Vascular Mechanisms for the Effects of Loss of Ovarian Hormone Function on Cognition in Women

Complaints about memory and thinking are common in women as they go through menopause and estrogen levels fall. The ovarian hormone estrogen is important for supporting normal cognitive function, and changes in brain activity and function occur when estrogen levels are decreased. Estrogen is also important for maintaining healthy blood vessels which also support normal cognitive function. In Alzheimer's disease and other types of dementia, there is significant damage to the blood vessels in the brain. This study will test whether changes in brain activity and function with the loss of estrogen are related to changes in vascular function. The investigators will measure vascular function using ultrasound, and brain activity using MRI scans in women who are enrolled in the Females, Aging, Metabolism and Exercise (FAME) study (NCT01712230). In the FAME study, healthy premenopausal women either take a medication to decrease their estrogen levels, or a placebo. This sub-study may provide new information about how estrogen affects vascular function and cognitive function, and lead to new ways to prevent or delay cognitive impairment or dementia.

Cognitive impairment, Executive function, Arterial stiffness, Endothelial function, Menopause, Women's health, Hormone therapy, functional MRI

Monthly injections of leuprolide acetate 3.75mg for 9 months; first 6 months under parent study (FAME) protocol (NCT01712230); months 6-9 under sub-study protocol. Weekly application of estradiol patch 0.075mg/d months 6-9. Daily medroxyprogesterone acetate 5mg by mouth for 12 days at week 30.

Lupron 3.75 mg for depot suspension delivered by monthly intramuscular injection for 9 months. First 6 months under parent study (FAME) protocol (NCT01712230); months 6-9 under sub-study.

Changes in patterns of brain activation in the prefrontal cortex using functional magnetic resonance imaging (fMRI) during a task of working memory will be measured at baseline, 6 months, and 9 months (GnRH agonist arm only). Beta weight is the percent signal change on the FMRI from one condition to another. The FMRI is measuring blood oxygen levels and blood flow in different regions of the brain and using that to determine activity changes in the brain. A positive number/increase indicates more blood flow and brain activity in that area.

Changes in patterns of brain activation in the prefrontal cortex using functional magnetic resonance imaging (fMRI) during a task of working memory will be measured at baseline, 6 months, and 9 months (GnRH agonist arm only). Beta weight is the percent signal change on the FMRI from one condition to another. The FMRI is measuring blood oxygen levels and blood flow in different regions of the brain and using that to determine activity changes in the brain. A positive number/increase indicates more blood flow and brain activity in that area.

Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 6 months

Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 9 months

Change in time (seconds) to complete Trails A test between baseline and 6 months. Negative value indicates faster time (better performance) at 6 months compared to baseline.

Change in time (seconds) to complete Trails A test between baseline and 9 months. Negative value indicates faster time (better performance) at 9 months compared to baseline.

Change in Rey Auditory Verbal Learning Test from baseline to 6 months. Score is the change in the number of items correct on delayed recall trial. Scores on the RAVLT range from 0-15 with higher scores indicating better performance. A positive change indicates improvement in recall.

Change in Rey Auditory Verbal Learning Test from baseline to 9 months. Score is the change in the number of items correct on delayed recall trial. Scores on the RAVLT range from 0-15 with higher scores indicating better performance. A positive change indicates improvement in recall.

Change in time (seconds) to complete Trails B test between baseline and 6 months. Negative value indicates faster time (better performance) at 6 months compared to baseline.

Change in time (seconds) to complete Trails B test between baseline and 9 months. Negative value indicates faster time (better performance) at 9 months compared to baseline.

Change in number of correct responses in one minute on Stroop Color Word Interference test between baseline and 6 months. A positive number indicates more items correct indicating better performance. There is no maximum score because the test measures how many correct responses a participant can return within one minute (minimum = 0), however 40 or fewer is considered low. The change in the number of correct responses is reported, and so a positive number indicates more correct responses and better/improved cognitive function.

Change in number of correct responses in one minute on Stroop Color Word Interference test between baseline and 9 months. Positive number indicates more items correct indicating better performance. There is no maximum score because the test measures how many correct responses a participant can return within one minute (minimum = 0), however 40 or fewer is considered low. The change in the number of correct responses is reported, and so a positive number indicates more correct responses and better/improved cognitive function.

Change in score on the Digit Span Test between baseline and 6 month. Raw scores on the Digit Span test range from 0-16 (Digits Forward) and 0-10 (Digits Backward) with higher scores indicating better performance. A positive change score indicates improved performance.

Change in score on the Digit Span Test between baseline and 9 months. Raw scores on the Digit Span test range from 0-16 (Digits Forward) and 0-10 (Digits Backward) with higher scores indicating better performance. A positive change score indicates improved performance.

Change in sum of scores on 3 COWAT trials (letters, F, A, and S) between baseline and 6 months. Participants are given one minute to think up as many words as they can associated with each letter (F, A, or S). Raw scores are the total number of words generated across all trials. Higher scores indicate more words generated and better performance. Positive change score indicates an increase in words generated, or improved performance.

Change in sum of scores on 3 COWAT trials (letters, F, A, and S) between baseline and 9 months. Participants are given one minute to think up as many words as they can associated with each letter (F, A, or S). Raw scores are the total number of words generated across all trials. Higher scores indicate more words generated and better performance. Positive change score indicates an increase in words generated, or improved performance.

Inclusion Criteria: Volunteers will be healthy women aged 40 to 60 years Are enrolled in the parent FAME study (NCT01712230). The Investigators will consent up to 80 subjects with the aim of enrolling 17 in each of the 2 groups (placebo, GnRH agonist). Exclusion Criteria: mini-mental state examination (MMSE) score 27 or less history of neurologic disease or major psychiatric illness major depressive episode within the past 12 months history of learning disability less than high-school education current smoking use of psychoactive medications in the past 3 months (stable use of anti- depressant medication is allowed) contraindications to MRI scanning