Estrogen elevates the peak overnight production rate of acylated ghrelin

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.