In a tightly controlled study where men’s testosterone and estrogen levels were kept constant, researchers found that younger men released more growth hormone (GH) than older men when given GHRP‑2 or GHRH. More importantly, the amount of belly fat (visceral fat) was a strong negative predictor of how well these GH‑releasing peptides worked, while higher IGF‑1 levels boosted the response to GHRP‑2. This means that body composition, not just age or sex hormones, can shape how effective GHRP‑2 is at raising GH.

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.