ABSENCE OF GROWTH-HORMONE (GH) SECRETION AFTER THE ADMINISTRATION OF EITHER GH-RELEASING HORMONE (GHRH), GH-RELEASING PEPTIDE (GHRP-6), OR GHRH PLUS GHRP-6 IN CHILDREN WITH NEONATAL PITUITARY-STALK TRANSECTION

GH-releasing peptide (GHRP-6; His-D-Trp-Ala-Trp-D-Phe-Lys-NH2) is a synthetic compound that releases GH in a specific and dose-related manner through mechanisms and a point of action that are mostly unknown, but different from those of GHRH. In man, GHRP-6 is more efficacious than GHRH, and a striking synergistic action occurs when both compounds are administered together. To explain such a synergistic effect, it has been postulated, but not proven, that GHRP-6 acts through a double mechanism, with actions exerted at the pituitary and the hypothalamic level. On the other hand, patients with the syndrome of GH deficiency due to perinatal pituitary stalk transection have any hypothalamic factor nonoperandi. The aim of the present study was S-fold: 1) to further understand how relevant, if at all, the hypothalamic action of GHRP-6 is for GH regulation; 2) to evaluate whether GHRP-6 plus GHRH could be a suitable diagnostic tool in children with pituitary stalk transection; and 3) to compare these results with similar published studies performed in patients with hypothalamo-pituitary disconnection, who developed the disease as adults. Seven patients with GH deficiency and different degrees of panhypopituitarism due to perinatal pituitary stalk transection and 7 age- and sex-matched normal controls were studied. The subjects underwent 3 different tests on separate occasions, being challenged with GHRH (1 mu g/kg, iv), GHRP-6 (1 mu/kg, iv), or GHRH plus GHRP-6. GH was analyzed as the area under the curve (mean +/- SE; micrograms per L/90 min). In normal subjects, GH secretion was 1029 +/- 202 after GHRH treatment, 1221 +/- 345 after GHRP-6, and 3542 +/- 650 after GHRH plus GHRP-6; the latter value was significantly (P<0.05) higher than the secretion elicited by GHRH or GHRP-6 alone. In the group of patients with perinatal pituitary stalk transection, the level of GH after GHRH treatment was 116 +/- 22 and was even more reduced (P<0.05) after GHRP-6 treatment (37 +/- 8). After GHRH plus GKRP-6, GH secretion in those patients was 177 +/- 27, significantly higher (P<0.05) than the secretion induced by either GHRH or GKRP-6 alone. Individually examined, none of the patients tested with the most potent stimulus known to date (GHRH plus GHRP-6) exhibited GH secretion greater than 5 mu g/L. As pointed out by GHRH action and in divergence with the situation observed in patients with hypothalamo-pituitary disconnection as adults, the somatotroph population is severely reduced or unresponsive to stimuli. Regarding the regulation of GH secretion, these results indicate that 1) the main action of GHRP-6 as well as its synergistic action on GHRH seem to be exerted at hypothalamic level; 2) when the pituitary is deprived of the hypothalamic regulation in the perinatal period, a reduced number or function of somatotrophs ensues, which is not observed when this deprivation happens in adulthood; and 3) GHRH plus GHRP-6 may be a suitable, cheap, and side effect-free test for screening patients with GH deficiency.