Mass General Hospital

Harvard Medical School

Neurokinin-3 Receptor Antagonists: A Novel Approach to the Treatment of Menopausal Symptoms

Over the last few years, we have seen a number of articles suggesting that the burden of menopausal symptoms is probably greater than generally perceived.  About 80% of women experience vasomotor symptoms (VMS) – hot flashes and night sweats — as they transition into the menopause.  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.

While hormone replacement therapy is highly effective for treatment of these symptoms, many women cannot or would prefer not to use hormonal treatments given the risks associated with longer use of hormonal treatment.    

Other studies suggest that treatment with antidepressants including the SSRIs (paroxetine, sertraline, citalopram, fluoxetine) and the serotonin-norepinephrine reuptake inhibitors or SNRIs (venlafaxine) result in significant improvement of vasomotor symptoms and constitute an important alternative for the management of menopausal women with hot flushes, even in the absence of depressive symptoms. Several new studies suggest that there may be a new class of medications which are effective for the treatment of menopausal vasomotor symptoms.  

This new class of drugs act as antagonists at the neurokinin-3 receptor (NK3R).  This receptor has recently emerged as a modulator of the pulsatile secretion of gonadotropin-releasing hormone (GnRH) release.

In the first study, 11 postmenopausal women with hot flashes were treated with the NK3R antagonist MLE4901, 40 mg twice daily for 7 days.   LH levels fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/l (p < 0.05) after 7 days of NK3R antagonist, with no change in FSH levels. Women treated with the NK3R antagonist also reported a reduction in hot flash frequency (3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008).

The second study published in Lancet was a randomized, double-blind, placebo-controlled, crossover trial assessing the effectiveness of  the same neurokinin 3 receptor antagonist (MLE4901) for the treatment of perimenopausal hot flushes. Healthy women aged 40–62 years who had seven or more hot flushes per day received either 4 weeks of oral MLE4901 (40 mg, twice daily) or placebo.

28 participants completed the trial and were included in the final analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45% compared to placebo. Others symptoms, including fatigue, irritability, and quality of sleep, also improved.

The only safety concern in this study was an asymptomatic rise in liver transaminase concentrations (alanine aminotransferase levels were 4.5 – 5.9 times the upper limit of normal) in a small subgroup of participants; this was not associated with other liver function abnormalities. The researchers noted that future clinical trials of MLE4901 will further explore this effect on transaminase concentrations and will assess the need for follow-up studies.

It’s always exciting to find a new approach to an old problem, and the neurokinin-3 receptor antagonists represent a novel strategy for the management of menopausal vasomotor symptoms.  While the data are promising in terms of finding a new type of medication for our armamentarium, further studies are required to better understand the impact of this medication on liver function.   

Ruta Nonacs, MD PhD

 

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. 2017 Apr 5.

Prague JK, Roberts RE, Comninos AN, Clarke S, 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 Apr 3.  Free Article

 

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