Menopausal Syndrome
Conditions
Keywords
Women, Healthy, Menopausal, Hormone treatment
Brief summary
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).
Detailed description
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.
Interventions
DRUGEstradiol (E2)
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.
DRUGProgesterone (P10) x90
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.
DRUGProgesterone (P10) x10
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.
Sponsors
National Institute on Aging (NIA)
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Postmenopausal women * Ages 45-55, 6 - 36 months from their last menstrual period.
Exclusion criteria
* Left handedness * Acute medical illness * Neurologic illness * Psychiatric illness * Heart disease * Thromboembolic disease * Liver disease * Uncorrected thyroid disease * Diabetes * Neurological disease * Porphyria * Allergy to estradiol * Progesterone or lactose * Lactose intolerance * Claustrophobia * Contraindications to MRI (including pacemakers, surgical clips or metallic surgical devices) * Smoking within the last 3 years * Use of hormones within the last 3 months * Current or past history of substance abuse * History of head injury or loss of consciousness * Medications with actions on the central nervous system * Endometrial lining greater than 5mm * Ovarian pathology on ultrasound * Abnormal mammogram * Migraines * Fasting cholesterol \>300 mg/dl, and fasting triglycerides \>300 mg/dl * Creatinine level \> 1.5 mg/dl * Aspartate transaminase (AST) or Alanine transaminase (ALT) greater than two times the top normal range * Follicle stimulating hormone (FSH) values \<40 IU/L * estradiol \>40 pg/ml. * Subjects with HAM-D score \> 8, HAM-A \> 6 during screening will not be eligible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | August 2010 - March 2012 | 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. |
| Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | August 2010 - March 2012 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychological Testing Scores - Verbal Learning Retention | August 2010 - March 2012 | 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. |
| Neuropsychological Testing Scores - Visual Learning Retention | August 2010 - March 2012 | 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. |
Countries
United States
Participant flow
Recruitment details
+++\_\_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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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). | 16 |
| 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). | 14 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Period Treatment or Placebo | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Estrogen and Placebo | Progesterone and Placebo | Total |
|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 2.2 | 51.2 years STANDARD_DEVIATION 2.9 | 51.5 years STANDARD_DEVIATION 2.5 |
| BMI | 27.13 kg/m² STANDARD_DEVIATION 6.13 | 28.38 kg/m² STANDARD_DEVIATION 3.8 | 27.69 kg/m² STANDARD_DEVIATION 5.17 |
| Education | 15.75 years STANDARD_DEVIATION 2.82 | 17.19 years STANDARD_DEVIATION 2.67 | 16.4 years STANDARD_DEVIATION 2.8 |
| Estradiol | 17.75 pg/mL STANDARD_DEVIATION 6.3 | 14.38 pg/mL STANDARD_DEVIATION 6.25 | 16.24 pg/mL STANDARD_DEVIATION 6.4 |
| Follicle-Stimulating Hormone | 92.34 mIU/mL STANDARD_DEVIATION 33.85 | 80.86 mIU/mL STANDARD_DEVIATION 21.6 | 87.19 mIU/mL STANDARD_DEVIATION 29.11 |
| Gender Female | 9 participants | 7 participants | 16 participants |
| Gender Male | 0 participants | 0 participants | 0 participants |
| Months since Last Menstrual Period | 19.81 months STANDARD_DEVIATION 9.57 | 16.69 months STANDARD_DEVIATION 9.8 | 18.41 months STANDARD_DEVIATION 9.63 |
| Region of Enrollment United States | 9 participants | 7 participants | 16 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 9 | 1 / 7 | 3 / 7 | 1 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 | 0 / 7 | 0 / 7 |
Outcome results
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.
Time frame: August 2010 - March 2012
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estrogen | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .14 percent BOLD signal changes | Standard Deviation 0.12 |
| Estrogen | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | -.06 percent BOLD signal changes | Standard Deviation 0.18 |
| Estrogen | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | -.04 percent BOLD signal changes | Standard Deviation 0.14 |
| Progesterone | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .13 percent BOLD signal changes | Standard Deviation 0.16 |
| Progesterone | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | -.06 percent BOLD signal changes | Standard Deviation 0.13 |
| Progesterone | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | -.01 percent BOLD signal changes | Standard Deviation 0.15 |
| Placebo (Estrogen) | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | -.13 percent BOLD signal changes | Standard Deviation 0.16 |
| Placebo (Estrogen) | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .05 percent BOLD signal changes | Standard Deviation 21 |
| Placebo (Estrogen) | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | -.14 percent BOLD signal changes | Standard Deviation 0.16 |
| Placebo (Progesterone) | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .13 percent BOLD signal changes | Standard Deviation 0.18 |
| Placebo (Progesterone) | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | .01 percent BOLD signal changes | Standard Deviation 0.24 |
| Placebo (Progesterone) | Changes in Brain Activation Patterns in Verbal Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | .09 percent BOLD signal changes | Standard Deviation 0.34 |
Comparison: Category = Medial Frontal Cortex~p-value for null hypothesis = \<0.05p-value: 0.222t-test, 2 sided
Comparison: Category = Left Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.107t-test, 2 sided
Comparison: Category = Right Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.127t-test, 2 sided
Comparison: Category = Medial Frontal Cortex~p-value for null hypothesis = \<0.05p-value: 0.954t-test, 2 sided
Comparison: Category = Left Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.385t-test, 2 sided
Comparison: Category = Right Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.31t-test, 2 sided
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.
Time frame: August 2010 - March 2012
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estrogen | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .25 percent BOLD signal changes | Standard Deviation 0.17 |
| Estrogen | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | .29 percent BOLD signal changes | Standard Deviation 0.17 |
| Estrogen | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | .21 percent BOLD signal changes | Standard Deviation 0.2 |
| Progesterone | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .47 percent BOLD signal changes | Standard Deviation 0.28 |
| Progesterone | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | .38 percent BOLD signal changes | Standard Deviation 0.29 |
| Progesterone | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | .38 percent BOLD signal changes | Standard Deviation 0.25 |
| Placebo (Estrogen) | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | .23 percent BOLD signal changes | Standard Deviation 0.38 |
| Placebo (Estrogen) | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .16 percent BOLD signal changes | Standard Deviation 0.41 |
| Placebo (Estrogen) | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | .21 percent BOLD signal changes | Standard Deviation 0.48 |
| Placebo (Progesterone) | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Medial Frontal Cortex | .20 percent BOLD signal changes | Standard Deviation 0.43 |
| Placebo (Progesterone) | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Right Hippocampus | .15 percent BOLD signal changes | Standard Deviation 0.29 |
| Placebo (Progesterone) | Changes in Brain Activation Patterns in Visual Tasks Determined With the Functional Magnetic Resonance Imaging (fMRI) Scans | Left Hippocampus | .21 percent BOLD signal changes | Standard Deviation 0.29 |
Comparison: Category = Medial Frontal Cortex~p-value for null hypothesis = \<0.05p-value: 0.452t-test, 2 sided
Comparison: Category = Left Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.868t-test, 2 sided
Comparison: Category = Right Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.549t-test, 2 sided
Comparison: Category = Medial Frontal Cortex~p-value for null hypothesis = \<0.05p-value: 0.124t-test, 2 sided
Comparison: Category = Left Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.158t-test, 2 sided
Comparison: Category = Right Hippocampus~p-value for null hypothesis = \<0.05p-value: 0.055t-test, 2 sided
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.
Time frame: August 2010 - March 2012
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen | Neuropsychological Testing Scores - Verbal Learning Retention | 96.79 percent retention | Standard Deviation 6.72 |
| Progesterone | Neuropsychological Testing Scores - Verbal Learning Retention | 97.12 percent retention | Standard Deviation 15.3 |
| Placebo (Estrogen) | Neuropsychological Testing Scores - Verbal Learning Retention | 94.94 percent retention | Standard Deviation 10.75 |
| Placebo (Progesterone) | Neuropsychological Testing Scores - Verbal Learning Retention | 98.44 percent retention | Standard Deviation 12.25 |
Comparison: p-value for null hypothesis = \<0.05p-value: 0.594t-test, 2 sided
Comparison: p-value for null hypothesis = \<0.05p-value: 0.653t-test, 2 sided
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.
Time frame: August 2010 - March 2012
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estrogen | Neuropsychological Testing Scores - Visual Learning Retention | 93.31 percent retention | Standard Deviation 19.22 |
| Progesterone | Neuropsychological Testing Scores - Visual Learning Retention | 97.59 percent retention | Standard Deviation 13.67 |
| Placebo (Estrogen) | Neuropsychological Testing Scores - Visual Learning Retention | 97.01 percent retention | Standard Deviation 14.79 |
| Placebo (Progesterone) | Neuropsychological Testing Scores - Visual Learning Retention | 96.19 percent retention | Standard Deviation 12.06 |
Comparison: p-value for null hypothesis = \<0.05p-value: 0.561t-test, 2 sided
Comparison: p-value for null hypothesis = \<0.05p-value: 0.726t-test, 2 sided