FNOA: Antioxidants (2011-2012)

Citation:
 
Study Design:
Class:
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Quality Rating:
Research Purpose:

To investigate whether soy-derived isoflavone extract improves performance in cognitive function and quality of life in Chinese post-menopausal women.

Inclusion Criteria:
  • Chinese ethnicity with Hong Kong residency
  • Age between 55 and 75 years
  • Post-menopausal status (defined as at least 12 months since the last menstrual cycle) for the last five years
  • Body mass index (BMI) between 18 and 32kg/m2
  • No history of mental, neurological or other chronic disorders such as chronic renal failure, chronic liver failure or thyroid disease
  • No surgery of the gastrointestinal tract
  • No history of drug or alcohol abuse
  • No use of hormone therapy (HRT) in the preceding six months
  • No use of medication known to affect the nervous system
  • No use of isoflavone and calcium supplements in the past 12 months.
Exclusion Criteria:
  • Dementia
  • Parkinsonism
  • Insomnia of one month's duration or longer
  • Known intellectual problems
  • A history of a venous thromboembolic event
  • A history of head injury with loss of consciousness
  • Psychiatric illness
  • For any reason inability to give informed consent
  • Depression assessed by the Center for Epidemiologic Studies Depression scale with a score of higher than 16.
Description of Study Protocol:

Recruitment

The potential participants were recruited over a six-month period from the community through newspaper advertising and health talks. Other print media such as newspapers, posters and advertisements at hospitals, health clinics, elderly centers, some associations, churches and housing estates in Shatin, Hong Kong were also used. 

Design

Six-month double-blinded, randomized, placebo-controlled, parallel group trial.

Blinding Used

Double blinded. 

Intervention

Soy-derived isoflavones, 80mg orally daily for six months or a daily placebo for the same length of time. 

Statistical Analysis

  • Intention-to-treat analysis was used as the primary analysis and performed for those participants who were randomly assigned to receive treatment, had received at least one dose of the trial supplement and had returned for the six-month post-treatment evaluation
  • Further analysis was also performed separately for participants with good compliance, defined as those consuming at least 80% of the supplement capsules
  • Sub-group analysis by age groups (55 to 65 and 66 to 76) was also conducted
  • Comparisons of the baseline characteristics of the participants receiving the two treatments were done by using T-test for the continuous variables and a chi-square test for the categorical variables
  • For the estimation of treatment effect, a calculation was done for the mean differences and 95% CI of the change values from baseline to post-treatment between the treatment arms
  • The changes from baseline to six months were compared between treatment arms using the repeated-measures analysis of variance method
  • Effects of treatment on neuropsychological test results were also assessed after controlling for covariates (age, education, sleep, vasomotor symptoms and dietary isoflavone intake over the period of intervention) using the general linear model approach.
Data Collection Summary:

Timing of Measurements

Baseline and six months post-treatment.

Dependent Variables

Standardized neuropsychological tests of:

  • Memory: Trials one to five, short delay recall and long delay recall of  the Hong Kong List Learning Test (HKLLT)
  • Executive function: Color Trail one and two and Verbal Fluency
  • Attention: Digit Symbol Wechsler Adult Intelligence Scale-Revised (WAIS-R)
  • Motor control: Finger tapping right and left
  • Language: Boston Naming test
  • Visual perception and constructional ability: Visual reproduction Copy Wechsler Memory Scale-Revised (WMS-R)
  • Global cognitive function: Mini-mental State Examination (MMSE)
  • Short Form-36 (SF-36) domains of:
    • Physical functioning
    • Role, physical
    • Bodily pain
    • Vitality
    • Social functioning
    • Role, emotional
    • Mental health
    • General health.

Independent Variables

Soy-derived isoflavones, 80mg orally daily for six months or a daily placebo. 

Control Variables

  • Age
  • Education
  • Occupation
  • Sources of income
  • Smoking and drinking habits
  • Sleeping problems, difficulty sleeping
  • Time since menopause
  • Height
  • Weight
  • BMI
  • Systolic blood pressure
  • Diastolic blood pressure. 
Description of Actual Data Sample:
  • Initial N: 238 women, 200 randomized
  • Attrition (final N): 168 women

Age 

  Intervention Placebo
55 to 65 64.7% 64.8%
66 to 76 35.3% 35.2%
  • Ethnicity: Chinese
  • Other relevant demographics: See sociodemographic characteristics in Key Findings
  • Anthropometrics: Baseline characteristics similar between groups
  • Location: Hong Kong, China. 
Summary of Results:

Key Findings

Sociodemographic characteristics were similar among the participants in the two study arms:

  • About half completed primary education or less and 64% were aged 55 to 65 years
  • Other than two current smokers and four ex-smokers in the placebo group, all the participants were non-smokers
  • About 20% of the women in each group claimed to have some sleep problems
  • Anthropometric and blood pressure measurements were similar between the groups
  • Approximately 12% of the participants in either group reported cold or hot flashes at baseline and the mean number of vasomotor symptoms was low
  • The dietary intake pattern and mean intakes of soy protein and isoflavones at baseline and over the intervention period as assessed at follow-up were similar between the treatment and placebo groups
  • The neuropsychological test results indicated no significant differences between the two groups in any of the objective tests at baseline
  • The mean values of the tests at follow-up and the mean differences in the changes of the scores between the intervention and placebo groups over the treatment period were similar
  • No significant differences in the changes at the follow-up between the two groups were noted
  • Similar analyses conducted for the good compliers who consumed more than 80% of the capsules provided revealed similar results
  • The results also remained unchanged after adjustment for the potential covariates of age, education, sleeping problems from baseline, vasomotor symptoms and dietary isoflavone intakes over the intervention period.

The following table shows the 95% CIs and P-values for the differences in the changes of the test results between the two test groups (intervention minus placebo).

   Intent-to-treat       Analysis            Evaluation Based on Good Compliance 
 d 95% CI P 95% CI P
Memory    
HKLLT (trials one to five) -0.16(-2.53 to 2.21) 0.9  -0.36(2.78 to 2.05)  0.77
HKLLT (short delay recall) -0.01(0.71 to 0.7) 0.99  -0.04(0.76 to 0.68)  0.92
HKLLT (long delay recall) -0.35(1 to 0.31) 0.3  -0.41(1.08 to 0.26) 0.23
Visual reproduction        
I (WMS-R) 0.33(-1.23 to 1.88) 0.68 0.4(-1.19 to 1.99) 0.62
II (WMS-R) -1.07(-3.5 to 1.35) 0.38 -0.89(-3.36 to 1.59) 0.48
Executive function    
 Color Trail One 0.74(-3.13 to 4.6) 0.71  1.07(-2.92 to 5.06) 0.6
 Color Trail Two 0.38(-8.8 to 9.56) 0.94 0.89(-8.58 to 10.36) 0.85
 Verbal fluency 0.71(-0.69 to 2.11) 0.32 0.71(-0.72 to 2.14) 0.33
 Attention    
 Digit Symbol (WAIS-R) -0.63(-2.33 to 1.06) 0.46  -0.83(-2.55 to -0.88) 0.34
 Motor    
 Finger tapping, right 0.68(-1.09 to 2.44) 0.45 0.9(-0.9 to 2.69) 0.33
 Finger tapping, left -0.26(-1.88 to 1.35) 0.75 0.09(-1.47 to 1.64) 0.91
 Language    
 Boston Naming Test -0.05(-0.68 to -0.58) 0.88 -0.08(-0.73 to 0.57) 0.8
 Visual perception and constructional ability    
 Visual reproduction    
 Copy (WMS-R) 0.31(-0.73 to 1.35) 0.56 0.45(-0.62 to 1.51) 0.41
 Composite cognitive score 0.01(-1.18 to 1.2) 0.99 0.09(-1.13 to 1.3) 0.89
 Global cognitive score        
 MMSE 0.06(-0.45 to 0.57) 0.81 0.05(0.48 to -0.58) 0.85

The 95% CIs for the differences in the changes of the test results between the two test groups (intervention minus placebo) all overlapped zero.

  • This indicated that the differences were not statistically significant
  • Six of the point estimates for the tests were positive (favoring isoflavones), five were negative (favoring placebo) and two were neutral
  • No pattern of favorable effects was noted.

The following table shows the 95% CIs and the P-values for the analysis of the SF-36 domains:

 

Intent to treat analysis          

Evaluation based on good compliance
  95% CI P 95% CI P
SF-36        
Physical functioning -1.1(5.4 to 3.21) 0.61 -1.17(-5.58 to 3.24) 0.6
Role, physical 0.14(9.24 to 9.52) 0.98 -1.50(10.97 to 7.97) 0.75
Bodily pain -2.22(-10.75 to 6.32) 0.61 -2.04(10.87 to 6.78) 0.65
Vitality -3.47(-10.15 to 3.21) 0.31 -4.21(-11.07 to 2.65) 0.23
Social functioning -0.19(-6.18 to 5.8) 0.95 -0.24(-6.41 to 5.93) 0.94 
Role, emotional -2.02(-11.92 to 7.88) 0.69  -3.39(-13.47 to 6.88)  0.51
Mental health 0.18(-4.45 to 4.8) 0.94

-0.12(4.9 to 4.67)

0.96 
General health -1.75(-6.38 to 2.87) 0.46  -2.63(-7.34 to 2.08)  0.27 
  • Except for general health, there was a decrease in the other domains in both groups at the six-month assessment, but no between group statistically significant differences in the mean changes were noted
  • No significant differences in the baseline values for any of the eight SF-36 domains between the treatment and placebo groups or in changes in scores over the treatment period were noted
  • Similar findings were noted after controlling for the same potential covariates as those used for the neuropsychological tests.
Author Conclusion:
  • Menopause is associated with an accelerated decline in estrogen. Estrogen deficiency has been proposed as one of the causes of age-related cognitive decline in menopausal women.  Phytoestrogens, especially soy-derived phytoestrogens, have been shown to have an estrogenic effect and show preferential binding affinity to the β-estrogen receptors present in brain cells. It is hypothesized that isoflavone supplements will be beneficial in the promotion and preservation of cognitive function and the overall quality of life, but without the adverse effects of hormone therapy (HRT). Laboratory studies have shown the attenuation of neurodegeneration and relevant modifications of brain proteins by dietary soy isoflavones on cognitive function performance and the results have been equivocal. Previous studies the effects of HRT on cognitive function seemed to indicate a potential positive effect in younger post-menopausal women and in symptomatic women. HRT is effective in relieving menopausal symptoms and improving quality of life.
  • In this six-month, double-blind, placebo-controlled, parallel group trial of isoflavone supplementation at 80mg orally daily, results from 13 different standardized neuropsychological tests covering memory, attention, executive function, naming and verbal fluency, visual reproduction and motor function were evaluated. None of the differences among the changes of scores from baseline to six months were statistically significant. The numbers of tests results favoring or disfavoring isoflavone supplementation were equivocal and all of the 95% CIs overlapped zero. A test of global cognitive function also showed no difference between the treatment and placebo groups. Overall, there was no improvement in cognitive function and overall quality of life in generally healthy and asymptomatic Chinese post-menopausal women taking soy isoflavone supplementation. Due to the study limitations, these null results should be considered preliminary and should be interpreted with caution.
Funding Source:
Government: Research Grants Council of Hong Kong
In-Kind support reported by Industry: Yes
Reviewer Comments:

The authors note the following limitations:

  • This study was limited by the short treatment period of only six months and only one single dose of 80mg isoflavones was given. It is possible that different doses, different soy isoflavone components or longer periods of exposure than those used in this study are necessary to detect changes.
  • This study initially included 191 participants with 85 and 91 women in the intervention and placebo groups, respectively, completing the six-month trial. Although the sample size was comparable to that of a few previous studies and larger than others, it may still not be adequate to detect any changes over a six-month observation of intervention. The mean differences in changes of test scores noted between the two treatment arms were small and thus a substantially larger sample size would have been required to detect a significant difference in the small changes if present.
  • The study was conducted in a middle-aged and "younger-older" group among whom the changes might be small over six-month period, and a longer observation time would probably be required to detect a significant change
  • It has been proposed that the equol status of individuals may alter their responses to isoflavone intake. Equol is a metabolic product of the intestinal bacteria of the biotransformation precursor daidzein, which has the strongest affinity to estrogen receptors of the components of isoflavones and has a slower plasma clearance. Because equol status was not measured in the women in the study, it was not possible to delineate the treatment effects among equol producers and non-producers. Further studies of the effects of equol status in the Asian population are warranted.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? No
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes