Hormone thERapy Effects on BRAin-HEART Health During the Menopausal Transition

Official title

HER BRAVE HEART Trial - Hormone thERapy Effects on BRAin-HEART Health During the Menopausal Transition: A Randomized Feasibility Study

Overview

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

• Drug Transdermal estradiol
  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
• Drug Standard 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 symp

Primary outcome measures

• Recruitment Rate [Time frame: At enrollment]
• 12-Month Retention Rate [Time frame: 12 months]
• CMR Completion Rate [Time frame: 12 months]
• Crossover Rate [Time frame: 12 months]

Secondary outcome measures (12)

• Myocardial oxygenation reserve [Time frame: Baseline and 12 months]
• Aortic distensibility [Time frame: Baseline and 12 months]
• Aortic cross-sectional area [Time frame: Baseline and 12 months]
• Left ventricular ejection fraction (LVEF) [Time frame: Baseline and 12 months]
• Left ventricular end-diastolic volume (LVEDV) [Time frame: Baseline and 12 months]
• Left ventricular end-systolic volume (LVESV) [Time frame: Baseline and 12 months]
• Left ventricular mass (LVM) [Time frame: Baseline and 12 months]
• LV mass-to-volume ratio (concentricity) [Time frame: Baseline and 12 months]
• Global longitudinal strain (GLS) [Time frame: Baseline and 12 months]
• Superficial retinal capillary plexus vessel density [Time frame: Baseline and 12 months]
• Deep retinal capillary plexus vessel density [Time frame: Baseline and 12 months]
• Foveal avascular zone (FAZ) area [Time frame: Baseline and 12 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07732452 · MP-37-2026-12489

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗