Mechanism of GnRH action in gonadotrophs

The principal physiological site of action of GnRH is on pituitary gonadotrophs. Although binding sites for this peptide are described in the gonads, placenta, breast and brain, their precise physiological/pharmacological relevance remains to be elucidated. The pituitary action of GnRH can be divided conveniently into an immediate release of LH and FSH within minutes, the synthesis of LH and FSH over a matter of hours (intermediate action), and long-term morphologic changes lasting several days. Most, if not all, of these actions are initiated following interaction with high-affinity (Kd = 0.5 nM) stereospecific receptors on gonadotrophs. GnRH receptor concentration is negatively regulated by testosterone and progesterone, and positively regulated by oestradiol in vivo as well as by the ligand itself. In-vivo and in-vitro GnRH regulates its own receptors depending on its pulsatile or continuous secretion which increase or decrease numbers (up-or down-regulation), respectively. In-vivo change in GnRH receptors probably reflect the extent or pituitary exposure to endogenous GnRH and is an indirect index of hypothalamic GnRH secretion. Up-regulation is not ligand specific since other activators of LH release e.g. depolarization, ionophores, and cAMP derivatives, are also effective in vitro. Down-regulation is specific to the ligand and contributes to 'desensitization' which also includes disruption of the signal transduction mechanism (uncoupling of receptors), and depletion of cellular LH stores. GnRH receptor occupation activates membrane phospholipase C to hydrolyse polyphosphoinositides with the formation of inositol-1-4-5-trisphosphate and diacylglycerol which activates protein kinase C.(ABSTRACT TRUNCATED AT 250 WORDS)