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Kisspeptin Role in Functional Hypothalamic Amenorrhea

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Menstrual Cycle Related Disorders

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Abstract

Functional hypothalamic amenorrhoea (FHA) is a disorder that, by definition, excludes organic disease. It is based on functional disruption of pulsatile, hypothalamic gonadotropin-releasing hormone (GnRH) secretion. KISS1 gene was discovered in 1996 in nonmetastatic melanoma cells as human malignant melanoma metastasis-suppressor gene. The role of KISS1 in regulation of reproduction was strongly suggested after discovery of mutation in GPR54 gene, leading to pubertal failure and normosomic hypogonadotropic hypogonadism. Kisspeptin is a novel neuromodulator that acts upstream of GnRH and is sensitive to sex steroid feedback and metabolic cues. Kisspeptin-54 was used numerous times in women with different endocrine disturbances in the last decade. However it should be stressed that kisspeptin administration was for the first time used in patients with hypothalamic amenorrhoea. Several such studies evaluated influence of kisspeptin administration on gonadotropin (FSH, LH) secretion in women with hypothalamic amenorrhoea. Results of these studies can have important implication for possible kisspeptin therapeutic use in patients with functional hypothalamic amenorrhoea.

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References

  1. Gordon CM, Ackerman KE, Berga SL, Kaplan JR, Mastorakos G, Misra M, Murad MH, Santoro NF, Warren MP. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102:1413–39. https://doi.org/10.1210/jc.2017-00131.

    Article  PubMed  Google Scholar 

  2. Gordon CM. Functional hypothalamic amenorrhea. N Engl J Med. 2010;363:365–71. https://doi.org/10.1056/NEJMcp0912024.

    Article  CAS  PubMed  Google Scholar 

  3. The Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008;90:S219–25. https://doi.org/10.1016/j.fertnstert.2008.08.038.

  4. Nattiv A, Loucks AB, Manore MM, Sanborn CF, Sundgot-Borgen J, Warren MP. The female athlete triad. Med Sci Sports Exerc. 2007;39:1867–82. https://doi.org/10.1249/mss.0b013e318149f111.

    Article  PubMed  Google Scholar 

  5. Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, Seminara SB, Boepple PA, Sidis Y, Crowley WF, Martin KA, Hall JE, Pitteloud N. A genetic basis for functional hypothalamic amenorrhea. N Engl J Med. 2011;364:215–25. https://doi.org/10.1056/NEJMoa0911064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. De Souza MJ, Toombs RJ, Scheid JL, O’Donnell E, West SL, Williams NI. High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures. Hum Reprod. 2010;25:491–503. https://doi.org/10.1093/humrep/dep411.

    Article  PubMed  Google Scholar 

  7. Ackerman KE, Cano Sokoloff N, de Nardo Maffazioli G, Clarke HM, Lee H, Misra M. Fractures in relation to menstrual status and bone parameters in young athletes. Med Sci Sports Exerc. 2015;47:1577–86. https://doi.org/10.1249/MSS.0000000000000574.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Johnston SL, Farrell SA, Bouchard C, Beckerson LA, Comeau M, Lefebvre G, Papaioannou A, SOGC Joint Committee-Clinical Practice Gynaecology and Urogynaecology. The detection and management of vaginal atrophy. J Obstet Gynaecol Can. 2004;26:503–8. https://doi.org/10.1016/S1701-2163(16)30662-4.

    Article  PubMed  Google Scholar 

  9. Bomba M, Gambera A, Bonini L, Peroni M, Neri F, Scagliola P, Nacinovich R. Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertil Steril. 2007;87(4):876–85. https://doi.org/10.1016/j.fertnstert.2006.09.011.

    Article  CAS  PubMed  Google Scholar 

  10. O’Donnell E, Goodman JM, Harvey PJ. Cardiovascular consequences of ovarian disruption: a focus on functional hypothalamic amenorrhea in physically active women. J Clin Endocrinol Metab. 2011;96:3638–48. https://doi.org/10.1210/jc.2011-1223.

    Article  CAS  PubMed  Google Scholar 

  11. Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA. 2005;293:1861. https://doi.org/10.1001/jama.293.15.1861.

    Article  CAS  PubMed  Google Scholar 

  12. Meczekalski B, Katulski K, Czyzyk A, Podfigurna-Stopa A, Maciejewska-Jeske M. Functional hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Investig. 2014;37:1049–56. https://doi.org/10.1007/s40618-014-0169-3.

    Article  CAS  Google Scholar 

  13. Meczekalski B, Podfigurna-Stopa A, Genazzani AR. Why kisspeptin is such important for reproduction? Gynecol Endocrinol. 2011;27:8–13. https://doi.org/10.3109/09513590.2010.506291.

    Article  CAS  PubMed  Google Scholar 

  14. 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;88:1731–7.

    Article  CAS  PubMed  Google Scholar 

  15. West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics. 1998;54:145–8. https://doi.org/10.1006/geno.1998.5566.

    Article  CAS  PubMed  Google Scholar 

  16. 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;411:613–7. https://doi.org/10.1038/35079135.

    Article  CAS  PubMed  Google Scholar 

  17. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden J-M, 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;276:34631–6. https://doi.org/10.1074/jbc.M104847200.

    Article  CAS  PubMed  Google Scholar 

  18. 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;446:103–7.

    Article  CAS  PubMed  Google Scholar 

  19. 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 CGC, 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;276:28969–75. https://doi.org/10.1074/jbc.M102743200.

    Article  CAS  PubMed  Google Scholar 

  20. Liu X, Lee K, Herbison AE. Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels. Endocrinology. 2008;149:4605–14. https://doi.org/10.1210/en.2008-0321.

    Article  CAS  PubMed  Google Scholar 

  21. Min L, Soltis K, Reis ACS, Xu S, Kuohung W, Jain M, Carroll RS, Kaiser UB. Dynamic Kisspeptin receptor trafficking modulates Kisspeptin-mediated calcium signaling. Mol Endocrinol. 2014;28:16–27. https://doi.org/10.1210/me.2013-1165.

    Article  CAS  PubMed  Google Scholar 

  22. Constantin S, Caligioni CS, Stojilkovic S, Wray S. Kisspeptin-10 facilitates a plasma membrane-driven calcium oscillator in gonadotropin-releasing hormone-1 neurons. Endocrinology. 2009;150:1400–12. https://doi.org/10.1210/en.2008-0979.

    Article  CAS  PubMed  Google Scholar 

  23. Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update. 2014;20:485–500. https://doi.org/10.1093/humupd/dmu009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, Kallo I. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci. 2010;31:1984–98. https://doi.org/10.1111/j.1460-9568.2010.07239.x.

    Article  CAS  PubMed  Google Scholar 

  25. Rometo AM, Krajewski SJ, Lou Voytko M, Rance NE. Hypertrophy and increased Kisspeptin gene expression in the hypothalamic Infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab. 2007;92:2744–50. https://doi.org/10.1210/jc.2007-0553.

    Article  CAS  PubMed  Google Scholar 

  26. de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci. 2003;100:10972–6. https://doi.org/10.1073/pnas.1834399100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, 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 MBL, Crowley WF, Aparicio SAJR, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–27. https://doi.org/10.1056/NEJMoa035322.

    Article  CAS  PubMed  Google Scholar 

  28. Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med. 2012;366:629–35. https://doi.org/10.1056/NEJMoa1111184.

    Article  CAS  PubMed  Google Scholar 

  29. Abacı A, Çatlı G, Anık A, Küme T, Çalan ÖG, Dündar BN, Böber E. Significance of serum neurokinin B and kisspeptin levels in the differential diagnosis of premature thelarche and idiopathic central precocious puberty. Peptides. 2015;64:29–33. https://doi.org/10.1016/j.peptides.2014.12.011.

    Article  CAS  PubMed  Google Scholar 

  30. Lapatto R, Pallais JC, Zhang D, Chan Y-M, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB. Kiss1 −/− mice exhibit more variable Hypogonadism than Gpr54 −/− mice. Endocrinology. 2007;148:4927–36. https://doi.org/10.1210/en.2007-0078.

    Article  CAS  PubMed  Google Scholar 

  31. d’Anglemont de Tassigny X, Fagg LA, Dixon JPC, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MBL, Aparicio SAJR, Colledge WH. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci U S A. 2007;104:10714–9. https://doi.org/10.1073/pnas.0704114104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mayer C, Boehm U. Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nat Neurosci. 2011;14:704–10. https://doi.org/10.1038/nn.2818.

    Article  CAS  PubMed  Google Scholar 

  33. B. Meczekalski, K. Katulski, A. Podfigurna-Stopa, A. Czyzyk, A.D. Genazzani, Spontaneous endogenous pulsatile release of kisspeptin is temporally coupled with luteinizing hormone in healthy women, Fertil Steril 2016;105. doi:https://doi.org/10.1016/j.fertnstert.2016.01.029.

    Article  PubMed  Google Scholar 

  34. Meczekalski B, Podfigurna-Stopa A, Warenik-Szymankiewicz A, Genazzani AR. Functional hypothalamic amenorrhea: current view on neuroendocrine aberrations. Gynecol Endocrinol. 2008;24:4–11. https://doi.org/10.1080/09513590701807381.

    Article  CAS  PubMed  Google Scholar 

  35. Smith JT, Li Q, Yap KS, Shahab M, Roseweir AK, Millar RP, Clarke IJ. Kisspeptin is essential for the full Preovulatory LH surge and stimulates GnRH release from the isolated ovine median Eminence. Endocrinology. 2011;152:1001–12. https://doi.org/10.1210/en.2010-1225.

    Article  CAS  PubMed  Google Scholar 

  36. d’Anglemont de Tassigny X, Fagg LA, Carlton MBL, Colledge WH. Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology. 2008;149:3926–32. https://doi.org/10.1210/en.2007-1487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Clarke H, Dhillo WS, Jayasena CN. Comprehensive review on Kisspeptin and its role in reproductive disorders. Endocrinol Metab (Seoul). 2015;30:124–41. https://doi.org/10.3803/EnM.2015.30.2.124.

    Article  CAS  Google Scholar 

  38. Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology. 2010;151:3479–89. https://doi.org/10.1210/en.2010-0022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Krajewski SJ, Anderson MJ, Iles-Shih L, Chen KJ, Urbanski HF, Rance NE. Morphologic evidence that neurokinin B modulates gonadotropin-releasing hormone secretion via neurokinin 3 receptors in the rat median eminence. J Comp Neurol. 2005;489:372–86. https://doi.org/10.1002/cne.20626.

    Article  CAS  PubMed  Google Scholar 

  40. Herbison AE, d’Anglemont de Tassigny X, Doran J, Colledge WH. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology. 2010;151:312–21. https://doi.org/10.1210/en.2009-0552.

    Article  CAS  PubMed  Google Scholar 

  41. Herbison AE. 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;57:277–87. https://doi.org/10.1016/j.brainresrev.2007.05.006.

    Article  CAS  PubMed  Google Scholar 

  42. Gaskins GT, Glanowska KM, Moenter SM. Activation of Neurokinin 3 receptors stimulates GnRH release in a location-dependent but Kisspeptin-independent manner in adult mice. Endocrinology. 2013;154:3984–9. https://doi.org/10.1210/en.2013-1479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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;29:11859–66. https://doi.org/10.1523/JNEUROSCI.1569-09.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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;101:4628–36. https://doi.org/10.1210/jc.2016-2132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ. Kisspeptin is present in ovine hypophysial portal blood but does not increase during the preovulatory luteinizing hormone surge: evidence that gonadotropes are not direct targets of kisspeptin in vivo. Endocrinology. 2008;149:1951–9. https://doi.org/10.1210/en.2007-1425.

    Article  CAS  PubMed  Google Scholar 

  46. Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci. 2006;26:6687–94. https://doi.org/10.1523/JNEUROSCI.1618-06.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Micevych PE, Chaban V, Ogi J, Dewing P, Lu JKH, Sinchak K. Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology. 2007;148:782–9. https://doi.org/10.1210/en.2006-0774.

    Article  CAS  PubMed  Google Scholar 

  48. M.A. Mittelman-Smith, A.M. Wong, P.E. Micevych, Estrogen and progesterone integration in an in vitro model of RP3V Kisspeptin neurons, Neuroendocrinology. 2017. doi:https://doi.org/10.1159/000471878.

    Article  PubMed  Google Scholar 

  49. Iwasa T, Matsuzaki T, Yano K, Mayila Y, Irahara M. The roles of kisspeptin and gonadotropin inhibitory hormone in stress-induced reproductive disorders. Endocr J. 2018;65(2):133–40. https://doi.org/10.1507/endocrj.EJ18-0026.

    Article  PubMed  Google Scholar 

  50. Kinsey-Jones JS, Li XF, Knox AMI, Wilkinson ES, Zhu XL, Chaudhary AA, Milligan SR, Lightman SL, O’Byrne KT. Down-regulation of hypothalamic Kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of Luteinising hormone secretion in the female rat. J Neuroendocrinol. 2009;21:20–9. https://doi.org/10.1111/j.1365-2826.2008.01807.x.

    Article  CAS  PubMed  Google Scholar 

  51. Clarkson J, d’Anglemont de Tassigny X, Colledge WH, Caraty A, Herbison AE. Distribution of Kisspeptin Neurones in the adult female mouse brain. J Neuroendocrinol. 2009;21:673–82. https://doi.org/10.1111/j.1365-2826.2009.01892.x.

    Article  CAS  PubMed  Google Scholar 

  52. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 Neurones are direct targets for Leptin in the Ob/Ob mouse. J Neuroendocrinol. 2006;18:298–303. https://doi.org/10.1111/j.1365-2826.2006.01417.x.

    Article  CAS  PubMed  Google Scholar 

  53. Navarro VM, Tena-Sempere M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat Rev Endocrinol. 2012;8:40–53. https://doi.org/10.1038/nrendo.2011.147.

    Article  CAS  Google Scholar 

  54. Morelli A, Marini M, Mancina R, Luconi M, Vignozzi L, Fibbi B, Filippi S, Pezzatini A, Forti G, Vannelli GB, Maggi M. Sex steroids and leptin regulate the “first kiss”; (KiSS 1/G-protein-coupled receptor 54 system) in human gonadotropin-releasing-hormone-secreting neuroblasts. J Sex Med. 2008;5:1097–113. https://doi.org/10.1111/j.1743-6109.2008.00782.x.

    Article  CAS  PubMed  Google Scholar 

  55. Cravo RM, Margatho LO, Osborne-Lawrence S, Donato J, Atkin S, Bookout AL, Rovinsky S, Frazão R, Lee CE, Gautron L, Zigman JM, Elias CF. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011;173:37–56. https://doi.org/10.1016/J.NEUROSCIENCE.2010.11.022.

    Article  CAS  PubMed  Google Scholar 

  56. Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG. Molecular mapping of the neural pathways linking Leptin to the neuroendocrine reproductive Axis. Endocrinology. 2011;152:2302–10. https://doi.org/10.1210/en.2011-0096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Anderson EJP, Çakir I, Carrington SJ, Cone RD, Ghamari-Langroudi M, Gillyard T, Gimenez LE, Litt MJ. 60 YEARS OF POMC: regulation of feeding and energy homeostasis by α-MSH. J Mol Endocrinol. 2016;56:T157–74. https://doi.org/10.1530/JME-16-0014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Thornton JE, Cheung CC, Clifton DK, Steiner RA. Regulation of hypothalamic Proopiomelanocortin mRNA by Leptin in ob/ob mice. Endocrinology. 1997;138:5063–6. https://doi.org/10.1210/endo.138.11.5651.

    Article  CAS  PubMed  Google Scholar 

  59. Manfredi-Lozano M, Roa J, Ruiz-Pino F, Piet R, Garcia-Galiano D, Pineda R, Zamora A, Leon S, Sanchez-Garrido MA, Romero-Ruiz A, Dieguez C, Vazquez MJ, Herbison AE, Pinilla L, Tena-Sempere M. Defining a novel leptin–melanocortin–kisspeptin pathway involved in the metabolic control of puberty. Mol Metab. 2016;5:844–57. https://doi.org/10.1016/J.MOLMET.2016.08.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pierroz DD, Catzeflis C, Aebi AC, Rivier JE, Aubert ML. Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary-testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats. Endocrinology. 1996;137:3–12. https://doi.org/10.1210/en.137.1.3.

    Article  CAS  PubMed  Google Scholar 

  61. Jain MR, Pu S, Kalra PS, Kalra SP. Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed Ovariectomized rats may involve neuropeptide Y Y1 and Y4 receptors 1. Endocrinology. 1999;140:5171–7. https://doi.org/10.1210/endo.140.11.7107.

    Article  CAS  PubMed  Google Scholar 

  62. Manfredi-Lozano M, Roa J, Tena-Sempere M. Connecting metabolism and gonadal function: novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front Neuroendocrinol. 2018;48:37–49. https://doi.org/10.1016/J.YFRNE.2017.07.008.

    Article  CAS  PubMed  Google Scholar 

  63. Backholer K, Smith JT, Rao A, Pereira A, Iqbal J, Ogawa S, Li Q, Clarke IJ. Kisspeptin cells in the ewe brain respond to Leptin and communicate with neuropeptide Y and Proopiomelanocortin cells. Endocrinology. 2010;151:2233–43. https://doi.org/10.1210/en.2009-1190.

    Article  PubMed  Google Scholar 

  64. Padilla SL, Qiu J, Nestor CC, Zhang C, Smith AW, Whiddon BB, Rønnekleiv OK, Kelly MJ, Palmiter RD. AgRP to Kiss1 neuron signaling links nutritional state and fertility. Proc Natl Acad Sci U S A. 2017;114:2413–8. https://doi.org/10.1073/pnas.1621065114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bacopoulou F, Lambrou GI, Rodanaki ME, Stergioti E, Efthymiou V, Deligeoroglou E, Markantonis SL. Serum kisspeptin concentrations are negatively correlated with body mass index in adolescents with anorexia nervosa and amenorrhea. Hormones. 2017;16:33–41. https://doi.org/10.14310/horm.2002.1717.

    Article  PubMed  Google Scholar 

  66. Hofmann T, Elbelt U, Haas V, Ahnis A, Klapp BF, Rose M, Stengel A. Plasma kisspeptin and ghrelin levels are independently correlated with physical activity in patients with anorexia nervosa. Appetite. 2017;108:141–50. https://doi.org/10.1016/j.appet.2016.09.032.

    Article  PubMed  Google Scholar 

  67. Fu L-Y, Acuna-Goycolea C, van den Pol AN. Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J Neurosci. 2004;24:8741–51. https://doi.org/10.1523/JNEUROSCI.2268-04.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Iwasa T, Matsuzaki T, Murakami M, Shimizu F, Kuwahara A, Yasui T, Irahara M. Decreased expression of kisspeptin mediates acute immune/inflammatory stress-induced suppression of gonadotropin secretion in female rat. J Endocrinol Investig. 2008;31:656–9. https://doi.org/10.1007/BF03345620.

    Article  CAS  Google Scholar 

  69. Hirano T, Kobayashi Y, Omotehara T, Tatsumi A, Hashimoto R, Umemura Y, Nagahara D, Mantani Y, Yokoyama T, Kitagawa H, Hoshi N. Unpredictable chronic stress-induced reproductive suppression associated with the decrease of kisspeptin immunoreactivity in male mice. J Vet Med Sci. 2014;76:1201–8. http://www.ncbi.nlm.nih.gov/pubmed/24871549. Accessed Feb 4 2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yang JA, Song CI, Hughes JK, Kreisman MJ, Parra RA, Haisenleder DJ, Kauffman AS, Breen KM. Acute psychosocial stress inhibits LH Pulsatility and Kiss1 neuronal activation in female mice. Endocrinology. 2017;158:3716–23. https://doi.org/10.1210/en.2017-00301.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Csabafi K, Jászberényi M, Bagosi Z, Lipták N, Telegdy G. Effects of kisspeptin-13 on the hypothalamic-pituitary-adrenal axis, thermoregulation, anxiety and locomotor activity in rats. Behav Brain Res. 2013;241:56–61. https://doi.org/10.1016/J.BBR.2012.11.039.

    Article  CAS  PubMed  Google Scholar 

  72. Tolson KP, Garcia C, Yen S, Simonds S, Stefanidis A, Lawrence A, Smith JT, Kauffman AS. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Invest. 2014;124:3075–9. https://doi.org/10.1172/JCI71075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of Kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004;16:850–8. https://doi.org/10.1111/j.1365-2826.2004.01240.x.

    Article  CAS  PubMed  Google Scholar 

  74. Caraty A, Smith JT, Lomet D, Ben Sad S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ. Kisspeptin synchronizes Preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. Endocrinology. 2007;48:5258–67. https://doi.org/10.1210/en.2007-0554.

    Article  CAS  PubMed  Google Scholar 

  75. Jayasena CN, Nijher GMK, Chaudhri OB, Murphy KG, Ranger A, Lim A, Patel D, Mehta A, Todd C, Ramachandran R, Salem V, Stamp GW, Donaldson M, Ghatei MA, Bloom SR, Dhillo WS. Subcutaneous injection of Kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab. 2009;94:4315–23. https://doi.org/10.1210/jc.2009-0406.

    Article  CAS  PubMed  Google Scholar 

  76. Jayasena CN, Nijher GMK, Abbara A, Murphy KG, Lim A, Patel D, Mehta A, Todd C, Donaldson M, Trew GH, Ghatei MA, Bloom SR, Dhillo WS. Twice-weekly Administration of Kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther. 2010;88:840–7. https://doi.org/10.1038/clpt.2010.204.

    Article  CAS  PubMed  Google Scholar 

  77. Jayasena CN, Comninos AN, Nijher GMK, Abbara A, De Silva A, Veldhuis JD, Ratnasabapathy R, Izzi-Engbeaya C, Lim A, Patel DA, Ghatei MA, Bloom SR, Dhillo WS. Twice-daily subcutaneous injection of Kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers. J Clin Endocrinol Metab. 2013;98:4464–74. https://doi.org/10.1210/jc.2013-1069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jayasena CN, Abbara A, Veldhuis JD, Comninos AN, Ratnasabapathy R, De Silva A, Nijher GMK, 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;99:E953–61. https://doi.org/10.1210/jc.2013-1569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ramaesh T, Logie JJ, Roseweir AK, Millar RP, Walker BR, Hadoke PWF, Reynolds RM. Kisspeptin-10 inhibits angiogenesis in human placental vessels ex Vivo and endothelial cells in Vitro. Endocrinology. 2010;151:5927–34. https://doi.org/10.1210/en.2010-0565.

    Article  CAS  PubMed  Google Scholar 

  80. Nijher GMK, Chaudhri OB, Ramachandran R, Murphy KG, Zac-Varghese SEK, Fowler A, Chinthapalli K, Patterson M, Thompson EL, Williamson C, Kumar S, Ghatei MA, Bloom SR, Dhillo WS. The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy. Br J Clin Pharmacol. 2010;70:674–81. https://doi.org/10.1111/j.1365-2125.2010.03746.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Podfigurna, A., Czyzyk, A., Szeliga, A., Meczekalski, B. (2019). Kisspeptin Role in Functional Hypothalamic Amenorrhea. In: Berga, S., Genazzani, A., Naftolin, F., Petraglia, F. (eds) Menstrual Cycle Related Disorders. ISGE Series. Springer, Cham. https://doi.org/10.1007/978-3-030-14358-9_3

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