Kisspeptin Hormone: Revolution in Reproductive System Physiology

REVIEW
Mohamed A. Abdelaziz

 
International Journal of Biomedicine. 2023;13(4):197-206.
DOI: 10.21103/Article13(4)_RA1
Originally published December 5, 2023

Abstract: 

The control of reproduction has been attributed to the actions and feedforward of the sex steroids gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). However, recent findings, including the identification of kisspeptin neurons and a kisspeptin-GnRH-LH/FSH axis, have prompted a reevaluation of reproductive regulation. At first, the KISS1 gene encoding kisspeptin was thought to belong to a group of genes called metastasis suppressors. Vertebrate and mammalian genomes have been enriched with Kiss and KissR gene variations during the last two decades. In 2003, kisspeptins and their receptor, KISS1R, and their role in the neuroendocrine-reproductive axis were discovered. This finding radically altered our understanding of reproductive physiology. These discoveries support the role of kisspeptins and their receptor as gatekeepers of sexual maturity at the outset of puberty and as key processors in the adult-life dynamic control of the gonadotropic axis.  The significance of kisspeptin signaling in spermatogenesis and sperm quality is still debatable, even though Kiss1 and Kiss1R are expressed peripherally in the testes. Numerous processes, including steroidogenesis, follicular maturation, ovulation, and ovarian senescence, are affected by kisspeptin activity. Therefore, kisspeptin analogs (both agonists and antagonists) may be useful as therapies for those with disorders affecting the reproductive system. This overview focuses on the evolution, localization, and reproductive importance of the Kiss–KissR pair.

Keywords: 
kisspeptin • KISS1 • KISS1R • kisspeptin analogs • kisspeptin-GnRH-LH/FSH axis
References: 
  1. Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996 Dec 4;88(23):1731-7. doi: 10.1093/jnci/88.23.1731. Erratum in: J Natl Cancer Inst 1997 Oct 15;89(20):1549. 
  2. West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998 Nov 15;54(1):145-8. doi: 10.1006/geno.1998.5566. 
  3. Hu KL, Zhao H, Chang HM, Yu Y, Qiao J. Kisspeptin/Kisspeptin Receptor System in the Ovary. Front Endocrinol (Lausanne). 2018 Jan 4;8:365. doi: 10.3389/fendo.2017.00365.
  4. Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-Nguyen AT, George SR, O'Dowd BF. Discovery of a receptor related to the galanin receptors. FEBS Lett. 1999 Mar 5;446(1):103-7. doi: 10.1016/s0014-5793(99)00009-5. 
  5. Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001 Aug 3;276(31):28969-75. doi: 10.1074/jbc.M102743200.
  6. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001 May 31;411(6837):613-7. doi: 10.1038/35079135.
  7. Kolakowski LF Jr, O'Neill GP, Howard AD, Broussard SR, Sullivan KA, Feighner SD, Sawzdargo M, Nguyen T, Kargman S, Shiao LL, Hreniuk DL, Tan CP, Evans J, Abramovitz M, Chateauneuf A, Coulombe N, Ng G, Johnson MP, Tharian A, Khoshbouei H, George SR, Smith RG, O'Dowd BF. Molecular characterization and expression of cloned human galanin receptors GALR2 and GALR3. J Neurochem. 1998 Dec;71(6):2239-51. doi: 10.1046/j.1471-4159.1998.71062239.x. PMID: 9832121.
  8. Szeliga A, Meczekalsk B. Kisspeptin Modulation of Reproductive Function. Endocrines.2022;3(3):367-374.  doi: 10.3390/endocrines3030029
  9. Anderson RA, Millar RP. The roles of kisspeptin and neurokinin B in GnRH pulse generation in humans, and their potential clinical application. J Neuroendocrinol. 2022 May;34(5):e13081. doi: 10.1111/jne.13081.
  10. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001 May 31;411(6837):613-7. doi: 10.1038/35079135.
  11. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001 Sep 14;276(37):34631-6. doi: 10.1074/jbc.M104847200. 
  12. Tsukamura H. Kobayashi Award 2019: The neuroendocrine regulation of the mammalian reproduction. Gen Comp Endocrinol. 2022 Jan 1;315:113755. doi: 10.1016/j.ygcen.2021.113755.
  13. Meccariello R. The kisspeptin system in male reproduction. Endocrines.2022;3(2):168-174.‏ doi:10.3390/endocrines3020015
  14. Sobrino V, Avendaño MS, Perdices-López C, Jimenez-Puyer M, Tena-Sempere M. Kisspeptins and the neuroendocrine control of reproduction: Recent progress and new frontiers in kisspeptin research. Front Neuroendocrinol. 2022 Apr;65:100977. doi: 10.1016/j.yfrne.2021.100977. 
  15. 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 Sep 16;100(19):10972-6. doi: 10.1073/pnas.1834399100.
  16. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003 Oct 23;349(17):1614-27. doi: 10.1056/NEJMoa035322.
  17. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001 Sep 14;276(37):34631-6. doi: 10.1074/jbc.M104847200.
  18. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001 May 31;411(6837):613-7. doi: 10.1038/35079135.
  19. Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005 Sep;146(9):3686-92. doi: 10.1210/en.2005-0488. Epub 2005 May 26.
  20. Clarkson J, Herbison AE. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology. 2006 Dec;147(12):5817-25. doi: 10.1210/en.2006-0787.
  21. Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K, Sugiura H, Ohtaki T, Matsumoto H, Uenoyama Y, Tsukamura H, Inoue K, Maeda K. 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. 
  22. 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 Jul 3;401(3):225-30. doi: 10.1016/j.neulet.2006.03.039.
  23. Li D, Mitchell D, Luo J, Yi Z, Cho SG, Guo J, Li X, Ning G, Wu X, Liu M. Estrogen regulates KiSS1 gene expression through estrogen receptor alpha and SP protein complexes. Endocrinology. 2007 Oct;148(10):4821-8. doi: 10.1210/en.2007-0154.
  24. Chianese R, Colledge WH, Fasano S, Meccariello R. Editorial: The Multiple Facets of Kisspeptin Activity in Biological Systems. Front Endocrinol (Lausanne). 2018 Dec 3;9:727. doi: 10.3389/fendo.2018.00727.
  25. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003 Oct 23;349(17):1614-27. doi: 10.1056/NEJMoa035322. 
  26. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev. 2009 Oct;30(6):713-43. doi: 10.1210/er.2009-0005.
  27. Pierantoni R, Cobellis G, Meccariello R, Fasano S. Evolutionary aspects of cellular communication in the vertebrate hypothalamo-hypophysio-gonadal axis. Int Rev Cytol. 2002;218:69-141. doi: 10.1016/s0074-7696(02)18012-0.
  28.  d'Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, Aparicio SA, Colledge WH. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10714-9. doi: 10.1073/pnas.0704114104.
  29. Trevisan CM, Montagna E, de Oliveira R, Christofolini DM, Barbosa CP, Crandall KA, Bianco B. Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction? Cell Physiol Biochem. 2018;49(4):1259-1276. doi: 10.1159/000493406.
  30. Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB. Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology. 2007 Oct;148(10):4927-36. doi: 10.1210/en.2007-0078. 
  31. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012 Jul;92(3):1235-316. doi: 10.1152/physrev.00037.2010.
  32. Novaira HJ, Fadoju D, Diaczok D, Radovick S. Genetic mechanisms mediating kisspeptin regulation of GnRH gene expression. J Neurosci. 2012 Nov 28;32(48):17391-400. doi: 10.1523/JNEUROSCI.2438-12.2012.
  33. Novaira HJ, Sonko ML, Radovick S. Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression. Mol Neurobiol. 2016 Jul;53(5):3315-3325. doi: 10.1007/s12035-015-9269-0.
  34. Motti ML, Meccariello R. Minireview: The Epigenetic Modulation of KISS1 in Reproduction and Cancer. Int J Environ Res Public Health. 2019 Jul 22;16(14):2607. doi: 10.3390/ijerph16142607.
  35. Santoro A, Chianese R, Troisi J, Richards S, Nori SL, Fasano S, Guida M, Plunk E, Viggiano A, Pierantoni R, Meccariello R. Neuro-toxic and Reproductive Effects of BPA. Curr Neuropharmacol. 2019;17(12):1109-1132. doi: 10.2174/1570159X17666190726112101.
  36.  Wyatt AK, Zavodna M, Viljoen JL, Stanton JA, Gemmell NJ, Jasoni CL. Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. Genet Epigenet. 2013 Oct 24;5:51-62. doi: 10.4137/GEG.S12897.
  37. Vazquez MJ, Toro CA, Castellano JM, Ruiz-Pino F, Roa J, Beiroa D, Heras V, Velasco I, Dieguez C, Pinilla L, Gaytan F, Nogueiras R, Bosch MA, Rønnekleiv OK, Lomniczi A, Ojeda SR, Tena-Sempere M. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat Commun. 2018 Oct 10;9(1):4194. doi: 10.1038/s41467-018-06459-9.
  38. D'Angelo S, Mele E, Di Filippo F, Viggiano A, Meccariello R. Sirt1 Activity in the Brain: Simultaneous Effects on Energy Homeostasis and Reproduction. Int J Environ Res Public Health. 2021 Jan 30;18(3):1243. doi: 10.3390/ijerph18031243.
  39. Herbison AE, Porteous R, Pape JR, Mora JM, Hurst PR. Gonadotropin-releasing hormone neuron requirements for puberty, ovulation, and fertility. Endocrinology. 2008 Feb;149(2):597-604. doi: 10.1210/en.2007-1139.
  40. Constantin S. Physiology of the gonadotrophin-releasing hormone (GnRH) neurone: studies from embryonic GnRH neurones. J Neuroendocrinol. 2011 Jun;23(6):542-53. doi: 10.1111/j.1365-2826.2011.02130.x.
  41. Dubois SL, Acosta-Martínez M, DeJoseph MR, Wolfe A, Radovick S, Boehm U, Urban JH, Levine JE. Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology. 2015 Mar;156(3):1111-20. doi: 10.1210/en.2014-1851.
  42. Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci. 2005 Dec 7;25(49):11349-56. doi: 10.1523/JNEUROSCI.3328-05.2005. 
  43. Uenoyama Y, Nakamura S, Hayakawa Y, Ikegami K, Watanabe Y, Deura C, Minabe S, Tomikawa J, Goto T, Ieda N, Inoue N, Sanbo M, Tamura C, Hirabayashi M, Maeda KI, Tsukamura H. Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. J Neuroendocrinol. 2015 Mar;27(3):187-97. doi: 10.1111/jne.12257.
  44. Uenoyama Y, Inoue N, Nakamura S, Tsukamura H. Central Mechanism Controlling Pubertal Onset in Mammals: A Triggering Role of Kisspeptin. Front Endocrinol (Lausanne). 2019 May 21;10:312. doi: 10.3389/fendo.2019.00312. 
  45. Avendaño MS, Vazquez MJ, Tena-Sempere M. Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty. Hum Reprod Update. 2017 Nov 1;23(6):737-763. doi: 10.1093/humupd/dmx025.
  46. Terasawa E, Guerriero KA, Plant TM. Kisspeptin and puberty in mammals. Adv Exp Med Biol. 2013;784:253-73. doi: 10.1007/978-1-4614-6199-9_12.
  47. Plant TM. 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-pituitary-gonadal axis. J Endocrinol. 2015 Aug;226(2):T41-54. doi: 10.1530/JOE-15-0113.
  48. Clarke IJ. Hypothalamus as an endocrine organ. Compr Physiol. 2015 Jan;5(1):217-53. doi: 10.1002/cphy.c140019.
  49. Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53-88. doi: 10.1016/b978-0-12-571136-4.50008-5.
  50. Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN. The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology. 2010 Jan;151(1):301-11. doi: 10.1210/en.2009-0541.
  51. Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology. 2007 Dec;148(12):5752-60. doi: 10.1210/en.2007-0961.
  52. Navarro VM. Metabolic regulation of kisspeptin - the link between energy balance and reproduction. Nat Rev Endocrinol. 2020 Aug;16(8):407-420. doi: 10.1038/s41574-020-0363-7.
  53. Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci. 2009 Sep 23;29(38):11859-66. doi: 10.1523/JNEUROSCI.1569-09.2009.
  54. Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014 Jul-Aug;20(4):485-500. doi: 10.1093/humupd/dmu009.
  55. Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Interactions Between Neurokinin B and Kisspeptin in Mediating Estrogen Feedback in Healthy Women. J Clin Endocrinol Metab. 2016 Dec;101(12):4628-4636. doi: 10.1210/jc.2016-2132.
  56. Castellano JM, Gaytan M, Roa J, Vigo E, Navarro VM, Bellido C, Dieguez C, Aguilar E, Sánchez-Criado JE, Pellicer A, Pinilla L, Gaytan F, Tena-Sempere M. Expression of KiSS-1 in rat ovary: putative local regulator of ovulation? Endocrinology. 2006 Oct;147(10):4852-62. doi: 10.1210/en.2006-0117.
  57. Gaytán F, Gaytán M, Castellano JM, Romero M, Roa J, Aparicio B, Garrido N, Sánchez-Criado JE, Millar RP, Pellicer A, Fraser HM, Tena-Sempere M. KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction. Am J Physiol Endocrinol Metab. 2009 Mar;296(3):E520-31. doi: 10.1152/ajpendo.90895.2008.
  58. Fernandois D, Na E, Cuevas F, Cruz G, Lara HE, Paredes AH. Kisspeptin is involved in ovarian follicular development during aging in rats. J Endocrinol. 2016 Mar;228(3):161-70. doi: 10.1530/JOE-15-0429.
  59. Jayasena CN, Abbara A, Comninos AN, Nijher GM, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Sridharan M, Mason AJ, Warwick J, Ashby D, Ghatei MA, Bloom SR, Carby A, Trew GH, Dhillo WS. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest. 2014 Aug;124(8):3667-77. doi: 10.1172/JCI75730.
  60. Abbara A, Clarke S, Islam R, Prague JK, Comninos AN, Narayanaswamy S, Papadopoulou D, Roberts R, Izzi-Engbeaya C, Ratnasabapathy R, Nesbitt A, Vimalesvaran S, Salim R, Lavery SA, Bloom SR, Huson L, Trew GH, Dhillo WS. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Hum Reprod. 2017 Sep 1;32(9):1915-1924. doi: 10.1093/humrep/dex253. 
  61. Cielesh ME, McGrath BM, Scott CJ, Norman ST, Stephen CP. The localization of kisspeptin and kisspeptin receptor in the canine ovary during different stages of the reproductive cycle. Reprod Domest Anim. 2017 Apr;52 Suppl 2:24-28. doi: 10.1111/rda.12841.
  62. Pierantoni R, Cobellis G, Meccariello R, Fasano S. Evolutionary aspects of cellular communication in the vertebrate hypothalamo-hypophysio-gonadal axis. Int Rev Cytol. 2002;218:69-141. doi: 10.1016/s0074-7696(02)18012-0.
  63. Chianese R, Cobellis G, Chioccarelli T, Ciaramella V, Migliaccio M, Fasano S, Pierantoni R, Meccariello R. Kisspeptins, Estrogens and Male Fertility. Curr Med Chem. 2016;23(36):4070-4091. doi: 10.2174/0929867323666160902155434.
  64. Sharma A, Thaventhiran T, Minhas S, Dhillo WS, Jayasena CN. Kisspeptin and Testicular Function-Is it Necessary? Int J Mol Sci. 2020 Apr 22;21(8):2958. doi: 10.3390/ijms21082958.
  65.  Meccariello R, Fasano S, Pierantoni R. Kisspeptins, new local modulators of male reproduction: A comparative overview. Gen Comp Endocrinol. 2020 Dec 1;299:113618. doi: 10.1016/j.ygcen.2020.113618.
  66. Ramzan MH, Ramzan M, Ramzan F, et al. (2015) Insight into the serum kisspeptin levels in infertile males. Arch. Iran Med. 18(1):12-7.
  67. Kotani M, Katagiri F, Hirai T, Kagawa J. Plasma kisspeptin levels in male cases with hypogonadism. Endocr J. 2014;61(11):1137-40.
  68. Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O'rahilly S, Aparicio SA. Two novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2005 Mar;90(3):1849-55. doi: 10.1210/jc.2004-1418.
  69.  Nimri R, Lebenthal Y, Lazar L, Chevrier L, Phillip M, Bar M, Hernandez-Mora E, de Roux N, Gat-Yablonski G. A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab. 2011 Mar;96(3):E536-45. doi: 10.1210/jc.2010-1676.
  70. León S, Barroso A, Vázquez MJ, García-Galiano D, Manfredi-Lozano M, Ruiz-Pino F, Heras V, Romero-Ruiz A, Roa J, Schutz G, Kirilov M, Gaytan F, Pinilla L, Tena-Sempere M. Direct Actions of Kisspeptins on GnRH Neurons Permit Attainment of Fertility but are Insufficient to Fully Preserve Gonadotropic Axis Activity. Sci Rep. 2016 Jan 12;6:19206. doi: 10.1038/srep19206.
  71. Goto T, Hirabayashi M, Watanabe Y, Sanbo M, Tomita K, Inoue N, Tsukamura H, Uenoyama Y. Testosterone Supplementation Rescues Spermatogenesis and In Vitro Fertilizing Ability of Sperm in Kiss1 Knockout Mice. Endocrinology. 2020 Sep 1;161(9):bqaa092. doi: 10.1210/endocr/bqaa092.
  72.  Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R. Kisspeptin receptor, GPR54, as a candidate for the regulation of testicular activity in the frog Rana esculenta. Biol Reprod. 2013 Mar 28;88(3):73. doi: 10.1095/biolreprod.112.103515.
  73. Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R. Kisspeptin drives germ cell progression in the anuran amphibian Pelophylax esculentus: a study carried out in ex vivo testes. Gen Comp Endocrinol. 2015 Jan 15;211:81-91. doi: 10.1016/j.ygcen.2014.11.008.
  74. Aytürk N, Firat T, Kükner A, Özoğul C, Töre F, Kandirali İE, Yilmaz B. The effect of kisspeptin on spermatogenesis and apoptosis in rats. Turk J Med Sci. 2017 Feb 27;47(1):334-342. doi: 10.3906/sag-1505-69.
  75. Ramzan F, Qureshi IZ. Intraperitoneal kisspeptin-10 administration induces dose-dependent degenerative changes in maturing rat testes. Life Sci. 2011 Jan 31;88(5-6):246-56. doi: 10.1016/j.lfs.2010.11.019.
  76. 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 May;147(5):2122-6. doi: 10.1210/en.2005-1550. 
  77. Wang JY, Hsu MC, Tseng TH, Wu LS, Yang KT, Chiu CH. Kisspeptin expression in mouse Leydig cells correlates with age. J Chin Med Assoc. 2015 Apr;78(4):249-57. doi: 10.1016/j.jcma.2015.01.004.
  78. Chiang CM, Chiu HY, Jong DS, Wu LS, Lee YJ, Chiu CH. Role of the kisspeptin/KISS1 receptor system in the testicular development of mice. J Chin Med Assoc. 2021 Feb 1;84(2):203-211. doi: 10.1097/JCMA.0000000000000443f. 
  79. Petrucci L, Maranesi M, Verini Supplizi A, Dall'Aglio C, Mandara MT, Quassinti L, Bramucci M, Miano A, Gobbetti A, Catone G, Boiti C, Zerani M. Kisspeptin/GnRH1 system in Leydig cells of horse (Equus caballus): Presence and function. Theriogenology. 2020 Aug;152:1-7. doi: 10.1016/j.theriogenology.2020.04.006.
  80. Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R. Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian. Reproduction. 2017 Oct;154(4):403-414. doi: 10.1530/REP-17-0030.
  81. Toolee H, Rastegar T, Solhjoo S, Mortezaee K, Mohammadipour M, Kashani IR, Akbari M. Roles for Kisspeptin in proliferation and differentiation of spermatogonial cells isolated from mice offspring when the cells are cocultured with somatic cells. J Cell Biochem. 2019 Apr;120(4):5042-5054. doi: 10.1002/jcb.27780. 
  82. Mele E, D'Auria R, Scafuro M, Marino M, Fasano S, Viggiano A, Pierantoni R, Santoro A, Meccariello R. Differential Expression of Kisspeptin System and Kisspeptin Receptor Trafficking during Spermatozoa Transit in the Epididymis. Genes (Basel). 2022 Feb 2;13(2):295. doi: 10.3390/genes13020295.
  83. Pinto FM, Cejudo-Román A, Ravina CG, Fernández-Sánchez M, Martín-Lozano D, Illanes M, Tena-Sempere M, Candenas ML. Characterization of the kisspeptin system in human spermatozoa. Int J Androl. 2012 Feb;35(1):63-73. doi: 10.1111/j.1365-2605.2011.01177.x.
  84. Hsu MC, Wang JY, Lee YJ, Jong DS, Tsui KH, Chiu CH. Kisspeptin modulates fertilization capacity of mouse spermatozoa. Reproduction. 2014 Jun;147(6):835-45. doi: 10.1530/REP-13-0368.
  85. Gloria A, Contri A, Mele E, Fasano S, Pierantoni R, Meccariello R. Kisspeptin Receptor on the Sperm Surface Reflects Epididymal Maturation in the Dog. Int J Mol Sci. 2021 Sep 19;22(18):10120. doi: 10.3390/ijms221810120.
  86. Whitlock BK, Daniel JA, Wilborn RR, Maxwell HS, Steele BP, Sartin JL. Interaction of kisspeptin and the somatotropic axis. Neuroendocrinology. 2010;92(3):178-88. doi: 10.1159/000318049.
  87. Corbett S, Shmorgun D, Claman P; REPRODUCTIVE ENDOCRINOLOGY INFERTILITY COMMITTEE; SPECIAL CONTRIBUTOR. The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2014 Nov;36(11):1024-1033. English, French. doi: 10.1016/S1701-2163(15)30417-5.
  88. Thomsen L, Humaidan P. Ovarian hyperstimulation syndrome in the 21st century: the role of gonadotropin-releasing hormone agonist trigger and kisspeptin. Curr Opin Obstet Gynecol. 2015 Jun;27(3):210-4. doi: 10.1097/GCO.0000000000000170.
  89. Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev. 2006 Apr;27(2):170-207. doi: 10.1210/er.2005-0015.
  90. Jayasena CN, Abbara A, Comninos AN, Nijher GM, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Sridharan M, Mason AJ, Warwick J, Ashby D, Ghatei MA, Bloom SR, Carby A, Trew GH, Dhillo WS. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest. 2014 Aug;124(8):3667-77. doi: 10.1172/JCI75730. 
  91. Owens LA, Abbara A, Lerner A, O'floinn S, Christopoulos G, Khanjani S, Islam R, Hardy K, Hanyaloglu AC, Lavery SA, Dhillo WS, Franks S. The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function. Hum Reprod. 2018 Feb 1;33(2):292-302. doi: 10.1093/humrep/dex357.
  92. Abbara A, Jayasena CN, Christopoulos G, Narayanaswamy S, Izzi-Engbeaya C, Nijher GM, Comninos AN, Peters D, Buckley A, Ratnasabapathy R, Prague JK, Salim R, Lavery SA, Bloom SR, Szigeti M, Ashby DA, Trew GH, Dhillo WS. Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy. J Clin Endocrinol Metab. 2015 Sep;100(9):3322-31. doi: 10.1210/jc.2015-2332. 
  93. Whitlock BK, Daniel JA, Amelse LL, Tanco VM, Chameroy KA, Schrick FN. Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes. PeerJ. 2015 Nov 5;3:e1382. doi: 10.7717/peerj.1382.
  94. Jayasena CN, Abbara A, Veldhuis JD, Comninos AN, Ratnasabapathy R, De Silva A, Nijher GM, Ganiyu-Dada Z, Mehta A, Todd C, Ghatei MA, Bloom SR, Dhillo WS. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of Kisspeptin-54. J Clin Endocrinol Metab. 2014 Jun;99(6):E953-61. doi: 10.1210/jc.2013-1569.
  95. Parker PA, Coffman EA, Pohler KG, Daniel JA, Aucagne V, Beltramo M, Whitlock BK. Acute and subacute effects of a synthetic kisspeptin analog, C6, on serum concentrations of luteinizing hormone, follicle stimulating hormone, and testosterone in prepubertal bull calves. Theriogenology. 2019 May;130:111-119. doi: 10.1016/j.theriogenology.2019.03.002. 
  96. Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, Pineda R, Gottsch ML, Tena-Sempere M, Moenter SM, Terasawa E, Clarke IJ, Steiner RA, Millar RP. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009 Mar 25;29(12):3920-9. doi: 10.1523/JNEUROSCI.5740-08.2009. 
  97. Millar RP, Roseweir AK, Tello JA, Anderson RA, George JT, Morgan K, Pawson AJ. Kisspeptin antagonists: unraveling the role of kisspeptin in reproductive physiology. Brain Res. 2010 Dec 10;1364:81-9. doi: 10.1016/j.brainres.2010.09.044.
  98. Sahin Z, Canpolat S, Ozcan M, Ozgocer T, Kelestimur H. Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats. Reproduction. 2015 May;149(5):465-73. doi: 10.1530/REP-14-0683.
  99. Cortés ME, Carrera B, Rioseco H, Pablo del Río J, Vigil P. The Role of Kisspeptin in the Onset of Puberty and in the Ovulatory Mechanism: A Mini-review. J Pediatr Adolesc Gynecol. 2015 Oct;28(5):286-91. doi: 10.1016/j.jpag.2014.09.017.
  100. Aguirre RS, Eugster EA. Central precocious puberty: From genetics to treatment. Best Pract Res Clin Endocrinol Metab. 2018 Aug;32(4):343-354. doi: 10.1016/j.beem.2018.05.008.

Download Article
Received September 10, 2023.
Accepted November 23, 2023.
©2023 International Medical Research and Development Corporation.