Metabolism and Effects of Synthetic Gonadotropin-Releasing Hormone (GnRH) in Children and Adults*

Abstract

To compare the metabolism and effects of synthetic GnRH (Parke-Davis CI-785) in children and adults, 24 children were given 10 μg GnRH/m2 iv; 5 adult male volunteers randomly received 1, 10, 25 and 100 μg GnRH/m2 iv at weekly intervals. Blood samples were withdrawn at frequent intervals during the 1 hr before and 4 hr after injection. GnRH concentrations were determined by a highly specific radioimmunoassay which utilizes Niswender antiserum #R-42 and 125I-GnRH purified by polyacrylamide disc gel electrophoresis. Sensitivity of this assay is 1 pg/tube or 5 pg/ml of unextracted plasma. Serum LH and FSH were determined by radioimmunoassay. No correlation was found between physiological state or serum gonadotropin concentrations, and endogenous GnRH values. Indeed, most plasma samples were at or below the sensitivity of the GnRH assay. Maximum GnRH concentrations occurred at +1 or +2 min and were significantly greater in children (4.02 ± 0.33 (se) ng/ml) than adults (2.05 ± 0.37 (se) ng/ml) given GnRH iv at 10 μg/m2. The plasma disappearance curve of GnRH in children and adults could be described by a double exponential function with an average distribution phase half-life of 2.5 min and a highly variable elimination phase half-life of approximately 20 min. Initial distribution volumes and plasma clearance rates were also similar: children 8.7 ± 0.8 (se) % body weight and 657 ± 42 (se) l/d/m2; adults 8.5 ± 2.2 (se) % body weight and 682 ± 44 (se) l/d/m2. In adults, plasma clearance decreased progressively with increasing doses of GnRH. Despite greater maximum concentrations of GnRH, prepubertal children had bluntedserum LH responses compared to adult males. Serum FSH responses were similar in prepubertal, pubertal and adult males, but greatly exaggerated responses were seen in some prepubertal females. Linear log dose-responses for LH and FSH were found between 1.0 and 100 μg/m2 doses of GnRH. Significant LH release occurred during all tests inadult males with only one exception at the 1.0 μg/m2 dose. Significant FSH release was not uniformly observed at any dose. These data indicate that: 1) endogenous concentrations of GnRH are less than earlier reports; 2)children and adults metabolize GnRH similarly, but plasma clearance is dose-dependent; 3) gonadotropin responses to iv GnRH are dependent on age, sex and degree of sexual maturation.