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Impaired Inhibitory Effects of Somatostatin on Growth Hormone (GH)-Releasing Hormone Stimulation of GH Secretion after Short Term Infusion^*

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Lawrence A. Frohman, M.D., Division of Endocrinology and Metabolism, University of Cincinnati Medical Center, 231 Bethesda Avenue, ML 547, Cincinnati, Ohio 45267.

We examined the effect of prior exposure to somatostatin (SRIH) on its inhibition of GH and TSH responses to GHRH and TRH stimulation to determine whether SRIH desensitization has physiological significance in man. Six men received GHRH (1 µg/kg, iv) and TRH (0.3 µg/kg, iv) 20 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion and again 6 h later. Hormone responses were quantified by measuring the area under the curve, corrected for GH concentration at injection time. Similar results were obtained when GH responses were quantified by measuring the hormone secretory rate using the program Detect. Plasma GH and TSH responses to the two GHRH and TRH injections during saline were similar. However, the effects of prior exposure to SRIH were hormone specific. SRIH blunted GH responses to GHRH at 20 min (1609 ± 286 µg/L·min vs. 451 ± 224), but did not significantly inhibit the responses 6 h later (1422 ± 410 µg/L·min vs. 1000 ± 302). In contrast, SRIH inhibition of TSH responses to the two TRH injections was similar (first, 946 ± 201 µg/L·min vs. 700 ± 148; second, 813 ± 175 µg/L·min vs. 562 ± 66). We next used these results to study whether the previously reported attenuation of GH responses to repeated GHRH stimulation at 2-h intervals is mediated by SRIH. Eight men received GHRH (1 µg/kg, iv) 380 min after starting a saline or SRIH (5.5 ng/kg/min, iv) infusion or 90 min after starting a primed (5 mg, iv) infusion of propranolol (80 µg/min, iv) and again 2 h later. As in the first protocol, GH responses to GHRH were not inhibited when preceded by a 6-h SRIH infusion. However, the 6-h SRIH infusion resulted in a partial restoration of plasma GH responses to the second GHRH injection (saline infusion: first, 1429 ± 342 µg/L·min; second, 254 ± 75; SRIH infusion: first, 1042 ± 247 µg/L·min; second, 468 ± 105). β-Blockade by propranolol resulted in enhanced GH responses to GHRH, but did not prevent the attenuation of GH responses to the second GHRH injection (first, 1937 ± 366 µg/L·min; second, 614 ± 99). The desensitization to SRIH inhibition of GH responses to GHRH after a 6-h SRIH infusion provides evidence of physiological consequences of SRIH receptor down-regulation. The impaired GH responses to repeated GHRH stimulation are mediated at least in part by enhanced SRIH secretion, which appears independent of a β-adrenergic mechanism.

^* This work was supported in part by USPHS Grants DK-30667 and RR-00068 and a grant from Genentech, Inc.

Received August 21, 1989.

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