KNDy Neurons Explained: The Brain Science Behind Hot Flashes and New Treatment Targets

In 'KNDy Neurons Explained: The Brain Science Behind Hot Flashes and New Treatment Targets,' our panel of experts delve into the following critical questions:

1. What patients can benefit from hormone therapies, and in what patients may a different class (such as KNDy receptor agonists) be a better fit?
2. Please explain the KNDy neuron system: what are these neurons, where are they located, and what do they normally do?
3. How does estrogen decline change the behavior of KNDy neurons and ultimately lead to the experience of a hot flash?
4. Please expand upon the neurokinin receptor subtypes (NK1, NK2, NK3) and how targeting may relieve specific VMS symptoms.

Led by the moderator, the panelists discussed how estrogen therapy remains the first-line treatment for VMS with a highly favorable benefit-to-risk ratio for most women, while also outlining the clinical algorithm used to determine candidacy, including the window of opportunity, indication, and contraindication framework, and identifying the growing populations of women, including breast cancer survivors, those past the window of opportunity, and those who have tried and discontinued hormone therapy, for whom newer non-hormonal agents represent a critical therapeutic advance. The panelists also provided a detailed explanation of the KNDy neuron system, describing how these hypothalamic neurons normally regulate reproductive hormone secretion and thermoregulation, and how the decline of estrogen during menopause causes KNDy neurons to hypertrophy and act erratically on the thermoregulatory center, ultimately hijacking heat dissipation responses to produce the hot flashes and night sweats characteristic of VMS. The discussion further explored the three neurokinin receptor subtypes, with the panelists clarifying that the NK3 receptor is the most central target for vasomotor symptom relief, that NK1 receptor antagonism offers additional benefits for sleep and hot flash reduction through its interaction with substance P, and that NK2 plays a comparatively lesser role, establishing the mechanistic foundation for the targeted therapies fezolinetant and elinzanetant.

Throughout the conversation, the experts provide a comprehensive reflection on the field and the factors that may shape how clinicians approach care moving forward.

Our next episode, 'NK3 as a Drug Target: From Scientific Discovery to Guideline-Recognized Therapy,' further explores vasomotor symptoms and menopause, highlighting how the identification of the KNDy neuron system led researchers to the NK3 receptor as a compelling drug development target, what this mechanism means for patients who cannot or will not take hormone therapy, and how clinical guidelines have evolved to incorporate KNDy receptor antagonists as recognized treatment options.