Estrogen Elevates the Peak Overnight Production Rate of Acylated Ghrelin

Abstract

CONTEXT: Acylated ghrelin is the putatively bioactive GH secretagogue. HYPOTHESIS: Estradiol (E2) stimulates the synthesis rather than inhibits the metabolic clearance of acylated ghrelin. SETTING: The study took place at an academic medical center. SUBJECTS: Healthy postmenopausal women participated. INTERVENTIONS: Interventions included prospectively randomized, double-blind separate-day iv infusions of saline or five graded doses of ghrelin in estrogen-deficient (n=12) and E2-supplemented (n=8) women. OUTCOMES: Metabolic clearance rate (MCR), volume of distribution, half-life, and secretion rate of acylated ghrelin were assessed. RESULTS: In pilot iv bolus ghrelin infusions, the median half-lives of acylated and total ghrelin were 21 and 36 min (P<0.01), MCRs 58 and 8.1 liters/kg.d (P<0.01), and volumes of distribution of 1.0 and 0.32 liters/kg (P<0.01), respectively. Transdermal E2 supplementation for 3 wk increased peak nighttime acylated ghrelin concentrations from 99+/-12 to 141+/-34 pg/ml (P=0.039). Exposure to E2 did not alter the linear relationships between 1) plasma acylated ghrelin concentration and ghrelin infusion rate (638+/-12 slope units), 2) MCR of acylated ghrelin and ghrelin infusion rate (10+/-2.5 slope units), and 3) MCR and plasma concentration of acylated ghrelin (0.017+/-0.004 slope units). These data predict peak nighttime production rates of acylated ghrelin of 3.8+/-0.9 (E2) and 1.9+/-0.2 (no E2) ng/kg.min (P=0.039). CONCLUSION: 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.