SUN-443 - Reevaluating Cortisol Responsiveness to Glucagon Stimulation in Children: Physiological and Clinical Insights

Background:
Glucagon stimulation tests (GSTs) are widely used to evaluate suspected growth hormone (GH) deficiency in children and allow simultaneous assessment of the hypothalamic–pituitary–adrenal (HPA) axis. However, the optimal cortisol response during a GST remains debatable, leading to uncertainty regarding its effectiveness in establishing a diagnosis of adrenal insufficiency (AI).

Objectives:
To determine the utility of assessing cortisol responses during GSTs as a marker of HPA axis function in children and to identify clinical and biochemical factors associated with the cortisol dynamics.

Methods:
This retrospective cohort study included 346 children aged 0-18 years who underwent GSTs at a tertiary center between 2017 and 2021. Data were extracted from electronic medical records, including demographics, anthropometric parameters, pubertal status, cortisol, glucose and GH dynamics, and subsequent HPA axis evaluations. Based on the 08:00 AM (baselineC) and peak cortisol (peakC) concentrations, participants were categorized into three cortisol response groups: normal (peakC≥450 nmol/L or baselineC≥280 nmol/L), intermediate (peakC < 450 nmol/L and baselineC 140-280 nmol/L), or low (peakC < 450 nmol/L and baselineC < 140 nmol/L).

Results:
Normal cortisol responses were observed in 251 (73.1%) children, intermediate responses in 81 (23.4%), and 12 (3.5%) had low cortisol values. Children in the normal cortisol group were younger than those in the two other groups (8.8 vs. 10.6 and 10.5 years, respectively). Higher proportions of males and pubertal children were observed to have low cortisol values. Glucose nadir levels and time to nadir did not differ between groups. Overall, peak cortisol occurred at a mean of 45.7±38.3 minutes after the glucose nadir. Seventeen children underwent further HPA axis evaluation, with AI confirmed in only two cases, both from the intermediate-cortisol group.

Conclusions:
Combined assessment of baseline and peak cortisol levels during GSTs is effective for excluding AI in children but has limited utility for establishing the diagnosis. While suboptimal cortisol levels during GSTs are common, they rarely indicate true AI. Based on this, we suggest that the cost-effectiveness of routine cortisol measurement during GSTs warrants further evaluation. The observed delay between the provoked glucose nadir and peak cortisol secretion, may have important implications for the interpretation of hypoglycemia-induced cortisol dynamics, particularly in cases of rapidly developing hypoglycemia.

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