Table 1.
Epidemiologic studies based on plasma/serum/urine Enterolactone concentrations and intake of Enterolactone in association with several cancer risks.
| Types of cancer | Country/ Region |
Design | Cases/ Controls |
Methodology | Analysis of EL | Findings related to EL | Interpretation | Ref. |
|---|---|---|---|---|---|---|---|---|
| Breast cancer | Boston, USA | Dietary Study | 10 omnivores, 10 vegetarians and 7 BC; PoM women | 72 h collection of urine, 3-day food record. | Nutrient composition, Urinary EL and ED by capillary GC. | Urinary excretion of EL in the BC group was significantly lower than in both the other groups. ED excretion was also lower in the BC group than in the vegetarian group. | PoM women with BC excreted significantly less EL in their urine than did healthy PoM women | (Adlercreutz et al., 1982) |
| Western Australia | CCS (RD) | 144 /144 women | SQ and FFQ, 72 h urine collection, Blood sample collection before the treatment. | Urinary PhE, ED, EL and MAT by isotope dilution GC-MS. | High excretion of both equol and EL was associated with a substantial reduction in BC risk, with significant trends through the quartiles: equol ORs were 1·00, 0·45 (95% CI 0·20, 1·02), 0·52 (0·23, 1·17), and 0·27 (0·10, 0·69)—trendp = 0·009—and EL ORs were 1·00, 0·91 (0·41, 1·98), 0·65 (0·29, 1·44),0·36 (0·15, 0·86)—trend p = 0·013. | High intake of equol and EL could be important in the prevention of BC. | (Ingram et al.,1997) | |
| Eastern Finland | CCS (RD) | 194 (68 PrM and 126 PoM)/208 women | FFQ, Serum samples collection before the examinations. | Serum EL by TR-FIA | The mean serum EL concentration in the lowest quintile was 3.0 nmol/l and 54.0 nmol/l in the highest (OR in the highest quintile of EL adjusted for all of the known risk factors for BC was 0.38 (95% CI, 0.18–0.77; P for trend, 0.03). The inverse association between serum EL and risk of BC was seen in both PrM and PoM women. | Serum EL level was significantly inversely associated with risk of BC | (Pietinen et al., 2001) | |
| Shanghai, China | CCS (RD) | 250 /250 women | SQ and FFQ Urine samples collection before cancer therapy. | Urinary isoflavonoids, ED, EL, and citrus flavonoids by LC-MS | The risk of BC was reduced with increasing excretion of total isoflavonoids and total mammalian lignans (ED and EL). The risk of BC was reduced with increasing excretion of total isoflavonoids (P for trend, 0.04) and total lignans (P for trend, <0.01), with adjusted ORs of 0.62 (95% CI, 0.39–0.99) and 0.40 (95% CI, 0.24–0.64) observed for the highest versus the lowest tertile of total isoflavonoid and lignan excretion, | Study suggested that high intake of certain PhE like flavonoids and lignans (dietary precursors of ED and EL) may reduce the risk of BC | (Dai et al., 2002) | |
| Western New York, USA | CCS (RD) | 96 / 86 PrM women 112 / 102l PoM women. |
SQ and FFQ Blood samples collection Lignan intake = EL + ED production from foods. |
Analysis of dietary lignans stratified by CYP17 genotype. | Women in the highest tertile of dietary lignans tended to have reduced breast cancer risk (OR 0.45, 95% CI 0.20–1.01 and OR 0.59, 95% CI 0.28–1.27, PrM and PoM women, respectively). Substantially reduced risks in the highest tertile of lignans were observed for PrM women with at least one A2 allele (OR 0.12, 95% CI 0.03–0.50). | Results suggested that CYP17 genotype may be important in modifying the effect on BC risk of ED and EL particularly for PrM women | (McCann et al., 2002) | |
| Western New York USA | CCS (RD) | 315 / 593 PrM women 807/ 1443 PoM women. |
Self administered 104-item FFQ Detailed in-person interviews. | ED and EL= SECO + MAT in diet. | PrM women in the highest quartile of dietary lignan intake had reduced breast cancer risk (OR= 0.66; 95% CI =0.44–0.98). No association was observed between lignan intakes and PoM BC. | Authors concluded that lignans may be important in the etiology of BC, particularly among PrM women. | (McCann et al., 2004) | |
| Southern Germany | CCS (RD) | 278 /666 PrM women | SARFQ, Validated FFQ. | By establishing the database of PhE containing foods usually consumed in Europe. | Both estimated mammalian lignans, ED and EL were inversely associated with BC risk, with ORs (95% CI) of 0.61 (0.39–0.98) and 0.57 (0.35–0.92), respectively | Authors suggested an important role of dietary intake of daidzein and genistein, MAT, Ed and EL to reduce PrM BC risk in this study population. | (Linseisen et al., 2004) | |
| Denmark | CCS (RD) | 381/381 PoM women | SQ and FFQ Blood samples collection | Plasma EL by TR-FIA | For estrogen receptor α-positive BC (n = 273) only a weak association was seen (IRR,0.97; 95% CI, 0.88-1.06), whereas for estrogen receptor α-negative BC (n = 80; IRR, 0.71; 95% CI, 0.53-0.94) a protective effect was seen per 20 nmol/L higher plasma EL. | Authors found a tendency toward a lower risk BC with higher concentrations of EL, which was restricted almost entirely to estrogen receptor α-negative BC | (Olsen et al., 2004) | |
| Genoa, Italy | Cohort Study (PD) | 383 women with palpable cysts | Serum samples collection at the time of first cyst aspiration. | Serum EL by TR-FIA | Median values of serum EL were significantly lower in women who subsequently developed BC: 8.5 nM/l versus 16.0 nM/l: P = 0.04. OR for BC were: 0.36 (P = 0.03), 0.57 (P = 0.3) and 0.38 (P = 0.25) for 25th (8 nM/l), 50th (16 nM/l) and 75th (24 nM/l) percentile values, respectively. | Authors concluded that the serum EL concentration was inversely correlated with the risk of BC in women with palpable cysts. | (Boccardo et al., 2004) | |
| Southern Germany | CCS (RD) | 220/ 237 PrM women | SARFQ and Validated FFQ, Blood samples collection. | Plasma EL by TR-FIA | PrM BC risk decreased with increasing plasma EL concentrations. Adjusted OR (95% CI) were 0.42 (0.20–0.90) and 0.38 (0.17–0.85) (P for trend 0.007) for women in the third and fourth quartile of plasma EL compared to those in the lowest quartile. | Authors concluded a strong inverse association between EL and PrM BC risk as found with dietary intake estimates. | (Piller et al., 2006) | |
| Breast cancer | France | Cohort Study (PD) | 1469 incident cases of primary invasive BC | SADHQ evaluating 208 food items. | Estimation of exposure to ED and EL from dietary lignan intake. | The inverse associations between PhE intakes and PoM BC risk were limited to estrogen receptor- and progesterone receptor-positive disease (e.g., RR for highest versus lowest quartiles of total plant lignan intake = 0.72, 95% CI = 0.58 to 0.88, Ptrend = .01, 174 versus 214 cases per 100 000 person-years, and RR for highest versus lowest quartiles of total enterolignan (ED and EL) level = 0.77, 95% CI = 0.62 to 0.95, Ptrend = .01, 164 versus 204 cases per 100 000 person-years) | High dietary intakes of plant lignans and high exposure to enterolignans (ED and EL) were associated with reduced risks of estrogen receptor and progesterone receptor positive PoM BC | (Touillaud et al., 2007) |
| Sweden | Nested CCS (PD) | 366 / 733 women | A modified diet history method, Direct anthropometric measurements, Blood samples collection. | Plasma EL by TR-FIA | EL concentrations above the median (16 nmol/L) were associated with reduced BC risk when compared with those below [OR, 0.75; 95% CI (95% CI), 0.58-0.98]. The reduced risk was only observed for estrogen receptor α ( + ); OR, 0.73; 95% CI, 0.55-0.97] and estrogen receptor β (−) tumors (OR, 0.60; 95% CI, 0.42-0.84), with significantly different risks for estrogen receptor β (−)and estrogen receptor β ( + ) tumors (P for heterogeneity = 0.04). | The protective association between EL and BC was significantly different between estrogen receptor β (−) and estrogen receptor β (+) tumors and most evident in tumors that express estrogen receptor α but not estrogen receptor β. | (Sonestedt et al., 2008) | |
| Germany | Meta Analysis | 11 prospective cohort studies and 10 CCS (total 21 studies) | A systematic MEDLINE search to identify epidemiologic studies published between 1997 and August 2009. | Pooled risk estimates (REs) for total lignan exposure, dietary lignan intake, enterolignan exposure, and EL in blood or urine were calculated. | BC risk was also inversely associated with enterolignan exposure (4 studies; RE: 0.84; 95% CI: 0.71, 0.97) but not with blood or urine EL concentrations. The associations were not significantly different between Estrogen receptor-status subgroups (6 studies). | Authors concluded that high lignan exposure may be associated with a reduced BC risk in PoM women | (Buck et al., 2010) | |
| Germany | Follow-up Study | 2653 PoM BC patients | A self-administered validated 176-items FFQ An intake in grams per day (g day–1) was calculated for each food item. | Bioavailable ED and EL were calculated per 100 g of ingested foods. | High estimated EL and ED levels were associated with significantly lower overall mortality (highest quintile, HR= 0.60, 95% CI= 0.40–0.89, PTrend= 0.02 and HR= 0.63, 95% CI= 0.42–0.95, PTrend= 0.02, respectively) | PoM BC patients with high estimated enterolignans (ED and EL) may have a better survival | (Buck et al., 2011a; 2011b) | |
| Denmark | Cohort Study (PD) | 24,697 PoM women | FFQ, A lifestyle questionnaire, Plasma samples collection. | Plasma EL by TR-FIA | When comparing women with EL levels above the median (20.5 nmol/l) to those with lower levels, decreased HR were seen for both ACM (HR: 0.47; 95% CI: 0.32–0.68) and BCRM (HR: 0.56; 95% CI: 0.36–0.87). | Higher prediagnostic plasma levels of ELwere found related to lower mortality among BC patients. | (Olsen et al, 2011) | |
| Germany | Prognosis Study | 1140 PoM BC patients | Clinical and pathologic records. Serum samples collection. | Serum EL by TR-FIA | Higher serum EL levels were associated with significantly reduced HRs for death (HR per 10 nmol/L increment, 0.94; P .04; HR for the highest quartile, 0.58; 95% CI, 0.34 to 0.99). The highest quartile of serum EL was associated with a significantly reduced risk of death only for estrogen receptor – tumors (HR, 0.27; 95% CI, 0.08 to 0.87). | PoM patients with BC who have high serum EL levels may have better survival. | (Buck et al., 2011a; 2011b) | |
| Italy | Cohort Study (RD) | 300 Patients operated on for BC | Operation and subsequent follow up, Blood samples collection. | Serum EL by TR-FIA. | An association between a decreased mortality risk and EL levels ≥ 10 nmol/l was found in respect to both all-cause and breast cancer-specific mortality. BCRM risk remained constantly lower in those patients with higher EL levels. | ED and EL might play an important role in reducing all-cause and cancer-specific mortality of the patients operated on for BC. | (Guglielmini et al., 2012) | |
| Germany | CCS (RD) | 1250/ 2164 PoM women | Self-administered FFQ, Serum samples collection. | Serum EL by TR-FIA. | Significant inverse association between serum EL and PoM BC risk, which was stronger for estrogen receptor− progesterone receptor− than for estrogen receptor + progesterone receptor + tumors but not differential by further expression of human epidermal growth factor receptor 2. | Study supported an inverse association between higher serum EL levels and PoM BC risk. | (Zaineddin et al.,2012) | |
| Germany | Prognosis Follow-up Study (PD) | 2182 PoM BC patients | Clinical and pathologic records, Serum samples collection. | Serum EL by TR-FIA. | High EL concentrations were significantly associated with lower ACM (per 10 nmol L−1: HR 0.94, 95% CI 0.90–0.98), BCSM(HR 0.94, 0.89–0.99), and DDFS (HR 0.94, 0.90–0.98). | Study showed that high lignan exposure (EL) is associated with reduced mortality in BC patients. | (Seibold et al.,2014) | |
| Prostate cancer | Sweden | CCS (RD) | 1499 / 1130 men Serum collection 209/214 men | FFQ Serum samples collection |
Serum EL by TR-FIA | Intermediate serum levels of EL were associated with a decreased risk of PC. The ORs comparing increasing quartiles of serum EL concentration to the lowest quartile were, respectively, 0.28 (95% CI: 0.15–0.55), 0.63 (95% CI: 0.35–1.14) and 0.74 (95% CI: 0.41–1.32) | Results supported the hypothesis that certain foods high in PhE are associated with a lower risk of PC | (Hedelin et al.,2006) |
| Scotland | CCS (RD) | 433/483 men | A validated FFQ Blood samples collection. | Serum EL by isotope dilution GC-MS | A significant inverse associations was found with increased serum concentrations of EL (adjusted OR 0·40, 95% CI 0·22, 0·71) and with the consumption of soy foods (adjusted OR 0·52, 95% CI 0·30, 0·91). | Study supported the hypotheses that soy foods and EL protect against PC in older Scottish men. | (Heald et al.,2007) | |
| Scotland | CCS (RD) | 247 PC/ 125 BPH/274 men | Serum samples collection, DNA extraction. | Serum EL by isotope dilution GC-MS | TT homozygotes who had low serum EL concentrations (below median) were more likely to have PC (OR= 2.90; 95% CI, 1.28–6.57) than individuals with CC/CT genotype and high serum EL concentrations (above median). | PC susceptibility was associated with TT genotype of SNP rs10993994 and increased risk of PC was modified by serum EL concentrations. | (Ho et al., 2012) | |
| USA | Multisite Phase II RCT | 147 PC patients | 30 g/day of whole-ground flaxseed supplementation for ~30 days before surgery. Pre and post surgery urine samples and tumor tissues collection. | Urinary EL by HPLC | Total urinary enterolignans and EL were significantly and inversely correlated with Ki67 in the tumor tissue (ρ= −0.217, P = .011, and ρ = −0.230, P = .007, respectively), and a near-significant inverse association was observed for ED (q =− 0.159, P = .064). An inverse association was observed between EL and VEGF (q= −0.143, P = .141), | Flaxseed-derived EL is inversely associated with tumor cell proliferation in men with localized PC | (Azrad et al.,2013) | |
| China | Meta-analysis | 2 Cohort and 9 CCS on PhE intake and 8 studies on serum concentrations of PhE | Relevant publications were identified in the MEDLINE database using PubMed, Web of Science, and the Cochrane Library up to June 2014 | The ORs were used as the common measure of association across studies by considering the RRs as ORs. | In stratified analysis, high genistein and daidzein intake and increased serum concentration of EL were associated with a significant reduced risk of PC. | Increased serum concentration of EL was associated with a significant reduced risk of PC | (He et al., 2015) | |
| Endometrial cancer | Denmark | Case Cohort Study | 173/149 women | SFQ, Blood samples collection. | Plasma EL by TR-FIA | A 20 nmol/l higher plasma concentration of EL was associated with a nonsignificant lower risk of EMC (IRR 0·93, 95% CI 0·84, 1·04) | Authors found some support for a possible inverse association between plasma EL concentration and EMC incidence. | (Aarestrup et al.,2013) |
| Colorectal cancer | Netherlands | CCS (RD) | 532/503 | SFQ, Blood samples collection. | Plasma EL by LC-MS | Plasma ED concentrations were associated with a reduction in CRA risk after adjustment for confounding variables, OR (95% CI) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), and 0.53 (0.320.88) with a significant trend (P = 0.01) through the quartiles. EL’s reduction in risk was not statistically significant (P for trend = 0.09). | Substantial reduction in CRA risk among subjects with high plasma concentrations of enterolignans | (Kuijsten et al.,2006) |
| United Kingdom | CCS (PD) | 221/886 | Prospective collection of lifestyle and 7-d records of diet | 509 food items by LC-MS | Among women, CRC risk was inversely associated with EL (OR: 0.33; 95% CI: 0.14, 0.74) and total enterolignans (OR: 0.32; 95% CI: 0.13, 0.79), with a positive trend detected for SECO (OR: 1.60; 95% CI: 0.96, 2.69). | EL, found at high concentration in eggs and dairy products, may influence the risk of CRC among women. | (Ward et al, 2010) | |
| Denmark | Case Cohort Study | 244 CoC/137 RC/370 | Lifestyle questionnaire, A 192-item FFQ, Blood samples collection. | Plasma EL by TR-FIA | For each doubling in EL concentration there was lower risk of colon cancer among women [IRR (95% CI) = 0.76 (0.60–0.96)] and a tendency toward lower risk of rectal cancer [IRR (95% CI) = 0.83 (0.60–1.14)]. | Study supported the hypothesis that EL may protect against colon cancer in women | (Johnsen et al.,2010) | |
| Gastric cancer | Korea | CCS | 462/670 | Meta-analysis. | Plasma EL by TR-FIA | Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low PhE levels (p interaction ≤0.05). | Interaction between CRK gene and PhE modify gastric cancer risk. | (Yang et al., 2012) |
| Lung cancer | USA | CCS (RD) | 1674/1735 | FFQs Quantification of dietary intake of 12 individual PhE | Intake of specific PhE was calculated using the DIETSYS + Plus version 5.9 dietary analysis program. | High intake of the EL and ED and use of hormone therapy were associated with a 50% (OR, 0.50; 95% CI, 0.31-0.68; P = .04 for interaction) reduction in risk of lung cancer. | Study supported growing epidemiologic evidence that PhE (EL, ED) are associated with a decrease in risk of lung cancer | (Schabath et al.,2005) |
CCS= Case Control Study, RD= Retrospective Design, PD= Prospective Design, PrM- Premenopausal, PoM= Postmenopausal, SQ = Structured Questionnaire, FFQ= Food Frequency Questionnaire, BC= Breast Cancer, PhE= Phytoestrogens, GC-MS = Gas Chromatography-Mass Spectroscopy, TR-FIA= Time Resolved-Fluoroimmunoassay, OR= Odds Ratio, CI= Confidence Interval, IRR= Incidence Rate Ratio, LC-MS = Liquid Chromatography-Mass Spectroscopy, SARFQ= self-administered risk factor questionnaire, SADHQ= Self-Administered Diet History Questionnaire, RR= Relative Risk, HR= Hazard Ratio, BCSS= Breast Cancer-Specific Survival, BCRM= Breast Cancer Related Mortality, BCSM= Breast Cancer Specific Mortality, BCUM= Breast Cancer Unrelated Mortality, ACM= All-Cause Mortality, PC= Prostate Cancer, BPH= Benign Prostatic Hyperplasia, RCT= Randomized Controlled Trial, SFQ= self-administrated questionnaires, HPLC= high-performance liquid chromatography, IHC= Immunohistochemistry, EMC= Endometrial Cancer, CRA= Colorectal adenoma, CRC= Colorectal Cancer, CoC= Colon Cancer, IRR= Incidence Rate Ratios, RC= Rectal Cancer.