The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

Abstract

Background and aims Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). Methods Rome III+ IBS patients and healthy controls underwent CRF (1 μg/kg ovine) and ACTH (250 μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n = 116). GR mRNA levels were measured using quantitative PCR (n = 143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. Results There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p = 0.009), but in women AUC was blunted in IBS (p = 0.006). Men also had reduced GR mRNA expression (p = 0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. Conclusion This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response.

Resilience is decreased in irritable bowel syndrome and associated with symptoms and cortisol response

“…We found a significant interaction between IBS status, resilience, and the stress hormone response, particularly the cortisol response to ACTH stimulation and the recovery of cortisol levels to baseline. We have previously shown that the ACTH‐stimulated cortisol response is divergent with greater responses in IBS men vs HC men and a blunted response in IBS women vs HC women . In prior studies evaluating the relationship between resilience and HPA axis response, more resilient healthy individuals were found to have lower cortisol levels in response to a psychosocial stressor .…”

“…A subset of patients who completed the resilience questionnaires underwent tests to measure the HPA axis response to a hormone challenge. The results of the hormone challenge tests in a larger group of IBS and HC subjects were previously published …”

“…Early adverse life events (EALs) have been found to increase the risk of developing IBS and can be associated with alterations in the central stress response systems, including the hypothalamic‐pituitary‐adrenal (HPA) axis . In addition, studies have supported a dysregulated HPA axis in IBS even in the absence of EALs . There are some data in the current literature suggesting that resilience can affect the response to stress, and that resilience scores are associated with changes in brain regions involved in stress responsiveness; however, to our knowledge, this has not been examined in IBS in regards to symptom severity, quality of life, and physiologic markers of stress.…”

Bifidobacterium longum and Lactobacillus helveticus Synergistically Suppress Stress-related Visceral Hypersensitivity Through Hypothalamic-Pituitary-Adrenal Axis Modulation

“…An exacerbated HPA axis in IBS patients after hormone challenge correlated with visceral pain and a reduction in GR protein expression in peripheral blood mononuclear cells. 44 Although, it has been shown in adult rats that an early life stress evokes a change of GR expression in the hippocampus and central amygdala, 45,46 which enhances an activation of somatosensory area and visceral hypersensitivity. 47 Moreover, in postnatal day 10, a single stress session for 4 hours induced an alteration of GR expression in the colon in pups, weakened the intestinal barrier integrity allowing bacterial translocation, 48 and subsequently provoked later visceral hypersensitivity.…”

Corticotropin-releasing hormone receptor 1 (CRH-R1) polymorphisms are associated with irritable bowel syndrome and acoustic startle response

“…As is usually done for genetic association studies, we controlled for race and sex (Cross et al, 2010). Furthermore, there is evidence of sex differences in IBS symptoms (Houghton et al, 2016) and neurobiologic mechanisms including the HPA axis response (Videlock et al, 2016). In addition, we also controlled for anxiety and depression symptom scores because these are often higher in IBS subjects vs. HCs and CRH-R1 and their SNPs have been associated with anxiety and depression (Bradley et al, 2008; Fond et al, 2014) (Heim et al, 2009) (Papiol et al, 2007) (Park et al, 2013) (Sumner et al, 2014).…”