GHRP-2 Test Substitutes Insulin Tolerance Test for Adrenal Axis Assessment in Specific Male Patients
Background
Evaluating the hypothalamic-pituitary-adrenal (HPA) axis is crucial for diagnosing conditions like hypopituitarism and adrenocortical insufficiency. The current gold standard is the insulin tolerance test (ITT), which induces hypoglycemia to stress the HPA axis and measure its cortisol response. However, the ITT is risky, unpleasant, and contraindicated in patients with seizure disorders or cardiovascular disease. GH-releasing peptide 2 (GHRP-2) stimulates the HPA axis through the GHSR (GH secretagogue receptor), where ghrelin is the endogenous ligand. This suggests the GHRP-2 test (GHRP2T) could be a safer alternative to the ITT for assessing HPA function, but its diagnostic accuracy across different patient populations needed validation.
Study Design
This retrospective study analyzed clinical and laboratory data from 254 patients admitted for evaluation of hypopituitarism. Each patient underwent both a GHRP-2 test (GHRP2T) and an insulin tolerance test (ITT). The primary endpoint was the maximum cortisol level (Fmax) reached during each test. Adrenocortical insufficiency was formally diagnosed based on the ITT results. The study then examined the correlation between Fmax values from the two tests and used receiver operating characteristic (ROC) curve analysis to determine the diagnostic suitability of the GHRP2T as a replacement for the ITT.
Results
A strong overall correlation was found between the maximum cortisol levels (Fmax) measured during the GHRP2T and the ITT (r = 0.777, P < 0.0001). However, when analyzing the entire cohort of 254 patients, the GHRP2T showed poor diagnostic performance, with a sensitivity of only 64% and specificity of 79%, making it unsuitable for general clinical use. The correlation was significantly influenced by factors such as the presence of a functional adenoma (P < 0.05) and sex (P < 0.05). In patients with prolactinoma (n = 30), no substantial correlation was found. After excluding patients with functional adenomas and analyzing by sex, a highly accurate subgroup emerged.
In male subjects without functional adenomas (n = 104), the
GHRP2Tdemonstrated high sensitivity (95%) and specificity (85%) for diagnosing adrenocortical insufficiency.
Key Findings
- Maximum cortisol levels during GHRP2T and ITT were strongly correlated across all patients (r = 0.777, P < 0.0001).
- In the full cohort (n=254), the GHRP2T had poor sensitivity (64%) and specificity (79%) for diagnosing adrenal insufficiency.
- In male patients without functional adenomas (n=104), the GHRP2T showed high sensitivity (95%) and specificity (85%).
- Patient sex (P < 0.05) and the presence of a functional adenoma (P < 0.05) significantly influenced the test's accuracy.
- No significant correlation was found between the two tests in patients with prolactinoma (n=30).
Why It Matters
The findings suggest that the GHRP-2 test can replace the riskier insulin tolerance test for HPA axis assessment, but its application is highly specific. Clinicians can consider using the GHRP2T in male patients without functional pituitary adenomas, offering a safer diagnostic alternative for this particular subgroup. The study highlights that sex and pituitary tumor type are critical variables that modify the HPA response to GHRP-2, likely through effects on ghrelin signaling via the GHSR. This research does not support the broad replacement of the ITT but provides a clear pathway for a more nuanced, personalized diagnostic approach. Further prospective studies are needed to confirm these findings before they can be adopted as a standard protocol.
