Kisspeptin – new control of reproduction: physiological aspects

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This article describes the physiological role of a recently discovered neuropeptide – kisspeptin, playing a key role in the regulation of reproductive function in humans and mammals. The features of structural and functional organization of kisspeptin system are discussed, as well as the impact of physiological aspects of activity of the suprachiasmatic nucleus neurons on it in the invitro studies.

  1. Adewale H.B., Jefferson W.N., Newbold R.R., Patisaul H.B. Neonatal bisphenol-A exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin releasing hormone neurons // Biol. Reprod. 2009. № 81. P. 690–699.
  2. Bai Y., Chang F., Zhou R., Jin P.P., Matsumoto H., Sokabe M. Increase of anteroventral periventricular kisspeptin neurons and generation of E2-induced LH-surge system in male rats exposed perinatally to environmental dose of bisphenol-A // Endocrinology. 2011. № 152. P. 1562–1571.
  3. Bateman H.L., Patisaul H.B. Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specifi c ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus // Neurotoxicology. 2008. № 29. P. 988–997.
  4. Burke M.C., Letts P.A., Krajewski S.J., Rance N.E. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus // J. Comp. Neurol. 2006. № 5. P. 712–726.
  5. Cao J., Mickens J.A., McCaffrey K.A., Leyrer S.M., Patisaul H.B. Neonatal bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus // Neurotoxicology. 2012. № 33. P. 23–36.
  6. Chan Y.M., Butler J.P., Sidhoum V.F., Pinnell N.E., Seminara S.B. Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle // J. Clin. Endocrinol. Metab. 2012. № 8. P. E1458–E1467.
  7. Cheng G., Coolen L.M., Padmanabhan V., Goodman R.L., Lehman M.N. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep // Endocrinology. 2010. № 1. P. 301–311.
  8. Ciofi P., Leroy D., Tramu G. Sexual dimorphism in the organization of the rat hypothalamic infundibular area // Neuroscience. 2006. № 4. P. 1731–1745.
  9. Clarkson J., Herbison A.E. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons // Endocrinology. 2006. № 12. P. 5817–5825.
  10. Constantin S., Caligioni C.S., Stojilkovic S., Wray S. Kisspeptin-10 facilitates a plasma membrane-driven calcium oscillator in gonadotropin-releasing hormone-1 neurons // Endocrinology. 2009. № 3. P. 1400–1412.
  11. De Roux N., Genin E., Carel J., Matsuda F., Chaussain J., Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 // Proc. Natl. Acad. Sci. USA. 2003. № 100. P. 10972– 10976.
  12. Dhillo W.S., Chaudhri O.B., Thompson E.L., Murphy K.G., Patterson M., Ramachandran R., Nijher G.K., Amber V., Kokkinos A., Donaldson M. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women // J. Clin. Endocrinol. Metab. 2007. № 10. P. 3958–3966.
  13. Dickerson S.M., Cunningham S.L., Gore A.C. Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus // Toxicol. Appl. Pharmacol. 2011. № 252. P. 36–46.
  14. Foradori C.D., Coolen L.M., Fitzgerald M.E., Skinner D.C., Goodman R.L., Lehman M.N. Colocalization of progesterone receptors in  arvicellular dynorphin neurons of the ovine preoptic area and hypothalamus // Endocrinology. 2002. № 11. P. 4366–4374.
  15. Franceschini I., Lomet D., Cateau M., Delsol G., Tillet Y., Caraty A. Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha // Neurosci. Lett. 2006. № 3. P. 225–230.
  16. Funes S., Hedrick J.A., Vassileva G., Markowitz L., Abbondanzo S., Golovko A., Yang S., Monsma F.J., Gustafson E.L. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system // Biochem. Biophys. Res. Commun. 2003. № 312. P. 1357–1363.
  17. George J.T., Anderson R.A., Millar R.P. Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback // Hum. Reprod. 2012. № 12. P. 3552–3559.
  18. George J.T., Millar R.P., Anderson R.A. Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes // Neuroendocrinology. 2010. № 4. P. 302–307.
  19. George J.T., Veldhuis J.D., Roseweir A.K., Newton C.L., Faccenda E., Millar R.P., Anderson R.A. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men // J. Clin. Endocrinol. Metab. 2011. № 8. P. E1228– E1236.
  20. George J.T., Veldhuis J.D., Tena-Sempere M., Millar R.P., Anderson R.A. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism // Clin. Endocrinol. (Oxf). 2013. № 1. P. 100–104.
  21. Goodman R.L., Lehman M.N.,Smith J.T., Coolen L.M., de Oliveira C.V., Jafarzadehshirazi M.R., Pereira A., Iqbal J., Caraty A., Ciofi P. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B // Endocrinology. 2007. № 12. P. 5752–5760.
  22. Goubillon M.L., Forsdike R.A., Robinson J.E., Ciofi P., Caraty A., Herbison A.E. Identification of neurokinin Bexpressing neurons as an highly estrogen-receptive, sexually dimorphic cell group in the ovine arcuate nucleus // Endocrinology. 2000. № 11. P. 4218–4225.
  23. Han S.K., Gottsch M.L., Lee K.J., Popa S.M., Smith J.T., Jakawich S.K., Clifton D.K., Steiner R.A., Herbison A.E. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty // J. Neurosci. 2005. № 49. P. 11349–11356.
  24. Herbison A.E. Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V) // Brain Res. Rev. 2008. № 2. P. 277–287.
  25. Herbison A.E., de Tassigny X., Doran J., Colledge W.H. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropinreleasing hormone neurons // Endocrinology. 2010. № 1. P. 312–321.
  26. Herbison A.E., Theodosis D.T. Localization of oestrogen receptors in preoptic neurons containing neurotensin but not tyrosine hydroxylase, cholecystokinin or luteinizing hormone-releasing hormone in the male and female rat // Neuroscience. 1992. № 2. P. 283–298.
  27. Horikoshi Y., Matsumoto H., Takatsu Y. Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans // J. Clin. Endocrinol. Metab. 2003. № 88. P. 914–919.
  28. Howdeshell K.L., Hotchkiss A.K., Thayer K.A., Vandenbergh J.G., vom Saal F.S. Exposure to bisphenol A advances puberty // Nature. 1999. № 401. P. 763–764.
  29. Hrabovszky E., Ciofi P., Vida B., Horvath M.C., Keller E., Caraty A., Bloom S.R., Ghatei M.A., Dhillo W.S., Liposits Z. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropinreleasing hormone and neurokinin B neurons. Eur. // J. Neurosci. 2010. № 11. P. 1984–1998.
  30. Irwig M.S., Fraley G.S., Smith J.T., Acohido B.V., Popa S.M., Cunningham M.J., Gottsch M.L., Clifton D.K., Steiner R.A. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat // Neuroendocrinology. 2004. № 4. P. 264–272.
  31. Jayasena C.N., Nijher G.M., Abbara A., Murphy K.G., Lim A., Patel D., Mehta A., Todd C., Donaldson M., Trew G.H. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea // Clin. Pharmacol. Ther. 2010. № 6. P. 840–847.
  32. Jayasena C.N., Nijher G.M., Chaudhri O.B., Murphy K.G., Ranger A., Lim A., Patel D., Mehta A., Todd C., Ramachandran R. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis // J. Clin. Endocrinol. Metab. 2009. № 11. P. 4315–4323.
  33. Kauffman A.S., Gottsch M.L., Roa J., Byquist A.C., Crown A., Clifton D.K., Hoffman G.E., Steiner R.A., TenaSempere M. Sexual differentiation of Kiss1 gene expression in the brain of the rat // Endocrinology. 2007. № 4. P. 1774–1783.
  34. Kotani M., Detheux M., Vandenbogaerde A., Communi D., Vanderwinden J.M., Le Poul E., Brezillon S., Tyldesley R., Suarez-Huerta N., Vandeput F. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54 // J. Biol. Chem. 2001. № 276. P. 34631–34636.
  35. Krajewski S.J., Anderson M.J., Iles-Shih L., Chen K.J., Urbanski H.F., Rance N.E. Morphologic evidence that neurokinin B modulates gonadotropin-releasing hormone secretion via neurokinin 3 receptors in the ratmedianeminence // J. Comp. Neurol. 2005. № 3. P. 372–386.
  36. Lee J.H., Miele M.E., Hicks D.J., Phillips K.K., Trent J.M.,Weissman B.E.,Welch D.R. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene // J. Natl. Cancer Inst. 1996. № 88. P. 1731–1737.
  37. Lee D.K., Nguyen T., O’Neill G.P., Cheng R., Liu Y., Howard A.D., Coulombe N., Tan C.P., Tang-Nguyen A.T., George S.R. Discovery of a receptor related to the galanin receptors // FEBS Lett. 1999. № 446. P. 103–107.
  38. Liu X., Lee K., Herbison A.E. Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels // Endocrinology. 2008. № 9. P. 4605–4614.
  39. Losa S.M., Todd K.L., Sullivan A.W., Cao J., Mickens J.A., Patisaul H.B. Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat // Reprod. Toxicol. 2010. № 31. P. 280–289.
  40. Messager S., Chatzidaki E.E., Ma D., Hendrick A.G., Zahn D., Dixon J., Thresher R.R., Malinge I., Lomet D., Carlton M.B. Kisspeptin directly stimulates gonadotropinreleasing hormone release via G protein-coupled receptor 54 // Proc. Natl. Acad. Sci. USA. 2005. № 5. P. 1761–1766.
  41. Min L., Soltis K., Reis A.C., Xu S., Kuohung W., Jain M., Carroll R.S., Kaiser U.B. Dynamic kisspeptin receptor trafficking modulates kisspeptin-mediated calcium signaling // Mol. Endocrinol. 2014. № 1. P. 16–27.
  42. Muir A.I., Chamberlain L., Elshourbagy N.A., Michalovich D., Moore D.J., Calamari A., Szekeres P.G., Sarau H.M., Chambers J.K., Murdock P. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1 // J. Biol. Chem. 2001. № 31. P. 28969–28975.
  43. Navarro V.M., Gottsch M.L., Chavkin C., Okamura H., Clifton D.K., Steiner R.A. Regulation of gonadotropinreleasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse // J. Neurosci. 2009. № 38. P. 11859–11866.
  44. Oakley A.E., Clifton D.K., Steiner R.A. Kisspeptin signaling in the brain // Endocr. Rev. 2009. № 6. P. 713–743.
  45. Ohtaki T., Shintani Y., Honda S., Matsumoto H., Hori A., Kanehashi K., Terao Y., Kumano S., Takatsu Y., Masuda Y. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor // Nature. 2001. №411. P. 613–617.
  46. Ojeda S.R., Dubay C., Lomniczi A., Kaidar G., Matagne V., Sandau U.S., Dissen G.A. Gene networks and the neuroendocrine regulation of puberty // Mol. Cell. Endocrinol. 2010. № 1–2. P. 3–11.
  47. Patisaul H.B. Effects of environmental endocrine disruptors and phytoestrogens on the kisspeptin system // Adv. Exp. Med. Biol. 2013. № 784. P. 455–479.
  48. Patisaul H.B., Jefferson W. The pros and cons of phytoestrogens // Front. Neuroendocrinol. 2010. № 31. P. 400–419.
  49. Patisaul H.B., Todd K.L., Mickens J.A., Adewale H.B. Impact of neonatal exposure to the ERalpha agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fi ber density in male and female rats // Neurotoxicology. 2009. № 30. P. 350–357.
  50. Pedersen-White J.R., Chorich L.P., Bick D.P., Sherins R.J., Layman L.C. The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome // Mol. Human Repr. 2008. № 14. P. 367–370.
  51. Pinilla L., Aguilar E., Dieguez C., Millar R.P., Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms // Physiol. Rev. 2012. № 3. P. 1235–1316.
  52. Ramaswamy S., Guerriero K.A., Gibbs R.B., Plant T.M. Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed by double immunofluorescence and confocal microscopy // Endocrinology. 2008. № 9. P. 4387–4395.
  53. Rometo A.M., Krajewski S.J., Voytko M.L., Rance N.E. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys // J. Clin. Endocrinol. Metab. 2007. № 7. P. 2744–2750.
  54. Seminara S.B., Messager S., Chatzidaki E.E., Thresher R.R., Acierno J.S. Jr., Shagoury J.K., Bo-Abbas Y., Kuohung W., Schwinof K.M., Hendrick A.G. The GPR54 gene as a regulator of puberty // New Eng. J. Med. 2003. № 349. P. 1614–1627.
  55. Smith J.T., Cunningham M.J., Rissman E.F., Clifton D.K., Steiner R.A. Regulation of Kiss1 gene expression in the brain of the female mouse // Endocrinology. 2005. № 9. P. 3686–3692.
  56. Steinberg R.M., Juenger T.E., Gore A.C. The effects of prenatal PCBs on adult female paced mating reproductive behaviors in rats // Horm. Behav. 2007. № 51. P. 364–372.
  57. Steinberg R.M., Walker D.M., Juenger T.E., Woller M.J., Gore A.C. Effects of perinatal polychlorinated biphenyls on adult female rat reproduction: development, reproductive physiology, and second generational effects // Biol. Reprod. 2008. № 78. P. 1091–1101.
  58. Teles M.G., Bianco S.D.C., Brito V.N., Trarbach E.B., Kuohung W., Xu S., Seminara S.B., Mendonca B.B., Kaiser U.B., Latronico A.C. A GPR54-activating mutation in a patient with central precocious puberty // New Eng. J. Med. 2008. № 358. P. 709–715.
  59. Teles M.G., Trarbach E.B., Noel S.D. A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism // Eur. J. Endocrinol. 2010. № 163. P. 29–34.
  60. Topaloglu A.K., Tello J.F., Kotan L.D. Inactivating KISS1 mutation and hypogonadotropic hypogonadism // New Eng. J. Med. 2012. № 366. P. 629–635.
  61. Uenoyama Y., Inoue N., Pheng V., Homma T., Takase K., Yamada S., Ajiki K., Ichikawa M., Okamura H., Maeda K.I. Ultrastructural evidence of kisspeptingonadotrophin-releasing hormone (GnRH) interaction in the median eminence of female rats: implication of axo-axonal regulation of GnRH release // J. Neuroendocrinol. 2011. № 10. P.863–870.
  62. Vandenberg L.N., Colborn T., Hayes T.B., Heindel J.J., Jacobs D.R. Jr., Lee D.H. Hormones and endocrinedisrupting chemicals: low-dose effects and nonmonotonic dose responses // Endocr. Rev. 2012. № 33. P. 378–455.
About the authors

  • A.N. Inyushkin
  • FGAOU VO «Samara national research university named after academician S.P. Korolyov», 443086, Samara, st. Moscow highway, 34, doctor of biological sciences, professor, head of the department of human and animal physiology

  • E.I. Grishina
  • FGAOU VO «Samara national research university named after academician S.P. Korolyov», 443086, Samara, st. Moscow highway, 34, graduate student of department of human and animal physiology

  • M.A. Tkacheva
  • FGAOU VO «Samara national research university named after academician S.P. Korolyov», 443086, Samara, st. Moscow highway, 34, graduate student of department of human and animal physiology