Neurokinin B and the hypothalamic regulation of reproduction

Brain Res. 2010 Dec 10;1364:116-28. doi: 10.1016/j.brainres.2010.08.059. Epub 2010 Aug 25.


Loss-of-function mutations in the genes encoding either neurokinin B (NKB) or its receptor, NK3 (NK3R), result in hypogonadotropic hypogonadism, characterized by an absence of pubertal development and low circulating levels of LH and gonadal steroids. These studies implicate NKB and NK3R as essential elements of the human reproductive axis. Studies over the last two decades provide evidence that a group of neurons in the hypothalamic infundibular/arcuate nucleus form an important component of this regulatory circuit. These neurons are steroid-responsive and coexpress NKB, kisspeptin, dynorphin, NK3R, and estrogen receptor α (ERα) in a variety of mammalian species. Compelling evidence in the human indicates these neurons function in the hypothalamic circuitry regulating estrogen negative feedback on gonadotropin-releasing hormone (GnRH) secretion. Moreover, in the rat, they form a bilateral, interconnected network that projects to NK3R-expressing GnRH terminals in the median eminence. This network provides an anatomical framework to explain how coordination among NKB/kisspeptin/dynorphin/NK3R/ERα neurons could mediate feedback information from the gonads to modulate pulsatile GnRH secretion. There is substantial (but indirect) evidence that this network may be part of the neural circuitry known as the "GnRH pulse generator," with NK3R signaling as an important component. This theory provides a compelling explanation for the occurrence of hypogonadotropic hypogonadism in patients with inactivating mutations in the TAC3 or TACR3 genes. Future studies will be needed to determine whether NKB signaling plays a permissive role in the onset of puberty or is part of the driving force initiating the maturation of reproductive function.

Publication types

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

MeSH terms

  • Aging / physiology
  • Animals
  • Arcuate Nucleus of Hypothalamus / cytology
  • Arcuate Nucleus of Hypothalamus / physiology
  • Dynorphins / physiology
  • Estrogens / physiology
  • Female
  • Gene Expression / genetics
  • Humans
  • Hypothalamus / physiology*
  • Kisspeptins
  • Macaca mulatta
  • Male
  • Neurokinin B / physiology*
  • Neurons / physiology
  • Postmenopause / physiology
  • Pregnancy
  • Receptors, Neurokinin-3 / agonists
  • Receptors, Neurokinin-3 / genetics
  • Receptors, Neurokinin-3 / physiology
  • Reproduction / physiology*
  • Sex Characteristics
  • Signal Transduction / physiology
  • Terminology as Topic
  • Tumor Suppressor Proteins / physiology


  • Estrogens
  • KISS1 protein, human
  • Kisspeptins
  • Receptors, Neurokinin-3
  • Tumor Suppressor Proteins
  • Dynorphins
  • Neurokinin B