Kisspeptin-10

Kisspeptin is encoded by the KISS1 gene and exists in multiple isoforms (KP-54, KP-14, KP-13, KP-10). The C-terminal 10 amino acids (Kisspeptin-10) represent the minimal active fragment responsible for full KISS1R agonist activity. The amidated C-terminus is essential for potency.

KISS1R (formerly GPR54) is a G-protein coupled receptor expressed on GnRH neurons in the hypothalamus. Kisspeptin-10 binding triggers Gq/11 signalling, depolarisation of GnRH neurons, and pulsatile GnRH release into the portal circulation — driving the LH/FSH pulse that underpins normal reproductive function in both sexes.

Clinical applications centre on reproductive medicine: Kisspeptin-10 is used as an alternative to hCG to trigger oocyte maturation in IVF, with a dramatically lower risk of ovarian hyperstimulation syndrome (OHSS). It is also in Phase II trials for hypothalamic amenorrhoea, hypogonadotropic hypogonadism, and male infertility.

// KISS1R AGONISM

Kisspeptin-10 binds KISS1R on hypothalamic GnRH neurons with high affinity (Ki ~1 nM). Receptor activation triggers phospholipase C-β via Gq/11, generating IP3 and DAG, leading to calcium mobilisation and neuronal depolarisation. The resulting action potentials drive pulsatile GnRH secretion into the hypophyseal portal blood.

// HPG AXIS ACTIVATION

GnRH released by Kisspeptin-10 stimulation binds pituitary GnRH receptors, triggering LH and FSH secretion. The LH surge drives ovulation in females and testosterone production in males. This upstream mechanism distinguishes Kisspeptin-10 from direct LH or hCG analogues — it works through the natural hypothalamic-pituitary cascade rather than bypassing it.

// FEEDBACK INTEGRATION

Kisspeptin neurons receive steroid hormone feedback (estradiol, testosterone) and integrate peripheral signals including leptin and insulin. This makes Kisspeptin-10 a key node where metabolic status (nutrition, body composition) gates reproductive function — explaining amenorrhoea in low-body-weight states and metabolic syndrome-related hypogonadism.

IVF trigger use: Multiple Phase II/III trials have established Kisspeptin-54 and Kisspeptin-10 as effective oocyte maturation triggers in IVF, with a superior safety profile vs. standard hCG in women at high OHSS risk (PCOS, previous OHSS). King's College London group led by Waljit Dhillo has published extensively in this area.

Hypogonadism: IV and SC Kisspeptin-10 infusions restore LH pulsatility in hypothalamic amenorrhoea and male hypogonadotropic hypogonadism. This supports the upstream GnRH-deficiency model and positions Kisspeptin as a potential alternative to exogenous testosterone therapy for preserving fertility.