{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T10:52:37Z","timestamp":1781866357085,"version":"3.54.5"},"reference-count":53,"publisher":"The Endocrine Society","issue":"7","funder":[{"name":"ZIA","award":["DK075122"],"award-info":[{"award-number":["DK075122"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Medical treatment of Cushing syndrome (CS) with steroidogenesis inhibitors or ACTH-directed agents is typically given using a titration strategy to achieve \u201cnormal\u201d exposure to cortisol, as determined by a 24-hour urine free cortisol (UFC) measurement. This approach generally achieves similar serum cortisol levels across the day and fails to provide a normal diurnal pattern of cortisol. Chronotherapy addresses this problem through weighted afternoon\/evening dosing of cortisol-lowering drugs. Additionally, because of day-to-day variability of cortisol production, patients may be undertreated on days of higher cortisol production and overtreated on days of lower cortisol production. A \u201cblock and replace\u201d strategy is an alternative approach in which consistent biochemical glucocorticoid deficiency is the goal, with added glucocorticoid replacement to provide physiologic diurnal exposure to cortisol.<\/jats:p>\n                  <jats:p>Recently, the term mild autonomous cortisol secretion (MACS) has been used to describe patients without clinical features of CS who fail to suppress cortisol after 1\u2005mg dexamethasone. MACS includes individuals with an adrenal mass(es) who may have hypertension, type 2 diabetes mellitus, and\/or osteoporosis. The role of medical vs surgical treatment of MACS is currently debated.<\/jats:p>\n                  <jats:p>We here review the advantages and disadvantages of each approach to medical treatment of CS and MACS, concluding that \u201cblock and replace\u201d deserves wider consideration, especially in patients who have severe disease, and to avoid adrenal insufficiency in those with highly variable UFC, or are taking agents that may cause adrenal insufficiency. Conversely, in those with mild disease, chronotherapy normalizes nighttime cortisol exposure while reducing drug burden.<\/jats:p>","DOI":"10.1210\/jendso\/bvag061","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:51:04Z","timestamp":1775130664000},"source":"Crossref","is-referenced-by-count":0,"title":["Aligning treatment to physiology: when to use chronotherapy, block and replace, or titration to treat hypercortisolism"],"prefix":"10.1210","volume":"10","author":[{"given":"Henrik","family":"Elenius","sequence":"first","affiliation":[{"name":"Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3101-5320","authenticated-orcid":false,"given":"James W","family":"Findling","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1231-3306","authenticated-orcid":false,"given":"Antoine","family":"Tabarin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Nutrition, CHU and University of Bordeaux , Pessac 3364 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0534-8025","authenticated-orcid":false,"given":"Lynnette K","family":"Nieman","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"issue":"5","key":"2026061906130843100_bvag061-B1","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1210\/jc.2008-0125","article-title":"The diagnosis of Cushing's syndrome: an endocrine society clinical practice guideline","volume":"93","author":"Nieman","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"2026061906130843100_bvag061-B2","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1210\/jc.2015-1818","article-title":"Treatment of Cushing's syndrome: an endocrine society clinical practice guideline","volume":"100","author":"Nieman","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"2026061906130843100_bvag061-B3","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1007\/s12020-016-1007-5","article-title":"Factors predicting the duration of adrenal 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