Oestrogen, Kisspeptin, GPR54 and the Pre-Ovulatory Luteinising Hormone Surge

Ovulation is central to mammalian fertility, yet the precise mechanism through which oestrogen triggers the gonadotrophin-releasing hormone (GnRH) surge that generates the pre-ovulatory luteinising hormone (LH) surge has remained elusive. The recent discovery that kisspeptin-GPR54 signalling is an essential regulator of the neuroendocrine axis at puberty has led investigators to evaluate the role of kisspeptin in the pre-ovulatory GnRH surge mechanism. Kisspeptin neurones are known to express oestrogen and progesterone receptors and have their cell bodies located in brain regions implicated in the positive-feedback mechanism in several mammalian species. In rodents, kisspeptin neurones located in the rostral periventricular area of the third ventricle (RP3V) are positively regulated by oestrogen and most likely are activated by oestrogen at the time of positive feedback. A similar scenario appears to exist for a sub-population of kisspeptin neurones located in the mediobasal hypothalamus of sheep and primates. The majority of GnRH neurones express GPR54, and kisspeptin causes an intense electrical activation of these cells. In concordance with this, kisspeptin administration in vivo results in an abrupt and prolonged release of LH in all mammalian species examined to date. Functional evidence from immunoneutralisation and knockout studies suggests that RP3V kisspeptin neurones projecting to GnRH neurones are an essential component of the surge mechanism in rodents. Taken together, the studies undertaken to date provide substantial evidence in support of a key role of kisspeptin-GPR54 signalling in the generation of the oestrogen-induced pre-ovulatory surge mechanism in mammals.