Perimenopausal Estrogen Replacement Therapy Study

Study Overview
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Brief Summary
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Study Background and Objectives: In the U.S. the majority of heart disease deaths are in women, not men. Much of the gender disparity in CVD rates relate to the burden of CV risk in women after the menopause. Depression has been associated with an increased risk for CVD morbidity and mortality. Even histories of recurrent depression in euthymic individuals are associated with elevated CV risk. Understanding the depression-CVD link may have particular relevance for women since women experience depression at a rate twice that of men. Substantial convergent evidence indicates that ovarian failure (estrogen deprivation) is one likely mechanism contributing to both CVD and depression in women. The perimenopause, a time associated with a two-fold increase in rates of depression, may provide an ideal opportunity for studying the pathophysiology of CV risk and depression in women. The primary objective of this study is to examine the prophylactic role of estradiol in the development of depressive symptoms and the progression of cardiovascular risk in perimenopausal women with or without histories of depression. The investigators predict that women susceptible to depression will be particularly vulnerable to the acceleration of CVD in the context of the perimenopause and, consequently, will show differentially greater benefit of estradiol treatment during the menopause transition for both indices of CV risk (e.g. inflammation, endothelial function, stress reactivity), as well as depressive symptoms.

Official Title
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Depression, Estrogen Replacement, and Cardiovascular Health in the Perimenopause

Conditions
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Menopause, Perimenopause, Depression

Intervention / Treatment
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* Drug: Estradiol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: must be between 45 and 60 years of age must be in the menopause transition (irregular/ absent menstrual cycles or hot flashes) must be are medically healthy Exclusion Criteria: - currently taking antidepressant medication

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo patches for 12 months and placebo pills for 12 days every 2 months. | Drug: Placebo<br>* Placebo patches for 12 months, to be worn continuously and replaced once a week. Also, placebo pills will be administered for 12 days every 2 months.<br>|
| Experimental: Estradiol<br>Transdermal 17β-estradiol (100 ug/day) for 12 months and oral micronized progesterone (200 mg/day) for 12 days every two months. | Drug: Estradiol<br>* Transdermal 17β-estradiol (100 ug/day) for 12 months, administered as patches to be worn continuously and replaced once a week. Also, every 2 months, oral micronized progesterone (200 mg/day x 12 days) will be administered.<br>* Other names: Climara and Prometrium.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depressive Symptoms as Indicated by The Center for Epidemiologic Studies Depression Scale (CES-D) | Change from pre-trial (baseline) to post-trial (month 12) in the Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D has a Range from 0-60, with higher scores indicating the presence of more symptomatology. A score of 16 or greater is indicative of clinically significant symptoms of depression. | Baseline, month 12 | 
| Change in Psychiatric Diagnosis as Assessed by the Structured Clinical Interview for DSM Disorders I/NP |  | Baseline and when prompted by CES-D score | 
| Change in Stress Reactivity During Laboratory Session Including Trier Social Stress Test | Primary measures reflecting stress reactivity will consist of mean arterial pressure (MAP), vascular resistance index (VRI), plasma cortisol, and plasma IL-6. For each of these four measures, a delta score (change from rest to stress) will be calculated and then standardized as Z scores. The individual Z scores will then be averaged to yield a single Stress Reactivity profile measure (average z score) - a composite Z score reflecting magnitude of activation in the four primary stress-responsive pathways. This composite z score at baseline will be subtracted from the composite z score at 12 months to yield this outcome measure. | Baseline, month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Functional Well-being as Assessed by the Medical Outcomes Study 36-item Short Form (SF-36) | The Medical Outcomes Study 36-item Short Form (SF-36) is a measure of functional well-being, including physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to emotional health problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. The range of this scale is 0-100, where higher scores indicates a more favorable health state. | Baseline, month 12 | 
| Percentage Meeting Criteria for Metabolic Risk [Baseline and Month 12] | Subjects will be classified as having metabolic risk if they either meet standard criteria for the metabolic syndrome (based on 3 of 5 risk factors: elevated blood pressure, fasting triglycerides, fasting glucose, waist circumference and low HDL-cholesterol) or they exhibit insulin resistance based on the homeostatic model assessment (HOMA) to derive HOMA-IR based on fasting insulin and glucose levels using the equation: HOMA-IR = fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5 | Baseline, month 12 | 
| Change in Percentage of Brachial Artery Diameter | Change (from Baseline-to-12 Month) in flow mediated dilatation (FMD) test of the brachial artery, dilatation occurs following an acute increase in blood flow, induced by via circulatory arrest in the arm for a period of time. Measured using high resolution ultrasound, yielding a measure of endothelial-dependent vasodilatation. The increase in brachial arterial diameter as a consequence of reactive hyperemia is compared to the baseline diameter of the artery and expressed as a percentage of the baseline diameter (% FMD). Flow-mediated vasodilatation at each time point was calculated as diameter of the brachial artery under reactive hyperemia minus baseline diameter of the brachial artery. The change presented here is calculated as 12 month %FMD minus baseline month %FMD. | Baseline, month 12 | 
| Change in Baroreceptor Sensitivity | A finometer noninvasive blood pressure devise (FMS) was used to collect a 10 minute recording of beat-to-beat blood pressure and pulse rate during spontaneous breathing under quiet recumbent conditions. baroreflex sensitivity was computed from the most stable 5-minute segment of this 10-minute period. Cross-spectral analysis was used to estimate the average transfer function modulus (i.e., gain) between systemic blood pressure oscillations and R-R interval oscillations in the frequency range of 0.07-0.14 Hz, also known as the low frequency band. The units of this baroreflex sensitivity (BRS) were msec/mmHg. The outcome presented here is the 12 month BRS minus baseline BRS. | Baseline, month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Perimenopause, Menopause, Depression, Cardiovascular health