GHRP-2 maintains full GH secretory efficacy during experimentally induced hypogonadism in young men
Background
GH secretion is regulated by an interplay of somatostatin (SS), GHRH, GH-releasing peptides (GHRPs), and the sex-steroid milieu. Testosterone and estradiol are known modulators of the GH–IGF-1 axis, and hypogonadism — whether age-related, drug-induced, or pathological — is associated with altered GH dynamics. A key unresolved question is whether GHRH and GHRP secretagog pathways remain pharmacologically intact when sex steroids are withdrawn, since this would determine whether these peptides retain clinical utility in hypogonadal states. Confounding factors such as abdominal visceral fat (AVF), IGF-1, IGFBP-1, and IGFBP-3 all modulate baseline GH output, but their interactions with secretagog-stimulated GH release during hypogonadism had not been systematically tested.
Study Design
A prospective, randomized, double-blind study enrolled n=24 healthy young men. All subjects received a GnRH agonist administered twice, 3 weeks apart, to induce experimental hypogonadism. Subjects were then randomized to placebo (n=13) or testosterone addback (n=11). Following hormonal manipulation, all subjects received consecutive i.v. infusions of l-arginine (to suppress somatostatin outflow) followed by a maximally effective dose of either GHRH or GHRP-2 to probe the respective secretagog pathways. Primary endpoints included stimulated GH secretion, fasting basal and pulsatile GH secretion, and circulating IGF-1, IGFBP-1, and IGFBP-3 concentrations, with AVF also assessed.
Results
GH secretion stimulated by l-arginine/GHRH and by l-arginine/GHRP-2 was unaffected by combined testosterone/estradiol depletion in either group. The low testosterone/estradiol milieu significantly decreased basal (nonpulsatile) GH secretion (p=0.038), but did not alter fasting pulsatile GH secretion or concentrations of IGF-1 or IGFBP-3. IGFBP-1 (p<0.0001) and AVF (p=0.017) correlated negatively with fasting basal GH secretion, while IGF-1 (p=0.0012) and IGFBP-3 (p=0.015) correlated positively with fasting pulsatile GH secretion. For GHRH-driven GH pulses, AVF was a negative determinant (p=0.0024) and IGF-1 a positive determinant (p=0.018).
GHRP-2 responses were entirely unrelated to hypogonadal status, AVF, IGF-1, IGFBP-1, or IGFBP-3 — no covariate examined attenuated its efficacy.
Key Findings
- l-arginine/GHRP-2-stimulated GH secretion was unaffected by testosterone/estradiol depletion
- Hypogonadism reduced basal (nonpulsatile) GH secretion (p=0.038) but not pulsatile GH
- IGFBP-1 (p<0.0001) and AVF (p=0.017) negatively correlated with basal GH secretion
- AVF (p=0.0024) negatively and IGF-1 (p=0.018) positively predicted GHRH-driven GH pulses
- GHRP-2 responses were unrelated to AVF, IGF-1, IGFBP-1, or IGFBP-3 concentrations
Why It Matters
GHRP-2's secretagog efficacy is uniquely insensitive to the hormonal and metabolic factors that blunt GHRH-driven GH release, including visceral adiposity and the IGF-1 / IGFBP axis. For clinicians and researchers designing GH stimulation protocols, this positions l-arginine/GHRP-2 as a more reliable diagnostic and therapeutic tool in populations where sex steroids are suppressed — such as during GnRH agonist therapy for prostate cancer, endometriosis, or precocious puberty. The GHRH pathway's dependence on AVF and IGF-1 levels suggests body composition and feedback tone must be accounted for when using GHRH-based secretagogs. Practitioners should note these findings apply only to short-term induced hypogonadism; whether chronic hypogonadism (e.g., Klinefelter syndrome, aging) preserves GHRP-2 robustness remains unknown and warrants separate investigation.
