Xenoestrogens & Phytoestrogens: Ultimate Estrogen 'Detox' Tips
Are parabens xenoestrogens?
Parabens are conspicuously “not” everywhere. Walking down any pharmacy aisle, one is assaulted by the number of labels boasting “paraben-free” labels. In an earlier article I had tackled the issues and non-issues regarding a number of other cosmetic additives and realized my glaring error in omitting parabens. Are parabens really dangerous enough to remove from all cosmecuticals?
Parabens are chemical derivatives of para-hydroxybenzoic acid. They are often used in products such as cosmetics, moisturizers, toothpaste, shampoo, and shaving gel. In addition to these regular consumer products, parabens may often be found as an ingredient in topical prescription drugs (drugs in lotion or drop form). However, paraben addition is not just limited to the cosmetic world, in fact, parabens can be found in many processed foods as well as naturally in others (blueberries have a relatively high content of nethylparaben). When combined with other preservatives, parabens are active discouragers of bacterial and fungal growth, thus protecting both the product and the user from microbial infection. By using a combination of preservatives, it allows manufacturers to use less parabens and decrease any associated risks.
The three most common parabens in cosmetics are methylparaben, propylparaben and butylparaben. Animal studies have indicated that paraben toxicology overall is minimal as these compounds are absorbed and then excreted as modified metabolites with very complicated, long names (so for our purposes we will know them as M1-M4). However, though they are excreted, the mere fact that the parabens are first absorbed means they can exert some biological effect on the human body.
Estrogens are the primary female sex hormones responsible for the onset of puberty and growth of hormone-sensitive/hormone-receptor positive breast cancers. Parabens happen to be xenoestrogens and therefore have the capability to act on the same cellular signaling pathways as estrogen. This being said, parabens have a greatly-reduced biological activity compared to inherent human estrogens. For instance, butylparaben, widely considered the most potent estrogen-imitator has an activity 10,000 to 100,000 times less than estradiol (a naturally produced estrogen compound), when used at concentrations 25,000 times less than found in cosmetics. Furthermore, it was found that these studies conducted outside the body had three times higher estrogen activity than when conducted within the body. To sum this science stuff up, it means at concentration way below those found in cosmeceuticals, the estrogen-like properties of parabens exert little to no effect in the human body.
So here comes the big question: do the use of parabens in cosmetics (and other products, let us not forget) put consumers at a higher risk for breast cancer? The short answer is maybe. The long answer involves studies showing that there is indeed parabens present in breast tumors (especially methylparaben) and that these parabens were most likely from a topical origin (i.e. paraben-containing creams, cosmetics, deodorant, antiperspirants). In addition, the use of paraben-containing deodorant and shaving under the arms may result in a diagnosis of breast cancer at an earlier age. There seems to be an association between paraben-containing products and breast cancer development and some scientists believe that the increased amount of parabens in consumer products may be correlated to the overall rise in the incidence of breast cancer.
In addition to breast cancer, some studies point to increased keratinocyte harm with exposure to UVB when using topicals containing methylparaben. Sunlight exposure causes altered metabolism of methylparaben by skin esterases, producing photo-metabolites such as 3-hydroxy methylparaben. These metabolites are further broken down causing oxidative DNA damage in skin cells. As I have harped on for many months, with sun damage and DNA mutation comes skin cancer. There may be an association between paraben-containing products and skin cancer though more research must be done on the subject to reach any conclusions.
However, it is prudent to note that government bodies dedicated to researching toxicity of additives have found that consumer safety is ensured if paraben content in cosmetics is below 25%, (in 2005 and later 2008, the safety of parabens was reassessed and it was found that there was no need to redefine parameters due to the continued low paraben-content of cosmetics). Actually, cosmetics contain 0.01%-0.3% paraben, levels well below that dictated by governmental regulations. With the low concentration of parabens in cosmetics, it is unlikely that parabens will penetrate the skin barrier to accumulate in tissue without being rapidly metabolized and excreted. Based on the maximum possible daily exposure limits of parabens, and taking into account that most cosmetics are well below these limits, it is thought that the health risks of paraben exposure from cosmetics are minimal.
As with any research subject regarding additives and the human body, there needs to be more research completed to really determine if there are paraben-related detrimental effects. So with that, it does no harm to go paraben-free. However, choices do become limited when you eliminate one of the most common cosmetic additives in the industry. Taking into account the extremely low dose of paraben in any cosmeceutical, it is probably safe to continue your life of guilt-free makeup.
Written by:
Margit Lai Wun Juhasz
Mount Sinai Medical Student
Is Xenoestrogen an endocrine disruptor?
Environmental xenoestrogens can be divided into natural compounds (e.g. from plants or fungi), and synthetically derived agents including certain drugs, pesticides and industrial by-products. Dietary exposure comes mainly from plant-derived phytoestrogens, which are thought to have a number of beneficial actions. However, high levels of exogenous estrogens including several well-known synthetic agents are associated with harmful effects. Chemicals like xenoestrogens, which can mimic endogenous hormones or interfere with endocrine processes, are collectively called endocrine disruptors. Adverse effects by endocrine disrupting chemicals (particularly xenoestrogens) include a number of developmental anomalies in wildlife and humans. Critical periods of urogenital tract and nervous system development in-utero and during early post-natal life are especially sensitive to hormonal disruption. Furthermore, damage during this vulnerable time is generally permanent, whereas in adulthood, ill effects may sometimes be alleviated if the causative agent is removed. The most commonly studied mechanism in which xenoestrogens exert their effects is through binding and activation of estrogen receptors a and similar to endogenous hormone. However, endocrine disruptors can often affect more than one hormone (sometimes in opposite directions), or different components of the same endocrine pathway, therefore making it difficult to predict effects on human health. In addition, xenoestrogens have the potential to exert tissue specific and nongenomic actions, which are sensitive to relatively low estrogen concentrations. The true risk to humans is a controversial issue; to date, little evidence exists for clear-cut relationships between xenoestrogen exposure and major human health concerns. However, because of the complexity of their mechanism and potential for adverse effects, much interest remains in learning how xenoestrogens affect normal estrogen signaling.
Is Xenoestrogen real?
J.L. Wittliff, S.A. Andres, in Encyclopedia of Toxicology (Third Edition), 2014
Exposure and Exposure Monitoring
Xenoestrogens are particularly dangerous to animal and human health because they are persistent, ubiquitous chemicals in the environment that bioaccumulate and may even be activated further as a result of biotransformation. An environmental EDC is defined as a man-made compound that interferes with one or more steps in the signal transduction pathway of natural hormones in the body responsible for the maintenance of homeostasis, reproduction, development, and behavior. In addition to direct exposure, xenoestrogen effects of exposure to a female or male fetus during development are irreversible. The enormous chemical complexity of xenoestrogens (e.g., more than 200 possible congeners of polychlorinated biphenyls (PCBs)) as well as variations in the degree of modification (e.g., extent of chlorination) preclude the establishment of common routes of accumulation and mechanisms of both biotransformation and biodegradation. Exposure to xenoestrogens occurs mainly by ingesting contaminated foods and liquids, although small amounts may be inhaled or absorbed through the skin and mucous membranes in the body. In the case of the developing fetus, the circulation connecting maternal, placental, and fetal tissues may transport a xenoestrogen to a variety of organs and tissues.
Environmental Stressors and Gene Responses
Werner E.G. Müller, ... Heinz C. Schröder, in Cell and Molecular Response to Stress, 2000
5.5. Xenoestrogens
Xenoestrogens are xenobiotics that cause an estrogenic or an antiestrogenic effect in Metazoa. Among them, the PCBs have a pronounced position (Krishnan and Safe, 1993). Vitellogenin has proven to be a valuable biomarker for xenoestrogens in vertebrates (Heppell et al., 1995). Adequate test systems for detection of estrogenic/antiestrogenic effects of PCBs in invertebrates did not exist. We found a suitable biomarker in invertebrates: the 14-3-3 protein, which was cloned from a G. cydonium cDNA library (Wiens et al., 1998). In Northern blotting experiments, PCB as well as 17β-estradiol strongly induced the expression of 14-3-3 in G. cydonium tissue (Wiens et al., 1999). Interestingly, a potentiation of the expression of 14-3-3 was observed after combination of both substances.
It might be stressed that no other biomarker proteins have yet been identified in lower invertebrates to monitor such effects of PCBs; in vertebrates, vitellogenin is well introduced as biomarker for environmental estrogens (Heppell et al., 1995).
The Effects of Environmental Hormone Disrupters on Fertility, and a Strategy to Reverse their Impact
Frank H. Comhaire MD, PhD, Wim A.E. Decleer MD, in Handbook of Fertility, 2015
Effect of antiestrogen treatment on semen quality and male fertility
Xenoestrogen contamination has been identified as a major source of deficient sperm quality. Indeed, these agents exert a deleterious influence at both the hypothalamo-pituitary levels, and on testicular spermatogenesis (Figure 8.6).
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Figure 8.6. Xenoestrogens (XE) inhibit the release of LHRH and of the gonadotropins LH and FSH by the hypothalamo-pituitary unit, impair Sertoli cell function, and damage spermatogenesis resulting in lower sperm production (oligozoospermia), and poor sperm quality (astheno- and teratozoospermia).
In 1976 we introduced the treatment of idiopathic oligozoospermia with the selective antiestrogen Tamoxifen [6]. In contrast to Clomiphene citrate, which is a racemic mixture of two isomers exerting both antiestrogenic and intrinsic estrogenic activity, Tamoxifen exclusively inhibits the binding to the cellular estrogen receptor. This effect involves not only the binding of the natural estrogens estradiol 17-beta and its metabolites, but equally the binding of xenoestrogens. Tamoxifen treatment increases the secretion of LHRH and of the gonadotropins LH and FSH, with doubling of the testosterone concentration in blood within one month of intake, and the 2.5-fold increase of sperm concentration within 3–6 months. When given to patients with idiopathic oligozoospermia and sperm concentration below 10 million/mL and LH and FSH levels not elevated, Tamoxifen treatment results in doubling of the pregnancy rate compared to placebo, and a number needed to treat (NNT) of 3.9 (CI: 2.9–7.8)[7].
Estrogen Concepts
Tolu Oyelowo DC, in Mosby's Guide to Women's Health, 2007
TERMINOLOGY
Xenoestrogens: Xeno = Foreign
Xenoestrogens are “foreign” estrogens, substances that are close enough in molecular structure to estrogen that they can bind to estrogen receptor sites with potentially hazardous outcomes.
Sources of Xenoestrogens include plastics, pesticides, chemicals, and water systems.
Phytoestrogens: Phyto = Plant
Phytoestrogens are plant derivatives that have a similar structure to estrogen and can bind to the estrogen receptor sites. They are weaker endogenous estrogens and, through competitive inhibition, can prevent the receptor binding of more potent estrogens.
ESTROGEN
Estrogen is a broad term used to describe the predominant female hormone. Estrogen has three major derivatives:
•
Estradiol—the primary form of estrogen before menopause
•
Estrone—the primary form of estrogen after menopause
•
Estriol—a byproduct of estrogen metabolism
Estrone and estradiol are created naturally in the steroidogenic pathways of the body (ovaries and adrenal glands). They are further metabolized by the liver and other tissues into approximately 40 metabolic products, called metabolites, one of which is estriol.
Many of the metabolites have important functions of their own. Examples include the catechol estrogens, liver metabolites formed from estradiol and estrone, which have a chemical structure that is part estrogen and part catecholamine. (Catechola-mines are biologically active amines, e.g., epinephrine and norepinephrine derived from the amino acid tyrosine, which have marked effects on the nervous and cardiovascular systems, metabolic rate, temperature, and smooth muscle.)
Catechol estrogens have been shown to decrease the growth of some existing cancers,1 inhibit abnormal growth of cardiac fibroblasts (thereby decreasing the risk of hypertension and myo-cardial infarction [MI]), and inhibit the action of leukotrienes2 (hence decreasing inflammation, arthrosclerosis, and osteoporosis). In addition, catechol estrogens have antioxidant properties. Estradiol is the most potent of estrogens occurring naturally in the body. It is the primary hormone produced by the ovaries during the reproductive years. It is the primary hormone responsible for the menstrual cycle and also affects bone, blood vessels, heart, brain, and skin health. In its function intensity, estradiol is 12 times stronger than estrone and 80 times stronger than estriol.
Blood levels of estradiol before menopause are 40 to 350 pg/ml; in menopause, blood levels drop to less than 15 pg/ml. Ovaries are the predominant producer of estradiol, with the adrenal glands contributing approximately 4% and the placenta during pregnancy also contributing some.
The major source of estradiol in postmenopausal women is the conversion of estrone to estradiol by the enzyme aromatase, which is present in adipose cells.
The estradiol-to-estrone dual conversion works two ways. However, it does not work as effectively each way: 15% of estradiol is converted to estrone, but only 5% of estrone is converted to estradiol.
Conversion of estradiol to estrone takes place in the liver and other tissues; estrone is converted back to estradiol by the aromatase enzymes in fat tissue; but, with less being made by the ovaries, estrone levels still dominate in the menopausal woman. Because aromatase enzyme is present in fat tissue, there is increased conversion of androstenedione to estrone with increased body fat (i.e., there are benefits that come with adequate estrogen during menopause, but also problems that come with increased estrogen during menopause, such as increased risk of certain cancers). Estradiol is responsible for growth and female development. It increases the amount of fat in subcutaneous tissues, especially the breasts, thighs, and buttocks, and increases hip bone formation, resulting in the characteristic female skeletal development.
Estrogens work by crossing the cell membrane and attaching to estrogen receptors on the nucleus. Each type of estrogen has a different ability (receptor affinity) to stay attached to the receptor on the nucleus (nuclear retention). The stronger the receptor ability and the longer the nuclear retention time, the more potent the physiologic action of the estrogen. Estradiol has a nuclear retention time of 6 to 24 hours; estriol has a nuclear retention time of 1 to 4 hours.
Some of the known catechol estrogens are 2-hydroxyestradiol, 4-hydroxyestradiol, 2-hydroxyestrone, and 4-hydroxyestrone. Studies have shown that 2-hydroxyestradiol and estrone may decrease the growth of some existing cancers and inhibit abnormal growth of cardiac fibroblasts, the risk of which increases in postmenopausal women and which are associated with increases in hypertension, MI, and cardiovascular disease.
Hazards and Diseases
P.D. Darbre, in Encyclopedia of Food Safety, 2014
Xenoestrogens
Types and Source
Xenoestrogens are synthetic chemicals released into the environment as pollutants from agricultural spraying (pesticides and herbicides), from industrial processes, and waste disposal (PCBs and dioxins). These persistent organochlorine pollutants are generally lipophilic and therefore passed up the food chain partitioned in animal fat. Although they can be found in fatty meat and fish, they are also found in dairy products (milk, butter, and cheese) in the fat content. These compounds are usually consumed in only small quantities but due to their lipophilic properties and long half-lives in the body, they tend to build up in body fat with age, being released only during times of weight loss during fasting or in females into milk during periods of lactation. This, of course, has implications for the diet of the baby who can consume a relatively high load of such compounds from the mother's milk.
Xenoestrogens may also enter food following storage procedures. Alkyl esters of p-hydroxybenzoic acid (parabens) are added as preservatives to some foods. Methylparaben, ethylparaben, propylparaben, and butylparaben have been shown to possess estrogenic activity in a range of in vitro and in vivo assays. On the grounds of endocrine and reproductive toxicity in dietary studies, the acceptable daily intake was withdrawn for propylparaben and butylparaben by the Joint Food and Agriculture Organization and World Health Organization Expert Committee on Food Additives in 2007. Although the other esters remain in use, it is thought that liver esterase activity should result in rapid metabolism and clearance when consumed by the oral route. Plastic containers are used widely for storage of food, and this can provide another source of exposure to estrogenic compounds such as bisphenol A and phthalate esters if they partition into fatty foods. Bisphenol A and some phthalate esters have been shown to possess estrogenic properties in assays in vitro and in vivo. Because of concern for endocrine disruption following exposure in young children, use of bisphenol A (Figure 4) in the manufacture of baby bottles has been ceased in Europe, Canada, and the USA.
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Figure 4. Source and structure of some xenoestrogens present in food.
Significance of the Hormonal, Adrenal, and Sympathetic Responses to Burn Injury
Derek Culnan, ... David Herndon, in Total Burn Care (Fifth Edition), 2018
Estrogens
The impact of xenoestrogens on mortality in burned patients has been investigated. Found in insecticides used from the 1950s to the 1970s, xenoestrogens are compounds that can act as estradiol receptor agonists or antagonists and that are stored in fat. During the hypermetabolic state following thermal injury, the xenoestrogens are released along with mobilized lipids from these fat stores. In older burn patients who were more likely to have higher concentrations of these compounds in their bodies, it was discovered that nonsurvivors had significantly increased levels of two xenoestrogens, heptachlor epoxide and oxychlordane. It was suggested that these compounds may induce the inactivation of estradiol, progesterone, testosterone, and glucocorticoids via the induction of steroid hydroxylases, as well as antagonizing estradiol receptors, which may result in decreased inflammation and cytokine release.117
Tutera Medical explains the best way to reduce xenoestrogens is to eliminate your source of exposure
Cancer and Developmental Origins of Health and Disease—Epigenetic Reprogramming as a Mediator
Shuk-Mei Ho, ... Yuet-Kin Leung, in The Epigenome and Developmental Origins of Health and Disease, 2016
Xenoestrogens
Distinct from xenoestrogens, phytoestrogens naturally occur in plant material and are ingested in the diet. Soy phytoestrogens, namely genistein and equol, are widely consumed and due to their structural similarity to estrogen, are known to cause both estrogenic and antiestrogenic effects [130]. There is contention, however, as to whether these phytoestrogens have a protective or negative effect on breast cancer risk. Some animal studies and human population cohorts have suggested that they are protective and that a diet high in soy products is beneficial [131,132]. Conversely, the proliferative effect of phytoestrogen was shown in breast cell models [133]. Other cancers that have been associated with dietary phytoestrogens include prostate [134], pancreatic [135], lung [136], and colorectal [137]. Studies in breast cancer cells MCF-7 and MCF-10A revealed the capacity of phytoestrogens to inhibit the expression and activity of the three DNA methyltransferase enzymes, mechanistically explaining changes in global methylation patterns observed in breast cells exposed to phytoestrogens [138]. miRNA targeting critical cancer pathway genes Ras-related C3 botulinum toxin substrate 1 (RAC1), EGFR, and E1A binding protein P300 (EP300) were upregulated in prostate cancer [139], and histone modifications due to the effects of phytoestrogens have also been shown [140]. These demonstrate a diverse range of effects that may be exerted by phytoestrogens.
Disrupters of Estrogen Action and Synthesis
Philippa D. Darbre, in Endocrine Disruption and Human Health, 2015
3.4.3 Can Binding of the Compound to ER Increase Proliferation of Estrogen-Responsive Cells In Vitro?
Although a xenoestrogen may increase expression of estrogen-regulated genes, a further question is whether the whole profile of gene expression produced by exposure to a xenoestrogen can then lead to a cellular response. For this, proliferation of estrogen-responsive human breast cancer cell lines has been used as an end-point assay. ZR-75-1 and some sublines of MCF-7 cells are dependent on estrogen for their growth [48], and the use of MCF-7 cells in the E-SCREEN is a widely validated assay [49]. Lines of MCF-7 and T-47-D cells, which are responsive to estrogen for their proliferation but which still proliferate in the absence of estrogen, can still give valid assays, but they provide less useful models in that the proliferative difference is smaller and it is less easy to assess small changes [48].
For human breast cancer cells to maintain dependence on estrogen for their proliferation, the stock cells need to be kept in the presence of estradiol, insulin, or both: long-term maintenance in the absence of estradiol and insulin results in the loss of proliferative dependence on estrogen [50]. For assay of estrogen regulation of cell proliferation, all sources of estrogen need to be removed from the cell culture medium, which necessitates using both a phenol-red-free medium [51] and dextran-charcoal-stripped serum [52]. The presence of a co-purifying estrogenic contaminant in phenol red preparations was identified in 1985, and the use of phenol-red-free media has become accepted practice [51]. Since serum from any source will contain endogenous steroids, steroids need to be removed from the serum by incubation with activated charcoal. This can be done for 30 min at 56°C to heat-inactivate the serum at the same time [52]; alternatively, it can be done at 4°C overnight if heat inactivation is not needed.
Figure 3.12 shows the effect of five parabens on the proliferation of MCF-7 human breast cancer cells [39,40]. All parabens had the same efficacy as estradiol in stimulating cell proliferation over a 14-day period. However, higher concentrations were needed for maximal agonist response for the parabens than for estradiol, which agrees with their lower relative binding affinities to ER [39,40].
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Figure 3.12. Effects of the indicated concentrations of parabens on the proliferation of MCF-7 human breast cancer cells in monolayer culture over 12–14 days. Higher concentrations were needed for parabens compared to 17β-estradiol (which is in line with their lower binding affinities to ER), but overall, the efficacies of methylparaben, ethylparaben, n-propylparaben, n-butylparaben, and isobutylparaben were similar to 17β-estradiol when sufficient concentrations were present.
Source: Data are amalgamated from two publications [39,40].
The ability to increase the proliferation of estrogen-responsive human breast cancer cells, especially the MCF-7 cell line, has become a well-validated assay for estrogenic activity of a compound. However, since regulation of proliferation can involve many cross-interacting pathways, it is necessary to also identify whether any alteration to proliferation is ER-mediated or not. The accepted way of achieving this is to carry out proliferation assays with or without the presence of an antiestrogen such as tamoxifen or fulvestrant. Any ER-mediated actions of the compound would be blocked by the presence of the antiestrogen, which would compete for binding to the ER [39]. Any proliferative effects mediated through GPER or other receptor systems would not be blocked by the antiestrogen.
This assay system can identify antagonist as well as agonist responses. However, any antagonist response must be distinguished from nonspecific inhibitory responses or toxicity by demonstrating that the antagonism is reversible with excess estrogen.
Interestingly, this assay system is also sensitive to additive effects. If estrogenic chemicals are combined at concentrations where each individually has a submaximal effect, then the combination can increase the proliferative response above that observed for any of the individual components. This is particularly striking when chemicals are combined at or below their no-observed-effect concentration (NOEC) and has been demonstrated for parabens when combined at NOEC values [53].
What is the difference between phytoestrogens and xenoestrogens?
Xenoestrogens and phytoestrogens are referred to as “foreign estrogens” that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen mimics potentially promote hormone-related cancers, an understanding of how they interact with estrogenic pathways in human cells is crucial to resolve their possible impacts in cancer. Here, we conducted an extensive literature evaluation on the origins of these chemicals, emerging research techniques, updated molecular mechanisms, and ongoing clinical studies of estrogen mimics in human cancers. In this review, we describe new applications of patient-derived xenograft (PDX) models and single-cell RNA sequencing (scRNA-seq) techniques in shaping the current knowledge. At the molecular and cellular levels, we provide comprehensive and up-to-date insights into the mechanism of xenoestrogens and phytoestrogens in modulating the hallmarks of cancer. At the systemic level, we bring the emerging concept of window of susceptibility (WOS) into focus. WOS is the critical timing during the female lifespan that includes the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands are more sensitive to environmental exposures. Lastly, we reviewed 18 clinical trials on the application of phytoestrogens in the prevention or treatment of different cancers, conducted from 2002 to the present, and provide evidence-based perspectives on the clinical applications of phytoestrogens in cancers. Further research with carefully thought-through concepts and advanced methods on environmental estrogens will help to improve understanding for the identification of environmental influences, as well as provide novel mechanisms to guide the development of prevention and therapeutic approaches for human cancers.
Keywords: cancer, endogenous estrogens, estrogen receptors, exogenous estrogens, patient-derived xenograft/PDX, phytoestrogens, single-cell RNA sequencing/scRNA-seq, window of susceptibility/WOS, xenoestrogens
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1. Introduction
Estrogens are classified as either endogenous or exogenous, according to their origins [1]. Yet, both can bind to estrogen receptors (ERs), and/or many other nuclear receptors, simultaneously triggering genomic and transcriptomic changes in various organ systems. These changes can consequently contribute to the initiation and progression of multiple types of cancers, including the classical hormone-related breast and prostate cancer [2,3], as well as the non-classical hormone-related cancers, such as lung cancer [4], colorectal cancer [5], and gastric cancer [6].
Endogenous estrogens (estradiol/E2, estrone/E1, and estriol/E3) in humans are produced by endocrine glands and/or by extra-glandular tissues through steroidogenesis enzymes, such as cytochrome P450 oxidases (CYPs), hydroxysteroid dehydrogenases (HSDs), and aromatase (CYP19) [7]. Although the sex gonads (ovaries and testes) and adrenal cortex are the primary sites of estrogen synthesis, extra-gonadal estrogens are also produced in the mammary glands, lungs, liver, and intestine, and play an equally important role in controlling biological activities [8]. The important roles of endogenous estrogens in the etiology of breast cancer have been extensively studied, leading to the development of well-tolerated endocrine therapy for breast cancer [9].
Exogenous estrogens are those which are produced outside of the human body. In addition to synthetic estrogens developed for pharmacological purposes, a group of chemicals have been found to have estrogen-like activities, such as the ability to bind to ERs and to modulate the expression of estrogen-regulated genes. These exogenous and unexpected estrogen mimics include synthetic industrial compounds (xenoestrogens) and phytochemicals (phytoestrogens) [10]. They can alter the activities of ERs and send false signals, disrupting the normal estrogen response, changing physiological functions, and promoting diseases, including cancer [11]. Xenoestrogens include synthetic industrial chemicals used as solvents/lubricants and their byproducts such as plastics (bisphenol A, BPA), plasticizers (phthalates), flame retardants (polybrominated diphenyl ethers, PBDEs), pesticides (dichlorodiphenyltrichloroethane, DDT), and pharmaceutical agents (diethylstilbestrol, DES). The scientific consensus on xenoestrogens characterizes them as serious environmental hazards that have hormone-disruptive effects on both wildlife and humans [12]. Phytoestrogens are plant-produced compounds found in a wide variety of herbs and foods, most notably, soy-containing foods. Phytoestrogens, made naturally, often share structural features with endogenous E2, allowing phytoestrogens to cause estrogenic and/or anti-estrogenic effects [13]. They have been suggested to have a large spectrum of beneficial effects, including the reduction of cancer risk and postmenopausal symptoms [14]. However, there is also concern that phytoestrogens may act as endocrine disruptors that adversely affect health [15]. Based on available research findings, it is not clear whether the potential health benefits of phytoestrogens outweigh their risks. The potential for endocrine disruption by phytoestrogens needs to be considered as well [13]. Compared with endogenous estrogens, exogenous estrogens represent an under-recognized contributor to the development and progression of cancers. Further research on exogenous estrogens will help to provide insights for the identification of environmental influences, as well as provide new perspectives in the development of prevention and therapeutic approaches against human cancers.
At the molecular and cellular levels, xenoestrogens/phytoestrogens can imitate endogenous estrogens by enhancing and/or interrupting endogenous estrogen signaling pathways. They may exert either beneficial or harmful activities in humans depending on a set of complex factors such as exposure dose, time, intracellular signal transduction, and tissue complexity [16]. The binding of estrogens to ERs results in the activation of estrogen signaling pathways. There are intracellular ERs, including ER-alpha (ERα) and ER-beta (ERβ), as well as membrane-associated ERs, such as membrane ERs (mERs) and G Protein-Coupled Estrogen Receptors (GPER/GPR30) [17]. In addition to binding to ERs, exogenous estrogens can exert estrogenic activity by cross-talk with many other pathways, including pathways related to membrane-associated growth factor receptors, such as human epidermal growth factor receptor (EGFR/HER) and insulin-like growth factor 1-receptor (IGF1R) [18], as well as nuclear receptors, including aryl hydrocarbon receptor (AhR) [19], peroxisome proliferator-activated receptors (PPARs) [20], and estrogen-related receptor alpha/gamma (ERRα/γ) [21]. Multiple synergistic signaling pathways may contribute to the outcome of exogenous estrogen exposure on overall health and/or cancer cells. At the tissue level, exogenous estrogens may exhibit another dimension of complexity by influencing both cancer cells and cancer-associated stromal cells, including immune cells, fibroblasts, and adipocytes [22]. At the systemic level, exposure to exogenous estrogens has been linked to increased breast cancer risk during certain life stages known as the windows of susceptibility (WOS) including the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands undergo anatomical and functional transformations. Therefore, environmental hormones (e.g., endocrine-disrupting chemicals/EDC) and certain therapeutics (e.g., prescribed for the coexisting medical conditions or in the form of the hormone replacement therapy) can influence breast cancer risk, development, or outcome [23]. Considering the spatial heterogeneity (variety of cell types) and temporal heterogeneity (various stages of differentiation) of cancer, xenoestrogens/phytoestrogens could display integrated activities in a tumor-selective and/or life stage(s)-specific manner.
The growing concerns of the exogenous estrogenic influence on health, especially towards cancer, have prompted considerable public attention and scientific interest. Knowledge of how these exogenous estrogens mimic endogenous estrogens, and how they exert their impacts on overall health, is crucial to resolve their impacts in the etiology of varying cancers. In this review, we conducted an exhaustive evaluation on the advanced research technology, molecular mechanisms, and ongoing translational studies in the development of prevention and therapeutic approaches towards human cancers. Here, we aim to provide thorough, updated understandings of xenoestrogens/phytoestrogens and their biological activities and mechanisms in cancer.
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2. Xenoestrogens and Phytoestrogens: Definitions and Origins
2.1. Xenoestrogens: Synthetic Industrial Chemicals
Xenoestrogens are synthetic industrial chemicals found in various plastics, sealants, consumer goods, preservatives, and pesticides. They have unexpected activities by acting as either estrogen, triggering receptor pathways, or anti-estrogens, blocking normal estrogenic activity. These synthetic industrial chemicals can affect health and possibly trigger cancer [24]. The impact of these estrogen mimics is dictated by their binding affinities towards different types of ERs, predominantly ERα and ERβ, with ERα binding playing a pro-oncogenic role and ERβ typically playing a tumor-suppressive role [25] (Table 1).
Table 1
Various xenoestrogens and their implications for cancer. Compilation of ten types of xenoestrogens and their sources, biological and experimental evidence from pre-clinical studies, and implications towards cancer. Relative binding affinities were adapted from Kuiper et al. [25], unless otherwise noted, with E2 set as 100.
Name Source Relative Binding Affinity Biological Activity Experimental Evidence Public Health Implications References
ERα ERβ
bisphenol A (BPA) chemical used to manufacture polycarbonate plastics, epoxy resins, and added to other plastics; found in food containers, utensils, dental sealants, protective coatings, flame retardants, water supply pipes 0.01 0.01 disrupts ER activity by mimicking, enhancing, or inhibiting endogenous estrogen; directly impacts intracellular signal transduction
↑ ER mRNA ↑ hyperplastic ducts
↑ ER+ cells
↑ PR+ cells
↑ cell proliferation
Phosphorylation of
AKT and ERK
↑ prostate cancer cell proliferation
Aberrant development of prostate and urethra
↑ prostate tumor size
AR antagonist
↑ SHBG increased risk of breast, prostate, and uterine cancer
no risk for ovarian cancer [26,27,28,29]
dichlorodiphenyltrichloroethane (DDT) pesticide; used to combat malaria, typhus, and other insect-borne human diseases 0–0.01 0–0.02 estrogenic activity Accumulates in adipose tissue
Stimulates uterine proliferation and impairs normal
follicle development
Inhibits PKA activation
Alters gene expression and hormone synthesis.
Inhibit PGE2 levels in ovaries increased breast cancer risk [30,31,32]
polychlorinated biphenyls (PCBs) used as flame retardants; found in electrical equipment, construction materials, coatings, textiles, furniture padding, etc. 0.01–3.4 <0.01–7.2 estrogenic/anti-estrogenic ↓ cell growth
↓ proliferation
↓ AR activity
↑ competitive inhibition to AR
↑ uterus weight increased breast cancer risk for certain PCBs [36,37,38]
polybrominated diphenyl ethers (PBDEs) used as flame retardants; found in electrical equipment, construction materials, coatings, textiles, furniture padding, etc. 1.3–20 a estrogenic activity ↑ viability and proliferation of human breast, cervical, and ovarian cancer cells
↑ cell contact
↑ phosphorylation of PKCa and ERK1/2 proteins in tumor cells and in CHO cells no clear association with breast cancer risk [39,40,41,42,43]
diethylstilbestrol (DES) used to prevent miscarriage, premature labor, and pregnancy complications 236 221 hydrophobic interactions; potent transcriptional activator through genomic signaling ↑ PI3 kinase signaling
↑ AKT phosphorylation
ERRγ antagonist
↑ SRC1
↑ SHBG
↓ LH, TSH, FSH, DHEA, testosterone, and E1 vaginal cancer risk [44,45]
methoxychlor (DMDT) used to protect pets, crops, and livestock from pests such as mosquitoes, cockroaches, and other insects <0.01 <0.01 ERα agonist
ERβ antagonist
anti-estrogen in ovaries Inhibit estrogen binding to ER
↓ serum progesterone
↑ uterotrophic activity
Impairs overall fertility increased ovarian cancer risk [33]
ethinyl estradiol (EE2) ovulation inhibitor; used in hormonal contraceptives 190 c ↑ERRγ and RAGE expression primarily through Erα ↑ cell proliferation but not
as much as E2↑ little/no breast cancer risk
reduced risk for ovarian, endometrial, colorectal, and lymphatic/hematopoietic cancers [46]
phthalates found in soft plastics used as packaging materials N/A d N/A d competitive binding with E2 for ER ↑ MCF7 cell proliferation
and viability increased breast cancer risk [47,48]
nonylphenols used in industrial processes and in consumer laundry detergents, personal hygiene, automotive, latex paints, and lawn care products 0.0032–0.037 c estrogen-like activity on ER+ breast cancer cells ↑ prostate epithelial cell proliferation
↓ prostate cell viability
Promotes cytoplasm-nucleus Translocation of ERα,
but not ERβ increased breast cancer risk [49,50]
parabens used as preservatives in many foods such as beer, sauces, sodas, and cosmetics 0.011–0.11 b 0.011–0.123 b ERRγ agonist breast cancer cell proliferation
↑ tumor size
Sulfotransferase inhibitor increased breast cancer risk [51,52]
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a values were adapted from Cao et al. [40] and include hydroxy PBDEs. b values were adapted from Golden et al. [52], which included data from Kuiper et al. [25]. c values adapted from Blair et al. [49] were obtained using a different methodology; use with caution when making comparisons. d specific relative binding affinity values were not found.
An extensively studied xenoestrogen is bisphenol A (BPA). BPA was first used as a pharmaceutical estrogen in the 1930s but is now commonly used in the manufacture of polycarbonate plastics and epoxy resins used in food containers, water bottles, and other protective coatings [26]. BPA has been shown to disrupt ER activity by mimicking, enhancing, or inhibiting endogenous estrogens, causing a direct impact on the intracellular signal transduction pathways [27]. It has a relative binding affinity of 0.01 for both ERα and ERβ and has been strongly correlated with an increased risk for breast, prostate, and uterine cancer [28]. Because of this, many organizations concerned with the environment have suggested that the public avoid using items made with BPA [29].
Another xenoestrogen of interest is the estrogenic pesticide DDT which has been banned in the US for almost 50 years. DDT was a commonly used pesticide sprayed across many agricultural fields and homes, acting as an insect neurotoxin to kill mosquitoes and other insect vectors that carry malaria, typhus, and other insect-borne diseases. It is still widely used, particularly in India and southern Africa [30]. Only later would it be known that DDT accumulates in adipose tissue and continues to persist in the environment [31]. Adverse environmental effects on non-insect species led to DDT being banned in many countries. Since then, scientists have continued to study its estrogenic activity and its impacts on gene expression and hormone synthesis through transgenerational studies. With a relative binding affinity of 0–0.01 and 0–0.02 to ERα and ERβ, respectively, DDT was previously not associated with increased cancer risk. However, DDT has been linked to increased breast cancer, especially if the tissue is exposed during certain WOS [32]. Following the banning of DDT, methoxychlor (DMDT) was synthesized as an alternative for vector control. It was used to protect pets, crops, and livestock from pests such as mosquitoes, cockroaches, and other insects. Despite growing evidence that DMDT is an ERα agonist and ERβ antagonist, with relative binding affinities of <0.01% for both, resulting in increased inhibition of estrogen binding, it is still currently being used today. DMDT has been associated with increased ovarian cancer risk, but not with other human cancers [33].
Although numerous studies indicating the toxic effects of both BPA and DDT, these two xenoestrogens are still being used today. BPA has continued to be used in plastics despite epidemiological studies correlating its exposure with decreased sperm quality in males [34]. On the other hand, while DDT has been banned in the US for a half-century, it is still used in regions where malaria is endemic, is concerning as both epidemiological and clinical data have reported a decrease in semen volume, concentration, motility, and normal morphology to be associated with DDT exposure [35].
Polychlorinated biphenyls (PCBs) are well-known xenoestrogens that are widely used to make various electrical equipment, such as transformers and capacitors, and are also found in hydraulic fluids and plasticizers. These materials eventually make their way into landfills, where PCBs can re-enter the environment by being released into the soil and air [36]. PCBs include many compounds that have relative binding affinities for ERα and ERβ between 0.01 and 3.4 and <0.01 and 7.2, respectively. These relative binding affinities were adapted from Kuiper et al. who used solid-phase competition experiments to calculate binding affinities by setting E2 as 100 [37]. Despite the almost two-fold difference in ERβ binding affinity, compared to ERα, PCBs are associated with an increased breast cancer risk, making them a significant topic of research [38].
PBDEs are used as flame retardants, electrical equipment coating, construction materials, textiles, and furniture padding [39,40]. PBDEs encompass a large umbrella of compounds that have a relative binding affinity range of 1.3–20 to ERs [41]. Despite PBDEs exhibiting a higher binding affinity to ERs than that of PCBs, there has been no clear conclusion between PBDE exposure and breast cancer risk. Studies from our group recently demonstrated in breast cancer PDX models that PBDEs induced the expression of estrogen-responsive genes, especially genes related to cell proliferation in cancer cells [42,43].
Unlike the previously mentioned xenoestrogens, DES was synthesized as an “estrogen” and was previously prescribed to women to prevent miscarriages, premature labor, and pregnancy complications, before it, too, was realized to be carcinogenic. However, DES is no longer used to treat pregnancies at risk for miscarriage and menopausal symptoms but is still rarely used to treat prostate and breast cancer [44]. DES was the first synthetic estrogen and the first carcinogen to be shown to cross the placenta to cause cancer in the offspring. It has a potent relative binding affinity of 236% and 221% to ERα and ERβ, respectively, due to the additional hydrophobic interactions causing DES to be a potent transcriptional activator through genomic signaling [45].
Ethinyl estradiol (EE2) is a xenoestrogen synthetically derived from E2. It works as an ovulation inhibitor and is mostly found in hormonal contraceptives. It has a strong relative binding affinity of 190% for ER and has been shown to increase cell proliferation, but at a lower rate than E2. There have been controversial data regarding EE2’s effects on cancer risk, but more recent studies have suggested that EE2 has little/no breast cancer risk, while having decreased ovarian, endometrial, colorectal, lymphatic cancer risks [46].
Other xenoestrogens of interest include phthalates, nonylphenols (NP), and parabens. Phthalates are found in soft packaging plastic materials and can competitively inhibit E2 binding to ER [47,48]. Meanwhile, NP is used in various industrial processes and is found in consumer goods, such as laundry detergents, personal hygiene, automotive, and lawn care products. NP has a low relative binding affinity to ER of 0.0032–0.037, compared to the relative binding affinities of other xenoestrogens. Even so, they can exhibit an estrogen-like activity on ER+ breast cancer cells [49,50]. On the other hand, parabens are preservatives used in many consumable items such as beer, sauce, soda, and several cosmetics. They have a relative binding affinity range of 0.011–0.11 and 0.011–0.123 for ERα and ERβ, respectively, and can increase breast cancer cell proliferation and tumor size in animals [51,52]. These three types of xenoestrogens have all been implicated with breast cancer risk and their continued presence jeopardizes future health standards.
The presence of xenoestrogens in our environment and our everyday products warrants more research into their implications concerning cancer. Although some compounds have lower binding affinities than others, their impact on ERα, as well as their increased cancer risks, necessitates more attention to understanding the exact mechanisms and route of exposure by which they function.
2.2. Phytoestrogens: Plant-Derived Chemicals
Phytoestrogens are a group of estrogen mimics present in plants. They are becoming subjects of interest due to their estrogenic potentials and constant exposure to humans (Table 2).
Table 2
Various phytoestrogens and their implications for cancer. Compilation of ten types of phytoestrogens and their sources, biological and experimental evidence from pre-clinical studies, and implications for cancer. Relative binding affinities were adapted from Kuiper et al. [25], unless otherwise noted, with E2 set as 100.
Name Source Relative Binding Affinity Biological Activity Experimental Evidence Public Health Implications References
ERα ERβ
genistein
(GEN) soybeans and soy-containing products 4 87 [low]: estrogenic
[high]: anti-estrogenic
↓ ERα protein/mRNa levels ↑ apoptosis
↑ cell cycle arrest
↑ demethylation of tumor suppressor genes
Inhibits ovarian cancer cell migration, invasion, and proliferation
↓ phosphorylation of PI3K
and GSK3b
RTK inhibitor
DNA topoisomerase II inhibitor
ER+ cell proliferation
↓ tumor associated macrophage
↓ proliferation
VEGF inhibitor (angiogenesis)
↓ breast CSCs
↑ cell adhesion
↓ migration/invasion breast and prostate cancer preventative
decreased ovarian cancer risk [53,54,55,56,57,58]
daidzein
(DAI) soybeans 0.1 0.5 anti-estrogenic in organs expressing more ERα
estrogenic in ERβ-presenting organs ↑ ERa expression/nuclear localization
↓ cell proliferation
↓ migration
↓ invasion
Induces cell cycle arrest
and apoptosis endometrial cancer preventative [59,60]
quercetin
(QUE) various fruits and vegetables such as apples, red grapes, onions, raspberries, honey, cherries, citrus fruits, green leafy vegetables, red wine, cappers, lovage, radish leaves, tea, cranberries,
and peppers 0.01 0.04 estrogenic
↓ cytoplasmic ER levels
↑ tighter nuclear association to ER ↑ antiproliferative
↓ mammospheres in
breast cancer cells
↓ breast CSC characteristics
↓ EMT
Regulates B-catenin signaling, leading to EMT inhibition
[low]: ↑proliferation
↑ migration
↑ invasion
↓ apoptosis
[high]: ↓cell growth
↓ metastatic process
↑ cell cycle arrest
↓ tumor volume anti-cancer for breast cancer [54,57,62,63,64,65,66,67,68]
apigenin
(APE) fruits and vegetables such as parsley chamomile, celery, vine-spinach, artichoke, oregano, red wine, and beer 0.3 6 ↓ ERα in uterus
estrogenic/anti-estrogenic
↓ estradiol levels [low]: ↑proliferation
↑ AKT phosphorylation
↑ invasion
[high]: ↓proliferation
↓ AKT phosphorylation
↓ invasion
↑ apoptosis
↑ cell cycle arrest
↓ cell growth
Inhibit MAPK decreased breast, prostate, and ovarian
cancer risk [61,62,69,70,71,72,73,74]
resveratrol (RES) Japanese knotweed grapes, wine, strawberries, and peanuts 6.11–11.2 a 4.7–15.66 a ERRγ agonist ↑ breast cancer cell proliferation
↑ tumor size
Sulfotransferase inhibitor increased breast cancer risk [75,76,77,78,79]
myricetin
(MYR) vegetables, fruits, nuts, berries, tea, and red wine N/A c N/A c Competitive binding to ER
ERα agonist Inhibits prostate cancer cell growth, key enzymes involved in the initiation and progression of cancer
↓ migration
↓ invasion
↓ adhesion
↓ tumor nodules
↓ MMP2 and MMP9
protein expression
↑ apoptosis
CK2 inhibitor decreased breast and prostate cancer risk [80,81,82,83,84,85]
kaempferol (KPF) tea, broccoli, apples, strawberries, beans, bee pollen, cabbage, capers, cauliflower, chia seeds, chives, cumin, moringa leaves, endive, fennel,
and garlic 0.1 3 estrogenic activity
ERα-dependent transcriptional activation activity ↑ apoptosis
↓ cancer cell growth
↓ angiogenesis
Preserve/protect cell viability
↓ migration
↓ MMP3 protein activity
Inhibit VEGF release in
breast cancer cells
Reduced VEGF mRNA in ovarian cancer cells
↓ tumor growth/metastasis
↓ EMT
↑ cell cycle arrest
Inhibits various cancer
cell lines decreased breast cancer risk [86,87,88,89,90,91]
luteolin
(LUT) celery, peppermint, thyme, rosemary, oregano, artichoke, green pepper, and perilla leaf N/A d N/A d Estrogenic ↑ cell cycle arrest
↑ apoptosis
↓ proliferation
Inhibit MAPK, EGFR, VEGF
↓ PSA
↓ aromatase
↓ ERK and FAK
phosphorylation anti-cancer for breast and prostate
endometrial cancer risk [92]
curcumin
(CUR) derived from the plant Curcuma longa; turmeric N/A b N/A b ↓ ER expression ↓ EMT and migration ability
↓ breast CSC population
↓ nuclear translocation of B-catenin (slug transactivation; restored E-cadherin expression)
↑ apoptosis
↑ cell cycle arrest
↑ senescence
↓ p53
Inhibits proliferation, migration, invasion, angiogenesis, and metastasis in breast cancer cells
Interferes with osteoblast formation in prostate cancer cell line anti-cancer [93,94,95,96]
coumestrol (COU) plants such as soybeans, clover, alfalfa sprouts, sunflower seeds, spinach, legumes, chickpeas, split peas, lima beans,
and pinto beans 20 140 ↓ ERα protein/mRNA levels Inhibits cell viability, cell growth, and proliferation
↑ Bax
↑ apoptosis
↑ cell cycle arrest
↑ ROS generation
↑ DNA damage
↑ ERK1/2 phosphorylation
↑ p53 proteins
↓ AKT phosphorylation anti-cancer for breast and prostate cancers
anti-tumor for ovarian, breast, lung, and cervical cancers
decreased endometrial cancer risk [98,99,100,101]
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a values adapted from Bowers et al. [75] were obtained using a different methodology; use with caution when making comparisons. b–d specific relative binding affinity values were not found.
The Top 5 High Estrogen Foods to Avoid | Dr. Josh Axe
Soybeans, a staple in many Asian cuisines, contain two major isoflavones: genistein (GEN) and daidzein (DAI). Although similar in structure and function, GEN has both stronger binding to ERβ than ERα. For GEN, the difference is 20-fold, and for DAI the difference is five-fold. This stronger binding affinity for ERβ, combined with the observation that GEN results in a decrease of ERα mRNA and protein levels [53,54,55,56,57,58], has led to clinical trials in cancer prevention and treatment. To date, GEN and DAI have been shown to reduce breast cancer-related gene expression [59,60], and reduce the increase in serum PSA during prostate cancer development [61]. Both GEN and DAI are well tolerated with minimal toxicity.
Other phytoestrogens, such as quercetin (QUE) [62,63,64,65,66,67,68], apigenin (APE) [69,70,71,72,73,74], resveratrol (RES) [75,76,77,78,79], myricetin (MYR) [80,81,82,83,84,85], and are found in many berries, leafy greens, and wine. Although their relative binding affinity differences between ERα and ERβ are not as great as in GEN and DAI, these compounds have been investigated due to their widespread presence in plants and extensive human consumption. More specifically, QUE, APE, and even RES have been noted to exhibit a biphasic effect; at low concentrations, these phytoestrogens display estrogenic activity, whereas, at higher concentrations, they display more protective anti-estrogenic activity [62,63,64,65,66,67,68,69,70,71,72,73]. Like GEN, RES has been extensively studied in many clinical trials. It has been shown that RES can significantly decrease epigenetic gene methylation in women at high risk for breast cancer and suppresses the important WNT signaling pathway [75,76,77,78,79]. These findings support the chemo-preventive effects of RES as possible cancer therapeutic. However, health beneficial effects of RES have not been established due to non-physiological research designs.
Kaempferol (KPF), found in tea, pollen, and garlic, has been shown to decrease breast cancer risk possibly due to its 30-fold difference in ERα and ERβ relative binding affinities. KPF, although fairly novel, is an exciting phytoestrogen due to its ability to decrease cancer cell growth and increase apoptosis [86,87,88,89,90,91]. On the other hand, luteolin (LUT) is another more recently studied phytoestrogen found in seasonings that exhibits similar results as KPF: increasing cell cycle arrest, apoptosis, and decreasing proliferation [92].
Of all the reviewed phytoestrogens, curcumin (CUR) has been the most evaluated in terms of both pre-clinical and clinical investigations. CUR is derived from the plant Curcuma longa, otherwise known as turmeric. In breast cancer cells and tissues exposed to CUR, it has been shown to decrease ER expression, leading to decreased cell proliferation, migration, invasion, and angiogenesis, while increasing apoptosis, cell cycle arrest, and senescence in breast cancer cell lines [93,94,95]. In clinical trials, CUR has been shown to slightly reduce fatigue in women with advanced, metastatic breast cancer and can be used as an anti-oxidation, anti-cancer agent that does not compromise the therapeutic efficacy of radiotherapy [96,97,98,99].
Meanwhile, coumestrol (COU), found in various beans, leafy greens, and sunflower seeds, has the strongest relative binding affinity for ERβ at 140. Dietary COU intake has been shown to decrease ERα mRNA and protein levels like GEN, indicating possible usage as an anti-cancer therapeutic [98,99,100,101].
In summary, the literature suggests that phytoestrogens can act as anti-cancer agents by competing with endogenous estrogens, particularly with differences in relative binding to different ERs. While outcomes vary with tissue location and cancer types, the physiologically relevant research into phytoestrogens seems promising and will help to better understand the biological activities of these plant-produced estrogen mimics.
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3. Advanced Methodology in Studying the Biological Effects of Xenoestrogens and Phytoestrogens
While population-based studies have defined correlations with environmental estrogen exposure and cancer, and cell/molecular studies have revealed some mechanisms for these effects, several novels approach to investigating the estrogen-cancer link are revealing more sophisticated insights [102,103]. Recently, nonbiased “multi-omic” approaches, including genomics, transcriptomics, proteomics, and metabolomics, have been widely applied to reveal the mechanisms at the molecular level [104,105,106]. In addition to these in vitro studies, the use of in vivo rodent models has been useful for studying the phenotypic changes and mechanisms of exogenous estrogen exposure. The main advantage of in vivo models is the ability to test a given chemical in a more relevant setting to humans so that the results can be more reasonably extrapolated at the tissue and systemic levels [107]. A better understanding of the “pros and cons” of each methodology and proper exploitation, or a transdisciplinary approach, will better progress the study of the causal relationship between exogenous estrogen exposure and human cancers. The Breast Cancer and the Environment Research Program (BCERP), funded by the US government, is a multi-institutional, multi-disciplinary group of teams of laboratory-based scientists, epidemiologists, social scientists, and clinicians with various specialties and from different perspectives. Our group is included in this program (https://bcerp.org/ (accessed on 16 May 2021). In this section, we describe our experience within the program context in developing new ways to study the biological effects of xenoestrogens and phytoestrogens in breast cancer.
3.1. In Vitro Models with Cultured Cells
In vitro models with cultured cells are powerful tools for screening and identifying the estrogenic activity of chemicals existing in the living environment [102,103]. E-screen is a cell-proliferation assay that uses estrogen-dependent cancer cell lines to elucidate the estrogenic effects of these environmental chemicals [108,109]. Additionally, many gene reporter assays have been developed using human cancer cell lines transfected with reporter genes to assess whether a given compound could induce ER-mediated gene expressions [110,111]. We previously generated a model cell line by stable transfection with the estrogen-responsive element (ERE)-driven luciferase reporter into an aromatase-overexpressing MCF7 human breast cancer cell line, named MCF7aro-ERE [112]. We successfully developed the AroER Tri-screen assay system with MCF7aro-ERE, which is an improved model that is suitable for a high-throughput screening system [113]. AroER Tri-screen assay shows luciferase activity when estrogen-bound ERs induce gene expression by binding to the ERE promoter region. The AroER Tri-screen is a robust bioanalytical assay that has a high signal-to-background ratio, enabling the application of a high-throughput format of up to 1536 wells in a single experiment. In addition, this system is a multiplex assay, used not only for the screening of ER-agonistic chemicals but also for screening of ER-antagonistic or an aromatase inhibitor (AI)-like compound [114]. The AroER Tri-screen system has been adopted into a collaborative project called “Tox21” (https://tox21.gov/ (accessed on 16 May 2021)), which aims to develop target-specific, mechanism-based, and biologically relevant in vitro assays to screen for health-hazard chemicals. In this Tox21 program, we have utilized AroER Tri-screen to test a library of 10,000 compounds for anti-aromatase activity. The screen revealed 10 novel inhibitors. For example, imazalil, a widely used agricultural fungicide, showed irreversible and long-lasting anti-aromatase activity [115]. These high-throughput screening assays remain important for exploring exogenous estrogens among a large collection of chemicals, in newly developed consumer products, industrial chemicals, and drugs, as well as in unknown phytoestrogens from foods or plants, in a timely and reproducibly manner.
3.2. In Vivo Models with Rodents
In vivo models with rodents have been useful for studying the phenotypic changes and mechanisms of exogenous estrogen exposure. These models include carcinogenesis models and therapeutic models, with the former consisting of healthy or genetically engineered mice upon long-term exposure and the latter using established tumor xenografts. Conventional xenograft models using human cell lines or spontaneous mouse tumors have the limitations that they do not necessarily recapitulate the nature of original human cancers, leading to a lack of predictive value of the results in a clinical setting [116,117]. More specific and cancer-relevant PDX models, generated by the direct implantation of tumor fragments from human patients into immune-deficient mice, are increasingly being utilized for translational cancer research because they have been proven to maintain many of the biological properties of human cancers, such as genetic features, histology, and tumor cell population heterogeneity [118,119,120]. Many studies have reported that the response to treatments in PDX models correlates well with the results of treatment in the patients whose tumors supplied the PDX cancer. Therefore, PDX models provide a suitable option for studying the effects of exogenous estrogens on human cancers [121,122,123]. For example, the xenoestrogen methylparaben was shown to promote tumor growth and stem-like features using an ER+ breast cancer PDX model [124]. Our group has also recently performed bulk RNA-seq analysis on an ER+ breast cancer PDX treated with PBDEs, concluding that PBDEs induced the expression of estrogen-responsive genes, especially those related to cell proliferation [125]. Other groups also reported the effect of GEN [126,127] and DES [128] on prostate cancer PDX models. Additionally, another study investigated the potential chemo-enhancing effects and mechanisms of GEN and its analog AXP107-11, which showed an improved bioavailability of AXP107-11 for clinical use compared to GEN [129]. These findings suggest that PDX models would help further the understanding of the biological effects of exogenous estrogens as relevant models of human cancers.
In addition to its advantage in mimicking the natural situation of tumor development, PDX models include all the cells in the surrounding tissues, rather than just the cancer cells, enabling the assessment of the biological effects on the whole population in a tissue and the specific cell-to-cell interactions [130]. Furthermore, we can observe various phenotypical changes, such as tumor invasion, metastasis, or immunomodulation [131], beyond simple cell proliferation or gene expression that can easily be observed in in vitro models. In contrast, there are also several disadvantages of in vivo models against in vitro models. First, animal models are often time- and cost-consuming, which limits their usefulness for exploratory studies as discussed in the in vitro screening assays [107]. Second, the experimental dosage used in animal studies is often much higher than typical human exposures, making the extrapolation to the human situation problematic [132]. In the real situation in human tumor development, exposure to low doses of xenoestrogens may result in subtle effects that accumulate over time. These are difficult to observe in animal studies. In addition, ethical considerations of animal use must be considered, especially when testing compounds in the cosmetic or consumer product industry [133].
3.3. Single-Cell RNA-Sequencing (scRNA-seq)
Tumor development and progression are widely recognized as complicated processes in which tumor cells, and many other contributors such as fibroblasts, immune cells, and other stromal cells from the tumor microenvironment, play distinct roles by their interactions with one another. Thus, the heterogeneity of cell populations within tissues of interest has been one of the major limitations of previous, especially with in vitro models. Additionally, even in the in vivo models, it is sometimes a challenge to capture the effect of estrogenic compounds in each type of cell, especially when those cells are too minor to cause apparent phenotypic changes. The recent development of scRNA-seq provides transcriptomic information at a single-cell resolution, enabling the ability to profile each isolated cell’s characteristics from a given tissue or organ [134,135]. This unprecedented capability of scRNA-seq technology allows us to capture subtle changes caused by xenoestrogens/phytoestrogens and their targeted cells, not only in the tumor cells of interest but also in the surrounding stromal cells (e.g., fibroblasts or immune cells), furthering the understanding of the potential interactions between these heterogeneous cell populations. Thus, this information can greatly help to reveal the mechanisms of cancer-initiating and/or promoting the effects of exogenous estrogens.
We have demonstrated that this state-of-art technology can overcome some of the limitations of the pre-existing in vitro and in vivo models. We previously reported a study using scRNA-seq analysis on normal mouse mammary glands of a surgically menopaused mouse model treated with estrogen and PBDEs [136]. Our results suggest that PBDEs enhance estrogen-mediated mammary gland regrowth through the up-regulation of Areg expression in mammary epithelial cells, which in turn affects its cognate receptor, EGFR expressed on mammary fibroblasts and further modulates the recruitment of tumor-promoting M2 macrophages. These findings support the hypothesis that PBDE exposure with estrogen treatment increases the risk of breast cancer development during a critical period, menopause. ScRNA-seq analysis also provides fundamental insights into the regulatory activity of PBDEs on distinct populations in normal mammary glands in the presence of estrogen. Furthermore, we expanded our scRNA-seq analysis to study the effect of PBDEs on the differentiation of mammary epithelial cells by integrating human and mouse datasets from our and others’ studies, thereby constructing a mammary cell gene expression atlas [137]. One group utilized scRNA-seq technology, although not directly related to cancer research, to investigate the transcriptomic changes induced by a known xenoestrogen, di (2-Ethylhexyl) phthalate (DEHP), exposure. They revealed the reproductive toxicity of DEHP in murine germ cells and pre-granulosa cells at a single-cell level [138]. Although scRNA-seq has some limitations, such as technical noise from the cell preparation process, loss of spatial information, higher costs than other models, and requirement for freshly prepared samples [139,140,141], it serves as an excellent option for studying the complicated activity of xenoestrogens/phytoestrogens in heterogeneous cell populations of target tissues.
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4. Biological Activities and Mechanisms of Xenoestrogens and Phytoestrogens in Cancers
4.1. Effects of Xenoestrogens and Phytoestrogens on the Bioavailability and Formation of Endogenous Estrogens
Human sex hormone-binding globulin (hSHBG) is a high-affinity binding protein in the bloodstream for endogenous estrogens, modulating the bioactivity of estrogens by limiting their diffusion into target tissues and cells [142]. By binding to hSHBG, xenoestrogens and phytoestrogens could modulate the bioavailability of endogenous estrogens [143]. Meanwhile, extra-glandular tissues can also synthesize estrogens from adrenal dehydroepiandrosterone (DHEA) and androstenedione (4-dione) by steroidogenesis enzymes, such as aromatase and 3beta- and 17beta-hydroxysteroid dehydrogenases (3β-HSDs and 17β-HSDs) [103]. These exogenous estrogens can also disrupt extra-glandular estrogen formation via interruption of steroidogenesis enzymes (Figure 1).
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Figure 1
Xenoestrogens and phytoestrogens modify endogenous estrogen bioavailability and formation. (A) Endogenous estrogens are produced by endocrine glands (ovaries, testes, and adrenal glands) and transported to endocrine-responsive tissues through blood circulation. Human sex hormone-binding globulin (hSHBG) is a high-affinity binding protein in the bloodstream for endogenous estrogens, modulating the bioactivity of estrogens by limiting their diffusion into target tissues and cells. Extra-glandular tissues can also synthesize estrogens from adrenal dehydroepiandrosterone (DHEA) and androstenedione (4-dione) by steroidogenesis enzymes, such as aromatase (CYP19) and 3beta- and 17beta-hydroxysteroid dehydrogenases (3β-HSDs and 17β-HSDs). (B) Xenoestrogens and phytoestrogens can modify the bioavailability of circulating endogenous estrogens by interfering with hSHBG binding. Xenoestrogens can also disrupt extra-glandular estrogen formation via interruption of steroidogenesis enzymes (A, aromatase, 3β, 3β-HSDs, and 17β, 17β-HSDs). Xenoestrogens are more likely to displace endogenous E2 from hSHBG binding sites, enhance E2 formation by inducing the steroidogenesis enzyme expressions, such as aromatase, consequently promoting the estrogenic responses in humans. However, phytoestrogens may lead to a decrease in plasma E2 levels via interaction with hSHBG levels and interruption of estrogen metabolism.
Xenoestrogens, such as BPA, NP, and monobutyl phthalate (MBP), have displayed a high binding affinity for hSHBG, with reversible and competitive binding activity for both testosterone and E2. Therefore, xenoestrogens may displace endogenous testosterone and E2 from hSHBG binding sites, leading to an increased level of free-form E2 in circulation. On the other hand, hSHBG may transport these xenoestrogens to target tissues and facilitate their diffusion into target cells [144]. Moreover, studies have found that xenoestrogens, such as BPA, exert their impacts on steroidogenesis by promoting aromatase expression in the adrenal cortex and ovaries; the increase of aromatase expression is responsible for the E2 increase [145,146]. This effect promotes the activation of ERα, which plays a pivotal role in the regulation of endocrine disorders such as cancer.
The flavonoid phytoestrogens, such as GEN and naringenin, have also been identified as hSHBG ligands [147]. Several studies in women have suggested a significant positive correlation between the intake of phytoestrogens and the concentration of plasma hSHBG [148]. Studies have also shown that the intake of phytoestrogens is negatively correlated with the plasma percentage of free-form E2 [149]. Such observations were further validated in large cross-sectional studies in postmenopausal women. Results have shown that phytoestrogen exposure is associated with lower plasma E2 in postmenopausal women and interacts with hSHBG levels and estrogen metabolism [150]. Dietary phytoestrogens suppress adrenal and ovarian 3β-HSDs and aromatase gene expression, therefore, decreasing estrogen formation [151]. Isoflavones have also been shown to exert inhibitory effects on 17β-HSD1 [152]. Amongst the phytoestrogens, isoflavones are the most potent inhibitors of aromatase [153]. Many phytoestrogens decrease the plasma estrogen levels, pointing towards a possible inhibitory effect in the regulation of E2 synthesis via suppressing the expression and activity of aromatase [154,155,156].
In summary, xenoestrogens and phytoestrogens may have distinct effects on the bioavailability and formation of endogenous estrogens. Xenoestrogens are more likely to displace endogenous E2 from hSHBG binding sites, enhance E2 formation by inducing steroidogenesis enzyme expression, such as aromatase, consequently promoting estrogenic responses in humans. Meanwhile, supplementation with phytoestrogens may lead to decreased plasma E2 levels via interaction with hSHBG levels and interruption of estrogen metabolism (Figure 1).
4.2. Effects of Xenoestrogens and Phytoestrogens on Estrogen Receptor Activation and Signaling
The variety of ERs reflects the diversity of receptor mechanisms involved with xenoestrogen and phytoestrogen effects on cells. This has relevance to the effects on these estrogenic molecules in cancer. There are two types of ERs: intracellular ERα and ERβ and membrane-associated mERs and GPER [157]. The intracellular ERα and ERβ belong to a group of nuclear receptors that act as ligand-activated transcription factors. They are also the primary receptors for both endogenous and exogenous estrogens. ERs are activated in four ways (Figure 2): (1) the classical genomic pathway where estrogens are bound to ERs that will activate the transcription of target genes, (2) the non-classical genomic pathway involving ER interactions with other transcription factors such as activator protein 1 (AP-1), including c-Fos, c-Jun, and c-myc, (3) the E2-independent pathway which activates ERs through phosphorylation induced by growth factor (EGFR/IGFR/Her2/3) signaling cascades [16], and (4) the non-genomic pathway involving membrane-associated ERs such as mERs and GPER [157].
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Figure 2
Xenoestrogens and phytoestrogens modulate multiple estrogen-mediated signaling pathways to shape the hallmarks of cancer. (A) Activation of estrogen receptor signaling. There are two types of ERs: intracellular ERα and ERβ and membrane-associated mERs and GPER [157]. ERs are activated in four manners: (1) the classical genomic pathway where estrogens are bound to ERs that will activate the transcription of target genes, (2) the non-classical genomic pathway involving ERs interactions with other transcription factors (TFs) such as activator protein 1 (AP-1), including c-Fos, c-Jun, c-myc, (3) the E2-independent pathway which activates ERs through phosphorylation induced by growth factors (EGFR/IGFR/Her2/3) signaling cascades [16], and (4) the non-genomic pathway involving membrane-associated ERs such as mERs and GPER. (B) Co-activation of AhR/PPARγ/ERRγ/ROS pathways. Xenoestrogens/phytoestrogens activate AhR signaling pathways and cross-talk with ER pathways: (1) AhR competes with ERs for promoter binding, leading to inhibition of ER signaling, (2) activation of AhR signaling regulates E2 production by controlling the gene expression of CYP19, also known as aromatase, and (3) activation of AhR signaling ubiquitinates ERs for degradation via the proteasome, leading to inhibition of ER signaling. Xenoestrogens/phytoestrogens activate peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptor gamma (ERRγ). Xenoestrogens/phytoestrogens could also induce oxidative stress-mediated signaling by generating reactive oxygen species (ROS). (C) Shaping the hallmarks of cancer. These features are linked to cell cycle and checkpoint disruption (An external file that holds a picture, illustration, etc.
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The activation of ER signaling pathways plays a vital role in the malignant progression of multiple cancers by comprehensively regulating downstream genes. ERα activation has been shown to exert pro-oncogenic responses while ERβ activation has been shown to exert tumor-suppressive responses. These differences play a large role in the overall prognosis of patients with cancers [158,159]. Most xenoestrogens, including PBDE congeners and BPA, are agonists of both ERα and ERβ. They can mimic endogenous estrogens by interacting with ERα and ERβ, leading to phenotypic changes in cell proliferation, apoptosis, or migration [160]. These cellular changes contribute to the development and progression of hormone-related cancers in the breast, ovaries, and prostate [161]. In recent studies, many lines of evidence have also revealed that BPA exerts its function via activation of human estrogen-related receptor gamma (ERRγ), which behaves as a constitutive activator of transcription [162]. BPA preserves ERRγ’s basal constitutive activity and protects the selective ER modulator, 4-hydroxytamoxifen from its deactivation of ERRγ. This provides possible support that BPA exposure from the environment may potentially induce tamoxifen resistance to breast cancer treatment [163].
However, according to the literature, phytoestrogens such as GEN, DAI, and COU, along with others, exert a much stronger binding affinity for ERβ than for ERα [164]. For instance, GEN is a full ERβ agonist and, to a much lesser extent (~20-fold) of ERα [25]. Therefore, it is believed that the anti-cancer effects of these phytoestrogens may be due to their interactions with ERβ. ERβ in MCF7 breast cancer cells increases the anti-cancer efficacy of GEN by affecting cell cycle transition [165]. Several studies have also reported that GEN inhibits the cell cycle division of human prostate cancer cells via ERβ activation [166]. It is worth noting that the ERα and ERβ may mediate distinct biological effects in many tissues such as the mammary glands, prostate, lungs, and intestine in both males and females. Therefore, the ERα/ERβ ratio is an important factor to consider when predicting the response of cancer cells to phytoestrogen treatment [167]. In addition to ERα/ERβ, flavone and isoflavone phytoestrogens were also ligands of estrogen-related receptors (ERRα/ERRγ). These phytoestrogens induced the activity of ERRs [168].
Although the majority of xenoestrogens/phytoestrogens are believed to exert their biological effects through ERα and ERβ modulation, many of these compounds also activate ERs via a non-genomic pathway which involves mERs and GPER [169,170]. Especially in cancer cells, exogenous estrogens can bind to mERs and/or GPER and activate signaling cascades (Akt, MAPK) through the recruitment of protein kinases (Src and PI3K), therefore mediating rapid transcriptional events [171]. Xenoestrogens/phytoestrogens also activate ERs through phosphorylation induced by growth factor signaling cascades, for instance, the crosstalk between the EGFR/IGFR/Her2/3 growth factor signaling pathways [172]. Phytoestrogens such as GEN can inhibit MCF7 cell proliferation by inactivating the IGF-1R-PI3K/Akt pathway and decreasing the Bcl-2/Bax mRNA and protein expressions [173]. However, xenoestrogens such as BPA and NP can mediate EGFR signaling activation in lung cancer, causing an increase in proliferation, clonogenic growth, and tumor spheroid formation [174].
In conclusion, xenoestrogens/phytoestrogens mimic endogenous estrogens by binding to and activating different types of ERs (ERα, ERβ, mER, and GPER), orphan nuclear receptors (such as ERRα and ERRγ), and cross-talking with many other membrane-associated growth factor receptors (Figure 2). Xenoestrogens/phytoestrogens could act as either an agonist or display antagonistic activity, when endogenous estrogen is present, in a tissue-selective and spatiotemporal manner in human cancers.
4.3. Effect of Xenoestrogens/Phytoestrogens on Activation of AhR/PPARγ/ROS Pathways
AhR (aryl hydrocarbon receptor), binds many types of molecules, including phytoestrogens and xenoestrogens, entering the nucleus and acting as a transcription factor. Because it is also activated by many environmental pollutants. AhR has been called a “xenobiotic sensor”. A major action for activated AhR is enhanced transcription of genes encoding CYPs, some of which are involved in estrogen biosynthesis [175]. In addition, there are interactions between the AhR and ER signaling pathways, with AhR agonists having anti-estrogenic activities. The mechanisms involve (1) AhR competes with ERs for promoter binding, leading to inhibition of ERs signaling, (2) activation of AhR signaling regulates E2 production by controlling the gene expression of CYP19, and (3) activation of AhR signaling ubiquitinates ERs for degradation via the proteasome, leading to inhibition of ER signaling (Figure 2) [176]. Phytoestrogens from soy (GEN, DAI, and S-equol) and licorice roots (liquidities) negatively regulate ERs activation via binding to AhR [177]. However, xenoestrogens, like PCBs and BPA, act selectively through AhR xenobiotic response element (XRE) and enhance AhR target-gene expression, including CYP19, therefore increasing endogenous E2 production [178]. Both ERs and AhR should be considered mediators of the biology, toxicology, and pharmacology of exogenous estrogens.
In addition to the AhR signaling pathway, PPARs can also be activated by exogenous estrogens. PPARs belong to a family of nuclear receptors that act as transcription factors. They have comprehensive impacts on diabetes, adipocyte differentiation, inflammation, and cancer [179]. PPARα stimulation appears to inhibit the proliferation of human colon cancer cell lines and reduce polyp formation in the mouse model of familial adenomatous. PPARβ (also referred to as PPARδ) has been described in the regulation of keratinocyte differentiation, apoptosis, inflammation, and wound healing. PPARγ not only controls the expression of genes involved in differentiation but also negatively regulates the cell cycle [180]. BPA analogs have been reported to be ligands of ERs and PPARs; the greater their capability to activate PPARγ, the weaker their estrogenic potential is [181]. Meanwhile, the activation of PPARγ by GEN can down-regulate the transcriptional activity of ERα or ERβ in breast cancer cells [180,182]. Xenoestrogens/phytoestrogens concurrently activate ERs and PPARs, which may exert opposite biological effects. As a result, the balance between activated ERs and PPARs determines the biological effects of exogenous estrogens and estrogen-like mimics on cells and tissues (Figure 2).
In addition to regulating cell functions through interactions with estrogen signaling, xenoestrogens and phytoestrogens can affect cells through oxidative stress signaling by generating reactive oxygen species (ROS) within healthy cells or cancer cells (Figure 2). Oxidative stress-mediated signaling is a double-edged sword in cancer cell behavior. Oxidative stresses are suggested to play important roles in estrogen-induced breast carcinogenesis [183]. There is growing evidence that the induction of ROS by BPA may contribute significantly to its genomic toxicity and carcinogenic potential [184,185]. On the contrary, many chemotherapeutic strategies are designed to significantly increase cellular ROS levels, leading to tumor cell apoptosis [186]. As noted above, the phytoestrogen COU is a potential chemotherapeutic agent for breast cancer. Evidence indicates that COU acts by inducing intracellular ROS, coupled with DNA fragmentation, up-regulation of p53/p21, cell cycle arrest, mitochondrial membrane depolarization, and caspases 9/3 activation [187].
4.4. Effects of Xenoestrogens/Phytoestrogens on Modulating the Hallmarks of Cancer
Xenoestrogens/phytoestrogens primarily modulate the hallmarks of cancer cells by inappropriately activating ERs, cross-talking with membrane-associated growth factor receptors (EGFR/IGFR/Her2/3), and many other nuclear receptors (AhR/PPARs/ERRα/γ). In the presence of active signaling, the hallmarks acquired by cancer cells are modulated and linked to cell cycle and checkpoint disruption, metabolic rewiring, regulation of apoptosis, and redox homeostasis [188]. In addition to cancer cells, tumors exhibit another dimension of complexity by recruiting heterogeneous cell types and creating a “tumor microenvironment”. These cells include tumor-infiltrating immune cells, cancer-associated fibroblasts (CAFs), cancer-associated adipocytes (CAAs), and more [189]. The impact of exogenous estrogens on tumor-associated cells is significant (Figure 3).
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Figure 3
Xenoestrogens/phytoestrogens modulate the cancer cells and cancer-associated cells. Xenoestrogens/phytoestrogens modulate the cancer cells and cancer-associated cells by inappropriately activating ERs, cross-talking with membrane-associated growth factor receptors (EGFR/IGFR/Her2/3) [16], and many other transcriptional factors (AhR/PPARs/ERRα/γ). In the presence of active signaling, the hallmarks acquired by cancer have been are modulated and linked to (A) cancer epithelial cells, (B) tumor-infiltrating immune cells, (C) cancer-associated fibroblasts and extracellular matrix (ECM), and (D) cancer-associated adipocytes.
Immune modulation has been recognized as an emerging hallmark feature of cancer, including tumor-promoting inflammation and evading immune destruction [190]. Tumor-promoting inflammation is mainly characterized by the activation of innate immune cells, such as monocytes, macrophages, and natural killer cells (NK) often within the tumor environment. The innate immune cells subsequently increase the release of pro-inflammatory mediators such as TNF-α, IL-6, and IL-1β, which in turn stimulates the production of cyclooxygenase products and promote cancer progression. Evading immune destruction involves mechanisms of the adaptive immune cells (cytotoxic T cells, T helper cells, and B cells) by modulating certain immune checkpoint pathways [191]. The receptors (ERs, PPARs, and AhR) that bind xenoestrogens/phytoestrogens are present in lymphocytes, macrophages, neutrophils, and other immune cells [192]. Exposure to xenoestrogens increases the incidence of inflammation by activation of AhR and PPARγ [193]. Considerable research has found that GEN, a natural PPARγ agonist found in soy foods, exhibits anti-inflammatory activities via TNFα-induced NF-κB-dependent IL-6 gene expression by interfering with the mitogen- and stress-activated protein kinase 1 activation pathways [194,195].
However, the mechanisms of xenoestrogens/phytoestrogens via ER pathways in human immune cells have not been well studied. Their molecular mechanisms are based on interactions with ERα and ERβ, as well as with membrane associated GPER [196]. The expression of ERs in immune cells has various levels. For example, human CD4+ T cells and macrophages express higher levels of ERα than ERβ [197]. Xenoestrogens (BPA, DEHP, and PBDE) tend to stimulate M2-like tumor-associated macrophage (TAM) polarization and migration via simultaneously activating ERα or ERβ signaling pathways [198]. ERβ is involved in mediating estrogen action on NK cell activity [199]. Isoflavones such as GEN decrease IL-12/IL-18-induced IFN-γ production in NK cells without altering NK cell cytotoxicity. The regulation of NK cells via ERβ may be linked as a benefit of the anti-inflammatory and anti-cancer process of phytoestrogens [200].
Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) within the tumor environment have recently been implicated in important aspects of epithelial cancer biology such as neoplastic progression, tumor growth, angiogenesis, and metastasis. CAAs from adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling [201]. Many xenoestrogens have been shown to cause obesity in animals at low-level exposures during critical periods of development. More specifically, DES and BPA have been implicated as environmental chemicals that increase fat accumulation by increasing the number of adipocytes, storage of fat within adipocytes, and facilitating obesity [202]. BPA is reported to exert estrogen-like activity on CAFs, particularly through the GPER. BPA induces the expression of GPER target genes, c-FOS, EGR-1, and CTGF, through the GPER/EGFR/ERK transduction pathway in CAFs, leading to their growth and migration in breast cancer [203]. On the contrary, dietary exposure to soy foods is associated with lower mammary tumor risk and a reduction in body weight and adiposity in human and rodent breast cancer models [204]. GEN has been shown to lower mammary adiposity and increase mammary tumor suppressor expressions, such as PTEN and E-cadherin, in female mice. These modulations mediate through ERβ and PPARγ by promoting the differentiation of stromal fibroblasts into mature adipocytes [205]. These results suggest that the direct regulation of mammary adiposity by GEN could be useful for breast cancer prevention.
The effects of xenoestrogens and phytoestrogens on the tumor microenvironment are challenging to study. Traditional animal models that use homogeneous cancer cells do not mimic the actual dynamic, multicellular environment of a human tumor. Therefore, advanced research models, such as PDXs and scRNA-seq technology, allow scientists to capture changes caused by xenoestrogens/phytoestrogens in both cancer cells and the surrounding stromal cells, ultimately improving the understanding of the interactions among these heterogeneous cell populations.
3 Foods to Reduce Estrogen to Lose Weight- Thomas DeLauer
4.5. Effects of Xenoestrogens/Phytoestrogens Determines on Critical Timing of Exposure
Endogenous estrogen flux has been linked to increased breast cancer risk through critical estrogen exposure during certain events and time points during the life cycle such as nulliparity, older age at first birth, early menarche, and late menopause [206]. By the same principle, there is a consensus that the influence of environmental estrogens on breast cancer risk may be greater during certain WOS in a woman’s life. WOS are key life stages in which mammary glands undergo anatomical or molecular transformations and are most vulnerable to environmental exposures. The risk of breast cancer development increases if xenoestrogen/phytoestrogen exposure occurs during WOS, including prenatal development, puberty, pregnancy, and menopausal transition [23]. Exposures to xenoestrogens such as BPA and triclosan can change the timing of puberty and cause early breast development [207]. Menopause is a critical WOS because of its hypersensitivity to endocrine-disrupting chemicals due to the decline of endogenous estrogen [208]. Studies from our group have discovered that PBDEs, the flame retardants in household products, enhance E2-mediated regrowth of mammary glands, augment E2-facilitated gene expression, and modulate immune regulation, thus increasing the risk of developing breast cancer [136,137,138,139]. Importantly, like the WOS in female breast cancer, there appears to be a heightened sensitivity of the prostate to these exogenous estrogens during the critical developmental windows, such as in utero, the neonatal period and puberty. Thus, it is suggested that infants and children may be considered a highly susceptible population for exogenous estrogenic exposure with increased prostate cancer risk with aging [209].
The biological effects of phytoestrogens on breast cancer have also been linked to age and critical time points in a woman’s life [210]. In premenopausal women, who are at high risk for early breast cancer, dietary isoflavone intake has been associated to increase breast cell cancer risk by promoting cancer cell growth. However, isoflavone intake appears to have a protective impact on later breast cancer recurrence and mortality among postmenopausal breast cancer patients [211]. On the other hand, some phytoestrogens appear to reduce breast cancer throughout life. Asian diets, with abundant soy products, include phytoestrogens that appear to be chemo-preventive for breast cancer in Asian women, who consume more soy than women who consume a Western diet [212]. However, the relevant research on phytoestrogens in breast cancer is complicated, inconsistent, and inconclusive [213].
In addition to their influences on the etiology of hormone-related cancers, the impacts of xenoestrogens/phytoestrogens on reproductive health are manifested and determined based on the critical timing of exposure. Early life exposure alters the development of both female and male reproductive systems. The greatest risk may be during the prenatal (fetus) and early postnatal (infant) developmental windows when the organs are forming and developing [214]. Xenoestrogenic/phytoestrogenic exposure in young children may lead to early activation or interference with the hypothalamic-pituitary-gonadal (HPG) axis and therefore contribute to the early onset of puberty [215]. In adults, BPA, phthalates, pesticides, etc. have been shown to decrease the number of primordial follicles in female ovaries [216] and decrease the number and motility of sperm in male semen [217].
Xenoestrogens/phytoestrogens can also influence non-reproductive tissues and are involved in the etiology of disorders including obesity and diabetes mellitus [218], cardiovascular and respiratory disease [219], neurological effects [220], and thyroid disease [1]. It is not surprising that the influences of xenoestrogens/phytoestrogens on these disorders are also associated to the critical timing of exposure. For instance, BPA exposure in women of reproductive age, including pregnant women, has been linked to an increased risk of insulin resistance and type 2 diabetes [221]. For women with BPA exposure during pregnancy, their offspring have a greater chance of having a higher diastolic blood pressure at an early age [222]. There is also correlative evidence suggesting that xenoestrogenic exposure during pregnancy, breastfeeding, and early in childhood may interfere with normal brain development, either directly or indirectly, by disrupting the thyroid hormone signaling axis [223]. More specifically, current literature has shown that many xenoestrogens disrupt thyroid functions through their influence on the thyroidal hormones, triiodothyronine (T3) and thyroxine (T4). These disruptions can lead to their indirect downstream effects in various developmental windows or human life stages. For instance, GEN and PCBs can disrupt thyroid transport proteins, resulting in hormone fluctuations that have been associated with impaired neurodevelopment in offspring [224], whereas PBDE exposure has been associated with hypothyroidism [225].
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5. Application of Phytoestrogens in the Prevention or Treatment of Cancers: Evidence from Clinical Trials
Phytoestrogens such as soy isoflavones DAI, GEN, and glycitein are dietary components that are thought to reduce the incidence and severity of various cancers [226]. The assumed benefits of this soy diet have led to numerous clinical studies on phytoestrogen efficacies to determine a suitable amount for human consumption without any adverse effects. Additionally, clinical studies of phytoestrogens combined with cancer treatments are underway to observe if there is a synergistic effect to treat cancer. Here, we have reviewed 18 clinical trials [61,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244], conducted between 2002 to present, focused on breast cancer (seven trials) [227,228,229,230,231,232,233,234], prostate cancer (eight trials) [61,235,236,237,238,239,240,241], endometrial cancer (two trials) [242,243], and colon cancer (two trials) [240,244], combined with two categories of phytoestrogens treatments: fruits/whole grains/seeds such as resveratrol and curcumin (eight trials) and soy isoflavones such as GEN (10 trials) (Table 3 and Supplementary Table S1).
Table 3
Clinical trials of phytoestrogens used as cancer prevention and/or cancer treatments.
Identifier Cancer Type/Prevention Chemicals Date Participants/ Type of Study Aims Results
NCT00597532
[226] Breast Genistein + Daidzein 8/2002–4/2016 140 women/ R P controlled study To examine the effects of soy supplementation on breast cancer-related genes and pathways Tumors- PRE vs POST = altered EXP of 21 out of 202 genes.
↑ FANCC & UGT2A1 EXP in TG vs. PG (p < 0.05)
Over-EXP of FGFR2, E2F5, BUB1, CCNB2, MYBL2, CDK1, and CDC20 (p < 0.01) in tumors with high-genistein signature
NCT00513916
[232,[233] Breast Isoflavones 7/2006–2/2012 82 multiethnic PR/ R, crossover ‡ To study the effects of dietary soy on estrogens in breast fluid, blood, and urine samples from healthy women High-soy diet resulted in a modest trend of a lower cytological subclass in breast epithelial cells
↑isoprostane excretion in high-soy diet (p = 0.02)
NCT00612560
[229] Breast Ground flaxseed (FS) ± anastrozole (AI) 11/2007–4/2014 24 PO; 2 x 2 factorial R intervention To examine the effect of flaxseed consumption compared to AI, and the effect of combined flaxseed and AI therapy on breast cancer treatment ↓ serum steroid hormone DHEA w/ AI treatment (p = 0.009) PRE vs POST in FS + AI = ~40%
↓ EXP of estrogen receptorβ
Lower Enterolactone excretion in FS + AI vs FS
NCT00290758
[230] Breast Mixed soy isoflavones 1/2006–7/2009 126 women (≥ 25 years)/ R *B To study how well genistein works in preventing breast cancer in women at high risk for breast cancer ↑ Ki-67 labeling index within PR TG (p = 0.04)
Within TG, ↑ EXP of 14/28 genes (p = 0.017–0.052), but no S changes in PG
TG vs PG = ↑ ESR1, FAS, FOXA1, MYB (p = NS)
NCT01219075
[231] Breast Daidzein, genistein, glycitein 7/2010–present 85 women (30–75 years)/ D-B, R, P-controlled To study soy isoflavones supplement in treating women at high risk or with breast cancer NS differences in breast density area (p = 0.23) and mammogrpahic density % (p = 0.38) in TG vs PG
University of North Dakota School of Medicine and Health Sciences [232] Breast Trans- resveratrol N/A 39 women/D-B, R, P-controlled To determine if trans-resveratrol had a dose-related effect on DNA methylation and prostaglandin expression in humans ↑ levels of trans-resveratrol & resveratrol-glucuronide in serum = ↓ RASSF-1α methylation (p = 0.047) & ↓ PGE2 EXP in breast (p = 0.045)
National Center of Oncology, Yerevan, Armenia (Ministry of Health Republic of Armenia Registration No.: Nr 5592-17-02-23)
[233] Breast Curcumin + Paclitaxel 3/2017–9/2018 150 women (18–75 years)/ *, single-institution, R, P-controlled, D-B, parallel group, two-arm trial To assess the efficacy and safety of intravenous curcumin infusion in combination with paclitaxel in patients with metastatic and advanced breast cancer ↑ objective response rate (ORR) of TG vs PG (16 weeks after beginning treatment, p < 0.05; completed treatment, p < 0.01)
3 months after treatment, ↑ ORR TG vs. PG (p < 0.07)
↑ fatigue in TG vs. PG (p = 0.05), but the overall physical performance was significantly higher with curcumin than the placebo during treatment and at the end of follow-up
NCT00596895
[234] Prostate soy milk containing isoflavonoid 11/2003–11/2007 20 men/ O-L, * nonrandomized trial To evaluate the efficacy of isoflavone in patients with PSA recurrent prostate cancer after prior therapy. Slope of PSA level (after vs. before study entry): ↓ in 6 men (p < 0.05), ↑ in 2 men (p < 0.05), and NS changes in 12 men
A decline in the rise of serum PSA after the initiation of soy milk.
NCT01009736
[61] Prostate Tomato-soy juice 1/2008–7/2009 60 men/ * dose-escalating To study the side effects of tomato-soy juice and its effect on biomarkers in patients with prostate cancer undergoing prostatectomy High TG vs PG, ↓prostate-specific antigen slope (p = 0.078)
NCT00255125
[235] Prostate Soy isoflavone capsules 9/2005–10/2009 86 men (≥18 years)/ D-B, R, P-controlled To evaluate the effects of soy isoflavone consumption on prostate specific antigen, hormone levels, total cholesterol, and apoptosis in men with localized prostate cancer. TG vs PG in malignant prostate tissue = down-regulated 12 genes involved in cell cycle control and 9 genes involved in apoptosis
No significant changes in serum total testosterone, free testosterone, total estrogen, estradiol, PSA, and total cholesterol
NCT00765479
[236] Prostate Soy protein isolate 9/2011–7/2013 284 men (40–75 years)/ R, P-controlled Secondary analysis of body weight, blood pressure, thyroid hormones, iron status, and clinical chemistry in a 2-y trial of soy protein supplementation in middle-aged to older men. Soy supplementation did not affect body weight, blood pressure, serum total cholesterol, iron status parameters, calcium, phosphorus, and thyroid hormones.
NCT00546039
[237] Prostate Synthetic genistein 4/2007–1/2009 47 Norwegian men/ * P-controlled, R, D-B To evaluate safety and mechanisms of possible chemopreventive effects of synthetic genistein (BONISTEIN) in patients with localized prostate cancer undergoing laparoscopic radical prostatectomy Genistein intervention significantly reduced the mRNA level of KLK4 in tumor cells (p = 0.033) and p27Kip1
In genistein intervention, no significant effects on proliferation-, cell cycle-, apoptosis-, or neuroendocrine biomarkers
NCT02724618
[238] Prostate Nanocurcumin 3/2016–present 64 men/ R, D-B, * P-controlled To determine the efficacy of oral nanocurcumin in prostate cancer patients undergoing radiotherapy. Nanocurcumin was well tolerated. No significant difference was found between two groups regarding tumor response.
NCT02138955
[239] Prostate, Colon Curcumin 3/2014–6/2017 32 participants (18–85 years)/ ∞, single-center, O-L To investigate the safety and tolerability of increasing doses of liposomal curcumin in patients with metastatic cancer 300 mg/m2 liposomal curcumin over 6 h was the maximum tolerated dose, and a recommended starting dose for anti-cancer trials
Anti-tumor activity was not detected
NCT01917890
[240] Prostate Curcumin 3/2011–10/2013 40 men (50–80 years)/ R, D-B, P-controlled To evaluate the effect of curcumin supplementation on oxidative status of patients with prostate cancer who undergo radiotherapy In TG: ↓ activity of superoxide dismutase (SOD) (p = 0.026), and ↑ plasma total antioxidant capacity (TAC) (p = 0.014)
↓ PSA level in both TG and PG
No significant differences in treatment outcomes were observed between TG and PG
NCT00118846
[241] Endometria Genistein, daidzein, glycitein, 3/2004–3/2009 350 women (45-92 years)/ R, D-B, P-controlled To determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women Soy-treated group did not significantly differ on the mean baseline or on-trial changes in endometrial thickness
ISP has been found to predominantly act on the beta-type estrogen receptor because of its structure similar to 17β-estradiol and selective estrogen receptor modulator (SERM)-like activity.
NCT02017353
[242] Endometrial Curcumin Phytosome (CP) 10/2013–10/2016 7 women (≥18 years)/ O-L, * non-randomized To determine whether curcumin can inhibit tumor induced inflammation in patients with endometrial carcinoma. In addition, curcumin could possibly induce a better functioning of chemotherapy and a decrease in toxicity from chemotherapy. In TG, downregulated MHC expression levels on leukocytes (p = 0.0313), frequency of monocytes (p= 0.0114), and ICOS expression by CD8+ T cells (p = 0.0002), but upregulated CD69 levels on CD16- NK cells (0.0313).
NCT00256334
[243] Colon Trans-resveratrol + quercetin 7/2005–4/2009 11 participants (≥18 years)/∞ pilot, O-L To evaluate the effects of a low dose of plant-derived resveratrol formulation and resveratrol-containing freeze-dried grape powder on Wnt signaling in the colon Resveratrol did not inhibit Wnt pathway in colon cancer, but did inhibit Wnt pathway in normal colonic mucosa (p < 0.03)
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R, randomized; D-B, double-blind; P, placebo; O-L, open-label; ∞, phase I; *, phase II; ‡, phase III; TG, treatment group; PG, placebo group; PRE, pre-treatment; POST, post-treatment; PR, premenopausal women; PO, postmenopausal women; B, baseline; NS, non-significant; S, significant; EXP, expression.
Of the 18 trials, in terms of safety, four trials have shown that phytoestrogens are well-tolerated, safe to use, and/or have no major safety concerns. One trial studies prostate and colon cancer in phase 1 (NCT02138955) while two trials studies breast cancer in phase 2 (Nr 5592-17-02-23) and 3 (NCT00513916). In terms of the efficacy, seven trials showed little or no evidence that phytoestrogens were antagonistic to breast cancer (four trials, NCT01219075, NCT00597532, NCT00612560, and NCT00290758), or prostate cancer (two trials, NCT00255125 and NCT02724618), or endometrial cancer (one trial, NCT00118846). Meanwhile, a total of six clinical trials have shown no significant differences between the treatment and placebo groups, including two breast cancer trials (NCT00290758, NCT00597532), three prostate cancer trials (NCT01009736, NCT01917890, NCT02724618), and one endometrial cancer trial (NCT00118846). Additionally, four clinical trials stated that the conclusions were not statistically significant, including one breast cancer trial (NCT00597532), two prostate cancer trials (NCT00255125, NCT0191789), and one endometrial cancer trial (NCT00118846). Lastly, five clinical trials consisting of two breast cancer studies (University of North Dakota School of Medicine and Health Sciences and NCT00513916), one prostate cancer study (NCT00546039), one endometrial cancer study (NCT02017353, phase 2), and one colon cancer study (NCT00256334, phase 1) suggested the need for larger and/or longer studies.
While the clinical rials of phytoestrogens noted above gave few promising results, combinations of a phytoestrogen with an established chemotherapy drug may be a more promising approach. For example, patients receiving CUR and Paclitaxel to treat metastatic breast cancers had a greater objective response rate (p < 0.05 16 weeks after starting treatment, and p < 0.01 after completed treatment) compared to patients receiving Paclitaxel alone (Ministry of Health Republic of Armenia Registration No.: Nr 5592-17-02-23). Moreover, some men observed a slow rise of serum PSA after consuming 141 mg of isoflavones per day (NCT00596895). This prostate cancer trial has also shown that GEN may have an inhibitory effect on androgen-related biomarkers and supports GEN as a chemo-preventive agent in prostate cancer (NCT00546039).
While tumor response has been used to evaluate the effectiveness of phytoestrogens in cancer treatment, more recent clinical trials have added gene expression analysis. Phytoestrogens alter cancer-related gene expression profiles in breast cancer (NCT00597532, NCT00290758, and University of North Dakota School of Medicine and Health Sciences trail), prostate cancer (NCT00546039), endometrial cancer (NCT02017353), and colon cancer (NCT00256334). More interestingly, some of the trials have shown that phytoestrogens are altering the cancer-related gene expression profiles [227,233,238,243,244]. Under the concept of personalized medicine, gene expression analyses could be an alternative and cost-effective way to predict the effectiveness of phytoestrogens in cancer prevention and treatments. However, a larger number of clinical trial participants and more studies of phytoestrogens and their impact on cancers are still needed to better define their anti-cancer potentials.
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6. Future Directions and Conclusions
According to Global Cancer Statistics 2020, the burden of cancer incidence and mortality is rapidly growing worldwide. The epidemiological features of cancer reflect both the aging and growth of the population, as well as the changes in the prevalence and distribution of the main cancer risk factors, several of which are particularly associated with the environment [245,246]. Exogenous estrogens, such as synthetic industrial estrogenic compounds (xenoestrogens) and estrogenic molecules from plants (phytoestrogens), are a group of environmental factors that potentially cause various cancers through their interactions with cellular signaling processes involving estrogen signaling pathways.
Current knowledge of environmental health, oncology, and epidemiology gives new insight into the etiology of human cancers because of the gene-environmental interactions [247]. However, available epidemiological assessments of the risk of human cancers, which are multifactorial and multistage diseases, do not reflect the complex interactions between the biology of humans and/or their chemical exposure, and any consequent adverse health effects [248]. Moreover, models for the risk assessment of cancers are often based on single-agent causality. Such approaches may miss the possibility of a relationship with exposure to multiple hazardous compounds [249]. For this reason, the effects of the mixture of xenoestrogens/phytoestrogens have not been adequately addressed. While in vitro models with cultured cancer cells provide an advantageous method to interpret the single-agent causality of exposure and disease. However, these models also fail to consider a multifactorial analysis to explore the causal relationship between exposure and cancer development/progression. A novel approach to investigate the complexity of cancer with advanced modes and emerging techniques will be helpful to interpret measurable environmental and biological parameters simultaneously. These emerging approaches include in vivo models with rodents, PDX models, multi-omics-based unbiased analyses, and single-cell analyses [250,251]. Using multidisciplinary approaches, the etiology of human cancer can be more thoroughly investigated.
The Breast Cancer and the Environment Program (BCERP), launched by the US National Institute of Environmental Health Science (NIEHS) and National Cancer Institute (NCI), is a representative multidisciplinary research program that explores the environmental factors that may contribute to breast cancer (https://bcerp.org/ (accessed on 16 May 2021)). The BCERP involves a network of lab-based biologists, clinicians, epidemiologists, and community partners to examine the effects of environmental exposures that may predispose a woman to breast cancer throughout her life. Our team is a member of this project. By taking advantage of the PDX-breast cancer model and scRNA-seq analysis in surgically menopausal (ovariectomized/OVX) mouse models, our group has identified the response to exposure to the xenoestrogen PBDE by various types of cells within mammary tumors and normal breast tissue [125]. At the single-cell level, by integrating mouse and human datasets, we also describe the landscape of transcriptional changes in mammary glands upon endogenous and PBDE at different WOS in a woman’s life [136,137,139]. Other key findings from the BCERP include (1) proteins produced by the developing mammary tissue may change after BPA exposure, which may alter the cell behavior in ways that contribute to breast cancer [252]. (2) DDT exposure during pregnancy may change the pattern of gene expression, leading to an increased chance of developing breast cancer in female offspring [253]. (3) The BCERP overarches a concept that the influence of environmental chemicals on breast cancer risk may be greater during certain WOS in a woman’s life, including prenatal development, puberty, pregnancy, and menopausal transition, during which the mammary glands undergo anatomical and functional transformations. Therefore, environmental hormones (e.g., endocrine-disrupting chemicals/EDC), and certain therapeutics (e.g., prescribed for the coexisting medical conditions or in the form of the hormone replacement therapy) can influence breast cancer risk, development, or outcome [23]. WOS is different from the well-known concept of “Sensitive Windows of Development”, which is referred to the period of fetal development and childhood when hormones regulate the formation and maturation of organs. Therefore, early-life exposures have been linked to developmental abnormalities and may increase the risk for a variety of diseases later in life [214]. (4) Finally, data from the BCERP have described the biological activities and molecular mechanisms of xenoestrogens on mammary gland biology and neoplasia, providing a scientific consensus with an integrated source of information and technology, of the development, function, and pathology of the mammary gland upon xenoestrogen exposure (https://bcerp.org/ (accessed on 16 May 2021)).
In addition to female breast cancer, there is increasing evidence from both epidemiology studies and animal models that environmental exposure to exogenous estrogens may influence the development or progression of prostate cancer, by interfering with estrogen signaling, either through interacting with ERs or by influencing steroid metabolism and altering estrogen levels within the body [254]. In humans, epidemiological evidence links specific pesticides such as the banned but still environmentally present PCBs exposures to elevated prostate cancer risk [255]. Studies in animal models also show augmentation of prostate carcinogenesis with several other environmental estrogenic compounds including BPA [256]. Recently, endogenous and exogenous estrogens have also been postulated as a contributor to non-classical hormone-related tumors, including lung cancer [257], colorectal cancer [258], and gastric cancer [259]. For instance, the etiology of lung cancer is mainly related to environmental exposure such as cigarette smoking and airborne genotoxic carcinogens. However, even correcting for carcinogen exposure, there appears to be an increased risk for lung cancer in women as compared to men. This suggests that sex hormones may be involved with lung carcinogenesis [260]. Several agents commonly present in the living environment can have dual biological effects: acting as genotoxic/carcinogenic and hormonally active xenoestrogens. The dualism of these environmental chemicals may contribute to the development and progression of lung cancer [261]. However, there has been a lack of solid evidence to prove the causal relationships between exogenous estrogen exposure and the increased risk of non-classical hormonal-related cancers.
Different from the xenoestrogens which are widely accepted as carcinogens, a wide range of beneficial effects of phytoestrogens on the cardiovascular, metabolic, and central nervous systems, as well as a reduction of cancer risk and postmenopausal symptoms, has been claimed [262]. The benefits of phytoestrogens such as the soy diet have led to numerous clinical studies on phytoestrogen efficacies to prevent or treat cancer [61,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242]. However, there is also concern that phytoestrogens may act as endocrine disruptors that adversely affect health [212]. Thus, clinical trials are underway to evaluate the safety and efficacy of phytoestrogens with breast, prostate, endometrial, and colon cancer, and more. Our review has included many phases I and II trials that have indicated the safety of phytoestrogens in humans. Existing data generally supports the safety of small doses of purified phytoestrogen consumption as a medication for breast cancer [225,226,227,228,229,230,231,232]. However, for the entire general population, including women with benign breast disorders, those at risk for breast cancer, and even survivors of cancer, the prescription of phytoestrogens is still not recommended due to insufficient evidence [211]. Under the framework of personalized medicine, several clinical trials [225,231,236,241,242] have suggested that phytoestrogens have been shown to change the cancer-related gene expression profiles, providing a perspective that gene expression analyses may help to better predict the effectiveness of phytoestrogens in cancer prevention and treatments. Moving forward, continued research into phase II and III trials with larger participant cohorts and more studies into phytoestrogens are needed to fully elucidate their anti-cancer benefits.
Understanding Xenoestrogens Vs Phytoestrogens
In conclusion, exogenous estrogens, particularly xenoestrogens and phytoestrogens are an important contributor to the development and progression of cancers. Future studies on etiology of human cancers related to environmental exogenous estrogen exposure should focus on synthesizing various perspectives: (1) at the molecular and cellular level, looking at different types of ERs (ERα, ERβ, mER, and GPER) and cross-talk with other signaling pathways, (2) at the tissue level, considering the spatial heterogeneity of tissue composition and temporal heterogeneity of cancer progression, (3) at the systematic level, studying the exposure time at critical developmental windows, and (4) at the individual or population level, considering gene-environment interactions. Incorporated analysis of all the data in a clearly understood fashion allows for the modeling of prevention and therapy on an individual basis and the potential for developing new diagnostic biomarkers and drugs. Moreover, in the future, closer collaboration among oncology, systems biology, and environmental health may provide a significant qualitative and quantitative leap forward in the elucidation of human cancer etiology. The information gained from such collaborations could be applied in the introduction of preventive measures, personalized medicine, and more relevant public health intervention, ultimately, improving the knowledge and management of the complex environmental interactions underlying this life-threatening disease.
Are Xenoestrogens in plastic?
In our practice, we regularly counsel patients on how to treat the negative effects of estrogen dominance and other hormone imbalances in the body. Many women come to us seeking help for hot flashes, sleep disturbances, weight gain, depression, anxiety and low libido caused by rapidly fluctuating hormone levels during perimenopause and menopause.
Men are also negatively affected by hormone imbalance as they age and often suffer from weight gain, depression, and exhaustion during “male menopause”, known as andropause.
But lifestyle factors can also throw your hormones out of balance.
Due to the added influence of "environmental" estrogens, hormonal fluctuations can occur for women and men at any age. Daily exposure to “xenoestrogens,” (man-made environmental estrogens) can accelerate the aging process, and/or create a condition of estrogen dominance at an earlier age.
Where Are Xenoestrogens Found?
Xenoestrogens are found in hormone-injected meats, certain pesticides, petrochemicals, herbicides, plastics, fuels, car exhausts, and drugs, as well as phthalates, or plastic-softening chemicals. When absorbed in the body, xenoestrogens act as endocrine disruptors that can decrease or increase normal hormone levels, mimic the body's natural hormones, or alter the natural production of hormones. (1) There are many surprising sources of endocrine-disrupting chemicals in the products we use every day.
How do Endocrine Disruptors Such as Xenoestrogens Damage the Body?
Endocrine disruptors can:
Mimic or partly mimic naturally occurring hormones in the body like estrogens (the female sex hormones), androgens (the male sex hormones), and thyroid hormones, potentially producing overstimulation.
Bind to a receptor within a cell and block the endogenous hormone from binding. The normal signal then fails to occur and the body fails to respond properly. Examples of chemicals that block or antagonize hormones are anti-estrogens and anti-androgens.
Interfere or block the way natural hormones or their receptors are made or controlled, for example, by altering their metabolism in the liver.
Chemicals that mimic or antagonize the actions of naturally occurring estrogens are defined as having estrogenic activity (EA), which is the most common form of endocrine disruptor activity. When this delicate system is disrupted, a variety of health-related problems in both women and men can result, including early puberty in females, altered functions of reproductive organs, obesity, and increased rates of some breast, ovarian, testicular, and prostate cancers. (2) Additionally, BPA exposure (see below) has been linked to heart disease, diabetes, weight gain, and asthma. (3)
BPA Plastic: A Pervasive Xenoestrogen to Avoid
BPA (or bisphenol A) is an industrial chemical and xenoestrogen that has been used to make certain plastics, resins and dental composites since the 1960s. Research has shown that BPA can leach into food or beverages from containers made with BPA.
Many plastic products are now marketed as BPA-free, but manufacturers have begun substituting other chemicals whose effects aren't as well known. In a recent study, researchers analyzed more than 450 plastic products such as baby bottles, deli packaging, and flexible bags and found that more than 70% of them released chemicals having estrogenic activity. Simulated sunlight, dishwashing and microwaving increased this percentage to 95%. Some of the “BPA-free” products tested in the study had even more activity than products known to contain BPA.
Avoiding plastic products wherever possible is a good first step in protecting your endocrine health but there are other ways you can reduce your exposure to xenoestrogens.
How To Protect Your Endocrine Health
Buy and store foods in glass jars (or stainless steel), not plastic
Use fresh, frozen, or dried products, not canned. (One study has suggested that, after just 3 days of eating a fresh food diet with no products taken from a can or plastic packaging, the levels of BPA in participants' bodies fell significantly.) (3)
Avoid microwaving foods in plastic containers
Do not wash plastic containers in the dishwasher or use harsh detergents on them
Choose wooden toys instead of plastic
Choose glass bottles for drinking water and bottle feeding (4)
How to Reverse the Negative Effects of Xenoestrogens
If you are experiencing any of the following symptoms, you may be suffering from estrogen dominance caused or exacerbated by prolonged exposure to environmental xenoestrogens:
Depression
Low libido
Mood swings
Hot flashes
Night sweats
Headaches/migraines
Tender/fibrocystic breasts
Weight gain
Insomnia
Bone loss
Irregular bleeding
Bloating
The hormone estrogen is an important key to a woman’s physical well-being; however, an overload of estrogen is destructive, causing a cascade of unpleasant symptoms and raising the risk of life-threatening diseases. As Dr. John Lee described the condition: “If estrogen is dominant and progesterone deficient, estrogen becomes toxic to the body.” Untreated estrogen dominance has been clinically-linked to an increased risk of breast and uterine cancers, osteoporosis, low thyroid, and dementia.
Fortunately, hormone balance is achievable at any age.
The best high-impact solution to resolve estrogen dominance in women and men is balancing estrogen levels with bioidentical progesterone cream. A "bioidentical" progesterone treatment is biochemically identical to the kind your body naturally produces!
Bioidentical progesterone is derived from a plant molecule found in wild yam, which is synthesized in a lab to be identical to naturally produced hormones. The synthesizing process ensures that these hormones have the same molecular structure and duplicate the same function as the hormones made by your body. When you use bioidentical hormones, the cells of your body recognize them as familiar and know how to put them to best use.
A Natural Solution to an Environmental Problem
Many people have found relief from their symptoms with Dr. Randolph's over-the-counter formulation of Natural Balance Progesterone Cream (for women and for men). However, for more severe hormone imbalances, the best approach is to have your hormone levels checked.
Our clinicians evaluate your health and lifestyle issues, check your hormones with a simple blood test, and write prescriptions for exactly the hormones that YOUR body needs. Restoring hormone balance is intricate endocrinology, and often there are several imbalances at play. Each bioidentical hormone formulation we offer is compounded at our on-site pharmacy and can be picked up or shipped as needed
How do xenoestrogens affect hormones?
Learn why xenoestrogens pose health risks for men and women.
Hormones play an essential role in just about every system of the body. In short, they tell different tissues and cells what to do. When these directions get garbled, serious health issues can result.
Unfortunately, a class of compounds known as endocrine disruptors can negatively impact the normal action of hormones in the body. Xenoestrogens are a specific type of endocrine disruptor that have estrogen-like effects on the body. Many types of xenoestrogens are not biodegradable, and will build up in fat cells. At high levels, the impact of xenoestrogens may be sufficient to artificially raise the total amount of estrogen in the body to uncomfortable or unsafe levels.
Effects of Xenoestrogens on Women
In women, xenoestrogens can contribute to a condition known as estrogen dominance. This is especially likely during perimenopause, when the normal balance of progesterone and estrogen is out of balance anyway, leaving women prone to high estrogen levels. In addition to causing symptoms, estrogen dominance can increase the risk of breast, uterine, and ovarian cancers.
Effects of Xenoestrogens on Men
While men need a little bit of estrogen in their system, too much can be dangerous. Excess estrogen can cause abnormal clot formation, raise triglycerides & LDL cholesterol, and increase the risk of stroke or heart disease. Another significant danger is that estrogen can be metabolized into a carcinogen that can cause prostate cancer. Men need to be especially wary of xenoestrogens if they are overweight. Fat tissue contains an enzyme that can convert testosterone to estrogen, meaning estrogen levels may already be approaching the danger zone. In addition to all of the above, excess estrogen causes many unpleasant symptoms for men.
Identifying & Avoiding Xenoestrogens
Xenoestrogens can be found in a wide variety of chemicals, many of which the average American may encounter on a daily basis. Some of the most worrisome xenoestrogens are:
Atrazene: Atrazene is just one of many pesticides and insecticides that contain xenoestrogens. To minimize exposure, always wash your produce thoroughly and choose organic foods whenever possible.
BPA: Bispenol A is a chemical used to make hard plastic items. Once very common, it has now been phased out of most products. Check for a BPA-free label when buying reusable water bottles, food containers, and other hard plastic items.
Phthalates: These chemicals are commonly used in home fragrance products as well as in soft, flexible plastics. To avoid them, cut back on your artificial fragrances and never reheat food in a flexible plastic container.
PCBs: Although PCBs have been phased out of most products, they still remain in the environment. The biggest concern is eating fish contaminated with PCBs, as these chemicals can build up to unsafe levels in freshwater predator fish and bottom-feeding fish. Stick to saltwater fish to avoid exposure.
It’s worth noting that phytoestrogens, or plant estrogens found in foods like soy, are technically xenoestrogens. However, when eaten as part of a normal, balanced diet, phytoestrogens do not build up in tissues to the point of causing problems with estrogen balance.
Get Treatment for Your Hormone Imbalance
If you are suffering from hormone decline—a.k.a. andropause or menopause—the effect of xenoestrogens acting on your already imbalanced hormones can be of even greater concern. Renew Youth™ can help to restore hormone balance with hormone replacement therapy. We’ll conduct ongoing testing during treatment to make sure your estrogen level stays in a healthy range. For more information, please contact us today.
How many xenoestrogens are there?
The role of steroids in carcinogenesis has become a major concern in environmental protection, biomonitoring, and clinical research. Although historically oestrogen has been related to development of reproductive system, research over the last decade has confirmed its crucial role in the development and homeostasis of other organ systems. As a number of anthropogenic agents are xenoestrogens, environmental health research has focused on oestrogen receptor level disturbances and of aromatase polymorphisms. Oestrogen and xenoestrogens mediate critical points in carcinogenesis by binding to oestrogen receptors, whose distribution is age-, gender-, and tissue-specific. This review brings data about cancer types whose eatiology may be found in environmental exposure to xenoestrogens. Cancer types that have been well documented in literature to be related with environmental exposure include the reproductive system, breast, lung, kidney, pancreas, and brain. The results of our data mining show (a) a significant correlation between exposure to xenoestrogens and increased, gender-related, cancer risk and (b) a need to re-evaluate agents so far defined as endocrine disruptors, as they are also key molecules in carcinogenesis. This revision may be used to further research of cancer aetiology and to improvement of related legislation. Investigation of cancers caused by xenoestrogens may elucidate yet unknown mechanisms also valuable for oncology and the development of new therapies.
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Background
Despite the considerable efforts to decrease environmental pollution we still witness uncontrolled introduction of new compounds in living and working environment. Additionally, pollution control in low income and developing countries has seen limited success. The balance between needs of a fast growing human population and technology/science development is questionable, partially as a consequence that the available knowledge is not always applied in an efficient way as it should be.
The last century's paradigm “one agent - one disease” has helped to identify the major causal pathways and the identification of pollution related diseases, including cancer. Based on this approach, epidemiological studies set off many activities to reduce pollution and prevent exposure. However, a large body of data accumulated over the last decade, with a recent significant contribution of molecular biology, clearly shows that this historical simplistic interpretation of biomonitoring data fails to answer a number of questions about environmental threats to human health.
Cancer incidence monitoring in developed countries is relatively accurate. A better classification of cancer types, the networking of cancer registries, and the increasing population coverage for cancer registration are unfortunately accompanied, due to unsolved technical and organizational difficulties, by publishing of cancer register reports with a lag of several years. This lag is a serious obstacle in identifying current environmental health risks and setting timely effective preventive measures.
According to recent data [1], childhood cancer incidence increases 1% a year all over Europe. In the adult population a rising trend is reported for soft tissue sarcoma, brain tumours, germ-cell tumours, lymphomas, renal cancers, leukemias, breast cancer, and lung cancer in women. Breast, colorectal, prostate, and lung cancer are the most commonly diagnosed cancers in the European population [2]. Only limited part of the detected increase may be related to screening programs.
During the last decade, environmental health and oncology have shown an increasing interest in oestrogen as an evolutionary conserved molecule. With its endocrine, paracrine, and neurotransmitting activity [3-5], oestrogen is not limited to the development and regulation of the reproductive system. The distribution of oestrogen receptors in mammalian tissues suggests that oestrogens could have a significant role in orchestrating a number of pathways in living organisms during development and adulthood. Additionally, new evidences confirm a strong impact of this molecule on carcinogenesis [6-9].
Very little is known about changes in oestrogen levels and the tissue ratio between alpha and beta oestrogen receptors (ER) during development [10]. In the second trimester of human foetal development the highest concentrations of ER beta mRNA are found in the testis and the ovary and of ER alpha mRNA in the uterus. Relatively high concentrations of either receptor are also present in the spleen, while low levels are detected in the kidney, thymus, skin, and lung [11]. The pre-pubertal ratio between ERs alpha and beta in human tissues in males and females is not known. Additionally, ER alpha and beta are polymorphically distributed and as such they play different roles in carcinogenesis [12-14].
At higher levels, oestrogen is carcinogenic [15]; similar to ionizing radiation it may produce reactive oxygen species and cause hypomethylation and microsatellite instability [9,16-18]. Its metabolites, quinones, cause the formation of DNA adducts, depurination, lipid-derived aldehyde-DNA adducts, and aneuploidy [15,19]. By decreasing glutathione-S-transferases, oestrogens may increase cellular oxidative DNA damage in oestrogen-responsive tissues, when the organism is simultaneously exposed to genotoxicants. This is an early step in the process of carcinogenesis [20].
Gender differences in the incidence of cancers such as the lung, kidney, or pancreas cancer suggest that hormones may play a role in their aetiology [21]. Recent findings suggest that all neoplastic mammalian tissues are characterized by disturbances in ER levels [6]. As gender related estrogen levels in foetal, and prepubertal tissues, the tissue specific ER distribution and oestrogen bimodal activity modulate the development of biological pathways and organogenesis [22,23] some cancer types may have origin in their prenatal and postnatal disturbance caused by exposure to xenoestrogens.
The general population is exposed to a number of hormonally active compounds on a daily basis. These compounds were introduced in the living environment during the last few decades, the majority of which are xenoestrogens. Chemicals like polycyclic aromatic hydrocarbons (PAH), pesticides, polychlorinated biphenyl (PCB), dichlorodiphenyl-trichlorethane (DDT), some drugs (e.g., antiepileptic drugs), fungicides, cotinine, phytoestrogens, mycotoxins, bisphenol A (a plastics additive), phthalates, alkylphenols, and metalloestrogens mimic oestrogen action, affect oestrogen levels, or bind to oestrogen receptors [24-29]. Xenoestrogens are present in a number of substrates such as cigarette smoke, automobile exhaust, chemical industry pollutants, grilled meat, volcano dust, forest fire smoke, milk, water, and cosmetic products. This means that all human population may be exposed to them.
This article seeks to give an insight in how environmental exposure to xenoestrogens relates to breast, lung, kidney, brain, pancreas, and reproductive system cancers, which are all characterized by disturbances in ER.
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Breast cancer
The reports on decrease of breast cancer incidence in women 50-69 years old are related to improvement of preventive measurements such as mammography screening in developed countries. In the United States, Australia, and Western Europe this decrease seems to follow a decrease in hormonal therapy [30], as oestrogen plays important role in pathogenesis of breast cancer [31,32].
Factors involved in the development of breast cancer incidence include the socioeconomic status, some food additives, pesticides, oestrogen and progesterone replacement therapy, some antibiotics, radiation, mutations at genes BRCA1, BRCA2, metabolizing enzyme polymorphisms, epidermal growth factor and its receptor (HER), androgen levels, and insulin-like growth factor [33-35]. Age (including transplacental, prepubertal) may also play an important role in oestrogen exposure-related breast cancer risk that probably involves epigenetic mechanisms [36-39].
Currently there are some 160 xenoestrogens that may be involved in breast cancer development [40-42]. Women are the largest consumers of cosmetic products which may be a significant source of xenoestrogens. Some, such as metalloestrogens (e.g., aluminium salts), parabens, cyclosiloxanes, triclosan, UV screeners, phthalates, Aloe Vera extracts, and musk are present in numerous cosmetics products. Humans are exposed to these chemicals transcutaneously and measurable levels have been detected in human breast tissue [23].
Alcohol is also related with increased risk of breast cancer development as even low alcohol consumption increases serum oestradiol (especially for carriers of a certain alcohol dehydrogenase allele) and stimulates ER alpha [43,44]. On animal model it is shown that alcohol increases oestradiol levels in dams, which leads to higher levels of ER alpha receptors in their offspring mammary gland and may launch tumorigenesis [37].
The effect of diet on breast cancer development was observed in Japanese women after the Second World War when dramatic changes in their diet happened such as increased consumption of meat, eggs, and milk containing oestrogens or oestrogen-like compounds [45]. Milk is a source of oestrogen due to the practice of milking pregnant cows [46].
Heterocyclic amine and their metabolites, especially 2-amino-1-methyl6-phenylimidazo (4,5-b) pyridine (PhIP) is present in high concentrations in well-cooked meat and it binds to and activates the breast cell ER alpha [47,48]. In animal model, it causes breast cancers [49]. The suggested mechanisms of PhIP mechanisms are formation of PhIP-DNA adducts and increase of proliferation in mammary gland terminals and buds [50]. Similarly, at concentrations higher than 140 μg/m3 polyaromatic hydrocarbons from food may increase breast cancer risk in postmenopausal women if they were exposed to it early in life [51].
Styrene, a widely used plastic for food packing, has been associated with breast cancer risk both in men and women [52]. Direct intake of styrene is via food packed or even cooked in styrene boxes with a direct migration of styrene to food. Styrene and its metabolites bind to ER alpha [53], cross the placental barrier, and also affect the development of reproductive organs [54,55].
The carcinogenic potential of xenoestrogens may also depend on polymorphism of metabolic enzymes. It is shown that subpopulation carrying a polymorphism of metabolic enzyme CYP1A1 m2 is more susceptible to breast cancer development after exposure to polychlorinated biphenyls (PCB), which may explain contradictory epidemiological reports on the association between breast cancer incidence and PCB exposure [35,56,57].
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Lung cancer
Lung cancer is the predominant cause of cancer mortality [58]).There is a gender difference in the incidence of lung cancer types. The leading cause in men is the squamous cell carcinoma, and in women adenocarcinoma. Oestrogen and ER distribution could be the main cause of this difference [59,60]. Despite the fact that lung cancer incidence is increasing in women [61-64] studies reporting lung cancer incidence basically rarely give attention to possibly gender related susceptibility [65-67]. Lung cancer is about 70% ER beta positive. The ratio between ER alpha and ER beta in the lung tissue seems to be relevant for lung cancer development and may explain the higher incidence of lung adenocarcinoma in women than in men [68]. Increased lung cancer risk in women is associated with a lower social status and high level of indoor pollution with PCBs during cooking as a consequence of coal usage [69,70]. ER beta levels in lung cancer are gender related and have impact on survival rate [71]. While ER beta receptor positive or negative lung cancers has no impact on survival in women, in men ER beta positive lung cancer is associated with a significantly lower mortality than ER beta negative lung cancer [72]. ER alpha modulates lung differentiation and maturation while ER -beta causes proliferation of lung cancer cells [73,74]. Gender specific distribution of CYP19 (aromatase) in lung cells puts in correlation oestrogen levels and lung cancer etiology [75]. Additionally, women taking oestrogen therapy have shown increased lung cancer incidence [76]. Same as for breast cancer epidermal growth factor and its receptor HER plays a significant role in non-small cell carcinoma and is associated with endogenous estrogen exposure [77].
Smoking remains the major cause of lung cancer in humans [78]. Methylnitrosamino-pyridyl-butanone, a powerful carcinogenic agent contained in cigarette smoke is ER beta receptor related [69]. The activity of nicotine is gender-specific [79], since cotinine, a nicotine metabolite, is an aromatase inhibitor [80] that decreases oestrogen end increases testosterone levels. Polonium 210 in cigarettes [81] may have similar activity as other metalloestrogens [24,82]. Other carcinogens in cigarette smoke should be re-evaluated for their xenoestrogen or aromatase inhibitor potency.
Traffic air pollution is also related to lung cancer [83,84]. A number of compounds from traffic emissions are oestrogen ligand active compounds [85]. PAHs represent one of the major mixtures of agents that are present in polluted air have been demonstrated to affect oestrogen homeostasis [86-88].
Industrial emissions also contain pollutants with oestrogen-like activity, such as heavy metals and dioxins [89]. A significant association between industrial air pollutants and lung cancer risk has been reported in women [90].
Arsenic is a known lung carcinogen [6] whose biological effects include increased ER alpha transcription. In animals, transplacental exposure to arsenic causes lung cancer in female offspring. This suggests that arsenic can modify genes during foetal development which may cause lung cancer later in life [91]. Figure Figure11 shows complex environmental exposures which may lead to the lung carcinogenesis.
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Figure 1
Schematic presentation of lung cancer development
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Kidney cancer
Data on the environmental aetiology of kidney cancer are not available, and much more research is needed. The fact that renal cell carcinoma, the most common type of kidney cancer, can be induced by exposure to oestrogens [92] in animal model suggests the involvement of oestrogen receptors in the aetiology of kidney cancer and of a possible role of xenoestrogens. Kidney cancer incidence seems to be gender -related, with an incidence that is two times higher in men than in women [93]. In addition, genetic polymorphisms of ER alpha in the kidney seem to play a significant role in the development of kidney cancer [92]. Cadmium and arsenic as xenoestrogens may also induce kidney cancer [94,95]
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Pancreatic cancer
Understanding of pancreatic cancer aetiology is crucial, as it is the fourth leading cause of cancer deaths in the USA [64] and one of the most aggressive diseases. The incidence of pancreatic cancer has been relatively stable worldwide over the last few decades [96-98]. It is more frequent in men than in women [99,100]. Pancreatic cancer cells are ER alpha and beta positive and consequently may be modulated by oestrogen [101] which is consistent with similar mechanisms observed in xenoestrogen-related cancers [102,103]. There are very few data on the effects of xenoestrogens on pancreatic cancer incidence.
Methylnitrosamino-pyridyl-butanone is the only compound demonstrated to cause pancreatic cancer in animal models [104]. This finding has also been reported for the adenocarcinoma of the lung and has been related to ER beta activation [68].
It is also known that consumers of fried meat run a higher risk of pancreatic cancer development probably due to exposure to benzo(a)pyrene and other food contaminants that have xenoestrogenic properties [45,105].
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Brain tumour
Brain tumours are characterized by disturbances in ERs [106-108]. Transplacental exposure to xenoestrogens may increase the risk of brain tumour development [79,80]. Xenobiotics that inhibit aromatase also inhibit the conversion of oestrogen to testosterone and may have a significant impact on brain pathology, given the evidence that disturbed levels of testosterone have impact on apoptosis and intracellular signaling [109] Increased brain cancer incidence has been reported in humans living near petrochemical industries [110]. Despite the fact that the exact chemical composition of the mixture of air pollutants remains unknown, polycyclic aromatic hydrocarbons (PAH) are present in polluted air in such areas [67]. PAHs as xenoestrogen-like agents [87] may have played a causal role on the excess of brain cancer incidence detected
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Reproductive system
Testicular cancer incidence has significantly increased over the last few decades with yet no clear hypothesis on impact of environment on its aetiology [111]. As this trend cannot be explained by cryptorchidism, smoking, genetic variations, or physiological stress, the role of environmental exposure is being investigated to elucidate its aetiology and to identify preventive measures [112].
Both ER alpha and beta are expressed in the human testis and are involved in the control of testicular function [113]. The role played by xenoestrogens on testis development is still only partly known in the animal model, with results showing very dynamic changes in tissue sensitivity to xenoestrogens with unknown consequences during puberty and adulthood [114].
There are a limited number of studies reporting possible association between testicular cancer and disturbances in oestrogen levels. Testicular cancer has been reported in sons of smoking mothers [115], but also in mothers who were taking antiepileptics during pregnancy [116]. Both antiepileptics and cotinine from cigarette smoke are aromatase inhibitors. Transplacental exposure to aromatase inhibitors and consequently increased levels of testosterone may have long-term effects in humans, as shown in an animal model [117].
Epidemiological studies also suggest increased risk of testicular cancer following prenatal exposure to oestrogens [118].
Styrene storage containers may contaminate food which becomes a source of styrene exposure. Transplacental exposure to low levels of styrene may lead to the disturbed development of male genital organ [54]. However, its effect on cancer development remains unknown.
Endocrine disrupting chemicals which disturb ERs can cause female reproductive dysfunction [119,120]. As ovarian cancer therapy is still not marked with significant success and mortality is very high it is of major significance elucidation of its aetiology [121].
Cadmium, one of most investigated heavy metals, has a significant role on ovarian and reproductive functions, as it lowers progesterone levels and mimics oestrogen in various tissues by binding to ER alpha. Cadmium is not confined to occupational exposure alone; it is found in cigarette smoke, food, nickel/cadmium batteries, pigments, and plastics [122].
Ovarian cancer is associated with milk and cheese consumption due to oestrogen and insulin growth factor present in milk of pregnant cows [46,123].
According to recent experimental evidence, uranium in water should be further considered in research as an additional risk for reproductive cancers [82].
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Conclusions
As an evolutionary conserved molecule, oestrogen is present in both plants and animals. Oestrogen is recognized today as a critical modulator of development, homeostasis in adulthood and orchestration of response to environment.
Although gene polymorphisms can change cancer incidence [124,125], it is clear that environment has predominance over genes in cancer risk. Responses to environmental stressors are age- and gender related, and transplacental exposure to xenoestrogens has been shown to have long-term effects in experimental models, as it modulates hormonal response in puberty This means that exposure to endocrine agents not only poses a health risk during exposure, but also increases susceptibility later in life [114,126,127]. Differences in susceptibility to xenoestrogens may be related to steroid and xenobiotic receptor levels, which are high in young adults (15-38y old) and decrease with age [128].
Current estimates of cancer risk in humans do not account properly for transplacental and environmental (including occupational) exposure to xenoestrogens. The role of xenoestrogens in cancer development should be re-evaluated using a new approach that would reflect the complexity of carcinogenesis.
Reductionism as the main scientific philosophy of the 20th century gave a significant input to environmental health. However, the quantity of data available in noosphere, systems biology as a tool and new softwares for data sharing enable the investigation of interactions between xenoestrogens and other environmental stressors, such as radiation, and add new dimensions to the research of cancer aetiology using complexity as a new scientific philosophy. Contemporary mathematical models and systems biology allows the incorporation of all available data and modeling cancer risk allowing free interaction and clustering of data.
The collaboration of environmental health with oncology would be of crucial significance in the study of xenoestrogens as estrogen has today significant position in oncological diagnostics and therapy what includes measurements of ER levels in different tissues. Clinical oncology today takes part in scientific projects in order to achieve optimal treatment at the individual level (tailored therapy) and produces large amounts of data that reflect a tight gene-environment interaction and point to age and gender specific susceptibility. Collaboration between pharmacokineticians, oncologists, histopathologists, molecular epidemiologists, and genotoxicologists may improve our knowledge of cancer aetiology and lead to gender specific and final individualized therapies.
Available information systems and building of integrated exposure-disease pathways will give policymakers much more useful input in future for more efficient regulations than a large number of agent- and disease-specific studies.
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Competing interests
There is no competing interest in interpretation of data or presentation of information in this article which may be influenced by personal or financial relationship with other people or organizations.
Where are xenoestrogens found?
The endocrine system is a sophisticated collection of glands that secrete hormones to ensure our cells receive the right information to regulate a wide variety of functions. When the endocrine system is humming along nicely, we’re more likely to experience good health. The endocrine system is susceptible to many external forces that can send it out of balance and one of the strongest influencers is a class of chemicals called xenoestrogens. It’s important to know what xenoestrogens are, where they’re found and also, what we can do avoid them and reduce their effect on us.
It doesn’t take much to throw the entire endocrine system out of balance, and exposure to xenoestrogens, often measured in parts per billion, can literally be the straw that breaks the camel’s back, and be the tipping point for a cascade of hormonal imbalance.
WHAT ARE XENOESTROGENS?
Xenoestrogens are man-made chemicals that disrupt the endocrine system and meddle with our ability to excrete estrogen, potentially leading to estrogen dominance as well as developmental, reproductive, neurological and immune effects. To my knowledge, xenoestrogens never have the potential for positive action. They are only a risk.
What’s The Difference Between Xenoestrogens and Phytoestrogens?
Xenoestrogens are very different from phytoestrogens, which are compounds found in certain plant foods that mimic our own production of estrogen in the body. Phytoestrogens may have a positive effect or a negative effect depending on the individual and his or her health circumstances.
WHERE ARE XENOESTROGENS FOUND?
Hold on to your hats, because xenoestrogens are almost everywhere. Sources of xenoestrogens include:
Water (tap water and bathing)
Pesticides, herbicides and insecticides, including glyphosate as found in conventional food, and even tampons
Cleaning products (home and industrial)
Plastics (food, beverages, storage containers, non-food packaging and industrial plastics)
Canned foods
Dental sealants
Receipts
Air and dust
Air fresheners
Laundry products (detergent, fabric softener, dryer sheets, etc.)
Hair dyes
Nail polish and nail polish removers
Cosmetics
Personal care products (shampoo, conditioner, deodorant, moisturizer, body wash, etc.)
Perfume
Sunscreen
Medical devices
Birth control pills
Toys
Building materials
Home furnishings (including furniture, carpets, window drapes, mattresses/foams, bedding)
Photocopiers and printers
Artificial food dyes
While this list may seem overwhelming, the good news is there are ways we can reduce our exposure in our own homes (more on that below).
If you’re interested in learning more about how we can reduce our exposure to xenoestrogens and other chemicals in the home, click here to check out my Healthy At Home course.
HEALTH RISKS OF XENOESTROGENS
The body naturally produces estrogen. This type of estrogen is called endogenous – or made by the body. We often start messing with its balance from a young age – with baby bottles, and toys (and now that slime craze), and top off our teens with some birth control pills. As you’ll note above, xenoestrogens are found in all forms of plastic.
What are Xenoestrogens??? - 107
Xenoestrogens mimic estrogen in the body and can out-compete the estrogen we make, leading to hormonal and endocrine disruption. Xenoestrogens can be up to 1,000 times more powerful than endogenous estrogens. The greater our exposure, the greater the impact. They are extremely powerful and are stored in our fat cells. In the last 50 years, researchers have noticed an increase in the incidence of diseases associated with these endocrine-disrupting chemicals.
Some of the health risks of xenoestrogens include:
Cancer
Endocrine disruptors are connected to hormone-dependent cancers like breast cancer and prostate cancer
Prostate cancer incidence has nearly tripled from 1975 to 2007
Breast cancer incidence in women has increased by 57% from 1977 to 2007
Xenoestrogens are linked to other cancers including pancreatic, lung, kidney, brain and testicular
Infertility
Xenoestrogens can cause infertility in couples and lower sperm count in men
Can influence endometriosis, pelvic inflammatory disease and PCOs in women
Can even be linked to the decline of sex ratios (male to female births)
Obesity
Xenoestrogens accumulate in fat tissue
This can lead to the accumulation of excess fatty tissues in the body, altered metabolism, increased appetite and obesity
Diabetes
Exposure to organochlorine pesticides, phthalates and PCBs are linked with insulin resistance and risk of developing Type 2 diabetes
Thyroid Disruption
Xenoestrogens can interfere with thyroid hormone production, signalling and receptors
HOW TO REDUCE XENOESTROGEN EXPOSURE
You can mitigate the effects of xenoestrogens in a variety of simple and straightforward ways. Yes, there are some sources of xenoestrogens that we cannot control, but overall there are many ways that we can reduce our exposure, as well as rid of xenoestrogens from our bodies.
Evidence indicates that in adults, the effects can be improved or reversed when we remove xenoestrogens from our lives. Unfortunately, fetuses, infants and children are more susceptible to the effects of xenoestrogens and the damage can be permanent. (For more on creating an optimal environment for babies and children, check out my posts on preconception planning, breastfeeding, baby food introductions and healthy nursery essentials.)
While this list of ways to reduce xenoestrogen exposure may seem long or overwhelming, each tip in and of itself isn’t excruciating or onerous, plus I provide plenty of additional links to help you. Prioritize and pick what makes the most sense for you to start with. You could begin with the xenoestrogen sources you use the most (like personal care products or cleaning products, for example), or decide based on what suits your budget.
15 WAYS TO REDUCE XENOESTROGEN EXPOSURE
1. Buy or Make Natural Beauty Care Products
Why Do It: The average woman uses 12 products with 168 chemical ingredients daily, while men use 6 products that contain about 85 ingredients. Altogether, 12.2 million adults are exposed to ingredients that are considered known carcinogens every single day because of their personal care products. The common ingredients in lotions and potions are considered safe in small amounts. But all those little small amounts add up.
How to Do It: 20 Best Natural Beauty Care Recipes and 13 Ingredients to Avoid In Personal Care Products
2. Switch to Natural Deodorant
Why Do It: Conventional deodorants and antiperspirants contain ingredients that are linked to allergic reactions, skin conditions, neurological issues and cancer.
How to Do It: How to Choose a Good Natural Deodorant
3. Skip Synthetic Perfumes
Why Do It: The chemicals in perfumes are associated with endocrine disruption, respiratory issues, asthma, dermatitis and headaches.
How to Do It: Is Your Perfume Poisoning Your Family?
4. Use Natural Cleaning Products
Why Do It: Conventional cleaning products contain a cocktail of chemicals that are worse for us than the dirt itself. Many have volatile organic compounds (VOCs) that are known carcinogens, plus cleaning products are connected with allergies, respiratory issues, hormone disruption, eczema, asthma and cancer. The chemicals in cleaning products linger in the air long after we clean and while they are stored.
How to Do It: The Ultimate Guide to Non-Toxic Home Cleaning, 10 Non-Toxic Home Cleaning Recipes and 5 Essential Oils to Clean Your Home
5. Get a Water Filter
Why Do It: Tap water is treated with chemicals that disrupt endocrine function and digestive health, and it can be contaminated with drugs, conventional beauty care products or cleaning products that people are using.
How to Do It: How to Choose a Water Filter
6. Install a Shower Filter
Why Do It: Most water sources are treated with chlorine and evidence indicates that showering in chlorinated water might actually be worse than drinking it. Combined with the heat of showers, chlorine and chlorine byproducts are absorbed through our skin and inhaling them through our lungs.
How to Do It: Is Your Shower Harming Your Health?
7. Ditch the Non-Stick Pans
Why Do It: Polytetrafluoroethylene (PFTE) and perfluorooctanoic acid (PFOA), the main chemicals in Teflon cookware, are carcinogenic, can cause flu-like symptoms and can even be found in human breastmilk. These chemicals leach into our food as we cook and then we consume them.
How to Do It: Your Guide to Healthy Cookware Options
8. Store Food Without Plastic
Why Do It: Plastics threaten our endocrine systems and hormonal health, the environment, our oceans and marine life. One of the main chemicals in plastics is bisphenol A (BPA), a known endocrine disruptor. This led companies to make products that were BPA-free; unfortunately, the evidence is showing that these BPA-free alternatives can be just as damaging.
How to Do It: 5 Ways to Store Food Without Plastic
9. Choose Organic Produce and Other Food
Why Do It: Chemically grown food is loaded with xenoestrogenic pesticides, insecticides and herbicides that affect hormone health and increase the risk of cancer. Studies show that organic produce has more anti-oxidants (which help to fight damage to our bodies) and lower pesticide residues, and can help reduce cancer risk.
How to Do It: Check out What’s On My Food?, an index of the pesticides in produce. If budgeting is a factor, use the Environmental Working Group’s Guide to Pesticides in Produce, which outlines the foods with the most and least pesticide residues. These 10 Questions to Ask Your Farmer at the Market are also helpful!
10. Poop Regularly
Why Do It: Effective and daily elimination allows us to excrete any harmful or damaging wastes, including excess estrogen.
How to Do It: 7 Ways to Reduce Constipation
11. Say No To Receipts
Why Do It: The thermal paper receipts are printed on contain BPA, which disrupts our hormones and can lead to cancer.
How to Do It: Say ‘no thank you’ to receipts you won’t need. Some stores offer electronic receipts, or you can shop online where receipts are sent via email.
12. Purchase Air Filtering Plants
Why Do It: Indoor air can be affected by a variety of factors, including dust, outdoor air pollution, chemicals in cleaning products and air fresheners, mold, or cigarette smoke. Plants are an easy way to help filter the air!
How to Do It: Plants such as ficus, aloe, spider plant and Boston fern can help with air filtration.
13. Replace Your Bedding
Why Do It: Conventional cotton is heavily sprayed with pesticides that can disrupt hormones and lead to cancer. These chemicals stay in our sheets, where we inhale them as we sleep, but they also spread throughout our homes and when we wash them, they have the potential to react with the chemicals in the municipal water to create harmful byproducts.
How to Do It: Natural Bedding and Linens Guide
14. Use an Infrared Sauna
Why Do It: We are able to release a number of toxins through sweating, including BPA, as well as heavy metals such as lead, arsenic, cadmium and mercury.
How to Do It: Health Benefits of Infrared Saunas
15. Swap Tampons and Pads for Better Alternatives
Why Do It: The average woman menstruating for five days a month for 38 years will use approximately 11,400 tampons in a lifetime, with direct contact to the chemicals in tampons for 2,200 days. One of the chemicals found in tampons and pads is dioxin, which interferes with our hormones.
How to Do It: Natural Alternatives to Tampons
You don’t have to do every single one of these things at once. Even if you only pick a couple of things on this list to start, you’re still going to be improving your health and you can always do more in the future.
How do I get rid of xenoestrogens?
We live in a toxic world. All around us there are thousands of FDA-approved chemicals in the air we breathe, the food and water we consume, the products we apply, and the surfaces we touch. Natural and synthetic chemicals enter our bodies through our organs of elimination; skin, lungs, and digestive systems1. Contaminants in our food, food containers, personal care items, and household cleaning products have been linked to disease outbreaks, cancer, birth defects, and brain impairments.2,3 Some of these chemicals were approved prior to fully understanding their safety levels. What we face now, as citizens, is an accumulation of toxic chemicals in our water, food, and air supply that are difficult to avoid and have the potential to cause health problems. As these chemicals accumulate in our environment, they also accumulate in our bodies.
There is a particular classification of synthetic and naturally occurring chemicals known as xenoestrogens that mimic natural estrogens found in our body. These estrogens are persistent organic pollutants, or POPs. That they are persistent means they don’t degrade, instead remaining for generations in our environment, food supply, and in fat cells. These pollutants remain in storage sites in estrogen sensitive organs like the breasts, prostate, as well as in our fat cells. The presence of these xenoestrogens can cause metabolic changes in the body.3 They have also been classified as endocrine disruptors because they disrupt the body’s natural hormone system including estrogen, progesterone, testosterone, insulin, cortisol, and appetite control.3 Xenoestrogens are part of a large group of endocrine disruptors because of their capacity to disturb normal hormonal actions. Some endocrine disruptors may contribute to the development of hormone-dependent cancers.4
Xenoestrogens
Xenoestrogens, or foreign estrogens that the body does not make, increase the size of our fat cells, promoting obesity in exposed people.4 A literature review identifying connections between exposures to these Persistent Organic Pollutants (POPs) and type 2 diabetes was found, proving the “obesogen” theory that these chemicals make us fat and may lead to chronic disease. The review also identified support for the “developmental obesogen” hypothesis, which suggests that chemical exposures in utero may increase the risk of obesity in childhood and later in life by altering fat cells and the hormones that regulate appetite and eating behaviors. When pregnant women are exposed to POPs, including cigarette smoke, their children are more likely to get diabetes type 2 and obesity, particularly when they consume a diet high in calories, carbohydrates, or high-fat diet later in life.5
Despite the fact that ingestion is a major source of exposure to these known reproductive and developmental toxins, thousands of chemicals have still been approved for use in the food supply, including hormone disrupting chemicals like BPA and phthalates found in the commonly consumed plastics:
What plastics are you eating?
Cling wrap
Lining of tin cans
Ziploc food storage
Bottled water
Baby bottles
“Microwaveable” pouches
Frozen dinner trays
Take out containers
Plastic forks, spoons, and knives
Styrofoam and plastic cups
What adds to the concern are recent studies that show residues on food may be an important route by which kids are exposed to harmful hormone disruptors e.g. pesticides, phenols, phthalates, BPA, phytoestrogens, genistein, dietary fat, and ionizing radiation. Exposure before and during puberty might set the stage for pre-pubertal overweight, obesity as well as increased breast cancer risk in adulthood.6 Studies have shown that the risk for breast cancer among those with an earlier age of menstrual onset is up to twice as high when contrasted with girls with later age of first period (menarche).6 An increased duration of hormone exposure over a lifetime promotes the development of breast cancer.6 Obesity during childhood may be associated with increased risk of obesity later in life as well as pre- and post-menopausal breast cancer.6 Obesity represents a collection of physical attributes that include Body Mass Index (BMI) and waist and hip circumference. New York University Women’s Health Study and the EPIC (European Prospective Investigation into Cancer and Nutrition) Study found that obesity markers such as BMI, waist, and hip circumference were associated with increased breast cancer risk.6
The good news is… you can get rid of them, at least to some extent. Try to do it before you nurse your babies since women pass our toxic load onto the next generation. But keep in mind, even breast milk with these contaminants has been shown more beneficial than any brand of infant formula.
Health Tips to Reduce the Accumulation of Harmful Xenoestrogens:
Maintain a healthy weight: Prevent higher exposures to endocrine disruptors by never becoming overweight. Once overweight, it can be difficult to rid the body of these stored chemicals, making weight loss more difficult as well.
Go chemical free: You can’t control the whole environment but you can avoid cigarette smoke in the home and purchase natural cosmetics and cleaning supplies that reduce your household exposure to harmful endocrine disruptors.
Eat organic, non-GMO foods: By selecting organic food when possible you reduce your overall load of chemicals added to the food supply such as pesticides and synthetic hormones. Avoid the “Dirty Dozen” fruits and vegetables that absorb the most pesticide. Each year this changes. According to the Environmental Working Group, the 2015 list is apples, peaches, nectarines, strawberries, grapes, celery, spinach, sweet bell peppers, cucumbers, cherry tomatoes, imported snap peas, and potatoes. “Each of these foods tested positive for a number of different pesticide residues and showed higher concentrations of pesticides than other produce items”. A single grape sample and a sweet bell pepper sample each contained 15 pesticides. Dont’ forget to check out the “Clean 15″ to see which fruits and veggies are better than others. Genetically Modified cash crops such as soy, corn, sugar, canola, Hawaiian papaya and, cotton seed produce their own endocrine-disrupting pesticides that cannot be washed off and get sprayed more heavily than conventional crops. Choose organic versions of these foods unless you think Round Up is somehow a good food option. Go for free range, pasture-fed, transition, or organic meat, poultry, eggs, and dairy products have not been fed GMO crops, or injected with synthetic hormones.
Detox: Help the body get rid of harmful xenoestrogens by consuming foods with nutrients that eliminate harmful extrogen metabolites. Flax seeds, sprouts, and cabbage family vegetables; broccoli, cauliflower, kohlrabi, cabbage, kale, bok choy.
Elimination: Prioritize daily bowel movements, as these hormones can be packaged up in fiber and eliminated from our stool. Fruits, veggies, whole grains, lemon water, and a diet low in animal products improve size and ease of bowel movements.
What foods are rich in xenoestrogens?
Xenoestrogens and phytoestrogens imitate estrogen – the primary female hormone responsible for regulating monthly cycles and impacting mood and libido, as well as the development of reproductive organs and breasts, fertility, supporting a healthy heart, healthy skin, nails, and hair, and maintaining bone density.
Xenoestrogen Sources & Issues
Xenoestrogens are synthetic,chemical compounds. Found in food, water, plastics and body products, they bind to oestrogen receptors and send false signals disrupting our endocrine system and altering our bodily functions, mainly through “estrogen dominance”
“The word xenoestrogen is derived from the Greek words ξένο (xeno, meaning foreign), οἶστρος (estrus, meaning sexual desire) and γόνο (gene, meaning “to generate”) and literally means “foreign estrogen”. Xenoestrogens are also called “environmental hormones” or “EDC” (Endocrine Disrupting Compounds). Most scientists that study xenoestrogens, including The Endocrine Society, regard them as serious environmental hazards that have hormone disruptive effects on both wildlife and humans.” ~ Wikipedia
Environmental sources of Xenoestrogens:-
Plastics (water bottles, disposable cups, plastic wrap, food containers)
Pesticides (on non-organic fruits and vegetables)
Tap Water (chlorine and other chemical treatments, runoff byproducts)
Chemicals in cosmetics, lotions, shampoos, and other body care products
Birth control pills
Issues associated with Xenoestrogens
There is a concern that xenoestrogens may act as false messengers and disrupt the process of reproduction. Xenoestrogens, like all estrogens, can increase growth of the endometrium (lining of the womb), so treatments for endometriosis symptoms will include avoidance of products which contain them. Likewise, they are avoided in order to prevent the onset or aggravation of adenomyosis.
Phytoestrogens: Sources & Issues
Phytoestrogens are plant-derived compounds found in a wide variety of foods and herbs, most notably, soy foods. they are also known as “dietary estrogens”. Because phytoestrogen compounds have a weaker estrogenic effect in the body, they are often beneficial in alleviating symptoms and conditions caused by estrogen deficiency. For example in menopausal women.
“It has been hypothesized that plants use a phytoestrogen as part of their natural defence against the overpopulation of herbivore animals by controlling female fertility.” ~ “Infertility in the Modern World“
Sources of phytoestrogens:
Soy products: tofu, tempeh, miso, and edamame
Red clover
Coffee
Flax seeds (linseed)
Oats
Lentils
Legumes (peanuts, beans, peas)
Apples
Sweet potatoes
Sesame seeds
Liquorice root
Issues associated with phytoestrogens/plant-based estrogen:
A wide range of beneficial effects of phytoestrogens on the cardiovascular, metabolic, central nervous systems as well as reduction of risk of cancer and post menopausal symptoms have been claimed. However, there is also concern that phytoestrogens may act as endocrine disruptors that adversely affect health. Based on currently available evidence, it is not clear whether the potential health benefits of phytoestrogens outweigh their risks. As always if you are suffering with hormonal issues, your first port of call should be a doctor to confirm exactly what is going on.
So where can we make changes?
Given that what we eat PLUS 60% of what we put ON our skin is absorbed into our body, perhaps its time to make more informed choices about what we choose to eat and wear, starting with our beauty products in an attempt to avoid harmful chemicals. See the infographic opposite.
Try and avoid those foods and substances listed above if suffering from estrogen dominance. Opt for organic fruit and vegetables (or ensure you thoroughly wash your produce to remove any toxins)
Use BPA-free plastic or glass containers.
Ways to naturally regulate estrogen levels in the body
Drink more water! This helps eliminate excess estrogen in your body
Exercise regularly to help clear excess estrogen and regulate insulin levels.
Stick with whole foods (a diet high in processed and refined carbohydrates and sugar can increase estrogen to unhealthy levels and lead to weight gain)
Cruciferous vegetables – broccoli, Brussel sprouts, kale – produce compounds in the body which can lower the effects of estrogen in the body and also help the liver effectively perform its detoxification processes.
Take a probiotic.
Limit alcohol and caffeine to support your kidney and liver, thus helping to support the natural detoxification of estrogen
Try reflexology or massage – stress can cause hormonal imbalance. Targeted reflexology and a relaxing massage can help you to de-stress and restore balance
What are examples of xenoestrogens?
Xenoestrogens – What are they? How to avoid them.
Xenoestrogens are found in a variety of everyday items. Many of us don’t think twice about the makeup we wear each day or the plastic container we use to pack our lunch. We know organic food is supposed to be better for us, but sometimes we just don’t want to pay the extra money. Unfortunately, all of the above may be altering the way our body naturally functions because they all contain endocrine disruptors called, xenoestrogens.
Endocrine disruptors are a category of chemicals that alter the normal function of hormones. Normally, our endocrine system releases hormones that signal different tissues telling them what to do. When chemicals from the outside get into our bodies, they have the ability to mimic our natural hormones; blocking or binding hormone receptors. This is particularly detrimental to hormone sensitive organs like the uterus and the breast, the immune and neurological systems, as well as human development.
Xenoestrogens are a sub-category of the endocrine disruptor group that specifically have estrogen-like effects. Estrogen is a natural hormone in humans that is important for bone growth, blood clotting and reproduction in men and women. The body regulates the amount needed through intricate biochemical pathways. When xenoestrogens enter the body they increase the total amount of estrogen resulting in a phenomenon called, estrogen dominance. Xenoestrogens are not biodegradable so, they are stored in our fat cells. Build up of xenoestrogens have been indicated in many conditions including: breast, prostate and testicular cancer, obesity, infertility, endometriosis, early onset puberty, miscarriages and diabetes.
Below is a list of some of the sources of xenoestrogens, but it is by no means exhaustive. We are constantly exposed to these substances in the world we live in. Examples of everyday items that may include xenoestrogens are: fruits and vegetables sprayed with pesticides, plastic water bottles and Tupperware, nail polish, makeup, birth control and on and on.
Here are some of the chemicals that are xenoestrogens:
Skincare:
4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)
Parabens (methylparaben, ethylparaben, propylparaben and butylparaben commonly used as a preservative)
Benzophenone (sunscreen lotions)
Industrial products and Plastics:
Bisphenol A (monomer for polycarbonate plastic and epoxy resin; antioxidant in plasticizers)
Phthalates (plasticizers)
DEHP (plasticizer for PVC)
Polybrominated biphenyl ethers (PBDEs) (flame retardants used in plastics, foams, building materials, electronics, furnishings, motor vehicles).
Polychlorinated biphenyls (PCBs)
Food:
Erythrosine / FD&C Red No. 3
Phenosulfothiazine (a red dye)
Butylated hydroxyanisole / BHA (food preservative)
Building supplies:
Pentachlorophenol (general biocide and wood preservative)
Polychlorinated biphenyls / PCBs (in electrical oils, lubricants, adhesives, paints)
Insecticides:
Atrazine (weed killer)
DDT (insecticide, banned)
Dichlorodiphenyldichloroethylene (one of the breakdown products of DDT)
Dieldrin (insecticide)
Endosulfan (insecticide)
Heptachlor (insecticide)
Lindane / hexachlorocyclohexane (insecticide, used to treat lice and scabies)
Methoxychlor (insecticide)
Fenthion
Nonylphenol and derivatives (industrial surfactants; emulsifiers for emulsion polymerization; laboratory detergents; pesticides)
Other:
Propyl gallate
Chlorine and chlorine by-products
Ethinylestradiol (combined oral contraceptive pill)
Metalloestrogens (a class of inorganic xenoestrogens)
Alkylphenol (surfactant used in cleaning detergents
So what can you do to avoid these common chemicals? The following list was adapted from the organic excellence website.
Guidelines to minimize your personal exposure to xenoestrogens:
Food
Avoid all pesticides, herbicides, and fungicides.
Choose organic, locally-grown and in-season foods.
Peel non-organic fruits and vegetables.
Buy hormone-free meats and dairy products to avoid hormones and pesticides.
Plastics
Reduce the use of plastics whenever possible.
Do not microwave food in plastic containers.
Avoid the use of plastic wrap to cover food for storing or microwaving.
Use glass or ceramics whenever possible to store food.
Do not leave plastic containers, especially your drinking water, in the sun.
If a plastic water container has heated up significantly, throw it away.
Don’t refill plastic water bottles.
Avoid freezing water in plastic bottles to drink later.
Household Products
Use chemical free, biodegradable laundry and household cleaning products.
Choose chlorine-free products and unbleached paper products (i.e. tampons, menstrual pads, toilet paper, paper towel, coffee filters).
Use a chlorine filter on shower heads and filter drinking water
Health and Beauty Products
Avoid creams and cosmetics that have toxic chemicals and estrogenic ingredients such as parabens and stearalkonium chloride.
Minimize your exposure to nail polish and nail polish removers.
Use naturally based fragrances, such as essential oils.
Use chemical free soaps and toothpastes.
Read the labels on condoms and diaphragm gels.
At the Office
Be aware of noxious gas such as from copiers and printers, carpets, fiberboards, and at the gas pump.
What is lignan extract?
What is Flax Seed Lignans?
Flax Seed Lignans is a high-quality extract of lignans from flax seed. Lignans are natural plant compounds that have been intensively studied for their phytoestrogenic effects.
Characteristic for phytoestrogens, lignans can weakly bind to estrogen receptors. A sufficient level of lignans can compete with natural estrogen for estrogen receptors, helping to balance estrogen levels. This basic mechanism has different effects in men and women.
The main lignan in flax is secoisolariciresinol diglucoside (SDG). When ingested, micro-organisms in the colon convert SDG into enterodiol and enterolactone, the so-called mammalian lignans. These are the body's own active forms of lignans.
What are the key benefits of Vitacost® Flax Seed Lignan Extract?
Can help modulate estrogen levels, thereby supporting some of the symptoms of menopause.*
May support healthy cognitive function in women 20 to 30 years postmenopausal.*
May support healthy bones.*
Helps maintain prostate health.*
Supplies 40 mg of lignans per capsule.
Features LinumLife, a high-quality, standardized source of flax seed lignans.
Contains 120 servings per bottle.
Are lignans flavonoids?
Lignans and flavonoids are naturally-occurring diphenolic compounds found in high concentrations in whole grains, legumes, fruits and vegetables. Seven lignans and six flavonoids were evaluated for their abilities to inhibit aromatase enzyme activity in a human preadipose cell culture system. The lignan, enterolactone (Enl) and its theoretical precursors, 3'-demethoxy-3O-demethylmatairesinol (DMDM) and didemethoxymatairesinol (DDMM) decreased aromatase enzyme activity, with Ki values of 14.4, 5.0 and 7.3 microM, respectively. The flavonoids, coumestrol, luteolin and kaempferol also decreased aromatase enzyme activity, with Ki values of 1.3, 4.8 and 27.2 microM, respectively. Aminoglutethimide, a pharmaceutical aromatase inhibitor, showed a Ki value of 0.5 microM. Kinetic studies showed the inhibition by all compounds to be competitive. Smaller decreases in aromatase activity were observed with the lignan, enterodiol (End) and its theoretical precursors, O-demethylsecoisolariciresinol (ODSI), demethoxysecoisolariciresinol (DMSI) and didemethylsecoisolariciresinol (DDSI). The flavonoids, O-demethylangolensin (O-Dma), fisetin and morin showed no inhibitory effects. The inhibition of human preadipocyte aromatase activity by lignans and flavonoids suggests a mechanism by which consumption of lignan- and flavonoid-rich plant foods may contribute to reduction of estrogen-dependent disease, such as breast cancer.
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Publication types
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
MeSH terms
Adipose Tissue / metabolism*
Adult
Aged
Aromatase Inhibitors*
Female
Flavonoids / pharmacology*
Humans
Kinetics
Lignans / pharmacology*
Substances
Aromatase Inhibitors
Flavonoids
Lignans
Related information
Cited in Books
PubChem Compound (MeSH Keyword)
What are lignans in flaxseed?
Lignans are phenolic compounds found frequently in fiber-rich plants, such as flax (Linum usitatissimum). Flax is particularly high in the lignans secoisolariciresinol diglucoside (SDG), SECO, and matairesinol. SDG is converted in the human colon by bacteria into the mammalian lignans enterodiol and enterolactone. Flaxseed, its lignans, and enterolactone have been studied for anticancer activity in vitro, in animal models, and among humans.1
Epidemiologic studies have evaluated both serum lignan concentrations and dietary intake for an association with cancer risk for several solid tumor types. Randomized controlled trials have evaluated the effect of dietary flaxseed on tumor tissue markers, with promising results.
How To Detox Xenoestrogens
A randomized controlled trial of cancer prevention or treatment has not, however, yet been conducted.
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Breast Cancer
Several epidemiologic studies evaluated serum concentrations of enterolactone and breast cancer risk and prognosis. A study of 1250 postmenopausal breast cancer cases and 2164 from a population-based study demonstrated that high levels of serum enterolactone were significantly associated with a reduced risk of breast cancer (odds ratio [OR], 0.65; 95% CI, 0.52-0.83; P-trend = <.0001).2 This association was evident for hormone receptor–positive disease, but was greatest with hormone receptor–negative disease. HER2 expression did not affect the associations.
A prospective cohort study of 2182 patients aged 50 to 74 years at breast cancer diagnosis demonstrated that high enterolactone concentrations were significantly associated with decreased all-cause mortality (hazard ratio [HR], 0.94; 95% CI, 0.90-0.98), breast cancer–specific mortality (HR, 0.94; 95% CI, 0.89-0.99), and distant disease–free survival (HR, 0.94; 95% CI, 0.90-0.98) among women with stage 0 to IIIA disease.3
Using another approach, a study of 2999 breast cancer cases and 3370 healthy controls demonstrated that breast cancer risk was significantly reduced by dietary consumption of flaxseed (OR, 0.82; 95% CI, 0.69-0.97) and flax bread (OR, 0.77; 95% CI, 0.67-0.89).4
Dietary flaxseed may also have an effect on tumors. Tumor tissue was assessed from a trial that randomly assigned patients with newly diagnosed breast cancer to receive a muffin containing 25 g of flaxseed or placebo at the time of diagnosis and then at the time of definitive surgery. Urine samples and dietary questionnaires were also collected.5 The flaxseed arm demonstrated a significant reduction in markers of tumor growth including Ki-67 labelling index (34.2%; P = .001), c-ERBB2 expression (71%; P = .003), and an increase in apoptosis (30.7%; P = .007). Mean urinary lignan excretion was also increased in the flaxseed group compared with the placebo group.
Another study conducted among postmenopausal women receiving aromatase inhibitors demonstrated that flaxseed consumption trended toward a reduction in estrogen receptor (ER) beta expression by 40%, but these findings were not significant.6 Urinary enterolactone excretion was lower among patients receiving flaxseed plus an aromatase inhibitor compared with flaxseed alone, suggesting that aromatase inhibition may somehow affect enterolactone concentrations.
What is the difference between lignin and lignan?
The lignans are a large group of low molecular weight polyphenols found in plants, particularly seeds, whole grains, and vegetables.[1] The name derives from the Latin word for "wood".[2] Lignans are precursors to phytoestrogens.[1][3] They may play a role as antifeedants in the defense of seeds and plants against herbivores.[4]
Contents
1 Biosynthesis and metabolism
2 Food sources
3 Prevalence and Health Effects
4 See also
5 References
6 External links
Biosynthesis and metabolism
Structures of some lignans
Matairesinol, illustrating the debenzylbutyrolactone motif
Secoisolariciresinol, illustrating the 9,9'-dihydroxydibenzylbutane motif
Justicidin A, illustrating the arylnaphthalene mofif
Pinoresinol, illustrating the furanofuran motif
Steganacin, illustrating the dibenzocyclooctadienelactone motif
Podophyllotoxin, illustrating the aryltetralin motif
Lignans and lignin differ in their molecular weight, the former being small and soluble in water, the latter being high polymers that are undigestable. Both are polyphenolic substances derived by oxidative coupling of monolignols. Thus, most lignans feature a C18 cores, resulting from the dimerization of C9 precursors. The coupling of the lignols occurs at C8. Eight classes of lignans are: "furofuran, furan, dibenzylbutane, dibenzylbutyrolactone, aryltetralin, arylnaphthalene, dibenzocyclooctadiene, and dibenzylbutyrolactol."[5]
Many lignans are metabolized by mammalian gut microflora, producing so-called enterolignans.[6][7]
Food sources
Flax seeds and sesame seeds contain high levels of lignans.[1][8] The principal lignan precursor found in flaxseeds is secoisolariciresinol diglucoside.[1][8] Other foods containing lignans include cereals (rye, wheat, oat and barley), soybeans, tofu, cruciferous vegetables, such as broccoli and cabbage, and some fruits, particularly apricots and strawberries.[1] Lignans are not present in seed oil, and their contents in whole or ground seeds may vary according to geographic location, climate, and maturity of the seed crop, and the duration of seed storage.[1]
Secoisolariciresinol and matairesinol were the first plant lignans identified in foods.[1] Typically, lariciresinol and pinoresinol contribute about 75% to the total lignan intake, whereas secoisolariciresinol and matairesinol contribute only about 25%.[1]
Foods containing lignans:[1][9]
Source Lignan amount
Flaxseeds 85.5 mg per oz (28.35 g)
Sesame seeds 11.2 mg per oz
Brassica vegetables 0.3-0.8 mg per half cup (125 ml)
Strawberries 0.2 mg per half cup
Prevalence and Health Effects
Lignans are the principal source of dietary phytoestrogens in typical Western diets, even though most research on phytoestrogen-rich diets has focused on soy isoflavones. Lignan's enterolignan products enterodiol and enterolactone have weak estrogenic activity, but they may also exert biological effects through non-estrogenic means.[1]
Dietary intake of lignan-rich foods may prevent certain types of cancers and cardiovascular disease.[10][9]
Are lignans good for your body?
Dietary guidelines universally advise adherence to plant-based diets. Plant-based foods confer considerable health benefits, partly attributable to their abundant micronutrient (e.g., polyphenol) content. Interest in polyphenols is largely focused on the contribution of their antioxidant activity to the prevention of various disorders, including cardiovascular disease and cancer. Polyphenols are classified into groups, such as stilbenes, flavonoids, phenolic acids, lignans and others. Lignans, which possess a steroid-like chemical structure and are defined as phytoestrogens, are of particular interest to researchers. Traditionally, health benefits attributed to lignans have included a lowered risk of heart disease, menopausal symptoms, osteoporosis and breast cancer. However, the intake of naturally lignan-rich foods varies with the type of diet. Consequently, based on the latest humans’ findings and gathered information on lignan-rich foods collected from Phenol Explorer database this review focuses on the potential health benefits attributable to the consumption of different diets containing naturally lignan-rich foods. Current evidence highlight the bioactive properties of lignans as human health-promoting molecules. Thus, dietary intake of lignan-rich foods could be a useful way to bolster the prevention of chronic illness, such as certain types of cancers and cardiovascular disease.
Keywords: lignans, diet, antioxidants, health promotion, chronic diseases
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1. Introduction
Polyphenol-rich diets are suggested to possess health benefits. Polyphenols are micronutrients found in plants, and include flavonoids, stilbenes, phenolic acids, lignans and others [1]. They are secondary plant metabolites implicated in protection against pathogens and ultraviolet radiation [2]. Given their diverse chemical structures, different polyphenol classes likely possess differing health benefits [3]. It is therefore important to elucidate the specific potential benefits of each polyphenolic compound. Significant interest has been elicited by lignans, due to their steroid-analogous chemical structure. Accordingly, they are considered to be phytoestrogens. Lignans are bioactive compounds exhibiting various biological properties, including anti-inflammatory, antioxidant and antitumor activities [4]. Additionally, some epidemiological studies have proposed that lignans decrease the risk of cardiovascular disease, but their effects on other chronic diseases (e.g., breast cancer) remain controversial [5].
Lignans are found in relatively low concentrations in various seeds, grains, fruits and vegetables, and in higher concentrations in sesame and flax seeds [6]. Therefore, the level of lignan ingestion—and, thus, lignan bioavailability, depends on the type of diet consumed [7,8] and can be highly variable. The present review attempts to describe the potential beneficial effects of lignan intake on human chronic disease, depending on the dietary source.
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2. Biosynthesis, Classification and Presence of Lignans in Foods
Lignans are a type of secondary plant metabolite exhibiting diverse structures [9]. Plants derive a complex array of secondary metabolites from only a handful of relatively simple propenyl phenols [10]. Biosynthesis of lignans is characterized by a remarkable increase in molecular complexity [10].
Lignans share common biosynthetic pathways, consist of two propyl-benzene units coupled by a β,β′-bond [11], and thus belong to the group of diphenolic compounds [12].
Lignans may be organized into eight structural subgroups (according to the manner in which oxygen is incorporated and the pattern of cyclization): Dibenzylbutyrolactol, dibenzocyclooctadiene, dibenzylbutyrolactone, dibenzylbutane, arylnaphthalene, aryltetralin, furan and furofuran (Figure 1). Each subgroup can be further subdivided according to lignan molecule oxidation level and identities of non-propyl aromatic rings present on side chains [13,14].
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Figure 1
Structural subgroups of lignans (Ar=Aryl).
Of the eight lignan subclasses, synthesis of furofurans—which exhibit a 2,6-diaryl-3,7-dioxabicyclooctane skeleton—is initiated by the enantioselective dimerization of two coniferyl alcohol units derived from the shikimate biosynthetic pathway (Figure 2) [14]. To date, 53 species of furofuran lignans have been reported in 41 genera of 27 plant families, including Thymelaeaceae, Styracaceae, Scrophulariaceae, Saururaceae, Rutaceae, Rhizophoraceae, Piperaceae, Pedaliaceae, Orobanchaceae, Myristicaceae, Magnoliaceae, Lauraceae, Lamiaceae, Geraniaceae, Dioscoreaceae, Cyperaceae, Cupressaceae, Compositae, Combretaceae, Cactaceae, Aristolochiaceae, Arecaceae, Araliaceae, Aquifoliaceae, Apocynaceae, Acoraceae and Acanthaceae. Furofuran lignans are present in the bark, bulbs, leaves, seeds, stems and roots of these plants [14].
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Figure 2
Biosynthetic pathway of lignans. NGT (pinoresinol glucosyltransferase), PSS (piperitol/sesamin synthase), PLR (pinoresinol/lariciresinol reductase), LGT (lariciresinol glycosyltransferase), SGT (secoisolariciresinol glycosyltransferase), SID (matairesinol O-methyltransferase), MMT (matairesinol O-methyltransferase), Glc (Glucoside).
However, depending on the enzyme that catalyzes modification of the precursor metabolite, a variety of lignans can be synthesized (Figure 2). The major lignans—which possess numerous pharmacological properties—are artigenin, enterodiol, enterolactone, sesamin, syringaresinol, medioresinol, (−)-matairesinol, (−)-secoisolariciresinol, (+)-lariciresinol and (+)-pinoresinol, among others [15].
Currently, there is a growing interest in the presence of lignans in foodstuffs, given the potentially beneficial bioactive properties of the former (anti-estrogenic, antioxidant and anti-carcinogenic activities) [16]. The chief sources of dietary lignans are various vegetables and fruits, legumes, whole grain cereals and oilseeds [16,17]. Among edible plant components, the most concentrated lignan sources are sesame and flax seeds (Table 1 and Table 2) [6]. Specifically, flax seeds contain approximately 294.21 mg/100 g lignan, at present the maximal known content of any foodstuff. Sesame seeds exhibit the second-highest lignan concentration, with sesaminol as the major constituent, at 538.08 mg/100 g [6]. Flaxseed and cashew nuts are also relatively rich in lignans (containing 257.6 and 56.33 mg/100 g, respectively) [6].
Table 1
Lignan content of sesame seed (mg/100g food). Data collected from phenol explorer [18].
Seeds HMA HSE OXO ARC CYC CON DIM
Sesame seed 7.2 0.01 0.7 0.01 1.77 0.75 0.39
ISO LAR LAS MAT MED NOR SEC
1.61 10.37 0.08 29.79 4.15 0.08 0.1
SECS SES SEI SEN SYR TOD Total
0.01 538.08 102.86 133.94 0.2 2.47 834.57
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Lignans: 7-Hydroxymatairesinol (HMA), 7-Hydroxysecoisolariciresinol (HSE), 7-Oxomatairesinol (OXO), Arctigenin (ARC), Conidendrin (CON), Cyclolariciresinol (CYC), Dimethylmatairesinol (DIM), Isohydroxymatairesinol (IHM), Isolariciresinol (ISO), Lariciresinol (LAR), Lariciresinol-sesquilignan (LAS), Matairesinol (MAT), Medioresinol (MED), Nortrachelogenin (NOR), Secoisolariciresinol (SEC), Secoisolariciresinol-sesquilignan (SECS), Sesamin (SES), Sesaminol (SEI), Sesamolin (SEN), Syringaresinol (SYR), Todolactol A (TOD).
Table 2
Lignan content of seeds (mg/100g food) [18].
LAR MAT MED SEC SYR Total
Other Seeds
Flaxseed 11.46 6.68 - 257.6 - 257.6
Sunflower seed 0.67 0.67 - 0.18 - 1.52
Nuts
Almond 0.03 3 × 10−4 - 0.07 - 0.10
Brazil nut - 0.01 - 0.77 - 0.78
Cashew nut 49.6 2.5 × 10−3 - 6.73 - 56.33
Chesnut 7.8 × 10−3 8.42 × 10−3 - 0.2 - 0.21
Hazelnut 0.01 3.3 × 10−3 - 0.05 - 0.06
Peanut 4.1 2.5 × 10−3 - 2.7 - 6.8
Pecan nut 8.4 × 10−3 3.15 × 10−3 - 0.01 - 0.02
Pistachio 0.12 1 × 10−4 - 0.04 - 0.16
Walnut 7.2 × 10−3 3.8 × 10−3 - 0.12 - 0.13
Pulses-Beans
Common bean white 0.12 1 × 10−3 - 0.08 8 × 10−3 0.2
Broad bean seed whole - 8.9 × 10−4 - 0.09 - 0.09
Mung bean - - - 0.18 - 0.18
Soy and soy products
Soy paste, miso 0.02 3.6 × 10−3 - 0.01 - 0.03
Soy flour - 7.5 × 10−3 - 0.3 - 0.3
Soy tempe 0.01 5 × 10−4 - 0.01 - 0.02
Soy tofu 0.04 7.27 × 10−5 8.5 × 10−3 9.91 × 10−3 0.04 0.09
Soy yogurt 0.01 3 × 10−3 - 0.02 - 0.03
Soyben edamame 0.07 - 0.02 0.07 0.2 0.3
Soybean sprout 0.03 5 × 10−4 0.01 0.03 0.05 0.12
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Regarding cereal grains (Table 3), lignans are largely concentrated in their outer layers [19,20]. In cereal grains, the highest lignan concentration is found in the fiber-rich outer layers (seed coat and pericarp), as well as the aleurone layer, whereas the lowest concentration is found in the inner endosperm [21,22].
Table 3
Lignan content of cereals (mg/100g food) [18].
LAR MAT MED SEC SYR Total
Cereal products
Bread (whole grain flour) 0.05 3.1 × 10−4 - 8.68 × 10−3 - 0.05
Bread (refined flour) 0.01 1.23 × 10−3 - 7.19 × 10−3 0.04 0.05
Bread, rye, whole grain flour 0.01 0.02 - 0.14 - 0.17
Breakfast cereals, bran 0.01 4.87 × 10−3 - 0.03 - 0.04
Breakfast cereals, corn - 1.67 × 10−3 - 5.5 × 10−3 - 0.007
Breakfast cereals, muesli 0.14 5.6 × 10−3 - 0.08 - 0.22
Breakfast cereal, oat - 0.06 - 0.02 - 0.08
Pasta - 1.85 × 10−3 - 2.3 × 10−3 - 0.004
Pasta Whole Grain - 1.5 × 10−3 - 5 × 10−3 - 0.006
Cereals
Barley, whole grain flour 0.08 3 × 10−3 0.01 0.03 0.16 0.28
Buckwheat, whole grain flour 0.36 1 × 10−3 0.03 0.13 0.24 0.76
Common wheat, germ - 9 × 10−3 - 0.02 - 0.02
Common wheat, refined flour 0.18 2.14 × 10−4 - 0.02 - 0.2
Common wheat, whole grain flour 0.1 9 × 10−4 0.03 0.02 0.37 0.52
Hard wheat, semolin - - - 2 × 10−3 - 0.002
Maize, whole grain 0.12 6.55 × 10−5 - 0.14 0.07 0.33
Oat, whole grain flour 0.18 0.07 0.04 0.01 0.35 0.65
Rye, whole grain flour 0.32 0.01 0.14 0.02 0.97 1.46
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Ordering species by lignan content produces the following list: Dhurra < brown rice < red rice < quinoa < millet < corn < amaranth < barley < buckwheat < wild rice < Japanese rice < spelt < oat < triticale < wheat < rye [6]. Regarding vegetables (Table 4), the brassica family may contain between 185 and 2.321 mg /100 g of lignan, mainly pinoresinol. Peppers, French beans, carrots and courgettes also exhibit a relatively high lignan content, ranging from 0.113 to 0.273 mg/100 g. Other foods, such as spinach, white potatoes and mushrooms—contain below 0.1 mg/100 g of lignan. Fruits exhibit a lower lignan content than seeds or vegetables (Table 5 and Table 6), ranging from 11.57 mg/100 g for apricots to 0 mg/100 g for banana, with green grapes and kiwi fruit falling somewhere between these extremes [6].
Table 4
Lignan contents of vegetables (mg/100g food) [18].
LAR MAT MED SEC SYR Total
Cabbages
Broccoli 97.2 2.44 × 10−5 - 1.31 - 98.51
Brussel sprouts 49.3 4 × 10−5 - 1.06 - 50.36
Cauliflower 9.31 2.4 × 10−5 0.02 0.13 0.02 9.48
Collards 0.06 4 × 10−4 - 5.9 × 10−3 - 0.06
Green cabbage 0.03 3.5 × 10−5 - 9.2 × 10−3 - 0.03
Red cabbage 17.8 4.44 × 10−5 - 0.3 - 18.1
White cabbage 21.2 - - 0.31 - 21.51
Kale 59.9 1.2 - 1.9 - 63
Sauerkraut 11.6 - - 6.7 - 18.3
Fruit vegetales
Avocado 0.03 7.67 × 10−3 0.24 0.02 0.44 0.73
Eggplant purple 0.05 - 7 × 10−3 7.79 × 10−3 6 × 10−3 0.07
Black olive 0.03 5.62 × 10−3 - 5.75 × 10−3 - 0.04
Green olive 3.9 × 10−3 3.34 × 10−3 - 0.02 - 0.02
Green sweet pepper 12.32 - 1 × 10−3 0.22 4 × 10−3 12.54
Red sweet pepper 7.97 - - 0.24 - 8.21
Yellow sweet pepper 0.07 - - 5.5 × 10−3 - 0.07
Tomato (Cherry) 0.03 - 3 × 10−3 0.01 4.5 × 10−3 0.04
Tomato (Whole) 2.1 8.33 × 10−6 3.5 × 10−3 0.05 4.5 × 10−3 2.15
Gourds
Cucumber 3.55 - - 0.25 - 3.8
Pumpkin 0.01 2.5 × 10−5 - 0.1 - 0.11
Squash - - - 9 × 10−3 - 0.009
Zucchini 6.4 - - 0.62 - 7.02
Leaf vegetables
Arugula - 2 × 10−4 - 0.1 - 0.1
Chicory (green) 0.6 1.24 × 10−4 - 0.57 - 1.17
Lettuce (green) 0.3 2.24 × 10−4 - 0.18 - 0.48
Spinach 0.06 2.37 × 10−5 - 4.85 × 10−3 - 0.06
Broad bean pod - - - 0.02 - 0.02
Pod vegetables
Green bean 22 - - 0.67 - 22.67
Pulse vegetables
Fresh pea 0.05 - 3.5 × 10−3 7.56 × 10−4 - 0.0542
Root vegetables
Carrot 4.5 3.89 × 10−3 - 3.16 - 7.66
Celeriac - 3 × 10−5 - 0.02 - 0.02
Parsnip - 0.02 - 0.03 - 0.05
Radish 0.01 1.25 × 10−4 5.5 × 10−3 6.57 × 10−3 0.02 0.04
Swede - 7.43 × 10−5 - 4.93 × 10−3 - 0.005
Turnip root 0.1 - 4 × 10−3 9.83 × 10−3 0.03 0.14
Shoot vegetables
Asparagus 0.07 3.97 × 10−3 4 × 10−3 0.25 0.05 0.37
Fennel - 0.01 - 0.05 - 0.06
Stalks vegetables
Celery stalks - - - 5.99 × 10−3 - 0.005
Tubers
Potato 2.8 7.69 × 10−4 - 0.09 - 2.89
Sweet potato 0.07 0.1 - 0.12 - 0.29
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Table 5
Lignan contents of fruits berries (mg/100g food) [18].
HMA OXO CON CYC LAR LAS
Fruit Berries
Bilberry - - - 6.24 × 10−3 0.04 0.09
Blackberry - - - 7.96 × 10−3 0.15 0.15
Blackcurrant - - - 0.01 7.3 × 10−3 0.01
Cloudberry - - - - 0.65 0.25
Black grape - - - - 5.2 -
Green grape - - - - 1.88 -
Lingonberry - - 1.04 × 10−3 0.03 0.03 0.01
Strawberry 8.55 × 10−4 4.59 × 10−4 9.45 × 10−3 0.01 5.87 0.1
MAT MED SEC SECS SYR Total
Bilberry - 0.08 0.06 0.01 0.12 0.4
Blackberry 9.07 × 10−4 0.05 0.1 0.13 0.19 0.77
Blackcurrant 1.47 × 10−3 0.01 0.09 0.03 - 0.15
Cloudberry - 0.48 0.05 0.01 0.41 1.85
Black grape 0.11 - 0.09 - - 5.4
Green grape 0.09 - 0.28 - - 2.25
Lingonberry - 0.23 0.37 0.02 0.14 0.83
Strawberry 1.58 × 10−5 0.03 0.14 0.01 0.03 6.2
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Table 6
Lignan contents of fruits (mg/100g food) [18].
LAR MAT MED SEC SYR Total
Fruits Citrus
Grapefruit 7.13 0.05 - 0.26 - 7.44
Lemon - - - 0.02 - 0.02
Orange 2.4 0.05 9.5 × 10−3 0.14 0.12 2.71
Tangerine 5.7 0.02 - 0.08 - 5.8
Fruits Drupes
Apricot 10.5 3.11 × 10−5 - 1.07 - 11.57
Nectarine 4.1 - - 0.61 - 4.71
Peach 6 1.71 × 10−4 - 0.83 - 6.83
Plum 0.31 2.22 × 10−4 1 × 10−3 0.09 - 0.4
Fruits-Gourds
Cantaloupe 1.8 × 10−3 - - 4.7 × 10−3 - 0.006
Melon 4.4 1.05 × 10−5 - 0.09 - 4.49
Watermelon 0.04 - 1 × 10−3 0.02 0.02 0.08
Fruits-Pomes
Apple 0.1 2.71 × 10−5 - 1.79 × 10−3 - 0.1
Pear 15.5 4.3 × 10−5 - 0.06 - 15.56
Fruits-Tropical
Banana 2.2 × 10−3 5.45 × 10−5 - 7.73 × 10−5 0.01 0.01
Kiwi 1.03 1.93 × 10−3 4.5 × 10−3 3.13 4 × 10−3 4.17
Mango - 1.06 × 10−3 - 0.01 - 0.01
Passion fruit - - - 0.02 - 0.02
Papaya - 2 × 10−3 - - - 0.002
Persimmon - - - 4 × 10−3 - 0.004
Pineapple 0.2 0.16 2 × 10−3 0.21 0.09 0.66
Pomegranate - 9 × 10−3 - 0.29 - 0.29
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The highest lignan content is observed in non-alcoholic beverages, such as tea (0.0392–0.0771 mg/100 g), which also contains other polyphenols (Table 7). Coffee is another important source of lignans, although concentration varies by type of coffee, ranging from 0.0187 to 0.0313 mg/100 g. Regarding alcoholic beverages, red wine contains an average of 0.080 mg/100 mL, whereas white wine contains only approximately 0.022 mg/100 g [23].
Table 7
Lignan content of beverages (mg/100g drink and mg/100 mL wine) [18].
ISO LAR MAT SEC SYR Total
Alcoholic Beverages
Red Wine 0.07 7.56 × 10−3 5.51 × 10−3 0.04 3.43 × 10−3 0.12
White Wine 0.03 6.65 × 10−3 2.68 × 10−3 7.45 × 10−3 1.45 × 10−3 0.04
Dark Beer - - - 0.04 - 0.04
Beer - - - 0.03 - 0.03
Cider - - - 0.04 - 0.04
Scotch whisky - - - 4 × 10−3 - 0.004
Sherry - - - 0.02 - 0.02
Non-alcoholic Beverages
Cocoa - - - 0.03 - 0.03
Coffee - 9 × 10−4 4 × 10−4 8.67 × 10−3 - 0.009
Decaffeinated Coffe - 1.1 × 10−3 4.25 × 10−4 8.35 × 10−3 - 0.009
Roman camomile - - 5 × 10−4 1 × 10−3 - 0.001
Lemon juice - - - 2 × 10−3 - 0.002
Orange juice - 2 × 10−4 - 8 × 10−3 - 0.008
Soy milk - 6.17 × 10−3 5 × 10−5 2.25 × 10−3 - 0.008
Black Tea - 2 × 10−4 2.65 × 10−3 0.03 - 0.03
Green Tea - 1 × 10−4 3.38 × 10−3 0.03 - 0.03
Oolong Tea - - 1.8 × 10−3 0.02 - 0.02
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Furthermore, the chief source of dietary fat in Mediterranean countries—extra virgin olive oil (EVOO)—has garnered much interest regarding its beneficial properties, largely attributable to its polyphenol profile (Table 8). Lignans are the second most abundant polyphenolic class present in EVOO; of these, the most abundant across different EVOO types are pinoresinol (1.17–4.12 mg/ 100 g) and 1-acetoxypinoresinol (0.27–6.69 mg/ 100 g) [7,24,25].
Table 8
Lignan content of oils (mg/100 g food) [18].
Fruit oils ACE LAR MAT PIN SEC Total
Extra virgin Olive Oil 0.66 3.43 × 10−3 7.5 × 10−5 0.42 2.5 × 10−4 1.08
Nut oils
Peanut, butter - 8.8 × 10−3 7.52 × 10−3 - 0.05 0.06
Other seed oils EPI EPL SES SEI SEO SEN SEL Total
Sesame seed oil 192.6 51.97 420.99 305.43 24.92 243.13 55.71 1294.75
Sesame seed black oil - - 644.5 226.92 21.55 287.33 43 1223.3
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1-Acetoxypinoresinol (ACE), Episesamin (EPI), Episesaminol (EPL), Pinoresinol (PIN), Sesamol (SEO), Sesamolinol (SEL).
Thus, given the presence of lignan in many common foodstuffs and beverages, its intake occurs frequently, on a near-daily basis. For example, in a Dutch population, the major dietary sources of lignan were fruits (7%), bread (9%), seeds and nuts (14%), vegetables (24%), and beverages (37%) [6]. Similarly, in a cohort of French women, the major dietary sources of lignan were vegetables and fruits (0.2% from legumes, 0.6% from potatoes, 30% from vegetables, and 35% from fruits), followed by alcoholic beverages (5%), coffee (5%), cereals (7%) and tea (11%) [6,26,27].
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3. Bioavailability
Only a handful of studies exist regarding post-consumption lignan bioavailability, including only very limited human pharmacokinetic studies. After ingestion, plant lignans are metabolized by intestinal bacteria, undergoing transformation to mammalian lignans (enterolactones and enterodiols (Figure 3)) prior to absorption [16,28]. This apparently considerably decreases the risk of diverse types of cancer, particularly of the colon, prostate and breast [16,29].
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Figure 3
Chemical structure of enterodiol (A) and enterolactone (B).
Many studies demonstrate a positive correlation between plant lignan intake and plasma enterolignan levels [30]. After lignan ingestion, enterolactone and enterodiol are the first lignans to become detectable in human biological fluids [28]. The half-lives of these compounds in plasma are approximately 13 and 5 h, respectively [31], and they remain detectable even up to 8–10 h after plant lignan consumption [32]. Furthermore, their intestinal metabolism into mammalian forms appears indispensable for colonic absorption, and the colonic barrier is capable of conjugating enterolignans [28,33].
The concentration of enterodiol and enterolactone in biological fluids varies significantly by geographic region [28]. A study examining mammalian lignan pharmacokinetics in both men and women after lignan solution intake found that enterodiol and enterolactone, respectively, exhibit absorption half-lives of 3.4 and 8.4 h, reach maximum plasma concentrations of 65 and 42 mmol/L [28], exhibit elimination half-lives of 4.6 and 15.1 h, and exhibit maximum retention times of 23.9 and 43.2 h [28,34]. Thus, while enterolactone is more rapidly absorbed than enterodiol, the former attains a lower maximum plasma concentration [28].
During lignan metabolism, the initial (cytochrome P450-mediated) step involves conjugation to glucuronic acid and sulfate, followed by enterohepatic recirculation [35]. Chaojie et al. (2013) that glucuronidation of flax seed lignans significantly involves liver and intestinal microsomes [36]. Some studies demonstrate that flax seed-derived lignan metabolites distribute mainly to the intestine (largely to the caecum), kidneys, uterus, prostate and liver [37]. Of these locations, the highest concentration of lignan metabolites is observed in the liver [37].
Human breast cyst, prostatic, and seminal fluid (as well as prostate tissue) lignan concentration has been determined [38,39]. As in circulation, the common mammary form of lignan is enterolignan, while urinary forms are essentially monoglucuronides [28]. Furthermore, inter-individual variations in gut microbiota and hepatic enzymes may modulate mammalian lignan metabolism and bioactivity [33].
Moreover, lignan bioavailability also depends on diet. For example, diets rich in flax seed increase production of gut microbiota-derived enterolignans in a murine model, and lead to high tissue and plasma concentrations of sulfate and glucuronide conjugates (the major flax-derived lignan metabolites) [8,40].
Other studies have demonstrated that plant lignans, such as sesamin are quickly absorbed, apparently from the small intestine and become detectable in systemic circulation within a few hours after ingestion [22,41]. For example, lignans have been observed in porcine plasma 3 h after cereal intake [42]. On the one hand, it has been empirically demonstrated that plant lignans are rapidly absorbed from the small intestine after intake of a diet rich in cereals [22]. On the other hand, various factors—e.g., the use of oral antibiotics and inter-individual variations in gut microflora, as well as diet—impact lignan pharmacokinetics [43]. For example, seed maturation state can alter oral lignan bioavailability [44].
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4. Lignan Content of Various Regional Diets
Dietary lignan consumption varies mainly with geographic location, but diet patterns are also subject to cultural and ethnic group influences.
4.1. Mediterranean Diet
The traditional Mediterranean diet is predominantly plant-based, characterized by a low intake of sweets; low meat products and red meat; a moderate intake of fish, poultry and fermented dairy products; a high intake of unprocessed cereals, legumes, nuts, fruits and vegetables [45]; the use of EVOO as the principal source of added fat; and moderate consumption of red wine [45]. Health benefits of this diet are essentially attributable to increased consumption of fiber and bioactive compounds (including antioxidants and functional fatty acids and lipids), as well as to a low intake of saturated fats [45,46].
Lignan sources in the diet of a Mediterranean population included garlic, onions, vegetables, including leafy greens, grains and seasonal fruits, including citrus, with each accounting for diverse proportions (11–70%) and subtypes of total polyphenols consumed [47].
Indeed, many typical Mediterranean diet foods (e.g., cereals) exhibit a high concentration of both lignans and other phenolic compounds [48].
Recently, the role of whole grain cereal intake in chronic disease prevention has been evaluated. Numerous studies propose a connection between lignan intake—as part of a wholegrain-based diet—and decreased incidence of chronic diseases, including cardiovascular disease, cancer and diabetes [5].
Thus, the major dietary lignan sources in the Mediterranean diet are vegetables and fruits, legumes, wholegrain cereals and oilseeds [3]. Additionally, another component of the Mediterranean diet, the chestnut, represents an excellent source of calcium, antioxidants and phenolic compounds [16,49]. Furthermore, EVOO consumption is an essential part of the Mediterranean diet. In fact, regular EVOO consumption is associated with a lower incidence of atherosclerosis, cardiovascular disease and some types of cancer [50,51,52]. This effect may be attributable to the high concentrations of (+)-1-acetoxypinoresinol and (+)-pinoresinol present in EVOO [53,54].
4.2. Northern Hemisphere Diet
This diet is observed in Northern and Nordic European regions, and is characterized by a high level of consumption of seaweed, shellfish, fatty fish (such as mackerel, herring and salmon), lean meats, rapeseed oil, legumes, nuts (such as almonds), vegetables, fruits (such as berries), whole grains (such as oats), low-fat dairy, and restricted salt and sugar intake [55,56]. In Nordic countries, the major dietary sources of plant lignans are vegetables, fruits and wholegrain cereals [57].
Among the many frequently-consumed plant species exhibiting a high lignan content, some species occur mainly in the Northern Hemisphere (e.g., Cirsium spp. of the family Asteraceae) [58]. The vegetative structures of these plants contain triterpenes, polyacetylenes, phenolic acids, flavonoids and alkaloids [58]. The most recent phytochemical studies of European Cirsium spp. demonstrate that their seeds are rich sources of neolignans and lignans [58,59].
4.3. Indian Diet
Various categories of food products make up a significant portion of the typical Indian diet, including fish, grapes, chocolate, oils, coffee, tea, biscuits and bread [60].
The fruit of Morinda citrifolia (Indian mulberry) has been extensively traditionally utilized in the treatment of cancer, diabetes, high blood pressure, diarrhea, headache and inflammation, largely due to its high lignan content [61,62].
Sesame is a typical component of the Indian diet, and both sesame seeds and oil are rich in lignans [63]. Sesame oil is recognized for both its notable resistance to oxidation and its nutritional value [64,65,66]. Despite lignans comprising only a small proportion (0.5 to 1.0%) of total sesame seed mass, the main sesame lignans—such as (+)-sesaminol, (+)-sesamolin and (+)-sesamin glucosides—have garnered attention for their notable health-promoting properties (demonstrated both in vitro and in vivo), including anti-inflammatory, antioxidant and anti-hypertensive activities [63].
Long-term intake of (+)-sesaminol has been proposed to inhibit the pathogenic extracellular β-amyloid aggregation observed in Alzheimer’s Disease [67]. Similarly, (+)-sesamin exhibits protective activity against prostate and breast cancers [68], and is a precursor to enterodiol and enterolactone (which have been shown to possess anti-cancer, antidiabetic and anti-ageing properties [64]).
4.4. Asian Diet
The Asian diet is characterized by an elevated consumption of rice, noodles, spices and vegetables, sesame seeds and oil [69]. Additionally, seafood, tofu and other soy products are commonly consumed [70]. Many major plant sources of lignans occur in Asia; these are habitually included in the diet, and in China are also used as medicinal plants. Such plants include Articum lappa, whose fruit extracts and seeds are a rich source of bioactive lignans [70], including arctiin and arctigenin. These two lignans exhibit anti-inflammatory activities (e.g., inhibition of lipopolysaccharide-induced nitric oxide production and release of pro-inflammatory cytokines in murine macrophages in vivo) [70,71]. In addition, when tested on diverse cancer cell lines, arctigenin possesses potent apoptotic and anti-proliferative activities [70,72].
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Certain medicinal herbs are usually used as an aqueous infusion. Among them, Isodon spp. and Tripterygium spp.
The genus Isodon comprises nearly 150 species found in the subtropical and tropical regions of Asia and represents an excellent lignan source [73]. Some species, such as Isodon japonica, have been used in traditional Chinese medicine to treat (for example) arthralgia, stomach-ache, mastitis, gastritis and hepatitis [73,74]. Isodon rubescens has also been used in traditional medicine for its hypotensive, antioxidant, immunological, antimicrobial, antitumor and anti-inflammatory properties [73].
Tripterygium wilfordii Hook f., a traditional medicinal herb, may ameliorate symptoms of rheumatoid arthritis and other autoimmune diseases [75]. Several phytochemical research studies have isolated hundreds of bioactive compounds—including lignans—from the root of this plant [75,76].
Chinese traditional medicine has long made use of Schisandra chinensis Baill. fruit as a sedative and antitussive tonic [77]. This fruit is additionally used in other countries in the production of functional foods, jam and beverages. Dibenzocyclooctadiene lignans isolated from S. chinensis exhibit anti-inflammatory and antioxidant properties, as well as improving cognitive functions (e.g., memory) [77]. In addition, prior studies have reported that S. chinensis fruit extracts—in which the major bioactive constituents are lignans—exert a neuroprotective effect and possess bioactivity which may help prevent Alzheimer’s Disease [78]. Furthermore, S. chinensis fruit may have positive effects on the liver, as well as on the gastrointestinal, immune, sympathetic and central nervous systems [79,80]. Lignan extracts have been shown to successfully suppress hepatocellular carcinoma cell proliferation and to prevent chemical toxin-induced hepatic injury [79]. However, only 2% of the total S. chinensis fruit is made up of lignans, and most of these are present in the seeds, which are usually removed during manufacture of fruit-derived products [79].
The Schisandra glaucescens Diels vine is extensively distributed across the Southeastern Sichuan and Western Hubei regions of China [81]. The stem of this vine has been used as an analgesic in diverse conditions, including arthritis, rheumatism, and contusions. As yet, one sesquiterpenoid, 25 lignans and 43 triterpenoids have been isolated from S. glaucescens [81]. In addition, S. glaucescens berries are thought to exert beneficial effects on the kidneys and lungs, relieving the symptoms of asthma for example [82].
Crataegus pinnatifida has been employed by the functional foods industry. Some studies have reported that it has the ability to protect against low-density lipoprotein (LDL) oxidation, to scavenge free radicals, and to exert an anti-inflammatory effect [83,84]. C. pinnatifida is mostly consumed as fresh fruit, processed juice or jam. Juice and jam manufacture results in a significant quantity of by-products, including seeds and leaves [84].
Schisandra sphenanthera is mainly located in Southwest China. A diversity of triterpenoids and lignans has been isolated from its leaves, stems, and fruit [85].
The roots, stems, fruit, and leaves of Kadsura coccinea are used medicinally, and its fruit, particularly, exhibits significant medicinal and nutritional properties [86]. Its bioactive triterpenoids and lignans have garnered interest for their reported bioactivities, including anti-inflammatory and anti-tumor effects [86,87,88].
Zanthoxylum schinifolium has been employed to stimulate blood circulation, as well as in the treatment of various diseases [89,90]. Due to its exceptional taste and characteristic aroma (usually described as green, spicy, floral, and fresh), Z. schinifolium fruit is used as a spice in many traditional Asiatic cuisines [89]. Prior pharmacological studies have demonstrated that the leaves and fruit of this plant possess medicinal properties, including antitumor, anti-inflammatory, and antioxidant activities, as well as inhibition of both platelet aggregation and monoamine oxidase production [89,91].
4.5. Latin-American Diet
The basis of the Latin-American diet consists of maize (corn), potatoes, peanuts and beans. This diet also includes flax seed. As mentioned above, Linum usitatissimum L. (flax seed) represents one of the best dietary sources of lignans, exhibiting a higher lignan content than legumes or grains [8]. Diets rich in flax seed are associated with a reduced risk of various diseases, including cardiovascular disease, osteoporosis, diabetes, and prostate and breast cancers [8,92]. Likely mechanisms include the ability to decrease circulating glucose, LDL and total cholesterol levels [93,94]. Furthermore, L. usitatissimum has significant commercial applications, in the manufacture of linen fiber for example [94]. In terms of lignans, flax seed contains mainly secoisolariciresinol and secoisolariciresinol diglucoside, but matairesinol is also present in small quantities [95]. Indeed, >95% of total flax seed mass consists of secoisolariciresinol diglucoside, which is predominantly localized in the seed’s fibrous hull [96] rather than its interior [97].
Asian diet appears to facilitate the highest intake of lignans, in forms which also result in higher bioavailability. This is due largely to a high level of vegetable consumption, as well as the use of lignan-rich plant infusions in traditional medicine.
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5. Human Studies Concerning Lignan Bioactivity
Recently, interest in identifying new sources of health-promoting natural compounds has increased. However, there are few human epidemiological studies that evaluate lignans bioactivity. Laboratory research, carried out on cell and animal models, concluded that lignans possess antimicrobial, anti-inflammatory and anti-oxidant activities, among others.
About antimicrobial activity, various lignans have exhibited antiviral and antibacterial activity, e.g., against Gram-positive bacteria through alteration of biofilm formation, bacteria metabolites, membrane receptors and ion channels [98]. For instance, pinoresinol has demonstrated activity against some virus [99].
Concerning anti-inflammatory activity, some lignans have the capacity to inhibit NF-kB activity (transcription factor involves on the expression of inflammatory cytokines) on human mast cells (HMC-1). Thus, reduced pro-inflammatory cytokines production. Furthermore, lignans are able to suppress nitric oxide (NO) generation and decrease inflammatory cell infiltration [100,101,102].
Regarding anti-oxidant activity, various bioactive natural compounds—including phenols from grains, vegetables and fruits—are rich dietary sources of phytochemicals and vitamins, both of which guard against oxidative stress [84,103]. A free radical formation is an inevitable byproduct of cellular metabolism, and cells also require a certain level of reactive oxygen species (ROS) to carry out a normal cellular process [70]. Nevertheless, accumulation and/or overproduction of ROS can damage cellular constituents, including DNA [70], and play an important role in the pathogenesis of various severe disorders, including chronic inflammation, cancer, neurodegeneration and atherogenesis [84].
Many studies have demonstrated the strong antioxidant activity of plant extracts, attributable to several highly-effective antioxidants, including lignans (e.g., lariciresinol, matairesinol, secoisolariciresinol, pinoresinol, and nortrachelogenin) [104]. Among the natural antioxidants, lignans exhibit particularly high antioxidant efficiency and thus have potential as preventive and/or therapeutic clinical tools [105].
In recent years, a significant effort has been devoted to analyzing the lignan consumption of various populations (Table 9). Most studies have focused on post-menopausal women, due to lignans being phytoestrogens that ameliorate menopausal symptoms and consequences (e.g., climacteric symptoms, osteoporosis and estrogen-dependent cancers) [106].
Table 9
Association between naturally lignan-rich foods and health promotion.
Author, Year Methods Results
Breast Cancer
Lowcock, E.C. et al. (2013) [111] Case-control study (2999 cases and 3370 controls)
FFQ Consumption of flaxseed and flax bread was associated with a significant reduction in breast cancer risk (OR 0.82, 95% CI 0.69–0.97; and OR 0.77, 95% CI 0.67–0.89), respectively.
McCann et al. (2012) [113] Case-control study (638 cases and 611 controls) BioRepository at Roswell Park Cancer Institute
FFQ Lignan intakes were inversely associated with risk of ER (−) breast cancer among premenopausal women (OR 0.16, 95% CI 0.03–0.44) and particularly triple negative tumors (OR 0.16, 95% CI 0.04–0.62).
Zaineddin AK et al. (2012) [114] Case-control study (2884 cases and 5509 controls)
FFQ High and low consumption of soybeans, as well as of sunflower and pumpkin seeds were associated with significantly reduced breast cancer risk compared to no consumption (OR 0.83, 95% CI 0.70–0.97; and OR 0.66, 95% CI 0.77–0.97, respectively).
Buck K et al. (2011) [112] 1140 postmenopausal patients (age 50 to 74 years)
FFQ
Serum Enterolactone Serum enterolactone was associated with a significantly reduced risk of death only for estrogen receptor-negative tumors (HR 0.27; 95% CI 0.08 to 0.87)
Buck K et al. (2010) [116] Meta-analyses Medline search to identify epidemiologic studies published between 1997 and August 2009 Lignan exposure was not associated with overall breast cancer risk (RE 0.92; 95% CI 0.81, 1.02).
McCann, S.E et al. (2010) [107] Breast cancer patients; National Death Index
Food frequency questionnaire (FFQ), DietSys (3.7) Lignan intake among post-menopausal women with breast cancer significantly reduced risk of mortality from breast cancer (HR 0.29, 95% CI, 0.11–0.76), as well as significantly reducing risk of all-cause mortality (HR 0.49, 95% CI 0.26–0.91).
Velentzis LS et al. (2009) [115] Meta-analy sesMedline, BIOSIS and EMBASE databases publications up to 30 September 2008 Overall, there was little association between high plant lignan intake and breast cancer risk (11 studies, OR 0.93, 95% CI 0.83–1.03).
Cotterchio, M et al. (2008) [109] Ontario Cancer Registry; Controls: Age-stratified random sample of women
FFQ Total phytoestrogen intake in pre-menopausal women was associated with a significant reduction in breast cancer risk among overweight women (OR 0.51, 95% CI 0.30, 0.87).
Suzuki, R. et al. (2008) [108] Swedish Mammography Cohort
FFQ and Swedish National Food database
Serum Enterolactone: Fluoroimmunoassay
Receptor status of tumors: Immunohistochemical A significant 17% risk reduction for breast cancer overall in high lignan intake was observed, but no heterogeneity across Estrogen Receptor/Progesterone Receptor subtypes.
Trock BJ et al. (2006) [110] Meta-analysis of 18 epidemiologic studies
published from 1978 through 2004 High soy intake was discreetly associated with reduction of breast cancer risk (OR 0.86, 95% CI: 0.75 to 0.99); association was not statistically significant among women in Asian countries (OR 0.89, 95% CI 0.71 to 1.12).
Gastroesophageal Cancer
Lin Y et al. (2012) [117] Case-control study (1995–1997); 806 controls, 181 cases of esophageal adenocarcinoma, 255 cases of gastroesophageal junctional adenocarcinoma, and 158 cases of esophageal squamous cell carcinoma.
Interviews and questionnaires; FFQ No clear associations were found between risk of esophageal carcinoma and lignan intake.
Lin Y et al. (2012) [118] Cohort study in Sweden, 81,670 (followed up 1998 to 2009). Cancer cases: Swedish Cancer Register
FFQ There was no statistically significant association between dietary intake of lignans and any of the studied adenocarcinomas.
Colon Cancer
Zamora-Ros, R. et al. (2015) [119] 409 CRC cases in Barcelona (Spain).
FFQ; Phenol-Explorer database. No associations were also observed with either total lignans or any flavonoid subclass intake.
Prostate Cancer
Wallström P et al. (2018) [120] Case-control study (1010 cases and 1817 controls)
National registers and hospital records
FFQ
Plasma Enterolactone: Fluoroimmunoassay There were no significant associations between plasma enterolactone and incidence of prostate cancer (OR 0.99, 95% CI 0.77–1.280)
Eriksen AK et al. (2017) [121] 1390 men diagnosed with prostate cancer from the Danish Diet, Cancer and Health cohort
Plasma Enterolactone: Fluoroimmunoassay No associations between plasma enterolactone concentrations and prostate cancer aggressiveness.
Hedelin M et al. (2006) [123] Swedish case-control study (1499 prostate cancer cases and 1130 controls)
FFQ No association was found between dietary intake of total or individual lignans or isoflavonoids and risk of prostate cancer.
Bylund A. et al. (2003) [122] 10 men with prostate cancer were randomized to a daily supplement of rye bran bread and 8 men of wheat bread
Blood and urine samples.
Ultrasound-guided core biopsies of the prostate. In the rye group, there was a significant increase in plasma enterolactone. However, only small changes were observed in plasma concentrations of prostate specific antigen (PSA).
Cardiovascular disease
Witkowska AM et al. (2018) [126] 2599 postmenopausal women, participants of the Multi-center National Population Health Examination Surveys.
24-h Dietary recall and food databases. In postmenopausal women, total and individual lignan intakes (secoisolariciresinol, pinoresinol, matairesinol) were not associated with the prevalence of CVD and its risk factors.
Pellegrini N et al. (2010) [127] Cross-sectional study in 151 men and 91 post-menopausal women.
Anthropometric characteristics.
Soluble intercellular adhesion molecule-1 (sICAM-1), CRP, insulin, glucose, total cholesterol, HDL-cholesterol and triacylglycerols.
Three-day weighed food record No relationship between intake of pinoresinol, lariciresinol or total lignans and sICAM-1 values was observed.
Jacobs DR. et al. (2000) [128] 11,040 postmenopausal women enrolled in the Iowa Women’s Health Study Followed from baseline 1986−997. Women who consumed on average 1.9 g refined grain fiber/2000 kcal and 4.7 g whole grain fiber/2000 kcal had a 17% lower mortality rate (RR = 0.83, 95% CI = 0.73–0.94) than women who consumed predominantly refined grain fiber.
Vanharanta M. et al. (2003) [129] A prospective study of Finnish men. 1889 men aged 42 to 60 years. Followed up 12.2 years. Multivariate analyses showed significant associations between elevated serum enterolactone concentration and reduced risk of CVD-related mortality.
Other diseases
Franco OH. et al. (2005) [130] Community-based survey among 394 postmenopausal women.
FFQ; Cognitive function:Mini-Mental Examination Increasing dietary lignans intake was associated with better performance on the MMSE (OR 1.49, 95% CI 0.94–2.38). Results were most pronounced in women who were 20–30 years.
Eichholzer M. et al. (2014) [131] 2028 participants of NHANES 2005-2008 and 2628 participants of NHANES 1999-2004 (aged ≥18 years)
Inflammatory marker: CRP Statistically significant inverse associations of urinary lignan, enterodiol, and enterolactone concentrations with circulating CRP counts were observed in the multivariate-adjusted models.
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FFQ: Food Frequency Questionnaire; CI: Confidence Interval; HR: Hazard Ratio; OR: Odds Ratio; CVD: Cardiovascular Disease; MMSE: Cognitive function Mini-Mental Examination; CRP: C-Reactive Protein.
5.1. Cancer
Various cohort studies have investigated dietary lignan anticancer bioactivity. As McCann et al. (2010) describe in the “Western New York Exposures and Breast Cancer” study, lignan intake among post-menopausal women with breast cancer significantly reduced the risk of mortality from breast cancer (Hazard Ratio (HR) 0.29, 95% Confidence interval (CI) 0.11–0.76), as well as significantly reducing the risk of all-cause mortality (HR 0.49, 95% CI 0.26–0.91) [107]. Other research based on the Swedish Mammography Cohort (SMC) also detected a statistically significant inverse association between breast cancer risk and lignan consumption among post-menopausal breast cancer patients [108]. Interestingly, the “Ontario Women’s Diet and Health Study” reported that neither lignan nor isoflavone consumption by a Canadian cohort correlated with a significant reduction in breast cancer risk [109]. Nonetheless, some studies do propose that isoflavone consumption correlates with a minor reduction in breast cancer risk in both pre- and post-menopausal women [109,110]. In addition, a cohort study examining the association between flax seed and flax bread intake and breast cancer risk demonstrated that flax seed intake was associated with a significant reduction in breast cancer risk (Odds Ratio (OR) 0.82, 95% CI 0.69–0.97) [111]. Furthermore, Buck et al. (2011) demonstrated that high serum enterolactone levels in post-menopausal breast cancer patients are associated with improved overall survival rates [109,112].
Another study, based on data from the United States Cancer Center Support Grant, investigated the association between individual breast cancer estrogen receptor (ER) status and lignan intake [113]. Higher lignan consumption was inversely correlated with the risk of ER− breast cancer among premenopausal women (OR 0.16, 95% CI 0.03–0.44) and with the risk of ER+ breast cancer among post-menopausal women (OR 0.64, 95% CI 0.42–1.00) [113]. Although this effect was largely independent of specific lignan class, it predominantly correlated with matairesinol and lariciresinol intake levels [113]. In addition, this study examined associations between breast tumor subtype and dietary lignan intake, demonstrating that a reduction in premenopausal triple-negative (HER2−PR−ER−) breast cancer risk (OR 0.16, 95% CI 0.04–0.62) was associated with higher lariciresinol and pinoresinol intake [113]. This finding agrees with that of a German case-control study that demonstrated a correlation between high intake of pumpkin and sunflower seeds (rich sources of lariciresinol and pinoresinol) and a statistically significant reduction in post-menopausal ER+ breast cancer risk (OR = 0.88, 95% CI = 0.77–0.99, p for trend = 0.02) [109,114].
Two recent meta-analyses have corroborated that high levels of plant lignan consumption correlate with a modest reduction in post-menopausal breast cancer risk (13 studies; Risk Estimated (RE) 0.86, 95% CI 0.78–0.94) [115,116].
Dietary lignan intake is also associated with a reduced risk for other cancer types (e.g., esophageal and gastric adenocarcinoma, as well as colon cancer), but very few human studies have been conducted.
A Swedish study indicates that dietary lignan intake correlates with decreased risk of gastroesophageal junction adenocarcinoma [117]. However, another Swedish study examining the Swedish Cancer Registry database did not find a clear association between dietary lignan consumption and development of gastric or esophageal adenocarcinoma [118]. Yet another (case-control) study indicated that a diet rich in resveratrol, quercetin and lignans (characterized by low intake of milk, but high intake of wholegrain bread, vegetables, wine and tea) may decrease the risk of developing such cancers [103].
Regarding colorectal cancer, Zamora-Ros et al. (2015) evaluated the association of lignan and flavonoid consumption with overall survival time and risk of recurrence in Barcelona (Spain) [119]. After a mean of 8.6 years’ follow-up, 77 of the 319 (24.1%) patients in the cohort had experienced recurrence (excluding cases with metastasis that could not be resected), 133 of 409 (32.5%) patients had died, and no association was noted between consumption of any flavonoid subclass or total lignans and colorectal cancer risk [119].
Concerning prostate cancer risk, it has been studied its association with plasma enterolactone concentrations. Wallström et al. (2018) evaluated a population of Swedish men with 1010 cases and 1817 controls. After a mean follow-up of 14.6 years; there were no significant associations between the incidence of prostate cancer and plasma enterolactone (OR 0.99, 95% CI 0.77–1.280) [120]. Other study carried out at Danish men, neither found an association between prostate cancer mortality and plasma enterolactone [121]. However, two other pieces of research on humans, from 2003 and 2006, obtained positive results based on dietary phytoestrogen intake [122,123]. A Swedish case-control study indicated that lower prostate cancer risk is related to certain phytoestrogen-rich foods [123].
Given such mixed results, additional studies examining the effect of human lignan intake on cancer risk are necessary. Specifically, most existing studies have not examined the relevance of the specific dietary lignan source.
5.2. Cardiovascular Disease
Neolignans and flax lignans are reportedly relevant in diabetes, hypercholesterolemia and cardiovascular disorders [124]. In addition, the anti-aging role of lignans has recently been described [125]. Such lignan characteristics may be relevant to the reduction of cardiovascular disease risk in post-menopausal women. Indeed, an inverse association exists between high lignan consumption and the development of hypertension and cardiovascular disease [126]. Furthermore, prospective and cross-sectional epidemiological evidence suggests that dietary lignan intake reduces cardiovascular disease risk in post-menopausal women and elderly men by modifying traditional risk factors [127].
Jacobs et al. (2000) demonstrated that the risk of mortality is inversely associated with whole grain consumption in post-menopausal women [128]. Another study described how four weeks’ consumption of a whole grain cereal-rich diet exerted a reasonable cholesterol-lowering effect in healthy post-menopausal women [17].
However, a Warsaw population-based cross-sectional study conducted by the National Institute of Cardiology demonstrated that total dietary lignan consumption does not correlate with the occurrence of cardiovascular diseases, nor with cardiovascular risk factors (including central obesity, hypercholesterolemia and hypertension) in post-menopausal women [126]. Nevertheless, this study attributed a potentially-beneficial effect of lignan intake on hypercholesterolemia specifically to lariciresinol [126].
In a Finnish population, the highest serum enterolactone concentrations correlated with a lower risk of all-cause mortality, including from cardiovascular disease [129]. Enterolactone is a metabolite of lariciresinol, pinoresinol, secoisolariciresinol and matairesinol, and very low matairesinol intake does demonstrate an inverse relationship with endothelial dysfunction and vascular inflammation [127].
5.3. Other Diseases
Most studies have focused on the effects of lignan-rich food consumption in the prevention of cancer and cardiovascular disease. However, some observational studies have investigated the relationship between regular consumption of plant lignans and the risk of developing other lifestyle-related diseases. A study based on the European Prospective Investigation into Cancer and Nutrition cohort proposed that improved cognitive performance in post-menopausal women is associated with higher dietary phytoestrogen consumption (predominantly lignans in Western diets) [130]. Thus, it has been suggested that low-grade chronic inflammation contributes to the prevalence of chronic lifestyle-related diseases. The relationship between lignan consumption and inflammatory markers (e.g., C-reactive protein (CRP)) was studied in a United States cohort, demonstrating that a beneficial inflammatory marker profile is associated with adult lignan consumption [131].
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6. Conclusions
Taken together, reviewed data support the recently increased interest in lignan health-promoting properties. Due to their various bioactive properties, dietary intake of lignan-rich foods may prevent certain types of cancers (e.g., breast cancer in post-menopausal women and colon cancer). Regarding chronic lifestyle-related diseases, some pieces of evidence indicate that lignan intake is associated with a lower risk of developing cardiovascular disease. Nonetheless, further human studies are warranted to evaluate lignan bioavailability resulting from different traditional dietary patterns, in order to influence the rational promotion of healthy lignan-rich diets.
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Author Contributions
All authors have participated actively in the design and conception of this review. All authors have assessed the present form of the review and have approved it for publication.
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Funding
Carmen Rodríguez-García received a pre-doctoral research grant from the University of Jaén (Ayudas predoctorales para la formación del personal investigador, Acción 4).
Are lignans in beans?
Ernie Gray, CDBAB Chairman, provided the following excerpts from the Miracle of Nature’s Healing Foods, an investing publication by J.E. O’Brien (Globe Communications Corp. 1189 Globe Mini Mag 231) available from Globe Communications Corp., 5401 N.W. Broken Sound Blvd., Boca Raton, FL 33487.
Beans, peas, lentils and chickpeas are warehouses of plant protein wrapped in beneficial fiber and free of the fats, harmful chemicals and industrial additives that accompany protein found in meats. In addition, legumes also contain a set of chemicals called protease inhibitors which actually neutralize the cancer causing free radicals called hydroxyl radicals, according to researchers at the University of Pennsylvania.
One cup of dried beans a day can reduce total cholesterol 19% and “bad” LDL cholesterol by about the same, according to investigators at the University of Kentucky. Eating beans regularly also lowers blood pressure, exports report.
The same amount of beans has the almost magical ability to control insulin and blood sugar levels so well that Type I diabetics (the kind who need daily shots of insulin) can reduce the amount of insulin by 38% or more. For Type II diabetics, the adult onset sufferers who do not produce enough insulin, legumes can virtually eliminate the need for insulin shots and often other diabetes drugs as well. What’s necessary is replacing meat with beans or peas as the source of protein in your diet, according to University of Kentucky authority Dr. James Anderson. The high content of gummy and pectin fiber produces the regulating effect.
A side-benefit of the large supply of these kinds of fiber is that they stifle hunger, keeping you from eating too many high-calorie foods, and promote the excretion of sodium, which is good for your blood pressure. Beans also make your digestive system work the way nature intended it to by regulating the function of the colon, preventing and curing constipation and preventing hemorrhoids and other bowel problems. Beans are rich in anti-cancer substances called lignans. Friendly bacteria in the colon, lignans convert into hormone-like substances which scientists say may fight off breast and colon cancers.
On the practical side, please note that canned baked beans work as well as the dried beans you painstakingly prepare yourself. A 7.5 ounce can supplies a therapeutic dose, says Dr. Anderson, and can lower blood cholesterol by 12% or more in a few weeks. A one-half cup of cooked beans contains the following:
Black Beans – 132 calories, less than 1 g fat and 10 g fiber.
Kidney Beans – 127 calories, less than 1 g fat and 9.5 g fiber.
Pinto Beans – 131 calories, less than 1 g fat and 10 g fiber.
White Beans – 143 calories, less than 1 g fat and 8 g fiber.
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Beans and Fiber
Edible Dry Beans – The High Fiber Food of the 21st Century
Today, beans are recognized by many health-related groups, including the American Heart Association, the American Cancer Society and the American Diabetes Association as an extremely beneficial addition to most diets.
That’s because they’re high in complex carbohydrates, protein and dietary fiber, low in fat and sodium, and completely cholesterol-free.
It’s long been recognized that increasing the fiber content in our diets promotes a healthy digestive tract and reduces the risk of many types of cancer. And fiber also plays a significant role in lowering high blood cholesterol rates, one of the main risk factors for the development of cardiovascular disease.
Beans are one of the best sources of fiber available, and they’re an excellent source of protein as well. In fact, a one pound can of beans contains more protein than a pint of milk, yet ounce for ounce, fewer calories and fat than eggs, meat or cottage cheese.
It’s no wonder the American Academy of Science and the National Research Foundation agree that dry beans are sure to be the high fiber food of the 21st century!
Nutritional Value of 100g Can of Baked Beans
ENERGY 64kcals (270KJ) PROTEIN 5.1g
DIETARY FIBER 7.3g
FAT 0.5g CARBOHYDRATE 10.3g
Saturated fat 0.08g Sugars 5.2g
Polyunsaturated 0.25g Starches 5.1g
Cholesterol 0mg
IRON 1.4mg CALCIUM 45mg
ZINC 0.7mg MAGNESIUM 31mg
SODIUM 480mg
Fiber Content of Beans Compared With Other Fiber-Rich Foods
FOOD TOTAL DIETARY
FIBER
Beans
Kidney beans, canned 20.9g
Navy beans, dried, cooked 23.0g
Pinto beans, dried, cooked 24.1g
Fruit
Banana, raw 7.3g
Orange, raw 11.4g
Pineapple, canned 9.5g
Cereal
Oat bran 15.7g
Corn flakes 1.6g
Puffed wheat 7.2g
Nutritional Composition of Beans With Recommended Daily Intake
225g of
Beans Rec. Daily
Intake*
Supplied
By Beans % of Rec.
Daily
Intake
Protein (g) 10.1 63 16
Fat (g) 1.1 NS
Carbohydrate (g) 29.5 NS
Calories 162 2,510 6
Calcium (mg) 102 500 20
Iron (mg) 3.8 10 38
Vitamin A (g) 110 750 15
Vitamin B (mg) 0.15 1 15
Vitamin B (mg) 0.11 1.6 7
Nicotinic Acid Equivs (mg) 2.9 18 16
Vitamin C (mg) 6.6 30 22
Vitamin D (g) - 10 -
Dietary Fiber (g) 16.3 NS
- = Nil
NS = Not Specified
* = Recommended daily intake for sedentary man aged 18-35
Information Courtesy of National Dry Bean Council
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Beans and Folate
Why You Need Folate
Even though many of us are familiar with folate and its positive effect on reducing birth defects, there’s increasing evidence that this B-vitamin, naturally found in abundance in beans, may also be important in reducing the risk of vascular disease and coronary death.
Canadian research has linked low blood levels of folate to increased odds for fatal coronary heart disease. A study of more than 5,000 people found that those in the quarter of the group with the lowest folate levels were 69 percent more likely to die of a coronary problem than those in the quarter with the greatest reserve of the vitamin. The data shows that as folate levels dropped, risk of death rose in a stepwise fashion. Folate appeared most protective in women and in people under age 65. An interesting finding in all age groups was that risk increased even at folate levels that are presently considered normal. The study was published in the June 26, 1996 issue of JAMA (Vol 275, pp. 1896-1896).
In a 1995 review of work exploring the relationships among homocysteine levels (homocysteine is an amino acid in the blood), folate and blood vessel disease (JAMA, vol. 274, pp. 1049-1057), University of Washington researchers proposed that increasing folate intake might prevent as many as 50,000 heart attack deaths a year. Folate may protect against heart disease because it breaks down homocysteine and allows it to be cleared from the blood stream. Among the studies reviewed by the University of Washington was Tufts University research which showed for the first time that inadequate intake of folate is the main determinant of the homocysteine-related increase in the risk of carotic blockage.
Because our bodies do not produce folate, it’s important to get it from the foods we eat. Foods high in folate include beans, leafy green vegetables, fruit and fruit juices, and whole cereal grains. Of all these, beans are the most concentrated source of folate. A mere cup of beans is packed with almost half the folate needed for a day.
How much folate?
Bean Variety (Cooked) Folate (mcg/cup)
Cranberry 364
Blackeye 358
Pinto 292
Pink 283
Garbanzo (chickpeas) 282
Baby Lima 273
Black 256
Navy 255
Small White 246
Great Northern 180
Large Lima 156
Kidney 131
* Source: National Nutrient Databank of the USDA
Information refers to cooked, dry packaged beans
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Nutritional Profile
Beans and Your Health – How Beans Contribute to a Healthier Life
Nutrition Profile of Cooked Dry Beans
Serving Size: 1 cup = 230 Calories
Nutrient Amount % US RDA
Protein 16.0 g 35
Iron 5.4 mg 30
Zinc 2.1 mg 14
Thiamin .30 mg 20
Folacin 123 mg 30
Magnesium 92 mg 23
Copper .5 mg 25
Manganese 1 mg 40
Potassium 620 mg *
Fiber 9 mg *
Cholesterol 0.0 mg *
Sodium 10 mg *
Fat 1.5 g *
*No U.S. Recommended Dietary Allowance has been established for this nutrient.
Bean Nutrition
PROTEIN: Dry beans are the richest source of vegetable protein (21-27% when cooked). Combining beans with a small amount of animal protein such as meat, cheese, or egg or small amounts of grain (corn, wheat, or rice) will create a complete protein equal to that of meat and other animal sources. Protein is important for human health because it supplies the materials for building and repairing body tissues, muscles, bones, glands, skin, and teeth. Beans consistently rank lowest of all foods in cost per gram of protein, according to the USDA.
ENERGY: Beans have long been valued as an energy source. Complex carbohydrates in dry beans digest more slowly than simple carbohydrate foods thereby satisfying hunger longer. One half cup of cooked beans contains 118 calories or less.
VITAMINS: A normal serving of cooked dry beans supplies as much as 40% of the minimum daily requirement of the B-vitamins, thiamine and pyridoxine, and significant amounts of other B-vitamins. The B-vitamins contribute to healthy digestive and nervous systems, skin and eyes.
MINERALS: Iron to build red blood cells, calcium and phosphorus for strong bones and teeth, and potassium, which is important in regulating body fluid balance, all plentiful in dry beans. Beans are high in fiber, contain no cholesterol, and are low in sodium. Sodium content is low so, when cooked without salt, they are good in low-salt diets.
How much lignan is in ground flaxseed?
Lignans are a group of phytonutrients which are widely distributed in the plant kingdom. Flaxseed is the richest source of providing lignan precursor such as secoisolariciresinol diglucoside (SDG). This article reviews the studies relevant to experimental models in animals and humans demonstrating the possible nutraceutical actions of SDG to prevent and alleviate lifestyle-related diseases. A local and international web-based literature review for this project was carried out to provide information relating to the study. The major key word “SDG” was selected to gather information using the electronic databases pertaining to the current state of flaxseed lignans composition, bioactive compounds, metabolism and to find out their role in terms of chemopreventive action. The extraction methods vary from simple to complex depending on separation, fractionation, identification and detection of the analytes. The majority of studies demonstrate that SDG interferes with the development of different types of diseases like cardiovascular, diabetic, lupus nephritis, bone, kidney, menopause, reproduction, mental stress, immunity, atherosclerosis, hemopoietic, liver necrosis and urinary disorders due to its various biological properties including anti-inflammatory, antioxidant, antimutagenic, antimicrobial, antiobesity, antihypolipidemic and neuroprotective effects. Moreover, SDG has a defending mediator against various cancers by modulating multiple cell signaling pathways. As discussed in this review, SDG has shown therapeutic potential against a number of human diseases and can be recommended for discerning consumers.
Keywords: Flaxseed, Processing, Lignan, Precursors, Diet, Therapy, Maladies
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Background
The flaxseed (Linum usitatissimum L.) is the seed from the flax plant, an annual herb which belongs to Linaceae family with more than 200 species. The Latin name of flaxseed means “very useful”, and it has brown and golden varieties. The shape of flaxseed is flat or oval up to 4–6 mm size with a pointed tip. Flaxseed has been a part of human diet for thousands of years in Asia, Europe, Africa, North America and more recently in Australia. The world flaxseed production remained static about 2.6 million tonnes as compared with other oilseed crops and represents 1 % of total world oilseeds supply. Currently, flaxseed has been the focus of increased interest in the field of diet and disease research due to the potential health benefits associated with some of its biologically active components such as dietary fiber (25–28 %) and α-linolenic acid (50–55 % of total fatty acids composition) [1].
Brain Talk: Balance Your Hormones Naturally
Among the compounds that present biological activity, phenolic compounds are of special interest. Lignans, very complex classes of bioactive polyphenolic phytochemicals, formed by the coupling of two coniferyl alcohol residues are widely distributed in the plant kingdom [2]. There are two general types of lignans: i) those found in plant seeds like secoisolariciresinol diglucoside (SDG), isolariciresinol, matairesinol, lariciresinol and ii) those found in animals and humans known as mammalian lignans [3]. Phenolic lignans are found in most fiber-rich plants, including pumpkin seed, sesame seed, grains such as wheat, barley, rye and oats; legumes such as beans, lentils, and soybeans; and vegetables such as garlic, asparagus, broccoli, and carrots. Flaxseed is particularly the richest known source of lignans (9–30 mg per g), with lignan production at 75–800 times that of other oil seeds, cereals, legumes, and fruit and vegetables [4]. The principal dietary lignan present in flaxseed is SDG which occurs as a component of a linear ester-linked complex. Chemically, the C6-OH of the glucose of SDG is esterified to the carboxylic acid of hydroxymethylglutaric acid. Accumulation of SDG is coherent with LuPLR gene expression and synthesis of PLR enzyme during mature seed development [5]. The understanding of the action mechanism of these SDG compounds is crucial for their possible exploitation as neutraceutical supplement in biological system.
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Methods for literature search
The search for relevant literature was conducted using electronic databases which were searched for peer-reviewed journal articles and further expanded our search to latest available books of food and nutrition by visiting websites and by consulting with reference librarians and experts in the field. Specifically, various words such as ‘Flaxseed’, ‘Processing’, ‘Lignan’, ‘Precursors’, ‘Diet’, ‘Therapy’, ‘Maladies’ were searched in keyword, title, or abstract of an article or related books. Particular databases used were: ‘American Society of Agriculture and Biological Engineers (ASABE)’, ‘SAGE online journals’, ‘Nature Publishing’, ‘Cambridge University Press’, ‘Elsevier (Science Direct)’, ‘Jastor’, ‘Science Online’, ‘Springerlink’, ‘Taylor and Francis Journals’, ‘Wiley-Blackwell Journals’, ‘Beech Tree Publishing’, ‘ISI Web of Knowledge’, ‘Agricola’, ‘Agris’, ‘Biomed Central’, ‘Cancer.gov’, ‘Directory of Open Access Journals’, ‘Google Directory’, ‘High Wire Press’, ‘Pubmed’, ‘SciELO-Scientific Electronic Library Online’, ‘Scopus’ and ‘Health Source’. Reference lists of all relevant articles were examined for additional studies. After collection of search literature, abstracts and articles were classified as highly relevant, moderately relevant or irrelevant. Highly relevant articles were those in which direct extraction of SDG and derived mammalian lignans from flaxseed or flaxseed by-products was carried out. Moderately relevant articles were those that failed to meet the ‘highly relevant’ criteria yet provided background information regarding other phenolic compounds of flaxseed. Inclusion criteria were based on animal and human models with respect to SDG treatment for different maladies. All other articles were deemed irrelevant to this review and considered as exclusion criteria based on insufficient information was available to permit methodological evaluation for SDG extraction, analysis and processing or if complex multimodal efficacy programmes were used. Three subject experts from the institute were invited for independently applied the inclusion/exclusion criteria to papers identified from the literature search as highly relevant before combining results. A consensus method was used to solve any dispute regarding the inclusion or exclusion of a study. A fourth reviewer was consulted to resolve disagreements [6]. On the basis of the criteria specified above, as of May of 2015, total 220 while 140 moderate relevant articles were found in electronic database. From which only 70 highly relevant articles were part of results.
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Extraction, isolation and purification of SDG
Most of the analytical techniques for the extraction, isolation, and purification of SDG have been conducted on whole flaxseed and defatted flaxseed meal. Flaxseed lignans especially SDG occur in ester-linkage form in the hulls enclosing the seeds, which require special pretreatments including various steps and combinations of enzymatic, acidic, and alkaline hydrolysis before extraction and analysis [7, 8]. Bakke and Klosterman firstly reported a laboratory process for extracting SDG from defatted flaxseed meal using equal parts of 95 % ethanol and 1,4-dioxane [9]. Furthermore, several scientists used a variety of organic solvents mixture such as of methanol, acetone, isopropanol and butanol to extract SDG [10]. Base hydrolysis treatments include sodium, calcium, ammonium and potassium hydroxides for the liberation of SDG from flaxseed lignan polymer [7]. Recent studies have evidenced that the applications of novel technologies for extraction of SDG compounds from flaxseed oilcake is of particular interest within the context of green chemistry as these technologies use reduced solvent consumption, reduced extraction time, lower temperature, less thermal damages to the extract and minimize the loss of bioactive compounds in comparison to other conventional published methods [11]. Considering the importance of the phenolic fraction of flaxseed, high performance analytical methods have been developed to characterize its complex lignan polymer pattern. The analytical methods depending upon separation methodology for SDG can be categorized into chromatographic and non-chromatographic techniques. In most research studies, gas chromatography, high-performance liquid chromatography coupled with photodiode array detector and mass spectrometric procedures have been used for the quantification and analysis of SDG purity [12, 13].
SDG-enrich foods
SDG can be successfully supplemented in numerous foods due to high stability percentage in finish products. SDG has been found to withstand baking temperatures (250 °C) and can be incorporated in cereal-based bakery products [14]. The SDG concentration of doughs, baked rye breads, graham buns, and muffins was found relatively stable during storage at room temperature for 1 week and at −25 °C for 2 months, respectively [15]. Similarly, macaroni fortified with whole ground flaxseed at levels of 10 to 20 %, dried under ultrahigh temperature (90 °C) and stored for 32 weeks under ambient conditions possessed approximately 80 to 95 % of the SDG contents [16]. Quantitative recovery of SDG from the commercially prepared breads was observed when product formulation was supplemented with pure SDG. However, 73–75 % recovery of SDG was noted from baked bread samples which contained flax meal or aqueous alcohol extracts in product recipe. The extent of grinding of the flaxseed was also shown to have a significant effect on the recovery of SDG from both flax meal breads and baked goods, with extraction of SDG from finely ground samples greater than that from course material [17]. A great part of the SDG content (89 %) was found stable during the heat treatment of ground flaxseed, either alone or as an ingredient in bread, under various conditions of temperature and during storage for several days [18]. Added SDG was retained in the whey fraction and 6 % was found in the cheese curd while up to 25 % of added SDG was lost in whey-based drinks during storage of 6 months at 8 °C [19]. SDG shows natural antioxidant mechanism in foods and prevents oxidation reactions resulting in enhanced shelf life of foods. The ethanolic flaxseed extracts enriched with SDG compounds exhibit antioxidant activity during frozen storage of meat products. However, antioxidant efficiency of the SDG-enriched extracts seems to depend on chemical composition of raw material and flax variety [20]. Moreover, thermal processing has been responsible for slight increase in extractability level of the lignans from raw flaxseed meal which is may be due to increasing porosity of the heated seeds. One recent scientific study reported that the flaxseed samples heated at 250 °C for 3.5 min possessed high SDG contents (1200 mg/100 g) when compared from unheated flaxseed samples (1099 mg/100 g) [14]. However, to conserve the relatively high content of lignans during production of commercial foods products, the initial raw material composition, the water content and the applied temperatures have to be considered.
Bio-activation of SDG
The biological activity of SDG results from their conversion to the mammalian lignans enterolactone (EL) and enterodiol (ED) by the intestinal microflora in the upper part of the large bowel. The mammalian lignans differ from plant lignans in that mammalian lignans have the hydroxyl groups in the meta position while plant lignans have the oxygenated substituents primarily in the para positions [21]. The mammalian lignans, firstly identified in humans and animals in 1980 [22], are formed in the human body by the action of diverse phylogenetically bacterial strains dominating Peptostreptococcus sp. SDG-1 and Eubacterium sp. SDG-2 present in the gastrointestinal (GI) tract through hydrolyzing the sugar moiety of plant lignan precursors followed by dehydroxylation and demethylation process [23]. Many factors, in addition to diet, such as intestinal microflora, smoking, antibiotics, and obesity affect circulating lignan levels in the body [24]. Due to variations in these factors, large differences among individuals have been observed in lignan bio-activation in urine, fecal and blood samples. Different studies have analyzed human intake of lignans. However, so far research has not shed light on what proportion of ingested mg of plant lignans is metabolized in the gut, absorbed and finally reaches target tissue [23]. Mammalian lignan production from intake of whole or milled flaxseed supplemented baked products is dependent on time and dose but not on processing. The processed flaxseed supplemented muffin or bread did not affect the quantity of lignan excretion in womens which reflect stability and bioavailability of plant and mammalian lignans in human biological metabolism [25].
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Chemopreventive properties of SDG
Flaxseed Lignan precursors and their mammalian metabolites may be appreciated as health promoting dietary micronutrients having chemopreventive properties in animals and humans by utilizing as nutraceutical agent against different chronic diseases like cancer, atherosclerosis, diabetes, kidney disorders and lupus nephritis [26]. Some of the health effects of flax SDG are discussed in the following sections.
Anti-cancer effect
The animal and human studies have shown the prevention role of SDG against some cancers (breast, lung and colon) as a result of its strong anti-proliferative, antioxidant, anti-oestrogenic and/or anti-angiogenic activity. It is proposed that the anticancer activity of SDG is associated with the inhibition of enzymes involved in carcinogenesis. The growth of crypts and crypts foci are the earlier risk factor for colon cancer. The animal studies have showed that flaxseed SDG and lignan supplementation in rat’s diet resulted in aberrant crypts and it foci showing the anticancer role of these molecules [27]. Similar, the anti carcinogenic effect of SDG molecule has been observed in pulmonary metastasis, mammary gland and breast cancer metastasis. The studies showed that the supplementation of SDG in mice diet resulted in reduction of volume, area and numbers of tumors significantly as compared to control mice group. The two week supplementation of SDG in mice diet led to 22 % more pulmonary metastasis tumors in melanoma cells than average tumors as compared to control group having 59 % more tumors than average [28]. The SDG of flaxseed are proven to initiate the differentiation of enhancement of terminal end buds in mammary gland and thus have role in prevention of breast cancer. The series of studies have shown that progression of N-methyl-N-nitrosourea-induced mammary tumorigenesis results in development of carcinogenesis and SDG has proven to delay the progression of this phenomenon by regulating the terminal end bud differentiation [29, 30]. There are several possibilities that how SDG can biologically involve in delay or prevention of carcinogenic phenomenon. It is supposed that plasma insulin-like growth factor I, endothelial growth factor is responsible for risk factor of breast cancer progression and SDG can lower these growth factors [31, 32]. Another possibility of prevention role of SDG is in mediation of Zn concentration which observed more in breast cancer tissue compared to tissue of normal breast which may provide protection against breast cancer by limiting angiogenesis in such cases [33].
Human studied have shown that there could be consisted possibility of correlation between SDG and cancer. SDG may affect hormonal levels and may influence cancer progression. The potential effects of SDG are attributed to concomitant fat restriction. The research studies conducted by Demark-Wahnefried and co-workers [34, 35] on prostate cancer proliferation in human subjects have shown that flaxseed-supplemented could affect the biomarkers of prostatic neoplasia. A randomized controlled trial test on 161 prostate cancer patients for 30 days before prostatectomy were conducted by assigning diet without flaxseed supplementation and flaxseed-supplemented of 30 g/day. The proliferation (Ki-67, the primary endpoint) and apoptosis were assessed for tumor development. Proliferation rates were significantly lowers among men assigned to the flaxseed supplemented diets. Their findings suggest that flaxseed is associated with biological alterations that may have prevention role against prostate cancer. The studies from two research groups of Boccardo et al. [36] and Pietinen et al. [37] have demonstrated a strong correlation between SDG metabolites and breast cancer in women. The serum level of intestinal microbial derived SDG metabolites enterodial and enterolactone have inversed association with breast cancer when studies were conducted on 508 breast cancer women cases. The overall animal and human studies have been suggested SDG and its metabolites may provide prevention against cancer as result of its antioxidant activity or ability to inhibit enzyme action involved in steroid hormone metabolism.
SDG and heart diseases
The major hearts diseases are stock, coronary artery disease, peripheral artery disease which are resulted from oxidative stress, inflammation, obesity, diabetes, dyslipidemia and hypertension and contribute to an atherogenic environment that promotes the development of myocardial infarction and stroke, leading causes of mortality among industrialized nations [38, 39]. The animal and human studies have suggested that SDG and its metabolites mediate the serum total cholesterol, low density lipoprotein, total cholesterol and high density lipoprotein ratio which lead to less androgenic complication and antioxidative prevention [40]. A series of research studies indicates that regular flaxseed with α-linolenic acid and flax lignan polymer (containing 34–38 % SDG, 10–11 % 3-hydroxy-3-methylglutaric acid and 15–21 % cinnamic acids) as potential bioactive components or purified SDG in equimolar concentration have similar antiatherogenic effects [41].
Similarly, the human studies showed the SDG as potential cardiovascular protector by mediating the mechanisms of total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerides and glucose metabolism. It was observed that 20 hypercholesterolaemia and hypertriglyceridaemia subjects receiving 600 mg SDG per day for 8 weeks led to significant reductions in total cholesterol, LDL-cholesterol and glucose concentrations compared with the placebo group [42]. Several other studies have shown that SDG anti-cardiovascular effects are associated with enterolactone mediating increased expression of vascular endothelial growth factor, endothelial NO synthase and haeme oxygenase-1 mediated myocardial angiogenesis. Overall, the majority of studies that used purified SDG found improvements in markers of CVD [43].
Anti-diabetic action of SDG
Diabetes is a metabolic syndrome and is characterized by increases in central adiposity, serum tirglycerides, serum glucose, blood pressure, inflammation and decreases in HDL-cholesterol that elevates risk of insulin resistance [44]. The animal and human studies revealed that high fat diet containing 0 · 5 to 1 · 0 % SDG reduces liver triglycerides content, serum triglycerides, total cholesterol, and insulin and leptin concentrations that resulted in significantly reduced visceral fat gain as compared to group of mice receiving high fat diet without SDG [45]. Another study have shown that female rats receiving glucosuria induced diet with SDG have 80 % less chances of glucosuria as compared to rats have 100 % chances of glucosuria receiving diet without SDG [46]. SDG reduces C-reactive protein concentrations which are associated with insulin resistance and diabetes mellitus in type 2 diabetics [47]. Daily consumption of low-fat muffin enriched with SDG (500 mg/day) for 6 week can reduce CRP concentrations [48]. The earlier studies indicate that flaxseed lignan supplements have beneficial associations with C-reactive protein and also suggest that lignans have possible lipid- and blood pressure-lowering associations [49].
SDG effect on liver necrosis
The free radicals and reactive oxygen species (ROS) are produced as a result of exogenous chemicals and/or to the endogenous metabolic processes involving redox enzymes and bioenergetic electron transfer in the biological system. These free radicals and ROS thus induce oxidative stress leading to damage of proteins, lipids and nucleic acid and results in cancer, diabetes, atherosclerosis, hepatic diseases. The actions of these molecules can be nullified through antioxidants mechanism [50, 51]. Antioxidant potential of SDG and its metabolites have been reported in several animal and human models. Animal studies have shown that SDG containing flaxseed extract significantly increases the levels of serum ALP, ALT, AST, Bilirubin, blood urea and creatinine with decrease in the levels of total protein and albumin in experimental rabbits exposed with induced hepatotocxicity compared to the control group. The SDG polymer complex can significantly prevent liver and renal damage from paracetamol induced hepatonephrotoxicity in rabbits. Thus, the flaxseed lignan act as a therapeutically useful hepato-nephroprotective agent [52]. Flaxseed supplementation may provide a new therapeutic strategy to reduce hypertriglyceridemia and fatty liver in rats [53]. Another study reported the rabbits exposure to SDG lignans for consecutive 8 weeks to assess histopathologic evaluation score of non-alcoholic fatty liver disease and suggested that SDG (8 mg/kg) can protective from liver diseases [54].
Intervention studies have shown that Flaxseed lignan can decreases liver disease risk factors in moderately hypercholesterolemia mens. The oral administration of SDG would decrease the level of blood cholesterol and liver disease risk factors induced by hypercholesterolemia in humans. Thirty men received placebo and capsules of SDG for 12 weeks and subjects received 100 mg of SDG exhibited a significant reduction in the ratio of low-density lipoprotein/high-density lipoprotein cholesterol, a significant percentage decrease in the levels of glutamic pyruvic transaminase and γ–glutamyl transpeptidase and a significant percentage decrease in the level of γ–glutamyl transpeptidase which may reduce the hepatic diseases risks [55].
SDG effect on lupus nephritis, bone strength and kidney disease
Faxseed SDG has a therapeutic role in animal and human lupus nephritis. SDG significant delays the onset of proteinuria with preservation in GFR and renal size in a dose-dependent fashion [56]. Purified SDG during early life of a young rat animal sensitize bone strength due to low endogenous levels of sex hormones but having no negative effects on bone strength and bone health, as measures of bone mass in adulthood [57, 58]. SDG in addition with low-dose estrogen therapy, provides the greatest protection against ovariectomy-induced bone loss [59]. However, SDG shows no effect on bone mineral density content, body composition, lipoproteins, glucose level and inflammation [44]. SDG have a beneficial role in chronic renal disease like reduces weight, renal inflammation and lipid peroxides in polycystic kidney disease [60].
Menopause, urinary composition and reproduction effect
The occurrence of menopause is associated with an increased risk of cardiovascular events and this has partially been attributed to the decline in circulating levels of estrogen. SDG supplementation produces a dose-related cessation or lengthening (by 18–39 %) of estrous cycles, reduces immature ovarian relative weight and delays puberty in experimental animals [61, 62]. The daily consumption of a low-fat muffin enriched with SDG (500 mg/day) for 6 week had no effect on endothelial functioning in healthy postmenopausal women [63]. Dietary flaxseed SDG (600 mg/day) can appreciably improve lower urinary tract symptoms in benign prostatic hyperplasia subjects [64]. Urinary composition or blood levels of radioactive lignans were not affected by the duration of SDG exposure while chronic SDG exposure alters lignan disposition in rats, however; it does not change the metabolite profile [65]. There were no significant effects of exposing male or female offspring to SDG during suckling on any measured reproductive indices [66]. SDG affects the reproductive development of offspring with caution when consuming flaxseed during pregnancy and lactation [67].
Mental stress and immunity effect
Flax lignan SDG may be associated with the least increase in peripheral resistance as result the greatest reduction in plasma cortisol and the smallest increase in plasma fibrinogen measured during mental stress [68, 69]. SDG has long acting hypotensive effect mediated through the guanylate cyclase enzyme. SDG supplementation shows no significant effects on lymphocyte proliferation indicating that SDG has no side effects on the immune system [70].
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Conclusions
The clinical and laboratory evidences indicate that flaxseed lignans particularly SDG have numerous biological properties that make them unique and very useful in promoting health and combating various diseases. Future biological and interventional studies need the confirmation of SDG as safe and effective for the prevention of lipid, protein and DNA oxidation associated with oxidative stress. The potential health benefits of SDG with supporting evidences from human and animal studies offers suggestions for future research.
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Acknowledgement
Authors thanks the Library Department, Government College University Faisalabad (GCUF) and IT Department, Higher Education Commission (HEC) for access to journals, books and valuable database.
Do pumpkin seeds have lignans?
What's New and Beneficial About Pumpkin seeds
Pumpkin seeds have long been valued as a source of the mineral zinc, and the World Health Organization recommends their consumption as a good way of obtaining this nutrient. If you want to maximize the amount of zinc that you will be getting from your pumpkin seeds, we recommend that you consider purchasing them in unshelled form. Although recent studies have shown there to be little zinc in the shell itself (the shell is also called the seed coat or husk), there is a very thin layer directly beneath the shell called the endosperm envelope, and it is often pressed up very tightly against the shell. Zinc is especially concentrated in this endosperm envelope. Because it can be tricky to separate the endosperm envelope from the shell, eating the entire pumpkin seed—shell and all—will ensure that all of the zinc-containing portions of the seed will be consumed. Whole roasted, unshelled pumpkin seeds contain about 10 milligrams of zinc per 3.5 ounces, and shelled roasted pumpkin seeds (which are often referred to pumpkin seed kernels) contain about 7-8 milligrams. So even though the difference is not huge, and even though the seed kernels remain a good source of zinc, you'll be able to increase your zinc intake if you consume the unshelled version.
While pumpkin seeds are not a highly rich source of vitamin E in the form of alpha-tocopherol, recent studies have shown that pumpkin seeds provide us with vitamin E in a wide diversity of forms. From any fixed amount of a vitamin, we are likely to get more health benefits when we are provided with that vitamin in all of its different forms. In the case of pumpkin seeds, vitamin E is found in all of the following forms: alpha-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocomonoenol, and gamma-tocomonoenol. These last two forms have only recently been discovered in pumpkin seeds, and their health benefits—including antioxidant benefits—are a topic of current interest in vitamin E research, since their bioavailability might be greater than some of the other vitamin E forms. The bottom line: pumpkin seeds' vitamin E content may bring us more health benefits that we would ordinarily expect due to the diverse forms of vitamin E found in this food.
In our Tips for Preparing section, we recommend a roasting time for pumpkin seeds of no more than 15-20 minutes when roasting at home. This recommendation supported by a new study that pinpointed 20 minutes as a threshold time for changes in pumpkin seed fats. In this recent study, pumpkin seeds were roasted in a microwave oven for varying lengths of time, and limited changes in the pumpkin seeds fat were determined to occur under 20 minutes. However, when the seeds were roasted for longer than 20 minutes, a number of unwanted changes in fat structure were determined to occur more frequently.
Pumpkin Seeds, dried, shelled
0.25 cup
(32.25 grams)Calories: 180
GI: low
NutrientDRI/DV
manganese64%
phosphorus57%
copper48%
magnesium45%
zinc23%
protein20%
iron16%
Health Benefits
Antioxidant Support
While antioxidant nutrients are found in most WHFoods, it's the diversity of antioxidants in pumpkin seeds that makes them unique in their antioxidant support. Pumpkin seeds contain conventional antioxidant vitamins like vitamin E. However, not only do they contain vitamin E, but they contain it in a wide variety of forms. Alpha-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocomonoenol and gamma-tocomonoenol are all forms of vitamin E found in pumpkin seeds. These last two forms have only recently been discovered, and they are a topic of special interest in vitamin E research, since their bioavailability might be greater than some of the other vitamin E forms. Pumpkin seeds also contain conventional mineral antioxidants like zinc and manganese. Phenolic antioxidants are found in pumpkin seeds in a wide variety of forms, including the phenolic acids hydroxybenzoic, caffeic, coumaric, ferulic, sinapic, protocatechuic, vanillic, and syringic acid. Antioxidant phytonutrients like lignans are also found in pumpkin seeds, including the lignans pinoresinol, medioresinol, and lariciresinol.
Interestingly, this diverse mixture of antioxidants in pumpkin seeds may provide them with antioxidant-related properties that are not widely found in food. For example, the pro-oxidant enzyme lipoxygenase (LOX) is known to be inhibited by pumpkin seed extracts, but not due to the presence of any single family of antioxidant nutrients (for example, the phenolic acids described earlier). Instead, the unique diversity of antioxidants in pumpkin seeds is most likely responsible for this effect.
Mineral Support
Plants that have a close relationship to the soil are often special sources of mineral nutrients, and pumpkin (and their seeds) are no exception. Our food rating process found pumpkin seeds to be a very good source of the minerals phosphorus, magnesium, manganese, and copper and a good source of the minerals zinc and iron.
Pumpkin seeds have long been valued as a special source of the mineral zinc, and the World Health Organization recommends their consumption as a good way of obtaining this nutrient. To get full zinc benefits from your pumpkin seeds, you may want to consume them in unshelled form. Although recent studies have shown there to be little zinc in the shell itself (the shell is also called the seed coat or husk), there is a very thin layer directly beneath the shell called the endosperm envelope, and it is often pressed up very tightly against the seed coat. Zinc is especially concentrated in this endosperm envelope. Because it can be tricky to separate the endosperm envelope from the shell, eating the entire pumpkin seed—shell and all—will ensure that all zinc-containing portions of the seed get consumed. Whole roasted, unshelled pumpkin seeds contain about 10 milligrams of zinc per 3.5 ounces, and shelled roasted pumpkin seeds (sometimes called pumpkin seed kernels) contain about 7-8 milligrams. So even though the difference is not huge, and even though the kernels still remain a good source of zinc, the unshelled version of this food is going to provide you with the best mineral support with respect to zinc.
Other Health Benefits
Diabetes
Most of the evidence we've seen about pumpkin seeds and prevention or treatment of diabetes has come from animal studies. For this reason, we consider research in this area to be preliminary. However, recent studies on laboratory animals have shown the ability of ground pumpkin seeds, pumpkin seed extracts, and pumpkin seed oil to improve insulin regulation in diabetic animals and to prevent some unwanted consequences of diabetes on kidney function. Decrease in oxidative stress has played a key role in many studies that show benefits of pumpkin seeds for diabetic animals.
Antimicrobial Benefits
Pumpkin seeds, pumpkin seed extracts, and pumpkin seed oil have long been valued for their anti-microbial benefits, including their anti-fungal and anti-viral properties. Research points to the role of unique proteins in pumpkin seeds as the source of many antimicrobial benefits. The lignans in pumpkin seeds (including pinoresinol, medioresinol, and lariciresinol) have also been shown to have antimicrobial—and especially anti-viral— properties. Impact of pumpkin seed proteins and pumpkin seed phytonutrients like lignans on the activity of a messaging molecule called interferon gamma (IFN-gamma) is likely to be involved in the antimicrobial benefits associated with this food.
Cancer-Related Benefits
Because oxidative stress is known to play a role in the development of some cancers, and pumpkin seeds are unique in their composition of antioxidant nutrients, it's not surprising to find some preliminary evidence of decreased cancer risk in association with pumpkin seed intake. However, the antioxidant content of pumpkin seeds has not been the focus of preliminary research in this cancer area. Instead, the research has focused on lignans. Only breast cancer and prostate cancer seem to have received much attention in the research world in connection with pumpkin seed intake, and much of that attention has been limited to the lignan content of pumpkin seeds. To some extent, this same focus on lignans has occurred in research on prostate cancer as well. For these reasons, we cannot describe the cancer-related benefits of pumpkin seeds as being well-documented in the research, even though pumpkin seeds may eventually be shown to have important health benefits in this area.
Possible Benefits for Benign Prostatic Hyperplasia (BPH)
Pumpkin seed extracts and oils have long been used in treatment of Benign Prostatic Hyperplasia (BPH). BPH is a health problem involving non-cancer enlargement of the prostate gland, and it commonly affects middle-aged and older men in the U.S. Studies have linked different nutrients in pumpkin seeds to their beneficial effects on BPH, including their phytosterols, lignans, and zinc. Among these groups, research on phytosterols is the strongest, and it centers on three phytosterols found in pumpkin seeds: beta-sitosterol, sitostanol, and avenasterol. The phytosterols campesterol, stigmasterol, and campestanol have also been found in pumpkin seeds in some studies. Unfortunately, studies on BPH have typically involved extracts or oils rather than pumpkin seeds themselves. For this reason, it's just not possible to tell whether everyday intake of pumpkin seeds in food form has a beneficial impact on BPH. Equally impossible to determine is whether intake of pumpkin seeds in food form can lower a man's risk of BPH. We look forward to future studies that will hopefully provide us with answers to those questions.
Description
Pumpkin seeds—also known as pepitas—are flat, dark green seeds. Some are encased in a yellow-white husk (often called the "shell"), although some varieties of pumpkins produce seeds without shells. Pumpkin seeds have a malleable, chewy texture and a subtly sweet, nutty flavor. While roasted pumpkins seeds are probably best known for their role as a perennial Halloween treat, these seeds are so delicious, and nutritious, that they can be enjoyed throughout the year. In many food markets, pepitas are available in all of the forms described above—raw and shelled, raw and unshelled, roasted and shelled, roasted and unshelled.
Like cantaloupe, watermelon, cucumber, and squash, pumpkins and pumpkin seeds belong to the gourd or Cucurbitaceae family. Within this family, the genus Cucurbita contains all of the pumpkins (and their seeds). The most common species of pumpkin used as a source of pumpkin seeds are Cucurbita pepo, Cucurbita maxima, Cucurbita moschata, and Cucurbita mixta.
History
Pumpkins, and their seeds, are native to the Americas, and indigenous species are found across North America, South America, and Central America. The word "pepita" is consistent with this heritage, since it comes from Mexico, where the Spanish phrase "pepita de calabaza" means "little seed of squash."
Pumpkin seeds were a celebrated food among many Native American tribes, who treasured them both for their dietary and medicinal properties. In South America, the popularity of pumpkin seeds has been traced at least as far back as the Aztec cultures of 1300-1500 AD. From the Americas, the popularity of pumpkin seeds spread to the rest of the globe through trade and exploration over many centuries. In parts of Eastern Europe and the Mediterranean (especially Greece), pumpkin seeds became a standard part of everyday cuisine, and culinary and medical traditions in India and other parts of Asia also incorporated this food into a place of importance.
Today, China produces more pumpkins and pumpkin seeds than any other country. India, Russia, the Ukraine, Mexico, and the U.S. are also major producers of pumpkin and pumpkin seeds. In the U.S., Illinois is the largest producer of pumpkins, followed by California, Ohio, Pennsylvania, Michigan, and New York. However, pumpkins are now grown commercially in virtually all U.S. states, and over 100,000 acres of U.S. farmland are planted with pumpkins.
How to Select and Store
Pumpkin seeds are generally available in prepackaged containers as well as bulk bins. Just as with any other food that you may purchase in the bulk section, make sure that the bins containing the pumpkin seeds are covered and that the store has a good product turnover so as to ensure the seeds' maximal freshness. Whether purchasing pumpkin seeds in bulk or in a packaged container, make sure that there is no evidence of moisture or insect damage and that they are not shriveled. If it is possible to smell the pumpkin seeds, do so in order to ensure that they are not rancid or musty.
We recommend that you purchase certified organic raw pumpkin seeds and then light-roast them yourself (see next section on how to do so). By purchasing organic, you will avoid unnecessary exposure to potential contaminants. By purchasing raw, you will be able to control the roasting time and temperature, and avoid unnecessary damage to helpful fats present in the seeds. At the same time, you will be able to bring out the full flavors of the pumpkin seeds through roasting.
Pumpkin seeds should be stored in an airtight container in the refrigerator. While they may stay edible for several months, they seem to lose their peak freshness after about one to two months.
How to Enjoy
A Few Quick Serving Ideas
Add pumpkin seeds to healthy sautéed vegetables.
Sprinkle pumpkin seeds on top of mixed green salads.
Grind pumpkin seeds with fresh garlic, parsley and cilantro leaves. Mix with olive oil and lemon juice for a tasty salad dressing.
Add chopped pumpkin seeds to your favorite hot or cold cereal.
Add pumpkin seeds to your oatmeal raisin cookie or granola recipe.
Next time you make burgers, whether it be from vegetables, turkey or beef, add some ground pumpkin seeds.
For some of our favorite recipes, click Recipes.
Safety
Nutritional Profile
Introduction to Food Rating System Chart
The following chart shows the nutrients for which this food is either an excellent, very good or good source. Next to the nutrient name you will find the following information: the amount of the nutrient that is included in the noted serving of this food; the %Daily Value (DV) that that amount represents (similar to other information presented in the website, this DV is calculated for 25-50 year old healthy woman); the nutrient density rating; and, the food's World's Healthiest Foods Rating. Underneath the chart is a table that summarizes how the ratings were devised. Read detailed information on our Food and Recipe Rating System.
Are lignans polyphenols?
Lignans
Lignans are phenolic dimers possessing a 2,3-dibenzylbutane structure. Such compounds are known to exist as minor constituents of many plants, where they form the building blocks for the formation of lignin in the plant cell wall. The compounds occur mainly in the glycosidic form. In rye, lignans are predominantly present in the bran fraction (Table 2). The glycosides are converted by fermentation in the proximal colon to mammalian lignans. The two major mammalian lignans, enterodiol and enterolactone, are the products of colonic bacterial metabolism of the plant lignans secoisolariciresinol and matairesinol.
Table 2. Lignan content of whole grains and brana
Secoisolariciresinol (μg per 100 g dry weight) Matairesinol (μg per 100 g dry weight)
Wheat bran (whole grain) 33 3
Wheat bran 110 0
Rye meal 47 65
Rye bran 132 167
Oat meal 13 0
Oat bran 24 155
Barley (whole grain) 58 0
Barley bran 63 0
a
Adapted from Mazur and Adlercreutz. Pure and Applied Chemistry 70: 1759–1776.
Gut Microbial Metabolism of Plant Lignans
Seth C. Yoder, ... Johanna W. Lampe, in Diet-Microbe Interactions in the Gut, 2015
Lignans are fiber-associated compounds found in many plant families and common foods, including grains, nuts, seeds, vegetables, and drinks such as tea, coffee or wine. The highest concentrations of dietary lignans are found in flaxseed as secoisolariciresinol diglucoside. Other dietary lignans include sesamin, matairesinol, pinoresinol and lariciresinol. Plant lignans can be converted by a consortium of intestinal bacteria to enterolignans, enterodiol and enterolactone. Enterolignans have a variety of biologic activities, including tissue-specific estrogen receptor activation, and anti-inflammatory and apoptotic effects, that may influence disease risk in humans. Differences in bioavailability of various plant lignans from foods, and variation in enterolignan production among gut microbial communities contribute to large interindividual variation in enterolignan exposure. Consequently, studying associations between lignan exposure and health and disease in humans is challenging. Current evidence suggests a diet rich in lignans may be beneficial, but further research is needed to characterize the specific role of lignans.
Metabolism of Dietary Polyphenols by Human Gut Microbiota and Their Health Benefits
Surajit Pathak, ... Francesco Marotta, in Polyphenols: Mechanisms of Action in Human Health and Disease (Second Edition), 2018
4.3 The Microbial Metabolism of Lignans
Lignans are ubiquitous in the human diet and their most important dietary sources are whole-grain cereals and legumes. They can also be found in various fruits and vegetables [63], the highest concentration being found in flaxseed. Most common lignans consumed with the diet are secoisolariciresinol, matairesinol, lariciresinol, and pinoresinol [64]. They are metabolized into the mammalian lignans enterodiol and enterolactone by human gut microbiota [65]. Due to their estrogen agonist and antagonist properties, lignans are recognized as phytoestrogens [63,66].
Alternative Therapies to Hormone Replacement Therapy
MICHELLE P. WARREN, RUSSALIND H. RAMOS, in Menopause, 2000
1. DIETARY SOURCES AND METABOLISM
Lignans are compounds possessing a 2,3-dibenzylbutane structure and exist as minor constituents of many plants, where they form the building blocks for the formation of lignin (as distinguished from lignan) found in the plant cell wall. They are constituents of higher plants (gymnosperms and angiosperms), such as whole grains, legumes, vegetables, and seeds, with exceptionally high concentrations of lignans found in flax seed [11] (Table II).
TABLE II. Food Sources of Lignansa
Study food Total lignans Enterodiol Enterolactone
Thompson et al. [26a]
Flax seed meal 675.4 85.2 590.2
Flax seed flour 526.8 118.2 408.6
Cereals
Triticale 9.2 5.2 4.0
Wheat 4.9 4.1 0.8
Oats 3.4 2.5 0.9
Brown rice 3.0 1.7 1.3
Corn 2.3 2.0 0.3
Rye 1.6 0.7 0.9
Barley 1.1 0.4 0.7
Cereal brans
Oat bran 6.5 2.6 3.9
Wheat bran 5.7 2.7 3.0
Rice bran 1.8 1.3 0.5
Oilseeds
Soy bean 8.6 6.9 1.7
Sunflower seeds 4.0 2.0 2.0
Peanuts 1.6 1.0 0.6
Legumes, dried whole
Lentil 17.9 7.9 10.0
Kidney 5.6 3.3 2.3
Navy bean 4.6 3.5 1.1
Pinto bean 2.0 1.5 0.5
Vegetables
Garlic 4.1 0.8 3.3
Asparagus 3.7 1.4 2.4
Carrot 3.5 2.8 0.6
Sweet potato 3.0 2.4 0.6
Broccoli 2.3 1.6 0.7
Mushroom 0.6 0.4 0.1
Celery 0.3 0.2 0.1
Cucumber 0.3 0.2 0.1
Tomato 0.2 0.1 0.1
Fruits
Pear 1.8 1.1 0.7
Plum 1.5 0.5 1.0
Strawberry 0.8 0.4 0.4
Banana 0.7 0.6 0.1
Orange 0.4 0.3 0.1
Canteloupe 0.4 0.2 0.2
Apple 0.3 0.3 0.0
a
Values are expressed as mammalian lignan production by fecal flora (micrograms) from foods (per gram). From Ref. [11], D. Tham, C. Gardner, and W. Haskell. Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. The Journal af Clinical Endocrinology and Metabolism 83(7), 2223–2235, 1998. © The Endocrine Society.
The chemical structure of plant lignans differs somewhat from that of mammalian lignans (Fig. 2). Most of the structural changes occur in the colon, liver, and small intestine during enterohepatic circulation. Mammalian lignans differ in structure from plant lignans in that they have phenolic hydroxyl groups in the meta position only in their aromatic rings. Once in the colon, they are absorbed and then are conjugated with glucuronic acid or sulfate in the liver, reexcreted through the bile duct, deconjugated by the bacteria, and reabsorbed. Some reach the kidney and are excreted in the urine [15]. Lignans are excreted in the urine as conjugated glucuronides and in feces in the unconjugated form [11].
Postmenopausal Hormones: Helpful Or Harmful?
The major mammalian lignans are known by the common names enterolactone and enterodiol, which are the products of colonic bacterial metabolism of the plant lignans matairesinol and secoisolariciresinol, respectively [27]. The higher the dietary intake of precursors, the higher the mammalian lignan production in the colon and the higher the excretion rate in the urine. Clinical trials performed by Kirkman et al. [28] demonstrated that the excretion of the lignans, enterodiol and enterolactone, was higher during a carotenoid (carrot and spinach) and cruciferous (broccoli and cauliflower) vegetable diet than during a vegetable-free diet, suggesting that these vegetables may provide a source of mammalian lignan precursors. Because dietary metabolism of lignans as well as isoflavones is determined predominantly by the gastrointestinal flora, antibiotic use or bowel disease and gender will modify metabolism [11].
Colorectal Cancer Prevention by Wheat Consumption
Gabriel Wcislo, Katarzyna Szarlej-Wcislo, in Wheat and Rice in Disease Prevention and Health, 2014
Lignans
Lignans are chemical compounds, defined as phytoestrogens, found in plants. Plant lignans are polyphenols derived from phenylanaline (pinoresinol, lericiresinol, secoisolariciresinol, syringaresinol, or sesamin), and can be metabolized by intestinal bacteria to form mammalian lignans such as enerodiol and enterolactone. Lignans act as antioxidants and can bind to estrogen receptors in the breast tissue. The crucial role in the synthesis of mammalian lignins via the phenylpropanoid pathway is played by pinoresinol lariciresinol reductase.104,105 Lignans (entroldiol and enterolactone) are involved in cytostatic activity against colon cancer cell lines. In spite of the lack of cytotoxicity, measured by proliferation capacity, DNA flow cytometry analysis revealed cell cycle arrest at the S phase with a readily seen decrease of cyclin A detected by Western blotting.106
Antioxidant Properties of Wheat Bran against Oxidative Stress
Masashi Higuchi, in Wheat and Rice in Disease Prevention and Health, 2014
Lignan
Lignans are a group of diphenolic compounds that are concentrated in the bran layer of cereal grain. The major lignan in wheat bran is secoisolariciresinol diglucoside,117 which when consumed is converted by intestinal microflora to two lignan metabolites: enterodiol and enterolactone (Fig. 15.9). Lignan metabolites function as antioxidants and free radical scavengers, leading to decreased risk of cancer development.118 A previous study has also found that enterolactone functions as an antioxidant against human LDL oxidation.119 In addition, it has been shown to be capable of preventing colon cancer cell growth by inducing the phase 2 detoxification enzyme, NADPH : quinone reductase, in vitro. Lignans in wheat bran have been shown to have antitumor properties in mice and human cells that may be mediated by cytostatic and apoptotic mechanisms.117 In addition, wheat bran inhibits the development of intestinal neoplasia, although the degree of inhibition differs significantly among the various wheat cultivars.120 Further study is needed to verify the safety profile and effects of lignan.
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FIGURE 15.9. Structures of lignans.
Extraction Techniques and Applications: Food and Beverage
M. Herrero, ... E. Ibáñez, in Comprehensive Sampling and Sample Preparation, 2012
4.08.2.10 Lignans
Lignans are phytoestrogens with estrogenic or antiestrogenic activity, comprising 2-phenylpropane units (Figure 1). Dietary lignan compounds are mainly found in linseed,36 which perhaps is the richest source. Other food sources that are also a good source of dietary fiber, protein, antioxidants, and other nutritional elements are oilseeds and nuts (sesame, sunflower, cashew, etc.), vegetables (such as curly kale, broccoli, and garlic), fruits (apricot, strawberry, and peach), olive oil, and beverages such as wine, beer, tea, and coffee, but only in small amounts.37
Lignans comprise a variety of compounds, both in food sources (secoisolariciresinol, matairesinol) and the human body (enterodiol, enterolactone). Some studies reported that the health effect of the lignans varied depending on the particular lignan type.
Engineering the biosynthesis of low molecular weight metabolites for quality traits (essential nutrients, health-promoting phytochemicals, volatiles, and aroma compounds)
Fumihiko Sato, Kenji Matsui, in Plant Biotechnology and Agriculture, 2012
Sesamins
Lignans are a large class of secondary metabolites in plants that have numerous biological effects in mammals, including antitumor and antioxidant activities. Some plant lignans, such as sesamin, can be converted by intestinal microbiota to the mammalian lignans (i.e., enterodiol and enterolactone), which may have protective effects against hormone-related diseases such as breast cancer (Liu et al., 2006). Sesamin, the most abundant lignan in sesame seeds (Sesamum plants), is produced by the cytochrome P450 enzyme CYP81Q1 from the precursor lignan pinoresinol. Recently, the CYP81Q1 gene was isolated (Ono et al., 2006), and some attempts have been made to increase the sesamin content in plants. When a model plant, Forsythia, was transformed with pinoresinol/lariciresinol reductase RNAi construct to inhibit the conversion of pinoresinol to matairesinol and further co-transformed with CYP81Q1 over-expression construct, transgenic cells produced sesamin and accumulated pinoresinol glucoside (Kim et al., 2009). These data suggested that the metabolic engineering of lignan production may be possible.
Other Plant Metabolites
D. Simpson, S. Amos, in Pharmacognosy, 2017
12.1.1 Lignans
Lignans are natural products that occur widely in the plant kingdom. They contain the same monomers as lignins (Fig. 12.1) but are dimeric instead of polymeric. They are characterized by a phenylpropanoid core. The International Union of Pure and Applied Chemistry (IUPAC) identifies lignans as dimeric C6C3 coupled motifs linked at carbons 8 and 8′ (Fig. 12.2) [4]. The IUPAC identifies compounds with the coupling of the two C6C3 units at positions different from C8–C8′ as neolignans (Fig. 12.2) [4].
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Figure 12.2. Lignan and neolignan core structures.
Lignans are biosynthesized via the phenylpropanoid pathway. Lignans are divided into several categories based on their molecular architecture. Categories of lignans include: arylnaphthalene, aryltetralin, dibenzylbutane, dibenzylbutyrolactone, tetrahydrofuran, and furofuran (Fig. 12.3).
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Figure 12.3. Structural categories of lignans.
Lignans have been attributed with a range of biological activities including anticancer, antioxidant, antihypertensive, antiviral, estrogenic, and insecticidal properties. Podophyllotoxin (Fig. 12.4) is the most prominent lignan due to the significant pharmacological activities of its derivatives. Semisynthetic derivatives of podophyllotoxin include the antineoplastic drugs etoposide and teniposide (Fig. 12.4). Etoposide is employed in the treatment of testicular and small cell lung cancers along with other tumors. Teniposide is approved for the treatment of acute lymphoblastic leukemia. The dietary lignans matairesinol and secoisolariciresinol (Fig. 12.4) are converted by intestinal flora to enterolactone and enterodiol (Fig. 12.4) [5]. Enterolactone and enterodiol possess estrogenic activity and have been attributed with lowered incidences of breast cancer mortality in patients with diets rich in matairesinol and secoisolariciresinol [6]. Several novel lignans have been reported in the recent literature, some of those will be discussed below.
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Figure 12.4. Examples of prominent lignans.
Female Reproduction
Radwa Barakat, ... CheMyong Ko, in Encyclopedia of Reproduction (Second Edition), 2018
Lignans
Lignans are a class of phytoestrogens that contain enterolactone and enterodiol. Enterolactone and enterodiol are formed by bacteria in the intestinal tract from the plant lignans matairesinol and secoisolariciresinol, which exist in various whole-grain cereals (barley, rye, and wheat), seeds, nuts, legumes, and vegetables. They are found mainly in fiber-rich food products such as cereals, vegetables, and fruits. The richest known dietary sources of enterolactone precursors are flaxseed and sesame seed. These lignans exert weak inhibitory actions on aromatase. Enterolactone levels are lower in breast cancer patients than in healthy controls, indicating its potential anticarcinogenic activity.
Are lentils lignans?
What are lignans?
Lignans are phytonutrients found in a wide variety of foods such as, flaxseed, whole grains, beans, legumes, fruits and vegetables. They are actually the components in these plants that develop into the hard outer tissue, known as lignin tissue. Our intestines convert lignan-rich foods into beneficial hormone-like compounds, phytoestrogens. (Although this conversion is blocked if you take antibiotics or have a high fat diet.) Flaxseed contains 75-800 times more lignans than any other plant.
Lignans are concentrated in the following foods:
Flaxseeds*, peanuts and caraway seeds; broccoli, garlic, carrots, lentils, soybeans and kidney beans; cranberry, strawberry, raspberry, banana, guava and cantaloupe; barley, rye and oats.
*Important to note that most flaxseed lignans are removed during the processing of seeds to oil, so they are generally not found in any great degree in flaxseed oil.
The most important lignan in flaxseed is secoisolariciresinol diglycoside, but we shall refer to it by its much simpler form, SDG. When eaten SDG in flaxseed is converted by bacteria in the colon to the mammalian lignans-enterolactone and enterodiol. This conversion is crucial as it is only in this form that lignans have beneficial effects for human health.
Benefits of lignans
Lignans have many biological properties, the most significant being that they are phytoestrogens, have potent antioxidant properties and are believed to be chemoprotective. This means they have beneficial roles to play in a variety of health issues ranging from a whole host of menopausal symptoms; breast disease; osteoporosis, and prostate enlargement, to heart disease, acne and hypercholesterolemia.
Women’s health
Because lignans are high in plant oestrogens, they have a plethora of positive roles to play in women’s health issues. Oestrogen levels are typically high in women during the childbearing years and then fall away through the peri-menopausal and post-menopausal years. While lignans have an oestrogen-like action, they are considerably weaker that our endogenous oestrogen, and act as hormone balancers. An important feature of these plant hormones is that they do not stimulate reproductive tissue. In conditions which are linked with excess oestrogen (such as PMS, unhealthy breast tissue and breast cancer) lignans compete with a woman’s own oestrogen, having an oestrogenic- lowering effect. Studies have shown that urinary excretion of mammalian lignans is frequently lower in breast cancer patients than in normal healthy postmenopausal women, suggesting that lignans may have a protective effect against breast cancer. In a randomized, double-blinded placebo-controlled trial of 39 women with newly diagnosed breast cancer, patients received 25 gms flaxseed or placebo daily for just over a month before surgery. The patients who received flaxseed meal had decreased tumor cell proliferation rate similar to the effects seen with the breast cancer drug,Tamoxifen.
In conditions associated with declining oestrogen levels such as menopause, lignans have the opposite effect, increasing levels of oestrogen. This balancing action is due to their ability to competitively lock onto our body’s oestrogen receptor sites. Consequently, lignans are used to reduce symptoms of menopause, such as hot flushes, night sweats, mood swings and breast tenderness. Other conditions where lignans may be helpful due to their ostrogenic effect includes bone health, prostate conditions, hair loss and acne.
Bone health
Hormone deficiency is a well know risk factor for osteoporosis in postmenopausal women.Oestrogen plays an important role in maintaining bone density by regulating the formation and resorption of bone. As phytoestrogens lignans may be an additional natural alternative for women with poor bone density. Some clinical studies suggest that these plant compounds are somewhat effective in maintaining bone mineral density, sharing a similar chemical structure with endogenous ostrogen. However further research and longer term studies need to be carried out in this area.
Prostate health
In the body testosterone is converted to a more potent form called dihydrotestosterone (DHT). Although normal healthy prostate cells require DHT for growth, too much of it can cause abnormal growth, leading to an enlarged prostate or causing prostate cancer cells to divide. Researchers have found that concentrations of lignans are higher in the urine and prostatic fluid of populations that have a lower risk of prostate cancer. In a Danish study undertaken in 2001, patients with newly diagnosed prostate cancer who supplemented their diets with 30 g flaxseed from the time of diagnosis to time of surgery, saw a significant reduction in tumor proliferation index, free androgen index, total serum testosterone and total cholesterol, and an increase in tumor apoptosis index (tumor cell death). Lignans may therefore play a role in influencing the metabolism of testosterone and its metabolites. It is thought that lignans can block the action of the enzyme 5 alpha-reductase that converts testosterone into the more potent form of DHT.Lignans may also reduce the amount of testosterone available due to their ability to increase sex hormone binding globulin (SHBG). This protein binds circulating testosterone, making less testosterone available to stimulate prostate cell growth.
Cardiovascular health
In addition to being a phytoestrogen, SDG the plant lignan isolated in flaxseed, is also a strong antioxidant. (Antioxidants are associated with a reduced risk of atherosclerosis).The antioxidant SDG is also metabolized to secoisolariciresinol (SECO), enterodiol(ED) and enterolactone (EL). These metabolites have three times more antioxidant potency than their precursor SDG and up to five times more potency than vitamin E. Furthermore, studies have repeatedly shown that the fibre and fatty acids found in flaxseeds (not to mention the lignans), when taken daily can reduce both total and LDL(low density lipoprotein) cholesterol levels significantly. The flax lignan can furthermore, additionally reduce cholesterol deposits and plaque on artery walls by as much as 73 per cent.
Acne
Hormone-generated acne may benefit from a diet rich in lignans. (While the cause of acne is not totally understood, hormones, bacteria, heredity and stress are all thought to be contributing factors). During puberty, the production of adrenal androgens is increased in both males and females. This elevation of androgens can cause a corresponding increase in sebum production, especially in the face, chest and back. Excess sebum leads to acne. Since androgens (testosterone) play a major role in acne, lignans may have a positive role to play in its treatment. Lignans have been shown to inhibit 5 alpha-reductase, (the enzyme involved in the conversion of testosterone to DHT), and inhibition of this enzyme is often successful in the treatment of androgen-dependant disorders.
Hair loss
One of the most common forms of hair loss or alopecia is androgenetic alopecia. (AGA).It is believed that an individual’s level of androgens -testosterone and its metabolites-is one factor in AGA. As we have seen in our discussion of prostate health, lignans have also been shown to be effective in inhibiting 5 alpha-reductase and other enzymes involved in the metabolism of testosterone. Therefore lignans clearly have a role to play in the treatment of hormone dependant hair loss.
Recommended therapeutic dose
Although there are not yet any set guidelines for lignan intake, a sensible amount would be to aim for be approximately 50 -150mg per day.*
This translates to one tablespoon of flaxseed meal daily (each rounded tablespoon equals 10 grams linseed meal which provides approx 50-150 mg of lignans), plus a diet rich in whole grains particularly barley and rye, legumes- think soybeans, vegetables-emphasize broccoli and carrots, and fruits, particularly strawberries and cranberries. Now that’s no hardship! We are fortunate to have a wide and delicious array of naturally occurring lignans available to us all year round. The plant kingdom never lets us down.
*It is important to note however that very few studies have been conducted examing the effect of lignans in pregnant and breastfeeding women, as well as in young children or women being treated for breast, uterine or ovarian cancer. Therefore until further definitive studies are conducted, lignans cannot be recommended for these groups.
Lignan-rich muesli
The grains are best left to soak overnight but even a half hour soak will still provide delicious results
1 cup rolled rye flakes
½ cup barley flakes
½ cup rolled oats
1 cup linseed meal
1 ½ cups water
2 cups raspberries, blueberries and strawberries
1 tablespoon toasted sesame seeds
Tahini to taste
Soak rye, oats and barley in the water overnight. Add the linseed meal and sesame seeds. Mix raspberries, blueberries and strawberries together. Add to the oats and barley. Drizzle with tahini and serve with soy yoghurt or soy milk.
What is the benefit of high lignan flax oil?
Flaxseed is emerging as an important functional food ingredient because of its rich contents of α-linolenic acid (ALA, omega-3 fatty acid), lignans, and fiber. Flaxseed oil, fibers and flax lignans have potential health benefits such as in reduction of cardiovascular disease, atherosclerosis, diabetes, cancer, arthritis, osteoporosis, autoimmune and neurological disorders. Flax protein helps in the prevention and treatment of heart disease and in supporting the immune system. As a functional food ingredient, flax or flaxseed oil has been incorporated into baked foods, juices, milk and dairy products, muffins, dry pasta products, macaroni and meat products. The present review focuses on the evidences of the potential health benefits of flaxseed through human and animals’ recent studies and commercial use in various food products.
Keywords: Flaxseed, α-linolenic acid, Lignans, Health benefits, Bakery products
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Introduction
Flaxseed is one of the oldest crops, having been cultivated since the beginning of civilization (Laux 2011). The Latin name of the flaxseed is Linum usitatissimum, which means “very useful”. Flax was first introduced in United States by colonists, primarily to produce fiber for clothing (Laux 2011). Every part of the flaxseed plant is utilized commercially, either directly or after processing. The stem yields good quality fibers having high strength and durability (Singh et al. 2011). Flax has been used until 1990s principally for the fabrication of cloths (linen) and papers, while flaxseed oil and its sub-products are used in animal feed formulation (Singh et al. 2011). There is a small difference in using the terms flaxseed and linseed. Flaxseed is used to describe flax when consumed as food by humans while linseed is used to describe flax when it is used in the industry and feed purpose (Morris 2008). In the last two decades, flaxseed has been the focus of increased interest in the field of diet and disease research due to the potential health benefits associated with some of its biologically active components. Flaxseeds have nutritional characteristics and are rich source of ω-3 fatty acid: α-linolenic acid (ALA), short chain polyunsaturated fatty acids (PUFA), soluble and insoluble fibers, phytoestrogenic lignans (secoisolariciresinol diglycoside-SDG), proteins and an array of antioxidants (Ivanova et al. 2011; Singh et al. 2011; Oomah 2001; Alhassane and Xu 2010). Its growing popularity is due to health imparting benefits in reducing cardiovascular diseases, decreased risk of cancer, particularly of the mammary and prostate gland, anti-inflammatory activity, laxative effect, and alleviation of menopausal symptoms and osteoporosis. This review is an attempt to cover the history of flax and flaxseed oil, its journey from being a medicine to a functional food source and its health benefits.
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Functional elements of flaxseed
Flaxseed is one of the richest plant sources of the ω-3 fatty acid i.e. α-linolenic acid (ALA) (Gebauer et al. 2006; Tonon et al. 2011) and lignans (phytoestrogens) (Singh et al. 2011). The important flaxseed growing countries are Canada, China, United States, India and Ethiopia. Canada is the world’s largest producer with a production of 0.42 million tonnes in 2010 (FAO 2012) and accounts for nearly 80 % of the global trade in flaxseed (Oomah and Mazza 1998). India ranks 4rth with 0.15 million tonnes of total flaxseed production (FAO 2012). Total average world production of linseed during the last decade and in last 5 years by top 5 producer countries (2005–2010) is shown in Figs. 1 and and2,2, respectively.
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Fig. 1
Average production of linseed/flaxseed in the world (2000–2010)
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Fig. 2
Linseed/flaxseed production by top 5 producer countries (2005–2010)
Flaxseeds are available in two basic varieties: (1) brown; and (2) yellow or golden. Both have similar nutritional characteristics and equal numbers of short-chain ω-3 fatty acids. The exception is a type of yellow flax called solin (trade name Linola), which has a completely different oil profile and is very low in ω-3 fatty acids (Dribnenki et al. 2007). Brown flax is better known as an ingredient in paints, varnish, fiber and cattle feed (Drouillard et al. 2000; Kozlowska et al. 2008; Singh et al. 2011; Faintuch et al. 2011). Various edible forms of flax are available in the food market—whole flaxseeds, milled flax, roasted flax and flax oil. According to its physico-chemical composition, flaxseed is a multicomponent system with bio-active plant substances such as oil, protein, dietary fiber, soluble polysaccharides, lignans, phenolic compounds, vitamins (A, C, F and E) and mineral (P, Mg, K, Na, Fe, Cu, Mn and Zn) (Bhatty 1995; Jheimbach and Port Royal 2009). The flaxseed composition is given in Table 1.
Table 1
Chemical composition of nutrient and phytochemicals in flaxseed
Nutrients/bioactive compounds Quantity/100 g of seed Nutrients/bioactive compounds Quantity/100 g of seed
Carbohydratesa 29.0 g Biotin 6 mg
Protein 20.0 g α-Tocopherolb 7 mg
Total fats 41.0 g δ-Tocopherolb 10 mg
Linolenic acid 23.0 g γ-Tocopherolb 552 mg
Dietary fiber 28.0 g Calcium 236 mg
Lignans 10–2,600 mg Copper 1 mg
Ascorbic acid 0.50 mg Magnesium 431 mg
Thiamin 0.53 mg Manganese 3 mg
Riboflavin 0.23 mg Phosphorus 622 mg
Niacin 3.21 mg Potassium 831 mg
Pyridoxin 0.61 mg Sodium 27 mg
Pantothenic acid 0.57 mg Zinc 4 mg
Folic acid 112 mg
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Source: Flax council of Canada (2007)
Values are adapted from http://www.flaxcouncil.ca/spanish/pdf/FlxPrmr-R11-Ch1_Span.pdf
aValues include dietary fiber
bValues in mg/kg of flaxseed lipids
Flaxseed oil/lipids
Flaxseed is the richest plant source of the ω-3 fatty acid i.e. α-linolenic acid (ALA) (Gebauer et al. 2006). Flaxseed oil is low in saturated fatty acids (9 %), moderate in monosaturated fatty acids (18 %), and rich in polyunsaturated fatty acid (73 %) (Cunnane et al. 1993). Of all lipids in flaxseed oil, α- linolenic acid is the major fatty acid ranging from 39.00 to 60.42 % followed by oleic, linoleic, palmitic and stearic acids (Table 2), which provides an excellent ω-6:ω-3 fatty acid ratio of approximately 0.3:1 (Pellizzon et al. 2007). Although flaxseed oil is naturally high in anti-oxidant like tocopherols and beta-carotene, traditional flaxseed oil gets easily oxidized after being extracted and purified (Holstun and Zetocha 1994). The bioavailability of ALA is dependent on the type of flax ingested (ALA has greater bioavailability in oil than in milled seed, and has greater bioavailability in oil and milled seed than in whole seed) (Austria et al. 2008).
Table 2
Major fatty acids profile in flaxseed oil
Fatty acids Percentage (%) (Range)
Palmitic acid (C16:0) 4.90–8.00
Stearic acid (C18:0) 2.24–4.59
Oleic acid (C18:1) 13.44–19.39
Linoleic acid (C18:2) (ω-6) 12.25–17.44
α-Linolenic acid (C18:3) (ω-3) 39.90–60.42
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Sources: Choo et al. (2007); Bozan and Temelli (2008); Pradhan et al. (2010); Pu et al. (2010); Condori et al. (2011); Long et al. (2011); Zhang et al. (2011); Anwar et al. (2013); Guimaraes et al. (2013); Khattab and Zeitoun (2013)
Proteins
The protein content of flaxseed varies from 20 to 30 %, constituting approximately 80 % globulins (linin and conlinin) and 20 % glutelin (Hall et al. 2006). Flaxseed has an amino acid profile comparable to that of soybean and contains no gluten (Hongzhi et al. 2004; Oomah 2001). Although flax protein is not considered to be a complete protein due to the presence of limiting amino acid- lysine (Chung et al. 2005). It also contains peptides with bioactivities related to the decrease in risk factors of CVD (Udenigwe and Aluko 2010). Whole flaxseed, flaxseed meals and isolated proteins are rich sources of glutamic acid/glutamine, arginine (Oomah and Mazza 1993), branched-chain amino acids (valine and leucine) and aromatic amino acid (tyrosine and phenylalanine). The total nitrogen content in flaxseed is 3.25 g/100 g of seed (Gopalan et al. 2007).
Dietary fibers
Flax fibers are amongst the oldest fiber crops in the world. The use of flax for the production of linen goes back at least to ancient Egyptian times. Flax fiber is extracted from the skin of the stem of the plant. Total flax plant is approximately 25 % seed and 75 % stem and leaves (Lay and Dybing 1989). The stem or non-seed parts are about 20 % fiber, which can be extracted by chemical or mechanical retting. A flax fiber is a natural and biodegradable composite, which exhibits good mechanical properties and low density (Singh et al. 2011). Flax fiber is soft, lustrous and flexible; bundles of fiber have the appearance of blonde hair, hence the description “flaxen”. It is stronger than cotton fiber but less elastic (Singh et al. 2011). Flax fiber is also a raw material for the high-quality paper industry for the use of printed banknotes and rolling paper for cigarettes and tea bags (Carter 1993).
Flax fibers include both soluble and insoluble dietary fibers. The proportion of soluble to insoluble fiber varies between 20:80 and 40:60 (Morris 2003; Mazza and Oomah 1995). The major insoluble fiber fraction consists of cellulose and lignin, and the soluble fiber fractions are the mucilage gums (Vaisey-Genser and Morris 2003; Mazza and Biliaderis 1989). The mucilage can be extracted by water and has good foam-stabilizing properties (Mazza and Biliaderis 1989). Mucilage gums are polysaccharides that become viscous when mixed with water or other fluids and have an important role in laxatives (Singh et al. 2011). The optimal pH range for viscosity of flaxseed mucilage is 6–8, the pH environment in human intestines. Only 10 g of flaxseed in the daily diet increases the daily fiber intake by 1 g of soluble fiber and by 3 g of insoluble fiber. Insoluble fiber helps improve laxation and prevent constipation, mainly by increasing fecal bulk and reducing bowel transit time (Greenwald et al. 2001). On the other hand, water-soluble fiber helps in maintaining blood glucose levels and lowering the blood cholesterol levels (Kristensen et al. 2012).
Lignans
Plant lignans are phenolic compounds formed by the union of two cinnamic acid residues. Lignans are ubiquitous within the plant kingdom and are present in almost all plants (Tarpila et al. 2005). Lignans act as both antioxidants and phytoestrogens. Phytoestrogens can have weak estrogen activity in animals and humans. Flax contains up to 800 times more lignans than other plant foods (Mazur et al. 1996; Westcott and Muir 1996). Lignan content in flaxseed is principally composed of secoisolariciresinol diglucoside (SDG) (294–700 mg/100 g), matairesinol (0.55 mg/100 g), lariciresinol (3.04 mg/100 g) and pinoresinol (3.32 mg/100 g) (Tourre and Xueming 2010; Milder et al. 2005). Johnsson et al. (2000) reported SDG content in the range of 11.7 to 24.1 mg/g and 6.1 to 13.3 mg/g in defatted flaxseed flour and whole flaxseed, respectively. Besides lignans, other phenolic compounds found in flaxseed are p-coumaric acid and ferulic acid (Strandas et al. 2008). The SDG found in flax and other foods is converted by bacteria in the gut to the lignans- enterodiol and enterolactone which can provide health benefits due to their weak estrogenic or antiestrogenic, as well as antioxidant effects (Adlercreutz 2007). Flax lignans have shown promising effects in reducing growth of cancerous tumors, especially hormone-sensitive ones such as those of the breast, endometrium and prostate (Tham et al. 1998).
Minerals
In relation to composition of minerals, the contents of calcium, magnesium and phosphorus are highlighted (Bozan and Temelli 2008) being that a 30 g portion of the seed constitutes 7 % to 30 % of the recommended dietary allowances (RDAs) for these minerals. Proximate content of different minerals is shown in Table 1. Its potassium (K+) content is high and comparable to those of recommended sources such as banana on a dry-matter basis. High K+ intake is inversely related to stroke incidence, blood platelet aggregation, oxygen-scavenging free radicals in blood and vascular smooth muscle proliferation (Carter 1993).
Anti-nutritional factors
Despite having functional elements, flax is not totally free of anti-nutritional factors, such as cyanogenic glycosides (CGs). Flaxseed contains CGs and linamarin (acetone–cyanohydrin-beta–glucoside C10H17O6N) in small amounts (Hall et al. 2006). Whole flaxseed contains 250–550 mg/100 g CG (Mazza 2008), of which linustatin and neolinustatin are the major components. Park et al. (2005) reported 207 and 174 mg/100 g seed of linustatin and neolinustatin, respectively in flaxseed. Upon seed damage, β-glucosidases are triggered and contribute to releasing the poisonous hydrogen cyanide (HCN). However, adequate processing of foodstuffs containing CG helps in reducing the potential risks associated with poisoning (Ernesto et al. 2002; Haque and Bradbury 2002). For example, more than 85 % of linustatin, neolinustatin were removed when flaxseed was heated for more than 2 h at 200 °C (Park et al. 2005). Flaxseed meal also contains 2.3–3.3 % phytic acid. Although phytic acid has been known in reducing bioavailability of micronutrients, recent research shows that phytic acid has antioxidant, anticancer, hypocholesterolemic, and hypolipidemic effects (Mazza 2008). Flaxseed meal also contains 10 mg/100 g Linatine (gammaglutamyl- 1-amino-D-proline) which induces vitamin B6 deficiency (Mazza 2008). Ratnayake et al. (1992) and Dieken (1992) found that the linatine (a vitamin B6 antagonist) in flaxseed did not affect vitamin B6 levels or metabolism in people fed up to 50 g of ground flaxseed per day. It has been reported that flaxseed depressed vitamin E levels in rats only when fed at very high levels (Ratnayake et al. 1992). The cyanogenic glycosides in flaxseed raise thiocyanate levels in the blood very briefly, after which the levels drop, but even these levels are less than those of persons smoking tobacco (Zimmerman 1988).
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Flax: a nutraceutical or functional food?
The words nutraceutical and functional food are wrongly interpreted to be one and the same, though there is a difference between the two. A functional food is one which is similar in appearance to a conventional food, consumed as a part of the usual diet, with demonstrated physiological benefits, and/or to reduce the risk of chronic disease beyond basic nutritional functions. While a nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms, not usually associated with foods (Health Canada 1998). A nutraceutical can be a part of functional foods while the latter has to provide essential nutrients often beyond qualities necessary for normal maintenance, growth and development. As flax is consumed in the form of whole/milled/roasted seeds, oil and flour as a food to provide basic nutrition as well as various health benefits in reducing cancer and cardiovascular diseases, lowering LDL-cholesterol and vasodilatory functions, flax can be considered as a functional food. On the other hand, various stable preparations of flax in the form of nutraceutical like neat oil, capsules and microencapsulated powder are available in market. Flax lignans- isolated SDG preparations are also commercially available as a dietary supplement (Chen et al. 2011b). Moreover, flaxseeds were also used as medicines in ancient times as cough remedy and to relieve the abdominal pain. Various medicinal preparations of flaxseed/oil are available in foreign markets, have been described under the next heading. Therefore, by keeping all these views in mind, flax can be considered a potential nutraceutical as well as functional food.
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Flax: an ayurvedic and historical medicine
Humans have been eating flax for thousands of years. Ayurveda remains one of the most ancient and yet alive tradition practiced widely in India, Sri Lanka and other countries that have a sound philosophical and experimental basis (Patwardhan et al. 2004). Atharvaveda (around 1200 BC), Charak Samhita (Dash and Sharama 2001) and Sushrut Samhita (1000–500 BC) are main classics that give detailed descriptions of over 700 herbs. A scholarly description of the legacy of Charaka and Sushruta in contemporary idiom, best attempted with a commentary from modern medicine and science viewpoint, gives some glimpses of ancient wisdom (Valiathan 2003). Ayurveda and traditional Chinese medical system share many common approaches and have a long history of practice (Patwardhan et al. 2005). Ayurvedic literature describes more than 200 herbs, minerals and fats for skin care.
Flaxseed oil is believed to bring mental and physical endurance by fighting fatigue and controlling aging process. According to Ayurveda, flaxseed has properties like Madhura (balances the skin pH), Picchaila (lubricous) Balya (improves tensile strength or elasticity of the skin), Grahi (improves moisture holding capacity of skin), Tvagdoshahrit (removes skin blemishes), Vranahrit (wound healing) and useful in Vata (skin) disorders including dryness, undernourishment, lack of luster/glow (Misra 1963). Flaxseed oil is rich source of essential fatty acids (EFAs): linoleic acid (ω-6) and α-linolenic acid (ω-3), which regulate prostaglandins synthesis and hence induce wound healing process. Deficiency of EFAs result in phrynoderma or toad skin, horny eruptions on the limbs and poor wound healing, etc. Flax preparations were widely used in medicine as an enveloping and wound-healing agent in the treatment of gastrointestinal disorders (Ivanova et al. 2011). In the Middle ages, flaxseed oil was administered as a diuretic for the treatment of kidney disorders (Moghaddasi 2011). Flaxseed was recommended as an antitumoral (in combination with sweet clover), pain and cough relieving, and anti-inflammatory remedy (Tolkachev and Zhuchenko 2000; Moghaddasi 2011). It was also used for the treatment of freckles (in a mixture with soda and figs) and nail disorders (with garden cress and honey) (Tolkachev and Zhuchenko 2000).
Ayurveda is too old than any history. After Ayurveda, historians wove the magic of flax into ancient historical times. Records show that the human race has eaten this seed since early times. The medicinal applications of linseed are mentioned in the works of Hippocrates, Qantes and Dioscorides as well as in medieval books on medicinal herbs in both Asia and Europe. Various medicinal and traditional uses of flax recommended by Hippocrates and other historians, and medicinal preparations available in market are shown in Tables 3, ,44 and and55.
Table 3
Medicinal uses of flax described in history
About 650 B.C. • Hippocrates, the father of medicine, advocated flax for the relief of abdominal pains; And Theophrastus recommended the use of flax mucilage as a cough remedy.
About 1st century A.D. • Tacitus praised the virtues of flax.
About 8th century A.D. • Charlemagne considered flax so important for the health of his subjects that he passed laws and regulations requiring its consumption.
About 15th century A.D. • Hildegard von Bingen used flax meal in hot compresses for the treatment of both external and internal ailments
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Source: Flax council of Canada (2012) http://www.flaxcouncil.ca/english/index.jsp?p=what1&mp=what
Table 4
Traditional and medicinal uses of flaxseeds in various health problems
Flax form consumed Preparation/Processing method Traditional/medicinal health benefits
Flaxseed tea Uncrushed flaxseeds are soaked in water for 30 min. Seeds are then removed while the water is warmed moderately • Useful against dyspnoea, asthma, dysphonia, bad cough and bronchitis
Flaxseed drink A teaspoon of flaxseed powder is put into a glass of hot water, brewed and drained. A cup of this water is to be taken daily. • Helps out constipation
Flaxseed flour Flaxseed flour 10-gram each for the concerned ailment is given a paste like consistency using honey, 30-40 g of this paste is swallowed on an empty stomach in the morning. • Used against pulmonary tuberculosis, haemoptysis, splenomegaly and stomach ulcer.
• Cures inflammations of intestines and abdominal pains.
• Disinfects gastrointestinal tract.
• Strengthens the nervous system.
• Strengthens the memory.
• Good in treating the impairment of concentration.
• Good in the management of age-associated distractibility.
• Ensures rapid healing of wounds through external use.
• Protects the skin against getting dry.
• Used in eczema and psoriasis diseases.
• Exercises a positive impact on respiratory tract diseases.
• Good in curing mental disorders.
• Cures bad cough.
• Used as mouthwash in oral cavity, throat and gingival disorders.
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Source: Moghaddasi (2011)
Table 5
Some medicinal preparations based on flaxseed oil
Product/medicine name Formulation Actions
Essentiale (Germany) Essential phospholipids, α-linolenic acid, pyridoxine, cyanocobalamin, nicotinamide, etc. Stimulates the detoxicating function of liver; restores and maintains the structure of liver cells
Lipostabil (Germany) Contains choline phospholipids, as well as α-linolenic and oleic acids. A moderate vasodilatory action, normalizes the ratio of α-and β-lipoproteins in the blood
Essaven (Germany) Contains phosphatidylcholine (linoleic acid, α-linolenic and oleic acids) Help in painful fatigue of legs; muscle contusions and strains; and superficial vein disorders
Linetol (Russia) Represents a mixture of linseed fatty acid ethylates, including oleic (15 %), linoleic (15 %) and linolenic (57 %) acids In treatment of atherosclerosis and for external use in cases of skin burn and radiation damage
Efamol (Great Britain) Capsules form containing linseed oil in combination with other oils and vitamin E Shows a positive effect when used for the treatment of eczemas
Esoman-ointment (Great Britain) Linseed PUFAs & hexachlorophane Protect skin from aggressive agents such as acids, alkalis, formaldehyde and phenols
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Source: Tolkachev and Zhuchenko (2000)
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Health benefits
Flaxseed has potential health benefits besides the nutrition, due to mainly 3 reasons: first, due to its high content of ω-3 α-linolenic acid; Second, being rich in dietary soluble and insoluble fibers; and third, due to its high content of lignans, acting as anti-oxidants and phytoestrogens. ALA can be metabolized in the body into docosahexaenoic acid (DHA) (ω-3) and eicosapentaenoic acid (EPA) (ω-3). The health benefits of all ω-3 fatty acids (ALA, EPA and DHA) have been widely reported for several conditions including cardiovascular disease, hypertension, atherosclerosis, diabetes, cancer, arthritis, osteoporosis, autoimmune and neurological disorders (Simopoulos 2000; Gogus and Smith 2010) (Fig. 3). Flaxseed has also been reported to act as anti-arrhythmic (Ander et al. 2004), anti-atherogenic (Dupasquier et al. 2006, 2007), and anti-inflammatory (Dupasquier et al. 2007) agent in addition to improving vascular function (Dupasquier et al. 2006).
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Fig. 3
Physiological effects imparted by functional elements of flaxseed (oil, fiber and lignans)
Health benefits of whole flax, flax flour, flax fibers and flaxseed oil
In treatment of diabetes mellitus Increased blood sugar (Diabetes mellitus) is a major risk factor of cardiovascular diseases, which is defined as having a fasting plasma glucose level ≥126 mg/dl. Diabetes mellitus is characterized by hyperglycemia and associated with aberrations in the metabolism of carbohydrate, protein, and lipid that result in development of secondary complications (Mani et al. 2011). Of the 57 million global deaths in 2008, 36 million (63 %) deaths were due to non-communicable diseases (NCDs), out of which, diabetes was responsible for 1.3 million (3 %) deaths (WHO 2010), with the number likely to be doubled by the year 2030 (WHO 2009). More interesting fact is that one in 10 adults has diabetes according to a new report of WHO (2012). The number of people with diabetes increased from 153 million in 1980 to 347 million in 2008 (Danaei et al. 2011). India has the largest diabetic population and one of the highest diabetes prevalence rates in the world (Bjrok et al. 2003; King et al. 1998). It was estimated that in 2008, about 2 % of total deaths in India were due to diabetes (WHO 2011). Untreated diabetes can lead to cardiovascular diseases, kidney failure and blindness. A positive correlation was reported between the raised blood glucose level and the risk of cardiovascular diseases (Boden-Albala et al. 2008). Moreover, diabetes was tends to occur together with other risk factors such as obesity, hypertension, low HDL cholesterol and a high triglyceride level (Simmons et al. 2010; Lakka et al. 2002).
Dietary fibers, lignans, and ω-3 fatty acids, present in flaxseed have a protective effect against diabetes risk (Prasad et al. 2000; Prasad 2001; Adlercreutz 2007). Flaxseed lignan SDG has been shown to inhibit expression of the phosphoenolpyruvate carboxykinase gene, which codes for a key enzyme responsible for glucose synthesis in the liver (Prasad 2002). Supplementation of diet of type 2 diabetics with 10 g of flaxseed powder for a period of 1 month reduced fasting blood glucose by 19.7 % and glycated hemoglobin by 15.6 % (Mani et al. 2011). It could be due to lower content of glycemic carbohydrates and higher content of dietary fibers of flaxseed. Several small studies using a fasting glucose tolerance approach have found a reduction in postprandial blood glucose levels of women consuming flaxseed (Cunnane et al. 1993, 1995). Kelley et al. (2009) studied that when conjugated linoleic acid (0.5 %) and flax oil (0.5 %) was supplemented in diet of rats susceptible to obesity and diabetic tumors, a 20 % reduction in glycemia was observed. Kapoor et al. (2011) studied the effect of supplementation of flaxseed powder on diabetic human females. Patients were provided 15 and 20 g/day of flaxseed powder for a period of 2 months. Post-prandial blood glucose levels were found to be decreased by 7.9 and 19.1 %, respectively. Similar results has also been reported by Nazni et al. (2006) who conducted a study on 25 diabetic subjects and supplemented flaxseed powder in bread form for 90 days and reported a significant reduction in blood glucose levels after supplementation. However, Dodin et al. (2008) measured fasting serum glucose and insulin levels and reported no change after flaxseed supplementation. Similarly, ingestion of 10 g/day of flaxseed oil had no effect on fasting blood serum glucose and insulin levels (Barre et al. 2008). Utilization of flaxseed for glycemic control may also be associated to the decrease in risk of obesity and dyslipidemia, since these are risk factors for the development of diabetes and resistance to insulin (Wu et al. 2010; Morisset et al. 2009).
Tumor and cancer reducing effects Interest in research on the association between flaxseed ingestion and risk of cancer emerged when epidemiologic evidences suggested a beneficial relationship. Research in laboratories has shown that flaxseed inhibits the formation of colon, breast, skin, and lung tumors and also reduces blood vessel cell formation in female rats, all suggesting a protective effect against breast, colon and ovarian cancer (Truan et al. 2012). Higher levels of insulin and insulin-like growth factor 1 (IGF-1) increase cancer risk by stimulating cell proliferation and increasing survival of DNA-damaged cells through antiapoptotic mechanisms (Sturgeon et al. 2011). Blood insulin has also been associated with increased risk of pancreatic and colorectal cancers (Pisani 2008). Various studies suggest that flaxseed added to the diet may lower circulating levels of insulin and IGF-1 (Woodside et al. 2006; Chen et al. 2011a). However, Sturgeon et al. (2011) reported that incorporation of 7.5 g of flaxseed daily for 6 weeks and 15 g of flaxseed for an additional 6 weeks into the diet of healthy postmenopausal women had little short-term effect on blood levels of IGF-1. Flaxseed has a breast tumor-reducing effect, possibly because of its high content of SDG lignan (Truan et al. 2012; Chen et al. 2011a; Chen et al. 2009; Saggar et al. 2010a, b; Wang et al. 2005). Enterodiol (ED) and enterolactone (EL) are produced from flax lignans in animal body. Because they are structurally similar to human estrogen-17β-estradiol (E2), they have binding affinity to estrogen receptors (ER) (Penttinen et al. 2007). Flaxseed and its SDG component have been shown to attenuate tumorigenesis through a reduction in cell proliferation and angiogenesis, as well as an increase in apoptosis via modulation of the estrogen receptor (ER)- and growth factor- signaling pathways (Saggar et al. 2010a; Chen et al. 2009). The potential breast cancer protective effect of flax lignans could be due to their weak estrogenic activity and antioxidant properties. Flaxseed oil with its exceptionally high ALA content was also shown to reduce human estrogen receptor-positive breast tumors (MCF-7) growth by 33 % compared to control (Truan et al. 2010). Chen et al. (2007) studied that the groups of mice that received 5 % and 10 % flaxseed in the diet for 8 weeks inhibited tumor growth by 26 % and 38 %, respectively. The researchers suggested the ability of flaxseed to help maintain more early stages of cancer is due to the fact that flaxseed contains the highest level of plant lignans, which have antioxidant activities (Hall et al. 2006) and have also been shown to alter estrogen metabolism, which may decrease ovarian cancer risk and improve health (McCann et al. 2007).
Prevention of kidney diseases Chronic kidney disease (CKD) is an important health problem among older adults and can lead to end-stage renal disease with its need for dialysis or transplantation for survival (Lauretani et al. 2009; Coresh et al. 2007). Due to the anti-inflammatory properties of ω-3 fatty acids, it has been suggested that these nutrients may protect the kidneys from damage in adults. PUFA supplementation was observed as reducing renal inflammation and fibrosis in animal models (Baggio et al. 2005). Gopinath et al. (2011) showed that increased dietary intake of long-chain ω-3 PUFA was inversely associated with the prevalence of CKD. Cicero et al. (2010) showed that long-term supplementation of omega-3 fatty acids was associated with a significant reduction in systolic and diastolic blood pressure. Hypertension is a risk factor for CKD; hence, the influence of long-chain n-3 PUFA on blood pressure may be a potential mechanism by which it protects the kidneys. However, a positive association between α-linolenic acid and moderate CKD was observed by Gopinath et al. (2011). One possibility behind the results could be lesser conversion of α-linolenic acid into EPA and DHA, which have been shown to be cardioprotective (Wang et al. 2006).
Reduction of dyslipidemia and cardiovascular diseases (CVD) Serum lipid profile is directly related to the risk factors of cardiovascular diseases. It is the most intensely investigated effect studied in animals and humans after supplementation of flax in diet. Studies with flaxseed and its bioactive components have been performed with postmenopausal women, showing positive effects, including hypocholesterolemic and antidiabetic effects of supplementation (Patade et al. 2008; Bloedon et al. 2008). The effects of flaxseed on risk factors for CVD in studies performed on animals are similar to those conducted in humans. Rats, mice, and rabbits presented positive responses for biochemical parameters, indicating the hypocholesterolemic activity of flaxseed, generally related to the greater fecal content of lipids (Kristensen et al. 2011, 2012; Hassan et al. 2012; Park and Velasquez 2012; Khalesi et al. 2011; Mani et al. 2011; Cardozo et al. 2010; Barakat and Mehmoud 2011; Leyvaa et al. 2011). However, there remains controversy in relation to effect on the high-density lipoprotein (HDL) fraction. Gillingham et al. (2011) reported reduced levels of HDL fraction in human serum after consuming flaxseed oil in diet for 28 days. Similarly, researchers have also reported reduced or no change in HDL fraction in different animals (Faintuch et al. 2011; Patade et al. 2008; Prim et al. 2012). When type 2 diabetic patients were fed defatted flaxseeds for 2 months, patients showed significant reduction of plasma glucose, improvement in plasma lipid profile and significant reduction of lipid peroxidation (Mohamed et al. 2012). Dietary flaxseed may also offer protection against ischemic heart disease by improving vascular relaxation responses and by inhibiting the incidence of ventricular fibrillation (Jennifer et al. 2010). However, Vedtofte et al. (2011) reported that higher intake of ALA was not significantly associated with decreased risk of ischemic heart disease among women or men. Some of the recent clinical studies regarding the consumption of whole flaxseed, flax flour or oil and their physiological effects are shown in Table 6.
Table 6
Recent clinical reports showing lipid profile and other health effects of flaxseed consumption in diet
Experiment Model system Significant findings References
Consumption of 5 g of flax fibres daily for 1 week in form of bread and drinks Young healthy adults Faecal excretion of fat increased by 50 %. Flax bread and Flax drink reduced the Total & the LDL-cholesterol by 7 & 9 and 12 & 15 %, respectively. Kristensen et al. (2012)
Consumption of 5 g of flaxseed gums per day for 3 months Type-2 diabetics Total and LDL-cholesterol were reduced by 10 and 16 %, respectively. Thakur et al. (2009)
15 % flaxseed meal enriched biscuits were fed for 8 weeks Hypercholesterolemic rats Cholesterol & triglyceride level decreased from 456.66 & 173.84 to 183.92 & 102.67 mg/dl, respectively. LDL and VLDL decreased from 199.46 & 34.95 to 84.08 & 20.53 mg/dl, respectively. While, HDL increased from 38.95 to 64.37 mg/dl. Hassan et al. (2012)
100 % flaxseed oil was used as shortening in preparation of biscuits, which were fed for 8 weeks Hypercholesterolemic rats Cholesterol & triglyceride level decreased from 456.66 & 173.84 to 170.48 & 96.79 mg/dl, respectively. LDL and VLDL decreased from 199.46 & 34.95 to 74.79 & 19.34 mg/dl, respectively. While, HDL increased from 38.95 to 66.09 mg/dl. Hassan et al. (2012)
Flaxseeds were consumed to see its effect on appetite -regulating hormones; lipemia and glycemia. Young men Decreased triglyceride levels (postprandial lipemia), Higher mean- ratings of satiety and fullness Kristensen et al. (2011)
Flaxseed powder enriched diets were consumed for 12-weeks to check body weight and lipid profile Rats Rats fed with high fat & high fructose diet along with 0.02 % flax powder showed decreased levels of TG, total cholesterol and LDL-cholesterol from 100, 69 and 10 to 96, 63 and 9 mg/dl, respectively Park and Velasquez (2012)
Feeding of basal diet & basal diet supplemented with 1 g flaxseed lignan per kg for 8 weeks Mice Reduction in breast tumor cell proliferation (or growth) without affecting the size of tumor Truan et al. (2012)
7.5 g per day of ground flaxseed was consumed for 6 weeks and 15 g per day for an additional 6 weeks Postmenopausal women Flaxseed supplementation did not impact circulating levels of IGF-1, IGF-BP3, or C-peptide, which increase cancer risk by stimulating cell proliferation and increasing survival of DNA-damaged cells Sturgeon et al. (2011)
Animals were fed with 10 %, 20 % & 30 % of raw and heated flaxseed in the basal diet for 30 days Rats Total cholesterol level got significantly reduced in all flaxseed groups and HDL- cholesterol got significantly increased in 20 % raw; 30 % raw and heated flaxseed groups. Significant reduction in LDL-cholesterol level was only observed in 30 % raw flaxseed groups Khalesi et al. (2011)
Diets containing 2·7 % flaxseed, 4·5 % fibre and 3·7 % ALA were fed for 10 weeks. Mice The median number of adenomas in the small intestine was 54 & 37 for control & flaxseed groups, respectively. Compared with controls (1·2 mm), the adenoma size was smaller in the flaxseed (0·9 mm) fed group Oikarinen et al. (2005)
Animals were fed the basal diet (control) and ω-3 rich flax cotyledon’s fraction (82 g/kg), respectively for 8 weeks Mice Flax diet reduced the cell proliferation; suppressed insulin growth factor (IGF)-1R and the growth of breast tumour Chen et al. (2011a, b)
Non-fiber beverage, Flax drink -flax fiber extract (2.5 g) and flax tablets Human Flax drink increased the sensation of satiety and fullness compared to Control and also a significant decrease in subsequent energy intake was observed after the Flax drink compared to Control (2,937 vs. 3,214 kJ) Ibrugger et al. (2012)
Isoenergetic diets were consumed for 28 days each containing approximately 36 % energy from fat, of which 70 % was provided by flaxseed oil Hypercholesterolemic subjects (Human) Compared with control, total, LDL & HDL-cholesterol levels were reduced by 11, 15.1 & 8.5 %. LDL:HDL ratio by was reduced by 7·5 % Gillingham et al. (2011)
Diet rich in flaxseed oil was given for 10 days and then a single dose of Cisplatin (6 mg/kg body weight) was administered intraperitoneally while still on diet Rats Dietary supplementation of flaxseed oil in Cisplatin (CP)-treated rats ameliorated the CP-induced hepatotoxic and other deleterious effects Naqshbandi et al. (2012)
Flaxseed powder (60 g/day, 10 g ALA) was administered in a double-blind routine for 12 weeks Obese population Total cholesterol level decreased from 197.2 to 179.4 mg/dl. LDL & HDL decreased from 122.3 & 50.9 to 106.6 & 47.9 mg/dl, respectively. While, VLDL increased from 25.8 to 26.6 mg/dl Faintuch et al. (2011)
Full fatty and partially defatted flaxseed flour @ concentration of 4-20 % supplemented diet was fed for 1 week in form of unleavened flat bread Albino rat 12 % full fat & 16 % defatted flaxseed flour increased TD from 79.4 to 81.45 & 84.6; NPU from 44.3 to 49.4 & 54.65; PER from 1.51 to 1.8 & 1.87; and BV from 55.79 to 60.65 & 64.6 Hussain et al. (2012)
Low-fat muffins supplemented with 500 mg flax lignan were fed for 6 weeks Postmenopausal women A significant decrease (0.88 to 0.80 mg/L) in C-reactive protein (CRP) was observed in test women Hallund et al. (2008)
30 g/day of flaxseeds were consumed in diet for a period of 3 months Hypercholesterolemic postmenopausal women Dietary flaxseed supplementation lowered the total and LDL-cholesterol level, approximately by 7 % and 10 %, respectively. However, the levels of HDL and triglyceride remained unaltered Patade et al. (2008)
Diet was supplemented daily with 10 g of flaxseed powder for a period of 1 month Type 2 diabetics Blood glucose level reduced by 19.7 %. A favorable reduction in total cholesterol (14.3 %), triglycerides (17.5 %), LDL-cholesterol (21.8 %), and an increase in HDL-cholesterol (11.9 %) were also noticed Mani et al. (2011)
Ground linseed was added in diet for 27 days (from day 29, till day 56) Hypercholesterolemic rabbit Total Cholesterol & LDL-cholesterol levels were reduced from 16.76 & 15.96 to 10.06 & 10.74 mg/L, respectively. There was no significant difference in serum HDL-cholesterol and TAG between the two groups Prim et al. (2012)
25 % flaxseed based diet was consumed by mothers during lactation. At weaning, pups received the same diet for 170 days Rats A reduction in total cholesterol levels from 63.43 to 45.71 mg/dL and triglycerides from 79.86 to 54.29 mg/dL was observed, without any alteration in HDL Cardozo et al. (2010)
40 g/day of ground flaxseed-containing baked products were fed for 10 weeks Human Flaxseed significantly reduced LDL-cholesterol at 5 weeks (by 13 %), but not at 10 weeks (by 7 %) and lipoprotein by a net of 14 %. In men, flaxseed reduced HDL-Cholesterol by a net of 16 % and 9 % at 5 and 10 weeks, respectively Bloedon et al. (2008)
One group was fed high cholesterol diet (2 g/100 g) and other was fed same diet supplemented with flax/pumpkin seed mixture in ratio of 5:1 Rats When compared with hypercholesterolemic group, flax group showed reduced levels of total cholesterol (220.35 vs 120.48 mg/dL), triacylglycerols (100.93 vs 77.99 mg/dL), VLDL-C (20.19 vs 15.59 mg/dL), LDL-C (171.83 vs 65.37 mg/dL), while increased level of HDL-C from 28.33 to 39.51 mg/dL Barakat and Mehmoud (2011)
Flaxseed oil was fed in basal diet @ 6.4 % for 165 days Trout Sensory evaluations showed the preference for the taste of the flaxseed oil-enriched fillets to the control fillets Simmons et al. (2011)
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LDL low density lipoprotein; VLDL very low density lipoprotein; HDL high density lipoprotein; TG triglycerides; TD true digestibility; NPU net protein utilization; PER protein efficiency ratio; BV biological value
Natural Solutions for Hormonal Symptoms
Prevention and treatment of obesity Traditionally, obesity-related disease conditions have been often treated and/or prevented using many plant materials including flax (Singh et al. 2011; Santos et al. 2010). Flaxseed fibers form highly viscous solutions upon hydration, which is similar to those observed for other gums (Goh et al. 2006). Particularly viscous fibers appear effective in suppression of hunger (Wanders et al. 2011; Kristensen et al. 2011). Soluble nonstarch dietary fibers of flaxseed mucilage are multibranched hydrophilic substances, forming viscous solutions that delay gastric emptying and nutrient absorption from the small bowel.
In obesity, leptin may be under-expressed by the adipose tissue in response to a consistently high caloric diet, or, leptin receptors may be down-regulated, thus leading to high plasma leptin levels (Dubey et al. 2006). Leptin is a protein encoded by the obese gene, named for the phenotype of the double knockout mouse (McCullough et al. 2011). These mice experience no satiety, and thus eat continuously when fed ad libitum, leading to severe diet-induced obesity. It decreases the secretion of neuropeptide Y (NPY) which is a potent appetite stimulator. McCullough et al. (2011) reported that consumption of flaxseed significantly increased plasma and adipose levels of ALA. Leptin protein levels were elevated in animals taking diet supplemented with 10 % flaxseed. Changes in leptin expression were strongly and positively correlated with adipose ALA levels and inversely correlated with risk of atherosclerosis.
Natural treatment of bowel syndrome In Western societies, constipation remains a major health problem mostly due to refined diet. It is well known that a sufficient amount of dietary fiber is a cornerstone in the prevention and treatment of constipation (Tarpila et al. 2005). The metabolism of flaxseed fiber can be stated as with any dietary fiber. Dietary fiber as a natural way to manage irritable bowel syndrome made it the first line treatment for this condition during 1970s and 1980s. Cunnane et al. (1995) studied the influence of consuming 50 g flaxseed per day for 4 weeks on several indices of nutrition in 10 young healthy adults. Various reviews and articles have described comprehensively the effects of flax fiber, including gastrointestinal (GI)-motility, constipation, glucose tolerance, hypocholesterolemic effect and fermentation (Mani et al. 2011; Kristensen et al. 2011, 2012).
Health benefits of flax proteins
Concerning the protein fraction, flax is not actually used as a source of food protein but used in animal feed as a cheaper material (Rabetafika et al. 2011). Recent reports have shown various techno-functional properties (Wang et al. 2010a; Mueller et al. 2010a, b; Green et al. 2005) and health benefits of flaxseed proteins. A study about flaxseed protein have shown the benefits of flaxseed proteins in coronary heart disease, kidney disease and cancer (Oomah and Mazza 2000; Wang et al. 2007, 2009). Flax protein contains abundant arginine and glutamine (Oomah and Mazza 1993), which are very important in the prevention and treatment of heart disease (Gornik and Creager 2004), and in supporting the immune system (Avenell 2006). Flaxseed contains bioactive peptides, such as cyclolinopeptide A, which have strong immunosuppressive and antimalarial activities, inhibiting the human malarial parasite Plasmodium falciparum in culture (Bell et al. 2000). A number of studies have shown that flaxseed proteins possess potential for therapeutic applications (Table 7). For example, peptides derived from enzymatic hydrolysis of flaxseed proteins inhibited angiotensin I–converting enzyme (ACE) activities, and also displayed in-vitro antioxidant activities (Omoni and Aluko 2006; Marambe et al. 2008). Peptide mixture from flaxseed with high levels of branched-chain amino acids, and low levels of aromatic amino acids have shown antioxidant properties by scavenging 2,2-diphenyl-1-picrylhydrazyl radical (DPPH), and antihypertensive properties by inhibiting the ACE activity (Udenigwe and Aluko 2010).
Table 7
Biological/functional properties of flaxseed proteins
Function of flax protein Effects/Mechanism Reference
Antifungal Act against food spoilage fungi Penicilliumchrysogenum, Fusariumgraminearum & Aspergillusflavus Xu et al. (2006, 2008)
Antioxidant Hydrolyzed flaxseed proteins exhibited antioxidant property by scavenging 2, 2-diphenyl-1- picrylhydrazyl radical, superoxide radical & hydroxyl radical Xu et al. (2008); Udenigwea et al. (2009)
Antihypertensive Inhibits angiotensin I-converting enzyme Udenigwe and Aluko (2010)
Cholesterol lowering effect Due to their bile acids binding activity Marambe et al. (2008)
Anti-diabetic Because flax proteins can interact with fiber and mucilage; And also by stimulating the secretion of insulin Oomah (2001)
Anti-thrombic Flax proteins- hirudine&linusitin Tolkachev and Zhuchenko (2000)
Anti-tumor Due to presence of low lysine/arginine ratio Oomah (2001)
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Commercial utilization of flaxseeds in food products
Functional food revolution
Functional foods are those that provide a specific health benefit to the consumer over and above their nutritional value. Functional foods are relatively recent developments that meet a strengthening consumer demand for foods that enhance health and wellbeing. According to a new report by Global Industry Analysts, Inc. the global market for functional foods and drinks is projected to reach exceed $130 billion by the year 2015 (Global Industry Analysts 2010). According to Leatherhead Food Research (2011) statistics, global functional food market in different sectors is shown in Fig. 4. The United States market dominates (>30 % of the total global market) and is showing a sustained growth of ~14 % per year, while its ~8 % per year across the world (Smithers 2008). In this large marketplace, the food industry is demanding economical, high-quality, novel and substantiated ingredients. In such a setting, flaxseed being rich in ω-3 fatty acids, lignans and fibers provide the industry with an excellent choice in developing the value-added food products. With the increasing rate of obesity and other chronic diseases in western societies, flax products are increasingly used as functional foods and nutraceuticals (Hasler et al. 2000; Lemay et al. 2002; Ogborn et al. 2002; Watkins et al. 2001). In recent years, as people have become more concerned about health, demand for flax in food and beverages, functional foods and dietary supplements has risen dramatically both in the U.S. and other countries. For example, Mintel’s Global New Products Database (GNPD) reported that in 2005, 72 new products were launched in the United States that listed flax or flaxseed as an ingredient (Wilkes 2007). In the first 11 months of 2006, there were 75 new products launched enriched with flax or flaxseed (Wilkes 2007). Interest in flax and other ω-3-containing foods heightened further in May 2003 when the White House issued a letter to the U.S. Department of Agriculture (USDA) and the U.S. Food and Drug Administration (FDA) that asked them to promote the intake of ω-3 fatty acids in the diet (Wilkes 2007).
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Fig. 4
Global functional foods market by sector, 2010 (% value)
Estimated intakes of whole and milled flaxseed, ALA and fibers
After reviewing various clinical studies regarding the health effects of flax elements, it can be concluded that flax in different forms can be consumed but the dietary intakes are equally important. The intended uses of whole and milled flaxseed are determined to generally recognized as safe (GRAS) (Jheimbach and Port Royal 2009). FDA previously authorized the addition of flaxseed to foods at up to 12 % levels by weight, and this may be taken as a representative maximum addition level for most foods (Jheimbach and Port Royal 2009). While it may be technologically and organoleptically feasible to add a somewhat higher proportion of flaxseed to a few food products, for many products even 12 % flaxseed addition is likely to be unattainable. Using the Reference Amounts Customarily Consumed (RACC) established by FDA, addition levels of 12 % by weight can be converted to g/serving by multiplying the RACC by the intended addition percentage. Various recommended levels of flaxseed in food products are shown in Table 8.
Table 8
Intended addition levels of flaxseed by weight and per serving
Food category RACCa (g) Maximum flaxseed contentb (g/serving)
Bread 50 6.0
Biscuits, bagels, tortillas 55 6.6
Doughnuts, muffins 55 6.6
Pancake/waffle mix 40 4.8
Pasta (dry weight) 55 6.6
Multi grain flours or meal 30 3.6
Breakfast cereals 30 3.6
Cookies 30 3.6
Nuts & seeds 30 3.6
Cheeses 30 3.6
Salad dressing 30 3.6
Mayonnaise 15 1.8
Margarine, table spreads 15 1.8
Yoghurt 225 27.0
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Source: Jheimbach and Port Royal (2009)
aReference amount customarily consumed (21 CFR § 101.12)
bBased on addition of flaxseed at 12 % by weight of the food
For optimal health, many government and public health authorities recommend increasing ω-3 fatty acids in diet. In fact as early as 1990, Health Canada recommended an ω-6 : ω-3 fatty acid dietary ratio of 4:1 to 10:1 (Health and Welfare Canada 1990). Supplemented products for clinical trials need to contain an amount and type of flaxseed that will significantly increase the levels of ALA in the blood over and above the recommended daily amount of 1.6 g/d for males and 1.1 g/d for females (Health Canada 2009; U.S. Department of Agriculture and U.S. Department of Health and Human Services 2010). Flaxseed contains approximately 23 g ALA per 100 g (USDA 2010) and thus, the recommended dietary amounts can be obtained by consuming about 9 g of flaxseed per day. Various expert committees recommended dietary intakes of ALA according to Table 9. The mean intake of dietary fibers among several European countries is 22 g/d, ranging from 12 to 34 g/d (Bingham et al. 2003), approximately 14.3 g/d in Japan and 21.9 g/d in USA, ranging from 12 to 36 g/d (Peters et al. 2003). It is commonly recommended dietary fiber intakes should be 30 g or more per day. This amount is expected to increase stool weight and frequency and normalize stool consistency (Devroede 1988).
Table 9
Recommendations of α-linolenic acid by various expert committees
Expert committee RDA of ALA (per day)
North Atlantic Treaty Organization workshop in 1989 3 g ALA
International Society for the Study of Fatty Acids and Lipids (ISSFAL) in 1999 2.2 g ALA
Eurodiet Commission in 2000 2 g ALA
French Apports Nutritionnels Conseilles in 2001 1.8 g ALA
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Source: Jheimbach and Port Royal (2009)
Use of whole flaxseeds/flax flour and flaxseed oil in products for human consumption
Flaxseed is regaining its status as a functional food after centuries of use as natural medicine. Flaxseeds can be used as roasted and milled seeds, while flaxseed oil can be used in various food formulations in the form of neat oils, stable emulsions and micro- and nano-encapsulated powder. Bakery sector in the west has resorted to the method of adding ground flax seed into mixed grain bread for the purpose of meeting customer demands. Flax or flaxseed oil has been incorporated into baked foods (Payne 2000; Pohjanheimo et al. 2006), juices, milk and dairy products (Dodin et al. 2008; 2005; Ivanova et al. 2011), muffins (Ramcharitar et al. 2005; Aliani et al. 2011), dry pasta products (Sinha and Manthey 2008; Lee et al. 2004; Hall et al. 2005; Marconi and Carcea 2001), macaroni (Hall et al. 2005) and beef patties (Bilek and Turhan 2009).
In bakery and other food products The wide consumption of bakery products makes them ideally suited for fortification as foods for the daily consumption as well as those used for clinical trials (Kadam and Prabhasankar 2010). With various positive reports regarding the health benefits of flax enriched food products, few reports showed neutral health impacts and lower sensory acceptability. Ramcharitar et al. (2005) found that the muffin containing 11.6 % milled flaxseed by weight was rated as significantly less acceptable than the control muffin. Pretzel type yeast bread containing 15 % flax was rated as significantly lower in flavor and overall acceptability compared to the control (Alpaslan and Hayta 2006).
The main advantage of milled flaxseed to be used in bakery products is its carbohydrate (gums) and protein fractions. Flaxseed gum has been reported to 1) enhance viscosity, best at pH 6–8; 2) stabilize foam and protein based emulsions (Wang et al. 2011), comparing favorably with ovalbumin; 3) increase absorption in bread while improving loaf volume, oven spring, and keeping quality; 4) significantly improve objective and subjective bread characteristics; 5) affect shear rate as gum arabic does; and 6) show promise as a “food thickener” and “improving agent” in baked goods (Carter 1993). Hall et al. (2005) recommended flaxseed particles could be used in breads to get the good quality baked products. Use of ground flaxseed at a 10 % level markedly increased loaf volume, specific loaf volume, Dallman degree, and retarded bread staling (Mentes et al. 2008). Incorporation of flaxseed hull into Chinese steamed bread (CSB) significantly enriched the phytochemical profile of the bread with a concomitant increase in the antioxidant activity (Hao and Beta 2012). Lipilina and Ganji (2009) prepared bread with 30 % flaxseed flour and observed a 15-fold increase in linolenic acid (28 g), a 100 % increase in linoleic acid (7 g) and a 70 % (16 g) increase in dietary fiber in enriched bread when compared with control.
The partial substitution of soy oil with flaxseed oil (25, 50 and 75 %) in bread formulations resulted in an increased ALA content and the gradual reduction of the ω-6 : ω-3 ratio without negative effects on bread technical quality or sensorial attributes (Aguiar et al. 2011). Minker et al. (1973) reported that linseed mucilage had emulsifying properties better than those of tween-80, gum arabic, and gum tragacanth, implying potential industrial use. Owing to the high mucilage content, the flaxseed hull has high-water absorption, moisture–binding capacity, as well as lubricity. This helps dough throughput and puffing during extrusion processing (cereals, snacks, or pet foods) or as a trans-fat free shortening alternative in cookies, muffins, breads, and other baked foods where the water absorption can impact the mixing time and dough-handling characteristics (Best 2004). Flaxseed contains no gluten, so useful for those with gluten allergy. Whole or ground flaxseed can replace some of the flour in bread, muffin, pancake, and cookie recipes. Cookies containing up to 20 % of full-fat flaxseed flour were acceptable in relation to their overall acceptability (Hussain et al. 2006). Ivanova et al. (2011) showed that butter with flaxseed additive has pure creamy flavor and odor without flavor and odor of additive, yellow color and good spreadability and plasticity.
Omega-3 enriched foods offer more food choices to consumers seeking to increase the ω-3 content of their diet. Giroux et al. (2010) prepared dairy beverages enriched with linseed oil. Matumoto- Pintroa et al. (2011) added commercially available flax lignan -SDG extract to the formulation of dairy beverages enriched with flaxseed oil to increase its oxidative stability. Some other food uses of flaxseed are ready-to-eat breakfast cereals, breakfast drinks, salad dressings made with cold-pressed flaxseed oil, salad toppings, biscuits, meat extenders, crackers, soups, bagels, fiber bars, and cakes. Recent research work on enrichment of flax in various food products is shown in Table 10.
Table 10
Recent reports of various food products enriched with whole flaxseed, flax flour and flax oil
Consumed flax form Amount supplemented Flax enriched food product Main results References
Flax flour 15 % Bread Musty aroma was significantly reduced in flax bread during 4 weeks of storage with addition of Vitamin C, BHA & BHT Conforti and Cachaper (2009)
Flax flour Not available Muffins & Snack bar Flax muffins & snack bar showed lower acceptability than non-flax products. However, flavouring enhanced the overall acceptability significantly Aliani et al. (2011)
Flaxseed oil 1 % Cheese High retention of flax oil (5.2 mg/g) was observed in cheese without affecting the shelf life of the product Aguirre and Canovas (2012)
Flaxseed oil 25, 50, 75 & 100 % Shortening & biscuits Biscuits made with 100 % substituted shortening were acceptable as control Hassan et al. (2012)
Flax flour 16 % Corn snacks 7 fold increase in dietary fibres, almost 100 % increase in protein content, with similar acceptability score when compared to control Trevisan and Areas (2012)
Flaxseed oil (powder) 1, 2.5, 5.0 & 10 % Bread Water absorption capacity increased from 62 (control) to 70 % (10 % flax-bread). No effects on sensorial properties were observed Gokmen et al. (2011)
Milled flaxseed (Flour) 15 & 25 % Yeast bread Highest taste & aroma acceptance scores were found for yeast bread with 15 % flax bread. No significant increase in peroxide value was observed with 25 % flax bread till bread staling Mentes et al. (2008)
Milled flaxseed 23 % Bagels Flax aroma & flavours were detected in fortified bagels as compared to non-fortified bagels, but still were acceptable Aliani et al. (2012)
Full fat and partially defatted flaxseed flour 4–20 % Unleavened flat bread 12 % full fat and 16 % defatted flaxseed flour enriched bread showed maximum acceptability. The level of soluble, insoluble and total dietary fibres and essential amino acids were higher in flax flour enriched bread than control Hussain et al. (2012)
Flaxseed oil 0–12 % Ice cream Flax-ice cream showed minimal fat flocculation, less stabilisation of air cells resulting in a soft ice cream that had a high meltdown rate. Incorporation of 2 % flaxseed oil in a 12 % (w/w) ice cream was possible affecting the ice cream functionality Goh et al. (2006)
Flaxseed cake 10 & 15 % Brown bread Bread samples with inclusion levels of 10 and 15 % flaxseed oil cake were acceptable to the consumer sensory panel. Ogunronbi et al. (2011)
Ground flaxseed 7.3, 11.6 & 15.5 % Muffins Control muffin had higher score than the flax muffin for appearance, colour, flavour, texture, overall acceptability & food acceptance. Flaxseed muffin (11.6 %) was “neither liked nor disliked” to “liked slightly” in overall acceptability Ramcharitar et al. (2005)
Flaxseed flour 0–18 % Cookies Cookie dough stickiness significantly decreased with flaxseed flour. The 18 % flaxseed cookies had the firmest texture & darkest colour, unacceptable by consumers. While 6 & 12 % flaxseed cookies were acceptable without negatively affecting the physical and sensory properties Khouryieh and Aramouni (2012)
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Omega-3 enriched eggs from laying hens fed a special flax diet are gaining in popularity amongst consumers on the North American continent and abroad. The organoleptic quality of ω-3 enriched eggs was acceptable without off-flavors when hens were fed 5 % (or less) flaxseed oil in diet (Cloughley et al. 1997). Generally, sensory quality of ω-3 enriched eggs tends to be similar to regular table eggs although in some cases panelists were able to detect off-flavors (Caston et al. 1994; Ahn et al. 1995). A ‘fishy’ or fish-product related flavor was detected in eggs from hens on diet containing 15–20 % flaxseed. Data from a study conducted by Leeson et al. (1998) also suggested that high (>10 %) levels of flaxseed would result in some decrease in overall egg acceptability as assessed by aroma and flavor. This remains a problem associated with the commercial production of this type of product. It has been suggested that the use of combinations of anti-oxidants in the hen’s diet could help to suppress these off-flavors. Other food products, such as ω-3 enriched pork, are produced by including flax in animal rations.
Use of flaxseed by-product as a protein source
Flaxseed is one of the oilseeds grown primarily for their oil content and fatty acid composition, leaving protein-rich meals as an underutilized by-product. To date flaxseed has not yet been widely exploited as a source of protein for human consumption. Within the food protein ingredient market, industry is pushing toward finding plant-based alternatives to animal-derived ingredients based on consumer perceived fears (e.g., prion disease), religious inhibitions, and dietary and moral preferences associated with consuming animal by-products (Karaca et al. 2011). The main product obtained from flaxseed is oil, and the residual paste is used as an ingredient for making animal feed. However, flaxseed grain and flaxseed paste contain about 21 % and 34 % protein, respectively. One way of adding flaxseed paste to conventional foods is to convert the paste into protein concentrate. In this way, it is possible to obtain a product with both high protein content and certain desirable functional characteristics. Flaxseed proteins have been investigated for their emulsifying properties with mixed results (Wang et al. 2010b, c).
It is shown that crude flaxseed protein (containing flaxseed mucilage) has better water absorption, oil absorption, emulsifying activity and emulsion stability compared to soybean protein (Dev and Quensel 1988, 1989). Karaca et al. (2011) reported that creaming stability of emulsions (96.6 %) stabilized by flaxseed proteins was comparable to whey protein isolates (WPI)-stabilized emulsions (90.8 %). Flax protein concentrate showed high oil and water absorption capacities of 150.25 and 253.5 %, respectively, better foam stability (83.33 %), emulsifying capacity (84.76 mL/g), and emulsifying activity (88.37 %) at a pH 6 (Flores et al. 2006). This property is very important if the protein concentrate is to be used in products such as salad dressings, mayonnaise, hamburgers and bread products.
Similarly, partial defatting of flax flour improved foam capacity, foam stability and water absorption capacity (Hussain et al. 2008). Same author reported that the replacement of roasted and partially defatted flaxseed flours upto a level of 16 % supplementation in whole wheat flour was found acceptable for sensory attributes of chapattis (Indian bread) (Hussain et al. 2008).
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Flaxseeds for a new millennium
To achieve optimal nutrition through the intake of healthy foods, Food Science and Technology experts are creating a new framework for food-based dietary recommendations, principally in the areas of food physics, methods of food storage and preservation, nutrient restoration and fortification of foods, as well as the development of health-focused designer foods and functional foods (FAO/WHO 1996; USDA 2010). Initiatives have been undertaken by the food industry to increase the level of ω-3 fatty acids, dietary fibers and anti-oxidants, etc. Flaxseed has drawn the attention of scientists, researchers and industry due to its ω-3 fatty acids and lignans and various health benefits. In the functional arena of 21st century, flaxseed’s use is not just limited to its fibers but has been extended to its various nutraceuticals and therapeutic attributes which make it a potent value added food ingredient. Although flaxseed oil unlike fish oil, does not contain EPA and DHA, but still it is gaining popularity in India and Western countries due to its high ALA content. A major hurdle with ω-3 rich fish oil is consumers’ increased awareness of environmental contaminants [e.g., heavy metals and polychloro biphenyls (PCBs)] and bioaccumulation of these contaminants in fish. If FDA approves the flax to be labeled as a whole grain, the fortified food products variety will see enormous growth in future. Flax is a rich source of ALA (ω-3 fatty acid), dietary fibers, high quality proteins, antioxidants, and lignans, some of which offer synergistic health benefits. Flax contains almost no digestible or glycemic carbohydrates. In all respects, flax offers a model for whole grains or seeds and underscores the recognition given to the nutritional value of “whole grains”, “whole seeds” and “whole foods”.
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Conclusions
Based on the information, it is evident that flaxseeds are the richest source of α-linolenic acid and lignans. It is also a considerable potential source of soluble fiber, antioxidants and high quality protein. Its long journey from being a medicine in ancient times to the health food source in 21st century has opened the doors for a large population. The role of flaxseed lignans and ω-3 fatty acid in reducing the risks associated with cardiac and coronary disease, cancer (breast, colon, ovary and prostate) and other human health risk factors has been well known. When healthy heart is one of the most desired and highly demanded health benefits from functional foods; and where food industry’s goal is to develop innovative solutions to address nutritional challenges, flaxseed is going to play a vital role for the same. Flaxseed can contribute in improving the availability of healthy food choices, specifically by improving the nutrient profile of foods through reductions in the salt, sugar and saturated fat content; and by increasing the content of ω-3 fatty acids and other bioactive compounds. With contribution from such factors, worldwide market for healthy heart foods is estimated to grow rapidly in the coming years. As a result, flax and flaxseed oil may be preferred ingredients of functional foods and nutraceuticals in future. There is no doubt that a change to an omega-3 rich and high fiber diet would be beneficial. Therefore the use of flaxseed in whole seed or ground form can be recommended as a dietary supplement. Modern techniques like high power ultrasound, micro-fluidization, spray granulation and nanoencapsulation will pave way for new approaches to the processing, stabilization and utilization of flaxseed oil. Further, enrichment of diets of the animals with flax/flaxseed oil for production of ω-3 enriched eggs, milk, meat and other animal origin products could be another approach in utilizing flaxseeds.
What does lignan mean in flax oil?
Let’s have a quick look at the question of lignans. Here is a simple quick guide which may be all you need, but for more, have a look on the web.
What are they, what do they do and what is the best way to get them in the diet?
Lignans are a group of chemical compounds found in plants and are one of the major classes of phytoestrogens, which are oestrogen-like chemicals and also act as antioxidants. Linseed (Flax seed) contains the highest content of Lignans than any other plant, sesame seed is next on the list but some way down. Remember do not confuse Lignans with Lignin’s. Lignin’s are a completely different thing altogether!
milled ground linseed flax seed flaxseed lignan lignans fibre omega 3 protein
Ground Linseed
The best way to incorporate lignans into your diet would be to use ground or milled linseed (flaxseed). The milled seed can be used in many day to day recipes and as you get used to lovely linseed it soon becomes second nature, your body really loves it. A couple of desert spoons are often recommended, about 20-30mg per day. Linseed meal is increasingly being recognised as being a major contributor to gut repair and health.
High Lignan Linseed (Flax seed) oil - Should I buy oil that says High in Lignans?
There are a couple of issues here: firstly, lignans are not part of the pressing process they are prepared linseeds (flaxseeds) added to the oil afterwards. As you can see you need up to twenty grams per day of lignans that would mean in a 250 ml bottle of oil consumed at 10ml per day (25 days) you would need to contain 500grams of lignans at 20grams per day, even at 10grams that would be 250 grams. From my observations there are only about a maximum of 10 grams of added prepared seed this would seem to me to be of very little value. But by far the most damaging issue is the bottle has to be shaken to liberate the seeds so you are daily oxygenating the oil which will be degraded by this process.
So advice from The Linseed Farm experts is buy farm fresh oil and gets your lignans from fresh linseed meal.
Useful tip.
Sprinkle some whole linseeds in your water bottle every day and you will be drinking water with amazing hydrating properties.
Do Almonds contain lignans?
Aug. 9, 2021 -- A new study finds a link between eating plant-based foods rich in certain nutrients and a lower risk of heart disease.
The study, which observed more than 200,000 men and women over 30 years, shows that those who regularly ate more plant-based foods rich in what are known as lignans had a much lower risk of developing coronary heart disease than those who did not.
Plant-based foods such as whole grains, fruits, vegetables, seeds, nuts, red wine, and coffee contain lignans, molecules that have antioxidant and anti-inflammatory effects, explains Yang Hu, a research fellow at the Harvard T.H. Chan School of Public Health in Boston.
"Lignan is an estrogen-like molecule, so it exerts some estrogenic effects which are cardioprotective. It also has ant-inflammatory properties," Hu says.
Hu and his team studied data on eating patterns of more than 200,000 men and women who were free of heart disease and cancer at the beginning of the observation period. Food frequency questionnaires were filled out every 2 years and how many lignan-rich foods they ate was tracked.
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Over time, the researchers found a significantly reduced risk of coronary heart disease among those who ate more plant-based foods rich in lignans. This was true for both men and women, and for various types of lignans.
The study also showed that when fiber was added to the diet, the protective association with diets higher in the lignan-rich plant foods was increased.
Participants with higher lignan intake were older, fitter, leaner, and had were less likely to have high blood pressure and high cholesterol.
Hu plans to take his research further to explore why fiber may help lignan molecules create their protective benefits..
The makeup of your gut matters, too, Hu says, because the lignans must go through the gut bacteria to reach the blood system.
"This opens another avenue of research because we can take further steps to see how the gut microbiota and fiber interact with the production of lignans and how these might affect disease risk for other conditions, such as diabetes." he added.
Nutrition expert David J.A. Jenkins, MD, professor of Medicine and Nutritional Sciences at the University of Toronto, who authored an editorial that appeared with the publication, says these new findings reaffirm the value of eating a variety of plant foods.
Jenkins also advocates eating such foods in a less-processed form, because they have higher amounts of their antioxidant, anti-inflammatory compounds.
"You are far better off eating your apple than having apple juice, and you’re far better off having your banana than making it into a smoothie," he says.
Do oats have lignans?
Need some healthy breakfast ideas? Look no further than oatmeal. Just a cup of cooked oatmeal contains 4 grams of fiber -- nearly the same amount that's in an apple or a cup of cooked brussels spouts. It's incredibly versatile and you can find it just about anywhere (even the drugstore!) so you don't have to compromise health when your stomach's grumbling and the options are limited. Below, find five reasons why eating oatmeal is an excellent choice for your health.
1. Oatmeal can keep you fuller than some other breakfast foods.
That glorious fiber that oatmeal boasts has the power to keep you from excessive snacking between mealtimes. A 2014 study published in Nutrition Journal showed that participants who ate oatmeal felt fuller for longer than those who ate the same serving size of Honey Nut Cheerios.
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2. Oatmeal can help lower your cholesterol.
High-fiber foods famously benefit cholesterol levels, and oatmeal is no exception. The soluble fiber in oatmeal helps to reduce the body's absorption of "bad" cholesterol that can increase the risk for heart attacks and strokes, LiveScience reports.
3. Eating oatmeal may reduce your risk of cancer.
High-fiber, whole-grain foods — including oatmeal — have been shown to reduce the risk of colorectal cancer. A 2011 review in the British Medical Journal showed that the risk of colorectal cancer was 20 percent lower for people who consumed an extra 90 grams of whole grains each day.
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4. Oatmeal is rich in a heart-protective plant chemical.
Delicious oatmeal is rich in lignans -- a plant chemical protective against cardiovascular diseases. Lignans can be found in other foods, like flax seed, broccoli and apricots.
5. Oatmeal is inexpensive.
You can buy a big container of the stuff for just a few bucks -- and a serving costs less than 20 cents. So it turns out oatmeal can leave both your stomach and wallet feeling satisfied.
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Bonus: There are endless ways to eat oatmeal.
If you think oatmeal is boring -- or just a breakfast food -- you are mistaken. You can make savory dishes from the stuff: Top it with some Sriracha and a fried egg, bake it with some bacon or even mix it with some greens (avocado and kale add a really nice texture). And you can get a little creative with your favorite flavors -- try a couple of these recipes and experience the wonders of carrot cake oatmeal, toasted coconut oatmeal, Nutella oatmeal and more.
What is the difference between lignan and fresh flax oil?
Flaxseeds are nutrient-rich seeds that contain various vitamins, minerals, antioxidants and lignans. Like most other nutrients, lignans aren't retained in flaxseed oil and have to be added back as a powder. While lignan benefits are numerous, they haven't been well studied.
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What Is Lignan Flax Oil?
Flaxseed, also known as linseed or Linum usitassimum, is a nutty, nutrient-rich seed. This seed is sold whole, as a meal or powder, and as an oil. Most of the nutrients in flaxseed are found in whole or ground seeds. Certain micronutrients, like lignans, can be added back into the oil.
Flaxseed is known for being a food that's extremely rich in lignans, with 75 to 800 times more than other plant-based foods. Lignans are a type of phytoestrogen that may help reduce the risk of diseases like cancers, heart disease and osteoporosis.
Oil-based flaxseed products are best suited for people who want to supplement their diets with healthy fatty acids. As shown in an April 2015 article in the Journal of Food Science and Technology, 71.8 percent of the fats in flaxseeds are healthy, polyunsaturated fats like omega fatty acids. Just 18.5 percent of the remaining fats are monounsaturated, while 10 percent are saturated.
Flaxseed oil benefits your health primarily because of two specific polyunsaturated fats: alpha-linolenic and linoleic acid. According to Harvard Health Publishing, both of these are essential fats that you can only obtain from your diet. Flaxseed is particularly unique, because it's hard to find plant-based foods that are rich in alpha-linolenic acid (ALA).
Read more: 17 Reasons Why You Probably Need More Omega-3s in Your Diet
Lignans' Benefits for Your Health
There are several types of lignans in flaxseed, but the main type is known as secoisolariciresinol diglycoside (SGD). The bacteria in your gut microbiome metabolize lignans like SGD and releases them into your bloodstream. Once they're in your bloodstream, lignans move throughout your body, where they are thought to provide you with a variety of benefits.
According to the Journal of Food Science and Technology article, lignans are able to act as antioxidants, scavenging harmful free radicals and preventing cancer. Lignans are also thought to help reduce the risk of a variety of other conditions, including high cholesterol, high blood pressure, atherosclerosis, diabetes and liver disease.
These claims are supported by various recent studies, like an April 2013 study in the journal Cancer Causes and Control, which showed how the lignans in flaxseed significantly reduced the risk of breast cancer. A May 2014 study in the Diabetes Care Journal also discussed how lignans can help reduce the risk of diabetes.
However, clinical studies that focus on the lignans' benefits are generally limited. Both a June 2017 review in the American Journal of Epidemiology and an April 2017 meta-analysis in the Molecular Nutrition and Food Research Journal agreed that studies on lignans were promising, but found limited evidence on the subject.
It is not yet completely understood how much or which specific lignans are needed to support good health. This ultimately means that while there are no real dangers to consuming high-lignan flax oil, this product may not provide you with any major benefits either.
Read more: Secrets of 16 Strange and Popular Superfoods
Flaxseed Oil’s Benefits
Flaxseed oil's most well-established benefits come from its healthy fats. This seed has a lot of ALA compared to linoleic acid. Although linoleic acid is an essential fat, it's an omega-6 rather than an omega-3 fatty acid. Omega-6 fats can be found in a variety of commonly consumed plant-based products, like mustard, soybeans, corn and olive oil. Most people who eat according to Western dietary standards tend to consume too many omega-6 and not enough omega-3 fats.
If you consume too many omega-6 fatty acids, you may increase your risk of various health issues, including inflammatory bowel disease, rheumatoid arthritis and obesity. However, don't misunderstand: Omega-6 fats aren't harmful like saturated fats or trans fats. Omega-6-related issues are often simply resolved by consuming more omega-3 fats.
This is where flaxseed oil's benefits come in: Since flaxseed has a higher than average amount of ALA, it can improve your health by adding more omega-3 fatty acids to your diet. According to a September 2015 review article in the BioMed Research International Journal, ALA also has the ability to protect your heart and brain and reduce inflammation and depression.
Some of the ALA you consume is converted into other omega-3 fatty acids, like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which have even more health benefits.
Read more: 13 Powerful Grains and Seeds
Regular vs. Lignan Flax Oil
There's not much difference between lignan flax oil and regular flax oil aside from the added lignans. The lignans are found in the carbohydrate portion of the flaxseed and aren't retained when these seeds are used to make oil. Fortunately, lignan bioavailability increases when flaxseeds are ground up, making it easy enough to add them back into oils and other products.
However, the beneficial fatty acid content doesn't really change when you add lignans into oil-based products. The finely ground flaxseed particles that have been mixed back into the oil aren't even substantial enough to affect your flax oil's macronutrient content.
For example, 1 tablespoon (15 milliliters) of Barlean's Organic Clear Flax Oil has 120 calories and 14 grams of fat. Out of this fat content, 1 gram is saturated, 9 grams are polyunsaturated and 2.5 grams are monounsaturated. Barlean's even notes the amount of omega fatty acids in each serving. Each tablespoon has:
7,640 milligrams of ALA (omega-3)
1,900 milligrams of linoleic acid (omega-6)
2,200 milligrams of oleic acid (omega-9)
In comparison, each tablespoon (15 milliliters) of Barlean's Organic Lignan Flax Oil has 120 calories and 13 grams of fat. Out of this fat content, 1 gram is saturated, 9 grams are polyunsaturated and 2.5 grams are monounsaturated. With:
7,230 milligrams of ALA (omega-3)
1,800 milligrams of linoleic acid (omega-6)
2,100 milligrams of oleic acid (omega-9)
As you can see, there are fewer healthy fatty acids in lignan flax oil, but this difference is fairly minimal. The Institute of Medicine considers between 1.1 and 1.6 grams of ALA per day to be adequate for adults, so a tablespoon of both regular flax oil or lignan flax oil can provide you with far more than your recommended daily intake of omega-3 fatty acids.
Regular vs. High-Lignan Oil Dangers
Although both regular flax oil and lignan flax oil are good sources of essential fats, these products are not for everyone. The Mayo Clinic states that flaxseed oil may:
How to Avoid Xenoestrogens: Balance your hormones by getting these out of your life!
Decrease blood clotting and increase the risk of bleeding
Lower blood pressure
Lower blood sugar levels
Reduce estrogen levels, decreasing the effectiveness of oral contraceptive drugs and hormone replacement therapy
Decrease the absorption of drugs that are consumed orally
If you're taking supplements or medications, particularly contraceptives or anti-coagulant, blood pressure or diabetes drugs, you may want to consume flaxseed oil in moderation.
You should also be aware that flaxseed oil is not appropriate for everyone. According to the Academy of Nutrition and Dietetics, ALA may make certain tumors, like prostate cancer tumors, more aggressive. People who have or have had prostate cancer may not want to supplement their diets with ALA-rich fats like flax oil.
However, lignans have been shown to reduce tumor aggressiveness, especially in hormone-related cancers. Given that lignan flax oil reduces the risk of tumor growth and counteracts further spread, this means that it is much more beneficial than regular flax oil.
However, lignan flax oil still has the potential to interact with medications. If you've had or are currently being treated for a hormone-related health problem, you should talk to your doctor before incorporating any type of flaxseed oil into your diet.
What vegetables contain lignans?
Lignans are plant compounds (meaning they naturally occur in plants) that act as antioxidants.
Aside from soy foods, lignans are among the best sources of phytoestrogens, which are plant-based compounds that have estrogen-like effects. Some people are concerned that phytoestrogens can increase your body's estrogen levels, but eating flaxseeds (which are rich in lignans and phytoestrogen) either decreases or has no effect on blood estrogen levels, according to May 2014 study in Integrative Cancer Therapies. The study also found that eating 1 ounce of ground flaxseeds is associated with a decreased risk of breast cancer and anti-tumor effects.
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Phytoestrogens also have antioxidant and anti-inflammatory properties and are linked to a reduced risk of heart disease and good ovarian health, according to the Linus Pauling Institute.
If you're going through menopause, here's another reason to include phytoestrogens in your diet: Phytoestrogen- and lignan-rich flaxseeds are associated with a higher quality of life and decreased menopause symptoms, according to a 2015 study in Holistic Nursing Practice.
While flaxseeds are the most well-known and most researched foods high in lignans, that doesn't mean they're the only good dietary sources.
How Many Lignans Do You Need?
There are no specific recommendations set for daily lignan intake.
But, eating lignan-rich foods is linked with lower rates of chronic diseases like heart disease and certain cancers, according to a March 2019 review in Molecules.
Note that the lignan amounts listed below are based on data from the Linus Pauling Institute.
1. Flaxseeds: 85.5 mg
Whole Golden Lignan-rich Flaxseeds on a Gold Spoon
Flaxseeds are chock-full of anti-inflammatory compounds like lignans, omega-3s and antioxidants.
Image Credit: Michelle Lee Photography/iStock/GettyImages
Flaxseeds are the best dietary source of lignans — they contain about 75 to 800 times more lignans than other foods, per an April 2015 review in the Journal of Food Science and Technology.
A 1-ounce serving of ground flaxseeds provides 85.5 milligrams of lignans. You'll want to eat flaxseeds ground or milled (rather than whole), as this improves lignan bioavailability. Add them as toppings on oatmeal, yogurt, cereals and desserts to enjoy the benefits of this powerful nutrient.
2. Sesame Seeds: 11.2 mg
After flaxseeds, sesame seeds are the next best source of dietary lignans: A 1-ounce serving of toasted sesame seeds provides 11.2 milligrams.
The lignans in sesame seeds — like sesamin, sesamol and sesaminol — are well-known for their antiaging, anticancer, anti-diabetes, anti-inflammatory and antioxidant properties, according to a December 2019 review in Molecules.
Try these tasty tahini recipes (FYI, tahini is made with sesame seeds) the next time you're looking for a lignan boost.
3. Curly Kale: 0.8 mg
Kale is one of those foods that people instantly think of as a "superfood," and for a good reason. This leafy green is nutrient-dense and rich in lignans, with 0.8 milligrams in a 1/2 cup. Kale is also an excellent source of vitamins A, C and K, according to the USDA.
If you're tired of salads, try these interesting kale recipes (no salad recipes in sight!).
4. Broccoli: 0.6 mg
Cruciferous vegetables — like broccoli, kale, cabbage, Brussels sprouts and cauliflower — are among the best sources of plant lignans. Broccoli is particularly rich, with 1 cup of chopped broccoli providing 0.6 milligrams of lignans.
Try adding broccoli to any of these healthy stir-fry recipes.
5. Apricots: 0.4 mg
Apricots are one of the fruits that contain lignans. Just 1 apricot gives you 0.4 milligrams of lignans as well as some fiber and vitamin C for just 17 calories, per the USDA.
6. Brussels Sprouts: 0.3 mg
Brussels sprouts are rich in many antioxidants, especially lignans, vitamin C, kaempferol and zeaxanthin. A 1/2 cup of Brussels sprouts provides 0.3 milligrams of lignans.
Try these inventive Brussels sprout recipes if you're looking for a more refreshing take on cooking sprouts other than simply roasting them.
7. Strawberries: 0.2 mg
Lignan-rich strawberries in a clay plate on wooden table
The bright-red fruit is also an excellent source of vitamin C.
Image Credit: Sanny11/iStock/GettyImages
A 1/2 cup of strawberries has 0.2 milligrams of the plant compound. Try these healthy strawberry breakfast recipes to start your day off on an antioxidant-rich foot.
Are chia seeds high in lignans?
Lignans in Flax and Chia Seeds Lower the Risk of Breast Cancer
The old adage “An ounce of prevention is worth a pound of cure” best describes what our focus should be regarding breast cancer, which is the most common form of cancer that affects women, and is the second leading cause of death for women after heart disease. While a great deal of money and attention is focused on breast cancer awareness, it would make more sense to concentrate on preventing the disease from occurring in the first place.
There are nutritional strategies that are safe, easily implemented and have been proven effective in reducing the risk of breast cancer.
A Great Breast Cancer Fighter: Lignans in a High-Nutrient Diet
Among the most powerful anti-cancer foods are flax and chia seeds, which are a rich source of lignans. Lignans have anti-estrogenic effects that inhibit cell growth in breast tumors.
Let’s take an in-depth look at lignans and why they are so effective in combating breast cancer:
Plant lignans are one of the four classes of phytoestrogens (isoflavones, lignans, stilbenes, coumestans). Phytoestrogens are a group of chemicals found in plants that can act like the hormone estrogen. In particular, lignans are structurally similar to the main mammalian estrogen, estradiol.1 Plant lignans are modified by bacteria in the human digestive tract into enteroligans.
Anti-cancer Effects of Lignans
Enterolignans are structurally similar to estrogen and can bind to estrogen receptors. This capability allows lignans to either have weak estrogenic activity or block the actions of estrogen in the body. For this reason, plant lignans are classified as phytoestrogens, and there has been much interest in the potential contribution of lignan-rich foods to reduced risk of hormone-related cancers.2,6
It is important to recognize the role of healthy bacteria in this process, because antibiotics can destroy beneficial bacteria in the gut, resulting in long-term reduction in enteroligans.2 Eating commercial meats expose us to antibiotics, as does the overuse and inappropriate prescribing of these drugs by physicians.
Best Sources of Plant Lignans
Flaxseeds are the richest source of plant lignans, having about three times the lignan content of chia seeds, and eight times the lignan content of sesame seeds. It is important to note that flaxseed oil does not contain lignans, because they bind to the fiber. The other plant foods on the list have about one-tenth or less the amount of lignans as sesame seeds per serving.2-3
Flaxseeds (85.5 mg/ounce)
Chia seeds (32 mg/ounce)4
Sesame seeds (11.2 mg/ounce)5
Kale (curly; 1.6 mg/cup)
Broccoli (1.2 mg/cup)
Enterolignans inhibits aromatase7 and estradiol production in general, lowering serum estrogen levels.8 Plant lignans also increase concentration of sex hormone binding globulin, which blunts the effects of estrogens.9-11 These benefits were documented when 48 postmenopausal women consumed 7.5 g/day of ground flax seeds for 6 weeks, then 15 g for 6 weeks — and significant decreases in estradiol, estrone, and testosterone were noted, with a bigger decrease in overweight and obese women.12
In a mouse model, a flaxseed diet (5%, 10%) shows dose-dependent inhibition of breast tumor growth.13 Human trials also confirmed similar beneficial effects. A double-blinded, randomized controlled trial of dietary flaxseed demonstrated dramatic protection.
Women ate either a control muffin with no flax seeds imbedded, or a 25g flax-containing muffin, starting at time of diagnosis of breast cancer for just 32-39 days until surgery. Tumor tissue analyzed at diagnosis and then at the time of surgery demonstrated surprising benefits even in this short time frame. There was a significant apoptosis (tumor cell death) and reduced cell proliferation in the flaxseed group in just the one month.14
Likewise, women eating more flaxseeds with a documented higher serum enterolactone were found to have a 42% reduced risk of death from postmenopausal breast cancer and a dramatic 40% reduction in all causes of death.15-16
Flaxseeds are clearly super foods; even with a mediocre diet they offer powerful protection against breast cancer. Another interesting study on flax followed women for up to 10 years and found a 51% reduced risk of all-cause mortality, and a 71% reduced risk of breast cancer mortality. In addition, intake of dried beans was associated with a 39% reduced risk of all-cause mortality.17Endometrial and ovarian cancer have not been as extensively studied, but the few studies that have been conducted suggest a protective effect.2,18
Bottom line: don’t forget to take your ground flax seeds (or chia seeds) every day. When used in conjunction with dietary exposure to greens, onions, mushrooms and beans, dramatic reductions in the risk of breast cancer are possible.
Dietary fiber has been recognized as a contributing factor in human health for more than 50 years (Hipsley, 1953). Building on the pioneering work of Burkitt and Trowell (1975) in East Africa in the early 1970s, medical researchers began to recognize that high levels of fiber in the diet play a significant role in offsetting chronic diseases such as diabetes, cardiovascular disease, and certain cancers. Even at that early stage, dietary fiber was recognized to be the remnants of plant cell walls that were resistant to digestion, including cellulose, hemicelluloses, lignin, and polysaccharides such as pectin (DeVries et al., 1999).
Flaxseed contains by far the highest level of lignans.Extensive research in the years following these discoveries has confirmed the protective role of dietary fiber. Medical and nutrition researchers have examined the role of various components of dietary fiber in an effort to understand the mechanism(s) of action. Dietary fiber, which is insoluble in aqueous conditions, is thought to bind toxins, increase fecal bulk, and reduce the severity of constipation and diverticular disease.
The chemical components of insoluble fiber include cellulose, lignin, and most hemicelluloses found in the primary and secondary cell walls of plants. The cellulose in cell walls is chemically bonded to hemicelluloses and lignin (Salisbury and Ross, 1978). The latter two polymers act to give significant structural rigidity and resistance to the action of enzymes and acids. Thus, insoluble fiber is poorly fermented by the bacteria in the colon.
Soluble fiber, such as pectin, β-glucans, and some hemicelluloses, are found in the primary cell walls and the space between adjacent cell walls, called the middle lamella. Soluble fiber acts to increase the viscosity of gastrointestinal fluid, which slows the digestion of starch and the transport of glucose. It is extensively fermented by bacteria in the large intestine. Thus, soluble fiber provides fuel for the colonic bacteria, which in turn produce the short-chain fatty acids that are the primary source of fuel for the cells lining the colon (Livesey and Elia, 1995). It is becoming increasingly clear that the action of colonic bacteria on dietary fiber produces a number of physiologically active molecules.
Fig. 1—Core structures of plant lignans.Lignans Are Different from Lignins
More recently, some of the minor components associated with dietary fiber have been isolated and found to produce important physiological effects. Of significant interest are the lignans, a group of relatively simple di-phenols, which share the same molecular origins as the much more complex polymeric lignins. However, the biosynthetic pathway to the lignans diverges from lignin at the early stage of the phenylpropenols, primarily coniferyl and sinapyl alcohols. Substantial evidence now indicates that the biosynthetic pathways to the lignans and lignins are fully independent after this stage (Lewis et al., 1998). All lignans share 2,3-dibenzylbutane as their common chemical backbone (Fig. 1).
In plants, lignans function as defensive chemicals, protecting them from attack by insects, microorganisms, and even other plants (Ayres and Loike, 1990). So it is not surprising that lignans are associated with plant cell wall material, especially the outermost layers of cells. It has been shown, for example, that lignans in cereal grains are concentrated in the outermost pericarp layer of cells, followed by the aleurone layer, and are therefore abundant in cereal brans, a rich source of dietary fiber (Glitso et al., 2000). At present, however, there is no evidence that lignans are chemically linked to plant cell wall components, such as lignin, even though they share a common biosynthetic origin. It is therefore possible to isolate intact lignans from plant material by solvent extraction and other chemical means.
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Fig. 2—Structure of mammalian lignans.Plant Lignans Are Precursors of Mammalian Lignans
Following ingestion, the lignans in plant-based foods—primarily oilseeds, cereal grains, vegetables, fruits, and legumes—are converted by bacteria in the large intestine into two simple diphenols: enterolactone and enterodiol (Fig. 2) (Stitch et al., 1980; Setchell et al., 1980). These compounds are called mammalian lignans because they have been found only in mammals. They are formed by the enzymatic removal of methyl and hydroxyl groups from the plant lignans.
Once formed, the two compounds are absorbed from the intestine and undergo enterohepatic circulation. Further processing results in conjugates being formed in the liver, which are subsequently excreted in the bile and reabsorbed from the intestine. Ultimately, both enterolactone and enterodiol are excreted in the urine as glucuronate and sulfate conjugates and in the feces as free phenols (Adlercreutz et al., 1995). Higher intake of dietary plant lignans is associated with higher levels of enterolactone in blood serum (Kilkkinen et al., 2003). Thus, lignans may serve as biomarkers of a healthy high-fiber diet containing whole grains, fruits, and vegetables (Lampe, 2003).
Mammalian lignans have been found to exhibit a number of significant physiological effects (Tham, et al., 1998). Enterolactone is a moderate inhibitor of estrogen synthetase (aromatase) and lowers estrogen levels, while enterodiol is a weaker inhibitor (Makela et al., 2000). Both compounds also increase the levels of sex hormone–binding globulin (SHBG), which is important in controlling the availability of androgens and estrogens in the body. Plant lignans are therefore considered to be one of several chemical classes of phytoestrogens. Lignans are also effective as antioxidants and may inhibit lipid peroxidation. Enterolactone decreases the plasma levels of F2-isoprostanes, a measure of lipid peroxidation (Vanharanta et al., 2002).
A number of epidemiological studies have found an inverse association between dietary intake of lignans and the risk of cardiovascular disease and certain types of cancer (Arts and Hollman, 2005). The studies have utilized both the concentrations of enterolactone and enterodiol found in blood serum and urine and the estimated dietary intake of two common plant lignans: matairesinol and secoisolariciresinol.
Vanharanta et al. (1999) found a 65% lower risk of acute coronary events for men with high serum concentrations of enterolactone. van der Schouw et al. (2005) found that a diet high in plant lignans both increased and decreased the levels of certain risk factors for cardiovascular disease in men.
The effects of lignans on cancer have been studied more thoroughly (Arts and Hollman, 2005). Several studies have found an inverse association between lignan levels and the risk of breast cancer. For example, an inverse association was found for breast cancer in premenopausal women, but not postmenopausal women, in the U.S. (McCann et al., 2002). Protective associations have also been reported for endometrial, ovarian, and thyroid cancer in women (Arts and Hollman, 2005). Possible protective roles in prostate and colon cancer require further study. However, in a recent in-vitro study, both enterolactone and enterodiol caused dose- and time-dependent decreases in the number of human colon cancer cells (Qu et al., 2005).
Table 1—Lignan content of foods.aPlant Lignans in Food
Lignans occur in a wide variety of plant-based foods. Table 1, adapted from Meagher and Beecher (2000), compares the levels of lignans found in many foods based on two different methods of analysis. The direct method is based on the work of Mazur et al. (1996, 1998a, b), who analyzed the content of two common plant lignans, secoisolariciresinol (SEC) and matairesinol (MAT), using isotope dilution gas chromatographic–mass spectrometric analysis of food extracts. The indirect method is based on the earlier work of Thompson et al. (1991), who used extraction and capillary gas chromatography to analyze the amount of enterolactone (ENL) and enterodiol (END) produced by in-vitro fermentation of various foods with human fecal microbiota. The latter results are in good agreement with the levels found in urine.
Flaxseed contains by far the highest level of lignans, but vegetables, cereal brans, and legumes are also good sources, based on the amounts consumed in a high-fiber diet. Tea is also a good source of lignans. A useful summary of phytoestrogen concentrations estimated in foods can be found in de Kleijn et al. (2001).
One of the greatest issues still facing researchers in this field is the limited information on the form and levels of plant lignans in food. This is best illustrated by comparing the levels found for SEC and MAT in foods with the levels of ENL and END produced by in-vitro fermentation, as shown in Table 1. In most cases, far higher levels of the mammalian lignans are produced by bacterial fermentation of food than would be predicted by the levels of SEC and MAT in food.
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Until fairly recently, it was assumed that SEC and MAT were the only sources of mammalian lignans in food. Recent studies by Heinonen et al. (2001) now show that other plant lignans are also important sources of the mammalian lignans. Pinoresinol, lariciresinol, syringaresinol, and others were shown to be precursors of ENL and END. These three plant lignans occur in rye bran in amounts 10–50 times higher than the amounts of SEC and MAT and can produce 10–12 times the amount of ENL.
Research on the extraction of plant lignans from food also demonstrates that alkaline hydrolysis of crude extracts dramatically increases the yields of most lignans (Milder et al., 2004). This step is apparently necessary to free the lignans from a variety of chemical forms present in food. Plant lignans generally occur in foods as glucosides. In addition, two studies have shown that the glucoside of SEC exists as oligomeric esters of hydroxymethyl glutaric acid in flaxseed (Ford et al., 2001; Kanal-Eldin et al., 2001). There are no reports on the oligomeric structures of other plant lignans in food, but they are likely formed by enzyme-mediated coupling of the diphenols. Thus, alkaline hydrolysis, followed by enzymatic removal of glucose, is necessary to free the lignans for complete extraction and analysis.
Lignans may also occur in different forms in different foods. For example, omitting the alkaline hydrolysis step decreases the yield of SEC from flaxseed by 81%, and from broccoli by 2–22%, while the yield from tea is unchanged (Milder et al., 2004). This suggests that lignans may occur as monomers in tea, as a mixture of monomers and oligomers in broccoli, and predominantly as oligomers in flaxseed.
Other foods may also contain a range of monomers and oligomers, which could affect accessibility for bacterial fermentation. Glitso et al. (2000), however, showed that lignans in the pericarp layer of cells are readily converted to mammalian lignans in pigs despite the very low degradability of this dietary fiber. Thus, plant lignans are not inextricably bound to dietary fiber. Also, Begum et al. (2004) showed that enterolactone was formed in rats from wheat bran and rye bran from which the plant lignans had previously been extracted. This suggests that plant cell wall lignins may also serve as a source of mammalian lignans. Should these results be confirmed in humans, it opens the possibility that mammalian lignans may be formed in greater amounts and in greater numbers of physiologically active compounds than previously thought.
Relatively little has been reported on the effects of food processing on plant lignans. Meagher and Beecher (2000) summarized the short list of publications that have examined the lignan content of breads, crackers, and breakfast cereals by either the direct or indirect method of analysis. It is not clear if processing affected lignan content. Matairesinol (MAT) has been shown to be sensitive to aqueous alkaline conditions. Recovery of a known amount of MAT added to bread was only about 50% following extraction by alkaline hydrolysis (Milder et al., 2004). Baking processes using alkaline leavening agents could therefore reduce the content of MAT in whole-grain breads (Jenkins, 1995). However, Nesbitt et al. (1999) showed that there was no difference in urinary excretion of lignans following the ingestion of raw flaxseed, or flaxseed incorporated into processed muffins and bread. The vast majority of the lignans in flaxseed is SEC, which may be more stable to processing conditions.
Looking Forward
Clearly, more research is needed to fully understand the different forms of lignans in food and their conversion to mammalian lignans. Effects of food processing on plant lignans should receive greater attention. It is also very important to determine if there are additional precursors of mammalian lignans, and how this might affect nutrition studies. Based on their effects in modulating steroid hormone metabolism, cell growth, and lipid peroxidation, the lignans may eventually be proven to exert protective roles in other human and animal diseases.
(Chris Woollams. CANCERactive) Xenoestrogens are man-made, or synthetic, chemicals which, once inside the body, can mimic the action of the female sex hormone oestrogen, or estrogen as it is called in some countries. Xenoestrogens are often dubbed oestrogen mimics. The word ’xeno’ comes from Ancient Greek, meaning ’foreign’. Xenoestrogens are environmental toxins.
Every animal body exists in a state of ’homeostasis’; that is to say that under normal conditions all the hormones are in balance as nature intended. Throw one of them out and all of them go out of kilter. So adding chemical oestrogens to the body doesn’t just increase the pool of oestrogen, it alters the levels (up or down) of all the other hormones in the body and so the body goes out of balance with consequent negative effects. The system of hormone production and interface is called the Endocrine System. For this reason xenoestrogens are often referred to as ’Endocrine disrupters’.
Hormones are incredibly potent natural chemicals and can work in the body at one part per trillion. That is to say that only one molecule of a hormone in a million molecules of blood may be enough to have an effect. Synthetic chemicals found in all manner of products we use, from pesticides to deodorants and shampoos are, of course regulated and safe levels set by Governments. Usually these safety limits are set in ’parts per million’. That is to say that these chemicals in your nail polish are permitted and deemed safe even though they could be present in concentrations a thousand times or more higher than your natural hormones.
Dr Anna Soto of Tufts has conducted numerous experiments on the issue of xenoestrogens and has concluded beyond all doubt that they are cumulative. Notwithstanding any safety limits set by Governments for any individual chemical, xenoestrogens add up and, depending upon the products you commonly come into contact with, xenoestrogens in the body can far exceed any Government safety limit.
The World Wildlife Fund has published several studies on toxins in the body, and we have covered these in Cancer Watch. Suffice it to say here that a study of blood samples when looking for almost 80 of the world’s most toxic chemicals found 29 in the average body, with 49 in the worst case. The pollution is growing ever worse: In another study of grandparents and grandchildren, the blood of the old contained 35, while that of the young averaged 65.
Fat is a wonderful solvent, and body fat can dissolve and hold all these chemical toxins, including hormones, that you would rather excrete. Indeed, claims that many of these toxic chemicals simply wash through the body have been found to be completely false. The most damaging fat is ’Visceral fat’, which lies inside your body around your organs bathing them in this sea of pollution.
Another area of fatty tissue is the female breast. Research has shown that when breast feeding, mothers can pass the accumulated toxins to their infants. Other research has shown that many xenoestrogens can pass to the foetus in the womb. Is it any wonder that
American research showed that the ’Lifetime safe Limits’ for toxins in the body were actually exceeded by those in the blood of an 18 month old baby.
Oestrogen:
Oestrogen, or estrogen in the USA, is the female sex hormone. Text books will tell you that it is produced by the female ovaries and production declines to virtually nothing after menopause. Those text books are wrong.
Oestrogen is not a single hormone but a family of similar chemicals. Those produced inside the human body are called endogenous; those made outside are called exogenous.
Oestrogen is typically produced in females in the first two weeks of their monthly cycle. In the second two weeks it is counterbalanced by the hormone progesterone. Guy’s Hospital, London, ran two studies in the 1990’s and showed that where women had breast cancer operations in the second two weeks of their cycles, they survived more than twice as long as women having identical operations in the first two weeks of their cycle. Sleep is also a great natural balancer of endogenous oestrogen. Women with disrupted sleep (for example night shift workers, or airline hostesses) have greater risk of breast cancer. Melatonin is a hormone produced by the pineal gland just under your brain about 90 minutes after falling asleep in a darkened room. It possesses the ability to regulate endogenous oestrogens in the body.
The raw material for oestrogen production in the body is fat. Oestrogen is not merely produced in the ovaries, but in stores of fat around the body such as those lying just under the skin. A little is produced in the kidneys. Cancer Research UK a few years ago estimated that levels of oestrogen had been increasing in women’s bodies by about two per cent a year over the last 30 years. When a women passes through the menopause nowadays her blood oestrogen levels merely fall to a level just below the threshold that stops her ovulating some experts estimate this fall at 30 per cent. Today’s women have far more oestrogen in their bodies than in the past. Their periods start earlier in their lives and end later; they have less babies. But these statistics are not the main reasons. Even men as they age can now have high levels of oestrogen in their bodies, made from their fatty deposits and stored from the hundreds of polluting environmental chemicals they come into contact with daily.
The dangers of oestrogen for women and men:
As I have explained, an excess of oestrogen in the body alters the levels of all the other hormones in the body away from the primary balance nature intended. An excess in your oestrogen pool will cause imbalance and therefore eventual illness. But this article is concerned with cancer.
Oestrogen causes cancer in three ways, all of which have been clearly evidenced:
1. Oestrogen, in fact one in particular (oestradiol, or estradiol in the USA), can cause havoc in basic biochemical systems and pathways inside the cell. For example levels of sodium are increased, levels of potassium decline. This makes the cellular power stations less efficient, pulling in less oxygen and producing less energy. The waste by-products, sodium salts, are more acid than the potassium salts nature intended, so the cell becomes more acid. At best you have a sick cell, at worst a cancerous one.
2. Oestrogen has been shown to be able to keep stem-cells in their trophoblastic state, dividing in an extremely rapid, almost out of control state. In plain English: Stem cells are the cells you had when you were a very elementary foetus that transformed into specialist eye, heart, lung, brain cells. Stem cells stay all over your body throughout your life. They are the basic repair cells, rushing to sites of inflammation and damage. Wang and his team in America showed that some cancers are caused by the action of oestrogen keeping your repair cells in their elementary state, and not letting them transform into new stomach lining, brain or breast cells. Rapidly dividing cells in your stomach lining? Cancer is likely.
3. Oestrogen has also been shown to be capable of directly altering the structure of DNA, your genetic code, causing mutation.
Oestrogen drives about 70 per cent of breast cancers. It is now shown to be involved in ovarian cancer and uterine, or womb, cancer. Studies from Bristol University first showed its involvement in some colon cancers, and US research shows oestrogen behind some stomach, lung and brain cancers. So clearly, this is not just a female phenomenon. No indeed, studies from Australia to Singapore, culminating in one by Dr Thompson of MD Anderson in Texas showed that oestrogen could turn nice, safe testosterone in men into an aggressive chemical DHT. This drives prostate cancer.
Perhaps more worrying was a research study we covered in Cancer Watch showing 13 chemicals linked to developing prostate cancer all were oestrogen mimics.
Not all oestrogens were created equal
As I said above, oestrogen is not one hormone but a family. All of this family have a similar chemical ’end’ to their molecule and this ’end’ can bind to receptor sites on the membrane of your cells, sometimes passing a message inside the cell, if the receptor is active.
One family member is the highly aggressive oestradiol. As I said above, if this binds to your cellular receptor sites it can create havoc inside your cells.
Another human endogenous oestrogen is oestrone. It is far, far weaker in its effects than oestradiol about 40 times less so. Research has repeatedly shown that indole 3 carbinol (or I3C, from broccoli and cruciferous vegetables) can convert oestradiol into its safer sister. Indeed I3C can even ’switch off’ the receptor sites.
But plants have oestrogens too. These are called phytoestrogens. Now, a number of commentators including Wikipedia and some oncologists get awfully confused about phytoestrogens. Phytoestrogens are exogenous, not endogenous oestrogens. But they are certainly not xenoestrogens. For a start, they are neither man-made or synthetic, but totally natural. The human animal is primarily a herbivore look at your teeth. Do they look like those of a dog or a leopard? No, humans evolved in balance with the vegetation around them. It kept us fit and healthy.
Phytoestrogens are oestrogens in that they have the same chemical ’end’ to their molecule that I described above. But, they are about 40 to 100 times weaker than even oestrone. Now, ask yourself this: A chemical is going to bind to the oestrogen receptor sites on your cells would you rather it was oestradiol, or a phytoestrogen. There really is no contest. Give me the phytoestrogen every time. Women in South East Asia have up to 1000 times the levels of phytoestrogens circulating in their blood than a New York lady has. Cancer Research has produced a number of papers on their protective powers. Professor Trevor Powles who was the top man for breast cancer at The Royal Marsden even calls them anti-oestrogens because they protect your receptor sites from aggressive oestrogens.
Phytoestrogens are commonly found in vegetables, but particularly in pulses. Pulses provided about 30 per cent of our protein in 1900. Who eats them nowadays? But they were protective. Red Clover, the herb of Hippocrates and used in a number of Alternative treatments like the Hoxsey Formula, is an excellent source of a protective phytoestrogen, genistein and its use as a protector in cases of breast cancer has been studied at The Royal Marsden.
When women develop an oestrogen positive breast cancer, the standard treatment is a formula of 5 years on Tamoxifen, followed by 3 years on an Aromatase Inhibitor. The Tamoxifen blocks the oestrogen receptor sites on your breast cells, just as phytoestrogens might, and indole 3 carbinol can turn off. The Aromatase Inhibitor cuts your body’s production of oestrogen.
But what if the oestrogen causing your cancer was not being made by you? What if it came primarily from outside sources?
Xenoestrogens
Of course, eating meat will bring the animal’s own oestrogens into your body, especially if those animals have been fed hormones to make them grow. But chemical sources can far outweigh this contribution. Xenoestrogens are everywhere; in our water, food, soil, and many of the products you know and trust in your family home. They come mainly from the petrochemical industry.
Colburn, Dumanoski, and Meyers identified 51 ’families’ of endocrine disrupters in their book ’Our Stolen Future’. The most common example of their damage is that of lowered sperm counts, hermaphrodite fish swimming off the coast of California, male babies born with diminished genitalia such is the power of a female sex hormone mimic on the male population. But this is only the start.
Strong xenoestrogens like organochlorides are produced by petroleum hydrocarbons reacting with chlorine. They are everywhere.
1. Pesticides:
Perhaps the most famous link between xenoestrogens and cancer was the discovery of very high rates of breast cancer in Israel in the seventies. This was directly linked to three organochloride pesticides, DDT, Lindane and BHC, which had contaminated pastures and invaded the food chain in cows’ dairy. You may think these poisons were banned. They were for use in the West; but they are still manufactured and sold to third world countries and could appear on imported vegetables and fruit in a supermarket near you. The Food Standards Agency in the UK has already cried that imported foods exceed pesticide safety levels set by the UK Government on home grown foods. But does anyone do anything about it? Worse, formulations have been changed. So now the compound called Difocal is used as a spray from California to Washington on apples and strawberries alike. It happens to contain DDT.
While the UK White Paper on cancer in 2004 ignored the dangers of pesticides completely, the European Union (July 26th 2006) is quite clear: ’Long-term exposure to pesticides can lead to serious disturbances to the immune system, sexual disorders, cancers, sterility, birth defects, damage to the nervous system and genetic damage’. So all quite harmless really!
My favourite is an article from a leading newspaper in Australia:
Fatal fish mutations at a fish farm in the Noosa river, Australia, have been laid firmly at the door of pesticides. The fish farm reported that all its Sea Bass larvae had been born with two heads and died. Then chicken, horses and sheep in a neighbouring farm were reported as experiencing birth defects. The cause has been identified as organophosphates used on a nearby macadamia nut plantation. Those in question were carbenzadim and endosulphan, which are recognized and even banned in some countries, but are actually recommended for use in Australia.
How to Detox Xenoestrogens | Dr. J9 Live
The UK Food Standards Agency is on record in 2009 as saying that organic food offers no benefit over mass-market food. Why do I have no respect for the FSA?
Herbicides are not much better, nor are weedkillers or insecticides. Dieldrin is primarily an insecticide, as are endosulphan, methoxychlor and heptachlor, while atrazine has had a lot of very negative comment and is a weedkiller. Toxaphene and dicofol (contains DDT) are other common xenoestrogen pesticides.
2. Synthetic hormone supplements
Some versions of the contraceptive pill use oestrogen and oestradiol. A report a few years ago showed increased risk of cancer with usage, of between 26 per cent if you took the pill in your 20’s to more than 50 per cent if you took it into your 40’s. HRT also uses synthetic oestrogens. Several US and UK studies show that the synthetic HRT pill increases breast cancer risk by 26 per cent. Other cancers, like ovarian, have been shown to have an increased risk of 40 per cent. Cancer Research UK has warned against the use of HRT.
3. Recycled water
Thanks to the use of recycled water in cities and the inability of filtration systems to keep up with the latest drug developments, chemical, pesticides and the volume of synthetic oestrogenic products like the pill and HRT in female urine, big city water has become a real area of concern. More and more people are turning to their own filtration systems at home, or the use of bottled water.
4. Plasticisers:
Organochlorines are used in plastics, and in the bleaching of paper. Plastic packaging, plastic bottles, cups, plastic wrappings and can liners may contain PVCs (polyvinyl chlorides), alkylphenols, nonylphenols, Bisphenol-A (BPA) and phthalates. Long-term storage in plastic containers involving these ingredients can make matters worse.
BPA has now been banned in Canada. It is found in plastic bottles, babies plastic bottles, white plastic liners in cans. In California its use in toys for children under three years of age has been banned.
Phthalates are similarly plasticisers. In particular research showed that heat could denature the plastic releasing higher levels of phthalates into the contents your trendy mountain mineral water left in the car in the heat, your sun cream plastic bottle left in the sun next to you on the beach, your plastic thermos coffee cup re-used over and over again.
DEHP, a PVC plasticiser, when found in the blood of pregnant women, resulted in 11 per cent of the male offspring having some form of genital deformity.
If you are using bottled water, stick to glass!
5. Preservatives
One big area of discussion is the preservative class of chemicals called Parabens. Esters of para-hydrobenzoic acid, they are found in foods and cosmetics from moisturizers to shampoos they are used because of their anti-bacterial and anti-fungicidal strengths. But they are now know to be mildly oestrogenic. However, they are ubiquitous.
Another such preservative and xenoestrogen is BHA, butylated hydroxyanisole, used as a food preservative in packaged foods to increase shelf life. Yet another is propyl gallate, which is used as a preservative in foods to help prevent fats and oils from going off. And a fourth is 4-hexylreorcinol, which is used as an additive to help shrimp and other shellfish from losing their natural colour. Erythrosine, which is a red food colouring agent sometimes used in sweets is also a proven xenoestrogen.
6. Household, personal care and toiletry products
Where do I start? Possibly by worrying you that Euro MP’s voted to restrict over 1000 common ingredients until a non-elected EU Commisioner asked them to rethink. Companies like Neways which make toxin-free products have banned over 3,000 ingredients from their list.
Go and find yourself a supplier of toxin-free products. The Chris Woollams 4 Health Shop has one of the UK’s most extensive ranges from a number of top supplier click here.
Perhaps the worst offender is perfume and perfumed products. Over 150 different ingredients can be called upon to make a perfume, and not one has to be listed. So DEHP may be an ingredient, as may toluene. And you are going to plaster body lotion containing xenoestrogens all over your skin? Nail polishes commonly use toluene. Your nails are porous and it will pass straight into the blood stream. Nail polish solvents ditto.
Never use perfumed products on your skin. Put perfume on your clothes.
Then there are ingredients like nonylphenol in liquid laundry detergent and all-purpose cleaners.
Or how about Triclosan? What a waste of time. Perfectly safe until you mix it with water, it is found in toothpaste, soap and shampoo to name but three of the hundreds of products. There is debate over whether its use in hand sanitisers and so on even causes the destruction of bacteria that is claimed. It is certainly pretty destructive when it gets into our waste water systems though. If you want to avoid it, why not use "Tee-Tree" oil; naturally anti-bacterial? Put some into your liquid soap and shampoo bottles.
Or Aluminium Chlorohydrate used as an antiperspirant and an xenoestrogen to boot.
Finally, I should mention Dichlorobenzene. This again is a family of chemicals, all found in-home and designed to make your toilet or living room smell like a fresh mountain meadow. But, in research conducted by Harvard and UCLA jointly, they were found to be the second most polluting airborne chemical after class A carcinogen Formaldehyde, and ahead of benzene (petrol, diesel etc). And there are serious concerns about these ’deodorisers’ in connection to cancer risk. And they are xenoestrogens.
Some final thoughts:
i) Remember you may consume these xenoestrogens from pesticides, or breathe them because of an incinerator nearby, or simply put them on your skin. They could have been an ingredient in the contents, or have leached into it from the plastic container, especially after heat. Your skin is a carrier not a barrier. If it were otherwise, nicotine and HRT patches would not work. Plasticisers can get into your sun creams, shampoos and body lotion, not just your sandwiches.
ii) Levels of beneficial bacteria decline in your gut as you age; if you do not eat whole foods; if you consume too much alcohol, chlorinated water and salt, or too many drugs and antibiotics. However, research is clear that some of these little helpers can chelate (bind) to oestrogenic products with the help of fibres like lignans, and expel them from the body. A daily multi-strain probiotic may be very helpful to keep levels up.
iii) Green foods like Broccoli which contains Indole 3 Carbinol, can help detoxify your cells of many of the xenoestrogens and research shows they can even prevent the effects of dioxins. Glutathione levels inside cells are increased in people who have a high intake of vegetables and fruits - especially ’greens’. Glutathione is a powerful antioxidant; and it detoxifies free-radicals and drugs and chemicals inside cells. Other ’greens’ that will help are whole foods like chlorella, and wheatgrass.
Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time. Incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.
Journal Information
\Environmental Health Perspectives (EHP) is a monthly peer-reviewed journal of research and news published with support from the National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services. The mission of EHP is to serve as a forum for the discussion of the interrelationships between the environment and human health by publishing high-quality research and news of the field. With an impact factor of 7.03, EHP is the third-ranked journal in Public, Environmental, and Occupational Health, the fourth-ranked journal in Toxicology, and the fifth-ranked journal in Environmental Sciences Current Issues of Environmental Health Perspectives are freely available to all users on the journal's website.
Publisher Information
The mission of the NIEHS is to reduce the burden of human illness and disability by understanding how the environment influences the development and progression of human disease. To have the greatest impact on preventing disease and improving human health, the NIEHS focuses on basic science, disease-oriented research, global environmental health, and multidisciplinary training for researchers.
Xenoestrogens are foreign chemicals that act like estrogen and bind to the estrogen receptors of cells in your body. They disrupt the endocrine system (which is responsible for hormone production), leading to disease, the growth of adipose tissue (fat) and infertility in humans and animals of all ages.
As you probably know, estrogen is a sex hormone that that plays a vital role in both men and women.
In women, estrogen is made by the ovaries and its production is influenced by the availability of other hormones (such as LH and FSH), which are released by the pituitary gland. It’s responsible for the development of the female reproductive system and breast growth, and it’s also involved in keeping your brain, bones and cardiovascular system healthy.
In men, estrogen is responsible for making sperm and influences libido and erectile function, among other things.
What you might not know is that every cell has an estrogen receptor. In other words, this hormone can relay information to — and thus, influence the operation of — any cell in your body.
That’s why exposure to xenoestrogens can have such a powerful (and negative) impact on health and well-being: it disrupts your endocrine system, which harms your reproductive system and increases your risk of several metabolic diseases, including cancer.
And while you may not have heard of xenoestrogens, I can guarantee you one thing with absolute certainty: you’re exposed to these estrogenic toxins every single day of your life.
Xenoestrogens Make You Sick Slowly
The problem with xenoestrogens is that they don’t make you sick right away. Their effects are so gradual that we often don’t even notice what’s happening to our bodies until it’s too late.
When you eat spoiled food, you usually experience the consequences within hours. If you overeat processed carbs for weeks in a row, you’ll likely gain a few pounds.
But the damage caused by xenoestrogens is sometimes unnoticeable for years or decades, and research suggests that it can even affect your descendants via inherited damage to their DNA and epigenetics.
Seven Ways Xenoestrogens Make You Sick
To understand the different ways that xenoestrogens make you sick, there are a few key facts you need to know.
Xenoestrogens (which are also called estrogenics) can impact almost every cell in the body (because every cell has an estrogen receptor).
Xenoestrogens are stored in fat, and can remain there for a very long time (sometimes, even for years).
Some of the damage xenoestrogens cause to our DNA and epigenetics (the layer on top of our DNA that influences gene expression) can be inherited. So your exposure to xenoestrogens might significantly increase the risk of obesity, cancer and infertility in your children, grandchildren and descendants.
So let’s talk about the specific health issues that are associated with exposure to estrogenics.
1. Fat Gain (Or the Inability to Lose Weight)
Photo of an estrogen-induced pot belly
Carbs aren’t the only thing that leads to a potbelly.
One of estrogen’s important functions is telling cells to store fat in expectation of an upcoming pregnancy. If you continuously expose your body to hormone-disrupting chemicals that mimic estrogen, your body is constantly storing fat for a pregnancy that may never materialize — especially if you’re male.
As a result of that cumulative exposure to estrogen, we see girls starting puberty much too early, and men developing breast tissue (known as “man boobs”) and/or potbellies.
So if you’re eating well, sleeping well and exercising regularly (in other words, living an all-around healthy lifestyle), yet still can’t seem to shake off those extra pounds, then environmental estrogens may be the culprit.
2. Low Testosterone Levels in Men
A photo of Michael's 2020 blood work, which shows that he had low testosterone levels.
My 2020 bloodwork showed low testosterone levels across the board.
Testosterone levels in men have been dramatically declining over the past few decades. In fact, in the 1940s, testosterone levels in men were approximately twice as high as they are today.
The reason? Aside from dangerous lifestyle factors — such as consuming a diet high in processed carbs, a lack of exercise, chronic stress and low-quality sleep — I strongly believe that xenoestrogens play a part in that decline.
That belief is informed by numerous scientific studies, including this one from Environmental Health Perspectives, a journal supported by the National Institute of Environmental Health Sciences.
If you’ve been following my blog, you probably know that I live a relatively healthy and performance-oriented lifestyle. But despite my serious commitment to optimizing my health and fitness, I suffered from low testosterone levels. And I didn’t understand why until I read Dr. Anthony Jay’s book Estrogeneration.
In the book, Dr. Jay digs into decades of science about how the xenoestrogens we’re exposed to on a daily basis make us fat, sick and infertile. He also provides strategies on how to reduce our exposure.
We decided to implement most of Dr. Jay’s recommendations at the Kummer household because two of my blood tests from 2020 showed testosterone levels between 250 and 320ng/dL.
While that’s still within the “normal” range, it’s much too low for a healthy and active adult of my age (I’m 39 as of this writing), as confirmed by the anti-aging specialist I’m working with. Instead, my levels should be somewhere between 800 and 1200ng/dL — which is in line with normal levels from 50 years ago.
Low testosterone often leads to reduced sex drive, low bone density, erectile dysfunction, poor recovery after physical activity, loss of lean muscle mass, fatigue, obesity and depression, among other issues.
3. Depression
One of the most common misconceptions about testosterone is that having low levels of the hormone is only a problem for males. To the contrary, disruptions to the endocrine system can cause hormonal imbalances in women, leading to higher rates of depression.
In fact, one study of 3,124 overweight premenopausal women linked depression to their excess body weight and concluded that a testosterone imbalance was likely the culprit.
Another study, conducted on elderly men, showed “a significant inverse relationship between serum testosterone levels and depressive symptoms.”
In other words, the men with the lowest levels of testosterone showed the most symptoms of depression.
4. Infertility and Feminization of Males
A photo of estrogen-induced man boobs.
In addition to belly fat, xenoestrogens can lead to male feminization, including the emergence of so-called “man boobs.”
Environmental factors, including exposure to xenoestrogens, negatively impacts the reproductive health of humans and animals and leads to the feminization (e.g., man boobs) of males.
This isn’t news. Scientists have known this since at least 1996, as demonstrated in a study titled “Male Reproductive Health and Environmental Xenoestrogens.”
The authors of that study concluded that “male reproductive health has deteriorated in many countries during the last few decades,” and confirmed that during the same period, semen quality declined (while the rates of testicular cancer increased).
This is notable because male feminization is a side effect of the negative impact xenoestrogens have on the male reproductive system.
Interestingly enough, these observations apply to both humans and wildlife. As we’ll learn below, certain xenoestrogens also cause reproductive issues in rats, while others turn male frogs into females.
But we don’t have to go as far back as 1996. In 2005, a study observed a phenomenon referred to as “gender-bending,” which is another term for male feminization.
In that study, the authors concluded that toxic chemicals mimicking the female hormone estrogen “can disrupt the development of baby boys, suggesting the first evidence linking certain chemicals in everyday plastics to effects in humans.”
5. Immune Dysfunction (Premature Births, Allergies, Etc.)
Our-Premie-Minutes-After-Borth
Our son Lucas was born prematurely at just 30 weeks and six days. (Click on the image to play the video)
Based on everything I’ve learned over the past few years, it appears that we still don’t know much about how exactly the immune system works. But one thing seems clear: there has to be a proper balance between immune system activity and inactivity.
If you have allergies or an autoimmune condition, your immune system is in overdrive and may even attack your own body (as is the case with Lupus). The other extreme is a suppressed immune system that can’t defend against invading pathogens.
What’s interesting is that estrogenic hormones possess both immunostimulating and immunosuppressive properties.
That’s important, because you wouldn’t want your body to destroy fetal cells during the early stages of a pregnancy. In this situation, estrogen suppresses the immune system, thus allowing the fetal cells to grow and develop into a baby.
Unfortunately, that well-balanced process of immune system suppression and stimulation can go haywire, leading to the attack of healthy cells in your joints (in the case of a lupus flareup) or the inability to destroy cancer cells.
That’s exactly what xenoestrogens do: they confuse your immune system, leading to an increased risk of premature birth, a higher likelihood of autoimmune diseases, allergies and more.
Interestingly enough, cases of allergies in the United States have been rising steadily since 1995, as have pre-term births, which now affect at least one in 10 newborns according to the CDC.
I just wish I had known about the impact of estrogenics on our immune function and reproductive health before my wife got pregnant with Lucas, our youngest child; maybe we could have prevented his premature birth at 30 weeks and six days (video), and his 57-day stay in the neonatal intensive care unit.
6. Blood Clotting
Estrogenics increase your risk of blood clots (also known as thrombophilia), because they influence coagulation factors and related pathways.
That’s why all oral contraceptives list that as a risk factor in their physician notes — as you can see in the example of Yaz, a popular birth control pill that contains ethinyl estradiol (a synthetic estrogen).
Fortunately, there are effective non-hormonal contraceptives available, such as certain intrauterine devices (IUDs). These devices have fewer side effects and can often remain in place for a decade or more.
7. Cancer
Cancer is prevalent in modern society, and xenoestrogens are part of the problem.
There is growing concern within the scientific community that environmental estrogenic compounds increase the risk of certain types of cancer, such as breast cancer.
That’s because studies have shown that estrogenics play an important role in the initiation and progression of cancer. They also appear to reduce the effectiveness of anti-cancer medication.
The authors of the study I linked to above also discovered that Bisphenol A (the BPA in plastic), as well as 17 β-estradiol (an estrogen), induce the transformation of human breast epithelial cells to enable them to form progressively growing tumors.
The underlying mechanisms of how estrogentics increase the risk of developing cancer aren’t entirely clear. But it appears that they negatively influence the immune system and cause genomic and epigenetic alterations. In turn, that can lead to widespread cell damage that enables cancer cells, through ancient survival mechanisms, to proliferate.
What’s even more concerning is a finding from a 2012 study on rats that concluded that exposure to the birth control hormone ethinyl-oestradiol (EE2) during pregnancy “increases mammary cancer risk in several generations of offspring.”
On a side note, the same study also concluded that feeding mice with corn oil — a popular cooking oil that is high in inflammatory omega-6 fatty acids — increases the risk of cancer.
Beef Liver is nature's ultimate multivitamin
Ad provided by MK Supplements.
I shouldn’t have to say it, but that doesn’t mean eating a high-fat diet, such as the ketogenic diet, increases your risk of cancer (as incorrectly concluded by Lindsay Abrams in the Atlantic); it just means that consuming industrial seed and vegetable oils does.
That’s the primary reason why I’m so vocal about the importance of removing seed oils from your diet.
The bottom line is that there’s sufficient evidence that exposing yourself to xenoestrogens increases the risk of cancer for you, and potentially for future generations. That should be reason enough to try and reduce your exposure to these environmental toxins.
Top 10 Xenoestrogens You Should Try to Avoid
Below is a list of the 10 most common xenoestrogens/estrogenics you’re likely exposed to every day from the food you eat, the water you drink, the medication you take, the personal care products you use and plastic containers you store your food in.
1. Mycotoxins
Infographic explaining mycotoxins
Mycotoxins affect both animals and humans.
Mycotoxins, such as aflatoxin and zearalenone (ZEA), are fungal metabolites that grow in damp and dark places — like the massive grain and peanut storage containers used on monoculture farms, for example.
Scientists have confirmed that mycotoxins damage human cells and DNA, cause cancer, and can cause a variety of reproductive disorders in farm animals — a realization that has led many scientists to suspect that mycotoxins (such as ZEA) are also major endocrine disruptors in humans.
Estrogen Balance: My Best Tips
If you eat grains or certain legumes — such as wheat, corn or peanuts — you’re consuming these mycoestrogens. However, the problem with ZEA (as with its cousins) is that it makes its way into our food chain through multiple channels.
In other words, you might be exposed even if you don’t eat grains and legumes, because these substances are used as animal feed. As a result, these toxins end up in the fat and muscle tissue of grain-fed animals — including cows, pigs and chickens.
That’s why I highly recommend consuming only 100% grass-fed beef and pastured-raised pork.
Finding high-quality chicken meat is much more difficult, because even pasture-raised and organic chickens are usually fed a soy and/or corn-based diet. That’s one of the reasons why we’re getting our own backyard chickens — so we have full control over what they eat.
If having a backyard flock isn’t in the cards for you, I recommend reducing your intake of chicken meat (unless you know what the bird was fed).
2. Atrazine
Atrazine is a widely-used toxic herbicide.
Atrazine is the second-most-common herbicide used in the United States (glyphosate is first) and is regularly used to spray grains (and corn in particular).
Fun fact: Atrazine has been illegal in Europe since 2004 but it’s still used in the United States as of this writing.
As a result of its popularity, atrazine ends up in the grains we eat. But it also ends up in our drinking water.
That’s a problem because, according to a study by UC Berkeley, atrazine can turn male frogs into females by reducing their testosterone levels by a factor of 10.
That’s absolutely nuts, and it should be enough reason to do everything you can to reduce your exposure to this herbicide — such as by avoiding grains and filtering your water.
In another study, scientists demonstrated that atrazine in our water system can lead to adverse birth outcomes, such as the child being small for its gestational age, having a low birth weight and pre-term birth.
Coincidentally, these are all conditions our son Lucas was diagnosed with. As a result, I highly recommend filtering your drinking water to reduce your exposure to Atrazine.
3. Triclosan and Alkylphenols (APEs)
Hand holding a bar of soap under a faucet
I don’t use soap or sanitizer unless I personally purchased it and know what’s in it.
Triclosan and APEs are both common ingredients in personal care products such as toothpaste, mouthwash, hand sanitizers, soaps and lubricants.
While the European Union has banned many alkylphenols, the United States is (as always) lagging behind by allowing manufacturers to put those toxins in their personal care products.
Note: Triclosan was banned from soap products by the FDA in 2016 but it remains in use in other personal care products, such as hand sanitizers.
The problem with triclosan and APEs (such as nonylphenol) is that they get absorbed by the skin in concentrations that lab studies have shown are high enough to cause mitochondrial dysfunction and reproductive and developmental defects in infants.
Other studies involving children and pregnant women have shown that the exposure to triclosan from antibacterial hand soaps and toothpaste negatively impacted thyroid hormone levels, sex hormone levels and the timing of puberty (and also increased asthma symptoms).
Another issue with APEs is that they’re lipophobic as opposed to hydrophobic. That means they’re more likely to bond with fat than with water molecules. So if you sanitize your hands with a product that contains APEs, those toxins will remain on your skin — even if you wash your hands with water afterward.
From there, they can enter your bloodstream through your skin and wreak havoc on your endocrine system.
I recommend using only “estrogenic-free” personal care products, such as the ones we use, and making sure the products you buy don’t include ingredients that contain the term “phen.”
4. Benzophenone (BP) and 4-Methylbenzylidene (4-MBC)
The back of a bottle of Hawaiian Tropic sunscreen, showing its long list of potentially harmful ingredients.
Hawaiian Tropic is like an estrogenic “best of” list, containing an insane number of “phen,” “benz” and “paraben” ingredients.
BP and 4-MBC are “sunscreen estrogenics” that you can sometimes find even in organic sunscreen.
The most popular of the bunch is oxybenzone, which is a major endocrine disruptor as confirmed by a recent review of the most endocrine-disrupting UV filters.
My recommendation is to stay away from any product with ingredients that contain the words “benz” or “phen.”
Instead, look for clean, mineral-based sunscreens, such as the ones we use.
5. Food Dyes
The back of a box of Bayer children's' aspirin showing its ingredients list, which contains estrogenic dyes.
Even Bayer aspirin for children has estrogenic dyes.
Scientists have determined that certain artificial food colors, including Red No. 3 and Red No. 40, have estrogen-like growth stimulatory properties and could be a significant risk factor in human breast carcinogenesis.
That’s why I recommend staying away from any processed foods that contain artificial ingredients, such as artificial preservatives, colors and sweeteners. That way, you won’t have to worry about all the pseudonyms these artificial colors hide behind.
I also recommend checking any over-the-counter or prescription medication you might have in your household. I’ve found artificial food dyes in pills and liquid non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen.
Additionally, I’ve found artificial colors in some of the old skincare products we used when our daughter was still a baby.
6. Parabens
Parabens are frequently used in the fragrances of scented candles.
Parabens are found predominantly in personal care products like cosmetics, perfumes, shampoos and lotions, but they are also in scented candles.
In a nutshell, any product that contains “fragrances” likely contains parabens. In fact, the word “fragrances” is usually a collective term for hundreds of different chemicals, including endocrine-disrupting toxins.
Researchers have found reduced sperm quality as well as changes in the prostate, testicles, ovaries and breast development in both male and female rats that were exposed to parabens.
That discovery led the European Union to ban five parabens from skincare products, and it should be enough reason for you to stay away from products that contain these endocrine-disrupting toxins.
Personally, I don’t want to wait for human studies to confirm what animal studies have already demonstrated: parabens screw with our reproductive system.
I recommend avoiding all products that have fragrances on their ingredients list, unless they specifically mention that the fragrance used is only from natural sources, such as essential oils.
Speaking of essential oils, stay away from lavender because it’s highly estrogenic!
7. Phthalates
A baby with plastic pacifiers.
Many common baby products contain endocrine disrupting chemicals called phthalates.
Phthalates are a common group of chemicals used in the manufacturing of plastic to make it softer. You can find these toxins in products such as wall coverings, vinyl floorings, toys, the gloves you wear when washing dishes, plastic food wraps and even perfume.
Besides direct exposure, scientists have found phthalates in food sources such as grains, beef, pork and chicken (because they leach into water bodies and soil and are thus consumed by plants and animals).
The problem with phthalates is that they negatively impact your reproductive health, leading to poorer sperm quality and a shorter anogenital distance (AGD), which is an indicator of abnormal male reproductive tract masculinization in boys.
Additionally, exposure to phthalates has been shown to trigger and worsen the symptoms of asthma.
What’s mind-boggling is that many medical devices are made from PVC plastic that contains phthalates. Just imagine what that can do to immunocompromised patients receiving radiation or chemotherapy together with an extra dose of estrogenics from their plastic medical devices.
My recommendation is to remove as much plastic as possible from your environment.
8. Bisphenol A and S (BPA/BPS)
Infographic explaining why BPS is just as bad as BPA
BPS is the most common substitute for BPA, but it’s also toxic.
I’m sure you’ve seen the “BPA-free” label on water bottles and other plastic products. Bisphenol is another common additive used in the production of plastics, and it too has endocrine-disrupting properties.
When the word got out about the dangers of BPA, manufacturers did what they always do: they found a quick alternative without worrying about its health implications.
In the case of BPA, manufacturers switched to Bisphenol S (BPS), which is equally toxic and has a higher dermal penetration capacity than BPA based on studies with rodents.
But since most consumers have never heard of BPS and its health implications, manufacturers continue using it.
As with parabens, however, I don’t want to wait until the scientific community confirms that BPS is an endocrine disruptor in humans; the signs of that are already on the wall.
My recommendation is to stay away from plastic products, regardless of whether they’re labeled BPA-free.
9. 17a-Ethinylestradiol (EE2)
A box of YAZ birth control.
Oral contraceptives influence hormone production by design.
EE2 is the most popular ingredient used in hormonal birth control pills. By definition, and as the name already implies, EE2 is a potent estrogen that disrupts the female endocrine system with the purpose of preventing an unwanted pregnancy.
The problem with all synthetic estrogens, including EE2, is that they interfere with the balance of the endocrine system by mimicking or antagonizing the effects of endogenous hormones, by altering the synthesis and metabolism of natural hormones, or by modifying hormone receptor levels (source).
That leads to the issues we’ve discussed throughout this article, including reproductive issues, growth of adipose tissue, inability to reduce your body fat, increased risk of developing cancer and more.
While I certainly appreciate the benefits of birth control for society, and for women in particular, you should be aware of the unwanted side effects these products have on your reproductive system.
To get an idea of all the possible side effects of oral contraceptives containing EE2, take the time to read through the drug sheet of Alessa.
Another problem with EE2 is that it ends up in our drinking water by way of urination, because most water treatment plants don’t test for or filter it out.
At first, I couldn’t believe that. But when I checked with the Fulton County Water Authority, which is responsible for providing the drinking water in our suburb of Atlanta, they confirmed that they do not test for any birth control hormones.
The problem is that scientists haven’t completely figured out how the compounding and cumulative effects of estrogens and other toxins in water affect humans in the long run. But if studies demonstrating the feminization and reproductive disruptions in fish are any indication, synthetic estrogens, such as EE2, can’t be good for your health — even in low concentrations.
The authors of the study linked to above labeled EE2 immunotoxic to fish. That means the “small” amounts of EE2 in our lakes and rivers are toxic to their immune systems.
Do you really want to wait for a study to tell you how many years you can drink EE2-tainted tap water before accumulating enough that it becomes immunotoxic for you?
10. Phytoestrogens
Graphic showing the similarity between natural estrogen and fake estrogen
Xenoestrogens are so similar to natural estrogen that they can dock to the same receptors.
“Phyto” means plant. Thus, phytoestrogens are estrogenic chemicals that naturally occur in plants. When you eat certain plants, your body gets naturally exposed to these phytoestrogens (and other toxins, such as antinutrients).
The good news is that if you’re healthy and have an optimally functioning gut microbiota (which most Americans don’t), then the bacteria in your gut can destroy some of these estrogenics before they get into your bloodstream.
A good indicator of a well-tuned microbiome is the absence of disease and suffering. If you’re overweight and have high blood pressure or other metabolic issues, there is a good chance that your gut microbiome is out of whack.
However, if your gut microbiome isn’t functioning optimally or if you overindulge in over-processed plant foods that contain extremely high levels of phytoestrogens (e.g., fake meat burgers or vegan protein bars), there is a real risk that you’re poisoning yourself with these plant toxins.
Soy isoflavones (the estrogenic compounds in soy) have already been linked to developmental issues, thyroid toxicity and cancer in rats.
The authors of the same study also concluded that, “the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern.”
The first problem with most food-related studies is that they’re observational and thus only prove correlation, not causation.
The second problem is that most food studies are either sponsored or influenced by industrial stakeholders, such as manufacturers of soy products.
For example, a 2015 paper on the benefits of soy consumption found a (statistically) “significant but tiny” positive impact on bone calcium retention in postmenopausal women.
One of the authors of this study (Connie M. Weaver) is on the advisory board of Pharmavite — the maker of SoyJoy energy bars. Another author (Stephen Barnes) holds a patent on a special formulation of estrogenic soy isoflavones.
In other words, it’s very difficult to get a clear picture of how soy and its byproducts cause us harm.
In cases where there’s a dearth of reliable information, I go back to what we’ve learned about and through human evolution.
Our ancestors and early humans didn’t consume large amounts of soy (or other plants, for that matter); plants were a survival food consumed between successful hunts. So it’s conceivable that our bodies haven’t evolved to deal with the amount of processed junk/plant food many of us consume today.
I’m referring to things like fake meat burgers, vegan cookies or protein bars, vegan pizza and other products that include plant-based fats and proteins instead of their healthier, animal-based versions.
That’s why I recommend that you don’t overindulge in plants, and that you avoid those that have the highest levels of phytoestrogens, such as soy and flaxseed.
How We Reduced Our Exposure to Xenoestrogens
Non-Toxic Food Storage Containers
These are some of the non-toxic food storage containers we use.
At the Kummer household, our goal isn’t to completely eliminate our exposure to xenoestrogens. As you’re probably aware by this point in the article, that would be a futile strategy given their prevalence.
Scientists have even found estrogenics in polar bears. If they can’t avoid exposure, then neither can we.
Instead, our goal is to significantly reduce our exposure to levels that our bodies can (hopefully) manage.
I touched on many of the steps we’ve taken in the environmental toxins section of my article titled “How to Live a Healthy Lifestyle.”
But considering their importance, these steps are worth repeating and expanding on here.
Note that we had already implemented some of these steps long before we discovered the negative impact estrogenics can have on our health. For example, we started reducing the use of plastics for environmental reasons several years ago, and we’ve been filtering our drinking water because we didn’t like the smell of chlorine.
In the video linked below, I walk you though some of the safe, non-toxic products we’ve started using around the house.
Safe Household Products Video
Click the image above to watch the video on YouTube.
Here are some of the key steps you can take to significantly reduce your exposure to endocrine-disrupting chemicals:
Filter your drinking water. All you need is a charcoal filter, but I recommend an under-the-sink reverse-osmosis water filtration system that remineralizes the water (we like the one from Radiant Life*). If you use a water pitcher with a built-in charcoal filter (e.g., a Britta), pour the filtered water into a glass bottle immediately rather than leaving it in the plastic pitcher.
Stay away from plastic water bottles. You don’t know how long the water has been in that bottle, whether or not it has been exposed to heat, and how many chemicals have leached into the water.
Replace your plastic food storage containers. Instead, use products made out of glass or silicone.
Avoid foods that are high in estrogenics. Many grains (and also peanuts) are contaminated with mycotoxins, a fungus that grows in grain storage facilities. Other foods, such as soy and flaxseed, are high in phytoestrogens and should be avoided.
Buy estrogenic-free skincare products. Most skincare products are loaded with toxins and should be avoided. When shopping, avoid products that have fragrances or that include the terms “phen” or “benz” on their ingredients list.
Avoid sanitizers with triclosan and all antibacterial soaps. The latter usually contain alkylphenols.
Avoid buying food shipped in plastic wraps or containers. That’s especially important for cooking oils and other liquids, such as dairy milk. For refrigerated or frozen food, move them to glass containers or silicone-based freezer bags when you get home.
Look for natural fibers in bedding and clothing. We try to stick to cotton undergarments (especially for the kids) and we use only 100% cotton sheets in our bed.
Avoid foods that include artificial ingredients. Artificial ingredients, and certain food dyes in particular, are highly estrogenic.
Avoid pharmaceuticals with dyes. Red food dyes are also often present in pills and liquid medication.
Consider the use of non-hormone-based contraceptives, such as copper-based intrauterine devices (IUDs).
Stop using scented candles and air fresheners: The synthetic fragrances (and natural lavender) in air fresheners (and the expensive candles you bought at the mall) contain estrogenics that can make you sick. If you must, stick to pure beeswax candles or essential oils (not lavender).
Buy organic fruits and veggies. Buying seasonal organic fruits and veggies reduces your exposure to pollutants like estrogenic herbicides (such as atrazine) and insecticides and pesticides (such as dichloro-diphenyl-trichloroethane, also known as DDT).
Be wary of BPA-free products. If a product is labeled as BPA-free, it often means that the manufacturer used BPS instead (which is equally estrogenic).
Eat less poultry. Most “free range,” “all natural,” and/or “organic” chickens are fed arsenic because it acts as an antibiotic. While organic arsenic is an essential nutrient for humans and naturally occurs in soil, water and air, inorganic arsenic is a toxin and a strong estrogenic. The issue is that organic arsenic can transform into inorganic arsenic in animals, and that’s what you end up eating.
In a nutshell, you can take a huge step forward by filtering your drinking water, reducing plastic in your environment and buying “clean” personal care products.
If you’re interested in finding out what brands we use at the Kummer household, check out this page, which I try to keep updated as we discover new products.
Frequently Asked Questions
Where can I learn more about estrogenics and their negative impact on our health?
One of the best resources on the subject I’ve found is Dr. Anthony Jay’s book Estrogeneration, which you can pick up on Amazon*. It’s an eye-opener, and it started me on my journey of removing estrogenics from my family’s environment.
How quickly do estrogenics leach from plastic into foods and drinks?
The amount and rate of estrogenic leaching depends on several factors, including the type of toxin, the ambient temperature and the temperature of the container’s contents. In general, leaching can occur immediately and often continues for several weeks, as demonstrated in this study involving BPA, phthalates and water bottles.
How does heat affect the safety of plastic storage containers?
Heat significantly increases the rate at which estrogenic chemicals leach into food or beverages. One study found that when plastic drinking bottles were exposed to boiling hot water, BPA (an environmental estrogen) was released 55 times more rapidly than before exposure to hot water.
Does plastic have estrogen?
Yes, most plastics contain estrogenic chemicals, such as BPA, BPS, phthalates and others. Most plastics labeled as BPA-free contain BPS, which is equally bad.
Should I risk a sunburn or use a toxic sunscreen, if I have no other option?
I’m a proponent of sensible sun exposure. In other words, I recommend exposing yourself to sunlight without sunscreen for 20 minutes or less every day.
If you have to stay in the sun for extended periods but don’t have access to a non-toxic sunscreen, I’d use the toxic sunscreen. However, mineral-based sunscreens are so ubiquitous these days that consistent use of toxic products shouldn’t be necessary.
Does drinking bottled water increase estrogen?
All plastic bottles are made with chemicals that mimic the sex hormone estrogen, thus increasing the estrogenic activity in our body when we drink contaminated water. As a result, I highly recommend that you avoid drinking bottled water (unless it comes in a glass bottle).
Where can I find products that are free of xenoestrogens and other toxins?
Check out this page to learn what products we use at the Kummer household. Additionally, I encourage you to download the Think Dirty app, we often use to check out or find non-toxic products.
What are PCBs?
Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that are now banned in the United States, but which were used heavily a few decades ago in the manufacturing of plastic resins and carbonless copy paper.
The problem is that many estrogenic chemicals and contaminants, including PCBs, have a very long half-life and you can still find them in fish, meat and dairy products (as well as many waterways).
Do all toxins have to be listed on ingredient labels?
Unfortunately, no! For example, alkylphenols don’t have to be listed on the label of antibacterial soaps. Additionally, manufacturers can include the word “fragrances” on the ingredients list without having to spell out the exact chemicals they used to produce that fragrance.
Haven’t testosterone levels been declining for thousands of years? If so, you can’t really blame xenoestrogens for that.
Indeed, testosterone levels in men have been declining for thousands of years. But we’ve seen massive drops in the past 50 years — a timeframe that coincides with the introduction of synthetic estrogens in our environment.
While that’s just a correlation and it doesn’t imply causation, I choose to err on the side of caution. Based on past experience (think lead paint), it’s usually only a matter of time until we’ve figured out that man-made chemicals aren’t good for us.
Plus, there is plenty of scientific evidence (as mentioned throughout this article) that xenoestrogens negatively impact the reproductive health in animals and humans alike. Abnormally low levels of the sex hormone testosterone are merely one of the indicators that our reproductive system isn’t functioning optimally.
Is soy a xenoestrogen?
While soy itself isn’t a xenoestrogen, it contains isoflavones (such as daidzein, genistein, ODMA and equol) and lignans (such as enterodiol and enterolactone) that have estrogenic properties.
Considering how much exposure we have to estrogenics overall, I don’t see a need to add isoflavones and lignans to the list by consuming soy and its byproducts.
Do phytoestrogens increase estrogen levels?
I haven’t seen any studies suggesting that phytoestrogens increase your endogenous estrogen levels. But they are estrogenic by definition, and can thus increase estrogenic activity in your body.
The problem with food-related studies is that most of them are observational in nature. So instead of placebo-controlled double-blind studies, most food studies rely on observation and food intake questionnaires to draw a correlation (which is different from causation).
What makes the situation even worse is the influence of food manufacturers on these studies. As a result, it’s almost impossible to find well-designed research on the impact of soy among the dozens of studies that were sponsored by the food industry.
My take on phytoestrogens is simple: there’s nothing in plants that have phytoestrogens that is essential to my health. So I avoid them, and I suggest you do too.
How does the body get rid of xenoestrogens?
The human body has mechanisms to remove environmental toxins via sweat and urine — mechanisms that date back millions of years.
All you have to do to support your body in the removal of xenoestrogens and other environmental toxins is to significantly reduce your continuous exposure to them. Additionally, hydrate well and break a sweat every day. That’s all there is to it.
What doesn’t help is overindulging in certain foods that some people think can detoxify your body — especially not flaxseed (as some recommend), which is estrogenic!
What is butylparaben, and should I be concerned about it?
As the name implies, butylparaben is a paraben and one of the ingredients in many skin care products you should stay away from because it’s been shown to be a potent endocrine-disruptor with immunotoxic properties that can cause allergies and other issues.
As a rule of thumb, I recommend staying away from any ingredient that has “paraben” in its name, including methylparaben, ethylparaben and others.
Does a diet that’s high in antioxidants mitigate the damaging effects of estrogenics?
While maintaining a proper diet is certainly important for your health and to support your body’s defenses, I don’t think that loading up on certain (plant-based) antioxidants is going to mitigate the damaging effects of xenoestrogens. Your best mitigation strategy is to reduce your estrogenic exposure.
Siemens Healthineers
Ein Assay für Heparin- und DOAK-Tests zur Erweiterung des Hämostase-Assaymenüs.
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Wrap-Up: How to Deal with Endocrine Disruption
A photo of plastic products that contain toxic chemicals.
Most plastic products contain xenoestrogens.
My wife and I were shocked and disheartened when we learned about the negative health impacts of xenoestrogens.
Siemens Healthineers
Ein Assay für Heparin- und DOAK-Tests zur Erweiterung des Hämostase-Assaymenüs.
INNOVANCE bietet kontinuierlichen Zugang zu schnellen spezifischen Tests und unterstützt die Behandlung. Jetzt Ihre Testung optimieren.
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We both thought that shifting our dietary habits to something that would mimic how our ancestors had been eating for millions of years (paleo/keto/carnivore) would be our last big lifestyle change.
We were wrong.
It took us a few weeks to go through the five stages of grief and admit something we had known all along:
Just because a product or ingredient is legal doesn’t mean it’s safe or healthy.
Most manufacturers don’t give a crap about what’s good for their customers, animals or the environment — as long as it’s legal, they’re fine selling the product.
Product labels are misleading. Just because a product is labeled as “all natural,” “plant-based,” “all vegetarian-fed” or something similar doesn’t mean it’s free of toxic ingredients.
There are exceptions to these rules, but it’s up to you to find them.
Once we got over the initial shock, we knew what we had to do: apply the same due diligence when buying household products as we apply when buying food.
8 Alarming Signs You Have Too Much Estrogen
Additionally, we took inventory of all the toxic items we had in our household and immediately replaced the worst offenders, including plastic food containers and skincare products we use every day.
Everything else, we started replacing at a slower pace to limit the financial impact. As of this writing, we still have a few items at home that we know aren’t great for us, including synthetic clothing or acrylic glassware that we barely use.
The bottom line is this: don’t freak out, and don’t set unrealistic goals like removing all estrogenics from your environment.
Remember, if a polar bear can’t do it, neither can you. Instead, find a reasonable approach that you can start implementing today; one that’s sustainable and that doesn’t break the bank.
Most importantly, enjoy the process and every step you make in the right direction.
Now I’d like to hear from you! Did you know about the dangers of xenoestrogens before reading this article? If not, how do you feel about fake estrogens and their impact on your health? Let me know by leaving a comment below!
Michael Kummer - Health and Technology
Michael Kummer
Some natural substances have been scientifically identified as estrogenic since the late 1930s when they were found to be deleterious at high doses for cattle reproduction. Several compounds belonging to different chemical families are considered here: isoflavonoids, coumestans, lignans, and resorcylic acid lactones. This list is not exhaustive. The vegetable sources of these compounds are probably not all identified yet, but all the compounds presented here were shown to act as endocrine disruptors, i.e., modifying the hormonal natural balance, at dietary doses either in human, in cattle, or in other vertebrates.
Estrogenic compounds mimic estradiol activities and can interact nearly with all biological functions in lower and higher vertebrates. Some mollusks are also sensitive to estrogens. The effective dose is crucial to consider since as other endocrine disruptors the natural substances may have opposite effects at low, dietary, and pharmacological concentrations. Different cell pathways are triggered by the natural estrogenic substances, including some that are not influenced by estradiol itself, and this explains why their effect is not a monotonic dose–response line. This questions the classical toxicological approach which considers acute exposure (short and high concentrations) as the key of the toxicity evaluation. The history of human exposure to isoflavones was recently casted on doubt, reinforcing the need for careful study of these compounds’ occurrence and effects on humans. It is clear now that the traditional soy food makings were able to remove isoflavones from foodstuffs. This is no longer the case in modern processing, and this means that the exposure to this estrogenic substances has increased markedly in recent times. Estrogens in mammals can have both beneficial and harmful effects which are evoked here.
Keywords
Natural estrogens
Food sources
Modern exposure
Bioavailability
Mechanism of actions
Breast cancer
Bone health
Thyroid
Reproductive disruption
History of flaxseed
Harvesting flaxseed
How flaxseed got a bad rep
Flaxseed is estrogenic, so it’s bad for me?
How does flaxseed work as an “estrogenic adaptogen”
The amazing healing benefits of flaxseed
– Helps with estrogen dominance
– Helps menopause and postmenopause
– Helps reduce risk and growth of estrogenic cancers
– Source of insoluble and soluble fiber
– Anti-inflammatory agent
– Cardiovascular health
Best ways to use (and not to use) flaxseed
What about flaxseed oil?
Who may get a negative response to flaxseed?
Flaxseed for men?
Bottom line – know your sources!
Few foods are as controversial as flaxseed. Some women swear by it, others fear it.
In this article, I will lay out the science and the oversimplification of information that has earned flaxseed its bad reputation. After reading this article, I hope you give this seed a well-deserved consideration.
History of flaxseed
“Flaxseed is one of the oldest crops, having been cultivated since the beginning of civilization (Laux 2011). The Latin name of the flaxseed is Linum usitatissimum, which means “very useful”. Flax was first introduced in the United States by colonists, primarily to produce fiber for clothing (Laux 2011).
Every part of the flaxseed plant is utilized commercially, either directly or after processing. The stem yields good quality fibers having high strength and durability (Singh et al. 2011). Flax has been used until the 1990s principally for the fabrication of clothes (linen) and papers, while flaxseed oil and its sub-products are used in animal feed formulation (Singh et al. 2011). There is a small difference in using the terms flaxseed and linseed. Flaxseed is used to describe flax when consumed as food by humans while linseed is used to describe flax when it is used in the industry and feed purpose (Morris 2008).” Source
Harvesting flaxseed
Have you ever seen flaxseed available anywhere other than a supermarket?
If you live in Canada or North Dakota where the majority of flaxseed is grown, you might have seen fields of these pretty purple flowers.
The flowers then transform into pods. Each pod holds between 6 and 8 flaxseeds. They get picked and shaken out of their pods.
Like with many foods, flaxseed can be a powerful, healing food that can help women, especially those struggling with their hormones. You will also learn that some women should not use it.
How flaxseed got a bad reputation
Flaxseed got a bad rep from the blogosphere – mainly for being called “estrogenic” and therefore “causing cancers” and hormonal problems in women. This could not be further from the truth (most of the time, see more below) and I have therefore spent hours researching and writing the below article to show you otherwise.
Just because something is estrogenic, does not make it a bad thing right away. Yes, skincare products containing parabens and phthalates are estrogenic and that’s not a form of estrogen you should ever be exposed to. These forms of estrogens, also known as xenoestrogens, have been linked to cancers.
The blogosphere has concluded that if flaxseed is estrogenic, then it must be as bad as the synthetic estrogens found in these toxic products.
This is an oversimplification. It makes no sense to compare a plant-derived estrogen with a synthetically-derived estrogen. Unfortunately, this is shabby journalism, poor research, and a pure laziness to fact-check.
It’s important to check where you are getting your information from. I searched for medical studies that show the harmful effects of flaxseed on women and…found none. Bloggers and social media “writers” who make such claims offer no citations. Be leery when a writer states “studies show” and offers no links to substantiating resources.
It’s a real shame because hundreds of thousands of readers are missing out on a food that can not only help with a ton of symptoms but could even save lives.
Having said that, there is a sliver of people who, like with many other foods, have a “paradoxical” response to flaxseed – more on that below. These people, however, are in a vast minority.
Bottom line: Be selective where you get your information from and whom you choose to trust.
Flaxseed is estrogenic, so it’s bad for me?
There is a fear of estrogen-containing foods, such as flaxseed, which is not only wrong and unjust but can also prevent you from reversing symptoms of estrogen dominance quickly and effectively.
Just because you experience estrogen dominance, does not mean you should stop ingesting gentle plant-based estrogens. You need estrogen – as a woman you need it to have healthy breasts, butt, periods, glowing hair, and skin, etc. The issue is not to cut out estrogen but to break it down properly.
Most women with estrogen dominance do not suffer because of too much estrogen but because they are not breaking down and evacuating these estrogens well enough. Flaxseed can help shift estrogen metabolism from the “dirty” estrogen in the direction of the “clean” ones.
The only thing you want to remove from your life as much as possible are xenoestrogens which are synthetic estrogens that mimic estrogen without doing the right work. They are found in all commercial skin care products, perfumes, and cleaning products.
Having said that, I have met a few women (they are the minority) who have a paradoxical response to flaxseed – their estrogen dominance symptoms worsen. If that’s you (be sure not to make any other significant changes during this time), please stop flaxseed and look into the supplement protocol to see how else you can support estrogen metabolism.
How does flaxseed work as an “estrogenic adaptogen”
Among all foods, flaxseed contains the highest amount of lignans, a form of polyphenols, which are high in phytoestrogens.
Let’s unpack this a little.
The word “phyto” comes from Greek and means “plant” or “that which has grown.” Therefore phytoestrogen is a plant-derived, completely natural form of estrogen.
You might have heard the word “polyphenols” being thrown around; so what is it?
Polyphenols are a group of over 500 phytochemicals which are naturally occurring micronutrients in plants. They are highly medicinal in nature and many supplement companies are cashing in on that.
Some of the polyphenols include quercetin (found in apples), catechins (in dark chocolate and cherries), lignans (in flaxseed), resveratrol (in pistachios, wine, and blueberries) and curcumin (in turmeric).
There are three types of phytoestrogens: Lignans (enterolactone, enterodiol), isoflavones (genistein, daidzein, biochanin A), and coumestans. Genistein and daidzein are found in soy, another phytoestrogen.
The highest concentration of phytoestrogens, however, is found in lignans.
When plant lignans are ingested, they can be metabolized by the intestinal bacteria in the large intestine into enterolactone. Enterolactone is the bioactive form of phytoestrogen.
It is enterolactone that binds to estrogen receptors, blocking and competing with estrogen which may help to reduce the growth of estrogenic cancers.
One of the most fascinating chemical phenomena about lignans is that can act as weak estrogen agonists (promoter), partial agonists, or as antagonists (blocker) to endogenous estrogens (internally produced) and xenoestrogens which are synthetic estrogens found in much commercial skincare, cosmetic and cleaning products.
In short, flaxseed is an estrogenic adaptogen; it can act as an estrogen amplifier or estrogen blocker depending on what the body needs.
How fascinating is that?! For that reason I coined the term “estrogenic adaptogen” – the seed adapts to what your body needs.
This explains why flaxseed has been used for a wide spectrum of women issues by menopausal and postmenopausal women by gently and naturally raising their estrogen levels as well as menstruating women who struggle with too much of the “dirty” estrogen that causes estrogen dominance (and the result is PMS, fibroids, endometriosis, thyroid nodules, etc).
I have written extensively about estrogen dominance (what it is) (what are estrogenic cancers) and I’m very passionate about it because I feel that 80% of women experience estrogen dominance at some point in their lives, yet, 80% of them don’t know that they have it.
One powerful yet simple way to use flaxseed in your daily life is the seed rotation method – you can learn about it by downloading the Seed Rotation Starter Kit.
The seed rotation method, however simple, has been one of the most popular methods used by our community. Because of the adaptogenic features of flaxseed, I see women both with too much estrogen and too little estrogen benefiting from this potent seed.
Many have reported:
Less or no hot flashes
Less or no night sweats
Less or no PMS (including bloating, pain, food swings)
Better sleep
More regular periods
Return of periods
Weight loss
The amazing healing benefits of flaxseed
There is a strong body of research to support the claim that flaxseed is hugely beneficial and can change lives. Here are the reasons why I use and recommend flaxseed to women suffering from PMS, all the way to post-menopausal symptoms.
#1 Helps with estrogen dominance
Symptoms of estrogen dominance include:
Irregular periods
Heavy flows
Terrible PMS (bloating, moods, pain, energy, headaches)
Fibroids
Endometriosis
Breast lumps
Thyroid Nodules
Fibrocystic and painful breasts
Low thyroid
Hair loss and brittle hair
Weight gain around the hip and thighs
Water retention
Cellulite
The reason why a woman experiences these is NOT that she has too much estrogen but because of how she BREAKS down these estrogens.
If you have a bit of biochemistry interest, the problematic estrogens are:
Too much estradiol E2 (the “aggressive” estrogen) as compared to estrone E1 and estriol E3
Estrone gets broken down to 2, 4 and 16 hydroxyestrone – 2 is protective where else 4 and 16 hydroxyestrones are antagonistic and cause symptoms of estrogen dominance.
The good news? Flaxseed has been proven to push the metabolism of these estrogens in the protective direction, hence helping with symptoms of estrogen dominance.
Flaxseed interrupts the circulation of estrogens in two ways:
It can bind unconjugated estrogens in the digestive tract, which are then excreted in the stool.
Beneficially affects the composition of intestinal bacteria and reduce intestinal b-glucuronidase activity, resulting in lowered estrogens via the conjugation of estrogen and reduced reabsorption.
Flaxseed also helps with:
It inhibits aromatase activity, thus decreasing conversion of testosterone and androstenedione into estrogens in fat and breast cells.
Women consuming 10g of flaxseed per day experienced longer menstrual cycle length, increased progesterone-to-estrogen ratios, and fewer anovulatory cycles, all of which are considered to reflect improved ovarian function.
A few studies to share with you:
– Flaxseed helps reduction of thyroid cancer
– Flaxseed alleviates PMS
– Reduction of fibroids in young women
– Flaxseed improves fertility
#2 Helps menopause and postmenopause
The adaptogenic properties of flaxseed can help women in menopause and postmenopause as well.
A few citations and benefits:
Reduction on hot flashes and vaginal dryness
Improved blood cholesterol
Increased anti-inflammatory Omega 3 markers and decreased LDL cholesterol
#3 Helps reduce risk and growth of estrogenic cancers
Estrogenic cancers include ER+ (estrogen receptor positive) breast, uterine, ovarian, thyroid and lung cancers in non-smokers.
Because of its adaptogenic quality, flaxseed can attach itself to an estrogen receptor and block the growth of the cancer cells. The “dirty” estrogens are the ones that cause and fuel the growth of some cancers.
Citations:
Flaxseed reduces ER+ breast cancers: “Our results suggest that flaxseed and its lignans have potent anti-estrogenic effects on estrogen receptor-positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.” –
Flaxseed helps reduction of thyroid cancer
Flaxseed reduces tumor growth and strengthened the effects of Tamoxifen: “FS inhibited the growth of human estrogen-dependent breast cancer and strengthened the tumor-inhibitory effect of TAM at both low and high E2 levels.”
#4 Source of insoluble and soluble fiber
Flaxseed is a wonderful source of both insoluble and soluble fiber.
Insoluble fiber does not dissolve in water and it moves through the digestive system quickly, “sweeping” the waste and debris through the colon, including metabolized and harmful hormones. It also helps to bulk up the stool which helps to create a well-formed stool. Chronic constipation is one of the causes of hormonal imbalances in women – which goes to say that a good, daily bowel movement is a prerequisite to good hormonal health.
Insoluble fiber also slows down sugar metabolism, helping balance blood sugar – one of the pillars of hormonal balance.
Soluble fiber forms a gel when combined with water, it helps you feel full and satisfied with a meal so you don’t reach out for snacks and unnecessary calories. It also stabilizes blood sugar levels, lowers LDL (“bad”) blood cholesterol and is high in prebiotics – the food for probiotics.
Two tablespoons of freshly ground flaxseed per day will give you the above-mentioned benefits.
This study also states that: “In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%”.
#5 Anti-inflammatory agent
If that was not enough, flaxseed also contains the highest level of plant-based Omega 3.
It can be beneficial but not for all – here is why. Flaxseed contains the highest levels of alpha-linolenic acid (ALA). It’s common amongst the vegans and vegetarians to say that nobody needs to eat fish for the Omega 3 because flaxseed is also very high in Omega 3. This is true but not for all.
The form of Omega 3 that the body benefits from is in the form of EPA and DHA. In the case of flaxseed and its ALA content, the body needs to convert ALA to EPA and DHA in the sufficient presence of vitamins B1 and B6, zinc, and magnesium. If a person is depleted in any of these (and many are), then flaxseed alone might not be the best source of the highly anti-inflammatory Omega 3. On the other hand, if the person is well nourished, then it is true – flaxseed can be a great source of Omega 3.
#6 Cardiovascular health
Cardiovascular health can be a concern in postmenopausal women. This study concluded: In conclusion, a high intake of phytoestrogens in postmenopausal women appears to be associated with a favorable metabolic cardiovascular risk profile.
This study states that ground flaxseed has LDL (“bad”) cholesterol-lowering properties and it improves insulin sensitivity.
Best ways to use (and not to use) flaxseed
A few tips on how to use flaxseed to reap its medicinal properties:
#1 Always buy it in seed form (not as pre-ground flax meal) and grind it freshly in a coffee or spice grinder. Grinding flaxseed makes lignans more bioavailable.
#2 Flaxseed oil does not contain lignans unless ground flaxseed has been added to it.
#3 Amount – One to two tablespoons per day of freshly ground flaxseed is the recommended medicinal dose.
Learn how to add more hormone-balancing ingredients to your meals with our FREE 19 Estrogen Balancing Superfoods Guide here.
What about flaxseed oil?
I’m not a fan of flaxseed oil for a few reasons:
It does NOT contain lignans, which are the beneficial phytoestrogens I covered above.
It gets oxidized very quickly and loses its medicinal properties – this is why it has to be refrigerated and kept in a dark container.
It contains ALA only which still needs to be converted to the bioavailable Omega 3 which is in EPA and DHA form.
It contains no fiber.
Who may get a negative response to flaxseed?
We get many emails from our readers confused why I would suggest flaxseed. As you can tell from the above narratives, why would I not?!
Having said that, I have met women who had, what is called, a paradoxical response to flaxseed. Instead of feeling better, their symptoms worsened.
It is not fully understood why some women experience an adverse reaction (from digestive issues to getting worse PMS, painful breasts and heavier periods) to flaxseed).
Here is my hypothesis on it:
#1 Food intolerances or allergies – some people have an allergy or intolerance to flaxseed, just the way it can happen with any other foods. If that’s you – do not eat flaxseed.
#2 Digestive sensitivity – Some people experience such dire digestive issues that the lignans and fiber found in the seeds might be too much to tolerate. If you are following the AIP diet, you can’t eat flaxseed until you are ready to re-introduce it when your GI tract is rebuilt.
#3 Gut bacteria – my research shows that for flaxseed to be active, it needs to be converted by a host of bacteria residing in the colon. It is likely that some people lack these beneficial bacteria and therefore don’t convert lignans to enterolactone which is the bioactive form of phytoestrogen.
Flaxseed for men?
I do not work with men so I have limited experience and feedback from men. The little research available shows that men might not be benefiting from flaxseed as much as women do. One study points out elevated prostate cancer risk and infertility.
Bottom line
It’s important to check where you are getting your information from. I searched for medical studies that show harmful effects of flaxseed on women and found none. I did, however, find a number of blogs that make such claims. None of them offer citations and only state “studies show.”
Be selective where you get your information from.
To know if flaxseed is your friend, it’s simple: Add it to your diet (just two tablespoons of freshly ground flaxseed is enough) for one to two months and see how your symptoms change.
If they improve – great! Keep going; you can use flaxseed in the long term. If you feel worse, stop it immediately.
Learn more with Overcoming Estrogen Dominance
Overcoming Estrogen Dominance
“The body has an amazing ability to heal. We just need to give it the right resources.”
In Overcoming Estrogen Dominance, my goal is to empower and give you the tools to take control of your hormones and health.
More than 70% of women experience estrogen dominance. The symptoms range from lumpy and fibrocystic breasts to thyroid nodules, hot flashes, fibroids, uterine polyps, painful, heavy or irregular periods to infertility and miscarriages, from mood swings to insomnia, weight gain to fatigue.
So many women have experienced the pain and frustration that comes when, sitting in their doctor’s exam room, they feel their symptoms and complaints are dismissed or minimized. They feel unheard, helpless, with no control over their bodies or the underlying issues that are causing their debilitating symptoms. This is particularly true for women who are experiencing the symptoms of hormone imbalance. Even when doctors do offer treatment, it’s typically in the form of prescription medication or invasive surgical procedures.
In Overcoming Estrogen Dominance, I hope to show that those extreme interventions are often unnecessary, and to give women a roadmap to ease and erase their symptoms using food, herbs, supplements and natural protocols to re-balance hormones.
My goal is to help reverse the impact of estrogen dominance naturally, helping you lead a symptom-free life, without fear.
Xenoestrogens (XEs) are substances that imitate endogenous estrogens to affect the physiologic functions of humans or other animals. As endocrine disruptors, they can be either synthetic or natural chemical compounds derived from diet, pesticides, cosmetics, plastics, plants, industrial byproducts, metals, and medications. By mimicking the chemical structure that is naturally occurring estrogen compounds, synthetic XEs, such as polychlorinated biphenyls (PCBs), bisphenol A (BPA), and diethylstilbestrol (DES), are considered the focus of a group of exogenous chemical. On the other hand, nature phytoestrogens in soybeans can also serve as XEs to exert estrogenic activities. In contrast, some XEs are not similar to estrogens in structure and can affect the physiologic functions in ways other than ER-ERE ligand routes. Studies have confirmed that even the weakly active compounds could interfere with the hormonal balance with persistency or high concentrations of XEs, thus possibly being associated with the occurrence of the reproductive tract or neuroendocrine disorders and congenital malformations. However, XEs are most likely to exert tissue-specific and non-genomic actions when estrogen concentrations are relatively low. Current research has reported that there is not only one factor affected by XEs, but opposite directions are also found on several occasions, or even different components stem from the identical endocrine pathway; thus, it is more challenging and unpredictable of the physical health. This review provides a summary of the identification, detection, metabolism, and action of XEs. However, many details of the underlying mechanisms remain unknown and warrant further investigation.
Keywords: xenoestrogen, bisphenol, polychlorinated biphenyls, phytoestrogen
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1. Introduction
As endocrine disruptors, xenoestrogens (XEs) are substances that imitate endogenous estrogens to affect the physiologic functions of humans or other animals. In the 1950s, some research demonstrated the hormone-like effects, mostly associated with environmental chemicals in wildlife. Either estrogenic xenobiotics or XEs are considered the major disruptors of endocrine, with a diverse chemical structure [1]. Exposure to not only nature, which phytoestrogens and mycoestrogens are the pertinent examples, but also industrial chemicals, estrogenic, and anti-estrogenic activity have been exhibited [2]. Through the imitations and obstacles in responses via the non-genomic and/or genomic signaling pathway, endogenous estrogens are largely disrupted by XEs [3]. Individuals are exposed to a complex mix of chemicals during their lifetime. XEs, which can be found in every aspect ranging from the environment, food, cosmetics, and other substances, have pros and cons to the human body [4,5]. By mimicking the chemical structure that is naturally occurring estrogen compounds, some XEs are considered the focus of a group of exogenous chemical, which can be derived from the sources as follows: diet, pesticides, cosmetics, some plastics, plants, fumes, industrial byproducts, metals and medications (such as oral contraceptives) [4,6,7,8]. The importance of new chemicals’ endocrine-disrupting potential cannot be ignored [1].
All About Xenoestrogens: Estrogen Mimicking Hormone Disruptors and How to Avoid Them
The estrogenic or antiestrogenic activity of chemicals is attributed to the interactions between estrogen receptor (ER) and other compounds. In fact, ER, as a ligand-inducible transcription factor, plays a vital role in development and neoplasia using regulating genes involved in cell proliferation and differentiation.
Muellery has clearly defined XEs in the review article, which described the mechanisms of action and detection methods, stressing the points of molecular cell biological mechanism to estrogen receptor-mediated hormone actions. Figure 1 has displays how the estrogen or XEs work in cells through several consecutive steps [9,10,11].
(1.)
Estradiol, a type of estrogen (E), is trapped over by carrier protein in the serum. After the estrogen is released from the blood by the carrier protein, it can pass through the cell membrane without disturbance and enter the cell;
(2.)
Located within the nucleus, before activation, the ERs will be bound to various receptor-associated proteins, such as heat-shock proteins (Hsp90);
(3.)
Estrogen will be bound to the ERs, replacing the receptor-associated proteins;
(4.)
ER dimer is bound to its corresponding DNA-binding domains, and the sequence is named estrogen-responsive element (ERE);
(5.)
Under the cooperation of assembled substances, including multiple transcription factors (TF), the RNA polymerase (RNA Pol) and other proteins, transcription can be started. The relevant mRNA sequence emerges as ER target genes transcription is in the process;
(6.)
Co-activators, including CBP/p300 and SRC-1, are all the linking brackets to ER dimer and could play an effect on DNA transcription;
(7.)
After DNA is transcribed into mRNA, RNA should be translated to produce protein to complete gene expression [10].
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Figure 1
The molecular mechanisms for the actions of estrogen receptors [9,10,11].
Like the ligand actions of endogenous hormones, the ER α and β shall be bound and activated before XEs bring their effects fully into play. There is not only one single factor affected by XEs, but opposite directions are also found on several occasions, or even different components stem from the identical endocrine pathway; thus, it is more challenging and unpredictable in terms of physical health. Interestingly, XEs are most likely to exert tissue-specific and non-genomic actions when the concentrations are relatively low. The debate on the risks that humans are exposed to remains a controversy, and a clear-cut relationship between XEs exposure and human health so far has only a little evidence. However, due to the complexity of their mechanisms and potential for adverse effects, how XEs affect normal estrogen signaling remains an open question and is worth investigating [12].
The estrogenic environmental compounds, including bisphenol A (BPA) and butyl benzyl phthalate (BBP), may trigger the adverse effects of endocrine-disrupting chemicals on organisms. As the natural estrogen, 17β-estradiol is the major factor in forming breast cancer and further to the progression. An in vitro- in vivo model has been developed to demonstrate the carcinogenicity of natural estrogen 17β-estradiol and xenoestrogenic substances in human breast epithelial cells MCF-10F. In this model, hypermethylation of NRG1, STXBP6, BMP6, SS3, SPRY1, and SNIP were found at different progression phases. Whether BPA and BBP are relevant to breast cancer initiation can be demonstrated using this unique model. The evidence mentioned earlier suggests that natural estrogen 17β-estradiol and xenoestrogenic substances, such as BPA, are considered to trigger a neoplastic transformation in human breast epithelial cells [13].
Ullah et al. have conducted an in vivo study and investigated whether chronic exposure to low doses of BPA and its analogs affects spermatogenesis with outcomes on oxidative stress and the male reproductive system of 22-day-old rats [14]. Oxidative stress in the testis was significantly elevated, while sperm motility was impaired. The daily sperm production and the number of sperm in the epididymis were reduced. This research confirmed that exposure to BPA and its analogs for a chronic duration could induce structural and functional changes in testicular tissue and endocrine alterations in the male rat reproductive system [14].
To investigate the effects of XEs on skeletal programming, Pelch et al. have compared the skeletal effects of low-dose BPA exposure to mice 9 days prenatal and 12 days postnatal in 2012 [15]. The skeletal health of these mice was assessed during adulthood when they had reached peak bone mass. The study revealed that exposure to 10 µg/kg/day BPA significantly increased the femoral length in the male mice but decreased the biomechanical strength in the female mice [15].
Research across the 1960s to 1970s demonstrated the estrogenicity of a couple of industrial compounds and pesticides, o,p-DDT, kepone, methoxychlor, phenolic derivatives, and polychlorinated biphenyls (PCBs). Several environmental chemicals have been categorized into the list of XEs, including the pesticide toxaphene, dieldrin, and endosulfan, and some different compounds used in the food industry, which are antioxidants, such as t-butylhydroxyanisole. The BBP and 4-OH-alkylphenols are components of plasticizers. The substance BPA was applied in dental restorations [1,5].
In Korach’s studies, it is indicated that even weakly active compounds could interfere with the hormonal balance with persistency or high concentrations of XEs. Congenital malformation of wildlife and humans born with birth defects are negatively affected by endocrine-disrupting chemicals XEs. The development of the urinary tract and nervous system is particularly sensitive to hormonal disruption over periods of in utero and early postnatal life [5,16]. On top of that, a birth defect can be considered permanent damage, whereas the structural changes of the body parts are less affected after reaching adulthood [12,17].
During the 1990s, male reproductive problems ranging from the decline in semen quality, testicular cancer, hypospadias, and cryptorchidism seem to be increasing health issues found in Belgium, Denmark, France, and Great Britain. In 1996, studies suggested that the supernormal levels of estrogens, specifically diethylstilbestrol (DES), were the leading cause of male fetus reproductive defects. Regarding common XEs stemming from environmental contaminants and chemicals, their adverse effects on male reproductive health are exceptionally crucial. The stages of fetus and childhood are more vulnerable than that of mature adulthood. An extensive study should explore the underlying problem further and strategically determine the intervention and potential treatment [18].
Estrogens can act on signaling pathways with pertinent examples in diseases, such as cancer, cardiovascular, metabolic, or immune system disorders. Many XEs gathered by natural and synthetic compounds can behave as estrogens and have a close interaction with ERs. These compounds are capable of bonding to the ER in the cell, leading to bioaccumulation as a whole [3,19,20,21]. In contrast, some XEs are not similar to estrogens in structure and can affect the physiologic functions in ways other than ER-ERE ligand routes. In fact, the high prevalence of XEs has brought tremendous interest in in-depth research concerning hormone-dependent cancers, including breast, ovarian, endometrial, prostate, thyroid, and cervical.
Between 1940 and 1971, nearly 2 to 4.8 million human offspring were exposed to DES, a strong synthetic estrogen. Research has concluded that prenatal women exposed to DES were subject to the growth of adenocarcinomas of the cervix and reproductive disorders [22,23,24]. Interestingly, DES has been applied in therapeutic hormone replacement for women, extensively using prostate and breast cancer treatment through having cancer-induced factors. On the other hand, DES also functions well to suppress the androgen action and induce apoptosis toward both androgen-dependent tumors and independent by interfering with the cell cycle. To sum up, XEs have their pros and cons, contributing differently to human beings and creatures [22,25,26]. Since XEs can act as endocrine disruptors to affect functions of humans and animals, how they can be detected and how they can act in the endocrine system are important to further studies. This overview provides a summary of the identification, detection, metabolism, and action of XEs.
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2. Identification and Detection of Xenoestrogens
The literature revealed that XEs, as active endocrine substances, can interact with estrogen receptors, androgen receptors, or peroxisome proliferative receptors [12]. By inhibiting or activating these nuclear receptors, XEs can affect circulating hormone levels and disrupt normal endocrine function, thus possibly resulting in metabolic syndrome, reproductive dysfunction, and the occurrence of cancers [3,4,27,28,29]. The exposed concentration, dose, and time of XEs, as well as the age of contact persons, have different impacts on affected individuals [30].
In the past, there were various in vivo and in vitro assays developed to measure the estrogenic-like activity of XEs, as well as the concentration and potency of the estrogenic and antiestrogenic compounds. For a better understanding of morphological, histological, biochemical, and molecular actions, researchers have completed different studies to analyze the estrogenic properties of XEs. Although the in vivo real actions of XEs are unpredictable, many in vitro tests have been continually used to explore the estrogenic potency of XEs [9,31,32,33,34].
Studies regarding the identification and detection of XEs, and investigating the molecular mechanisms of interactions between XEs and ERs were solicited from the literature. They described in detail the characteristics of the estrogenic or antiestrogenic potency of different XEs. A summary of the results of these studies is shown in Table 1.
Table 1
A summary of in vitro assays for the measurement of estrogenic and antiestrogenic compounds, partially according to Ref [35].
In Vitro Assay Endpoint of Measurement Advantages Limitations Reference
E-Screen ERα (+) cell proliferation Measures physiological endpoint of estrogen action, measures estrogens and antiestrogens No defined ER expression, no mechanistic data [33]
Ligand-binding (EDSTAC) a ERα- or ERβ-binding affinity Simple, high-throughput method Does not measure ER activation does not measure physiological response [36,37]
ER-binding to ERE ERα- or ERβ-binding affinity to ERE High-throughput method, various EREs can be used Does not measure ER activation, low sensitivity, does not measure physiological response [38,39]
GST pull-down/FRET/ two-hybrid assay ERα- or ERβ-ligand-dependent association with coactivators Analysis of molecular interaction, defined ER subtype or ER domain as well as coactivators can be used, measures estrogens and antiestrogens Does not measure direct ER activation, low throughput, does not measure physiological response [40,41,42]
Analysis of gene expression ER-regulated gene expression Analysis of physiological response, versatile, measures estrogens and antiestrogens Low throughput [43,44]
Analysis of enzyme activity ER-regulated enzyme activity Analysis of physiological response measures estrogens and antiestrogens Cell lines or primary cell cultures with active marker enzymes suitable only [45,46]
Analysis of steroidogenesis (EDSTAC)a Induction and inhibition of estrogen biosynthesis Analysis of physiological response measures ER-independent pathways Cells with active steroidogenesis suitable only [47,48,49,50,51]
The fluorescence-based multianalyte chip platform(a fluorescence-based multiplexed protein microarray) The proliferative effect in hormone-sensitive cancer cell line MCF-7 was measured with a resazurin assay.
Quantification of 10 proteins from MCF-7 cells, representing endpoints of estrogen-and antiestrogen action High throughput screening.
Multiparameter panels, fast and highly specific diagnosis binding affinities, different concentrations and different periods will be necessary to refine the specific secretion patterns [52,53,54,55]
Transcriptional activation assays Luciferase activity Rapid screening, identification, and characterization of EDCs, the first human ovarian cell bioassay of this kind for detecting estrogens Response observed in cell lines does not necessarily reflect the toxic or biological potential of a compound in vivo. [56]
Triple functional small-molecule–protein conjugate mediated optical biosensor Dye-labeled estradiol (E2) -streptavidin conjugate (estrogenic activity) Easy-to-use and efficient with the high reusable capability Expensive [57]
Estrogen receptor recombinant yeast screening (Y ES ) assay Estrogenic activity The simplicity
The product of the reporter gene is secreted in the medium, and no cell lysis is required. The presence of yeast cell wall and active transport mechanisms that may differ from those found in mammalian cells and may affect the activity of some test compounds [58]
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a Recommended for the screening of xenoestrogens by EDSTAC/OECD [46,47] ER estrogen receptor; ERE estrogen-responsive element; GST glutathione-S-transferase; FRET fluorescence resonance energy transfer.
Mueller et al. [9] reported a review article in 2004, focusing on several in vitro tests for screening estrogenicity and antiestrogenicity of XEs. These assays were all powerful tools elucidating and describing the effects and mechanisms for XEs actions. While they had discussed in the essay, some mechanism-based assays are inappropriate to high-throughput screening for potent estrogenic and antiestrogenic XEs. Instead, other research [9,35], including high-throughput screening methods published recently, was presented. In vitro assays for identifying and detecting estrogenicity and antiestrogenicity toward different XEs were all summarized in Table 1.
2.1. E-SCREEN
Soto et al. [33] used the E-SCREEN assay to investigate the effects of XEs and 17β-estradiol on cells. Employing human MCF-7 (breast cancer cells) as a target in the assay, XEs were observed competing with E2 for binding to the ER and increased the levels of progesterone receptor (PR) and pS2 in MCF-7 cells. The E-SCREEN assay results have confirmed the estrogenic materials, including alkylphenols, phthalates, PCB congeners, and hydroxylated PCBs. The insecticides dieldrin, endosulfan, and toxaphene are also detected in the assay.
2.2. Ligand-Binding
In 1998, Randall Bolger et al. reported a novel technique for detecting XEs named the fluorescence polarization (FP) method. Under room air, the method could measure the capacity of XEs to displace a high-affinity fluorescent ligand from purified, recombinant human ERα. The ERs in mice have two subtypes, including ERα and ERβ, which are different in the structures of the C-terminal ligand-binding domain and N-terminal transactivation domain. In the mouse model, Kuiper et al. observed ERα- and ERβ-mediated messenger RNA expression via ligand binding and compared the specificity and affinity of ligand binding to ERα and ERβ via RT–PCR. They also found differences in the distribution and expression of ERα and ERβ in tissues and organs of mice. There were more distribution and expression of ERα in the uterus, testis, pituitary, ovary, kidney, epididymis, and adrenal, while there were more distribution and expression of ERβ in the prostate, lung, bladder, and brain [36,37].
2.3. ER-Binding to ERE
Nikov et al. observed differences in affinity of phytoestrogens when combined with ERα or ERβ, respectively. They also mentioned the combinations and interactions of ligand–ER complexes and estrogen response element (ERE) sequences. In their experiments, the FP methods were employed to measure binding affinities of various phytoestrogens, such as genistein, coumestrol, daidzein, glyceollin, and zearalenone to human cells. This article revealed a higher affinity of the phytoestrogens for ERβ than for ERα. The effect of these phytoestrogens on the ability of ERα and ERβ to associate with specific DNA sequences (EREs) was also investigated. In 2000, Boyer et al. performed a similar method on human ERα for probe of its molecular way on functional specificity. The implemented binding assays to study the interaction of the receptor with a palindromic estrogen response element derived from the vitellogenin ERE [38,39].
2.4. Mammalian Two-Hybrid Assays
DES is a well-known carcinogen [37]. As a mixture of indenestrol A (IA) S and R enantiomers [39], IA is a metabolic derivative of DES and has a high affinity to bind ER but a weaker biological activity [38]. Mueller et al. found that the estrogenic properties of the S and R enantiomers of IA, IA-S, and IA-R, respectively, had different affinities with ERα and ERβ in cells. Using human endometrial (Ishikawa) and breast MDA cell lines, which stably express either ERα or ERβ, IA-S was found more potent to activate cell transcription through ERα compared to IA-R. However, IA-R had more potency to stimulate ERβ rather than ERα in MDA cells, but this was not the case in endometrial cells. Although IA-R could effectively activate ERβ in vivo, it had a low affinity to bind both ERα and ERβ in vitro. These results showed that IA-R was cell-selective when bound to ERβ. In addition, there existed a single residue within the ligand-binding domains to determine the stereoselectivity of both ERα and ERβ [40,41,42].
2.5. Analysis of Gene Expression
Jorgensen et al. demonstrated that estrogenic activity could be evaluated by assaying induction or repression of endogenous estrogen-regulated “marker genes” in human breast cancer MCF-7 cells. The authors mentioned that a cell-based endogenous gene expression assay is very sensitive to what could be used to assay the estrogenicity of different putative estrogenic chemicals. They performed an assay in human MCF-7 that was estrogen-dependent and used a method of polymerase chain reaction (PCR) to observe the changes in gene expression. After differential display using reverse-transcribed (DDRT) PCR technology, the levels of expression could be quantified by phosphor-imaging [43,44].
2.6. Analysis of Enzyme Activity
Holinka et al. [46] described alkaline phosphatase as a convenient endpoint to examine mechanisms of hormonal actions. Alkaline phosphatase activity in human endometrial cancer cells of the estrogen-responsive Ishikawa line was markedly stimulated by estrogens, 5a-dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA). In the previous report, E2 and several other estrogens were noticed to greatly enhance the activity of alkaline phosphatase, an enzyme known to be regulated by ovarian hormones in the nonpregnant and pregnant rodent and monkey uterus. The results suggested that estrogen and androgen receptors mediate the stimulation of alkaline phosphatase by the C19 steroids [45,46].
2.7. Analysis of Steroido-Genesis
In H295R cells, various pesticides that had been suspected of interfering with the functions of steroid hormones were examined for their effects on the mRNA expression and catalytic activity of aromatase. Sanderson et al. focused mainly on interactions of XEs with sex hormone receptors, particularly the estrogen receptor. After a period of time, other mechanisms of interference with endocrine functions have gained attention, including the effects of pesticides on the enzymes that are involved in the synthesis and metabolism of steroid hormones. As a key role in producing many endogenous steroid hormones of high potency, the enzymes cytochrome P450 (CYP) that are responsible for the reactions in the biosynthetic pathways of steroids is a research focus [47]. H295R cell line was used to screen several pesticides known or suspected to interfere with steroid hormone function for potential effects on the catalytic activity and mRNA expression of aromatase [47,48].
2.8. The Fluorescence-Based Multi-Analyte Chip Platform
Using a parallel-proliferation measurement, the fluorescence-based multiplexed protein microarray (Figure 2) presents the bidirectional estrogenic and anti-estrogenic actions of XEs in human MCF-7 cells [52,53,54,55]. As a new in vitro tool for screening environmental samples, the fluorescence-based chip platform can analyze multiple targets to detect the estrogenic and anti-estrogenic actions of XEs by observing the expression of proteins. It can quantify 10 proteins secreted by MCF-7 cells, which represent different physiological and pathological endpoints of endocrine actions. Its potential is demonstrated by distinct protein secretion patterns of the cancer cell line after exposure to known ER agonists ß-estradiol, BPA, genistein, and nonylphenol as well as antagonists fulvestrant and tamoxifen. In parallel, the proliferating effect of endocrine-disrupting substances in MCF-7 cells can be assessed in a proliferation assay based on resazurin. Unlike the detection tools developed earlier, the chip has two advantages, including high-output screening for the endocrine effects of environmental disruptors on human cells and providing messages of the complicated cellular effects on a molecular level. Compared with single marker detection, this multiplexed protein microarray in the chip is more convenient and arrives at better accuracy [52].
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Figure 2
The fluorescence-based multianalyte chip platform. This equipment contains MCF-7 cells, which are exposed to estrogen receptor agonists and antagonists. Using a resazurin assay, the proliferative effect in hormone-sensitive cancer cell line MCF-7 can be measured. Using a multiplexed protein microarray with fluorescence detection, biomarkers can be quantified in the supernatant. By employing immobilized antibodies, the on-chip sandwich immunoassay captures the biomarker and a fluorescently labeled detection antibody for confirmation [52].
2.9. Transcriptional Activation Assays
A plasmid vector contains firefly luciferase genes that are controlled by DNA enhancers, which can react with androgens, estrogens or retinoic acids. The transfection of a plasmid vector into corresponding receptor-containing cells reflects its ability to respond to respective hormones under luciferase induction. An estrogen-responsive luciferase reporter plasmid has steadily transfected the recombinant ovarian carcinoma (BG-1) lines in humans. The subsequent recombination of cell lines (BG1Luc4E(2)) can respond to 17β-estradiol of a low concentration (≤1 pM). As a screening system for environmental hormones, the detectivity of BG1Luc4E(2)-cell bioassay was identified by the individual response to common XEs, and also by two novel estrogenic chemicals of PCBs (2,3′,4,4,′-tetrachlorobiphenyl and 2,2′,3,5′,6-pentachlorobiphenyl). These cell bioassay systems have applications for rapid screening, identification, and characterization of endocrine-disrupting chemicals. Transcriptional activation assays allow rapid identification of compounds with the potential to affect the ER signaling pathway directly or indirectly [56].
2.10. Triple Functional Small-Molecule–Protein Conjugate-Mediated Optical Biosensor
It is a challenge to create biosensors for a comprehensive mapping of potential estrogenic chemicals. Using triple functional small-molecule–protein conjugates as probes, fluorescent ER-based-wave biosensors were reported in 2019 to detect estrogenic activities in water samples [57]. The probe containing a Cy5.5-labeled streptavidin (STV) part and a 17β-estradiol part can act as signal conversion and recognition. When XEs are competing with the E2 part of the probe in binding to ERs, the unbound conjugates will be released. The STV parts then bind with desthiobiotin (DTB) modified with the optical fiber through an STV-DTB affinity interaction. The detection with signal probes is completed by fluorescence emission induced by a descending field, which correlates with estrogenic activities in the samples.
A facile method for quantifying estrogenic activities is developed by using a triple functional small-molecule–protein conjugate as a sensing element. Following optimization of detection, exposure to environmental estrogens can result in the release of the fluorescein-labeled conjugate in the supernatant. It will increase the amount of fluorescein that is attached to the fiber surface, which can be observed by increases in the fluorescent signals. By means of the approach, samples’ estrogenic activities can be measured at a limit of detection (LOD) of 1.05 μg/L, using E2 as a reference. The biosensors provide a reliable application for the detection of estrogenic activities in real samples of wastewater [57].
2.11. Estrogen Receptor Recombinant Yeast Screening (YES) Assay
Described by Professor Sumpter, this estrogen receptor recombinant yeast screening (YES) assay can be used to assess the estrogenic activity of chemicals or their metabolites, such as the surfactants and their major degradation products. In principle, the DNA sequence of the human estrogen receptor (hER) is integrated into the yeast (Saccharomyces cerevisiae) genome, which also contains expression plasmids carrying estrogen-responsive sequences (ERE) that control the expression of the reporter gene lac-Z (encoding the enzyme β-galactosidase). Thus, in the presence of estrogens, β-galactosidase is subsequently synthesized via the formation of ER-ligand and secreted into the medium, where it causes a colorful change from yellow to red [58]. This recombinant yeast is used to determine whether chemicals or their metabolites, such as the surfactants and their principal degradation products, possess estrogenic activity. The results are compared to the effects of the main natural estrogen 17β-estradiol [58]. Using the YES assay, the study revealed none of the parent surfactants tested possessed estrogenic activity. However, one class of surfactants, the alkylphenol polyethoxylates, degrade to persistent metabolites that were weakly estrogenic. Another group of degradation products, the sulfophenyl carboxylates, which were derived from the biodegradation of linear alkylbenzene sulfonates, did not appear to possess estrogenic activity [58]. Hence, the estrogen receptor recombinant YES assay can evaluate the estrogenic stimulation provided by estrogens, XEs and other endocrinal disruptors.
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3. Metabolism and Action of Xenoestrogens
3.1. The Metabolism of Xenoestrogens
The estrogenic or antiestrogenic activity of chemicals is attributed to the interactions between ER and other compounds. In fact, ER, as a ligand-inducible transcription factor, plays a vital role in development and neoplasia, regulating genes involved in cell proliferation and differentiation [9].
As a role of the major transcription factor in cell proliferation and differentiation, ER is sensitive to any disruption of the signaling pathways, leading to infertility, developmental abnormalities, or endocrine cancer discovered in both human beings and wildlife. The damage to health may be originated from exposure to the estrogenic or antiestrogenic activities of chemicals [59]. Endocrine-active compounds may also interfere with other signaling systems, most significantly the androgen and thyroid hormone system, steroidogenesis [60], and part of the aryl hydrocarbon (Ah) receptor [61].
The ER, as the nuclear receptor superfamily, is a factor of ligand-inducible transcription. Hence, far, two subtypes of the ER are ER α [62,63,64,65] and ER β [64], respectively, and both receptors have unique tissue distribution, playing a significant role in physiology [66,67]. In 1999, Korach suggested that most aberrant phenotypes are proved to be linked to ER α from the ER knockout mice study. (e.g., hypotrophy of the uterus, infertility, and rudimentary mammary gland development) [67].
While the reproductive system is significantly affected by the ER α, another impact upon non-classical estrogen target tissues, such as brain, skeletal, immune, cardiovascular system, adipose tissue, and the male reproductive tract, is also crucial [66,68]. As opposed to ER α, with diverse influences on multiple systems, ER β impacts are more specific to the female ovarian function [69,70]. Therefore, more attention has been paid to the XEs in which the dominance of ER α is much more than ER β; however, the interesting findings indicate that than ER α, ER β has correctly shown higher affinity [10,71].
Researchers have made attempts to reach the conclusions of the distribution and locations of the ER through the study of mice or even human body tissues. In 2001, Mueller and Korach et al. demonstrated the RNA and protein expression of ER in the human body [10,70]. There were published data regarding the distribution of relative qualitative tissue expression of ER α and ER β on cells and tissues of humans and mice [37,72,73,74,75].
Estrogen contributes largely to cells in various aspects, including development, proliferation, migration, and survival [67,76]. The action can be divided into two, namely genomic and non-genomic pathways [76,77]. Receptors, such as ER α, ER β, or even GPER, function well through these pathways [11,78,79]. The binding of estrogens to ERs in the cytoplasm contributes to the genomic pathway. The estrogen/receptor complex then swift to the nucleus; thus, changes are made to gene expression [80].
Additionally, non-genomic pathways, as influential as they could be, are via the binding to receptors (GPER) in cell membranes to activate secondary cellular messengers without incorporating gene expression in the nucleus. While both pathways are essential to further actions, non-genomic pathways, with their unique feature, have made the processing time faster from seconds to minutes; in contrast, genomic pathways are considered less efficient as it could take from an hour up to a few days for the transmission of messages in the organism [76,77].
The ER is located within the nucleus and dimerizes on ligand binding, and then the ER dimer is bound to the estrogen response element (ERE), which is in the sequence of the promoter of the estrogen target gene, being called the ER transcription complex. Dimers, including ER, ER α or ER β homodimer and ER α /ER β heterodimers are capable of binding to the corresponding ERE, which in turn prompts gene expression. Unlike ER β homodimers, ER α/ER β heterodimers seem to be more intensive in all ER activities. Additionally, ER α is discouraged by the existence of ER β activity [81,82]. The factors that accelerate gene transactivation are known as coactivators [79,83]; however, DNA is suppressed by the corepressors [84,85]. Both coactivators and corepressors are defined as the provider of the ER action.
The most common classical mechanism is displayed in Figure 1. Nevertheless, channels that will affect ER would not only be considered a single classical pathway but also the multiple interveners [11]. Moreover, then, the Kinase cascades or ER phosphorylation may be signaling information toward the ligand-independent activation. To be more specific, the estrogen ligand is connected to the ERE in which the signal of E2-target genes can be clearly expressed, such as the ER-DNA interaction classical pathway [12]. However, not all of the ERE would be found in the E2-sensitive gene promoter sequence, implying that the ER modes of action are diverse rather than a simple pathway.
Almeida et al. reported that ERα in osteoblast progenitors expressing Osterix1 (Osx1) potentiates Wnt/β-catenin signaling, thereby increasing proliferation and differentiation of periosteal cells [86]. Further, this signaling pathway was required for optimal cortical bone accrual at the periosteum in mice. Notably, this function did not require estrogens. The osteoblast progenitor ERα mediated a protective effect of estrogens against endocortical but not cancellous bone resorption. ERα in mature osteoblasts or osteocytes did not influence cancellous or cortical bone mass. Hence, the ERα in both osteoblast progenitors and osteoclasts functions to optimize bone mass, but at distinct bone compartments and in response to different cues [86].
In another study, it was hypothesized that ERα in osteocytes was important for trabecular bone in male mice and for cortical bone in both males and females [87]. Dmp1-Cre mice were crossed with ERα(flox/flox) mice to generate mice lacking ERα protein expression specifically in osteocytes (Dmp1-ERα (−/−)). Male Dmp1-ERα (−/−) mice displayed a substantial reduction in trabecular bone volume (−20%, p < 0.01) compared with controls. ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice, but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. The authors proposed that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males but via ERα in osteoclasts in females [87].
Kapara et al. have adopted a nondestructive approach for detecting and localizing ERα expression at the single-cell level using surface-enhanced Raman spectroscopy (SERS) combined with functionalized gold nanoparticles (AuNPs) [88]. The author developed an approach based on the percentage area of SERS response to qualitatively measure expression level in ERα-positive (ERα+) breast cancer cells. Specifically, the calculation of relative SERS response demonstrated that MCF-7 cells (ERα+) exhibited higher nanotag accumulation resulting in a 4.2-times increase in SERS signal area compared to SKBR-3 cells (ERα-) [88]. The result of this article confirmed the strong targeting effect of ERα-AuNPs towards the ERα receptor. It opened up the possibilities of using SERS as a tool for the estimation of ERα expression levels without the requirement of destructive and time-consuming techniques. Therefore, the potential of using SERS as a rapid and sensitive method to understand the activity of SERDs in breast cancer is demonstrated [88].
ER β has been suggested to possess antiproliferative and antitumor effects in breast and prostate cancer cells in some previous articles, but other studies have indicated its tumor-promoting effects [89]. The author studied the effects of ERB-041-treated colon cancer cells in a zebrafish xenograft model and found significantly less distant metastasis of ERB-041-treated cells compared to vehicle-treated cells. These results further support ERβ’s antitumor role in colorectal cancer and the possible use of its agonist in colorectal cancer patients [89].
Estrogen-related receptor β (ERRβ) is a nuclear receptor critical for many biological processes. Despite the biological and pharmaceutical importance of ERRβ, deciphering the structure of ERRβ has been hampered by the difficulties in obtaining a pure and stable protein for structural studies [90]. In fact, the ERRβ ligand-binding domain remains the last unsolved ERR structure and also one of only a few unknown nuclear receptor structures. The authors confirmed a critical single-residue mutation resulted in robust solubility and stability of an active ERRβ ligand-binding domain, thereby providing a protein tool enabling the first probe into the biochemical and structural studies of this important receptor [90].
The promoter context and estrogenic ligands are the joint dependents upon the expression of ER-target genes and ER-mediated cellular functions. In the previous discussion regarding the classic pathway, estrogenic ligands are highlighted as the trigger of ER conformational changes, and with further interactions with other coregulators and subsequent transcriptional activity moving forward [91,92].
It is indicated that the XEs work in different functions, even if they are identical. The tissue specificity marks its uniqueness, and XEs could also turn to other tissues with complexity. As ERα and ERβ have different functions and effects, the physiological functions and the organs and tissues are also distributed differently in the body parts; thus, identical XEs could lead to different consequences and effects on the body. Generally, XEs are either partial agonists or partial antagonists, which indicate that they are possibly less effective than estrogen in the human body [9].
As mentioned above, the complexity of mechanisms that affect XEs in the human body includes the genomic pathway, non-genomic pathway, and various transcription factors. Hereafter, coactivators, corepressors, or even the interactions between signaling cascades and other receptors will lead to estrogenic effects. Therefore, the mechanisms mentioned above should be considered in the experiment and evaluation. The diversification of ER action is the key to be understood [93].
In recent decades, people became aware of the exogenous compounds that work on the signaling pathways of endogenous hormones in the human body or organisms, including synthesis, storage, metabolism, transport, and elimination in organisms [94,95].
As endocrine-disrupting chemicals (EDCs), these XEs may lead to biological and pathological changes or even accumulated damage to future generations (e.g., bioaccumulation). There are various sources and types of XEs in the environment, and many of these XEs have the similarity of structures with estrogens [19,96]. The chemical structural similarity between these XEs and naturally occurring estrogen compounds can cause the human body and organism simulations (e.g., 17β-estradiol). EDCs behave like natural (estrone (E1), E2, estriol (E3)) and synthetic estrogens DES, [4,7]. Among all estrogens, including E1, E2 and E3, E2 is the most potent and serves as the major estrogen that exerts endocrinal functions in human bodies.
The mechanisms of action of XEs could be divided into critical factors as follows: Endogenously occurring estrogens simulation, an antagonist of endogenous estrogens, and the intervention of metabolism and biosynthesis production of estrogen [8]. Additionally, EDCs have been mentioned to act through complex tissue-selective modulation on ERs and other signaling pathways in vivo [19].
As mentioned above, ER α and ER β act as an intermediary in various tissues and those with distinct biological effects, including mammary glands, bone, brain, and vascular system in both genders. Due to the partial different tissue distribution and distinct physiological functions, XEs could show agonist or antagonist activity at the time of development [94].
The relationship between ERs and coactivators/corepressors is critical to the regulation of DNA and RNA, which will also impact the expression of ER-target genes. In fact, the characteristic of tissues specific to different organs includes expression of specific cofactors, the ER α/ER β ratio, and the level of expression of specific intracellular kinases (including cytoplasmic tyrosine kinases). For example, the affinity of the phytoestrogen genistein to ER β is much greater than that of ER α. There is even more evidence to show that genistein impacts the proliferation or antiproliferation in cancer cells [97].
3.2. The Actions of Xenoestrogens
3.2.1. Selective Estrogen Receptor Modulators (SERMs) and Aromatase Interferer
Due to the characteristics mentioned above, tamoxifen and raloxifene have been applied to the current treatments, and the process is so-called selective ER modulators (SERMs). These kinds of XEs sometimes could have impacts on the ER nongenomic pathways that increase endocrine disruption. There were examples showing XEs in different structures, with high concentrations, BPA, and DES, all capable of activating ERs, thus increasing the risk of developing breast cancer [98].
SERMs were found to demonstrate selectivity toward ERs in the bone, thereby reducing side effects. However, they lack the efficacy of traditional estrogen. SERMs are generally influenced by their binding affinity for ER α and ER β and the effect of the bound ligand on the ER structure. However, the precise mode of action of each SERM remains unknown. One endogenous compound—27-hydroxycholesterol (27HC)—has been found to bind to and modulate the activity of ERs in vivo and to behave like a SERM. In mice, 27HC behaves as an ER antagonist and reduces the protective effects of estradiol. However, in cellular models of ER-positive breast cancer, 27HC acts as a partial ER agonist. In ovariectomized mice with elevated 27HC levels, a dramatic loss of bone was observed. Further research on 27HC could lead to developing new drugs.
Aromatase inherently existed in the human body to convert androgens to estrogens. However, a type of XE, such as tributyltins, has an aromatase suppressing effect, leading to an imbalance between androgens and estrogen. Tributyltins is a kind of coating, which often exists in the hull of fishing boats or plastic products, and the potential health effects on organisms are as follows: teratogen; teratogenicity; diabetes mellitus; hyperlipidemia; metabolic syndrome; increase in fat depot size; obesity; hepatic steatosis; hypertrichosis; osteoporosis; decreased sperm production; breast cancer; endometrial cancer [99,100]; polycystic ovary syndrome (PCOS) [101,102,103,104].
3.2.2. Polycyclic Aromatic Hydrocarbons (PAHs)
Some XEs are combined with sex hormone-binding globulin, which decreases E2 plasma transport in the cell. An example is an interaction between polycyclic aromatic hydrocarbons (PAHs) and ERE-dependent E2-target gene transcription. PAHs are a collective term for more than a hundred different chemical substances, which are formed when coal, fuel oil, gas, trash, or other organic substances are incompletely burnt, and some PAHs are artificially manufactured. PAHs are found in coal tar, crude oil, and a few are applied in medicines or manufacturing dyes, plastics, and pesticides [105,106,107]. On the other hand, some metabolites of PAHs could be combined with ERs to recruit other coregulators, and the enhancing performance of E2 target genes could be achieved. Dioxin is one of the metabolites of PAHs. In the case of dioxin, it could be bound with aryl hydrocarbon receptor (AhR) that leads to heterodimerization along with aryl hydrocarbon nuclear translocator (Arnt). If so, the interaction between ER and ERE could facilitate the expression of the E2 target gene through such a complex [94].
3.2.3. DDT [2,2-Bis(p-chlorophenyl)-1,1,1-trichloroethan] and Its Metabolite DDE
Another example of XEs is DDE, a metabolite of DDT and a component of pesticides. DDE is seen as more effective due to its affinity and lipophilicity, and it is unlikely to be catabolized by organisms. Both DDT and DDE are XEs with estrogenicity, which could influence the reproduction function of organisms in the environment. For instance, in the alligators of Lake Apopka, biologists have discovered that male crocodiles have a micropenis and various abnormalities of the testes due to their exposure to DDT and DDE substances [108].
Fujisaki et al. have reviewed past data records from the early 1980s that the American alligator (Alligator mississippiensis) population decreased in Lake Apopka after DDT and DDE exposure. Thus, the US government has conducted the extensive restoration of the swamp of Lake Apopka and proposed environmental-related restrictions on the lake in response to such a decrease. According to monitoring by the Florida Fish and Wildlife Conservation Commission, the adult alligator population gradually began to increase in the early 1990s after such efforts were made [109].
The consequences of DDT and DDE have also been found in human bodies; this was in Wolff et al.′s findings in the organochlorine article in 1993, including DDT, PCBs and other substances in relation to the risk of breast cancer. The correlation between breast cancer and DDT or DDE was mentioned [12,110].
Due to the inefficiency of metabolism and their solubility in lipids, these agents have been found in human tissue that causes lifelong sequestration in adipose tissue. Wolff et al. have concluded that DDE in serum is the most significant trigger of breast cancer development instead of associating with PCBs. This research suggests that environmental chemical contamination with organochlorine residues may be a critical factor in breast cancer [110].
In addition to the impacts of breast cancer, there is also evidence that shows methoxychlor (pesticide) and DDT have the potential to cause uterine proliferation and weakening of normal follicle development in the female reproductive system [19].
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3.2.4. Polychlorinated Biphenyls (PCBs)
Although Wolff et al. in 1993 reported that breast cancer was less associated with PCBs level in serum, other studies have suggested that PCBs work the same way in humans as scientists have long observed the effects of PCBs on other organisms. Bergeron noted the relationship between turtle sex determination and environmental contamination and the EDCs, such as PCB isomers, can alter sex ratios in turtles [12,111].
In the early 1970s, the findings in the experiments regarding PCBs in mice showed that exposure at birth reduced the reproductive ability of male rats [112] because of the alternation of steroid hormone-metabolizing enzymes [113]. Although Wolff et al. concluded that breast cancer was not associated with PCBs in serum in the early days, there have been many reports about PCBs and breast cancer progression in the future. Exposure to PCB174 has been confirmed to be associated with an increase in breast cancer mortality, and it is still positively related to breast cancer-specific mortality after 5 or even 15 years of follow-up after being diagnosed. Moreover, there are various reports, which made similar conclusions [93,114].
3.2.5. The Relationship between EDCs and Diseases
It has been realized that estrogenic or antiestrogenic effects of different EDCs involve environmental pollution and affect human hormonal discrepancies. According to the historical data, breast cancer incidence and prevalence have been increasing since the 1940s [12,115,116,117]. The risk of breast cancer accelerates with increased cumulative estrogen exposure or the rise of XEs in the environment. Many researchers are dedicated to identifying related risk factors, DDT and its metabolite (metabolite) DDE [110]. As PAHs, dioxin, PCBs and DES were mentioned earlier, and all have been reviewed in the literature for the associated carcinogenic effects (carcinogenic effects, carcinogenic elements) or toxicity to the mammary gland (toxicant). 2,3,7,8-chlorodibenzo-p-dioxin has been proved to be toxic to the mammary glands of mice. Dioxin delays the proliferation and differentiation of the mammary glands of breast development. This finding has an identical conclusion obtained in the human body [118]. Another study reported that 200 young Belgian girls had delayed pubertal development related to their blood doubling of serum dioxin levels [119]. Similarly, PAHs have also affected a significant increase in postmenopausal women’s breast cancer development. Additionally, DES exposure during human pregnancy can trigger oncogenesis in the vagina and breast [120,121,122]. Moreover, Hoover proposed in 2011 that mothers who have been exposed to diethylstilbestrol will influence their next generation in utero, with the incidence and progress of future breast cancer development. In fact, the growth may become more significant due to the age of these DES daughters [123].
In 2016, Ellinon Axiomaticon reviewed studies that investigated the relationship between endometriosis and endocrine disruptors. Hormonal influences may be the key factor that affects the extrauterine growth and proliferation of endometrial cells [12]. Other reports demonstrated the association of membranous ectopic diseases of rodents or primates with the common environmental pollutants, including TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), dioxin, BPA, and DES [124,125,126,127,128]. For the pathophysiology in relation to endometriosis that TCDD may cause, changes in the relative levels of ERβ and ERα in endometrial tissue determine the performance of the estradiol-regulated progesterone receptor (PR). The reduction of the ERα-to-ERβ ratio may result in the expression of PR being suppressed [129,130]. If the mother is exposed to specific-XEs, such as DES or BPA during pregnancy, increased endometriosis will be passed into the next generation, either in the human body or mice [125,127,131].
Similarly, endometrial cancer has the same trigger for developing ovarian cancer, which is considered estrogen and XEs [132,133]. For instance, methoxychlor [MXC; 1,1,1-trichlor-2,2-bis(4-methoxyphenyl) ethane] is an organochlorine pesticide used in agriculture since DDT was banned. The metabolite of methoxychlor is 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), activating ER in ovarian cancer cells and mitogenic activities in ovarian tissues. Moreover, triclosan is often used as a common ingredient in soaps, deodorants, toothpaste, and other hygiene products. Methoxychlor and triclosan are substances that contain organochlorine, regulating cell cycles and apoptosis-related genes by combining with ERs, thereby stimulating the growth of ovarian cancer cells and the consequences of cancer reaction [134]. In addition, genistein, which is a type of phytoestrogen, is similar in structure to estrogen, thus mimicking E2 and stimulating cell proliferation activity [135].
3.2.6. Bisphenol A (BPA)
Industrial compounds, such as BPA and 4-nonylphenol (NPH), have residues in food (e.g., in canned vegetables) or dental materials. BPA is a chemical compound used in food or plastic containers. The coating on metal cans could protect food and beverages. Potentially, the residual compounds may all be detected [4,136,137,138].
If the mother mouse is exposed to the environment with BPA before delivery, the number of precancerous lesions will increase after the next generations turn into adulthood, and such correlation can be considered dose-related. However, high dosage BPA and 4-NPH can induce the occurrence of breast cancer cells in situ [137,139,140]. The possibility of XEs increase the risk of carcinogenesis in different vertebrate reproductive systems has been discussed. Moreover, current scientific and medical research has found that the impact of these environmental pollutants has been subjected to cancer-related and metabolic diseases, such as obesity, diabetes mellitus, hypertension, and cardiovascular disease [141,142].
Low levels of estrogen are related to developing glucose intolerance and insulin resistance [143]. As is, BPA can increase or decrease insulin production in the body by mimicking the effect of the body’s endogenous estrogen, which mechanism is similar to insulin regulation by 17β-estradiol. Recently, different research has proved the effects of BPA on insulin resistance, both for children and adults. BPA, as an environmental hormone, plays an important role in the pathophysiology of diabetes mellitus [144,145,146]. In addition, BPA can also reduce glycogen synthesis, thereby reducing glucose oxidation and reducing the use of glucose by muscle cells, and the sensitivity of muscle cells to insulin will be decreased [147].
BPA Exposure can also contribute to weight gain in mice, especially in female mice; the para-physiological mechanism may result from interference with the neurotransmitter signaling pathway, which causes the change in energy metabolism [142,148]. A study researching children’s obesity has confirmed that compared with normal weight, overweight and obesity are significantly associated with the urinary BPA levels of the children. Moreover, BPA may trigger insulin resistance in children and increase the risk of diabetes mellitus, especially for obese children [149]. In 2017, Lidia Caporossi conducted a literature review to analyze the effects of BPA on different metabolic diseases. Most of the reports are cross-sectional studies [141]. Fénichel pointed out that the prevalence of type-2 diabetes in the world has increased dramatically in the last few decades. There is also increasing evidence that shows these EDCs may also play a key role in the occurrence of metabolic diseases. In the observations of rodents, it was found that BPA stimulated the production and secretion of pancreatic β cells, interfering with insulin signals, which cause insulin resistance and β cell destruction/damages [150].
In addition to the risks regarding BPA that may result in various types of reproductive organ cancers and metabolic diseases, recent studies have also suggested that BPA can affect healthy bones. Except for the characteristics of estrogenicity and antiandrogenicity, it has been hypothesized that BPA can bind to the ER and exert its antiandrogenic, inflammatory, and oxidative properties [151]. Because bones will transform in response to the stimulation of hormones, inflammatory and oxidative status, BPA exposure can impair bone health. In 2018, Chin et al. reviewed the evidence of the effects of BPA and its derivatives on skeletal health in humans and animals and reported that BPA would decrease the proliferation of osteoblast and osteoclast precursor cells and induce apoptosis [151]. In various (in vivo and in vitro) animal models, BPA and its derivatives have different positive and negative actions. While BPA increased femoral bone mineral content in male rats, it decreased femoral mechanical strength in female rats. In estrogen-deficiency models, BPA improved bone mineral density and microstructures in aromatase-knockout mice; however, it lowered the trabecular density in ovariectomized rats. The major limitations of current evidence are the small sample size and the cross-sectional rather than longitudinal study design. In conclusion, BPA can affect the skeletal health of vertebrate animals, and its impacts depend on the types and sex of animals. However, the effects of BPA on bone mineral density and bone health of humans warrant further investigation [151].
Another study conducted by Kim et al. had attempted to analyze the relationships between serum BPA concentration, bone mineral density (BMD) and biochemical bone markers in postmenopausal women with osteoporosis [152]. The relationship between BPA and clinical variables was analyzed by the Pearson’s correlation test and the Kruskal–Wallis test. Serum BPA concentration was measured by enzyme-linked immunosorbent assay (ELISA). The mean BPA concentration of 51 postmenopausal women was 1.44 ± 0.52 ng/mL. The results showed no statistically significant correlation between BPA concentration and clinical variables. The author concluded that there was no statistically significant correlation between serum BPA and clinical variables related to bone metabolism [152].
Upson et al. have conducted a population-based case-control study to investigate the association of BPA exposure with the risk of endometriosis [153]. The authors measured and analyzed urinary BPA concentrations for more than 400 cases. For cases and controls, the median creatinine-uncorrected total BPA concentrations (µg/L) were 1.02 (IQR: 0.43–2.12) and 0.86 (IQR: 0.36–2.01), and the median creatinine-corrected total BPA concentrations (µg/g) were 1.32 (IQR: 0.79–2.21) and 1.24 (IQR: 0.65–2.54), respectively. The result showed statistically significant positive associations when evaluating total urinary BPA concentrations was only in relation to non-ovarian pelvic endometriosis, but not in relation to ovarian endometriosis [153].
Except for the association with female reproductive diseases, including breast cancer, ovarian cancer, vaginal cancer and endometriosis, literature has confirmed the effects of XEs on the male genital system. Increasing evidence has shown the connection between exposure and EDCs and impairment of male reproductive function. The impact can originate from the interference of hormone, cell signaling pathway and metabolism, and will be augmented, especially if the exposure to XEs occurs during early growth development [154]. Recent research has highlighted the possible relationship between unexplained male infertility and exposure to low-dose EDCs in the fetal testis and adult endocrine system [155]. Exposure to EDC may result in the impairment of testis functions in different spermatogenesis stages, depending on the time point of exposure. BPA induced meiotic abnormalities in the reproductive system of adult male mice [156] and significantly reduced the number of sperms in juvenile male mice as a result of interruption of meiotic progression [157,158]. Dibutyl phthalate (DBP) and methoxychlor (MXC) can significantly lower the weight of the testes as a consequence of a reduction in the number of spermatogenic elements and spermatozoa [159,160]. The use of DBP can block spermatogenesis, thus prohibiting the production of sperms and even leading to necrosis of the seminiferous tubules [159,160].
3.2.7. Heavy Metals: Cadmium (Cd) and Arsenic (As)
Heavy metals can act as XEs and influence female reproduction systems. One example is the chemical Cd, which can be found in cigarettes, paints, plastics, batteries, and foods. As toxins to humans, inorganic Cd and As are cytotoxic at a high concentration level [4]; however, they can simulate estrogen and exert XEs-like actions at a low concentration level. Although the literature has confirmed the estrogenicity of inorganic Cd in tumor cell lines, the underlying mechanisms remain unclear and need more research. Both inorganic Cd and As stimulate cell proliferation in the pituitary gland and uterus by increasing the expression of proliferation markers, thus affecting hormone-dependent tumor progression. The anterior pituitary gland is responsible for hormone synthesis and secretion (such as prolactin and luteinizing hormone). Both inorganic Cd and As can increase prolactin synthesis. In 2016, Ronchetti et al. found that low doses of Cd can exert strong xenoestrogenic effects on the anterior pituitary gland [161].
3.2.8. Phytoestrogens
Phytoestrogens are another type of XEs, including isoflavonoids, lignans, coumestans, and pisatin [24]. Some plants, such as soybeans, contain phytoestrogens with active ingredients of genistein and daidzein [4,162]. Phytoestrogens can combine and activate estrogen receptors in the brain to influence functions of the brain, thus possibly resulting in neurobehavioral disruptions. On the other hand, other studies indicated that pregnant women might benefit from the intake of soybean foods that contained phytoestrogens [163].
In vitro or in vivo studies to analyze the final effects of phytoestrogens may be quite different. For instance, at low doses (from 10 nM to 1 µM), genistein showed mitogenic effects on breast cancer cell growth, whereas, at higher concentrations (>10 µM), it showed antiproliferative effects [164]. Some of these effects are explained by their interactions with ER subtypes. As mentioned above, the ratios and the expressions of ERα and ERβ are different in various tissues depending on the period of life. Moreover, the abilities of ER subtypes to recruit cofactors, regulate gene expression and stimulate or inhibit cell growth are slightly different. Therefore, in vivo, phytoestrogens may have a complex role, acting as weak estrogens and antiestrogens depending on the tissue. Furthermore, it is believed that the signaling pathways induced by phytoestrogens are not completely identical to those induced by estrogens [164].
Regarding the preventive effects on diseases or cancers, a higher intake of phytoestrogens, such as isoflavones, is associated with a moderately lower risk of developing coronary heart disease. It may also reduce the risks of breast and colorectal cancer as well as the incidence of breast cancer recurrence. Consumption of phytoestrogens or soy foods is associated with reduced risks of endometrial and bladder cancer [165,166]. Regarding the therapeutic effects on menopausal syndrome or other diseases, phytoestrogens have been found to alleviate vasomotor syndromes even after considering placebo effects, reduce bone loss in the spine and ameliorate hypertension and in vitro glycemic control. They may also alleviate depressive symptoms during pregnancy. On the other hand, phytoestrogens have not shown definitive effects regarding improving cognition and urogenital symptoms [165,166]. Because of lacking standardization in the study designs, such as the ingredients and doses of phytoestrogens and the durations and outcomes of trials, it currently remains difficult to draw overall conclusions for all aspects of phytoestrogens. These limitations warrant further investigations of the use of phytoestrogens for women’s health.
3.2.9. Diethylstilbestrol (DES) and 17-α-ethinylestradiol
DES is one type of synthetic estrogen with strong potency. During 1940–1971, several million people were exposed to DES [21,22,167]. DES can inhibit the actions of adrenal androgens and possibly interfere with cell cycles to induce apoptosis of prostate cancer cell lines [22,25,26]. A study from Egypt pointed out a higher incidence of uterine, cervical, and ovarian cancer in urban areas than in rural areas. The incidence of uterine cancer is 6-fold in urban areas than in rural areas. Correspondingly, there was a higher exposure to XEs (e.g., DES) for females living in the urban areas of Egypt than those living in rural areas [136]. Such a difference in exposure to XEs between urban and rural areas could be noted in other countries [136,168,169,170,171].
Voisin et al. exposed mangrove rivulus (Kryptolebias marmoratus) for first post-hatching 28 days to 4 and 120 ng/L 17-α-ethinylestradiol, as a model of XE environment [172]. The results showed the effects of 17-α-ethinylestradiol were tissue- and dose-dependent. A total of 31, 51 and 18 proteins were differentially abundant at 4 ng/L in the brain, liver and ovotestis, compared to 20, 25 and 39 proteins at 120 ng/L, respectively. This study demonstrated the long-term effects of early-life endocrine disruption at the proteomic level in diverse estrogen-responsive pathways 5 months after the exposure. The lowest tested and environmentally relevant concentration of 4 ng/L 17-α-ethinylestradiol had the highest impact on the proteome in the brain and liver, highlighting the potency of endocrine disruptors at low concentrations [172].
Hill Jr et al. have researched the concentration-dependent effects of a weak estrogen receptor agonist, 4-NPH and a potent estrogen receptor agonist, 17α-ethinylestradiol (EE) on sex ratios, gonad morphology, vitellogenin (VTG) induction and breeding success in zebrafish (Danio rerio) [173]. Fish were exposed from 2 to 60 days post-hatch (dph) to NPH (10, 30, or 100 microg/L nominal), EE (1, 10, or 100 ng/L nominal), or solvent control (acetone; 0.2% v/v) in a static-renewal system with replacement every 48 h. The percentage of males at 60 dph changed from 45% in solvent controls to 0% at 10 ng/L EE and 10% at 100 microg/L NPH. In the EE exposure group, a concentration-dependent increase in the number of fish with undeveloped gonads at 60 dph was observed. However, the sex ratios of adults determined at 160 dph revealed no significant departure from 1 male: 1 female, suggesting that exposure of zebrafish to estrogenic chemicals during sexual differentiation and early gametogenesis did not irreversibly alter phenotypic sex. These results suggest that functional reproductive capacity (breeding success) may be more sensitive than gross morphological endpoints (condition, ovo-somatic index, sex ratio) in adult zebrafish exposed to XEs during sexual differentiation and early gametogenesis [173].
Liao et al. have compared the sensitivities of rare minnows during different life stages to 17β-estradiol (E(2)) at environmentally relevant (5, 25, and 100 ng L−1 and high (1000 ng L−1) concentrations by using VTG and gonad development as biomarkers under semistatic conditions [174]. After 21 days of exposure, VTG concentrations in whole-body homogenates were analyzed. The results indicated that the lowest observed effective concentration for VTG induction was 25 ng L−1 E(2) in the adult stage but 100 ng L−1 E(2) in the larval and juvenile stages. After exposure in the early life stage, the larval and juvenile fish were transferred to clean water until gonad maturation. No significant difference in VTG induction was found between the exposure and control groups in the adults, but a markedly increased proportion of females and appearance of hermaphrodism in the juvenile-stage group exposed to 25 ng L−1 E(2). These results showed that VTG induction in the adult stage is more sensitive than in larval and juvenile stages following exposure to E(2). The juvenile stage may be the critical period of gonad development [174].
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4. Discussion
On the molecular level, many XEs are known to be structurally related to the steroid hormones produced by the human body (structural similarity to the natural estrogens). Therefore, they have estrogenicity or antiestroginecity and can be bound with the receptors of the organism, manipulating differentiation and modulation of cell proliferation, apoptosis, cytokine production, and cell cycle progression, which should have been controlled over by the endogenous 17β-estradiol [3,6]. On the other hand, some substances, such as Cd, PCB and dioxin, can function as potential endocrine disruptors despite no structural similarity to the natural estrogens. However, the exact mechanism by which this metal Cd may interfere with the reproductive system has not been fully elucidated. The interruption in the steroidogenic pathway by Cd toxic action may be explained in a few different ways [175]. The changes in E2 and progesterone levels may result from the impairment of steroidogenic enzymatic activities by Cd. Under the actions of Cd, conversion of cholesterol to pregnenolone is supposed to be the cause of abnormalities in the metabolism of sex hormones. Thus, endocrine disruptors, including Cd, PCB and dioxin, can exert effects via various pathways other than classical ER-signaling.
Evidence shows the possible impacts of environmental XEs on developing humans and animal groups’ evolution in recent years. The issue could be considered crucial in the long run instead of a short-term (maldevelopment) effect. Some accumulated effects of XEs or EDCs may only occur until the individual matures, reaching adulthood, rather than being effective in a short period [12]. Xenoestrogen-related endometriosis, which damages the reproductive system, precancerous lesions, and proliferation of cancer cells are pertinent examples. For example, cervical cancer or prostate cancer is reported to be relevant environmental estrogens cases. An article reporting how XEs or EDCs affect the female reproductive system, particularly the endometrium, was published by Karoutsou et al. in 2016 [12], in which it includes the idea of the term window. Explaining from a period in a development perspective, the term window of susceptibility means that the developing organisms can be altered by environmental factors, which results in structural, functional, and/or cellular changes. The occurrence of such alterations during these windows could only be identified until the late stages [12].
The use of certain pesticides, which refers to the XEs in relation to the biological damage and adverse events to the reproductive system, was initially documented back in the 20th-century [27,28,29]. Nowadays, the indirect evidence shows that endocrine disruptors are related to various diseases, and their relationship can also be observed in the studies, including metabolic syndrome (especially hypertension and diabetes, obesity), asthma, and various reproductive system-related cancers [6]. Such diseases are not subject, particularly to males or females. Evidence can also be found in breast, cervical, prostate, and vaginal cancer [4].
Previous studies have shown indirect evidence regarding the diseases or harmful organisms triggered by XEs. As mentioned before, these reports focus on the more common XEs, such as DDT and its metabolites DDE, PCBs, DES, 2,3,7,8-TCDD (dioxin), and BPA. As mentioned previously, DDE has a higher affinity and lipophilicity and is not easily catabolized by organisms. Lake Apopka in Florida is seriously affected by DDT and its metabolites. It is discovered that male crocodiles have a micropenis, various abnormalities of the testes, and the cause may be with the exposure of DDT and DDE to crocodiles [108]. Moreover, metallic endocrine disruptors, such as Cd and phytoestrogens, are other examples. Notably, the damages that isoflavones, coumestrol, and clover do to the human body will reflect on the reproductive system and possibly position as the trigger of cancer development. They will also affect other systems, such as the nervous, skeletal, human brains, and even the entire body’s metabolism. However, it can be more beneficial to apply natural and synthetic XEs as they can be considered medications to improve human health, treat and prevent diseases if used appropriately.
The current review has some inherent limitations. The first limitation lies in the focus of the research XEs per se. Because of considering the moral hazard in conducting studies regarding the harmful effects of XEs on humans, many of the studies were observational and animal, thus limiting the application of the review results to humans. Second, studies were conducted with different research designs and subjects (human; animals), and different results were reported with researchers of different skills and training. Therefore, it is somewhat difficult to make comparisons and inferences in the analysis. Moreover, there are fewer randomized controlled trials found on the topic of XEs after selection. Thus, the evidence available in XEs is not as strong as that in other topics. Furthermore, there are many intermediating factors, which affect the outcomes, so the direct causal relationship of XEs effects is hard to be proved. Finally, many of the beneficial and harmful effects of XEs, which have been accumulated in organisms, are dose-dependent and time-dependent, which may not be observed during a shorter period. Maybe a better investigation for the action of XEs can be achieved by a longer and closer follow-up of the research subjects.
Currently, more experiments are required to study the substances in the environment. This is due to the great spectrum of toxins that organisms in the world are exposed to. The worst case of malignant tumors can develop over the years, and many factors also determine the complex process of carcinogenesis development. It is understandable to review the documentary of environmental estrogens and their influences on individual development, as well as to conduct more studies for further clarification.
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5. Conclusions
As endocrine disruptors, XEs can be either synthetic or natural chemical compounds derived from sources, including diet, pesticides, cosmetics, plastics, plants, industrial byproducts, metals, and medications. By mimicking the chemical structure that is naturally occurring estrogen compounds, even the weakly active compounds could interfere with the hormonal balance with persistency or high concentrations of XEs, thus possibly being associated with the occurrence of the reproductive tract or neuroendocrine disorders and congenital malformations. In contrast, some XEs are not similar to estrogens in structure and can affect the physiologic functions in ways other than ER-ERE ligand routes. In addition to the classical ER-signaling pathway, some endocrine disruptors can exert effects via various pathways other than classical ER-signaling.
The dose-related and time-dependent effects of XEs on organisms should be considered. XEs are most likely to exert tissue-specific and non-genomic actions when estrogen concentrations are relatively low. Current research reported that there is not only a single factor affected by XEs, but opposite directions are also found on several occasions, or even different components stem from the identical endocrine pathway. Thus, the roles of XEs are more challenging and unpredictable in terms of physical health. Although there are numerous studies of XEs or endocrinal disruptors in the literature, many of them are observational and animal, thus limiting the application of the studies to humans. In addition, there are fewer randomized controlled trials of this topic found in the literature. Furthermore, many intermediating factors, which affect the outcomes are difficult to be controlled in these studies, so the direct causal relationship of XEs effects is hard to be proved. Moreover, many of the beneficial and harmful effects of accumulated XEs are dose-dependent and time-dependent, which may not be observed during a shorter period, and may need a longer and closer follow-up of the research subjects. This review provides a current summary of the identification, detection, metabolism, and action of XEs. However, many details of the underlying mechanisms remain unknown and warrant further investigation.
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Author Contributions
L.-H.W. and K.-H.C. conceived and designed the study; L.-H.W., L.-R.C. and K.-H.C. performed the data collection; L.-H.W., L.-R.C. and K.-H.C. analyzed the data; L.-H.W. and K.-H.C. wrote the paper. All authors have read and agreed to the published version of the manuscript.
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Funding
This work and APC were funded by a grant from Taipei Tzu-Chi Hospital, Taiwan (TCRD-TPE-110-06) for KH Chen. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
please I need True or false answer without an explanations:
1. lignans in plant foods can destroy xenoestrogens through the action of gi gut bacteria
2.natural estrogens that bind more strongly have a greater estrogen effect than those that bind less.
3.quercetin in plant foods is considered a xenoestrogen
4. when the estrogen receptor dimer binds to the dna docking site it switches on specific genes that code for proteins that result in cellular feminization
what are xenoestrogens
Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.
Xenoestrogens are clinically significant because they can mimic the effects of endogenous estrogen and thus have been implicated in precocious puberty and other disorders of the reproductive system.[1][2]
Xenoestrogens include pharmacological estrogens (in which estrogenic action is an intended effect, as in the drug ethinylestradiol used in contraceptive pills), but other chemicals may also have estrogenic effects. Xenoestrogens have been introduced into the environment by industrial, agricultural and chemical companies and consumers only in the last 70 years or so, but archiestrogens exist naturally. Some plants (like the cereals and the legumes) are using estrogenic substances possibly as part of their natural defence against herbivore animals by controlling their fertility.[3][4]
The potential ecological and human health impact of xenoestrogens is of growing concern.[5] The word xenoestrogen is derived from the Greek words ξένο (xeno, meaning foreign), οἶστρος (estrus, meaning sexual desire) and γόνο (gene, meaning "to generate") and literally means "foreign estrogen". Xenoestrogens are also called "environmental hormones" or "EDC" (Endocrine Disrupting Compounds). Most scientists that study xenoestrogens, including The Endocrine Society, regard them as serious environmental hazards that have hormone disruptive effects on both wildlife and humans.[6][7][8][9][10]
Contents
1 Mechanism of action
2 Effects
2.1 Impact
2.2 Precocious puberty
2.2.1 Thelarche in Puerto Rico
2.2.2 Tuscany precocious puberty cases
2.2.3 Dairy contamination
2.2.4 Fish contamination
2.2.5 Implications
2.3 In other animals
3 Common environmental estrogens
3.1 Atrazine
3.2 BPA
3.3 DDT
3.4 Dioxin
3.5 Endosulfan
3.6 PBB
3.7 PCBs
3.8 Phthalates
3.9 Zeranol
3.10 Miscellaneous
4 See also
5 References
6 External links
Mechanism of action
The onset of puberty is characterized by increased levels of hypothalamic gonadotropin releasing hormone (GnRH). GnRH triggers the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland, which in turn causes the ovaries to respond and secrete estradiol. Increases in gonadal estrogen promote breast development, female fat distribution and skeletal growth. Adrenal androgen and gonadal androgen result in pubic and axillary hair.[11][12] Peripheral precocious puberty caused by exogenous estrogens is evaluated by assessing decreased levels of gonadotrophins.[13]
Xenoestrogens in plastics, packaged food, drink trays and containers, (more so, when they've been heated in the Sun, or an oven), may interfere with pubertal development by actions at different levels – hypothalamic-pituitary axis, gonads, peripheral target organs such as the breast, hair follicles and genitals. Exogenous chemicals that mimic estrogen can alter the functions of the endocrine system and cause various health defects by interfering with synthesis, metabolism, binding or cellular responses of natural estrogens.[12][14][15][16]
Although the physiology of the reproductive system is complex, the action of environmental exogenous estrogens is hypothesized to occur by two possible mechanisms. Xenoestrogens may temporarily or permanently alter the feedback loops in the brain, pituitary, gonads, and thyroid by mimicking the effects of estrogen and triggering their specific receptors or they may bind to hormone receptors and block the action of natural hormones. Thus it is plausible that environmental estrogens can accelerate sexual development if present in a sufficient concentration or with chronic exposure.[14][16][17][18] The similarity in the structure of exogenous estrogens and the estrogens has changed the hormone balance within the body and resulted in various reproductive problems in females.[12] The overall mechanism of action is binding of the exogenous compounds that mimic estrogen to the estrogen binding receptors and cause the determined action in the target organs.[19]
vte Affinities of estrogen receptor ligands for the ERα and ERβ
Effects
Xenoestrogens have been implicated in a variety of medical problems, and during the last 10 years many scientific studies have found hard evidence of adverse effects on human and animal health.[31][excessive citations]
There is a concern that xenoestrogens may act as false messengers and disrupt the process of reproduction. Xenoestrogens, like all estrogens, can increase growth of the endometrium, so treatments for endometriosis include avoidance of products which contain them. Likewise, they are avoided in order to prevent the onset or aggravation of adenomyosis. Studies have implicated observations of disturbances in wildlife with estrogenic exposure. For example, discharge from human settlement including runoff and water flowing out of wastewater treatment plants release a large amount of xenoestrogens into streams, which lead to immense alterations in aquatic life. With a bioaccumulation factor of 105 –106, fish are extremely susceptible to pollutants.[32] Streams in more arid conditions are thought to have more effects due to higher concentrations of the chemicals arising from lack of dilution.[33]
When comparing fish from above a wastewater treatment plant and below a wastewater treatment plant, studies found disrupted ovarian and testicular histopathology, gonadal intersex, reduced gonad size, vitellogenin induction, and altered sex ratios.[33]
The sex ratios are female biased because xenoestrogens interrupt gonadal configuration causing complete or partial sex reversal. When comparing adjacent populations of white sucker fish, the exposed female fish can have up to five oocyte stages and asynchronously developing ovaries versus the unexposed female fish who usually have two oocyte stages and group-synchronously developing ovaries. Previously, this type of difference has only been found between tropical and temperate species.[33]
Sperm concentrations and motility perimeters are reduced in male fish exposed to xenoestrogens in addition to disrupt stages of spermatogenesis.[22][33] Moreover, xenoestrogens have been leading to vast amounts of intersex in fish. For example, one study indicates the numbers of intersex in white sucker fish to be equal to the number of males in the population downstream of a waste water treatment plant. No intersex members were found upstream from the plant. Also, they found differences in the proportion of testicular and ovarian tissue and its degree of organization between the intersex fish.[33] Furthermore, xenoestrogens expose fish to CYP1A inducers through inhibiting a putative labile protein and enhancing the Ah receptor, which has been linked to epizootics of cancer and the initiation of tumors.[32]
The induction of CYP1A has been established to be a good bioindicator for xenoestrogen exposure. In addition, xenoestrogens stimulate vitellogenin (Vtg), which acts as a nutrient reserve, and Zona readiata proteins (Zrp), which forms eggshells. Therefore, Vtg and Zrp are biomarkers to exposure for fish.[34]
Another potential effect of xenoestrogens is on oncogenes, specifically in relation to breast cancer. Some scientists doubt that xenoestrogens have any significant biological effect, in the concentrations found in the environment.[35] However, there is substantial evidence in a variety of recent studies to indicate that xenoestrogens can increase breast cancer growth in tissue culture.[36][37][38][39]
It has been suggested that very low levels of a xenoestrogen, Bisphenol A, could affect fetal neural signalling more than higher levels, indicating that classical models where dose equals response may not be applicable in susceptible tissue.[40] As this study involved intra-cerebellar injections, its relevance to environmental exposures is unclear, as is the role of an estrogenic effect compared to some other toxic effect of bisphenol A.
Other scientists argue that the observed effects are spurious and inconsistent, or that the quantities of the agents are too low to have any effect.[41] A 1997 survey of scientists in fields pertinent to evaluating estrogens found that 13 percent regarded the health threats from xenoestrogens as "major," 62 percent as "minor" or "none," and 25 percent were unsure.[42]
There has been speculation that falling sperm counts in males may be due to increased estrogen exposure in utero.[43] Sharpe in a 2005 review indicated that external estrogenic substances are too weak in their cumulative effects to alter male reproductive functioning, but indicates that the situation appears to be more complex as external chemicals may affect the internal testosterone-estrogen balance.[44]
Impact
The ubiquitous presence of such estrogenic substances is a significant health concern, both individually and for a population. Life relies on the transmission of biochemical information to the next generation, and the presence of xenoestrogens may interfere with this transgenerational information process through "chemical confusion" (Vidaeff and Sever),[45] who state: "The results do not support with certainty the view that environmental estrogens contribute to an increase in male reproductive disorders, neither do they provide sufficient grounds to reject such a hypothesis."
A 2008 report demonstrates further evidence of widespread effects of feminizing chemicals on male development in each class of vertebrate species as a worldwide phenomenon.[46] Ninety-nine percent of over 100,000 recently introduced chemicals are underregulated, according to the European Commission.[46]
Agencies such as the United States Environmental Protection Agency and the World Health Organization International Programme on Chemical Safety are charged to address these issues.[citation needed]
Precocious puberty
Puberty is a complex developmental process defined as the transition from childhood to adolescence and adult reproductive function.[11][17][47] The first sign of female puberty is an acceleration of growth followed by the development of a palpable breast bud (thelarche). The median age of thelarche is 9.8 years. Although the sequence may be reversed, androgen dependent changes such as growth of axillary and pubic hair, body odor and acne (adrenarche) usually appears 2 years later. Onset of menstruation (menarche) is a late event (median 12.8 years), occurring after the peak of growth has passed.[11]
Puberty is considered precocious (precocious puberty) if secondary sex characteristics occur before the age of 8 in girls and 9 years in boys.[11][13] Increased growth is often the first change in precocious puberty, followed by breast development and growth of pubic hair. However, thelarche, adrenarche, and linear growth[clarification needed] can occur simultaneously and although uncommon, menarche can be the first sign.[11] Precocious puberty can be classified into central (gonadotropin-dependent) precocious puberty or peripheral (gonadotropin-independent) puberty.[11][17] Peripheral precocious puberty has been linked to exposure to exogenous estrogenic compounds.
Age of onset of puberty is influenced by many factors such as genetics, nutritional status, ethnicity and environmental factors including socio-economic conditions and geographical location.[1][48] A decline of age at onset of puberty from 17 years of age to 13 years of age has occurred over a period of 200 years until the middle of the 20th century.[1][14][47] Trends toward earlier puberty have been attributed to improved public health and living conditions.[49] A leading hypothesis for this change toward early puberty is improved nutrition resulting in rapid body growth, increased weight and fat deposition.[50] However, many opponents believe that chemical exposure may play a role. Two recent epidemiologic studies in the United States (PROS and NMANES III)[51] highlighted a recent unexpected advance in sexual maturation in girls.[1][2][52] American, European and Asian studies suggest breast development in girls occurs at a much younger age than a few decades ago, irrespective of race and socioeconomic conditions.[14][47][50] Environmental chemical exposure is one of the factors implicated in the recent downward trend of earlier sexual maturation.[14][47][52]
Thelarche in Puerto Rico
Since 1979, pediatric endocrinologists in Puerto Rico recognized an increase in number of patients with premature thelarche.[53] The presence of phthalates were measured in the blood of 41 girls experiencing early onset breast development and matched set of controls. The average age of girls with premature thelarche was 31 months. They found high phthalate levels in the girls suffering from premature thelarche compared to the controls.[54] Not all cases of premature thelarche in the study sample contained elevated levels of phthalate esters and there was concern whether artificial contamination from vinyl lab equipment and tubing invalidated the results, hence weakening the link between exposure and causation.[53][55]
Tuscany precocious puberty cases
Dr. Massart and colleagues from the University of Pisa studied the increased prevalence of precocious puberty in a region of northwest Tuscany. This region of Italy is represented by a high density of navy yards and greenhouses where exposures to pesticides and mycoestrogens (estrogens produced by fungi) are common. Although unable to identify a definitive cause of the high rates of precocious puberty, the authors concluded environmental pesticides and herbicides may be implicated.[56]
Dairy contamination
Animal feed was contaminated with several thousand pounds of polybrominated biphenyl in Michigan in 1973 resulting in high exposures of PBB in the population via milk and other products from contaminated cows. Perinatal exposure of children was estimated by measuring PBB in serum of mothers some years after exposure. Girls that had been exposed to high PBB levels through lactation had an earlier age of menarche and pubic hair development than girls who had less perinatal exposure. The study noted there no differences found in the timing of breast development among the cases and controls.[14][18][55]
Fish contamination
The Great Lakes have been polluted with industrial wastes (mainly PCBs and DDT) since the beginning of the 20th century. These compounds have accumulated in birds and sports fish. A study was designed to assess the impact of consumption of contaminated fish on pregnant women and their children. Concentrations of maternal serum PCB and DDE and their daughters' age at menarche were reviewed. In multivariate analysis, DDE but not PCB was linked with a lowered age of menarche.[18][53][55] Limitations of the study included indirect measurement of the exposure and self reporting of menarche.[18]
Implications
Precocious puberty has numerous significant physical, psychological and social implications for a young girl. Unfortunately, premature pubertal growth spurt and accelerated bone maturation will result in premature closure of distal epiphysis which causes reduced adult height and short stature.[57] In 1999, US Food and Drug Administration has recommended to not take estrogen in food of more than 3.24 ng per day for females.[58] Precocious puberty has also been implicated in pediatric and adult obesity.[52][57] Some studies have suggested precocious puberty places girls at a higher risk of breast cancer later in life.[52] Precocious puberty is linked with other gynecologic disorders such as endometriosis, adenomyosis, polycystic ovarian syndrome and infertility.[15][59][60] Precocious puberty can lead to psychosocial distress, a poor self-image, and poor self-esteem. Girls with secondary sex characteristics at such a young age are more likely to be bullied and suffer from sexual abuse.[15][59] Studies indicate that girls who become sexually mature at earlier ages are also more likely to engage in risk-taking behaviors such as smoking, alcohol or drug use, and engage in unprotected sex.[57]
The current literature is inadequate to provide the information we need to assess the extent to which environmental chemicals contribute to precocious puberty.[52] Gaps in our knowledge are the result of limitations in the designs of studies, small sample sizes, challenges to conducting exposure assessment and the few number of chemicals studied.[52] Unfortunately exposure is inferred and not actually measured in available studies.[15] The ability to detect the possible role of chemicals in altering pubertal development is confounded by many nutritional, genetic and lifestyle factors capable of affecting puberty and the complex nature of the reproductive endocrine system.[50][61] Other research challenges include shifts in exposure levels among populations over time and simultaneous exposures to multiple compounds.[61] Overall the literature does not with certainty support the contention that environmental chemicals or dietary factors are having widespread effects on human sexual development. However data does not refute such a hypothesis either. Accelerated sexual development is plausible in individuals exposed to high concentration of estrogenic substances. There is a concerning steady increase in exposure to a wide variety of xenoestrogens in the industrial world. Further research is needed to assess the impact of these compounds on pubertal development.[citation needed]
In other animals
Non-human animal studies have shown that exposure to environmental contaminants with estrogenic activity can accelerate the onset of puberty. A potential mechanism has been described in rats exposed to DDT or beta-estradiol in which GnRH pulsatile secretion was found to be increased.[18][62] Oral exposure of female rats to xenoestrogens has been shown to cause pseudo precocious puberty (early vaginal opening and early first estrus).[48][63][64][65] A study of dioxin in immature female rats induced early follicular development[66] and phthalates are known to decrease the anogenital distance in newborn rats.[55] Although this article focuses on the effects of xenoestrogens and reproductive function in females, numerous animal studies also implicate environmental estrogens' and androgens' adverse effects on the male reproduction system.[66] Administration of estrogens to developing male animals reduces testicular weight and decreases sperm production.[16] The small phallus size of male alligators has been linked to contamination of their natural Florida habitat with DDT.[57][66] Data from animal research is abundant demonstrating the adverse effects on reproduction of hormonally active compounds found in the environment.[16][66][67][68]
Common environmental estrogens
Atrazine
Atrazine is widely used as an herbicide to control broad-leaf weed species that grow in crops such as corn, sugarcane, hay and winter wheat. Atrazine is also applied to Christmas trees, residential lawns, golf courses, and other recreational areas. Atrazine is the second largest selling pesticide in the world and estimated to be the most heavily used herbicide in the United States.[12]
BPA
BPA (Bisphenol A) is the monomer used to manufacture polycarbonate plastic and epoxy resins used as a lining in most food and beverage cans. BPA global capacity is in excess of 6.4 billion pounds (2.9×109 kg) per year and thus is one of the highest-volume chemicals produced worldwide.[69] The ester bonds in the BPA-based polycarbonates could be subject to hydrolysis and leaching of BPA. But in the case of epoxypolymers formed from bisphenol A, it is not possible to release bisphenol A by such a reaction. It is also noteworthy that, of the bisphenols, bisphenol A is a weak xenoestrogen. Other compounds, such as bisphenol Z, have been shown to have stronger estrogenic effects in rats.[70]
It has been suggested that biphenol A and other xenoestrogens might cause disease to humans[61] and animals.[67] One review suggests that bisphenol A exposure as a result of feasible scenarios could cause disease in humans.[69]
Bisphenol S (BPS), an analog of BPA, has also been shown to alter estrogenic activity.[71][72] One study demonstrated that when cultured rat pituitary cells were exposed to low levels of BPS, it altered the estrogen-estradiol signaling pathway and led to the inappropriate release of prolactin.[72]
DDT
DDT (Dichlorodiphenyltrichloroethane) was widely used in pesticides for agriculture until it was banned in 1972 in the United States due to its hazardous effects on the environment. DDT continues to be used in many parts of the world for agricultural use, insect control and to fight the spread of malaria. DDT and its metabolites DDE and DDD are persistent in the environment and accumulate in fatty tissues.[12][15][55][67]
Dioxin
Dioxin, a group of highly toxic chemicals are released during combustion processes, pesticide manufacturing and chlorine bleaching of wood pulp. Dioxin is discharged into waterways from pulp and paper mills. Consumption of animals fats is thought to be the primary pathway for human exposure.[12][15][49]
Endosulfan
Endosulfan is an insecticide used on numerous vegetables, fruits, cereal grains and trees. Endosulfan can be produced as a liquid concentrate, wettable powder or smoke tablet. Human exposure occurs through food consumption or ground and surface water contamination.[12][73]
PBB
PBB (Polybrominated biphenyls) are chemicals added to plastics used in computer monitors, televisions, textiles and plastics foams to make them more difficult to burn. Manufacturing of PBBs in the United States stopped in 1976, however because they do not degrade easily PBBs continue to be found in soil, water and air.[12][18][67]
PCBs
PCBs (Polychlorinated biphenyls) are man made organic chemicals known as chlorinated hydrocarbons. PCBs were manufactured primarily for use as insulating fluids and coolants given their chemical stability, low flammability and electrical insulating properties. PCBs were banned in 1979 but like DDT continue to persist in the environment.[12][15][55]
Phthalates
Phthalates are plasticizers providing durability and flexibility to plastics such as polyvinyl chloride. High molecular weight phthalates are used in flooring, wall coverings and medical device such as intravenous bags and tubing. Low molecular weight phthalates are found in perfumes, lotions, cosmetics, varnishes, lacquers and coatings including timed releases in pharmaceuticals.[12][67][74]
Zeranol
Zeranol is currently used as an anabolic growth promoter for livestock in the US[75] and Canada.[76] It has been banned in the EU since 1985,[77] but is still present as a contaminant in food through meat products that were exposed to it.[12]
Miscellaneous
alkylphenols (intermediate chemicals used in the manufacture of other chemicals)
4-Methylbenzylidene camphor (4-MBC) (sunscreen lotions)
bisphenol S, BPS (an analog of BPA)
butylated hydroxyanisole, BHA (food preservative)
dichlorodiphenyldichloroethylene (one of the breakdown products of DDT)
dieldrin (banned insecticide)
DDT (banned insecticide)
endosulfan (widely banned insecticide)
erythrosine, FD&C Red No. 3 (E127)
ethinylestradiol (combined oral contraceptive pill) (released into the environment as a xenoestrogen)[78]
heptachlor (restricted insecticide)
lindane, hexachlorocyclohexane (restricted insecticide)
metalloestrogens (a class of inorganic xenoestrogens)
methoxychlor (banned insecticide)
nonylphenol and derivatives (industrial surfactants; emulsifiers for emulsion polymerization; laboratory detergents; pesticides)
pentachlorophenol (restricted general biocide and wood preservative)
polychlorinated biphenyls, PCBs (banned; formerly used in electrical oils, lubricants, adhesives, paints)
parabens (lotions)
phthalates (plasticizers)
DEHP (plasticizer for PVC)
Propyl gallate (used to protect oils and fats in products from carbonization)
what are lignans
Lignans are polyphenolic compounds found in plants. (More information)
Lignan precursors are found in a wide variety of plant-based foods, including seeds, whole grains, legumes, fruit, and vegetables. (More information)
Flaxseeds are the richest dietary source of lignan precursors. (More information)
When consumed, lignan precursors may be converted to the enterolignans, enterodiol and enterolactone, by bacteria that normally colonize the human intestine. (More information)
Enterodiol and enterolactone have weak estrogenic activity but may also exert biological effects through non-estrogenic mechanisms. (More information)
Lignan-rich foods are part of a healthy diet, but the roles of lignans in the prevention of hormone-associated cancers, osteoporosis, and cardiovascular disease are not yet clear. (More information)
Introduction
The enterolignans, enterodiol and enterolactone (Figure 1), are formed by the action of intestinal bacteria on lignan precursors found in plants (1). Because enterodiol and enterolactone can mimic some of the effects of estrogens, their plant-derived precursors are classified as phytoestrogens. Lignan precursors that have been identified in the human diet include pinoresinol, lariciresinol, secoisolariciresinol, matairesinol, and others (Figure 2). Secoisolariciresinol and matairesinol were among the first lignan precursors identified in the human diet and are therefore the most extensively studied. Lignan precursors are found in a wide variety of foods, including flaxseeds, sesame seeds, legumes, whole grains, fruit, and vegetables. While most research on phytoestrogen-rich diets has focused on soy isoflavones, lignans are the principal source of dietary phytoestrogens in the typical Western diet (2, 3).
Figure 1. Chemical Structures of the Enterolignans, Enterodiol and Enterolactone.
Figure 2. Chemical Structures of Some Dietary Lignan Precursors: secoisolariciresinol, matairesinol, lariciresinol, and pinoresinol.
Metabolism and Bioavailability
When plant lignans are ingested, they can be metabolized by intestinal bacteria to the enterolignans, enterodiol and enterolactone, in the intestinal lumen and then absorbed into the bloodstream (4). Enterodiol can also be converted to enterolactone by intestinal bacteria. Thus, enterolactone levels measured in blood and urine reflect the activity of intestinal bacteria in addition to dietary intake of plant lignans. Not surprisingly, antibiotic use has been associated with lower serum enterolactone concentrations (5).
Because data on the lignan content of foods are limited, blood and urinary enterolactone levels are sometimes used as markers of dietary lignan intake. A pharmacokinetic study that measured plasma and urinary levels of enterodiol and enterolactone after a single dose (0.9 mg/kg of body weight) of secoisolariciresinol, the principal lignan in flaxseed, found that at least 40% was available to the body as enterodiol and enterolactone (6). Plasma enterodiol concentrations peaked at 73 nanomoles/liter (nmol/L) an average of 15 hours after ingestion of secoisolariciresinol, and plasma enterolactone concentrations peaked at 56 nmol/L an average of 20 hours after ingestion. Thus, substantial amounts of ingested plant lignans are available to humans in the form of enterodiol and enterolactone.
Considerable variation among individuals in urinary and serum enterodiol:enterolactone ratios has been observed in flaxseed feeding studies, suggesting that some individuals convert most enterodiol to enterolactone, while others convert relatively little (1). Individual differences in the metabolism of lignans, likely due to differing composition and activities of gut microbes, can influence the biological activities and health effects of these compounds (7). Several other factors, including antibiotic use, age, BMI, and smoking, may also help explain the variation of circulating enterolignan concentrations among individuals (7); these and other potential confounding factors should be controlled for in observational studies.
Challenge #4: Reduce Your Xenoestrogen Exposure
Biological Activities
Estrogenic and anti-estrogenic activities
Estrogens are signaling molecules (i.e., hormones) that exert their effects by binding to estrogen receptors within cells (Figure 3). The estrogen-receptor complex interacts with DNA to change the expression of estrogen-responsive genes. Estrogen receptors are present in numerous tissues other than those associated with reproduction, including bone, liver, heart, and brain (8). Although phytoestrogens can also bind to estrogen receptors, their estrogenic activity is much weaker than endogenous estrogens, and they may actually block or antagonize the effects of estrogen in some tissues (9). Scientists are interested in the tissue-selective activities of phytoestrogens because anti-estrogenic effects in reproductive tissue could help reduce the risk of hormone-associated cancers (breast, uterine, ovarian, and prostate cancers), while estrogenic effects in bone could help maintain bone mineral density. The enterolignans, enterodiol and enterolactone, are known to have weak estrogenic activity. At present, the extent to which enterolignans exert weak estrogenic and/or anti-estrogenic effects in humans is not well understood.
Figure 3. Chemical Structures of Some Endogenous Mammalian Estrogens: 17 beta-estradiol, estriol, and estrone.
Estrogen receptor-independent activities
Enterolignans have biological activities that are unrelated to their interactions with estrogen receptors. By altering the activity of enzymes involved in estrogen metabolism, lignans may change the biological activity of endogenous estrogens (10). Lignans have also been shown to display antioxidant activity in laboratory studies (11), although the significance in humans is not entirely clear since lignans are rapidly and extensively metabolized. For example, a cross-sectional study found that a biomarker of oxidative damage was inversely associated with serum enterolactone concentrations in men (12), but this association could be due to enterolactone and/or other antioxidants present in lignan-rich foods. Moreover, enterolignans may have anti-inflammatory properties, as well as anti-proliferative and anticancer activities that are independent of estrogen signaling (13-15).
Disease Prevention
Cardiovascular disease
Diets rich in foods containing plant lignans (whole grains, nuts and seeds, legumes, and fruit and vegetables) have been consistently associated with reductions in risk of cardiovascular disease. However, it is likely that numerous nutrients and phytochemicals found in these foods contribute to their cardioprotection.
Higher dietary intakes of two lignans, matairesinol and secoisolariciresinol, were not linked to total cardiovascular disease in 16,162 middle-aged and older women participating in the Dutch PROSPECT European Prospective study Into Cancer and nutrition (EPIC) study (16). A large prospective cohort study conducted within Spain’s PREDIMED trial — a trial evaluating the effects of a Mediterranean diet on cardiovascular disease outcomes — followed 7,172 older adults at high risk of cardiovascular disease for a mean of 4.3 years (17). In this study, the highest quintile of dietary lignan intake (mean intake, 0.94 mg/day), measured by a food frequency questionnaire at baseline, was associated with a 49% lower risk of incident cardiovascular disease compared to the lowest quintile (mean intake, 0.44 mg/day of lignans). The primary dietary source of lignans in this cohort was virgin olive oil (17), which itself is known to be cardioprotective.
Coronary heart disease
In a prospective, nested case-control study in 334 middle-aged Finnish men, followed for an average of 7.7 years, higher serum enterolactone concentrations (a marker of plant lignan intake) were associated with a lower risk of acute coronary events (18). A prospective cohort study of 1,889 Finnish men followed for an average of 12 years, found those with the highest serum enterolactone concentrations were significantly less likely to die from coronary heart disease (CHD) or cardiovascular disease than those with the lowest concentrations (19). However, a study in male smokers did not find strong support for an association between serum enterolactone concentration and CHD (20). Additionally, a nested case-control study in men and women residing in the Netherlands did not find association between plasma concentrations of enterolactone or enterodiol and nonfatal myocardial infarction (236 cases and 283 controls), although the study population was young (ages 20-59 at baseline) and followed for only a mean of 4.5 years (21). A 2017 meta-analysis of three of these studies found no association between blood enterolactone concentration and non-fatal myocardial infarction (22). Moreover, dietary lignan intake was not linked to coronary cardiovascular disease in women participating in the Dutch PROSPECT EPIC study (16).
Clinical trials of lignan supplementation would be needed to determine the effects of lignans on coronary heart disease.
Cardiovascular risk factors
Blood lipids. Flaxseeds are among the richest sources of plant lignans in the human diet, but they are also good sources of other nutrients and phytochemicals with cardioprotective effects, such as omega-3 fatty acids (i.e., α-linolenic acid) and fiber. Supplementation trials have generally used ground or milled flaxseed (i.e., flax meal), which has a higher bioavailability of enterolignans compared to whole flaxseed (23). Five small clinical trials found that adding 30 to 50 g/day of flaxseed to the usual diet for 4 to 12 weeks resulted in modest 8%-20% decreases in low-density lipoprotein (LDL-cholesterol concentration (24-28), but four other trials did not observe significant reductions in LDL-cholesterol after adding 30 to 40 g/day of flaxseed to the diet (29-32). A double-blind, randomized controlled trial in adults, ages 44 to 75 years, found that supplementation with 40 g/day of flaxseed led to significant reductions in LDL-cholesterol after five weeks, but the cholesterol reductions were not statistically significant following 10 weeks’ supplementation (33). Additionally, a one-year clinical trial in postmenopausal women reported that supplementation with 40 g/day of flaxseed did not lower LDL-cholesterol compared to a placebo containing wheat germ (34). Most of these trials were in healthy participants free of cardiovascular disease. In a randomized, double-blind, placebo-controlled trial in 84 patients with peripheral artery disease, 30 g/day of flaxseed for 12 months did not reduce total or LDL-cholesterol compared to placebo, although cholesterol reductions within the flaxseed-supplemented group were evident at 1 month and 6 months compared to baseline but not at 12 months (35).
Any effect of flaxseed supplementation on blood lipids might be attributed to flaxseed constituents other than lignans (i.e., protein, fiber, omega-3 fatty acids, phytochemicals). At least two trials have investigated the effect of supplementation with isolated flaxseed lignan. In a randomized, double-blind, placebo-controlled cross-over trial in 22 healthy postmenopausal women, six-week supplementation with 500 mg/day of secoisolariciresinol diglucoside — derived from flaxseed — had no effect on LDL-cholesterol concentration or other measured blood lipids despite significant increases in serum enterolactone concentration (36). Additionally, a randomized, double-blind, placebo-controlled cross-over trial in 68 patients with type 2 diabetes and mild hypercholesterolemia found no effect of 360 mg/day of secoisolariciresinol diglucoside for 12 weeks on concentration of blood cholesterol or other blood lipids (37).
Large-scale supplementation trials with isolated lignans would be needed to determine whether lignans have cholesterol-lowering effects.
Blood pressure. A 2016 meta-analysis pooled the results of 15 randomized controlled trials, some in healthy participants and some in participants with chronic disease (i.e., type 2 diabetes, metabolic syndrome, peripheral arterial disease) or risk factors of cardiovascular disease. Supplementation with flaxseed was linked to a 2.9 mm Hg reduction in systolic blood pressure and a 2.4 mm Hg reduction in diastolic blood pressure; these blood pressure reductions were greater in trials of longer duration (≥12 weeks vs. <12 weeks; 38). Additionally, data stratification by supplement type revealed a benefit of supplemental flaxseed powder but not of lignan extracts containing 360 to 600 mg/day of secoisolariciresinol diglucoside (38), suggesting the non-lignan constituents of flaxseed may be responsible for any blood pressure-lowering effects.
Hormone-associated cancers
Breast cancer
Overall, there is limited evidence that dietary intake of plant lignans is associated with breast cancer risk; studies on the association have reported conflicting results. Two prospective cohort studies examining plant lignan intake and breast cancer found no association (39, 40). A more recent prospective study reported no association between total lignan intake and breast cancer in premenopausal women (41). In another prospective analysis, the same group of authors found postmenopausal women in the highest quartile of dietary lignan intake had a 17% lower risk of breast cancer compared to women in the lowest quartile, but this protective association was only observed in women with estrogen-positive and progesterone-positive tumors (42). A prospective cohort study of 51,823 postmenopausal Swedish women, followed for an average of 8.3 years, found that women in the highest quartile of lignan intake (≥1,036 mg/day) had a 17% lower risk of invasive breast tumors compared to those in the lowest quartile (lignan intake <712 mg/day) (43). In this study, a strong inverse association of lignan intake and breast cancer risk was observed in women who had used postmenopausal hormones at some point in their life, but no association was evident in those who had never used such hormones (43). A 2009 meta-analysis did not find an overall association between dietary lignan intake and breast cancer, but when the analysis was limited to postmenopausal women, the authors reported a 15% reduction in risk of breast cancer with high lignan intake (44). A similar result was found in a subsequent meta-analysis that included 11 prospective cohort and 10 case-control studies: no association of lignan intake and breast cancer was observed in women overall, but data stratification by menopausal status revealed that the highest lignan intakes were associated with a 14% lower risk of breast cancer among postmenopausal women (13 studies; 45).
Several studies, mainly case-control studies, have examined the relationship between blood or urine concentrations of enterolactone and breast cancer, reporting conflicting results (46-48). Two meta-analyses did not find an association between blood concentrations of enterolactone and breast cancer (44, 45).
At present, it is not clear whether high intakes of plant lignans or high circulating levels of enterolignans offer significant protection against breast cancer. Randomized controlled trials of lignan supplementation would be needed to address this question.
Endometrial and ovarian cancers
Overall, there is limited evidence that dietary lignan intake or circulating enterolignan concentration (a marker of lignan intake) is associated with endometrial cancer or ovarian cancer.
In a case-control study of lignans and endometrial cancer, US women with the highest intakes of plant lignans had the lowest risk of endometrial cancer, but the reduction in risk was statistically significant in postmenopausal women only (49). However, two population-based, case-control studies, one conducted in the US (50) and one in Australia (51), found dietary lignan intake was not linked to endometrial cancer. Moreover, a prospective case-control study in three different countries (US, Sweden, and Italy) did not find an association between circulating enterolactone and endometrial cancer in premenopausal or in postmenopausal women (52). A large case-cohort study among Danish women, ages 50-64 years, also reported no association of plasma enterolactone concentration and endometrial cancer (53).
In an early case-control study among US women ages 40 to 85 years, those with the highest combined intakes of the lignans, secoisolariciresinol and matairesinol, had the lowest risk of ovarian cancer — intakes greater than 708 mg/day of these lignans were associated with a 57% lower risk of ovarian cancer compared with intakes less than 304 mg/day (54). A case-control study in Australia reported no association of total dietary lignans and risk of ovarian cancer but found a significant, inverse association of matairesinol and lariciresinol, individually, with ovarian cancer (51). However, two other studies, a population-based case-control study in the US (55) and a prospective cohort study in Sweden (56) found no relationship between dietary lignan intake and ovarian cancer.
Although some of these studies support the hypothesis that diets rich in plant foods may be helpful in decreasing the risk of hormone-associated cancers, they do not provide strong evidence that lignans in particular are protective against endometrial or ovarian cancer.
Prostate cancer
Several observational studies have examined the association between dietary lignan intake or circulating enterolignan concentration (a marker of lignan intake) and prostate cancer, with most reporting no association. A meta-analysis of three studies (two population-based, case-control studies and one nested case-control study) found lignan intake was not linked to prostate cancer risk (57). Moreover, a meta-analysis of nested case-control studies did not find circulating concentration of enterolactone (total of 2,828 cases and 5,593 controls pooled from five studies) or enterodiol (total of 1,002 cases and 1,197 controls pooled from two studies) to be associated with prostate cancer (58). Yet another meta-analysis found no association between dietary lignan intake (total lignans, or matairesinol or secoisolariciresinol, separately) or circulating enterolactone concentration and prostate cancer risk (59). While adherence to a plant-based diet may be linked to a lower risk of prostate cancer (60), evidence that dietary lignans are protective is lacking.
Osteoporosis
Research on the effects of dietary lignan intake on osteoporosis risk is very limited. In a prospective cohort study of 2,580 postmenopausal women and 4,973 men enrolled in the European Prospective Investigation into Cancer (EPIC) study, dietary intake of matairesinol and secoisolariciresinol was not associated with bone density, when assessed by ultrasound of the heel bone (61). In two much smaller observational studies, urinary enterolactone excretion was used as a marker of dietary lignan intake. One study of 75 postmenopausal Korean women, who were classified as osteoporotic, osteopenic, or normal on the basis of bone mineral density (BMD) measurements, found that urinary enterolactone excretion was positively associated with BMD of the lumbar spine and hip (62). However, a study of 50 postmenopausal Dutch women found that higher levels of urinary enterolactone excretion were associated with higher rates of bone loss (63).
In two separate placebo controlled trials, supplementation of postmenopausal women with 25 to 40 g/day of ground flaxseed for three to four months did not significantly alter biochemical markers of bone formation or bone resorption (loss) (31, 64). In a placebo-controlled trial that included a daily walking intervention in both groups of older adults, supplementation with a flaxseed lignan complex (containing 543 mg/day of secoisolariciresinol) for six months had no effect on bone mineral density measured by DXA (65).
More research is necessary to determine whether high dietary intakes of plant lignans can decrease the risk or severity of osteoporosis.
Type 2 diabetes mellitus
More than 10% of the US population has type 2 diabetes mellitus and another 35% has impaired glucose control (prediabetes) that places them at high risk of developing type 2 diabetes (66). A number of dietary polyphenols found in plant-based foods may affect glucose metabolism and thus aid in the prevention or management of the condition. A few observational studies have examined the association of lignan intake and incidence of diabetes. A prospective cohort study in 6,547 Iranian adults, followed for a mean of 3.0 years, reported an inverse association between dietary lignan intake (measured by food frequency questionnaire) and incidence of type 2 diabetes (67). In particular, this study found the highest versus lowest quartile of lignan intake (median of 9.1 mg/day vs. 1.6 mg/day) to be associated with a 40% lower risk of type 2 diabetes (67). However, no association between lignan intake (highest vs. lowest quintile of intake, median of 2.3 mg/day vs. 0.6 mg/day) and type 2 diabetes was reported in a prospective, case-cohort study conducted in Europe that included more than 15,000 adults (EPIC-InterAct; 68).
Studies that utilize biomarkers of lignan intake, such as urinary concentrations of enterodiol or enterolactone, provide a more accurate estimate of lignan intake compared to self-reported questionnaires (69). A prospective, nested case-control study of two cohorts of US women participating in the Nurses’ Health Study (NHSI with mean age of 66 years and NHSII with mean age of 45 years) found lower concentrations of enterodiol and enterolactone in diabetic case subjects than in controls (70). Upon adjustment for potential confounders, only higher concentrations of urinary enterolactone were associated with a lower risk of developing type 2 diabetes, and this was driven by a significant association in the younger cohort of women (70). A nested case-control study within men and women participating in the Singapore Chinese Health Study (mean age, 59.8 years) reported no association between urinary enterodiol or enterolactone and type 2 diabetes (71).
Because higher lignan intakes may be a marker of a healthy diet in general, randomized controlled trials of lignan supplementation in healthy individuals would inform whether lignans affect glucose homeostasis and risk of developing type 2 diabetes. Interestingly, an eight-week, double-blind, placebo-controlled trial in hypercholesterolemic individuals found that a flaxseed lignan extract containing 600 mg/day of secoisolariciresinol diglucoside decreased fasting glucose concentrations compared to placebo, and the effect was stronger in those with higher baseline glucose concentrations (72). Supplementation with an extract containing 300 mg/day of secoisolariciresinol diglucoside had no effect on fasting glucose concentrations (72).
Mortality
A few studies have examined whether dietary lignan intake is related to all-cause and cause-specific mortality. The European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain prospective cohort study investigated the relationship between lignan intake and all-cause mortality in 40,622 adults (ages 29-70 years) (73). After a mean follow-up of 13.6 years, dietary lignan intake was not associated with all-cause mortality (73). Additionally, dietary lignan intake was not linked to all-cause mortality in a much smaller study that followed 570 older Dutch men for 15 years (74). In this study, an inverse association was observed for intake of a specific lignan, matairesinol, with all-cause mortality and cardiovascular-related mortality, including death from coronary heart disease, although wine consumption modified these associations (74). However, an analysis of a 4.8-year trial that investigated the health effects of a Mediterranean diet in 7,172 older adults at high risk for cardiovascular disease (the PREDIMED trial in Spain) revealed that those in the highest quintile of lignan intake (mean of 0.94 mg/day) had a 40% lower risk of all-cause mortality compared to the lowest quintile (mean of 0.44 mg/day of lignans; 75). A 2017 meta-analysis found no association of lignan intake with all-cause mortality (3 studies mentioned above) or with mortality related to cardiovascular disease (2 studies; 76).
Other studies have assessed whether blood or urinary biomarkers of lignan intake are associated with mortality. In a prospective cohort study of 1,889 healthy, middle-aged Finnish men, followed for a mean of 12.2 years, the highest quartile of serum enterolactone concentration was associated with a 56% lower risk of coronary heart disease-related mortality and a 45% lower risk of cardiovascular disease-related mortality; no association of serum enterlactone and all-cause mortality was found in this study (19). However, serum enterolactone was not associated with coronary death in a case-cohort study in Finnish male smokers (20). In a national cross-sectional survey of US adults (NHANES 1999-2004), those in the highest tertile of urinary total enterolignan concentration had a lower risk of cardiovascular-related and all-cause mortality, and those with the highest urinary enterolactone concentrations had a significantly lower risk of all-cause mortality (77). These measures were not associated with mortality from cancer in this analysis, and urinary enterodiol concentration was not related to any of the mortality endpoints (77). A 2017 meta-analysis that combined results of these studies of lignan biomarkers found that enterolactone was inversely associated with both cardiovascular disease-related mortality and all-cause mortality (22). Most recently, a case-cohort study within the Danish Diet, Cancer and Health cohort found that higher pre-diagnostic plasma concentrations of enterolactone were linked to a lower risk of all-cause and diabetes-specific mortality among adults with type 2 diabetes (78).
Xenoestrogens and Phytoestrogens
Sources
Food sources
Lignans are present in a wide variety of plant foods, including seeds (flax, pumpkin, sunflower, poppy, sesame), whole grains (rye, oats, barley), bran (wheat, oat, rye), beans, fruit (particularly berries), vegetables, and beverages like tea, coffee, and wine (47, 79, 80). Secoisolariciresinol, matairesinol, pinoresinol, and lariciresinol contribute substantially to total dietary lignan intakes, although this varies with dietary pattern (80).
Flaxseed is by far the richest dietary source of plant lignans (81), and lignan bioavailability can be improved by crushing or milling flaxseed (23). Lignans are not associated with the oil fraction of foods, so flaxseed oils do not typically provide lignans unless ground flaxseed has been added to the oil. A variety of factors may affect the lignan content of plants, including geographic location, climate, maturity, and storage conditions. Table 1 provides the total lignan (secoisolariciresinol, matairesinol, pinoresinol, and lariciresinol) content of selected lignan-rich foods (82). The Phenol-Explorer (version 3.6) database lists content of 25 different lignans in various foods.
Surveys have found median total lignan intake to be 0.98 mg/day in the Netherlands (83), 0.85 mg/day in Canada (84), and 0.76 mg/day in Spain (85). Plant lignans are the principal source of phytoestrogens in the diets of people who do not typically consume soy foods. The daily phytoestrogen intake of postmenopausal women in the US was estimated to be less than 1 mg/day, with 80% from lignans and 20% from isoflavones (86).
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