Factors Other than Sex Steroids Modulate GHRH and GHRP-2 Efficacies in Men: Evaluation Using a GnRH Agonist/Testosterone Clamp

Abstract

Sex steroids are prominent regulators of pulsatile GH secretion. An experimentally controlled sex-steroid milieu will permit detection of nonsteroidal factors that determine GH secretion. Eleven young (age, 24 +/- 0.99 yr) and 11 older (64 +/- 2.4 yr) men participated in the study. The study was conducted at a tertiary medical center. The study consisted of GnRH-agonist down-regulation of the gonadal axis followed by fixed-dose testosterone (T) replacement (leuprolide/T clamp) and consecutive infusion of l-arginine and GHRH or GH-releasing peptide-2 (GHRP-2) to quantify peptide-secretagogue efficacies. The experimental leuprolide/T clamp yielded statistically age-comparable total, bioavailable, and free T and estradiol (E(2)) concentrations. In this controlled milieu, sequential l-arginine/GHRH infusion stimulated 1.4-fold more (P = 0.021) and l-arginine/GHRP-2 1.3-fold more (P = 0.045) GH release in young than older men. Abdominal visceral fat (AVF) correlated negatively with both GHRH (P = 0.0006; R(2) = 0.39) and GHRP-2 (R(2) = 0.29) efficacy, whereas IGF-I positively predicted the same endpoints (R(2) = 0.25 to 0.30). In multivariate analysis, AVF emerged as a dominant negative determinant of GHRH efficacy (P = 0.002; R(2) = 0.41) and IGF-I as a primary positive determinant of GHRP-2 efficacy (P = 0.007; R(2) = 0.31). During fixed T/E(2) availability, AVF contributes 41% of the GH-response variability to maximal GHRH drive, whereas IGF-I accounts for 31% of that for GHRP-2. Accordingly, a statistically equalized sex-steroid milieu permits dissection of age-independent and T/E(2)-independent modulators of GHRH and GHRP efficacy in men.