Equolibrium by Nature's Sunshine

POSSIBLY EFFECTIVE

• Menopausal symptoms. Oral S-equol may modestly reduce menopausal symptoms, including hot flashes, in postmenopausal patients. Details: A meta-analysis of five clinical trials in postmenopausal patients shows that taking equol, or soy isoflavones for those patients who are equol producers, reduces hot flash scores when compared with placebo (103204). Two clinical trials included in this meta-analysis show that taking a specific S-equol supplement (Otsuka Pharmaceutical Co., Ltd.) 10-30 mg daily modestly reduces symptoms of menopause, including hot flashes, in patients who are considered to be equol nonproducers (19072,19073). In one of these clinical trials, S-equol 30 mg daily for 12 weeks reduced total menopause symptom scores by 19% when compared with placebo, with the largest effect on mood-related symptom scores. However, no change in hot flash frequency was seen at the 30 mg dose, and lower doses of 10 mg daily were not effective for improving total symptom scores (19072). However, in the other clinical trial, S-equol 10 mg daily for 12 weeks reduced hot flash frequency by 59%, compared with a 35% reduction in the placebo groups. Additionally, hot flash severity and neck or shoulder muscle stiffness improved in the S-equol group when compared with placebo (19073). Another small clinical study in postmenopausal Japanese patients shows that taking equol (FlavoCel EQ-5, Daicel Corp.) 10 mg daily for 3 months reduces menopausal symptom scores when compared with placebo. Scores were reduced by 81% and 53% with equol and placebo, respectively. Improvements in menopausal symptoms were reported regardless of equol producing status (107438). Most clinical research has been conducted in Japanese patients; however, one clinical trial has evaluated equol in North Americans. In this study, postmenopausal adults taking S-equol 10 mg, 20 mg, or 40 mg daily had similar reductions in hot flash frequency to those treated with a soy isoflavone tablet containing 24 mg daidzein, 22 mg genistein, and 2 mg glycitein. Hot flashes were reduced by around three events per day after 8 weeks of supplementation. Those taking S-equol 10 mg and 20 mg daily had modest reductions in muscle and joint pain when compared with soy isoflavone. The 20 mg and 40 mg doses were superior to soy isoflavone for reducing hot flash frequency in subjects with more than 8 hot flashes a day (19075). However, the validity of these findings is limited by the lack of a placebo comparator group.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. It is unclear if oral S-equol is beneficial for aging skin. Details: A small clinical trial in postmenopausal, equol nonproducing Japanese adults shows that taking a specific S-equol supplement (Otsuka Pharmaceutical Co., Ltd.) 10 mg or 30 mg daily for 12 weeks reduces crow's feet wrinkle area when compared with placebo. Taking S-equol 30 mg also decreased wrinkle depth by 4.5%, compared with an increase of 6.5% in the placebo group. No differences were noted for skin hydration, skin elasticity, or trans-epidermal water loss (19077).
• Breast cancer. Although there has been interest in using oral equol for breast cancer, there is insufficient reliable information about the clinical effects of equol for this purpose.
• Cardiovascular disease (CVD). It is unclear if oral equol is beneficial for preventing or treating CVD. Details: One small, low-quality study in Japanese females shows that taking 10 mg of a specific equol supplement (FlavoCel EQ-5, Daicel Corp.) daily for one year reduces arterial stiffness and triglyceride levels when compared to baseline (99643). However, this study included both pre- and post-menopausal patients, equol producers and nonproducers, and patients who were receiving hormone replacement therapy as well as those that were not. The validity of these findings is further reduced by the lack of a control group. Observational research in Japanese males aged 40 to 79 without cardiovascular (CV) or chronic kidney disease suggests that being an equol producer is associated with 38% lower odds of aortic calcification compared with equol nonproducers (110530). However, this association was not shown in other observational research of Japanese males aged 40 to 49 years without CV disease (110529).
• Cognitive impairment. It is unclear if oral equol is beneficial for preventing or treating cognitive impairment. Details: Observational research in elderly Japanese adults has found that being an equol producer is associated with an 8% incidence of mild cognitive impairment, compared with a 21% incidence in equol nonproducers (100334).
• Diabetes. It is unclear if oral equol is beneficial for the prevention of type 2 diabetes. Details: Observational research in Chinese adults has found that greater concentrations of equol in the urine are associated with a lower risk for type 2 diabetes (103203). However, it is unknown whether supplementation with equol is effective for diabetes treatment or prevention.
• Hyperlipidemia. Although there has been interest in using oral equol for hyperlipidemia, there is insufficient reliable information about the clinical effects of equol for this purpose.
• Metabolic syndrome. It is unclear if oral S-equol is beneficial in patients with metabolic syndrome. Details: A small clinical study in overweight or obese Japanese adults shows that taking S-equol (Otsuka Pharmaceutical Co., Ltd.) 10 mg daily for 12 weeks modestly reduces glycated hemoglobin (HbA1c), low-density lipoprotein (LDL) cholesterol, and cardio-ankle vascular index (CAVI) scores when compared with placebo. These effects were more profound in females who were equol nonproducers. Taking equol did not affect body mass index (BMI), blood pressure, blood glucose, total cholesterol, high density lipoprotein (HDL) cholesterol, or triglyceride levels (19078). Observational research in females aged 54-64 years in Japan suggests that the incidence of metabolic syndrome is 7% in equol producers compared with 11% in equol nonproducers. Equol producers also have modestly lower body weight, body mass index, and triglycerides than equol nonproducers (110527).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral equol is beneficial for lean NAFLD. Details: A large observational study in Japanese adults suggests the incidence of equol production is 43% in males who do not develop lean NAFLD compared with 8% in males who do develop lean NAFLD (110528). However, it is unknown whether supplementation with equol is effective for NAFLD prevention or treatment.
• Osteoporosis. It is unclear if oral S-equol is beneficial in patients with osteoporosis. Details: A small clinical trial in postmenopausal, equol nonproducing Japanese adults shows that taking a specific S-equol supplement (Otsuka Pharmaceutical Co., Ltd.) 10 mg daily for one year reduces urinary deoxypyridinoline, a biomarker of bone resorption, by around 21% when compared with placebo. Taking equol also attenuated a reduction in whole body bone mineral density (BMD) when compared with placebo; however, no benefit was seen in lumbar spine or total hip BMD (19076). While this preliminary study in equol non-producers shows some promising results, it is unclear whether providing daidzen to equol producers is beneficial for BMD. One clinical study in postmenopausal, equol-producing Chinese adults shows that taking soy flour 40 grams or purified daidzein 63 mg daily for 6 months does not improve bone turnover markers when compared to baseline (107437).
• Prostate cancer. Although there has been interest in using oral equol for prostate cancer, there is insufficient reliable information about the clinical effects of equol for this purpose. More evidence is needed to rate equol for these uses.

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LIKELY SAFE ...when used orally and appropriately. Equol supplements in doses up to 30 mg daily have been safely used in studies lasting up to 12 weeks (19072,19073,19074,19077,19078). Equol supplementation at a dose of 40 mg daily has been safely used in one study lasting 8 weeks, while supplementation with equol 10 mg daily has been safely used for one year (19075,19076).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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CONTRACEPTIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, equol might increase the levels and clinical effects of ethinyl estradiol found in contraceptive drugs.  Details In vitro research shows that equol inhibits the binding of estradiol to serum proteins (19259). Theoretically, this might increase the concentration of free, bioactive estradiol, thereby increasing the risk of adverse effects from ethinyl estradiol, including headaches, breast tenderness, dysmenorrhea, and weight gain.

DIURETIC DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, equol might cause additive diuretic effects when used with diuretic drugs.  Details In vitro and animal studies suggest that equol has diuretic effects, likely via inhibition of the Na-K-Cl cotransporter (19081,19261,19262).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, equol might increase the levels and clinical effects of estrogens.  Details In vitro research shows that equol inhibits the binding of estradiol to serum proteins (19259). Theoretically, this might increase the concentration of free, bioactive estradiol, thereby increasing the risk of adverse effects from estrogen replacement therapy, including headaches, breast tenderness, and weight gain.

TESTOSTERONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, equol might increase the levels and clinical effects of testosterone.  Details In vitro research shows that equol inhibits the binding of testosterone to serum proteins (19259). Theoretically, equol supplementation might increase the concentration of free, bioactive testosterone, thereby increasing the risk of adverse effects from testosterone replacement therapy, including fluid retention, headache, acne, and gynecomastia.

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General ...Orally, equol is generally well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal distension and constipation.
Serious Adverse Effects (Rare):
Orally: Depression.

Endocrine ...One particular concern with estrogen-like compounds is their potential effect on breast and reproductive system tissue. Endometrial hypertrophy was found in three subjects treated with S-equol 10 mg daily for two months in one clinical trial (19075). However, no changes to endometrial thickness were seen in other studies assessing vaginal cytology in response to equol supplementation using doses of 10-30 mg for up to three months (19074,19077). No abnormal mammography results were reported with equol in clinical trials that assessed this outcome (19075,19077).

Gastrointestinal ...Orally, equol has been reported to cause abdominal distention and constipation (19075).

Psychiatric ...Orally, equol has been rarely reported to cause depression (19075).

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