{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:44:28Z","timestamp":1788374668293,"version":"build-2803163510"},"reference-count":111,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing\u2019s syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing\u2019s syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and\/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and\/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the\u2014nowadays\u2014rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-\u03b2hydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus\/impaired glucose tolerance and\/or uncontrolled systolic hypertension.<\/jats:p>","DOI":"10.3390\/ijms222111521","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T23:54:33Z","timestamp":1635292473000},"page":"11521","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Management and Medical Therapy of Mild Hypercortisolism"],"prefix":"10.3390","volume":"22","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"}]},{"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":[[2021,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"M33","DOI":"10.1530\/EJE-15-0464","article-title":"Cushing\u2019s syndrome: Update on signs, symptoms and biochemical screening","volume":"173","author":"Nieman","year":"2015","journal-title":"Eur. 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