Learning


Phytoestrogens
  1. Food and Drink
  2. Possible Health Benefits
  3. Possible Health Risks
  4. An Explanation
  5. Further Resources
  6. References

fruits and vegetablesMany plants produce chemicals that mimic or interact with hormone signals in animals. At least 20 such phytohormones have been identified in at least 300 plants from more than 16 different plant families (Barrett 1996; Colborn et al. 1996). The estrogen-like phytoestrogens are the most studied of all the phytochemicals. In general, phytoestrogens are weaker than the natural estrogen hormones (such as estradiol) found in humans and animals or the very potent synthetic estrogens used in birth control pills and other drugs (Jefferson et al. 2002a).

CAPTION: Many fruits and vegetables contain phytoestrogens. CREDIT: National Cancer Institute

Exposure to phytoestrogens is mainly through diet. The estrogenic plant compounds are widespread in food, including herbs and seasonings (garlic, parsley), grains (soybeans, wheat, rice), vegetables (beans, carrots, potatoes), fruits (date, pomegranates, cherries, apples), and drinks (coffee). The two most studied phytoestrogen groups are lignans and isoflavones. Lignans are products of intestinal microbial breakdown of compounds found in whole grains, fibers, flax seeds and many fruits and vegetables. Enterodiol and enterolactone are examples of lignans. Isoflavones, such as genistein and daidzein, occur in soybeans and other legumes.




Food and Drink

soybeansSince scientists have found phytoestrogens in human urine and blood samples, we know these compounds can be absorbed into our bodies. In fact, phytoestrogens have one of several fates after being eaten: they can be excreted; they can be absorbed into our bodies; or they can be broken down into other compounds that can also be potent phytoestrogens.

We are exposed daily to highly variable amounts of phytoestrogens. While adults eating a vegetarian diet or those taking dietary supplements containing phytoestrogens have high levels of exposure, infants drinking soy-based formula have the highest exposure levels by far. In most cases, the soy formula is the only source of nutrition for these infants during their first few months of life. The infants, then, are exposed to 10 times greater concentrations of phytoestrogens than adult vegetarians.

CAPTION: Plant compounds, such as the isoflavones found in soybeans and other legumes, can have health benefits and risks. CREDIT: CTIC Perdue University

According to recent estimates in the United States, more than 15 percent of babies are given soy formula. In the United States, soy formula is easily available “over-the-counter.” However, in European countries, it is available by prescription only. The isoflavones genistein and daidzein are two phytoestrogens found at very high levels in soy formula.

There are currently differing opinions about the role of phytoestrogens in health. For adults, when consumed as part of an ordinary diet, phytoestrogens are considered safe and possibly beneficial. Some studies on cancer incidences in different countries suggest that phytoestrogens may help protect against certain cancers (breast, uterus, and prostate). However, it is still unclear whether this beneficial effect is due to increased amounts of phytoestrogens in the diet or to the resulting low fat content of the diet. Similar beneficial effects of dietary phytoestrogen supplements have not been documented. On the contrary, eating very high levels of phytoestrogens may pose health risks. Studies with laboratory and farm animals, as well as wildlife eating high amounts of phytoestrogen-rich plants, have documented reproductive problems.




Possible Health Benefits

genisteinRecent research may help identify potential health benefits and shed light on how plant compounds may protect against certain diseases. Phytoestrogens have been suggested as cancer preventatives and as treatments for menopausal symptoms and osteoporosis (Adlercreutz and Mazur 1997; Messina et al. 2002).

CAPTION: Soybeans and other legumes contain the estrogen-like genistein. (click image for 3-D interactive animation) CREDIT: National Library of Medicine

Laboratory animal studies and comparisons of Asian and Western human populations suggest that diet plays a large role in these types of health problems. Asian populations generally eat large quantities of soy products compared to Western populations. One study found that Asian populations have lower rates of hormone-dependent cancers (breast, endometrial) and lower incidences of menopausal symptoms and osteoporosis than Westerners. Asian immigrants living in Western nations also have increased risk of these maladies as they “Westernize” their diets to include more protein and fat and reduce their fiber and soy intake (Kao and P'Eng F 1995).

Other studies also suggest that phytoestrogens may offer long-term protection against some cancers including breast, colon, prostate, liver, and leukemia. According to some animal studies, phytoestrogens (mostly those found in soy-based products) eaten as part of an adult diet can protect against some types of cancer and may even inhibit tumor growth. Another animal study found that young rats injected with genistein (a soy isoflavone) and then exposed to a cancer-causing agent later in life developed fewer mammary tumors and waited longer to develop them than the non-exposed rats (Lamartiniere et al.1998). Another study reported that infants on soy based infant formulas have improved cholesterol synthesis rates later in life (Setchell et al. 1997). This study supports the idea that phytoestrogens are bioactive and can have an effect in humans even at levels found in soy infant formulas.

Gaining these possible benefits may involve more than just eating more soy products. Asians, for instance, have been eating these compounds for thousands of years and may have evolutionary adaptations that allow them to use phytoestrogens to their advantage. And, some plant and soy products contain other potential anti-cancer substances (such as protease inhibitors and antioxidants) that may be responsible for the proposed health benefits (Makela et al. 1995).

Evaluating health effects of phytoestrogens is difficult and depends on numerous factors, including the kind and dose (amount) of phytoestrogens eaten and the age, gender, and health of the person.

For instance, the very foods that interfere with the endocrine messaging centers during a baby's development may help protect against breast and prostate cancer in adults. Why? There is strong evidence that lifetime exposure to natural estrogens, such as estradiol, increases the risk of certain kinds of cancer, such as uterine cancer. Phytoestrogens may help reduce that risk because they may lower a person's lifetime exposure to natural estrogens by competing for estrogen receptor sites or changing the way natural estrogens are broken down. It is possible that these endocrine interferences can reduce a person's exposure to natural estrogens thus reducing the cancer risk in so called target tissues, mostly reproductive organs that respond to sex hormone signals. 




Possible Health Risks

As for adverse health effects, the most likely risks associated with phytoestrogens deal with infertility and developmental problems. Humans have used plants for medicinal and contraceptive purposes for eons. According to modern-day analyses, many of the plants historically noted for their ability to prevent pregnancies or cause miscarriages contain phytoestrogens and other hormonally-active substances. For instance, during fourth century BC, Hippocrates noted that the wild carrot (now known as Queen Anne's lace) prevented pregnancies (Riddle 1991). Its seeds, we now know, contain a chemical that blocks progesterone, a hormone that is necessary for establishing and maintaining pregnancy.

grazing sheepDiets rich in certain phytoestrogens also adversely affect the fertility of experimental and domestic animals. For instance, phytoestrogens in dry, summertime grasses reduced the number of offspring in wild populations of California quail (Leopold et al. 1976) and deer mice (Berger et al. 1977).

CAPTION: Animals eating phytoestrogen-rich diets, such as sheep grazing exclusively on clover, can experience infertility and reproductive problems. CREDIT: USDA

Australian sheep suffered from reproductive problems and infertility after grazing in pastures with the phytoestrogen-containing clover Trifolium subterraneum (Bennetts and Underwood 1951). Two phytoestrogens, equol and coumestrol, were identified as the culprits. A group of captive cheetahs experienced infertility while on a diet rich in soy (Setchell et al. 1987). When the soy was replaced with corn, their fertility was restored.

Additionally, phytoestrogens may influence development and trigger life-long effects. Mice and rats exposed before or right after birth to several phytoestrogens, including coumestrol and genistein, develop adverse reproductive function later in life. The studies report altered ovarian development, altered estrous cycles, problems with ovulation, and subfertility (fewer pregnancies; fewer pups per litter), and infertility (Delclos et al. 2001; Jefferson et al. 2002b, 2005, 2006; Kouki et al. 2003; Nagao et al. 2001; Nikaido et al. 2004; Whitten et al. 1993). Other rat studies find developmental exposure to genistein alters pituitary responses that contribute to the ovulation problems (Faber and Hughes 1993; Levy et al. 1995). Altered mammary gland differentiation leading to increased cancer risk is also reported following developmental exposure to genistein (Hilakivi-Clarke et al. 1999). In addition, mice treated right after birth with genistein had an increased incidence of uterine cancer later in life (Newbold et al. 2001).

developing fetusSome researchers are most concerned about exposure of unborn fetuses and infants to high levels of phytoestrogens since development is highly controlled by hormones of the endocrine system. Human epidemiology studies document adverse effects of genistein. One study found that women eating a vegetarian diet during pregnancy have male offspring with an increased incidence of hypospadias (a birth defect in boys where the penis opening is not located in the normal position at the tip of the penis), possibly due to high maternal levels of soy isoflavones (North and Golding 2000).

CAPTION: Developing fetuses and infants may be at the most risk from exposure to high levels of hormone-like plant compounds. CREDIT: USDA

Other studies show young adult men and women fed soy based formulas as infants had increased use of allergy medicines and women had longer menstrual bleeding and more discomfort during the menstrual cycle than their counterparts who were fed cow based formula (Goldman et al. 2001; Strom et al. 2001). This is remarkable considering the small sample size in that study (268 women in the cow based formula group and 128 in the soy based formula group). Therefore, the adverse effects of developmental exposure to genistein remain of particular concern.

Phytoestrogens behave like hormones, although they are generally less potent. Like any hormone, too much or too little can alter hormone-dependent tissue functions. Taking too much of any hormone may not be good for humans or animals. Similarly, too many phytoestrogens, at the wrong time, may lead to adverse health effects. Experimental animal studies, such as those outlined, can help us define dietary levels that are safe and clarify the possible reproductive and developmental risks associated with phytoestrogens.




An Explanation

Some scientists believe that plants make phytoestrogens as a defense mechanism to stop or limit predation by plant-eating animals (Ehrlich and Raven 1964; Guillette et al. 1995; Hughes 1988). Instead of protecting themselves with thistles or thorns or tasting bad, these plants use chemicals that affect the predatory animal's fertility.

Although using estrogen-mimicking compounds for protection may sound far-fetched, it makes sense from an evolutionary stance. Many real-life examples support the theory that plants and animals change together, or co-evolve, over time.

The explanation goes something like this: to avoid predation, plants produce compounds (phytoestrogens) that limit an herbivores reproduction. Thus, the predator's population decreases and more plants can prosper.

But remember, because of genetic differences, not all species or individuals of a given species will react to the phytoestrogens in the same way. While some herbivores may show fertility problems, others may acquire resistance - like some insects are resistant to pesticides and some bacteria can survive antibiotics. Likewise, some humans may be more susceptible to the benefits and risks of phytoestrogens than others would be.




Further Resources

About Herbs, Botanicals and Other Products Web site. Memorial Sloan-Kettering Cancer Center. Available: http://www.mskcc.org/mskcc/html/11570.cfm

Database on the Isoflavone Content of Foods. US Department of Agriculture and Iowa State University. Available: http://www.nal.usda.gov/fnic/foodcomp/Data/isoflav/isoflav.html





References
  • Adlercreutz H and Mazur W. 1997. Phyto-oestrogens and Western diseases. Ann Med 29(2):95-120.
  • Barrett J. 1996. Phytoestrogens: Friends or foes? Environmental Health Perspectives 104:478-482.
  • Bennetts HW and Underwood EJ. 1951. The oestrogenic effects of subterranean clover (Trifolium subterraneum); Uterine maintenance in the ovariectomised ewe grazing on clover. Aust J Exp Biol Med Sci 29(4): 249-53.
  • Berger, PJ, Sanders EH, et al. 1977. Phenolic plant compounds functioning as reproductive inhibitors in Microtus montanus. Science 195(4278):575-577.
  • Colborn T, Dumanski D, and Myers JP. 1996. Our Stolen Future. New York:Penguin Books, Inc.
  • Delclos KB, Bucci TJ, et al. 2001. Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats. Reproductive Toxicology 15(6): 647-63.
  • Ehrlich P and Raven PH. 1964. Butterflies and plants: A study of coevolution. Evolution 18:586-608.
  • Faber KA and Hughes, Jr. CL. 1993. Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats. Reproductive Toxicology 7(1):35-9.
  • Goldman LR, Newbold R, and Swan S. 2001. Exposure to soy-based formula in infancy. JAMA 286(19):2402-3.
  • Guillette, Jr. LJ, Crain, DA, et al. 1995. Organization versus activation: The role of endocrine-disrupting contaminants (EDCs) during embryonic development in wildlife. Environmental Health Perspectives 103(Suppl 7):157-64.
  • Hilakivi-Clarke L, Cho E, et al. 1999. Maternal exposure to genistein during pregnancy increases carcinogen-induced mammary tumorigenesis in female rat offspring. Oncology Reports 6(5):1089-1095.
  • Hughes, Jr. CL. 1988. Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens. Environmental Health Perspectives 78:171-174.
  • Jefferson WN, Padilla-Banks E, Clark G, and Newbold RR. 2002a. Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses. Journal of Chromatography. B Analytical Technologies in the Biomedical and Life Sciences 777(1-2):179-189.
  • Jefferson WN, Couse JF, Padilla-Banks E, Korach KS, and Newbold RR. 2002b. Neonatal exposure to genistein induces estrogen receptor (ER) alpha expression and multioocyte follicles in the maturing mouse ovary: Evidence for ERbeta-mediated and nonestrogenic actions. Biology of Reproduction 67(4):1285-1296.
  • Jefferson WN, Padilla-Banks E, and Newbold R. 2005. Adverse effects on female development and reproduction in CD-1 mice following neonatal exposure to the phytoestrogen genistein at environmentally relevant doses. Biology of Reproduction 73(4):798-806.
  • Jefferson WN, Newbold R, Padilla-Banks E, and Pepling M. 2006. Neonatal Genistein Treatment Alters Ovarian Differentiation in the Mouse: Inhibition of Oocyte Nest Breakdown and Increased Oocyte Survival. Biology of Reproduction 74(1):161-168.
  • Kao PC and P'Eng F K. 1995. How to reduce the risk factors of osteoporosis in Asia. Zhonghua Yi Xue Za Zhi (Taipei) 55(3):209-213.
  • Kouki T, Kishitake M, et al. 2003. Effects of neonatal treatment with phytoestrogens, genistein and daidzein, on sex difference in female rat brain function: Estrous cycle and lordosis. Hormones and Behavior 44(2):140-145.
  • Lamartiniere CA, Zhang JX, et al. 1998. Genistein studies in rats: Potential for breast cancer prevention and reproductive and developmental toxicity. American Journal of Clinical Nutrition 68(6 Suppl):1400S-1405S.
  • Leopold AS, Erwin M, et al. 1976. Phytoestrogens: Adverse effects on reproduction in California quail. Science 191(4222):98-100.
  • Levy JR,Faber KA, et al. 1995. The effect of prenatal exposure to the phytoestrogen genistein on sexual differentiation in rats. Proceedings of the Society for Experimental Biology and Medicine 208(1):60-66.
  • Makela S, Santti R, et al. 1995. Phytoestrogens are partial estrogen agonists in the adult male mouse. Environmental Health Perspectives 103(Suppl 7): 123-127.
  • Messina, M, Gardner C, et al. 2002. Gaining insight into the health effects of soy but a long way still to go: Commentary on the fourth International Symposium on the Role of Soy in Preventing and Treating Chronic Disease. J Nutr 132(3):547S-551S.
  • Nagao T, Yoshimura S, et al. 2001. Reproductive effects in male and female rats of neonatal exposure to genistein. Reproductive Toxicology 15(4):399-411.
  • Newbold RR, Banks EP, et al. 2001. Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Research 61(11):4325-4328.
  • Nikaido Y, Yoshizawa K, et al. 2004. Effects of maternal xenoestrogen exposure on development of the reproductive tract and mammary gland in female CD-1 mouse offspring. Reproductive Toxicology 18(6):803-811.
  • North K and Golding J. 2000. A maternal vegetarian diet in pregnancy is associated with hypospadias. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. British Journal of Urology International 85(1):107-113.
  • Riddle JM. 1991. Oral contraceptives and early-term abortifacients during classical antiquity and the Middle Ages. Past Present No. 132:3-32.
  • Setchell KD, Gosselin SJ, et al. 1987. Dietary estrogens: A probable cause of infertility and liver disease in captive cheetahs. Gastroenterology 93(2):225-233.
  • Setchell KD, Zimmer-Nechemias L, et al. 1997. Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350(9070):23-27.
  • Strom BL, Schinnar R, et al. 2001. Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood. JAMA 286(7):807-814.
  • Whitten PL, Lewis C, et al. 1993. A phytoestrogen diet induces the premature anovulatory syndrome in lactationally exposed female rats. Biology of Reproduction 49(5): 1117-1121.