Hot Flashes, the KNDy Mechanism, and the New Non-Hormonal Pill

Why It Matters

Recognizing hot flashes as a long‑lasting condition and offering an effective non‑hormonal therapy expands safe treatment for high‑risk women, potentially improving quality of life and reducing reliance on estrogen.

Key Takeaways

• Hot flashes average 7.4 years, not just months.
• KNDy neurons drive vasomotor symptoms via neurokinin B signaling.
• Fezolinetant cuts hot flashes 60‑65% at 45 mg dose.
• FDA warns of liver toxicity; monitor enzymes first three months.
• New NK1/NK3 antagonist elinzanetant offers better efficacy, no liver risk.

Summary

The video reviews a 2015 JAMA Internal Medicine analysis of the SWAN cohort, which tracked 1,449 women prospectively and found that frequent vasomotor symptoms persist a median of 7.4 years, with post‑menopause duration of 4.5 years and notable racial variation.

It then explains the neurobiological basis: enlarged KNDY neurons in the arcuate nucleus lose estradiol inhibition, release neurokinin B onto NK3 receptors in the median preoptic nucleus, destabilizing the thermoneutral zone and triggering hot flashes.

Two 2023 Skylight trials showed that the NK3 antagonist fezolinetant (45 mg) reduced moderate‑to‑severe hot flashes by 60‑65% versus placebo, albeit with a FDA‑mandated liver‑enzyme monitoring warning; a newer dual NK1/NK3 blocker, elinzanetant, appears more effective and lacks the hepatic risk.

For clinicians, these data shift hot flashes from a transient nuisance to a chronic condition warranting treatment, expanding options beyond hormone therapy for women with contraindications and highlighting a rapid bench‑to‑bedside translation in menopause care.

Original Description

The mechanism behind hot flashes and the new pharmacology that blocks it. Dr. Jordan Feigenbaum walks the Avis 2015 SWAN data on VMS duration, the KNDy neuron mechanism, and the SKYLIGHT 1 and 2 trials of fezolinetant. Dr. Austin Baraki walks who actually gets this medication in clinic.

Timestamps:

• 00:00 7.4 years of hot flashes

• 02:00 The KNDy mechanism: from autopsy to drug target

• 04:00 SKYLIGHT 1 and 2: fezolinetant trials

• 05:40 Austin: who actually gets fezolinetant

• 07:00 Elinzanetant: the newer agent

Resources

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• Avis NE et al. JAMA Intern Med, 2015. https://pubmed.ncbi.nlm.nih.gov/25686030/

• Lederman S et al. SKYLIGHT 1, Lancet, 2023. https://pubmed.ncbi.nlm.nih.gov/36924778/

• Johnson KA et al. SKYLIGHT 2, JCEM, 2023. https://pubmed.ncbi.nlm.nih.gov/37410020/

• Pinkerton JV et al. OASIS elinzanetant, JAMA, 2024. https://pubmed.ncbi.nlm.nih.gov/39163087/