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Hypothalamic-pituitary-adrenal dysregulation and psychological distress in Crohn’s disease: Insights from acute and chronic stress responses
Effrosini Laoudi, Demetra Papalouka, Georgios Kokkotis, Michael Gkizis, Aimilia Mantzou, Georgios Lyrakos, Panagiotis Markopoulos, Paraskevi Prapa, Theodoros Voulgaris, John Vlachogiannakos, Ioannis Papaconstantinou, Giorgos Bamias
Effrosini Laoudi, Georgios Kokkotis, Michael Gkizis, Paraskevi Prapa, Giorgos Bamias, Gastroenterology Unit-Third Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens 11527, Attikí, Greece
Demetra Papalouka, John Vlachogiannakos, Ioannis Papaconstantinou, Department of Surgery II, School of Medicine, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens 11528, Attikí, Greece
Aimilia Mantzou, First Department of Pediatrics, School of Medicine, Unit of Clinical and Translational Research in Endocrinology, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, Athens 11526, Attikí, Greece
Georgios Lyrakos, Department of Psychiatric, General State Hospital of Nikaia, Nikaia 18454, Attikí, Greece
Panagiotis Markopoulos, Department of Gastroenterology, Metaxa Cancer Hospital, Piraeus 18537, Greece
Theodoros Voulgaris, Department of Endoscopy, Second Academic Surgical Unit, Aretaieion Hospital, National and Kapodistrian University of Athens, Athens 11528, Attikí, Greece
Author contributions: Laoudi E and Papalouka D collected the samples and clinical data; Laoudi E, Kokkotis G, Lyrakos G, Markopoulos P, Voulgaris T, Vlachogiannakos J, Papaconstantinou I, and Bamias G participated in the interpretation of the results; Laoudi E, Kokkotis G, Markopoulos P, and Voulgaris T drafted the manuscript; Laoudi E and Mantzou A performed the laboratory analysis; Kokkotis G performed the statistical analysis; Gizis M and Prapa P collected the clinical data; Lyrakos G supervised the Depression Anxiety Stress Scales data collection, and ensured the validity of the results; Vlachogiannakos J, Papaconstantinou I, and Bamias G supervised the data collection and critically revised the manuscript; Bamias G was the guarantor, conceived and designed the study. All authors have approved the final manuscript.
Institutional review board statement: The study was approved by the Department of Quality Assurance for Research and Continuing Education of Sotiria Hospital, National and Kapodistrian University of Athens (Approval No. 19/07-06-2019).
Clinical trial registration statement: The study has been registered in the PhD database of National and Kapodistrian University of Athens.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CONSORT 2010 statement: The authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Data sharing statement: No additional data are available.
Corresponding author: Panagiotis Markopoulos, MD, PhD, Consultant, Department of Gastroenterology, Metaxa Cancer Hospital, 51 Mpotasi Street, Piraeus 18537, Greece.
panosmarkmd@gmail.com
Received: July 2, 2025
Revised: August 7, 2025
Accepted: November 27, 2025
Published online: March 19, 2026
Processing time: 240 Days and 21.3 Hours
BACKGROUND
Crohn’s disease (CD) is a chronic inflammatory bowel disease associated with both physical and psychological stressors. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in various autoimmune diseases; however, its role in CD remains insufficiently explored.
AIM
To evaluate HPA axis responses to acute/chronic stress in patients with CD and assess perceived stress, anxiety, and depression.
METHODS
This study involved two groups: (1) Surgical group: 22 patients with CD and 28 surgery-controls without inflammatory bowel disease; and (2) Outpatient group: 101 patients with CD and 52 positive-control patients with cancer. In the surgical group, acute stress was measured using six postoperative salivary cortisol samples and chronic stress was assessed by hair cortisol measurements. In the outpatient group, emotional distress was evaluated using the Depression Anxiety Stress Scale 21 questionnaire. Demographic and clinical data were analyzed for associations with stress, anxiety, and depression.
RESULTS
Hair cortisol levels were significantly lower in patients with CD compared to controls (median 6.375 pgF/mg vs 9.643 pgF/mg, P = 0.038), suggesting impaired HPA axis function in response to chronic stress. No significant differences in postoperative salivary cortisol levels were found between patients with CD and controls. According to Depression Anxiety Stress Scale 21 responses, 58% of patients with CD experienced elevated stress levels, while 27% and 24% experienced severe or extremely severe anxiety and depression, respectively. Higher Harvey-Bradshaw Index scores, smoking, and lower hemoglobin levels were independently associated with higher perceived stress and anxiety. Among the controls, 53% exhibited elevated stress levels, while 37% and 13% experienced severe or extremely severe anxiety and depression, respectively.
CONCLUSION
Patients with CD exhibit a blunted HPA axis response to chronic stress and high psychological distress - comparable to patients with cancer - highlighting the need for a multidisciplinary, holistic approach to disease management.
Core Tip: In this prospective study, we evaluated both acute and chronic stress responses in patients with Crohn’s disease using objective biomarkers - salivary and hair cortisol - in two distinct patient groups. In addition, we assessed perceived psychological stress via validated psychometric tools and compared these findings with those of a control group of patients with cancer. Our findings reveal a significantly decreased cortisol response to chronic stress in patients with Crohn’s disease, along with high levels of perceived stress, anxiety, and depression.
