title: The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression.
abstract: 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).
  
  
  
  Rome III+ IBS patients and healthy controls underwent CRF (1μg/kg ovine) and ACTH (250μg) 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: evidelock@mednet.ucla.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Videlock
authors.affiliation: Department of Biostatistics David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: wshih3737@gmail.com.
authors.forename: Wendy
authors.initials: W
authors.lastname: Shih
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: maadeyemo@gmail.com.
authors.forename: Mopelola
authors.initials: M
authors.lastname: Adeyemo
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: swapnajoshi@mednet.ucla.edu.
authors.forename: Swapna
authors.initials: S
authors.lastname: Mahurkar-Joshi
authors.affiliation: Division of Epidemiology, Department of Internal Medicine, University of Utah, 295 Chipeta Way, Salt Lake City, UT 84132, United States. Electronic address: angela.presson@hsc.utah.edu.
authors.forename: Angela P
authors.initials: AP
authors.lastname: Presson
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: cpolytarchou@gmail.com.
authors.forename: Christos
authors.initials: C
authors.lastname: Polytarchou
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: melissa.alberto3@gmail.com.
authors.forename: Melissa
authors.initials: M
authors.lastname: Alberto
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: diliopoulos@mednet.ucla.edu.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Iliopoulos
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: emayer@ucla.edu.
authors.forename: Emeran A
authors.initials: EA
authors.lastname: Mayer
authors.affiliation: Oppenheimer Center for Neurobiology of Stress and Resilience, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, CA 90095-7378, United States. Electronic address: linchang@mednet.ucla.edu.
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D016022:Case-Control Studies; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000502:physiology; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000503:physiopathology / Q000523:psychology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone
keywords: Adrenal cortex hormones; Glucocorticoids receptors; Hypothalamic pituitary-regulating hormones; Irritable bowel syndrome; Sex differences