Title: Phytoestrogens Friend or foe?

Key words: oestrogen, oestrogenic activity, post-menopausal women, isoflavones, lignans, coumestans, stilbenes, breast cancer, prostate cancer, bowel cancer, coronary heart disease, LDL-cholesterol, HDL-cholesterol, atherosclerosis, soy protein, antioxidant, mentstrual cycle, bone density, infant feeding, fertility, thyroid

Date: May 2001

Category: Micronutrients

Type: Article

Author: Pam Brown

 

Phytoestrogens Friend or foe?

Phytoestrogens are naturally-occurring polyphenolic plant compounds with oestrogenic or anti-oestrogenic activity. They have a similar structure to 17-oestradiol and can therefore bind to oestrogen receptors. Phytoestrogens have weak oestrogenic effects compared with oestradiol, but may be present in significant amounts in those eating a phytoestrogen-rich diet. Individual phytoestrogens have different binding capacities and stimulation at ER- and ER- receptors. Total effects depend on relative amounts of phytoestrogen and oestradiol in circulation. Oestrogenic effects of phytoestrogens predominate in oestrogen-depleted post-menopausal women, while oestrogen antagonist actions occur in those with oestrogen excess eg pre-menopausal obese women1.

There are three main classes of phytoestrogens:

Isoflavones and lignans are extensively metabolised by gut flora. The amount of active equol absorbed following isoflavone metabolism appears to vary inversely with the fat content of the diet3.

 

Friend

Population-based studies suggest that phytoestrogen-rich diets may be protective against breast, prostate and bowel cancer, and cardiovascular disease, and improve some menopausal problems4. Countries with higher phytoestrogen intake from soya isoflavones show lower incidence of breast cancer (52/100,000 compared with 1999/100,000 in UK), CHD, prostatic disease and colon cancer5.

Coronary heart disease6

Phytoestrogens help reduce the incidence of coronary heart disease (CHD) by:

Animal studies show that feeding isoflavone-rich diets reduces LDL-cholesterol and increases HDL-cholesterol. Consumption of soy containing isoflavone phytoestrogens reduces lipid peroxidation and increases resistance of LDL to oxidation in vivo, which may markedly decrease risk of atherosclerosis and cardiovascular disease and also cancer7. A meta-analysis of 38 human clinical studies8 using isolated soya protein or textured soya protein supplementation demonstrated a mean reduction of 9.3% in cholesterol and 12.9% decrease in LDL-cholesterol with intakes of 47g soya protein/day. Largest reductions were seen in those in the highest initial quartile of cholesterol/LDL levels. Hypocholesterolaemic effects have also been demonstrated using 60g/day textured soya protein in men without effects on hormonal status.

Both in vitro9 and in vivo, phytoestrogens have been shown to have weak antioxidant effects, increasing resistance of LDL to oxidation. Genistein inhibits tyrosine kinase, important in preventing plaque propagation; other phytoestrogens also have anti-proliferative properties, and beneficial effects on platelet aggregation6.

Hormone modulation and disease

Pre-menopausal women consuming high isoflavone diet (45mg isoflavones/day) had lengthening of the follicular phase of the menstrual cycle in some studies; this would extrapolate to lower life-time exposure to oestrogen, which may explain some of the decreased risk of breast cancer in Japanese women10. Increasing phytoestrogen intake decreases hot flushes in some studies, especially using supplements, but is less effective in preventing vaginal dryness11,12.

Cancer

Reductions in the risk of breast, colon, prostate and other cancers have been proposed in those eating a high phytoestrogen diet5. Inhibition of cancer cell growth by soya isoflavones may occur by a variety of different mechanisms13,14,15,16,17:

Prospective and case-control studies have shown decreased risk of breast cancer in those consuming Miso soup, tofu or soya bean protein. Early life exposure to phyoestrogens may be particularly important for prevention13. Genistein has antineoplastic effects with inhibition of cellular proliferation and angiogenesis15,17.

Countries with low incidence of prostate cancer have high phytoestrogen intakes14. In vitro studies have shown that genistein can inhibit the growth of prostate cancer cell lines14. Isoflavone rich diets reduce the incidence of prostate cancer in rats however studies in humans have not yet demonstrated lower risk14.

Osteoporosis18

Oestrogen has an important role in preventing bone loss in postmenopausal women. Studies have shown reduced bone resorption with increased ingestion of isoflavone19, and markers of bone turnover decrease by 10-24% in postmenopausal women eating 60g soya protein/day. Postmenopausal women fed soya versus casein protein20 or 45g soy enriched bread21 or 40mg clover isoflavones22 demonstrated increased bone mineral density at the lumbar spine only.

Or foe?

Davis4 reminds us that it is naïve to assume that only benefits will accrue from phytoestrogen exposure. Differences in individual gut microflora, absorption and metabolism make the activity of phytoestrogens unpredictable. Epidemiological studies show effects of isoflavone intake from foods; these effects cannot be extrapolated to concentrated isoflavone supplements which may have beneficial or detrimental effects.

In animals, Clover disease due to adverse effects of phytoestrogens was shown to cause infertility in sheep11, and veno-occlusive disease and infertility in captive cheetah were due to phytoestrogens in their diet11. In vitro studies have shown that genistein but not daidzein can induce structural chromosomal damage such as chromatid breaks, gaps and interchanges24. These may be beneficial, increasing apoptosis or increase risk of cancer24.

Isoflavones are polyphenols which act on many biochemical targets, not just oestrogen receptors, therefore interference with effects of tamoxifen is unlikely; however, oophorectomised women may be at increased risk of breast cancer recurrence on a phytoestrogen-containing diet13.

Potential dangers associated with high soy consumption in humans include phytate content interfering with absorption of minerals, goitrogenic effects, carcinogenic effects on breast tissue and toxic effects from soy-based infant feeds. Protease inhibitors in soya may cause pancreatic hyperplasia in animals, but the relationship to pancreatic cancer remains unproven. Other sources stress that far from being a problem, phytic acid in phytoestrogens is a potent antioxidant and hydroxyl radical scavenger, metal-chelator and enhancer of natural killer cell activity.

Infant feeding

Concerns have been raised by levels of phytoestrogens, mainly isoflavones, in soy-based infant-formulas. 4 month-olds ingest 4.5-8mg/kg body weight/day, 6-11 times more than the levels shown to have hormone-like effects in adults25. This dose is said to provide equivalent of 5 combined oral contraceptive pills per day26. Studies have shown that isoflavones are absorbed and metabolised by the infant27. Growth appears to be normal with no changes in timing of puberty or subsequent fertility rates of those who were fed soy formulae as infants28. Other studies have shown increased infections and lower antibody responses to immunisations compared with breast or ordinary formula-fed babies and hypothyroidism has been reported11. At present there is little information on other potential risks or benefits of high phytoestrogen intakes in infants but there may be long-term effects on risk of hormone-dependent disease in later life29 as was found previously with stilboestrol30.

Pregnancy and infertility

Isoflavones have not been demonstrated to cause infertility in humans. High levels of isoflavone phytoestrogens are found in pregnant Japanese women and there is free transfer to the infants31. In one study, vegetarian mothers had 5 times greater risk of giving birth to males with hypospadias, an effect which the authors attributed to increased intake of phytoestrogens32. Omnivores who supplemented with iron during the first half of pregnancy had double the risk of hypospadias than non-supplementing omnivorous mothers32.

Interference with normal thyroid function

Isoflavones can act as substrate for thyroid peroxidase, leading to depletion of iodine and hypothyroidism33. Hypothyroidism has been reported in infants fed soya formula34.

 

 

Conclusion

Thus it can be seen that there are still many unanswered questions regarding the actions of phytoestrogens in the diet, and particularly where these are used in more concentrated forms as supplements. Phytoestrogens are a disparate group of compounds and much further research is needed before we can say whether individual phytoestrogens are friend or foe.

 

References

  1. Adlercreutz H Phyto-oestrogens and Western diseases Ann Med 1997; 29:95-120
  2. Mazur W Phytoestrogen content in foods Bailleres Clin Endocr & Metabol 1998; 12:729-42
  3. Rowland IR et al Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr and Cancer 2000; 36:27-32
  4. Davis SR et al Phytoestrogen in health and disease. Recent Progress in Hormone Res 1999; 54: 185-210
  5. Adlercreutz H Epidemiology of phytoestrogens Bailleres Clin Endocr & Metabol 1998; 12:605-23
  6. Clarkson TB, Anthony MS Phytoestrogens and coronary heart disease Bailleres Clin Endocr & Metabol 1998; 12:589-604
  7. Wiseman H et al Isoflavone phytoestrogens consumed in soy decrease F(2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans Am J Clin Nutr 2000; 72:395-400
  8. Anderson JW et al Meta-analysis of the effects of soy protein intake on serum lipids NEJM 1995; 333: 276-82
  9. Tikkanen MJ, Adlercreutz H Dietary soy-derived isoflavone phytoestrogens. Could they have a role in coronary heart disease prevention? Biochem Pharmacol 2000; 60(1):1-5
  10. Cassidy A et al Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women Am J Clin Nutr 1994; 60:333-40
  11. Whitten PL, Naftolin F Reproductive actions of phytoestrogens Bailleres Clin Endocr & Metabol 1998; 12:667-90
  12. Eden J Phytoestrogens and the menopause Bailleres Clin Endocr & Metabol 1998; 12:581-7
  13. Barnes S Phytoestrogens and breast cancer Bailleres Clin Endocr & Metabol 1998; 12:559-79
  14. Griffiths K et al Phytoestrogens and diseases of the prostate gland Bailleres Clin Endocr & Metabol 1998; 12:625-47
  15. Fotsis T et al Phytoestrogens and inhibition of angiogenesis Bailleres Clin Endocr & Metabol 1998; 12:649-66
  16. Thompson L Experimental studies on lignans and cancer Bailleres Clin Endocr & Metabol 1998; 12:691-705
  17. Messina M, Bennink M Soyfoods, isoflavones and risk of colonic cancer: a review of the in vitro and in vivo data Bailleres Clin Endocr & Metabol 1998; 12:707-28
  18. Anderson JJB, Garner SC Phytoestrogens and bone Bailleres Clin Endocr & Metabol 1998; 12:543-557
  19. Lissin LW, Cooke JP Phytoestrogens and cardiovascular health J Am Coll Cardiol 2000; 35(6):1403-10
  20. Scheiber MD, Rebar RW Isoflavones and postmenopausal bone health: a viable alternative to oestrogen therapy? Menopause 1999; 6(3):233-41
  21. Potter SM et al Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women Am J Clin Nutr 1998; 6(Suppl):1375S-1379S
  22. Dalais FS et al Dietary soy supplementation increases vaginal cytology maturation index and bone mineral content in postmenopausal women Am J Clin Nutr 1998; 68:1518S
  23. Atkinson C et al The effects of isoflavone phytoestrogens on bone: preliminary results from a large randomized controlled trial Abstract Br Menopause Soc 2000
  24. Adams 1995
  25. Kulling SE et al the phyoestrogens coumoestrol and genistein induce structural chromosomal aberrations in cultured human peripheral blood lymphocytes. Arch Toxicol 1999; 73:50-4
  26. Setchell KD et al Exposure of infants to phyto-oestrogens from soy-based infant formula Lancet 1997; 350: 23-7
  27. Fitzpatrick N Z Med J 1995; 318
  28. Irvine CH et al Phytoestrogens in soy-based infant foods: concentrations, daily intake, and possible biological effects Proc Soc Exper Biol Med 1998; 217:247-53
  29. Klein KO Isoflavones, soy-based infant formulas and relevant to endocrine function Nutr Rev 1998; 56:193-204
  30. Setchell KD et al isoflavone content of infant forumlas and the metabolic fate of these phytoestrogens in early life Am J Clin Nutr 1998; 68 (Suppl):1453S-1461S
  31. Sheehan DM Herbal medicines, phytoestrogens and toxicity: Risk:benefit considerations Proc Soc Exper Biol Med 1998; 21:379-85
  32. Adlercreutz H et al Maternal and neonatal phytoestrogens in Japanese women during birth Am J Ob Gyne 1999; 180:737-43
  33. North K Golding J A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team Avon Longitudinal Study of Pregnancy and Childhood BJU Int 2000 85:107-13
  34. Divi RL et al Anti-thyroid isoflavones from soybean: isolation, characterization and mechanisms of action Biochem Pharmacol 1997; 54: 1087-96
  35. Chorazy PA et al Persistent hypothyroidism in an infant receiving a soy formula: case report and review of the literature Ped 1995; 96: 148-50