Focus on Phytoestrogens

US Pharm. 2007;32(12):HS-27-HS-32.

Phytoestrogens are trace biochemicals produced by plants that act like estrogens in animal cells and bodies. A number of epidemiological studies have reported a connection between high dietary intake of phytoestrogens and lower rates of certain cancers, cardiovascular problems, and menopausal symptoms.¹ It is believed that phytoestrogens could compete with estradiol for binding to intercellular estrogen receptors. Although still inconclusive, scientific evidence is accumulating to suggest that phytoestrogens may have a role in preventing chronic disease.² An especially strong body of evidence suggests that they may be effective in preventing and treating prostate cancer, due to their antiandrogenic properties.³

Phytoestrogens are a comparatively recent discovery, and researchers are still exploring the nutritional role of these substances in such diverse metabolic functions as the regulation of cholesterol and maintaining of postmenopausal bone density.

Phytoestrogens mainly fall into the class of flavonoids: the most potent in this class are coumestans and isoflavones (genistein and daidzein). The best-researched group is isoflavones, which are commonly found in soy and red clover. The uses for these isoflavones are just like that of soy, simply because isoflavones are found in soy.

Lignan--which is not a flavenoid--has also been identified as a phytoestrogen. The estrogenic properties of these biochemicals have been shown to be due to their structural similarities to the hormone estradiol. The major types of phytoestrogens and lignans are all examples of phenolic phytoestrogens. Other kinds of molecules (including plant steroids and terpenoids) have demonstrated varying estrogenic activity as well; however, this short article will focus mainly on phytoestrogens and their health benefits.⁴

Sources of Phytoestrogens
Although phytoestrogens of one kind or another occur in many different plants, only certain species contain medicinally significant amounts. Among the food plants, legume seeds (beans, peas) and especially soy products are the most prominent sources of isoflavones. Flax seed contains the highest total phytoestrogen content followed by soy bean and tofu. Isoflavones are found in high concentration in soy bean and soy bean products (e.g., tofu), whereas lignans are mainly found in flax seed.

The content varies in different foods with some foods having a stronger effect than others. The content varies within the same group of foods, e.g., soy beverages depending on processing and type of soy bean used. The list of foods that contain phytoestrogens includes soy beans, tofu, tempeh, soy beverages, linseed (flax), sesame seeds, wheat, berries, oats, barley, dried beans, lentils, rice, alfalfa, mung beans, apples, carrots, wheat germ, ricebran, and soy linseed bread.⁴ Daily intakes of 45 mg of phytoestrogens have been shown to have beneficial stabilizing effects on hormone balance.

Various kinds of phytoestrogens are also found in many medicinal herbs, including red clover, black cohosh, alfalfa, hops, licorice, and turmeric.⁴

Human Estrogens Versus Phytoestrogens
The three different kinds of estrogen made by the human body: estradiol, estrone, and estriol, known as endogenous estrogens, are produced in the ovaries, the placenta, and, in small amounts, in the testes. There are also various metabolites of estrogen that circulate in the blood. Chemically, all of the above are known as steroids. Some plant seeds (i.e., pomegranate, date palm) actually contain small amounts of estrone, but many of the phytoestrogens are not steroidal. The main ones known so far are chemically classified as coumestans, isoflavones and lignans, or phenolic phytoestrogens. They are not identical to steroids but have enough features in common that they can affect estrogen receptors and hormone metabolism in cells. Lignan should not be mistaken with lignin, the rigid wood polymer that give plants a superstructure to deal with wind and gravity.⁵

Mechanism of Action
Current research suggests that phytoestrogens may be natural selective estrogen receptor modulators (SERMs),⁸ which means that they can bind to certain estrogen receptors in some tissues, either activating or down-regulating cellular responses. The estrogen response system consists of two forms of the estrogen receptor (ER-alpha), prominent in breast and uterine tissue, and (ER-beta) activate cardioprotective and bone-stabilizing metabolic processes. Numerous coregulators act in concert to regulate the transcriptional machinery of cells sensitive to estrogenic compounds. As a result, depending on concentrations of endogenous estrogens, as well as on which receptor complexes are activated or down-regulated, SERMs can have either estrogenic or anti-estrogenic effects.

Simultaneously, the phytoestrogens appear to down-regulate the activity of the alpha-type estrogen receptors (ER alpha) prominent in breast and uterine tissue. This is one possible mechanism behind their proposed anticancer effects.

In addition, accumulating evidence suggests that phytoestrogens can favorably affect the balance of estrogen metabolites in the body. "Bad" metabolites (16 alpha-hydroxyestrone, 4-hydroxyestrone and 4-hydroxyestradiol) are genotoxic and mutagenic.  The ratio of "good" (2-hydroxyestrone) to "bad" metabolites is increasingly being used as a marker to assess cancer risk. Non-ER–mediated effects on growth regulation in human breast cancer cells have also been documented for phytoestrogens role in these disease.⁶

Phytoestrogens and Cancer

The connection between androgens with prostate cancer has long been known, but the role of the estrogens in prostate cancer has been a controversial matter.³ The reason is that treatment of prostate cancer with estrogens results in inhibition of cancer growth, but on the other hand, estrogens have also been shown to be associated with growth of both benign prostatic hyperplasia  and prostate cancer. It has been reported that Japanese men who eat soy have lower prostate weights than do Western men at similar ages. As a result, dietary estrogens could be both beneficial and deleterious to prostate disease. New research indicates it is possible that the beneficial effects of these compounds on prostate disease are mediated via mechanisms not involving the estrogen receptor. The possible mechanisms that could be involved are inhibition of tyrosine and other protein kinases, 3-beta-hydroxysteroid dehydrogenase, 17-beta-hydroxysteroid dehydrogenase, 5-alpha-reductase, and aromatase. All of these effects have been demonstrated for phytoestrogens.⁶ It is concluded that dietary phytoestrogens are strong candidates for a role as protective compounds with regard to prostate diseases.⁷

Soy has clearly been a functional food in the spotlight since 1990's. In addition to being a high-quality protein, soy is now known to play a preventive and/or therapeutic role in a number of chronic diseases, including heart disease, osteoporosis, and cancer.⁷

Several classes of anticarcinogens have also been identified in soybeans, including protease inhibitors, phytosterols, saponins, phenolic acids, phytic acid, and isoflavones. Of these, isoflavones (genistein and daidzein) are particularly noteworthy because soybeans are the only significant dietary source of these compounds. Isoflavones are heterocyclic phenols structurally similar to the estrogenic steroids and thus have been shown to possess both estrogenic and antiestrogenic activity. Because they are weak estrogens, isoflavones may act as antiestrogens by competing with the more potent, naturally occurring endogenous estrogens (e.g., 17-beta-estradiol) for binding to the estrogen receptor. This has important implications for reducing breast cancer risk. While not all studies agree epidemiologic evidence indicates that women in Southeast Asian populations that consume diets containing high amounts of soy (10-50 g/day) have a four- to six-fold decreased risk of breast cancer compared to American women, who routinely consume negligible amounts of this legume (1-3 g/day).⁸

Phytoestrogens (Isoflavones) in Infant Formulas
Estimates of isoflavone intake in the traditional Japanese diet range from 15 to 200 mg/day. However, scientific data on human exposure to higher doses is difficult to find. Nonetheless, approximately one million American infants ingest large doses of phytoestrogens in soy-based formula every year. These children sustain plasma phytoestrogen concentrations of up to 7,000 nm/L (compared to an average of 744 nm/L in adult Japanese women).⁹ A recent study in theLancet noted that the average daily exposure to phytoestrogens from baby formula was six to 11 times higher than a hormonally active dose in adults, and plasma concentrations of isoflavones were some 13,000 to 22,000 times higher than endogenous estrogen concentrations in the infants studied.¹⁰

The only conclusive reports of negative reactions to soy formulas have been due to allergies (an estimated 3%-4% of infants are allergic to soy).¹⁰

All this points to the fact that human breastfeeding is by far the preferable form of nourishment for human infants.

The National Institutes of Health is sponsoring a long-term follow-up study on the safety of soy infant formula. The study is a "longitudinal retrospective epidemiological" assessment in which young adults who consumed soy formula as infants will be compared with young adults who consumed milk-based formulas as infants. They will be evaluated for any adverse effects from infancy into their childbearing years.

Phytoestrogens and Their Effects on the Thyroid
Soy has long been known to have effects on the thyroid. Isoflavones in soy (and flavonoids from other sources as well) inhibit the enzyme thyroid peroxidase, which is involved in thyroid hormone synthesis. This study explored the inhibitory effects of genistein and daidzein, which were completely reversed with the addition of sufficient iodine. Clinical problems from ingesting high levels of phytoestrogens, such as aggravated hypothyroidism or goiter, can occur in iodine-deficient or hypothyroid individuals.¹¹

A recent review from investigators at the National Center for Toxicological Research reaffirms that iodine deficiency increases the antithyroid effects of soy, while iodine supplementation reverses them. In studies with rats, genistein-fortified diets decreased thyroid peroxidase activity in a dose-dependent manner; however, other parameters of thyroid function were unaffected (including serum levels of the hormones triiodothyronine, thyroxine, and thyroid-stimulating hormone). ¹²

Summary and Conclusion
Soy protein products can be good substitutes for animal products because, unlike some other beans, soy offers a "complete" protein profile. Soybeans contain all the amino acids essential to human nutrition, which must be supplied in the diet because they cannot be synthesized by the human body. Soy protein products can replace animal-based foods--which also have complete proteins but tend to contain more fat, especially saturated fat. Many patients with cancers that are hormone related such as breast and prostate cancer will benefit from low animal fat diet. As a result, soy products are a good substitute. The FDA determined that diets with four daily soy servings can reduce levels of low-density lipoproteins, the so-called bad cholesterol that builds up in blood vessels, by as much as 10%. This number is significant because heart experts generally agree that a 1% drop in total cholesterol can equal a 2% drop in heart disease risk.

References

1. Adlercreutz H, Phytoestrogens and Cancer, Lancet Oncology. 2002;3:364-373.

2. Thompson LU, Boucher BA, Lui Z, et al. Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans and coumestan. Nutrition and Cancer. 2006;54:184-201.

3. Castle EP, Thrasher JB. The role of soy phytoestrogens in prostate cancer. Urol Clin North Am. 2002; 29:71-81.

4. Mazur W, Adlercreutz H. Naturally occurring estrogens in food. Pure & Applied Chem. 1998;70:1759-1776.

5. Setchell, D. R. Soy Isoflavones--benefits and risks from nature's selective estrogen receptor modulators (SERMs). J Am Coll Nutr. 2001;20:354S-362S.

6. MacMahon B, Cole P, Brown J. Etiology of human breast cancer: a review. J Natl Cancer Inst. 1973;50:21-42.

7. Adlercreutz H, et al. Phytoestrogens and Prostate Disease. J. Nutr. 2000;130:658S-659S.

8. Birt DF, Hendrich S, Wang W. Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 2001;90:157-161. 

9. Setchell KD. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet. 1997;350:23-27.

10. Cantani A, Lucenti P. Natural history of soy allergy and/or intolerance in children, and clinical use of soy-protein formulas. Pediatric Allergy Immunology. 1997;8:59-74.

11. Doerge DR, Sheehan DM. Goitrogenic and estrogenic activity of soy isoflavones Environ Health Perspect. 2002;3:349-353.

12. Divi RL, Chang HC, Doerge DR. Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochem Pharmacol. 1997;54:1087.

To comment on this article, contact editor@uspharmacist.com.