Concern has been raised about the effects of phytoestrogenic plants and plant extracts on estrogen-sensitive cancers, largely based on in vitro and animal research. Soy (Glycine max) and other legumes and their isoflavones, notably genistein and daidzein, are the plants and constituents most studied, including the potential importance of metabolism of these isoflavones by gut flora to equol and its cogeners. Flax (Linum usitatissimum) and its lignans, notably secoisolariciresinol, is also discussed. Essentially, all existing epidemiologic and clinical trial research shows either benefit or absence of harm from these compounds, with some subtleties about dose and equol or enterolactone formation potentially being important. This paper will review the human research and discuss why it is at odds with in vitro research.
Get full access to this article
View all access options for this article.
References
1.
CornwellT, CohickW, RaskinI. Dietary phytoestrogens and health. Phytochemistry, 2004; 65:995–1016.
2.
HelferichWG, AndradeJE, HoaglandMS. Phytoestrogens and breast cancer: A complex story. Inflammopharmacology, 2008; 16:219–226.
3.
AllredCD, AllredKF, JuYH, et al.Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner. Cancer Res, 2001; 61:5045–5050.
4.
MageePJ, RowlandIR. Phyto-oestrogens, their mechanism of action: Current evidence for a role in breast and prostate cancer. Br J Nutr, 2004; 91:513–531.
5.
KuiperGG, LemmenJG, CarlssonB, et al.Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor b. Endocrinology, 1998; 139:4252–4263.
6.
BöttnerM, ThelenP, JarryH. Estrogen receptor beta: Tissue distribution and the still largely enigmatic physiological function. J Steroid Biochem Mol Biol, 2014; 139:245–251.
7.
ChangEC, CharnTH, ParkSH, et al.Estrogen Receptors alpha and beta as determinants of gene expression: Influence of ligand, dose, and chromatin binding. Mol Endocrinol, 2008; 22:1032–1043.
8.
PihlajamaaP, ZhangFP, SaarinenL, et al.The phytoestrogen genistein is a tissue-specific androgen receptor modulator. Endocrinology, 2011; 152:4395–4405.
9.
ThelenP, WuttkeW, Seidlová-WuttkeD. Phytoestrogens selective for the estrogen receptor beta exert anti-androgenic effects in castration resistant prostate cancer. J Steroid Biochem Molec Biol, 2014; 139:290–293.
10.
SimonsR, GruppenH, BoveeTF, et al.Prenylated isoflavonoids from plants as selective estrogen receptor modulators (phytoSERMs). Food Funct, 2012; 3:810–827.
11.
SetchellKD, ClericiC, LephartED, et al.S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr, 2005; 81:1072–1079.
12.
MatthiesA, BlautM, BrauneA. Isolation of a human intestinal bacterium capable of daidzein and genistein conversion. Appl Environ Microbiol, 2009; 75:1740–1744.
13.
JinJS, KitaharaM, SakamotoM, et al.Slackia equolifaciens sp. nov., a human intestinal bacterium capable of producing equol. Int J Syst Evol Microbiol, 2010; 60:1721–1724.
14.
MaruoT, SakamotoM, ItoC, et al.Adlercreutzia equolifaciens gen. nov., sp. nov., an equol-producing bacterium isolated from human faeces, and emended description of the genus Eggerthella. Int J Syst Evol Microbiol, 2008; 58:1221–1227.
15.
TakagakiA, NanjoF. Biotransformation of (-)-epigallocatechin and (-)-gallocatechin by intestinal bacteria involved in isoflavone metabolism. Biol Pharm Bull, 2015; 38:325–330.
16.
DuncanAM, Merz-DemlowBE, XuX, et al.Premenopausal equol excretors show plasma hormone profiles associated with lowered risk of breast cancer. Cancer Epidemiol Biomarkers Prev, 2000; 9:581–586.
17.
AtkinsonC, SkorHE, Dawn FitzgibbonsE, et al.Urinary equol excretion in relation to 2-hydroxyestrone and 16alpha-hydroxyestrone concentrations: An observational study of young to middle-aged women. J Steroid Biochem Mol Biol, 2003; 86:71–77.
18.
Virk-BakerMK, BarnesS, KrontirasH, NagyTR. S-(-)equol producing status not associated with breast cancer risk among low isoflavone consuming US postmenopausal women undergoing a physician recommended breast biopsy. Nutr Res, 2014; 34:116–125.
19.
AkazaH, MiyanagaN, TakashimaN, et al.Is daidzein non-metabolizer a high risk for prostate cancer? A case-controlled study of serum soybean isoflavone concentration. Jpn J Clin Oncol, 2002; 32:296–300.
20.
AkazaH, MiyanagaN, TakashimaN, et al.Comparisons of percent equol producers between prostate cancer patients and controls: Case-controlled studies of isoflavones in Japanese, Korean and American Residents. Jpn J Clin Oncol, 2004; 34:86–89.
21.
GayaP, MedinaM, Sánchez-JiménezA, LandeteJM. Phytoestrogen metabolism by adult human gut microbiota. Molecules, 2016; 21:E103–4.
22.
RenGY, ChenCY, ChenWG, et al.The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1. Appl Physiol Nutr Metab, 2016; 41:1303–1310.
23.
AdolpheJL, WhitingSJ, JuurlinkBH, et al.Health effects with consumption of the flax lignan secoisolariciresinol diglucoside. Br J Nutr, 2010; 103:929–938.
24.
DelmanDM, FabianCJ, KimlerBF, et al.Effects of flaxseed lignan secoisolariciresinol diglucosideon preneoplastic biomarkers of cancer progression in a model of simultaneous breast and ovarian cancer development. Nutr Cancer, 2015; 67:857–864.
25.
WooHD, ParkS, OhK, et al.Diet and cancer risk in the Korean population: A meta-analysis. Asian Pac J Cancer Prev, 2014; 15:8509–8519.
26.
LiuXO, HuangYB, GaoY, et al.Association between dietary factors and breast cancer risk among Chinese females: Systematic review and meta-analysis. Asian Pac J Cancer Prev, 2014; 15:1291–1298.
27.
ZhongX, ZhangC. Soy food intake and breast cancer risk: A meta-analysis. Wei Sheng Yan Jiu, 2012; 41:670–676 [in Chinese].
28.
QinLQ, XuJY, WangPY, HoshiK. Soyfood intake in the prevention of breast cancer risk in women: A meta-analysis of observational epidemiological studies. J Nutr Sci Vitaminol (Tokyo), 2006; 52:428–436.
29.
ChenM, RaoY, ZhengY, et al.Association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women: A meta-analysis of epidemiological studies. PLOS ONE, 2014; 9:e8928–8.
30.
DongJY, QinLQ. Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. Breast Cancer Res Treat, 2011; 125:315–323.
31.
AndresS, AbrahamK, AppelKE, LampenA. Risks and benefits of dietary isoflavones for cancer. Crit Rev Toxicol, 2011; 41:463–506.
32.
ZhangM, WangK, ChenL, et al.Is phytoestrogen intake associated with decreased risk of prostate cancer? A systematic review of epidemiological studies based on 17,546 cases. Andrology, 2016; 4:745–756.
33.
HwangYW, KimSY, JeeSH, et al.Soy food consumption and risk of prostate cancer: A meta-analysis of observational studies. Nutr Cancer, 2009; 61:598–606.
34.
YanL, SpitznagelEL. Soy consumption and prostate cancer risk in men: A revisit of a meta-analysis. Am J Clin Nutr, 2009; 89:1155–1163.
35.
van DieMD, BoneKM, WilliamsSG, PirottaMV. Soy and soy isoflavones in prostate cancer: A systematic review and meta-analysis of randomized controlled trials. BJU Int, 2014; 113:E119–E130.
36.
ZhangQ, FengH, QluwakemiB, et al.Phytoestrogens and risk of prostate cancer: An updated meta-analysis of epidemiologic studies. Int J Food Sci Nutr, 2016Aug9 [Epub ahead of print].
37.
TouillaudMS, PillowPC, JakovljevicJ, et al.Effect of dietary intake of phytoestrogens on estrogen receptor status in premenopausal women with breast cancer. Nutr Cancer, 2005; 51:162–169.
38.
LinkLB, CancholaAJ, BernsteinL, et al.Dietary patterns and breast cancer risk in the California Teachers Study cohort. Am J Clin Nutr, 2013; 98:1524–1532.
39.
BagliaML, ZhengW, LiH, et al.The association of soy food consumption with the risk of subtype of breast cancers defined by hormone receptor and HER2 status. Int J Cancer, 2016; 139:742–748.
40.
ZhangC, HoSC, LinF, et al.Soy product and isoflavone intake and breast cancer risk defined by hormone receptor status. Cancer Sci, 2010; 101:501–507.
41.
GuoX, CaiQ, BaoP, et al.Long-term soy consumption and tumor tissue MicroRNA and gene expression in triple-negative breast cancer. Cancer, 2016; 122:2544–2551.
42.
WooHD, ParkKS, RoJ, KimJ. Differential influence of dietary soy intake on the risk of breast cancer recurrence related to HER2 status. Nutr Cancer, 2012; 64:198–205.
43.
LowcockEC, CotterchioM, BoucherBA. Consumption of flaxseed, a rich source of lignans, is associated with reduced breast cancer risk. Cancer Causes Control, 2013; 24:813–816.
44.
IngramD, SandersK, KolybabaM, LopezD. Case-control study of phyto-oestrogens and breast cancer. Lancet, 1997; 350:990–994.
45.
McCannSE, MoysichKB, FreudenheimJL, et al.The risk of breast cancer associated with dietary lignans differs by CYP17 genotype in women. J Nutr, 2002; 132:3036–3041.
46.
PillerR, Verla-TebitE, Wang-GohrkeS, et al.CYP17 genotype modifies the association between lignan supply and premenopausal breast cancer risk in humans. J Nutr, 2006; 136:1596–1603.
47.
SaarinenNM, TuominenJ, PylkkänenL, SanttiR. Assessment of information to substantiate a health claim on the prevention of prostate cancer by lignans. Nutrients, 2010; 2:99–115.
48.
SartippourMR, RaoJY, AppleS, et al.A pilot clinical study of short-term isoflavone supplements in breast cancer patients. Nutr Cancer, 2004; 49:59–65.
49.
NikanderE, KilkkinenA, Metsa-HeikkilaM, et al.A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol, 2003; 101:1213–1220.
50.
Van PattenCL, OlivottoIA, ChambersGK, et al.Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: A randomized, controlled clinical trial. J Clin Oncol, 2002; 20:1449–1455.
51.
QuellaSK, LoprinziCL, BartonDL, et al.Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol, 2000; 18:1068–1074.
52.
MahadyGB. Do soy isoflavones cause endometrial hyperplasia?. Nutr Rev, 2005; 63:392–397.
53.
UnferV, CasiniML, CostabileL, et al.Endometrial effects of long-term treatment with phytoestrogens: A randomized, double-blind, placebo-controlled study. Fertil Steril, 2004; 82:145–148.
54.
FritzH, SeelyD, FlowerG, et al.Soy, red clover, and isoflavones and breast cancer: A systematic review. PLOS ONE, 2013; 8:e819–6.
55.
FlowerG, FritzH, BalneavesLG, et al.Flax and breast cancer: A systematic review. Integr Cancer Ther, 2014; 13:181–192.
56.
McCannSE, EdgeSB, HicksDG, et al.A pilot study comparing the effect of flaxseed, aromatase inhibitor, and the combination on breast tumor biomarkers. Nutr Cancer, 2014; 66:566–575.
57.
FischerL, MahoneyC, JeffcoatAR, et al.Clinical characteristics and pharmacokinetics of purified soy isoflavones: Multiple-dose administration to men with prostate neoplasia. Nutr Cancer, 2004; 48:160–170.
58.
HussainM, BanerjeeM, SarkarFH, et al.Soy isoflavones in the treatment of prostate cancer. Nutr Cancer, 2003; 47:111–117.
59.
van DieMD, BoneKM, WilliamsSG, PirottaMV. Soy and soy isoflavones in prostate cancer: A systematic review and meta-analysis of randomized controlled trials. BJU Int, 2014; 113:E119–E130.
