Efficacy and safety of fezolinetant and its different doses in the treatment of vasomotor symptoms in menopausal women: a systematic review and meta-analysis

Abstract

Introduction

Fezolinetant, an oral NK3R antagonist, selectively blocks NKB signaling, improving vasomotor symptoms by reducing KNDy neuron activity. Our review assesses fezolinetant’s efficacy and safety in treating VMSs in menopausal women.

Methods

We conducted a systematic review and meta-analysis synthesizing randomized controlled trials, which were retrieved by systematically searching PubMed, Scopus, Web of Science, Cochrane, Embase, MEDLINE, Ovid full text, and CINAHL until May 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio and continuous data using the mean difference with a 95% confidence interval.

Results

We included eight studies from seven RCTs. Fezolinetant showed significant efficacy in reducing the frequency of vasomotor symptoms in menopausal women, with a mean difference reduction of 1.96 episodes per day (95% CI [− 2.48, − 1.45], P < 0.00001). Additionally, women in the fezolinetant group were more likely to acquire a reduction of at least 70% from baseline in VMS frequency (OR = 2.22, 95% CI [1.55, 3.18]: P < 0.0001). Fezolinetant also showed significant efficacy in reducing the VMS severity after 12 weeks (MD = − 0.18, 95% CI [− 0.26, − 0.10], P < 0.0001). Quality of life measures also favored fezolinetant, showing a significant reduction in MENQOL score by 0.32 points (95% CI [− 0.52, − 0.13], P = 0.0009). Importantly, fezolinetant exhibited a favorable safety profile, with no significant difference in liver test elevations compared to placebo after 12 weeks (OR = 1.00, 95% CI [0.68, 1.47], P = 0.99). It also exhibited no statistically significant difference in treatment-emergent adverse events after 12 weeks by different doses (30, 45, and 180 mg).

Conclusion

Fezolinetant demonstrated significant efficacy in reducing VMS frequency and severity and improving quality of life. Safety outcomes revealed no significant differences in liver safety assessments or treatment-emergent adverse events compared to placebo.

Trial registration

PROSPERO CRD42023484019.

Introduction

The menopause transition is defined as the transition from reproductive life to post-reproductive life in women due to the depletion of follicles in both ovaries and the subsequent marked decrease of estrogen and progesterone [1, 2]. This transition is associated with many symptoms and signs that occur due to hormonal alterations [1,2,3]. Vasomotor symptoms (VMSs), such as hot flashes, sweating, and chills, are the main complaints reported by menopausal patients seeking medical treatment [4]. Approximately 80% of the reported women were suffering from VMSs during their transition periods [5]. Various studies have reported that untreated VMSs have a large negative impact on the individual level and society, such as a decline in the quality of life [6, 7] and inflicting a significant, direct cost burden on society [8, 9].

Hormone replacement therapy (HRT) with combined estrogen and progesterone or estrogen alone is the most effective treatment for VMSs during the menopausal period in afflicted females [2, 10]. However, HRT is associated with a serious increase in the risk of developing breast cancer and thromboembolic manifestations. Thus, it is contraindicated in many women with a high risk of developing these conditions due to underlying medical disorders or the presence of other risk factors [11, 12]. Hence, alternative safe, effective, and nonhormonal medical treatments are important for women suffering from VMS who are unable or unwilling to receive HRT.

The hypothalamus contains a thermoregulatory center that is responsible for the regulation of body heat [3, 13]. This center is innervated by Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons. The main neurotransmitter in this center is the neuropeptide neurokinin B (NKB), which stimulates KNDy neurons by acting on neurokinin 3 receptors [14]. These receptors are inhibited by estrogen [15, 16]. The progressive decline of estrogen during the menopausal transition leads to overstimulation of neurokinin 3 receptors (NK3R), hypertrophy of KNDy neurons, and eventually dysregulation of the thermoregulatory center due to the unopposed effect of NKB [17]. Finally, the dysregulated thermoregulatory center produces VMSs by causing vasodilation of the skin blood vessels [1, 2, 17].

Fezolinetant is an oral, non-hormonal NK3R antagonist with the ability to block NKB signaling selectively and reversibly, which results in decreasing the activity of KNDy neurons and restoring the normal sensitivity and balance of the thermoregulatory center. So, the administration of fezolinetant may lead to improvements in the VMSs [18,19,20].

We conducted this systematic review and meta-analysis to investigate the efficacy and safety of different doses of fezolinetant in treating VMSs in menopausal women.

Methods and materials

Study protocol and registration

We conducted a systematic review of randomized controlled trials (RCTs) according to the Cochrane Handbook for systematic reviews of interventions [21]. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [22]. The protocol of this study is registered in PROSPERO (CRD42023484019).

Literature search

We searched eight electronic databases: PubMed, Scopus, Web of Science, Cochrane, Embase, MEDLINE, Ovid full text, and CINAHL to yield any relevant studies published until 1 st May 2023. We used the following search strategy: (Fezolinetant OR neurokinin-3 receptor antagonist OR ESN364 OR Veozah) AND (menopause OR change of life, female). No filters or limitations were applied during the search (Table S1).

Eligibility criteria

The population of interest was postmenopausal women who suffered from VMS, in which episodes occurred at least 7 to 8 times per day or 40 to 50 times per week. The diagnosis of menopause was made according to the duration of amenorrhea, the biochemical state (hormonal level), as well as oophorectomy. Women diagnosed with any medical condition that could alter the results or diagnosed with any major psychological disease in the last 3 years, using any hormonal medications such as cytochrome P450 or other medications that could affect the VMSs, such as norepinephrine or SSRIs, or having a history of a previous or existing malignant tumor or disordered endometrial condition, or recent vaginal bleeding of unknown cause, were excluded from all included studies.

Our intervention was fezolinetant doses (30 mg QD, 15 mg BID, and 45 mg QD, 60 mg BID, and 90 mg BID) compared to placebo. Our outcomes of interest were both efficacy and safety. We included all randomized controlled trials (RCTs) that met our eligibility criteria. Non-original articles (i.e., reviews, commentaries, guidelines, editorials, correspondence, letters to editors, etc.) were excluded.

Study selection

After Endnote version X9 software omitted duplicate articles, we performed the screening process mentioned in the PROSPERO registration.

Quality assessment and certainty of evidence

We assessed the quality of the included studies using the Cochrane Risk of Bias Assessment Tool-II (ROB-II) [23], which consists of six domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported result, and overall bias.

For the evaluation of the evidence, we used the Grading of Recommendations Assessment,

Development and Evaluation (GRADE) guidelines [24, 25]. Any disagreements regarding the quality assessment and GRADE were resolved through discussion.

Data extraction and outcome measurements

According to the retrieved full texts of eligible studies, a data extraction sheet was formatted in Excel. It consisted of three main parts: The first part included a summary of the included studies (study ID, year of publication, study design, centers, time frames, sample size of each comparison group with doses, and follow-up period).

Primary outcomes:

• The effect of fezolinetant at different doses versus placebo in treating VMSs in menopausal women after 12 weeks (Fig. S1).

Secondary outcomes:

• The safety of fezolinetant at different doses versus placebo in treating VMSs in menopausal women after 12 weeks.

• The safety of the fezolinetant (45 mg/day) group versus the fezolinetant (30 mg/day) in treating the VMSs in menopausal women after 52 weeks (Fig. S2).

The included studies evaluated the impact of fezolinetant on liver function through a series of liver function tests, such as alkaline phosphatase (ALP), more than 1.5 times the Upper Limit of Normal (ULN), and ALT, or aspartate transferase (AST), more than 3 times the ULN.

Assessment of publication integrity

We used the REAPPRAISED checklist tool to systematically evaluate the included studies in 11 categories for publication integrity. The integrity rating for each included study was presented as good, poor, and unclear in all the categories.

Data analysis

We used Review Manager (RevMan) version 5.4 to compare the different doses of fezolinetant versus placebo. We performed a subgroup analysis based on dose. The Mantel–Haenszel technique was used for dichotomous data to display the risk ratio (RR) and 95% confidence intervals (CI). The inverse variance method was used for continuous data to display the mean difference (MD) and 95% CI with statistical significance when P value < 0.05. To assess the degree of heterogeneity, we conducted chi-square and I² tests with significant heterogeneity when the I² > 50% and the P-value of the chi-square < 0.05. If the data were heterogeneous, we would apply a leave-one-out sensitivity analysis. We used the fixed effect model to pool homogenous data and the random effect model for heterogeneous data. Additionally, we implemented a trial sequential analysis (TSA) in light of the relatively small number of studies included in our primary outcomes subgroups and to evaluate the reliability of our results [26, 27].

Results

Study selection

Our search yielded 158 unique citations after eliminating 128 duplicates. We excluded 127 citations based on title/abstract screening and 25 citations based on full-text screening. We conducted an updated search of PubMed on July 2, 2024, and included two RCTs in our meta-analysis. Finally, eight studies from seven RCTs were eligible for our meta-analysis, as shown in Fig. 1. While our analysis included data from seven randomized controlled trials (RCTs), one of these trials reported results across two separate publications [18] and [28] that met our inclusion criteria. Each publication provided distinct outcome data relevant to our analysis, and therefore, both were included as separate study entries in the meta-analysis.

Fig. 1

PRISMA flow diagram of our systematic review

Study characteristics

This systematic review and meta-analysis include eight RCTs. Most of the studies were conducted in several regions of the USA, Belgium, Japan, and East Asia. All of these studies were multicenter studies. Our sample size was 3740 (fezolinetant = 2502). The mean patient age was around 55 years old. The baseline frequency of moderate-to-severe vasomotor symptoms per day across studies ranged from 9.5 to 11.5. The mean baseline severity of vasomotor symptoms was 2.5. More details regarding the study and baseline characteristics are shown in Table 1 and Table 2, respectively.

Table 1 Summary of the included studies

Table 2 Baseline characteristics of the included studies

Quality assessment

The summary of the quality assessment of the included studies is presented in Fig. 2. The overall ROB of Depypere et al. [20], Santoro et al. (2020), and Fraser et al. [18] showed an overall low ROB. Only one study, Neal-Perry et al. [31], showed some concerns due to their allocation based on a haphazard method: smoking status. The remaining four studies, Takamatsu et al. [29], Ruan et al. [30], Johnson et al. [19], and Lederman et al. [32], showed an overall high risk of bias due to different causes, such as deviation from the intended intervention. Detailed ROB-II is presented in Fig. 3. Additionally, a significant proportion of > 0.05 was omitted. More details about the quality assessment were reported in the supplementary file (Tables S2–S8). Certainty of evidence is demonstrated in a GRADE evidence profile (Tables 3 and 4).

Fig. 2

Detailed graph of risk of bias assessment of the included studies

Fig. 3

Summary graph of risk of bias assessment of the included studies

Table 3 GRADE system of the most important outcomes of the Fenzolinetant compared to placebo for vasomotor symptoms in menopausal women after a 12-week follow-up

Table 4 GRADE system of the most important outcomes of the Fezolinetant 45 mg compared to Fezolinetant 30 mg for menopause-associated vasomotor symptoms in menopausal women after a 52-week follow-up

Publication integrity

High compliance was observed across several domains. All studies demonstrated good adherence to research governance standards, with all studies reporting funding sources and trial registration. Ethical conduct was consistently rated as good, with no reports of unethical practices. No evidence of plagiarism or text recycling was identified, and no image duplication or manipulation instances were detected. In terms of authorship, two studies—Takamatsu et al. [29] and Neal-Perry et al. [31]—were rated as poor due to the absence of contributorship statements. Four studies [18, 19, 30] (Santoro et al. 2020) scored poorly in the analyses and methods domain, primarily due to missing data or inappropriate data handling. Additionally, three studies [18, 19, 30] presented inconsistencies in reported participant numbers, raising concerns about data reliability. Data duplication without acknowledgment was observed in two studies—Lederman et al. [32] and Neal-Perry et al. [31]—resulting in an “unclear” rating. While Takamatsu et al. [29] demonstrated poor authorship transparency, they excelled in statistical rigor. Ruan et al. [30] and Johnson et al. [19] exhibited methodological flaws, including missing data and potential outcome switching. Depypere et al. [20] was the only study without major weaknesses across all evaluated categories. Summary of Publication Integrity was presented in Table 5. More details of Publication integrity were presented in Tables S11–S18.

Table 5 Summary of assessment of publication integrity

Primary outcomes

Reduction in VMS frequency

By the 12 th week, fezolinetant significantly reduced the daily frequency of VMSs compared to placebo with both 30 mg (MD = − 1.96, 95% CI [− 2.48, − 1.45], P < 0.00001, I² = 0%, P = 0.46) and 45 mg (MD = − 2.54, 95% CI [− 3.21, − 1.87], P < 0.00001, I² = 0%, P = 0.99) (Fig. 4). According to TSA, the cumulative Z-score passed the required information size and monitoring boundaries, providing firm evidence favoring fezolinetant (30 mg/day) (Fig. 5).

Fig. 4

Forest plot of the effect of both fezolinetant 30 mg and 45 mg compared to placebo on the frequency of moderate-severe VMSs after a 12-week follow-up

Fig. 5

The trial sequential analysis of the fezolinetant effect on the frequency of moderate-severe VMSs after a 12-week follow-up

By week 12, fezolinetant significantly increased the number of participants achieving at least a 50% reduction in VMSs frequency in both the fezolinetant 30 mg (OR = 1.94, 95% CI [1.51, 2.50], P < 0.00001, I² = 37%, P = 0.18) and 45 mg groups compared to placebo (OR = 2.56, 95% CI [1.82, 3.60], P < 0.00001, I² = 41%, P = 0.19) (Fig. 6). According to TSA, the cumulative Z-score passed the required information size and monitoring boundaries, providing firm evidence favoring fezolinetant (30 mg/day) (Fig. 7).

Fig. 6

Forest plot of the effect of both fezolinetant 30 mg and 45 mg compared to placebo on the incidence of a 50% reduction of the frequency of moderate-severe VMSs after a 12-week follow-up

Fig. 7

The trial sequential analysis of the fezolinetant effect on the incidence of a 50% reduction of the frequency of moderate-severe VMSs after a 12-week follow-up

By the 12 th week, fezolinetant significantly increased the number of participants, achieving at least a 70% reduction in VMSs frequency in both 30 mg (OR = 2.22, 95% CI [1.55, 3.18]: P < 0.0001, I² = 37%, P = 0.74) and 45 mg (OR = 2.90, 95% CI [1.96, 4.30], P < 0.00001, I² = 41%, P = 0.48), compared to placebo (Fig. 8).

Fig. 8

Forest plot of the effect of both fezolinetant 30 mg and 45 mg compared to placebo on the incidence of 70% reduction of the frequency of moderate-severe VMSs after 12-week follow-up

Daily severity of VMSs

By the 12 th week, the efficacy of fezolinetant significantly reduced the daily severity of VMSs compared to placebo with both 30 mg (MD = − 0.18, 95% CI [− 0.26, − 0.10], P < 0.0001, I² = 0%, P = 0.82) and 45 mg (MD = − 0.24, 95% CI [− 0.34, − 0.13], P < 0.0001, I² = 0%, P = 0.41) (Fig. 9). According to TSA, the cumulative Z-score passed the required information size and monitoring boundaries, providing firm evidence favoring fezolinetant (30 mg/day) (Fig. 10).

Fig. 9

Forest plot of the effect of both fezolinetant 30 mg and 45 mg compared to placebo on the daily severity of moderate-severe VMSs after 12-week follow-up

Fig. 10

The trial sequential analysis of the fezolinetant effect on the daily severity of moderate-severe VMSs after a 12-week follow-up

Hot Flash Related Daily Interference Scale (HFRDIS) score by week 12

The pooled data from two studies showed that the fezolinetant 180 mg significantly reduced the score compared to placebo (MD = − 1.69, 95% CI [− 2.36, − 1.02], P < 0.0001; I² = 30%, P = 0.23) (Fig. 11).

Fig. 11

Forest plot of the effect of fezolinetant 180 mg compared to placebo on the Hot Flash Related Daily Interference Scale (HFRDIS) Score after a 12-week follow-up

The Menopause-Specific Quality of Life (MENQOL) score by week 12

Johnson et al. [19] and Lederman et al. [32] provided data on the total MENQOL score, while Lederman et al. [32] and Santoro et al. (2020) reported data on the MENQOL vasomotor domain score. The pooled data demonstrated that fezolinetant significantly reduced the total MENQOL score with both 30 mg (MD = − 0.32, 95% CI [− 0.52, − 0.13], P = 0.0009; I² = 0%, P = 0.36) and 45 mg (MD = − 0.49, 95% CI [− 0.67, − 0.30], P < 0.00001; I² = 0%, P = 0.96) compared to placebo (Fig. 12). Furthermore, fezolinetant 30 mg significantly reduced the MENQOL vasomotor domain score compared to placebo (MD = − 0.90, 95% CI [− 1.28, − 0.53], P < 0.000; I² = 0%, P = 0.68) (Fig. 13).

Fig. 12

Forest plot of the effect of both fezolinetant 30 mg and 45 mg compared to placebo on MENQOL total score after a 12-week follow-up

Fig. 13

Forest plot of the effect of fezolinetant 30 mg compared to placebo on MENQOL vasomotor domain score (change) after 12-week follow-up

The Patient-Reported Outcomes Measurement Information System Sleep Disturbance: Short Form 8b (PROMIS SD-SF-8b) total score by weeks 12 and 52

By the 12 th week, fezolinetant 45 mg achieved a statistically significant reduction in PROMIS SD-SF-8b total score compared to placebo (MD = − 1.55, 95% CI [− 2.53, − 0.57], P = 0.002; I² = 17%, P = 0.27). However, fezolinetant 30 mg failed to gain any significant difference compared to the placebo group (MD = − 0.61, 95% CI [− 1.64, 0.42], P = 0.24; I² = 0%, P = 0.85) (Fig. 14). Johnson et al. [19] and Lederman et al. [32] compared the effect of fezolinetant 30 mg and fezolinetant 45 mg on PROMIS SD-SF-8b total score at week 52. The pooled results showed that there was no significant difference between the two doses (MD = − 0.14, 95% CI [− 1.60, − 1.32], P = 0.85, I² = 13%, P = 0.28) (Fig. 15).

Fig. 14

Forest plot of the effect of both fezolinetant 30 mg and 45 mg compared to placebo on PROMIS SD SF 8b total score after a 12-week follow-up

Fig. 15

Forest plot of the effect of fezolinetant 30 mg compared to 45 mg on PROMIS SD SF 8b total score after a 52-week follow-up

Secondary outcomes

Safety outcomes by week 12

The safety of fezolinetant was assessed through many outcomes reported in 7 studies [18,19,20, 29, 30, 32]. There was no significant difference between each of the following: fezolinetant 30 mg, 45 mg, and 180 mg were compared to placebo in the incidence of treatment-emergent adverse events (TEAEs) or the incidence of TEAEs causing permanent discontinuation of the study drug (Figs. S3 and S4). Fezolinetant 30 mg reported a statistically significant increase in the incidence of drug-related TEAEs compared to placebo. On the other hand, both fezolinetant 45 mg and 180 mg failed to report a statistically significant difference compared to placebo (Fig. S5).

Furthermore, our pooled analysis demonstrated that both fezolinetant 30 mg and 45 mg have no statistically significant difference compared to placebo regarding arthralgia, bone fracture, depression, nasopharyngitis, nausea, liver test elevations, serious TEAEs, drug-related TEAEs causing permanent discontinuation of the study drug, and uterine bleeding (Figs. S6–S15).

Additional safety analysis from pooled results demonstrated that fezolinetant 30 mg and 180 mg have no statistically significant difference compared to placebo regarding diarrhea, fatigue, and headache (Figs. S16–S18). We also reported no significant difference between fezolinetant 45 mg and placebo regarding headache and abdominal pain (Figs. S18 and S19). There was no significant heterogeneity across all variables.

By the 12 th week, the fezolinetant 30 mg and 45 mg groups had no statistically significant difference compared to the placebo in increasing the risk of elevated liver function tests, as demonstrated by the pooled analysis of ALP more than 1.5 times ULN, ALT more than 3 times ULN, and ALT or AST more than 3 times ULN (Figs. S20–22). Additionally, fezolinetant 30 mg showed no difference compared to placebo regarding the number of participants having an increase in AST more than 3 times ULN (Fig. S23).

All safety outcomes of fezolinetant at different doses compared to placebo in treating VMSs at 12 weeks are presented in Table 6.

Table 6 Summary of safety outcomes of fezolinetant at different doses compared to placebo in treating VMSs at 12 weeks

Safety outcomes by week 52

Three studies [19, 31, 32] compared fezolinetant 45 mg with fezolinetant 30 mg at week 52 and reported multiple outcomes related to the safety analysis of each drug. Our pooled analysis showed that there was no statistically significant difference between the two doses regarding TEAEs, serious TEAEs, drug-related TEAEs, TEAEs causing permanent discontinuation of the study drug, drug-related TEAEs causing permanent discontinuation of the study drug, drug-related serious TEAEs, bone fracture, depression, endometrial hyperplasia or cancer, headache, liver test elevation, and uterine bleeding (Figs. S24–35). All pooled results were homogeneous.

By the 52-week follow-up, three studies [19, 31, 32] compared fezolinetant 45 mg with fezolinetant 30 mg according to the number of participants suffering from elevated function tests in both groups. Despite fezolinetant 45 mg causing a higher proportion of patients to suffer from elevated function tests, there was no statistically significant difference between the two doses regarding the outcomes of ALT more than 3 times ULN, AST more than 3 times ULN, ALT or AST more than 3 times ULN, and ALT more than 1.5 times ULN (Figs. S36–39), respectively.

All safety outcomes of fezolinetant 45 mg vs. 30 mg in treating VMSs at 52 weeks are presented in Table 7.

Table 7 All safety outcomes of Fezolinetant 45 mg vs. 30 mg in treating VMSs at 52 weeks

Discussion

Targeting the neurokinin-3 (NK-3) receptor with an antagonist could be a revolutionary treatment for VMS in postmenopausal women. Conventional hormone replacement therapy (HRT) for menopause has drawbacks, including risks for certain patients [10, 11]. According to the literature, HRT raises the risk of developing breast cancer and thromboembolic events, which makes it unsuitable for patients with contributing risk factors to develop these events [11, 12]. So, our systematic review and meta-analysis of pooled data from multiple clinical trials provide a comprehensive evaluation of fezolinetant’s efficacy, impact on hepatic function tests, and short- and long-term safety in managing VMS.

The efficacy outcome in our analysis included examining fezolinetant’s impact on VMS frequency, VMS severity, and the other four different scoring systems: MENQOL score, PROMIS score, and HFRDIS score. We categorized data based on the dose of fezolinetant starting at 30 mg, passing by 45 mg, and ending at 180 mg. We assessed adverse events of fezolinetant at two different time points (at week 12 and week 52) to study short- and long-term adverse events. We also compared two different doses in our meta-analysis (30 mg and 45 mg) at week 52 to analyze the dosages’ long-term impact on the safety profile.

Regarding the frequency of VMS, fezolinetant showed a significantly lowered frequency of VMS at week 12. This reduction in VMS frequency is dose-dependent. The dose–response relationship is observed and proved across subgroup analyses of various dosages of 30 mg and 45 mg. Forty-five milligrams of fezolinetant is the most likely dose to reduce the frequency of VMS by at least 70% from baseline at week 12. Meanwhile, the 30 mg dose of fezolinetant was also effective in reducing the frequency of VMS by at least 50% from baseline at week 12.

An analysis of both fezolinetant 30 mg and 45 mg impact compared to placebo on VMS severity and other three different severity scoring systems yielded a statistically significant reduction in all VMS severity scoring systems at week 12, except PROMIS SD SF 8b total score by 30 mg fezolinetant. Fezolinetant was effective in lowering and improving the MENQOL score, which was consistent across various dosages. When fezolinetant was administered at 30 mg and 45 mg, the HFRDIS score showed a statistically significant reduction in VMS severity. On the other hand, we found no significant difference in PROMIS scores between 45 and 30 mg at week 52. Sleep disturbance is a rising health condition in 50% of postmenopausal women, in addition to reduced sleep quality, disruptions during the night, and increased sleepiness during the day [33, 34]. The findings of our analysis assume that a high dose of fezolinetant could be a valuable treatment for VMS.

Our pooled data on VMS frequency and severity correspond with Phase 3 SKYLIGHT 1 and 2 outcomes [19, 32]. They also reported that the fezolinetant’s efficacy in reducing these symptoms was observed from early treatment courses, first week, and sustained over 12 weeks. This phenomenon is attributed to the mechanism of action of the neurokinin 3 receptor antagonist. For further explanation, neurokinin and estrogen exhibit contrasting effects on the thermoregulatory center in the hypothalamus [15, 16]. Therefore, in postmenopausal women, we can counteract the impact of neurokinin by using a blocker, effectively balancing out the diminished influence of estrogen on the hypothalamus [17].

Additionally, we studied fezolintant’s impact on hepatic enzymes. Our pooled data suggests there is no statistically significant impact of fezolinetant on liver function, whatever the administered dose is. AST and ALT showed no increase or may be transient elevation but were not associated with liver injury. This is similar to the comprehensive hepatic safety monitoring that was applied by Neal-Perry et al. according to Hy’s law criteria, Lederman et al., Johanson et al., and Fraser et al. [18, 19, 31, 32]. Hy’s law criteria state that there is no significant drug-induced liver impairment, as evidenced by ALT or AST levels over three times the ULN, total bilirubin levels surpassing two times the ULN, an absence of alkaline phosphatase increase, and no alternative explanation for the observed combination [35].

The safety outcomes of fezolinetant were meticulously evaluated. TEATS, drug-related TEAEs, TEAEs causing permanent discontinuation of the drug, and serious TEAEs showed no significant difference between the placebo group and different doses of the fezolinetant-treated groups in the short term (week 12). Moreover, at week 52, when we compared 2 doses (30 mg and 45 mg), the analysis showed no significant difference between these commonly used doses regarding drug-related TEAEs, TEAEs causing permanent discontinuation of the drug, and serious TEAEs. However, on drug-related TEAEs, the fezolinetant group demonstrated a significant difference compared to the placebo at week 12 at a dose of 30 mg. Both Lederman et al. and Johanson et al. found no serious TEAEs with 45 mg [19, 32]. Additionally, Fraser et al. made the same observation but with a higher dose of 120 mg [18]. Also, Depypere et al. proved that fezolinetant has fewer drug-related TEAEs and serious TEAEs [20].

Upon analyzing the safety outcomes for the fezolinetant-treated group, no statistically significant difference was observed when compared to the placebo group at week 12 regarding adverse events such as abdominal discomfort, bone fracture, depression, diarrhea incidence, endometrial hyperplasia, cancer, headache, nasopharyngitis, nausea, and uterine bleeding. The safety profile incorporated bone fractures and uterine bleeding, as both are notable health conditions in postmenopausal women [36, 37]. Furthermore, traditional HRT is known for its protective effect on bone health by reducing osteoclast activity and maintaining bone density [38]. Moreover, uterine bleeding in postmenopausal women often occurs due to thinning of the mucosa or as a side effect of unopposed estrogen replacement therapy [37, 39]. Therefore, bone fractures and uterine bleeding were incorporated into the analysis due to their increased risk in postmenopausal women [36, 37]. Unlike our meta-analysis result, Depypere et al. found that the fezolinetant-treated group experienced gastrointestinal events in the form of abdominal discomfort and diarrhea more commonly than the placebo group [20]. The explanation for this finding is that the neurokinin 3 receptor is present and expressed in the gastrointestinal muscle wall [40].

At week 52, there was no significant difference in long-term adverse events, particularly endometrial hyperplasia, or cancer between the 30 mg dose of fezolinetant and the 45 mg dose. Our meta-analysis result aligns with Neal-Perry et al. [31]. According to Depypere et al., the fezolinetant effect on LH-sparing FSH levels and plasma levels of estradiol (E2) is important for those at risk for endometrial hyperplasia, and cancer [20]. Also, Fraser et al. proved the same result about fezolinetant: it suppresses the LH level but doesn’t alter the plasma level of estradiol (E2) [18]. Hence, Feraser et al. recommended using fezolinetant in postmenopausal women with an increased risk of endometrial hyperplasia, and cancer which is like our pooled data results [18].

Notably, our paper highlights fezolinetant endometrial safety, which demands further observational studies and clinical trials with larger samples to evaluate. Additionally, our analysis evaluated the long-term adverse events of fezolinetant.

According to Antonia et al., in their systematic review, they agreed with us that fezolinetant, especially at the 45 mg dose, is more effective in reducing VMS frequency and severity than placebo in addition to non-hormonal therapy [41]. Contrary to Antonia et al., our comprehensive meta-analysis extends these findings by demonstrating that the positive effects of fezolinetant persist in the long term, with week 52 data confirming ongoing efficacy and a safety profile that includes a non-significant impact on liver function. Furthermore, our review provides a detailed analysis of adverse events, such as abdominal discomfort, bone fracture, depression, diarrhea, endometrial hyperplasia, cancer, headache, nasopharyngitis, nausea, and uterine bleeding. This long-term safety profile was lacking in the Antonia et al. networking meta-analysis; however, our analysis showed a non-significant difference between the fezolinetant and placebo groups, reinforcing that fezolinetant has a favorable safety profile [41]. Unlike Antonia et al., we focused on comparing fezolinetant in different dosages (30 mg, 45 mg, and 180 mg) to placebo rather than comparing fezolinetant to conventional HRT and other non-hormonal therapy [41].

The results reported by Rahman et al. in their systematic review of fezolinetant agree with our findings [42]. Both analyses highlighted that fezolinetant significantly reduces VMS frequency and severity and improves certain severity scores compared to a placebo at week 12 [42]. Rahman et al. also demonstrated these benefits at the 30 mg and the 45 mg doses through subgroup analyses, matching our findings [42]. However, our systematic review and meta-analysis provide a more comprehensive assessment of fezolinetant’s efficacy. We evaluated additional outcome measures, such as a reduction in VMS frequency by specific percentages (50% and 70%). We also directly compared multiple doses of fezolinetant up to 180 mg. Therefore, while Rahman et al. corroborate the key findings, our review offers superior insight into fezolinetant’s clinical profile and benefits through a more rigorous and extensive evaluation of the available RCTs [42]. Regarding the safety analysis reported by Rahman et al. and our review, neither review found any significant differences between fezolinetant and placebo in overall adverse events, serious TEAEs, or discontinuations due to TEAEs [42]. Both also assessed certain adverse events, such as uterine bleeding, diarrhea, and nausea, without identifying increased risks with fezolinetant [42]. Our review provided additional in-depth analysis of outcomes for the 30 mg and 45 mg doses, as well as comparisons between these doses at week 52. Our paper also examined additional adverse events such as arthralgia and depression, which were neglected by Rahman et al. [42]. While the overall profiles agreed in supporting the favorable safety of fezolinetant, our analysis offered more safety insights and a longer duration of follow-up.

Similar to our results, Elnaga et al. found that fezolinetant decreased the frequency of vasomotor symptoms from baseline at week 12. Moreover, fezolinetant decreased the VMS severity index at week 12. These reductions were positively reflected in the menopause-specific quality of life score [43]. Contrary to our results, Elnaga et al. reported significant increase in the risk of drug-related TEAEs, serious TEAEs, fatigue, arthralgia and ALT or AST > 3 times [43]. Another systematic review by Akhtar et al. reported frequency and severity results similar to our results [44]. They reported that fezolinetant has a significant effect in reducing the frequency of daily VMS compared to placebo. Fezolinetant demonstrated superiority over the placebo group on the severity of daily VMS [44]. Fezolinetant (120 mg) consistently exhibited a considerable decrease in the severity of daily moderate to severe vasomotor symptoms compared to other dosages at both 4 and 12 weeks. Patient-reported outcomes from the PROMIS Sleep Disturbance Short Form 8b and MENQoL assessments demonstrated substantial enhancement with fezolinetant. No notable differences in TEAEs after 12 weeks were seen between fezolinetant and placebo regarding safety [44].

Therefore, fezolinetant has the potential to be a game-changing non-hormonal option for alleviating VMS, particularly when conventional HRT is contraindicated due to safety concerns. Its proven efficacy and safety profile make it a highly appealing drug.

Limitations and strengths

We acknowledge the presence of heterogeneity in the data due to the multiple doses studied, for which we applied a leave-one-out sensitivity analysis and subgroup analysis. Furthermore, assessing VMS severity based on scores from MENQOL, PROMIS, and HFRDIS questionnaires is liable to be subjective because these scores resemble patients’ points of view about VMS severity. The present RCT was not efficient in studying long-term adverse events such as endometrial hyperplasia and cancer. In addition, the eight included studies have a moderate to high ROB, which reduces the quality of the evidence. Consequently, new RCTs studying fezolinetant should minimize its ROB. That is, we open new avenues for future research to compare different doses and different time points to address any neglected or non-addressed adverse events of the treated group. This opens a new avenue for RCTs with efficient sampling to measure the efficacy and safety outcomes of fezolinetant.

Regarding strength points, we studied multiple dosages’ impact on VMS frequency, severity, and liver function tests. Including multiple doses from 30 to 180 mg in our analysis strengthens our results. Additionally, our subgrouping analysis provides a high level of evidence for physicians. Also, a pooled data meta-analysis provides comprehensive evidence. Additionally, we evaluated the safety profile at two time points (week 12 and week 52). This enabled us to study the short- and long-term adverse events of fezolinetant. Moreover, at week 52, we studied two doses'impact on the safety profile (30 mg and 45 mg). There is a gap in the literature regarding the long-term effects of fezolinetant and dosage-related responses, which adds outstanding strength to our paper. As well as this detailed safety assessment is also lacking in the literature. Furthermore, applying the ROB-2 tool ensures a standardized bias assessment of the included trial, enhancing the validity and reliability of safety and efficacy outcomes.

One of the strengths of our study is assessing the outcomes using a novel approach to meta-analysis, which is TSA, in light of the relatively small number of studies included in our main outcomes and the reliability of our results. The TSA approach was employed to balance between type-I and type-II errors, providing an estimate of when the effect size becomes substantial enough to withstand the impact of additional studies. Consequently, TSA enhances transparency and informed decision-making in our meta-analysis. This method helps clarify the level of certainty in our findings and whether further studies are needed for confirmation. We also used the GRADE system to assess the certainty of the evidence for each outcome.

According to publication integrity, the findings indicate high transparency in research governance, with consistent reporting of funding sources and trial registration, as well as strong adherence to ethical standards—suggesting robust institutional oversight. The absence of plagiarism and image manipulation further reflects the effectiveness of current peer-review processes. However, several weaknesses were identified. Authorship concerns, particularly incomplete contributorship disclosures, compromise accountability. Methodological issues, such as missing data, were present in approximately half of the studies, posing a threat to reproducibility. Additionally, unacknowledged data duplication in some studies raises concerns about selective publication practices. To address these issues, contributorship statements based on ICMJE criteria should be mandated to enhance transparency in authorship. Pre-registration of analysis plans is recommended to mitigate outcome switching, and peer-review protocols should include standardized checks for participant numbers and unit consistency to minimize reporting errors. It is important to note that the REAPPRAISED checklist depends on publicly reported data; discrepancies in unreported materials (e.g., raw datasets) could not be verified. Moreover, certain assessments—such as evaluations of recruitment plausibility—may be subject to evaluator interpretation and variability.

Conclusion

In conclusion, fezolinetant demonstrates promising efficacy in reducing the frequency and severity of VMS in postmenopausal women, as well as improving quality of life measures associated with menopause. Our meta-analysis of multiple clinical trials provides robust evidence supporting fezolinetant’s effectiveness, with significant reductions in VMS frequency and severity observed across various dosage regimens. Notably, fezolinetant’s efficacy extends to both short-term and long-term treatment periods, with sustained benefits observed at week 52. Furthermore, fezolinetant exhibits a favorable safety profile, with no significant impact on liver function tests and comparable rates of adverse events to placebo. The drug demonstrates a favorable risk–benefit profile for managing VMS in postmenopausal women. However, further research, including larger observational studies and clinical trials, is warranted to confirm fezolinetant’s long-term safety and efficacy, particularly regarding endometrial health.