{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T22:25:41Z","timestamp":1793053541360,"version":"4.5.0"},"reference-count":135,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T00:00:00Z","timestamp":1641600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009433","name":"Istituto Auxologico Italiano","doi-asserted-by":"publisher","award":["Grant Precor Study, 29_01_06."],"award-info":[{"award-number":["Grant Precor Study, 29_01_06."]}],"id":[{"id":"10.13039\/501100009433","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing\u2019s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).<\/jats:p>","DOI":"10.3390\/ijms23020673","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside"],"prefix":"10.3390","volume":"23","author":[{"given":"Vittoria","family":"Favero","sequence":"first","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Cremaschi","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Parazzoli","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6739-4417","authenticated-orcid":false,"given":"Alberto","family":"Falchetti","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20149 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9958-9606","authenticated-orcid":false,"given":"Agostino","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Gennari","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Scillitani","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology and Diabetology \u201cCasa Sollievo Della Sofferenza\u201d Hospital, IRCCS, 71013 San Giovanni Rotondo (FG), Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Vescini","sequence":"additional","affiliation":[{"name":"Endocrinology and Metabolism Unit, University-Hospital S. M. Misericordia of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6716-3045","authenticated-orcid":false,"given":"Valentina","family":"Morelli","sequence":"additional","affiliation":[{"name":"Unit of Endocrinology, Fondazione IRCCS C\u00e0 Granda-Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-2134","authenticated-orcid":false,"given":"Carmen","family":"Aresta","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20149 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7594-3300","authenticated-orcid":false,"given":"Iacopo","family":"Chiodini","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy"},{"name":"Department of Endocrine and Metabolic Diseases, IRCCS, Istituto Auxologico Italiano, 20149 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12020-019-01888-y","article-title":"Autonomous cortisol secretion in adrenal incidentalomas","volume":"64","author":"Marazuela","year":"2019","journal-title":"Endocrine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1097\/MED.0000000000000159","article-title":"Update on subclinical Cushing\u2019s syndrome","volume":"22","author":"Nieman","year":"2015","journal-title":"Curr. 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