kisspeptins

Kisspeptins are a family of peptides encoded by the KISS1 gene that act as key regulators of the reproductive axis. They bind to the G protein–coupled receptor GPR54 (also known as KISS1R) and stimulate the secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons, which in turn drives the pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Through this pathway, kisspeptins initiate and regulate vertebrate puberty and maintain reproductive function.

Kisspeptins were first identified as metastasis suppressors in certain cancers; the peptide family was named after the Hershey’s “kiss” branding. The receptor GPR54 was later found to be the cognate receptor for kisspeptins, establishing their central role in GnRH control. The most studied isoform is kisspeptin-54, with shorter fragments also active.

Mechanistically, kisspeptin signaling activates GnRH neurons, leading to pulsatile GnRH release and downstream gonadotropin secretion. In mammals, kisspeptin neurons are concentrated in the arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC neurons often co-express neurokinin B and dynorphin (the KNDy phenotype) and participate in pulsatile GnRH release, while AVPV kisspeptin neurons contribute to estrogen-positive feedback and the preovulatory LH surge in many species.

Clinical relevance includes roles in puberty timing and reproductive disorders. Mutations in KISS1 or KISS1R can cause central hypogonadotropic hypogonadism, whereas premature kisspeptin signaling can contribute to central precocious puberty. Kisspeptin-based therapies are under investigation for fertility treatments; kisspeptin-54 has been explored as a trigger for ovulation in assisted reproduction to reduce ovarian hyperstimulation syndrome risk. Kisspeptins may also reflect reproductive status and metabolic signals that influence fertility.