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Accelerated Escape from GH Autonegative Feedback in Midpuberty in Males: Evidence for Time-Delimited GH-Induced Somatostatinergic Outflow in Adolescent Boys

Division of Endocrinology and Metabolism (E.R., A.D.R., D.B., O.L.V., W.C., J.D.V.), Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; and Division of Endocrinology (C.Y.B.), Department of Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: J.D. Veldhuis, M.D., Endocrine Division, Mayo Clinic and Medical School, 200 First Street SW, Rochester, Minnesota 55905.

Abstract

A single injected pulse of GH inhibits the time-delayed secretion of GH in the adult by way of central mechanisms that drive somatostatin and repress GHRH outflow. The marked amplification of spontaneous GH pulse amplitude in puberty poses an autoregulatory paradox. We postulated that this disparity might reflect unique relief of GH-induced autonegative feedback during this window of development. The present study contrasts GH autonegative feedback in: 1) normal prepubertal boys (PP) (n = 6; Tanner genital stage I, chronologically aged 8 yr, 9 months to 10 yr, 1 month; median bone age 8.5 yr); 2) longitudinally identified midpubertal boys (MP) (n = 6; Tanner genital stages III/IV, aged 12 yr, 6 months to 15 yr, 6 months; median bone age 15 yr); and 3) healthy young men (YM) (n = 6, aged 18–24 yr; bone age >18 yr). Subjects each underwent four randomly ordered tandem peptide infusions on separate mornings while fasting: i.e. 1) saline/saline infused iv bolus at 0830 h and 1030 h; 2) saline/GHRH (0.3 µg/kg iv bolus) at the foregoing times; 3) recombinant human (rh) GH (3 µg/kg as a 6-min square-wave iv pulse)/saline; and 4) rhGH and GHRH. To monitor GH autofeedback effects, blood samples were obtained every 10 min for 5.5 h beginning at 0800 h (30 min before GH or saline infusion). Serum GH concentrations were quantitated by ultrasensitive chemiluminometry (threshold 0.005 µg/liter). On the day of successive saline/saline infusion, MP boys maintained higher serum concentrations of: 1) GH (µg/liter), 2.2 ± 0.25, compared with PP (0.61 ± 0.10) or YM (0.88 ± 0.36) (P = 0.011); 2) IGF-I (µg/liter), 493 ± 49 vs. PP (134 ± 16) and YM (242 ± 22) (P < 0.001); 3) T (ng/dl), 524 ± 58 vs. PP (<20) (P < 0.001); and 4) E2 (pg/ml),19 ± 3 vs. PP (< 10) (P = 0.030) (mean ± SEM). Consecutive saline/GHRH infusion elicited comparable peak (absolute maximal) serum GH concentrations (micrograms per liter) in the three study groups, i.e. 18 ± 5.0 (PP), 9.6 ± 1.7 (MP), and 14 ± 5.3 (YM) (each P < 0.01 vs. saline; P = NS cohort effect). Injection of rhGH attenuated subsequent GHRH-stimulated peak serum GH concentrations (micrograms per liter) to 7.8 ± 1.9 (PP), 5.8 ± 1.2 (MP), and 4.8 ± 1.1 (YM) (each P < 0.01 vs. saline; P = NS pubertal effect). GH autofeedback reduced non-GHRH-stimulated (basal) serum GH concentrations by 0.74 ± 0.28 (PP), 5.7 ± 1.7 (MP) and 1.4 ± 0.27 (YM) fold, compared with saline (P = 0.016 for MP vs. PP or YM). In addition to greater fractional autoinhibition, MP boys exhibited markedly accentuated postnadir escape (4.6-fold steeper slope) of suppressed GH concentrations (P < 0.001 vs. PP or YM). Linear regression analysis of data from all 18 subjects revealed that the fasting IGF-I concentration negatively predicted fold-autoinhibition of GHRH-stimulated peak GH release (r = -0.847, P = 0.006) and positively forecast fold-autoinhibition of basal GH release (r = +0.869, P < 0.001). In contrast, the kinetics of rhGH did not differ among the three study cohorts. In summary, boys in midpuberty manifest equivalent responsiveness to exogenous GHRH-stimulated GH secretion; heightened susceptibility to rhGH-induced fractional inhibition of endogenous secretagogue-driven GH release, compared with the prepubertal or adult male; and accelerated recovery of GH output after acute autonegative feedback. This novel tripartite mechanism could engender recurrent high-amplitude GH secretory bursts that mark sex hormone-dependent activation of the human somatotropic axis.

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