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Research Investigation of Soy and Estrogen (RISE)

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ClinicalTrials.gov Identifier: NCT00997893
Recruitment Status : Completed
First Posted : October 19, 2009
Last Update Posted : July 27, 2015
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of this study is to examine the effects of soy (NovaSoy®) and estrogen on menopausal symptoms such as hot flashes, sleep disturbances, and mood alteration in perimenopausal women.

Condition or disease Intervention/treatment Phase
Menopause Hot Flashes Dietary Supplement: Phytoestrogen Drug: Estradiol Drug: medroxyprogesterone acetate Other: Placebo Phase 2

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Detailed Description:

Recent research suggests that in addition to playing a role in disease prevention and menopausal symptom reduction, phytoestrogens can reduce anxiety-related behaviors in animals and improve memory in both animals and humans. This project seeks to investigate the potential anxiolytic (anti-anxiety) and cognition-enhancing effects of phytoestrogen treatment, in comparison to another popular treatment, estradiol, and placebo, for perimenopausal women. Given the detrimental effects of stress on memory performance, a widely used laboratory stressor will be implemented to investigate whether phytoestrogens and/or estradiol enhance memory by counteracting the negative effects of stress on memory processes.

Estrogen and Anxiety Recent animal studies suggest that estrogen can play an important role in modulating anxiety, yet there has been little human research on this topic. Research suggests that the anxiolytic effects of estrogens are mediated by estrogen receptor-beta 1 (ER-beta), one of two known estrogen receptors in the brain 2. ER-beta agonists decreased the release of stress hormones after immobilization stress in rats compared to no treatment and treatment with ER-alpha agonists 3. Additionally, transgenic female mice lacking ER-beta exhibited increased anxiety and decreased serotonin in several brain areas, including the hippocampus 4. The regulation of anxiety by ER-beta is likely to be related to the effects of ER-beta on serotonin transmission 5. The inhibition of anxiety-related behaviors in female rats is mediated by ER-beta in the hippocampus 6. Whereas ER-beta agonists decrease anxiety-related behaviors in female rats, ER-alpha agonists may work in an opposite fashion 3,7.

Phytoestrogens and Anxiety Unlike estrogen, which binds equally to ER-alpha and ER-beta, phytoestrogens have a much greater affinity for ER-beta than ER-alpha 8. Phytoestrogens are plant compounds that are structurally and functionally similar to endogenous estrogens and are currently being widely investigated to determine their potential role in disease prevention. Phytoestrogens have been shown to have anxiolytic effects in female rats. Specifically, female rats fed soy diets or soy supplements exhibited less anxiety-related behavior in a well-validated behavioral maze task compared to control-fed counterparts 9. Though the animal literature supports a role for phytoestrogens in reducing anxiety and/or stress responses following an acute stressor, current research in humans is inconclusive and is based on self-report measures of day-to-day stress rather than responses to acute stressors. Trials examining the effects of different soy-based preparations and diets on cognition and menopausal complaints have yielded inconsistent results. To date, three trials have found improved overall mood, depressive symptoms, anxiety symptoms or better reaction to the stress of testing 10,11 while five trials have shown no changes in these outcomes 12-15. No human studies have examined the potential anxiolytic effects of phytoestrogens on stress and anxiety following a laboratory stressor. Past studies have shown mixed evidence for whether phytoestrogens are beneficial in regards to menopausal symptoms. A recent study has shown that women who have a specific intestinal microflora, and thus are able to produce the isoflavan equol, are the ones who receive the benefit from the phytoestrogens, such as reduced anxiety, as equol has a greater estrogenic activity and affinity for both estrogen receptors (Ishiwata et al., 2009).

Stress and Anxiety in Midlife Women Recent studies demonstrate notable age and sex differences in stress responsivity. Postmenopausal women have larger increases in salivary cortisol after psychosocial laboratory stressors compared to premenopausal women 16. This finding was corroborated by a recent meta-analysis which indicated that the effect of aging on cortisol response to pharmacological or psychological challenge was about three times greater in women compared to men 17. A community-based study of adults in their 70s found greater 12-hour free cortisol excretion to be associated with poorer delayed verbal recall for women only 18. Women in this study who exhibited increases in cortisol excretion two and a half years later were more likely to show declines in memory performance at that time compared to women without increased cortisol excretion. Using a well-validated psychosocial laboratory stressor, Wolf and colleagues found a stronger detrimental effect of psychosocial stress on visual-verbal memory (pictorial memory for common items) for older women compared to older men 19. These data suggest that interventions that lower cortisol, particularly in women, may lower age-related memory declines.

Phytoestrogens and Cognition Soy isoflavones have been shown to enhance hippocampal (memory) and frontal lobe (executive) functioning in both clinical trials and animal studies. Research indicates that the neuroprotective properties of phytoestrogens include a positive impact on choline acetyltransferase and nerve growth factor in the hippocampus and frontal cortex of female rats 20 and a weakening of tau phosphorylations associated with Alzheimer's disease in primates 21. Cognitive improvements such as enhanced working memory and visual-spatial memory have been noted for female rats fed phytoestrogen-rich diets or supplements 22. Clinical trials have revealed a consistent improvement in mental flexibility and planning abilities (complex executive tasks) in samples of postmenopausal women (17, 18) as well as younger men and women (16). Further research examining the effects of phytoestrogens on executive tasks is warranted, as many trials, including a large recently published trial have not adequately tested this cognitive domain (15, 19-21, Ho et al., 2007). To date, seven randomized trials in humans have been published which examine the effects of phytoestrogens on verbal memory. Results indicated significant verbal memory improvements with phytoestrogens in young men and women 11 and non-significant trends toward improved verbal memory in four additional trials of younger postmenopausal women 12,13. Phytoestrogen treatment did not benefit verbal memory in the one trial involving only older postmenopausal women 14 and a recent trial of women aged 55-76 (Ho et al., 2007). Interestingly, these findings are largely consistent with the "critical period hypothesis" that proposes estrogen therapy benefits cognitive functioning only when initiated during the menopausal transition or shortly thereafter 23. Accumulating evidence suggests that phytoestrogen treatment may also specifically enhance cognition in the early menopause.


Study Design

Study Type : Interventional  (Clinical Trial)
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
Study Start Date : December 2009
Primary Completion Date : May 2015
Study Completion Date : May 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Menopause
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Estradiol/Medroxyprogesterone Acetate

Women in estradiol intervention group will take one active estradiol pill (1 mg) and one placebo pill at dinner, for a total daily dose of 1 mg estradiol and 0 mg Novasoy®. The UIC investigational drug service will obtain the estradiol tablets through the regular Hospital Pharmacy Purchases vendor, will encapsulate them, and will manufacture an identical appearing placebo to maintain blind.

Medroxyprogesterone acetate (MPA): The UIC IDS will dispense MPA (10 mg/d for 10 days) at the time of randomization. This progestin treatment is necessary to protect the uterine lining. These pills will be encapsulated in order to maintain blind .

Drug: Estradiol
Women in estradiol intervention group will take one active estradiol pill (1 mg) at breakfast and one placebo pill at dinner, for a total daily dose of 1 mg estradiol and 0 mg Novasoy®.
Other Name: estrogen, estradiol acetate
Drug: medroxyprogesterone acetate
At week 12 , after the participant completes her final assessments, women will begin taking MPA (10 mg/d for 10 days).
Other Name: MPA
Experimental: Phytoestrogen
Phytoestrogen: Women in the phytoestrogen intervention group will take one active Novasoy® (55 mg) pill at breakfast and active Novasoy® (55 mg) pill at dinner, for a total daily dose of 110 mg Novasoy® and 0 mg estradiol. The UIC Investigational Drug Service will obtain the Novasoy® tablets from Archer Daniels Midland and will encapsulate the tablets to maintain blind.
Dietary Supplement: Phytoestrogen
Women in the phytoestrogen intervention group will take one active Novasoy® (55 mg) pill at breakfast and active Novasoy® (55 mg) pill at dinner, for a total daily dose of 110 mg Novasoy® and 0 mg estradiol.
Other Name: NovaSoy 400
Other: Placebo
At week 12, after the participant completes her final assessments, women will begin taking placebo(10 days).
Other Name: sugar pill
Placebo Comparator: Placebo
Placebo: Women in this intervention group will take one placebo pill at breakfast and one placebo pill at dinner, for a total daily dose of 0 mg Novasoy® and 0 mg estradiol. The UIC investigational drug service will encapsulate the placebo tablets (lactose) in the same manner that they will encapsulate the estradiol and Novasoy® tablets to maintain blind.
Other: Placebo
Women in this intervention group will take one placebo pill at breakfast and one placebo pill at dinner, for a total daily dose of 0 mg Novasoy® and 0 mg estradiol.
Other Name: sugar pill
Other: Placebo
At week 12, after the participant completes her final assessments, women will begin taking placebo(10 days).
Other Name: sugar pill


Outcome Measures

Primary Outcome Measures :
  1. quality of life [ Time Frame: 18 weeks ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 65 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00997893


Locations
United States, Illinois
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
More Information

Responsible Party: Pauline M. Maki, Ph.D, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT00997893     History of Changes
Other Study ID Numbers: 2009-0052
5R01MH083782-05 ( U.S. NIH Grant/Contract )
First Posted: October 19, 2009    Key Record Dates
Last Update Posted: July 27, 2015
Last Verified: July 2015

Keywords provided by Pauline M. Maki, University of Illinois at Chicago:
menopause
hot flashes
soy
estrogen
anxiety

Additional relevant MeSH terms:
Hot Flashes
Signs and Symptoms
Estradiol
Polyestradiol phosphate
Estrogens
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Estradiol valerate
Medroxyprogesterone
Medroxyprogesterone Acetate
Phytoestrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Contraceptives, Oral, Synthetic
Contraceptives, Oral
Contraceptive Agents, Male
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogens, Non-Steroidal