CLIMACTERIC I999;2:75-78

Editorial

Is there a proven place for phytoestrogens in the menopause? Jean Ginsbztrg and Gordana M . Preleuic

From the endocrine point of view, the menopause is a deficiency state, and estrogen replacement therapy (ERT) could be considered a means of restoring the premenopausal endocrine milieu. Menopausal therapy is not, however, without risks, and current preparations are poorly toler- ated by many women. Although in recent years compliance has been improved with the avail- ability of more user-friendly preparations, fear of breast cancer and side-effects limit long-term usage of conventional hormone replacement therapy (HRT). An alternative to such prepara- tions would therefore have a considerable poten- tial, and there is currently increasing interest in non-estrogen treatment for the menopause.

Epidemiological data indicate the frequent use of alternative medicine, including dietary supple- ments and plant-derived replacement therapy in postmenopausal women’J. A recent study from Sweden of over 6000 women showed that, while 21% ,took HRT, 45% took a non-hormonal variety’. An Australian population survey of some 3000 individuals revealed the use of at least one non-medically prescribed alternative medicine preparation in 48.5% of those interviewed. The users of alternative medicines were more likely to be better educated women and per imen~pausal~.

Phytoestrogens or plant-derived estrogens are being increasingly promuted as the ‘natural’ alter- native to ERT. The main plank of this platform is tenuous, however. Thus, the lower prevalence of hot flushes in Asia and particularly in Japan, com- pared to that in Europe and North America, has been attributed to the traditional Asian diet rich in phytoestrogens, with an average daily content of up to 200 mg of isoflavones4-’. Epidemiological studies also suggest that the incidence of certain diseases influenced by estrogens - cardiovascular disease, osteoporosis and breast cancer, for example - is lower in populations with a diet high in phytoestrogens8-10. However, this does not pro- vide a scientific basis for the claim that phyto- estrogens are important for the health and well-being of postmenopausal women.

Phytoestrogens are diphenolic compounds found in cereals, legumes and green vegetables. There are numerous varieties, isoflavones, lignans and coumestans being the best known”. Of these, the most investigated are the isoflavones, which are in particularly high concentration in soy bean and soy products.

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Editorial Ginsburg and Prelevic

The phytoestrogens occurring naturally, as in plants, are estrogenically inert. Tetracyclic phenols, which are similar in structure to estrogen and biologically active, are formed by metabolic conversion in the gastrointestinal tract12.

Phytoestrogens have weak, estrogen-like bio- logical activity, expressing their effects at the level of the estrogen receptorlo. It has recently been proposed that, at the menopause, phytoestrogens might act as natural selective estrogen receptor modulators (SERMs), i.e. acting as estrogen ago- nists in the cardiovascular system, bone and brain but as estrogen antagonists in the breast and ~ t e r u s ' ~ .

Plant estrogens have, however, to be consumed in large amounts to exert a biological effect. The biological potency of the different phytoestrogens is variable, and small compared with that of estradiol. The relative potencies, determined by cell culture bioassays (compared to estradiol, which was given an arbitrary value of loo) , are: coumestrol 0.202, genistein 0.084, daidzein 0.013, etc.l4. Concentrations of the different phytoestrogen metabolites vary widely between individuals, even when a controlled quantity of an isoflavone or lignan supplement is administered. Factors that can affect phytoestrogen absorption include intestinal bacteria, antibiotics, bowel disease, alcohol consumption, and the fat, fiber and protein content of the diet'j, which may explain why studies on the estrogenic effects of soy diets are limited and inconclusive. Also, the level of activity of phytoestrogens apparently depends on the concentration of endogenous estrogen. Thus, in the estrogen-deprived milieu of the menopause, they act as weak estrogens where- as, in women of reproductive age, they may partially inhibit the effects of endogenous estro- gens' The interaction at receptor level is there- fore dependent on both the concentration of endogenous estrogen and phytoestrogen and the specific end-organ involved. There is also evidence that phytoestrogens can act through mechanisms other than that of the estrogen receptor.

With the foregoing in mind, we obviously need to find out whether there are adequate data to support the clinical use of these products, and also whether 'natural' necessarily implies safer and effective treatment.

Is there reliable evidence that phytoestrogens reduce hot flushes? The results of the few pub- lished studies do not show a convincing effect. Claims that a daily consumption of 45 g of soy flower, bean curd or isoflavones in pill form can decrease hot flushes to a mild degree (a reduction

of 40%) is equivalent to a placebo respon~e '~~' ' . There is, moreover, a marked variation in response, depending on the particular population studied, the type of soy product taken and study design, particularly with respect to duration of exposure, variability in response and even non- response in some postmenopausal women to phytoestrogen supplementation]*.

Two placebo-controlled prospective studies published in this i~sue '~ ,~O, which have used a semipurified isoflavone extract in a tablet form as dietary supplement, showed no significant differ- ence in alleviation of hot flushes, compared to placebo. The finding of a negative correlation between urinary isoflavone excretion and hot flushesz0 requires confirmation in appropriately controlled conditions. The observed variation in phytoestrogen metabolite excretionz0Yz1 could be the result of variations in dietary intake, in indi- vidual absorption or in phytoestrogen metabo- lism. Hence, further trials addressing this issue must be performed with strictly controlled dietary conditions.

Hot flushes are, however, a relatively minor, albeit unpleasant aspect of the plethora of health problems associated with the menopause and administration of ERT. The suggestion that phytoestrogen consumption might be associated with a lower risk of cardiovascular disease and of breast cancer is clearly of much greater importance.

Evidence to support a cardioprotective effect of phytoestrogen consumption is based mainly on a meta-analysis of 38 published controlled trials, which showed that eating soy protein (an average of 47 g per day) lowers serum cholesterol, low- density lipoprotein (LDL) cholesterol and trigly- ceride concentrationsz2. Studies in rhesus monkeys also showed a significant increase in high-density lipoprotein (HDL) cholesterol (up to 50%) with isoflavone-intact soy protein supplementationz3. A hypocholesterolemic effect appeared to be signifi- cantly related to pretreatment blood cholesterol levels, as observed with estrogens.

Studies in female macaque monkeys showed soy to be as effective as conjugated equine estro- gens in preventing atherosclerosis without stimu- lating mammary or uterine tissuez4. A dilator response to acetylcholine was demonstrated in atherosclerotic coronary arteries of female monkeys fed a diet high in isoflavones. Decreased vascular plaque formation has also been shown with isoflavone-rich diets in the monkey mode12j. Vascular endothelial effects have also been reported in women. Systemic arterial compliance

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Editorial Ginsburg and Prelevic

was found to be significantly improved in peri- menopausal and menopausal women taking soy isoflavones (80 mg daily) over 5-10 weeks, to about the same extent as is achieved with conven- tional ERT26. Based on this evidence, the US Food and Drug Administration (FDA) proposed recently that some soy products carry a label indi- cating that they may reduce heart disease13, although there is no hard evidence to support this assertion.

As for a possible role of phytoestrogens in pre- vention or treatment of osteoporosis, ipriflavone (a synthetic derivative of naturally occurring iso- flavones) has been shown to inhibit bone resorp- tion2’ and to counteract the rapid bone loss which occurs after iatrogenic or surgical menopau~e28,~~. It also prevents bone loss in the early years after menopause30 and increases bone mineral density in older women with established o s t e o p o r ~ s i s ~ ~ . ~ ~ . However, the effect of ‘natural’ phytoestrogens on skeletal integrity in postmenopausal women has not been evaluated.

An added potential benefit from phyto- estrogens might be a protection against breast cancer, as suggested in population studies9. While in vitro data and animal studies indicate an anti- proliferative effect of p h y t o e s t r o g e n ~ ~ ~ ? ~ ~ , extra- polation from such studies to postmenopausal women is not justified.

Finally, although possible adverse effects such as a deficit in sexual behavior of male offspring and enhanced mammary gland p r o l i f e r a t i ~ n ~ ~ ? ~ ~ have been observed in animals given toxic levels of phytoestrogens, it is difficult for women to consume sufficient amounts of isoflavones from natural soy foods to reach the levels that induced pathological effects in animals. The current

References

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Hitherto, we have used the descriptive term ‘phytoestrogens’ as a blanket cover for the variety of plant constituents, extracts thereof and derived synthetic products. However, if we are to assess the real benefits from their administration, we need to differentiate between the effect of phyto- estrogens present as a natural component of the diet and that of plant extracts prepared in pill form, with consequent potential for toxic as well as therapeutic effects, and that of synthetic products such as ipriflavone. We will also have to consider what is in the pipeline - second- and third-generation products of isoflavone metabolites, which may exert biological actions different from those of the parent compound. Future studies devised to assess benefits from the administration of phytoestrogens must be controlled from all points of view. Also, as with any medicine, standardization of dosage, together with safety and efficacy labelling, is essential to ensure proper use of phytoestrogens. Until we have the results of controlled and appropriately designed long-term studies, it is impossible to draw any conclusion regarding their benefits, particularly in the long term. Currently, as there is no reliable evidence con- firming a substantial role for phytoestrogens in the treatment of postmenopausal women, their increasing promotion should not be endorsed by the medical profession by accept- ing promotional material in journals or at meetings.

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