Pharmacokinetics and Pharmacodynamics of GnRH Agonists: Clinical Implications in Pediatrics

Abstract

Since 1981, GnRH agonist administration has been the treatment of choice for central precocious puberty. Continuous administration of the agonist, instead of permanently stimulating gonadotropin secretion, deeply suppresses LH and FSH levels and induces a marked inhibition of gonadal activity and regression of clinical symptoms. This inhibitory effect is due both to specific kinetic parameters relative to natural GnRH, and to marked alterations of the biosynthetic pathways of gonadotropin subunits. The half disappearance time of infused agonists is 3-10 fold that of natural GnRH. This means that the residence time of GnRH agonists is significantly longer than that of GnRH. The resistance of agonist to enzymatic degradation, mainly due to the substitution of a hydrophobic D-amino acid for glycine 6, is one of the factors involved in the increased availability of GnRH superagonists. The paradoxical effects of GnRH superagonists are still incompletely understood. 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 not totally desensitized. Despite the sustained stimulation of a-subunit secretion, no deleterious side effects, either during therapy or during post-therapy follow-up, have been reported in children treated with GnRH agonists. It should be noted that alpha-subunit responsiveness to exogenous GnRH 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 chromatographic fractions from children treated with triptorelin. This differential pattern of secretion parallels that of mRNA levels in rat pituitary after in vivo exposure to triptorelin. Both pharmacodynamic and pharmacokinetic data can help diagnose the situations of resistance or escape. The lack 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 abnormal metabolism. Measurement of serum alpha-subunit level, and, if needed, of serum agonist level, generally provides the answer.

Central precocious puberty: revisiting the diagnosis and therapeutic management

“…GnRHa acts on the anterior pituitary, competing for GnRH receptor with endogenous GnRH, promoting endocytosis and reducing the amount of GnRH receptors ("down-regulation") (46)(47)(48). Initially, GnRHa stimulates the synthesis and secretion of LH and FSH but when it is administered chronically, GnRHa suppresses the production of these hormones, which in turn suppress the production of sex steroid hormones by the gonads (28,48). Of the available GnRHa, leuprorelin acetate (LA) and triptorelin are the most commonly used, and their efficacy and safety on the treatment of CPP has been demonstrated by several studies.…”

MANAGEMENT OF ENDOCRINE DISEASE: Long-term outcomes of the treatment of central precocious puberty

“…They derive from a chemical substitution at position 6 and 10 of the native GnRH molecule, which increases its resistance to the enzymatic degradation and affinity to the GnRH-pituitary receptor leading to desensitization of the receptor, ultimately resulting in the inhibition of gonadotropin secretion and return of sex steroids to prepubertal levels (9). Several active principles and formulations are available.…”

The use of GnRH agonists in precocious puberty

“…The present view is that kisspeptins have an essential role in the activation of the gonadotrophic axis (6). Despite these developments, the mainstay of the treatment of CPP is still targeted at the desensitization of the pituitary by agonists of native GnRH (7). This review summarizes the use of GnRHa in children, with particular emphasis on CPP and early puberty.…”