Phyto-oestrogens

There are more than 20 compounds that can be found in more than 300 plants, such as herbs, grains, and fruits. The three main classes of dietary phyto-oestrogens are isoflavones, lignans, and coumestans:

• Isoflavones (genistein, daidzein, glycitein, and equol) are primarily found in soy beans and soy products, chickpeas and other legumes
• Lignans (enterolactone and enterodiol) are found in oilseeds (primarily flaxseed), cereal bran, legumes, and alcohol (beer and bourbon)
• Coumestans (coumestrol) can be found in alfalfa and clover.

Most food sources containing these compounds include more than one class of phyto-oestrogens.

Much of the evidence about phyto-oestrogens in bone metabolism is based on animal studies. Soybean protein, soy isoflavones, genistein, daidzein and coumestrol have all been shown to have a protective effect on bone in animals after oophorectomy.

In humans the evidence is conflicting:

• Epidemiological studies show that compared to Caucasian populations, women in Hong Kong, China and Japan, where dietary phyto-oestrogen intake is high, have lower rates of hip fracture. Vertebral fractures are almost as common in Asian women as they are in white women.
• In addition, reports suggest that Japanese women have a greater risk of sustaining a vertebral fracture than Caucasian women.
• Several studies have explored the effects of soy isoflavones on bone, but results have been mixed, ranging from a modest impact to no effect. Most of these studies have serious limitations, including their short duration and small sample size, making it difficult to evaluate fully the impact of these compounds on metabolism of bone.
• A 3-year study of more than 400 postmenopausal women concluded that ipriflavone did not prevent bone loss. The substance was also linked to lymphocytopenia in a significant number of subjects.²
• A Cochrane review also concluded they had no effect on post-menopausal vasomotor symptoms.³
• There is some evidence of soya protein and isoflavones having beneficial effect on both blood lipid profile and bone density in post-menopausal women.^4,5 Soy isoflavones have no effect on bone density in younger, menstruating women.⁶
• A systematic review of RCTs was unable to give unequivocal support for the benefit of phyto-oestrogens for the prevention of osteoporosis.⁷ There is some evidence of adverse effects on laboratory animals, but studies to assess the problem in humans are not yet forthcoming.⁸ There is also suggestion that phyto-oestrogens may enhance osteogenesis at low concentration and inhibit it at higher concentrations.⁹

Some studies suggest that, unlike oestrogens, phyto-oestrogens do not appear to increase the risk of breast cancer or uterine cancer. They seem more like selective oestrogen receptor modulators (SERMs) such as raloxifene and tamoxifen. However, in other studies, high isoflavone levels have been linked to an increased risk of breast cancer. Clearly, additional research is needed and is currently being undertaken.
The effect of consumption of soy as a risk for breast cancer is controversial:

• A review concluded that the evidence was not strong in any direction and that even women who have had breast cancer may safely consume soy.¹⁰ Foods, herbs and spices may contain phyto-oestrogens and phyto-progestins that may function as agonists or antagonists.¹¹
• Studies have indicated that countries with the highest phyto-oestrogen consumption have the lowest rates of breast cancer,^12,13 but other epidemiological studies suggest the lack of a causative relationship. No studies, have found an increased risk of breast cancer with increased soy consumption. It may be dangerous to read too much into epidemiological studies on diet for a multi-factorial condition.
• There is also evidence that isoflavones and lignans may exert protection against cancer through mechanisms not associated with oestrogenic activity.¹⁴ Isoflavones exhibit some antioxidant activity, which may contribute to cancer prevention.^15,16
• Several studies have reported that phyto-oestrogens have anti-angiogenesis effects, discouraging the growth of new blood vessels in tumours.¹⁰

Phyto-oestrogens are also recommended as anti-androgens and hence are of possible protective benefit with regard to carcinoma of prostate and benign prostatic hyperplasia.^17,18 Whether they also reduce sperm count has not been examined.

Children with lactose intolerance or atopic eczema are often given a soya based feed instead of milk:

• These children may have plasma phyto-oestrogen concentrations of up to 7,000 nm/L, which compares with an average of 744 nm/L in adult Japanese women.¹⁹
• The daily exposure to phyto-oestrogens from baby formula is 6 to 11 times higher than a hormonally active dose in adults and plasma concentrations of isoflavones are some 13,000 to 22,000 times higher than endogenous oestrogen concentrations in infants.²⁰ This seems disastrous, but the only readily identified problem in these children is allergy in 2 or 3% and possibly inadequate intake of calcium.
• Studies following children through adolescence have not reported any obvious adverse reproductive effects.¹⁹
• A retrospective cohort study examined 811 subjects in their 20s and 30s, and found no statistically significant differences between those who had soy formula and those who had cow's milk as infants.²⁰

Whether or not early exposure to high doses of isoflavones has any positive or negative effects on cancer rates or cognitive and neurological parameters in later life is not yet known.

The American National Institute for Health funded a cohort study which followed 3,734 Japanese men in Hawaii who had been tracked since 1965 for a cardiovascular longitudinal study:²¹

• Cognitive function was assessed according to standard parameters in the living participants and their wives (aged 71 - 93 years).
• MRI and later autopsies looked for changes in brain tissue.
• Those who had consumed the greatest quantity of tofu in midlife had lower cognitive test performance and lower brain weight than those who had consumed the least tofu.
• The authors noted that the degree of impairment in the highest consumption versus the lowest consumption group was "roughly of the magnitude as would be caused by a four year difference in age or a three year difference in education."

They postulated that the observed effect might be due to isoflavones inhibiting key enzymes in oestrogen synthesis pathways. Oestrogen is known to be involved in repair of neural structures that degenerate over time, and it has been observed that higher levels of oestrogen are associated with lower incidence of Alzheimer's disease in women. Around the menopause some women become forgetful. Another study found a beneficial effect of phyto-oestrogens on mood and cognitive function in postmenopausal women.²²

Isoflavones in soy and flavonoids from other sources inhibit the enzyme thyroid peroxidase, which is involved in the synthesis of thyroxine. The inhibitory effects of genistein and daidzein can be completely reversed by the addition of sufficient iodine.²³ It would appear only to be a problem where there is borderline iodine deficiency.

This is a substance that is recommended by herbalists for a variety of conditions and it is highly recommended for menopausal symptoms although some authorities say that it has anti-oestrogenic effects. There are many side-effects associated with it and the European Medicines Agency has given warning about the possibility of hepatitis resulting from its use.²⁴

There is some evidence of a protective effect against the progression of chronic renal failure by phyto-oestrogens.²⁵

There is a great deal of evidence about phyto-oestrogens, but there is also much confusion. As Aristotle observed in the 4th century BC, The more you know, the more you know you don't know.

• Much of the evidence relates to animals and in vitro studies and there are questions as to how readily it should be extrapolated to humans
• Oestrogens and similar substances are highly complex and variable. Some may have an agonistic effect on bone, an antagonistic effect on breast tissue and a neutral effect on the endometrium as we have seen with SERMs. There may be considerable variation with regard to the effect of plant chemicals too.
• When a substance is not given as a drug in a predetermined dose but is part of the diet the amount ingested may be highly variable and there may also be problems such as an agonist effect at low dose and an antagonist effect at higher doses.
• Some of the results, such as those related to cognition, are contradictory. This may be due to agonists and antagonists working in different directions.
• Epidemiological studies about multifactorial diseases must be interpreted with care. When comparing different populations we cannot be sure that only one parameter is changed.
• There is very little good, long term evidence about the effects of phyto-oestrogens in human populations. Many questions remain to be answered. If a diet high in phyto-oestrogens does protect women against breast cancer, osteoporosis and heart disease, does it also impair fertility? If it protects men against prostatic cancer, does it also impair spermatogenesis?
• The evidence to suggest that phyto-oestrogens are protective against osteoporosis is at best poor. Long term safety is not established.
• There have been many studies on the efficacy and safety of mammalian HRT including the enormous "million women study".^26,27 The million women study was basically very reassuring but it did outline some causes for concern. The assumption that plant oestrogens are as effective but safer is a very unsafe premise.

For patients who still insist that anything produced by the pharmaceutical industry is hazardous whilst anything that is "natural" is safe there is one piece of mischief to drop in their direction. Most soya comes from America, both the USA and further south such as Argentina and much of the soya that we import is genetically modified.²⁸ There is no evidence that GM food is dangerous to those who eat it, but the response will be interesting.