IngredientsPhytoestrogens are defined as polyphenol molecules of plant origin with a chemical structure similar to that of the main female sex hormone, 17-β-estradiol, and due to this structural similarity are able to bind to estrogen receptors (ERs). The name derives from the Greek phyto ("plant") and "estrogen," the hormone which gives fertility to female mammals.
Phytoestrogens are plant-derived secondary metabolites that mimic mammalian estrogen 17β-estradiol structurally and functionally. They are secondary metabolites of plants, where they are produced in order to protect plants against pathogen attack, ultraviolet radiation, and stress-related responses. It has been hypothesized that plants use phytoestrogens as part of their natural defense against the overpopulation of herbivore animals by controlling female fertility.
The most well-known phytoestrogens — including flavonoids, isoflavonoids, lignans, coumestans, stilbenes, and prenylflavonoids — are the isoflavonoids, which are important active ingredients in medicinal and food plants. They include a wide variety of structurally different compounds: isoflavones (mainly found in soy), lignans (found in grains), stilbenes (found in the skin of grapes), and other less investigated compounds including flavones, flavans, isoflavanes, and coumestans.
Phytoestrogens are present in many human foodstuffs including fruits (plum, pear, apple, grape, berries), vegetables (beans, sprouts, cabbage, spinach, soybeans, grains, hops, garlic, onion), wine, tea, and they have been identified in a number of botanical dietary supplements.
The major source of plant-derived phytoestrogen compounds is soy (genistein). Isoflavonoids are highly abundant in the Fabaceae family. More than 1,000 types of isoflavonoids have been isolated from nearly 300 kinds of plants, and more are being discovered through modern analytical methods.
Key botanical sources include:
Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Available forms include:
Glycosides O and C of isoflavonoids are poorly absorbed in the intestine. They are converted by bacterial esterases and/or β-glycosidase enzymes to aglycones, which are absorbed more efficiently.
Phytoestrogens were first observed in 1926, but it was unknown if they could have any effect in human or animal metabolism. Medicinal herbs containing phytoestrogens have a long history of use in traditional medicine and were officially discovered in the late 1800s.
Although such phytoestrogens have only recently come to the attention of Western medicine, the use of plants to treat female patients for conditions related to the reproductive system has been known in Chinese medicine for hundreds of years. In Traditional Chinese medicine, several herbs rich in phytoestrogens are used to prevent and cure various diseases such as osteoporosis, cardiovascular diseases, and diabetes mellitus. In China, Korea, and Japan, herbs have been used for thousands of years to relieve perimenopausal symptoms.
Angelicae sinensis, Panax ginseng, Flemingia macrophylla, Pueraria lobata, Trifolium pratense preparations, Vigna unguiculata, and Glycine max have special importance in TCM. Dong Quai (Angelica sinensis) has been used in traditional Chinese medicine as a "female ginseng" or tonifier, restoring many of the body's functions.
Black cohosh (Cimicifuga racemosa), another compound with selective estrogen receptor modulator (SERM)-like properties, is an indigenous North American plant historically used by Native Americans for its analgesic effects to treat dysmenorrhea, labor pain, and arthralgias. In the 19th century, herbal physicians used the alcohol extract of the root to treat menstrual and menopausal complaints. Black cohosh is widely used in Europe for menopausal complaints.
Asian populations have historically had lower rates of cardiovascular disease, menopausal symptoms, breast cancer and other hormone-dependent cancers, diabetes, and obesity than Western populations. Soy is the cornerstone of a traditional Asian diet, an observation which has long fueled the widely held belief that consumption of soy foods reduces the risk of disease. These potential health benefits are consistent with the epidemiological evidence that rates of heart disease, various cancers, osteoporotic fractures, and menopausal symptoms are more favorable among populations that consume plant-based diets, particularly among cultures with diets that are traditionally high in soy products.
In traditional ethnobotanical practice, in more than 60% of cases fresh plant material was used to prepare remedies. Over 70% of remedies were applied orally, while the remaining ones were applied topically. Many remedies were prepared as mixtures of multiple ingredients.
Phytoestrogens are plant-derived dietary compounds with structural similarity to 17-β-oestradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)oestrogenic effects by binding to the oestrogen receptors. A common diphenolic structure resembling the structure of the potent synthetic estrogen diethylstilbestrol and hexestrol is possessed by them.
The estrogenic or antiestrogenic activity of any chemical depends on the ability of the compound to interact with the ERs (ERα, ERβ). The soy-derived genistein, coumestrol, and equol display a preference for transactivation of ERβ compared to ERα and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ERα. All other phytoestrogens tested, including resveratrol and human metabolites of daidzein and enterolactone, were weak ER agonists.
Affinity of ERs for phytoestrogens is about 4-fold lower than 17β-estradiol, but with dietary intake of precursors reaching 10 to 100 mg per day, the circulating concentrations could reach micromolar levels, and thus impact could be significant. Phytoestrogens have much higher affinity for ERβ compared to ERα, which might be of evolutionary significance since estrogen-dependent breast cancers are usually mediated by ERα while other physiological actions are mediated by ERβ.
Owing to their predominant dose-dependent relative binding and transactivation preference for ERβ over ERα, phytoestrogens may elicit tissue-specific biological responses, including estrogenic-like actions in ERβ-enriched tissues such as bone and vasculature, and modulation of ERα-mediated proliferative signaling in organs including the breast. This receptor selectivity has been proposed to contribute to a more favorable safety profile relative to synthetic estrogens; however, robust clinical evidence confirming reductions in estrogen-sensitive pathologies remains limited.
Phytoestrogens potentially modulate signaling molecules via: (1) blocking the nuclear and membrane estrogen receptors (ER), (2) interfering with the growth factor receptor, (3) inhibiting the G protein-coupled receptor in ER-deficient cells, and (4) activating apoptosis. It has been established that phytoestrogens interact with ERs, activating the transcription of several target genes. This results in the increase of the levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (Gpx), as well as an improvement of mitochondrial function.
Proposed mechanisms include estrogenic and antiestrogenic effects, induction of cancer cell differentiation, inhibition of tyrosine kinase and DNA topoisomerase activities, suppression of angiogenesis, and antioxidant effects.
In the gut, phytoestrogens are broken down by glucosidases to their respective aglycones, allowing more efficient absorption, although intestinal bacteria may further metabolize these products. For example, genistein and daidzein can be further metabolized to p-ethyl phenol and to equol and/or O-desmethylangolensin (O-DMA) respectively; only 30%–50% of the population can produce equol and approximately 80%–90% can produce O-DMA. Thus, not only will dietary factors contribute to phytoestrogen intake, but also individual variations in metabolism. Their bioavailability shows significant differences due to variation in the intestinal microflora of various races.
This is the most extensively studied indication for phytoestrogen supplementation. Menopause is characterized by a decrease in estrogen, which triggers uncomfortable symptoms of hot flushes, night sweats, sleep disturbances, and vaginal dryness.
Meta-analyses and Systematic Reviews: A meta-analysis and systematic review concluded that phytoestrogens appear to reduce the frequency of hot flushes in menopausal women, without serious side effects. This review analyzed 15 RCTs meeting inclusion criteria, with mean age of subjects ranging from 49 to 58.3 and 48 to 60.1 years in the placebo and phytoestrogen groups, respectively.
However, evidence from other systematic reviews is more cautious. One review concluded that the available evidence suggests that phytoestrogens do not improve hot flushes or other menopausal symptoms, although they are well tolerated.
Frequency of hot flushes was not reduced in meta-analysis of trials of red clover isoflavone extracts and results were mixed for soy isoflavone extracts. Of the reviewed studies, a few found a slight reduction in frequency and severity of hot flushes and night sweats compared to placebo, but many of these studies were underpowered and of low quality. In addition, there was a strong placebo effect in many of the studies. Overall, there did not appear to be evidence supporting the effectiveness of phytoestrogen treatments in the treatment of menopausal vasomotor symptoms.
Specific Preparations: After reviewing articles and meeting inclusion and exclusion criteria, 18 clinical trials of 2,351 female patients were analyzed. The phytoestrogen plants studied included soy, red clover, cohosh, hops, flax, pomegranate, anise, and Vitex agnus. Studies showed beneficial effects of phytoestrogens in controlling hot flashes, but in some cases, including soybeans, there were contradictory effects. More clinical trials are needed to achieve reliable results.
Evidence Strength: Overall, mixed to modest. Meta-analyses show statistically significant but clinically small reductions in hot flush frequency. High heterogeneity between studies, variable phytoestrogen compounds and doses, and significant placebo effects limit conclusions. The Cochrane review conclusion remained cautious.
Data from many studies on cultured bone cells and rat models of postmenopausal osteoporosis support a significant bone-sparing effect of the soy isoflavones genistein and daidzein. Translating this research to the clinic has been more challenging, and thus far only a few clinical studies have attempted to tease out the influence of phytoestrogens on bone from the many other components of the diet. Human studies have shown promising although variable results. Studies have been mostly of short duration and with relatively small sample sizes, making it difficult to observe significant and accurate changes in bone. Levels of intake of the soy protein and isoflavones are varied, and the optimal isoflavone intake for bone-sparing effects remains to be determined.
Key Human Trial: A randomized, double-blind, placebo-controlled trial set at three university medical centers in Italy enrolled 389 postmenopausal women with a bone mineral density (BMD) less than 0.795 g/cm² at the femoral neck and no significant comorbid conditions. After a 4-week stabilization period during which participants received a low-soy, reduced-fat diet, participants were randomly assigned to receive placebo (n = 191) or 54 mg of genistein (n = 198) daily for 24 months. The primary outcome was BMD at the anteroposterior lumbar spine and femoral neck at 24 months.
In osteoporosis, phytoestrogens bind to ERs, inhibit the RANKL-RANK pathway, suppress osteoclast activity, and activate the Wnt/β-catenin pathway to improve bone density and structure.
One 2-year RCT examined isoflavone effects specifically in premenopausal women: ninety-nine healthy premenopausal women were randomized to isoflavones (136.6 mg aglycone equivalence) and 98 to placebo for 5 days per week for up to 2 years. BMD, serum calcium, and urinary excretion of daidzein and genistein were measured before and during treatment. In 129 adherent subjects, isoflavone exposure, determined by urinary excretion levels, but not by dose assignment, interacted with serum calcium in affecting whole body BMD, but not hip and spine BMD.
Regarding equol and bone: At least one study found that consumption of isoflavones (18 g soy protein powder or 105 mg isoflavone aglycone equivalents) for a year failed to improve bone-mineral density in postmenopausal women, even among equol producers. However, this finding conflicts with prior studies, including one which found a 2.4% increase in lumbar spine bone-mineral density among equol producers following ingestion of an isoflavone-rich soy milk over 2 years.
Evidence Strength: Preliminary to moderate for specific preparations. Preclinical evidence is strong; human RCT data are promising but inconsistent, with the best evidence supporting genistein at doses of approximately 54 mg/day for at least 24 months in postmenopausal women with osteopenia.
Epidemiologic data indicate that women ingesting high amounts of phytoestrogens, particularly as isoflavones in soy products, have less cardiovascular disease, breast and uterine cancer, and menopausal symptoms than those eating Western diets. Preclinical and clinical studies have found that isoflavones have lipid-lowering effects as well as the ability to inhibit low-density lipoprotein (LDL) oxidation.
Phytoestrogens exert their effects through various mechanisms, including interactions with estrogen receptors, growth factor receptors, inflammatory mediators, thrombogenic reactions, and apoptotic pathways. This results in cardioprotective effects like modulating endothelial function, decreasing vessel tone, reducing inflammation, altering lipid profiles, and influencing arrhythmogenesis.
There have been no published trials on the effects of phytoestrogens on mortality or cardiovascular events, so studies currently rely on biomarkers of risk. Most evidence relates to soy isoflavones, but there is some evidence for lignans. Despite overwhelming evidence that phytoestrogen intake lowers the risk of myocardial infarction, prevents atherosclerosis, improves cardiac function, prevents hypertension, and reduces the risk of arrhythmias, there have been studies that show contradictory outcomes.
Evidence Strength: Promising but insufficient for cardiovascular event endpoints. The absence of hard endpoint trials (mortality, MI events) is a major limitation. Lipid-profile improvements are better documented than clinical outcome reductions.
The relationship between phytoestrogens and cancer risk is among the most debated areas in the literature.
Breast Cancer: While there is some evidence supporting a chemoprotective role for phytoestrogens in breast cancer, there is also evidence suggesting the possible adverse effects of phytoestrogen consumption. Despite numerous investigations, the mechanisms of phytoestrogen action in breast cancer have yet to be elucidated. It remains uncertain whether these plant compounds are chemoprotective or whether they may produce adverse outcomes related to breast carcinogenesis.
Phytoestrogens can bind weakly to oestrogen receptors and some have a preferential affinity for ERβ, which can inhibit the transcriptional growth-promoting activity of ERα. However, only saturating doses of phytoestrogens, stimulating both ERα and β, exert growth inhibitory effects.
The consumption of soy and soy foods among the Asian population has been associated with a decrease in the incidence of some types of tumors. However, there are concerns about whether these compounds may also have harmful effects, such as interfering with cancer treatments.
Prostate Cancer: One study suggested that soybean isoflavones can prevent the onset of prostate cancer either through mechanisms directly involving equol or daidzein's transformation to equol. It was thought that being an equol producer provides a protective effect against prostate cancer.
Phytoestrogens have antineoplastic effects with inhibition of cellular proliferation as well as angiogenesis, properties that could be protective against cancer development.
Evidence Strength: Inconsistent and controversial. Epidemiological data from soy-consuming populations suggest potential protective associations, but clinical intervention studies are lacking, and basic research signals are bidirectional (both pro- and anti-proliferative depending on dose, receptor status, and timing of exposure).
In diabetes, the targets of phytoestrogens extend to the PPAR and AMPK pathways, enhancing insulin sensitivity, promoting cholesterol transport, and reducing inflammation. Various beneficial health effects have been ascribed to phytoestrogens, including a lowered risk of obesity, metabolic syndrome, and type 2 diabetes.
Evidence Strength: Preliminary. Evidence is largely from preclinical studies and mechanistic investigations; large-scale human RCTs specifically addressing glycemic outcomes remain limited.
Various beneficial health effects have been ascribed to phytoestrogens, including a lowered risk of brain function disorders. In vitro and animal data suggest neuroprotective effects via ERβ-mediated pathways in the central nervous system. ERβ is expressed at higher levels than ERα in certain tissues, including specific regions of the central nervous system.
Evidence Strength: Preliminary; primarily preclinical. Human evidence for cognitive or neuroprotective endpoints remains sparse and inadequately powered.
A double-blind, randomized clinical trial evaluated hyaluronic acid concentration in postmenopausal facial skin after topical estradiol and genistein treatment. A 2020 PMC review examined anti-aging effects of phytoestrogens on collagen, water content, and oxidative stress, noting both genomic and non-genomic estrogen receptor signaling pathways are involved.
Evidence Strength: Preliminary. Small pilot studies show interest in topical and oral phytoestrogen effects on skin aging parameters, but clinical relevance and optimal dosing remain undefined.
The following dosages are drawn directly from cited clinical studies and should not be taken as established therapeutic recommendations:
Efficacy in achieving acute therapeutic endpoints — particularly vasomotor symptom relief — generally appears lower than that of high-potency synthetic estrogen analogs such as ethinyl estradiol.
Humans have estrogen receptors throughout the body that play a significant role in physiology; they are involved in reproduction, metabolism, digestion, mood, cognition, bone formation, cardiovascular health, and more. Given the widespread distribution of ERs, phytoestrogens have been studied across numerous physiological systems:
A litany of health benefits are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora.
As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general.
A Cochrane Database Systematic Review did not find evidence that treatment with phytoestrogens causes oestrogenic stimulation of the endometrium when used for up to two years.
Determining if phytoestrogens increase or reduce the risk of developing breast cancer has proven to be one of the most challenging human health impacts to address. It is well established that estrogens promote breast tumorigenesis, and that parameters which increase lifetime estrogen exposure are associated with elevated breast cancer risk. In contrast to beneficial health claims, the (anti)oestrogenic properties of phytoestrogens have raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects.
In the Mayo Clinic flaxseed pilot study, 50% of participants experienced mild or moderate abdominal distention, almost 30% experienced mild diarrhea, and about 20% withdrew because of side effects.
In humans, not everyone can produce equol from gut metabolism. It is postulated that equol producers benefit more than non-equol producers for all the endocrine-related effects.
Tamoxifen: Genistein, an isoflavone present in soy, may stimulate the proliferation of breast tumors and interfere with the action of tamoxifen. Soy seems to affect estrogen activity in the body. Taking soy with tamoxifen might change the effects of tamoxifen, and healthcare provider guidance is warranted.
Warfarin: Soy has been reported to decrease the effects of warfarin. This might increase the risk of clotting and regular blood monitoring is advisable.
Aromatase Inhibitors: Natural products showing estrogen-like activity, including Angelica sinensis, Paeonia lactiflora, Rehmannia glutinosa, Astragalus mongholicus, and Glycyrrhiza glabra, may reduce the anti-cancer effect of aromatase inhibitors and other hormonal cancer therapies.
Other Hormonal Therapies: Certain herbs can cause significant pharmacodynamic interactions when used with drugs used in cancer treatment. Examples include phytoestrogens vs hormones; "blood thinning" herbs vs anticoagulants; antioxidants vs chemotherapeutic agents; and immunostimulant herbs vs immunosuppressants.
Some phytoestrogens interfere with steroid hormone biosynthesis; for example, dehydrogenases of 17β-hydroxysteroids, 3β-hydroxysteroids, and aromatase, thereby lowering testosterone and estradiol production. Soy isoflavones have also been studied for effects on thyroid peroxidase activity, though clinical significance at dietary intake levels remains unresolved.
Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. Some soy-based infant formulas manufactured with soy protein contain isoflavones. The long-term endocrine effects of phytoestrogen exposure during infancy remain an area of active research concern.
The literature illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible adverse effects. For this reason, the therapeutic use of phytoestrogens for the treatment of cardiovascular diseases and other conditions, which appears to be extremely promising, should be handled cautiously, considering individual variances, dosage, and the specific components of phytoestrogens.
Health conditions that Estrogen may help support.
Body systems that Estrogen may help support.
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