RISE: Research Investigation of Soy and Estrogen
Study Details
Study Description
Brief Summary
The purpose of this study is to determine the effects of oral estradiol and soy phytoestrogens on anxiety, stress responsivity and cognition in perimenopausal women.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
Anxiety is a common, but understudied complaint in midlife women, and increases during the menopausal transition. Changes in estrogen are dramatic during the menopausal transition, and indirect data suggest a potential role for estrogen, particularly estrogen receptor beta, in mediating anxiety. Two subtypes of the estrogen receptor, alpha and beta (ER-alpha and ER-beta), appear to be critically involved in the expression of anxiety in females. Compounds that preferentially target ER-beta, including plant-derived estrogens (phytoestrogens), lower both anxiety behaviors and responsivity to discrete stressors, including social stress, in laboratory animals. The primary aim of this proposal is to carry out the first study to translate these preclinical studies to humans by comparing and contrasting of the effects of phytoestrogens, estradiol, and placebo on daily anxiety and responses to moderate psychosocial stress in the laboratory. As second focus is emotional and non-emotional cognition. This focus stems from evidence that estrogen can protect against the negative impact of glucocorticoids on memory. These aims will be accomplished in a 12-week randomized placebo-controlled, clinical trial comparing three treatments: 1) a phytoestrogen supplement (Novasoy® 400, 55 mg tablet twice daily); 2) oral estradiol (1 mg/daily; plus 10 mg medroxyprogesterone acetate at study end 10 for 10 days); and 3) placebo (identical appearing tablets twice daily). The enrollment target is 120 healthy women in the menopausal transition (40 per group). To measure anxiety, women will complete the State-Trait Anxiety Inventory (STAI). To measure responsivity to psychosocial stress, parallel forms of the Trier Social Stress Test, a widely used laboratory induction that involves unanticipated public speaking and social evaluative fear, will be used to induce moderate psychosocial stress before and after treatment. At both laboratory sessions, measures of subjective stress (STAI), cortisol, and emotional memory performance will be obtained at multiple points during a control condition and during the psychosocial stress condition. Lastly, we will measure treatment effects on measures of verbal memory.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Estradiol/Medroxyprogesterone Acetate 1 mg/d oral Estradiol pill and 0 mg/d oral placebo pill for 12 weeks, followed by 10 mg/d oral medroxyprogesterone acetate (MPA) pill, for 10 days. |
Drug: Estradiol
Estradiol pill (1 mg)
Other Names:
Drug: Medroxyprogesterone Acetate (MPA)
medroxyprogesterone acetate (MPA) (10mg)
Other Names:
Drug: Soy Placebo
oral placebo pill (0mg Soy Phytoestrogen)
Other Names:
|
Experimental: Soy Phytoestrogen 55 mg/twice daily oral Novasoy®/Soy Phytoestrogen pill for 12 weeks, followed by 0 mg/d oral placebo pill, for 10 days. |
Dietary Supplement: Soy Phytoestrogen
Novasoy® pill (55 mg)
Other Names:
Drug: MPA Placebo
oral placebo pill (0mg MPA)
Other Names:
|
Placebo Comparator: Placebo 0 mg tablet/twice daily oral placebo pill for 12 weeks, followed by 0 mg/d oral placebo pill, for 10 days. |
Drug: Soy Placebo
oral placebo pill (0mg Soy Phytoestrogen)
Other Names:
Drug: MPA Placebo
oral placebo pill (0mg MPA)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in STAI-6 Score [Week 0, 10, 12, and 16-18]
STAI-6; State-Trait Anxiety Inventory- Short Form is a measure of anxiety where higher scores indicate higher/elevated anxiety. Minimum value 6 is and maximum value is 24.
- Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time [Baseline (Week 0) and Treatment (Week 12)]
STAI-6; State-Trait Anxiety Inventory- Short Form is a measure of anxiety where higher scores indicate higher/elevated anxiety. Minimum value 6 is and maximum value is 24.
- Memory for Emotionally Valent Words and Neutral Words [Baseline (Week 0) and Treatment (Week 12)]
Proportion correct out of 18 word pairs (6 positive, 6 negative and 6 neutral) after laboratory-induced stress using Trier Social Stress Test (TSST). Maximum score is 18 and minimum score is 0; higher scores indicate a better score.
- Change in Verbal Memory, Immediate Recall [Baseline and 12 weeks]
Immediate recall on the Logical Memory subset of the Wechsler Memory Scale-Revised, in which higher scores indicate a better recall and outcome. The minimum value is 0 and maximum value is 25.
- Change in Verbal Memory, Delayed Recall [Baseline and 12 weeks]
Delayed recall on the Logical Memory subset of the Wechsler Memory Scale-Revised, in which higher scores indicate a better recall and outcome. The minimum value is 0 and maximum value is 25.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Female
-
Perimenopausal as defined by the Stages of Reproductive Aging Workshop (STRAW) criteria, specifically in either of the two following stages: a) early transition defined as changes in cycle length of seven days or more in either direction in consecutive cycles or b) late transition defined as > 60 days amenorrhea and FSH > 40 IU/mL
-
Intact uterus/ovaries (i.e. no surgical menopause)
-
at least 1 self-reported hot flash per week
-
Estrogen therapy not contraindicated
-
Able to give informed consent
-
Age between 40 and 65 years
-
English as first and primary language
Exclusion Criteria:
-
Positive pregnancy test or breastfeeding (pregnancy tests will be given to all women)
-
Obesity > 35 BMI
-
Previous history of endometrial hyperplasia/neoplasia
-
Previous history of cancers of the breast or reproductive tract
-
History of presence of myocardial infarction (MI) or stroke
-
Current clinical diagnosis or a diagnosis within the past year of an anxiety disorder, severe recurrent depression, or severe psychiatric disturbance
-
History of head injury with more than 60 minutes loss of consciousness
-
History of neurological condition affecting cognitive function (e.g., brain tumor, multiple sclerosis)
-
History of developmental disability affecting cognitive function (e.g., mental retardation, attention deficit)
-
Current use of CNS-acting medication (e.g., antidepressants, anxiolytics, diphenhydramine)
-
History or presence of cerebrovascular accident, sickle cell anemia
-
History of alcohol or drug abuse as defined by DSM criteria
-
Abnormal vaginal bleeding of undetermined cause
-
Untreated or uncontrolled hypertension defined as systolic blood pressure greater than 165 mm hg or diastolic blood pressure greater than 95 mm hg
-
Concurrent administration of medication containing estrogen, progestin, SERM within four months of enrollment
-
Concurrent administration of medication containing St. John's wort, bisphosphonates, or dietary phytoestrogens within one month of enrollment
-
History of migraine associated with hormone use
-
History or presence of deep vein thrombosis, thrombophlebitis or thromboembolic disorder
-
Current participation in any other clinical trial within 30 days of enrollment
-
Smoker
-
Diabetes
-
Premature ovarian failure (defined as having last menstrual period before age 40)
-
Abnormal PAP smear in previous year
-
Abnormal mammogram in previous year
-
Vegans (vegetarians who tend to consume greater than average doses of phytoestrogens)
-
Allergy to soy (affects ~1% of people in the United States; reactions are typically mild)
-
Symptomatic fibroids (significant size or significant menstrual changes)
-
Menorrhagia
-
Lactose intolerant
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Illinois at Chicago | Chicago | Illinois | United States | 60612 |
Sponsors and Collaborators
- University of Illinois at Chicago
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Pauline M Maki, PhD, University of Illinois at Chicago
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 2009-0052
- 5R01MH083782-05
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | A total of 63 of the 96 enrolled subjects met the post-enrollment eligibility criteria. Twenty-three of 63 enrolled subjects withdrew prior to randomization. A total of 40 subjects were randomized. |
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Soy Phytoestrogen | Placebo |
---|---|---|---|
Arm/Group Description | 1 mg/d oral Estradiol pill and 0 mg/d oral placebo pill for 12 weeks, followed by 10 mg/d oral medroxyprogesterone acetate (MPA) pill, for 10 days. | 55 mg/twice daily oral Novasoy®/Soy Phytoestrogen pill for 12 weeks, followed by 0 mg/d oral placebo pill, for 10 days. | 0 mg tablet/twice daily oral placebo pill for 12 weeks, followed by 0 mg/d oral placebo pill, for 10 days. |
Period Title: Overall Study | |||
STARTED | 14 | 13 | 13 |
COMPLETED | 12 | 12 | 13 |
NOT COMPLETED | 2 | 1 | 0 |
Baseline Characteristics
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo | Total |
---|---|---|---|---|
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. (Total daily dose 110 mg) | Placebo pill b.i.d. (0 mg Novasoy® and 0 mg estradiol) | Total of all reporting groups |
Overall Participants | 14 | 13 | 13 | 40 |
Age (Count of Participants) | ||||
<=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Between 18 and 65 years |
14
100%
|
13
100%
|
13
100%
|
40
100%
|
>=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Age (years) [Mean (Standard Deviation) ] | ||||
Mean (Standard Deviation) [years] |
50.07
(4.16)
|
51.38
(3.90)
|
49.31
(3.84)
|
50.25
(3.97)
|
Sex: Female, Male (Count of Participants) | ||||
Female |
14
100%
|
13
100%
|
13
100%
|
40
100%
|
Male |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Region of Enrollment (Count of Participants) | ||||
United States |
14
100%
|
13
100%
|
13
100%
|
40
100%
|
Outcome Measures
Title | Change in STAI-6 Score |
---|---|
Description | STAI-6; State-Trait Anxiety Inventory- Short Form is a measure of anxiety where higher scores indicate higher/elevated anxiety. Minimum value 6 is and maximum value is 24. |
Time Frame | Week 0, 10, 12, and 16-18 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo |
---|---|---|---|
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. | Placebo pill b.i.d |
Measure Participants | 14 | 13 | 13 |
Baseline (Week 0) |
12.31
(0.74)
|
11.85
(0.74)
|
10.76
(0.76)
|
Early-Treatment(Week 10) |
11.69
(0.73)
|
11.38
(0.71)
|
11.24
(0.74)
|
Late-Treatment(Week 12) |
12.88
(0.75)
|
10.99
(0.72)
|
10.55
(0.75)
|
Post-Treatment (Week 16-18) |
11.84
(0.74)
|
11.19
(0.72)
|
11.15
(0.76)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Estradiol/Medroxyprogesterone Acetate, Phytoestrogen, Placebo |
---|---|---|
Comments | ||
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | .004 |
Comments | treatment x time p=.004 | |
Method | Mixed Models Analysis | |
Comments | ||
Other Statistical Analysis | A mixed effects regression model (Estimation method=maximum likelihood; Random intercept) was conducted to compare the effects of phytoestrogens and estradiol to placebo. Primary predictor variables in the model included treatment and time, as well the treatment by time interaction. |
Title | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time |
---|---|
Description | STAI-6; State-Trait Anxiety Inventory- Short Form is a measure of anxiety where higher scores indicate higher/elevated anxiety. Minimum value 6 is and maximum value is 24. |
Time Frame | Baseline (Week 0) and Treatment (Week 12) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo |
---|---|---|---|
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. | Placebo pill b.i.d |
Measure Participants | 14 | 13 | 13 |
Baseline (Week 0), Before Stressor |
8.73
(0.89)
|
8.69
(0.89)
|
9.77
(0.89)
|
Baseline (Week 0), After Stressor |
12.61
(0.89)
|
12.92
(0.89)
|
12.23
(0.89)
|
Post-Treatment (Week 12), Before Stressor |
8.25
(0.94)
|
10.87
(0.91)
|
9.61
(0.89)
|
Post-Treatment (Week 12), After Stressor |
13.70
(0.94)
|
15.37
(0.91)
|
12.69
(0.89)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Estradiol/Medroxyprogesterone Acetate, Phytoestrogen, Placebo |
---|---|---|
Comments | ||
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | .98 |
Comments | visit x time x treatment interaction p=.98 | |
Method | Mixed Models Analysis | |
Comments | ||
Other Statistical Analysis | A mixed effects regression model (Estimation method=maximum likelihood; Random intercept) was conducted to compare the effects of phytoestrogens and estradiol to placebo before and after a psychosocial stressor. Predictor variables in the model included treatment, time (before and after the psychosocial stressor), visit (Baseline, 12 weeks), and all two and three way interactions. |
Title | Memory for Emotionally Valent Words and Neutral Words |
---|---|
Description | Proportion correct out of 18 word pairs (6 positive, 6 negative and 6 neutral) after laboratory-induced stress using Trier Social Stress Test (TSST). Maximum score is 18 and minimum score is 0; higher scores indicate a better score. |
Time Frame | Baseline (Week 0) and Treatment (Week 12) |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo |
---|---|---|---|
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. | Placebo pill b.i.d |
Measure Participants | 14 | 13 | 13 |
Baseline (Week 0)- Control |
0.45
(0.08)
|
0.45
(0.08)
|
0.38
(0.08)
|
Baseline (Week 0)- TSST |
0.48
(0.08)
|
0.40
(0.08)
|
0.47
(0.08)
|
Post-Treatment (Week 12)- Control |
0.47
(0.08)
|
0.42
(0.08)
|
0.37
(0.08)
|
Post-Treatment (Week 12)-TSST |
0.51
(0.08)
|
0.46
(0.08)
|
0.44
(0.08)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Estradiol/Medroxyprogesterone Acetate, Phytoestrogen, Placebo |
---|---|---|
Comments | ||
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | .68 |
Comments | treatment x time (before and after the psychosocial stressor) x visit p=.68 | |
Method | Mixed Models Analysis | |
Comments | ||
Other Statistical Analysis | A mixed effects regression model (Estimation method=maximum likelihood; Random intercept) was conducted to compare the effects of phytoestrogens and estradiol to placebo on emotional memory following a laboratory induced stress. Primary predictor variables in the model included treatment, time (before and after the psychosocial stressor), visit (Baseline, 12 weeks), and all two and three way interactions. |
Title | Change in Verbal Memory, Immediate Recall |
---|---|
Description | Immediate recall on the Logical Memory subset of the Wechsler Memory Scale-Revised, in which higher scores indicate a better recall and outcome. The minimum value is 0 and maximum value is 25. |
Time Frame | Baseline and 12 weeks |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo |
---|---|---|---|
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. | Placebo pill b.i.d |
Measure Participants | 14 | 13 | 13 |
Mean (Standard Error) [test scores on the Logical Memory test] |
-.02
(0.87)
|
2.31
(0.82)
|
2.08
(0.82)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Estradiol/Medroxyprogesterone Acetate, Phytoestrogen, Placebo |
---|---|---|
Comments | ||
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | .11 |
Comments | treatment x time p=.11 | |
Method | Mixed Models Analysis | |
Comments | ||
Other Statistical Analysis | A mixed effects regression model (Estimation method=maximum likelihood; Random intercept) was conducted to compare the effects of phytoestrogens and estradiol to placebo on verbal memory (logical memory; immediate). Primary predictor variables in the model included treatment and time, as well the treatment by time interaction. |
Title | Change in Verbal Memory, Delayed Recall |
---|---|
Description | Delayed recall on the Logical Memory subset of the Wechsler Memory Scale-Revised, in which higher scores indicate a better recall and outcome. The minimum value is 0 and maximum value is 25. |
Time Frame | Baseline and 12 weeks |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo |
---|---|---|---|
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. | Placebo pill b.i.d |
Measure Participants | 14 | 13 | 13 |
Mean (Standard Error) [Test scores on the Logical Memory test] |
.87
(1.03)
|
1.61
(0.96)
|
1.08
(0.96)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Estradiol/Medroxyprogesterone Acetate, Phytoestrogen, Placebo |
---|---|---|
Comments | ||
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | .86 |
Comments | treatment x time p=.86 | |
Method | Mixed Models Analysis | |
Comments | ||
Other Statistical Analysis | A mixed effects regression model (Estimation method=maximum likelihood; Random intercept) was conducted to compare the effects of phytoestrogens and estradiol to placebo on verbal memory (logical memory; immediate)Primary predictor variables in the model included treatment and time, as well the treatment by time interaction. |
Adverse Events
Time Frame | Adverse event reporting forms have been completed for all participants reporting adverse events during bi-weekly phone safety screenings (Week 2, 4, 6 and 8), as well as in person visits during Week 10, and Week 12. | |||||
---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||
Arm/Group Title | Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo | |||
Arm/Group Description | 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 55 mg Novasoy pill b.i.d. | Placebo pill b.i.d | |||
All Cause Mortality |
||||||
Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/14 (0%) | 0/13 (0%) | 0/13 (0%) | |||
Serious Adverse Events |
||||||
Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/14 (0%) | 0/13 (0%) | 0/13 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
Estradiol/Medroxyprogesterone Acetate | Phytoestrogen | Placebo | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 1/14 (7.1%) | 0/13 (0%) | 0/13 (0%) | |||
Reproductive system and breast disorders | ||||||
Non-serious; irregular uterine bleeding | 1/14 (7.1%) | 1 | 0/13 (0%) | 0 | 0/13 (0%) | 0 |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Dr. Pauline Maki |
---|---|
Organization | University of Illinois at Chicago |
Phone | 312 996-6941 |
pmaki1@uic.edu |
- 2009-0052
- 5R01MH083782-05