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Soy as an Endocrine Disruptor: Cause for Caution?



Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.
© Freund Publishing House Ltd., London Journal of Pediatric Endocrinology & Metabolism, 23, 855-861 (2010)
VOLUME 23, NO. 9, 2010 855
Soy as an Endocrine Disruptor: Cause for Caution?
Bar-El Dadon S and Reifen R
School of Nutritional Sciences, The Robert H. Smith Faculty of Agriculture, Food and Environment,
The Hebrew University of Jerusalem, Rehovot, Israel
Endocrine disrupting compounds (EDCs) alter
the function of the endocrine system and
consequently cause adverse health effects.
Phytoestrogens, natural plant compounds
abundantly found in soy and soy products,
behave as weak estrogen mimics or as anti-
estrogens. They are considered to be EDCs,
and have some beneficial effects on health,
including reducing the risk of breast cancer
and improving metabolic parameters. How-
ever, the supporting evidence that con-
sumption of phytoestrogens is beneficial is
indirect and inconsistent. Lifetime exposure to
estrogenic substances, especially during
critical periods of development, has been
associated with formation of malignancies and
several anomalies of the reproductive systems.
Phytoestrogen consumption in infants, through
soy-based formulas, is of particular concern.
Prospective epidemiological studies for the
evaluation of the effect of phytoestrogens
alone, and in combination with other estro-
genic chemicals, are lacking, yet possible
adverse effects should not be taken lightly.
Endocrine disrupting compounds (EDCs) are
chemicals with the potential to elicit negative
effects on the endocrine systems of humans and
wildlife. They include a broad class of chemicals
such as natural estrogens/androgens, synthetic
estrogens/androgens, and industrial chemicals1.
Synthetic chemicals are not the only exogenous
agents that have caused health concerns because
Corresponding author:
Ram Reifen MD MSc
of their hormone-like activity. Of particular
interest are the phytoestrogens, which are defined
as any plant compounds structurally and/or
functionally similar to ovarian and placental
estrogens and their active metabolites2. These
compounds can be found in blood and urine
samples of virtually every person and animal on
this planet, often in high concentrations. The
main phytoestrogens derived from the diet are
genistein, daidzein and glycitein, which are
isoflavones. Soy is considered to be the richest
source of plant estrogens. Soybeans are
ubiquitously used in the food industry, including
milk formula substitutes, and have become
increasingly popular over the past 20 years.
Studies have shown that there is a large
variability in isoflavone content and composition
in soybeans, depending on the variety of soy
grown, as well as environmental conditions3. The
metabolism of isoflavones is rather complex. The
two major isoflavones, genistein and daidzein, are
present in soy as glycosides, which are bio-
logically inactive4. Once ingested, isoflavone
glycosides are hydrolyzed in the intestinal wall,
resulting in the conversion to their corresponding
bioactive aglycones. Isoflavones are similar in
their spatial conformation to mammalian
estrogens, bind to estrogen receptors and affect
estrogen-regulated gene products5. They have
traditionally been considered to be weak estro-
gens5. However, isoflavones have the potential to
exert physiologic effects in humans consuming
soy foods, since serum isoflavone levels are 100-
1000 times higher than endogenous estrogen
levels6. In addition, several phytoestrogens,
mostly genistein and its analogs, possess binding
affinities for the ER far greater than many of the
EDCs of concern7,1, such as bisphenol A, and
diethylstilbestrol (DES). Hence, from a potency
standpoint, the phytoestrogens exert a far greater
impact on human exposure to exogenous
estrogens than do the synthetic chemicals. This
denotes that the estrogenic activities derived from
phytoestrogens cannot be neglected.
This review summarizes the health-effect of
different exposures to phytoestrogens as a class of
A number of clinical and epidemiological
studies have evaluated the effects of soy and its
isoflavones on human metabolism, among which
some suggest that soy protein or isoflavones
consumption is associated with lower risk of
diabetes and a reduction in plasma concentration
of total and LDL cholesterol8,9. However, a
significant number of studies reported an absence
of beneficial effects of soy on classical metabolic
parameters such as body weight, serum lipid
profiles, fat mass, blood glucose and insulin
profiles10,11. These discrepancies make it difficult
to draw firm conclusions regarding the beneficial
effect of soy on glucose and lipid metabolism. As
in humans, reports in rodents also indicate that
the effect of soy isoflavones is not always
towards an improvement in metabolic parameters,
but rather differs, depending on the tissue
investigated, and the dose and timing of exposure.
For example, neonatal exposure to genistein
caused a significant increase in body weight in
mice at 4 months of age12. Dang et al. suggest
that genistein affects adipogenesis of mouse
progenitor cells in a biphasic way; an inhibition
of adipogenesis at low concentrations and stimu-
lation of adipogenesis at high concentrations13.
Overall, the effects of soy isoflavones are com-
plex and their mechanism of action is yet to be
clarified, and though positive dietary trends for
the use of soy have been demonstrated in several
studies, it still cannot be considered a substitute
for pharmacological therapy for people with
hypercholesterolemia. Taking into account also
the inconsistency in the results, any discussion
regarding its beneficial effect should be handled
with caution.
It has long been known that grazing on clover-
rich pastures high in phytoestrogens precursors
causes infertility in sheep14. More recently,
considerable evidence from laboratory animal
studies exists of the adverse effects of exposure
of males and females to estrogen disruptors,
including genistein, during critical periods of
A study by Eustache et al. provides evidence
that lifelong exposure to low-dose genistein
and/or vinclozolin results in reproductive devel-
opmental anomalies, alterations in sperm
production and quality, and fertility disorders15.
This study contrasts previous reports based on
short windows of exposure to these compounds,
showing only mild or no reproductive alterations.
You et al.16 reported that exposure to either
genistein or methoxychlor (MXC) resulted in
extensive developmental alterations in both male
and female reproductive tracts. In addition, in
utero and lactational exposure to maternally
dosed genistein and MXC affects development in
male rats at the prepubertal stage17. Exposure to
high-dosage of these compounds, particularly to a
combination of the two, also caused marked
feminization of the adult male mammary gland,
well recognizable through morphological evalua-
tion and detection of milk protein expression18.
Neonatal exposure of mice to genistein at
environmentally relevant doses caused abnormal
estrous cyclicity, altered ovarian function, early
reproductive senescence, subfertility/infertility19.
Although genistein was administered as s.c
injections in this study, its circulating serum
levels were similar to the range of those found in
infants consuming soy-based formulas20. Similar
doses were used in another study, in which
neonatal rat pups were orally treated with
genistein, also showing adverse effects, including
multiple ovarian follicles in the ovary and
reduced female fertility21. Early developmental
stages were not the only sensitive stages to
exposure of phytoestrogens. Studies conducted on
adult male rats have also shown that acute
exposure to a diet of high phytoestrogen content
transiently reduces their fecundity22.
Studies using other phytoestrogens including
daidzein23 have also demonstrated disruptions in
reproduction, supporting the concept that phyto-
estrogens, although weaker than 17β-estradiol,
VOLUME 23, NO. 9, 2010
can cause adverse effects on the developing
reproductive tract.
In human trials, Chavarro et al. found an
inverse association between consumption of soy
foods and sperm concentration which was more
pronounced at the higher end of the sperm
concentration distribution and among overweight
or obese men24. Studies have also shown
prolongation of the menstrual cycle in healthy
premenopausal women given soy protein daily
containing 45 mg of isoflavones, attributed to
prolongation of the follicular phase due to
suppression of the normal midcycle surge in FSH
and LH 25. It was also found that vegetarian diets
containing high levels of soy during pregnancy
have been associated with increased incidence of
hypospadias in the male offspring26.
These observations, together with the in-
creasing incidence of testicular dysgenesis syn-
drome (hypospadias, cryptorchidism, poor semen
quality and testicular cancer)27 in the last decade,
may propose a link between exposure to EDCs, as
phytoestrogens, during critical periods of repro-
ductive development and disorders of impaired
masculinization in males. Overall, it is evident
that an exposure to various estrogenic compounds
during critical periods of development can have
adverse consequences on reproductive systems,
both in rodents and humans. Therefore, an
extensive use of soy and its products, especially
in infants' formulas, should be of great concern.
Over the past decades, the age of onset of
puberty has tended to decrease. This phenomenon
could be partially attributed to the presence of
environmental factors, such as dietary phyto-
estrogens. Several studies have noted that
pubertal onset may be hastened, delayed, or
unchanged by early exposure to phytoestrogens,
an effect to which females seem to be particularly
susceptible, and that it is dependent upon
compound, dose, and timing of exposure. For
instance, gestational and lactational exposure to a
mixture of isoflavones hastened the onset of
puberty in female mice, while males were
unaffected28. Postnatal exposure to genistein and
coumestrol hastened the onset of puberty in
female rats23,29. Treatment with genistein during
gestation and lactation reduced anogenital
distance (AGD) and body mass during pre-
pubertal development and increased the
expression of defensive behaviors in adult male
mice30. It is important to mention that the
abnormal development of AGD induced by
genistein showed a non-linear dose response;
genistein at low-dose exerted a greater effect than
the high dose. This non-monotonic pattern has
been reported in other studies of endocrine
disrupting chemicals, such as bisphenol A and
diethylstilbestrol (31), and it is proposed that high
doses of EDCs can induce toxicity, whereas low
doses often show increased bioactivity32. These
data suggest that puberty is a sensitive endpoint
upon which perinatal phytoestrogens may exert
their effects with a relatively long latency.
The anti-carcinogenic potential of phyto-
estrogens on the risk for various cancers,
especially of the breast, has been evaluated in
several studies. Despite this, no clear consensus
has emerged regarding the preventive action of
phytoestrogens against cancer. Experimental
studies support the human observations that
timing of exposure may be a critical factor in
determining the effects of phytoestrogens. For
example, isoflavones found in soy products have
been generally thought to confer reduced breast
cancer risk33. However, experimental evidence
from other studies in rats and mice provides
support for the view that phytoestrogens may
negatively affect breast cells. Genistein
administration in rats during gestation resulted in
a dose-dependent increase in mammary tumor
susceptibility in the F1 animal34, and a significant
increase in mammary tumor weight and volume,
and lung metastases were observed in female rats
receiving soy-isoflavones35. Genistein at low
concentration stimulated cell growth in mammary
epithelia cells (MCF-7)36. Dietary genistein
stimulated growth of estrogen-dependent breast-
cancer tumors37,38, and also negated the inhibitory
effect of tamoxifen on growth of estrogen-
dependent human breast cancer (MCF-7) cells
implanted in athymic mice39. A recent study by
Taxvig et al. found that a mixture of phyto-
estrogens increased estradiol production and
decreased testosterone production in H295R
human adrenal corticocarcinoma cells, indicating
an induced aromatase activity40. In addition,
various mixtures of phytoestrogens significantly
stimulated MCF-7 human breast adenocarcinoma
cell growth and induced aromatase activity in
JEG-3 choriocarcinoma cells. Overall, their
results indicate that nutrition-relevant concentra-
tions of phytoestrogens possess various endocrine
disrupting effects. In humans, findings from
epidemiological studies of isoflavone intake and
breast cancer risk are equivocal. However, most
studies suggest that soy consumption is not
associated with a reduced breast cancer risk41-43.
Moreover, soy supplementation might also
increase the proliferation rate of cells in breast
biopsies of premenopausal women44. Overall,
epidemiologic and clinical data support the view
that lifetime exposure to estrogens has significant
influence on increased breast cancer risk45. As for
phytoestrogens, studies suggest that both
proliferative and antiproliferative effects are
observed, depending on tumor cell type, dose,
timing of phytoestrogen exposure, and phyto-
estrogen given. This may be because phyto-
estrogens can act via multiple mechanisms of
action, both estrogen-receptor mediated and non-
receptor mediated, and compounds like genistein
have been shown to possess both estrogenic and
antiestrogenic properties. This raises the question
of whether foods rich in phytoestrogens may have
complex actions in such diseases as breast cancer,
exerting both preventive and promoting effects
and perhaps depending on whether or not the
tumor is estrogen dependent. Thus, caution is
necessary in promoting the beneficial effects of
phytoestrogens, in particular with respect to
breast cancer.
The most disquieting aspect of misuse of soy
is in the perinatal period, mostly in infant foods.
Approximately one million American infants
ingest large doses of phytoestrogens in soy-based
formula every year. Total isoflavone concentra-
tions in soy-based infant formulas were found to
be much higher than the isoflavone concen-
trations in human breast milk and cow's milk-
based infant formulas, which were negligible46,47.
Circulating plasma concentrations of isoflavones
in 4-month-old infants fed exclusively soy-based
formula were found to be 13,000 to 22,000 times
higher than plasma estradiol concentration in
early life48. Therefore it is hard to believe that
soy-derived isoflavones, circulating at these
enormous concentrations, are biologically inert in
infants. To date, there is very little research on the
effects of soy consumption by infants. Therefore,
it is only logical to take a precautionary approach
in cases where there are potential adverse effects
due to soy consumption.
Data on the effect of exposure to
phytoestrogens on puberty in humans is in-
sufficient. A recent study by Zung et al. reports a
higher prevalence of breast buds during the
second year of life in female infants fed with soy-
based formulas, possibly due to the estrogenic
effect of the isoflavones in soy49. Similar studies
in neonates and children are lacking.
The relationship between early life exposures
to EDCs and functioning in adult life is poorly
understood. The period of highest susceptibility
to adverse effects from environmental exposure is
in utero. Other important critical development
stages include lactation, adolescence and
senescence. The critical period represents a
developmental window during which endocrine
signals can program genes, which regulate the
functioning of a tissue. If proper programming
fails to occur during this time, structural or
functional abnormalities can result. Therefore, it
is essential to study exposure at each stage rather
than to extrapolate risk associated with
developmental exposure based on data from
The difference in cancer risk in Asian vs.
Western populations should also be addressed.
Asian men consume 5–10 times more
VOLUME 23, NO. 9, 2010
phytoestrogens than Western men, and exhibit
low rates of incidence and mortality of breast,
prostate and colorectal cancers33,50. Some studies
suggest that lifestyle and diets are the two main
causes of these differences. However, there may
be other factors that could make Western men
more susceptible to phytoestrogens. The long
term exposure of the east Asian population to
soy-based foods has probably resulted in an array
of adaptations at the population level, namely in
different allelic repertoire compared with
European or North American human populations.
Such likely adaptations could be reduced
sensitivity to different phytochemicals, and
different patterns of receptors to phytochemicals,
governed by the respective alleles.
Human exposure to environmental estrogens
has increased tremendously over the past 20
years. Estrogenic compounds are abundant in
both agricultural and industrial products as well
as increased consumption of nutritional
supplements containing soya.
Several studies, mostly in animals, denote that
soy products, and specifically through phyto-
estrogens, have a beneficial effect on health,
including breast cancer and improved metabolic
parameters. However, data from human studies
do not support these findings, and often
contradict them, indicating that phytoestrogens
could potentially be hazardous to human health.
Phytoestrogens, as an endocrinal disruptor,
probably have a much broader impact which goes
beyond identifying the effects of one substance.
One should consider the possible additive,
antagonistic or synergistic activity of simul-
taneous exposure to various agents, as industrial
contaminants and pharmaceutical estrogens,
which may synergistically affect health.
The putative physiological effects of phyto-
estrogens have created a market that has been
utilized by the food industry as a cheap ingredient
in an array of products. The public perceives soy
as a natural product and hence has a positive
attitude towards it and is unaware of the potential
cellular and molecular targets common with
synthetic EDCs, which have been proved to be of
concern. Future efforts in the study of
phytoestrogens need more focus on timing,
frequency and duration of exposure to these
compounds. Studies undertaken in uncontrolled
situations or done retrospectively should be
replaced with prospective controlled studies.
Until the effect of soy is thoroughly investigated,
soy should be consumed with caution, especially
during the perinatal period but also in the adult
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... Formulas made from soy protein are useful options for infants with galactosemia or congenital lactase deficiency and are also used for infants with milk allergies [152]. Because of the phytoestrogen content in this type of formula, its use is limited by the concern of potential harm to infants [152,166], but evidence on this subject is controversial [167]. ...
... An additional issue to consider when discussing complementary food and puberty is the introduction of soy-based foods. Indeed, this issue has been extensively researched, primarily because of the amount of isoflavones provided by these foods [166,180]. Isoflavones, initially classified as phytoestrogens, have been more recently considered selective estrogen receptors [180]. In their review, Chakraborty et al. [167] suggested that phytoestrogens may play a role in precocious puberty [181]. ...
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Puberty is a critical phase of growth and development characterized by a complex process regulated by the neuroendocrine system. Precocious puberty (PP) is defined as the appearance of physical and hormonal signs of pubertal development at an earlier age than is considered normal. The timing of puberty has important public health, clinical, and social implications. In fact, it is crucial in psychological and physical development and can impact future health. Nutritional status is considered as one of the most important factors modulating pubertal development. This narrative review presents an overview on the role of nutritional factors as determinants of the timing of sexual maturation, focusing on early-life and childhood nutrition. As reported, breast milk seems to have an important protective role against early puberty onset, mainly due to its positive influence on infant growth rate and childhood overweight prevention. The energy imbalance, macro/micronutrient food content, and dietary patterns may modulate the premature activation of the hypothalamic–pituitary–gonadal axis, inducing precocious activation of puberty. An increase in knowledge on the mechanism whereby nutrients may influence puberty will be useful in providing adequate nutritional recommendations to prevent PP and related complications.
... As well, being among the eight most allergenic foods in the world, extensive research has been done in this area. Another important problem is the discussion of the consequences of long-term consumption of soy-based products that may lead to unwanted improvements in sexual and reproductive development, immune functions, visual activity, and thyroid functions (Ito, 2015;Bar-El Dadon & Reifen, 2010). Due to these above-mentioned reasons, soy will eventually be replaced with chickpeas. ...
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Abstract Today, there are hundreds of different diets recommended around the world for healthy nutrition from the “Karatay diet” to the “Stone Age diet” or “Paleo diet”. Almost none of these diets prohibit the consumption of legumes. In fact, physicians have also recommended eating a small amount of chickpeas regularly in order to reduce stomach acidity. Chickpeas also have a distinct place in the vegetarian diet due to the nutritional components they contain. Leblebi stands out as a healthy and tasty traditional product that can be consumed at any time of the day. Although chickpeas contains 30% starch, the glycaemic index of leblebi is low (20-30), indicating that it will not suddenly increase the blood glucose level. The aim of this review is to provide an overview of probiotic opportunities for new product development and nutrition research of the traditional chickpea product of Turkey known as leblebi.
... If the survey respondent was female, the average discount associated with fresh edamame is about 71 cents. This observation may be related to public uncertainty surrounding the safety of phytohormones in soy products for women's health (White et al., 2000;Duffy et al., 2007;Bar-El and Reifen, 2010;Cederroth et al., 2012), which are present in lower levels in frozen edamame products (Simonne et al., 2000). Meanwhile, the more likely a respondent was to shop local, the less they were willing to pay for a fresh edamame product. ...
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Introduction of locally adapted, commercially viable edamame varieties can allow it to be marketed as fresh, local, organic, or on the stalk. Here, we utilized a one-and-one-half bounded (OOHB) elicitation format to estimate mean willingness to pay (WTP) for these external attributes in relation to a vector of explanatory variables. Results showed 84-, 85-, and 28-cent premiums for fresh, local, and organic edamame (10 oz). Pro-environmental attitudes drove WTP for all three of these attributes, while shopping location significantly increased mean WTP for fresh and organic attributes. A 40-cent price discount was observed for the “on-the-stalk” attribute, suggesting that convenience also plays an important role in marketing edamame. The results suggest that more research regarding edamame demand is warranted.
... Importantly, flavonoids have numerous subclasses, e.g., flavones, flavanones, flavonols, isoflavones, and isoflavanes. The main phytoestrogens derived from the diet are genistein, daidzein, and glycitein, which belong to isoflavones [53]. You can find a graphical classification of phytoestrogens with a focus on phytoestrogens described in the article in Figure 1. 4 Oxidative Medicine and Cellular Longevity Soy seems to be the richest source of plant estrogens. ...
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Alzheimer's disease (AD) is the most common form of dementia with a growing incidence rate primarily among the elderly. It is a neurodegenerative, progressive disorder leading to significant cognitive loss. Despite numerous pieces of research, no cure for halting the disease has been discovered yet. Phytoestrogens are nonestradiol compounds classified as one of the endocrine-disrupting chemicals (EDCs), meaning that they can potentially disrupt hormonal balance and result in developmental and reproductive abnormalities. Importantly, phytoestrogens are structurally, chemically, and functionally akin to estrogens, which undoubtedly has the potential to be detrimental to the organism. What is intriguing, although classified as EDCs, phytoestrogens seem to have a beneficial influence on Alzheimer's disease symptoms and neuropathologies. They have been observed to act as antioxidants, improve visual-spatial memory, lower amyloid-beta production, and increase the growth, survival, and plasticity of brain cells. This review article is aimed at contributing to the collective understanding of the role of phytoestrogens in the prevention and treatment of Alzheimer's disease. Importantly, it underlines the fact that despite being EDCs, phytoestrogens and their use can be beneficial in the prevention of Alzheimer's disease.
... Another interesting fact to be highlighted is that some phytoestrogens from soya derivatives presented in ice cream, for instance, may act like estrogen mimics or even as antiestrogen, acting as endocrine disruptors, thereby altering the function of the endocrine system. [82] Remarkably, the APVMA reported that if regulators are worried about hormonal intake levels, especially those which lead to estrogenic effects, then many different staple foods need to be investigated, such as dairy, legumes, eggs and soy-based products. [21] Codex raised a concern about the hormone residues left at injection sites, where the hormone application is administered. ...
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Growth Promoters (GP) have been used for decades in animal production, although some countries restrict or forbid their use. With the increasing population worldwide, the demand for animal protein is also increasing, together with concerns about health, animal welfare and food safety. In this sense, the use of GP in cattle and pigs is an attempt to produce protein more efficiently. This review covers the legislation from the main meat-producing countries, GP restrictions, pharmacokinetics and mechanisms, besides possible effects of GP on human health.
... PEs possesses different health benefits like a lowered risk of heart disease, osteoporosis, menopausal symptoms, breast cancer, etc. (Sunita and Pattanayak, 2011). Many scientific studies also considered PEs as endocrine disruptors, indicating that they have probable adverse health effects as well (Bar-El Dadon and Reifen, 2010). Limited studies have been accompanied by the consequence of PE exposure on the fetus. ...
Carotenoids are widely distributed in nature. They are present in all living organisms, from bacteria, yeast, marine, and freshwater organisms including microalgae, phytoplankton, crustaceans, and fish to higher plants and animals. Naturally occurring carotenoids are important sources of antioxidants, antiinflammatory and antitumor compounds. Epidemiological studies have shown a correlation between a high carotenoid intake in the diet with a reduced risk of colorectal, cervical, ovarian, and breast cancers. The mechanisms of carotenoids for cancer chemoprevention include nuclear receptors, growth factor signaling, effects on gap -junctional intercellular communication, cell cycle progression, differentiation-related proteins, retinoid-like receptors, antioxidant response element, and inflammatory cytokines. The present chapter focuses on the potential role of carotenoids for the treatment of breast cancer.
... In subsequent years, much in the same way interest in the benefits of isoflavones expanded, concern about isoflavones expanded to include areas such as thyroid function (Divi, Chang, and Doerge 1997;Divi and Doerge 1996) and cognitive function (White et al. 2000). In fact, both isoflavones (and other phytoestrogens) and soy are routinely referred to as endocrine disruptors Bar-El and Reifen 2010;Chung et al. 2019;Fernandez-Lopez et al. 2016;Beszterda and Min, Wang, and Liang 2020), a designation first made >20 years ago (Ginsburg 1996), although there has also been pushback against this classification, especially in the case of soyfoods (Messina 2011). ...
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Soybeans are a rich source of isoflavones, which are classified as phytoestrogens. Despite numerous proposed benefits, isoflavones are often classified as endocrine disruptors, based primarily on animal studies. However, there are ample human data regarding the health effects of isoflavones. We conducted a technical review, systematically searching Medline, EMBASE, and the Cochrane Library (from inception through January 2021). We included clinical studies, observational studies, and systematic reviews and meta-analyses (SRMA) that examined the relationship between soy and/or isoflavone intake and endocrine-related endpoints. 417 reports (229 observational studies, 157 clinical studies and 32 SRMAs) met our eligibility criteria. The available evidence indicates that isoflavone intake does not adversely affect thyroid function. Adverse effects are also not seen on breast or endometrial tissue or estrogen levels in women, or testosterone or estrogen levels, or sperm or semen parameters in men. Although menstrual cycle length may be slightly increased, ovulation is not prevented. Limited insight could be gained about possible impacts of in utero isoflavone exposure, but the existing data are reassuring. Adverse effects of isoflavone intake were not identified in children, but limited research has been conducted. After extensive review, the evidence does not support classifying isoflavones as endocrine disruptors.
... In particular, estrogens and oral contraceptives or creams containing testosterone or estrogens can cause an early closure of the growth plate. Similarly, an excessive intake of foods containing phytoestrogens such as soya, according to some studies, may have an effect on bone age progression (56)(57)(58)(59)(60)(61)(62)(63). ...
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Bone age represents a common index utilized in pediatric radiology and endocrinology departments worldwide for the definition of skeletal maturity for medical and non-medical purpose. It is defined by the age expressed in years that corresponds to the level of maturation of bones. Although several bones have been studied to better define bone age, the hand and wrist X-rays are the most used images. In fact, the images obtained by hand and wrist X-ray reflect the maturity of different types of bones of the skeletal segment evaluated. This information, associated to the characterization of the shape and changes of bone components configuration, represent an important factor of the biological maturation process of a subject. Bone age may be affected by several factors, including gender, nutrition, as well as metabolic, genetic, and social factors and either acute and chronic pathologies especially hormone alteration. As well several differences can be characterized according to the numerous standardized methods developed over the past decades. Therefore, the complete characterization of the main methods and procedure available and particularly of all their advantages and disadvantages need to be known in order to properly utilized this information for all its medical and non-medical main fields of application.
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Soy is a key food in human nutrition. It is widely used in eastern traditional cuisine and it has recently diffused among self-conscious and vegetarian diets. The success of soy mainly depends on versatility and supposed healthy properties of soy foods and soy components. Meanwhile, the possible influence on endocrine system, in particular by isoflavones, raised concerns among some researchers. The present paper aims to conduct a review of available data on the effect of soy, soy foods and soy components on women's fertility and related outcomes. Eleven interventional studies, eleven observational studies and one meta-analysis have been selected from the results of queries. A weak, not clinically relevant effect has been highlighted on cycle length and hormonal status. However, a suggestive positive influence has been shown among women with fertility issues and during assisted reproductive technologies. Overall, soy and soy components consumption do not seem to perturb healthy women's fertility and can have a favourable effect among subjects seeking pregnancy. However, because of the paucity of studies exploring the impact of soy intake on women's fertility, as well as the limited population sample size, the frequently incomplete specimens' collection to investigate all cycle phases and the insufficient characterisation of participants, the evidence is suggestive and it needs further in-depth research taking into account all these aspects.
Phytoestrogens (PEs) are natural estrogen-like substances. They are subdivided into four main classes: isoflavones, lignans, stilbenes (polyphenols), and coumestans. PEs are broadly distributed in regular diet and herbs. They have multiple targets within cells, including the epigenome, that could be advantageous to the development of a chemopreventive drug. Breast cancer is one of the most common cancers found in women. It is the second leading cause of cancer-related death after lung cancer. Chemoprevention using PEs against breast cancer may be an effective approach. PEs have shown anticancer activity via mechanisms, including modulation of estrogen receptors (ERs), redox homeostasis, cell signaling pathways, regulation of the cell cycle, and inhibition of enzyme, angiogenesis, and epigenetic alterations. PEs can bind inadequately to ERs and have a special affinity for ER-β that can inhibit the transcriptional activity of ER-α. Genistein, daidzein, and resveratrol are some of the well-studied PEs. There are some critical issues in developing PEs as effective chemopreventive agents for breast cancer. Still, the multiple targets in breast cancer cells and their capability to modulate the cancer cell homeostasis may lead to the development of new, nontoxic, long-acting, and highly specific therapeutic agents.
Isoflavone (IF), a type of phytoestrogen, has multiple beneficial effects, but too much phytoestrogen can have adverse effects on offspring. To examine whether chronic exposure to high IF has adverse effects on reproductive development, mice offspring were exposed to IF through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning until sacrifice. In male offspring, there was no difference between the IF group and controls; however, in female offspring in the IF group, remarkably earlier puberty and induction of multioocyte follicles on postnatal day (PND) 21 were observed. Gene expression levels of estrogen receptor decreased in the ovary and vagina on PND 21. These results suggest that chronic exposure to higher than normal levels of IF induces alterations in the reproductive development of female mice through an estrogenic effect.
The hormonal activity of natural estrogens is influenced by the degree to which they bind to serum proteins. In the pregnant female and in the fetus, greater than 99% of estradiol may be bound by serum binding proteins. Therefore, even though total serum levels of estradiol appear very high in fetuses, we have found that in rodent fetuses, there is a very low free concentration of estradiol (0.2 pg/ml). Naturally occurring variation in fetal serum estradiol predicts differences in numerous postnatal traits, including prostate size. In addition, when this low level of free estradiol was experimentally increased from 0.2 to 0.3 pg/ml during the last third of fetal life, treated male mice showed an increase in adult prostate weight. Fetal exposure to low doses of xenobiotic estrogens by feeding to pregnant females, including the compounds methoxychlor (20 and 2000 μg/kg body weight), DES (0.02 to 2 μg/kg body weight) and bisphenol A (2 and 20 μg/kg body weight), also led to increased prostate weight in adulthood. In contrast, fetal doses of natural estradiol and DES above the physiological range of estrogenic activity, and within a toxicological dose range, led to the opposite outcome, a reduction in subsequent adult prostate weight. This indicates that it may be impossible to assess endocrine-disrupting activities in response to low doses within a physiological range of activity by using high, toxic doses of xenoestrogens in testing procedures. We have developed approaches in vitro to predict the potential estrogenic bioactivity of compounds in the physiologically relevant range in animals and humans. We address the following factors in predicting the final observed endocrine-disrupting effect in the animal: (1) the intrinsic estrogenic activity of a given molecule, (2) the effective free concentration determined by how the molecule is carried in serum, (3) partitioning between aqueous and lipid compartments in body and cell lipids, and (4) absorption and metabolism relative to the route of exposure. The studies and strategies we describe are important in developing criteria for a tiered testing system for the detection of estrogenic chemicals as well as endocrine-disrupting chemicals with different modes of action.
This paper complies animal and human data on the biologic effects and exposure levels of phytoestrogens in order to identify areas of research in which direct species comparisons can be made. in vitro and in vivo assays of phytoestrogen action and potency are reviewed and compared to actions, dose-response relationships, and estimates of exposure in human subjects. Binding studies show that the isoflavonoid phytoestrogens are high-affinity ligands for estrogen receptors (ERs), especially ER beta, but have lower potency in whole-cell assays, perhaps because of interactions with binding proteins. Many other enzymatic actions require concentrations higher than those normally seen in plasma, in vivo data show that phytoestrogens have a wide range of biologic effects at doses and plasma concentrations seen with normal human diets. Significant in vivo responses have been observed in animal and human tests for bone, breast, ovary, pituitary, vasculature, prostate, and serum lipids. The doses reported to be biologically active in humans (0.4-10 mg/kg body weight/day) are lower than the doses generally reported to be active in rodents (10-100 mg/kg body weight/day), although some studies have reported rodent responses at lower doses. However, available estimates of bioavailability and peak plasma levels in rodents and humans are more similar. Steroidogenesis and the hypothalamic-pituitary-gonadal axis appear to be important loci of phytoestrogen actions, but these inferences must be tentative because good dose-response data are not available for many end points. The similarity of reported proliferative and antiproliferative doses illustrates the need for fuller examination of dose-response relationships and multiple end points in assessing phytoestrogen actions.
The estrogenic isoflavone genistein is a common dietary component that has been shown to affect reproductive development in experimental animals at high doses. The objective of the present study was to examine interactions of genistein and the hormonally active pesticide methoxychlor on mammary gland development in juvenile rats. Timed-pregnant Sprague-Dawley rats were fed a soy- and alfalfa-free diet containing different combinations of genistein (300 and 800 ppm) and methoxychlor (800 ppm). Rats were fed these diets starting on gestation day (GD)1 and continuing through pregnancy and lactation until postnatal day (PND) 22, when the pups were killed. Inguinal mammary glands from both female and male pups were processed as whole-mount preparations for morphometric analysis. The total glandular area and the numbers of branch points, lateral buds, and terminal end buds in the male rats were found to be significantly greater in the groups exposed to methoxychlor than those exposed to genistein only. These effects were not observed in the female rats. In the male rats, methoxychlor had the most prominent effect on elongating the glandular ducts, while genistein enhanced the ductile branching. The 2 compounds in combination promoted the development of alveolar-lobular structure, an effect not observed with either compound alone. Immunostaining for proliferating cell nuclear antigen revealed a high percentage of immunopositive cells in the mammary epithelia of the males exposed to methoxychlor and genistein (800 ppm) compared to the controls. While no significant changes in serum levels of mammotrophic hormones were detected, increased immunostaining for insulin-like growth factor-1 receptor, estrogen receptor a, and progesterone receptor in the genistein 1 methoxychlor group suggested that local factors involved in regulating mammary growth may have played a role in propagating the endocrine effects of these two compounds. These
Objective To investigate the possible role of the maternal diet, particularly vegetarianism and consumption of phytoestrogens, in the origin of hypospadias, which is reported to be increasing in prevalence. Subjects and methods Detailed information was obtained prospectively from mothers, including previous ob-stetric history, lifestyle and dietary practices, using structured self-completed questionnaires during pregnancy. Previously recognized associations with en-vironmental and parental factors were examined, focusing particularly on the hypothesized hormonal link. Multivariate logistic regression was used to identify independent associations. Results Of 7928 boys born to mothers taking part in the Avon Longitudinal Study of Pregnancy and Childhood, 51 hypospadias cases were identified. There were no significant differences in the proportion of hypospadias cases among mothers who smoked, consumed alcohol or for any aspect of their previous reproductive history (including the number of previous pregnancies, number of miscarriages, use of the contraceptive pill, time to conception and age at menarche). Significant differences were detected for some aspects of the maternal diet, i.e. vegetarianism and iron supplementation in the first half of pregnancy. Mothers who were vegetarian in pregnancy had an adjusted odds ratio (OR) of 4.99 (95% confidence interval, CI, 2.10–11.88) of giving birth to a boy with hypospadias, compared with omnivores who did not supplement their diet with iron. Omnivores who supplemented their diet with iron had an adjusted OR of 2.07 (95% CI, 1.00–4.32). The only other statistically significant association for hypospadias was with influenza in the first 3 months of pregnancy (adjusted OR 3.19, 95% CI 1.50–6.78). Conclusion As vegetarians have a greater exposure to phytoestrogens than do omnivores, these results support the possibility that phytoestrogens have a deleterious effect on the developing male reproductive system.
Estrogens used in hormone replacement therapy regimens may increase the risk of developing breast cancer. Paradoxically, high consumption of plant-derived phytoestrogens, particularly soybean isoflavones, is associated with a low incidence of breast cancer. To explore the molecular basis for these potential different clinical outcomes, we investigated whether soybean isoflavones elicit distinct transcriptional actions from estrogens. Our results demonstrate that the estrogen 17β-estradiol effectively triggers the transcriptional activation and repression pathways with both estrogen receptors (ERs) ERα and ERβ. In contrast, soybean isoflavones (genistein, daidzein, and biochanin A) are ERβ-selective agonists of transcriptional repression and activation at physiological levels. The molecular mechanism for ERβ selectivity by isoflavones involves their capacity to create an activation function-2 surface of ERβ that has a greater affinity for coregulators than ERα. Phytoestrogens may act as natural selective estrogen receptor modulators that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ERβ that trigger transcriptional pathways.
The amounts of 12 isoflavones were measured in 8 American and 3 Japanese soybean varieties by using C-18 reversed-phase high-performance liquid chromatography. In Vinton 81 soybeans of 1989-1991, variation in total isoflavone ranged from 1176 to 3309 mu g/g. Isoflavone amounts of soybeans grown in different locations in 1991 ranged from 1176 to 1749 mu g/g. Crop year seemed to have a much greater influence on isoflavone content in Vinton 81 than did location. Isoflavones in the other seven American varieties (Pioneer 9111, Pioneer 9202, Prize, HP204, LS301, XL72, Strayer 2233) ranged from 2053 to 4216 mu g/g. The major isoflavone constituents were 6''-O-malonylgenistin, genistin, 6''-O-malonyldaidzin, and daidzin. Isoflavone contents in three Japanese varieties (Keburi, Kuro diazu, Raiden) ranged from 2041 to 2343 mu g/g and from 1261 to 1417 mu g/g for soybeans grown in 1991 and 1992, respectively. Compared with American varieties, Japanese varieties had higher 6''-O-malonylglycitin contents and higher ratios of 6''-O-malonyldaidzin to daidzin and 6''-O-malonylgenistin and genistin.
Recently, significant concerns have been placed on the widespread use of chemicals with persistent estrogenic activity for their long-term effects on human health. In this communication, we investigated whether fetal exposure to some of these chemicals at doses consumed by people, has any long-term effect on the reproductive functions of the male offspring. Thus, time-pregnant CD-1 mice were fed diethylstilbestrol (DES), bisphenol A (BPA), and aroclor (aroclor 1016) at an average concentration of 100 ng/kg/day, 50 μg/kg/day, and 50 μg/kg/day, respectively, during Days 16–18 of gestation. A high dose of DES (200 μg/kg/day) was also tested to compare the results of the current study with those of others using the high dose only. The offspring were examined at Day 3, Day 21, and Day 60 following birth. We demonstrated that BPA, aroclor, and the lower dose of DES enhanced anogenital distance, increased prostate size, and decreased epididymal weight. No effect was found on the testicular weight or size. The chemicals also permanently increased androgen receptor (AR) binding activity of the prostate at this dosage. This is the first demonstration that environmental chemicals program AR function permanently at the dosage consumed by the general population. The higher dosage of DES, on the other hand, produced an opposite effect, decreasing prostate weight, prostate AR binding, and anogenital distance, thus confirming the previous reports. To investigate whether the above mentioned effects of the chemicals represent direct or indirect effects, we also tested the effect of the chemicals on prostate development in vitro. Thus fetal urogenital sinus (UGS), isolated at the 17th day of gestation was cultured with the chemicals in the presence and absence of testosterone (10 ng/ml) for 6 days, and prostate growth was monitored by determining the size and branching of the specimen following histology. Results showed that these chemicals induced prostate growth in the presence and absence of testosterone. They also increased androgen-binding activity. Thus, the results of the in vivo studies were reproduced in the in vitro experiments, suggesting a direct effect of these chemicals on the development of fetal reproductive organs. This is the first demonstration that estrogenic chemicals induce reproductive malformation by direct interference with the fetal reproductive organs and not by interfering with the maternal or fetal endocrine system. The chemicals are able to induce malformation even in the absence of fetal testosterone; however, they are more effective in the presence of testosterone.
High isoflavone intake has been related to decreased fertility in animal studies, but data in humans are scarce. Thus, we examined the association of soy foods and isoflavones intake with semen quality parameters. The intake of 15 soy-based foods in the previous 3 months was assessed for 99 male partners of subfertile couples who presented for semen analyses to the Massachusetts General Hospital Fertility Center. Linear and quantile regression were used to determine the association of soy foods and isoflavones intake with semen quality parameters while adjusting for personal characteristics. There was an inverse association between soy food intake and sperm concentration that remained significant after accounting for age, abstinence time, body mass index, caffeine and alcohol intake and smoking. In the multivariate-adjusted analyses, men in the highest category of soy food intake had 41 million sperm/ml less than men who did not consume soy foods (95% confidence interval = -74, -8; P, trend = 0.02). Results for individual soy isoflavones were similar to the results for soy foods and were strongest for glycitein, but did not reach statistical significance. The inverse relation between soy food intake and sperm concentration was more pronounced in the high end of the distribution (90th and 75th percentile) and among overweight or obese men. Soy food and soy isoflavone intake were unrelated to sperm motility, sperm morphology or ejaculate volume. These data suggest that higher intake of soy foods and soy isoflavones is associated with lower sperm concentration.