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Estradiol Supplementation in Postmenopausal Women Doubles Rebound-Like Release of Growth Hormone (GH) Triggered by Sequential Infusion and Withdrawal of Somatostatin: Evidence that Estrogen Facilitates Endogenous GH-Releasing Hormone Drive

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; Division of Endocrinology (S.M.A.), Department of Internal Medicine, Department of Health Evaluation Sciences (J.T.P.), General Clinical Research Center, University of Virginia Health System, Charlottesville, Virginia 22908; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, Tulane University Medical Center, 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, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

We postulated that short-term estradiol replacement in postmenopausal women may act, in part, by facilitating endogenous GHRH release or action. A prediction of this hypothesis is that estradiol repletion should enhance postsomatostatin rebound GH secretion, which appears to be driven by hypothalamic outflow of GHRH. To this end, we administered placebo and estradiol to eight healthy estrogen-withdrawn postmenopausal volunteers in a prospectively randomized, patient-blinded, within-subject crossover design for a total of 36 d. Rebound release of GH was assessed between d 7 and 36 of intervention on separate randomly ordered mornings after continuous iv infusion of saline or somatostatin (9 µg/kg·h for 3 h). Secretion was quantitated by frequent (10-min) blood sampling for 7 h, GH chemiluminescence assay, and deconvolution analysis. Compared with placebo, estradiol replacement: 1) stimulated spontaneous pulsatile GH secretion by 3.5-fold (95% confidence interval, 2.1- to 5.6-fold) (P < 0.001); and 2) amplified the mass of GH secreted in response to abrupt somatostatin withdrawal by 2.1-fold (95% confidence interval, 1.3- to 3.4-fold) (P = 0.003). Estrogenic augmentation of rebound-like GH secretion was specific, because the pharmacological effects of exogenous GHRH (1 µg/kg) and GH-releasing peptide-2 (1 µg/kg, a synthetic ghrelin analog) were not affected.

In summary, short-term supplementation with estradiol in postmenopausal individuals doubles the mass of rebound-like GH secretion induced by abrupt somatostatin withdrawal without modifying stimulation by a pharmacological dose of GHRH or GH-releasing peptide-2. Accordingly, we hypothesize that estradiol stimulates pulsatile GH secretion, at least in part, by enhancing the release and/or action of hypothalamic GHRH.

This work was supported, in part, by General Clinical Research Center Grants MO1 RR00847 and RR00585 to the University of Virginia and Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD); and Clinical Associate Physician Award (to S.M.A.) and Grant R01 NIA AG 14799-06 (to J.D.V.) from the National Institutes of Health (Bethesda, MD).

Abbreviations: CI, Confidence interval; CV, coefficient of variation; GHRP, GH-releasing peptide; rh, recombinant human.

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