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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 \u201cprimary stress system disorders\u201d 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 \u201chypocortisolemic symptom triad\u201d 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\u2013genome-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.<\/jats:p>","DOI":"10.1210\/clinem\/dgae412","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T11:48:43Z","timestamp":1718365723000},"page":"2161-2172","source":"Crossref","is-referenced-by-count":33,"title":["Cortisol, Stress, and Disease\u2014Bidirectional Associations; Role for Corticosteroid-Binding Globulin?"],"prefix":"10.1210","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8643-1773","authenticated-orcid":false,"given":"Jessica H","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia"},{"name":"Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7450-5808","authenticated-orcid":false,"given":"Emily Jane","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia"},{"name":"Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia"},{"name":"Endocrine and Diabetes Services, The Queen Elizabeth Hospital , Woodville South, SA 5011 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8478-5022","authenticated-orcid":false,"given":"Marni Anne","family":"Nenke","sequence":"additional","affiliation":[{"name":"Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia"},{"name":"Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia"},{"name":"Endocrine and Diabetes Services, The Queen Elizabeth Hospital , Woodville South, SA 5011 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8546-9646","authenticated-orcid":false,"given":"Stafford L","family":"Lightman","sequence":"additional","affiliation":[{"name":"Systems Neuroendocrinology Research Group, University of Bristol , Bristol, BS1 3NY , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5069-0981","authenticated-orcid":false,"given":"David J","family":"Torpy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Adelaide University , Adelaide, SA 5000 , Australia"},{"name":"Endocrine and Metabolic Unit, Royal Adelaide Hospital , Adelaide, SA 5000 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,6,15]]},"reference":[{"issue":"9","key":"2024081223512734400_dgae412-B1","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1001\/jama.1992.03480090092034","article-title":"The concepts of stress and stress system disorders. 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