The Effect of Sex and Irritable Bowel Syndrome (IBS) on the Integrated Hypothalamic-Pituitary-Adrenal (HPA) Axis Response to Hormone Challenge

Abstract

Introduction: Irritable bowel syndrome (IBS), a stress-related and female-predominant disorder, is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Men and women have different HPA response to hormone challenge and stress. IBS-related changes in the HPA response to corticotropin-releasing factor (CRF) and adrenocorticotrophic hormone (ACTH) differ by sex and can be affected by early adverse life events (EALs).(Adeyemo, Gastro 2015) Aims of this study were to create measures of the integrated response to hormone challenge through factor analysis of the response to CRF and ACTH and to determine the effect of sex and IBS status on these measures. Methods: Rome III+ IBS patients and healthy controls (HCs) underwent CRH (1μg/kg ovine) and ACTH (250μg) stimulation with serial plasma ACTH and cortisol levels. Baseline, area under the curve with respect to the minimum value (AUCi), rise and decline slopes were included in the factor analysis. Factors were extracted by principal components (threshold of eigenvalue>1), followed by Varimax rotation. Differences in factor scores (regression method) were determined with linear models controlling for Age and BMI. Results: Participants (Table 1) were 46 IBS patients (63% women) and 49 HCs (53% women). Factor structure is shown in Table 2. Based on the variables with the highest loadings, the factors can be described as: 1: ACTH response to CRF; 2: Cortisol response to CRF & ACTH; 3: Baseline PM ACTH & cortisol; and 4: Low AM cortisol & fast decline of ACTH stimulated cortisol. Factor scores by IBS and sex are shown in Figure 1. For all factors, IBS-related changes were opposite in men (M) vs. women (F) Cortisol response was higher in IBS M vs. HC M (p=0.041). Baseline PM ACTH and cortisol (Factor 3) scores were higher in M vs. F (p=0.0008), with M>F within both IBS and HC. There was a trend for higher Cortisol response in EAL vs. No EAL among M (p=0.08). There was a correlation between the number physical abuse-related EALs and Cortisol (r=0.2908, p=0.0080). There was no correlation with factors and IBS symptoms or pain.Figure 1Table 1: Participant CharacteristicsTable 2: Factor StructureConclusion: IBS-related HPA changes differ by sex. These results suggest the presence of an IBS endophenotype characterized by men with enhanced cortisol response and a history of physical abuse. Supported by NIH grants: P50 DK064539 and T32 DK07180-40.