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Physiological cortisol production is tightly regulated by the hypothalamic\u2013pituitary\u2013adrenal axis, and disruption at any level may lead to clinically significant cortisol excess. Endogenous hypercortisolism is broadly classified into corticotropin\u2010dependent and corticotropin\u2010independent forms. The clinical phenotype varies according to the source, severity, and duration of cortisol excess. Overt Cushing syndrome is classically associated with centripetal adiposity, proximal myopathy, skin fragility, hypertension, and glucose intolerance, whereas MACS lacks overt cushingoid features despite conferring substantial cardiometabolic and skeletal risk. Cortisol excess affects multiple organ systems, including endocrine, cardiovascular, hepatic, musculoskeletal, neuropsychiatric, immune, dermatologic, and reproductive pathways. Importantly, many complications persist despite biochemical remission, underscoring the long\u2010term burden of disease. This review summarises the aetiologies, pathophysiology, clinical manifestations, and systemic consequences of hypercortisolism.<\/jats:p>","DOI":"10.1111\/dom.71022","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:20:14Z","timestamp":1782937214000},"page":"3-16","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypercortisolism: Causes, Consequences and Clinical Significance \u2013 A Review of Pathophysiology"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0783-5088","authenticated-orcid":false,"given":"Mohamed","family":"Eldib","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2627-1448","authenticated-orcid":false,"given":"Francisco Emilio","family":"Fierro","sequence":"additional","affiliation":[{"name":"Escuela de Medicina, Universidad San Francisco de Quito  Quito Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Ortega","family":"Abad","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Correa","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1505550"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.11305"},{"issue":"3","key":"e_1_2_10_4_1","first-page":"270","article-title":"Cushing's Syndrome: Rapid Evidence Review","volume":"110","author":"Maness D. 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