Menopause, Perimenopause, Vasomotor Symptoms, Cardiovascular Disease Risk Factor, Menopausal Hormone Therapy, Cardiac Remodeling, Myocardial Fibrosis, Microvascular Dysfunction, Cognitive Function Assessment
Conditions
Brief summary
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
Interventions
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
DRUGStandard of care - non hormonal
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.
Sponsors
McGill University Health Centre/Research Institute of the McGill University Health Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women aged ≥ 45 years. * Perimenopausal or postmenopausal, defined as at least one of the following: * Perimenopause, defined as menstrual cycle irregularity (changes in cycle length, skipped cycles, or amenorrhea ≥ 60 days) accompanied by vasomotor symptoms consistent with the menopausal transition. * Postmenopause, defined as at least one of: * ≥ 12 months of spontaneous amenorrhea, or * bilateral oophorectomy, or * hysterectomy with FSH \> 40 IU/L when menstrual history is unavailable. * Vasomotor symptoms with a negative impact on quality of life, defined as : * Recurrent hot flashes (sudden sensations of heat, typically involving the face, neck, or chest, often associated with flushing and/or sweating), and/or * Night sweats (episodes of excessive sweating during sleep), With associated interference in daily functioning, sleep, or overall quality of life, such that the participant would be an appropriate candidate for systemic menopausal hormone therapy in clinical practice. * Presence of at least one cardiovascular risk factor, defined as either: * Hypertension (diagnosed hypertension, use of antihypertensive medication, or blood pressure ≥ 140/90 mmHg on screening). * Dyslipidemia (diagnosed dyslipidemia, use of lipid-lowering therapy, LDL ≥ 3.0 mmol/L, or total cholesterol ≥ 5.2 mmol/L). * Type 2 diabetes mellitus, defined as HbA1c ≥ 6.5%, fasting plasma glucose ≥ 7.0 mmol/L, or use of glucose-lowering medication. * Obesity (body mass index ≥ 30 kg/m²). * Current smoking. * First-degree family history of premature cardiovascular disease, defined as myocardial infarction, stroke, or documented coronary artery disease occurring before age 55 years in a male relative or before age 65 years in a female relative. * Eligible for systemic MHT (i.e., no formal contraindication to MHT). * Able and willing to undergo research CMR and attend the 12-month follow-up assessment. * Able to provide written informed consent. * Not currently using systemic MHT at baseline, or willing to discontinue systemic MHT prior to randomization and remain off systemic MHT until allocation and baseline assessments are complete.
Exclusion criteria
* Prior cardiovascular event or established cardiovascular disease, including myocardial infarction, stroke or TIA, coronary artery disease, heart failure, cardiomyopathy, or clinically significant valvular heart disease. * Uncontrolled hypertension or other unstable cardiovascular condition (e.g., unstable angina, decompensated heart failure, uncontrolled arrhythmia). * Formal contraindication to systemic menopausal hormone therapy, including estrogen-dependent cancer, unexplained vaginal bleeding, active severe liver disease, severe thrombophilia, antiphospholipid syndrome, prior or active VTE. * Standard contraindications to MRI (e.g., MRI-incompatible pacemakers or intracardiac devices, certain metallic implants, metallic foreign bodies in the eye, or severe claustrophobia not manageable). * Pregnant. * Active cancer on ongoing cardiotoxic chemotherapy. * Current use of systemic hormonal therapy outside the study strategy, including systemic menopausal hormone therapy, combined hormonal contraception, or systemic progestin-only contraception, with unwillingness or inability to discontinue prior to baseline and randomization. * Ten years or more since menopause, defined as ≥10 years from the final menstrual period or from bilateral oophorectomy * Participants currently using combined hormonal contraception or systemic progestin-only contraception who are willing to discontinue must complete a washout period of at least 4 weeks prior to the baseline visit and randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recruitment Rate | At enrollment | Proportion of eligible women approached who consent to randomization, Percentage (%) |
| 12-Month Retention Rate | 12 months | Proportion of randomized participants completing the 12-month follow-up visit, Percentage (%) |
| CMR Completion Rate | 12 months | Proportion of participants completing both baseline and 12-month CMR examinations, Percentage (%) |
| Crossover Rate | 12 months | Proportion of participants in the no-MHT group who initiate systemic MHT during follow-up, Percentage (%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial oxygenation reserve | Baseline and 12 months | Percent change in myocardial signal intensity (ΔSI%) during breath-hold at 30 seconds relative to rest, assessed by OS-CMR (B-MORE) |
| Aortic distensibility | Baseline and 12 months | assessed by CMR, mmHg-¹ |
| Aortic cross-sectional area | Baseline and 12 months | assessed by CMR, cm² |
| Left ventricular ejection fraction (LVEF) | Baseline and 12 months | Assessed by CMR, Percentage (%) |
| Left ventricular end-diastolic volume (LVEDV) | Baseline and 12 months | Assessed by CMR, mL |
| Left ventricular end-systolic volume (LVESV) | Baseline and 12 months | Assessed by CMR, mL |
| Left ventricular mass (LVM) | Baseline and 12 months | Assessed by CMR, grams (g) |
| LV mass-to-volume ratio (concentricity) | Baseline and 12 months | Assessed by CMR, g/mL |
| Global longitudinal strain (GLS) | Baseline and 12 months | Assessed by CMR, Percentage (%) |
| Superficial retinal capillary plexus vessel density | Baseline and 12 months | Assessed by OCT-A, Percentage (%) |
| Deep retinal capillary plexus vessel density | Baseline and 12 months | Assessed by OCT-A, Percentage (%) |
| Foveal avascular zone (FAZ) area | Baseline and 12 months | Assessed by OCT-A, mm2 |
| FAZ perimeter | Baseline and 12 months | Assessed by OCT-A, mm |
| PROMIS Cognitive Function Short Form 8a score | Baseline and 12 months | Patient-reported cognitive function; scores range 8-40, higher scores indicate better cognitive function |
| RBANS Total Scale Score | Baseline and 12 months | Objective neuropsychological assessment of global cognitive function; standardized score (mean 100, SD 15), higher scores indicate better performance |
| Global native myocardial T1 according to vasomotor symptom burden | Baseline | Baseline native T1 (ms) assessed by CMR, compared between women with high vs. low vasomotor symptom burden at baseline, defined by HFRDIS score |
| LVEF according to vasomotor symptom burden | Baseline | Baseline LVEF assessed by CMR, compared between women with high vs. low vasomotor symptom burden at baseline, defined by HFRDIS score, Percentage (%) |
| Multivariable regression analysis of baseline predictors of 12-month change in global native myocardial T1 | Baseline and 12 months | 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. |
Contacts
CONTACTAmytis HEIM, MD
Outcome results
None listed