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Dual Effects of Growth Hormone (GH)-Releasing Hormone Isfusion in Normal Men: Somatotroph Desensitization and Increase in Releasable GH^*

Department of Internal Medicine, University of Virginia School of Medicine Charlottesville, Virginia 2290
Clayton Foundation Laboratories for Peptide Biology, Salk Institue San Diego, California 92138-9216

Address all correspondence and requests for reprints to: Dr. Mary Lee Vance, Box 511, University of Virginia, Medical Center, Charlottesville, Virginia 22908.

Continuous infusion of human GH-releasing hormone (GHRH) stimulates GH secretion in normal subjects, but a single supramaximal iv dose of GHRH thereafter elecits a diminished serum GH response compared to that after a saline infusion; the response to the single dose challenge is inversely related to the dose of GHRH previously infused. To determine if this attenuated GH response is a result of depletion of available GH or desensitization of the somatotroph, a 6-h infusion of saline or GHRH (10 ng/kg-min) was administered to 10 normal men, and an iv bolus dose of either GHRH (3.3 µg/kg) or regular insulin (0.15 U/kg) was given after 5.5 h of infusion. On both days of GHRH infusion, there was significant stimulation of GH secretion compared to that after saline infusion. The GH response to the supramaximal dose of GHRH was greater after saline infusion than after GHRH infusion, and the GH response to insulin-induced hypoglycemia was significantly greater after GHRH infusion compared with the responses on the other 3 study days. The greatest GH secretion occurred during GHRH infusion followed by insulin administration; therefore, pituitary reserve was not decreased by prior exposure to GHRH. These studies suggest that somatotrophs become partially refractory to GHRH stimulation over time, but remain responsive to an alternate stimulus of GH secretion. We suggest that the hypoglycemia- induced GH response occurs via a reduction in hypothalamic somatostatin secretion, and the attenuated GH response to the supramaximal GHRH dose after GHRH infusion probably represents either partial desensitization or down-regulation of the GHRH receptor.

^* This work supported by USPHS Grants 1-R23-HD-17120 (to M.L.V.), AM-32632 (to M.O.T.), and AM-26741, AM-20917, AA-03504, and HD-13527 (to Clayton Foundation Laboratories for Peptide Biology). This research project took place at the University of Virginia General Clinical Research Center (RR-00847), and data handling and analysis were made possible by use of CLINFO.

Received April 24, 1985.

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