Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial
Julia K Prague, Rachel E Roberts, Alexander N Comninos, Sophie Clarke, Channa N Jayasena, Zachary Nash, Chedie Doyle, Deborah A Papadopoulou, Stephen R Bloom, Pharis Mohideen, Nicholas Panay, Myra S Hunter, Johannes D Veldhuis, Lorraine C Webber, Les Huson, Waljit S Dhillo, Julia K Prague, Rachel E Roberts, Alexander N Comninos, Sophie Clarke, Channa N Jayasena, Zachary Nash, Chedie Doyle, Deborah A Papadopoulou, Stephen R Bloom, Pharis Mohideen, Nicholas Panay, Myra S Hunter, Johannes D Veldhuis, Lorraine C Webber, Les Huson, Waljit S Dhillo
Abstract
Background: Hot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes.
Methods: This phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40-62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185.
Findings: 68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22-67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81-58·56] vs MLE4901 19·35 [15·99-23·42]; adjusted estimate of difference 29·66 [17·39-42·87], p<0·0001). Treatment was well tolerated. Three participants developed a transaminase rise (alanine aminotransferase 4·5-5·9 times the upper limit of normal) with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days.
Interpretation: Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated.
Funding: UK Medical Research Council and National Institute for Health Research.
Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.
Figures
References
- Avis NE, Crawford SL, Greendale G. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med. 2015;175:531–539.
- Carpenter JS, Woods NF, Otte JL. MsFLASH participants' priorities for alleviating menopausal symptoms. Climacteric. 2015;18:859–866.
- Stearns V, Ullmer L, Lopez JF, Smith Y, Isaacs C, Hayes D. Hot flushes. Lancet. 2002;360:1851–1861.
- 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.
- Collaborative Group on Epidemiological Studies of Ovarian Cancer. Beral V, Gaitskell K, Hermon C, Moser K, Reeves G, Peto R. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet. 2015;385:1835–1842.
- Drewe J, Bucher KA, Zahner C. A systematic review of non-hormonal treatments of vasomotor symptoms in climacteric and cancer patients. Springerplus. 2015;4:65.
- Ayers B, Smith M, Hellier J, Mann E, Hunter MS. Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Menopause. 2012;19:749–759.
- Franco OH, Chowdhury R, Troup J. Use of plant-based therapies and menopausal symptoms: a systematic review and meta-analysis. JAMA. 2016;315:2554–2563.
- Office for National Statistics UK census. 2011. (accessed Jan 7, 2017).
- 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;34:211–227.
- Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H. Methodologic lessons learned from hot flash studies. J Clin Oncol. 2001;19:4280–4290.
- Bahr DE, Webster JG, Grady D. Miniature ambulatory skin conductance monitor and algorithm for investigating hot flash events. Physiol Meas. 2014;35:95–110.
- 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;151:3479–3489.
- 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;109:19846–19851.
- Nakamura K, Morrison SF. A thermosensory pathway mediating heat-defense responses. Proc Natl Acad Sci USA. 2010;107:8848–8853.
- Dacks PA, Krajewski SJ, Rance NE. Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. Endocrinology. 2011;152:4894–4905.
- Mittelman-Smith MA, Krajewski-Hall SJ, McMullen NT, Rance NE. Neurokinin 3 receptor-expressing neurons in the median preoptic nucleus modulate heat-dissipation effectors in the female rat. Endocrinology. 2015;156:2552–2562.
- 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.
- Rance NE, Young WS., 3rd Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology. 1991;128:2239–2247.
- Jayasena CN, Comninos AN, Stefanopoulou E. Neurokinin B administration induces hot flushes in women. Sci Rep. 2015;5:8466.
- Crandall CJ, Manson JAE, Hohensee C. 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;24:252–261.
- George JT, Kakkar R, Marshall J. Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2016;101:4313–4321.
- Joffe H, Guthrie KA, LaCroix AZ. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med. 2014;174:1058–1066.
- Carpenter JS. The Hot Flash Related Daily Interference Scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage. 2001;22:979–989.
- Hilditch JR, Lewis J, Peter A. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas. 1996;24:161–175.
- Veldhuis JD, Keenan DM, Pincus SM. Motivations and methods for analyzing pulsatile hormone secretion. Endocr Rev. 2008;29:823–864.
- Freeman EW, Guthrie KA, Caan B. Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. JAMA. 2011;305:267–274.
- Newton KM, Carpenter JS, Guthrie KA. Methods for the design of vasomotor symptom trials: the menopausal strategies: finding lasting answers to symptoms and health network. Menopause. 2014;21:45–58.
- Gordon PR, Kerwin JP, Boesen KG, Senf J. Sertraline to treat hot flashes: a randomized controlled, double-blind, crossover trial in a general population. Menopause. 2006;13:568–575.
- Loprinzi CL, Diekmann B, Novotny PJ, Stearns V, Sloan JA. Newer antidepressants and gabapentin for hot flashes: a discussion of trial duration. Menopause. 2009;16:883–887.
Source: PubMed