Revisiting peak serum cortisol response to insulin-induced hypoglycemia in children and adolescents

Purpose: To evaluate factors that could potentially affect the hypothalamic-pituitary adrenal (HPA) axis response to insulin-induced hypoglycemia in children without history or symptoms of adrenal insufficiency and to propose a cut-off value to define a normal response in this population. Methods: Exploratory single-centre study involving 78 children that prospectively underwent insulin tolerance test (ITT) for suspected growth hormone (GH) deficiency. Methods: Glucose, cortisol, GH, adrenocorticotropic hormone (ACTH), epinephrine and norepinephrine levels were measured at baseline and after insulin-induced hypoglycemia. Serum cortisol was measured using Access automated immunoassay. Results: Mean (range) basal morning serum cortisol of 8 (2.2-19.5) µg/dL/ 222 (61-542) nmol/L increased after hypoglycemia to  20.5 (14.6-29.5) µg/dL / 570 nmol/L (405 -819) nmol/L. Peak serum cortisol levels of 14.6 µg/dL (405nmol/L) and 15.4 µg/dL (428 nmol/L) corresponded to the 2.5^th and 5^th percentiles, respectively. Peak serum cortisol correlated with peak plasma epinephrine (r = 0.367; P = 0.0014) but did not correlate with age, BMI-SD or peak serum GH. Children with intact and abnormal GH responses presented similar mean peak serum cortisol levels (20.0 vs. 20.6 µg/dL / 555 vs. 572 nmol/L; P = 0.21). Conclusion: Our data indicate that the current cut-off to define normal HPA axis response in children after insulin-induced hypoglycemia warrants reevaluation in order to avoid overdiagnosis of adrenal insufficiency. Our results suggest that peak serum cortisol levels ³ 15.4 µg/dL (428 nmol/L) in children undergoing ITT might represent a normal cortisol response to stress, regardless of age, BMI or GH secretory capacity.