Impact of mutations in kisspeptin and neurokinin B signaling pathways on human reproduction

The involvement of kisspeptin and neurokinin in B pathways in the reproductive axis was first suspected by linkage analysis in consanguineous families with isolated hypogonadotropic hypogonadism (IHH). Since then, several loss-of-function mutations affecting the kisspeptin receptor and neurokinin B and its receptor were associated with sporadic and familial IHH without olfactory abnormalities or other associated developmental alterations. Clinical manifestations were indistinguishable in individuals with mutations affecting these pathways. Micropenis and cryptorchidism were common findings among male patients. Response to acute GnRH stimulation varied from blunted to normal, and many affected males and females were successfully treated for infertility with either exogenous gonadotropins or long term pulsatile GnRH infusion. More recently, rare activating mutations of the kisspeptin and its receptor were identified in children with idiopathic central precocious puberty, supporting the crucial role of this system in the human pubertal onset. Kisspeptin is a potent excitatory regulator of the GnRH secretion, whereas the role of neurokinin B in the neuroendocrine control of the reproductive axis is still poorly understood. Interestingly, kisspeptin and neurokinin B are coexpressed in the arcuate nucleus in the mammalian hypothalamus, suggesting that these systems are closely related and potential partners of the regulation of the reproductive axis.

Research Highlights►Recessive loss-of-function mutations in KISS1R, NKB and NKBR cause normosmic isolated hypogonadotropic hypogonadism. ►Rare activating mutations in KISS1 and KISS1R were associated with central precocious puberty. ►Kisspeptin is a potent excitatory regulator of hypothalamic GnRH secretion. ►Kisspeptin, neurokinin B and dynorphyn A are co-expressed in hypothalamic neurons and may act sinergically in the modulation of GnRH pulsatility.