Integrative Testing for Breast Health

Estrogen Metabolism in the Body is Important for Breast Cancer Risk

Estrogen metabolism significantly impacts the risk of breast cancer, particularly in postmenopausal women, as it plays an important role in tumor initiation and development.
Evaluating estrogen metabolism has been part of an integrative approach for health management for two reasons: it is part of a root cause analysis of a symptom of hormone imbalance and it can be largely impacted by lifestyle factors. Sleep, nutrition, stress management, avoiding exposure to endocrine disrupting substances may all contribute to improved estrogen metabolism and thus improvement in symptoms such as PCOS, endometriosis, mood disruptions and cancer risks. Supplement support has also been demosntrated to be beneficial.

Estrogen is Metabolized in 2 Phases in the Liver and Excreted in the Gut and Urine

Phase I: Liver

The principal endogenous estrogens—estrone (E1), estradiol (E2), and estriol (E3)—undergo extensive metabolism, which includes hydroxylation, oxidation, and reduction reactions. These reactions are mediated by enzymes such as cytochrome P450 3A4 (CYP3A4).
This metabolism of estrogens involves hydroxylation at different positions on the steroid ring, leading to various metabolites that can influence cancer risk.

Phase II: Liver and Gut

Phase II metabolism involves conjugation reactions, where estrogens are converted into more water-soluble forms through sulfation and glucuronidation. These conjugates are then excreted via urine and bile.
Enterohepatic recirculation also plays a significant role, where conjugated estrogens are secreted into the bile, hydrolyzed in the gut, and reabsorbed.
Additionally, the gut microbiota, through the "estrobolome," influences estrogen metabolism by deconjugating estrogen conjugates, thereby affecting their bioavailability and enterohepatic recirculation.

Phase I Pathways and Breast Cancer Risk

The 2-hydroxylation pathway, which produces 2-hydroxyestrone and other metabolites, is generally associated with a reduced risk of breast cancer. Studies have shown that a higher ratio of 2-hydroxylation metabolites to parent estrogens correlates with a lower risk of breast cancer.
The 16α-hydroxylation pathway, which produces 16α-hydroxyestrone, has been linked to an increased risk of breast cancer, although this association is less consistent.
The 4-hydroxylation pathway, which produces potentially genotoxic catechol estrogens, has been associated with an increased risk of breast cancer when there is less extensive methylation of these catechols.
In summary, more extensive 2-hydroxylation of parent estrogens is associated with a lower risk of breast cancer, while less extensive methylation of 4-hydroxylation pathway catechols and higher levels of 16α-hydroxyestrone are associated with a higher risk. This suggests that the balance between different estrogen metabolites, rather than the absolute levels of estrogens, plays a crucial role in modulating breast cancer risk.

Summary of Estrogen Metabolism in the Liver

Mechanisms of Harmful Metabolites

16α-Hydroxyestrone has been implicated in promoting tumor proliferation. Studies have shown that higher levels of 16α-hydroxyestrone are associated with an increased risk of breast cancer, particularly in postmenopausal women. This metabolite is biologically active and can form covalent adducts with macromolecules, contributing to its tumorigenic potential.
Catechol estrogens, particularly those from the 4-hydroxylation pathway, are also significant. These metabolites can be further oxidized to form catechol estrogen quinones, which are highly reactive and can form depurinating DNA adducts. These adducts can lead to mutations and initiate carcinogenesis. The less extensive methylation of these catechols, resulting in higher levels of genotoxic catechol estrogen quinones, has been associated with an increased risk of breast cancer.
In summary, 16α-hydroxyestrone and genotoxic catechol estrogens from the 4-hydroxylation pathway are the key estrogen metabolites linked to an increased risk of breast cancer.

Influencers of Estrogen Metabolism

Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites.
Estrogen metabolism involves complex biochemical pathways primarily occurring in the liver, where estrogens are converted into various metabolites through hydroxylation and conjugation processes. These transformations are influenced by several factors, including gut microbiota, genetic polymorphisms, and the presence of specific enzymes.
The gut microbiota plays a significant role in estrogen metabolism through the "estrobolome," a collection of bacterial genes encoding enzymes like β-glucuronidases and β-glucosidases. These enzymes deconjugate and reactivate estrogens, influencing their circulating levels and bioavailability. Alterations in gut microbiota composition can impact estrogen metabolism and have been associated with estrogen-related diseases such as breast cancer and polycystic ovarian syndrome (PCOS).
Additionally, cytochrome P450 enzymes, particularly CYP3A4, are involved in the metabolism of estrogens. Inducers of CYP3A4, such as St. John's Wort, phenobarbital, and rifampin, can reduce plasma concentrations of estrogens, potentially decreasing their therapeutic effects. Conversely, inhibitors of CYP3A4, such as erythromycin and grapefruit juice, can increase plasma concentrations of estrogens, leading to potential side effects.
Furthermore, the metabolic pathways of estrogens can be influenced by hormonal therapies. For instance, conjugated equine estrogens (CEE) alone have been shown to induce estrogen hydroxylation along the 2-pathway rather than the 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk.
Lifestyle factors significantly influence the balance of estrogen metabolites, which in turn impacts breast cancer risk. Body mass index (BMI), diet, physical activity, alcohol consumption, and smoking are key lifestyle factors that modulate estrogen metabolism.
Body mass index (BMI): Elevated BMI also correlates with a higher ratio of 16α-hydroxyestrone to parent estrogens, which is associated with increased breast cancer risk.
Diet: Dietary patterns can influence estrogen metabolism. Diets high in fiber, fruits, and vegetables, particularly cruciferous vegetables, are associated with increased 2-hydroxylation of estrogens, which is protective against breast cancer. Conversely, diets high in refined grains, red meat, and alcohol are linked to higher levels of 16α-hydroxyestrone and other metabolites associated with increased breast cancer risk. A diet high in cruciferous vegetables (e.g., broccoli, cauliflower, Brussels sprouts) is associated with increased 2-hydroxylation of estrogens, which is protective against breast cancer. These vegetables contain compounds like indole-3-carbinol, which promote the 2-hydroxylation pathway. Mediterranean dietary patterns, characterized by high intake of fruits, vegetables, whole grains, legumes, nuts, and olive oil, and low intake of red meat and processed foods, have been associated with a favorable balance of estrogen metabolites. This pattern is linked to increased 2-hydroxylation and reduced levels of 16α-hydroxyestrone, thereby reducing breast cancer risk.
High-fiber diets are also beneficial. Increased fiber intake is associated with lower circulating estrogen levels and a shift towards more favorable estrogen metabolism, including increased 2-hydroxylation.
Gut health: The diversity of the microbiome impacts estrogen metabolism. Probiotics and a low inflammatory, high fiber diet can help restore and maintain a healthy gut microbiome
Physical activity: Regular physical activity is associated with a favorable balance of estrogen metabolites, reducing breast cancer risk.
Alcohol consumption: Alcohol intake is positively associated with higher levels of metabolites that increase breast cancer risk. Limiting alcohol consumption to less than one drink per day is recommended to mitigate this risk.
Smoking: Smoking is associated with altered estrogen metabolism, including increased levels of 16α-hydroxyestrone and other harmful metabolites, thereby increasing breast cancer risk.
In summary, maintaining a healthy BMI, consuming a diet rich in fruits, vegetables, and fiber, engaging in regular physical activity, limiting alcohol intake, and avoiding smoking can favorably influence estrogen metabolism and reduce breast cancer risk. Diets rich in cruciferous vegetables, fruits, vegetables, whole grains, and fiber, and low in red and processed meats and refined grains are linked to favorable estrogen metabolite profiles, promoting increased 2-hydroxylation and reduced 16α-hydroxyestrone levels, thereby aiding in breast cancer prevention.

Supplements to Help Estrogen Metabolism

Red clover and its isoflavones, such as biochanin A, formononetin, genistein, and daidzein, can influence estrogen metabolism. Specifically, red clover extract and its isoflavones can enhance genotoxic estrogen metabolism in breast cancer cells by modulating the expression of cytochrome P450 enzymes, particularly CYP1A1 and CYP1B1.
Seaweed supplementation has also been shown to modify estrogen metabolism. In a study involving postmenopausal women, seaweed supplementation was associated with a decrease in serum estradiol levels and an increase in the urinary excretion of 2-hydroxy estrogen, which is considered a less genotoxic metabolite compared to 16α-hydroxyestrone.
Phytoestrogens, which are found in various plant-based foods, can mimic estrogen and influence its metabolism. These compounds can modulate the activity of estrogen by interacting with estrogen receptors and affecting the metabolic pathways of estrogen, potentially impacting bone health and reducing the risk of osteoporosis.
Several studies have demonstrated that DIM, a bioactive compound derived from cruciferous vegetables, modulates estrogen metabolism by increasing the ratio of 2-hydroxyestrone (2-OHE1) to 16α-hydroxyestrone (16α-OHE1). This shift is considered beneficial as 2-OHE1 is a less estrogenic metabolite compared to 16α-OHE1, which is associated with higher estrogenic activity and potential carcinogenicity. For instance, a pilot study involving patients with thyroid proliferative disease showed that DIM supplementation increased the urinary ratio of 2-OHE1 to 16α-OHE1, indicating enhanced estrogen metabolism towards a less estrogenic pathway. Similarly, a randomized, placebo-controlled trial in breast cancer patients taking tamoxifen found that DIM significantly increased the 2/16α-OHE1 ratio, suggesting a favorable modulation of estrogen metabolism. Moreover, a pilot study in postmenopausal women with a history of early-stage breast cancer also reported that DIM supplementation led to a significant increase in urinary 2-OHE1 levels and a non-significant increase in the 2-OHE1/16α-OHE1 ratio. These findings collectively support the notion that DIM can alter estrogen metabolism by promoting the formation of less estrogenic metabolites, which may have implications for reducing the risk of estrogen-dependent cancers.

Several supplements can support estrogen metabolism by promoting the breakdown and elimination of excess estrogen from the body. These supplements can help balance estrogen levels and reduce the risk of estrogen dominance-related symptoms. Below are some of the most commonly recommended supplements for improving estrogen metabolism:

1. DIM (Diindolylmethane)

Function: DIM is a compound found in cruciferous vegetables (like broccoli, cauliflower, kale, and Brussels sprouts). It helps promote the metabolism of estrogen into more beneficial forms, reducing the production of harmful estrogen metabolites that can contribute to estrogen dominance.
Benefit: DIM helps the liver convert estrogen into a form that can be easily eliminated from the body and supports hormonal balance. It may also help reduce the risk of estrogen-related cancers, such as breast and endometrial cancer.

2. Calcium-D-Glucarate

Function: This compound supports detoxification processes in the liver and helps prevent estrogen reabsorption in the intestines. It aids in the elimination of excess estrogen by inhibiting an enzyme called beta-glucuronidase, which can cause estrogen to be reabsorbed back into the bloodstream.
Benefit: By promoting the excretion of estrogen, calcium-D-glucarate can help balance estrogen levels and support the body’s detoxification of hormone metabolites.

3. I3C (Indole-3-Carbinol)

Function: Like DIM, I3C is found in cruciferous vegetables and is converted to DIM in the stomach. It promotes the metabolism of estrogen into its safer, less potent forms, thereby reducing estrogen dominance.
Benefit: I3C can help with estrogen detoxification and lower the risk of estrogen-sensitive cancers. It also supports the balance of estrogen-related symptoms.

4. Methylated B Vitamins (B6, B12, and Folate)

Function: Methylated B vitamins play an important role in the methylation process, a biochemical reaction that helps the liver metabolize and detoxify estrogen. Proper methylation helps ensure that estrogen is broken down efficiently and safely.
Benefit: Methylated B vitamins, especially vitamin B6, support estrogen metabolism and can help reduce symptoms related to estrogen dominance, such as PMS, mood swings, and breast tenderness.

5. Milk Thistle (Silymarin)

Function: Milk thistle is a herb that supports liver function, which is crucial for estrogen detoxification. The liver is responsible for metabolizing estrogen, and milk thistle enhances the liver’s ability to break down and excrete excess estrogen.
Benefit: By supporting liver health, milk thistle can improve the body’s capacity to process and eliminate excess estrogen, contributing to hormonal balance.

6. Probiotics

Function: Probiotics support gut health, which plays a role in estrogen metabolism. Certain strains of gut bacteria can influence the reabsorption of estrogen from the intestines, and maintaining a healthy gut microbiome can reduce estrogen recirculation.
Benefit: Probiotics help ensure proper estrogen elimination through the gut, reducing the likelihood of estrogen dominance and promoting overall hormonal balance.

7. Magnesium

Function: Magnesium is involved in over 300 biochemical processes in the body, including estrogen detoxification. It helps activate enzymes that promote estrogen metabolism in the liver and supports proper hormonal function.
Benefit: Supplementing with magnesium can help regulate estrogen levels, improve mood, reduce stress, and support overall hormone health.

8. Omega-3 Fatty Acids (Fish Oil)

Function: Omega-3 fatty acids have anti-inflammatory properties and can help regulate hormonal balance. They are also involved in reducing inflammation, which can help modulate estrogen’s effects on the body.
Benefit: Omega-3 supplements may help reduce symptoms of estrogen dominance, such as breast tenderness, bloating, and mood swings.

9. Choline

Function: Choline is an essential nutrient that supports liver function and methylation, both of which are important for estrogen metabolism. It helps the body convert estrogen into a form that can be safely excreted.
Benefit: Choline supplementation can support the body’s estrogen detoxification processes and promote hormonal balance.

10. Resveratrol

Function: Resveratrol is a plant compound with antioxidant properties that has been shown to modulate estrogen metabolism by inhibiting the aromatase enzyme, which converts testosterone into estrogen.
Benefit: Resveratrol may help balance estrogen levels by reducing the overproduction of estrogen and supporting estrogen detoxification.

11. Turmeric (Curcumin)

Function: Curcumin, the active compound in turmeric, has anti-inflammatory and antioxidant properties. It supports liver detoxification and helps in reducing the harmful effects of excessive estrogen.
Benefit: Turmeric can support liver function, helping the body metabolize and eliminate estrogen, which contributes to overall hormone balance.

Summary of Supplements for Estrogen Metabolism

DIM and I3C: Support the conversion of estrogen into less harmful forms.
Calcium-D-Glucarate: Enhances estrogen detoxification and elimination.
Methylated B Vitamins: Support methylation, a critical process for estrogen metabolism.
Milk Thistle: Supports liver detoxification of estrogen.
Probiotics: Promote gut health for proper estrogen elimination.
Magnesium: Supports liver detoxification and reduces stress-related hormone imbalances.
Omega-3 Fatty Acids: Help reduce inflammation and balance estrogen.
Choline: Supports liver detoxification.
Resveratrol: Modulates estrogen production.
Turmeric (Curcumin): Supports liver function and reduces inflammation.

These supplements can be effective in promoting healthy estrogen metabolism. However, it’s always recommended to consult with a healthcare provider before starting any new supplementation regimen to ensure it is appropriate for your individual health needs.

Genetics and Estrogen Metabolism

Genes encoding for important proteins may be altered and thus contribute to aberrant estrogen metabolism. Alterations in these genes can be considered simultaneously with models for breast cancer risk assessment.

The COMT Gene

Catechol-O-methyl transferase (COMT) occurs in variable amounts in most tissues such as endometrium and mammary gland. COMT blocks estrogenicity of catechol metabolites of estradiol and estrone, particularly 2-hydroxy and 4-hydroxy estradiol/estrone, and prevents their oxidation to reactive quinone. It is an essential participant in the detoxification of catechol substrates by transferring a methyl group from S-adenosyl-L-methionine (SAM) to one of the hydroxyls in a molecule of a substrate. Along with NAD(P)H-quinone oxidoreductase (NQO1), it is quantitatively the most significant contributor to inactivation of catechol estrogens, intermediates in the formation of reactive oxygen species causing different types of DNA damage in breast tissue. In addition, methyl estrogens formed by COMT, especially 2-methoxyestradiol, also have tumor-suppressing properties and cardioprotective effects mediated through antiangiogenic and growth inhibitory effects. Hence, COMT generates potentially protective metabolites along with blocking genotoxic effects of catechol estrogens.
The COMT gene plays a key role in estrogen metabolism and is associated with a number of health issues, including: premature ovarian insufficiency, breast cancer, menstrual symptoms, and bone size. A meta-analysis of 26 case-control studies found that the COMT Val158Met polymorphism was associated with an increased risk of breast cancer.

MTHFR Gene

MTHFR is the key enzyme of folate metabolism, catalyzing 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which allows the remethylation of homocysteine to methionine, a precursor of S-adenosylmethionine (SAM). In turn, SAM is the methyl donor for COMT catalyzed reactions, which allow inactivation of catechol estrogens. In this regard, MTHFR activity alterations will indirectly affect the inactivation of catechol estrogens by COMT.

The polymorphism of MTHFR C677T promotes a lower activity of MTHFR and a consequent decrease of detoxification via COMT. Low COMT activity leads to a compromise 4-OH-E2 detoxification and eventually will contribute to tumor development due to inefficient estrogens detoxification during reproductive life. It has been demonstrated that some polymorphisms in MTHFR can lead to an inefficient detoxification associated with exposure to endogenous or exogenous estrogens during life, and might be a trigger to hormone-dependent breast cancer development at later ages.

The Link Between COMT and Estrogen Metabolism

There are three distinct pathways of Phase I metabolism of Estrone, resulting in 2-hydroxyestrone (the most favorable pathway of metabolism), 16-alpha-hydroxyestrone (a result of inflammation) and 4-hydroxyestrone (a carcinogenic pathway). These Phase I pathways are directly impacted by lifestyle and dietary choices.

The Link Between COMT and MTHFR

Estrogen Elimination

Once the catechol estrogen metabolites have been metabolized (COMT), they have to be excreted (urine or feces). The gut microbiome comes into play here in making sure that the metabolites are excreted and not reabsorbed. The estrogen that has been metabolized and is ready to be eliminated through feces can actually be recycled back into circulation due to an interaction with certain bacteria in the gut microbiome. Beta-glucuronidase, an enzyme produced by the gut microbiome, that can cause the estrogen metabolites to be reabsorbed from the intestines and go back into circulation. Calcium D-glucarate can suppress the beta-glucuronidase activity in the gut, thus increasing the number of estrogen metabolites that are excreted.

Testing for Estrogen Metabolism

Metabolites

There are a number of commercial companies which perform estrogen metabolism testing. These are usually done on urine samples.

Resources

Estrogen Metabolism

DUTCH https://dutchtest.com/

ZRT Labs https://www.zrtlab.com/

Genova Diagnostics https://www.gdx.net/

Gut Microbiome

Viome https://www.viome.com/

Genova https://www.gdx.net/

Zoe https://zoe.com/

Genetics

There are a number of companies which perform genetics for estrogen metabolism, such as COMT, MTHFR and genes important in liver metabolism.

3x4 Genetics: 36 key insights and practical, personalized recommendations for women to start taking control of their health

https://3x4genetics.com