The mammalian lignans, enterodiol and enterolactone (see chemical structures), 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 (see chemical structures). 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, legumes, whole grains, fruits and vegetables. While most research on phytoestrogen-rich diets has focused on soy isoflavones, lignans are the principal source of dietary phytoestrogens in typical Western diets (2, 3).

Summary

* Lignan precursors are found in a wide variety of plant-based foods, including seeds, whole grains, legumes, fruits and vegetables.

* Flaxseeds are the richest dietary source of lignan precursors.

* When consumed, lignan precursors are converted to the mammalian lignans, enterodiol and enterolactone, by bacteria that normally colonize the human intestine.

* Enterodiol and enterolactone have weak estrogenic activity but may also exert biological effects through nonestrogenic mechanisms.

* Lignan-rich foods are part of a healthy dietary pattern, but the role of lignans in the prevention of hormone-associated cancers, osteoporosis, and cardiovascular diseases is not yet clear.

Metabolism and Bioavailability

When plant lignans are ingested, they can be metabolized by intestinal bacteria to the mammalian lignans, enterodiol and enterolactone (4). Enterodiol can also be converted to enterolactone by intestinal bacteria. Not surprisingly, antibiotic use in the past year was associated with lower serum enterolactone levels (5). Thus, enterolactone levels measured in serum and urine reflect the activity of intestinal bacteria in addition to dietary intake of plant lignans. Because data on the lignan content of foods are limited, serum and urinary enterolactone levels are sometimes used as markers of dietary lignan intake in research. 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 ingesting 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 between 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). It is likely that individual differences in the metabolism of lignans influence the biological activities and health effects of these compounds.

Biological Activities

Estrogenic and Anti-Estrogenic Activities

Estrogens are signaling molecules (hormones) that exert their effects by binding to estrogen receptors within cells (see chemical structures). 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 (7). 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 (8). 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), while estrogenic effects in bone could help maintain bone density. The mammalian lignans, enterodiol and enterolactone, are known to have weak estrogenic activity. At present, the extent to which mammalian lignans exert weak estrogenic and/or anti-estrogenic effects in humans is not well-understood.

Estrogen Receptor-Independent Activities

Mammalian lignans also have biological activities that are unrelated to their interactions with estrogen receptors. By inhibiting the activity of enzymes involved in estrogen metabolism, lignans may alter the biological activity of endogenous estrogens (9). Lignans can act as antioxidants in the test tube, but the significance of such antioxidant activity in humans is not clear because lignans are rapidly and extensively metabolized (4). Although one cross-sectional study found that a biomarker of oxidative damage was inversely associated with serum enterolactone levels in men (10), it is not clear whether this effect was related to enterolactone or other antioxidants present in lignan-rich foods.

Disease Prevention

Cardiovascular Disease

Diets rich in foods containing plant lignans (whole grains, nuts and seeds, legumes, fruits and vegetables) are consistently associated with reductions in cardiovascular disease risk. However, it is likely that numerous nutrients and phytochemicals found in these foods contribute to their cardioprotective effects. In a prospective cohort study of 1,889 Finnish men followed for an average of 12 years, those with the highest serum enterolactone levels (a marker of plant lignan intake) were significantly less likely to die from coronary heart disease or cardiovascular disease than those with the lowest levels (11). 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 and fiber. Three small clinical trials found that adding 38-50 g/d of flaxseed to the usual diet for 4-6 weeks resulted in modest 8-14% decreases in LDL cholesterol levels (12-14), while three other trials did not observe significant reductions in LDL cholesterol after adding 30-40 g/d of flaxseed to the diet (15-17). Although the results of prospective cohort studies consistently indicate that diets rich in whole grains, nuts, fruits and vegetables are associated with significant reductions in cardiovascular disease risk, it is not yet clear whether lignans themselves are cardioprotective.

Hormone-associated Cancers

Breast cancer

Presently, there is little evidence that dietary intake of plant lignans is significantly associated with breast cancer risk. Neither of the two prospective cohort studies that examined plant lignan intake and breast cancer risk found them to be related (18, 19). Although one retrospective case-control study found that German women with the highest dietary intakes of matairesinol were significantly less likely to have breast cancer than those with the lowest intakes (20), two other case-control studies conducted in the US did not observe significant relationships between dietary lignan intake and breast cancer risk (21, 22). Two retrospective case-control studies found breast cancer risk to be lower in those with higher rates of urinary enterolactone excretion (23, 24), but the only prospective study found no significant association between urinary enterolactone excretion and breast cancer risk (25). Similarly, two case-control studies found breast cancer risk to be higher in those with very low serum enterolactone concentrations (26, 27), but two prospective studies found no significant association between serum enterolactone concentrations and breast cancer risk (28, 29). A recent prospective study in Denmark found that serum enterolactone concentrations were not associated with the risk of estrogen receptor alpha (ER?)-positive breast cancer, but the risk of ER?-negative breast cancer was significantly lower in women with higher serum enterolactone concentrations (30). In general, ER?-negative breast tumors tend to be more aggressive and less responsive to treatment than ERa-positive breast tumors. At present, it is not clear whether high intakes of plant lignans or high circulating levels of mammalian lignans offer significant protective effects against breast cancer.

Endometrial and Ovarian Cancer

In the only 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 (31). Similarly, in the only case-control study of lignans and ovarian cancer, US women with the highest intakes of plant lignans had the lowest risk of ovarian cancer (32). However, high intakes of other phytochemicals associated with plant-based diets like fiber, carotenoids and phytosterols were also associated with decreased ovarian cancer risk. Although 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 are protective against endometrial or ovarian cancer.

Prostate Cancer

Although dietary lignans are the principal source of phytoestrogens in the typical Western diet, relationships between dietary lignan intake and prostate cancer risk have not been well-studied. Three prospective case-control studies examined the relationship between circulating enterolactone concentrations, a marker of lignan intake, and the subsequent development of prostate cancer in Scandinavian men (33, 34). In all three studies, initial serum enterolactone concentrations in men who were diagnosed with prostate cancer 5-14 years later were not significantly different from serum enterolactone levels in matched control groups of men who did not develop prostate cancer. In a retrospective case-control study, recalled dietary lignan intake did not differ between US men diagnosed with prostate cancer and a matched control group (35). At present, limited data from epidemiological studies do not support a relationship between dietary lignan intake and prostate cancer risk.

Osteoporosis

Research on the effects of dietary lignan intake on osteoporosis risk is very limited. In two small 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 (36). However, a study of 50 postmenopausal Dutch women found that higher levels of urinary enterolactone excretion were associated with higher rates of bone loss (37). In two separate placebo controlled trials, supplementation of postmenopausal women with 25-40 g/d of ground flaxseed for 3-4 months did not significantly alter biochemical markers of bone formation or bone resorption (loss) (17, 38). More research is necessary to determine whether high dietary intakes of plant lignans can decrease the risk or severity of osteoporosis.

Sources

Food Sources

Lignans are present in a wide variety of plant foods, including seeds (flax, pumpkin, sunflower, poppy), whole grains (rye, oats, barley), bran (wheat, oat, rye), fruits (particularly berries) and vegetables (39). Secoisolariciresinol and matairesinol were the first plant lignans identified in foods (40). Pinoresinol and laricresinol are more recently identified plant lignans contribute substantially to total dietary lignan intakes. A survey of 4660 Dutch men and women during 1997-1998 found that the median total lignan intake was 0.98 mg/day (41). Lariciresinol and pinoresinol contributed about 75% to the total lignan intake while secoisolariciresinol and matairesinol contributed only about 25%. 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 (42).

Flaxseed is by far the richest dietary source of plant lignans (43). 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 contents of plants, including geographic location, climate, maturity, and storage conditions. The table below provides the total lignan (secoisolariciresinol, matairesinol, pinoresinol and lariciresinol) contents of selected lignan-rich foods (44).

Supplements

Dietary supplements containing lignans derived from flaxseed are available in the U.S. without a prescription. One such supplement provides 50 mg of secoisolariciresinol diglycoside per capsule.

Safety

Adverse Effects

Lignan precursors in foods are not known to have any adverse effects. Flaxseeds, which are rich in lignan precursors as well as fiber, may increase stool frequency or cause diarrhea in doses of 45-50 g/day in adults (12, 45). 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, breastfeeding or trying to conceive.

References

Written by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University