Detailed definition
KNDy neurons (named for the three peptides they co-express: Kisspeptin, Neurokinin B, and Dynorphin) are located in the hypothalamic arcuate nucleus and are central regulators of GnRH pulse generation and reproductive function. They also project to the median preoptic nucleus, which controls thermoregulation. Estrogen normally restrains KNDy neuron activity through negative feedback. When estrogen is withdrawn at menopause, KNDy neurons hypertrophy and neurokinin B signaling increases, dysregulating the thermoregulatory neurons and narrowing the thermoneutral zone — the basis for the increased frequency and severity of vasomotor symptoms. Fezolinetant blocks the neurokinin-3 receptor on these thermoregulatory targets, reducing the impact of excess neurokinin B without altering estrogen levels.
Why it matters in menopause
KNDy biology is the answer to "what causes hot flashes." The KNDy/NK3 mechanism is also why fezolinetant works without estrogen. Understanding this circuit helps explain why hot flashes don't correlate well with absolute estrogen level (it's the rate and degree of estrogen withdrawal that matters most).
Related terms
Sources
External references: Wikipedia.