Enterolactone

The highest-evidence application — and the honest headline is that it is inconsistent. A pooled meta-analysis found a modest inverse association of enterolignans with breast-cancer risk restricted to postmenopausal women ^{4Reference 4Buck K et al. · 2010Meta-analysisMeta-analyses of lignans and enterolignans in relation to breast-cancer riskView study →}, while a well-powered prospective serum study found no protective association at all ^{5Reference 5Zeleniuch-Jacquotte A et al. · 2004Circulating enterolactone and risk of breast cancer: a prospective study in New YorkView study →}.

For prognosis, higher enterolactone is associated with lower all-cause and breast-cancer mortality in postmenopausal patients ^{6,8Reference 6Seibold P et al. · 2014Meta-analysisEnterolactone concentrations and prognosis after postmenopausal breast cancer: effect modification and meta-analysisView study →Reference 8Micek A et al. · 2021Meta-analysisDietary phytoestrogens and biomarkers of their intake in relation to cancer survival and recurrence: a systematic review with meta-analysisView study →}, but one meta-analysis found the direction differs by menopausal status (postmenopausal benefit; a premenopausal signal toward higher mortality) ^{7Reference 7Liu Z et al. · 2021Meta-analysisLignan intake and enterolactone concentration and prognosis of breast cancer: a systematic review and meta-analysisView study →}.

Gap: entirely observational and biomarker-based — serum enterolactone co-tracks a high-fiber, plant-rich, lower-BMI, health-conscious phenotype, so residual confounding is unresolved, effect sizes are small, and no isolate RCTs exist ^{5,7Reference 5Zeleniuch-Jacquotte A et al. · 2004Circulating enterolactone and risk of breast cancer: a prospective study in New YorkView study →Reference 7Liu Z et al. · 2021Meta-analysisLignan intake and enterolactone concentration and prognosis of breast cancer: a systematic review and meta-analysisView study →}.

Low serum enterolactone was associated with higher risk of acute coronary events in a prospective Finnish study ^{9Reference 9Vanharanta M et al. · 1999ObservationalRisk of acute coronary events according to serum enterolactone: a prospective population-based case-control studyView study →} and with higher cardiovascular and all-cause mortality in the Kuopio cohort ^{10Reference 10Vanharanta M et al. · 2003Risk of cardiovascular-disease-related and all-cause death according to serum enterolactone: Kuopio Ischaemic Heart Disease Risk Factor StudyView study →}; higher enterolactone was associated with lower mortality among people with type 2 diabetes in a Danish cohort ^{11Reference 11Eriksen AK et al. · 2019ObservationalPre-diagnostic plasma enterolactone and lower mortality among individuals with type 2 diabetes: Danish Diet, Cancer and Health cohortView study →}.

Gap: the same biomarker confound in a different disease — enterolactone is a proxy for a high-fiber/Mediterranean dietary pattern that is independently cardioprotective, and no interventional evidence shows that raising enterolactone changes outcomes ^{9,10Reference 9Vanharanta M et al. · 1999ObservationalRisk of acute coronary events according to serum enterolactone: a prospective population-based case-control studyView study →Reference 10Vanharanta M et al. · 2003Risk of cardiovascular-disease-related and all-cause death according to serum enterolactone: Kuopio Ischaemic Heart Disease Risk Factor StudyView study →}.

The largest Nordic nested case-control study found no association between circulating enterolactone and prostate-cancer risk ^{12Reference 12Stattin P et al. · 2002ObservationalCirculating enterolactone and prostate-cancer risk: a Nordic nested case-control studyView study →}.

Gap: predominantly null, with small numbers and the same biomarker confound — included for honest completeness, not as a positive signal ^{12Reference 12Stattin P et al. · 2002ObservationalCirculating enterolactone and prostate-cancer risk: a Nordic nested case-control studyView study →}.

Enterolactone binds ERα/ERβ weakly and behaves in a SERM-like (mixed agonist/antagonist) fashion ^{13Reference 13Cosentino M et al. · 2007Estrogenic activity of 7-hydroxymatairesinol potassium acetate and of its active metabolite enterolactone in MCF-7 cellsView study →}, and molecular modeling places lignans as aromatase (CYP19) ligands, supporting weak modulation of estrogen biosynthesis ^{14Reference 14Karkola S · 2009The binding of lignans, flavonoids and coumestrol to CYP450 aromatase: a molecular-modelling studyView study →}.

Gap: affinities are orders of magnitude below estradiol, the direction is concentration-dependent, and this is mechanistic, not clinical ^{13,14Reference 13Cosentino M et al. · 2007Estrogenic activity of 7-hydroxymatairesinol potassium acetate and of its active metabolite enterolactone in MCF-7 cellsView study →Reference 14Karkola S · 2009The binding of lignans, flavonoids and coumestrol to CYP450 aromatase: a molecular-modelling studyView study →}.

Enterolactone is described as a stronger radical scavenger than its parent lignans, and flaxseed lignan (SDG) reduces NF-κB signaling and mammary inflammation in models ^{15Reference 15Bowers LW et al. · 2019The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NF-κB signalling and inhibits mammary tumour growthView study →}.

Gap: preclinical only, and much of it is on precursor lignans rather than isolated enterolactone — a human flax-lignan trial found no change in antioxidant capacity ^{15Reference 15Bowers LW et al. · 2019The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NF-κB signalling and inhibits mammary tumour growthView study →}.