Cognitive Changes, Memory Loss, Postmenopausal Symptoms
Conditions
Keywords
aging, postmenopausal women, estrogen, memory
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.
Interventions
DRUGEstradiol oral capsule
1 oral capsule (1 mg estradiol) administered daily for one month
DRUGtransderman estrogen patch
transdermal estrogen patch (50 mcg/day) for one month
DRUGtrasdermal placebo patch
transdermal placebo patch with patch change every 84 hr for one month
DRUGplacebo oral capsule
placebo oral capsule administered daily for one month.
Sponsors
National Institute on Aging (NIA)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomization was performed by the Research Pharmacy and the investigative team was blinded.
Intervention model description
Each participant was randomized to placebo or estrogen using a block randomized design by age group
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
1. young postmenopausal (age 45-55) or older (age 65-80) postmenopausal women 2. 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 3. prescription hormone replacement treatment discontinued at least 3 months before study 4. Normal or corrected normal vision 5. Intelligence quotient (IQ) \> 70 on the Wechsler Adult Reading Test (WTAR)\* 6. Absence of Mild Cognitive Impairment (MCI) and depression on the Mini Mental State Examination (MMSE)\*\* and Beck Depression Inventory II (BDI-II).\*\*\* 7. Normal mammogram or breast MRI within the past 2 years
Exclusion criteria
1. On gonadal hormone replacement medication, herbal supplements and/or over the counter menopause treatment within three months of study 2. History of radiotherapy or chemotherapy. 3. Absolute contraindications to the use of physiologic replacement doses of estrogen and/or history of coronary artery disease 4. History of breast cancer, blood clot, pulmonary embolus, hypercoagulability and stroke. 5. On centrally acting medications 6. History of head trauma and/or neurologic disorder 7. Contraindication to MRI (eg. metal implants) or PET imaging (eg. PET imaging studies in the previous 12 months) 8. Concurrent participation in research studies involving medications and/or PET scans. 9. Left handedness. 10. Current breast lump(s) or family/genetic history of breast cancer in younger women (\< 40 years old). 11. Current smoking
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Young Postmenopausal Women - Estrogen 1 oral capsule (1 mg estradiol) administered daily for one month OR 1 transdermal estrogen patch (50 mcg/day) with patch change every 84 hr for one month in younger postmenopausal women | 12 |
| Older Postmenopausal Women - Estrogen 1 oral capsule (1 mg estradiol) administered daily for one month OR 1 transdermal estrogen patch (50 mcg/day) with patch change every 84 hr for one month in older postmenopausal women | 9 |
| Younger Postmenopausal Women - Placebo 1 placebo capsule administered daily for one month OR 1 placebo patch with patch change every 84 hr for one month in younger postmenopausal women | 7 |
| Older Postmenopausal Women - Placebo 1 placebo capsule administered daily for one month OR 1 placebo patch with patch change every 84 hr for one month in older postmenopausal women | 7 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Young Postmenopausal Women - Estrogen | Total | Older Postmenopausal Women - Placebo | Younger Postmenopausal Women - Placebo | Older Postmenopausal Women - Estrogen |
|---|---|---|---|---|---|
| Age, Customized Age | 51.9 years STANDARD_DEVIATION 0.7 | 61.3 years STANDARD_DEVIATION 1.5 | 71.4 years STANDARD_DEVIATION 1.1 | 51.1 years STANDARD_DEVIATION 1 | 69.8 years STANDARD_DEVIATION 1.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 35 Participants | 7 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 28 Participants | 7 Participants | 5 Participants | 8 Participants |
| Region of Enrollment United States | 12 Participants | 35 Participants | 7 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Female | 12 Participants | 35 Participants | 7 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 9 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 1 / 12 | 2 / 9 | 1 / 7 | 1 / 7 |
| serious Total, serious adverse events | 0 / 12 | 0 / 9 | 0 / 7 | 0 / 7 |
Outcome results
Primary
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.
Time frame: baseline to 1 month
Population: all young and older postmenopausal women who completed one month of placebo or estrogen and in whom structural and functional MRI data were of significant quality for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Young Postmenopausal Women - Estrogen | Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC) | 455.8 linear beta extractions | Standard Error 164.3 |
| Older Postmenopausal Women - Estrogen | Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC) | -214.4 linear beta extractions | Standard Error 90.1 |
| Young Postmenopausal Women - Placebo | Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC) | -348.1 linear beta extractions | Standard Error 215.3 |
| Older Postmenopausal Women - Placebo | Functional Magnetic Resonance Imaging (fMRI) Changes in Response to Estrogen and Aging - Dorsolateral Pre-frontal Cortex (DLPFC) | 90.1 linear beta extractions | Standard Error 215.3 |