Low dose hexarelin and growth hormone (GH)-releasing hormone as a diagnostic tool for the diagnosis of GH deficiency in adults: Comparison with insulin-induced hypoglycemia test

GH deficiency (GHD) in adults must be shown by provocative testing of GH secretion. Insulin-induced hypoglycemia (ITT) is the test of choice, and severe GHD, treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 μg/L. GHRH plus arginine (ARG) is a more provocative test and is as sensitive as ITT provided that appropriate cut-off limits are assumed. GH secretagogues are a family of peptidyl and nonpeptidyl GH-releasing molecules that strongly stimulate GH secretion and, even at low doses, truly synergize with GHRH. Our aim was to verify the diagnostic reliability of the hexarelin (HEX; 0.25 μg/kg, iv) and GHRH (1 μg/kg, iv) test for the diagnosis of adult GHD. To this goal, in the present study we 1) defined the normal ranges of the GH response to GHRH + HEX in a group of normal young adult volunteers (NS; n = 25; 18 men and 7 women; age, 28.5 ± 0.6 yr) and in 11 of them verified its reproducibility in a second session, and 2) compared the GH response to GHRH + HEX with that to ITT in a group of normal subjects (n = 33; 12 men and 21 women; age, 34.1 ± 1.5 yr) and hypopituitaric adults with GHD (n = 19; 10 men and 9 women; age, 39.9 ± 2.2 yr; GH peak < 5 μg/L after ITT). The GH response to GHRH + ARG was also evaluated in all GHD and in 77 normal subjects (40 men and 37 women; age, 28.1 ± 0.6 yr). The mean GH peak after GHRH + HEX in NS was 83.6 ± 4.5 μg/L; the third and first percentile limits of the normal GH response were 55.5 and 51.2 μg/L, respectively). The GH response to GHRH + HEX in NS showed good intraindividual reproducibility. In GHD the mean GH peak after GHRH + HEX (2.6 ± 0.7 μg/L) was similar to that after GHRH + ARG (3.6 ± 1.0 μg/L), and both were higher (P < 0.001) than that after ITT (0.6 ± 0.1 μg/L); the GH responses to GHRH + HEX were positively associated with those to ITT and GHRH + ARG. Analyzing individual GH responses, 100% had severe GHD after ITT (GH peak, < 3 μg/L). After GHRH + HEX all GHD had GH peaks below the third percentile limit of normality appropriate for this test (i.e. 55.5 μg/L). Thirteen of 19 (68.4%) GHD subjects had GH peaks below 3 μg/L after GHRH + HEX but all 19 (100%) had GH peaks below the first percentile limit of normality (i.e. 51.2 μg/L). The GH responses to GHRH + HEX were highly concordant with those after GHRH + ARG. In conclusion, the present results define normal limits of the GH response to stimulation with low dose HEX + GHRH in normal adults and show that this test is as sensitive as ITT for the diagnosis of adult GHD provided that appropriate cut-off limits are considered.