Have You Heard About Equol?

Abstract & Commentary

Synopsis: People are either equol producers or nonequol producers, and the clinical benefits of soy isoflavones may be limited to equol producers.

Source: Setchell KR, et al. J Nutr. 2003;133: 1027-1035.

Setchell and colleagues from the University of Cincinnati College of Medicine studied the pharmacokinetics of isoflavones in 10 healthy women; half were postmenopausal. The women were administered increasing oral doses of soy nuts in single boluses that provided known amounts of daidzein and genistein (from 16 mg to 66 mg of isoflavones—equivalent to the amounts ingested by individuals who use soy regularly). The pharmacokinetics of daidzein and genistein were similar in premenopausal and postmenopausal women. Peak blood levels were attained after 4-8 hours, indicating that absorption occurs throughout the small intestine. With increasing doses, the levels of daidzein and genistein declined, indicating the activation of metabolic pathways or reduced absorption. Because of the pharmacokinetics (for example, the half-life of the isoflavones), Setchell et al concluded that reduced absorption occurred with increasing doses. Most of the ingested isoflavone that was excreted appeared in the urine within 2 days. However, a significant portion, an average of 50% for daidzein and 84% for genistein, in amounts that increased with increasing does, was not recovered, due to metabolic degradation in the intestine. The metabolite equol was identified in only 3 of the 10 women, being consistently present in the blood and urine in the same individuals and appearing relatively late consistent with an origin in the colon. Setchell et al concluded that optimal blood levels of isoflavones would be best obtained from modest intakes of soy found consumed throughout the day, rather than from a single intake of a high dose.

Comment by Leon Speroff, MD

Although the number of subjects in this study was not large, the results provide some interesting clinical insights. For example, because the bioavailability of the isoflavones decreases with the ingestion of increasing doses, the practice of ingesting large doses, especially single doses, is not advisable.

"Phytoestrogens" is a descriptive term applied to nonsteroidal compounds that have estrogenic activity or are metabolized into compounds with estrogen activity. Phytoestrogens are classified into 3 groups: isoflavones, lignans, and coumestans. They are present in about 300 plants, especially legumes, and bind to the estrogen receptor. Soybeans, a rich source of phytoestrogens, contain isoflavones, the most common form of phytoestrogens, mainly genistein and daidzein, and a little glycitin.

Isoflavones exist in plants bound as glycoside conjugates called glycones. The carbohydrate component requires gut bacteria to remove the sugar moiety to produce active compounds, the aglycones. Intestinal metabolism is essential for the bioactivity of the isoflavones because the conjugated forms are not absorbed. After hydrolysis of the isoflavone glycoside conjugates, the isoflavones are further metabolized by bacterial reactions in the colon. Individual variability in gastrointestinal microflora, as well as absorption, influences the bioavailability of isoflavones. The results of this study are consistent with this very important characteristic: There are marked individual differences in intestinal absorption and metabolism.

The average Japanese intake of isoflavones is about 50 mg per day.1 The rest of Asia has an average consumption of about 25-45 mg per day, and Western consumption is less than 5 mg per day.2,3 Most of the studies in the literature have used relatively large intakes of soy isoflavones, much greater than the average intake in Asia.

Equol was first isolated and its structure determined in 1932. It is one of the estrogenic compounds in pregnant mare’s urine, hence its name. It is now apparent that it is derived from plant intake.4 Equol is a bacterial metabolite of daidzein (not genistein), and it is believed to be the only hormonally active metabolite. Genistein has a high binding affinity for the beta estrogen receptor and daidzein considerably less so. Equol binds to the alpha and beta estrogen receptors in a fashion similar to genistein (greater affinity for beta). At least in vitro, equol stimulated gene transcription with both estrogen receptors and greater potency than any other isoflavone.5

Bochanin and formononetin are methylated precursors that are metabolized to genistein and daidzein. Red clover and lentils contain significant amounts of these precursors that are converted to the isoflavones by ruminal bacteria, and then to the estrogenic equol. Because equol is estrogenic, its high intake was responsible for disruption of reproduction in sheep (but not in cattle), a problem known as "Clover disease." A similar daily intake in humans would have to amount to more than 1000 liters of soy milk, 8600 soy burgers, or 360 kilograms of tofu.4

Equol formation is totally dependent on intestinal microflora; therefore, strictly speaking, it is not a phytoestrogen. To be accurate, equol is a nonsteroidal estrogen, a member of the isoflavone family, and exclusively a metabolic product of intestinal bacteria. When given as a single bolus, equol reaches peak blood levels after 4-6 hours, and disappears with a half-life of about 9 hours.4 Thus its pharmacokinetics are similar to daidzein and genistein. Antibiotics that reduce the intestinal flora will cause a decrease in equol production.

The most important observation regarding equol is that 30-50% of adults do not produce equol, even when challenged with high doses of soy.4 This is a contrast to nonhuman primates and other animals; all that have been studied produce high levels of equol. Thus, there are 2 human populations: equol producers and nonequol producers. The equol-producing status of individuals can be determined by measuring the plasma equol concentration (equol producers have concentrations greater than 20 mg/L). Unfortunately, equol measurement requires mass spectrometry. Dietary studies have determined that equol producers consume less fat and more carbohydrates and fiber. This suggests that the nature of the dietary intake influences the characteristics of the intestinal bacterial population. However, the administration of large amounts of dietary fiber did not change urinary equol excretion.6 Furthermore, equol producers are always equol producers, suggesting that dietary intake is not the most critical factor. The key question is whether equol producers receive greater clinical effects from phytoestrogens than nonequol producers.

Clinical Effects

Thus far the clinical effects of isoflavones on hot flushing and bone have not been impressive. The study of hot flushing requires randomization to placebo treatment because placebo treatment is associated with an average 51% reduction in hot flush frequency. An Italian study found a 45% reduction in flushing with 60 g of isolated soy protein daily (76 mg isoflavones), compared with a 30% reduction in the placebo group.7 Two other studies, both with 50 mg/day of isoflavones, found a similar 15% reduction in the number of flushes compared with placebo.8,9 Another placebo-controlled short-term trial found a greater reduction in flushes with 70 mg isoflavones daily.10 In a randomized, crossover study of a high dose of isoflavones, 150 mg/day, for flushes in breast cancer survivors, the treated group and the placebo group demonstrated equal effects.11 The dose was 150 mg isoflavones per day, similar to 3 glasses of soymilk daily.

An Australian study randomized women to 118 mg/day isoflavones or placebo and could detect no difference after 3 months in hot flushing, libido, vaginal dryness, or any of a long list of symptoms.12 In a randomized study in Iowa, no differences were found in hot flush frequency comparing isoflavone-rich soy protein to a whey protein control.13 And finally, another randomized trial of breast cancer survivors found no difference comparing placebo with 90 mg isoflavones daily.14 Overall, the effects have been either similar to placebo treatment or there has been a small beneficial reduction that would have little clinical effect. Phytoestrogens are effective in preventing bone loss in rats but not in monkeys.15 In women, studies have demonstrated at best a slight effect on spinal bone, but no effect on hip bone.16-18

In view of the apparent importance of equol, all previous studies assessing the effect of isoflavones must be reassessed. In a 2-year randomized trial of postmenopausal women, isoflavone-rich soy milk increased spinal bone mass in the 45% of the subjects who were equol producers, with essentially no effect in nonequol producers.19 More profound beneficial effects on the lipid profile have been reported in equol-producing women.4 And in a case-control study, women with a high excretion of equol had a reduced risk of breast cancer.20

The population destined to receive a benefit from soy intake may be limited to equol producers. Studies need to be repeated measuring the responses in individuals who are identified as equol producers or nonequol producers. If the population destined to receive a benefit from soy intake is limited to equol producers, a convenient, inexpensive method must be developed to identify equol production. In addition, methods need to be developed to convert nonproducers to producers.

Dr. Speroff is Professor of Obstetrics and Gynecology Oregon Health Sciences University Portland.

References

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4. Setchell KR, et al. J Nutr. 2002;132:3577-3584.

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13. St. Germain A, et al. Menopause. 2001;8:17-26.

14. Van Patten CL, et al. J Clin Oncol. 2002;20:1449-1455.

15. Lees CJ, Ginn TA. Calcif Tissue Int. 1998;62:557-558.

16. Alekel DL, et al. Am J Clin Nutr. 2000;72:844-852.

17. Potter SM, et al. Am J Clin Nutr. 1998;68(Suppl): 1375S-1379S.

18. Gallagher JC, et al. The effect of soy protein on bone metabolism (abstract), North American Menopause Society Annual Meeting, 1999.

19. Lydeking-Olsen E, et al. J Nutr. 2002;132: 581S(abstract).

20. Ingram D, et al. Lancet. 1997;350:990-994.