Neurokinin B signalling in the human reproductive axis

Recent human genetic studies have established that neurokinin B (NKB) signalling via the neurokinin 3 receptor (NK3R) is required for normal developmental activation of pulsatile GnRH secretion from the hypothalamus. As increasing numbers of patients with loss-of-function mutations have been described, evidence has emerged that peripheral NKB is not necessary for normal pregnancy despite high placental expression and high plasma levels of NKB in late gestation. Nevertheless many key questions about the role of NKB in the function of the GnRH pulse generator remain to be answered. Differences in requirement for NKB/NK3R for hypothalamic-pituitary-gonadal (HPG) maturation amongst different species, and their varied responses to stimulation with NKB represent a challenge for higher resolution studies. Neuroanatomical investigation has, however, identified key "KNDy" (Kisspeptin, Neurokinin B, Dynorphin) arcuate neurones that are conserved amongst different species and that are intimately connected both to each other and to the GnRH nerve termini. Several lines of evidence suggest that these may be the core of the GnRH pulse generator, and with experimental tools now in place in humans, monkeys and other experimental animals to pursue the function of these interconnected neurones and the functional hierarchy of their neuroendocrine inputs, understanding of the enigmatic GnRH pulse generator may at last be within reach.