Semin Reprod Med 2019; 37(03): 125-130
DOI: 10.1055/s-0039-3400241
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Neurokinin B and Neurokinin-3 Receptor Signaling: Promising Developments in the Management of Menopausal Hot Flushes

Manish Modi
1   Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
,
Waljit S. Dhillo
1   Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
› Author Affiliations
Funding Sources M.M. is funded by an NIHR Academic Clinical Fellowship. W.S.D. is funded by an NIHR Research Professorship.
Further Information

Publication History

Publication Date:
23 December 2019 (online)

Abstract

Vasomotor symptoms, including hot flushes and night sweats, pose a significant symptomatic burden to women undergoing menopause, and negatively impact on both their physical and psychological well-being. Management of these symptoms can be challenging, with the use of conventional hormone replacement therapy limited by duration of treatment and clinical contraindications. Recent advances in our understanding of the neuroendocrine regulation of the reproductive axis and thermoregulation postmenopause has helped identify a promising new therapeutic target to ameliorate hot flushes. Antagonism of the neurokinin B/neurokinin-3 receptor (NK3R) signaling pathway has emerged as an efficacious treatment in managing vasomotor symptoms, with evidence of rapid and sustained reduction in hot flush frequency and severity and improvements in secondary quality-of-life measures such as sleep. Within this review, we will explore the growing body of evidence supporting the use of NK3R antagonists in the management of vasomotor symptoms, and the possible utility in managing dysfunctional sex-hormone–dependent disorders and glycolipid metabolism disorders such as polycystic ovarian syndrome.

Statement of Ethics

The authors have no ethical conflicts to disclose.


Disclosure Statement

M.M. has no conflicts of interest to declare. W.S.D. has undertaken consultancy work with Myovant Sciences, Inc. and KaNDy Therapeutics. W.S.D. has filed a patent for the use of NK3R antagonists in menopausal flushing.


Authors' Contributions

M.M. researched and prepared the manuscript. W.S.D. edited the manuscript for important intellectual content.


 
  • References

  • 1 Avis NE, Crawford SL, Greendale G. , et al; Study of Women's Health Across the Nation. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015; 175 (04) 531-539
  • 2 Freeman EW, Sammel MD, Sanders RJ. Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. Menopause 2014; 21 (09) 924-932
  • 3 Freedman RR. Menopausal hot flashes: mechanisms, endocrinology, treatment. J Steroid Biochem Mol Biol 2014; 142: 115-120
  • 4 Padilla SL, Johnson CW, Barker FD, Patterson MA, Palmiter RD. A neural circuit underlying the generation of hot flushes. Cell Rep 2018; 24 (02) 271-277
  • 5 Gallicchio L, Whiteman MK, Tomic D, Miller KP, Langenberg P, Flaws JA. Type of menopause, patterns of hormone therapy use, and hot flashes. Fertil Steril 2006; 85 (05) 1432-1440
  • 6 Chang HY, Jotwani AC, Lai YH. , et al. Hot flashes in breast cancer survivors: Frequency, severity and impact. Breast 2016; 27: 116-121
  • 7 Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017; 1: CD004143
  • 8 Rossouw JE, Anderson GL, Prentice RL. , et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002; 288 (03) 321-333
  • 9 Santen RJ, Stuenkel CA, Davis SR, Pinkerton JV, Gompel A, Lumsden MA. Managing menopausal symptoms and associated clinical issues in breast cancer survivors. J Clin Endocrinol Metab 2017; 102 (10) 3647-3661
  • 10 McGarry K, Geary M, Gopinath V. Beyond estrogen: treatment options for hot flashes. Clin Ther 2018; 40 (10) 1778-1786
  • 11 Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA. A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause. Hum Reprod 2008; 23 (03) 699-708
  • 12 Han SY, McLennan T, Czieselsky K, Herbison AE. Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion. Proc Natl Acad Sci U S A 2015; 112 (42) 13109-13114
  • 13 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; 29 (38) 11859-11866
  • 14 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 (07) 2744-2750
  • 15 Rance NE, Young III WS. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology 1991; 128 (05) 2239-2247
  • 16 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; 84 (06) 2111-2118
  • 17 Cholanian M, Krajewski-Hall SJ, McMullen NT, Rance NE. Chronic oestradiol reduces the dendritic spine density of KNDy (kisspeptin/neurokinin B/dynorphin) neurones in the arcuate nucleus of ovariectomised Tac2-enhanced green fluorescent protein transgenic mice. J Neuroendocrinol 2015; 27 (04) 253-263
  • 18 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 U S A 2012; 109 (48) 19846-19851
  • 19 Morrison SF, Nakamura K. Central neural pathways for thermoregulation. Front Biosci 2011; 16: 74-104
  • 20 Shughrue PJ, Lane MV, Merchenthaler I. In situ hybridization analysis of the distribution of neurokinin-3 mRNA in the rat central nervous system. J Comp Neurol 1996; 372 (03) 395-414
  • 21 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; 34 (03) 211-227
  • 22 Dacks PA, Krajewski SJ, Rance NE. Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. Endocrinology 2011; 152 (12) 4894-4905
  • 23 Jayasena CN, Comninos AN, De Silva A. , et al. Effects of neurokinin B administration on reproductive hormone secretion in healthy men and women. J Clin Endocrinol Metab 2014; 99 (01) E19-E27
  • 24 Jayasena CN, Comninos AN, Stefanopoulou E. , et al. Neurokinin B administration induces hot flushes in women. Sci Rep 2015; 5: 8466
  • 25 Crandall CJ, Manson JE, Hohensee C. , et al. Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study. Menopause 2017; 24 (03) 252-261
  • 26 National Center for Biotechnology Information. Fezolinetant (ESN364) [Internet]. PubChem Compound Database; CID = 117604931. [cited November 9, 2018]. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/117604931 . Accessed October 23, 2019
  • 27 National Center for Biotechnology Information. Pavinetant (MLE4901). PubChem Compound Database; Available at: https://pubchem.ncbi.nlm.nih.gov/compound/23649245 . Accessed October 23, 2019
  • 28 Depypere H, Timmerman D, Donders G. , et al. Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes. Maturitas 2017; 103: 89-90
  • 29 Fraser GL, Lederman S, Waldbaum A, Lee M, Skillern L, Ramael S. OR33–6 The neurokinin 3 receptor antagonist, fezolinetant, is effective in treatment of menopausal vasomotor symptoms: a randomized, placebo-controlled, double-blind, dose-ranging study. J Endocr Soc 2019; 3 (Suppl. 01) OR33-OR36
  • 30 Prague JK, Roberts RE, Comninos AN. , et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2017; 389 (10081): 1809-1820
  • 31 Prague JK, Roberts RE, Comninos AN. , et al. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause 2018; 25 (08) 862-869
  • 32 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 receptor antagonism reveals roles for neurokinin B in the regulation of gonadotropin secretion and hot flashes in postmenopausal women. Neuroendocrinology 2018; 106 (02) 148-157
  • 33 Ridler K, Gunn RN, Searle GE. , et al. Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET. J Psychopharmacol 2014; 28 (03) 244-253
  • 34 Pawsey S, Ballantyne E, Trower M, Kerr M. NT-814, a novel dual NK1,3 receptor antagonist results in immediate improvements in bothersome post-menopausal symptoms. North American Menopause Society (NAMS) Annual Meeting; San Diego, CA, 2018
  • 35 Skorupskaite K, George JT, Veldhuis JD, Anderson RA, Neurokinin B. Neurokinin B regulates gonadotropin secretion, ovarian follicle growth, and the timing of ovulation in healthy women. J Clin Endocrinol Metab 2018; 103 (01) 95-104
  • 36 George JT, Kakkar R, Marshall J. , et al. Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 2016; 101 (11) 4313-4321
  • 37 Trower MK, Ratti E, Burgess C, Kerr MB. P-58. Evidence for rapid and sustained target engagement by a dual mechanism neurokinin-3,1 receptor antagonist on hypothalamic KNDy neurons; results from Phase 1 studies with NT-814, a potential novel therapy for sex hormone-dependent diseases. The 3rd World Conference on Kisspeptin; Orlando, FL, 2017
  • 38 Shi Y, Zhu X, Liu Y. NK3R antagonist ameliorates metabolic status and reverses obesity in mice. In: ESHRE [Internet]. 2019 . Available at: https://www.eshre.eu/books/eshre2019/Programme2019/files/basic-html/page61.html . Accessed October 23, 2019