Preservation of GHRH and GH-releasing peptide-2 efficacy in young men with experimentally induced hypogonadism

Background: Somatostatin (SS), GHRH, GH-releasing peptide (GHRP), and the sex-steroid milieu regulate GH secretion. Objective: To test whether GHRH and GHRP remain effective secretagogs in the face of short-term hypogonadism. Design: Prospective, randomized double-blind. Methods: Healthy young men (n = 24) received a GnRH agonist twice 3 weeks apart followed by placebo (n = 13, Pl) or testosterone (n = 11, testosterone) addback. Subjects were then given consecutive i.v. infusions of L-arginine (to restrain SS outflow) and a maximally effective dose of GHRH or GHRP-2 (to test corresponding secretagog pathways). Results: GH secretion stimulated by L-arginine/GHRH and by L-arginine/GHRP-2 was unaffected by combined testosterone/estradiol (E ₂) depletion. The low testosterone/E2 milieu decreased basal (nonpulsatile) GH secretion (P = 0.038), without altering fasting pulsatile GH secretion or IGF1 or IGF-binding protein (IGFBP)-3 concentrations. IGFBP-1 (P < 0.0001) and abdominal visceral fat (AVF, P = 0.017) correlated negatively with fasting basal GH secretion. By contrast, IGF1 (P = 0.0012) and IGFBP-3 (P = 0.015) correlated positively with fasting pulsatile GH secretion. AVF (P = 0.0024) was a negative determinant, and IGF1 a positive determinant (P = 0.018), of GHRH-driven GH pulses. Responses to GHRP-2 were unrelated to any of these factors. Conclusion: L-arginine/GHRP-2 appears to be an especially robust stimulus of GH secretion, since efficacy is unmodified by profound short-term hypogonadism, a range of AVF estimates, and a spectrum of IGF1, IGFBP-1, and IGFBP-3 concentrations. Whether robustness also applies to chronic hypogonadism is not known.