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The role of the hypothalamus in VMS

A closer look at where hot flashes and night sweats begin

Estrogen decline contributes to altered neuronal activity in the hypothalamus1,2

However, VMS are not caused by declining estrogen alone. VMS result from altered activity of the KNDy neurons in the thermoregulatory centre of the hypothalamus.2-4

Inside the source of VMS

Estrogen and NKB modulate KNDy neurons in a delicate balance, contributing to body temperature regulation. KNDy neurons are stimulated by NKB and inhibited by estrogen.2,5,6

KNDY neuron, estrogen, and NKB

Inside the source of VMS

Through the menopausal transition, estrogen declines, disrupting the balance with NKB.2,5,7

Estrogen and NKB

Inside the source of VMS

Unopposed, NKB signalling causes heightened KNDy neuronal activity, which leads to hypertrophy of KNDy neurons and altered activity on the thermoregulatory centre.2,5,7

Neuronal activity flashing

Inside the source of VMS

As a result, the thermoregulatory centre triggers heat dissipation effectors that cascade into VMS, also referred to as hot flashes and night sweats.2,5,7

Brain with hypothalamus lit up

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KNDy: kisspeptin/neurokinin B/dynorphin; NK3: neurokinin B receptor; NKB: neurokinin B; VMS: vasomotor symptoms.

References

  1. Monteleone P, Mascagni G, Giannini A, Genazzani AR, Simoncini T. Symptoms of menopause - global prevalence, physiology and implications. Nat Rev Endocrinol. 2018;14(4):199-215.
  2. Padilla SL, Johnson CW, Barker FD, Patterson MA, Palmiter RD. A neural circuit underlying the generation of hot flushes. Cell Rep. 2018;24(2):271-7.
  3. Rapkin AJ. Vasomotor symptoms in menopause: physiologic condition and central nervous system approaches to treatment. Am J Obstet Gynecol. 2007;196(2):97-106.
  4. Modi M, Dhillo WS. Neurokinin 3 receptor antagonism: a novel treatment for menopausal hot flushes. Neuroendocrinology. 2019;109(3):242-8.
  5. Krajewski-Hall SJ, Blackmore EM, McMinn JR, Rance NE. Estradiol alters body temperature regulation in the female mouse. Temperature. 2018;5(1):56-69.
  6. Wakabayashi Y, Nakada T, Murata K, et al. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci. 2010;30(8):3124-32.
  7. Krajewski-Hall SJ, Miranda Dos Santos F, McMullen NT, Blackmore EM, Rance NE. Glutamatergic neurokinin 3 receptor neurons in the median preoptic nucleus modulate heat-defense pathways in female mice. Endocrinology. 2019;160(4):803-16.