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Activation of Somatostatin-Receptor Subtype-2/-5 Suppresses the Mass, Frequency, and Irregularity of Growth Hormone (GH)-Releasing Peptide-2-Stimulated GH Secretion in Men

Endocrine Service, Medical Section, Salem Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; Division of Endocrinology and Metabolism, Department of Internal Medicine, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699; and Endocrine Research Unit (J.D.V.), Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Endocrine Research Unit, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Somatostatin antagonizes the stimulatory actions of GHRH and GH-releasing peptides (GHRPs). However, precisely how the inhibitory susceptibilities of the two secretagogues differ is not clear. One interpretative difficulty is that native somatostatin activates six different receptor subtypes. The present study adopts the complementary strategy of enforcing feedback inhibition via the preferential somatostatin receptor subtype 2 and 5 (SSTR-2/-5) agonist, octreotide. We postulated that putative SSTR-2/-5 agonism would unmask secretagogue-selective interactions in the control of GH secretory burst mass, frequency, and/or regularity. To this end, 10 healthy men each underwent eight randomly ordered, separate-day, fasting morning infusion sessions. Interventions comprised sc administration of octreotide (1 µg/kg), followed by bolus iv injection of saline, GHRH (1 µg/kg), GHRP-2 (1 µg/kg), or both peptides. Compared with placebo, the SSTR-2/-5 agonist reduced fasting GH concentrations from 0.27 ± 0.07 to 0.12 ± 0.02 µg/liter (P = 0.020), GH secretory burst mass from 2.7 ± 0.65 to 0.55 ± 0.11 µg/liter (P = 0.013), and basal GH secretion from 0.24 ± 0.043 to 0.11 ± 0.015 µg/liter·100 min (P = 0.0063). The foregoing outcomes were selective, because octreotide did not alter GH secretory burst frequency (3.1 ± 0.5 vs. 3.3 ± 0.21 events/3 h) or the regularity of the GH release process (approximate entropy, 0.58 ± 0.048 vs. 0.68 ± 0.064). In the GHRP-2-stimulated setting, presumptive SSTR-2/-5 agonism suppressed all three GH secretory burst masses, from 28 ± 3.2 to 18 ± 2.0 (P = 0.045); GH pulse frequency, from 3.3 ± 0.30 to 2.0 ± 0.18 (P = 0.0025); and the irregularity (approximate entropy) of GH release, from 0.648 ± 0.049 to 0.433 ± 0.047 (P < 0.01). In contrast, in the GHRH and combined GHRH/GHRP-2-stimulated contexts, octreotide decreased only GH secretory burst mass (P = 0.047). In summary, the present data indicate that GH secretory burst mass, frequency, and orderliness are subject to interactive control by at least SSTR-2/-5-dependent feedback and GHRP-dependent feedforward signals.

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