NK3 and Menopausal Vasomotor Symptoms

Menopausal vasomotor symptoms, or hot flashes, are caused by a dysfunction in body temperature regulation that is directly linked to the hallmark biological changes of menopause. During menopause, the levels of estrogen in a woman’s body naturally decrease with reduced ovarian production. In the brain, the decline in estrogen triggers an increase in production of Neurokinin-B, an endogenous neuropeptide that binds to and activates NK3 receptors. 

Humans are typically able to regulate body temperature within a narrow range through a delicate balance of heat conservation and heat dissipation. The area of the brain responsible for monitoring and regulating body temperature is the median preoptic nucleus (MnPO). In postmenopausal women, elevated levels of Neurokinin-B result in excessive activation of the NK3 receptors in the MnPO, evoking an excessive heat dissipation response that women experience symptomatically as hot flashes. NK3 antagonists are believed to restore normal thermoregulation and alleviate hot flashes by binding to the NK3 receptors and reducing the excessive Neurokinin-B signaling.

The central role of NK3 signaling in menopausal vasomotor symptoms has been well characterized. In clinical trials, NK3 antagonists have demonstrated reductions in hot flash frequency and severity comparable to hormone therapy. A genome wide association study of nearly 18,000 women participating in the Women’s Health Initiative study revealed that polymorphisms in the TACR3 gene that encodes for the NK3 receptor are associated with self-reported hot flashes. Numerous non-clinical studies have also demonstrated the central role of NK3 signaling in thermoregulation. 


References

  • Crandall C. et al. (2017) “Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women’s Health Initiative Study.” Menopause 24(3): 252–261

  • Dacks P. et al. (2011) “Activation of Neurokinin 3 Receptors in the Median Preoptic Nucleus Decreases Core Temperature in the Rat.” Endocrinology, 152(12): 4894–4905

  • Depypere et al. (2017) “Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes.” Maturitas 103 89–94

  • McKinley et al. (2015) “The median preoptic nucleus: front and centre for the regulation of body fluid, sodium, temperature, sleep and cardiovascular homeostasis.” Acta Physiol (Oxf). 214(1):8-32

  • Padilla et al. (2018) “A Neural Circuit Underlying the Generation of Hot Flushes.” Cell Reports 24, 271–277

  • Rance et al. (2009) “Menopause and the Human Hypothalamus: Evidence for the Role of Kisspeptin/Neurokinin B Neurons in the Regulation of Estrogen Negative Feedback.” Peptides 30(1): 111–122

  • Rance et al. (2013) “Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes.” Frontiers in Neuroendocrinology 34(3)