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Summary

Recently, Shapiro et al. [1] assessed the impact of fezolinetant on sleep disruption and impairment in menopausal women experiencing vasomotor symptoms (VMS). The analysis was based on combined data from two phase 3 trials, SKYLIGHT 1 and 2, where participants were randomly assigned to receive placebo, fezolinetant 30 mg/day, or fezolinetant 45 mg/day for a duration of 12 weeks. Sleep assessments were conducted using PROMIS SD SF 8b, PROMIS SRI SF 8a, and PGI-C SD/PGI-S SD scales at baseline, week 4, and week 12. A total of 1,022 menopausal women were included in the study. The findings indicate that both doses of fezolinetant (30 mg and 45 mg) resulted in significant improvements in sleep disruption and impairment compared to placebo; however, the efficacy was greater with the higher dose of fezolinetant. By week 12, a larger proportion of participants receiving fezolinetant reported feeling much/moderately better regarding sleep disruption and exhibited lower severity ratings. These results are consistent with earlier phase-2 studies that also demonstrated enhanced sleep quality with fezolinetant treatment. These outcomes suggest that fezolinetant effectively alleviates sleep disruption and impairment associated with VMS in menopausal women, offering a promising nonhormonal treatment option.

Commentary

Fezolinetant is a non-hormonal neurokinin 3 receptor (NK3R) antagonist, which primary mechanism of action is blocking the binding of neurokinin B (NKB) to NK3R, thus reducing the frequency and severity of moderate-to-severe VMS [2]. NK3R, a member of the neuropeptide Y receptor family, is distributed primarily in the central nervous system, particularly in regions such as the cerebral cortex, hypothalamus, and hippocampus, where it modulates various activities, encompassing thermoregulation, appetite, and sleep [3]. The KNDy neurons, comprising kisspeptin, neurokinin B, and dynorphin, are predominantly located in the arcuate nucleus of the hypothalamus and its surrounding areas. These neurons play a pivotal role in regulating circadian rhythms and thermoregulation. The activity of these neurons is orchestrated by various neurotransmitters and hormones, with NKB and estrogen exerting paramount importance [4,5]. Research indicates that in postmenopausal women, reduced estrogen levels decrease its inhibitory effect on KNDy neurons, leading to a more pronounced activation of KNDy neurons via NKB through NK3R, thereby triggering VMS, such as hot flashes and night sweats. These symptoms disrupt body temperature homeostasis, contributing to difficulties in initiating sleep, frequent nighttime awakenings, and decreased total sleep duration. While KNDy neurons do not directly act on the sleep centers of the hypothalamus (e.g. ventrolateral preoptic area) they indirectly modulate sleep through their influence on thermoregulation and overall physiological state [6,7].

The locus coeruleus, a critical nucleus in the brainstem, is primarily responsible for the synthesis and release of norepinephrine, playing a key role in maintaining arousal [8]. While direct evidence for NK3R expression in the locus coeruleus is limited, the widespread distribution of NKB and its receptor NK3R throughout the central nervous system suggests they may influence the activity of the locus coeruleus and consequently the sleep-wake cycle via indirect pathways. For instance, NK3R activation may alter the responsiveness of locus coeruleus neurons to external stimuli by modulating dendritic spine density, morphology, and synaptic transmission efficiency [9]. The precise molecular and cellular mechanisms that underlie the effects of NK3R activation on the activity patterns within the locus coeruleus remain largely unexplored and partially obscure. Consequently, future research endeavors must meticulously dissect these signaling cascades, with a particular emphasis on elucidating the role of neurotransmitters in orchestrating the functional dynamics of the locus coeruleus.

In summary, the selective NK3R antagonist fezolinetant, by blocking NK3R signaling, holds promise in mitigating sleep disturbances through modulating KNDy neuronal activity and impacting pivotal central nuclei, notably the locus coeruleus. This approach introduces a novel therapeutic paradigm for the management of sleep disorders frequently encountered during menopause, thus offering a potential alternative to existing treatment modalities.

Yang You
Qi Yu
Peking Union Medical College Hospital
Beijing, People’s Republic of China

 

References

      1. Shapiro C M M, Cano A, Nappi RE, et al. Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause. Maturitas. 2024;186:107999.
        https://pubmed.ncbi.nlm.nih.gov/38749864/
      2. Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab. 2023;108(8):1981-1997.
        https://pubmed.ncbi.nlm.nih.gov/36734148/
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        https://pubmed.ncbi.nlm.nih.gov/23872331/
      6. Williams RE, Levine KB, Kalilani L, Lewis J, Clark RV. Menopause-specific questionnaire assessment in US population-based study shows negative impact on health-related quality of life. Maturitas. 2009;62(2):153-159.
        https://pubmed.ncbi.nlm.nih.gov/19157732/
      7. Thurston RC, Chang Y, Buysse DJ, Hall MH, Matthews KA. Hot flashes and awakenings among midlife women. Sleep. 2019 Sep 6;42(9):zsz131.
        https://pubmed.ncbi.nlm.nih.gov/31152182/
      8. Berridge CW, Schmeichel BE, España RA. Noradrenergic modulation of wakefulness/arousal. Sleep Med Rev. 2012;16(2):187-297.
        https://pubmed.ncbi.nlm.nih.gov/22296742/
      9. Zerari F, Karpitskiy V, Krause J, Descarries L, Couture R. Immunoelectron microscopic localization of NK-3 receptor in the rat spinal cord. Neuroreport. 1997;8(12):2661-2664.
        https://pubmed.ncbi.nlm.nih.gov/9295096/

 


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