The KiNG of reproduction: Kisspeptin/ nNOS interactions shaping hypothalamic GnRH release

Mol Cell Endocrinol. 2021 Jul 15:532:111302. doi: 10.1016/j.mce.2021.111302. Epub 2021 May 5.


Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating a GnRH pulse and surge remain a topic of debate. In this review we challenge the view of kisspeptin as an absolute "monarch", and instead present the idea of a Kisspeptin-nNOS-GnRH or "KiNG" network that is responsible for generating the "GnRH pulse" and "GnRH surge". In particular, the neuromodulator nitric oxide (NO) has opposite effects to kisspeptin on GnRH secretion in many respects, acting as the Yin to kisspeptin's Yang and creating a dynamic system in which kisspeptin provides the "ON" signal, promoting GnRH release, while NO mediates the "OFF" signal, acting as a tonic brake on GnRH secretion. This interplay between an activator and an inhibitor, which is in turn fine-tuned by the gonadal steroid environment, thus leads to the generation of GnRH pulses and surges and is crucial for the proper development and function of the reproductive axis.

Keywords: Estrogen; GnRH pulse; GnRH surge; Kisspeptin; Nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Gonadotropin-Releasing Hormone / metabolism*
  • Humans
  • Hypothalamus / metabolism*
  • Kisspeptins / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type I / metabolism*


  • KISS1 protein, human
  • Kisspeptins
  • Nitric Oxide
  • Gonadotropin-Releasing Hormone
  • NOS1 protein, human
  • Nitric Oxide Synthase Type I