Kisspeptin and clinical disorders.

The hypothalamic hormone GnRH has traditionally been viewed as a central driver of the hypothalamic-pituitary-gonadal axis. Pulsatile GnRH release is required for pulsatile gonadotropin secretion, which then modulates gonadal steroid feedback and brings about full fertility in the adult. Pathways governing GnRH ontogeny and physiology have been discovered by studying humans with disorders of GnRH secretion. In this chapter, the human genetics of the kisspeptin signaling pathway in patients with diverse reproductive phenotypes will be explored. The discovery of defects in the kisspeptin system in several reproductive disorders has shed light on the mechanisms involved in regulating GnRH secretion, revealing the critical role played by the kisspeptin signaling pathway in pubertal initiation and reproductive function.

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.

Genetic insights into human isolated gonadotropin deficiency.

The identification of naturally occurring genetic mutations has provided unique insight into the current knowledge of the human hypothalamic-pituitary-gonadal axis. In the past decade, several monogenic causes have been reported in patients with isolated gonadotropin deficiency. Kallmann Syndrome is a clinically and genetically heterogeneous disorder, characterized by isolated hypogonadotropic hypogonadism and anosmia or hyposmia. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. More recently, several heterozygous, homozygous or compound heterozygous mutations in the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2) were described in Kallmann syndrome. In addition, complex genetic transmission (digenic inheritance) was recently demonstrated in this condition. Regarding isolated hypogonadotropic hypogonadism without olfactory abnormalities, loss-of-function mutations in the Gonadotropin-releasing hormone (GnRH) receptor (GnRH-R) or the G-protein coupled receptor 54 (GPR54) genes, both encoding transmembrane receptors, have been described, as well as FGFR1 mutations. Finally, mutations of the beta sub-units of LH and FSH have been described in patients with selective gonadotropin deficiency. We review the role of these distinct genetic factors in human isolated hypogonadotropic hypogonadism.