This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shah, N. Articles by Veldhuis, J. D. Search for Related Content PubMed PubMed Citation Articles by Shah, N. Articles by Veldhuis, J. D.

Oral Estradiol Administration Modulates Continuous Intravenous Growth Hormone (GH)-Releasing Peptide-2-Driven GH Secretion in Postmenopausal Women¹

Division of Endocrinology, Department of Internal Medicine (N.S., W.S.E., J.D.V.), General Clinical Research Center, National Science Foundation Center for Biological Timing, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202; and Division of Endocrinology and Metabolism, Department of Internal Medicine (C.Y.B.), Tulane University Medical Center, New Orleans, Louisiana 70112-2699

Address correspondence and requests for reprints to: J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: JDV{at}Virginia.Edu

Exactly how estradiol (E₂) regulates the human GH-insulin-like growth factor I axis is not known. Here, we explore the impact of oral E₂ supplementation on the stimulatory actions of a potent and specific synthetic GH-releasing peptide (GHRP), GHRP-2. To this end, we studied 10 healthy postmenopausal women following the administration of placebo or 17ß-estradiol (1 mg twice daily orally) for 7–12 days in a prospectively randomized, double-blind, within-subject crossover design. To drive GH secretion via the GHRP-receptor/effector pathway, we infused GHRP-2 (1 µg/kg·h) or saline continuously iv for 24 h. Deconvolution analysis was used to quantitate the separate basal and pulsatile modes of GH secretion based on 24-h serum GH concentrations profiles collected at 10-min intervals and assayed by chemiluminescence. As complementary (nonpulsatile) measures, we used the approximate entropy (ApEn) statistic and cosine regression to define feedback-dependent and circadian-related changes, respectively. E₂ administration amplified the mass of GH secreted per burst by 1.9-fold over placebo, 24-h GHRP-2 infusion by 7.0-fold, and, the two agonists together by 8.8-fold (P < 10^-14). Intravenous GHRP-2 infusion augmented the basal (nonpulsatile) rate of GH secretion by 4.4-fold (P < 10^-4). E₂ treatment had no effect alone, but doubled the stimulatory effect of GHRP-2, on basal GH secretion. Neither E₂ nor GHRP-2 influenced 24-h GH pulse frequency, interburst interval, half-life or pulse duration. Combined E₂ and GHRP-2 elevated the ApEn of GH secretory profiles significantly above control, thereby indicating a marked alteration of within-axis feedback control (P = 0.00033). Dual stimulation with E₂ and GHRP-2 also synergistically increased the amplitude (by 11-fold, P < 10^-11) and the mesor (by 10-fold, P < 10^-10) of the 24-h GH rhythm. Infusion of GHRP-2 advanced the GH acrophase (time of daily maximum of GH release) by 8.75 h, whereas combined treatment with E₂ and GHRP-2 normalized the acrophase. Cross-correlation analysis showed that GHRP-2 infusion (but not E₂ administration) significantly synchronized paired 24-h serum GH concentration profiles (P < 10^-3).

In summary, short-term oral E₂ replacement in post-menopausal women strongly modulates the actions of a synthetic hexapeptide GH secretagogue on three quantifiable modes of GH secretion [i.e. 1) basal (nonpulsatile) GH release; 2) feedback-dependent ApEn; and 3) the mesor, amplitude and timing of the 24-h GH rhythm]. Moreover, a continuous GHRP-2 stimulus also synchronizes inter diem GH secretory patterns. The present pharmacological study, thus, offers a further framework for exploring the nature of the interactions of E₂ with the GHRP-receptor/effector pathway in the aging and/or gonadoprival human.

This article has been cited by other articles:

				L. S. Farhy, C. Y. Bowers, and J. D. Veldhuis Model-projected mechanistic bases for sex differences in growth hormone regulation in humans Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1577 - R1593. [Abstract] [Full Text] [PDF]

				J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood. Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99. [Abstract] [Full Text] [PDF]

				C. Soares-Welch, L. Farhy, K. L. Mielke, F. H. Mahmud, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2225 - 2232. [Abstract] [Full Text] [PDF]

				A. Iranmanesh, C. Y. Bowers, and J. D. Veldhuis Activation of Somatostatin-Receptor Subtype-2/-5 Suppresses the Mass, Frequency, and Irregularity of Growth Hormone (GH)-Releasing Peptide-2-Stimulated GH Secretion in Men J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4581 - 4587. [Abstract] [Full Text] [PDF]

				D. Erickson, D. M. Keenan, K. Mielke, K. Bradford, C. Y. Bowers, J. M. Miles, and J. D. Veldhuis Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Postmenopausal Compared with Premenopausal Women Studied under an Experimental Estradiol Clamp J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4746 - 4754. [Abstract] [Full Text] [PDF]

				C. Y. Bowers, R. Granda, S. Mohan, J. Kuipers, D. Baylink, and J. D. Veldhuis Sustained Elevation of Pulsatile Growth Hormone (GH) Secretion and Insulin-Like Growth Factor I (IGF-I), IGF-Binding Protein-3 (IGFBP-3), and IGFBP-5 Concentrations during 30-Day Continuous Subcutaneous Infusion of GH-Releasing Peptide-2 in Older Men and Women J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2290 - 2300. [Abstract] [Full Text] [PDF]

				F. Broglio, A. Benso, C. Castiglioni, C. Gottero, F. Prodam, S. Destefanis, C. Gauna, A. J. van der Lely, R. Deghenghi, M. Bo, et al. The Endocrine Response to Ghrelin as a Function of Gender in Humans in Young and Elderly Subjects J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1537 - 1542. [Abstract] [Full Text] [PDF]

				M. Gasperi, E. Cecconi, L. Grasso, L. Bartalena, R. Centoni, G. Aimaretti, F. Broglio, P. Miccoli, C. Marcocci, E. Ghigo, et al. GH Secretion Is Impaired in Patients with Primary Hyperparathyroidism J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 1961 - 1964. [Abstract] [Full Text] [PDF]

				A. Gentili, T. Mulligan, M. Godschalk, J. Clore, J. Patrie, A. Iranmanesh, and J. D. Veldhuis Unequal Impact of Short-Term Testosterone Repletion on the Somatotropic Axis of Young and Older Men J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 825 - 834. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, W. S. Evans, and C. Y. Bowers Impact of Estradiol Supplementation on Dual Peptidyl Drive of GH Secretion in Postmenopausal Women J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 859 - 866. [Abstract] [Full Text] [PDF]

				S. M. Anderson, L. Wideman, J. T. Patrie, A. Weltman, C. Y. Bowers, and J. D. Veldhuis E2 Supplementation Selectively Relieves GH's Autonegative Feedback on GH-Releasing Peptide-2-Stimulated GH Secretion J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5904 - 5911. [Abstract] [Full Text] [PDF]

				M. J. Bray, T. M. Vick, N. Shah, S. M. Anderson, L. W. Rice, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin's Dose-Dependent Inhibition of Fasting Growth Hormone Secretion J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3143 - 3149. [Abstract] [Full Text] [PDF]

				W. S. Evans, S. M. Anderson, L. T. Hull, P. P. Azimi, C. Y. Bowers, and J. D. Veldhuis Continuous 24-Hour Intravenous Infusion of Recombinant Human Growth Hormone (GH)-Releasing Hormone-(1-44)-Amide Augments Pulsatile, Entropic, and Daily Rhythmic GH Secretion in Postmenopausal Women Equally in the Estrogen-Withdrawn and Estrogen-Supplemented States J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 700 - 712. [Abstract] [Full Text]