Kisspeptin, KNDy neurons and the first non-hormonal hot-flash drug

The first non-hormonal hot-flash drug came out of kisspeptin research. It is not kisspeptin. That one detail explains most of the confusion in what gets claimed about kisspeptin online.

From a metastasis gene to a puberty gatekeeper

Kisspeptin was discovered in 1996 in Hershey, Pennsylvania, and named after Hershey's Kisses. It was first studied as the product of a gene linked to suppressing cancer metastasis.

In 2003, two research groups, de Roux and colleagues in PNAS and Seminara and colleagues in NEJM, reported that mutations in the kisspeptin receptor stopped puberty entirely. From that point kisspeptin became known as a gatekeeper of the reproductive hormone axis. It signals GnRH neurons, which drive the release of LH and FSH.

KNDy neurons and the hot-flash circuit

The link to menopause runs through a cluster of brain cells called KNDy neurons, named for the three signals they carry: kisspeptin, neurokinin B and dynorphin. When estrogen falls, these neurons enlarge and become overactive. Neurokinin B signaling from them is tied to hot flashes.

What is known

• Blocking the neurokinin B receptor reduced hot-flash frequency in Phase 3 trials, including SKYLIGHT 1 (Johnson and colleagues, Lancet 2023). That work led to FDA approval of fezolinetant in 2023.
• In clinical research, kisspeptin reliably raises LH (Jayasena and colleagues, JCI 2014), and it has been studied as a trigger for egg maturation in IVF.

What is claimed, and why it does not follow

Online, kisspeptin is often described as resolving menopause or balancing hormones. No trial shows that. The approved drug works by blocking one signal in the KNDy circuit, neurokinin B, not by adding kisspeptin.

Same neurons, very different interventions. Kisspeptin research mapped the circuit; a different molecule acting on a different receptor in that circuit is what reached approval.