Differentiating hypothalamic from pituitary adrenal insufficiency: underlying causes and diagnostic utility of the corticotropin-releasing hormone and growth hormone-releasing peptide-2 stimulation tests.

In Japan, the Corticotropin-releasing hormone (CRH) stimulation test is widely used to evaluate secondary adrenal insufficiency (SAI); however, the insulin tolerance test (ITT) is sometimes required to assess hypothalamic dysfunction. This study aimed to identify the clinical conditions in which the ITT is necessary in addition to CRH testing. We retrospectively analyzed 69 patients who underwent both tests between August 2015 and December 2024. Forty-three patients with insufficient cortisol responses during the ITT were diagnosed with SAI and the others with non-SAI. Among SAI cases, cortisol level ≥18 μg/dL during CRH testing defined hypothalamic SAI and <18 μg/dL defined pituitary SAI. Clinical profiles and ACTH responses were compared. Pituitary SAI was associated with tumors, immune-related adverse events, glucocorticoids, COVID-19, hypophysitis and empty sella. Hypothalamic SAI was mainly associated with tumors, opioids, and COVID-19. During CRH testing, ACTH responses alone poorly distinguished hypothalamic SAI from non-adrenal insufficiency among patients with normal cortisol responses to CRH; however, a specific pattern of low basal level combined with a high peak of ACTH after CRH stimulation suggested hypothalamic SAI. In addition, a peak cortisol level <12 μg/dL in the growth hormone-releasing peptide-2 (GHRP-2) stimulation test was also specific to hypothalamic SAI among patients with normal cortisol responses to CRH. In conclusion, even when cortisol responses to CRH appear adequate, the ITT remains necessary for patients with clinical or etiological features suggestive of hypothalamic dysfunction. When the ITT is contraindicated, analyzing ACTH values during the CRH stimulation test and peak cortisol levels during the GHRP-2 test would effectively support hypothalamic SAI diagnosis.