Vasomotor symptoms (VMS), which include hot flashes and night sweats, affect approximately 75% of menopausal women and persist between 7–10 years in many individuals. These symptoms contribute to problems with both sleep and cognition.
Genitourinary syndrome of menopause (GSM), encompassing vaginal dryness, dyspareunia, and urinary symptoms, demonstrates chronic and progressive characteristics without treatment intervention. Menopausal hormone therapy (MHT) is the most effective therapy for VMS and serves as a core therapy for GSM.
The basis of menopausal symptoms stems from declining ovarian function and subsequent estrogen deficiency. This deficiency affects the body in many areas, including: the brain’s hypothalamic thermoregulatory center, urogenital tissue, bone, and cardiovascular function.
A review was conducted to synthesize evidence from prior randomized control trials, long-term follow up and observational studies between 2015-2025.
Evidence: Symptom Control
Vasomotor Symptom Management
Systemic estrogen therapy (with appropriate endometrial protection) maintains its position as the most effective treatment for VMS, superior to non-hormonal pharmacological intervention. Both transdermal and oral estradiol formulations demonstrate efficacy; however, transdermal administration may be preferentially selected for individuals with specific higher-risk profiles.
VMS pathophysiology involves interactions between declining estrogen levels and hypothalamic thermoregulatory dysfunction, with recent evidence suggesting roles for neurokinin B signaling and kisspeptin pathways. This mechanistic understanding has informed the development of targeted nonhormonal therapies, while reinforcing the central role of estrogen replacement in symptom management.
Genitourinary Syndrome of Menopause Management
Low-dose vaginal estrogen preparations, available as creams, tablets, or ring formulations, along with intravaginal DHEA, effectively ameliorate vaginal dryness and dyspareunia with minimal systemic absorption. Symptom relief demonstrates durability with continued use, and observational data from the Nurses’ Health Study indicates no increase in cardiovascular disease or cancer incidence with utilization of vaginal estrogen.
Application of vaginal estrogen directly addresses urogenital atrophy through restoration of vaginal epithelial thickness, increased blood flow, enhanced lubrication, and normalization of vaginal pH. These improvements translate to meaningful benefits, including reduced pain with sexual activity, improved urinary symptoms, and decreased risk for recurrent UTI.
Quality of Life (QOL), Sleep, and Sexual Function
Randomized controlled trials evaluating estrogen formulations, specifically conjugated estrogens combined with bazedoxifene (CE/BZA), demonstrate significant improvements in VMS, sleep quality, and menopause-specific QOL metrics while maintaining endometrial safety profiles. This combination offers an alternative to traditional pro-estrogen supplementation in women with intact uteri, though long-term fracture prevention outcomes require further study.
Bone Health Considerations
MHT effectively prevents bone loss and reduces fracture risk during active treatment. This option merits consideration for fracture prevention in symptomatic women presenting with elevated fracture risk, requiring careful balance against potential systemic risks and consideration of non-estrogen osteoporosis therapies, including bisphosphonates, denosumab, and selective estrogen receptor modulators.
Evidence: Safety
Breast Cancer Risk Assessment
Twenty years of cumulative follow-up data, from the Women’s Health Initiative (WHI) trials, reveals distinct patterns based on hormone formulation. Conjugated equine estrogen (CEE) monotherapy following hysterectomy demonstrates association with reduced breast cancer incidence and mortality compared to placebo. Conversely, combined CEE plus medroxyprogesterone acetate (MPA) therapy results in increased breast cancer incidence, though mortality remains neutral. These findings position regimen selection as central to individualized risk counseling.
Observational data, including the 2019 Collaborative Group analysis, indicates that breast cancer risk varies according to MHT type and duration of use. Risk incrementally increases with extended duration of therapy and generally demonstrates higher magnitude with combined estrogen-progestin formulations compared to estrogen monotherapy. Micronized progesterone may confer lower relative risk compared to certain synthetic progestins, though high-quality randomized data supporting this observation remains limited.
Mortality Outcomes
Analysis across pooled WHI trials demonstrates that 5–7 years of MHT administration was not associated with increased all-cause or cause-specific mortality over approximately 18 years of cumulative follow-up. Notably, women aged 50–59 years demonstrated more favorable mortality ratios during the active intervention phase, supporting the concept of a critical window for hormone therapy initiation.
Venous Thromboembolism, Stroke, and Cardiovascular Considerations
Oral estrogen administration increases venous thromboembolism (VTE) risk through first-pass hepatic metabolism effect on coagulation factors. Large, nested case-control studies demonstrate lower VTE risk with transdermal estradiol, supporting route selection strategies to mitigate thrombotic risk. Stroke risk appears both dose-dependent and route-related; therefore, clinicians should utilize the lowest effective estrogen dose and consider transdermal administration in women presenting with higher baseline risk profiles.
Contemporary guidelines achieve consensus that MHT should not be employed for primary prevention of chronic disease including cardiovascular disease and cognitive decline. Treatment indication remains focused on symptom relief and short-term bone protection, with cardiovascular risk modification addressed through established preventive strategies including lifestyle interventions and appropriate pharmacotherapy.
Cognition and Dementia Risk
The WHI Memory Study demonstrated that initiating combined MHT after age 65 years or greater increased dementia risk. Consequently, MHT lacks indication for cognitive decline prevention. Current evidence supports neither neuroprotective benefits nor routine use for cognitive enhancement in the menopausal transition.
Endometrial Protection Requirements
Women with intact uteri require adequate endometrial protection through continuous micronized progesterone, cyclic progestogen regimens, or tissue-selective alternatives such as CE/BZA. Any unscheduled bleeding patterns warrant prompt evaluation to exclude endometrial pathology.
Gallbladder, Lipid, and Hepatic Considerations
Oral estrogen administration increases gallbladder disease risk and elevates triglyceride levels through hepatic first-pass effects. Transdermal routes effectively mitigate both risks. Active liver disease represents an absolute contraindication to systemic MHT.
Evidence: Nonhormonal Therapeutic Options
Neurokinin 3 Receptor Antagonist Therapy
Two phase 3 randomized controlled trials, SKYLIGHT 1 and SKYLIGHT 2, demonstrated that fezolinetant 45 mg once daily significantly reduced VMS frequency and severity with early onset of therapeutic action. However, in 2024, the FDA added a black box warning for serious liver injury and mandated liver function monitoring protocols. Clinicians must follow label specifications for baseline and ongoing monitoring recommendations and discontinue therapy upon signs of hepatotoxicity.
Additional Nonhormonal Interventions
SSRIs/SNRIs, gabapentin, oxybutynin, and cognitive behavioral therapy with hypnosis provide modest VMS relief and prove useful when MHT is declined or contraindicated, or as adjunctive therapies for sleep and mood symptoms. Treatment selection should be individualized according to comorbidities, such as SSRI/SNRI selection for coexisting depression or anxiety, or gabapentin for predominant nocturnal symptoms. Guideline summaries from NAMS and NICE endorse these approaches within shared decision-making frameworks.
Genitourinary Syndrome Management Without Systemic MHT
Low-dose vaginal estrogen, intravaginal DHEA, or nonhormonal moisturizers and lubricants improve genitourinary symptoms. In women with histories of estrogen-dependent breast cancer, ACOG supports consideration of low-dose vaginal estrogen following shared decision-making with oncology teams when nonhormonal measures prove insufficient.
Evidence: Special Populations
Premature Ovarian Insufficiency
Multiple professional societies, including the American College of Obstetricians and Gynecologists (ACOG) and the European Society of Human Reproduction and Embryology (ESHRE) recommend systemic hormone therapy, or combined hormonal contraception when pregnancy prevention is desired, until typical age of natural menopause (approximately 50–51 years), absent contraindication. This approach mitigates bone and cardiometabolic risks while improving QOL.
Higher Cardiometabolic Risk or Prior VTE
Management strategies should prioritize transdermal estradiol, avoid high oral doses, optimize nonhormonal risk reduction including blood pressure control, LDL cholesterol management, weight optimization, and physical activity enhancement. Shared decision-making processes should address whether anticipated benefits justify residual risks.
Post-Hysterectomy Management
Estrogen monotherapy regimens, including transdermal or oral estradiol and CEE formulations, avoid progestogen exposure. In WHI analyses, these regimens demonstrated association with favorable long-term breast cancer outcomes.
Practical Guideline-Concordant Clinical Approach
Systematic Clinical Algorithm
Step 1: Confirm indications and establish treatment goals. Document VMS and GSM burden with validated assessment tools (Menopausal Vasomotor Symptoms survey and the Female Sexual Function Index, respectively) and quality of life impact measurements. Thoroughly review contraindications including active or prior estrogen-sensitive cancer without oncology consultation, unexplained vaginal bleeding, prior VTE/stroke/MI where risk exceeds benefit, and active liver disease.
Step 2: Select appropriate route and regimen. Preferentially consider transdermal estradiol for women with VTE risk factors, hypertriglyceridemia, migraines with aura, or gallbladder disease risk. For women with intact uteri, add endometrial protection through continuous micronized progesterone, cyclic progestogen, levonorgestrel intrauterine system, or consider CE/BZA as a tissue-selective alternative.
Step 3: Initiate therapy with dose titration. Begin with low doses and titrate to achieve symptom control. Re-evaluate treatment response at 3 months and conduct assessments at least annually thereafter.
Step 4: Provide comprehensive risk-benefit counseling. Discuss breast cancer data stratified by regimen, VTE and stroke mitigation through route selection, and available nonhormonal alternatives. Align treatment plans with individual patient priorities and values.
Step 5: Implement monitoring protocols. Track symptom scores using validated instruments, monitor blood pressure and weight, document adverse effects, investigate any unscheduled bleeding, and follow liver monitoring requirements for patients receiving fezolinetant.
Step 6: Establish duration and discontinuation strategies. No mandatory cessation date exists; consider tapering when symptoms resolve or risk profiles change. For GSM management, local therapy may continue long-term at the lowest effective dose.
Future Research Directions
Critical knowledge gaps require head-to-head trials comparing transdermal estradiol plus micronized progesterone versus CE/BZA regarding breast, thrombotic, and cardiometabolic outcomes. Long-term safety data for nonhormonal neurokinin 3 receptor antagonists remain essential. Implementation studies should address the disparity in access to MHT and evidence-based nonhormonal care while refining individualized risk prediction models, integrating: genetic markers, advanced imaging modalities, and metabolomic profiles.
Development of precision medicine approaches incorporating pharmacogenomics may optimize hormone therapy selection and dosing while minimizing adverse effects. Additionally, investigation of novel selective estrogen receptor modulators and tissue-selective hormone formulations holds promise for expanding therapeutic options with improved safety profiles.
Conclusions
For appropriately selected symptomatic women, contemporary MHT, particularly when initiated within 10 years of the final menstrual period and individualized for risk using transdermal routes and physiologic progesterone formulations, offers substantial and often transformative quality of life benefits with favorable benefit-risk profiles. Nonhormonal therapies meaningfully expand treatment options for women with contraindications or preferences against hormone therapy. The clinical imperative involves precise, guideline-concordant, and patient-centered implementation of evidence-based menopause management strategies.