Kisspeptin

The KISS1 gene encodes a precursor cleaved into kisspeptin-54 and shorter fragments of 14, 13 and 10 residues, all sharing the amidated C-terminal decapeptide that carries essentially all receptor activity, so kisspeptin-10 is nearly as potent as the full-length peptide. The receptor, KISS1R or GPR54, is a Gq-coupled receptor expressed directly on GnRH neurons. Arcuate kisspeptin neurons, co-expressing neurokinin B and dynorphin and known as KNDy cells, generate the pulse pattern, while a separate preoptic population mediates the preovulatory surge.

The gene was named for something else: it was identified in 1996 as a metastasis suppressor in melanoma, hence the alias metastin. Its reproductive role emerged in 2003, when two groups reported loss-of-function GPR54 mutations in families with hypogonadotropic hypogonadism, with activating mutations later linked to central precocious puberty. Infused kisspeptin-54 raises LH in healthy volunteers and can trigger oocyte maturation in IVF with less ovarian hyperstimulation than hCG, but that work remains investigational and no kisspeptin product is approved anywhere.

Kisspeptin explains why the reproductive axis is sensitive to things unrelated to the gonads. Energy availability, leptin signalling, stress and inflammation converge on kisspeptin neurons rather than GnRH neurons directly, placing the gate a level higher than the classical diagram suggests and accounting for hypothalamic amenorrhoea and delayed puberty in chronic illness.

The error is the one that follows any clean acute signal. Research-market kisspeptin-10 is sold as a testosterone stimulant on the strength of the LH rise after a single infusion in volunteers, but an acute gonadotropin response is a pharmacodynamic observation, not evidence of durable benefit, and the KNDy circuit desensitises to continuous stimulation like the rest of the axis.