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Growth Hormone (GH) Secretion in Patients with an Inactivating Defect of the GH-Releasing Hormone (GHRH) Receptor Is Pulsatile: Evidence for a Role for Non-GHRH Inputs into the Generation of GH Pulses

Departments of Endocrinology and Metabolism (F.R., N.R.B., R.G.V.), Pediatrics (W.H.S.-B., J.-M.W.), and Clinical Chemistry (M.F.), Leiden University Medical Center, 2333AA Leiden, The Netherlands; Division of Endocrinology and Metabolism, National Science Foundation Center for Biological Timing, General Clinical Research Center (J.D.V.); and Department of Internal Medicine, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908

Abstract

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10–20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26–63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96–390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P < 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 µg GHRH failed to increase the plasma GH concentration in both patients, but 100 µg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning.

In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.

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