The Neurobiology of GnRH Pulsatility: A Mode of Hypothalamic Activity Essential for Folliculogenesis, Ovulation and Spermatogenesis.

Pulsatile GnRH stimulation of the pituitary gonadotrophs is essential for puberty and the maintenance of gonadal function in the adult. In the hypothalamus, some several hundred GnRH neurons are diffusely distributed throughout the preoptic and mediobasal hypothalamus, and many of these neurons send their projections to the median eminence: the site of the primary plexus of the hypophysial portal circulation. More than 30 years ago it was noted that discrete lesions of the arcuate nucleus, which is located immediately above the median eminence, abolished gonadotropin secretion in the monkey. At the time, it was difficult to appreciate why such a small lesion had such a profound impact on gonadotropin secretion, while more extensive damage to the MBH, which spared the arcuate region, preserved gonadotropin secretion. It is now known that the arcuate nucleus contains a major population of neurons that express KISS1, the gene that encodes for kisspeptin. Loss of function mutations of kisspeptin or the kisspeptin receptor in man results in hypogonadotropic hypogonadism and delayed or absent puberty (1-3), and pulsatile administration of kisspeptin in physiological primate models of hypogonadotropism restores gonadotropin secretion, presumably as a result of a direct action on GnRH terminals in the median eminence. Interestingly, loss of function mutations in another neuropeptide signaling pathway, namely neurokinin B results in a similar human phenotype (4) to that observed for the kisspeptin pathway. Neurokinin B, like kisspeptin, stimulates GnRH release in primate models, and, remarkably, neurokinin B is found in the same arcuate neurons that express kisspeptin. The action of neurokinin B to stimulate GnRH release is upstream from that of kisspeptin: a finding consistent with data in mice indicating that neurokinin B dramatically activates electrical activity of arcuate kisspeptin neurons (5). These and other findings have contributed to the emerging view that the kisspeptin neurons of the arcuate nucleus provide the cornerstone of the neurobiological machinery that generates GnRH pulsatility.1) de Roux et al.(2003)PNAS 100: 10972, 2) Seminara et al. (2003) NEJM 349: 1614, 3) Topaloglu et al. (2009) Nature Genetics 41:354, 4) Topaloglu et al. (2012) NEJM 366:629,5) Navarro et al. (2011) Endocrinology 152:4265.