The study shows that, even when estrogen levels are kept the same, older women (post‑menopausal) release far less growth hormone (GH) than younger women after being given GHRP‑2, GHRH, or arginine. Their GH response drops to about one‑third of that seen in younger women, and the usual ranking of which peptide works best (GHRP‑2 being strongest) disappears. More belly fat predicts a weaker GH boost from arginine, while higher IGF‑I levels predict a stronger response to GHRP‑2 and GHRH.

Studies of how aging attenuates GH secretion are confounded by differences in sex-steroid milieus, abdominal visceral fat mass (AVF), and IGF-I concentrations and limited in interpretability by the use of pharmacological doses of secretagogues. In a controlled estrogenic milieu, near-physiological secretagogue drive will unmask distinct influences of age, AVF, and IGF-I on GH secretion. The study was conducted at an academic medical center. Subjects included 10 healthy pre- (PRE) and 10 postmenopausal (POST) women. In a defined estradiol (E(2)) milieu, we compared GH secretion after submaximal stimulation with GH-releasing peptide (GHRP)-2 (ghrelin analog), GHRH, and l-arginine (an inhibitor of somatostatin outflow). We related GH responses to age stratum (dichotomous variable) and AVF and IGF-I concentrations (continuous variables). In the face of comparable concentrations of E(2), testosterone, and SHBG: 1) age (P < 0.001) and secretagogue type (P < 0.001) independently determined GH secretion; 2) GH responses in POST subjects were only 26-33% of those in PRE (P < or = 0.002) across all secretagogues; 3) POST women lost the PRE order of secretagogue potency (GHRP-2 > GHRH = l-arginine); and 4) in the combined cohorts, higher AVF predicted reduced l-arginine-stimulated GH secretion (R(2) = 0.46, P = 0.0013), whereas higher IGF-I concentrations forecast increased GHRP-2 and GHRH drive (R(2) > or = 0.52, P < or = 0.013). A paradigm of near-physiological secretagogue drive in an E(2)-clamped milieu unmasks tripartite deficits in peptide-signaling pathways in healthy POST, compared with PRE, women. Post hoc analyses indicate that both greater visceral adiposity and lower IGF-I concentrations mark this triple regulatory defect.