Highlights
Even though foods rich in lignans (a source of dietary phytoestrogen with structure similar to estrogen) may have key active compounds that may help in reducing the risk of different types of cancers, the association between plasma enterolactone levels and the risk of cancers is not clear. A recent study found that high enterolactone levels may be associated with a reduced risk of colorectal cancer-specific deaths among women and an increased risk of deaths among men. Other studies which evaluated the impact of plasma enterolactone concentration on breast, prostate and endometrial cancers found no association or ended up with conflicting results. Hence, so far, there is no clear evidence which suggest that high circulating levels of enterolactone can offer significant protective effects against the risk of hormone-associated cancers.
What are Lignans?
Lignans are polyphenols as well as a principal dietary source of phytoestrogen (a plant compound with structure similar to estrogen), found abundantly in various plant-based foods such as flax seeds and sesame seeds and in smaller amounts in nuts, whole grains, fruits and vegetables. These lignan-rich foods are usually used as part of a healthy diet. Some of the most common lignan precursors identified in plant-based diets are secoisolariciresinol, pinoresinol, lariciresinol and matairesinol.
What is Enterolactone?
The plant lignans that we consume are enzymatically converted by the intestinal bacteria leading to the formation of compounds called Enterolignans. The two main enterolignans that circulate in our body are:
a. Enterodiol and
b. Enterolactone
Enterolactone is one of the most abundant mammalian lignans. Enterodiol may also be further converted to enterolactone by intestinal bacteria. (Meredith A. J. Hullar et al, Cancer Epidemiol Biomarkers Prev., 2015) Both enterodiol and enterolactone, are known to have weak estrogenic activity.
Apart from the amount of intake of plant lignans, enterolactone levels in serum and urine may also reflect the activity of intestinal bacteria. Also, the use of antibiotics has been associated with lower serum enterolactone concentration.
When it comes to phytoestrogen (plant compound with structure similar to estrogen)-rich foods, soy isoflavones often comes into limelight, however, lignans are in fact the principal sources of phytoestrogens especially in Western diets.
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Plasma Enterolactone Concentration and Cancer Risk
Even though foods rich in lignans (a source of dietary phytoestrogen with structure similar to estrogen) are considered to be healthy and consist of various key active compounds that may help in reducing the risk of different types of cancers, the association between enterolactone levels and the risk of cancers is unclear.
Plasma Enterolactone Concentration and Colorectal Cancer Deaths
In a study published in 2019 by the researchers from Denmark, they evaluated the association between plasma concentrations of enterolactone (the main lignan metabolite) before cancer diagnosis, and survival after colorectal cancer, based on data from 416 women and 537 men diagnosed with colorectal cancer, who participated in the Danish Diet, Cancer and Health cohort Study. During the follow-up period, a total of 210 women and 325 men died, out of which 170 women and 215 men died due to colorectal cancer. (Cecilie Kyrø et al, Br J Nutr., 2019)
The findings of the study were quite interesting. The study found that high Enterolactone concentrations were associated with lower colorectal cancer-specific deaths among women, especially in those who did not use antibiotics. Doubling of plasma enterolactone concentration in women was associated with a 12% lower risk of deaths due to colorectal cancer. Also, women with very high plasma enterolactone concentration had 37% lower rate of deaths due to colorectal cancer, compared with those with low plasma levels of enterolactone. However, in men, high enterolactone concentrations were associated with higher colorectal cancer-specific deaths. In fact, in men, the doubling of plasma enterolactone concentration was associated with a 10% higher risk of deaths due to colorectal cancer.
This aligns with a previous study which demonstrated that estrogen, the female sex hormone, has an inverse association with colorectal cancer risk and mortality (Neil Murphy et al, J Natl Cancer Inst., 2015). Enterolactone is considered as a phytoestrogen. Phytoestrogens are plant compounds with structure similar to estrogen, and lignan rich plant-based foods are their principal dietary source.
In short, the researchers concluded that high enterolactone levels may be associated with a reduced risk of colorectal cancer-specific deaths among women and an increased risk of deaths among men.
Plasma Enterolactone Concentration and Endometrial Cancer Risk
Enterolactone Concentration and Endometrial Cancer Risk in Danish Women
In a study published by the researchers of Danish Cancer Society Research Center in Denmark, they evaluated the association between levels of plasma enterolactone and incidence of endometrial cancer, based on data from 173 endometrial cases and 149 randomly selected Danish women who were enrolled in the ‘Diet, Cancer and Health’ cohort Study between 1993 and 1997 and were aged between 50 and 64 years. (Julie Aarestrup et al, Br J Nutr., 2013)
The study found that women with a 20 nmol/l higher plasma concentration of enterolactone may be associated with a reduced risk of endometrial cancer. However, the reduction was not so significant. The study also assessed the association after excluding data from women with low enterolactone concentrations due to antibiotic use and found that the association became slightly stronger, however, it still remained non-significant. The study also found no variations in the association due to menopausal status, hormone replacement therapy or BMI.
The researchers concluded that high plasma enterolactone concentration may reduce the risk of endometrial cancer, but the impact may be non-significant.
Enterolactone Concentration and Endometrial Cancer Risk in US women
Researchers from the New York University School of Medicine in the US had previously conducted a similar study which evaluated the association between endometrial cancer and circulating levels of enterolactone. The data for the study was obtained from 3 cohort studies in New York, Sweden and Italy. After a mean follow-up of 5.3 years, a total of 153 cases were diagnosed, which were included in the study along with 271 matched controls. The study did not find a protective role of circulating enterolactone against endometrial cancer in premenopausal or postmenopausal women. (Anne Zeleniuch-Jacquotte et al, Int J Cancer., 2006)
These studies do not provide any evidence that enterolactone is protective against endometrial cancer.
Plasma Enterolactone Concentration and Prostate Cancer Deaths
In a study published in 2017 by the researchers from Denmark and Sweden, they evaluated the association between prediagnostic enterolactone concentrations and deaths among Danish men with prostate cancer. The study included data from 1390 men diagnosed with prostate cancer who were enrolled in the Danish Diet, Cancer and Health cohort Study. (A K Eriksen et al, Eur J Clin Nutr., 2017)
The study found no significant association between a 20 nmol/l higher plasma concentration of enterolactone and deaths in Danish men with prostate cancer. The study also found no variations in the association due to factors such as smoking, body mass index or sport, as well as prostate cancer aggressiveness.
In short, the study found no association between enterolactone concentrations and deaths among Danish men diagnosed with prostate cancer.
Based on the limited data, there is no evidence to support an inverse association between lignan (a source of dietary phytoestrogen with structure similar to estrogen)-rich food intake, serum enterolactone concentrations and prostate cancer risk.
Plasma Enterolactone Concentration and Breast Cancer
Enterolactone Concentration and Breast Cancer Prognosis in Danish Postmenopausal Women
In a study published in 2018 by the researchers of the Danish Cancer Society Research Center and Aarhus University in Denmark, they evaluated the association between pre-diagnostic plasma concentrations of enterolactone and breast cancer prognosis in postmenopausal women such as recurrence, breast cancer-specific deaths and all-cause deaths. The study included data from 1457 breast cancer cases from the Danish Diet, Cancer and Health cohort Study. During a mean follow-up period of 9 years, a total of 404 women died, out of which 250 died of breast cancer, and 267 experienced recurrence. (Cecilie Kyrø et al, Clin Nutr., 2018)
The study found that high plasma enterolactone had only a slight association with lower breast cancer-specific deaths in postmenopausal women, and no association with all-cause deaths and recurrence after taking into account the factors such as smoking, schooling, BMI, physical activity and use of menopausal hormones. The results didn’t change after including factors such as clinical characteristics and treatment.
The study concluded that there was no clear association between pre-diagnostic plasma concentrations of enterolactone and breast cancer prognosis in postmenopausal women.
Enterolactone and Postmenopausal breast cancer risk by estrogen, progesterone and herceptin 2 receptor status
In a meta-analysis done by the researchers of German Cancer Research Center, Heidelberg, Germany, they evaluated the association between serum enterolactone and postmenopausal breast cancer risk. Data for the analysis was obtained from 1,250 breast cancer cases and 2,164 controls from a large population-based study. (Aida Karina Zaineddin et al, Int J Cancer., 2012)
The study found that increased serum enterolactone levels was associated with a reduced postmenopausal breast cancer risk. The study also highlighted that the association was more significant for Estrogen Receptor (ER) -ve/ Progesterone Receptor (PR) -ve breast cancers compared to ER+ve/PR+ve breast cancers. Further, the expression of HER2 had no impact on the association.
This study suggested that higher serum enterolactone levels may be associated with a reduced postmenopausal breast cancer risk, especially in Estrogen Receptor (ER) -ve/ Progesterone Receptor (PR) -ve breast cancers.
Enterolactone Concentration and Breast Cancer Risk in French Postmenopausal Women
A previous study published in 2007 by the researchers of the Institut Gustave-Roussy, France also evaluated the associations between the risk of postmenopausal breast cancer and dietary intakes of four plant lignans -pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol, and exposure to two enterolignans – enterodiol and enterolactone. The study used data from a self-administered diet history questionnaire from 58,049 postmenopausal French women who were not taking soy isoflavone supplements. During a mean follow-up of 7.7 years, a total of 1469 cases of breast cancer were diagnosed. (Marina S Touillaud et al, J Natl Cancer Inst., 2007)
The study found that compared with women with the lowest intake of lignans, those with the highest total lignan intake corresponding to >1395 microg/day, had a reduced risk of breast cancer. The study also found that the inverse associations between phytoestrogen intakes and postmenopausal breast cancer risk were limited to Estrogen Receptor (ER) and Progesterone Receptor (PR)-positive breast cancers.
Key Take-away : So far, there are conflicting results and hence, we cannot conclude whether high lignan (a source of dietary phytoestrogen with structure similar to estrogen)-rich food intake and plasma concentration of enterolactone has protective effects against breast cancer.
Conclusion
Even though intake of foods rich in lignans (a source of dietary phytoestrogen with structure similar to estrogen) is healthy and may have key active compounds that can help in reducing the risk of different types of cancers, the association between plasma enterolactone levels and the risk of different cancers is not yet clear. One of the recent studies suggested a protective role of enterolactone against colorectal cancer deaths in women, however, the associations were opposite in case of men. Other studies which evaluated the impact of plasma enterolactone concentration on hormone-associated cancers such as breast cancer, prostate cancer and endometrial cancer found no association or ended up with conflicting results. Hence, at present, there is no clear evidence which suggest that high circulating levels of enterolactone can offer significant protective effects against risk of hormone-associated cancers.
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