowel syndrome: support for a psy-chophysiological model.J Behav Med, 2003; 26(4):361-372.

10. Whitehead WE, Palsson O, Jones KR. Systematic review of the

comorbidity of irritable bowel syndrome with other disorders:what are the causes and implications? Gastroenterology, 2002;122(4):1140-1156.

11. Simren M, Axelsson J, Gillberg R, Abrahamsson H, Svedlund J,Bjornsson ES. Quality of life in inflammatory bowel disease inremission: the impact of IBS-like symptoms and associated psy-chological factors.Am J Gastroenterol, 2002; 97(2):389-396.

12. Scherl EJ. Irritable-inflammatory bowel disease: recognizing anew overlap syndrome and an enigma wrapped inside a puzzle.

Inflamm Bowel Dis, 2002; 8(5):373-374.13. Minderhoud IM, Oldenburg B, Wismeijer JA, van Berge Hene-

gouwen GP, Smout AJ. IBS-like symptoms in patients withinflammatory bowel disease in remission: relationships withquality of life and coping behavior.Dig Dis Sci, 2004; 49(3):469-474.

14. Frank L, Kleinman L, Rentz A, Ciesla G, Kim JJ, Zacker C.Health-related quality of life associated with irritable bowel syn-

drome: comparison with other chronic diseases. Clin Ther, 2002;24(4):675-689.

15. Koloski NA, Talley NJ, Boyce PM. The impact of functional gas-trointestinal disorders on quality of life. Am J Gastroenterol,2000; 95(1):67-71.

16. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. Theimpact of irritable bowel syndrome on health-related quality of life.Gastroenterology, 2000; 119(3):654-660.

17. Schuster MM. Defining and diagnosing irritable bowel syndrome.Am J Manag Care, 2001; 7(8 Suppl):S246-S251.

18. Silk DB. Impact of irritable bowel syndrome on personal relation-ships and working practices.Eur J Gastroenterol Hepatol, 2001;13(11):1327-1332.


9/9


19. Dancey CP, Backhouse S. Towards a better understanding ofpatients with irritable bowel syndrome. J Adv Nurs, 1993;

18(9):1443-1450.20. International Foundation for Functional Gastrointestinal Disor-

ders. IBS in the Real World Survey: Summary Findings. Mil-waukee, Wis: International Foundation for Functional Gastroin-testinal Disorders; 2002.

21. Martin R, Barron JJ, Zacker C. Irritable bowel syndrome: towarda cost-effective management approach.Am J Manag Care, 2001;7(8 Suppl):S268-S275.

22. American Gastroenterological Association. The Burden of Gas-trointestinal Diseases. Bethesda, Md: American Gastroenterolog-ical Association; 2001:1-86. Available at: http://www.gastro.org/clinicalRes/pdf/burden-report.pdf. Accessed November 16,2004.

23. Houghton LA, Jackson NA, Whorwell PJ, Morris J. Do male sexhormones protect from irritable bowel syndrome? Am J Gas-troenterol, 2000; 95(9):2296-2300.

24. Kane SV, Sable K, Hanauer SB. The menstrual cycle and itseffect on inflammatory bowel disease and irritable bowel syn-drome: a prevalence study. Am J Gastroenterol, 1998;93(10):1867-1872.

25. Whitehead WE, Cheskin LJ, Heller BR, et al. Evidence for exac-erbation of irritable bowel syndrome during menses. Gastroen-terology, 1990; 98(6):1485-1489.

26. Heitkemper M, Carter E, Ameen V, Olden K, Cheng L. Womenwith irritable bowel syndrome: differences in patients and physi-cians perceptions. Gastroenterol Nurs, 2002; 25(5):192-200.

27. Houghton LA, Lea R, Jackson N, Whorwell PJ. The menstrualcycle affects rectal sensitivity in patients with irritable bowel syn-drome but not healthy volunteers. Gut, 2002; 50(4):471-474.

28. Wald A, Van Thiel DH, Hoechstetter L, et al. Gastrointestinaltransit: the effect of the menstrual cycle. Gastroenterology, 1981;80(6):1497-1500.

29. Turnbull GK, Thompson DG, Day S, Martin J, Walker E,

Lennard-Jones JE. Relationships between symptoms, menstrualcycle and orocaecal transit in normal and constipated women.Gut, 1989; 30(1):30-34.

30. Heitkemper MM, Shaver JF, Mitchell ES. Gastrointestinal symp-toms and bowel patterns across the menstrual cycle in dysmenor-rhea.Nurs Res, 1988; 37(2):108-113.

31. Jackson NA, Houghton LA, Whorwell PJ, Currer B. Does themenstrual cycle affect anorectal physiology?Dig Dis Sci, 1994;39(12):2607-2611.

32. Crowell MD, Dubin NH, Robinson JC, et al. Functional boweldisorders in women with dysmenorrhea. Am J Gastroenterol,1994; 89(11):1973-1977.

33. Chang L, Heitkemper MM. Gender differences and irritablebowel syndrome. Gastroenterology, 2002; 123(5):1686-1701.

34. Lewis MJV, Houghton LA, Whorwell PJ. Abdominal distensionin females with irritable bowel syndrome (IBS): the effect of the

menopause and hormone replacement therapy. Gut, 2001;48(3Suppl 1):A-43. [Abstract #168].35. Coco AS. Primary dysmenorrhea. Am Fam Physician, 1999;

60(2):489-496.36. Eliakim R, Abulafia O, Sherer DM. Estrogen, progesterone and

the gastrointestinal tract.J Reprod Med, 2000; 45(10):781-788.37. Copas P, Bukovsky A, Asbury B, Elder RF, Caudle MR. Estro-

gen, progesterone, and androgen receptor expression in levatorani muscle and fascia.J Womens Health Gend Based Med, 2001;10(8):785-795.

38. Papka RE, Storey-Workley M. Estrogen receptor-alpha and -betacoexist in a subpopulation of sensory neurons of female rat dor-sal root ganglia.Neurosci Lett, 2002; 319(2):71-74.

39. Rae GA, Calixto JB, DOrleans-Juste P. Effects and mechanismsof action of endothelins on non-vascular smooth muscle of the

respiratory, gastrointestinal and urogenital tracts. Regul Pept,1995; 55(1):1-46.

40. Takeuchi K, Kato S, Tanaka A. Gastrointestinal protective actionof prostaglandin E2 and EP receptor subtypes. In: Cho C-H,Wang J-Y, eds. Gastrointestinal Mucosal Repair and Experimen-tal Therapeutics. Basel, Switzerland: Karger; 2002:227-242.Scarpignato C, Hunt RH, eds. Frontiers of GastrointestinalResearch Series; Vol 25.

41. Chan WY, Dawood MY. Prostaglandin levels in menstrual fluidof nondysmenorrheic and of dysmenorrheic subjects with andwithout oral contraceptive or ibuprofen therapy. AdvProstaglandin Thromboxane Res, 1980; 8:1443-1447.

42. Laine L, Connors LG, Reicin A, et al. Serious lower gastroin-testinal clinical events with nonselective NSAID or coxib use.Gastroenterology, 2003; 124(2):288-292.

43. Kane S. Gender issues in the management of inflammatory boweldisease and irritable bowel syndrome.Int J Fertil Womens Med,2002; 47(3):136-142.

44. Kamm MA, Farthing MJ, Lennard-Jones JE. Bowel functionand transit rate during the menstrual cycle. Gut, 1989; 30(5):605-608.

45. Heitkemper MM, Jarrett M. Pattern of gastrointestinal andsomatic symptoms across the menstrual cycle. Gastroenterology,1992; 102(2):505-513.

46. Triadafilopoulos G, Finlayson M, Grellet C. Bowel dysfunctionin postmenopausal women. Womens Health, 1998; 27(4):55-66.

47. Moos RH. The development of a menstrual distress question-naire. Psychosom Med, 1968; 30(6):853-867.

48. Costa PT, Jr., McCrae RR. The NEO Personality InventoryManual, II. Towson, Md: Clinical Psychometric Research;1983.

49. Heitkemper MM, Cain KC, Jarrett ME, Burr RL, Hertig V, Bond

EF. Symptoms across the menstrual cycle in women withirritable bowel syndrome.Am J Gastroenterol, 2003; 98(2):420-430.

50. Heitkemper MM, Cain KC, Jarrett ME, Burr RL, Crowell MD,Woods NF. Relationship of bloating to other GI and menstrualsymptoms in women with irritable bowel syndrome.Dig Dis Sci,2004; 49(1):88-95.

51. Crowell MD, Shetzline MA, Moses PL, Mawe GM, Talley NJ.Enterochromaffin cells and 5-HT signaling in the pathophysiol-ogy of disorders of gastrointestinal function. Curr Opin Investig

Drugs, 2004; 5(1):55-60.52. Crowell MD. The role of serotonin in the pathophysiology of irri-

table bowel syndrome. Am J Manag Care, 2001; 7(8 Suppl):S252-S260.

53. Coates MD, Mahoney CR, Linden DR, et al. Molecular defects inmucosal serotonin content and decreased serotonin reuptake

transporter in ulcerative colitis and irritable bowel syndrome.Gastroenterology, 2004; 126(7):1657-1664.54. Li TJ, Yu BP, Dong WG, Luo HS, Xu L, Li MQ. Ovarian hor-

mone modulates 5-hydroxytryptamine 3 receptors mRNA expres-sion in rat colon with restraint stress-induced bowel dysfunction.World J Gastroenterol, 2004; 10(18):2723-2726.

55. Camilleri M, Atanasova E, Carlson PJ, et al. Serotonin-trans-porter polymorphism pharmacogenetics in diarrhea-predominantirritable bowel syndrome. Gastroenterology, 2002; 123(2):425-432.

56. Scherl E, Frissora CL. Irritable bowel syndrome genophenomics:correlation of serotonin-transporter polymorphisms and alosetronresponse. Pharmacogenomics J, 2003; 3(2):64-66.



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