Introduction
Vasomotor symptoms (VMS)—hot flashes and night sweats—represent the most commonly reported manifestation of the menopausal transition, affecting 75–80% of women globally35. Despite their near-universal prevalence, VMS impose a highly variable burden, ranging from mild, transient episodes to severe, prolonged symptoms that profoundly disrupt sleep, mood, and quality of life. Current international and Chinese guidelines (2018–2026) establish evidence-based frameworks for VMS management, with hormone therapy (HT) remaining the most effective first-line treatment when appropriately timed and individualized123. However, contraindications, safety concerns, and patient preferences necessitate a robust understanding of alternative pharmacologic and nonpharmacologic strategies. This review synthesizes epidemiology, risk stratification, guideline-recommended treatments, contraindications, and practical clinical decision-making for managing menopausal VMS.
Epidemiology and Burden
Prevalence and Duration
VMS prevalence demonstrates substantial racial and ethnic variation. The Study of Women's Health Across the Nation (SWAN), a community-based survey of 16,065 women aged 40–55 years, documented that African-American women report the highest burden (adjusted prevalence odds ratio 1.17–1.63 compared to Caucasian women), while Japanese and Chinese women report substantially lower rates (OR 0.47–0.67)36. Population-based data confirm 80% of Black women experience VMS with a median duration of 10.1 years, compared to 65% of White women with 6.5 years median duration—a 4.6-year difference35. A nationally representative Australian study (AMY Study, n=8,096) using STRAW+10 staging found moderate-to-severe hot flushes increased dramatically from 8.8% in premenopausal women to 37.3% in late perimenopausal women (adjusted prevalence ratio 4.74)37.
Symptom duration averages 1–6 years but extends to 15 years in 10–15% of postmenopausal women35. This heterogeneity underscores the need for individualized, potentially long-term management strategies.
Impact on Sleep, Mood and Quality of Life
VMS profoundly disrupt nocturnal sleep: 62.6% of women report waking due to hot flashes at least twice nightly38. A prospective randomized trial documented that greater reduction in nocturnal hot flash frequency directly correlated with improvements in sleep quality (Pittsburgh Sleep Quality Index) and wakefulness after sleep onset (β = −1.88, P=.02)38. Psychogenic symptoms affect up to 70% of perimenopausal women, including irritability, anxiety, depression, and cognitive impairment35. Importantly, the Women's Health Initiative Calcium and Vitamin D trial (n=20,050) found that the number of concurrent moderate-to-severe menopausal symptoms (≥2) was associated with increased stroke risk (HR 1.40) and total cardiovascular disease (HR 1.35), suggesting polysymptomatic burden may serve as a cardiovascular risk marker11.
Risk Factors and Modifiers
Menopausal stage is the strongest predictor of VMS (OR 2.06–4.32 for peri- or postmenopausal status)36. Modifiable risk factors include elevated BMI (BMI ≥27 vs. 19–26.9 kg/m²: OR 1.15–2.18), current smoking (OR 1.21–1.78), and lower physical activity (OR 1.24–2.33)36. A 7-year prospective Australian cohort identified >10 pack-years of smoking, decreased estradiol levels, and higher symptom burden at early perimenopause as independent predictors of hot flush onset (P<.01 for each)41. Bilateral oophorectomy, particularly at younger ages, significantly increases VMS prevalence and severity39. Socioeconomic stress, quantified as difficulty paying for basics, also confers elevated risk (OR 1.15–2.05)36.
Guideline-Recommended Treatments
Hormone Therapy
Efficacy and Timing Hypothesis
The North American Menopause Society (NAMS) 2023 position statement and Endocrine Society 2015 guideline affirm that hormone therapy remains the most effective treatment for vasomotor symptoms23. Chinese primary care guidelines specify optimal timing as age 50–60 years or <10 years since final menstrual period, with patients beyond this window requiring specialist evaluation. The "timing hypothesis"—supported by the KEEPS and ELITE trials—indicates that HT may reduce cardiovascular disease and all-cause mortality when initiated early in the menopausal transition (age <60 or within 10 years of menopause)492326. Conversely, the Women's Health Initiative (WHI) estrogen-progestin trial (mean age 63 years, mean 5.2 years follow-up) documented increased risks when HT was initiated remote from menopause: coronary heart disease (HR 1.29, 95% CI 1.02–1.63), breast cancer (HR 1.26, 95% CI 1.00–1.59), stroke (HR 1.41, 95% CI 1.07–1.85), and pulmonary embolism (HR 2.13, 95% CI 1.39–3.25)44. Meta-analyses confirm particularly elevated venous thromboembolism (VTE) risk in the first year of use (RR 3.49, 95% CI 2.33–5.59)46.
Regimen Selection
Individualized regimens are essential: estrogen monotherapy for hysterectomized women; sequential or continuous combined estrogen-progestin for those with an intact uterus. NICE guideline NG23 (updated November 2024) recommends transdermal rather than oral HT for individuals at increased VTE risk, including those with BMI >30 kg/m²43. For genitourinary syndrome of menopause without systemic symptoms, vaginal estrogen provides local relief with minimal systemic absorption143.
Contraindications
Absolute contraindications include estrogen-dependent malignancies (breast, endometrial cancer), active or recent thromboembolic disease, untreated endometrial hyperplasia, unexplained vaginal bleeding, and severe hepatic or renal impairment. Relative contraindications (requiring caution and specialist consultation) include uterine fibroids, endometriosis, benign breast disease or family history of breast cancer, gallbladder disease, and migraine. NICE 2024 updated guidance now recommends individualized discussion and specialist evaluation for those with prior coronary heart disease or stroke, moving away from absolute contraindication43.
Nonhormonal Pharmacologic Options
SSRIs, SNRIs, and Gabapentinoids
NAMS 2023 identifies Level I evidence supporting selective serotonin reuptake inhibitors (SSRIs; paroxetine, citalopram, escitalopram), serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine, desvenlafaxine), and gabapentin for VMS management2. Meta-analysis of 19 RCTs (n=3,519) demonstrated gabapentin reduced hot flash frequency by 1.62 episodes/day at 4 weeks and 2.77 episodes/day at 12 weeks, with efficacy in both menopausal women and breast cancer patients10. However, gabapentin carries increased risk of dizziness (RR 4.45) and somnolence (RR 3.29)10. Cardiovascular safety reviews indicate SSRIs/SNRIs should be used cautiously in women with cardiac arrhythmias, atherosclerotic disease, or stroke history6.
Critical Drug Interaction: SSRIs and Tamoxifen
For breast cancer survivors receiving tamoxifen, CYP2D6-mediated drug interactions are clinically significant. Tamoxifen is converted to its active metabolite endoxifen primarily by CYP2D6; potent inhibitors paroxetine and fluoxetine reduce endoxifen formation50. The National Comprehensive Cancer Network (NCCN) recommends avoiding paroxetine and fluoxetine in patients on tamoxifen; the Clinical Pharmacogenetics Implementation Consortium (CPIC) suggests aromatase inhibitors as alternatives for CYP2D6 poor metabolizers50.
Neurokinin-3 Receptor Antagonists: Fezolinetant
Fezolinetant, a neurokinin-3 receptor (NK3R) antagonist, received FDA approval in 2023 as a nonhormonal option for moderate-to-severe VMS29. Phase 3 trials (SKYLIGHT 1 and 2) demonstrated robust efficacy: at week 12, fezolinetant 45 mg reduced VMS frequency by 2.53–2.55 episodes/day compared to placebo (P<.001) and severity by 0.20–0.29 units (P≤.007), with improvements evident from week 1 and sustained through 52 weeks5153. Pooled safety analysis of three phase 3 studies (n=3,155) documented asymptomatic transaminase elevations (ALT/AST >3× ULN) in 1.5–2.3% of fezolinetant-treated participants, with no cases meeting Hy's law criteria for severe drug-induced liver injury52. However, in December 2024, the FDA added a boxed warning for rare but serious liver injury3031, while the European Medicines Agency's Pharmacovigilance Risk Assessment Committee concluded in November 2024 that insufficient evidence supported a causal relationship33. Hepatic monitoring is now a critical safety requirement.
Behavioral and Complementary Approaches
NAMS 2023 assigns Level I evidence to cognitive-behavioral therapy (CBT) and clinical hypnosis for VMS reduction2. An Italian Sleep Medicine guideline noted CBT and aerobic exercise provide long-term benefits for postmenopausal insomnia9. In contrast, NAMS does not recommend paced respiration, supplements/herbal remedies, cooling techniques, yoga, mindfulness-based intervention, acupuncture, or soy extracts based on Levels I–II evidence2.
Chinese Medicine Approaches
Chinese menopause guidelines provide Level 1B evidence for Kuntai capsule (4 capsules three times daily for 3 months) and Linglianhhua granules (for insomnia-predominant symptoms), with safety profiles showing lower rates of abnormal bleeding and breast tenderness compared to HT.
Decision-making for Clinical Practice
Shared Decision-Making Framework
Guidelines uniformly emphasize individualized assessment integrating symptom severity (modified Kupperman score: ≤6 normal, 6–15 mild, 16–30 moderate, >30 severe), cardiovascular and breast cancer risk profiles, contraindications, and patient preferences. Validated screening tools—PHQ-9 for depression, GAD-7 for anxiety, MENQOL for quality of life—should be incorporated to assess psychogenic comorbidity requiring concurrent management.
Treatment Selection Algorithm
For women <60 years or <10 years postmenopause without contraindications:
- First-line: systemic HT (transdermal preferred if BMI >30 or VTE risk factors)
- Add menopause-specific CBT if desired or for residual symptoms
- Follow-up at 1, 3, 6, and 12 months, then annually.
For women with absolute HT contraindications (e.g., breast cancer survivors):
- Avoid paroxetine/fluoxetine if on tamoxifen; consider venlafaxine, desvenlafaxine, or gabapentin
- Fezolinetant 45 mg once daily (phase 3b trial demonstrated efficacy specifically in HT-ineligible populations54)
- Baseline and periodic liver enzyme monitoring for fezolinetant3052
For mild symptoms or patient preference against pharmacotherapy:
- Menopause-specific CBT or clinical hypnosis
- Lifestyle optimization: weight management, smoking cessation, regular physical activity
When to Refer
Referral to a menopause specialist is indicated for: history of CHD or stroke considering HT, uncertainty regarding HT contraindications, complex medical comorbidities, persistent symptoms despite first-line therapy, or abnormal uterine bleeding requiring evaluation43.
Unmet Needs and Research Gaps
Despite substantial progress, critical gaps remain. Long-term safety data (>5 years) for NK3R antagonists are limited, and the clinical significance of transaminase elevations and divergent regulatory interpretations (FDA boxed warning vs. EMA insufficient evidence) require ongoing surveillance303352. For the 10–15% of women with VMS persisting >15 years, evidence-based strategies remain inadequate35. Large epidemiological cohorts underrepresent non-White populations, limiting precision in risk stratification across diverse demographics. Finally, optimal management of VMS in breast cancer survivors balancing efficacy, oncologic safety, and drug interactions demands further investigation.
Conclusion
Menopausal VMS impose a substantial, heterogeneous burden necessitating individualized, evidence-based management. Hormone therapy remains the most effective first-line option when appropriately timed and in suitable candidates, while nonhormonal alternatives—including SSRIs/SNRIs, gabapentin, and the recently approved NK3R antagonist fezolinetant—provide efficacious options for those with contraindications or preferences against HT. Clinicians must integrate symptom severity, risk profiles, contraindications, and patient values through shared decision-making, with attention to drug interactions (particularly SSRI–tamoxifen) and emerging safety signals (fezolinetant hepatotoxicity). Ongoing research into long-term safety, persistent symptoms, and outcomes in diverse populations will continue to refine evidence-based VMS care.