RISE: Research Investigation of Soy and Estrogen

Sponsor
University of Illinois at Chicago (Other)
Overall Status
Completed
CT.gov ID
NCT00997893
Collaborator
National Institute of Mental Health (NIMH) (NIH)
96
1
3
65
1.5

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
  • Dietary Supplement: Soy Phytoestrogen
  • Drug: Estradiol
  • Drug: Medroxyprogesterone Acetate (MPA)
  • Drug: Soy Placebo
  • Drug: MPA Placebo
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

Study Type:
Interventional
Actual Enrollment :
96 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Effects of Estradiol and Soy on Menopausal Symptoms
Actual Study Start Date :
Dec 1, 2009
Actual Primary Completion Date :
May 1, 2015
Actual Study Completion Date :
May 1, 2015

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:
  • estrogen, estradiol acetate
  • Drug: Medroxyprogesterone Acetate (MPA)
    medroxyprogesterone acetate (MPA) (10mg)
    Other Names:
  • MPA
  • Drug: Soy Placebo
    oral placebo pill (0mg Soy Phytoestrogen)
    Other Names:
  • sugar pill
  • 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:
  • NovaSoy 400
  • Drug: MPA Placebo
    oral placebo pill (0mg MPA)
    Other Names:
  • sugar pill
  • 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:
  • sugar pill
  • Drug: MPA Placebo
    oral placebo pill (0mg MPA)
    Other Names:
  • sugar pill
  • Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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

    Ages Eligible for Study:
    40 Years to 65 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    No
    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.
    Responsible Party:
    Pauline M. Maki, Ph.D, University of Illinois at Chicago
    ClinicalTrials.gov Identifier:
    NCT00997893
    Other Study ID Numbers:
    • 2009-0052
    • 5R01MH083782-05
    First Posted:
    Oct 19, 2009
    Last Update Posted:
    Dec 7, 2020
    Last Verified:
    Nov 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by Pauline M. Maki, Ph.D, University of Illinois at Chicago
    Additional relevant MeSH terms:

    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

    1. Primary Outcome
    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.
    2. Primary Outcome
    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.
    3. Primary Outcome
    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.
    4. Primary Outcome
    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.
    5. Primary Outcome
    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

    Enrollment goals of 120 women were not met. Many declined to participate due to concerns about the safety of taking estrogens (the study was performed shortly after publication of the Women's Health Initiative) and due to the time commitment.

    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
    Email pmaki1@uic.edu
    Responsible Party:
    Pauline M. Maki, Ph.D, University of Illinois at Chicago
    ClinicalTrials.gov Identifier:
    NCT00997893
    Other Study ID Numbers:
    • 2009-0052
    • 5R01MH083782-05
    First Posted:
    Oct 19, 2009
    Last Update Posted:
    Dec 7, 2020
    Last Verified:
    Nov 1, 2020