IngredientsAnti-aromatase compounds (also called natural aromatase inhibitors, abbreviated natural AIs) are a pharmacologically defined category of naturally occurring substances — drawn principally from plants, fungi, and marine organisms — that suppress the activity of the enzyme aromatase (CYP19A1). Unlike synthetic aromatase inhibitors developed as pharmaceutical agents, these are found in foods, botanical preparations, and dietary supplements. The category is not a single chemical entity but a broad functional class united by a shared molecular target. With the clinical success of several synthetic aromatase inhibitors in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating natural products — including those traditionally used for nutritional or medicinal purposes, such as botanical dietary supplements — for their aromatase-inhibitory potential.
Numerous natural compounds have been found to inhibit aromatase in noncellular, cellular, and in vivo studies. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. The study of these substances has been motivated in large part by oncology research but has extended to endocrinology, reproductive medicine, and preventive nutrition.
Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily — monooxygenases that catalyze many reactions involved in steroidogenesis — and is specifically responsible for the aromatization of androgens into estrogens. CYP19A1 is the rate-limiting enzyme in the biosynthesis of estrogens from their corresponding androgens.
The enzyme aromatase can be found in many tissues including gonads (granulosa cells), brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer. In females, aromatase is most active in the ovaries; in males, aromatase is most active in fat (adipose) tissue. In both males and females, estrogen plays a role in regulating bone growth and blood sugar levels.
Critical reactions catalyzed by CYP19A1 include the biosynthesis of estrone (E1) from androstenedione, estriol (E3) from 16-hydroxytestosterone, and 17β-estradiol (E2) from testosterone. Androstenedione and testosterone are well known as the most common physiological steroid substrates for CYP19A1. Aromatase CYP19A1 catalyzes the synthesis of estrogens in endocrine, reproductive, and central nervous systems. Higher levels of 17β-estradiol (E2) are associated with malignancies and diseases of the breast, ovary, and endometrium, while low E2 levels increase the risk for osteoporosis, cardiovascular diseases, and cognitive disorders.
CYP19A1 plays a critical role in estrogen biosynthesis by catalyzing the conversion of C19 androgens into aromatic C18 estrogens, and alterations in aromatase activity have been implicated in the development and progression of estrogen-dependent diseases. CYP19A1, a member of the cytochrome P450 gene superfamily, encodes aromatase, which catalyzes the last, rate-limiting step in estrogen biosynthesis.
The natural anti-aromatase literature encompasses several chemically distinct classes of compounds. In non-cellular testing, flavonoids were the most commonly reported class of active aromatase-inhibitory natural compounds found in non-cellular assays — including flavones, flavanones, biflavanones, chalcones, and isoflavones — with active compounds also found among xanthone, chromanone, fatty acid, terpenoid, alkaloid, coumarin, and depsidone classes.
Flavonoids are polyphenolic compounds distributed widely across the plant kingdom and are among the most intensively studied natural aromatase inhibitors. One of the earliest reports on phytoestrogen compounds inhibiting aromatase activity was published by Kellis Jr. and Vickery in 1984, who showed that several naturally occurring flavones altered estrogen biosynthesis. Later, in the late 1980s and into the 1990s, other investigators examined naturally occurring lignan and flavonoid compounds that inhibited aromatase activity in human preadipocytes, human placental tissue, JEG-3 cells, and ovarian tissue in rainbow trout.
The binding characteristics and structural requirements necessary for inhibition of human aromatase by flavones and isoflavones were obtained by computer modeling and confirmed by site-directed mutagenesis. It was found that these compounds bind to the active site of aromatase in an orientation in which their rings A and C mimic rings D and C of the androgen substrate, respectively.
Chrysin (5,7-dihydroxyflavone) is a naturally occurring flavone found in high concentrations in honey, bee propolis, and the passionflower plant (Passiflora caerulea). Chrysin, as a flavone present in high concentration in honey and propolis, has been studied for its potential in inhibiting aromatase for chemoprevention or treatment of hormone-dependent diseases. A 2020 systematic review in PMC identified 20 relevant articles on chrysin and aromatase: Twenty relevant articles were chosen from a total of 1,721 articles. Only one study was performed on humans and two were on rats, while all other studies were in vitro. All the studies except one showed that chrysin had the potency of aromatase inhibition; only one study performed on endometrial stromal cells showed that chrysin and naringenin did not indicate aromatase inhibitory properties. Various assay methods and experimental conditions were important factors leading to different results between studies.
Previous studies have shown chrysin, 7-hydroxyflavone, and 7,4′-dihydroxyflavone to be the most potent flavonoid inhibitors of aromatase; however, very poor oral bioavailability is a major limitation for the successful use of dietary flavonoids as chemopreventive agents. Methylated flavones, including 5,7-dimethoxyflavone, 7-methoxyflavone, and 7,4′-dimethoxyflavone, are much more resistant to metabolism than their unmethylated analogs and have much higher intestinal absorption. Among these, 7-methoxyflavone and 7,4′-dimethoxyflavone were almost equipotent to their unmethylated analogs, with IC50 values of 2 to 9 μM.
Apigenin is a flavone found in parsley, celery, and chamomile. Apigenin was found to be strongly active in microsomes in recent studies, consistent with much of the previous AI research on this compound, including in non-cellular and cellular tests.
Myricetin is a flavonol found in berries, red wine, and various vegetables. Myricetin was reported as a moderately active inhibitor of aromatase, consistent with previous literature reports of this compound.
Genistein, biochanin A, and other isoflavones from soy and red clover (Trifolium pratense) have also been studied. Biochanin A (5,7-dihydroxy-4′-methoxyisoflavone) is an isoflavone extracted from red clover. Although biochanin A was moderately active in inhibiting microsomal aromatase activity (IC50: 5–10 μM), it was strongly active when tested in JEG-3 cells (human placental choriocarcinoma cell line); however, it did not inhibit aromatase activity in granulosa-luteal cells, human preadipocyte cells, and was also inactive in a trout ovarian aromatase assay.
Lignans are a group of polyphenolic compounds found in seeds (especially flaxseed), whole grains, legumes, fruits, and vegetables. The inhibition of human preadipocyte aromatase activity by lignans and flavonoids suggests a mechanism by which consumption of lignan- and flavonoid-rich plant foods may contribute to reduction of estrogen-dependent disease, such as breast cancer. Aminoglutethimide, a pharmaceutical aromatase inhibitor, showed a Ki value of 0.5 μM; kinetic studies showed the inhibition by lignan and flavonoid compounds to be competitive.
Resveratrol (3,5,4′-trihydroxystilbene) is a stilbene polyphenol found primarily in grape skins, red wine, peanuts, and Japanese knotweed (Polygonum cuspidatum). Resveratrol, a naturally occurring stilbene found in the human diet, has been shown to mediate a host of biological activities. It has been reported to display both estrogenic and anti-estrogenic activities, depending on cell type and conditions, but inhibition of aromatase activity is weak (IC50 = 25 μM). Red wine, but not white wine, may have aromatase-inhibiting properties, though the exact mechanisms of action are not fully known. Polyphenols, tannins, and resveratrol have all been implicated as aromatase blockers, and there may also be synergistic interplay among selected constituents.
Research has also revealed complexity in resveratrol's steroidogenic actions. In cell studies, resveratrol inhibited the formation of the conjugated metabolites DHEA-S, E1-S, E2-S, and E2-G, as well as the formation of E3, in a dose-dependent manner. The literature highlights aromatase activity of natural stilbenes, chalcones, and flavanones and draws attention to new and under-investigated areas within each class worthy of further pursuit.
Grape seed extract (GSE) is a concentrated preparation from the seeds of Vitis vinifera containing oligomeric proanthocyanidins (OPCs), including procyanidin dimers. The main active ingredient for the aromatase-inhibitory bioactivity of grape seed extract is procyanidin dimers. While animal studies have demonstrated that red wine contains constituents that could block aromatase in vivo, the benefits also exist with non-alcoholic grape seed extract. Phytochemicals including quercetin, isoliquiritigenin, resveratrol, and grape seed extracts have been studied for their effect on the activation of breast cancer-associated aromatase promoters and their aromatase inhibitory potential.
White button mushrooms (Agaricus bisporus) are a potential breast cancer chemopreventive agent, as they suppress aromatase activity and estrogen biosynthesis. The major active compounds found in the ethyl acetate fraction of mushroom extract are unsaturated fatty acids such as linoleic acid, linolenic acid, and conjugated linoleic acid. The white button mushroom suppressed aromatase activity dose dependently, and enzyme kinetics demonstrated mixed inhibition, suggesting the presence of multiple inhibitors or more than one inhibitory mechanism.
The interaction of linoleic acid and conjugated linoleic acid with aromatase mutants expressed in Chinese hamster ovary cells showed that these fatty acids inhibit aromatase with similar potency and that mutations at the active site regions affect their interaction; while these results suggest the two compounds bind to the active site of aromatase, kinetic analysis indicates they are noncompetitive inhibitors with respect to androstenedione. Because only conjugated linoleic acid was found to inhibit testosterone-dependent proliferation of MCF-7aro cells, the physiologically relevant aromatase inhibitors in mushrooms are most likely conjugated linoleic acid and its derivatives.
Curcumin and related curcuminoids are the principal bioactive polyphenols of turmeric (Curcuma longa), a rhizomatous plant used extensively in South Asian culinary and medicinal traditions. Curcuminoids, including curcumin and its derivatives, show potent inhibition of aromatase (CYP19A1), crucial for estradiol synthesis. Studies evaluating 10 curcuminoids and their metabolites against human and rat CYP19A1 revealed species-specific IC50 values; cyclocurcumin (IC50, 4.43 μM) and curcumin (IC50, 3.49 μM) were the most effective inhibitors for human and rat CYP19A1, respectively. These compounds acted as mixed or competitive inhibitors, reducing estradiol production in human BeWo cells. Docking analysis showed that curcuminoids interact with CYP19A1's active site, forming a hydrogen bond with Met374.
Indole-3-carbinol (I3C) is derived from glucosinolates in cruciferous vegetables through hydrolysis catalyzed by the plant enzyme myrosinase. 3,3′-Diindolylmethane (DIM) is generated in the acidic environment of the stomach following dimerization of indole-3-carbinol (I3C) monomers present in cruciferous vegetables. Sources include broccoli, cauliflower, kale, cabbage, Brussels sprouts, and related Brassica species. CYP1A1 mediates the 2-hydroxylation of estrone, leading to increased levels of 2-hydroxyestrone — one of the two major competing hydroxylation pathways of estrone metabolism — and epidemiological and dietary studies have provided a link between high dietary intake of cruciferous vegetables and lowered cancer risks.
Cruciferae family vegetables are remarkably high in phytochemicals such as I3C and DIM, which are widely known as nutritional supplements and have been studied extensively in different types of cancers including breast, prostate, endometrial, colorectal, and others.
Berberine is a protoberberine alkaloid found notably in Coptis japonica (goldthread), Berberis spp. (barberry), and related plants used in traditional Chinese and Ayurvedic medicine. The protoberberine alkaloid berberine was found to be the main active compound in the extract of Coptis japonica, and its aromatase-inhibitory properties were studied in combination with fulvestrant, a clinically used estrogen receptor antagonist. Using the combination of berberine and fulvestrant, a synergistic inhibition of cell growth in MCF-7 cells was found, significantly different than either agent alone.
The potent enzymatic and cellular AI activities of γ-mangostin, one of the most abundant isolates from the pericarp of Garcinia mangostana, make it a promising lead for further in vivo and preclinical studies to determine the potential role of mangosteen botanical dietary supplements in cancer chemoprevention and/or chemotherapy for postmenopausal women with hormone-dependent breast cancer.
No traditional culture historically knew of the CYP19A1 enzyme or the concept of "aromatase inhibition." Rather, many of the plants now recognized as containing natural anti-aromatase compounds have long traditions of use for purposes that are retrospectively consistent with estrogen modulation, including management of menstrual disorders, fertility, breast complaints, and general vitality.
The anticancer properties of cruciferous vegetables were first recognized by the Roman statesman Cato the Elder (234–149 BC), who in his treatise of medicine wrote about applying a crushed cabbage leaf to cancerous ulcers. It is now well established that cruciferous vegetables contain a precursor phytochemical — glucosinolate — that undergoes hydrolysis by the plant enzyme myrosinase, yielding the bioactive compound indole-3-carbinol (I3C).
Turmeric (Curcuma longa), the source of curcumin, has been used in Ayurvedic medicine (India) and Traditional Chinese Medicine (TCM) for thousands of years, primarily for digestive complaints, pain, and inflammatory conditions. The connection to hormonal mechanisms is a modern scientific discovery. Similarly, Glycyrrhiza (licorice root), whose flavonoid constituents have been identified as aromatase inhibitors, has an extensive history in Greek, Chinese, Middle Eastern, and European herbal traditions as a treatment for respiratory, digestive, and adrenal conditions. Trifolium pratense (red clover), the source of biochanin A and other isoflavones, was used historically in European and North American folk medicine for respiratory conditions and as a "blood purifier," and its estrogenic effects in livestock grazing on red clover pastures were an early documented observation. The first evidence that red clover has estrogenic activity was reported after observing breeding problems in sheep grazing on red clover pastures, attributed to the isoflavone and coumestrol content of red clover. Serious fertility disturbances indicating estrogenic stimulation of cattle fed with red clover silage were also reported.
Flaxseed (Linum usitatissimum), rich in the lignan secoisolariciresinol, has long use in European and Middle Eastern culinary traditions, and was valued medicinally as a laxative and anti-inflammatory. Soy (Glycine max), the richest dietary source of isoflavones including genistein and daidzein, has been a staple food across East Asia for millennia. In the late 1990s, premenopausal women were fed soy isoflavones for approximately 100 days and urine samples were collected to quantify estrogen excretion levels; this study demonstrated that soy isoflavone consumption may exert cancer-preventive effects by decreasing estrogen synthesis, presumably by altering aromatase enzyme activity.
Since phytoestrogens are known to be constituents of animal and human food sources, these compounds have received increased research attention because of their potential significance and applications in human cancers and other diseases.
The primary mechanism shared by most flavones and isoflavones is direct interaction with the catalytic site of aromatase. The binding characteristics and structural requirements necessary for the inhibition of human aromatase by flavones and isoflavones were obtained by computer modeling and confirmed by site-directed mutagenesis. These compounds bind to the active site of aromatase in an orientation in which their rings A and C mimic rings D and C of the androgen substrate, respectively. Non-steroidal AIs interact reversibly with the active site of the aromatase through non-covalent interaction. Non-steroidal derivatives generally possess planar aromatic structures joined to an azole ring system, and the heterocyclic nitrogen interacts with the heme iron of the aromatase enzyme.
Synthetic treatments may lead to untoward side effects, and so the search for new aromatase inhibitors continues, especially those for which the activity is promoter-specific, targeting the breast-specific promoters I.3 and II. Several natural compounds, including resveratrol and grape seed extract, have been shown to suppress aromatase gene transcription through interaction with breast-cancer-specific promoters, representing a distinct and potentially more targeted mechanism compared to direct enzyme inhibition.
CYP1A1 mediates the 2-hydroxylation of estrone, one of the two major competing hydroxylation pathways of estrone metabolism, leading to increased levels of 2-hydroxyestrone. I3C and DIM shift estrogen metabolism toward the 2-hydroxylation pathway, producing less proliferative estrogen metabolites. Indole-3-carbinol activates two pathways linked to cancer prevention: aryl hydrocarbon receptor (AhR) signalling, which leads to expression of phase I enzymes (e.g., CYP1A1) via the xenobiotic response element, and antioxidant/electrophilic response element signalling, resulting in expression of phase II detoxifying enzymes such as glutathione-S-transferases. The ability of I3C to induce enzymes that metabolize genotoxic agents may contribute to cancer prevention.
Some compounds demonstrate mixed or non-competitive inhibition kinetics. Enzyme kinetics of white button mushroom demonstrated mixed inhibition, suggesting the presence of multiple inhibitors or more than one inhibitory mechanism. Kinetic analysis of linoleic acid and conjugated linoleic acid from mushrooms indicates they are noncompetitive inhibitors with respect to androstenedione.
Previous studies have shown chrysin, 7-hydroxyflavone, and 7,4′-dihydroxyflavone to be among the most potent flavonoid inhibitors of aromatase; however, very poor oral bioavailability is a major limitation for the successful use of dietary flavonoids as chemopreventive agents. This poor bioavailability gap between the inhibitory potency demonstrated in in vitro assays and what can be achieved in human tissue is a central challenge in the entire natural AI field. Some unsaturated fatty acids found to be active in non-cellular radiometric AI assays have been shown to be interference compounds, since they do not generally show activity in cellular AI screens.
The most scientifically developed area of natural AI research concerns estrogen receptor-positive (ER+) breast cancer. Estrogen-dependent breast cancer is more affected by the local production of estrogen via aromatase than by serum estrogen. The aromatase enzyme converts endogenous androgen to estrogenic compounds; its blockade lowers the in situ production of estrogen, which is demonstrated to encourage tumor proliferation. High CYP19A1 expression is highly significantly associated with poor overall, disease-free, and metastasis-free survival in estrogen receptor-positive breast cancer patients; CYP19A1 mRNA is significantly elevated in postmenopausal patients and in patients older than 50 years.
White button mushroom (in vitro/in vivo): White button mushrooms are a potential breast cancer chemopreventive agent. Mushroom extracts were evaluated in the estrogen receptor-positive/aromatase-positive MCF-7aro cell line both in vitro and in vivo. Mushroom extract decreased testosterone-induced cell proliferation in MCF-7aro cells but had no effect on MCF-10A, a nontumorigenic cell line. The in vivo action of mushroom chemicals was shown using nude mice injected with MCF-7aro cells; studies showed that mushroom extract decreased both tumor cell proliferation and tumor weight with no effect on the rate of apoptosis. A translational clinical trial was initiated to test anti-estrogenic activity of mushroom extract in humans. The research group discovered that an extract from white button mushroom has an aromatase inhibitory effect in a hormone-dependent xenograft murine model, with preliminary data suggesting an active phytochemical. As of the available literature, robust completed randomized controlled trials in humans specifically confirming clinical anti-aromatase efficacy of mushroom extract as a dietary supplement are not established in the reviewed peer-reviewed sources.
Grape seed extract (in vitro / limited clinical): Grape seed extract has been shown to act as an aromatase inhibitor in both men suffering from erectile dysfunction as well as postmenopausal women at high risk for breast cancer. However, a human clinical evaluation produced notably mixed results. A 6-week randomized study was conducted in postmenopausal women consuming 94 g of freeze-dried grape powder daily (a composite of red, green, and blue-black California grapes containing resveratrol, catechins, quercetin, and anthocyanins). In this study, there was no evidence that plasma hormone levels are altered by six weeks of daily consumption of 94 g of freeze-dried grape powder. This negative finding in a dietary-dose study highlights the translation gap between in vitro activity and human biological outcomes. A separate Mayo Clinic phase II clinical trial (ClinicalTrials.gov NCT00566553) investigated grape seed extract specifically as a "natural" aromatase inhibitor in postmenopausal women at elevated breast cancer risk. There is preliminary evidence that grape seed extract acts as a "natural" aromatase inhibitor, and such a study has potential to quantify the effectiveness of a natural substance that mimics the action of pharmaceutical aromatase inhibitors. Final published outcomes of this trial were not available within the sourced literature.
Chrysin (predominantly in vitro): Chrysin has potency in inhibition of the aromatase enzyme and thus can be useful in preventing and treating hormone-dependent breast cancer and as adjuvant therapy for estrogen-dependent diseases. However, the systematic review of 20 articles found only one human study; the evidence base is predominantly in vitro. The bioavailability limitation for chrysin is well-documented and substantially constrains translational relevance.
Curcumin (in vitro): Curcuminoids including curcumin and its derivatives show potent inhibition of aromatase (CYP19A1); of 10 curcuminoids tested, cyclocurcumin (IC50, 4.43 μM) and curcumin (IC50, 3.49 μM) were the most effective inhibitors for human and rat CYP19A1, respectively. Evidence at this stage is preclinical.
Overall evidence quality for breast cancer: While in vitro and animal data supporting aromatase inhibitory activity of multiple natural compounds are substantial and reproducible across independent laboratories, robust, completed human clinical trials demonstrating meaningful changes in circulating estrogen levels or breast cancer incidence/recurrence via natural AI supplements remain limited or inconclusive in the peer-reviewed literature reviewed here. Several synthetic aromatase inhibitors are currently in clinical use for the treatment of postmenopausal women with hormone-receptor positive breast cancer; these treatments may lead to untoward side effects, so a search for new aromatase inhibitors — especially those for which activity is promoter-specific — continues.
Emerging preclinical evidence reveals an alteration in the urinary estrogen metabolite associated with reduced risk of estrogen-dependent cancers in women such as breast, cervical, and endometrial cancers following high consumption of cruciferous vegetables. I3C and DIM at supplemental doses have been investigated in clinical trials for their influence on the urinary 2-OHE1 / 16α-OHE1 ratio, considered a marker of estrogen metabolism favoring less proliferative pathways. Both I3C and DIM have been investigated for their use in preventing, inhibiting, and reversing the progression of cancer as chemopreventive agents.
Indole derivatives have been shown to suppress the proliferation of various cancer cell lines at concentrations of 50–100 μM, including breast, colon, prostate, and endometrium, by targeting a wide spectrum of signaling pathways governing hormonal homeostasis, cell cycle progression, and cell proliferation and survival.
Conflicting reports can be found in the literature as to whether DIM is an agonist or antagonist of AhR in the expression of the CYP1 family of genes. Furthermore, DIM activates ERα in a ligand-independent manner, which involves the protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signaling pathways under certain conditions. This complexity underscores that DIM is not a simple aromatase inhibitor but a pleiotropic phytochemical with tissue- and concentration-dependent effects.
The ability of I3C and DIM to inhibit growth of human prostate cancer cells has raised interest in I3C for prostate cancer prevention. DIM inhibited dihydrotestosterone (DHT)-stimulated cell proliferation and DHT-induced activation of the prostate-specific antigen promoter in LNCaP cells, acting as an AR antagonist. White button mushroom extract is categorized as a complementary and alternative medicine agent or nutraceutical used primarily in the context of hormone-dependent cancers, such as prostate and breast cancer. Evidence in prostate cancer for natural aromatase-inhibitory supplements is preliminary and largely confined to cell lines and animal models.
The enzyme aromatase can be found in tissue of endometriosis and uterine fibroids. Because local aromatase activity contributes to estrogen excess in these conditions, interest has developed in natural AI compounds for management. However, clinical trial evidence for natural AI dietary supplements in these specific gynecological conditions was not identified in the peer-reviewed literature reviewed here. The evidence base at this time remains largely mechanistic.
In males, aromatase is most active in fat (adipose) tissue. Elevated aromatase activity in adipose tissue can convert testosterone to estradiol, contributing to reduced testosterone-to-estrogen ratios in men. Grape seed extract has been shown to act as an aromatase inhibitor in men suffering from erectile dysfunction. This claim originates from in vitro and limited human data; robust controlled clinical trials in men specifically assessing natural AI supplements for testosterone/estrogen balance and sexual function were not identified in the peer-reviewed sources reviewed here.
Natural anti-aromatase compounds are consumed in several forms:
With respect to dosages, the peer-reviewed sources reviewed here report:
It must be emphasized that in vitro IC50 values do not directly translate to human effective doses, given extensive first-pass metabolism, variable bioavailability, and distribution differences between in vitro and in vivo systems.
Patients who have hormone receptor-positive breast cancer and who are taking aromatase inhibitors should understand the benefits and risks of concomitant dietary supplement use. Among patients with cancer, those with breast cancer report the highest frequency of dietary supplement use. Patients with hormone-receptor-positive breast cancer have the risk for dietary supplement interactions not only with cytotoxic chemotherapy, but also with endocrine therapies such as tamoxifen and the third-generation aromatase inhibitors.
Some of the more problematic supplements are commonly found in over-the-counter herbal preparations marketed to help with signs and symptoms of menopause in women. There is genuine concern that phytoestrogenic compounds — many of which are the same sources as natural AIs — could act as estrogen receptor partial agonists and potentially interfere with, or counteract the effects of, pharmaceutical aromatase inhibitor therapy in cancer patients. Among the natural products tested as AIs, phytoestrogens such as flavones and isoflavones are able to bind ER and induce estrogen action.
Higher levels of 17β-estradiol are associated with malignancies; conversely, low E2 levels increase the risk for osteoporosis, cardiovascular diseases, and cognitive disorders. Excessive suppression of aromatase — even by natural compounds — carries theoretical risks for bone density, particularly in postmenopausal women. This mirrors documented adverse effects of pharmaceutical AIs, though the degree of inhibition achievable with dietary supplements is substantially lower.
Resveratrol has been reported to display both estrogenic and anti-estrogenic activities, depending on cell type and conditions, and its inhibition of aromatase activity is weak (IC50 = 25 μM). Conflicting reports can be found in the literature as to whether DIM is an agonist or antagonist of the aryl hydrocarbon receptor in the expression of the CYP1 family of genes. Furthermore, DIM activates ERα in a ligand-independent manner under certain conditions. These dual or context-dependent hormonal effects mean that the net in vivo outcome of consuming these compounds is not simply "anti-estrogenic."
Some natural compounds, including certain unsaturated fatty acids, have been shown to be interference compounds in non-cellular AI assays since they do not generally show activity in cellular AI screens. This underscores that positive findings in biochemical (non-cellular) assays should be interpreted cautiously and confirmed in cellular and in vivo systems before drawing conclusions about human efficacy.
The possibility of drug interactions between conventional drugs and herbal medicines is an emerging concern for therapeutic safety, as subsequent side effects and direct toxicities constitute a possible threat to successful clinical therapy. Simultaneous use of herbal products and other synthetic drugs can modify, increase, or decrease the therapeutic effects of a drug; in addition, new side effects can arise. Despite the considerable literature on resveratrol, little is known about potential drug interactions.
Serious fertility disturbances indicating estrogenic stimulation of cattle fed with red clover silage have been reported. While these are animal data, they illustrate the potential for isoflavone-containing supplements at high doses to interfere with reproductive hormone signaling.
With the clinical success of several synthetic aromatase inhibitors in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have been investigating the potential of natural products as AIs, particularly those used traditionally for nutritional or medicinal purposes, that may also afford AIs with reduced side effects. Despite extensive in vitro and growing animal-model evidence across flavonoids, stilbenes, lignans, and food-derived extracts, the body of completed, well-powered, randomized human clinical trials confirming meaningful endocrine endpoints from natural AI dietary supplements remains limited. For example, a six-week dietary grape powder intervention found no evidence that plasma hormone levels were altered. In the chrysin systematic review, only one study was performed on humans and two on rats, with all other studies conducted in vitro.
Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of tumor-specific aromatase promoters, further development of more specific and efficacious agents without adverse effects is still warranted. Plants are rich in chemopreventive agents that have great potential to be used in chemotherapy for hormone-dependent breast cancer, serving as a source for natural AIs. The scientific community regards natural aromatase inhibitors as a promising area requiring substantially more human clinical investigation before definitive conclusions on clinical efficacy can be drawn.
Health conditions that Anti-aromatase may help support.
Body systems that Anti-aromatase may help support.
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