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E2 Supplementation Selectively Relieves GH’s Autonegative Feedback on GH-Releasing Peptide-2-Stimulated GH Secretion

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

Address all correspondence and requests for reprints to: S. M. Anderson, M.D., Division of Endocrinology, Department of Internal Medicine, Box 800-746, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0746. E-mail: sg4c{at}virginia.edu

Abstract

Female gender confers resistance to GH autonegative feedback in the adult rat, thereby suggesting gonadal or estrogenic modulation of autoregulation of the somatotropic axis. Here we test the clinical hypothesis that short-term E2 replacement in ovariprival women reduces GH’s repression of spontaneous, GHRH-, and GH-releasing peptide (GHRP)-stimulated GH secretion. To this end, we appraised GH autoinhibition in nine healthy postmenopausal volunteers during a prospective, randomly ordered supplementation with placebo vs. E [1 mg micronized 17ß-E2 orally twice daily for 6–23 d]. The GH autofeedback paradigm consisted of a 6-min pulsed iv infusion of recombinant human GH (10 µg/kg square-wave injection) or saline (control) followed by iv bolus GHRH (1 µg/kg), GHRP-2 (1 µg/kg), or saline 2 h later. Blood was sampled every 10 min and serum GH concentrations were measured by chemiluminescence. Poststimulus GH release was quantitated by multiparameter deconvolution analysis using published biexponential kinetics and by the incremental peak serum GH concentration response (maximal poststimulus value minus prepeak nadir). Outcomes were analyzed on the logarithmic scale by mixed-effects ANOVA at a multiple-comparison type I error rate of 0.05. E2 supplementation increased the (mean ± SEM) serum E2 concentration from 43 ± 1.8 (control) to 121 ± 4 pg/ml (E2) (158 ± 6.6 to 440 ± 15 pmol/liter; P < 0.001), lowered the 0800 h (preinfusion) serum IGF-I concentration from 127 ± 7.7 to 73 ± 3.6 µg/liter (P < 0.01), and amplified spontaneous pulsatile GH production from 7.5 ± 1.1 to 13 ± 2.3 µg/liter per 6 h (P = 0.020). In the absence of exogenously imposed GH autofeedback, E2 replacement enhanced the stimulatory effect of GHRP-2 on incremental peak GH release by 1.58-fold [95% confidence interval, 1.2- to 2.1-fold] (P = 0.0034) but did not alter the action of GHRH (0.83-fold [0.62- to 1.1-fold]). In the E2-deficient state, bolus GH infusion significantly inhibited subsequent spontaneous, GHRH-, and GHRP-induced incremental peak GH responses by, respectively, 33% (1–55%; P = 0.044 vs. saline), 79% (68–86%; P < 0.0001), and 54% (32–69%; P = 0.0002). E2 repletion failed to influence GH autofeedback on either spontaneous or GHRH-stimulated incremental peak GH output. In contrast, E2 replenishment augmented the GHRP-2-stimulated incremental peak GH response in the face of GH autoinhibition by 1.7-fold (1.2- to 2.5-fold; P = 0.009). Mechanistically, the latter effect of E2 mirrored its enhancement of GH-repressed/GHRP-2-stimulated GH secretory pulse mass, which rose by 1.5-fold (0.95- to 2.5-fold over placebo; P = 0.078). In summary, the present clinical investigation documents the ability of short-term oral E2 supplementation in postmenopausal women to selectively rescue GHRP-2 (but not spontaneous or GHRH)-stimulated GH secretion from autonegative feedback. The secretagogue specificity of E’s relief of GH autoinhibition suggests that this sex steroid may enhance activity of the hypothalamopituitary GHRP-receptor/effector pathway.

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