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Estradiol Supplementation Modulates Growth Hormone (GH) Secretory-Burst Waveform and Recombinant Human Insulin-Like Growth Factor-I-Enforced Suppression of Endogenously Driven GH Release in Postmenopausal Women

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, General Clinical Research Center, Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22908; Department of Internal Medicine (P.K.), Leiden University Medical Center, Leiden, The Netherlands; Endocrine Service (A.I.), Medical Section, Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Institute of Experimental Clinical Research (J.F., H.Ø.), Medical Research Laboratory, Aarhus University Hospital, Aarhus, Denmark DK-8000

Address all correspondence and requests for reprints to: J. 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.

The present study tests the mechanistic postulate that estrogen confers resistance to negative feedback by systemic IGF-I. To this end, eight postmenopausal women received a constant iv infusion of recombinant human (rh)IGF-I (10 µg/kg·h x 6 h) and saline in randomized order on the 10th day of supplementation with oral estradiol (E₂) and placebo (Pl). GH secretion was quantitated by 10-min blood sampling, immunochemiluminometry assay, and deconvolution analysis. Administration of E₂ compared with Pl followed by saline infusion: 1) stimulated pulsatile GH secretion (µg/liter·6 h), viz., 12 ± 3.3 (Pl) and 18 ± 4.6 (E₂) (mean ± SEM, paired comparison, P < 0.05); 2) halved the time latency (min) to achieve peak GH secretion after GHRH injection, 24 ± 2.2 (Pl) and 12 ± 2.1 (E₂) (P < 0.01); and 3) did not alter the mass of GH secreted (µg/liter) in response to a maximally effective dose of GHRH, 30 ± 7.2 (Pl) and 37 ± 11 (E₂). Exposure to E₂ compared with Pl followed by rhIGF-I infusion: 1) accelerated the rate of decline of GH concentrations by 3.3-fold, viz., absolute slope (µg/liter·1000 min), 3.8 (range, 2.5–5.0) (Pl) and 12 (range, 10–14) (E₂) (P < 0.001); 2) augmented the algebraic decrement in GH concentrations (µg/liter) enforced by rhIGF-I infusion, 0.73 ± 0.21 (Pl) and 1.6 ± 0.25 (E₂) (P < 0.01); 3) halved the time delay (min) to peak GHRH-induced GH secretion, 20 ± 1.2 (Pl) vs. 10 ± 1.3 (E₂) min (P < 0.01). In contradistinction, E₂ did not alter: 1) the capability of rhIGF-I to suppress GHRH-stimulated GH secretory burst mass significantly, viz., by 50 ± 8% (Pl) and 52 ± 14% (E₂) (P < 0.05 each vs. saline); 2) the hourly rate of rise of infused (total) IGF-I concentrations; and 3) total and ultrafiltratably free IGF-I concentrations (µg/liter) attained at the end of the two rhIGF-I infusions.

In summary, compared with Pl, E₂ supplementation in postmenopausal women: 1) amplifies endogenously driven GH secretory-burst mass; 2) initiates rapid onset of GHRH-stimulated GH release; and 3) potentiates IGF-I-dependent suppression of unstimulated GH concentrations. Based upon companion modeling data, we postulate that E₂ facilitates the upstroke and IGF-I enforces the downstroke of high-amplitude GH secretory bursts in estrogen-replete individuals.

This work was supported, in part, by Grants MO1 RR00847, a Clinical Associate Physician Award, and RR00585 to the GCRCs of the University of Virginia and Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD); R01 NIA AG 14799 and K01 NIA AG 19164 from the National Institutes of Health (Bethesda, MD); and the Hørslev Foundation, Danish Health Research Council (Grant 22020141) and Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration.

Abbreviations: CI, Confidence interval; CV, coefficient of variation; E₂, estradiol; GCRC, General Clinical Research Center; Pl, placebo; PRL, prolactin; rh, recombinant human.

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