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

Front Neuroendocrinol. 2013 Aug;34(3):211-27. doi: 10.1016/j.yfrne.2013.07.003. Epub 2013 Jul 17.


Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK₃R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.

Keywords: Estrogen; GnRH; LH; Menopause; Reproduction; Thermoregulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Body Temperature Regulation / drug effects
  • Body Temperature Regulation / physiology*
  • Dynorphins / physiology*
  • Estradiol / pharmacology
  • Estrous Cycle / drug effects
  • Female
  • Hot Flashes / physiopathology*
  • Humans
  • Hypothalamus / metabolism*
  • Kisspeptins / physiology*
  • Luteinizing Hormone / metabolism
  • Models, Biological
  • Neurokinin B / physiology*
  • Neurons / physiology
  • Ovariectomy
  • Postmenopause / physiology
  • Preoptic Area / metabolism
  • Rats
  • Receptors, Neurokinin-3 / metabolism
  • Signal Transduction
  • Skin / blood supply
  • Tail / blood supply
  • Vasodilation


  • Kisspeptins
  • Receptors, Neurokinin-3
  • Estradiol
  • Dynorphins
  • Neurokinin B
  • Luteinizing Hormone