S-equol

S -Equol [7-hydroxy-3-(49-hydroxyphenyl)-chroman] is a metabolite of the soy isoflavone daidzein. S-equol thus is characterized as an isoflavan. It is not of plant origin. Rather, S-equol is produced by intestinal bacteria in some, but not in all, humans after soy consumption. The ability of S-equol to play a role in the treatment of estrogen or androgen-mediated diseases or disorders was first proposed in 1984. Although still under investigation, the ability to produce S-equol may be associated with other health benefits, according to data from epidemiological and intervention studies. Studies in both animal models and humans have yielded data about the potential of S-equol use in menopause, breast, bone and prostate health. Supplements containing S-equol are under development, and testing in humans is ongoing for the management of menopausal symptoms, including the reduction in the frequency and severity of hot flashes as well as neck and shoulder stiffness.

History

Equol was first isolated from horse urine in 1932,^[1] and the name was suggested by this equine connection.^[2] Since then, equol has been found in the urine or plasma of many other animal species, although these animals have significant differences in their effectiveness in metabolizing the soy isoflavone daidzein into equol.^[3] In 1980, scientists reporting the discovery of equol in humans.^[4] The ability of S-equol to play a role in the treatment of estrogen- or androgen-mediated diseases or disorders was first proposed in 1984.^[5]

Chemical Structure

Equol is a compound that can exist in two forms, known as the enantiomers S-(-) equol and R-(+)equol, which means the compounds mirror each other, just as a person's left hand mirrors the right hand. Both forms are of interest from a medical and pharmacological perspective and are under development as nutraceutical and pharmacological agents for the treatment of a number of hormone-related conditions.^[6] However, only S-equol is produced in humans and animals with the ability to produce equol after soy isoflaovone consumption. S-Equol [7-hydroxy-3-(49-hydroxyphenyl)-chroman] is not of plant origin. It is a metabolite of the soy isoflavone daidzein. S-equol thus is characterized as an isoflavan.^[7] In contrast, R-equol is not made in humans, but can be chemically synthesized, such as in the laboratory.^[8] The molecular and physical structure of S-equol is similar to that of estradiol, the naturally occurring main sex hormone found in women.^[9]

S-equol Production in Humans

Not all humans can produce S-equol after soy consumption.^[10] The ability to do so depends on two things: soy and bacteria. First, the soy must contain the soy isoflavone daidzein and the amount may influence equol production. Second, the human must have certain strains of bacteria living within the intestine. Twenty-one different strains of intestinal bacteria cultured from humans have the ability to transform daidzein into S-equol or a related intermediate compound.^[11] Several studies indicate that only 25 to 30 percent of the adult population of Western countries produces S-equol after eating soy foods containing isoflavones,^{[12][13][14][15]} significantly lower than the reported 50 to 60 percent frequency of equol-producers in adults from Japan, Korea, or China.^{[16][17][18][19]} In research studies, the ability of a person to produce S-equol is determined with a standardized test in which the person, who has not had antibiotics for at least a month prior to testing, drinks two 240 milliliter glasses of soy milk or eats a soy food equivalent for three days followed by measurement of S-equol concentrations in their urine on the test's fourth day.^[20]

Biological Activity

Only S-equol is believed to have biological activity in the body.^[21] No other compound has yet been identified that has selective estrogen action and yet also has the ability to be an antagonist of androgen action.^[22][23]

Estrogen Receptor Binding

When comparing their relative affinities to bind to the human estrogen receptor alpha (ERα) S-equol has only about 2 percent of the affinity possessed by naturally occurring estrogen, 17-estradiol. Moreover, S-equol has a stronger affinity for the human estrogen receptor beta (ERβ), yet this affinity remains far less than that of estradiol, with S-equol just 20 percent of estradiol. The preferential binding of S-equol to ERβ, compared to ERα and to that of estradiol, indicates the molecule shares some, but not all, of the characteristics of a selective ER modulator (SERM).^[24]

Dihydrotestosterone Binding

S-equol binds to dihydrotestosterone (DHT), an androgen (male sex hormone), and it can inhibit DHT's stimulatory effect on prostate growth.^[25] S-equol does not bind to the androgen receptor, but S-equol may have potential use in a number of androgen-mediated conditions.^[26]

Pharmacokinetics

S-equol is a very stable molecule that essentially remains unchanged when digested, and this lack of further metabolism explains its very quick absorption and high bioavailability.^[27] When S-equol is consumed, it is rapidly absorbed and achieves a T_max (rate of peak plasma concentration) in two to three hours. In comparison, the T_max of the daidzein is 4 to 10 hours because it occurs in a glycoside (with a glucose (sugar) side chain) form and the body must, in order to use daidzein, convert daidzein to its aglycone form (without the glucose side chain), achieved through removal of the sugar during digestion. If consumed directly in aglycone form, daidzein has a T_max of one to three hours.^[28] Also, the percent fractional elimination of S-equol in urine after oral administration is extremely high and, in some adults, can be close to 100 percent, which is far higher than the percent fractional eliminations of either daidzein (30 to 40 percent) or genistein (7 to 15 percent).^[29] Recovery of S-equol in urine when S-equol was given in a nutritional supplement averaged 82 percent, in comparison to 61 percent when given as pure S-equol, which means S-equol has a very high bioavailability. Bioavailability is a measure of the amount of a substance that becomes available for activity in the body after the substance is administered.

S-equol Producer Status and Health Conditions

Based on decades of research, Kenneth D.R. Setchell, Ph.D., proposed in 2002 that "the clinical effectiveness of soy protein in cardiovascular, bone and menopausal health may be a function of the ability to biotransform soy isoflavones to the more potent estrogenic isoflavone, equol," noting that ability depends on the presence of intestinal bacteria capability carrying out that metabolism.^[30]

Menopause

Hot flashes and night sweats, both menopausal vasomotor symptoms, are reported frequently by women in Western countries experiencing menopause. However milder vasomotor symptoms are reported by menopausal Japanese women, who mainly experience a higher amount of shoulder stiffness and general fatigue relative to their hot flashes and night sweats, which are classified as somatic symptoms.^[31][32] Studies of Japanese postmenopausal women documented that those who can produce equol after soy consumption had milder menopause symptoms than those who were unable to produce equol.^[33]

Breast Health

Three recent studies using animal models of breast cancer found that S-equol did not stimulate the growth of mammary tumors, including one study using a cancer-causing chemical, dimethylbenz[a]anthracene, as well as two others that examined the effects of S-equol in mice implanted with human breast cancer cells.^[34][35][36] Controlled studies in Chinese or Asian American women who consumed high amounts of soy suggest that the ability to produce S-equol may be associated with reduction in breast cancer risk.^[37][38] However, the number of women in each study was small and the results showed a positive trend but did not reach statistical significance. Thus, a protective relationship between equol-producing status and breast cancer occurrence has not been established.

Bone Health

A one-year controlled study in Japanese postmenopausal women who consumed soy isoflavones documented that equol-producers, compared to equol-non-producers, had significant differences in their bone mineral density as measured at the total hip and intertrochanter (part of the femur, the leg bone that is part of the hip joint) regions. Also, women in the study who consumed a placebo instead of soy did not have differences in their bone mineral density. ^[39][40] A second controlled study of S-equol supplements documented inhibited bone resorption, attenuated bone loss and no sex or thyroid hormone concentration differences with the supplements compared to placebo, in non-equol-producing postmenopausal Japanese women.^[41]

Cardiovascular Health

Whether the ability to produce S-equol can have cardiovascular benefits is still under investigation.^{[42] [43]} A placebo-controlled study of S-equol supplement use documented significant changes to three metabolic syndrome factors: a significant lowering of a measure of blood sugar, hemoglobin A1c (HbA1c), and of "bad" LDL cholesterol as well as a significant improvement in a measure of artery wall stiffness known as cardio-ankle vascular index (CAVI). For all three measures, these changes remained significant and even more prominent among participants who were not S-equol producers.^[44] Another study in S-equol producers has documented that soy isolfavone-enriched pasta improved markers of cardiovascular risk.^[45] However, two other studies found that being able to produce S-equol had no effects on cardiovascular benefits from isoflavone supplementation^[46] or eating soy foods.^[47]

Prostate Health

Controlled studies among men residing in countries with high levels of soy consumption have suggested that equol levels are associated with reduced prostate cancer risk. In general, the studies of Japanese and Korean men suggest a protective effect of the ability to produce equol, lowering prostate cancer risk.^[48]

See also

• Daidzein
• Equol
• Estrogen
• Hormone Replacement Therapy
• Menopause
• Soy

References

External links

• Menopause: Medline Plus
• Menopause and Menopause Treatments
• North American Menopause Society (NAMS)