New pathways in the treatment for menopausal hot flushes
Authors: Jenifer Sassarini, Richard A Anderson
Journal: The Lancet (2017)

Within the next 25 years, an estimated 1 billion women worldwide will be older than 50 years, and therefore likely to be nearing menopause or postmenopausal.1UN Department of Economic and Social AffairsThe world population prospects: 2015 revision.http://www.un.org/en/development/desa/publications/world-population-prospects-2015-revision.htmlDate: 2015Google Scholar Hot flushes (vasomotor symptoms) are experienced by approximately 73% of postmenopausal women, and the associated sleep disturbances, fatigue, and decreased cognitive function lead to a reduction in their quality of life and an increased use of medical resources.2Whiteley J DiBonaventura M Wagner JS Alvir J Shah S The impact of menopausal symptoms on quality of life, productivity, and economic outcomes.J Womens Health (Larchmt). 2013; 22: 983-990Crossref PubMed Scopus (99) Google Scholar A hypothalamic mechanism is well established in the understanding of hot flushes,3Freedman RR Menopausal hot flashes: mechanisms, endocrinology, treatment.J Steroid Biochem Mol Biol. 2014; 142: 115-120Crossref PubMed Scopus (160) Google Scholar but the pathways involved have been unclear, thus reducing therapeutic options. Novel hypothalamic neuropeptide-signalling pathways have shed light on the central regulation of both reproductive and thermoregulatory systems and the links between them,4Rance 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: 211-227Crossref PubMed Scopus (181) Google Scholar and might now lead to specific therapies. The menopause results in oestrogen deficiency, with loss of feedback regulation of hypothalamic gonadotropin-releasing hormone (GnRH). The kisspeptin–neurokinin B (NKB)–dynorphin (KNDy) signalling system in the hypothalamus is the proximate and obligate stimulus of GnRH secretion, and is hypertrophied after the menopause.4Rance 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: 211-227Crossref PubMed Scopus (181) Google Scholar, 5Skorupskaite K George JT Anderson RA The kisspeptin-GnRH pathway in human reproductive health and disease.Hum Reprod Update. 2014; 20: 485-500Crossref PubMed Scopus (267) Google Scholar Hypothalamic NKB neurons also project to the medial preoptic area, the hypothalamic site of thermoregulatory neuronal pathways, and evidence exists that these NKB neurons are a key link between the endocrine changes of the menopause and vasomotor symptoms.4Rance 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: 211-227Crossref PubMed Scopus (181) Google Scholar Flushing, like thermoregulation, is controlled centrally but effected peripherally, and blood flow to the skin is also increased in postmenopausal women with severe flushing.6Sassarini J Lumsden MA Vascular function and cardiovascular risk factors in women with severe flushing.Maturitas. 2015; 80: 379-383Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar NKB neurons might also facilitate cutaneous vasodilatation and contribute to oestrogenic modulation of body temperature.7Mittelman-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: 19846-19851Crossref PubMed Scopus (119) Google Scholar In The Lancet, Julia Prague and colleagues8Prague 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; (published online April 3.)http://dx.doi.org/10.1016/S0140-6736(17)30823-1PubMed Google Scholar report the findings from their phase 2, randomised, double-blind, placebo-controlled trial investigating the oral neurokinin 3 receptor (NK3R) antagonist MLE4901 as a new therapy for menopausal hot flushes. In 28 healthy women aged 40–62 years, oral administration of a 40 mg dose twice per day for 4 weeks reduced the number of hot flushes during week 4 by 45 percentage points (95% CI 22–67) compared with 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). This finding was also supported by an objective assessment of flushes, using the Bahr sternal skin conductance monitor. Reductions in the number of flushes might be less important to women than measures of quality of life, thus it is of interest that the authors found hot flush severity, bother, and interference to be significantly reduced during treatment with MLE4901. However, in Prague and colleagues' study, no improvements occurred in the sexual symptoms commonly reported after menopause (MENQOL sexual domain score adjusted means: placebo 2·15 [95% CI 1·84–2·51] vs MLE4901 1·98 [1·68-2·30]; p=0·24). As an index of GnRH secretion, luteinising hormone pulse frequency was unchanged in the treatment group, although other measures of pulsatile secretion altered with increases in amplitude and orderliness of luteinising hormone pulse. Thus, although NKB pathways regulate both the vasomotor and reproductive systems, separate effects can be identified, and these might vary with the endocrine environment. Most withdrawals from the study were for reasons unrelated to treatment, and no serious adverse events occurred with MLE4901, although three women developed liver enzyme elevations (alanine aminotransferase was 4·5–5·9 times the upper limit of normal), which normalised within 90 days. The limitations of the trial include its small size (of 68 women screened, only 28 completed the trial and were included in the per-protocol analysis) and short duration of treatment. The current gold-standard treatment for menopausal hot flushes is oestrogen, but in some women its maximum efficacy might take many weeks to achieve.9MacLennan AH Broadbent JL Lester S Moore V Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes.Cochrane Database Syst Rev. 2004; 18 (CD002978)Google Scholar Selective serotonin-reuptake inhibitors are a non-hormonal alternative with similar improvements in flush reduction,10Drewe J Bucher KA Zahner C A systematic review of non-hormonal treatments of vasomotor symptoms in climacteric and cancer patients.SpringerPlus. 2015; 4: 65Crossref PubMed Scopus (52) Google Scholar but might not be well tolerated. And, although oestrogen is an effective treatment for flushing, oestrogen-free therapies are necessary for women with breast cancer. The severity of hot flushes in these women might be a major contributor to reduced adherence to the recommended 10 years of endocrine therapy, increasing recurrence and mortality.11Chirgwin JH Giobbie-Hurder A Coates AS et al.Treatment adherence and its impact on disease-free survival in the breast international group 1-98 trial of tamoxifen and letrozole, alone and in sequence.J Clin Oncol. 2016; 34: 2452-2459Crossref PubMed Scopus (135) Google Scholar Additionally, hot flushes are not the sole preserve of women: 44–80% of men treated for advanced prostate cancer have hot flushes, and 25% describe them as the most significant adverse effect on their quality of life.12Holzbeierlein JM Managing complications of androgen deprivation therapy for prostate cancer.Urol Clin North Am. 2006; 33 (vi.): 181-190Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar Although the role of oestrogen in the maintenance of bone and cardiovascular health is crucial to post-reproductive health and quality of life during older age, vasomotor symptoms are the most commonly reported, and often the most acutely distressing, symptom of menopause. Therefore, NKB antagonists are an exciting development in an area in which the last development in mechanistic understanding is more than 20 years old. Larger trials of clinically relevant duration examining benefits relative to established treatments are needed and might lead to a much needed addition to a very small toolbox of treatments for hot flushes. JS declares no competing interests. RAA has received consultancy fees relating to MLE4901 (previously named AZD4901), the drug discussed in this Comment, for polycystic ovary syndrome and research support (supply of AZD4901) for a range of studies, including in postmenopausal women, from AstraZeneca; advisory board fees from Takeda Pharmaceuticals unrelated to research on MLE4901; and consultancy fees from NeRRe Pharmaceuticals on a related drug (NT814) across a range of indications, including menopause; and has a patent PCT/GB2016/050494 for AZD4901 for female contraception pending to the University of Edinburgh. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trialTreatment 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. Full-Text PDF Open Access