Aging and Estrogen on Cortical Function

Phase 1

Completed

Conditions: Memory Loss
Cognitive Changes
Postmenopausal Symptoms

Interventions: Drug: Estradiol oral capsule
Drug: trasdermal placebo patch
Drug: transderman estrogen patch
Drug: placebo oral capsule

Registration Number: NCT01268046

Lead Sponsor: Massachusetts General Hospital

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 38

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Older postmenopausal women - estrogen	Estradiol oral capsule	transdermal estrogen patch OR estradiol oral capsule for 1 month
Young postmenopausal women - placebo	trasdermal placebo patch	transdermal placebo patch for 1 month or placebo oral capsule for 1 month
Young postmenopausal women - estrogen	transderman estrogen patch	transdermal estrogen patch OR estradiol oral capsule for 1 month
Older postmenopausal women - estrogen	transderman estrogen patch	transdermal estrogen patch OR estradiol oral capsule for 1 month
Young postmenopausal women - placebo	placebo oral capsule	transdermal placebo patch for 1 month or placebo oral capsule for 1 month
Older postmenopausal women - placebo	trasdermal placebo patch	transdermal placebo patch for 1 month or placebo oral capsule for 1 month
Older postmenopausal women - placebo	placebo oral capsule	transdermal placebo patch for 1 month or placebo oral capsule for 1 month
Young postmenopausal women - estrogen	Estradiol oral capsule	transdermal estrogen patch OR estradiol oral capsule for 1 month

Primary Outcome Measures

Name	Time	Method
Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC)	baseline to 1 month	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.

Secondary Outcome Measures