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

Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905, USA¹ Department of Statistics, University of Virginia, Charlottesville, Virginia 22904, USA² Division of Endocrinology, Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA

(Correspondence should be addressed to J D Veldhuis; Email: veldhuis.johannes{at}mayo.edu)

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 (E₂) 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.