Morning cortisol and central adrenal insufficiency: new thresholds from low-dose ACTH test and second-generation assay

PURPOSE: According to current guidelines, a morning serum cortisol < 30 µg/L confirms central adrenal insufficiency (CAI), whereas a value > 150 µg/L rules it out. 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 ≥ 95% specificity or sensitivity (SP/SE) to determine which patients may safely avoid ACTH stimulation testing, using a second-generation immunoassay. METHODS: We retrospectively evaluated 435 adults (236 males; overall median age 58.5 [IQR 20.3] years) with pituitary disorders. Based on the 1 µg ACTH test, patients were classified as having or not having CAI using a peak cortisol cut-off of 180 µg/L (guideline) or 127 µg/L (Roche Elecsys® Cortisol II–based studies). RESULTS: With the 180 µg/L threshold, a morning cortisol ≤ 80.8 µg/L best predicted CAI (SE 37.1%, SP 95.2%), while > 144.0 µg/L best excluded it (SE 95.2%, SP 29.1%). Using the 127 µg/L threshold, a value ≤ 60.9 µg/L best predicted CAI (SE 54.7%, SP 96.3%), whereas > 141 µg/L (SE 96.2%, SP 21.2%) best ruled it out. CONCLUSIONS: 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.