Research Investigation of Soy and Estrogen

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Estradiol and Soy on Menopausal Symptoms

Conditions
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Menopause, Hot Flashes

Intervention / Treatment
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* Dietary Supplement: Soy Phytoestrogen
* Drug: Estradiol
* Drug: Medroxyprogesterone Acetate (MPA)
* Drug: Soy Placebo
* Drug: MPA Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estradiol/Medroxyprogesterone Acetate<br>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<br>* Estradiol pill (1 mg)<br>* Other names: estrogen, estradiol acetate;Drug: Medroxyprogesterone Acetate (MPA)<br>* medroxyprogesterone acetate (MPA) (10mg)<br>* Other names: MPA;Drug: Soy Placebo<br>* oral placebo pill (0mg Soy Phytoestrogen)<br>* Other names: sugar pill;|
| Experimental: Soy Phytoestrogen<br>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<br>* Novasoy® pill (55 mg)<br>* Other names: NovaSoy 400;Drug: MPA Placebo<br>* oral placebo pill (0mg MPA)<br>* Other names: sugar pill;|
| Placebo Comparator: Placebo<br>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<br>* oral placebo pill (0mg Soy Phytoestrogen)<br>* Other names: sugar pill;Drug: MPA Placebo<br>* oral placebo pill (0mg MPA)<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 0, 10, 12, and 16-18 | 
| 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. | Baseline (Week 0) and Treatment (Week 12) | 
| 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. | Baseline (Week 0) and Treatment (Week 12) | 
| 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. | Baseline and 12 weeks | 
| 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. | Baseline and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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menopause, hot flashes, soy, estrogen, anxiety