Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals

Lance J. Kriegsfeld*, Dan Feng Mei, George E. Bentley, Takayoshi Ubuka, Alex O. Mason, Kasuhiko Inoue, Kazuyoshi Ukena, Kazuyoshi Tsutsui, Rae Silver

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

483 Citations (Scopus)


Successful reproduction requires maintenance of the reproductive axis within fine operating limits through negative feedback actions of sex steroids. Despite the importance of this homeostatic process, our understanding of the neural loci, pathways, and neurochemicals responsible remain incomplete. Here, we reveal a neuropeptidergic pathway that directly links gonadal steroid actions to regulation of the reproductive system. An RFamide (Arg-Phe-NH2) peptide that inhibits gonadotropin release from quail pituitary was recently identified and named gonadotropin-inhibitory hormone (GnIH). Birds are known to have specialized adaptations associated with gonadotropin-releasing hormone (GnRH) regulation to optimize reproduction (e.g., encephalic photoreceptors), and the existence of a hypothalamic peptide inhibiting gonadotropins may or may not be another such specialization. To determine whether GnIH serves as a signaling pathway for sex steroid regulation of the reproductive axis, we used immunohistochemistry and in situ hybridization to characterize the distribution and functional role of this peptide in hamsters, rats, and mice. GnIH-immunoreactive (GnIH-ir) cell bodies are clustered in the mediobasal hypothalamus with pronounced projections and terminals throughout the CNS. In vivo GnIH administration rapidly inhibits luteinizing hormone secretion. Additionally, GnIH-ir neurons form close appositions with GnRH cells, suggesting a direct means of GnRH modulation. Finally, GnIH-ir cells express estrogen receptor-α and exhibit robust immediate early gene expression after gonadal hormone stimulation. Taken together, the distribution of GnIH efferents to neural sites regulating reproductive behavior and neuroendocrine secretions, expression of steroid receptors in GnIH-ir nuclei, and GnIH inhibition of luteinizing hormone secretion indicate the discovery of a system regulating the mammalian reproductive axis.

Original languageEnglish
Pages (from-to)2410-2415
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number7
Publication statusPublished - 2006 Feb 14
Externally publishedYes


  • Luteinizing
  • Mating
  • Reproduction

ASJC Scopus subject areas

  • Genetics
  • General


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