The emergence of kisspeptin as a crucial regulator of the hypothalamo-pituitary-gonadal (HPG) axis over the last 14 years has answered many questions as to the control of reproductive hormone secretion from the hypothalamus. More recently, the role of kisspeptin outside the HPG axis has received increasing attention in the hope of delineating the pathways linking various sensory and social behaviours to reproduction. These studies, in a range of species from zebrafish to humans, have identified a role for kisspeptin in behavioural networks related to reproduction including olfaction, audition, fear, anxiety, mood, and sexual arousal. The available evidence suggests that extrahypothalamic kisspeptin signalling encourages positive aspects of emotional and sexual brain processing in a presumed drive towards reproduction and ultimately maintenance of the species at a population level. In this review, we examine these studies, which collectively propose that kisspeptin may integrate sexual and emotional brain processing with the control of the HPG axis.

Keywords:
Kisspeptin, Kiss1, Kiss1r, Gpr54, Amygdala, Reproductive behaviour, Sexual behaviour, Sexual arousal, Behaviour, Limbic system
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;88:1731-1737.
2.
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;100:10972-10976.
3.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF Jr, Aparicio SA, Colledge WH: The GPR54 gene as a regulator of puberty. New Engl J Med 2003;349:1614-1627.
4.
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. New Engl J Med 2012;366:629-635.
5.
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. New Engl J Med 2008;358:709-715.
6.
Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M, Escobar ME, Arnhold IJ, Mendonca BB, Kaiser UB, Latronico AC: Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab 2010;95:2276-2280.
7.
Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M: Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 2012;92:1235-1316.
8.
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;145:4073-4077.
9.
Clarkson J, Herbison AE: Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 2006;147:5817-5825.
10.
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;21:673-682.
11.
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;80:264-272.
12.
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;26:6687-6694.
13.
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;148:1774-1783.
14.
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: Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA 2005;102:1761-1766.
15.
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;446:103-107.
16.
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;31:1984-1998.
17.
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;92:2744-2750.
18.
Smith JT, Shahab M, Pereira A, Pau KY, Clarke IJ: Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biol Reprod 2010;83:568-577.
19.
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brezillon 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;276:34631-34636.
20.
Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC: AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem 2001;276:28969-28975.
21.
Kim J, Semaan SJ, Clifton DK, Steiner RA, Dhamija S, Kauffman AS: Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 2011;152:2020-2030.
22.
Di Giorgio NP, Semaan SJ, Kim J, Lopez PV, Bettler B, Libertun C, Lux-Lantos VA, Kauffman AS: Impaired GABAB receptor signaling dramatically up-regulates Kiss1 expression selectively in nonhypothalamic brain regions of adult but not prepubertal mice. Endocrinology 2014;155:1033-1044.
23.
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;151:312-321.
24.
Pineda R, Plaisier F, Millar RP, Ludwig M: Amygdala kisspeptin neurons: putative mediators of olfactory control of the gonadotropic axis. Neuroendocrinology 2017;104:223-238.
25.
Comninos AN, Anastasovska J, Sahuri-Arisoylu M, Li X, Li S, Hu M, Jayasena CN, Ghatei MA, Bloom SR, Matthews PM, O'Byrne KT, Bell JD, Dhillo WS: Kisspeptin signaling in the amygdala modulates reproductive hormone secretion. Brain Struct Funct 2016;221:2035-2047.
26.
Catani M, Dell'acqua F, Thiebaut de Schotten M: A revised limbic system model for memory, emotion and behaviour. Neurosci Biobehav Rev 2013;37:1724-1737.
27.
Vandenbergh JG: Pheromones and mammalian reproduction; in Neill JD (ed): Knobil and Neill's Physiology of Reproduction, 3rd ed. Elsevier, 2006, pp 2041-2058.
28.
Insel TR: The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron 2010;65:768-779.
29.
Skuse DH, Gallagher L: Dopaminergic-neuropeptide interactions in the social brain. Trends Cogn Sci 2009;13:27-35.
30.
Kauffman AS, Park JH, McPhie-Lalmansingh AA, Gottsch ML, Bodo C, Hohmann JG, Pavlova MN, Rohde AD, Clifton DK, Steiner RA, Rissman EF: The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J Neurosci 2007;27:8826-8835.
31.
Adekunbi DAL, Li XF, Colledge WH, O'Byrne K: Kisspeptin in the posterodorsal medial amygdala modulates mate preference and anxiety in male mice. Endocr Rev 2017;38:SAT 445.
32.
Bakker J, Pierman S, Gonzalez-Martinez D: Effects of aromatase mutation (ArKO) on the sexual differentiation of kisspeptin neuronal numbers and their activation by same versus opposite sex urinary pheromones. Horm Behav 2010;57:390-395.
33.
Watanabe Y, Ikegami K, Ishigaki R, Ieda N, Uenoyama Y, Maeda KI, Tsukamura H, Inoue N: Enhancement of the LH surge by male olfactory signals is associated with AVPV Kiss1 cell activation in female rats. J Neuroendocrinol 2017;29:e12505.
34.
Asaba A, Osakada T, Touhara K, Kato M, Mogi K, Kikusui T: Male mice ultrasonic vocalizations enhance female sexual approach and hypothalamic kisspeptin neuron activity. Horm Behav 2017;94:53-60.
35.
Speedie N, Gerlai R: Alarm substance induced behavioral responses in zebrafish (Danio rerio). Behav Brain Res 2008;188:168-177.
36.
Ogawa S, Nathan FM, Parhar IS: Habenular kisspeptin modulates fear in the zebrafish. Proc Natl Acad Sci USA 2014;111:3841-3846.
37.
Nathan FM, Ogawa S, Parhar IS: Kisspeptin1 modulates odorant-evoked fear response via two serotonin receptor subtypes (5-HT1A and 5-HT2) in zebrafish. J Neurochem 2015;133:870-878.
38.
Nathan FM, Ogawa S, Parhar IS: Neuronal connectivity between habenular glutamate-kisspeptin1 co-expressing neurons and the raphe 5-HT system. J Neurochem 2015;135:814-829.
39.
Rao YS, Mott NN, Pak TR: Effects of kisspeptin on parameters of the HPA axis. Endocrine 2011;39:220-228.
40.
Comninos AN, Wall MB, Demetriou L, Shah AJ, Clarke SA, Narayanaswamy S, Nesbitt A, Izzi-Engbeaya C, Prague JK, Abbara A, Ratnasabapathy R, Salem V, Nijher GM, Jayasena CN, Tanner M, Bassett P, Mehta A, Rabiner EA, Honigsperger C, Silva MR, Brandtzaeg OK, Lundanes E, Wilson SR, Brown RC, Thomas SA, Bloom SR, Dhillo WS: Kisspeptin modulates sexual and emotional brain processing in humans. J Clin Invest 2017;127:709-719.
41.
Kinsey-Jones JS, Li XF, Knox AM, 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;21:20-29.
42.
Csabafi K, Jaszberenyi M, Bagosi Z, Liptak 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.
43.
Ogawa S, Ng KW, Ramadasan PN, Nathan FM, Parhar IS: Habenular Kiss1 neurons modulate the serotonergic system in the brain of zebrafish. Endocrinology 2012;153:2398-2407.
44.
Tanaka M, Csabafi K, Telegdy G: Neurotransmissions of antidepressant-like effects of kisspeptin-13. Regul Pept 2013;180:1-4.
45.
Silvers JA, Wager TD, Weber J, Ochsner KN: The neural bases of uninstructed negative emotion modulation. Soc Cogn Affect Neurosci 2015;10:10-18.
46.
Benagiano G, Carrara S, Filippi V: Sex and reproduction: an evolving relationship. Hum Reprod Update 2010;16:96-107.
47.
Stoleru S, Gregoire MC, Gerard D, Decety J, Lafarge E, Cinotti L, Lavenne F, Le Bars D, Vernet-Maury E, Rada H, Collet C, Mazoyer B, Forest MG, Magnin F, Spira A, Comar D: Neuroanatomical correlates of visually evoked sexual arousal in human males. Arch Sex Behav 1999;28:1-21.
48.
Carver CS, White TL: Behavioral inhibition, behavioral activation, and affective responses to impending reward and punishment: the BIS/BAS scales. J Pers Soc Psychol 1994;67:319-333.
49.
Costumero V, Barros-Loscertales A, Bustamante JC, Ventura-Campos N, Fuentes P, Rosell-Negre P, Avila C: Reward sensitivity is associated with brain activity during erotic stimulus processing. PLoS One 2013;8:e66940.
50.
Beaver JD, Lawrence AD, van Ditzhuijzen J, Davis MH, Woods A, Calder AJ: Individual differences in reward drive predict neural responses to images of food. J Neurosci 2006;26:5160-5166.
51.
Gresham R, Li S, Adekunbi DA, Hu M, Li XF, O'Byrne KT: Kisspeptin in the medial amygdala and sexual behavior in male rats. Neurosci Lett 2016;627:13-17.
52.
Bialy M, Sachs BD: Androgen implants in medial amygdala briefly maintain noncontact erection in castrated male rats. Horm Behav 2002;42:345-355.
53.
Acevedo BP, Aron A, Fisher HE, Brown LL: Neural correlates of long-term intense romantic love. Soc Cogn Affect Neurosci 2012;7:145-159.
54.
Bartels A, Zeki S: The neural correlates of maternal and romantic love. Neuroimage 2004;21:1155-1166.
55.
Wan MW, Downey D, Strachan H, Elliott R, Williams SR, Abel KM: The neural basis of maternal bonding. PLoS One 2014;9:e88436.
56.
Beauregard M, Courtemanche J, Paquette V, St-Pierre EL: The neural basis of unconditional love. Psychiatry Res 2009;172:93-98.
57.
Corona G, Isidori AM, Buvat J, Aversa A, Rastrelli G, Hackett G, Rochira V, Sforza A, Lenzi A, Mannucci E, Maggi M: Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med 2014;11:1577-1592.
58.
O'Carroll R, Bancroft J: Testosterone therapy for low sexual interest and erectile dysfunction in men: a controlled study. Br J Psychiatry 1984;145:146-151.
59.
Ramasamy R, Wilken N, Scovell JM, Lipshultz LI: Effect of testosterone supplementation on symptoms in men with hypogonadism. Eur Urol 2015;67:176-177.
60.
d'Anglemont de Tassigny X, Jayasena C, Murphy KG, Dhillo WS, Colledge WH: Mechanistic insights into the more potent effect of KP-54 compared to KP-10 in vivo. PLoS One 2017;12:e0176821.
61.
Hanchate NK, Parkash J, Bellefontaine N, Mazur D, Colledge WH, d'Anglemont de Tassigny X, Prevot V: Kisspeptin-GPR54 signaling in mouse NO-synthesizing neurons participates in the hypothalamic control of ovulation. J Neurosci 2012;32:932-945.
62.
Fergani C, Navarro V: Expanding the role of tachykinins in the neuroendocrine control of reproduction. Reproduction 2016, pii: REP-16-0378.
63.
Millar RP: New developments in kisspeptin, neurokinin B and dynorphin A regulation of gonadotropin-releasing hormone pulsatile secretion. Neuroendocrinology 2014;99:5-6.
64.
True C, Verma S, Grove KL, Smith MS: Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females. Endocrinology 2013;154:2821-2832.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.