The kisspeptin-GnRH pathway in human reproductive health and disease

Karolina Skorupskaite, Jyothis T George, Richard A Anderson, Karolina Skorupskaite, Jyothis T George, Richard A Anderson

Abstract

Background: The discovery of kisspeptin as key central regulator of GnRH secretion has led to a new level of understanding of the neuroendocrine regulation of human reproduction. The related discovery of the kisspeptin-neurokinin B-dynorphin (KNDy) pathway in the last decade has further strengthened our understanding of the modulation of GnRH secretion by endocrine, metabolic and environmental inputs. In this review, we summarize current understanding of the physiological roles of these novel neuropeptides, and discuss the clinical relevance of these discoveries and their potential translational applications.

Methods: A systematic literature search was performed using PUBMED for all English language articles up to January 2014. In addition, the reference lists of all relevant original research articles and reviews were examined. This review focuses mainly on published human studies but also draws on relevant animal data.

Results: Kisspeptin is a principal regulator of the secretion of gonadotrophins, and through this key role it is critical for the onset of puberty, the regulation of sex steroid-mediated feedback and the control of adult fertility. Although there is some sexual dimorphism, both neuroanatomically and functionally, these functions are apparent in both men and women. Kisspeptin acts upstream of GnRH and, following paracrine stimulatory and inhibitory inputs from neurokinin B and dynorphin (KNDy neuropeptides), signals directly to GnRH neurones to control pulsatile GnRH release. When administered to humans in different isoforms, routes and doses, kisspeptin robustly stimulates LH secretion and LH pulse frequency. Manipulation of the KNDy system is currently the focus of translational research with the possibility of future clinical application to regulate LH pulsatility, increasing gonadal sex steroid secretion in reproductive disorders characterized by decreased LH pulsatility, including hypothalamic amenorrhoea and hypogonadotropic hypogonadism. Conversely there may be scope to reduce the activity of the KNDy system to reduce LH secretion where hypersecretion of LH adds to the phenotype, such as in polycystic ovary syndrome.

Conclusions: Kisspeptin is a recently discovered neuromodulator that controls GnRH secretion mediating endocrine and metabolic inputs to the regulation of human reproduction. Manipulation of kisspeptin signalling has the potential for novel therapies in patients with pathologically low or high LH pulsatility.

Keywords: GnRH; LH pulsatility; kisspeptin; kisspeptin-neurokinin B-dynorphin.

© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Figures

Figure 1
Figure 1
Schematic diagram showing the neuroanatomy of the kisspeptin-GnRH pathway and the relationship between KNDy neurones and GnRH neurones in humans and rodents. Kisspeptin signals directly to the GnRH neurones, which express kisspeptin receptor. The location of kisspeptin neurone populations within the hypothalamus is species specific, residing within the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus in rodents, and within the preoptic area (POA) and the infundibular nucleus in humans. Kisspeptin neurones in the infundibular (humans)/arcuate (rodents) nucleus co-express neurokinin B and dynorphin (KNDy neurones), which via neurokinin B receptor and kappa opioid peptide receptor autosynaptically regulate pulsatile kisspeptin secretion, with neurokinin B being stimulatory and dynorphin inhibitory. Negative (red) and positive (green) sex steroid feedback is mediated via distinct kisspeptin populations in rodents, via the AVPV and the arcuate nucleus, respectively. In humans KNDy neurones in the infundibular nucleus relay both negative (red) and positive (green) feedback. The role of the POA kisspeptin population in mediating sex steroid feedback in humans is incompletely explored. ME, median eminence; +, stimulatory; −, inhibitory; ERα, estrogen receptor alpha; PR, progesterone receptor; Kiss1/KiSS1, kisspeptin; NKB, neurokinin B; Dyn, dynorphin.
Figure 2
Figure 2
Kisspeptin stimulates LH secretion in healthy men (filled squares) and women (filled circles). The stimulatory effect of kisspeptin on LH secretion is shown in both healthy men and women, when kisspeptin is administered in different isoforms (kisspeptin-54 and kisspeptin-10) and by different protocols (intravenous or subcutaneous, single boluses or continuous infusion). Note that stimulated LH values are either mean LH or peak LH concentrations depending on how the data are originally presented. Where authors do not state exact LH concentration following kisspeptin administration, this was obtained from the relevant figures. 0% change in LH secretion is reported if no statistically significant change in LH secretion was reported and authors do not show actual LH concentrations. iv, intravenous; sc, subcutaneous; BD, twice daily; Implanon, etonogestrel contraceptive implant; COCP, combined oral contraceptive pill.
Figure 3
Figure 3
Increase in LH secretion following the administration of kisspeptin in human disease models. The stimulatory effect of kisspeptin on LH secretion is shown in reproductive endocrine disorders, when kisspeptin is administered in different isoforms (kisspeptin-54 and kisspeptin-10) and by different protocols (i.v. or s.c., single boluses or continuous infusion) as indicated. Note that stimulated LH values are either mean LH or peak LH concentrations depending on how the data are originally presented. Where authors do not state an exact LH concentration following kisspeptin administration, this is obtained from the relevant figures. BD, twice daily; T2DM, type 2 diabetes; NKB (TAC3), neurokinin B; NKB3R (TAC3R), neurokinin B receptor.
Figure 4
Figure 4
Potential clinical applications of novel kisspeptin-based modulation of LH secretion. Schematic presentation of LH pulses in health and in reproductive endocrine disorders. In health, an LH pulse occurs about every 90 min. The frequency of LH pulses is diminished in patients with hypothalamic amenorrhoea, male hypogonadism and pubertal delay, whereas LH pulse frequency is enhanced in women with polycystic ovary syndrome, menopause and precocious puberty. Therapeutic opportunities to correct abnormal LH pulse frequency by manipulating KNDy neurones with relevant agonists and antagonists are emerging. PCOS, polycystic ovary syndrome.

References

    1. Abbara A, Jayasena CN, Nijher GK, Comninos AN, Christopoulos G, Ashby D, Ghatei MA, Bloom SR, Carby A, Trew G, et al. Kisspeptin—a novel physiological trigger for oocyte maturation in IVF treatment. Hum Reprod. 2013 Supplement 1; European Society of Human Reproduction and Embryology 29th Annual Meeting, London, Abstract O-107.
    1. Abel TW, Voytko ML, Rance NE. The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause. J Clin Endocrinol Metab. 1999;6:2111–2118.
    1. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978;4368:631–633.
    1. Billings HJ, Connors JM, Altman SN, Hileman SM, Holaskova I, Lehman MN, McManus CJ, Nestor CC, Jacobs BH, Goodman RL. Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology. 2010;8:3836–3846.
    1. Burke MC, Letts PA, Krajewski SJ, Rance NE. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol. 2006;5:712–726.
    1. Caraty A, Smith JT, Lomet D, Ben Said 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;11:5258–5267.
    1. Casper RF, Alapin-Rubillovitz S. Progestins increase endogenous opioid peptide activity in postmenopausal women. J Clin Endocrinol Metab. 1985;1:34–36.
    1. Castellano JM, Navarro VM, Fernandez-Fernandez R, Nogueiras R, Tovar S, Roa J, Vazquez MJ, Vigo E, Casanueva FF, Aguilar E, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;9:3917–3925.
    1. Castellano JM, Navarro VM, Fernandez-Fernandez R, Roa J, Vigo E, Pineda R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes. 2006;9:2602–2610.
    1. Castellano JM, Navarro VM, Roa J, Pineda R, Sanchez-Garrido MA, Garcia-Galiano D, Vigo E, Dieguez C, Aguilar E, Pinilla L, et al. Alterations in hypothalamic KiSS-1 system in experimental diabetes: early changes and functional consequences. Endocrinology. 2009;2:784–794.
    1. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update. 2005;3:293–307.
    1. Chan YM, Butler JP, Pinnell NE, Pralong FP, Crowley WF, Jr, Ren C, Chan KK, Seminara SB. Kisspeptin resets the hypothalamic GnRH clock in men. J Clin Endocrinol Metab. 2011;6:E908–E915.
    1. Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB. Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle. J Clin Endocrinol Metab. 2012;8:E1458–E1467.
    1. 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;1:301–311.
    1. Christian CA, Moenter SM. The neurobiology of preovulatory and estradiol-induced gonadotropin-releasing hormone surges. Endocr Rev. 2010;4:544–577.
    1. Ciofi P, Krause JE, Prins GS, Mazzuca M. Presence of nuclear androgen receptor-like immunoreactivity in neurokinin B-containing neurons of the hypothalamic arcuate nucleus of the adult male rat. Neurosci Lett. 1994;2:193–196.
    1. Ciofi P, Leroy D, Tramu G. Sexual dimorphism in the organization of the rat hypothalamic infundibular area. Neuroscience. 2006;4:1731–1745.
    1. Clarke IJ, Cummins JT. GnRH pulse frequency determines LH pulse amplitude by altering the amount of releasable LH in the pituitary glands of ewes. J Reprod Fertil. 1985;2:425–431.
    1. Clarkson J, Herbison AE. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology. 2006;12:5817–5825.
    1. Clarkson J, d'Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci. 2008;35:8691–8697.
    1. 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;8:673–682.
    1. Clifton D, Steiner RA. Neuroendocrinology of Reproduction. In: Strauss J, Barbieri R, editors. Yen & Jaffe's Reproductive Endocrinology. Philadelphia: Elsevier; 2009. pp. 3–33.
    1. 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;3:1400–1412.
    1. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science. 2006;5775:927–930.
    1. d'Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB, et al. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA. 2007;25:10714–10719.
    1. Dahl SK, Amstalden M, Coolen L, Fitzgerald M, Lehman M. Dynorphin immunoreactive fibers contact GnRH neurons in the human hypothalamus. Reprod Sci. 2009;8:781–787.
    1. Dandona P, Dhindsa S, Chaudhuri A, Bhatia V, Topiwala S, Mohanty P. Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. Curr Mol Med. 2008;8:816–828.
    1. 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 USA. 2003;19:10972–10976.
    1. Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;12:6609–6615.
    1. Dhillo WS, Chaudhri OB, Thompson EL, Murphy KG, Patterson M, Ramachandran R, Nijher GK, Amber V, Kokkinos A, Donaldson M, et al. Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women. J Clin Endocrinol Metab. 2007;10:3958–3966.
    1. Donato J, Jr, Cravo RM, Frazao R, Gautron L, Scott MM, Lachey J, Castro IA, Margatho LO, Lee S, Lee C, et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest. 2011;1:355–368.
    1. Farooqi IS, O'Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr. 2009;3:980S–984S.
    1. Ferin M, Van Vugt D, Wardlaw S. The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res. 1984;40:441–485.
    1. Finn PD, Cunningham MJ, Pau KY, Spies HG, Clifton DK, Steiner RA. The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology. 1998;11:4652–4662.
    1. Foradori CD, Coolen LM, Fitzgerald ME, Skinner DC, Goodman RL, Lehman MN. Colocalization of progesterone receptors in parvicellular dynorphin neurons of the ovine preoptic area and hypothalamus. Endocrinology. 2002;11:4366–4374.
    1. Foradori CD, Goodman RL, Adams VL, Valent M, Lehman MN. Progesterone increases dynorphin a concentrations in cerebrospinal fluid and preprodynorphin messenger ribonucleic Acid levels in a subset of dynorphin neurons in the sheep. Endocrinology. 2005;4:1835–1842.
    1. 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;3:225–230.
    1. Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun. 2003;4:1357–1363.
    1. Genazzani AD, Gastaldi M, Petraglia F, Battaglia C, Surico N, Volpe A, Genazzani AR. Naltrexone administration modulates the neuroendocrine control of luteinizing hormone secretion in hypothalamic amenorrhoea. Hum Reprod. 1995;11:2868–2871.
    1. George JT, Seminara SB. Kisspeptin and the hypothalamic control of reproduction: lessons from the human. Endocrinology. 2012;11:5130–5136.
    1. George JT, Millar RP, Anderson RA. Hypothesis: kisspeptin mediates male hypogonadism in obesity and type 2 diabetes. Neuroendocrinology. 2010;4:302–307.
    1. George JT, Veldhuis JD, Roseweir AK, Newton CL, Faccenda E, Millar RP, Anderson RA. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011;8:E1228–E1236.
    1. George JT, Anderson RA, Millar RP. Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback. Hum Reprod. 2012;12:3552–3559.
    1. George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. 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;1:100–104.
    1. Goodman RL, Coolen LM, Anderson GM, Hardy SL, Valent M, Connors JM, Fitzgerald ME, Lehman MN. Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology. 2004;6:2959–2967.
    1. Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, et al. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology. 2007;12:5752–5760.
    1. Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;9:4073–4077.
    1. Gottsch ML, Clifton DK, Steiner RA. From KISS1 to kisspeptins: an historical perspective and suggested nomenclature. Peptides. 2009;1:4–9.
    1. Goubillon ML, Forsdike RA, Robinson JE, Ciofi P, Caraty A, Herbison AE. Identification of neurokinin B-expressing neurons as an highly estrogen-receptive, sexually dimorphic cell group in the ovine arcuate nucleus. Endocrinology. 2000;11:4218–4225.
    1. Gutierrez-Pascual E, Martinez-Fuentes AJ, Pinilla L, Tena-Sempere M, Malagon MM, Castano JP. Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion. J Neuroendocrinol. 2007;7:521–530.
    1. Hall JE, Taylor AE, Martin KA, Rivier J, Schoenfeld DA, Crowley WF., Jr Decreased release of gonadotropin-releasing hormone during the preovulatory midcycle luteinizing hormone surge in normal women. Proc Natl Acad Sci USA. 1994;15:6894–6898.
    1. 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;49:11349–11356.
    1. 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;2:277–287.
    1. Herbison AE, Theodosis DT. 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;2:283–298.
    1. Herbison AE, 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;1:312–321.
    1. Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, et al. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci. 2010;11:1984–1998.
    1. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, Gottsch ML, Clifton DK, Steiner RA. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology. 2004;4:264–272.
    1. 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 Invest. 2008;7:656–659.
    1. Jayasena CN, Nijher GM, Chaudhri OB, Murphy KG, Ranger A, Lim A, Patel D, Mehta A, Todd C, Ramachandran R, et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab. 2009;11:4315–4323.
    1. Jayasena CN, Nijher GM, Abbara A, Murphy KG, Lim A, Patel D, Mehta A, Todd C, Donaldson M, Trew GH, et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin Pharmacol Ther. 2010;6:840–847.
    1. Jayasena CN, Nijher GM, Comninos AN, Abbara A, Januszewki A, Vaal ML, Sriskandarajah L, Murphy KG, Farzad Z, Ghatei MA, et al. The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans. J Clin Endocrinol Metab. 2011;12:E1963–E1972.
    1. Jayasena CN, Abbara A, Comninos AN, Ratnasabapathy R, Veldhuis JD, Nijher GK, Ganiyu-Dada Z, Mehta A, Todd C, Ghatei MA, et al. Kissppeptin-54 administration stimulates pulsatile luteinising hormone secretion in women with hypothalamic amenorrhea. Hum Reprod. 2013a Supplement 1: European Society of Human Reproduction and Embryology 29th Annual Meeting, London, Abstract O-268.
    1. Jayasena CN, Comninos A, Nijher G, Abbara A, De Silva A, Veldhuis J, Ratnasabapathy R, Izzi-Engbeaya C, Lim A, Patel D, et al. Twice-daily subcutaneous injection of kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers. J Clin Endocrinol Metab. 2013b;11:4464–4474.
    1. Jayasena CN, Comninos AN, Veldhuis JD, Misra S, Abbara A, Izzi-Engbeaya C, Donaldson M, Ghatei MA, Bloom SR, Dhillo WS. A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women. Clin Endocrinol (Oxf) 2013c;4:558–563.
    1. Karsch FJ. Central actions of ovarian steroids in the feedback regulation of pulsatile secretion of luteinizing hormone. Annu Rev Physiol. 1987;49:365–382.
    1. Kauffman AS, Gottsch ML, Roa J, Byquist AC, Crown A, Clifton DK, Hoffman GE, Steiner RA, Tena-Sempere M. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology. 2007;4:1774–1783.
    1. Keen KL, Wegner FH, Bloom SR, Ghatei MA, Terasawa E. 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. 2008;8:4151–4157.
    1. Khan AR, Kauffman AS. The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian-timed preovulatory luteinising hormone surge. J Neuroendocrinol. 2012;1:131–143.
    1. Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K, Yamada S, Inoue K, Ohtaki T, Matsumoto H, et al. Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology. 2005;10:4431–4436.
    1. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;37:34631–34636.
    1. 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;3:372–386.
    1. Krajewski SJ, Burke MC, Anderson MJ, McMullen NT, Rance NE. Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat. Neuroscience. 2010;2:680–697.
    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;23:1731–1737.
    1. Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-Nguyen AT, George SR, et al. Discovery of a receptor related to the galanin receptors. FEBS Lett. 1999;1:103–107.
    1. Lehman MN, Robinson JE, Karsch FJ, Silverman AJ. Immunocytochemical localization of luteinizing hormone-releasing hormone (LHRH) pathways in the sheep brain during anestrus and the mid-luteal phase of the estrous cycle. J Comp Neurol. 1986;1:19–35.
    1. 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;8:3479–3489.
    1. Li XF, Kinsey-Jones JS, Cheng Y, Knox AM, Lin Y, Petrou NA, Roseweir A, Lightman SL, Milligan SR, Millar RP, et al. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS One. 2009;12:e8334.
    1. Li Q, Roa A, Clarke IJ, Smith JT. Seasonal variation in the gonadotropin-releasing hormone response to kisspeptin in sheep: possible kisspeptin regulation of the kisspeptin receptor. Neuroendocrinology. 2012;3:212–221.
    1. Lippincott MF, Y C, Sidhoum VF, Seminara S. Continuously administered kisspeptin as a pseudo-antagonist of the kisspeptin receptor. The Endocrine Society's 95th Annual Meeting, ENDO 2013; 2013. San Francisco, Abstract SAT 2134-2163.
    1. 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;9:4605–4614.
    1. MacLean D, Matsui H, Suri A, Neuwirth R, Colombel M. The investigational Kisspeptin/GPR54 agonist peptide analog, TAK-448, given as single-dose then 13-day continuous subcutaneous infusion, stimulates then suppresses the LH-testosterone axis in healthy male volunteers. Endocr Rev. 2013;34 SAT-323, Abstracts.
    1. Mason DR, Arora KK, Mertz LM, Catt KJ. Homologous down-regulation of gonadotropin-releasing hormone receptor sites and messenger ribonucleic acid transcripts in alpha T3-1 cells. Endocrinology. 1994;3:1165–1170.
    1. Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun. 2004;2:383–388.
    1. McArdle CA, Gorospe WC, Huckle WR, Conn PM. Homologous down-regulation of gonadotropin-releasing hormone receptors and desensitization of gonadotropes: lack of dependence on protein kinase C. Mol Endocrinol. 1987;6:420–429.
    1. McNeilly AS, Crawford JL, Taragnat C, Nicol L, McNeilly JR. The differential secretion of FSH and LH: regulation through genes, feedback and packaging. Reprod Suppl. 2003:463–476.
    1. Melis GB, Paoletti AM, Gambacciani M, Mais V, Fioretti P. Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women using naloxone. Neuroendocrinology. 1984;1:60–63.
    1. Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005;5:1761–1766.
    1. 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. 2010:81–89.
    1. Min L, Soltis K, Reis AC, Xu S, Kuohung W, Jain M, Carroll RS, Kaiser UB. Dynamic kisspeptin receptor trafficking modulates kisspeptin-mediated calcium signaling. Mol Endocrinol. 2014;1:16–27.
    1. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, McMullen NT, Rance NE. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc Natl Acad Sci USA. 2012;48:19846–19851.
    1. Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001;31:28969–28975.
    1. Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M. 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. 2004a;10:4565–4574.
    1. Navarro VM, Fernandez-Fernandez R, Castellano JM, Roa J, Mayen A, Barreiro ML, Gaytan F, Aguilar E, Pinilla L, Dieguez C, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54. J Physiol. 2004b;(Pt 2):379–386.
    1. Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A, Barreiro ML, Casanueva FF, Aguilar E, Dieguez C, et al. Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology. 2005a;4:1689–1697.
    1. Navarro VM, Castellano JM, Fernandez-Fernandez R, Tovar S, Roa J, Mayen A, Nogueiras R, Vazquez MJ, Barreiro ML, Magni P, et al. Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology. 2005b;1:156–163.
    1. 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;38:11859–11866.
    1. Novaira HJ, Ng Y, Wolfe A, Radovick S. Kisspeptin increases GnRH mRNA expression and secretion in GnRH secreting neuronal cell lines. Mol Cell Endocrinol. 2009;1–2:126–134.
    1. Oakley AE, Clifton DK, Steiner RA. Kisspeptin signaling in the brain. Endocr Rev. 2009;6:713–743.
    1. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;6837:613–617.
    1. Ojeda SR, Dubay C, Lomniczi A, Kaidar G, Matagne V, Sandau US, Dissen GA. Gene networks and the neuroendocrine regulation of puberty. Mol Cell Endocrinol. 2010;1–2:3–11.
    1. Pampillo M, Camuso N, Taylor JE, Szereszewski JM, Ahow MR, Zajac M, Millar RP, Bhattacharya M, Babwah AV. Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. Mol Endocrinol. 2009;12:2060–2074.
    1. Pineda R, Garcia-Galiano D, Roseweir A, Romero M, Sanchez-Garrido MA, Ruiz-Pino F, Morgan K, Pinilla L, Millar RP, Tena-Sempere M. Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology. 2010;2:722–730.
    1. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;3:1235–1316.
    1. Plant TM, Ramaswamy S, Dipietro MJ. 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. 2006;2:1007–1013.
    1. Pompolo S, Pereira A, Scott CJ, Fujiyma F, Clarke IJ. Evidence for estrogenic regulation of gonadotropin-releasing hormone neurons by glutamatergic neurons in the ewe brain: an immunohistochemical study using an antibody against vesicular glutamate transporter-2. J Comp Neurol. 2003;1:136–144.
    1. Pompolo S, Pereira A, Estrada KM, Clarke IJ. Colocalization of kisspeptin and gonadotropin-releasing hormone in the ovine brain. Endocrinology. 2006;2:804–810.
    1. Quigley ME, Yen SS. The role of endogenous opiates in LH secretion during the menstrual cycle. J Clin Endocrinol Metab. 1980;1:179–181.
    1. Ramaswamy S, Seminara SB, Pohl CR, DiPietro MJ, Crowley WF, Jr, Plant TM. Effect of continuous intravenous administration of human metastin 45–54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta) Endocrinology. 2007;7:3364–3370.
    1. Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM. 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;9:4387–4395.
    1. Rance NE. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides. 2009;1:111–122.
    1. Rance NE, Young WS., III Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology. 1991;5:2239–2247.
    1. Rance NE, McMullen NT, Smialek JE, Price DL, Young WS., III Postmenopausal hypertrophy of neurons expressing the estrogen receptor gene in the human hypothalamus. J Clin Endocrinol Metab. 1990;1:79–85.
    1. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;3:211–227.
    1. Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML. KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and differentially regulated in vivo by oestradiol and gonadotrophin-releasing hormone. J Neuroendocrinol. 2008;3:381–393.
    1. Roa J, Garcia-Galiano D, Varela L, Sanchez-Garrido MA, Pineda R, Castellano JM, Ruiz-Pino F, Romero M, Aguilar E, Lopez M, et al. The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology. 2009;11:5016–5026.
    1. Rometo AM, Rance NE. Changes in prodynorphin gene expression and neuronal morphology in the hypothalamus of postmenopausal women. J Neuroendocrinol. 2008;12:1376–1381.
    1. Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab. 2007;7:2744–2750.
    1. Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, Pineda R, Gottsch ML, Tena-Sempere M, Moenter SM, et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;12:3920–3929.
    1. Sandoval-Guzman T, Stalcup ST, Krajewski SJ, Voytko ML, Rance NE. Effects of ovariectomy on the neuroendocrine axes regulating reproduction and energy balance in young cynomolgus macaques. J Neuroendocrinol. 2004;2:146–153.
    1. Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;4:633–638.
    1. Schwanzel-Fukuda M, Pfaff DW. Origin of luteinizing hormone-releasing hormone neurons. Nature. 1989;6211:161–164.
    1. Scott G, Ahmad I, Howard K, MacLean D, Oliva C, Warrington S, Wilbraham D, Worthington P. Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men. Br J Clin Pharmacol. 2013;2:381–391.
    1. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;17:1614–1627.
    1. Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA. 2005;6:2129–2134.
    1. Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab. 2010;4:1955–1961.
    1. Shoupe D, Montz FJ, Lobo RA. The effects of estrogen and progestin on endogenous opioid activity in oophorectomized women. J Clin Endocrinol Metab. 1985;1:178–183.
    1. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;5:2276–2280.
    1. Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;9:3686–3692.
    1. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006a;4:298–303.
    1. 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. 2006b;25:6687–6694.
    1. Smith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M, Bateman K, Goodman RL, Tilbrook AJ, Ubuka T, et al. Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 2008a;11:5770–5782.
    1. 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. 2008b;4:1951–1959.
    1. Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S, Seminara SB, Mendonca BB, Kaiser UB, Latronico AC. A GPR54-activating mutation in a patient with central precocious puberty. N Engl J Med. 2008;7:709–715.
    1. Tello JA, George JT, Millar M, Anderson RA, Millar RP. Laying the foundation for neuroendocrine control of human reproduction: an investigation into the development of kisspeptin and neurokinin B networks. Endocrine Abstracts. 2010 Society for Endocrinology, 2010, 2021, OC2012.2016.
    1. 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;10:850–858.
    1. Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009;3:354–358.
    1. Tovar S, Vazquez MJ, Navarro VM, Fernandez-Fernandez R, Castellano JM, Vigo E, Roa J, Casanueva FF, Aguilar E, Pinilla L, et al. Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats. Endocrinology. 2006;6:2696–2704.
    1. Uenoyama Y, Inoue N, Pheng V, Homma T, Takase K, Yamada S, Ajiki K, Ichikawa M, Okamura H, Maeda KI, et al. Ultrastructural evidence of kisspeptin-gonadotrophin-releasing hormone (GnRH) interaction in the median eminence of female rats: implication of axo-axonal regulation of GnRH release. J Neuroendocrinol. 2011;10:863–870.
    1. Wahab F, Ullah F, Chan YM, Seminara SB, Shahab M. Decrease in hypothalamic Kiss1 and Kiss1r expression: a potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta) Horm Metab Res. 2011;2:81–85.
    1. West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1) Genomics. 1998;1:145–148.
    1. Yamada S, Uenoyama Y, Kinoshita M, Iwata K, Takase K, Matsui H, Adachi S, Inoue K, Maeda KI, Tsukamura H. Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats. Endocrinology. 2007;5:2226–2232.
    1. Young J, George JT, Tello JA, Francou B, Bouligand J, Guiochon-Mantel A, Brailly-Tabard S, Anderson RA, Millar RP. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology. 2013;2:193–202.
    1. Zhang C, Roepke TA, Kelly MJ, Ronnekleiv OK. Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels. J Neurosci. 2008;17:4423–4434.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe