Clinical studies with human growth hormone releasing factor in normal adults and patients

Abstract The recent availability of human growth hormone releasing factor (hGRF) encouraged thorough investigations of human growth hormone secretion. Moreover it is now possible to put forward a therapeutic application for this hormone. Herein, we report the dose-effect relationship obtained between hGRF and GH response in normal young men submitted to IV administration of doses ranging from 2.5 to 600 μg per subject, in three protocols. In some subjects the 2.5 μg dose elicited GH secretion as compared with placebo. A highly significant dose-effect was observed (based on GH-AUC and GH-peak) for doses ranging from 5 to 80 μg. Responses were identical above 80 μg. We conclude that the optimal dose required to elicit maximum GH release with minimal unwanted effects is 80 μg in adults. These are related to the dose and observed for doses up to 80–150 μg. Subcutaneous administration also induced GH-release, with relationship to the doses used (100, 300 and 600 μg per subject). The mean response to the highest dose (600 μg) was comparable in timing and magnitude to that obtained with a 100 μg intravenous dose. Bioactivity of GH released under hGRF was proven in the Nb2 lymphoma cell multiplication assay and a high correlation was obtained between bioassay and radioimmunoassay. GH was present in blood after hGRF under 3 molecular forms corresponding to little, big and big-big GH with percentages of 50, 30 and 20, respectively. An early and slight increase in prolactin was found to be related to the hGRF doses above 80 μg. No change was observed for doses less than 80 μg. Pharmacokinetic parameters were calculated from the IR-GRF concentrations obtained in the IV protocols. The half-life of distribution phase was 6.8±0.4 min and of the elimination phase was 43±2.98 min. Comparison of IR-GRF concentrations after IV and SC administration showed a massive loss of hGRF between SC space and plasma. The time required for IR-hGRF to disappear from the plasma was not greatly different from one route to another. When hGRF was associated with other hypothalamic hormones and the responses to separate and combined administration were compared, FSH, LH, cortisol and GH were comparably stimulated while TSH and prolactin responded significantly more to combined than separate administration. In adults presenting GH deficiency, idiopathic or secondary to hypothalamic tumors, IV administration of hGRF (1 μg/kg) induced GH responses which were always lower than in normal subjects. The older the patient and the longer the post-operative period, the lower the response. Short-term repeated IV or SC administrations of hGRF did not modify the magnitude of the GH responses and, in responders, induced a rise in Sm-C levels. IR-GRF basal concentrations determined in 45 acromegalic patients, were abnormal only in 3 cases with proven GRF-secreting tumors. Responses to IV 100 μg hGRF in acromegalic patients were highly variable without correlation with basal GH levels nor with functional aspects of their GH-secreting pituitary adenomas.