Pharmacokinetics and pharmacodynamics of GnRH agonists: Clinical implications in pediatrics

Since 1981, GnRH agonist administration has been the treatment of choice fo r central precocious puberty. Continuous administration of the agonist, ins tead of permanently stimulating gonadotropin secretion, deeply suppresses L H and FSH levels and induces a marked inhibition of gonadal activity and re gression of clinical symptoms. This inhibitory effect is due both to specif ic kinetic parameters relative to natural GnRH, and to marked alterations o f the biosynthetic pathways of gonadotropin subunits. The half disappearanc e time of infused agonists is 3-10 fold that of natural GnRH. This means th at the residence time of GnRH agonists is significantly longer than that of GnRH. The resistance of agonist to enzymatic degradation, mainly due to th e substitution of a hydrophobic D-amino acid for glycine 6, is one of the f actors involved in the increased availability of GnRH superagonists. The paradoxical effects of GnRH superagonists are still incompletely unders tood. In children long-term treated with depot formulations of triptorelin or leuprorelin, alpha-subunit secretion is markedly increased, and remains sensitive to exogenous GnRH, which demonstrates that the gonadotrophs are n ot totally desensitized. Despite the sustained stimulation of alpha-subuuit secretion, no deleterious side effects, either during therapy or during po st-therapy follow-up, have been reported in children treated with GnRH agon ists. It should be noted that alpha-subunit responsiveness to exogenous GnR H decreases progressively after several years of treatment, although it is never completely abolished. On the other hand, LH beta-subunit secretion is suppressed as evidenced by radioimmunoassay of LH beta-subunit in serum ch romatographic fractions from children treated with triptorelin. This differ ential pattern of secretion parallels that of mRNA levels in rat pituitary after in vivo exposure to triptorelin. Both pharmacodynamic and pharmacokin etic data can help diagnose the situations of resistance or escape. The lac k of clinical effect of GnRH in the treatment of precocious puberty can be due to true resistance, or to an inappropriate injection schedule, or to ab normal metabolism. Measurement of serum alpha-subunit level, and, if needed , of serum agonist level, generally provides the answer.