Advances in clinical applications of kisspeptin-GnRH pathway in female reproduction

Abstract

Background: Kisspeptin is the leading upstream regulator of pulsatile and surge Gonadotrophin-Releasing Hormone secretion (GnRH) in the hypothalamus, which acts as the key governor of the hypothalamic-pituitary-ovary axis.

Main text: Exogenous kisspeptin or its receptor agonist can stimulate GnRH release and subsequent physiological gonadotropin secretion in humans. Based on the role of kisspeptin in the hypothalamus, a broad application of kisspeptin and its receptor agonist has been recently uncovered in humans, including central control of ovulation, oocyte maturation (particularly in women at a high risk of ovarian hyperstimulation syndrome), test for GnRH neuronal function, and gatekeepers of puberty onset. In addition, the kisspeptin analogs, such as TAK-448, showed promising agonistic activity in healthy women as well as in women with hypothalamic amenorrhoea or polycystic ovary syndrome.

Conclusion: More clinical trials should focus on the therapeutic effect of kisspeptin, its receptor agonist and antagonist in women with reproductive disorders, such as hypothalamic amenorrhoea, polycystic ovary syndrome, and endometriosis.

Keywords: Female reproduction; Hypothalamic-pituitary-ovarian axis; Hypothalamus; KISS1R; Kisspeptin.

Fig. 1

The structure of kisspeptins in humans. Kisspeptins are derived from a 145-amino-acid prepro-kisspeptin (encoded by KISS1 gene). The cleavage sites at 68 and 121 of prepro-kisspeptin lead to the production of the RF-amidated KP54. Shorter kisspeptins (KP-10, − 13, and − 14) share a common C terminus and RF-amidated motif with KP54. Modified from [12, 17]

Fig. 2

Kisspeptin/KISS1R signalings. When kisspeptin binds to the seven-transmembrane domain receptor, KISS1R, the intracellular portion of KISS1R leads to the phosphorylation of Gq/11. The α-subunit of Gq/11 then activates PLC, which subsequently cleaves PIP2 into IP3 and DAG. IP3 promotes intracellular Ca2+ release from the endoplasmic reticulum, while DAG promotes the phosphorylation of PKC which further induces the phosphorylation of ERK1/2 and p38. DAG, diacylglycerol; ERK1/2, extracellular signal-regulated kinase; IP3, inositol 1,4,5-triphosphate; PI3K, phosphatidylinositol-3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C. Modified from [17]

Fig. 3

Schematic diagram showing how kisspeptin regulates hypothalamus-pituitary-ovary axis in rodents and humans. In rodents, KISS1 neurons within anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC) are responsible for the positive feedback (red) and negative feedback (blue) of sex steroids, respectively. While in humans, KISS1 neurons within the infundibular nucleus are responsible for the negative feedback (blue) of sex steroids. The area where KISS1 neurons mediate the positive feedback (red) is unclear. KISS1 neurons in the infundibular (humans)/arcuate (rodents) nucleus co-express neurokinin B (NKB) and dynorphin (Dyn), and are therefore named KNDy neurons. NKB and Dyn autosynaptically regulate pulsatile kisspeptin secretion in KNDy neurons, with NKB being stimulatory and Dyn inhibitory. POA, preoptic area; ME, median eminence

Fig. 4

Critical residues in KP10. Residues highlighted with red are important for KISS1R binding; Residues highlighted with blue are important for KISS1R activation. Modified from [84]

Fig. 5

Clinical application of kisspeptin in female reproductive health. CPP, central precocious puberty; IHH, idiopathic hypogonadotropic hypogonadism; HA, hypothalamic amenorrhea; PCOS, polycystic ovary syndrome; IVF, in vitro fertilization