Menopause, retrospectively defined after 12 consecutive months of amenorrhoea, occurs on average at the age of 51 and represents the end of a woman’s reproductive life
Among the most prevalent clinical manifestations are vasomotor symptoms (VMSs), characterized by hot flashes (sudden heat waves) and night sweats
In addition to physical discomfort, VMSs are associated with reduced quality of life, sleep disturbances, irritability, fatigue, subjective cognitive decline, and even increased cardiovascular risk, especially in women who develop early and intense symptoms
The clinical management of these symptoms remains one of the main challenges in women’s health care during the climacteric period. Hormone therapy (HT), when not contraindicated, is considered the most effective treatment, providing up to a 75% reduction in frequency and an 87% in intensity of hot flashes
Over the past two decades, there has been increasing interest in safe and effective non-hormonal strategies. Among them are well-established pharmacological agents such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and clonidine
In parallel, complementary therapies and lifestyle modifications have also been investigated, such as weight loss, cognitive behavioral therapy (CBT), hypnosis, physical exercise, and acupuncture, although with varying levels of evidence
This narrative review aims to compile and critically discuss current evidence regarding the pathophysiology, clinical impact, and treatment strategies for VMS, with an emphasis on emerging non-hormonal approaches.
This is a narrative literature review designed to synthesize and critically discuss the main available evidence on menopause and vasomotor symptoms (VMSs).
The literature search was conducted between June and August 2025 in electronic databases such as PubMed/MEDLINE, SciELO, Embase, and Cochrane Library. The following keywords were used in both Portuguese and English: menopausa, climatério, vasomotor symptoms, hot flashes, night sweats, hormone therapy, non-hormonal therapy, NK3 receptor antagonist, fezolinetant, and cognitive behavioral therapy.
A qualitative analysis of the selected articles was performed, extracting the most relevant data related to the pathophysiology, prevalence, impact on quality of life, therapeutic indications, and adverse effects of different treatment modalities.
This methodology allowed the construction of a broad, updated, and critical overview of the topic, aiming to support evidence-based clinical practice and shared decision-making between healthcare professionals and patients.
Vasomotor symptoms (VMSs) are the most characteristic clinical manifestation of the menopausal transition. Although widely described, their pathophysiology is not yet fully understood.
The decline in estradiol levels is considered the main trigger for the development of hot flashes. Estrogen plays a crucial role in modulating hypothalamic thermoregulation, acting on neurons in the preoptic nucleus of the hypothalamus
Recent studies highlight the importance of KNDy neurons (kisspeptin, neurokinin B, and dynorphin), located in the arcuate nucleus of the hypothalamus
Estrogen reduction leads to hyperactivity of KNDy neurons, with increased release of neurokinin B (NKB), which acts on NK3 receptors in the medial preoptic nucleus. This overstimulation promotes central thermoregulatory dysregulation, triggering VMS
The reduction of estrogen levels during menopause leads to hyperactivity of KNDy neurons, resulting in increased release of neurokinin B (NKB). NKB acts on NK3 receptors located in the medial preoptic nucleus, a region crucial for body temperature regulation. This overstimulation causes dysregulation of the thermoregulatory center, which manifests in peripheral responses characteristic of hot flashes, such as cutaneous vasodilation, increased sweating, and a sudden sensation of heat.
Recognition of this pathophysiological mechanism has supported the development of NK3 receptor antagonists, such as fezolinetant, which has demonstrated robust clinical efficacy in reducing hot flashes in phase III clinical trials
Evidence suggests that hypoestrogenism is also associated with increased sympathetic activation and altered cutaneous blood flow
Several factors influence the frequency and intensity of symptoms, including:
Hormone therapy (HT) remains the gold standard for the treatment of menopausal vasomotor symptoms (VMSs). Several randomized trials and systematic reviews demonstrate its superior efficacy compared to any other available therapeutic modality
HT involves the administration of estrogen alone (in hysterectomized women) or in combination with a progestogen (in women with an intact uterus) to partially replace the hormonal deficiency characteristic of menopause
This mechanism results in a rapid decrease in the frequency and intensity of hot flashes, which is often observed within the first 2 to 4 weeks of treatment
HT should not be used in patients with:
The Women’s Health Initiative (WHI) study, published in 2002, raised concerns about increased cardiovascular and breast cancer risks associated with hormone therapy (HT), leading to a significant global decline in its prescription
However, subsequent analyses have shown that:
Therefore, the current consensus is that the window of opportunity is associated with greater benefit and lower risk
The regimen should be individualized, considering the risk profile, patient preferences, and therapeutic availability.
The search for alternatives to hormone therapy (HT) stems from the presence of absolute or relative contraindications in some women, as well as the refusal of certain patients to use hormones. In such cases, non-hormonal therapies play a crucial role.
They can be classified into:
1) Established non-hormonal drugs: Antidepressants, gabapentin, clonidine;
2) New pharmacological agents: Neurokinin-3 receptor (NK3R) antagonists, notably fezolinetant;
3) Herbal and complementary therapies.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most studied non-hormonal drugs for VMS.
Mechanism: They modulate serotonergic and noradrenergic circuits involved in hypothalamic thermoregulation
Efficacy: They reduce hot flash frequency by 40–65%; less effective than HT but superior to placebo
Main options:
Adverse effects: Nausea, dry mouth, sexual dysfunction, and insomnia
Mechanism: Modulates voltage-gated calcium channels, reducing neuronal excitability
Efficacy: Reduces hot flash frequency by 45% - 60%, especially effective in women with nighttime symptoms and sleep disturbances
Advantages: Useful in patients with contraindications to HRT and with predominantly nocturnal symptoms.
Adverse effects: Dizziness, drowsiness, fatigue, and peripheral edema
Adverse effects: Dry mouth, constipation, drowsiness, and hypotension
In recent years, a new class of drugs targeting the pathophysiological mechanism of VMS has emerged: neurokinin-3 receptor (NK3R) antagonists.
Interest in natural products remains high, though the evidence is inconsistent.
Therapeutic Class |
Average VMS Reduction |
Onset Time |
Main Side Effects |
SSRIs/SNRIs |
40% - 65% |
1 - 2 weeks |
Nausea, dry mouth, insomnia, sexual dysfunction |
Gabapentin |
45% - 60% |
1 – 2 weeks |
Drowsiness, dizziness, fatigue |
Clonidine |
20% - 40% |
2% - 4% weeks |
Hypotension, dry mouth, sedation |
Fezolinetant (NK3R ant.) |
50% - 70% |
<4 weeks |
Headache, insomnia, mild liver enzyme elevation |
Herbal Therapies |
10% - 30% (variable) |
4% - 8% weeks |
Hepatotoxicity (black cohosh), mild gastrointestinal effects |
Although pharmacological therapies—both hormonal and non-hormonal—are the most effective for managing vasomotor symptoms (VMSs), non-pharmacological interventions play an important complementary role, especially for women with contraindications to medications or those who prefer natural approaches.
Observational studies have shown an association between high body mass index (BMI) and increased frequency and intensity of hot flashes
Regular physical activity:
CBT is one of the most well-studied behavioral interventions for VMS.
Clinical hypnosis has been evaluated in controlled trials for VMS.
Acupuncture is widely used, though evidence remains controversial.
Nighttime VMS contributes to insomnia and daytime fatigue.
Health education programs for menopausal women and support groups help reduce anxiety and the stigma associated with menopause.
Therapeutic options for managing vasomotor symptoms (VMSs) vary widely in terms of efficacy, safety profiles, availability, and cost.
Hormone Therapy (HT): Remains the most effective treatment, reducing VMS by 70% - 90%. It has a rapid onset (1% - 2% weeks) and significantly improves quality of life. Limitation: increased risks in some populations (e.g., breast cancer, thromboembolic events, cardiovascular disease).
VMS treatment is evolving, driven by the need for effective and safe options for women who cannot or do not wish to use hormones.
NK3 Receptor Antagonists: These drugs act by blocking neurokinin 3 (NK3) receptors in hypothalamic KNDy neurons, which play a central role in body temperature regulation. Fezolinetant, currently approved by the FDA, has been shown to significantly reduce the frequency and severity of hot flashes in menopausal women. Other NK3 antagonists under investigation, such as elinzanetant and pavinetant, demonstrate promising clinical efficacy and may expand non-hormonal therapeutic options, particularly for women with contraindications to hormone therapy.
Endocannabinoid System Modulation: Emerging research suggests that the endocannabinoid system—involved in regulating physiological processes such as sleep, mood, and thermoregulation—could be a valuable target for managing hot flashes. Compounds modulating CB1 and CB2 receptors may stabilize hypothalamic thermoregulatory centers, reducing the intensity and frequency of vasomotor responses. However, most studies are still in preclinical or early clinical stages.
Digital Neurotherapies: Wearable technologies and AI-based digital platforms are being developed to monitor real-time physiological signals, including heart rate, body temperature fluctuations, and sleep patterns. Based on these data, personalized interventions such as biofeedback exercises, relaxation techniques, and behavioral adjustments can be applied to modulate autonomic responses associated with hot flashes and improve quality of life. This represents an innovative, non-pharmacological approach with potential for integration with conventional treatments.
Vasomotor symptoms (VMSs) represent the most prevalent and impactful clinical manifestation of the menopausal transition, significantly impairing women’s quality of life. Their pathophysiology is closely related to estrogen deficiency and instability of the hypothalamic thermoneutral zone, modulated by neurotransmitters such as norepinephrine, serotonin, and neurokinins.
Hormone therapy (HT) remains the most effective treatment option, promoting reductions of up to 90% in VMS. However, its use must be carefully individualized, taking into account factors such as age, time since menopause, and contraindications.
Non-hormonal therapies, including SSRIs/SNRIs, gabapentin, clonidine, and more recently, fezolinetant, expand the therapeutic arsenal and are essential for women who cannot or do not wish to use hormones.
Behavioral interventions—such as cognitive-behavioral therapy, hypnosis, and lifestyle changes—play an important adjunctive role, especially in subjective improvement and quality of life, although their efficacy in objectively reducing hot flashes is limited.
From a practical standpoint, the management of VMS should be individualized, evidence-based, and multidisciplinary, combining pharmacological and non-pharmacological strategies according to the clinical profile, preferences, and expectations of the patient.
On the horizon, the arrival of neurokinin-3 receptor (NK3) antagonists and the advancement of personalized medicine promise to inaugurate a new era in menopause treatment, with greater efficacy, safety, and individualized profiles.
The ideal management of vasomotor symptoms should be multidisciplinary and evidence-based, incorporating the shared decision-making model, which values the patient’s preferences and expectations and promotes safer and more appropriate therapeutic choices. Advances such as NK3 receptor antagonists and personalized medicine promise to further enhance treatment efficacy and safety, reaffirming that woman-centered care is key to preserving well-being, mental health, and quality of life during the climacteric and postmenopause.
Thus, understanding and appropriately managing VMS is essential not only to relieve symptoms but also to promote overall well-being, mental health, and quality of life for women in the climacteric and postmenopausal phases.