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Estrogen Elevates the Peak Overnight Production Rate of Acylated Ghrelin

Departments of Pediatrics (R.C.P.) and Internal Medicine (M.C., K.L.M., J.D.V.), Endocrine Research Unit, Clinical Translational Research Center, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester, Minnesota 55901; Department of Pharmacology (R.B.), University of Minnesota, Minneapolis, Minnesota 55414; and Division of Endocrinology (C.Y.B.), Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Department of Internal Medicine, Endocrine Research Unit, Clinical Translational Research Center, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester, Minnesota 55901. E-mail: Veldhuis.Johannes{at}mayo.edu.

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.

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