[GnRH and its analogs--structure, mechanism of action and therapeutic applications]

In the last decade, much has been learned about the physiology and cellular biology of GnRH. In addition more than 2000 analogs agonists and antagonists have been synthesized. The GnRH precursor cDNA has been cloned from human placenta and hypothalamus mRNA's. The GnRH gene is located on the short arm of chromosome 8. The mechanism of action of GnRH requires Ca and its two intracellular receptors calmodulin and protein kinase C. The physiological effect of GnRH is to induce the release of both gonadotropins and to increase the alpha and beta subunit mRNA. In addition, GnRH stimulates terminal glycosylation of LH and FSH. Pulsatile GnRH exposure induces an up regulation of the receptors. In contrast continuous GnRH or GnRH agonist administration induces a receptor loss and a pituitary desensitization. The process of desensitization is unclear and requires some post receptor events which remain to be elucidated. Changes in the aminoacid composition of GnRH result in 2 classes of analogs agonists and antagonists. Both are used to induce a reversible medical castration. GnRH agonists lead to an initial rise in gonadotropins and gonadal steroid secretion. They are not able to suppress bioactive FSH. In contrast, GnRH antagonists compete with GnRH for its receptors and have an immediate and sustained suppressive effect on LH and FSH secretion. GnRH analogs are useful tools to study the gonadotropin regulation.