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| ID | Type | Description | Link |
|---|---|---|---|
| 1R21AG031951-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
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The objective of this study is to evaluate the neurobiological effects of hormone therapy (HT) in healthy early postmenopausal women. The studies proposed in this project seek to define the association between different hormone forms (estradiol only and progesterone only) versus placebo on brain functional measures. The functional measures will include the performance of the volunteers on a comprehensive neuropsychological testing battery, and the brain functional responses to episodic memory (verbal and non-verbal) challenges as well as emotional processing determined with functional magnetic resonance imaging (fMRI).
Specific Aims
Aim 1. To examine the effects of estradiol alone on brain functioning in early post-menopausal women during verbal and non-verbal cognitive tasks.
Hypothesis: It is expected that with estradiol treatment brain activation will be more prominent in the hippocampus and prefrontal cortical areas compared to placebo. The magnitude of activation in these regions will be positively correlated with task performance in the scanner and with the results of neuropsychological tests assessing verbal and non-verbal delayed recall.
Aim 2. To determine the effects of progesterone alone on brain functioning in early postmenopausal women during verbal and non-verbal cognitive tasks.
Hypothesis: It is expected that with progesterone treatment brain activation in the hippocampus and prefrontal cortical areas will be decreased compared to both the placebo condition (within subjects) and the estradiol condition (between subjects). Interindividual variations in the magnitude of activation in these regions will be positively correlated with task performance in the scanner and with the results of neuropsychological tests assessing verbal and non-verbal delayed recall.
Aim 3. To determine the individual effects of estradiol and progesterone on brain functioning in early postmenopausal women during emotional processing stimuli.
Hypothesis: During negative stimuli estradiol-treated women compared to placebo group, are expected to have increased activity in the amygdala, posterior cingulate, and orbitofrontal cortex, while in progesterone-treated women compared to placebo, decreased activity is expected in these brain regions.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Estrogen followed by Placebo | Active Comparator | Estrogen treatment with Estradiol (E2) followed by Placebo. |
|
| Progesterone followed by Placebo | Active Comparator | Progesterone (P10) treatment followed by Placebo. |
|
| Placebo followed by Estrogen | Active Comparator | Placebo followed by Estrogen treatment with Estradiol (E2) |
|
| Placebo followed by Progesterone | Active Comparator | Placebo followed by Progesterone (P10) treatment. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Estradiol (E2) | Drug | One Estradiol capsule (1mg) once a day, at the same time each day, for 90 days; followed by one Progesterone (200mg) once a day, at the same time each day, for 10 days to slough endometrial lining; followed by one Placebo capsule once a day, at the same time each day, for 90 days. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Measure the changes in brain activity in verbal tasks with hormone use (either estradiol or progesterone) versus placebo. The test is a deep and shallow verbal processing task, where the subjects are presented lists of words, one word at a time, and are asked to make one of 2 decisions about each list. One decision is whether each word is written in upper or lower case letters (shallow processing), and the other decision is whether each word denotes an abstract or concrete concept (deep processing). The test was administered 3 months after baseline and 38 weeks after baseline. | August 2010 - March 2012 |
| Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Measure the changes in brain activity in visual tasks with hormone use (either estradiol or progesterone) versus placebo. The test is a visual working memory task, where the women are presented with 3 geometric grids on the screen. The target grid is on top, and 2 test grids are on the bottom. The women must decide if the right or left test grid matches the grid on top. There are 3 conditions: a match condition where all 3 grids are shown simultaneously, and 2 delay conditions, where the target grid is shown first, disappears, and the test grids appear after a 1 or a 4 second delay. The test was administered 3 months after baseline and 38 weeks after baseline. | August 2010 - March 2012 |
| Measure | Description | Time Frame |
|---|---|---|
| Neuropsychological Testing Scores - Verbal Learning Retention | Changes in neuropsychological testing measures (verbal learning retention) with hormone use (either estradiol or progesterone) versus placebo. Subjects are given tests that present them with a series of words. They are asked to recall how many items they can remember, and then some time later, are asked to recall the items again. The retention measure is how many items they can remember at the later time point, compared to the earlier time point. Adapted from the Benton Visual Memory Test, Revised. The tests were administered 3 months after baseline and 38 weeks after baseline. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yolanda R. Smith, M.D. | University of Michigan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The University of Michigan | Ann Arbor | Michigan | 48109 | United States |
Several enrolled participants were excluded from the trial prior to assignment in groups on the basis of the risk factors identified at the pre-screening appointment. Some others did not qualify due to their lab results which did not meet the inclusion criteria.
+++__Women were recruited from 3/1/2010 to 7/29/2011 through local newspaper ads, flyers, electronic newsletters, bulletin boards, clinics and the Women's Health Registry, a University of Michigan database of women interested in participating in women's health related clinical research.
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| ID | Title | Description |
|---|---|---|
| FG000 | Estrogen Followed by Placebo | Estrogen treatment with Estradiol (E2) One Estradiol capsule (1mg) once a day, at the same time each day, for 90 days followed by one Placebo capsule once per day for 90 days, at the same time each day |
| FG001 | Progesterone Followed by Placebo | Progesterone (P10) treatment One Progesterone (P10) (200 mg) capsule once a day, at the same time each day, for 90 days, followed by one Placebo capsule once per day for 90 days, at the same time each day. |
| FG002 | Placebo Followed by Estrogen | One Placebo capsule once per day for 90 days, at the same time each day, followed by one Estradiol capsule (E2) (1mg) once a day, at the same time each day, for 90 days. |
| FG003 | Placebo Followed by Progesterone | One Placebo capsule once per day for 90 days, at the same time each day, followed by one Progesterone (P10) (200 mg) capsule once a day, at the same time each day, for 90 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Period Treatment or Placebo |
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| Washout Period |
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| Second Period Treatment or Placebo |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Estrogen and Placebo | Estrogen treatment with Estradiol (E2) Participants received both an Estradiol capsule (E2) (1mg) and a Placebo capsule in a randomized sequence (for a total of two sequences of 90 days each, consisting of one capsule, once per day at the same time each day). |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Measure the changes in brain activity in verbal tasks with hormone use (either estradiol or progesterone) versus placebo. The test is a deep and shallow verbal processing task, where the subjects are presented lists of words, one word at a time, and are asked to make one of 2 decisions about each list. One decision is whether each word is written in upper or lower case letters (shallow processing), and the other decision is whether each word denotes an abstract or concrete concept (deep processing). The test was administered 3 months after baseline and 38 weeks after baseline. | Within the Estrogen/Placebo groups, 3 participants were unable to complete the needed fMRI analyses due to adverse events, and in the Progesterone/Placebo groups, 1 participant's fMRI scans were damaged and unable to be used in the analysis. | Posted | Mean | Standard Deviation | percent BOLD signal changes | August 2010 - March 2012 |
|
2 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Estrogen Followed by Placebo | Estrogen treatment with Estradiol (E2) One Estradiol capsule (E2) (1mg) once a day, at the same time each day, for 90 days followed by one Placebo capsule once per day for 90 days, at the same time each day. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Claustrophobia | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Yolanda Smith | The University of Michigan | (734) 936-7401 | ysmith@med.umich.edu |
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| ID | Term |
|---|---|
| D004958 | Estradiol |
| D011374 | Progesterone |
| D017306 | Annexin A2 |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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Not provided
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|
|
| Progesterone (P10) x90 | Drug | One Progesterone capsule (200mg) once a day, at the same time each day, for 90 days; followed by one Placebo capsule (to mirror Progesterone capsule to slough endometrial lining in Estradiol recipients) once a day, at the same time each day, for 10 days ; followed by one Placebo capsule once a day, at the same time each day, for 90 days. |
|
|
| Progesterone (P10) x10 | Drug | One Progesterone (200mg) capsule once a day for 10 days, to slough endometrial lining for patients taking Estradiol. Patients taking Progesterone will take an equivalent Placebo capsule during this time period. |
|
|
| August 2010 - March 2012 |
| Neuropsychological Testing Scores - Visual Learning Retention | Changes in neuropsychological testing measures (visual learning retention) with hormone use (either estradiol or progesterone) versus placebo. Subjects are given tests that present them with a series of pictures. They are asked to recall how many items they can remember, and then some time later, are asked to recall the items again. The retention measure is how many items they can remember at the later time point, compared to the earlier time point. Adapted from the California Verbal Learning Test - 2nd edition. The tests were administered 3 months after baseline and 38 weeks after baseline. | August 2010 - March 2012 |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
| Progesterone and Placebo |
Progesterone treatment (P10) Participants received both a Progesterone capsule (P10) (200 mg) and a Placebo capsule in a randomized sequence (for a total of two sequences of 90 days each, consisting of one capsule, once per day at the same time each day). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Gender | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Months since Last Menstrual Period | Mean | Standard Deviation | months |
|
| Education | Mean | Standard Deviation | years |
|
| Estradiol | Mean | Standard Deviation | pg/mL |
|
| Follicle-Stimulating Hormone | Mean | Standard Deviation | mIU/mL |
|
| BMI | Mean | Standard Deviation | kg/m² |
|
| OG000 |
| Estrogen |
Estrogen treatment with Estradiol (E2) Estradiol (E2) : One Estradiol capsule (1mg) once a day, at the same time each day, for 90 days |
| OG001 | Progesterone | Progesterone treatment Progesterone (P10) : One Progesterone (200 mg) capsule once a day, at the same time each day, for 90 days |
| OG002 | Placebo (Estrogen) | Placebo phase of Estradiol (E2) treatment One Placebo capsule once a day, at the same time each day, for 90 days |
| OG003 | Placebo (Progesterone) | Placebo phase of Progesterone (P10) treatment One Placebo capsule once a day, at the same time each day, for 90 days |
|
|
|
| Secondary | Neuropsychological Testing Scores - Verbal Learning Retention | Changes in neuropsychological testing measures (verbal learning retention) with hormone use (either estradiol or progesterone) versus placebo. Subjects are given tests that present them with a series of words. They are asked to recall how many items they can remember, and then some time later, are asked to recall the items again. The retention measure is how many items they can remember at the later time point, compared to the earlier time point. Adapted from the Benton Visual Memory Test, Revised. The tests were administered 3 months after baseline and 38 weeks after baseline. | Within the Estrogen/Placebo groups, 3 participants were unable to complete the needed fMRI analyses due to adverse events, and in the Progesterone/Placebo groups, 1 participant's fMRI scans were damaged. | Posted | Mean | Standard Deviation | percent retention | August 2010 - March 2012 |
|
|
|
|
| Primary | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Measure the changes in brain activity in visual tasks with hormone use (either estradiol or progesterone) versus placebo. The test is a visual working memory task, where the women are presented with 3 geometric grids on the screen. The target grid is on top, and 2 test grids are on the bottom. The women must decide if the right or left test grid matches the grid on top. There are 3 conditions: a match condition where all 3 grids are shown simultaneously, and 2 delay conditions, where the target grid is shown first, disappears, and the test grids appear after a 1 or a 4 second delay. The test was administered 3 months after baseline and 38 weeks after baseline. | Within the Estrogen/Placebo groups, 3 participants were unable to complete the needed fMRI analyses due to adverse events, and in the Progesterone/Placebo groups, 1 participant's fMRI scans were damaged. | Posted | Mean | Standard Deviation | percent BOLD signal changes | August 2010 - March 2012 |
|
|
|
|
| Secondary | Neuropsychological Testing Scores - Visual Learning Retention | Changes in neuropsychological testing measures (visual learning retention) with hormone use (either estradiol or progesterone) versus placebo. Subjects are given tests that present them with a series of pictures. They are asked to recall how many items they can remember, and then some time later, are asked to recall the items again. The retention measure is how many items they can remember at the later time point, compared to the earlier time point. Adapted from the California Verbal Learning Test - 2nd edition. The tests were administered 3 months after baseline and 38 weeks after baseline. | Within the Estrogen/Placebo groups, 3 participants were unable to complete the needed fMRI analyses due to adverse events, and in the Progesterone/Placebo groups, 1 participant's fMRI scans were damaged. | Posted | Mean | Standard Deviation | percent retention | August 2010 - March 2012 |
|
|
|
|
| 0 |
| 9 |
| 1 |
| 9 |
| EG001 | Progesterone Followed by Placebo | Progesterone treatment One Progesterone (P10) (200 mg) capsule once a day, at the same time each day, for 90 days, followed by one Placebo capsule once per day for 90 days, at the same time each day. | 0 | 7 | 1 | 7 |
| EG002 | Placebo Followed by Estrogen | One Placebo capsule once per day for 90 days, at the same time each day, followed by one Estradiol capsule (E2) (1mg) capsule once a day, at the same time each day, for 90 days. | 0 | 7 | 3 | 7 |
| EG003 | Placebo Followed by Progesterone | One Placebo capsule once per day for 90 days, at the same time each day, followed by one Progesterone (P10) (200 mg) capsule once a day, at the same time each day, for 90 days. | 0 | 7 | 1 | 7 |
| Side effects of hormone use | General disorders | Non-systematic Assessment |
|
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| D011083 |
| Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D003339 | Corpus Luteum Hormones |
| D045167 | Progesterone Congeners |
| D017302 | Annexins |
| D002135 | Calcium-Binding Proteins |
| D002352 | Carrier Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| .653 |
| 95 |
| No |
| Superiority or Other |
| Left Hippocampus |
|
| Right Hippocampus |
|
| t-test, 2 sided |
| .868 |
Category = Left Hippocampus |
| 95 |
| No |
| Superiority or Other |
| Category = Right Hippocampus p-value for null hypothesis = <0.05 | t-test, 2 sided | .549 | Category = Right Hippocampus | 95 | No | Superiority or Other |
| Category = Medial Frontal Cortex p-value for null hypothesis = <0.05 | t-test, 2 sided | .124 | Category = Medial Frontal Cortex | 95 | No | Superiority or Other |
| Category = Left Hippocampus p-value for null hypothesis = <0.05 | t-test, 2 sided | .158 | Category = Left Hippocampus | 95 | No | Superiority or Other |
| Category = Right Hippocampus p-value for null hypothesis = <0.05 | t-test, 2 sided | .055 | Category = Right Hippocampus | 95 | No | Superiority or Other |
| .726 |
| 95 |
| No |
| Superiority or Other |