Discordant Cortisol Responses to Spontaneous Hypoglycaemia Versus Adrenocorticotropic Hormone Stimulation: A Diagnostic Challenge for Hypothalamic-Pituitary-Adrenal Axis Assessment

Introduction: The hypothalamic-pituitary-adrenal (HPA) axis is a critical regulator of cortisol secretion, assessed via dynamic tests such as the insulin tolerance test and adrenocorticotropic hormone (ACTH) stimulation test. Discordant cortisol responses in recurrent hypoglycaemia that is, blunted secretion during hypoglycaemia but preserved under ACTH stimulation, pose a diagnostic challenge in evaluating adrenal insufficiency (AI). Methods: A retrospective study was conducted in five patients (two females, three males) with spontaneous fasting hypoglycaemia (blood glucose <55 mg/dL). All patients had undergone critical sampling at the time of hypoglycaemia, including measurements of serum cortisol, insulin, C-peptide, urine ketone whereas ACTH-stimulated cortisol response was assessed using the long-acting porcine sequence ACTH (Acton Prolongatum ® ). Results: All five patients [insulinoma: 2, insulin autoimmune syndrome: 2 (presumed in 1), presumed insulin-like growth factor 2 related hypoglycaemia: 1] with spontaneous fasting hypoglycaemia had suboptimal cortisol levels (range: 6.15–14 μg/dL) during hypoglycaemia but adequate cortisol response (>18 μg/dL) post-ACTH stimulation. Conclusion: Low cortisol levels during recurrent hypoglycaemia should be interpreted cautiously, and AI should be diagnosed only after a comprehensive evaluation. A normal ACTH stimulation test can rule out AI assertively in such scenario. Further studies are needed to clarify the mechanisms of this discordance.