Kisspeptin

Kisspeptin is the master upstream regulator of the reproductive axis — the peptide that tells the hypothalamus to release GnRH. Encoded by the KISS1 gene, kisspeptin binds KISS1R (GPR54) on hypothalamic GnRH neurons, triggering GnRH pulsatile release which then drives LH and FSH secretion. The discovery of kisspeptin's role (2003) was a paradigm shift in reproductive neuroendocrinology: loss-of-function KISS1R mutations cause hypogonadotropic hypogonadism, while gain-of-function causes precocious puberty. In clinical trials, kisspeptin-54 (the full-length active form) potently stimulates LH release in healthy men — a single 1 nmol/kg IV injection produces an 8-fold LH surge (Dhillo et al., 2005). Now being developed for IVF (oocyte maturation trigger with lower OHSS risk than HCG), functional hypothalamic amenorrhea, and as a diagnostic tool for HPG axis assessment. In the peptide/TRT space, kisspeptin represents the most upstream point of intervention possible — stimulating the entire cascade (GnRH → LH/FSH → testosterone/spermatogenesis) from the top. Research-phase for TRT adjunct use; the short half-life and need for frequent dosing are current limitations.