Challenges in Diagnosing Central Adrenal Insufficiency in Children: Cortisol‐Stimulating Tests are Safe and Often Required

INTRODUCTION: The accuracy and safety of cortisol-stimulating tests (CSTs) for assessing hypothalamic-pituitary-adrenal (HPA) axis integrity, including the diagnosis of central adrenal insufficiency (CAI), in children remain uncertain. Although these tests can simultaneously evaluate cortisol and growth hormone secretion, the present study focuses exclusively on cortisol measurements. METHODS: We evaluated the diagnostic accuracy and safety profile of CST in pediatric patients submitted to insulin tolerance test (ITT) or glucagon-stimulation test (GST) in a tertiary center for 15 years in this retrospective cohort study. According to cortisol (F; nmol/L), we classified patients as having CAI (Fbasal < 138 or Fpeak < 414), indeterminate (Fbasal = 138-358.7 or Fpeak = 414-496.6), and normal (Fbasal > 358.7 or Fpeak > 496.6). Cutoffs were selected based on the literature and on our University Hospital protocol. Plasma cortisol was measured using a consistent radioimmunoassay (RIA) following extraction, with duplicate analyses. The assay had a detection limit of 33.11 nmol/L, with intra- and inter-assay coefficients of variation of 5% and 10.5%, respectively. We evaluated the sensitivity, specificity, likelihood ratios (LR), and clinicopathological variables associated with Fbasal and Fpeak. RESULTS: Among 904 patients (60.1% males; median age 10.1 years [0.1-17.1]), CAI was confirmed in 79 (8.7%). Mild hypoglycemia (ITT), and nausea and vomiting (GST) occurred in 46% and 17.5%, respectively. No serious adverse events occurred. Fbasal classified 58% of patients as indeterminate. A Fbasal cutoff of 96.6 had a specificity of 99% and LR+ of 7.6, but low sensitivity (5.3%). In GST, a Fpeak of 303.5 had weak diagnostic accuracy (LR+ of 2.8) and low sensitivity (17%). Concomitant central hypothyroidism and a Fbasal < 154.5 were associated with lower Fpeak, and pituitary stalk interruption was associated with lower Fbasal and Fpeak. CONCLUSIONS: Fbasal did not present good diagnostic accuracy. However, Fbasal < 96.6 nmol/L predicted lower Fpeak. Therefore, many patients require CST to confirm or exclude CAI. ITT and GST are safe for young patients when performed in experienced centers in a controlled environment.