Tripartite Control of Growth Hormone Secretion in Women during Controlled Estradiol Repletion

Abstract

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.