IngredientsEquol [7-hydroxy-3-(4′-hydroxyphenyl)-chroman] is a nonsteroidal estrogen of the isoflavone class. First isolated and identified from pregnant mare's urine in 1932, equol has a structure similar to the steroidal estrogen estradiol. Unlike the soy isoflavones daidzein or genistein, equol has a chiral center and therefore can occur as two distinct diastereoisomers. These mirror-image molecules — designated R-equol and S-equol (also written as R-(+)-equol and S-(-)-equol) — differ significantly in their biological activity.
By virtue of a chiral center, equol occurs as a diastereoisomer, and intestinal bacteria are enantiospecific in synthesizing exclusively the S-(-)equol enantiomer, an enantiomer that has selective affinity for the estrogen receptor-β. S-equol thus shows ER selectivity with a high affinity for ERβ, whereas R-equol can, at best, be classified as a weak estrogen.
Equol was first isolated from equine urine in 1932 and identified 50 years later in human urine as a metabolite of the soy isoflavones daidzin and daidzein, produced by intestinal bacteria in some, but not all, adults. Isoflavone phytoestrogens are bioactive plant constituents found mainly in conjugated forms in the products of more than 40 plant species, including soybeans, other legumes, whole grains, berries, and nuts. Two of the widely studied isoflavones from soybeans are daidzin and genistin, the glycoside forms of daidzein and genistein, respectively.
Recent evidence suggests that equol is found naturally in white cabbage. Equol (presumably S-equol) is present naturally in some plants, such as beans, cabbage, and lettuces, having a botanical origin. However, the primary route by which humans encounter equol is not through direct dietary intake of the compound itself, but through the microbial metabolism of daidzein in the gut. Phytoestrogen supplements made from extracts of red clover increasingly popular as alternative therapies for menopausal symptoms, indirectly provide a source of daidzein because the methoxylated isoflavone formononetin in red clover is efficiently biotransformed in the human intestinal tract to daidzein.
Because only a subset of people can produce equol endogenously, the compound has been developed as a stand-alone proprietary supplement ingredient. The most extensively studied proprietary form is SE5-OH, developed by Otsuka Pharmaceutical Co., Ltd. SE5-OH is the product of fermentation of soy germ by the bacterial strain Lactococcus garvieae 20-92 using a patented and proprietary process by Otsuka Pharmaceutical Co., Ltd. The patented fermentation process converts daidzein, a naturally occurring compound in soy germ, to natural S-equol, steadily increasing the concentration of natural S-equol until reaching a maximum concentration at 72 to 96 hours and decreasing daidzein by 95 percent. Following fermentation, the SE5-OH powder undergoes a sterilization process using heat denaturation that deactivates the bacteria.
Tablets are compressed from the fermented soy product and mixed with excipients for tablet stability and dissolution. The supplement formulated in 250-mg tablets contains 5 mg of S-(-)equol. Each tablet also contains 30–40% protein, 10–15% fat, 25–30% carbohydrate, and 5–15% fiber. The ingredient has self-affirmed GRAS (Generally Recognized As Safe) status. Equol is also available in racemic (R+S) and synthetic forms for research purposes, and both enantiomers are being explored as nutraceutical and pharmacological agents. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents.
Equol itself was not identified as a distinct compound until the twentieth century, and its direct use as an isolated supplement has no traditional precedent. However, the concept of equol production is deeply embedded in the context of traditional Asian soy consumption, which has been practiced for millennia.
Asians have a long life expectancy that may be related to their consumption of soy-containing phyto-estrogens. In addition, Asians produce S-equol, a gut bacterial metabolite of soy daidzein that is a potent antioxidant and binds selectively to estrogen receptor β (ERβ). Observational epidemiology has long noted that populations consuming traditional East Asian diets rich in fermented and unfermented soy foods — including tofu, miso, natto, and tempeh — experience lower rates of several chronic diseases including hormone-dependent cancers, cardiovascular disease, and menopausal symptoms compared to Western populations.
These individuals (equol producers) comprise 30% and 60% of populations consuming Western and soy-rich Asian diets, respectively. Since the higher percentage of equol producers in populations consuming soy-rich diets is correlated with a lower incidence of hormone-dependent diseases, considerable efforts have been made to detect the specific colonic bacteria involved in the metabolism of daidzein to the more estrogenic compound equol.
In 1932, Marrian and Haslewood, working at University College London, first isolated and elucidated the chemical structure of the isoflavone metabolite equol. The "unknown" was also present in the urine of nonpregnant mares and stallions, leading to the conclusion that its excretion was "quite unspecific for pregnancy." Its identification in human urine as a microbial metabolite of dietary daidzein — and its subsequent characterization as a biologically active, ERβ-selective molecule — occurred in the latter decades of the twentieth century, ultimately leading to its development as a proprietary supplement ingredient.
After soy products are consumed, the bacteria of the intestinal microflora metabolize isoflavones to metabolites with altered absorption, bioavailability, and estrogenic characteristics. Daidzin, the precursor of daidzein, is the glycosidic form that contains a carbohydrate portion of the molecule. Daidzin is metabolized in the gastrointestinal tract by intestinal bacteria, which hydrolyze the carbohydrate moiety, to the biologically active isoflavone daidzein. Daidzein is then further metabolized in the intestine to equol at relatively low or high levels dependent upon several biological, dietary, and presumably environmental factors. Dihydrodaidzein then branches into two pathways to form O-desmethylangolensin or equol.
The conversion of daidzein to equol requires specific anaerobic bacteria. One of the widely studied metabolites produced by bacteria residing in the gut of subjects consuming soy-containing isoflavones is equol, which until recently was thought to be produced only by anaerobic colonic bacteria. Key equol-producing species identified in human studies include Adlercreutzia equolifaciens, Asaccharobacter celatus, and Slackia isoflavoniconvertens. Twelve species identified in fecal samples with equol-producing capacity include Asaccharobacter celatus, Bacteroides ovatus, Bifidobacterium breve, Bifidobacterium longum, Finegoldia magna, Limosilactobacillus mucosae, Lacticaseibacillus paracasei, Latilactobacillus sakei, Lactococcus garvieae, Proteus mirabilis, Slackia isoflavoniconvertens, and Streptococcus intermedius.
Of the participants in one cohort study, 30.9% were stable producers, 26.1% unstable producers, and 43.0% non-producers. Stable producers showed significantly higher gut bacterial diversity than unstable producers and non-producers and a distinct microbiota composition, despite comparable daidzein intake across groups. Equol-producer status is a relatively stable phenomenon, as evidenced from repeat testing over prolonged periods of time in adults.
S-equol showed the greatest affinity for ERβ (Ki = 0.73 ± 0.2 nmol/L), whereas its affinity for ERα (Ki = 6.41 ± 1 nmol/L) was relatively poor. In contrast, R-equol possessed only 4.8% and 25.0% as much relative binding affinity, respectively, for ERβ and for ERα as did S-equol. For comparison, 17β-estradiol binds ERα with a Kd of 0.13 nmol and ERβ with a Kd of 0.15 nmol.
S-(-)equol possesses unique properties. It preferentially binds to ERβ and therefore can be considered to have selective estrogen receptor modulator-like properties, but it also antagonizes the action of the potent androgen dihydrotestosterone (DHT). Equol resembles the chemical structure of the female hormone estrogen and it is thought to exert estrogenic actions by genomic pathways through estrogen receptors α and β in the cytoplasm and nucleus and by a rapid nongenomic pathway through G protein-coupled estrogen receptors.
Equol has the ability to bind specifically the potent androgen 5alpha-dihydrotestosterone (5α-DHT) with no affinity for a variety of other steroids. It has the unique characteristic to bind specifically 5α-DHT by sequestering 5α-DHT from the androgen receptor (AR), thus decreasing androgen hormone actions to improve prostate health by acting as a selective androgen modulator (SAM). Equol administration reduces PSA levels from LNCaP cells under 5alpha-DHT stimulation, decreases rat prostate size, decreases serum 5alpha-DHT levels and androgen hormone action, while not altering other circulating sex steroids or LH levels.
Equol's antioxidant effects operate via Nrf2 activation and include effects on extracellular matrix proteins like collagen and elastin and protection against oxidative stress. S-equol, through its binding to ERβ in skin, upregulates the expression of key genes and proteins to reduce oxidative stress. In the cardiovascular system, S-equol binds to endothelial GPR30 (GPER), a membrane-associated estrogen receptor, to enhance endothelial cell activity and to give a favorable cardiovascular risk profile.
Equol has a chiral carbon resulting in two isomers. Both equol isomers exhibit antioxidant, anti-inflammatory, skin protectant (against ROS/oxidative stress) and specifically anti-androgen hormonal actions by binding free 5α-dihydrotestosterone (5α-DHT) as a selective androgen modulator (SAM). Equol, a metabolite of isoflavones produced by gut bacteria, may contribute substantially to beneficial lipid-lowering effects.
About 50% of Asians and 25% of non-Asians host the intestinal bacteria that convert daidzein into S-equol. About 50 percent of Asians and 20 to 30 percent of North Americans and Europeans, who in general consume less soy than Asians, have the ability to produce equol.
In one study in Japan, the prevalence of equol producers was more than 40%, consistent with a previous Japanese study. Moreover, the equol producers were significantly older than the non-producers. In the younger Japanese generation, the consumption of soy products has been decreasing with the increase of Western food intake. Equol production was not determined by intake of soy isoflavones alone, which suggested that gut microbiota composition is critical in the equol production process.
This observation led to the term equol-producers to define those adults that could make equol in response to consuming soy isoflavones and the hypothesis that the health benefits of soy-based diets may be greater in equol-producers than in equol nonproducers. A gene expression study reported striking differences in expression of a number of estrogen-responsive genes in postmenopausal women who were equol producers compared with those that were non-equol producers after chronic administration of a soy isoflavone supplement.
This is the area with the most extensive clinical research on proprietary equol preparations.
Systematic Review and Meta-Analysis: A systematic review and meta-analysis assessed the efficacy of equol for the alleviation of hot flashes, a major menopausal symptom, by analyzing existing evidence from randomized clinical trials (RCTs) using equol treatment and soy isoflavones, especially daidzein, in equol producers and nonequol producers.
Key RCT — Japanese Women (Journal of Women's Health): An 8-week randomized, double-blind, active comparator trial with SE5-OH was conducted in postmenopausal women aged 45–65 years who experienced ≥5 hot flashes per day. The trial used supplement tablets which each contained 5 mg of S-equol, and trial participants took one tablet twice daily. Controlled clinical trials documented that SE5-OH containing S-equol reduces the frequency of hot flashes as well as muscle discomfort associated with menopause, both in women in Japan and the United States.
US Pilot RCT — Active Comparator Design: The only randomized controlled trial carried out in the United States found that S-equol significantly reversed the severity and frequency of hot flashes, but the study lacked a placebo group, although it did include an active control. In the double-blinded study of 102 US postmenopausal women, eight weeks of daily SE5-OH supplement doses containing 10, 20, or 40 milligrams (mg) of natural S-equol reduced the frequency of moderate to severe hot flashes, as did 50 mg doses of a soy isoflavone supplement used as a comparator.
Dose-Frequency Pilot RCT: One study randomized 130 peri- and postmenopausal women with an average of 5+ moderate/severe hot flashes per day to treatment arms with varying total daily isoflavone doses and dosing frequency, separately for equol producers and non-producers. Results suggested that a 2–3 times per day dosing frequency may improve the benefit of isoflavones for vasomotor symptom relief, particularly in equol producers and for nighttime symptoms. Larger studies are needed to confirm these findings.
Evidence Strength: Clinical trials that evaluated the efficacy of an S-equol-containing product found that vasomotor symptoms were alleviated, but these trials were limited in scope and primarily involved Japanese women for whom hot flashes are a minor complaint. Many clinical studies measuring the effectiveness of dietary sources of soy isoflavones for the treatment of menopausal vasomotor symptoms have been negative. It must be noted that in many of the trials, hot flashes improved in both placebo and treatment groups, indicating high placebo response rates. Thus, it is difficult to distinguish between the beneficial effects of soy, placebo response, and non-specific effects of monitoring and study participation. The overall evidence base remains promising but is limited by relatively small sample sizes, short study durations, and predominant enrollment of Japanese women.
Prospective Observational Study (Japanese Women, 12 Months): To examine changes in bone and cardiovascular parameters and tolerability in middle-aged Japanese women taking equol supplement for a year, this was a prospective observational study of 74 women receiving outpatient care, who received per oral equol-containing supplement at 10 mg/day. Significant reductions in respective parameters were observed in women with moderate and high risk for arteriosclerosis and bone resorption risk, and bone fracture risk (−26.68% [−76.43 to −5.99]). All 15 women with high baseline parathyroid hormone levels achieved a median of 50% reduction from their baseline values.
Patent-Supported Findings: Equol is reported to be an important bone-trophic agent that, unlike estrogens, has the ability to not only reduce the activity of the bone-resorbing cells, but can actually increase bone mineral density in postmenopausal women.
Evidence Strength: One-year equol supplementation was tolerable and induced improvement of certain bone and cardiovascular parameters, especially in higher risk groups. Further controlled studies are needed to explore long-term equol use for wellbeing of middle-aged women. Evidence is preliminary; the primary published study lacked a randomized placebo-controlled design and was conducted in a single clinic setting.
Crossover RCT (Metabolic/Lipid Outcomes): In a double-blind randomized controlled crossover trial of 54 overweight or obese Japanese people, S-equol treatment (10 mg daily, orally, Otsuka Pharmaceutical Co., Ltd.) for 12 weeks led to a significant decrease in serum LDL-cholesterol levels and arterial stiffness (measured by the cardio-ankle vascular index).
Arterial Stiffness (Observational Study): Reduction in arterial stiffness was observed after 12 months of equol supplementation (1402.3 cm/s vs. 1367.3 cm/s, p < 0.001). In the cardiovascular system, S-equol binds to endothelial GPR30 (GPER), a membrane-associated estrogen receptor, to enhance endothelial cell activity and to give a favorable cardiovascular risk profile.
ACE Trial (Ongoing, Phase II RCT): The Arterial Stiffness, Cognition, and Equol (ACE) trial investigates whether daily equol supplementation can slow the progression of arterial stiffness, brain white matter lesions, and cognitive decline in older adults without dementia. Community-dwelling adults aged 65 to 85 years without dementia were enrolled and randomized 1:1 to receive either 10 mg/day of equol or placebo for 24 months.
Evidence Strength: Although some observational and intervention studies suggest that the ability to produce equol is associated with reduced risk of breast and prostate cancer, CVD, improved bone health, and reduced incidence of hot flushes, others have reported null or adverse effects. Results on blood cholesterol from observational data are hard to discern and further well-designed clinical trials are warranted to examine the effects of equol on blood cholesterol levels. Current cardiovascular evidence is preliminary and largely derived from small, short-duration, or observational studies in Japanese populations.
In Vitro and Animal Evidence: The original discovery that equol also specifically binds 5α-dihydrotestosterone (DHT), and that sub-acute treatment with equol for intact male rats induces a pronounced reduction of DHT secretion followed by a decrease in prostate weight, opened a new age in the treatment of androgen-mediated prostatic disorders and cancer.
Clinical Signal (Benign Prostatic Hyperplasia, BPH): The results of one study showed a low dose of equol positively improved moderate to severe BPH symptoms according to IPSS indices. In moderately symptomatic men (n=10), 5 out of 7 of the IPSS parameters significantly improved by 4 weeks of equol treatment. In severely symptomatic men (n=8), all 7 of the IPSS parameters significantly improved with 4 weeks of equol treatment. There were no significant changes in androgen levels, general blood chemistries, or cardiac and hepatic function parameters. However, 5α-DHT levels declined by 21% in severely symptomatic men.
Evidence Strength: In examining the evidence that Asian cultures have lower prostate cancer rates compared to Western cultures, when data is stratified examining individuals that "produce equol" naturally after soy, equol production emerges as a relevant factor. The published human evidence for equol in prostate health is limited in sample size and study design; definitive conclusions require larger controlled trials.
Mechanisms: Equol has been found to improve skin health by increasing elastin and collagen content to improve skin characteristics or robustness. The mechanism of this action is believed to block the hormone action of 5α-DHT, which would in turn decrease oil production from the sebaceous glands to decrease acne and other skin disorders. Since equol, and particularly S-equol, binds estrogen receptor(s), the protective effects of the estrogen-like molecules stimulate production of elastin and collagen in the skin, thought to be mediated via ERβ.
Pilot RCT (Skin Aging, Postmenopausal Women): A pilot randomized, placebo-controlled trial investigated the effects of natural S-equol supplementation on skin aging in postmenopausal women (published in Menopause, 2012). The main focus of this research covers the characteristics of equol (phytoestrogenic, antioxidant, and enhancement of extracellular matrix properties) to reduce skin aging along with its anti-aging skin influences via reducing oxidative stress cascade events.
Evidence Strength: Skin-related evidence is largely derived from in vitro organotypic culture studies, patent documentation, and a small pilot RCT. The anti-aging skin evidence base for equol is mechanistically coherent but remains preliminary in terms of clinical human trials.
Equol, a gut microbiome-derived metabolite of soy isoflavone daidzein, functions as a selective estrogen receptor beta (ERβ) agonist. In preclinical studies, it has demonstrated vascular protective and antioxidant effects, with emerging evidence suggesting potential neuroprotective properties. However, its role in preventing vascular aging and cognitive decline in humans remains unexplored.
Equol, a metabolite of a soy isoflavone transformed by the gut microbiome, is anti-oxidant and anti-amyloidogenic, and a randomized controlled trial of equol targeting white matter lesion volume is warranted. So far, small clinical trials of S-equol have not shown cognitive benefits.
Ongoing Pivotal Trial: The ACE trial is an early-stage multi-center randomized controlled trial designed to test the effect of a 24-month intervention of 10 mg/day equol supplementation on arterial stiffness, white matter lesions (WMLs) in the brain, and cognitive decline among approximately 400 individuals aged 65 and 85 without dementia. The multisite trial enrolled 369 self-reported White and Black older adults aged 65 to 85 years.
Evidence Strength: As of the time of this writing, no completed, adequately powered RCT has demonstrated a significant cognitive benefit for equol in humans. The ACE trial represents the first major effort to address this gap. Evidence remains preclinical and observational.
A crossover study of overweight or obese Japanese participants found that S-equol supplementation at 10 mg daily for 12 weeks led to reductions in LDL cholesterol levels and arterial stiffness. One cross-sectional study found that equol production was significantly associated with the prevalence of dyslipidemia, including a marginal increase in serum lipids. Studies on metabolic syndrome parameters have had mixed results, and this area requires larger, better-controlled trials.
Researchers from China reviewed the metabolism of soy isoflavones into equol by specific gut bacteria and its role in hormone-dependent and non-hormone-dependent cancers, discussing relevant gut microbiota and molecular mechanisms to understand equol's anti-tumor effects and potential in cancer treatment. Epidemiological studies suggest a complex relationship between equol levels and cancer risk, with some conflicting evidence regarding its effects on non-hormone-dependent cancers. Future research should focus on understanding equol's effective concentration range, its impact on tumors with varying ER expressions, and the actions of its different isomers.
Epidemiological data suggest that regular intake of isoflavones from soy reduces the incidence of estrogen-dependent and aging-associated disorders. This soy isoflavone is decomposed to equol under the action of gut microflora, and this degradation product has been shown to be more bioactive than its precursor daidzein, revealing a strong and multifaceted anticancer potential.
Evidence Strength: Evidence for equol in cancer prevention is currently epidemiological and mechanistic (in vitro and animal models). No completed RCT has yet established a causal preventive relationship between equol supplementation and reduced cancer incidence in humans.
The daily dose of S-equol used in most trials was 10 mg, and because the half-life of S-equol is 7–10 hours, to maximize efficacy, it was taken twice daily. The following specific doses have been reported in clinical studies and trials:
S-equol was well tolerated and there were no significant drug-related adverse events, even at the highest dose tested of 320 mg. There were also no meaningful changes in routine serum chemistry values, complete blood count, electrocardiogram, or systolic or diastolic blood pressure in both studies. In both studies, all adverse events were considered mild or moderate (none were severe), and none required any action or led to study drug discontinuation.
In the 12-month Japanese observational study, there were no reported adverse events or abnormal findings in the blood chemistry, Pap smear, mammography, and transvaginal ultrasound during periodic follow-ups.
SE5-OH was negative for chromosome aberrations in Chinese hamster lung cells up to 3,000 μg/ml with and without metabolic activation.
In female mammals, weak estrogen-like effects of equol are often observed in estrogen-sensitive organs such as the uterus, vagina, and mammary gland. The clinical trial NCT00962585 recorded selected gynecological adverse events. Observed adverse events included endometrial hypertrophy (4.65% at 10 mg BID; 7.14% at 50 mg BID), breast tenderness (2.33% at 10 mg BID), vaginal hemorrhage, and vaginal discharge at various doses; these events were also present at low rates in the placebo group. These findings merit attention given equol's estrogenic activity, particularly at higher doses and in women with pre-existing estrogen-sensitive conditions.
Drug interactions with S-equol are not well-documented. S-equol binds to estrogen receptors, so it is likely to interact with drugs that target the estrogen system. Studies have shown that isoflavones including S-equol bind directly to the G protein-coupled estrogen receptor (GPER) at the same position as 17β-estradiol, suggesting that some of the effects of S-equol may be exerted in part by GPER signal transduction pathways. Potential pharmacodynamic interactions with tamoxifen, aromatase inhibitors, hormone replacement therapy, and other selective estrogen receptor modulators are biologically plausible but have not been systematically studied in clinical pharmacology trials.
The SE5-OH ingredient has self-affirmed GRAS (Generally Recognized As Safe) status. Equol is regulated in the United States as a dietary supplement ingredient and has not received FDA approval as a drug. Its use in Japan and parts of Asia is more established, with several published trials conducted in Japanese clinical and community settings.
Although some observational and intervention studies suggest that the ability to produce equol is associated with reduced risk of breast and prostate cancer, CVD, improved bone health, and reduced incidence of hot flushes, others have reported null or adverse effects. Studies to date have been limited and well-designed studies that are sufficiently powered to investigate the relations are needed. Although equol shows promise in cancer prevention and treatment, its effective concentration range and specific mechanisms in different tumor types remain unclear. Many clinical trials of equol or its precursor daidzein have been funded or supported by Otsuka Pharmaceutical Co., Ltd., which should be considered when evaluating conclusions drawn from industry-supported research.
Health conditions that Equol may help support.
Equol is a non-steroidal estrogen metabolite produced from daidzein by gut bacteria in ~30–50% of Westerners, with higher prevalence in Asian populations. It has higher ERβ affinity than its parent daidzein and has been studied specifically as a SERM for menopausal symptoms and bone turnover. RCTs show equol supplementation improves bone biomarkers in postmenopausal women, including non-producers.
Equol is a metabolite of the soy isoflavone daidzein, produced by intestinal bacteria, and is considered a more potent phytoestrogen than its parent compound. A meta-analysis of RCTs confirmed significant benefit of equol supplementation for reducing hot flash scores in postmenopausal women, particularly among non-equol-producers who cannot synthesize it endogenously.
Body systems that Equol may help support.
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