“Sex does matter. It matters in ways that we did not expect. Undoubtedly, it also matters in ways that we have not begun to imagine.”
Mary-Lou Pardue, PhD Chair of the Institute of Medicine committee on understanding of sex differences.
Sex (relating to chromosomal complement and reproductive organs and functions) and gender (referring to a person’s self representation as male or female) specific differences in health and disease have been recognized for centuries. These differences likely involve a complex interaction between biology, psychology, and sociocultural factors. For example, the heterogeneous expression of some diseases within and between sexes is attributed to the presence of either single (in case of XY genotype) or double (in case of XX genotype) copies of the gene and phenomenon of X chromosome inactivation and genetic imprinting. Other sex differences are believed to be related to hormonal events and differences in energy storage that may contribute to variable onset, manifestation, and progression of diseases in males and females such as obesity, autoimmune disorders, and coronary artery disease.1 In addition, basic genetic differences together with environmental factors result in behavior and perception differences between genders, which have clinical implications, such as pain perception. It is becoming increasingly evident that many normal physiologic functions, and in many cases pathologic functions, are influenced directly or indirectly by sex- based differences in biology. Recently, there has been an increase in research efforts related to studying sex and gender specific characteristics in irritable bowel syndrome (IBS), a common medical disorder with an unexplained female predominance. This increased attention to sex differences in IBS has perhaps resulted from growing evidence that men and women differ in their responses to newly released pharmacologic agents for IBS (Tegaserod and Alosetron).2,3 Whatever the cause, attention toward gender related differences in IBS is timely and relevant.
The article by Dr. Whorwell and colleagues “Gender and Irritable Bowel Syndrome: the Male Connection” is based on a novel idea borne through clinical observation, which is the way sound research questions are often generated. This study is one of the first efforts to determine specific psychologic features that characterize males with IBS. As frequently occurs in explorative medical research, the findings may generate more questions than answers. Nevertheless, this work highlights the need to establish normative data on clinical and psychosocial factors for both men and women with and without IBS, in order to better understand gender differences.
Are there any existing data on sex and gender specific findings in IBS? The answer is difficult, because men are underrepresented in this area of clinical research. Thus, it is not surprising that our knowledge of the pathophysiology and treatments for males with IBS is based almost exclusively on data obtained from females with IBS. However, the gap in knowledge about IBS in men may be closing. Several differences have become evident.
- Diagnosis: to begin with, our ability to discuss differences may be limited because even the diagnostic criteria for IBS may be female specific. The symptom based Manning criteria for IBS is reported to be more valid in females than males.4,5 When Manning criteria were compared to the clinical diagnosis of IBS made by 2 independent Gastroenterologists, the correlation between the Manning criteria and the clinical diagnosis of IBS in women was significant (r = 0.47; P < 0.01). In men, however, the correlation was in the opposite direction, although it was not significant (r = −0.16)4,5 Furthermore, there have been no studies comparing the validity of the currently accepted symptom-based diagnostic Rome II criteria for IBS in males.
- Physiology: studies have demonstrated differences in physiologic and subjective responses to pain in females and males. Females rate noxious stimuli as more intense and are better at discriminating between different pain intensities than males.6 Rectal hyperalgesia, in response to repetitive high pressure distention of the sigmoid colon, is greater in females than males with IBS or control groups.7 At the CNS level, females with IBS show greater activation of limbic/emotional centers of the brain with rectal distention when compared to males with IBS, who preferentially activate prefrontal and descending inhibitory pain pathways, but the clinical relevance of this finding requires further investigation.8 Nevertheless, these data suggest different patterns of perception of visceral afferent signals.
- Symptoms: women with and without IBS report more constipation as well as a higher frequency of certain intestinal and nonintestinal sensory symptoms (abdominal distention, nausea, myalgias, etc.), although symptom severity, abdominal pain, psychologic symptoms, and illness impact are similar.9,10 Further work is needed to determine if these differences relate primarily to physiologic differences (i.e. sex- based) or to differences in reporting tendencies that may be socioculturally determined (i.e. gender based).
- Psychologic characteristics: females have a higher tendency to respond to pain with anxiety and are more likely to disclose their symptoms to others.11 Frequencies of prior sexual or physical abuse are reported in up to 50% of female IBS patients seen in tertiary referral centers,12 but are only reported for about 20% of male-patients.13 It is noteworthy that IBS seems prevalent in the male veteran population, possibly related to increased psychologic distress, traumatic experiences, and Post Traumatic Stress Disorder.14,15
- Treatment: current clinical treatment trials have either not studied males16 or are underpowered for men.3 Given that 2 novel treatments recently approved for the treatment of IBS (Tegaserod and Alosetron) are not indicated for males172,3 identifying proper treatment strategies for males is becoming an area of great interest, with important implications for medical practice. The possible difference in gender related treatment benefit may relate to genetic (e.g., SERT transporter function)18 or central (e.g., differences in cingulate activation)8 or peripheral (e.g., differences in GI motility) effects.19,20 Non-pharmacologic treatments, such as cognitive behavior therapy for IBS, are based solely on treatment strategies18 and results from data obtained from studying females.16
- Medical profession attitudes toward IBS: even physician perception of IBS management seems to be different for women and men—physicians perceive IBS in women to be less easy to diagnose, but easier to manage than in men.21
In this issue of the Journal of Clinical Gastroenterology, the study by Dr. Peter Whorwell et al, Gender and Irritable Bowel Syndrome: The Male Connection, (Journal of Clinical Gastroenterology, in press) addresses gender related differences with regard to certain psychosocial features that may have clinical implications. The investigators compared 70 male patients with IBS to 70 male controls without IBS. Subjects completed the Bem Sex Role Inventory (BSRI), (Bem SL, 1974) and the hospital anxiety and depression (HAD) questionnaire. The BSRI is a validated questionnaire designed to measure masculine (e.g., “act as a leader, aggressive, ambitious, competitive, dominant, forceful, and independent”) and feminine (e.g., “affectionate, cheerful, companionate, gentle, sensitive to needs of others, shy, and tender”) characteristics (traits). The inventory consists of 20 items in each of the “masculine,” “feminine” and “neutral” groups with a scale used 1 to 7 (1 = not at all desirable, 7 = extremely desirable). The study found significant reductions in male- trait scores in the IBS group compared to the non-IBS controls. (−10.5 [−15.7,−5.2] P < 0.001, 95% CI). There were no significant differences between groups with respect to female characteristic scores or prevalence of homosexuality. Males with IBS had higher depression and anxiety scores than those without IBS, as expected, with a difference of 4.9 [3.7–6.2] P < 0.001, 95% CI for depression and 5.9 [4.8, −7.2], P < 0.001, 95% CI for anxiety. The authors concluded that men with IBS exhibit fewer male characteristics than men without IBS, but it remains to be determined whether this finding is cause or effect.
There are some issues that need to be considered. First, it is not clear if there were an a priori hypothesis or whether the findings were post hoc observations. Second, the males with IBS sought medical attention, therefore, the results may not apply to all males with IBS. Also, we do not know if a reduction in male trait scores is unique to IBS or occurs in males with other chronic illnesses, or to health care seekers, or if higher depression and anxiety scores in males with IBS (such as self- reliance, assertiveness, ability to make decisions easily) can account for some of the reduction in male traits. Third it is not known if the self-reporting of homosexuality is reliable, particularly in the control group, which consisted primarily of research site hospital employees. Also, the questionnaire used in this study to measure psychologic androgyny (the presence of both male and female psychologic characteristics in the same person) was developed 30 years ago, thus it is possible that the stereotyped “masculine” and “feminine” characteristics are not fully applicable today. In fact, this anachronism led to a major revision for the gender scale of revised Minnesota multiphasic personality inventory.22 Finally, the degree of difference between study groups, although statistically significant with a difference of 10.5, is difficult to quantify in terms of clinical significance and pertinence to clinical practice.
Despite these limitations, the study demonstrates that male patients with IBS do indeed have different psychologic characteristics than males without IBS, and issues of causality, generalizability and comparability to females are topics for future investigation. Therefore, this study begins a new area of investigation, and for that reason, its value lies in the generation of research hypotheses to be further tested. Further work is needed comparing males to females with IBS. Examining sex differences in IBS presents an opportunity to better understand the pathogenesis and pathophysiology of this common and complex disorder, to develop more specific treatments for IBS, and ultimately, to improve health care.
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