Abstract
Background
Recent studies have found that kisspeptin/neurokinin B/dynorphin neurons (KNDy neurons) in the infundibular nucleus play a crucial role in the reproductive axis. Analogs, both agonists and antagonists, of kisspeptin and neurokinin B (NKB) are particularly important in explaining the physiological role of KNDy in the reproductive axis in animals. The use of kisspeptin and NKB analogs has helped elucidate the regulators of the hypothalamic reproductive axis.
Purpose
This review describes therapeutic uses of Kiss-1 and NKB agonists, most obviously the use of kisspeptin agonists in the treatment for infertility and the induction of ovulation. Kisspeptin antagonists may have potential clinical applications in patients suffering from diseases associated with enhanced LH pulse frequency, such as polycystic ovary syndrome or menopause. The inhibition of pubertal development using Kiss antagonists may be used as a therapeutic option in precocious puberty. Kisspeptin antagonists have been found capable of inhibiting ovulation and have been proposed as novel contraceptives. Hypothalamic amenorrhea and delayed puberty are conditions in which normalization of LH secretion may potentially be achieved by treatment with both kisspeptin and NKB agonists. NKB antagonists are used to treat vasomotor symptoms in postmenopausal women, providing rapid relief of symptoms while supplanting the need for exogenous estrogen exposure.
Conclusions
There is a wide spectrum of therapeutic uses of Kiss-1 and NKB agonists, including the management of infertility, treatment for PCOS, functional hypothalamic amenorrhea or postmenopausal vasomotor symptoms, as well as contraceptive issues. Nevertheless, further research is needed before kisspeptin and NKB analogs are fully incorporated in clinical practice.
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References
Skorupskaite K, George JT, Anderson RA (2014) The kisspeptin–GnRH pathway in human reproductive health and disease. Hum Reprod Update 20(4):485–500
Szeliga A, Czyzyk A, Podfigurna A, Genazzani AR, Genazzani AD, Meczekalski B (2018) The role of kisspeptin/neurokinin B/dynorphin neurons in pathomechanism of vasomotor symptoms in postmenopausal women: from physiology to potential therapeutic applications. Gynecol Endocrinol 34(11):1–7
West A, Vojta PJ, Welch DR, Weissman BE (1998) Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics 54(1):145–148
Roseweir AK, Millar RP (2008) The role of kisspeptin in the control of gonadotrophin secretion. Hum Reprod Update 15(2):203–212
Cortés ME, Carrera B, Rioseco H, Pablo del Río J, Vigil P (2015) The role of kisspeptin in the onset of puberty and in the ovulatory mechanism: a mini-review. J Pediatr Adolesc Gynecol 28(5):286–291
Tomita K, Oishi S, Cluzeau J et al (2007) SAR and QSAR studies on the N-terminally acylated pentapeptide agonists for GPR54. J Med Chem 50(14):3222–3228
Tomita K, Oishi S, Ohno H, Peiper SC, Fujii N (2008) Development of novel G-protein-coupled receptor 54 agonists with resistance to degradation by matrix metalloproteinase. J Med Chem 51(23):7645–7649
Roseweir AK, Millar RP (2013) Kisspeptin antagonists. Adv Exp Med Biol 784:159–186
Roseweir AK, Kauffman AS, Smith JT et al (2009) Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 29(12):3920–3929
Corbett S, Shmorgun D, Claman P et al (2014) The prevention of ovarian hyperstimulation syndrome. J Obstet Gynaecol Canada 36(11):1024–1033
Thomsen L, Humaidan P (2015) Ovarian hyperstimulation syndrome in the 21st century. Curr Opin Obstet Gynecol 27(3):210–214
Macklon NS, Stouffer RL, Giudice LC, Fauser BCJM (2006) The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev 27(2):170–207
Owens LA, Abbara A, Lerner A et al (2018) The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function. Hum Reprod 33(2):292–302
Whitlock BK, Daniel JA, Wilborn RR, Maxwell HS, Steele BP, Sartin JL (2010) Interaction of kisspeptin and the somatotropic axis. Neuroendocrinology 92(3):178–188
Abbara A, Jayasena CN, Christopoulos G et al (2015) Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy. J Clin Endocrinol Metab 100(9):3322–3331
Albers-Wolthers CHJ, de Gier J, Rutten VPMG et al (2016) The effects of kisspeptin agonist canine KP-10 and kisspeptin antagonist p271 on plasma LH concentrations during different stages of the estrous cycle and anestrus in the bitch. Theriogenology 86(2):589–595
Caraty A, Decourt C, Briant C, Beltramo M (2012) Kisspeptins and the reproductive axis: potential applications to manage reproduction in farm animals. Domest Anim Endocrinol 43(2):95–102
Whitlock BK, Daniel JA, Amelse LL, Tanco VM, Chameroy KA, Schrick FN (2015) Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes. PeerJ 3:e1382
Jayasena CN, Abbara A, Veldhuis JD et al (2014) Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of kisspeptin-54. J Clin Endocrinol Metab 99(6):E953–E961
Parker PA, Coffman EA, Pohler KG et al (2019) Acute and subacute effects of a synthetic kisspeptin analog, C6, on serum concentrations of luteinizing hormone, follicle stimulating hormone, and testosterone in prepubertal bull calves. Theriogenology 130:111–119
Millar RP, Roseweir AK, Tello JA et al (2010) Kisspeptin antagonists: unraveling the role of kisspeptin in reproductive physiology. Brain Res 1364:81–89
Li X-F, Kinsey-Jones JS, Cheng Y et al (2009) Kisspeptin signalling in the hypothalamic arcuate nucleus regulates gnrh pulse generator frequency in the rat. PLoS One 4(12):e8334
Junqueira FRR, Lara LAS, Martins WP et al (2015) Gonadotropin and estradiol levels after leuprolide stimulation tests in Brazilian girls with precocious puberty. J Pediatr Adolesc Gynecol 28(5):313–316
Sahin Z, Canpolat S, Ozcan M, Ozgocer T, Kelestimur H (2015) Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats. Reproduction 149(5):465–473
Pineda R, Garcia-Galiano D, Roseweir A et al (2010) Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology 151(2):722–730
Albers-Wolthers CHJ, de Gier J, Walen M et al (2017) In vitro and in vivo effects of kisspeptin antagonists p234, p271, p354, and p356 on GPR54 activation. PLoS One 12(6):e0179156
Aguirre RS, Eugster EA (2018) Central precocious puberty: from genetics to treatment. Best Pract Res Clin Endocrinol Metab 32(4):343–354
Samir H, Nagaoka K, Watanabe G (2018) Effect of kisspeptin antagonist on goat in vitro Leydig cell steroidogenesis. Theriogenology 121:134–140
Page NM (2005) New challenges in the study of the mammalian tachykinins. Peptides 26(8):1356–1368
Navarro VM (2013) Interactions between kisspeptins and neurokinin B. Adv Exp Med Biol 784:325–347
Rance NE, Krajewski SJ, Smith MA, Cholanian M, Dacks PA (2010) Neurokinin B and the hypothalamic regulation of reproduction. Brain Res 1364:116–128
Satake H, Kawada T (2006) Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors. Curr Drug Targets 7(8):963–974
Rance NE, Young WS (1991) Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women*. Endocrinology 128(5):2239–2247
Topaloglu AK, Reimann F, Guclu M et al (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 41(3):354–358
Young J, Bouligand J, Francou B et al (2010) TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 95(5):2287–2295
Tusset C, Noel SD, Trarbach EB et al (2012) Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders. Arq Bras Endocrinol Metabol 56(9):646–652
Wormser U, Laufer R, Hart Y, Chorev M, Gilon C, Selinger Z (1986) Highly selective agonists for substance P receptor subtypes. EMBO J 5(11):2805–2808
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(3):237–245
Young J, George JT, Tello JA et al (2013) Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology 97(2):193–202
Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ (2013) 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 34(3):211–227
Dacks PA, Krajewski SJ, Rance NE (2011) Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. Endocrinology 152(12):4894–4905
Newton CL, Anderson RC, Millar RP (2016) Therapeutic neuroendocrine agonist and antagonist analogs of hypothalamic neuropeptides as modulators of the hypothalamic–pituitary–gonadal axis. Endocr Dev 30:106–129
Dawson LA, Langmead CJ, Dada A et al (2010) In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics. Eur J Pharmacol 627(1–3):106–114
Skorupskaite K, George J, Anderson RA (2015) Role of a neurokinin B receptor antagonist in the regulation of ovarian function in healthy women. Lancet 385(Suppl 1):S92
Katulski K, Podfigurna A, Czyzyk A, Meczekalski B, Genazzani AD (2018) Kisspeptin and LH pulsatile temporal coupling in PCOS patients. Endocrine 61(1):149–157
George JT, Kakkar R, Marshall J et al (2016) Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 101(11):4313–4321
Jayasena CN, Comninos AN, Stefanopoulou E et al (2015) Neurokinin B administration induces hot flushes in women. Sci Rep 5(1):8466
Modi M, Dhillo WS (2019) Neurokinin 3 receptor antagonism—a novel treatment for menopausal hot flushes. Neuroendocrinology 109(3):242–248
Prague JK, Roberts RE, Comninos AN et al (2017) Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet (Lond, Engl) 389(10081):1809–1820
Prague JK, Roberts RE, Comninos AN et al (2018) Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause 25(8):862–869
Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA (2018) Neurokinin 3 receptor antagonism reveals roles for neurokinin B in the regulation of gonadotropin secretion and hot flashes in postmenopausal women. Neuroendocrinology 106(2):148–157
Anderson RA, Skorupskaite K, Sassarini J (2019) The neurokinin B pathway in the treatment of menopausal hot flushes. Climacteric 22(1):51–54
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Szeliga, A., Podfigurna, A., Bala, G. et al. Kisspeptin and neurokinin B analogs use in gynecological endocrinology: where do we stand?. J Endocrinol Invest 43, 555–561 (2020). https://doi.org/10.1007/s40618-019-01160-0
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DOI: https://doi.org/10.1007/s40618-019-01160-0