Effects of Aging and Estrogen on Memory and Cognition

This study will focus on how aging affects changes in the way the brain works when affected by estrogen in areas of the brain associated with memory.

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 indicate that aging alters the effect of estrogen on brain regions involved in cognition and thus, the current proposal will focus 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 young women with Premature Ovarian Insufficiency (POI) < 45 yrs. old (but diagnosed at < 40 yrs.) and postmenopausal women who are younger (45-55) or older (65-80). We will investigate the effects of both short-term (48 hr) and prolonged (28-30 days) estrogen exposure to determine whether the changes in brain regions involved in cognition that were seen with short-term estrogen exposure persist with 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 the human.

• Memory Loss
• Cognitive Changes
• Postmenopausal Symptoms

• Postmenopausal women 45-55 years old
  Intervention: Drug: Estradiol
• Postmenopausal women 65-80 years old
  Intervention: Drug: Estradiol
• Women with Premature Ovarian Insufficiency (POI) < 45 yrs
  Intervention: Drug: Estradiol

Inclusion Criteria

1. Three groups of menopausal women will be recruited for these studies:

   • young (age 45-55)
   • older (age65-80) postmenopausal women (PMW)
   • women with Premature Ovarian Insufficiency (POI) < 45 yrs. old (but diagnosed at < 40 yrs.)
2. The subjects will be otherwise healthy, non-obese women, normotensive and non-smokers
3. History of normal menopause, defined by the absence of menses for at least 12 months

4. Subjects with premature menopause will have had:

   • menarche between the ages of 10 and 15
   • regular menstrual cycles before the onset of ovarian failure at < 35
   • at least 1 year of amenorrhea before study or no unscheduled menses while on HRT (discontinued at least 3 months before study, as above)
   • have normal adrenal function and not be carriers for the Fragile X premutation
5. FSH > 26 IU/L (2nd IRP HMG) and E2 < 25 pg/mL at screening and on the initial day of study and normal TSH, and Factor V activity
6. Normal or corrected normal vision
7. IQ > 70 on the Wechsler Adult Reading Test (WTAR)*
8. Absence of Mild Cognitive Impairment (MCI) and depression on the Mini Mental State Examination (MMSE)** and Beck Depression Inventory II (BDI-II).***
9. Normal mammogram or breast MRI within the past 2 years (age 45 and older only).

Exclusion Criteria

1. On gonadal hormone replacement medication, herbal supplements and/or over the counter menopause treatment for 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).