The goal of this clinical trial is to learn whether it is feasible to conduct a larger study comparing transdermal menopausal hormone therapy (MHT) versus no hormone therapy in menopausal women with vasomotor symptoms (hot flashes and night sweats) and at least one cardiovascular risk factor. The main questions it aims to answer are: * What proportion of eligible women agree to be randomly assigned to either receive MHT or not? * How many participants complete the 12-month follow-up, including repeat heart imaging? * Does transdermal MHT affect early changes in heart muscle tissue as measured by cardiac MRI? Researchers will compare immediate initiation of transdermal estradiol (a skin gel or patch) to a no-hormone therapy strategy to see if MHT influences early cardiovascular and brain-vascular changes over 12 months. Participants will: * Be randomly assigned to start transdermal MHT within 2 weeks, or to use no hormone therapy for at least the first 3 months * Undergo a cardiac MRI and retinal eye imaging at the start of the study and again at 12 months * Complete cognitive testing and questionnaires about symptoms, sleep, and stress at both visits * Provide a blood sample for storage and future analysis of heart and brain health markers * Receive follow-up phone calls at 3, 6, and 9 months to review symptoms, medications, and any health changes
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
100
Participants randomized to this arm will initiate systemic transdermal estradiol within 2 weeks of the baseline visit. The specific formulation and dose will be selected through shared decision-making between the participant and her physician based on individual clinical factors, tolerability, and patient preference. Permitted formulations include: Estrogel® (0.06% estradiol gel): 1 pump (0.75 mg) to 2 pumps (1.5 mg) applied daily Divigel® (0.1% estradiol gel): 1.0 mg sachet applied once daily Estradot® (estradiol patch): 25, 37.5, or 50 mcg, changed twice weekly Climara® (estradiol patch): 25, 37.5, or 50 mcg, changed once weekly Participants with a uterus will receive endometrial protection. First-line therapy is micronized progesterone (Prometrium® 100 mg orally once daily, continuous regimen). Alternative progestogens (medroxyprogesterone acetate 2.5 mg orally once daily or a levonorgestrel-releasing intrauterine device) may be used if clinically indicated or not tolerated. Dose ad
Participants randomized to this arm will not initiate systemic menopausal hormone therapy for at least the first 3 months following randomization. Non-hormonal management of vasomotor symptoms is permitted at the discretion of the treating physician, and may include lifestyle interventions, supplements, and/or guideline-recommended non-hormonal pharmacologic therapies such as SSRIs/SNRIs, gabapentin, oxybutynin, or fezolinetant. If participants experience persistent or intolerable vasomotor symptoms despite non-hormonal management, initiation of systemic MHT may be proposed after 3 months based on shared decision-making between the participant and her treating physician. All crossovers will be documented including timing, reason, and regimen. Participants will remain analyzed in their originally assigned group for intention-to-treat analyses.
Recruitment Rate
Proportion of eligible women approached who consent to randomization, Percentage (%)
Time frame: At enrollment
12-Month Retention Rate
Proportion of randomized participants completing the 12-month follow-up visit, Percentage (%)
Time frame: 12 months
CMR Completion Rate
Proportion of participants completing both baseline and 12-month CMR examinations, Percentage (%)
Time frame: 12 months
Crossover Rate
Proportion of participants in the no-MHT group who initiate systemic MHT during follow-up, Percentage (%)
Time frame: 12 months
Myocardial oxygenation reserve
Percent change in myocardial signal intensity (ΔSI%) during breath-hold at 30 seconds relative to rest, assessed by OS-CMR (B-MORE)
Time frame: Baseline and 12 months
Aortic distensibility
assessed by CMR, mmHg-¹
Time frame: Baseline and 12 months
Aortic cross-sectional area
assessed by CMR, cm²
Time frame: Baseline and 12 months
Left ventricular ejection fraction (LVEF)
Assessed by CMR, Percentage (%)
Time frame: Baseline and 12 months
Left ventricular end-diastolic volume (LVEDV)
Assessed by CMR, mL
Time frame: Baseline and 12 months
Left ventricular end-systolic volume (LVESV)
Assessed by CMR, mL
Time frame: Baseline and 12 months
Left ventricular mass (LVM)
Assessed by CMR, grams (g)
Time frame: Baseline and 12 months
LV mass-to-volume ratio (concentricity)
Assessed by CMR, g/mL
Time frame: Baseline and 12 months
Global longitudinal strain (GLS)
Assessed by CMR, Percentage (%)
Time frame: Baseline and 12 months
Superficial retinal capillary plexus vessel density
Assessed by OCT-A, Percentage (%)
Time frame: Baseline and 12 months
Deep retinal capillary plexus vessel density
Assessed by OCT-A, Percentage (%)
Time frame: Baseline and 12 months
Foveal avascular zone (FAZ) area
Assessed by OCT-A, mm2
Time frame: Baseline and 12 months
FAZ perimeter
Assessed by OCT-A, mm
Time frame: Baseline and 12 months
PROMIS Cognitive Function Short Form 8a score
Patient-reported cognitive function; scores range 8-40, higher scores indicate better cognitive function
Time frame: Baseline and 12 months
RBANS Total Scale Score
Objective neuropsychological assessment of global cognitive function; standardized score (mean 100, SD 15), higher scores indicate better performance
Time frame: Baseline and 12 months
Global native myocardial T1 according to vasomotor symptom burden
Baseline native T1 (ms) assessed by CMR, compared between women with high vs. low vasomotor symptom burden at baseline, defined by HFRDIS score
Time frame: Baseline
LVEF according to vasomotor symptom burden
Baseline LVEF assessed by CMR, compared between women with high vs. low vasomotor symptom burden at baseline, defined by HFRDIS score, Percentage (%)
Time frame: Baseline
Multivariable regression analysis of baseline predictors of 12-month change in global native myocardial T1
Exploratory multivariable linear regression will be used to identify associations between baseline clinical, lifestyle, and menopause-related factors (including age, BMI, blood pressure, lipid levels, smoking status, time since menopause, and vasomotor symptom burden) and 12-month change in global native myocardial T1 assessed by CMR. This analysis aims to identify candidate predictors for future cardiovascular risk stratification. The dependent variable is change in global native T1 (ms) from baseline to 12 months.
Time frame: Baseline and 12 months
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