Women and irritable bowel syndrome: Is the gain in pain mainly in the brain? (2006)

See article in J. Gastroenterol. Hepatol. 2006; 21: 468–473. It is by now common knowledge that, at least in the Western world, irritable bowel syndrome (IBS) is a disease predominantly of women. In fact, this appears to be true not only for IBS, but for most other functional bowel as well as somatic disorders characterized by chronic pain such as fibromyalgia and migraine.1 However, the underlying mechanisms responsible for this phenomenon remain to be understood although several theories abound, as reviewed extensively elsewhere.2 These can be classified as sociocultural, psychological or biological in nature, with perhaps considerable overlap amongst these categories. Sociocultural factors include issues such as sex-based differences in access to healthcare, rate of healthcare utilization and perhaps the proclivity to report physical discomfort. Such factors could for instance account for the differences in sex distribution of IBS patients in countries such as India.3 Psychological factors include the higher rates of somatization in women along with differences in the prevalence of conditions such as depression4 and coping responses to stress.5 Biological factors include cross-sensitization from neighboring organs such as the urinary bladder and genital tract,6 influence of sex hormones or other circulating factors, or intrinsic differences in the neuronal substrate of motility and/or pain perception.2,7–12 Finally, it should also be borne in mind that most commonly used criteria for diagnosing IBS in population surveys were distilled from symptoms reported mainly by women; it is therefore conceivable that these criteria may not necessarily be as sensitive or accurate in men. Irritable bowel syndrome is a multifaceted disease that appears to result in disturbances of both motility and sensation. Patients with IBS experience pain at distention pressures or volumes that produce, at best, normal internal sensation in healthy volunteers (allodynia); they also experience more severe discomfort at noxious distention pressures or volumes (hyperalgesia).13 Together these phenomena suggest sensitization (enhanced responsiveness to a stimulus) of the pain processing (nociceptive) circuitry. What causes sensitization in IBS is not known for certain but many of the factors described above may contribute to it. The question of whether the nociceptive system is more sensitized in women than in men (regardless of the pathogenesis of this difference) is therefore very important and was addressed in the study reported by Kim et al. in this issue of the Journal.14 Using a standardized barostat protocol, these investigators studied rectal sensation in men and women with IBS and in healthy controls. As expected, sensory thresholds were lower in the IBS population than in controls. However, no differences were found between men and women within the IBS population who appeared to be well matched for possible confounding factors such as psychological profiles. These findings are not particularly surprising. Despite data from animal studies to the contrary,15 several studies in the literature, with few exceptions,16 have previously failed to demonstrate a sex difference in colonic perception of painful stimuli in either healthy volunteers17,18 or in patients with IBS.19–21 What insight do these results provide us with respect to the female dominance of IBS? In keeping with other studies in the human literature cited, we may conclude that healthy men and women respond similarly to painful stimuli and that the nociception per se is similar in both male and female patients with IBS. However, these results do not mean that sex-based differences in nociceptive sensitization are not important. On the contrary, there is evidence that, while their response to single stimuli may not be different, women respond differently to repetitive noxious sigmoid stimuli with a significant reduction in discomfort threshold to subsequent testing, a phenomenon that is not observed in men.22 In the clinical context this means that the nociceptive system in women may be more vulnerable to sensitization after a period of intense frequent contractions such as that may occur after a bout of infectious colitis. Indeed, in postinfectious IBS, the same sex difference is perpetuated as in other forms of IBS.23 Thus, differences in susceptibility to nociceptive sensitization may explain why a greater proportion of women develop IBS. Once IBS has developed, however, their responses are expected to be similar to other patients including men. In this context, it is also important to understand that increased afferent signaling to the central nervous system is not by itself sufficient to make a patient with pain seek medical attention; that is, become a patient.24 For this to happen, pain perception needs to result in suffering (a combination of anxiety, fear, stress, uncertainty and loss of loved objects).25 Further, this suffering then leads to illness behavior, which reflects how pain is acted upon by an individual (such as rate and intensity of healthcare utilization) and results from a complex mixture of physiological (e.g. pain intensity/severity or associated features), psychological (e.g. mental state, stress, mood, coping style, prior memories or experiences with pain) and social factors (e.g. concurrent negative life events, attitudes and behavior of family and friends, perceived benefits such as avoidance of unpleasant duties.).26 Increasingly, these attributes are being recognized to have a specific neural substrate and indeed important sex differences have been detected by objective tests such as positron emission tomography imaging. Thus the work of Mayer et al. show that in response to colonic stimulation, women with IBS have greater activation of parts of the brain that deal with emotional responses, such as specific regions of the prefrontal and cingulate cortex and amygdala.21 In conclusion, we are entering an exciting era in understanding the fundamental processes that govern not only why some patients are more susceptible to functional bowel disease such as IBS, but also why some of them are driven to healthcare seeking behavior. These insights have the promise to unravel many of the mysteries surrounding these syndromes, of which sex bias is only one.