Summary

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.

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).

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).

Table 1. Total Lignan Content of Selected Foods
Food Serving Total Lignans (mg)
Flaxseeds 1 oz
85.5
Sesame seeds 1 oz
11.2
Curly kale ½ cup, chopped
0.8
Broccoli ½ cup, chopped
0.6
Apricots ½ cup, sliced
0.4
Cabbage ½ cup, chopped
0.3
Brussels sprouts ½ cup, chopped
0.3
Strawberries ½ cup
0.2
Tofu ¼ block (4 oz)
0.2
Dark rye bread 1 slice
0.1

Supplements

Dietary supplements containing lignans derived from flaxseed are available in the US without a prescription (87); secoisolariciresinol is the primary lignan in such supplements (82).

Safety

Adverse effects

Lignan precursors in food are not known to have any serious adverse effects. Flaxseeds, which are rich in lignan precursors as well as dietary fiber, may increase stool frequency or cause diarrhea in doses of 45 to 50 g/day in adults (24, 88). One small, placebo-controlled study found that 50 mg/day of sesame lignans (1:1 mixture of sesamin and episesamin) for 28 days did not result in any serious adverse effects, although abdominal flatulence was associated with the sesame lignan supplementation (89). The safety of lignan supplements in pregnant or lactating women has not been established; therefore, lignan supplements should be avoided by women who are pregnant, breast-feeding, or trying to conceive.


Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2010 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2021 by:
Susan McCann, R.D., Ph.D.
Member and Professor
Roswell Park Comprehensive Cancer Center
Buffalo, New York

Copyright 2004-2021  Linus Pauling Institute 


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