GHRP-2 test matches ITT for diagnosing HPA axis failure with 100% specificity
Background
Hypothalamic-pituitary-adrenal (HPA) axis failure is a serious consequence of hypothalamic/pituitary disease that requires accurate dynamic testing to diagnose. The ITT (insulin tolerance test) is the current gold standard for probing HPA axis reserve, but it carries significant risks including severe hypoglycemia, making it contraindicated in patients with epilepsy, ischemic heart disease, or adrenal insufficiency. GH-releasing peptide-2 (GHRP-2) is an established diagnostic tool for GH deficiency due to its potent GH-stimulating activity, and is known to also activate the HPA axis via distinct mechanisms. No head-to-head comparison of pituitary-adrenal responsiveness between the GHRP-2 test and ITT had previously been conducted in patients with suspected hypopituitarism, leaving a critical clinical gap.
Study Design
A pilot study enrolled 15 patients suspected of hypopituitarism who underwent both ITT and GHRP-2 stimulation tests. GHRP-2 at 100 µg was administered intravenously as a single bolus. Plasma ACTH and serum cortisol concentrations were measured as primary endpoints following both tests. The ITT cut-off of a peak cortisol >18 µg/dl served as the diagnostic reference standard for normal HPA axis function, defining two patient subgroups: 9 patients classified as HPA axis failure and 6 patients classified as normal HPA axis status.
Results
Among the 9 patients diagnosed with HPA axis failure by ITT, median peak cortisol in response to GHRP-2 was 11.4 µg/dl. The 6 patients with normal HPA axis status by ITT had a median peak cortisol of 21.4 µg/dl on GHRP-2 test, a difference that reached statistical significance at p=0.0032. Peak cortisol responses across the two tests showed a strong positive correlation.
Peak cortisol in GHRP-2 test vs. ITT: r=0.817, p**<0.0001** — a near-linear relationship across the full cohort of 15 patients.
When a diagnostic cut-off of 13–14 µg/dl peak cortisol was applied to the GHRP-2 test for identifying HPA axis failure, specificity reached 100% and sensitivity reached 88.9%, indicating that false positives were entirely eliminated while one HPA failure case may have been missed.
Key Findings
- Peak cortisol correlation between GHRP-2 test and ITT: r=0.817, p<0.0001 (n=15)
- Median peak cortisol in HPA failure group (GHRP-2 test): 11.4 µg/dl vs. 21.4 µg/dl in normal group
- Group difference in GHRP-2 cortisol response: p=0.0032
- GHRP-2 cut-off 13–14 µg/dl yielded 100% specificity and 88.9% sensitivity for HPA failure
- GHRP-2 dose used: 100 µg IV; 9/15 patients diagnosed as HPA axis failure by ITT
Why It Matters
GHRP-2 testing may offer a safer, equally informative alternative to ITT for evaluating adrenal reserve in patients with hypothalamic or pituitary disease, particularly those for whom insulin-induced hypoglycemia is contraindicated or medically high-risk. A cut-off of 13–14 µg/dl peak cortisol in the GHRP-2 test could serve as a preliminary diagnostic threshold pending validation in larger cohorts. Clinicians already using GHRP-2 for GH deficiency diagnosis may gain dual-axis diagnostic information from a single stimulation test, reducing patient burden. Full clinical protocol adoption requires validation in normal subjects and larger patient populations before the GHRP-2 test can replace ITT in routine practice.
