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Short-Term Estradiol Supplementation Augments Growth Hormone (GH) Secretory Responsiveness to Dose-Varying GH-Releasing Peptide Infusions in Healthy Postmenopausal Women¹

Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia Health Sciences Center (S.M.A., N.S., W.S.E., J.T.P., J.D.V.), Charlottesville, Virginia 22908; and Division of Endocrinology and Metabolism, Department of Internal Medicine, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Dr. S. M. Anderson, Division of Endocrinology, Department of Internal Medicine, Box 800-202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0746. E-mail: sg4c{at}virginia.edu

Estrogen is a prominent stimulus to GH secretion throughout the human life span, albeit via neuroendocrine mechanisms that are incompletely defined. Here, we test the hypothesis that estradiol replacement in postmenopausal women enhances the responsiveness of the hypothalamo-pituitary unit to the GH-releasing effect of GH-releasing peptide-2 (GHRP-2). GHRP-2 is a potent and selective synthetic hexapeptide capable of activating an endogenous GHRP receptor/effector pathway, for which a ³Ser-octanoylated 28-amino acid ligand was cloned recently. To examine this postulate, we studied 10 healthy estrogen-withdrawn postmenopausal women, who were given oral placebo or estrogen supplementation [1 mg micronized 17ß-estradiol (E₂) twice daily for 7–15 days] in a patient-blinded, prospective, randomized, and within-subject cross-over design. The GH-releasing actions of five semilogarithmically increasing doses of GHRP-2 (absolute range, 0.03–3 µg/kg by bolus iv infusion) vs. saline were evaluated by frequent blood sampling on separate days in the morning while fasting. Serum GH concentrations were determined in blood sampled every 10 min using an ultrasensitive chemiluminescence assay and analyzed by multiparameter deconvolution to calculate the summed mass of GH secreted during the 2-h interval after bolus GHRP-2 infusion. Logarithmically transformed secretory responses were compared across the different dosages of infused GHRP-2 by two-way repeated measures ANOVA. Estradiol replacement increased the global mean (±SEM) serum E₂ concentration from 15 ± 0.8 to 470 ± 17 pg/mL (55 ± 2.9 to 1725 ± 62 pmol/L; P = 0.004) and lowered insulin-like growth factor I levels by approximately 27% (P = 0.087). Administration of E₂ elevated the geometric mean basal (saline-infused) GH secretory burst mass by 2.1-fold (95% confidence interval, 1.4- to 3.1-fold) compared with placebo ingestion (geometric mean ratios; P < 0.001). E₂ exposure enhanced the efficacy of the highest GHRP-2 dose tested (3 µg/kg) by 2.1-fold (1.3- to 3.3-fold; P = 0.010). Compared with the effect of placebo and saline, E₂ combined with the highest dose of GHRP-2 stimulated GH secretory burst mass by a total of 31-fold (24- to 41-fold; P < 0.001). Random coefficient regression analysis of the relationship between the logarithm of GHRP-2 dose and GH secretory burst mass revealed that E₂ significantly augmented the amount of GH secreted per unit GHRP-2 dose (E₂, 16.6 ± 1.8 slope units; placebo, 10.1 ± 1.4 slope units; P = 0.03). Although the global mean endogenous GH half-life did not differ between the E₂ and placebo sessions (E₂, 18 ± 0.6 min; placebo, 17 ± 0.5 min), GH half-life varied directly with dose of GHRP-2 (and, hence, the mean serum GH concentration) in both the E₂ and placebo sessions (test of zero slope hypothesis, P = 0.0018). The deconvolved GH secretory burst peaked within 8–13 min of the bolus iv injection of GHRP-2, and this latency was not altered by E₂. Based on a mixed effects analysis of covariance model, GHRP-2 dose and E₂, but not the plasma insulin-like growth factor I concentration, determined the magnitude of the GH secretory response (P < 0.001).

We conclude that short-term oral E₂ repletion in postmenopausal women selectively augments GH secretory pulse mass, enhances the steepness of the GHRP-2 dose-GH secretory response relationship (greater sensitivity), and heightens the maximal GH secretory response to the highest dose of GHRP-2 tested (greater efficacy). These data point to a facilitative interaction between E₂ and the GHRP receptor/effector pathway in driving the mass of GH secreted per burst.

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