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Estradiol Potentiates Ghrelin-Stimulated Pulsatile Growth Hormone Secretion in Postmenopausal Women

Endocrine Research Unit (J.D.V., K.M., J.M.M.), Department of Internal Medicine, Mayo School of Graduate Medical Education, Rochester, Minnesota 55905; Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904; Research and Development Office (A.I.), Veterans Affairs Medical Center, Salem, Virginia 24153; and Department of Medicine (C.Y.B.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Context: Ghrelin and an estrogen-rich milieu individually amplify pulsatile GH secretion by increasing the amount of hormone released per burst. However, how these distinct agonists interact in controlling pulsatile GH output is not known.

Objective: The objective of the study was to test the hypothesis that elevated estradiol (E₂) concentrations potentiate hypothalamo-pituitary responses to a near-physiological ghrelin stimulus.

Design: This was a double-blind, placebo-controlled, prospectively randomized, parallel-cohort study.

Setting: The study was conducted at an academic medical center.

Subjects: Twenty-one postmenopausal women participated in the study.

Interventions: Eleven subjects received placebo (Pl) and 10 others E₂ transdermally in escalating doses over 3 wk to mimic late follicular-phase E₂ concentrations. Saline or a submaximally stimulatory amount of ghrelin (0.3 µg/kg) was infused iv on separate randomly ordered mornings fasting after 17–21 d of Pl or E₂ administration.

Outcomes: Outcomes included serum concentrations of E₂, ghrelin, GH, IGF-I, IGF binding protein (IGFBP)-1 and IGFBP-3, and the estimated mass and waveform of stimulated GH secretory bursts.

Results: Administration of E₂ yielded late follicular-phase E₂ concentrations. Compared with Pl, E₂ did not alter ghrelin concentrations but reduced IGF-I and IGFBP-3 and elevated IGFBP-1 concentrations. Compared with saline, ghrelin infusion amplified pulsatile GH secretion by 7.1-fold (P < 0.01). The effect of E₂ alone was 2.0-fold placebo and that of combined ghrelin/E₂ 10.4-fold (P < 0.01). Ghrelin and E₂ accelerated initial GH release individually but nonadditively by more than 2-fold (P < 0.01).

Conclusions: 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.

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