{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:30:40Z","timestamp":1783661440534,"version":"3.55.0"},"reference-count":28,"publisher":"The Endocrine Society","issue":"10","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K24HL092902"],"award-info":[{"award-number":["K24HL092902"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23DK113220"],"award-info":[{"award-number":["K23DK113220"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23DK115903"],"award-info":[{"award-number":["K23DK115903"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Accurate diagnosis of adrenal insufficiency is critical because there are risks associated with overdiagnosis and underdiagnosis. Data using liquid chromatography tandem mass spectrometry (LC\/MS\/MS) free cortisol (FC) assays in states of high or low cortisol-binding globulin (CBG) levels, including cirrhosis, critical illness, and oral estrogen use, are needed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>Cross-sectional.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Determine the relationship between CBG and albumin as well as total cortisol (TC) and FC in states of normal and abnormal CBG. Establish the FC level by LC\/MS\/MS that best predicts TC of &lt;18 \u03bcg\/dL (497 nmol\/L) (standard adrenal insufficiency diagnostic cutoff) in healthy individuals.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Subjects<\/jats:title>\n                  <jats:p>This study included a total of 338 subjects in four groups: healthy control (HC) subjects (n = 243), patients with cirrhosis (n = 38), intensive care unit patients (ICU) (n = 26), and oral contraceptive (OCP) users (n = 31).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Main Outcome Measure(s)<\/jats:title>\n                  <jats:p>FC and TC by LC\/MS\/MS, albumin by spectrophotometry, and CBG by ELISA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>TC correlated with FC in the ICU (R = 0.91), HC (R = 0.90), cirrhosis (R = 0.86), and OCP (R = 0.70) groups (all P &lt; 0.0001). In receiver operator curve analysis in the HC group, FC of 0.9 \u03bcg\/dL (24.8 nmol\/L) predicted TC of &lt;18 \u03bcg\/dL (497 nmol\/L; 98% sensitivity, 91% specificity; AUC, 0.98; P &lt; 0.0001). Decreasing the cutoff to 0.7 \u03bcg\/dL led to a small decrease in sensitivity (92%) with similar specificity (91%).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>A cutoff FC of &lt;0.9 \u03bcg\/dL (25 nmol\/L) in this LC\/MS\/MS assay predicts TC of &lt;18 \u03bcg\/dL (497 nmol\/L) with excellent sensitivity and specificity. This FC cutoff may be helpful in ruling out adrenal insufficiency in patients with binding globulin derangements.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/jc.2019-00022","type":"journal-article","created":{"date-parts":[[2019,4,22]],"date-time":"2019-04-22T09:03:11Z","timestamp":1555923791000},"page":"4827-4836","source":"Crossref","is-referenced-by-count":28,"title":["Plasma Free Cortisol in States of Normal and Altered Binding Globulins: Implications for Adrenal Insufficiency Diagnosis"],"prefix":"10.1210","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6989-2308","authenticated-orcid":false,"given":"Laura E","family":"Dichtel","sequence":"first","affiliation":[{"name":"Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Schorr","sequence":"additional","affiliation":[{"name":"Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Loures de Assis","sequence":"additional","affiliation":[{"name":"Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M","family":"Rao","sequence":"additional","affiliation":[{"name":"Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica K","family":"Sims","sequence":"additional","affiliation":[{"name":"Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen E","family":"Corey","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, Massachusetts"},{"name":"Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puja","family":"Kohli","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, Massachusetts"},{"name":"Division of Pulmonology and Critical Care Medicine, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M","family":"Sluss","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, Massachusetts"},{"name":"Clinical Pathology, Massachusetts General Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"McPhaul","sequence":"additional","affiliation":[{"name":"Endocrinology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen K","family":"Miller","sequence":"additional","affiliation":[{"name":"Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2019,4,22]]},"reference":[{"issue":"16","key":"2019091012000526400_bib1","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1056\/NEJMoa020266","article-title":"Measurements of serum free cortisol in critically ill patients","volume":"350","author":"Hamrahian","year":"2004","journal-title":"N Engl J Med"},{"issue":"Pt 6","key":"2019091012000526400_bib2","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1258\/acb.2009.009030","article-title":"Serum total cortisol and free cortisol index give different information regarding the hypothalamus-pituitary-adrenal axis reserve in patients with liver impairment","volume":"46","author":"Vincent","year":"2009","journal-title":"Ann Clin Biochem"},{"issue":"5","key":"2019091012000526400_bib3","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.jhep.2010.05.020","article-title":"Characterising adrenal function using directly measured plasma free cortisol in stable severe liver disease","volume":"53","author":"Tan","year":"2010","journal-title":"J Hepatol"},{"issue":"6","key":"2019091012000526400_bib4","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.jhep.2010.01.026","article-title":"Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred","volume":"52","author":"Galbois","year":"2010","journal-title":"J Hepatol"},{"issue":"3","key":"2019091012000526400_bib5","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/j.1478-3231.2010.02431.x","article-title":"Assessment of adrenal function in cirrhotic patients using concentration of serum-free and salivary cortisol","volume":"31","author":"Thevenot","year":"2011","journal-title":"Liver Int"},{"issue":"5","key":"2019091012000526400_bib6","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1210\/jc.2010-2395","article-title":"A longitudinal study of plasma and urinary cortisol in pregnancy and postpartum","volume":"96","author":"Jung","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2019091012000526400_bib7","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1111\/j.1365-2265.2007.02784.x","article-title":"The influence of the route of oestrogen administration on serum levels of cortisol-binding globulin and total cortisol","volume":"66","author":"Qureshi","year":"2007","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"3","key":"2019091012000526400_bib8","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1177\/0004563216687335","article-title":"Measuring cortisol in serum, urine and saliva: are our assays good enough","volume":"54","author":"El-Farhan","year":"2017","journal-title":"Ann Clin Biochem"},{"issue":"5","key":"2019091012000526400_bib9","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1111\/cen.12039","article-title":"Method-specific serum cortisol responses to the adrenocorticotrophin test: comparison of gas chromatography-mass spectrometry and five automated immunoassays","volume":"78","author":"El-Farhan","year":"2013","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"13","key":"2019091012000526400_bib10","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/j.steroids.2008.08.001","article-title":"Preface. CDC workshop report improving steroid hormone measurements in patient care and research translation","volume":"73","author":"Rosner","year":"2008","journal-title":"Steroids"},{"issue":"5","key":"2019091012000526400_bib11","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1210\/jc.2012-3576","article-title":"Free and total plasma cortisol measured by immunoassay and mass spectrometry following ACTH1\u201324 stimulation in the assessment of pituitary patients","volume":"98","author":"Burt","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2019091012000526400_bib12","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1007\/s12020-017-1371-9","article-title":"Total and free cortisol levels during 1 \u03bcg, 25 \u03bcg, and 250 \u03bcg cosyntropin stimulation tests compared to insulin tolerance test: results of a randomized, prospective, pilot study","volume":"57","author":"Peechakara","year":"2017","journal-title":"Endocrine"},{"issue":"3","key":"2019091012000526400_bib13","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1210\/jc.2015-2285","article-title":"Cosyntropin-stimulated serum free cortisol in healthy, adrenally insufficient, and mildly cirrhotic populations","volume":"101","author":"Rauschecker","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"2019091012000526400_bib14","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.4158\/EP15820.OR","article-title":"Performance of free versus total cortisol following cosyntropin stimulation testing in an outpatient setting","volume":"21","author":"Bancos","year":"2015","journal-title":"Endocr Pract"},{"issue":"3","key":"2019091012000526400_bib15","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/hep.21563","article-title":"The model for end-stage liver disease (MELD)","volume":"45","author":"Kamath","year":"2007","journal-title":"Hepatology"},{"issue":"14","key":"2019091012000526400_bib16","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1001\/jama.286.14.1754","article-title":"Serial evaluation of the SOFA score to predict outcome in critically ill patients","volume":"286","author":"Ferreira","year":"2001","journal-title":"JAMA"},{"issue":"11","key":"2019091012000526400_bib17","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1097\/00003246-199811000-00016","article-title":"Working group on \u201csepsis-related problems\u201d of the European Society of Intensive Care Medicine. Use of the SOFA score to assess the incidence of organ dysfunction\/failure in intensive care units: results of a multicenter, prospective study","volume":"26","author":"Vincent","year":"1998","journal-title":"Crit Care Med"},{"issue":"12","key":"2019091012000526400_bib18","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1007\/s00134-011-2342-x","article-title":"Assessing adrenal insufficiency of corticosteroid secretion using free versus total cortisol levels in critical illness","volume":"37","author":"Molenaar","year":"2011","journal-title":"Intensive Care Med"},{"issue":"1","key":"2019091012000526400_bib19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1210\/jc.2005-0265","article-title":"Septic shock and sepsis: a comparison of total and free plasma cortisol levels","volume":"91","author":"Ho","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2019091012000526400_bib20","doi-asserted-by":"crossref","first-page":"716","DOI":"10.4158\/EP161720.RA","article-title":"Evaluation and management of adrenal insufficiency in critically ill patients: disease state review","volume":"23","author":"Hamrahian","year":"2017","journal-title":"Endocr Pract"},{"issue":"8","key":"2019091012000526400_bib21","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1172\/JCI103904","article-title":"Transcortin: a corticosteroid-binding protein of plasma. II. Levels in various conditions and the effects of estrogens","volume":"38","author":"Sandberg","year":"1959","journal-title":"J Clin Invest"},{"issue":"6","key":"2019091012000526400_bib22","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/0010-7824(95)00098-U","article-title":"Effect of two oral contraceptives containing ethinylestradiol and gestodene or norgestimate upon androgen parameters and serum binding proteins","volume":"51","author":"Wiegratz","year":"1995","journal-title":"Contraception"},{"issue":"8","key":"2019091012000526400_bib23","doi-asserted-by":"crossref","first-page":"2965","DOI":"10.1210\/jc.2007-0181","article-title":"Measurement of salivary cortisol concentration in the assessment of adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol","volume":"92","author":"Arafah","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"issue":"1-2","key":"2019091012000526400_bib24","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.clinbiochem.2008.09.115","article-title":"Validation of a simple method of estimating plasma free cortisol: role of cortisol binding to albumin","volume":"42","author":"Dorin","year":"2009","journal-title":"Clin Biochem"},{"key":"2019091012000526400_bib25","first-page":"359","article-title":"Corticosteroid-binding globulin: a review of basic and clinical advances","volume-title":"Horm Metab Res","author":"Meyer","year":"2016"},{"issue":"4","key":"2019091012000526400_bib26","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1210\/jc.2017-02602","article-title":"The short cosyntropintest revisited: new normal reference range using LCMSMS","volume":"103","author":"Ueland","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2019091012000526400_bib27","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.clinbiochem.2010.07.008","article-title":"Liquid chromatography tandem mass spectrometry for analysis of steroids in clinical laboratories","volume":"44","author":"Kushnir","year":"2011","journal-title":"Clin Biochem"},{"issue":"3-5","key":"2019091012000526400_bib28","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.jsbmb.2010.05.001","article-title":"Advantages and challenges of mass spectrometry assays for steroid hormones","volume":"121","author":"Stanczyk","year":"2010","journal-title":"J Steroid Biochem Mol Biol"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/jc.2019-00022\/28489306\/jc.2019-00022.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/104\/10\/4827\/29643050\/jc.2019-00022.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T12:37:06Z","timestamp":1569242226000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/104\/10\/4827\/5475551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,22]]},"references-count":28,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2019,10,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2019-00022","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,10]]},"published":{"date-parts":[[2019,4,22]]}}}