Clinical Utility of Salivary Cortisol for Diagnosis and Therapeutic Monitoring in Adrenal Insufficiency

Abstract Purpose: To evaluate the diagnostic utility of salivary cortisol (CS) as a non-invasive screening and monitoring tool for adrenal insufficiency (AI), and to assess its capacity to reflect cortisol exposure in patients receiving hydrocortisone (HC) replacement therapy. Methods: This prospective study included adult patients with clinical suspicion of primary or secondary AI who underwent ACTH stimulation testing (ACTH-t) and provided ambulatory CS samples at five time points (08:00, 13:00, 18:00, 24:00, and 08:00 the following day). CS was quantified via electrochemiluminescence immunoassay. Diagnostic performance, optimal thresholds, and correlations with morning serum cortisol (CB) and HC dosing were analyzed. Results: Out of 60 patients included, 11 (18.3%) were diagnosed with AI. CS at 08:00 (CS8) showed superior diagnostic performance over CB (AUC 0.804 vs. 0.739, P < 0.01). A CS8 threshold < 0.0975 µg/dL yielded 100% sensitivity and 75% positive predictive value, while > 0.708 µg/dL achieved 100% negative predictive value. Afternoon and evening CS levels were significantly higher in HC-treated patients, with elevated diurnal 08:00–24:00 cortisol exposure (AUC 7.82[2.57–11.14] vs. 2.73[2.19–3.79] ng·h/mL;p = 0.017) and a trend toward lower morning CS, suggesting overtreatment during the day and under-replacement at night 24:00–8:00 (AUC 2.06[0.67–6.13] vs. 1.6 [1.33–2.43] ng·h/mL;ns). Conclusions: CS is a reliable, non-invasive biomarker for both screening and monitoring of AI. Its ability to reflect circadian cortisol dynamics offers clinical value in assessing replacement adequacy. Salivary profiling may guide individualized HC dose titration and help avoid overtreatment. Larger studies including salivary cortisone are warranted to refine monitoring strategies.