Title: Phytoestrogens and the Menopause

Key words: epidemiological evidence, hormone-dependent diseases, isoflavones, lignans, coumestans, lactones, phenolic ring, oestrogens, menopausal symptoms

Date: Feb 1999

Category: 11. Life Changes

Type: Article

Author: Dr van Rhijn

Phytoestrogens and the Menopause

The potential health benefits of Phytoestrogen-rich diets in menopausal women.

Introduction

There is currently a great interest in Phytoestrogens1 (from plant-based foods), which are thought to be the key factor in explaining the epidemiological variance of many hormone-dependent (oestrogen) diseases among menopausal women from different western populations. Epidemiological evidence shows a lower incidence of these diseases in populations consuming high intakes of soy and other plant-based foods. They may, therefore, be of preventative2 and therapeutic value in the incidence of chronic diseases such as cancer, osteoporosis, menopausal symptoms, cognitive function and cardiovascular diseases, in which postmenopausal women have a similar mortality to men. Most recently reviewed3,4,5 data, supportive of these effects are from animal and in vitro studies, but clinical data are still in their infancy.

What are Phytoestrogens

The major classes of plant Phytoestrogens (bioactive non-nutrients) are isoflavones (soya), lignans (flax & linseed), coumestans (alfalfa) and resorcyclic acid lactones (oats). They occur predominantly as glycoside conjugates daidzein & genistein (an isoflavone precurser) and are structurally very similar to the mammalian oestrogen, estradiol 17b . They are metabolised by intestinal bacteria, readily absorbed into the enterohepatic circulation, reconjugated in the liver to glucuronic acid and sulfuric acid and excreted in urine. Little is known about their exact metabolism, which shows considerable individual variability, but they have been found to have a wide range of hormonal and non-hormonal activities. A chemical characteristic that this entire group of compounds share with oestrogens6 is the presence of a phenolic ring, which is required to bind with the oestrogen receptor. They are able to act as both partial agonist 7 and partial antagonist 8, mediated by competition with estradiol 17b for the oestrogen receptor (Era & ERb 9), albeit with much lower affinity, and with variable induction of oestrogen regulated end-products.

Potential Health Benefits

Menopausal symptoms, especially hot flushes10, are much less common in countries (Asia11) where the diet is rich in Phytoestrogens (soy products). A twelve week supplementation of 45g soya flour reduced the number of hot flushes by 40%12, which is more than one would expect by natural improvement with time. Another study found that a six week supplementation of the diets of postmenopausal women with Phytoestrogens showed significant changes in vaginal cytology and suppression of follicle stimulating hormone (FSH)13. A four week period of supplementation with 60 g/d of soya in postmenopausal women, suppressed luteinising hormone (LH) levels, and 40 g linseed (rich lignans source) over a six week period, significantly suppressed LH and follicle stimulating hormone (FSH)14.

It is well established that HRT is cardioprotective15, by altering the lipoprotein metabolism16 and lowering serum cholesterol. Dietary intervention trials demonstrated the beneficial effects of Phytoestrogens on lipoprotein-mediated CHD risk. Isoflavone supplements increased HDL levels by 14% over a four-week period and linseed suppressed total cholesterol and LDH levels by 15% and 8% respectively over a six-week period in postmenopausal women16.

Substituting soy protein for animal protein in the diet reduces serum concentrations of total and LDL cholesterol in animal studies17. A meta analysis18 of 38 clinical studies concluded a mean reduction in serum total cholesterol (9.3%) and LDLc (12.3%) with soy protein, although the mechanism remains unknown, but increased bile excretion of cholesterol may be involved19. A later study confirmed these lipid lowering effects of soya and isoflavones were identified as the active component20, 21. In vitro studies have demonstrated that genistein inhibits coagulation22, thrombin formation23 (inhibition of tyrosine kinase24) and platelet activation. It may therefore, although speculative, have the potential to slow the development or progression of atherosclerotic25 disease by modifying coagulation responses in vivo. Isoflavones may act as antioxidants, where genistein has been shown to enhance resistance of LDLc to oxidation26, as well as increasing blood flow by vasodilatation27.

Isoflavones possess weak oestrogenic properties, and may therefor potentially be beneficial in the prevention of osteoporosis. Ipriflavone (isoflavone derivative), directly inhibits bone resorption in a human model of osteoblasts28. Phytoestrogen-rich diets, through their oestrogenic effects, are likely to have beneficial effects for the prevention of bone loss in the menopause, as demonstrated in animal models (ovarectomised rat) with genistein29 and soyabeans30. Human studies confirmed an increase in bone mineral content31 in postmenopausal women consuming soy protein over a six months period32. The effects of isoflavones may be explained by the identification of the ERb receptor9, with its ligand specific towards Phytoestrogens.

The evidence for the suspected role of Phytoestrogens in cancer prevention33 is mainly based on in vitro studies. It is suggested that genistein acts as a potent inhibitor of both oestrogen negative and oestrogen positive breast cancer cells34, angiogenesis, endothelial cell proliferation and through an antioxidant mechanism. The levels required to achieve these inhibitions are almost two orders of magnitude higher than estimates of blood isoflavones concentrations reported in humans consuming soy products. The relevance of all these in vitro studies is unknown, despite using human cancer cell lines, for the mechanisms may not be a reflection of the complexities in vivo. These hormonal modifications induced by Phytoestrogens (via the hypothalamic-pituitary-gonadal axis) may be potentially protective with respect to risk factors for breast cancer. Epidemiological, animal and in vitro data encourage further assessment of the role of Phytoestrogens in cancer prevention35.

Cautious Interpretation

Interpretation remains difficult due to inconsistent trial design, variable compliance and the types of diet regimes used in the studies. These preliminary results (animal & in vitro studies) suggest that it appears logical and attractive to advocate Phytoestrogen-rich foods (or supplements) as a natural dietary alternative36 to hormone replacement therapy (HRT), especially considering the poor compliance due to side effects and fear of developing breast cancer from HRT37. There is a lack of the clinical research required to assess the potential synergistic effects in women with high intakes of Phytoestrogens and who are also taking synthetic oestrogens, because of the ERb receptor38 present (high affinity) in tissues which are responsive to classical HRT39. Many questions remain unanswered regarding the mechanism involved in explaining the biological effects of isoflavones, which are divergent (agonistic or antagonistic), tissue-specific (Era & ERb ) and dependent on the intrinsic oestrogen state of the target tissue (pre- or postmenopausal). Numerous other factors such as pharmacokinetics, bioavailability, metabolism, half-life, timing and level of exposure add to the complexity of extrapolating in vitro experimental data to in vivo situations. Further research is required before making recommendations regarding long-term efficacy or even optimal dose and duration of intake for clinical effectiveness.

Conclusion

Phytoestrogen-rich diets (especially with life time exposures) may have enormous benefits on health40 by positively influencing the morbidity and mortality of hormone-dependent diseases in menopausal women from western societies, where the diet is generally short of supply of Phytoestrogens. Vigilance is required, however, as to potential health risks with supplementation of these bioactive compounds, especially genetically modified soybeans. Collectively, however, these studies raise the awareness of the importance of their oestrogenic effects41, which can be utilised in preventative medicine via dietary means.

 

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