6 - Gonadotrophin regulation and clinical applications of GnRH

Abstract

Gonadotrophin secretion is determined by the interplay of neural and gonadal influences. The neural influence is mediated for both LH and FSH by the decapeptide GnRH which is secreted into the hypophyseal portal vessels. LH is secreted in a pulsatile fashion apparently driven by episodic release of GnRH. Unremitting exposure of the pituitary to GnRH eventually abolishes gonadotrophin secretion. In primates, as opposed to the rat, GnRH appears to have a permissive role in the regulation of gonadotrophin secretion, priming the pituitary to secrete and show both negative and positive feedback responses to oestrogen in adult females. Striking physiological changes occur from fetal life to puberty in gonadotrophin regulation. GnRH acts on surface receptors. Chemical dissection of the GnRH molecule has disclosed a structure-activity relationship, allowing the development of both antagonist and 'superagonist' analogues. The initial stage in activation of gonadotrophs by GnRH appears to be binding to and clustering--probably dimerization--of GnRH receptors. Subsequent intracellular events are not fully clarified but grounds exist to suggest the involvement of both cyclic AMP and calcium fluxes within the cell. There is strong evidence that GnRH secretion influences the number of its own receptors in various situations in the rat. The phenomenon of pulsatile GnRH release in experimental animals survives hypothalamic deafferentation. Catecholamines are probably intimately involved in the generation of GnRH pulses--which for noradrenaline poses a paradox as all noradrenergic cell bodies lie outside the MBH. LH pulse frequency can be absent or altered in various states (e.g., Kallman's syndrome, hyperprolactinaemia and exposure to opiates--exogenous or apparently endogenous). The existence of GnRH receptors in gonadal tissue has been described but it is debatable whether this is true in man. Therapeutic uses of GnRH initially was aimed at correcting hypogonadotrophic hypogonadism. Development of GnRH superagonists demonstrated desensitization and thus their paradoxical application to the areas of contraception, precocious puberty and endocrine-dependent cancers. The development of miniaturized programmable infusion pumps has made pulsatile GnRH therapy a practical prospect. It holds considerable therapeutic promise in selected cases of hypogonadotrophic hypogonadism, especially in women.