Hot Flashes, Menopause
Conditions
Keywords
menopause, hot flashes, soy, estrogen, anxiety
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.
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.
Interventions
DIETARY_SUPPLEMENTSoy Phytoestrogen
Novasoy® pill (55 mg)
DRUGEstradiol
Estradiol pill (1 mg)
medroxyprogesterone acetate (MPA) (10mg)
DRUGSoy Placebo
oral placebo pill (0mg Soy Phytoestrogen)
DRUGMPA Placebo
oral placebo pill (0mg MPA)
Sponsors
National Institute of Mental Health (NIMH)
University of Illinois at Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 65 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Estradiol/Medroxyprogesterone Acetate 1 mg oral estradiol for 12 weeks followed by 10 mg/d oral MPA | 14 |
| Phytoestrogen 55 mg Novasoy pill b.i.d. (Total daily dose 110 mg) | 13 |
| Placebo Placebo pill b.i.d. (0 mg Novasoy® and 0 mg estradiol) | 13 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Pain/pain meds during Visit 4 | 0 | 1 | 0 |
| Overall Study | Unable to meet study timelines | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Phytoestrogen | Placebo | Estradiol/Medroxyprogesterone Acetate | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 13 Participants | 14 Participants | 40 Participants |
| Age, Continuous | 51.38 years STANDARD_DEVIATION 3.9 | 49.31 years STANDARD_DEVIATION 3.84 | 50.07 years STANDARD_DEVIATION 4.16 | 50.25 years STANDARD_DEVIATION 3.97 |
| Region of Enrollment United States | 13 Participants | 13 Participants | 14 Participants | 40 Participants |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 14 Participants | 40 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 1 / 14 | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Change in STAI-6 Score
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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estradiol/Medroxyprogesterone Acetate | Change in STAI-6 Score | Baseline (Week 0) | 12.31 score on STAI scale | Standard Error 0.74 |
| Estradiol/Medroxyprogesterone Acetate | Change in STAI-6 Score | Early-Treatment(Week 10) | 11.69 score on STAI scale | Standard Error 0.73 |
| Estradiol/Medroxyprogesterone Acetate | Change in STAI-6 Score | Late-Treatment(Week 12) | 12.88 score on STAI scale | Standard Error 0.75 |
| Estradiol/Medroxyprogesterone Acetate | Change in STAI-6 Score | Post-Treatment (Week 16-18) | 11.84 score on STAI scale | Standard Error 0.74 |
| Phytoestrogen | Change in STAI-6 Score | Post-Treatment (Week 16-18) | 11.19 score on STAI scale | Standard Error 0.72 |
| Phytoestrogen | Change in STAI-6 Score | Baseline (Week 0) | 11.85 score on STAI scale | Standard Error 0.74 |
| Phytoestrogen | Change in STAI-6 Score | Late-Treatment(Week 12) | 10.99 score on STAI scale | Standard Error 0.72 |
| Phytoestrogen | Change in STAI-6 Score | Early-Treatment(Week 10) | 11.38 score on STAI scale | Standard Error 0.71 |
| Placebo | Change in STAI-6 Score | Post-Treatment (Week 16-18) | 11.15 score on STAI scale | Standard Error 0.76 |
| Placebo | Change in STAI-6 Score | Early-Treatment(Week 10) | 11.24 score on STAI scale | Standard Error 0.74 |
| Placebo | Change in STAI-6 Score | Late-Treatment(Week 12) | 10.55 score on STAI scale | Standard Error 0.75 |
| Placebo | Change in STAI-6 Score | Baseline (Week 0) | 10.76 score on STAI scale | Standard Error 0.76 |
p-value: 0.004Mixed Models Analysis
Primary
Change in Verbal Memory, Delayed Recall
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estradiol/Medroxyprogesterone Acetate | Change in Verbal Memory, Delayed Recall | .87 Test scores on the Logical Memory test | Standard Error 1.03 |
| Phytoestrogen | Change in Verbal Memory, Delayed Recall | 1.61 Test scores on the Logical Memory test | Standard Error 0.96 |
| Placebo | Change in Verbal Memory, Delayed Recall | 1.08 Test scores on the Logical Memory test | Standard Error 0.96 |
p-value: 0.86Mixed Models Analysis
Primary
Change in Verbal Memory, Immediate Recall
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Estradiol/Medroxyprogesterone Acetate | Change in Verbal Memory, Immediate Recall | -.02 test scores on the Logical Memory test | Standard Error 0.87 |
| Phytoestrogen | Change in Verbal Memory, Immediate Recall | 2.31 test scores on the Logical Memory test | Standard Error 0.82 |
| Placebo | Change in Verbal Memory, Immediate Recall | 2.08 test scores on the Logical Memory test | Standard Error 0.82 |
p-value: 0.11Mixed Models Analysis
Primary
Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estradiol/Medroxyprogesterone Acetate | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Baseline (Week 0), Before Stressor | 8.73 score on STAI scale | Standard Error 0.89 |
| Estradiol/Medroxyprogesterone Acetate | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Baseline (Week 0), After Stressor | 12.61 score on STAI scale | Standard Error 0.89 |
| Estradiol/Medroxyprogesterone Acetate | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Post-Treatment (Week 12), Before Stressor | 8.25 score on STAI scale | Standard Error 0.94 |
| Estradiol/Medroxyprogesterone Acetate | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Post-Treatment (Week 12), After Stressor | 13.70 score on STAI scale | Standard Error 0.94 |
| Phytoestrogen | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Post-Treatment (Week 12), After Stressor | 15.37 score on STAI scale | Standard Error 0.91 |
| Phytoestrogen | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Baseline (Week 0), Before Stressor | 8.69 score on STAI scale | Standard Error 0.89 |
| Phytoestrogen | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Post-Treatment (Week 12), Before Stressor | 10.87 score on STAI scale | Standard Error 0.91 |
| Phytoestrogen | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Baseline (Week 0), After Stressor | 12.92 score on STAI scale | Standard Error 0.89 |
| Placebo | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Post-Treatment (Week 12), After Stressor | 12.69 score on STAI scale | Standard Error 0.89 |
| Placebo | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Baseline (Week 0), After Stressor | 12.23 score on STAI scale | Standard Error 0.89 |
| Placebo | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Post-Treatment (Week 12), Before Stressor | 9.61 score on STAI scale | Standard Error 0.89 |
| Placebo | Changes in STAI-6 Scores Before and After Psychosocial Stressor Over Time | Baseline (Week 0), Before Stressor | 9.77 score on STAI scale | Standard Error 0.89 |
p-value: 0.98Mixed Models Analysis
Primary
Memory for Emotionally Valent Words and Neutral Words
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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Estradiol/Medroxyprogesterone Acetate | Memory for Emotionally Valent Words and Neutral Words | Baseline (Week 0)- Control | 0.45 Proportion Correct | Standard Error 0.08 |
| Estradiol/Medroxyprogesterone Acetate | Memory for Emotionally Valent Words and Neutral Words | Baseline (Week 0)- TSST | 0.48 Proportion Correct | Standard Error 0.08 |
| Estradiol/Medroxyprogesterone Acetate | Memory for Emotionally Valent Words and Neutral Words | Post-Treatment (Week 12)- Control | 0.47 Proportion Correct | Standard Error 0.08 |
| Estradiol/Medroxyprogesterone Acetate | Memory for Emotionally Valent Words and Neutral Words | Post-Treatment (Week 12)-TSST | 0.51 Proportion Correct | Standard Error 0.08 |
| Phytoestrogen | Memory for Emotionally Valent Words and Neutral Words | Post-Treatment (Week 12)-TSST | 0.46 Proportion Correct | Standard Error 0.08 |
| Phytoestrogen | Memory for Emotionally Valent Words and Neutral Words | Baseline (Week 0)- Control | 0.45 Proportion Correct | Standard Error 0.08 |
| Phytoestrogen | Memory for Emotionally Valent Words and Neutral Words | Post-Treatment (Week 12)- Control | 0.42 Proportion Correct | Standard Error 0.08 |
| Phytoestrogen | Memory for Emotionally Valent Words and Neutral Words | Baseline (Week 0)- TSST | 0.40 Proportion Correct | Standard Error 0.08 |
| Placebo | Memory for Emotionally Valent Words and Neutral Words | Post-Treatment (Week 12)-TSST | 0.44 Proportion Correct | Standard Error 0.08 |
| Placebo | Memory for Emotionally Valent Words and Neutral Words | Baseline (Week 0)- TSST | 0.47 Proportion Correct | Standard Error 0.08 |
| Placebo | Memory for Emotionally Valent Words and Neutral Words | Post-Treatment (Week 12)- Control | 0.37 Proportion Correct | Standard Error 0.08 |
| Placebo | Memory for Emotionally Valent Words and Neutral Words | Baseline (Week 0)- Control | 0.38 Proportion Correct | Standard Error 0.08 |
p-value: 0.68Mixed Models Analysis