Estrogen Supplementation Selectively Enhances Hypothalamo-Pituitary Sensitivity to Ghrelin in Postmenopausal Women

Abstract

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 (E2) 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 E2 supplementation potentiates ghrelin’s stimulation of pulsatile GH secretion. Setting: The study was conducted at an academic medical center. Subjects: Healthy postmenopausal women (n = 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 = 8) or not receive (n = 12) transdermal E2 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: E2 supplementation augmented ghrelin’s stimulation of basal (nonpulsatile) GH secretion by 3.6-fold (P = 0.022), increased GH responses to low-dose ghrelin by 2.9-fold (P = 0.035), did not alter ghrelin efficacy, and elicited more regular patterns of acylated ghrelin concentrations during saline infusion (P = 0.033). Abdominal visceral fat negatively determined responses to ghrelin (R = −0.346; P < 0.005). Conclusions: Transdermal E2 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.