Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: the first kiss—a crucial role for kisspeptin-1 and its receptor, G-protein-coupled receptor 54, in puberty and reproduction

Abstract

Although the hypothalamic secretion of gonadotropin-releasing hormone (GnRH) is the defining hormonal event of puberty, the physiologic mechanisms that drive secretion of GnRH at the time of sexual maturation have been difficult to identify. After puberty is initiated, the factors that modulate the frequency and amplitude of GnRH secretion in rapidly changing sex-steroid environments (i.e. the female menstrual cycle) also remain unknown. The discovery that, in both humans and mouse models, loss-of-function mutations in the gene that encodes G-protein-coupled receptor 54 result in phenotypes of hypogonadotropic hypogonadism with an absence of pubertal development has unearthed a novel pathway regulating GnRH secretion. Ligands for G-protein-coupled receptor 54 (KiSS-1R), including metastin (derived from the parent compound, kisspeptin-1) and metastin's C-terminal peptide fragments, have been shown to be powerful stimulants for GnRH release in vivo via their stimulation of G-protein-coupled receptor 54. This article reviews the discovery of the GPR54 gene, places it into the appropriate biological context, and explores the data from in vitro and in vivo studies that point to this ligand–receptor system as a major driver of GnRH secretion.

Key Points

  • Mutations in G-protein-coupled receptor 54 cause hypogonadotropic hypogonadism in mice and men, indicating that this receptor is essential for normal gonadotropin-releasing hormone physiology and puberty in mammals

  • Metastin is a potent stimulus for gonadotropin-releasing hormone and, by extension, luteinizing-hormone secretion

  • Expression of kisspeptin-1, the ligand for G-protein-coupled receptor 54, increases throughout the pubertal transition in rodents and primates

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Belchetz PE et al. (1978) Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 202: 631–633

    Article  CAS  Google Scholar 

  2. Spratt DI et al. (1988) Neuroendocrine–gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol 254: E658–E666

    CAS  PubMed  Google Scholar 

  3. Santoro N et al. (1988) Alterations of the hypothalamic GnRH interpulse interval sequence over the normal menstrual cycle. Am J Physiol 255: E696–E701

    CAS  PubMed  Google Scholar 

  4. Spratt DI et al. (1987) The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab 64: 283–291

    Article  CAS  Google Scholar 

  5. Santoro N et al. (1986) Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev 7: 11–23

    Article  CAS  Google Scholar 

  6. Berga SL et al. (1989) Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab 68: 301–308

    Article  CAS  Google Scholar 

  7. Perkins RB et al. (1999) Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation. J Clin Endocrinol Metab 84: 1905–1911

    CAS  PubMed  Google Scholar 

  8. Waldstreicher J et al. (1988) Hyperfunction of the hypothalamic–pituitary axis in women with polycystic ovarian disease: indirect evidence for partial gonadotroph desensitization. J Clin Endocrinol Metab 66: 165–172

    Article  CAS  Google Scholar 

  9. Tomera K et al. (2001) The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. J Urol 165: 1585–1589

    Article  CAS  Google Scholar 

  10. McLeod D et al. (2001) A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 58: 756–761

    Article  CAS  Google Scholar 

  11. Trachtenberg J et al. (2002) A phase 3, multicenter, open label, randomized study of abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer. J Urol 167: 1670–1674

    Article  CAS  Google Scholar 

  12. Weckermann D and Harzmann R (2004) Hormone therapy in prostate cancer: LHRH antagonists versus LHRH analogues. Eur Urol 46: 279–283

    Article  CAS  Google Scholar 

  13. Griesinger G et al. (2005) GnRH-antagonists in reproductive medicine. Arch Gynecol Obstet 273: 71–78

    Article  CAS  Google Scholar 

  14. Waldstreicher J et al. (1996) The genetic and clinical heterogeneity of gonadotropin-releasing hormone deficiency in the human. J Clin Endocrinol Metab 81: 4388–4395

    CAS  PubMed  Google Scholar 

  15. de Roux N et al. (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Nat Acad Sci USA 100: 10972–10976

    Article  CAS  Google Scholar 

  16. Seminara SB et al. (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349: 1614–1627

    Article  CAS  Google Scholar 

  17. Muir AI et al. (2001) AXOR12, a novel human G protein-coupled receptor, activated by the peptide Kiss-1. J Biol Chem 276: 28969–28975

    Article  CAS  Google Scholar 

  18. Lee DK et al. (1999) Discovery of a receptor related to the galanin receptors. FEBS Lett 446: 103–107

    Article  CAS  Google Scholar 

  19. Ohtaki T et al. (2001) Metastasis suppressor gene Kiss-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411: 613–617

    Article  CAS  Google Scholar 

  20. Kotani M et al. (2001) The metastasis suppressor gene Kiss-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 276: 34631–34636

    Article  CAS  Google Scholar 

  21. Shahab M et al. (2005) Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Nat Acad Sci USA 102: 2129–2134

    Article  CAS  Google Scholar 

  22. Gottsch ML et al. (2004) A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145: 4073–4077

    Article  CAS  Google Scholar 

  23. Irwig MS et al. (2004) Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of Kiss1 mRNA in the male rat. Neuroendocrinology 80: 264–272

    Article  CAS  Google Scholar 

  24. Messager SM et al. (2005) Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Nat Acad Sci USA 102: 1761–1766

    Article  CAS  Google Scholar 

  25. Navarro VM et al. (2004) Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145: 4565–4574

    Article  CAS  Google Scholar 

  26. Smith JT et al. (2005) Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146: 2976–2984

    Article  CAS  Google Scholar 

  27. Smith JT et al. (2005) Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146: 3686–3692

    Article  CAS  Google Scholar 

  28. Simerly RB (1998) Organization and regulation of sexually dimorphic neuroendocrine pathways. Behav Brain Res 92: 195–203

    Article  CAS  Google Scholar 

  29. Gu GB and Simerly RB (1997) Projections of the sexually dimorphic anteroventral periventricular nucleus in the female rat. J Comp Neurol 384: 142–164

    Article  CAS  Google Scholar 

  30. Matsui H et al. (2004) Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 320: 383–388

    Article  CAS  Google Scholar 

  31. Thompson EL et al. (2004) Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic–pituitary–gonadal axis. J Neuroendocrinol 16: 850–858

    Article  CAS  Google Scholar 

  32. Navarro VM et al. (2004) Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol 561: 379–386

    Article  CAS  Google Scholar 

  33. Dhillo WS et al. (2005) Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 90: 6609–6615

    Article  CAS  Google Scholar 

  34. Navarro VM et al. (2005) Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 146: 156–163

    Article  CAS  Google Scholar 

  35. Castellano JM et al. (2005) Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 146: 3917–3925

    Article  CAS  Google Scholar 

  36. Kinoshita M et al. (2005) Involvement of central metastin in the regulation of preovulatory LH surge and estrous cyclicity in female rats. Endocrinology 146: 4431–4436

    Article  CAS  Google Scholar 

  37. Lanfranco F et al. (2005) Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 153: 845–852

    Article  CAS  Google Scholar 

  38. Semple RK et al. (2005) Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 3: 1849–1855

    Article  Google Scholar 

  39. Cortes D et al. (1987) Proliferation of Sertoli cells during development of the human testis assessed by stereological methods. Int J Androl 10: 589–596

    Article  CAS  Google Scholar 

  40. Muller J and Skakkebaek NE (1984) Fluctuations in the number of germ cells during the late foetal and early postnatal periods in boys. Acta Endocrinol 105: 271–274

    Article  CAS  Google Scholar 

  41. Habiby RL et al. (1996) Adrenal hypoplasia congenita with hypogonadotropic hypogonadism. Evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. J Clin Invest 98: 1055–1062

    Article  CAS  Google Scholar 

  42. Seminara SB et al. (1999) X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females. J Clin Endocrinol Metab 84: 4501–4509

    CAS  PubMed  Google Scholar 

  43. Yu RN et al. (1998) Role of Ahch in gonadal development and gametogenesis. Nat Genet 20: 353–357

    Article  CAS  Google Scholar 

  44. Jeffs B et al. (2001) Blockage of the rete testis and efferent ductules by ectopic Sertoli and Leydig cells causes infertility in Dax1-deficient male mice. Endocrinology 142: 4486–4495

    Article  CAS  Google Scholar 

  45. Finkelstein JS et al. (1989) Pulsatile gonadotropin secretion after discontinuation of long term gonadotropin-releasing hormone (GnRH) administration in a subset of GnRH-deficient men. J Clin Endocrinol Metab 69: 377–385

    Article  CAS  Google Scholar 

  46. Quinton R et al. (1999) Kallmann's syndrome: is it always for life? Clin Endocrinol 50: 481–485

    Article  CAS  Google Scholar 

  47. Pitteloud N et al. (2001) The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 86: 2470–2474

    CAS  PubMed  Google Scholar 

  48. Pitteloud N et al. (2005) Reversible Kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. J Clin Endocrinol Metab 90: 1317–1322

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephanie B Seminara.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seminara, S. Mechanisms of Disease: the first kiss—a crucial role for kisspeptin-1 and its receptor, G-protein-coupled receptor 54, in puberty and reproduction. Nat Rev Endocrinol 2, 328–334 (2006). https://doi.org/10.1038/ncpendmet0139

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0139

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing