Flaxseed is the richest known dietary source of mammalian lignans . Thompson et al. demonstrated that secoisolariciresinol diglucoside (SDG), isolated from flaxseed, was metabolized into both enterodiol (END) and enterolactone (ENL), and showed chemopreventive properties in the DMBA-induced mammary tumor model in rats.
The inverse association between a high enterolactone (ENL) concentration in both urine and serum, and the risk of breast cancer found in epidemiological studies suggests a chemopreventive action for ENL.
Plant lignans, such as secoisolariciresinol (SECO) and matairesinol found in many edible plants, are transformed by intestinal microbiota into mammalian lignans END and ENL, respectively.
ENL is the quantitatively most important lignan in human serum. An inverse association between the urinary or serum ENL contents and the risk of breast cancer has been described in several epidemiological studies. The finding has stimulated considerable interest in the possible chemopreventive properties of ENL and its precursors.
In pilot human studies, dietary flaxseed given preoperatively to newly diagnosed breast cancer patients markedly reduced the Ki67 labeling index and c-erb2 of the breast cancer tissue, suggesting direct antiproliferative effects.
As expected, there was a marked increase in the urinary excretion of mammalian lignans after the ingestion of flax. A recent study of short-term flaxseed supplementation and fat restriction in diet additionally showed significantly lower proliferation rates and higher rates of apoptosis in prostate cancer of men before operation.
However, the observed effects of flax do not allow for any conclusions on the possible role of lignans in the inhibition of cancer growth, because other potentially bioactive multiple compounds are present in flaxseed.
ENL is assumed to mediate the anticarcinogenic action of plant lignans shown in experimental breast cancer and account for the antiproliferative effects seen in the clinical studies of flaxseed supplementation. Until recently, there was no direct evidence for the anticarcinogenic action of ENL in humans or experimental cancer models in animals.
The possible anticarcinogenic effects of ENL on breast cancer were tested for the first time by using a DMBA-induced mammary carcinoma of the rat in this study
Hutchins et al. reported increased serum prolactin concentrations, and decreased serum 17ß-estradiol and estrone concentrations in postmenopausal women after a 7-week administration of flaxseed in a daily dose of 10 g.
It is possible that a long-term exposure to elevated concentrations of lignans may alter the composition and metabolic activities of intestinal microbiota, possibly resulting in altered metabolism of other dietary polyphenols.
This study showed elevated serum concentrations of equol (EQ) and O-desmethylangolensin (O-DMA), metabolites of daidzein (DA), were observed. In premenopausal women, high EQ excretion has been associated with lower serum concentration of estrogens and androgens, and higher concentration of sex hormone-binding globulin, a hormonal pattern consistent with lower risk for breast cancer.
Thus, the increased serum concentrations of EQ and O-DMA could account for chemopreventive properties observed in this study
Are ENL And Breast Cancer related?
The study by Saarinen N et al provided the first evidence that ENL (derived from flaxseed) produced growth inhibition on cancer cells.
In this study rats with 7,12-dimethylbenz(a)anthracene-induced mammary cancers were maintained on a standard open-formula chow diet. Daily p.o. administration of ENL at a dose of 10 mg/kg of body weight for 7 weeks was shown to significantly inhibited tumor growth.
The growth-inhibitory effect of ENL was more pronounced on the new tumors, which developed during the treatment period, but ENL also inhibited the growth of those tumors established before the start of the lignan administration.
The rat serum concentration of ENL, which illustrated a permanent positive effect on breast cancer growth, was 0.4 µM, which is >10-fold as compared with the serum concentrations found in the general human population.
The effect of ENL was not restricted to any specific histological tumor type. ENL was demonstrated to act as a weak aromatase inhibitor in vitro and to reduce the relative uterine weight of the 7,12-dimethylbenz(a)anthracene-treated non ovariectomized rats. (1)
How Flaxseed lignan provide a range of health benefits?
Flaxseeds are a rich source of secoisolariciresinol diglycoside (SLD) and other mammalian lignan precursors. Flaxseed contains 800-times more of these mammalian lignan precursors than is found in any other food (i.e. beans, nuts).
The presence of SLD and related lignan precursors as well as its rich alpha-linolenic acid (omega-3 fat) content makes Flaxseed a very unique dietary supplement providing a broad range of health-promotion effects.
The consumption of Flaxseed or processed Flaxseed (i.e. muffin or bread) has been shown to significantly raise blood levels of the mammalian lignans enterolactone and enterodiol in a dose-dependent manner.
Enterolactone and enterodiol are produced in the colon by the action of bacteria on SLD.1,4 Both enterolactone and enterodiol act as phytoestrogens and can thus, bind to estrogen receptors on breast (and other reproductive tissues) cells and inhibit certain enzymes (i.e., aromatase enzyme in adipose tissue, also known as estrogen synthase) 2
These, and other synergistic effects have made Flaxseed a target for breast cancer research. Other Flaxseed attributes have stimulated research to examine its potential benefits in the prevention of cardiovascular disease, cancer (i.e. breast, prostate, colon), osteoporosis and the management of menopausal symptoms. 3,4
What are Principle Active Constituents?
1. Mammalian Lignan Precursors
In particular: Secoisolariciresinol and matairesinol. These are converted into the mammalian lignans, enterolactone and enterodiol by colonic bacteria. Enterolactone and enterodiol are phytoestrogens and exhibit other functions (i.e. antioxidants).
2. Alpha-Linolenic Acid (an Omega-3 fat)
The amount of alpha-linolenic acid in Flaxseed Powder is far less than in flaxseed oil (see flaxseed oil, alpha-linolenic acid), which is more likely to provide more significant health-promotion effects related to Omega-3 fat consumption (e.g., anti-inflammatory effects)
Soluble and insoluble fiber 4,5,6
How ENL and END Clinical Application and Mechanism of Action favoured Cancer Inhibition?
1. Cancer Prevention and Support
1. Experimental Evidence - Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions on an experimental basis:
- Compete with estradiol for nuclear binding estrogen binding sites in rat uteri
- Inhibit growth of estrogen-sensitive breast cancer cell lines
- Inhibit angiogenesis of cancer cells
- Inhibit aromatase enzyme, reducing the synthesis of estrone hormone in adipose tissue
- Decrease aberrant crypt and foci in rat colonic epithelium
- Inhibit epithelial cell proliferation in rat mammary gland
- Decrease tumor size in promotion stage of breast cancer in animal studies 5
- Reduced colon cancer development with concurrent intake of Flaxseed in carcinogen-induced colon cancer experiments with rats 4
- Provide antioxidant protection 7
- Lifetime exposure and gestational exposure to Flaxseed lignans induces cancer prevention structural changes to mammary glands and endocrine changes consistent with a reduced risk of breast cancer development in animals 12
- Induce cancer cell differentiation
- Inhibition of tyrosine kinase and DNA topoisomerase – two key enzymes that determine the rate of cell division 8
- Anti-mitotic effect 4
- Reduction of plasma insulin-like growth factor-1 levels (IGF-1) in rats. Higher IGF-1 blood levels is associated with an increased risk of breast cancer in women studies 9
- Reduction of pulmonary metastasis of melanoma cells and inhibit the growth of metastasic tumors that formed in the lungs of mice 10
2. Human Evidence - Enterolactone and enterodiol have been shown to exhibit the following anti-cancer functions in human studies:
- Antiproliferative effect on the breast, similar to that of other selective estrogen receptor modulators, such as tamoxifen and raloxifen 11
- Stimulate production of sex hormone-binding globulin (SHBG), decreasing levels of free unbound sex hormones 12
- Decrease the synthesis of 16-alpha hydroxyestrone and increase the synthesis of 2 hydroxyestrone. 13 A higher 2 hydroxyestrone to 16-alpha hydroxyestrone ratio (urinary metabolites) has been shown to be related to a decreased risk of breast cancer in women. This is a suggested “chemoprotective properties”. 14
- Breast cancer patients excrete very low levels of lignans compared with non breast cancer subjects 4
- Vegetarian women are known to have a lower incidence of breast cancer and exhibit higher blood levels of mammalian lignans 15
- Improvement in cystic mastalgia, a potentially precancerous condition in women 16
- Increased or longer luteal phase, increased progesterone to estradiol ratios during the luteal phase, fewer anovulatory cycles, and a decreased tendency to ovarian dysfunction; all of which are linked to a reduced risk of breast cancer in women 4
2. Cyclical Mastalgia
In a double blind placebo-controlled study by Plu-Bureau et al, they demonstrated that patients ingesting the flaxseed muffin (25gm Flaxseed ) reported a significant improvement in breast pain reduction compared to the placebo group, during the three consecutive menstrual cycle duration of the trial. Results were attributed to the antiestrogen effects of Flaxseed lignans. 16
3. Cholesterol Lowering and Other Effects on Reducing Cardiovascular Disease
Animal studies originally suggested that Flaxseed intake had a hypocholesterolemic effect, that is due to its soluble fiber concentration, not to its alpha-linolenic acid content.16
In human trials including men and postmenopausal women with high blood cholesterol levels, Flaxseed Powder or Flaxseed supplementation in various forms has been shown to reduce total cholesterol (approximately 7-10 percent), reduce LDL-cholesterol (approximately 15 percent), reduce lipoprotein (a) (Lp(a)) concentrations by approximately 7 percent.
Lp(a) is emerging as an important risk factor for cardiovascular disease as it increases clotting behaviour of platelets, cholesterol deposition in the artery wall and it oxidizes LDL-cholesterol, making it very atherogenic.
Flaxseed supplementation is the only dietary factor shown to reduce Lp(a) to date.
Estrogen replacement therapy reduces Lp(a) levels, but cholesterol lowering drugs (i.e. statin drugs) do not 17,18,19
Flaxseed lignans inhibit the cholesterol-7-alpha hydroxylase and acyl CoA cholesterol transferase enzymes, involved in cholesterol synthesis, thus reducing total cholesterol. 24
4. Chronic Renal Failure and Renal Disease In Lupus
Animal and human studies indicate that a diet rich in soy based protein and isoflavones, and/or Flaxseed lignans retard the development and progression of chronic renal disease.
The protective effect is considered to be due to effects on cell growth and proliferation, extracellular matrix synthesis, reduced oxidative stress and inflammation reduction 20
In humans (and animals) Flaxseed supplementation has demonstrated renoprotective effects in human lupus nephritis, with significant delay in the onset of proteinuria, and preservation of the glomerular filtration rate (GFR) and renal size.
5. Bone Density and Menopausal Symptom Support
Preliminary evidence in women suggests that the phytoestrogen influence of enterolactone and enterodiol (from Flaxseed supplementation) has a positive effect on bone density and menopausal symptoms (i.e. hot flashes) 11
6. Prostate Cancer Protective Effect
Flaxseed lignans interfere with steroid metabolism and bioavailablity in a fashion that is linked to reduced prostate cancer risk. They also inhibit enzymes such as tyrosine kinase and topoisomerase, which initiate the cellular proliferation rate. Epidemiological studies link the above endocrine and molecular events with up to an 80 percent reduction in risk of prostate cancer 22
Human studies reveal that Flaxseed supplementation improves laxation 5 It appears that Flaxseed intake increases fecal excretion of bile acids, increasing laxation and reducing the conversion of bile acids to cholesterol in the liver; thereby lowering blood cholesterol 23,5
What are the recommended Dosage Ranges?
- General Health and Cholesterol Lowering: 25–50 gms of ground flaxseeds per day (unground seeds are significantly less bioavailable in regards to their lignan precursors content) 1, 13,14,17,18,19
- Cyclical Mastalgia: 25 gm per day of ground Flaxseed Powder1,13,14,16
- Female Menopausal Support: 25-50 gm per day of ground Flaxseed Powder13,14
Are There Any Adverse Side Effects And Toxicity
Ground Flaxseed is extremely non-toxic. It is well tolerated according to human trails with no significant side effects, other than the occasional report of mild abdominal discomfort 5,16,23,24
There are no well-known drug-nutrient interactions for ground Flaxseed , Flaxseed Powder or Flaxseed -containing products 1,16,25
- Saarinen N, Huovinen R, Warri A, Makela S, Valentin-Blasini L et al. Enterolactone inhibits the growth of 7,12,-dimethylbenz(a) anthracene-induced mammary carcinomas in rat. Molecular Cancer Therapeutics. 2002;1:869-876
- Nesbitt PD et al. Human metabolism of mammalian lignan precursors in raw and processed flaxseed. Am J Clin Nutr 1995;69(3):549-55
- Huthcins AM et al. Flaxseed influences urinary lignan excretion in a dose-dependent manner in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9(10):1113-8
- Tham DM et al. Clinical Review 97 : Potential health benefits of dietary phytoestrogens : a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998;83(7):2223-35
- Zeigler J. Just the Flax, Ma’am: Researchers Testing Linseed. J Natl Cancer Instit 1994;86(23):1746-8
- Cunnane SC et al. Nutritional attributes of traditional flaxseed in healthy young adults. Am J Clin Nutr 1995;61(1):62-8
- Prasad K et al. Reduction in hypercholesterolemia atherosclerosis by CDC-flaxseed with very low alpha-linolenic acid. Atherosclerosis 1998;136(2):367-75
- Kitts DD et al. Antioxidant activity of the flaxseed lignan secoisolariciresinol diglycoside and its mammalian lignan metabolites enterodiol and enterolactone. Mol Cell Biochem 1999;202(1-2):91-100
- Kurzer MS et al. Dietary Phytoestrogens. Annu Rev Nutr 1997;17:353-81
- Richard SE et al. Plasma insulin-like growth factor-1 levels in rats are reduced by dietary supplementation of flaxseed or lignan secoisolariciresinol diglycoside. Cancer Lett (Ireland) 2000;161(1):47-55
- Li D et al. Dietary supplementation with secolariciresinol diglycoside (SDG) reduce experimental metastasis of melanoma cells in mice. Cancer Lett 1999;142(1):91-96
- Brzzinski A, Debi A. Phytoestrogens: the natural selective estrogen receptor modulators? Eur J Obstet Gynecol Reprod Biol 1999;85(1):47-51
- Tou JC, Thompson LU. Exposure to flaxseed or its lignan component during different developmental stages influences rat mammary gland structures. Carcinogenesis 1999;20(9):1831-5
- Haggans CJ et al. Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women. Nutr Cancer 1999;33(2):188-95
- Haggns CJ et al. The effect of flaxseed and wheat bran consumption on urinary estrogen metabolism in premenopausal women. Cancer Epidemiol Biomarkers Prev 2000;9(7):719-25
- Thompson LU et al. Antitumorigenic effect of mammalian lignan precursor from flaxseed. Nutr Cancer 1996;26:159-65
- Gross PE et al. Effect of dietary flaxseed in women with cyclical mastalgia. Program and abstract of the 23rd Annual San Antonio Breast Cancer Symposium. Dec 6-9 2000; San Antonio Texas. Abstract 153. Breast Cancer Res Treat. 2000;64:49
- Arjmandi BH et al. Whole flaxseed consumption lowers serum LDL-cholesterol and lipoprotein (a) concentrations in postmenopausal women. Nutr Res 1998;18:1203-14
- Jenkins DJA et al. Health aspects of partially defatted flaxseed, including effects on serum lipis, oxidative measures, and ex vivo androgen and progestin activity : a controlled cross over trial. Am J Clin Nutr 1999;69(3):395-402
- Flaxseed Lowers Cholesterol. Nutr Science News 1998;3(11):575
- Velasquez M et al. Dietary Phytoestrogens : A possible role in renal disease prtection. Am J Kidney Dis 2001;37(5):1056-68
- Clark WF et al. A novel treatment for lupus nephritis : lignan precursor derived from flaxseed. Lupus 2000;9(6):429-36
- Denis L et al. Diet and its preventive role in prostate disease. Eur Urol 1999;35(5-6):377-87
- Chen WJL et al. Hypocholesterolemic effects of soluble fibers. In Kritchevsky D, Yahouny GD, eds. Dietary Fiber: basic and clinical aspects. New York: Plenum Press, 1986:275-89
- Sanghui A et al. Inhibition of rat liver cholesterol 7-alha hydroxylase and acyl CoA : cholesterol acyl transferase activities by enterodiol and enterolactone. In Kritchevsky D, ed. Proceedings of the Symposium on Drugs Affecting Lipid Metabolism. New York: Plenum Press, 1984:311-322