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Estradiol Supplementation Enhances Submaximal Feed-Forward Drive of Growth Hormone (GH) Secretion by Recombinant Human GH-Releasing Hormone-1,44-Amide in a Putatively Somatostatin-Withdrawn Milieu

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Department of Internal Medicine (W.S.E.), General Clinical Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908; and Department of Internal Medicine (C.Y.B.), Division of Endocrinology and Metabolism, Tulane Medical School, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, 200 First Street Southwest, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

To test the clinical hypothesis that an estrogen-enriched milieu enhances GHRH action, we administered placebo (Pl) and estradiol-17ß (E₂) orally for 23 d to six postmenopausal women in a prospectively randomized, double-masked, within-subject crossover design with 6 wk intervening. The GHRH stimulation protocol entailed consecutive iv infusion of L-arginine and a single iv pulse of saline or one of five randomly ordered doses of recombinant human GHRH-1,44-amide (0.03, 0.1, 0.3, 1.0, or 3.0 µg/kg) in a total of 12 separate morning, fasting sessions. GH secretion was monitored by sampling blood every 10 min for 6 h; chemiluminescence assay of GH concentrations; deconvolution analysis of stimulated GH release; and nonlinear dose-response reconstruction. Supplementation with E₂, compared with Pl: 1) increased (mean ± SEM) E₂ concentrations from 18 ± 3 (Pl) to 164 ± 12 pg/ml (to convert to picomoles per liter, multiply by 3.57) (P < 0.001); 2) decreased IGF-I concentrations from 181 ± 14 to 120 ± 11 µg/liter (P < 0.01); 3) elevated mean GH concentrations from 0.27 ± 0.06 to 0.59 ± 0.08 µg/liter (P = 0.014); 4) potentiated GH secretion stimulated by L-arginine alone by 1.43-fold (P = 0.012); 5) reduced the ED₅₀ of GHRH from 0.27 ± 0.02 to 0.13 ± 0.01 µg/kg (P < 0.01), denoting enhanced GHRH potency; and 6) heightened the maximal slope of the dose-response function from 1.1 ± 0.1 to 1.4 ± 0.05 [(µg/liter) (µg/kg)^-1] (P < 0.05), signifying augmented pituitary sensitivity. The foregoing facilitative mechanisms were specific because E₂ replacement did alter maximal L-arginine/GHRH-induced GH secretion, indicating unchanged secretagogue efficacy. In conclusion, inasmuch as E₂ also attenuates inhibition of GH secretion by infused somatostatin and potentiates stimulation of GH secretion by GH-releasing peptide-2, we postulate that estrogenic steroids drive pulsatile GH production in part via mechanisms that include all three of GHRH, somatostatin, and putatively GH-releasing peptide/ghrelin signaling.

This work was supported in part by Grants MO1 RR00847 and MO1 RR00585 to the General Clinical Research Centers of the University of Virginia and Mayo Clinic from the National Center for Research Resources and RO1 AG19596 and AG14779 from the National Institutes of Health (Bethesda, MD).

Abbreviations: CI, Confidence interval; E₂, estradiol; GHRP, GH-releasing peptide; Pl, placebo; rh, recombinant human.

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