GHRP-2 fails to stimulate arginine vasopressin secretion in healthy men
Background
Arginine vasopressin (AVP) is a critical regulator of water homeostasis and osmotic balance, and its deficiency underlies central diabetes insipidus. Accurate provocative tests for AVP secretion are clinically essential yet imperfect. Ghrelin, the endogenous ligand of GHSR, has been shown to stimulate AVP release, raising the hypothesis that synthetic GHSR agonists might share this property. GHRP-2 is a well-characterized synthetic ghrelin receptor agonist already used clinically to provoke GH secretion, making it an attractive candidate for a dual-purpose pituitary challenge test. Whether it also activates the AVP axis had not been determined in men prior to this study.
Study Design
GHRP-2 at 100 µg was administered as an intravenous bolus to 10 healthy men under two conditions: fasting and non-fasting. Blood samples were drawn at 0, 15, 30, 45, and 60 minutes post-injection and assayed for ACTH, GH, FSH, LH, PRL, TSH, and AVP, alongside plasma glucose, osmolality, sodium, and hematocrit. Blood pressure was recorded at 15-minute intervals. The primary endpoint was AVP response; secondary endpoints included pituitary hormone peaks and physiological parameters under each dietary condition.
Results
AVP secretion was not stimulated by GHRP-2 under either fasting or non-fasting conditions. Hematocrit, blood pressure, and plasma osmolality showed no significant differences before versus after GHRP-2 injection, ruling out hemodynamic or osmotic confounds as explanations. Significant peaks in blood GH and ACTH were observed at 30 minutes post-injection (p < 0.001), while PRL peaked at 15 minutes post-injection (p < 0.001), in both dietary states.
Maximal peaks of GH, ACTH, and PRL were significantly higher with fasting than without fasting (p < 0.05), yet AVP remained unresponsive in both states.
The dissociation between robust pituitary hormone responses and a flat AVP response indicates that GHSR activation by GHRP-2 does not translate to posterior pituitary stimulation in men. FSH, LH, and TSH responses were not highlighted as significant in the abstract.
Key Findings
- AVP secretion was not stimulated by 100 µg IV GHRP-2 with or without fasting (n=10)
- GH and ACTH peaked significantly at 30 min post-injection (p < 0.001)
- PRL peaked significantly at 15 min post-injection (p < 0.001)
- Maximal GH, ACTH, and PRL peaks were significantly higher with fasting vs. without (p < 0.05)
- Hematocrit, blood pressure, and plasma osmolality showed no significant changes post-GHRP-2
Why It Matters
GHRP-2 cannot substitute for, or add value as, an AVP secretion provocateur, meaning it should not be used to assess posterior pituitary function in clinical workups for diabetes insipidus or SIADH. Clinicians evaluating pituitary reserve with GHRP-2 can be confident the test probes anterior pituitary axes — GH, ACTH, PRL — without confounding AVP-related endpoints. For peptide users and researchers designing pituitary challenge protocols, fasting substantially amplifies GH, ACTH, and PRL responses to GHRP-2, a practical timing variable for provocation testing. The divergence from native ghrelin's AVP-stimulating effect suggests receptor-subtype selectivity or downstream signaling differences that warrant further mechanistic investigation.
