Introduction

Menopause (permanent loss of ovarian follicular activity and estrogen production, mainly estradiol [E2]), marks a universally experienced transition from a woman’s reproductive years to non-reproductive years [ ]. Menopause is typically diagnosed retrospectively after a woman has experienced 12 consecutive months without menstruation [ ]. Menopause is one of the ageing processes without another pathological or physiological cause. Although menopause may not be considered “a disease”, menopause-associated symptoms or signs (MA-S&S) may cause a big troublesome problem for post-menopausal women (PMW) because of its significantly negative impact to their quality of life (QoL) and further impairment of the relationship to their family and society [ ]. MA-S&S are relatively complex with a great variation of prevalence, severity and levels. Most of symptomatic MA-S&S women are underreported, under-screened, undertreated, under-estimated and subsequently resulting in heavy socio-economic burden [ ].

MA-S&S include at least three main parts: (i) vasomotor symptoms (VMS, cold or night sweats, hot flushes [flashes], and palpitation, and other minors); (ii) genitourinary syndrome of menopause (GSM, incontinence, vulvovaginal atrophic changes, vaginal dryness, vaginal burning, vaginal pruritus, urinary urgency and recurrent urinary tract infections); (iii) many others, such as joint and muscle pains, cognitive changes (mood fluctuation), sleep disturbance, low libido (sexual dysfunction, dyspareunia), and many others ( Fig. 1 ). A great variation of MA-S&S often makes both physicians and victims confused and results in the diagnostic challenge and following treatment strategy. Many ageing-related organic diseases also appear during this menopause transition period, and the overlapping age-period (51.4 years with standard deviation [SD] 3.3 years) by peak incidences cause much challenge for both physicians and patients. For example, well-known gynecologic cancers (GC) also occurred in the aforementioned age-period, such as 57 years of a median age of cervical cancer (CC), 56 years of endometrial cancer (EC) and 55 years of ovarian cancer (OC), respectively in Taiwan, resulting in much complicated in the management of symptomatic PMW [ ]. Therefore, women during the menopause transition need our special care, and in fact, menopause has really gained much attention not only in person but also in public.

Menopause associated symptoms and signs and their related factors.

Among these MA-S&S, VMS may be one of the most hallmark symptoms, since VMS appears early before the menopause and crossing over the entire menopausal transition period and progressing into the post-menopausal state. The review will summarize current evidence regarding treatment of VMS in these symptomatic women.

Vasomotor symptoms (VMS)

VMS, defined as sudden increases in corporal (core) body temperature (CBT) by sensations of extreme heat and sweating and episodes of peripheral vasodilation, are a form of temperature dysfunction that is mainly related to changes in ovarian hormones (E2 and progesterone [P4]), and disruption of this tightly controlled temperature circuit results in exaggerated heat-loss responses presenting as VMS, with peripheral vasodilation and elevated skin blood flow and temperature, typically experienced in the head, neck, and chest [ , ]. The prevalence, severity, and level of negative impacts of VMS on symptomatic women vary greatly with conflicted data [ ], because many factors may involve in their variety, including racial/ethnic differences, environmental or sociocultural factors, and un-avoidable studied biases [ ]. In general, an estimated prevalence of VMS ranges from 41 %∼46 % of women during the early menopausal transition (called as perimenopausal status from the beginning of menstrual irregularities to menopause) to approximately 60 %∼82 % at any time of women passing through the menopause transition to post-menopausal state [ ]. Conventionally, it is believed that the highest prevalence is reported in Black women, while East Asian women have the lowest prevalence [ ]. However, the different studies may show some controversies. For example, the same race but living in different countries may present the different prevalence patterns. For example, one report showed the higher prevalence among Asian Indian women in the UK, but lower among Asian women in India, compared with White women in the UK [ ], suggesting strong influence by environmental and socioeconomic issues. However, Dhanoya et al. found a higher prevalence of hot flushes in Bangladeshi women, regardless of their location (Bangladesh or the UK), compared with European women in the UK [ ], suggesting race plays a determining factor. In agreement of critical role of race, the LEAVeS (Life time Exposures and Vasomotor Symptoms) study showed a lower prevalence of hot flashes and night sweats in Asian Indian women than in White women in both premenopausal and perimenopausal to postmenopausal subgroups [ ]. Furthermore, the WARM (Vasomotor Symptoms Associated with Menopause) study also favored the determined factor as race, because Canadian subgroup had a prevalence rate of moderate to severe VMS similar to that of Mexico and Nordic Europe (14.7 % vs 16.5 % and 11.6 %, respectively) and less than half the prevalence rate for the Brazilian subgroup (36.2 %) [ ].

In term of severity of VMS, more than three quarters of peri-menopausal women experienced VMS and at least one third of these symptomatic women reported to seek health care for their MS-S&S, with VMS being the most common symptoms discussed with a health-care professional [ , ]. Similar to variety of prevalence of VMS, the severity of VMS is affected by racial/ethical differences, although it is also modified by environmental and socio-economic influences. It is reported a higher prevalence of moderate/severe VMS occurred in Black women than in White women; however, this finding is only found among those with a body mass index (BMI) < 30 kg/m ² , but not among those with a BMI ≥30 kg/m ² [ ].

In term of level of VMS, the US-based Study of Women’s Health Across the Nation (SWAN) showed that median total duration of symptoms was 7.4 years among women experiencing frequent VMS (occurring on ≥6 days in past 2 weeks) and these persisted for 4.5 years after the final menstrual period [ , , ]. The shortest median VMS duration (3.4 years) was in women who were postmenopausal at VMS onset, whereas those who were premenopausal or early perimenopausal at their first VMS had the longest median VMS duration (≥11.8 years) and post-final menstrual period persistence (9.4 years) [ , , ].

In summary, the prevalence, severity, and level of VMS was highly variable across studies and races/ethnicities, which may be related to genetic and psychosocial factors and culturally determined health beliefs and perceptions and of course, these inconsistency may be secondary to the differences of the original study design, such as differences in patient questionnaires, symptom definition/interpretations and recall periods) [ ]. Therefore, VMS is a biggest troubling problem for symptomatic women, but the effects of health-providers’ assistance may be varied greatly. The following information needed standard definitions of VMS and further validated clinical outcome measurement of therapeutic effects by new approach or treatment. The current review attempts to explore current evidence opening the new chapter in the management of moderate-to-severe VMS women (≥one quarter of PMW), because moderate-to-severe VMS not only impairs overall QoL of PMW but also involves in poor correlation between symptomatic PMW and their relatives and additionally blocks their social-economic connection, with subsequent loss of global performance [ , ].

Pathophysiology of vasomotor symptoms ( Fig. 2 )

The underlying pathophysiology of VMS is not fully understood. VMS is often accompanied with menopause transition and postmenopausal status, which is characterized by erratic E2 concentration, to reach at lowest level with a simultaneous increased level of follicular stimulating hormone (FSH) and luteinizing hormone (LH); but shutdown of ovarian function associated with menopause rarely happens overnight [ ]. Instead, many women will experience years of bumpy ovarian decline, with erratic female hormone production, meaning years of fluctuating female hormones that no longer rise and fall in their once-predictable patterns [ ].

Based on well-known changes of female hormone orchestrated by central nervous system (CNS), such as the hypothalamic-pituitary-gonadal (HPG) axis involving in the feedback mechanism (gonadotrophin-releasing hormone [GnRH]-FSH + LH-E2+P4), GnRH produced in the hypothalamus acts on gonadotrophs in the anterior pituitary gland, triggering the secretion of LH and FSH and subsequently control follicular growth, ovulation, and menstruation [ ]. However, estrogen receptors (ER) play a major role in positive and negative feedback mechanisms, are not expressed on GnRH neurons, suggesting that higher CNSlevels may involve in the reproductive function, which is supported by recent study showing GnRH function is mediated by an upstream hypothalamic neural construct, considered as the GnRH pulse generator and mainly located in the arcuate nucleus, including neurons expressing stimulatory neuropeptides (kisspeptin [ KISS1 or Kp] and neurokinin B [NKB or N]) and inhibitory neuropeptides (dynorphin [DYN or Dyn]) [ ].

The hypothalamic neural construct, containing Kp/NKB/DYN secreting neurons (hypothalamic kisspeptin/neurokinin/dynorphin neurons, KNDy neurons) is regulated by mainly E2 levels and possible P4 levels [ ]. The KISS1 gene is mapped to the long arm of chromosome 1 (1q32-q41), comprising 4 exons of which only 2 are translated, and results in 145 amino acid (aa) prepropeptide which then post-translationally cleaved into biologically active Kp peptides of different aa lengths indicated by their suffix, such as Kp54 (the major product), Kp14, Kp13, and KP10 [ , ]. All native Kp peptides share a common C-terminal decapeptide sequence, equivalent to Kp10, which includes a terminal RF-amide sequence (Arg-Phe-NH2) and act with Kiss1 R (G protein-coupled receptor 54 [GPR54], containing 398 aa peptide encoded by a gene on chromosome 19 [19p13.3] with 5 coding exons interrupted by 4 introns) to induce a biphasic response in downstream signaling, with an acute response (lasting ∼5 min) and a prolonged phase (lasting >30 min), and then to regulate GnRH secretion upstream of GnRH [ , ]. Kp neurons in the infundibular nucleus co-express NKB (located on chromosome 12) and DYN are hence known as KNDy neurons and are regulated in an autocrine/paracrine manner, with NKB stimulating (via NKB [NK] receptor-mainly tachykinin 2 receptor as TAC3R) and Dyn inhibiting (via kappa opioid receptor) neuronal activity [ ]. This synchronized episodic action results in Kp release, which in turn activates distal dendrons of GnRH neurons and leads to the secretion of GnRH pulse [ ]. Three tachykinin receptors (TACRs) have been identified, including NK1R, NK2R, and NK3R, with the latter having a longer a sequence and exhibiting strong preferential binding capacity, coded by TACR gene [ ].

Besides KNDy neurons-mediated signaling pathway, many other signals may be involved in physical and/or pathological reproductive performance and/or other associated physiological or pathological functions (for example, menopause), including (i) the inhibitory γ-aminobutyric acid (GABA), acting on this system affecting GnRH pulse frequency and while reducing glutamate-related excitatory input secondary to aging process and an increased GABAergic signaling in the hypothalamus, with effects on GnRH pulse frequency; (ii) changes in neurotransmission, such as catecholaminergic (norepinephrine [NE], or noradrenaline) and/or serotonergic (5-hydroxytryptamine; 5-HT) pathways, nerve cell-cell interactions, and hormone receptor (ER) expression disrupting the neurological balance [ , ].

The study found that KNDy neurons in the infundibular nucleus of the hypothalamus are significantly increased in size (hypertrophy or hyperplasia) and overexpressed (for Kp and NKB) during the menopause [ ]. By contrast, the infundibular nucleus that expresses DYN is significantly decreased in the PMW. All suggest that this KNDy pathway may involve the physical changes induced by the menopausal transition, and additionally, dysregulation of temperature in the PMW may be mediated by KNDy pathway [ ]. The thermoregulatory circuitry contains three main parts, including (i) the brain (hypothalamus, specifically the pre-optic area [POA]); (ii) the internal body cavity; and (iii) the peripheral vasculature [ ]. VMS are a consequence of a malfunction of one or more of the thermoregulatory control mechanisms, and three possible hypotheses are proposed: (i) a change or miscommunication in the pre-defined acceptable temperature set-points or a narrowing of the thermoneutral zone with hyper-reactive sensor for minimal changes of corporal (core) body temperature (CBT); (ii) malfunction of vascular reactivity and reduction of the elasticity of blood vessels with hypersensitive or delayed responses to minimal changes of CBT due to loss of E2 and/or P4 modulation; (iii) neurochemical alterations of the brain secondary to loss of feedback of E2 as an underlying cause of thermoregulatory dysfunction [ ]. Moreover, a narrowing thermoneutral zone may be presented as two thresholds, and one is the upper one triggers heat loss (sweating, and provoking increased blood flow [vasodilatation to diminish heat]) and the other is the lower one triggers heat conservation (shivering, and reducing blood flow [vasoconstriction to conserve heat] to peripheral blood vessels) [ ]. Although peripheral vasodilatation and vasoconstriction are also modulated by noradrenergic and serotonergic input, and it is believed that CNS may be involved in this control, since autonomic thermoeffector pathways in the median POA nucleus responds to fluctuations in body temperature outside of the thermoregulatory zone, which subsequently leads to cutaneous vasodilatation, which is the hallmark of VMS. KNDy neurons in the hypothalamus regulates the heat defense pathway through NKB signaling and the negative feedback of E2 activating Kp and NK3R on KNDy neuron is out of function during the menopause transition. Based on the aforementioned findings, the management of women with VMS may be accorded by the underlying changes from the neurons of median POA and infundibular nucleus of the thalamus of these symptomatic PMW with moderate-to-severe VMS.

The recent publication by Dr. Kingsberg attempted to investigate the real-world data of treatment utilization by PMW experiencing VMS in the United States (US) and Europe and the data showed the followings, which may offer additional valuable messages to deal with these relatively complicated symptomatic PMW. The main findings included (i) nearly 30 % of women with moderate-to-severe VMS were not prescribed treatment; (ii) menopause hormonal therapy (MHT, 76 %) and serotonergic antidepressants (19 %) were most commonly prescribed for VMS; and (iii) more than one half (54 %) and three quarters (79 %) of women commonly used over-the-counter products (OTC) and lifestyle changes (LC), suggesting that there is an unmet need for symptomatic women with VMS [ ].

Management of women with vasomotor symptoms by conventional menopause hormone therapy (MHT)

Since menopause is defined by deficient E2, using MHT is, in theory, the best treatment for these women with deficient E2-complicating VMS. As predicted by theory, MHT is the most efficacious therapy for reducing VMS and also considered the standard of care (or gold standard) for these symptomatic PMW with VMS [ ]. In women who report experiencing VMS, FDA-approved MHT preparations decrease the frequency of vasomotor symptoms by approximately 75 % compared with placebo [ ], and the therapeutic effect of MHT is far more superior to other nonhormonal alternative therapy [ ], contributing to favoring choice of using MHT for treating VMS in more than three quarters of PMW [ ]. MHT is particularly recommended to those women without the following contraindications, such as age <60 years or menopause <10 years, absence of a history of breast cancer (BC), absence of advanced EC, absence of cardiovascular accident (CVA, such as coronary heart disease [CHD], stroke, myocardial infarction [MI], venous thromboembolism [VTE], and pulmonary embolism), absence of neurological diseases, as Alzheimer’s disease or others who not interesting to MHT [ , ]. The transient and short-term use of MHT takes benefits may outweigh their risks [ , ]. Additionally, extra-benefits, such as preventing and treating osteoporosis, and GSM are also apparent, and finally some are believed MHT have rejuvenescence effects. However, the potential and possible MHT-related adverse events (AEs) are always in concern and warning in public, particularly regarding a long-term poor safety profile of MHT [ , , ]. These unexpected AEs not only challenge both physicians and patients, but also result in a long-term debased issue, making the widespread confusing. These AEs are always worrisome and unacceptable, particularly occurrence after the Women’s Health Initiative (WHI) study conducted in the 1991-early 2000 timeframe [ , , ]. For PMW, the WHI randomized clinical trials (RCTs) are against using MHT for preventing CVD or other chronic diseases. However, the key person- Dr. Manson also agrees that MHT is an appropriate therapy to treat bothersome VMS among women in early menopause, without contraindications, who are interested in taking MHT [ ].

Management of women with VMS by complementary and alternative medicine (CAM) or lifestyle changes (LC)

Based on worrisome AEs secondary to MHT of many PMW and also physicians, as shown above, these PMW commonly use OTC products and LC for symptom management, which can be grouped as complementary or alternative medicine (CAM)–an umbrella term for products and practices that are not part of standard or allopathic medical care and may include acupuncture, yoga, and nutritional supplements, among others (mainstream psychological approaches like cognitive-behavioral therapy are generally not included under CAM [ ]. The use of CAM has gain popularity as menopause therapy over the past few decades [ ], because this approach may offer several benefits that make it an attractive option for many women, including this treatment may avoid the MHT-related long-term health risks, with peace of mind for women who are anxious about the potential AEs or risk of MHT; it can be tailored to an individual’s specific needs and pattern of symptoms, allowing for personalized treatment plans, recognizing that every woman’s experience of menopause transition is unique [ ]. There are many strategies of CAM reporting their potential and possible benefits to reduce the severity and frequency of VMS or improve mood and sleep, such as cognitive behavioral therapy, stellate ganglion blockade, trigger avoidance, cooling techniques, dietary modification, exercise, mindfulness-based interventions, acupuncture, electroacupuncture, yoga, traditional Chinese medicine (TCM) and some natural-like supplements (soy foods, S-equol, other soy extracts or derivatives, cannabinoids, herbal medical, as ashwagandha, evening primrose oil) [ ]. However, there is little consistent evidence regarding the efficacy or safety of LC and/or CAM, because of high possibility of methodological deficiencies, contributing to urgent warranting of larger RCTs to provide more conclusive evidence regarding the ratio of benefits and risks in VMS management [ , , , ]. Although it is doubtful for the positive impact of LC and CAM on VMS management, two strategies, such as weight loss and clinical hypnosis, a therapeutic technique that involves guiding individuals into a state of deep relaxation and increased focus, making individuals more receptive to suggestions and accessing their subconscious mind are included in the recommended choice by guidelines [ ].

Management of women with VMS by conventional nonhormone pharmacological agent therapy

Due to absence of evidence supporting the benefits/risks of CAM for VMS, nonhormone pharmacologic agents remain a valuable tool for VMS relief, based on the better understanding of pathophysiology of VMS in CNS level [ ]. These therapeutic agents include selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reupdate inhibitor (SNRIs) which have long been recognized for the therapeutic effects in depression and anxiety; gabapentinoids (GABA modulators, including gabapentin by typical doses of 900 mg daily and pregabalin by typical doses of 75–150 mg twice daily, considered the first-line treatments for the management of neuropathic pain), antimuscarinic agent (oxybutynin), alpha-2 adrenergic agonist (clonidine) and a newer class of medication known as neurokinin-receptor (NKR) antagonists [ , ]. Among the aforementioned non-hormone pharmacologic agents, the US Food and Drug Administration (FDA) only approved two classes for treating menopause-associated VMS, including a low dose 7.5 mg paroxetine salt and NKR antagonists [ ]. We should know that nonhormonal therapies, except paroxetine and NKR antagonists have been applied on off-labelled use, since nearly all of them are not indicated for VMS [ ].

Management of women with VMS by neurokinin-receptor (NKR) antagonists

As shown by our editorial comment published in the last year [ ], breakthroughs in women’s health seldomly occur; however, NKR antagonists may be one of the most landscapes for treating PMW with moderate-to-severe VMS [ ]. In 2012, Mittelman-Smith et al. provided unique evidence that KNDy neurons promote cutaneous vasodilatation and participate in the E2 modulation of body temperature and due to cutaneous vasodilatation as cardinal sign of a hot flush, supporting the hypothesis that KNDy neurons participate the generation of flushes and suggesting blocking the KNDy neuroendocrine pathway is associated with improved VMS [ , ]. The genome-wide associated studies (GWAS) showing the TACR3 (gene locus on chromosome 14) variation is closely correlated with VMS, and NKB receptor is coded by TACR3 gene [ ]. All data from bench to epidemiology support the critical role of KNDy neuroendocrine pathway participating thermoregulation, contributing to the new breakthrough to target this pathway as the therapy of choice in the management of women with VMS. Therefore, pharmacy companies developed many compounds that target the NK3R, including fezolinetant, MLE4901 (AZD4901, pavinetant, which is terminated in the phase 2 study for VMS, NTC02668181), MT-8554 (Elismetrep), and Q-122, and clinical treatments for VMSs by blocking NK3R appears to be a highly specific intervention and has led to some promising initial findings [ , ]. Additionally, a selective NK1,3R antagonist (BAY-3427080 GSK-1144814, NT-814, elinzanetant) for the treatment of moderate-to-severe VMS, containing two RCTs (OASIS 1 [NCT05052362] and OASIS 2 [NCT05099159], which are “A Study to Learn More About How Well Elinzanetant Works and How Safe it is for the Treatment of Vasomotor Symptoms (Hot Flashes) That Are Caused by Hormonal Changes Over 26 Weeks in Women Who Have Been Through the Menopause” was also well tolerated and efficacious for symptomatic women with moderate-to-severe VMS [ , ].

Since fezolinetant is the most studies compound to date, including the studies performed by Lederman et al., Johnson et al., and Neal-Perry et al., the results for fezolinetant and improvement of VMS are dramatically significant and exciting ( Fig. 3 ) [ ]. Therefore, the current review is only limited to introduce this product-fezolinetant. The positive safety and positive efficacy (significantly reduced the frequency and severity of moderate-to-severe VMS associated with menopause at W4 and W12, and maintaining effect throughout the active treatment extension period up to W52 in women from the US and Europe) in phase 3 RCTs (SKYLIGHT [Study to Find Out How Safe Long-Term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause] 1 [NCT04003155], SKYLIGHT 2 [NCT04003142] and SKYLIGHGT 4 [NCT04003389]) have been shown in detail in the next paragraph.

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