Summary
Evidence Report/Technology Assessment: Number 126
Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
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Introduction / Methods / Reporting the Evidence / Results / Limitations / Conclusions / Future Research / Availability of Full Report / References
Authors: Balk E, Chung M, Chew P, Ip S, Raman G, Kupelnick B,
Tatsioni A, Sun Y, Wolk B, DeVine D, Lau J.
Introduction
The aims of this evidence report are to summarize
the current evidence on the health effects of soy and its isoflavones on
the following: menopausal symptoms, bone health, cancers, cardiovascular
diseases, kidney diseases and cognitive function, as well as safety issues
and drug interactions. In addition, this report also summarizes the formulations
of soy products and/or soy food used in clinical trials. This report is requested
and funded by the National Center for Complementary and Alternative Medicine
(NCCAM) and the Office of Dietary Supplements at the National Institutes of Health (NIH), through the Evidence-based
Practice Center (EPC) program at the Agency for Healthcare Research and Quality
(AHRQ).
There is increasing interest in soy and health
since the U.S. Food and Drug Administration (FDA) approved a health claim
in October 1999 for use on food labels stating that a daily diet containing
25 grams of soy protein, also low in saturated fat and cholesterol, may reduce
the risk of heart disease. This claim was based on the beneficial results
in reducing plasma low-density lipoprotein (LDL) levels from dozens of human
controlled clinical trials.1 The health claim, however, covers
only soy protein, since research results surrounding soy isoflavones were
controversial.2
The aims of this report are to summarize the formulations
of soy products and/or soy food used in clinical trials, and to reflect the
current evidence on the health effects of soy and its isoflavones on the
following:
- Cardiovascular disease.
- Menopausal symptoms.
- Endocrine function.
- Cancer.
- Bone health.
- Reproductive health.
- Kidney disease.
- Cognitive function.
- Glucose metabolism.
In addition, safety issues and drug interactions
of using soy and its isoflavones as reported in the literature are summarized.
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Methods
Key Questions
Five general questions are addressed in this report:
- In
the clinical trial literature, what formulations of soy were used? At what
dose? For what purpose(s) (e.g., trial endpoints)?
- Does
current clinical trial evidence indicate that whole soy products and individual
constituents of soy have an effect on:
- Cardiovascular
events, risk factors, and measures.
- Menopausal
symptoms.
- Endocrine
function.
- Cancer
and tumor-related biomarkers.
- Osteoporosis
and osteoporosis risk factors.
- Reproductive
health.
- Kidney
function.
- Other
outcomes, based on results of Key Question 1?
- What
is the scientific evidence of a dose-response effect of different forms of
soy and individual constituents of soy for the conditions specified in Key
Question 1?
- What
are the frequency and type(s) of adverse events associated with consumption
of soy that are reported in the scientific literature (both trials and epidemiology)?
- What
is the scientific evidence of a dose-response effect of whole soy products
and individual constituents of soy on their safety?
Approach to Analyzing the Literature
Inclusion Criteria
This report encompasses several health conditions
and many outcomes of interest. Therefore, specific inclusion criteria were
needed for each of the health conditions and sometimes for different outcomes
of the same health condition. The common inclusion criteria for studies analyzed
in this report consist of:
- Human subjects 13 years and older.
- Prospective studies including randomized controlled trials, cohorts, crossover and non-randomized comparison studies.
- At least 5 subjects in the soy arm.
- Any health condition.
- Quantification of the amount of soy.
- Reported outcomes of interest.
In
general, the minimum duration for all serum marker, urine marker, and vascular
outcome studies was 4 weeks (exceptions are noted in Specific
Inclusion Criteria for Health Conditions Examined).
For assessments of adverse events, we also included
prospective observation studies and case-control studies, with no limitations
on study size or duration, or quantification of soy product.
Health Conditions of Interest
In addition to the health conditions of interest
listed under Key Question 3, the Technical Expert Panel (TEP) convened by
the EPC suggested the category of neurocognitive outcomes. NCCAM was also
interested in knowing about research that might have been done in other health
conditions. Therefore, our literature search was conducted to broadly include
soy studies for any health conditions. We screened all citations to identify
health conditions not on the list agreed upon with the TEP. During our review
process, we included the additional category of endocrine function.
Soy Products (and Controls) Considered
in this Report
We accepted studies that
used soy supplements and foods that quantified the amount of soy ingredients
or products. We categorized various soy products and soy food into
the following groups:
- Refined soy products:
- Isolated soy protein with isoflavones.
- Isolated soy protein without isoflavones.
- Textured soy protein.
- Soy derived isoflavone:
- Genistein/genistin.
- Daidzein/daidzin.
- Glycitein/glycitin.
- Soy/soya food products (ingested amount must be quantified):
- Whole soy beans (edamame).
- Soy flour.
- Soy drink (soy milk).
- Tofu (bean curd).
- Miso.
- Other processed soy bean products (tempeh,
natto, okara, etc.).
For the purpose of this
report, all study arms with a soy product of any type were considered to
be soy interventions. Only study arms with a non-soy intervention were
categorized as controls.
Specific Inclusion Criteria for Health
Conditions Examined
In addition to the above common inclusion criteria,
with input from TEP members we established the following additional criteria
and specific outcomes for each of the specific health conditions.
Cardiovascular outcomes. These included total cholesterol, LDL, high density
lipoprotein (HDL), triglycerides, lipoprotein(a) [Lp(a)], blood pressure
(BP), C-reactive protein (CRP), homocysteine, endothelial function, systemic
arterial compliance, and oxidized LDL. We also sought studies of clinical
cardiovascular outcomes (e.g., death, myocardial infarction, angina) but
found none. The list of outcomes was determined in consultation with the
TEP, based on expert opinion of the likelihood of an effect on the outcomes,
clinical importance, and estimates of the numbers of studies likely to
be available.
Because of the relatively large number of available
studies reporting on lipids, triglycerides, and blood pressure, it was decided
with the TEP to limit inclusion of these studies to randomized controlled
trials with a minimum of 10 subjects consuming a soy product. For all cardiovascular
outcomes, we required a minimum duration of 4 weeks.
Menopausal Symptoms. Studies evaluated
peri-menopausal women, post-menopausal women, or women on breast cancer
therapies with menopausal symptoms. A minimum duration of 4 weeks was required
for studies of menopausal symptoms.
Endocrine Function. We included in our analyses the following endocrine
markers: testosterone, follicle stimulating hormone (FSH), total estradiol
and thyroid stimulating hormone (TSH). In addition, we evaluated menstrual
cycle outcomes. The decisions for which outcomes to investigate were based
on expert opinion of the likelihood of an effect on the outcomes, clinical
importance, and estimates of the numbers of studies likely to be available.
Studies that did not report numerical data on effect for these outcomes were
not summarized; however, these studies were maintained in the database. For
all endocrine outcomes, we required a minimum duration of 4 weeks (or 1 menstrual
cycle).
Cancer and Tumor-Related Biomarkers. To evaluate whether soy may prevent cancer or reduce
cancer risk factors, we included only studies that recruited subjects without
a diagnosis of cancer. We limited our analyses to studies with tumor-related
biomarkers or cancer risk factors as outcomes and to studies of clinical
cancer outcomes (e.g., diagnosis of prostate cancer). We did not include
studies that used soy products as "treatments" for cancer. The only outcome
that fulfilled these criteria was testosterone. The studies that reported
testosterone as an outcome in men without diagnoses of cancer were analyzed
in the endocrine section. The decision to investigate only testosterone
was based on expert opinion of the likelihood of an effect on the outcomes,
and clinical importance. For all tumor-related biomarkers, we broadened
the eligibility criteria to include a minimum duration of 1 week.
Bone Endpoints. For bone resorption and/or formation biomarkers, the
general inclusion criteria were used, including a minimum duration of 4
weeks. Because effects on bone mineral density occur slowly over time,
we used minimum study duration of 1 year; although we did briefly review
studies with a duration less than 1 year.
Miscellaneous Outcomes. For all other outcomes (neurocognitive, kidney, glucose
metabolism), the general inclusion criteria were used in combination with
the restriction to populations without the related specific diseases or
conditions.
Literature Search Strategy
We conducted a comprehensive literature search
to address the key questions.* Primary literature searches for English
language publications on soy studies were conducted in EMBASE® on March 25,
2004, in MEDLINE® on April 20, 2004, and in CAB Abstracts on June 24, 2004.
Search terms included subject headings and textwords with filters to limit
the publications to English language and primary studies of the adult and
adolescent human populations. Subject headings and text words were selected
so that the same set could be applied to each of the different databases.
A supplemental search was performed in MEDLINE® on April 30, 2004, to retrieve
articles using the textword "miso". A search update was performed in MEDLINE®
In-Process & Other Non-Indexed Citations and MEDLINE® on September 30,
2004, and CAB Abstracts on October 4, 2004. A search of the TOXLINE® database
was conducted in March 31, 2005 to identify additional reports for adverse
events in humans. Additional sources of published and unpublished data were
sought by contacting members of the TEP, and from reference lists of selected
review articles and meta-analyses.
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Reporting the Evidence
Methodological Quality Grade
We used a 3-category grading system (A, B, C) to
denote the methodological quality of each study. This system defines a generic
grading system that is applicable to varying study designs including randomized
controlled trials, cohort, and case-control studies:
- A—Least bias; results are valid; a study that mostly adheres to the commonly held concepts of high quality.
- B—Susceptible to some bias, but not sufficient to invalidate the results, study that does not meet all the criteria in category A, above.
- C—Significant bias that may invalidate the results; a study with serious errors in design, analysis, or reporting.
Applicability Grade
In this report, the focus is on the U.S. population
and on specific subgroups within that population (i.e., post-menopausal women,
peri-menopausal women, pre-menopausal women, men, and people with relevant
medical histories, such as breast cancer). Even though a study may focus
on a specific target population, limited study size, eligibility criteria,
and the patient recruitment process may result in a narrow population sample
that is of limited applicability, even to the target population. To address
this issue, we categorized studies within a target population into 1 of 3
levels of applicability that are defined as follows: sample is representative
of the target population; sample is representative of a relevant sub-group
of the target population, but not the entire population; sample is representative
of a narrow subgroup of subjects only, and is of limited applicability to
other subgroups.
Meta-analysis
Meta-analysis was performed for several cardiovascular
outcomes. We used the random effects model for continuous outcomes to combine
studies. We also performed several random effects model meta-regression analyses
to explore possible reasons for discrepancies across studies and to address
Key Questions related to dose-response.
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Results
Soy Products
Soy supplements were used in about three-quarters
of all the trials analyzed in this report; soy foods were used in the remaining
trials. In this report, soy milk was categorized as a soy supplement. Among
the soy supplement trials, 57 percent used soy protein with isoflavones, 36 percent used
isoflavones alone, and 6 percent soy protein without isoflavones. In about one-half
of the soy foods trials, textured soy protein was used. Soy flour was used
in about one-quarter of the soy foods trials. There are 146 separate treatment
arms of soy supplementations and 68 separate treatment arms of soy foods
or diets. Across studies, the total isoflavones ranged from 0 mg to 185 mg
per day and the total protein intake from soy ranged from 0 g to 154 g per
day. Of note, the median soy product dose across studies (36 g soy protein
per day) was equivalent to over a pound of tofu daily or about 3 soy protein
shakes daily.
Cardiovascular Endpoints
No study evaluated clinical cardiovascular
events. A total of 68 randomized studies reported data on total cholesterol,
LDL, HDL, and/or triglycerides. The total isoflavones ranged from
0 mg to 185 mg per day, with a median of 80 mg. Among studies with soy protein,
the total protein intake from soy ranged from 14 to 113 g per day, with a
median of 36 g.
There is a great deal of heterogeneity of effects
found on lipoprotein and triglyceride levels. Overall, the majority of studies
reported small to moderate effects on the lipids, despite a wide range of
net effects for total cholesterol, LDL, and triglycerides. Sixty-one studies
reported data on the effect of consumption of soy products on total cholesterol
levels. The median net change compared to control found was approximately
-5 (interquartile range -10, +1) mg/dL decrease (about -2.5%). A meta-analysis
of 52 studies that reported data on the effect of soy consumption on LDL
levels yielded a statistically significant net decrease of 5 (95%
confidence interval [CI] -8 to -3) mg/dL (about -3%). A meta-analysis of
56 studies that reported data on the effect of soy consumption on HDL levels
found a statistically non-significant net change of +0.6 (95%
CI -0.5, +1.8) mg/dL. A meta-analysis combining 54 studies that reported
data on the effect of soy consumption on triglyceride levels yielded a net change of -8 (95% CI -11, -5) mg/dL (about -6%).
Across studies, there is the possible suggestion that higher doses of soy
protein are associated with greater LDL reduction among those with elevated
baseline LDL (although not if studies with minimal soy protein doses are
excluded), but not with HDL or triglycerides. Dose of isoflavones was not
associated with effect for any lipid. Higher baseline LDL or triglycerides
may also be associated with net effect for these 2 lipids; the effect of
baseline HDL is unclear. For all lipids, in individual studies the effect
of dose and baseline was generally inconsistent.
A total of 22 studies reported data on the effect
of consumption of soy products on systolic and diastolic BP. Overall, across
studies, there was no discernable effect.
Some of the well known emerging risk factors for
cardiovascular disease included for analysis in this report are: Lp(a), CRP,
homocysteine, endothelial function, systemic arterial compliance, and oxidized
LDL. The total number of studies that reported data on the effect of soy
consumption are: 18 studies on Lp(a), 3 on CRP, 5 on homocysteine, 10 on
endothelial function, 3 on systemic arterial compliance, and 13 on oxidized
LDL. Across these studies, there is no discernable effect based on the type
of soy products. The majority of studies were of poor quality with a narrow
range of applicability. Given the limited evidence and poor quality studies,
no conclusions could be drawn on the beneficial or harmful effects of consumption
of soy protein on these putative risk factors for cardiovascular disease.
Menopausal Symptoms
A total of 21 trials examine the effects of soy
and/or its isoflavones on hot flashes and night sweats in women. These trials
generally measured frequency and severity of the symptoms. However, a large
number of vasomotor symptom scores or indexes that employed a variety of
frequency intervals were used by the investigators. These factors made meta-analyses
unsuitable and limited the comparisons of results across studies. Furthermore,
many of the studies had high withdrawal or dropout rates that were frequently
uneven between soy treatment and control arms, further limiting the validity
of these trials.
Overall, the effects of soy protein and/or its isoflavones
are inconsistent across studies. Every trial found a decrease in hot flash
frequencies or scores in both the treatment groups and the control groups.
Thus, the results are difficult to interpret. A third of the studies found
no or worsening effects compared to control; two-thirds showed soy protein
and/or its isoflavones either non-significantly or significantly decreased
hot flash frequencies or scores compared to control in post-menopausal women.
The evidence of a benefit was stronger among the randomized trials of isoflavone
supplements, which mostly showed positive results—the net reduction in
weekly hot flash frequency ranged from 7 to 40 percent. However, these trials are
mostly rated as poor quality due to high dropout rates.
There are only 4
studies that evaluated the effect of soy consumption on menopausal symptoms
in peri-menopausal women or those receiving breast cancer therapy. Among
these studies there is no evidence that soy consumption is better than control
to reduce menopausal symptoms.
Endocrine Function
Measures of endocrine function were reported from
50 trials in 47 articles. Five studies with a total of 179 participants reported
testosterone levels in healthy males before and after soy consumption. Four
of these trials found a statistically non-significant decrease in testosterone
levels. The small total number of subjects as well as the low quality of
these studies precluded any meaningful conclusion. No statistically significant
effect was found on FSH level, which is commonly measured in the initial
evaluation of male and female infertility; results were conflicting.
Twelve studies reported estradiol levels at the
follicular phase in 434 pre-menopausal women. The overall effect of soy on
estradiol levels was not consistent. Most of the studies showed a trend for
soy reducing estradiol, although they failed to demonstrate a statistically
significant effect. Six randomized trials reported the effect of soy on TSH.
No overall effect of soy on TSH and thyroid function is clear.
An additional 11 trials (in 10 publications) evaluated
the effect of soy on menstrual cycle length in pre-menopausal women. A wide
range of soy interventions was used in these trials making a conclusion of
the effects from soy difficult. These trials did not show statistically significant
changes in menstrual cycle length after treatments of soy and/or its isoflavones.
Cancer and Tumor-Related Biomarkers
Twenty-four trials evaluated subjects without a
history of cancer for effects of soy on tumor-related biomarkers. No study
reported the development of cancer as an outcome. Most studies measured the
effect of soy on estrogens and estrogen metabolites as well as on estrogenicity
indicators. There were also trials that evaluated correlations between soy
and possible cellular pathways of cancer prevention. No causal relationship
could be established between these markers and cancer because they do not
represent known risk factors for cancer disease. Only 4 studies reported
on testosterone levels, which is a risk factor for prostate cancer, and are
discussed under Endocrine Function.
Bone Endpoints
Overall, 31 studies evaluated various markers of
bone health, including bone mineral density (BMD), bone formation biomarkers
(bone specific alkaline phosphatase and osteocalcin) and bone resorption
biomarkers (urinary hydroxyproline, urinary cross-linked N-telopeptide, urinary
pyridinoline, and urinary deoxypyridinoline).
Because there are few long-term randomized trials
and a wide variety of soy interventions used across studies, it is difficult
to draw an overall conclusion about the effects of soy on bone outcomes.
Overall, among the 5 studies of 1-year minimum duration, no consistent effect
on BMD was seen with soy consumption. Studies of shorter duration, likewise
found no effect of soy. Similar to the results in BMD, studies of bone formation
biomarkers generally found no effect of soy consumption when compared to
control. While a number of studies reported reductions in 2 markers of bone
resorption—urinary pyridinoline and deoxypyridinoline—no effects were
found on the other markers of bone resorption and the effects were not consistent
across studies. For these markers there is no clear evidence of a dose effect
for either soy isoflavones or soy protein.
Only one study found a consistent effect on these
markers. The study differed from other studies in that it evaluated a unique
formulation of soy genistein and that it excluded subjects with denser femoral
neck BMD.
Kidney Function, Neurocognitive Function, and Glucose Metabolism
Only 1 small study in patients with type 2 diabetes
assessed the effect of soy on kidney function. No statistically significant
changes in glomerular filtration rate was seen after 8 weeks of soy protein
diet. Four studies examined the effects of soy on cognitive function of post-menopausal
women and college students of both sexes. Overall, no statistically significant
or consistent effect was noted on neurocognitive functions such as verbal
episodic memory. Six studies evaluated the effect of soy on fasting blood
glucose. No statistically significant changes were reported.
Adverse Events
In general, the rates of adverse events reported
were greater in the soy treatment arms than in their respective control arms,
but adverse events related to soy consumption were generally minor. Overall,
soy products including isoflavones were well tolerated in the trials we examined.
The most frequently reported adverse events among
a total of 3,518 subjects in 49 studies (including 5 non-randomized and 3
pharmacokinetic studies) that reported adverse events were gastrointestinal
in nature. These were reported in 33 of 41 comparison studies
of soy diets, soy proteins, isoflavones, and phytoestrogen supplements. Most
of the gastrointestinal adverse events were reported in soy diet and soy
protein trials, especially the 12 studies that used purified isoflavone interventions
in dosages ranging from 40 to 100 mg/day. The amount of soy protein in these
trials ranged from 20 to 60 g/day, but there was no clear dose relationship
between the amount consumed and subsequent adverse events. Menstrual complaints,
reported in 15 studies, were also common. Six of these studies used purified
isoflavone interventions in dosages ranging from 40 to 80 mg/day. However,
most women in these studies were post-menopausal and the controls frequently
included hormone therapy regimens. Other adverse events included musculoskeletal
complaints, headache, dizziness, and rashes. In addition, there were somewhat
more withdrawals from the soy arms due to taste aversion.
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Limitations
Despite the large number of trials that have been
performed, the health effects of soy for many conditions that have been studied
remain uncertain. The methodological quality of over half the studies (about
55%) evaluated in this report was poor (Grade C). One-third of the poor quality
studies were either uncontrolled, single cohort studies, non-randomized comparative
studies, or comparative studies that were unclear whether they were randomized.
Another third of the poor quality studies had dropout rates that exceeded
20% or unequal dropout rates between soy and control. Among other reasons
studies were graded poor quality were lack of reporting of baseline data,
inadequate accounting of important confounders, major discrepancies between
text, tables, and/or figures or irreconcilable data that indicate likely
improper statistical analysis, and substantial missing data.
There was also great heterogeneity among studies, particularly
among the interventions analyzed. Comparisons across the myriad types of
soy are intrinsically very difficult. This difficulty was compounded by the
use of soy as both a supplement and as an integral part of the diet; furthermore
for numerous studies, it is difficult to distinguish between supplement and
diet. It is likely that studies of supplements and diet are not easily comparable.
Most studies involved a small number of study subjects and were of short
duration. About one-half of studies were of less than 12 weeks' duration
and about one-third were shorter than 6 weeks. Few studies directly compared
soy products, mostly comparing soy protein with varying amounts of soy isoflavones.
Only one study performed a factorial design study comparing both present
and absent soy protein and present and absent soy isoflavones, thus allowing
analysis of both the effect of soy protein and soy product. The universal
issue of possible publication bias, where negative studies are less likely
to be published and are more likely to be published later, is a potential
concern. However, for most outcomes, the majority of studies reported negative
outcomes, and there was no obvious evidence of publication bias among the
lipid studies (where there is evidence of a positive effect).
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Conclusions
Most of the studies evaluated the effects of soy on various
biomarkers or measures, not clinical outcomes, although, several of the endpoints,
such as blood pressure, LDL, and bone mineral density, do have known meaningful
correlations with clinical outcomes. Cardiovascular surrogate endpoints were
assessed by the largest number of studies. Overall, soy was found to have
a small effect on lipids. However, the duration of these studies were generally
short, and it is uncertain whether the results would be sustained. No study
evaluated clinical cardiovascular disease.
Reduction of hot flashes by soy was seen in trials involving
post-menopausal and peri-menopausal women. Most of the trials lasted only
3 to 4 months, thus the long-term benefits remain unclear. In addition, different
measurements were used to assess benefits across studies making comparisons
and synthesis difficult. Soy phytoestrogens are seen by some as an alternative
to estrogen therapy to treat post-menopausal symptoms. However, the estrogenic
effect of soy in potentially promoting tumor recurrence raises the concern
for its use by breast cancer survivors. The current literature provides no
data to address this issue.
The evidence does not support an effect of soy
products on endocrine function, menstrual cycle length, or bone health; although
evidence was often limited and of poor quality. No study evaluated clinical
endocrine or bone disease.
This report was limited to human studies, and
thus was unable to fully respond to biological or biochemical hypotheses
of benefits or harms of phytoestrogens suggested by various animal, in vitro,
or assay detection studies: the correlations between specific nutrients and
their effects remain unclear. While the evidence does suggest a greater likelihood
of adverse events with soy consumption, these were mostly minor in nature.
There were a limited number of studies with duration of 1 year or longer,
thus the long-term adverse effect of soy in a large population is uncertain.
For all outcomes, including adverse events, there is no
conclusive evidence of a dose-response effect for either soy protein or isoflavone.
However, for LDL reduction, there is a suggestion of a possible dose-response
effect for soy protein.
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Future Research
This report dealt with a broad range
of health conditions and endpoints, thus it is difficult to focus research
recommendations on a specific area. Common to most bodies of evidence
regarding medical fields, better quality, well-reported, larger
and longer duration studies are needed to address the questions
of interest. Future studies should fully report the components of soy products
being tested; compare different doses, soy products, and populations; more
closely evaluate the effects of different soy components, including non-protein,
non-isoflavone components; fully consider the types of foods being replaced
by soy products and the controls being used; and use the CONSORT statement
as a guide to designing and reporting studies. 3,4
Conducting clinical
trials in the area of health effects of food substance is fraught with
difficulties. There is a complex interplay among the various components
and potentially active substances within the foods and with other foods,
dietary variations, as well as with other lifestyle and clinical variations
among individuals. Controlling for these factors is difficult within a
trial. Interpreting discrepant results among trials is even more difficult.
Isoflavones are believed to be the key active substance in soy, but this
is by no means certain. Little data suggest that the amount of soy isoflavones
is associated with an incremental effect and studies of soy protein with
little or no isoflavones frequently had similar effects as isoflavone studies.
Difficulties with attempting to ascribe a food health benefit to a specific
component of the food are highlighted by the recent spate of disappointing
results from antioxidant trials, which suggest that the evaluation of potential
nutrient benefits may need a paradigm different from the traditional clinical
trial model.
The bioavailability
of an ingested nutrient may also be an important factor in the determination
of the beneficial effect. Several factors may affect the bioavailability
of ingested nutrients:
- Absorption rate, affected by the interactions with competitive nutrients, the usual diet compositions, and types of foods or supplements.
- Incorporation rate into the blood stream, in which complex mechanisms might be involved, such as the functions of facilitated transporters, receptors on the membrane, or cellular binding proteins.
- Metabolism of the intestinal bacterial environment.
Any one of these factors alone
does not determine the bioavailability. In order to gain insights on the
question of dose-response relationship, we not only need the information
on the soy isoflavone contents, including types and amount, but also on
the bioavailability of the ingested soy isoflavones.
Unfortunately studies that attempt to control for
the myriad factors that interfere with clear interpretation of the effect
of food products such as soy tend to be highly artificial, with little applicability
to the average person. Clarity is needed to define what study questions are
of interest. Metabolic laboratory studies or investigations of highly structured
or restricted diets (such as those where soy protein constitutes the bulk
of daily protein consumption) are of potential value only to possibly determine
which components of soy are bioactive or to determine what extremes of diet
may be necessary to achieve a benefit. Studies that substitute practical
amounts of soy products into average people's diets would better address
the question of whether people should make the effort to include more soy
in their diets, but these studies will invariably be difficult to interpret.
An exception to this may be studies of soy isoflavone supplements (e.g.,
non-food capsules), which may be interpreted more like usual drug trials.
Carefully controlled efficacy studies (those conducted
under the artificial conditions of a clinical trial) may still be useful
to pin down the relative effects of various components of soy. Once this
is better clarified, more practical effectiveness studies (that aim to test
the value of an intervention in more real-world scenarios) with feasible
interventions might be more important.
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Availability of Full Report
The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Tufts-New England Medical Center under Contract No.
290-02-0022. Printed copies of the final report may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 126, Effects of Soy on Health Outcomes.
The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a PDF File (8.5 MB) with Appendixes in PDF (5 MB), or as Zipped PDF Files (8 MB) [PDF Help].
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References
1. Anderson JW, Johnstone BM, Cook-Newell
ME. Meta-analysis of the effects of soy protein intake on serum lipids. N
Engl J Med 1995;333(5):276-82.
2. Henkel J. Soy: Health Claims for Soy Protein,
Questions About Other Components. FDA Consumer magazine 34(3);2000.
3. Moher D, Schulz KF, Altman DG, for the
CONSORT group. The CONSORT Statement: Revised Recommendations for Improving
the Quality of Reports of Parallel-Group Randomized Trials. Ann Intern Med
2001;134(8):657-62.
4. Altman DG, Schulz KF, Moher D, et al. The
Revised CONSORT Statement for Reporting Randomized Trials: Explanation and
Elaboration. Ann Intern Med 2001;134(8):663-94.
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AHRQ Publication Number 05-E024-1
Current as of August 2005
* Appendix
A (Search Strategy) is available in the full report electronically at http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1b.chapter.5490.
Internet Citation:
Balk E, Chung M, Chew P, et al. Effects of Soy on Health Outcomes. Summary, Evidence Report/Technology Assessment: Number 126. AHRQ Publication Number 05-E024-1, August 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/soysum.htm