Kisspeptin and Puberty in Mammals

  • Ei TerasawaEmail author
  • Kathryn A. Guerriero
  • Tony M. Plant
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 784)


Since the discovery of the G-protein coupled receptor 54 (kisspeptin receptor) and its ligand, kisspeptin, our understanding of the neurobiological mechanisms that govern the pituitary-gonadal axis has evolved dramatically. In this chapter, we have reviewed progress regarding the relationship between kisspeptin and puberty, and have proposed a novel hypothesis for the role of kisspeptin signaling in the onset of this crucial developmental event. According to this hypothesis, although kisspeptin neurons in the arcuate nucleus (ARC) are critical for puberty, this is simply because these cells are an integral component of the hypothalamic GnRH pulse generating mechanism that drives intermittent release of the decapeptide, as an increase in GnRH is obligatory for the onset of puberty. In our model, ARC kisspeptin neurons play no “regulatory” role in controlling the timing of puberty. Rather, as a component of the neural network responsible for GnRH pulse generation, they subserve upstream regulatory mechanisms that are responsible for the timing of puberty.


GnRH Neuron GnRH Release Medial Basal Hypothalamus GnRH Pulse Puberty Onset 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Arcuate nucleus


Anteroventral periventricular nucleus




Estrogen receptor alpha


γ-Aminobutyric acid IPI Inter-pulse interval


Kisspeptin gene (primates)


Kisspeptin gene (non-primates)


Kisspeptin-1 receptor (primates)


Kisspeptin-1 receptor (non-primates)




Medial basal hypothalamus


Median eminence


Stalk-median eminence


Neuropeptide Y


Preoptic area



Supported by grants R01 HD15433 and R01 HD11355 for ET, R01 HD 013254 and U54 HD 08160 for TMP, T32 HD041921 for KAG, and P51 0D011106 for WNPRC.


  1. 1.
    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 (2003) The GPR54 gene as a regulator of puberty. N Engl J Med 349:1614–1627PubMedCrossRefGoogle Scholar
  2. 2.
    de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E (2003) Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 100:10972–10976PubMedCrossRefGoogle Scholar
  3. 3.
    Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O’rahilly S, Aparicio SA (2005) Novel missense mutations in g protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 90:1849–1855PubMedCrossRefGoogle Scholar
  4. 4.
    Cerrato F, Shagoury J, Kralickova M, Dwyer A, Falardeau J, Ozata M, Van Vliet G, Bouloux P, Hall JE, Hayes FJ, Pitteloud N, Martin KA, Welt C, Seminara SB (2006) Coding sequence analysis of GnRHR and GPR54 in patients with congenital and adult onset forms of hypogonadotropic hypogonadism. Eur J Endocrinol 155:S3–S10PubMedCrossRefGoogle Scholar
  5. 5.
    Tenenbaum-Rakover Y, Commenges-Ducos M, Iovane A, Aumas C, Admoni O, de Roux N (2007) Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54. J Clin Endocrinol Metab 92:1137–1144PubMedCrossRefGoogle Scholar
  6. 6.
    Nimri R, Lebenthal Y, Lazar L, Chevrier L, Phillip M, Bar M, Hernandez-Mora E, de Roux N, Gat-Yablonski G (2011) A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. J Clin Endocrinol Metab 96:E536–E545PubMedCrossRefGoogle Scholar
  7. 7.
    Lanfranco F, Gromoll J, von Eckardstein S, Herding EM, Nieschlag E, Simoni M (2005) Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol 153:845–852PubMedCrossRefGoogle Scholar
  8. 8.
    Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC (2008) A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med 358:709–715PubMedCrossRefGoogle Scholar
  9. 9.
    Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL (2003) The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 312:1357–1363PubMedCrossRefGoogle Scholar
  10. 10.
    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 (2007) Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA 104:10714–10719PubMedCrossRefGoogle Scholar
  11. 11.
    Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB (2007) Kiss1−/− mice exhibit more variable hypogonadism than Gpr54−/− mice. Endocrinology 148:4927–4936PubMedCrossRefGoogle Scholar
  12. 12.
    Topaloglu AK, Tello JA, Kotan LD, Ozbek MN, Yilmaz MB, Erdogan S, Gurbuz F, Temiz F, Millar RP, Yuksel B (2012) Inactivating KISS1 mutation and hypogonadotropic hypogonadism. N Engl J Med 366:629–635PubMedCrossRefGoogle Scholar
  13. 13.
    Wildt L, Marshall G, Knobil E (1980) Experimental induction of puberty in the infantile female rhesus monkey. Science 207:1373–1375PubMedGoogle Scholar
  14. 14.
    Loose MD, Terasawa E (1985) Pulsatile infusion of luteinizing hormone-releasing hormone induces precocious puberty (vaginal opening and first ovulation) in the immature female guinea pig. Biol Reprod 33:1084–1093PubMedCrossRefGoogle Scholar
  15. 15.
    Plant TM (2001) Neurobiological bases underlying the control of the onset of puberty in the rhesus monkey: a representative higher primate. Front Neuroendocrinol 22:107–139Google Scholar
  16. 16.
    Grumbach MM, Styne DM (1998) Puberty, ontogeny, neuroendocrinology, physiology, and disorders. In: Williams RH, Foster DW, Kroenenberg H, Larsen PR, Zorab R (eds) Williams textbook of endocrinology, 9th edn. W.B. Saunders, Philadelphia, PA, pp 1509–1625Google Scholar
  17. 17.
    Terasawa E, Fernandez DL (2001) Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 22:111–151PubMedCrossRefGoogle Scholar
  18. 18.
    Plant TM, Witchel SF (2006) Puberty in nonhuman primates and primates. In: Neill J (ed) The physiology of reproduction, vol 2, 3rd edn. Academic, San Diego, CA, pp 2177–2230Google Scholar
  19. 19.
    Ojeda SR, Skinner MK (2006) Puberty in the rat. In: Neill J (ed) The physiology of reproduction, vol 2, 3rd edn. Academic, Elsevier, San Diego, CA, pp 2061–2126Google Scholar
  20. 20.
    Terasawa E, Kurian JR (2012) Neuroendocrine mechanism of puberty. In: Fink G, Pfaff DW, Levine JE (eds) Handbook of neuroendocrinology. Academic, Elsevier, London, pp 433–484CrossRefGoogle Scholar
  21. 21.
    Plant TM (1986) Gonadal regulation of hypothalamic gonadotropin-releasing hormone release in primates. Endocr Rev 7:75–88PubMedCrossRefGoogle Scholar
  22. 22.
    Plant TM (2012) A comparison of the neuroendocrine mechanisms underlying the initiation of the preovulatory LH surge in the human, Old World monkey and rodent. Front Neuroendocrinol 33:160–168PubMedCrossRefGoogle Scholar
  23. 23.
    Plant TM (1985) A study of the role of the postnatal testes in determining the ontogeny of gonadotropin secretion in the male rhesus monkey (Macaca mulatta). Endocrinology 116:1341–1350PubMedCrossRefGoogle Scholar
  24. 24.
    Pohl CR, de Ridder CM, Plant TM (1995) Gonadal and nongonadal mechanisms contribute to the prepubertal hiatus in gonadotropin secretion in the female rhesus monkey (Macaca mulatta). J Clin Endocrinol Metab 80:2094–2101PubMedCrossRefGoogle Scholar
  25. 25.
    Conte FA, Grumbach MM, Kaplan SL (1975) A diphasic pattern of gonadotropin secretion in patients with the syndrome of gonadal dysgenesis. J Clin Endocrinol Metab 40:670–674PubMedCrossRefGoogle Scholar
  26. 26.
    Ross JL, Loriaux DL, Cutler GB Jr (1983) Developmental changes in neuroendocrine regulation of gonadotropin secretion in gonadal dysgenesis. J Clin Endocrinol Metab 57:288–293PubMedCrossRefGoogle Scholar
  27. 27.
    Chongthammakun S, Terasawa E (1993) Negative feedback effects of estrogen on luteinizing hormone-releasing hormone release occur in pubertal, but not prepubertal, ovariectomized female rhesus monkeys. Endocrinology 132:735–743PubMedCrossRefGoogle Scholar
  28. 28.
    Foster DL, Jackson LM (2006) Puberty in the sheep. In: Neill J (ed) The physiology of reproduction, vol 2, 3rd edn. Academic, Elsevier, San Diego, CA, pp 1415–1482Google Scholar
  29. 29.
    Goldman BD, Gorski RA (1971) Effects of gonadal steroids on the secretion of LH and FSH in neonatal rats. Endocrinology 89:112–115PubMedCrossRefGoogle Scholar
  30. 30.
    Fraser MO, Plant TM (1989) Further studies of the role of the gonads in determining the ontogeny of gonadotropin secretion in the guinea pig (Cavia porcelus). Endocrinology 125:906–911PubMedCrossRefGoogle Scholar
  31. 31.
    Oakley AE, Clifton DK, Steiner RA (2009) Kisspeptin signaling in the brain. Endocr Rev 30:713–743PubMedCrossRefGoogle Scholar
  32. 32.
    Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M (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 145:4565–4574PubMedCrossRefGoogle Scholar
  33. 33.
    Takase K, Uenoyama Y, Inoue N, Matsui H, Yamada S, Shimizu M, Homma T, Tomikawa J, Kanda S, Matsumoto H, Oka Y, Tsukamura H, Maeda KI (2009) Possible role of oestrogen in pubertal increase of Kiss1/kisspeptin expression in discrete hypothalamic areas of female rats. J Neuroendocrinol 21:527–537PubMedCrossRefGoogle Scholar
  34. 34.
    Takumi K, Iijima N, Ozawa H (2011) Developmental changes in the expression of kisspeptin mRNA in rat hypothalamus. J Mol Neurosci 43:138–145PubMedCrossRefGoogle Scholar
  35. 35.
    Bentsen AH, Ansel L, Simonneaux V, Tena-Sempere M, Juul A, Mikkelsen JD (2010) Maturation of kisspeptinergic neurons coincides with puberty onset in male rats. Peptides 31:275–283PubMedCrossRefGoogle Scholar
  36. 36.
    Clarkson J, Herbison AE (2011) Dual phenotype kisspeptin-dopamine neurones of the rostral periventricular area of the third ventricle project to gonadotrophin-releasing hormone ­neurones. J Neuroendocrinol 23:293–301PubMedCrossRefGoogle Scholar
  37. 37.
    Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE (2005) Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25:11349–11356PubMedCrossRefGoogle Scholar
  38. 38.
    Gill JC, Wang O, Kakar S, Martinelli E, Carroll RS, Kaiser UB (2010) Reproductive hormone-­dependent and -independent contributions to developmental changes in kisspeptin in GnRH-deficient hypogonadal mice. PLoS One 5:e11911PubMedCrossRefGoogle Scholar
  39. 39.
    Kauffman AS, Navarro VM, Kim J, Clifton DK, Steiner RA (2009) Sex differences in the regulation of Kiss1/NKB neurons in juvenile mice: implications for the timing of puberty. Am J Physiol Endocrinol Metab 297:E1212–E1221PubMedCrossRefGoogle Scholar
  40. 40.
    Poling MC, Kauffman AS (2012) Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-Kiss1r and GnRH signaling. Endocrinology 153:782–793PubMedCrossRefGoogle Scholar
  41. 41.
    Jean-Faucher C, el Watik N, Berger M, De Turckheim M, Veyssiere G, Jean C (1985) Regulation of gonadotrophin secretion in male mice from birth to adulthood. Response to LHR injection, castration, and testosterone replacement therapy. Acta Endocrinol (Copenh) 110:193–199Google Scholar
  42. 42.
    Ojeda SR, Ramirez VD (1973–1974) Short-term steroid treatment on plasma LH and FSH in castrated rats from birth to puberty. Neuroendocrinology 13:100–114Google Scholar
  43. 43.
    Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM (2005) Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 102:2129–2134PubMedCrossRefGoogle Scholar
  44. 44.
    Clarkson J, Herbison AE (2006) Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone (GnRH) neurons. Endocrinology 147:5817–5825PubMedCrossRefGoogle Scholar
  45. 45.
    Mayer C, Boehm U (2011) Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nat Neurosci 14:704–710PubMedCrossRefGoogle Scholar
  46. 46.
    Yeo SH, Herbison AE (2011) Projections of arcuate nucleus and rostral periventricular kisspeptin neurons in the adult female mouse brain. Endocrinology 152:2387–2399PubMedCrossRefGoogle Scholar
  47. 47.
    Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM (2012) Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. Endocrinology 153:2756–2765PubMedCrossRefGoogle Scholar
  48. 48.
    Dwarki K, Ramaswamy S, Gibbs R and Plant TM. The arrest of GnRH pulsatility during infancy that guarantees the quiescence of the primate gonad during juvenile development is correlated with a reduction in immunopositive kisspeptin neurons in the arcuate nucleus of the male rhesus monkey (Macaca mulatta). In: 93rd Annual Meeting of The Endocrine Society, Boston, June 2011, Abstract #P2-262Google Scholar
  49. 49.
    Clarkson J, Boon WC, Simpson ER, Herbison AE (2009) Postnatal development of an estradiol-­kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 150:3214–3220PubMedCrossRefGoogle Scholar
  50. 50.
    Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE (2010) Timing and completion of puberty in female mice depend on estrogen receptor alpha-­signaling in kisspeptin neurons. Proc Natl Acad Sci USA 107:22693–22698PubMedCrossRefGoogle Scholar
  51. 51.
    Rometo AM, Krajewski SJ, Voytko ML, Rance NE (2007) Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 92:2744–2750PubMedCrossRefGoogle Scholar
  52. 52.
    Smith JT, Shahab M, Pereira A, Pau KY, Clarke IJ (2010) Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biol Reprod 83:568–577PubMedCrossRefGoogle Scholar
  53. 53.
    Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, Kallo I (2010) The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci 31:1984–1998PubMedCrossRefGoogle Scholar
  54. 54.
    Parhar IS, Ogawa S, Sakuma Y (2004) Laser-captured single digoxigenin-labeled neurons of gonadotropin-releasing hormone types reveal a novel G protein-coupled receptor (Gpr54) during maturation in cichlid fish. Endocrinology 145:3613–3618PubMedCrossRefGoogle Scholar
  55. 55.
    Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA (2005) Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 102:1761–1766PubMedCrossRefGoogle Scholar
  56. 56.
    Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA (2004) Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80:264–272PubMedCrossRefGoogle Scholar
  57. 57.
    Herbison AE, de Tassigny X, Doran J, Colledge WH (2010) Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151:312–321PubMedCrossRefGoogle Scholar
  58. 58.
    Guerriero KA, Keen KL, Millar RP, Terasawa E (2012) Developmental changes in GnRH release in response to kisspeptin agonist and antagonist in female Rhesus monkeys (Macaca mulatta): Implication for the mechanism of puberty. Endocrinology 153:825–836PubMedCrossRefGoogle Scholar
  59. 59.
    Plant TM, Ramaswamy S, DiPietro MJ (2006) Repetitive activation of hypothalamic G protein coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges. Endocrinology 147:1007–1013PubMedCrossRefGoogle Scholar
  60. 60.
    Constantin S, Caligioni CS, Stojilkovic S, Wray S (2009) Kisspeptin-10 facilitates a plasma membrane-driven calcium oscillator in gonadotropin-releasing hormone-1 neurons. Endocrinology 150:1400–1412PubMedCrossRefGoogle Scholar
  61. 61.
    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 (2001) Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411:613–617PubMedCrossRefGoogle Scholar
  62. 62.
    Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffman SN, Vassart G, Parmentier M (2001) The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 276:34631–34636PubMedCrossRefGoogle Scholar
  63. 63.
    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, Miller RP (2009) Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 29:3920–3929PubMedCrossRefGoogle Scholar
  64. 64.
    Frost SI, Keen KL, Levine JE, Terasawa E (2008) Microdialysis methods for in vivo neuropeptide measurement in the stalk-median eminence in the rhesus monkey. J Neurosci Methods 168:26–34PubMedCrossRefGoogle Scholar
  65. 65.
    Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E (2008) An increase in kisspeptin-­54 release occurs with the pubertal increase in luteinizing hormone-releasing hormone-1 release in the stalk-median eminence of female rhesus monkeys in vivo. Endocrinology 149:4151–4157PubMedCrossRefGoogle Scholar
  66. 66.
    Guerriero KA, Keen KL, Terasawa E (2012) Developmental increase in kisspeptin-54 in vivo is independent of the pubertal increase in estradiol in female rhesus monkeys (Macaca mulatta). Endocrinology 153:1887–1897PubMedCrossRefGoogle Scholar
  67. 67.
    Watanabe G, Terasawa E (1989) In vivo release of luteinizing hormone releasing hormone (LHRH) increases with puberty in the female rhesus monkey. Endocrinology 125:92–99PubMedCrossRefGoogle Scholar
  68. 68.
    Chongthammakun S, Claypool LE, Terasawa E (1993) Ovariectomy increases in vivo LHRH release in pubertal, but not prepubertal, female rhesus monkeys. J Neuroendocrinol 5:41–50PubMedCrossRefGoogle Scholar
  69. 69.
    Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ (2007) Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 148:5752–5760PubMedCrossRefGoogle Scholar
  70. 70.
    Wakabayashi Y, Nakada T, Murata K, Ohkura S, Mogi K, Navarro VM, Clifton DK, Mori Y, Tsukamura H, Maeda K, Steiner RA, Okamura H (2010) Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci 30:3124–3132PubMedCrossRefGoogle Scholar
  71. 71.
    Kawakami M, Uemura T, Hayashi R (1982) Electrophysiological correlates of pulsatile gonadotropin release in rats. Neuroendocrinology 35:63–67PubMedCrossRefGoogle Scholar
  72. 72.
    Wilson RC, Kesner JS, Kaufman JM, Uemura T, Akema T, Knobil E (1984) Central electrophysiologic correlates of pulsatile luteinizing hormone secretion in the rhesus monkey. Neuroendocrinology 39:256–260PubMedCrossRefGoogle Scholar
  73. 73.
    Ohkura S, Takase K, Matsuyama S, Mogi K, Ichimaru T, Wakabayashi Y, Uenoyama Y, Mori Y, Steiner RA, Tsukamura H, Maeda KI, Okamura H (2009) Gonadotrophin-releasing hormone pulse generator activity in the hypothalamus of the goat. J Neuroendocrinol 21:813–821PubMedCrossRefGoogle Scholar
  74. 74.
    Navarro VM, Gottsch ML, Wu M, Garcia-Galiano D, Hobbs SJ, Bosch MA, Pinilla L, Clifton DK, Dearth A, Ronnekleiv OK, Braun RE, Palmiter RD, Tena-Sempere M, Alreja M, Steiner RA (2011) Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 152:4265–4275PubMedCrossRefGoogle Scholar
  75. 75.
    Ramaswamy S, Seminara SB, Plant TM (2011) Evidence from the agonadal juvenile male rhesus monkey (Macaca mulatta) for the view that the action of neurokinin B to trigger gonadotropin-releasing hormone release is upstream from the kisspeptin receptor. Neuroendocrinology 94:237–245PubMedCrossRefGoogle Scholar
  76. 76.
    Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM (2008) 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 149:4387–4395PubMedCrossRefGoogle Scholar
  77. 77.
    Li XF, Kinsey-Jones JS, Cheng Y, Knox AM, Lin Y, Petrou NA, Roseweir A, Lightman SL, Milligan SR, Millar RP, O’Byrne KT (2009) Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS One 4:e8334PubMedCrossRefGoogle Scholar
  78. 78.
    Blake CA, Sawyer CH (1974) Effects of hypothalamic deafferentation on the pulsatile rhythm in plasma concentrations of luteinizing hormone in ovariectomized rats. Endocrinology 94:730–736PubMedCrossRefGoogle Scholar
  79. 79.
    Krey LC, Hess DL, Butler WR, Espinosa-Campos J, Lu KH, Piva F, Plant TM, Knobil E (1981) Medial basal hypothalamic disconnection and the onset of puberty in the female rhesus monkey. Endocrinology 108:1944–1948PubMedCrossRefGoogle Scholar
  80. 80.
    Plant TM, Moossy J, Hess DL, Nakai Y, McCormack JT, Knobil E (1979) Further studies on the effects of lesions in the rostral hypothalamus on gonadotropin secretion in the female rhesus monkey (Macaca mulatta). Endocrinology 105:465–473PubMedCrossRefGoogle Scholar
  81. 81.
    Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, Lai J, Ciofi P, McMullen NT, Rance NE (2012) Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 153:2800–2812PubMedCrossRefGoogle Scholar
  82. 82.
    Clarkson J, Han SK, Liu X, Lee K, Herbison AE (2010) Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Mol Cell Endocrinol 324:45–50PubMedCrossRefGoogle Scholar
  83. 83.
    Chan YM, Broder-Fingert S, Wong KM, Seminara SB (2009) Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. J Neuroendocrinol 21:1015–1023PubMedCrossRefGoogle Scholar
  84. 84.
    Mitsushima D, Hei DL, Terasawa E (1994) GABA is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. Proc Natl Acad Sci USA 91:395–399PubMedCrossRefGoogle Scholar
  85. 85.
    Keen KL, Burich AJ, Mitsushima D, Kasuya E, Terasawa E (1999) Effects of pulsatile infusion of the GABAA receptor blocker bicuculline on the onset of puberty in female rhesus monkeys. Endocrinology 140:5257–5266PubMedCrossRefGoogle Scholar
  86. 86.
    El Majdoubi M, Sahu A, Ramaswamy S, Plant TM (2000) Neuropeptide Y: a hypothalamic brake restraining the onset of puberty in primates. Proc Natl Acad Sci USA 97:6179–6184PubMedCrossRefGoogle Scholar
  87. 87.
    Horvath TL, Bechmann I, Naftolin F, Kalra SP, Leranth C (1997) Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non GABAergic subpopulations. Brain Res 756:283–286PubMedCrossRefGoogle Scholar
  88. 88.
    Vong L, Ye C, Yang Z, Choi B, Chua S Jr, Lowell BB (2011) Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71:142–154PubMedCrossRefGoogle Scholar
  89. 89.
    Kurian JR, Keen KL, Guerriero KA, Terasawa E (2012) Tonic control of kisspeptin release in prepubertal monkeys: implications to the mechanism of puberty onset. Endocrinology 153:3331–3336PubMedCrossRefGoogle Scholar
  90. 90.
    Plant TM, Fraser MO, Medhamurthy R, Gay VL (1989) Somatogenic control of GnRH neuronal synchronization during development in primates: a speculation. In: Plant TM, van Rees GP, Schoemaker J, Delamarre-van de Waal HA (eds) Control of the onset of puberty III. Excerpta Medica, Amsterdam, pp 111–121Google Scholar
  91. 91.
    Wilson ME, Gordon TP, Rudman CG, Tanner JM (1989) Effects of growth hormone on the tempo of sexual maturation in female rhesus monkeys. J Clin Endocrinol Metab J68:29–38CrossRefGoogle Scholar
  92. 92.
    Mann DR, Plant TM (2010) The role and potential sites of action of thyroid hormone in timing the onset of puberty in male primates. Brain Res 1364:175–185PubMedCrossRefGoogle Scholar
  93. 93.
    Terasawa E, Kurian JR, Keen KL, Shiel NA, Colman RJ, Capuano SV (2012) Body weight impact on puberty: effects of high-calorie diet on puberty onset in female rhesus monkeys. Endocrinology 153:1696–1705PubMedCrossRefGoogle Scholar
  94. 94.
    Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA (2006) Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 26:6687–6694PubMedCrossRefGoogle Scholar
  95. 95.
    Cravo RM, Margatho LO, Osborne-Lawrence S, Donato J Jr, Atkin S, Bookout AL, Rovinsky S, Frazão R, Lee CE, Gautron L, Zigman JM, Elias CF (2011) Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173:37–56PubMedCrossRefGoogle Scholar
  96. 96.
    Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A (2006) Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha. Neurosci Lett 401:225–230PubMedCrossRefGoogle Scholar
  97. 97.
    Foster DL, Ryan KD (1979) Endocrine mechanisms governing transition into adulthood: a marked decrease in inhibitory feedback action of estradiol on tonic secretion of luteinizing hormone in the lamb during puberty. Endocrinology 105:896–904PubMedCrossRefGoogle Scholar
  98. 98.
    Dohrn M, Hohlweg W (1931) Hormonale beziehungen zwischen hypohysenvorderlappen und keimdrusen. In: Proceedings of the second International Congress on Sex Research. Oliver and Boyd, Edinburgh, pp 436–442Google Scholar
  99. 99.
    Steele RE, Weisz J (1974) Changes in sensitivity of estradiol-LH feedback system with puberty in the female rat. Endocrinology 95:513–520PubMedCrossRefGoogle Scholar
  100. 100.
    Andrews WW, Advis JP, Ojeda SR (1981) The maturation of estradiol-negative feedback in female rats: evidence that the resetting of the hypothalamic “gonadostat” does not precede the first preovulatory surge of gonadotropins. Endocrinology 109:2022–2031PubMedCrossRefGoogle Scholar
  101. 101.
    Kulin HE, Grumbach MM, Kaplan SL (1969) Changing sensitivity of the pubertal gonadal hypothalamic feedback mechanism in man. Science 166:1012–1013PubMedCrossRefGoogle Scholar
  102. 102.
    Rapisarda JJ, Bergman KS, Steiner RA, Foster DL (1983) Response to estradiol inhibition of tonic luteinizing hormone secretion decreases during the final stage of puberty in the rhesus monkey. Endocrinology 112:1172–1179PubMedCrossRefGoogle Scholar
  103. 103.
    Wilson ME (1995) IGF-1 administration advances the decrease in hypersensitivity to oestradiol negative feedback inhibition of serum LH in adolescent female monkeys. J Endocrinol 145:121–130PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Ei Terasawa
    • 1
    Email author
  • Kathryn A. Guerriero
    • 1
  • Tony M. Plant
    • 2
  1. 1.Wisconsin National Primate Research CenterUniversity of WisconsinMadisonUSA
  2. 2.University of Pittsburgh School of MedicinePittsburghUSA

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