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Kevin W. Olden, M.D., Series Editor
Hormonal Influences on the Gastrointestinal Tract and Irritable Bowel Syndrome
by Sharmela Thevarajah, Margaret Polaneczky, Ellen J. Scherl and Christine L. Frissora
Irritable bowel syndrome (IBS) is a common disorder of gastrointestinal (GI) function that affects more women than men in most Western countries. Often among women, symptoms of IBS appear to be related to hormone status (e.g., menstruating, pregnant, menopausal, taking oral contraceptives or hormone replacement therapy). In some women, symptoms wax and wane in concert with their menstrual cycle. One potential explanation for the observed variability in IBS symptoms is that sex hormones affect GI motility and function. The purpose of this review is to describe the growing body of evidence that supports a role for sex hormones in the pathophysiology and/or symptom presentation of IBS.
IBS: CLINICAL SYMPTOMS
Reported prevalence rates range from 3% to 20%, with most estimates concentrated between 10% and 15% (2). Although IBS affects individuals of all races and both sexes, women are more commonly affected than men in Western nations at a ratio of approximately 2:1, a phenomenon that has yet to be completely explained (3–6). In North American studies, the female predominance is greater among individuals who seek medical attention (3–4:1) as compared with those who do not (<2:1) (7); however, it is unclear if this reflects underreporting in men or a true predominance in women. Sex differences in presentation of symptoms have been described, including more IBS with diarrhea among men and more IBS with constipation and bloating among women (8). IBS is one of the most common disorders seen in the primary care setting. Women often present to their gynecologist first, as this may be
BS is a disorder in which abdominal pain or discomfort is a primary symptom. It is accompanied by a change in bowel habit and abnormal stool frequency (defined as >3 bowel movements per day [diarrhea] or <3 bowel movements per week [constipation]) (1). IBS patients also commonly report hard or loose/watery stools, a feeling of incomplete evacuation after bowel movement, bloating and/or abdominal distension, and the passage of mucus.
Sharmela Thevarajah, M.D., Resident; Margaret Polaneczky, M.D., Associate Professor of Clinical Medicine, Ellen J. Scherl, M.D., Associate Professor of Clinical Medicine; and Christine L. Frissora, M.D., FACP, FACG, Associate Professor of Medicine; The Weill Medical College of Cornell University, New York, NY. 62
PRACTICAL GASTROENTEROLOGY • MAY 2005
chronic constipation) and organic (e. This results in IBD overtreatment and IBS undertreatment. as well as on work-related and social activities (17–20). IBS can contribute to symptoms of IBD. which is increased during the follicular phase compared with the luteal phase (28. Several studies have reported negative effects on quality of life (14–16).. or immediate postmenstrual phase. Studies have shown that more than 40% to 57% of Crohn’s disease patients and one third of ulcerative colitis patients who were in remission had comorbid IBS (11.22). Men with IBS have lower serum luteinizing hormone (LH) than men without IBS. if the symptoms of IBS are mistaken for an IBD flare. primarily among women who are not receiving hormone replacement therapy (HRT) (34).. inflammatory bowel disease [IBD]) (10). Responding to follicle-stimulating hormone (FSH) secretion from the pituitary gland. the granulose cells of the ovarian follicles secrete gradually increasing levels of estradiol.g. During pregnancy. a time during which estrogen and progesterone levels are high. and indirect costs as high as $20 billion annually (excluding prescription and over-the-counter drug costs) (21. and prostacyclin. their menstrual cycles and that flares occur in the perimenstrual and perimenopausal phases (24–26). comorbid IBS tends to be underdiagnosed and undertreated. once a diagnosis of IBD is established. which peak around day 13. Reports of abdominal bloating increase after menopause. estrogen predominates and progesterone levels are low. It also has been proposed that hormonal disparities and fluctuations may be responsible. IBS is diagnosed more often in women with dysmenorrhea than in those who cycle normally (32). The PRACTICAL GASTROENTEROLOGY • MAY 2005 IBS: A ROLE FOR HORMONES? A variety of observations support the hypothesis that female sex hormones. The intraovarian events leading to ovulation involve estrogeninduced production of prostaglandins.33). However.. These thoughts are all intriguing. and fluctuations thereof. Cycling Female Sex Hormones During the reproductive years in women.12). the normal menstrual cycle is characterized by predictable and cyclic changes in estrogen and progesterone levels (Figure 1) that may influence bowel activity. In the follicular phase.31). Alterations in rectal sensitivity (27) (increased during menses) and GI transit. including the simple fact that more women than men experience IBS. Other studies showed that menses (a time of declining/minimal ovarian hormone levels) was associated with looser stools compared with the follicular and luteal phases (30. Furthermore. gastroesophageal reflux disease. also have been reported. Furthermore. IBS accounts for 12% of diagnoses in the primary care setting (5) and is responsible for 30% to 50% of referrals to gastroenterologists (9). at least in part. GI symptoms increase and intestinal transit decreases (28).g.g. Changes in hormone status associated with pregnancy or menopause also may influence symptoms. suggesting a potential protective effect of this hormone (23). PGE2. for differences in prevalence and symptom presentation among women and between women and men (23. both functional (e. There also exists the question as to whether hormone differences are associated with specific symptoms (e. Many women with IBS report that symptoms fluctuate with 63 . especially in quiescent disease. Additional evidence comes from reports of menstrual cycle-related symptom fluctuations.Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. but exactly how hormonal factors influence IBS remains unclear. bloating) or with the wider spectrum of IBS symptoms. inducing the pituitary LH surge that heralds ovulation. dyspepsia. Coexistence of IBS and Other GI Disorders IBS often coexists with other GI disorders. IBS: IMPACT IBS symptoms affect the lives of patients and their families. primarily prostaglandin F2α (PGF2α). may have an impact on IBS. many patients with IBD are diagnosed initially with IBS (11. celiac disease. all of which are measurable in follicular fluid. SERIES #7 the only physician they ever see. The direct costs associated with IBS are estimated to be as high as $10 billion per year.29).13).
LH = luteinizing hormone. Rising luteal phase estrogen levels are thought to induce luteolysis. The endometrium also produces prostaglandins. TNF-α. New York. triggering the events in the uterine endometrium that lead to menstruation. Levels are highest (continued on page 67) . and cytokines. et al. metalloproteinases. ischemia. endometrial. PGE2 is a smooth muscle relaxant. Bradshaw KD. Disorders of the ovary and female reproductive tract. E2 = estrogen. SERIES #7 Figure 1. ovarian. After ovulation. and sensitization of nerve endings. NY: McGraw-Hill. With the decline of the corpus luteum. estrogen and progesterone levels drop. Hormonal. with lower levels of PGE2 also produced.Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. and other lytic enzymes. Other molecules produced include endothelin-1. 15th ed. and basal body temperature changes and relationships throughout the normal menstrual cycle. Progesterone levels peak 8 to 9 days after ovulation. In: Braunwald E. cytokines. eds. These events involve complex interplay of 64 PRACTICAL GASTROENTEROLOGY • MAY 2005 prostaglandins. FSH = follicle-stimulating hormone. the predominant one being PGF2α. release of this prostaglandin-rich fluid is thought to cause the pain that sometimes occurs with ovulation. Fauci AS. the corpus luteum secretes both estrogen and progesterone. PGF2α release leads to smooth muscle contraction. 2001:2154-2172. Endometrial prostaglandin levels are three times higher in the luteal than in the follicular phase. mediated by PGF2α via endoethelin-1 and tumor necrosis factor-alpha (TNF-α) in the corpus luteum.) P = progesterone. (Reprinted with permission from Carr BR. Kasper DL. Harrison’s Principles of Internal Medicine.
maintaining homeostasis. suggesting that female sex hormones may play a role in IBS symptomatology. there is a significant increase in the uterine expression of PGF2α (41). neutralize the acid. The perimenopausal transition is characterized by its unpredictability and by wide fluctuations in estrogen levels throughout the cycle. It also is a potent stimulator of gallbladder motility. colonic contractions. This nitrogen oxide synthetase induced smooth muscle relaxation clinically results in bloating. particularly those of the E type. Endothelin has potent effects on GI smooth muscle. In contrast. and has a modulatory effect on GI motility (39). delays gastric emptying. and they have higher levels of PGF2α in their menstrual fluid (35). leading to contraction of the esophagus. misoprostol should not be used in women known or thought to be pregnant. including premature labor and abortion (Pfizer. high levels of estradiol and progesterone during PRACTICAL GASTROENTEROLOGY • MAY 2005 67 . and decreases trans-sphincteric flow (39). Bloating can occur when estrogen induces nitric oxide synthetase. use of these agents can lead to GI depletion of prostaglandins (42). TNF-α. In the 1980s. endothelin. and leads to irritability. are implicated in the proper maintenance of mucosal blood flow. However. when most PGF2α release from the endometrium occurs. medications that inhibit production of gastric acid or coat the lining of the GI tract can provide protection to patients on long-term NSAID therapy. Potential Hormonal Influences on the GI Tract Estrogen. Clinical Evidence Linking Female Hormones to Bowel Function It has been postulated that cycling female sex hormones are related to changes in bowel habits. In the gut. and prostaglandins also exert effects on the GI tract. and induces flow of fluid into GI tissues. data on file). Studies have shown that estrogen and progesterone exert many effects on the GI tract (36). Prostaglandins are a diverse set of molecules derived from the modification of essential fatty acids. these local chemical messengers play a vital role in numerous functions. This estrogen-dominant environment can occur even in the presence of hot flushes. Alternatively. When present at the proper time. which is the likely explanation for the increased pain associated with their menstruation. Altered prostaglandin levels can result in abdominal pain. There may be a relative progesterone deficiency due to lack of ovulation or luteal phase deficiencies as the quality of the ovarian follicles diminish. Prostaglandin production has been thought to influence diarrhea associated with menses by inhibiting transepithelial ion transport in the small intestine. Therefore. Estrogen receptors are found throughout the GI tract (36) in components of the pelvic floor (37) and in sensory neurons of the dorsal root ganglia (38).29) were reported. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment modality. Misoprostol (Cytotec®) is a synthetic PGE1 analog that stimulates secretion of gastric mucus and production of bicarbonate. and diarrhea. misoprostol also invokes prostaglandin effects in the uterus (uterine muscle contractions) that can lead to complications in pregnancy. or coat the lining of the GI tract often are used as adjunctive therapies in patients taking NSAIDs for chronic conditions. stimulates sphincter of Oddi motility. stimulation of GI motility. Levels of estradiol may be markedly increased because of ovarian follicular response to elevated FSH levels. stomach. and bloating. however. breast tenderness. alterations in GI transit (increased during the follicular phase compared with the luteal phase) (28. and secretion of bicarbonate to help neutralize acids (40). These hormones have a relaxing effect on the lower esophageal sphincter and decrease colonic transit. stimulation of the mucous secretion lining the gut surface. SERIES #7 (continued from page 64) during menstruation. and amount. prostaglandins. prostaglandins provide a protective effect for patients taking medications that inhibit GI COX enzymes. increases colonic transit time. In women who experience dysmenorrhea. place. Medications to reduce acid production. Heitkemper and colleagues (1988) reported that menses (a time of declining/minimal ovarian hormone levels) was associated with looser stools compared with the follicular and luteal phases (30). which relaxes the smooth muscle in the gut. Women who experience dysmenorrhea have greater endometrial prostaglandin levels than do asymptomatic women.Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. TNF-α induces inflammation. and intestines.
Kamm and colleagues (1989) reported that. Jackson and colleagues (1994) reported that. the release of prostaglandins. Furthermore.45). This increase in rectal sensitivity was not related to changes in rectal compliance or wall tension. investigators used a previously validated GI symptom questionnaire designed to evaluate symptoms consistent with IBS (46). which may account for firmer stools during this phase of the menstrual cycle. and that GI transit time was significantly (P < 0. known to induce afferent nerve sensitization. The authors also posed a second explanation—that prostaglandin release during menses may play a role in rectal sensitivity. and women with IBD experience an even higher prevalence of GI symptom–related fluctuations. Similar to past studies.Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. Healthy women describe changes in bowel habits during their menstrual cycle. SERIES #7 the luteal phase were reported to be associated with delayed GI transit (28). sex hormones have no major effect on bowel function (44). this may be an explanation for the increased rectal sensitivity noted in IBS patients at menses. or luteal phase. under normal physiologic conditions. Because the GI system of IBS patients may already be sensitive. They measured serum estradiol and progesterone levels and GI transit times at 2 points during the menstrual cycle. et al (2002) reported a significant worsening of abdominal pain and bloating and more frequent bowel movements during menses (27). they concluded that the menstrual cycle plays a role in determining GI transit time in normally menstruating women. selfreported bowel frequency and stool consistency were not significantly different during the menstrual. (At the time of their participation in the study. follicular. once in the follicular phase (days 8–10) when progesterone levels are low. Houghton. as expected. women with IBS had increasing levels of rectal sensitivity at the time of menses compared with all other phases of the menstrual cycle (27). GI transit was determined via monitoring of breath hydrogen levels at 10-minute intervals after the ingestion of lactulose (to determine time from ingestion until delivery to the cecum). because acute episodes of diarrhea are associated with increases in rectal sensitivity in women (but not men) and IBS patients are more susceptible to sensitizing events. They also reported firmer consistency of the stool during the luteal phase. Houghton and colleagues concluded that women with IBS are predisposed to fluctuations in visceral sensitivity associated with the menstrual cycle. Wald and colleagues (1981) described different findings in a more recent report of their study of hormone levels and GI transit times in 15 normally menstruating women (28). However. may be enough to trigger a further increase in this sensitivity. none of these women presented for evaluation of abdominal or genitourinary symptoms. Based on these findings. a growing body of evidence suggests that such a relationship exists. and once in the luteal phase (days 18–20) when progesterone levels are elevated. They based this conclusion on their observation that mean transit times (whole gut transit) and stool weights were not significantly different during the follicular versus the luteal phase of the menstrual cycle in 18 healthy women. in contrast to healthy women. although the phase of the menstrual cycle may affect 68 PRACTICAL GASTROENTEROLOGY • MAY 2005 transit. The authors also noted that anxiety and depression remained unaltered throughout the menstrual cycle—a finding that was consistent with past studies demonstrating that psychological traits are not associated with perimenstrual bowel-related symptoms (25. it did not appear to affect rectal motility or sensitivity in 20 healthy women (31). The authors considered the possibility that. in their later study of 29 female patients with IBS. The authors reported that progesterone levels did increase during the luteal phase. Triadafilopoulos and colleagues (1998) prospectively studied 228 women (170 postmenopausal and 58 premenopausal) who presented for evaluation at a primary care practice facility.) The authors (continued on page 70) . they found that. However. A suggestive physiologic mechanism may be the increased intestinal prostaglandin production that causes contraction of colonic smooth muscle or the increased intestinal secretions related to variation in progesterone levels (43).01) prolonged during this phase as compared with the follicular phase. Further evidence for a role of female hormones in bowel function comes from studies conducted in women in the perimenopausal and postmenopausal states. Whereas other early clinical studies failed to show a relationship between female hormones and bowel function.
with prevalence rates of 9.. Estrogen receptor (ER) expression in the levator ani fascia was increased significantly (P < 0. Dysmenorrhea. diarrhea. as 70 PRACTICAL GASTROENTEROLOGY • MAY 2005 identified via history and physical examination. estrogen use did not affect GI symptoms in either group. This is in agreement with what is known about premenstrual syndrome—those who suffer from this condition do not exhibit differences in ovarian hormone levels compared with healthy individuals. but that long-term use of estrogen leads to a significant decrease in ER expression. and heartburn/acid regurgitation were also more common among postmenopausal women than premenopausal women.Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. women rated their GI. A relationship between bowel symptoms (bowel symptom inventory ) and menstrual symptoms (Moos’ Menstrual Distress Questionnaire ) was evident throughout the study and was independent of psychological differences (i. Crowell and colleagues (1994) noted an overlap in diagnoses of dysmenorrhea and functional bowel disorders (FBDs) in their 12-month evaluation of 383 women (aged 20 to 40 years) who presented to a single Planned Parenthood clinic (32). Each day. The authors concluded that the observed relationship between menstrual and bowel symptoms and the overlap in diagnoses of dysmenorrhea and functional bowel disease were evidence of a common physiologic basis for many of the symptoms characteristic of these disorders. In this study. were receiving HRT. perimenstrual. Stomach pain was higher during the remaining days as well.01). but was significantly lower (P < 0. including fecal incontinence. as opposed to 14% of premenopausal women (P < 0. age-matched women. Interestingly. Serum estrogen and progesterone concentrations were measured during menses and during the follicular and luteal phases.8% of patients. neuroticism. Data from an earlier study conducted by Heitkemper and colleagues (1992) also suggested a relationship between symptoms and the menstrual cycle in women with FBD.001).4% vs 3. The group with FBD also reported higher levels of perimenstrual symptoms on six of the eight Menstrual Distress Questionnaire-T subscales (P < 0. The authors concluded that there is a high prevalence of altered bowel function and IBS-like GI complaints among women in the perimenopausal and postmenopausal periods. Copas and colleagues (2001) attempted to explain various pelvic floor disorders. and constipation. the two groups did not differ in occurrence of abdominal pain. defined as abdominal pain with altered bowel function. The authors concluded that ER expression is significantly higher in symptomatic women when compared with asymptomatic women of the same age.to 49-year-old age group. which are symptoms suggestive of IBS. by evaluating hormone receptor expression in the levator ani muscle and fascia. and 34% vs 18%. they differ in their (continued on page 72) . was diagnosed in 61% of patients with dysmenorrhea compared with 20% of patients without dysmenorrhea (P < 0. Twenty-four of the women. all of whom were symptomatic. and other symptoms and recorded stool frequency and consistency. Interestingly.e. and diarrhea higher at menses than did the group without FBD.001) in symptomatic women receiving long-term HRT when compared with age-matched women without HRT. The prevalence of IBS-type complaints peaked at a high of 36% among the 40.03) in symptomatic women not receiving HRT when compared with asymptomatic. Prostaglandin levels were measured in vaginal dialysate on the first day of menses in a subset of subjects (n = 44) and were elevated in women with dysmenorrhea regardless of bowel symptoms. which make up the pelvic floor (37).4%. rather. gaseousness/excessive flatulence. patterns of GI symptoms and select mood and somatic symptoms were evaluated across two menstrual cycles in a group of 19 women with and 39 women without FBD (45). 48% vs 27%. SERIES #7 (continued from page 68) found that 38% of postmenopausal women reported altered bowel function. was present in 19. respectively. The study looked at 55 women undergoing surgery for asymptomatic gynecological (n = 10) or symptomatic urogynecological (n = 45) conditions. as measured using the NEO Personality Inventory ). Functional bowel disorder. However. The group with FBD rated stomach pain. the authors reported no significant group differences in ovarian hormone levels or stool consistency/frequency scores.05). This may explain why longterm HRT does not appear to favorably impact pelvic floor disorders and suggests that down-regulation of receptors or relative tissue dominance of the progestin component of therapy is the cause. nausea. Laxative usage.
these results suggest that 5-HT3 receptor activity. mediating secretion in the GI tract. Among women with IBS. However.Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. constipation. in the central nervous system and other target organs. when premenopausal women with IBS were compared with postmenopausal women. women with IBS had significantly more severe GI symptoms. GI symptoms also appear to be influenced by the menstrual cycle in women with IBS. Collectively. et al (2001) reported that 40% of all female patients with IBS reported menstrual cycle-related worsening of symptoms (8). there were no significant differences between the two groups with respect to gas. bloating. Compared with controls. In a study of 477 female patients with IBS. psychological. 5-HT3 receptor transcript levels returned to normal. oral contraceptive users reported fewer symptoms of abdominal pain than did nonusers. however. . et al (2003) reported in another study that women with IBS had higher symptom severity. Hormonal Influences on Serotonin Activity? Serotonin (5-hydroxtryptamine [5-HT]). or alternating constipation and diarrhea). in predicting response to treatment is an area of interest. Heitkemper and colleagues (2004) described a specific relationship between bloating and menses-associated symptoms such as uterine cramping and breast tenderness (50). than did women in a control group (49). Heitkemper. First.) All patients were asked whether gas. SERIES #7 (continued from page 70) responses to normal hormonal fluctuations. Furthermore. In ovariectomized rats. patients with IBS were significantly more likely to experience exacerbations of each of these bowel symptoms. including abdominal pain. with complaints worse during menses. Lee. a 5-HT3 receptor antagonist that is used to treat diarrhea-predominant IBS (55. which is a target of pharmacologic intervention in patients with diarrhea-predominant IBS. (Criteria for diagnosis of IBS were abdominal pain plus altered bowel habits. It is responsible for initiating and maintaining peristalsis. et al (1990) assessed differences in GI complaints between female patients at a family planning clinic and women with IBS or FBD who were referred to a gastroenterology clinic (25). diarrhea. However. GI symptoms were significantly affected by the menstrual cycle phase. and also reported a higher percentage of days with hard and with loose stools. especially increased bowel gas. When ovariectomized animals were treated with estradiol and progesterone.e. is vital to normal gut function. The authors did report. In a subsequent study of women with IBS. there was no significant difference in bowel habit predominance (i. 50. also is regulated by female sex hormones.52). and diarrhea. which is produced mainly by and stored in enterochromaffin cells in the GI tract. A recent study has shown that estrogen and progesterone influence the level of 5-HT type 3 (5-HT3) receptor mRNA (54). and GI symptoms.8% reported experiencing menstrual cycle-related worsening of symptoms. when postmenopausal women were compared with a group of age-matched men. however. The potential effect of sex hormones such as estrogen and progesterone on serotonin remains to be elucidated. the authors 72 PRACTICAL GASTROENTEROLOGY • MAY 2005 argued against a significant role for menstrual cyclerelated hormone fluctuations in causing symptom differences. Additional studies highlight the importance of the serotonin reuptake transporter in IBS as polymorphisms in this gene resulted in a differential response to alosetron. however. the importance of serotonin and its receptors. and bloating. The authors noted also that reports of bowel symptoms during menstruation were not associated with psychological traits or with menses-related changes in mood. gas. in terms of somatic. lower levels of PGE2 and progesterone resulted in significantly higher amounts of 5-HT3 receptor mRNA. diarrhea. Whitehead. constipation. highlighting the concept that menstrual status does not affect bowel habit predominance. that premenstrual women were two times more likely to complain of nausea than were postmenopausal women with IBS.. but restrictive criteria for IBS were not satisfied. or constipation occurred during menstruation. as well as serotonin polymorphisms. Recent research has uncovered a potential role for abnormal serotonin expression and/or signaling in IBS and other GI disorders (53). in this case. Similarly. the same difference as in the total male and female samples was observed. based on two findings. Of women younger than age 45.56). and modulating the sensation of pain (51. One third of patients who denied symptoms of IBS or FBD reported that menstruation was associated with one or more bowel symptoms.
Hormonal Influences on the Gastrointestinal Tract and IBS TREATMENT OF IRRITABLE BOWEL SYNDROME. Schmulson M. An important next step is to determine whether sex or hormone status affects the efficacy of standard management approaches. 13 Suppl 2:65-69. 119(3):654-660. Brandt LJ. The effects of various types of HRT on the GI tract are not yet understood.. 2001. PhD. Review article: gender-related differences in functional gastrointestinal disorders. The impact of irritable bowel syndrome on health-related quality of life. Systematic review on the management of irritable bowel syndrome in North America. Naliboff B. have been described. Frank L. 97(2):389-396. Am J Gastroenterol. Talley NJ. especially in patients with functional nausea who are also thin. 10. Drospirenone. is the primary component of the recently introduced oral contraceptive Yasmin®. Whitehead WE. J Behav Med. and alternators).e. 2002. Mayer EA. patients experience less bloating and less weight gain. 97(11 Suppl):S1-S5. Zacker C. Wismeijer JA. Bjorkman D. Gastroenterology. Am J Gastroenterol. Patients taking Yasmin® should avoid potassium supplementation or other medications that affect potassium levels. PRACTICAL GASTROENTEROLOGY • MAY 2005 SUMMARY There now exists a considerable body of evidence supporting a role for sex hormones in the development of IBS symptoms. The impact of functional gastrointestinal disorders on quality of life. Simren M.g. I 73 . Gillberg R. Functional bowel disorders and functional abdominal pain. Mayer EA. Sykes MA. Am J Manag Care. 14. Koloski NA. Gastroenterology. Aliment Pharmacol Ther. constipation. 1999. Clin Ther. Kim JJ. 2000. Chang L. Chang L. 96(7):2184-2193. Am J Gastroenterol. Rentz A. Whether “natural” progestins will offer any advantage is not known. Jones KR. Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors. Palsson O. Kleinman L. 2002. 6. Schuster MM. Drossman DA. a C21 progestin derivative of spironolactone that has both progestational and mineralocorticoid effects. 2002. Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Svedlund J. Krasner S. 8. Irvine EJ. Blanchard EB. Abrahamsson H. Fennerty MB. Keefer L. Inflamm Bowel Dis. 7(8 Suppl):S246-S251. or Alesse®). they should also focus on sex and hormone status. bloating. Defining and diagnosing irritable bowel syndrome. IBS-like symptoms in patients with inflammatory bowel disease in remission: relationships with quality of life and coping behavior. Because estrogen excess can cause nausea. To this end. 18. Gastroenterology. HRT) in the management of patients with IBS symptoms remains to be defined. 49(3):469474. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. Lee OY. 1999. 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