Evaluation of hypothalamic dysfunction in growth hormone (GH)-deficient patients using single versus multiple doses of GH-releasing hormone (GHRH-44) and evidence for diurnal variation in somatotroph responsiveness to GHRH in GH-deficient patients.

To examine the efficacy of multiple doses of GHRH-44 to enhance GH secretion and to determine the number of GHRH-44 doses required to exclude hypothalamic dysfunction, 12 doses of GHRH-44 were administered iv every 2 h to 4 GH-deficient patients beginning in the morning (group A) and to 4 GH-deficient patients beginning in the evening (group B). Five additional GH-deficient patients (group C) were given 4-18 GHRH-44 doses. The first and last doses were 5 micrograms/kg; all others were 1 microgram/kg. Higher GH responses were attained by 9 of the 13 patients after multiple GHRH-44 doses than after the initial GHRH-44 dose. After the first GHRH-44 dose, the peak plasma GH concentrations were less than 7 micrograms/L in 9 patients; 4 of 9 achieved GH concentrations above 7 micrograms/L after 5-7 GHRH-44 doses; 2 had measurable levels below 7 micrograms/L. GH concentrations remained undetectable in 3 older patients in group C. In the patients who had detectable GH levels after GHRH-44 treatment, serum somatomedin-C concentrations increased from 0.67 +/- 0.14 (+/- SEM) to 0.79 +/- 0.14 U/mL after 6 GHRH-44 doses (P less than 0.01; n = 10) then to 1.00 +/- 0.14 (+/- SEM) U/mL after an additional 4-6 GHRH-44 doses (P less than 0.05; n = 9). After 6 GHRH-44 doses in groups A and B, the integrated GH concentrations between 2000 and 0800 h were greater than the integrated GH concentrations between 0800 and 2000 h (P less than 0.02). These findings indicate that a hypothalamic defect cannot be excluded on the basis of an impaired response to a single dose of GHRH-44, that the number of GHRH doses required to stimulate GH release in GH-deficient patients is variable, and that in addition to the possibility of genetically determined GHRH insensitivity some non-responding patients have developed severe acquired resistance to GHRH. Evidence for diurnal variation in the responsiveness of somatotropes to GHRH-44 in GH-deficient patients was also found.