Aging and Estrogen on Cortical Function

Study Overview
=================
Brief Summary
-----------------
This study will focus on how estrogen affects parts of the brain associated with memory and how the effect of estrogen is altered with aging in postmenopausal women.

Detailed Description
-----------------
The broad goal of this proposal is to determine the effect of aging on areas of the brain whose function is impacted by gonadal steroids in women. The overarching hypothesis is that aging differentially alters the effects of estrogen on the brain. Our preliminary data indicated that aging alters the effect of estrogen on brain regions involved in cognition and thus, the current study focused on the impact of aging on functional changes induced by estrogen in cortical and subcortical areas associated with verbal working memory and declarative/episodic memory. As our model, we will use women in whom the absence of gonadal function makes it possible to control the duration and amount of estrogen exposure, specifically postmenopausal women who are younger (45-55) or older (65-80) who receive either oral or transdermal estradiol to achieve premenopausal early follicular phase estradiol levels.. We evaluate the effects of low dose estrogen exposure at 48 hr and 1 month to determine whether the short-term changes in brain regions involved in cognition with low dose estrogen exposure seen in our preliminary studies are confirmed and whether changes with short-term estrogen exposure persist with more prolonged exposure, a finding that would have enormous clinical relevance. These studies, using sophisticated neuroimaging tools (structural and functional magnetic resonance imaging [MRI] and [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography [FDG-PET]), provide a unique window into the brain in women.

Official Title
-----------------
The Effect of Low Dose Estrogen on Cortical Function as a Function of Age in Postmenopausal Women.

Conditions
-----------------
Memory Loss, Cognitive Changes, Postmenopausal Symptoms

Intervention / Treatment
-----------------
* Drug: Estradiol oral capsule
* Drug: transderman estrogen patch
* Drug: trasdermal placebo patch
* Drug: placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: young postmenopausal (age 45-55) or older (age 65-80) postmenopausal women otherwise healthy, non-obese women with normal blood pressure and a history of normal menopause, defined by the absence of menses for at least 12 months prescription hormone replacement treatment discontinued at least 3 months before study Normal or corrected normal vision Intelligence quotient (IQ) > 70 on the Wechsler Adult Reading Test (WTAR)* Absence of Mild Cognitive Impairment (MCI) and depression on the Mini Mental State Examination (MMSE)** and Beck Depression Inventory II (BDI-II).*** Normal mammogram or breast MRI within the past 2 years Exclusion Criteria On gonadal hormone replacement medication, herbal supplements and/or over the counter menopause treatment within three months of study History of radiotherapy or chemotherapy. Absolute contraindications to the use of physiologic replacement doses of estrogen and/or history of coronary artery disease History of breast cancer, blood clot, pulmonary embolus, hypercoagulability and stroke. On centrally acting medications History of head trauma and/or neurologic disorder Contraindication to MRI (eg. metal implants) or PET imaging (eg. PET imaging studies in the previous 12 months) Concurrent participation in research studies involving medications and/or PET scans. Left handedness. Current breast lump(s) or family/genetic history of breast cancer in younger women (< 40 years old). Current smoking

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Each participant was randomized to placebo or estrogen using a block randomized design by age group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Young postmenopausal women - estrogen<br>transdermal estrogen patch OR estradiol oral capsule for 1 month | Drug: Estradiol oral capsule<br>* 1 oral capsule (1 mg estradiol) administered daily for one month<br>* Other names: Estradiol;Drug: transderman estrogen patch<br>* transdermal estrogen patch (50 mcg/day) for one month<br>* Other names: Estrogen patch;|
| Experimental: Older postmenopausal women - estrogen<br>transdermal estrogen patch OR estradiol oral capsule for 1 month | Drug: Estradiol oral capsule<br>* 1 oral capsule (1 mg estradiol) administered daily for one month<br>* Other names: Estradiol;Drug: transderman estrogen patch<br>* transdermal estrogen patch (50 mcg/day) for one month<br>* Other names: Estrogen patch;|
| Placebo Comparator: Young postmenopausal women - placebo<br>transdermal placebo patch for 1 month or placebo oral capsule for 1 month | Drug: trasdermal placebo patch<br>* transdermal placebo patch with patch change every 84 hr for one month<br>* Other names: Placebo patch;Drug: placebo oral capsule<br>* placebo oral capsule administered daily for one month.<br>* Other names: Placebo capsule;|
| Placebo Comparator: Older postmenopausal women - placebo<br>transdermal placebo patch for 1 month or placebo oral capsule for 1 month | Drug: trasdermal placebo patch<br>* transdermal placebo patch with patch change every 84 hr for one month<br>* Other names: Placebo patch;Drug: placebo oral capsule<br>* placebo oral capsule administered daily for one month.<br>* Other names: Placebo capsule;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC) | Change in extracted beta coefficients of the blood oxygen level dependent (BOLD) signal response to a cognitive task (N-back) in the DLPFC (x,y,z coordinates = -34 44 16) from baseline to 1 month as a function of aging and estrogen (young vs older and estrogen vs placebo). A positive change indicates an increase in oxygen utilization (inferring increased neuronal functioning) between baseline and treatment during the cognitive task, while a negative change indicates a decrease in oxygen utilization between baseline and treatment during the cognitive task. | baseline to 1 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
aging, postmenopausal women, estrogen, memory