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However, these thresholds are based on older assays, and intermediate values require further testing. Newer, specific monoclonal antibody immunoassays may have lower diagnostic thresholds. This study aimed to identify morning cortisol cut-offs with \u2265\u200995% specificity or sensitivity (SP\/SE) to determine which patients may safely avoid ACTH stimulation testing, using a second-generation immunoassay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively evaluated 435 adults (236 males; overall median age 58.5 [IQR 20.3] years) with pituitary disorders. Based on the 1\u00a0\u00b5g ACTH test, patients were classified as having or not having CAI using a peak cortisol cut-off of 180\u00a0\u00b5g\/L (guideline) or 127\u00a0\u00b5g\/L (Roche Elecsys\n                      <jats:sup>\u00ae<\/jats:sup>\n                      Cortisol II\u2013based studies).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>With the 180\u00a0\u00b5g\/L threshold, a morning cortisol\u2009\u2264\u200980.8\u00a0\u00b5g\/L best predicted CAI (SE 37.1%, SP 95.2%), while\u2009&gt;\u2009144.0\u00a0\u00b5g\/L best excluded it (SE 95.2%, SP 29.1%). Using the 127\u00a0\u00b5g\/L threshold, a value\u2009\u2264\u200960.9\u00a0\u00b5g\/L best predicted CAI (SE 54.7%, SP 96.3%), whereas &gt;\u2009141\u00a0\u00b5g\/L (SE 96.2%, SP 21.2%) best ruled it out.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified updated morning cortisol thresholds, specific to a second-generation immunoassay, that accurately predict ACTH test results and may streamline the diagnostic workup of suspected CAI. Based on these data, we propose a refined diagnostic algorithm.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s40618-026-02807-5","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T06:33:16Z","timestamp":1769841196000},"page":"1271-1284","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Morning cortisol and central adrenal insufficiency: new thresholds from low-dose ACTH test and second-generation assay"],"prefix":"10.1007","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6491-5731","authenticated-orcid":false,"given":"Valentina","family":"Gasco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Bioletto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Lucisano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Camoirano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Cuboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Varaldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Sibilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi Simone","family":"Aversa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mocellini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro Maria","family":"Berton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzia","family":"Prencipe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezio","family":"Ghigo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Maccario","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Grottoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"issue":"11","key":"2807_CR1","doi-asserted-by":"publisher","first-page":"4855","DOI":"10.1210\/jc.2010-0982","volume":"95","author":"AB Grossman","year":"2010","unstructured":"Grossman AB (2010) The diagnosis and management of central hypoadrenalism. 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Prof. Silvia Grottoli and Dr. Nunzia Prencipe are among the Members of the Editorial Board of the Journal of Endocrinological Investigation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The protocol was in accordance with the principles of the Declaration of Helsinki and was approved by the Local Ethics Committee (cod. 0040828). All subjects gave their written informed consent to participate in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"The study was approved by the local Ethics Committee and was in accordance with the principles of the Declaration of Helsinki.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Research involving human participants and\/or animals"}},{"value":"All subjects gave their informed consent to the processing of their data.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}