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Lack of in Vivo Somatotroph Desensitization or Depletion After 14 Days of Continuous Growth Hormone (GH)-Releasing Hormone Administration in Normal Men and a GH-Deficient Boy^*

Departments of Internal Medicine and Pediatrics, University of Virginia Medical Center (M.L.V., D.L.K., P.M.M., M.O.T.) Charlottesuille, Virginia 22908
the Department of Pediatrics, University of Pennsylvania (R.F.) Philadelphia, Pennsylvania 19104
The Clayton Foundation for Peptide Biology (J.R., W. V.), Salk Institute La Jolla, California 92138

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

In vitro and in vivo studies of somatotroph responsivity to GHRH stimulation indicate that partial loss of GH responsiveness occurs during constant GHRH stimulation. To determine if these observations reflect either a short term effect of GHRH or if the absence of somatostatin effects somatotroph desensitization (as occurred in in vitro studies), we administered GHRH-40 (10 ng/kg-min) by continuous iv infusion for 14 days to five normal men and one GH-deficient boy. Serum insulin-like growth factor I (IGF-I) concentrations were measured at frequent intervals to assess the biological effect of GHRH on GH secretion. The GH secretory profiles were assessed by measuring serum GH levels every 20 min for 24 h before (day 0), on the 14th GHRH infusion day, and 14 days after discontinuation of the GHRH infusion in the normal men. The GH-deficient boy was studied before and during the 14th GHRH infusion day. A supramaximal iv GHRH dose was administered at the end of the 24-h sampling period, and the GH responses were compared. Serum IGF-I concentrations increased on the 14th day of GHRH infusion in the normal men [day 0 mean, 0.84 ± 0.14 (±SE) x 10³; day 14, 1.74± 0.20 x 10³ U/L; P < 0.05] and from 0.20 x 10³ on day 0 to a maximum of 0.67 x10³ U/L on day 3 in the GH-deficient boy; they declined to pretreatment levels after discontinuation of GHRH. The mean integrated serum GH concentrations in the normal men were 1.44 ± 0.10 µg/L · h on day 0 and 3.11 ± 0.95 on day 14 of GHRH infusion. The integrated GH concentration in the GH-deficient boy was 1.53 ±g/L·h on day 0 and 4.23 on day 14 of GHRH infusion. Pulsatile GH secretion, assessed by cluster analysis, was preserved in the normal men and occurred de novo in the GH-deficient boy on the 14th GHRH infusion day. The GH response to bolus GHRH administration was also preserved; no attenuation of the response occurred in the normal men or the GH-deficient boy after 14 days of GHRH infusion. The increase in IGF-I concentrations during 14 days of continuous GHRH administration, the persistence of pulsatile GH release in normal men, the de novo appearance of GH pulses in the GH-deficient boy, and the preservation of the response to a supramaximal GHRH dose indicates that the somatotrophs remain responsive to prolonged constant stimulation. Thus, in vivo, constant GHRH infusion for 14 days does not cause somatotroph desensitization or depletion.

^* This work was supported by USPHS Grants RR-0847 (to GCRC); 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 C.F.L.P.B.).

Received June 30, 1988.

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