Development and validation of a sex- and age-adjusted dehydroepiandrosterone sulfate index for suspected adrenal insufficiency.

IMPORTANCE: Adrenal insufficiency (AI) diagnosis is challenging, particularly with indeterminate morning cortisol levels (5-11 µg/dL). This study aimed to develop and validate a sex- and age-adjusted dehydroepiandrosterone sulfate (DHEAS)-index to improve AI diagnosis and reduce the need for ACTH stimulation tests. DESIGN: A 2-phase study was conducted. First, a retrospective training cohort of 3.307 DHEAS and morning cortisol measurements from 1.720 adult patients was analyzed to develop sex- and age-specific DHEAS cutoffs. Subsequently, these cutoffs were used to calculate a DHEAS-Index, which was then validated in a prospective external cohort of 71 patients undergoing ACTH stimulation testing for suspected AI. RESULTS: In the training cohort, DHEAS levels were significantly lower in patients with morning cortisol <5 µg/dL (0.10 [0.10-0.22] µg/mL) compared to those with cortisol >5 µg/dL (P = .000). Linear regression showed higher morning cortisol, male sex, and younger age were independently associated with higher DHEAS, while older age predicted lower levels (all P = .000). Optimal DHEAS cutoffs, determined by ROC analysis, demonstrated high discriminatory capacity (AUC ranging from 75.2% to 90.5%) for AI across all age and sex subgroups, with men aged 18-29 showing the highest AUC (90.5%). In the validation cohort, the DHEAS-Index achieved a sensitivity of 93% and specificity of 79% for classifying AI (cortisol 60' < 18 µg/dL), with a negative predictive value of 98%. The DHEAS-Index also correlated with the delta increase of cortisol during the ACTH test (rho=0.571, P < .001). Among patients with cortisol values 5-11 µg/dL, a DHEAS-Index >1 was associated with a very low probability of AI (5%), whereas a DHEAS-Index <1 increased the likelihood of AI (40%). Finally, a universal DHEAS threshold of <0.2 µg/mL yielded 80% sensitivity and 89% specificity, with a 94% negative predictive value, demonstrating the superior performance of the DHEAS-Index. CONCLUSIONS AND RELEVANCE: Age- and sex-adjusted DHEAS thresholds improve screening for adrenal insufficiency diagnosis, reducing unnecessary ACTH testing and enhancing clinical decision-making, particularly in patients with borderline baseline cortisol.