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, Jessica H Lee Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia Search for other works by this author on: Oxford Academic Emily Jane Meyer Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia Endocrine and Diabetes Services, The Queen Elizabeth Hospital , Woodville South, SA 5011 , Australia Search for other works by this author on: Oxford Academic Marni Anne Nenke Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia Endocrine and Diabetes Services, The Queen Elizabeth Hospital , Woodville South, SA 5011 , Australia Search for other works by this author on: Oxford Academic Stafford L Lightman Systems Neuroendocrinology Research Group, University of Bristol , Bristol, BS1 3NY , UK Search for other works by this author on: Oxford Academic David J Torpy Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia Correspondence: David J. Torpy, MBBS, PhD, Endocrine and Metabolic Unit, Level 8G480, Royal Adelaide Hospital, 1 Port Rd, Adelaide, SA 5000, Australia. Email: david.torpy@sa.gov.au. Search for other works by this author on: Oxford Academic
https://orcid.org/0000-0001-8643-1773 The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 9, September 2024, Pages 2161–2172, https://doi.org/10.1210/clinem/dgae412
Published:
15 June 2024
Article history
Received:
14 May 2024
Editorial decision:
09 June 2024
Published:
15 June 2024
Corrected and typeset:
28 June 2024
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Jessica H Lee, Emily Jane Meyer, Marni Anne Nenke, Stafford L Lightman, David J Torpy, Cortisol, Stress, and Disease—Bidirectional Associations; Role for Corticosteroid-Binding Globulin?, The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 9, September 2024, Pages 2161–2172, https://doi.org/10.1210/clinem/dgae412
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Abstract
Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent “primary stress system disorders” were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the “hypocortisolemic symptom triad” of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation–genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.
stress, HPA axis, chronic disease, cortisol, SERPINA6, corticosteroid-binding globulin
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)
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