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.

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.

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

De-identified information will be made available on request to the PI once the primary data analysis has been published.

From time of publication of initial 2 manuscripts (December 2019) for 5 years

Academic investigator with funding for analysis, approval of PI

4 months

Randomization was performed by the Research Pharmacy and the investigative team was blinded.