KNDy Neurons
Definition
KNDy (kisspeptin/neurokinin B/dynorphin) neurons are a population of cells in the hypothalamus that become hypertrophied and hyperactive when estrogen declines. Their overactivity is now understood to be the direct trigger for hot flashes and night sweats, and they are the molecular target of new non-hormonal therapies.
In Depth
KNDy neurons sit in the infundibular nucleus of the hypothalamus and were named for the three signaling molecules they co-express: kisspeptin, neurokinin B (NKB), and dynorphin. In a premenopausal brain, estrogen restrains these cells. When estrogen is withdrawn — surgically, or naturally at menopause — KNDy neurons enlarge and fire excessively, releasing pulses of neurokinin B that propagate into the adjacent thermoregulatory center and trigger the vasodilation, sweating, and flushing of a hot flash.
This mechanism was confirmed when blocking the neurokinin 3 (NK3) receptor — the receptor that NKB acts on — reproducibly stopped hot flashes in clinical trials. The first NK3 antagonist, fezolinetant, received FDA approval in May 2023 for moderate-to-severe vasomotor symptoms associated with menopause. A second compound, elinzanetant, has shown similar efficacy in late-stage trials.
The clinical importance is significant: until 2023, the only proven treatments for hot flashes were hormone therapy and lower-efficacy off-label options (SSRIs, gabapentin, clonidine). NK3 antagonism gives women — particularly breast cancer survivors and others who cannot take estrogen — a mechanism-based, non-hormonal option with efficacy approaching that of hormone therapy.
Why It Matters
For the first time, women who cannot or choose not to take hormone therapy have access to a non-hormonal medication that targets the actual neural cause of hot flashes, rather than working around it.