Overnight Dexamethasone Suppression Test: Enhanced Accuracy with Late-Afternoon Cortisol and Morning/Late-Afternoon ACTH

Context Overnight dexamethasone suppression test (ODST) is precise and highly sensitive; however, its specificity ranges from 80-90%. Objective To assess whether late-afternoon ODS cortisol and morning/late-afternoon ODS ACTH measurements improve ODST accuracy. Methods Prospective, single-centre study included healthy adults (n=60), combined oral contraceptive pill users (COCP, n=29), chronic kidney disease (CKD, n=29), treatment-naïve ACTH-dependent Cushing syndrome (A-CS, n=33), post-treatment Cushing Disease in remission (CD-R, n=23) or persistence (CD-P, n=31). Participants underwent the standard 1-mg dexamethasone suppression test; blood samples were collected at 8-9 AM for cortisol, ACTH, dexamethasone; and at 3-4 PM for cortisol and ACTH. Results ODS 4-PM cortisol was significantly lower than 8-AM in healthy adults (p=0.003), COCP (p<0.001), CKD (p<0.001), and CD-R (p=0.001), while this difference was not significant in treatment-naïve A-CS and CD-P. ODS 8-AM and 4-PM cortisol (cut-off: 1.8 μg/dL) showed high specificity in healthy adults (95% and 100%), but its specificity was low in COCP (55% and 79%) and CKD (17% and 52%). ODS 8-AM and 4-PM ACTH (cut-off: 10 pg/mL) showed high specificity in healthy adults (95%, 100%), COCP (100%, 100%), and CKD (96.6%, 100%), with 100% sensitivity for diagnosing A-CS. The diagnostic accuracy of ODS 4-PM cortisol, ODS 8-AM ACTH and ODS 4-PM ACTH in differentiating CD-R from CD-P was 98.1%, 81.5% and 81.5%, respectively. Conclusion Late-afternoon cortisol measurement is a novel modification which enhances ODST specificity. ACTH measurement was particularly useful in COCP and CKD. Before widespread integration in clinical practice, further validation is required.