The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E(2) along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.
Context: Sex-steroid hormones amplify pulsatile GH secretion by unknown mechanisms. Ghrelin is the most potent natural GH secretagogue discovered to date. A plausible unifying postulate is that estradiol (E 2 ) enhances hypothalamo-pituitary sensitivity to ghrelin (a physiological effect). The hypothesis is relevant to understanding the basis of hyposomatotropism in aging and other relatively hypogonadal states.
Objective:Our objective was to test the hypothesis that E 2 supplementation potentiates ghrelin's stimulation of pulsatile GH secretion.
Setting:The study was conducted at an academic medical center.
Subjects:Healthy postmenopausal women (n ϭ 20) were included in the study.Interventions: Separate-day iv infusions of saline vs. five graded doses of ghrelin were performed in volunteers prospectively randomly assigned to receive (n ϭ 8) or not receive (n ϭ 12) transdermal E 2 for 21 d were performed.Measures: GH secretion was estimated by deconvolution analysis and abdominal visceral fat mass determined by computerized axial tomography were calculated.Results: E 2 supplementation augmented ghrelin's stimulation of basal (nonpulsatile) GH secretion by 3.6-fold (P ϭ 0.022), increased GH responses to low-dose ghrelin by 2.9-fold (P ϭ 0.035), did not alter ghrelin efficacy, and elicited more regular patterns of acylated ghrelin concentrations during saline infusion (P ϭ 0.033). Abdominal visceral fat negatively determined responses to ghrelin (R ϭ Ϫ0.346; P Ͻ 0.005).
Conclusions:Transdermal E 2 supplementation potentiates GH secretion stimulated by physiological but not pharmacological concentrations of acylated ghrelin, and concomitantly regularizes patterns of bioactive ghrelin secretion in postmenopausal women. Accordingly, the estrogen milieu appears to control sensitivity of the hypothalamopituitary unit to acylated ghrelin. A ging is associated with a progressive decline in GH and IGF-I availability (1-3). Healthy older individuals with relative hyposomatotropism and patients with pathological GH deficiency share a similar physical phenotype marked by osteopenia, sarcopenia, visceral adiposity, insulin resistance, hyperlipidemia, increased risk of cardiovascular disease, and di-
Estrogen augments ghrelin's near-physiological stimulation of pulsatile GH secretion and mimics ghrelin's acceleration of initial GH release. Thus, we hypothesize that estrogen and a GH secretagogue act via independent as well as convergent mechanisms.
We show that in an experimentally enforced estradiol-predominant milieu, postmenopausal compared with premenopausal women maintain 1) decreased fasting GH and IGF-I concentrations, 2) reduced basal and pulsatile GH secretion, and 3) attenuated GH secretion after maximal stimulation by the paired secretagogues l-arginine/GH-releasing peptide (GHRP)-2, l-arginine/GHRH, and GHRP-2/GHRH. These foregoing outcomes are selective, because menopausal status did not determine mean GH secretory-burst frequency or peptide-induced waveform shortening. Abdominal visceral fat mass predicted up to 25% of the variability in fasting and stimulated GH secretion in the combined cohorts under fixed systemic estradiol availability. Accordingly, as much as three-fourths of interindividual differences in burst-like GH secretion among healthy pre- and postmenopausal women arise from age-related mechanisms independently of short-term systemic estrogen availability and relative intraabdominal adiposity.
Acylated ghrelin has a multifold larger distribution volume and MCR than total ghrelin. An estrogenic milieu augments synthesis and/or acylation of ghrelin peptide without altering its MCR.
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