About 80% of women experience vasomotor symptoms (VMS) – hot flashes and night sweats — as they transition into the menopause phase.  For most, the symptoms are manageable, but for a sizeable subset of midlife women, these symptoms can negatively affect sleep, mood, and quality of life.  While clinical guidelines suggest that menopausal vasomotor symptoms (VMS) typically last from 6 months to 2 years, new research suggests that for many women, the duration of symptoms is much longer.

Recent studies indicate that a  sizeable proportion of women entering into menopause experience vasomotor symptoms over a period of 5 or more years.  Given this finding, many women may not want to “tough it out” without treatment and will require interventions that are both safe and well-tolerated over long-term use. However, most women with menopausal symptoms receive no treatment.

Low levels of treatment in this population may reflect a tendency to underestimate the impact of vasomotor symptoms, to label these problems as annoying but not severe enough to merit treatment.  Or perhaps, given the concerns related to long-term use of hormone replacement therapy, women may be reluctant to pursue treatment and may be unaware that non-hormonal treatments may also effective for managing their symptoms.

It is postulated that the variable and ultimately falling levels of estrogen which a woman experiences as she transitions into the menopause are responsible for vasomotor symptoms.  However, exactly how changes in estrogen levels lead to these symptoms is not fully understood. Most recently, the neurokinin B (NKB) signalling pathway has been implicated in the development of vasomotor symptoms, and researchers are now exploring the potential of pharmacologic agents which modulate NKB activity to ameliorate menopausal symptoms.  

In animal and human studies, it has been demonstrated that stimulation of NKB-neurokinin 3 receptor (NK3R) signalling can induce hot flashes, thus researchers have focused on antagonism of this signalling pathway as a potential target for mitigating menopausal symptoms. 

The NK3R antagonist MLE4901 was the first to be tested in humans.In a randomized, double-blind, placebo-controlled, crossover trial, women aged 40 to 62 years, experiencing hot flashes/day received oral MLE4901 for four weeks.  By day 3, women receiving MLE4901, experienced a 72% reduction in hot flash frequency (95% CI, 81.3 to 63.3%), compared to 20% in the placebo group. Hot flash frequency and severity improved over the first two weeks of the study and then were stable.  

Other NK3R antagonists are now in Phase 1 and 2 studies.  In a Phase 2a trial, fezolinetant (ESN364) significantly reduced total VMS scores compared to placebo (-26.5 versus -12.2, P<0.001) and decreased mean frequency of moderate/severe VMS by 5 episodes per day versus placebo. Severity and frequency of moderate to severe VMS were reduced from the first day of treatment.  No serious adverse events were reported.  

Because the NK3R antagonists are a new type of drug, further studies are required to establish the long-term safety of this class of medication.  Phase 2 studies with MLE4901 or Pavinetant were discontinued because some women experienced transient elevations of liver transaminase enzymes. Other, structurally dissimilar, NK3R antagonists have not demonstrated any liver toxicity, and it is believed that the elevation in transaminases reported with MLE4901 may be an idiosyncratic effect related to its chemical structure rather than a class effect of NK3R antagonists as a whole.  

Further studies will help to further clarify the effectiveness and safety profile of the NK3R antagonists in peri- and postmenopausal women.


Ruta Nonacs, MD PhD


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Modi M, Dhillo WS.  Neurokinin 3 Receptor Antagonism: A Novel Treatment for Menopausal Hot Flushes.  Neuroendocrinology. 2019; 109(3):242-248. 

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 May 6;389(10081):1809-1820. Free Article

Simpson P, Currie H, Morris E.  Neurokinin 3 receptor antagonism – Is this the end of HRT?  Post Reprod Health. 2018 Jun;24(2):61-62. 

Timmerman D, Donders G, Sieprath P, Ramael S, Combalbert J, Hoveyda HR, Fraser GL, Depypere H.  Treatment of Menopausal Vasomotor Symptoms with Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial.  J Clin Endocrinol Metab. 2019 Aug 15. 


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