Kisspeptin

Kisspeptin is a neuropeptide produced by KNDy neurons (kisspeptin/neurokinin B/dynorphin neurons) in the arcuate nucleus of the hypothalamus. It is encoded by the KISS1 gene and acts on KISS1R (GPR54) receptors on hypothalamic GnRH neurons, making it the master upstream regulator of the hypothalamic-pituitary-gonadal axis. Kisspeptin is investigational for reproductive disorders including hypothalamic amenorrhea, IVF oocyte triggering, and idiopathic hypogonadotropic hypogonadism; no therapeutic form has received regulatory approval.

The most studied forms are kisspeptin-10 (KP-10, 10 amino acids, C-terminal fragment) and kisspeptin-54 (KP-54, 54 amino acids, full-length). Both bind KISS1R with equivalent receptor-level potency; KP-54 has longer plasma half-life. The sequence listed above is KP-10 (the research-grade vendor form typically sold as lyophilized powder).

Kisspeptin binds KISS1R, a Gαq-coupled GPCR expressed specifically on GnRH neurons in the hypothalamus. KISS1R activation → Gαq → PLC → IP3 → Ca²⁺ release → GnRH vesicle exocytosis → pulsatile GnRH secretion into the hypothalamic-pituitary portal circulation → LH/FSH release → gonadal steroidogenesis.

KNDy neurons in the arcuate nucleus form the GnRH pulse generator through an autocrine/paracrine circuit: - **Kisspeptin:** Excitatory; drives GnRH pulse initiation - **Neurokinin B (NKB):** Excitatory; amplifies KNDy synchronization - **Dynorphin:** Inhibitory; terminates GnRH pulse and resets cycle

This coordinated circuit produces the ~90-minute GnRH pulse frequency critical for normal gonadotropin secretion. Loss of kisspeptin signaling (KISS1/KISS1R null mutations) causes complete hypogonadotropic hypogonadism. The KNDy model also explains menopausal hot flashes: estrogen withdrawal disinhibits NKB signaling in the same neurons, driving dysregulated thermogenesis — the mechanistic basis for fezolinetant (NKB antagonist, FDA-approved 2023 for menopausal vasomotor symptoms).

Sex steroid feedback operates through kisspeptin: estrogen negative feedback (cycle phase) and the preovulatory estrogen positive feedback surge both act on KISS1R-expressing neurons, with kisspeptin mediating the LH surge that triggers ovulation.