The Biological Significance of Secoisolariciresinol Diglucoside (SDG) Lignan

Sue McGarrigle - ND, DipION, NTCC, CNHC  Registered,  MBANT

Lignans are widely found in natural foods such as seeds, wholegrain cereals, legumes, fruits and vegetables and are the principal source of dietary phytoestrogens in typical Western diets and in people who do not generally consume soy foods. (1, 2)

Phytoestrogens are a group of biologically active diphenolic compounds that are present in several plants that mimic the hormone oestrogen that have been shown to influence not only hormone metabolism but also intracellular enzymes, protein synthesis, growth factors, malignant cell proliferation, and angiogenesis. (3) There are two general types of lignans: those found in plants and those found in animals and humans. Most of the plant lignans in human foods are converted by the intestinal microflora in the upper part of the large bowel to enterodiol(ED) and enterolactone (EL),called mammalian enterolignans which are biologically active. (4)

Flaxseed is one of the richest sources of plant lignans (see Table 1) including matairesinol, pinoresinol, lariciresinol, isolariciresinol and secoisolariciresinol  (SECO). SECO is the major lignan present in flaxseed, which is found as the conjugate diglycoside - secoisolariciresinol diglucoside (SDG) and is metabolized to ED and, subsequently, EL. This phytonutrient is classed as a polyphenol. Among foods, flaxseed is the richest source of SDG (7 mg/g or 3.7 mg SECO 2/g). It contains 75 to 800 times more SDG than any other foods but variation in flaxseed lignan concentrations depend on the variety, location, and crop year. (5) The first mammalian lignans ED and EL were identified in humans and animals by Setchell and others in 1980.The first interest in the biological activity of SDG arose in the early 1980’s when these investigators also reported that the level of lignans in the body were lower in patients with breast cancer than in tumour free patients. It was also noted that vegetarians had higher concentrations of lignan substances than non-vegetarians. (6) Research has since shown flax lignans may offer incredible health benefits in combating oxidative stress, colon health, hormonal health for men and women, acne, bone health, heart health, skin and hair health, blood sugar regulation and inflammation. (See below)  The main health benefits from flaxseed lignans are due to their antioxidant activity, primarily from the hydroxyl radical scavengers and also due to their oestrogenic and anti-oestrogenic compounds and their structural similarity  to 17-b-oestradiol. (4)

Mounting scientific evidence shows how important it is to consume a lignan-rich diet and/or through supplementation and the important health benefits that exist due to the conversion of flax lignan in the body and the protective role of these compounds, particularly in chronic Western diseases. Radd and Setchell indicate that the intake of phytoestrogens in the United States and Britain is estimated to be less than 1 mg per day - due to low intake of protective plant based foods in the Western diet and not through limited availability. 
Certain factors however in addition to diet, such as intestinal microflora, smoking, antibiotics, and obesity affect circulating lignan levels in the body. Lignan-rich diets therefore may be beneficial, particularly if consumed for life. (1, 8)The addition of essential fats may also provide additional benefits alongside SDG lignans.

Antioxidant properties
SDG as an antioxidant in flaxseed is metabolized in the body and these metabolites have antioxidant activity which is even more potent than SDG. Increase in exposure to free radicals such as unhealthy diets and environmental pollutants may disrupt the balance between health and disease. SDG, ED and EL have been shown to be effective antioxidants against DNA damage and lipid peroxidation (8). Known for their hydrogen-donating antioxidant activity as well as their ability to complex divalent transition metal cations, these lignans are very promising to human health. (9) In a study at the University Of Saskatchewan, College Of Medicine, tests were performed to determine the effectiveness and potency of SDG isolated from flaxseed as an antioxidant, along with its mammalian metabolites SECO, ED and EL. Vitamin E was also tested for a comparison. The results of the tests show that the metabolites of SDG have strong antioxidant activity. In comparison to vitamin E, SDG was 1.27 times more potent as an antioxidant. However, the lignan EL was 4.35 times, more potent, SECO was 4.86 times more potent, and ED was 5.02 times more potent than vitamin E. (10)

To investigate the immunomodulatory effect of ED and EL in human cells, peripheral blood lymphocytes were treated with increasing physiologically relevant concentrations of ED and EL (0−1000 μM) and stimulated with lipopolysaccharide (LPS) and anti-CD3 plus anti-CD28 monoclonal antibodies.
A dose-related inhibition of cell proliferation and cytokine production was observed, with EL being the most active. Molecular investigations in THP-1 cells showed that both EL and ED prevented inhibitory-κB (I-κB) degradation and nuclear factor-κB (NF-κB) activation, which in turn resulted in decreased tumour necrosis factor-α (TNF-α) production. EL and ED were also able to pass the intestinal barrier and modulate cytokine production. (11)

Colon Health
Since the plant lignan SDG is converted into the mammalian lignans enterolactone and enterodiol directly within the colon, SDG has been shown to cut colon cancer by up to almost two thirds in animal studies. Although not extensively evaluated, flaxseed has been shown to inhibit colon and skin cancers in cell cultures and in animal studies. In a 1992 study, it was discovered that flaxseed ingestion produced anticarcinogenic lignans in the colon.Following an injection of azoxymethane (to induce carcinogenesis) five groups  of male rats were fed a high-fat diet with or without supplementation with flax meal for 4 weeks. In the colons of the supplemented groups, it was discovered that the total number of aberrant crypt and foci were significantly reduced by 41-53% and 48-57% respectively. This suggested that consumption of flaxseed and its lignans may reduce the risk for colon carcinogenesis. (12) Another study was performed in 2005 which involved ED and EL derived from SDG. In this research, four human colon tumour cell lines were incubated with various levels of EL, ED, or 17 beta-oestradiol for 8 to 10 days. At 100 microM concentration, both lignans significantly reduced cell proliferation of all cell lines. EL was more than twice as effective as ED at this concentration. The growth was not affected by the presence of 17 beta-oestradiol, implying that those cells are not oestrogen-sensitive. The conclusion was that lignans are growth inhibitors of colon tumour cells and may act through mechanisms other than anti-oestrogenic activity. (13) In 2006 at South Dakota University researchers supplemented the diets of rats with linseed meal or cornmeal then injected them with azoxymethane, known to cause colon cancer. After 35 weeks 29% of the linseed fed rats had colon tumours compared with 83% of the cornmeal group. (14)

Women’s Health Flaxseed is a particularly abundant source of phytoestrogens, and has shown promise in studies where people who eat more lignan-containing foods have a lower incidence of breast cancer due to the phytoestrogen effect and reduction of  growth of cancerous tumours, especially hormone-sensitive ones such as those of the breast and endometrium.
When ingested in relatively large amounts, phytoestrogens have been shown to have significant oestrogen agonist/antagonist effects in animals and humans. The behaviour of the lignans depends on the biological levels of oestradiol. At normal oestradiol levels, the lignans act as oestrogen antagonists, but in postmenopausal women (at low oestradiol levels) they can act as weak oestrogens. Other activities related to oestrogen include the in vivo synthesis of 2-hydroxy oestrogen, a compound that may protect against cancer and inhibit the binding of oestrogen and testosterone to receptors on sex-binding globulin. There is epidemiological, laboratory and clinical evidence which indicates that phytoestrogens, like certain selective oestrogen receptor modulators, have an antiproliferative effect on the breast, and also positive effects on lipoprotein profile and bone density. They might also improve some of the climacteric symptoms. Women consuming lignan-rich flaxseed food and supplement products generally report a reduction in breast tenderness, bloating, hot flushes, sweating, vaginal dryness, and other systems related to PMS and menopause. (5)

An over-exposure to oestrogen contributes to breast disease, be it breast pain, breast lumps or breast cancer. There are two types of oestrogen exposure, the first is from the natural oestrogen that your body produces each month, and the second is the amount of synthetic oestrogen you are exposed to throughout your lifetime. Exposure to synthetic oestrogen can come from plastic food packaging, plastics, water and medicines including - foods high in saturated fat, non-filtered tap water (in certain areas), soft plastic food containers and cling film, medicines such as the Pill and HRT, plus other household factors like carpets and cleaning products. (15)

Oestrogen is metabolized in the liver and broken down into three different metabolites: 2-OH oestrone, 4-OH oestrone and 16-alpha OH oestrone. The liver has two ways in which it can process oestrogen. One pathway produces a breakdown product, which is extremely harmful to breast cells, called 16-OH and the other produces a breakdown product which is considered safe to breast cells called 2-OH. Studies now show that your ratio of harmful 16-OH to safe 2-OH can act as a good indicator for your risk of developing breast cancer. Urinary oestrogen metabolites remain relatively fixed, whereas the proportions of 2OH and16OH may fluctuate widely under varying physiological and pathological conditions including exposure to synthetic oestrogens.

Shifting oestrogen balance toward a less oestrogenic state through promotion of the 2-OH pathway may prove very beneficial in improving a variety of conditions related to elevated or imbalanced oestrogen levels. (16-22) Controlling menstrual cycles has several health benefits including decreasing the risk of breast cancer. Lignans in flaxseed have been shown to regulate women’s menstrual cycles. The effect of the phytochemicals on the menstrual cycle is a lengthening of the luteal phase (LP), larger LP Progesterone/Oestrogen (P/E2) ratios, fewer anovulatory cycles and a lower tendency for ovarian dysfunction. Flaxseed ingestion had no direct effect on the LP progesterone concentration, but the LP progesterone/oestradiol ratios were elevated; this was due to a decreased LP oestradiol (E2) concentration.  The women supplemented their diets with a dose of 10g/day of flax during the flax cycles. Between the flax cycles and the control cycles, no significant alterations of weight, total calories, and fat, protein, or carbohydrate levels occurred.  There was a small rise in fibre content noted during the flax cycles; due to the fibre associated with flax. Flaxseed had no significant changes on the follicular phase. A crossover study had women ingesting their normal diets for the first cycle, and then subjects consumed flax supplements during cycles 2-4 or cycles 5-7. Concentrations of the lignans measured in the urine and faecal matter showed the levels of lignans absorbed. Clearly, flax has a significant impact on controlling women’s menstrual cycles. In one study, women consuming lignans in flaxseed did not miss a single cycle, compared to the control group that missed several cycles. (23)

Breast cancer is now the most common cancer in the UK
. Each year more than 49,000 women are diagnosed with breast cancer
. Female breast cancer incidence is strongly related to age, with the highest incidence rates overall being in older women, supporting a link with hormonal status. In the UK between 2008 and 2010, an average of 45% of cases were diagnosed in women aged 65 years and over, and 80% were diagnosed in the 50s and over. In 2010, there were 49,961 new cases of breast cancer in the UK: 49,564 (99%) in women and 397 (less than 1%) in men - Cancer Research UK 2013

The control flaxseed has over the menstrual cycle has an influence on cancer growth. The oestrogen window hypothesis proposed by Korenman states that luteal inadequacy, ovarian dysfunction, and normal oestrogen stimulation characterized by a decreased progesterone secretion is a major cause of breast cancer. Studies show a linkage between ovarian dysfunction and breast cancer risk; flax exerts a controlling influence on this dysfunction through regulation. Flax increases the LP of women and decreases the tendency for ovarian dysfunction. This study states mitotic activity of breast cancer cells tends to reach a peak during LP, which is in contrast to endothelial cancer cells. According to the study, the less time a woman spends in the luteal phase the lower the breast cancer risk. The popular drug tamoxifen is structurally similar to the lignans. Tamoxifen has similar properties including increasing LP oestrogen and progesterone concentrations and lengthening the LP. Another essential component of flax, EL combined with estradiol inhibits MCF-7 breast cancer cell growth in vitro. (24-25)
In a recent French study conducted over seven years with 58,049 women participants, high dietary intakes of plant lignans and high exposure to enterolignans were associated with reduced risks of ER- and PR-positive postmenopausal breast cancer in a Western population that does not consume a diet rich in soy. (26) Furthermore the ability of flaxseed to reduce testosterone levels in post-menopausal women could also be important where testosterone can trigger the growth of some breast cancers that are not oestrogen dependant. (27)

The more oestrogen a woman is exposed to over her lifetime, the higher her risk of breast cancer is. Aromatase is an enzyme involved in the production of oestrogen. If this enzyme is blocked, the level of oestrogen in the body will go down and so will the risk of breast cancer.  This is exactly how the anti-breast cancer drug Arimidex works. Lignans have also been found to have an inhibitory effect. (28) A further 2011 animal study found that EL works like Tamoxifen preventing breast cancer tumours from forming their own blood vessels. (29) A study involved postmenopausal women who had been newly diagnosed with breast cancer and given a muffin containing 25g of SDG or a placebo containing none revealed after 32 days breast tumour growth had decreased by 34.2 per cent, apoptosis increased by 30.7 per cent and the protein HER2 which causes aggressive cancer growth had decreased by 71 per cent. (30) A further study paralleled the 2005 findings (31)  A 2011 German study also found that postmenopausal breast cancer risk decreased significantly in women with higher EL levels. (32)

SDG lignan was tested for effects on mammary tumourigenesis in rats. The consumption of the flaxseed lignan SDG resulted in a 37% reduction in the number of tumours per tumour-bearing rat, and a 46% reduction in the number of tumours per number of rats in each group. This study showed that SDG has an anti-tumour effect when provided at the early promotion stage of tumourigenesis. (33) Another study was conducted to determine if the lignan SDG could reduce mammary tumour growth at the late stage of carcinogenesis. Flax SDG supplementation began 13 weeks after carcinogen administration to see if it would reduce the size of established mammary tumours (present at the start of treatment), and the appearance of new tumours in rats. After 7 weeks of SDG treatment established tumour volume was over 50% smaller in all treatment groups, while there was no change in the rats on the normal control diet. New tumour number and volume were also lower in the SDG group. The conclusions were that SDG is beneficial throughout the promotional phase carcinogenesis, and at the stage when tumours have already been established. (34) In a similar study, not only did the use of SDG inhibit mammary tumour development in rats, but it was also noted that certain growth factors were lowered. It is known that increased plasma insulin-like growth factor (IGF-I) concentration is associated with increased breast cancer risk. Thus the anti-cancer effect of flaxseed SDG may also be related, in part, to reductions it causes in plasma IGF-I. (35)

During lactation, breast development occurs involving the terminal end bud (TEB) structures in the breast. A test was conducted to see if flaxseed lignans affected the development of the mammary gland in rats during lactation. This was important because mammary glands with more TEBs are more susceptible  to carcinogens. The results were that lignans taken during early postnatal life may reduce the risk of developing breast cancer. (36) Because of the potential effects lignans have on oestrogen, women who are pregnant or breast-feeding should avoid taking large amounts of this supplement. It is considered safe when used in moderation at such times.

Diabetes
Several studies by K.Prasad at the University of Saskatchewan indicate that the lignan SDG from flaxseed can help prevent or significantly delay the development of diabetes. In an animal study published in 2001, it was found that SDG reduced development of adult-onset (type 2) diabetes by 80 per cent, and delayed the development of the disease significantly. Prasad has shown that both type 1 and type 2 diabetes are associated with oxidative stress (increase in oxygen free radicals). But because of SDG’s potent antioxidant activity, its ingestion is effective in preventing and reducing the development of diabetes by reducing this oxidative stress. As a complex carbohydrate, lignans can help reduce blood sugar levels. Prasad stresses that diabetes patients would have to consume very large amounts of whole flaxseed to get enough SDG to provide the equivalent beneficial effect found in the animal studies. Drawbacks to doing this would also include high calorie intake (flaxseed is 35-40 percent oil) and a laxative effect. For that reason, SDG extracts derived from newly developed extraction methods would be needed. (37-38)

Heart Disease
It is well known that flax oil combats heart disease by lowering LDL cholesterol and triglycerides, and reducing the build up of atherosclerotic plaque on artery walls.  But now, evidence is revealing that SDG lignan in a concentrated form has an equal or greater effect in fighting heart disease. Diets rich in foods containing plant lignans 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 cardio protective effects. The ability of SDG in reducing atherosclerosis is partly due to its antioxidant activity. 
Lignans are platelet-activating factor-receptor antagonists that inhibit the production of oxygen radicals by polymorph nuclear leukocytes. Oxygen free radicals have been implicated in the development of heart disease, damage to the lining of the blood vessels and setting the stage for development of atherosclerosis. SDG antioxidant activity has the ability to remove toxic metabolites of oxygen radicals, thus retarding atherosclerosis. 

Recent work from the University of Saskatchewan has demonstrated the reduction of hypercholesterolaemic atherosclerosis is greater with SDG than with the whole flaxseed.  The effect is associated with a decrease in serum cholesterol, LDL cholesterol, and lipid peroxidation with an increase in HDL cholesterol and antioxidant reserve. Pre-treatment with flaxseed attenuated endotoxin induced cardiac dysfunction and cellular damage. Flaxseed antioxidant and anti-PAF agents may be effective in the treatment of ET shock. (39)

An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300 or 600 mg/d of dietary SDG from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. (40)
In a prospective cohort study of 1,889 Finnish men followed for an average of 12 years, those with the highest serum EL levels (a marker of plant lignan intake) were significantly less likely to die from coronary heart disease (CHD) or cardiovascular disease than those with the lowest levels. (41)
Flaxseed lignans are potent inhibitors of platelet-activating factor, a mediator of inflammation. Through these effects, flaxseed has the potential to be used for the treatment of disorders characterized in part by activated lymphocytes and a hyper-stimulated immune response. Such disorders include rheumatoid arthritis, psoriasis, multiple sclerosis and systemic lupus erythematosus.

Kidney Disease and Lupus Nephritis
In recent years, researchers have been investigating whether phytoestrogens and lignans from foods such as flaxseed can play a beneficially therapeutic role in kidney disease, which often involves destructive inflammatory, oxidative and sclerotic processes. The answer seems to be quite positive.
Reno protection was evidenced, in a dose-dependent fashion in an animal study, by a significant delay in the onset of proteinuria with preservation in GFR and renal size. This study suggests that Flaxseed SDG may have a therapeutic role in lupus nephritis.  (42)

Men’s Health
The biological properties of lignans have several beneficial effects for men:

Prostate Health
Flaxseed lignans are currently being researched for their role in men’s health issues, such as Benign Prostatic Hyperplasia (BPH) or enlargement of  the prostate gland, and prostate cancer. BPH is a disorder that regularly occurs in ageing men and leads to symptoms such as painful and difficult urination. It’s generally believed that there is a relation between BPH and increased risk of prostate cancer. Although the exact cause of BPH is unknown, it is generally accepted that the hormone testosterone is involved. Lignans can interfere with indigenous levels of testosterone, and thus have a positive effect on prostate health. Prostate cancer is the most common cancer in men in the UK in 2010, 40,975 men in the UK were diagnosed with prostate cancer Cancer UK 2013. About 4 out of every 10 men over the age of 50 (40 per cent) and 3 out of 4 men in their 70s (75 per cent) have urinary symptoms that are caused by an enlarged prostate. Prostate Cancer UK 2013. Flaxseed ingestion produces large amounts of mammalian lignans with weak oestrogenic / anti-oestrogenic properties. In tests, these properties reduced adult relative prostate weight and cell proliferation, suggesting potential protection against prostatic disease, without affecting sex hormone levels. (43) Researchers from the University of Wales, College of Medicine determined the concentration of lignans in prostate fluid from Portuguese, Chinese, and British men. The mean concentrations of enterolactone and other plant estrogens were very high among Portuguese and Asian men, respectively. The research team concluded that the level of lignans and related plant oestrogens may be responsible, in part, for lower incidence of prostate cancer in men from Mediterranean countries. (44) It is also noted that vegetarian men have lower incidence of prostate cancer than non- vegetarian males. This is partly due to the higher level of plant lignans consumed by vegetarians.  In addition to their oestrogenic activity, these plant compounds can interfere with steroid metabolism and bioavailability, and also inhibit enzymes, such as tyrosine kinase and topoisomerase, which are crucial to cellular proliferation and hence contribute to lower incidences of prostate cancer. (45) A recent study involved twenty-five patients with prostate cancer who were given a lignan-rich flaxseed supplementation. The results show a favourable effect on prostate cancer biology and associated biomarkers. (46) A four month study which included 87 men with BPH found that SDG decreased prostate symptoms significantly better than placebo, which improved quality of life. (47)

Pulmonary metastasis of melanoma cells Dietary supplementation of mice with SDG has shown to significantly reduce pulmonary metastasis of melanoma cells and inhibited the growth of metastasis tumours that formed in the lungs. Tumour occurrence reduced by up to 63%. The addition of SDG to the diet also caused a dose-dependent decrease on tumour area and volume, showing that it could be beneficial in both prevention and treatment. Further, the rich source of lignans reduced a metastasis (the spread of cancerous cells) and inhibited the growth of the metastatic secondary tumours in the animals tested. (48)

Conclusion
There is still much research needed into various health aspects of SDG Lignans since the biological activity was first discovered in the 1980’s but certain studies have demonstrated and confirmed significant health benefits in prevention and support of a variety of chronic diseases.

For references click below:
http://www.bant.org.uk/bant/jsp/member/pdf/eNewsletter/articles/BIOLOGICAL_SIGNIFICANCE_ OF_SDG_LIGNANS_REFERENCES_BANT_ENEWS_MAR2013_ISSUE_46.pdf