Contribution of Gender to Pathophysiology and Clinical Presentation of IBS

Should Management Be Different in Women?

Abstract

The irritable bowel syndrome (IBS) is found more commonly in women than men. It is more prevalent in patients with chronic fatigue syndrome, fibromyalgia, and chronic pelvic pain, all syndromes characterized by pain and found predominantly in women. This article reviews evidence for a role of biological sex factors and gender on the pathways mediating visceral pain. The effect of gonadal hormones on gastrointestinal motility and the sensory afferent pathway and central processing of visceral stimuli and the contribution of gender role to the clinical presentation are discussed. Although differences in responses to treatment modalities between genders exist, the approach to IBS patients in both genders is quite similar. Nevertheless, a special attention to gender role and stress-related factors should be addressed. New developments in research, outlined in the paper, might bring more gender-specific treatments in the future.

INTRODUCTION

Irritable bowel syndrome (IBS) is one of the functional bowel disorders, characterized by a defined symptom complex in the absence of any biochemical or pathological structural abnormalities. The symptom complex has been refined over the years with a goal of making IBS a positive symptom diagnosis, and to group patients with a relatively homogeneous presentation for the purpose of clinical studies and treatment trials. The most commonly used symptom criteria are the Rome II criteria: abdominal discomfort or pain for at least 12 wk in preceding 12 months; where the pain should have two out of three of the following features: (a) relieved with defecation; (b) onset associated with change in frequency of stool; and (c) onset associated with change in form of stool (¹): IBS is classified as diarrhea-predominant, constipation-predominant, or alternating based on the predominant bowel habit.

The proposal that management of IBS symptoms might be different in women stems from the higher prevalence of IBS in women and from studies suggesting an effect of the menstrual cycle on symptom severity and the more recent drug studies suggesting that the 5HT-3 antagonist alosetron and the partial 5 HT-4 agonist tegaserod are more effective in women than in men. In addition, there is a greater prevalence of IBS in patients with other chronic pain conditions, which are more common in women, such as fibromyalgia, chronic fatigue syndrome, chronic pelvic pain, compared with the general population, and similarly there is a greater prevalence of these conditions in patients with IBS (²).

The prevalence of IBS in women compared with men varies from 1:1 to 2:1 in most population-based studies in the United States. The ratio of women to men is higher in the patients who seek medical attention and are seen in a tertiary care setting (^3–6). In countries other than the United States, such as Korea, China, and India, the reported difference in the prevalence of IBS between genders is less dramatic and supports the hypothesis that gender-related issues are more important than the biological basis of sex in this disorder (⁷). A recent population-based study indicated that, in the United States, the predominantly female prevalence is present both in whites and non-whites, suggesting that the difference in gender prevalence between societies is not based on race (⁸).

The age at which IBS most commonly presents is in the late teenage to mid-forties (⁴). This, along with the findings of a predominance in women, raises the question of the role of reproductive hormones in the pathobiology of the disease as well as other gender-related societal factors which may impact on patients either manifesting or being diagnosed with this condition.

The pathophysiology of IBS remains poorly understood, although there are several physiologic processes that appear altered in IBS: (a) alterations in the response of the gut to stimuli such as food (motor response), (b) an altered perception of a visceral stimuli (the afferent sensory pathway or the brain-gut axis), and (c) the perception of a non-noxious visceral stimulus as noxious (psychological profile and altered cortical processing of visceral stimuli). The neuronal connection between the gut and the central nervous system (CNS) is referred to as the brain-gut axis. This axis is hardwired and involves the stretch receptors in the wall of the gut as well as chemical receptors in the mucosa, the enteric nervous system which relays information from these receptors to the autonomic nervous system, the autonomic pathway and spinal pathways which relay information to the CNS, and the cortices which need to be activated for a stimulus to be perceived consciously. How these pathophysiologic processes are impacted by factors related to sex and gender will be discussed. A framework to conceptualize this is provided in Figure 1. The main findings reported in the literature related to the effect of gonadal hormones and gender on the physiologic pathways involved in IBS are summarized in Table 1. The evidence for differences in afferent and efferent pathways of the brain-gut axis and in pathophysiology in women and men with IBS is summarized in Table 2.

Figure 1: Model of sites of action of modulating factors related to sex and gender on the brain-gut axis affecting the clinical expression of irritable bowel syndrome.

Table 1: Summary of Effects of Sex Hormones or Gender on Physiologic Pathways Controlling the Brain-Gut Axis

Table 2: Evidence for Differences in Pathophysiology or Response to Treatment Between Men and Women with IBS

ESTROGENS AND GONADAL HORMONES—EFFECT ON MOTILITY

Differences in motility and pain pathways are present between sexes. Several studies indicate that there is an effect of gonadal steroids on motility. Alterations in the lower esophageal sphincter pressure have been reported in pregnancy (⁹). In animals, progesterone has been shown to affect gallbladder contractility (¹⁰). Gallbladder emptying, however, seems to be similar in nonpregnant women and in men (¹¹). There is a slower rate of gastric emptying reported in menstruating women than men of a similar age, which suggests a role for sex hormones on either the autonomic nervous system or gastric smooth muscle (¹²). Gastrointestinal complaints during the menstrual cycle can be related to motor changes or a change in perception of colonic motor events. Approximately 35% of women without IBS and up to 50% with IBS reporting greater gastrointestinal symptoms at the time of their menstrual period (^13–15).

ESTROGENS AND GONADAL HORMONES—EFFECT ON VISCERAL AFFERENT, AUTONOMIC NERVOUS SYSTEM, AND PAIN PATHWAYS

The cardinal symptom in patients with IBS is abdominal pain. This, along with the association of IBS with other pain-syndromes, has led to a focus on the pain pathways in patients compared with healthy controls (^{2, 16}). Neurotransmitters involved in the afferent pathway include substance P and glutamate, which are released by primary afferent neurons at their synapses with second-order neurons. Estrogens modulate the responsiveness of primary afferent neurons to substance P in the guinea pig (¹⁷). In a model of chronic stress, chronic glucocorticoid administration, sexually dimorphic changes in the dendritic processes of the pyramidal neurons in the CA3 areas of the hippocampus are seen, with greater atrophy of dendrites in male than female mice. There are changes in the distribution of glutamate receptor subtypes between sexes (¹⁸). An effect of gonadal hormones on the antinociceptive effect of opioids has been described in rodents with a suggestion that testosterone increases the antinociceptive effect of μ and κ opioids to somatic pain in adult male rats, while the effect of estrogen and progesterone in different stages of the estrus cycle is complex and opioid receptor subtype specific (¹⁹).

Although animal studies support an effect of estrogen on nociception neurotransmitter pathways and some gender differences have been noted in the responses of healthy men and women to neurotransmitters such as adrenergic agonists, there are no studies to examine differences in these specific pathways in male and female IBS patients. However, studies of autonomic function have indicated differences between healthy males and females, and studies in women with IBS suggest less parasympathetic activity as detected by R-R interval variation to deep breathing and a greater sympathetic response to stimuli such as orthostatic testing and isometric handgrip exercise in women with IBS compared with healthy controls (²⁰). A similar altered autonomic response was reported to sigmoid balloon distention in IBS compared with controls, but interestingly, this effect was more prominent in males with IBS than females (²¹). The potential effect of these differing neuroendocrine responses to somatic and visceral stimuli to symptom presentation in women and men with IBS remains unclear.

Studies in animals have also indicated that the estrous cycle affects the visceromotor response to colonic balloon distention (²²). This visceromotor response is considered a surrogate marker for pain in the conscious animal. Opiates such as morphine, which can act centrally or peripherally, decrease the visceromotor response with a greater potency in male compared with female rats. This sex difference is predominantly via its supraspinal effect and less through its peripheral effect (²³). Corticotropin-releasing hormone (CRH) is thought to play a role in the pathophysiology of depression. Produced mainly in the paraventricular nucleus of the hypothalamus, it is released as part of the stress response. Interestingly, CRH affects gastrointestinal physiological functions via both central and peripheral receptors. CRH-R1 is found in the brain and both myenteric and submucosal neurons in the guinea pig and appears to play a more important role in the brain-gut response to stress than CRH-R2 (²⁴). There is colocalization of estrogen receptor-alpha with CRH in the hypothalamus, suggesting a possible interaction between these systems (²⁵).

Thus, evidence exists for an effect of gonadal hormones in both the motor and sensory responses of the brain-gut axis in animals. Whether these gender differences persist in disease states is not yet determined.

The reports in healthy human volunteers are conflicting. In healthy women, a lower sensitivity has been reported during both the follicular (¹³) and luteal (¹⁵) phases of the cycle, others have described a greater sensitivity at the late luteal and premenstrual phase. Others and we have described a greater sensitivity during the follicular phase (^{13, 26}). In IBS patients, some authors have described a greater sensitivity across the cycle (⁹), or at the premenstrual period, while others have failed to note any differences between healthy and IBS subjects during the menstrual cycle (^{13, 15, 27–29}). These differences probably reflect the small sample size, the symptom scale used, the lack of rigorous definition of the phases, and the fact that the effects of hormonal changes over the menstrual cycle may be complex. Exactly what stage of the menstrual cycle is studied during the menstrual cycle may affect the reported responses.

One hallmark of IBS is a decreased tolerance to visceral distention with a sensation of discomfort or pain at either a level which would not produce any discomfort in a “normal subject,” i.e., allodynia, or greater discomfort or pain than would be experienced by a “normal subject,” i.e., hyperalgesia (¹⁶). In women with IBS, a lower threshold to rectal distention has been described compared to men with IBS (³⁰).

CNS processing of visceral stimuli has been examined in human volunteers and patients using either positron emission tomography (PET) scan or functional magnetic resonance imaging (fMRI). These techniques allow imaging of brain areas that have greater metabolic activity or blood flow in response to a stimulus. Even using these techniques, conflicting results have been reported, which reflects the complex nature of experiencing pain. Most studies have examined the difference between asymptomatic volunteers and subjects with IBS (^{31, 32}). Only a few studies have specifically examined the differences in brain activation in males and females, either healthy controls or with IBS. Kern et al. reported that the volume of cortical activation by rectal balloon distention is greater in women than men at all levels of stimulation and differences in area activated are described between men and women (³³). Berman et al. found greater activation of the insular cortex in males than females with IBS in response to nonpainful but clearly perceived rectal distention pressures (³⁴). In a more recent study, the same group demonstrated different areas of activation in response to 45 mmHg rectal distention with greater activation in the dorsal pons and PAG in males and activation of the left amygdala and right ACC in females only. Differences were also seen between the male and female patients in response to anticipation of a noxious stimulus. The investigators conclude that there is a fundamental difference between the sexes, with greater activation of brain areas involved in cognitive processing and central sympathetic areas with inhibition of limbic areas in males, while in female patients there is greater activation of the affective and autonomic regions (³⁵). Other investigators found contrasting results, with a greater activation of the insular region associated with the perception of rectal distention in women with IBS compared to men (³⁶). This study had only a few men in the study group, but an editorial from these authors succinctly outlined the multitude of potentially important factors which might contribute to differing results (³⁷), ranging from differences in patient population, technical differences in balloon stimulation to stimulus paradigm, and methods of analysis. One study examining a single patient demonstrated markedly different areas of brain activation in the same patient to the same stimulus under different psychological conditions (³⁸). Functional brain imaging studies are usually from referral centers. It is known that patients at referral centers have significant psychomorbidity and the results may represent a subset of patients making it difficult to generalize findings to the population with symptoms of IBS as a whole. It would be fair to say that understanding the brain processing of visceral stimulation in healthy subjects and patients with IBS, as well as determining the effect of gender on these responses, is still an area of active research, but there does appear to be gender differences in central processing of visceral stimulation, both in health and in IBS.

Interpretation of pain in studies can be markedly influenced by patient selection, particularly if sample size is small, interpretation of pain scales, gender of the subject and the person performing the study, and the level of anxiety. Several studies indicate that women tend to report more pain to a given noxious stimulus than do men (^{39, 40}). However, a recently published paper of the largest number of subjects reported so far found only small and subtle differences in nociceptive neurotransmission and neuronal sensitization to somatic pain (⁴¹). The authors suggest that the differences in findings relate to size of sample, the type of pain reporting, and anxiety of the subjects. The visual analog scale is interpreted differently by men and women and probably reflects a socialization difference rather than true pain sensation differences (⁴²).

EFFECT OF GENDER ON PSYCHOLOGICAL RESPONSE TO PAIN: IMPACT OF ABUSE HISTORY

Patterns of accompanying symptom complaints are different between men and women with symptoms of abdominal distention, anxiety, and depression, being more common in women (^43–46). An interesting study of psychology students demonstrated that the female students tended to score greater on a pain catastrophizing scale than men. This scale incorporates the degree of rumination, magnification, and helplessness that a subject feels when experiencing pain (⁴⁷). This study suggests that the affective component to experiencing pain is different between men and women, even when they have no chronic illness.

Recent studies indicate that infection or inflammation contribute to increasing both the nociceptive response to visceral stimulation and the motor activity of the gut (^{48, 49}). Initial studies indicated that women and patients with a psychological profile of neuroticism and anxiety were more at risk for developing postinfectious IBS (⁵⁰). Subsequent studies confirm the greater prevalence of these psychological traits, but the female gender appeared to be less of a risk factor (⁵¹). In light of the reported predisposing risk factor of infection and the report of a greater number of mucosal mast cells in the colon of subjects with IBS, it is of interest that there are more constitutive mast cell populations in the jejunum and colon in female rats compared with male rats (^{52, 53}). Whether any similar difference is seen in humans is unknown.

An important factor contributing to the degree of pain experienced by women with IBS is a history of abuse. At a tertiary referral center, the prevalence of a history of abuse was greater in patients presenting with IBS or functional abdominal pain than with organic GI disease (⁵⁴). This is clearly more prevalent in female patients than in males, and needs to be identified and addressed if treatment is to be effective. Gender socialization can impact reporting of pain even without any history of abuse or psychopathology. There is a potential impact of the sex of the patient and of the researcher or physician on pain reporting (⁵⁵).

IMPACT OF GENDER ON TREATMENT OF PATIENTS WITH IBS

Gender-Associated Response to Medication

Although the studies discussed so far would leave an impression that gender socialization factors are more important than biological sex factors in contributing to the greater prevalence and severity of IBS symptoms in women, clinical drug studies suggest an important role of biology in the symptom complex. Serotonin, 5-hydroxytryptamine, is an important neurotransmitter in both the motor and sensory pathways of the gut. Gastric accommodation is enhanced by 5-HT1 and 5-HT4 receptor activation. GI transit is enhanced by agonists at 5HT3 and 5HT4 but decreased by agonists at 5HT1 receptors. Colonic tone is increased by 5HT 3 agonists, and decreased by 5HT1 agonists. Alosetron, the 5-HT3 antagonist, has been shown to be more effective in improving urgency and diarrhea in IBS diarrhea-predominant women than men (⁵⁶). The basis for this gender difference is not known at present. There is a mild difference in clearance of alosetron between women and men, particularly in the older age group, with a slightly higher serum drug level in women, but this is insufficient to explain the difference in therapeutic effect (⁵⁷). 5-HT3 antagonists inhibit the gastrocolonic reflex and reduce the visceromotor response to colorectal distention in animals and compliance in patients with IBS. Interestingly, alosetron did not affect the pressure at which pain was perceived (⁵⁸), but did alter the compliance of the rectum. This was a small study and the data were not evaluated by gender. Pharmacogenetic studies have demonstrated that polymorphism in the promoter region of the serotonin transporter (SERT), which controls reuptake of 5-HT by the neuron, affects response to alosetron (⁵⁹). Homozygous short and heterozygous long/short polymorphisms of the promoter region are associated with decreased function of the transporter in lymphoblasts (⁶⁰). The polymorphisms, however, do not appear to be gender related. Interestingly, polymorphisms do appear to account for a percentage of patients with affective disorders, and anxiety and depression are more common in women with IBS (⁶¹). Although the polymorphisms are seen equally often in both men and women, their effect may be different. Recently, Mizuno et al. reported that females with both allelic variations, long and short (l/s genotype), in the 5-HTT linked promoter region showed higher anxiety than those with the s/s genotype, whereas males with the s/s genotype showed higher anxiety than those with the l/s genotype, suggesting a difference in response of the CNS to serotonin in the different sexes (⁶¹). A preliminary study, using PET to examine 5-HT synthesis in subjects treated with alosetron and placebo, suggests gender-different areas of greater synthesis. Although the number of subjects was very small, this study offers another potential site for gender-specific responses (⁶²). There may also be a connection between serotonin transporter activity and inflammation. In animal studies, inflammatory mediators can induce serotonin-selective reuptake transporter downregulation (⁶³).

Tegaserod, the 5-HT4 partial agonist, is indicated in patients with constipation-predominant IBS. It is also effective in accelerating gastric emptying and transit through the small intestine and colon. In small sample studies, the effect was greater in healthy men than women (⁶⁴), although initial studies suggested a greater efficacy of tegaserod in constipation-predominant female patients (⁶⁵).

Are there gender-related differences in drug clearance that might impact on many medications used in the treatment of patients with IBS? Many medications are cleared through the cytochrome P450 pathway that can be affected by estrogen and progesterone. Differences in clearance of medications via one of these enzymes, CYP3A4, have been described, with women clearing drugs metabolized by this enzyme more quickly than men. Women are generally smaller than men and have a different adipose tissue compartment, which might impact on drug clearance. Specific trials examining clearance, however, fail to show clinically significant differences to the extent that dosage recommendations would need to be changed (⁶⁶).

How do these findings affect whether treatment of IBS in women should be different from men? The approach to treating patients with IBS is directed to the predominant bowel habit as well as to managing symptoms of bloating and pain. For diarrhea-predominant IBS, either opiate-based constipating medication such as loperamide and atropine/diphenoxylate can be used. There is no evidence for gender differences in response to these medications. Probiotics have recently been shown to help the symptoms in patents with IBS, again without gender specificity (⁶⁷). Probiotics are considered to affect the immune response (⁶⁸). If patients are unresponsive to these medications or changes in diet or increased fiber, alosetron should be considered for women. Alosetron is currently available only on a prescriber's program for use in women because of the complications of ischemic colitis.

Psychological Treatment Approaches

The psychological and gender role aspects of symptoms of IBS in women need to be recognized and are important to consider in the care of patients. The history of abuse needs to be explored, particularly in the population of patients seeking health care. The potential of psychological disorders needs to be considered and addressed in all patients. While women scored higher on the Beck Depression Inventory and demonstrated higher trait anxiety, structured psychological interviews did not reveal a difference in the percentages of patients of either sex meeting criteria for one or more Axis 1 psychiatric disorders. In this study, 65.6% of the total sample of 250 participants met these criteria, again underscoring the need to address the possible impact of these psychological disorders on the symptoms of IBS in all patients (⁶⁹). Very few treatment studies have evaluated the effect of gender on response, other than recent studies with serotonin antagonists or agonists. The greater prevalence of anxiety and depression in patients with IBS, along with the finding of greater vigilance to gut stimulation and a perception of gut stimulation as more unpleasant and painful than non-IBS subjects, would suggest that psychological approaches might be beneficial (⁷⁰). Studies using approaches such as relaxation therapy and cognitive-behavioral therapy can often be problematic to interpret because of unvalidated outcome measures or lack of adequate blinding with marked difference between treatment and control. Psychotherapy does appear to be effective, particularly in patients with anxiety and depression and those who have a clear association of symptom with stress (⁷¹). Given the association of anxiety and depression with this response, the efficacy of the SSRI, paroxetine, compared with psychotherapy and treatment as usual was studied (⁷²). Although no difference in results was seen at the end of a 15-month treatment follow-up, psychotherapy was slightly cheaper. No gender effect was reported. Random controlled trials of SSRIs suggest an improvement in global well-being but not necessarily in abdominal pain or bowel habits, suggesting a central effect of SSRIs (⁷³). Alternative treatments such as hypnotherapy have been reported to be effective in patients with IBS. A report of the experience in 250 patients treated with hypnotherapy indicated that women had a higher IBS score with more bloating and extracolonic complaints prior to hypnotherapy and had a greater improvement in score than men (⁷⁴). This was a result of more males having diarrhea-predominant IBS and this group having the worst response. Interestingly, the women with diarrhea responded better. The mechanism by which hypnotherapy is effective is not known.

SUMMARY

In summary, there is a large body of literature demonstrating that there are biological sex-related effects on intestinal motor and sensory pathways and function. Clearly, the differences in biological action and pharmacokinetics of serotonin antagonists in males and females suggest a biological difference in pain pathways. These findings and data indicating gender differences in response to antinociceptive drugs and stress-related peptides support a need to evaluate gender in studying efficacy of new pharmaceuticals to treat IBS. Studies in patients are complicated by the impact of gender roles and socialization in pain perception and reporting and the impact of psychological distress on the CNS response to gut stimuli. Although psychological distress and coping mechanisms may be different in men and women, the overlap in the psychiatric diagnoses in men and women with IBS underscores the importance of addressing both the psychological and physiologic alterations in all patients with this condition, but particularly in women. The review of the literature would suggest that although there are gender differences in pathophysiology, the management approach to men and women suffering from IBS is more similar than different.

STUDY HIGHLIGHTS

What Is Current Knowledge

• Effect of gonadal hormones on the physiologic processes affecting the brain-gut axis.
• Effect of gender on these processes
• Differences in brain-gut axis and pathophysiology in men and women with irritable bowel syndrome.
• Differences in responses of men and women with IBS. to treatment.

What Is New Here

• This is a review, therefore it summarized published data and does not provide new data. It is a review which includes very recent publications (2006).

CONFLICT OF INTEREST

Work in this article was supported in part by NIH grants 1R21 DK57053, NIDDK, MOIRR010732, and C06RR016499.