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

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT02122198
• Collaborator: (none)
• Enrollment: 17
• Locations: 2
• Arms: 2
• Actual Duration (Months): 36.2
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Cognitive Impairment; Executive Dysfunction; Endothelial Dysfunction; Cardiovascular Disease	Drug: Leuprolide acetate; Drug: Estradiol; Drug: Medroxyprogesterone; Drug: Placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Vascular Mechanisms for the Effects of Loss of Ovarian Hormone Function on Cognition in Women
• Actual Study Start Date: Sep 8, 2014
• Actual Primary Completion Date: May 30, 2017
• Actual Study Completion Date: Sep 15, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230)	Drug: Placebo; placebo
Active Comparator: GnRH agonist 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.	Drug: Leuprolide acetate; 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.; Other Names: Lupron ; Drug: Estradiol; Climara transdermal patch 0.075mg/day applied weekly months 6-9; Other Names: Climara ; Drug: Medroxyprogesterone; Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.; Other Names: Provera

Outcome Measures

Primary Outcome Measures

1. Changes in Prefrontal Cortex Brain Activation at 6 Months [Baseline, 6 months]

   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.

2. Changes in Prefrontal Cortex Brain Activation at 9 Months [Baseline, 9 months]

   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.

Secondary Outcome Measures

1. Changes in Endothelial Function at 6 Months [Baseline, 6 months]

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

2. Changes in Endothelial Function at 9 Months [Baseline, 9 months]

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

3. Changes in Artery Compliance at 6 Months [Baseline, 6 months]

   Changes in carotid artery compliance will be measured using ultrasound in at baseline, 6 months.

4. Changes in Artery Compliance at 9 Months [Baseline, 9 months]

   Changes in carotid artery compliance will be measured using ultrasound in at baseline, 9 months.

5. Changes in Executive Cognitive Function: Trails A, 6 Months [Baseline, 6 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.

6. Changes in Executive Cognitive Function: Trails A, 9 Months [Baseline, 9 months]

   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.

7. Changes in Executive Cognitive Function: RAVLT, 6 Months [Baseline, 6 months]

   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.

8. Changes in Executive Cognitive Function: RAVLT, 9 Months [Baseline, 9 months]

   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.

9. Changes in Executive Cognitive Function: Trails B, 6 Months [Baseline, 6 months]

   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.

10. Changes in Executive Cognitive Function: Trails B, 9 Months [Baseline, 9 months]

    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.

11. Changes in Executive Cognitive Function: Stroop, 6 Months [Baseline, 6 months]

    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.

12. Changes in Executive Cognitive Function: Stroop, 9 Months [Baseline, 9 months]

    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.

13. Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months [Baseline, 6 months]

    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.

14. Changes in Executive Cognitive Function: Digits, 9 Months [Baseline, 9 months]

    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.

15. Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 6 Months [Baseline, 6 months]

    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.

16. Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 9 Months [Baseline, 9 months]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 60 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Volunteers will be healthy women aged 40 to 60 years

2. 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:

1. mini-mental state examination (MMSE) score 27 or less

2. history of neurologic disease or major psychiatric illness

3. major depressive episode within the past 12 months

4. history of learning disability

5. less than high-school education

6. current smoking

7. use of psychoactive medications in the past 3 months (stable use of anti- depressant medication is allowed)

8. contraindications to MRI scanning

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045
2	University of Colorado Boulder Intermountain Neuroimaging Consortium	Boulder	Colorado	United States	80309

Sponsors and Collaborators

• University of Colorado, Denver

Investigators

• Principal Investigator: Kerry L Hildreth, MD, University of Colorado, Denver

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 12, 2017

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT02122198
• Other Study ID Numbers: 14-0193; UL1TR001082
• First Posted: Apr 24, 2014
• Last Update Posted: Jan 10, 2022
• Last Verified: Dec 1, 2021

• Keywords provided by University of Colorado, Denver: Cognitive impairment; Executive function; Arterial stiffness; Endothelial function; Menopause; Women's health; Hormone therapy; functional MRI
• Additional relevant MeSH terms: Cardiovascular Diseases; Cognitive Dysfunction; Leuprolide; Medroxyprogesterone Acetate; Medroxyprogesterone; Estradiol

Study Results

Participant Flow

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Period Title: Overall Study
STARTED	5	12
COMPLETED	3	10
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Placebo	GnRH Agonist	Total
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.	Total of all reporting groups
Overall Participants	5	12	17
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.6 (2.5)	47.7 (4.0)	47.1 (3.7)
Sex: Female, Male (Count of Participants)
Female	5 100%	12 100%	17 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 40%	0 0%	2 11.8%
Not Hispanic or Latino	3 60%	12 100%	15 88.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 20%	1 8.3%	2 11.8%
White	3 60%	11 91.7%	14 82.4%
More than one race	1 20%	0 0%	1 5.9%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Changes in Prefrontal Cortex Brain Activation at 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	2	7
Frontal Pole (L)	90.64 (3.88)	-62.20 (57.61)
Frontal Orbital Cortex (L)	28.07 (37.48)	-79.04 (71.85)
Superior Frontal Gyrus (R)	92.45 (33.66)	-53.05 (41.13)

2. Primary Outcome

Title	Changes in Prefrontal Cortex Brain Activation at 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

This outcome measure was only collected for a subset of the GnRH Agonist group.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	2
Frontal Pole (L)	-27.15 (67.37)
Frontal Orbital Cortex (L)	-88.87 (0.34)
Superior Frontal Gyrus (R)	-77.23 (68.22)

3. Secondary Outcome

Title	Changes in Endothelial Function at 6 Months
Description	Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 6 months
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

This outcome cannot be reported due to corruption of the collected image data.

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	0	0

4. Secondary Outcome

Title	Changes in Endothelial Function at 9 Months
Description	Changes in endothelial function will be measured using brachial artery flow-mediated dilation at baseline, 9 months
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was collected for a subset of the GnRH agonist arm only. This outcome cannot be reported due to corruption of the collected image data.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	0

5. Secondary Outcome

Title	Changes in Artery Compliance at 6 Months
Description	Changes in carotid artery compliance will be measured using ultrasound in at baseline, 6 months.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	4	3
Mean (Standard Deviation) [mm^2/mmhgx10^-1]	-0.048 (0.057)	-0.095 (0.011)

6. Secondary Outcome

Title	Changes in Artery Compliance at 9 Months
Description	Changes in carotid artery compliance will be measured using ultrasound in at baseline, 9 months.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was only collected for a subset of the GnRH agonist arm.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	2
Mean (Standard Deviation) [mm^2/mmhgx10^-1]	-0.002 (0.006)

7. Secondary Outcome

Title	Changes in Executive Cognitive Function: Trails A, 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3	8
Mean (Standard Deviation) [seconds]	2.79 (8.54)	-5.82 (3.11)

8. Secondary Outcome

Title	Changes in Executive Cognitive Function: Trails A, 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was only collected for a subset of the GnRH agonist arm.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3
Mean (Standard Deviation) [time (seconds)]	-5.46 (7.12)

9. Secondary Outcome

Title	Changes in Executive Cognitive Function: RAVLT, 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3	8
Mean (Standard Deviation) [number of items recalled]	-1.00 (2.65)	-1.38 (1.85)

10. Secondary Outcome

Title	Changes in Executive Cognitive Function: RAVLT, 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was only collected for a subset of the GnRH agonist arm.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3
Mean (Standard Deviation) [number of items recalled]	0 (2.00)

11. Secondary Outcome

Title	Changes in Executive Cognitive Function: Trails B, 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3	8
Mean (Standard Deviation) [time (seconds)]	14.23 (4.77)	-4.32 (16.27)

12. Secondary Outcome

Title	Changes in Executive Cognitive Function: Trails B, 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was only collected for a subset of the GnRH agonist arm.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3
Mean (Standard Deviation) [time (seconds)]	14.14 (12.09)

13. Secondary Outcome

Title	Changes in Executive Cognitive Function: Stroop, 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3	8
Mean (Standard Deviation) [number correct in one minute]	-0.67 (10.97)	0.25 (13.76)

14. Secondary Outcome

Title	Changes in Executive Cognitive Function: Stroop, 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was only collected for a subset of the GnRH agonist arm.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3
Mean (Standard Deviation) [number correct in one minute]	7.33 (3.06)

15. Secondary Outcome

Title	Changes in Executive Cognitive Function: Digits Span Forward and Backward, 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3	8
Digits Forward (trials correct)	1.00 (1.00)	-0.88 (1.89)
Digits Backward (trials correct)	-0.67 (3.06)	0.00 (1.51)

16. Secondary Outcome

Title	Changes in Executive Cognitive Function: Digits, 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

Outcome measure was only collected for a subset of the GnRH agonist arm.

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3
Digits Forward (trials correct)	1.00 (3.61)
Digits Backward (trials correct)	1.0 (1.0)

17. Secondary Outcome

Title	Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 6 Months
Description	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.
Time Frame	Baseline, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3	8
Mean (Standard Deviation) [words generated]	-5.33 (7.77)	0.25 (9.50)

18. Secondary Outcome

Title	Changes in Executive Cognitive Function: Controlled Oral Word Association Test, 9 Months
Description	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.
Time Frame	Baseline, 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GnRH Agonist
Arm/Group Description	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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
Measure Participants	3
Mean (Standard Deviation) [words generated]	7.33 (5.51)

Adverse Events

Time Frame	9 months
Arm/Group Title	Placebo		GnRH Agonist
Arm/Group Description	Monthly placebo injections for 6 months under parent study (FAME) protocol (NCT01712230) Placebo: placebo		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. Leuprolide acetate: 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. Estradiol: Climara transdermal patch 0.075mg/day applied weekly months 6-9 Medroxyprogesterone: Provera 5mg tablets once daily by mouth for 12 days beginning at week 30.
All Cause Mortality
	Placebo		GnRH Agonist
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/12 (0%)
Serious Adverse Events
	Placebo		GnRH Agonist
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		GnRH Agonist
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		1/12 (8.3%)
Nervous system disorders
calcification of the falx cerebri right of midline	0/5 (0%)	0	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.