Evidence for Hypothalamic PituitaryAdrenal Dysfunction

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Human studies have demonstrated the effects of CRH and its antagonism, both in healthy subjects and in FGD. Fukudo et al. demonstrated that intravenous CRH induced greater abdominal symptoms, higher ACTH levels, and exaggerated gut motility in IBS patients compared to controls (128). This suggests a heightened sensitivity of the HPA axis in IBS patients, which may be at the hypothalamic-pituitary level as no significant difference was found between levels of cortisol response between the two groups. Peripheral administration of a-helical CRH has been shown to improve GI motility, visceral perception, and negative mood in response to gut stimulation in IBS patients, suggesting that CRH-signalling pathways play an important role in the pathophysiology of IBS. The precise site of action of intravenously administered CRH antagonists on GI function is unknown. Human studies have reiterated the findings of animal studies regarding the involvement of mast cells in the immunoregula-tory response. Indeed, oral disodium chromoglycate has been shown to improve symptoms in selected subtypes of patients with diarrhea predominant IBS (129).

Conflicting results exist in the literature regarding the detection of humoral markers of the HPA axis in FGD. This is important, as assaying these various markers varies in expense, availability, and collection requirements with cortisol (plasma, salivary, or urinary) probably being the most favorable on all counts. Posserud et al. (130) examined the effects of mental stress on rectal distension thresholds in IBS patients and healthy controls. Thresholds increased during stress in controls but not in IBS patients; however, thresholds were lower in all groups after stress. Patients demonstrated higher stress ratings, higher ACTH content in blood during stress, and lower basal CRH content than controls. CRH content increased significantly during stress but did not in controls. No significant rise or group differences were seen in cortisol responses to stress. Other studies have demonstrated higher morning cortisol content in IBS patients both in the saliva (131) and in the urine (122), and different cortisol responses between IBS subgroups with elevated postprandial cortisol seen in diarrhea predominant IBS (132). Autonomic assessments in this latter study also suggested heightened postprandial sympathetic dominance and vagal withdrawal that correlated with increased symptoms in diarrhea predominant IBS (132).

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