Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats

J Reprod Dev. 2007 Apr;53(2):367-78. doi: 10.1262/jrd.18146. Epub 2007 Jan 10.


Metastin/kisspeptin, the KiSS-1 gene product, has been identified as an endogenous ligand of GPR54 that reportedly regulates GnRH/LH surges and estrous cyclicity in female rats. The aim of the present study was to determine if metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges. We demonstrated that preoptic area (POA) infusion of the anti-rat metastin/kisspeptin monoclonal antibody blocked the estrogen-induced LH surge, indicating that endogenous metastin/kisspeptin released around the POA mediates the estrogen positive feedback effect on GnRH/LH release. Metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) may be responsible for mediating the feedback effect because the percentage of c-Fos-expressing KiSS-1 mRNA-positive cells to total KiSS-1 mRNA-positive cells was significantly higher in the afternoon than in the morning in the anteroventral periventricular nucleus (AVPV) of high estradiol (E(2))-treated females. The percentage of c-Fos-expressing metastin/kisspeptin neurons was not different between the afternoon and morning in the arcuate nucleus (ARC). Most of the KiSS-1 mRNA expressing cells contain ERalpha immunoreactivity in the AVPV and ARC. In addition, AVPV KiSS-1 mRNA expressions were highest in the proestrous afternoon and lowest in the diestrus 1 in females and were increased by estrogen treatment in ovariectomized animals. On the other hand, the ARC KiSS-1 mRNA expressions were highest at diestrus 2 and lowest at proestrous afternoon and were increased by ovariectomy and decreased by high estrogen treatment. Males lacking the surge mode of GnRH/LH release showed no obvious cluster of metastin/kisspeptin-immunoreactive neurons in the AVPV when compared with high E(2)-treated females, which showed a much greater density of these neurons. Taken together, the present study demonstrates that the AVPV metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges in female rats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anterior Thalamic Nuclei / drug effects
  • Anterior Thalamic Nuclei / metabolism*
  • Antibodies, Monoclonal / administration & dosage
  • Arcuate Nucleus of Hypothalamus / drug effects
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Estradiol / administration & dosage
  • Estrogen Receptor alpha / drug effects
  • Estrogen Receptor alpha / genetics
  • Estrogens / metabolism*
  • Estrous Cycle / physiology
  • Feedback, Physiological
  • Female
  • Gene Expression Regulation
  • Gonadotropin-Releasing Hormone / metabolism
  • Kisspeptins
  • Luteinizing Hormone / metabolism*
  • Male
  • Neurons / metabolism*
  • Preoptic Area / drug effects
  • Proteins / genetics
  • Proteins / immunology
  • Proteins / metabolism*
  • Proto-Oncogene Proteins c-fos / drug effects
  • Proto-Oncogene Proteins c-fos / genetics
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / drug effects
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Kisspeptin-1


  • Antibodies, Monoclonal
  • Estrogen Receptor alpha
  • Estrogens
  • Kiss1 protein, rat
  • Kiss1r protein, rat
  • Kisspeptins
  • Proteins
  • Proto-Oncogene Proteins c-fos
  • Receptors, G-Protein-Coupled
  • Receptors, Kisspeptin-1
  • Gonadotropin-Releasing Hormone
  • Estradiol
  • Luteinizing Hormone