The kisspeptins are a family of neuropeptides which act as upstream stimulators of gonadotrophin releasing hormone (GnRH) neurons. Kisspeptin signalling is prerequisite to establishing the normal human reproductive phenotype; loss of function mutations in the KISS1 or KISS1R gene produces normosmic hypogonadotrophic hypogonadism in humans and mice, whilst increased activation of KISS1R causes precocious puberty. Administration of exogenous kisspeptin to human subjects stimulates an acute gonadotrophin rise. Serum kisspeptin levels also markedly increase during pregnancy. The identification of kisspeptin has been one of the biggest discoveries in the field of reproductive endocrinology, since the isolation and sequencing of GnRH in 1977, and has generated a novel research avenue which has received much attention over the past decade. This research has delineated many properties of the KISS1-KISS1R system, but there is still further work to do. Understanding kisspeptin’s role throughout our reproductive lifetime should help us better understand—and therefore treat—disorders of reproductive function. Promisingly, the current data supports the potential to develop kisspeptin based therapies. As an outlook article this paper focusses predominantly on our groups recent investigations into the effects of kisspeptin administration to humans and the potential therapeutic role of kisspeptin. 1. Introduction 1.1. Molecular Structure, Function, and Neuroanatomy of Kisspeptin Kisspeptins are coded for by the KISS1 gene and act via binding with the G-protein coupled receptor 54 (GPR54) also known as the KISS1 receptor (KISS1R). The initial protein product of the KISS1 gene is a 145-amino-acid peptide, a member of the arginine phenylalanine (RF) amide group. It is cleaved into shorter, biologically active peptides known as kisspeptin-54, kisspeptin-14, kisspeptin-13, and kisspeptin-10, where each number corresponds to the number of amino acids and with kisspeptin-10 representing the common C-terminal decapeptide sequence shared by all [1]. Kisspeptin expression has been identified in multiple tissues, including pancreas, adipose tissue, gonads, and placenta [1–3]; however, its main functional role is mediated by its expression within the central nervous system. Kisspeptin is produced by neurones in the infundibular (arcuate) nucleus of the hypothalamus. These neurons have been shown to have direct afferent connections onto GnRH neurons of the mediobasal hypothalamus in humans, and kisspeptin activity has been shown to induce upregulation of KISS1R within these GnRH
References
[1]
M. Kotani, M. Detheux, A. Vandenbogaerde et al., “The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54,” The Journal of Biological Chemistry, vol. 276, no. 37, pp. 34631–34636, 2001.
[2]
J. H. Lee, M. E. Miele, D. J. Hicks et al., “KiSS-1, a novel human malignant melanoma metastasis-suppressor gene,” Journal of the National Cancer Institute, vol. 88, no. 23, pp. 1731–1737, 1996.
[3]
T. Ohtaki, Y. Shintani, S. Honda et al., “Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor,” Nature, vol. 411, no. 6837, pp. 613–617, 2001.
[4]
A. Abbara, R. Ratnasabapathy, C. N. Jayasena, and W. S. Dhillo, “The effects of kisspeptin on gonadotropin release in non-human mammals,” Advances in Experimental Medicine and Biology, vol. 784, pp. 63–87, 2013.
[5]
W. S. Dhillo, O. B. Chaudhri, M. Patterson et al., “Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 12, pp. 6609–6615, 2005.
[6]
C. N. Jayasena, G. M. K. Nijher, A. Abbara et al., “Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea,” Clinical Pharmacology and Therapeutics, vol. 88, no. 6, pp. 840–847, 2010.
[7]
J. T. George, J. D. Veldhuis, A. K. Roseweir et al., “Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men,” The Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 8, pp. E1228–E1236, 2011.
[8]
C. N. Jayasena, G. M. K. Nijher, A. N. Comninos et al., “The effects of kisspeptin-10 on reproductive hormone release show sexual dimorphism in humans,” The Journal of Clinical Endocrinology & Metabolism, vol. 96, no. 12, pp. E1963–E1972, 2011.
[9]
Y. M. Chan, J. P. Butler, V. F. Sidhoum, N. E. Pinnell, and S. B. Seminara, “Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle,” Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 8, pp. E1458–E1467, 2012.
[10]
C. N. Jayasena, A. N. Comninos, J. D. Veldhuis et al., “A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women,” Clinical Endocrinology, vol. 79, no. 4, pp. 558–563, 2013.
[11]
W. S. Dhillo, O. B. Chaudhri, E. L. Thompson et al., “Kisspeptin-54 stimulates gonadotropin release most potently during the preovulatory phase of the menstrual cycle in women,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 10, pp. 3958–3966, 2007.
[12]
C. N. Jayasena, G. M. K. Nijher, O. B. Chaudhri et al., “Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 11, pp. 4315–4323, 2009.
[13]
J. T. George, J. D. Veldhuis, M. Tena-Sempere, R. P. Millar, and R. A. Anderson, “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,” Clinical Endocrinology, vol. 79, no. 1, pp. 100–104, 2013.
[14]
J. T. George, R. A. Anderson, and R. P. Millar, “Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback,” Human Reproduction, vol. 27, no. 12, pp. 3552–3559, 2012.
[15]
J. Young, J. T. George, J. A. Tello et al., “Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications,” Neuroendocrinology, vol. 97, no. 2, pp. 193–202, 2013.
[16]
C. N. Jayasena, A. N. Comninos, G. M. K. Nijher, et al., “Twice-daily subcutaneous injection of kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers,” Journal of Clinical Endocrinology & Metabolism, vol. 98, pp. 4464–4474, 2013.
[17]
Y.-M. Chan, J. P. Butler, N. E. Pinnell et al., “Kisspeptin resets the hypothalamic GnRH clock in men,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 6, pp. E908–E915, 2011.
[18]
G. M. K. Nijher, O. B. Chaudhri, R. Ramachandran et al., “The effects of kisspeptin-54 on blood pressure in humans and plasma kisspeptin concentrations in hypertensive diseases of pregnancy,” The British Journal of Clinical Pharmacology, vol. 70, no. 5, pp. 674–681, 2010.
[19]
M. L. Gottsch, M. J. Cunningham, J. T. Smith et al., “A role for kisspeptins in the regulation of gonadotropin secretion in the mouse,” Endocrinology, vol. 145, no. 9, pp. 4073–4077, 2004.
[20]
S. D. C. Bianco and U. B. Kaiser, “The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism,” Nature Reviews Endocrinology, vol. 5, no. 10, pp. 569–576, 2009.
[21]
L. F. G. Silveira and A. C. Latronico, “Approach to the patient with hypogonadotropic hypogonadism,” The Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 5, pp. 1781–1788, 2013.
[22]
D. K. Lee, T. Nguyen, G. P. O'Neill et al., “Discovery of a receptor related to the galanin receptors,” The FEBS Letters, vol. 446, no. 1, pp. 103–107, 1999.
[23]
Y. Horikoshi, H. Matsumoto, Y. Takatsu et al., “Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 2, pp. 914–919, 2003.
[24]
N. de Roux, E. Genin, J. Carel, F. Matsuda, J. Chaussain, and E. Milgrom, “Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 19, pp. 10972–10976, 2003.
[25]
S. B. Seminara, S. Messager, E. E. Chatzidaki et al., “The GPR54 gene as a regulator of puberty,” The New England Journal of Medicine, vol. 349, no. 17, pp. 1614–1627, 2003.
[26]
S. Funes, J. A. Hedrick, G. Vassileva et al., “The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system,” Biochemical and Biophysical Research Communications, vol. 312, no. 4, pp. 1357–1363, 2003.
[27]
L. G. Silveira, A. C. Latronico, and S. B. Seminara, “Kisspeptin and clinical disorders.,” Advances in Experimental Medicine and Biology, vol. 784, pp. 187–199, 2013.
[28]
M. G. Teles, E. B. Trarbach, S. D. Noel et al., “A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism,” European Journal of Endocrinology, vol. 163, no. 1, pp. 29–34, 2010.
[29]
A. K. Topaloglu, J. A. Tello, L. D. Kotan et al., “Inactivating KISS1 mutation and hypogonadotropic hypogonadism,” The New England Journal of Medicine, vol. 366, no. 7, pp. 629–635, 2012.
[30]
J. R. Pedersen-White, L. P. Chorich, D. P. Bick, R. J. Sherins, and L. C. Layman, “The prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndrome,” Molecular Human Reproduction, vol. 14, no. 6, pp. 367–370, 2008.
[31]
M. G. Teles, S. D. C. Bianco, V. N. Brito et al., “A GPR54-activating mutation in a patient with central precocious puberty,” The New England Journal of Medicine, vol. 358, no. 7, pp. 709–715, 2008.
[32]
J. Roa, E. Vigo, J. M. Castellano et al., “Hypothalamic expression of KiSS-1 system and gonadotropin-releasing effects of kisspeptin in different reproductive states of the female rat,” Endocrinology, vol. 147, no. 6, pp. 2864–2878, 2006.
[33]
J. T. Smith, “Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects,” Peptides, vol. 30, no. 1, pp. 94–102, 2009.
[34]
A. K. Topaloglu, F. Reimann, M. Guclu et al., “TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction,” Nature Genetics, vol. 41, no. 3, pp. 354–358, 2009.
[35]
P. Limonta and M. Manea, “Gonadotropin-releasing hormone receptors as molecular therapeutic targets in prostate cancer: current options and emerging strategies,” Cancer Treatment Reviews, vol. 39, no. 6, pp. 647–663, 2013.
[36]
S. B. Seminara, M. J. DiPietro, S. Ramaswamy, W. F. Crowley Jr., and T. M. Plant, “Continuous human metastin 45–54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications,” Endocrinology, vol. 147, no. 5, pp. 2122–2126, 2006.
[37]
S. Ramaswamy, S. B. Seminara, C. R. Pohl, M. J. Dipietro, W. F. Crowley Jr., and T. M. Plant, “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, vol. 148, no. 7, pp. 3364–3370, 2007.
[38]
E. L. Thompson, V. Amber, G. W. H. Stamp et al., “Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms,” British Journal of Pharmacology, vol. 156, no. 4, pp. 609–625, 2009.
[39]
E. L. Thompson, K. G. Murphy, M. Patterson et al., “Chronic subcutaneous administration of kisspeptin-54 causes testicular degeneration in adult male rats,” American Journal of Physiology-Endocrinology and Metabolism, vol. 291, no. 5, pp. E1074–E1082, 2006.
[40]
V. M. Navarro, R. Fernández-Fernández, J. M. Castellano et al., “Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54,” The Journal of Physiology, vol. 561, no. 2, pp. 379–386, 2004.
[41]
T. M. Plant, S. Ramaswamy, and M. J. DiPietro, “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, vol. 147, no. 2, pp. 1007–1013, 2006.
[42]
J. M. Castellano, V. M. Navarro, R. Fernández-Fernández et al., “Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition,” Endocrinology, vol. 146, no. 9, pp. 3917–3925, 2005.
[43]
C. N. Jayasena, A. Abbara, J. D. Veldhuis et al., “Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of kisspeptin-54,” Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 6, pp. E953–E961, 2014.
[44]
Y.-M. Chan, “Effects of kisspeptin on hormone secretion in humans,” Advances in Experimental Medicine and Biology, vol. 784, pp. 89–112, 2013.
[45]
E. Hrabovszky and Z. Liposits, “Afferent neuronal control of type-I gonadotropin releasing hormone neurons in the human,” Frontiers in Endocrinology, vol. 4, article 130, 2013.
[46]
X. F. Li, J. S. Kinsey-Jones, Y. Cheng et al., “Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat,” PLoS ONE, vol. 4, no. 12, Article ID e8334, 2009.
[47]
B. Francou, J. Bouligand, A. Voican et al., “Normosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutations,” PLoS ONE, vol. 6, no. 10, Article ID e25614, 2011.
[48]
I. Sawyer, S. Smillie, J. V. Bodkin, E. Fernandes, K. T. O'Byrne, and S. D. Brain, “The vasoactive potential of kisspeptin-10 in the peripheral vasculature,” PLoS ONE, vol. 6, no. 2, Article ID e14671, 2011.
[49]
T. Ramaesh, J. J. Logie, A. K. Roseweir et al., “Kisspeptin-10 inhibits angiogenesis in human placental vessels ex vivo and endothelial cells in vitro,” Endocrinology, vol. 151, no. 12, pp. 5927–5934, 2010.
[50]
A. C. Hauge-Evans, C. C. Richardson, H. M. Milne, M. R. Christie, S. J. Persaud, and P. M. Jones, “A role for kisspeptin in islet function,” Diabetologia, vol. 49, no. 9, pp. 2131–2135, 2006.
[51]
J. E. Bowe, A. J. King, J. S. Kinsey-Jones et al., “Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats,” Diabetologia, vol. 52, no. 5, pp. 855–862, 2009.
[52]
R. A. Steiner, “Kisspeptin: past, present, and prologue,” Advances in Experimental Medicine and Biology, vol. 784, pp. 3–7, 2013.
[53]
L. Pinilla, E. Aguilar, C. Dieguez, R. P. Millar, and M. Tena-Sempere, “Kisspeptins and reproduction: physiological roles and regulatory mechanisms,” Physiological Reviews, vol. 92, no. 3, pp. 1235–1316, 2012.
[54]
G. Cheng, L. M. Coolen, V. Padmanabhan, R. L. Goodman, and M. N. Lehman, “The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep,” Endocrinology, vol. 151, no. 1, pp. 301–311, 2010.
[55]
M. N. Lehman, L. M. Coolen, and R. L. Goodman, “Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion,” Endocrinology, vol. 151, no. 8, pp. 3479–3489, 2010.
[56]
J. Young, J. Bouligand, B. Francou et al., “TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans,” The Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 5, pp. 2287–2295, 2010.
[57]
E. Hrabovszky, M. T. Sipos, C. S. Molnár et al., “Low degree of overlap between kisspeptin, neurokinin B, and dynorphin immunoreactivities in the infundibular nucleus of young male human subjects challenges the KNDy neuron concept,” Endocrinology, vol. 153, no. 10, pp. 4978–4989, 2012.
[58]
C. N. Jayasena, A. N. Comninos, A. de Silva et al., “Effects of neurokinin B administration on reproductive hormone secretion in healthy men and women,” Journal of Clinical Endocrinology and Metabolism, vol. 99, no. 1, pp. E19–E27, 2014.
[59]
A. K. Roseweir, A. S. Kauffman, J. T. Smith et al., “Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation,” Journal of Neuroscience, vol. 29, no. 12, pp. 3920–3929, 2009.
[60]
H. Matsui, Y. Takatsu, A. Tanaka et al., “251 potent and efficient testosterone suppression by chronic administration of novel metastin analogues, TAK-448 and TAK-683, in male rats,” European Journal of Cancer Supplements, vol. 8, article 66, 2010.
[61]
G. Scott, I. Ahmad, K. Howard et al., “Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men,” British Journal of Clinical Pharmacology, vol. 75, no. 2, pp. 381–391, 2013.
