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The neuroendocrine physiology of kisspeptin in the human

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Abstract

Kisspeptin is a 54-amino acid peptide, encoded by the KiSS-1 gene, which activates the G protein-coupled receptor GPR54. Recent evidence suggests the kisspeptin/GPR54 system is a key regulator of reproduction. GPR54-deficient mice have abnormal sexual development. Central or peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis in animal models. This review discusses the evidence that kisspeptin also plays a key role in human reproduction. Inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism in humans. Mutations which increase GPR54 signaling are associated with gonadotrophin-dependant premature puberty. Acute intravenous administration of kisspeptin to healthy human male volunteers potently increased plasma LH levels and significantly increased plasma FSH and testosterone without side effects. Plasma kisspeptin is found at low concentrations in the circulation of men and non-pregnant women, but is markedly increased in pregnancy. The placenta is believed to be the source of these high levels of circulating kisspeptin. The kisspeptin-GPR54 system is also implicated in tumour biology. Consistent with this role, plasma kisspeptin concentrations are elevated in patients with abnormal proliferation of placental tissue (gestational trophoblastic neoplasia or GTN) at presentation and fall after treatment with chemotherapy. The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans. Kisspeptin represents a novel tool for the manipulation of the HPG axis in humans and plasma kisspeptin may be a novel tumour marker in patients with GTN.

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References

  1. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le PE, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001;276(37):34631–6.

    Article  PubMed  CAS  Google Scholar 

  2. Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996;88(23):1731–7.

    Article  PubMed  CAS  Google Scholar 

  3. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003;100(19):10972–6.

    Article  PubMed  CAS  Google Scholar 

  4. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Jr., Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349(17):1614–27.

    Article  PubMed  CAS  Google Scholar 

  5. Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 2003;312(4):1357–63.

    Article  PubMed  CAS  Google Scholar 

  6. Smith JT, Clifton DK, Steiner RA. Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling. Reproduction 2006;131(4):623–30.

    Article  PubMed  CAS  Google Scholar 

  7. Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF, Jr., Seminara SB. Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Mol Cell Endocrinol 2006;254–255:70–7.

    Article  PubMed  CAS  Google Scholar 

  8. Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, et al. Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005;90(3):1849–55.

    Article  PubMed  CAS  Google Scholar 

  9. Lanfranco F, Gromoll J, von ES, Herding EM, Nieschlag E, Simoni M. Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 2005;153(6):845–52.

    Article  PubMed  CAS  Google Scholar 

  10. Teles M, Bianco SZ, Brito VN, Trarbach E, Seminara SB, Arnhold IJ, et al. An activating mutation in GPR54 gene causes gonadotrophin-dependent precocious puberty. American Endocrine Society Meeting, Boston, USA, 2006. OR34–3.

  11. Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005;90(12):6609–15.

    Article  PubMed  CAS  Google Scholar 

  12. Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004; 320(2):383–8.

    Article  PubMed  CAS  Google Scholar 

  13. Thompson EL, Murphy KG, Patterson M, Bewick GA, Stamp GW, Curtis AE, et al. Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats. Am J Physiol Endocrinol Metab 2006;291(5):E1074–82.

    Article  PubMed  CAS  Google Scholar 

  14. Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A, et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology 2005;146(4):1689–97.

    Article  PubMed  CAS  Google Scholar 

  15. Mead EJ, Maguire JJ, Kuc RE, Davenport AP. Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor GPR54, to atherosclerosis prone vessels. Endocrinology 2007;148(1):140–7.

    Article  PubMed  CAS  Google Scholar 

  16. Seminara SB, Dipietro MJ, Ramaswamy S, Crowley WF, Jr., Plant TM. Continuous human metastin 45–54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology 2006;147(5):2122–6.

    Article  PubMed  CAS  Google Scholar 

  17. Wollesen F, Swerdloff RS, Odell WD. LH and FSH responses to luteinizing-releasing hormone in normal, adult, human males. Metabolism 1976;25(8):845–63.

    Article  PubMed  CAS  Google Scholar 

  18. Hudson RW, Crawford VA, McKay DE. The gonadotropin response of men with varicoceles to a four-hour infusion of gonadotropin-releasing hormone. Fertil Steril 1981;36(5):633–7.

    PubMed  CAS  Google Scholar 

  19. Fauser BC, Dony JM, Doesburg WH, Rolland R. The effect of pulsatile and continuous intravenous luteinizing hormone-releasing hormone administration on pituitary luteinizing hormone and follicle-stimulating hormone release in normal men. Fertil Steril 1983;39(5):695–9.

    PubMed  CAS  Google Scholar 

  20. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006;18(4):298–303.

    Article  PubMed  CAS  Google Scholar 

  21. Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 2005;146(9):3917–25.

    Article  PubMed  CAS  Google Scholar 

  22. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382(6588):250–2.

    Article  PubMed  CAS  Google Scholar 

  23. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111(9):1409–21.

    Article  PubMed  CAS  Google Scholar 

  24. Chan JL, Matarese G, Shetty GK, Raciti P, Kelesidis I, Aufiero D, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci USA 2006;103(22):8481–6.

    Article  PubMed  CAS  Google Scholar 

  25. Kalra SP, Sahu A, Kalra PS, Crowley WR. Hypothalamic neuropeptide Y: a circuit in the regulation of gonadotropin secretion and feeding behavior. Ann N Y Acad Sci 1990;611:273–83.

    Article  PubMed  CAS  Google Scholar 

  26. Watanobe H, Nigawara T, Anzai J, Sakihara S, Kageyama K, Nasushita R, et al. Neuropeptide Y potentiates the luteinizing hormone (LH) response to LH-releasing hormone in men. Biochem Biophys Res Commun 1994;200(2):1111–7.

    Article  PubMed  CAS  Google Scholar 

  27. Schainker BA, Cicero TJ. Acute central stimulation of luteinizing hormone by parenterally administered N-methyl-D,L-aspartic acid in the male rat. Brain Res 1980;184(2):425–37.

    Article  PubMed  CAS  Google Scholar 

  28. Medhamurthy R, Gay VL, Plant TM. Repetitive injections of L-glutamic acid, in contrast to those of N-methyl-D,L-aspartic acid, fail to elicit sustained hypothalamic GnRH release in the prepubertal male rhesus monkey (Macaca mulatta). Neuroendocrinology 1992;55(6):660–6.

    PubMed  CAS  Google Scholar 

  29. van Berckel BN, Lipsch C, Gispen-de WC, Wynne HJ, Blankenstein MA, van Ree JM, et al. The partial NMDA agonist D-cycloserine stimulates LH secretion in healthy volunteers. Psychopharmacology (Berl) 1998;138(2):190–7.

    Article  Google Scholar 

  30. Vijayan E, McCann SM. In vivo and in vitro effects of substance P and neurotensin on gonadotropin and prolactin release. Endocrinology 1979;105(1):64–8.

    Article  PubMed  CAS  Google Scholar 

  31. Coiro V, Volpi R, Capretti L, Caiazza A, Marcato A, Bocchi R, et al. Luteinizing hormone response to an intravenous infusion of substance P in normal men. Metabolism 1992;41(7):689–91.

    Article  PubMed  CAS  Google Scholar 

  32. Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S, et al. Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans. J Clin Endocrinol Metab 2003;88(2):914–9.

    Article  PubMed  CAS  Google Scholar 

  33. Carvalho-Bianco SD, Teles M, Kuohung W, Xu S, Latronico AC, Kaiser UB. Role of GPR54 desensitization in kisspeptin action. American Endocrine Society Meeting, Boston, USA, 2006. P3–25.

  34. Panidis D, Rousso D, Koliakos G, Kourtis A, Katsikis I, Farmakiotis D, et al. Plasma metastin levels are negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome. Fertil Steril 2006; 85(6):1778–83.

    Article  PubMed  CAS  Google Scholar 

  35. Dhillo WS, Savage P, Murphy KG, Chaudhri OB, Patterson M, Nijher GM, et al. Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment. Am J Physiol Endocrinol Metab 2006;291(5):E878–84.

    Article  PubMed  CAS  Google Scholar 

  36. Kuohung W, Ni JJ, Mukhtyar D, Crowley WF, Glicksman MA, Kaiser UB. High throughput screening for modulators of the G protein-coupled receptor GPR54. American Endocrine Society Meeting, Boston, USA, 2006. OR25–3.

  37. Tomita K, Niida A, Oishi S, Ohno H, Cluzeau J, Navenot JM, et al. Structure-activity relationship study on small peptidic GPR54 agonists. Bioorg Med Chem 2006;14(22):7595–603.

    Article  PubMed  CAS  Google Scholar 

  38. Niida A, Wang Z, Tomita K, Oishi S, Tamamura H, Otaka A, et al. Design and synthesis of downsized metastin (45–54) analogs with maintenance of high GPR54 agonistic activity. Bioorg Med Chem Lett 2006;16(1):134–7.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

W.S.D. is funded by a Department of Health Clinician Scientist Fellowship. K.G.M. is supported by a Biotechnology and Biological Sciences Research Council New Investigator Award.

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  1. Department of Metabolic Medicine, Faculty of Medicine, Imperial College London, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12-ONN, UK

    Waljit S Dhillo, Kevin G Murphy & Stephen R Bloom

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  1. Waljit S Dhillo
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  2. Kevin G Murphy
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Correspondence to Stephen R Bloom.

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Dhillo, W.S., Murphy, K.G. & Bloom, S.R. The neuroendocrine physiology of kisspeptin in the human. Rev Endocr Metab Disord 8, 41–46 (2007). https://doi.org/10.1007/s11154-007-9029-1

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  • DOI: https://doi.org/10.1007/s11154-007-9029-1

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