4-OH-E1and 4-OH-E2 are referred to as the “bad” estrogens, along with 16a-OHE1. They are primarily produced by CYP1B1 and CYP34A, respectively, enzymes localized in tissues, including breast and prostate as well as liver. Some have suggested that increased expression of CYP1B1 and 4-hydroxylation of estradiol are biomarkers of tumorigenesis.
Human breast cancer tissue produces much higher levels of 4-OH than 2-OH, while normal breast tissue produces approximately equal amounts of the two metabolites. Women taking hormone therapy with a polymorphism in CYP1B1 had twice the risk of developing breast cancer compared to other HRT users.
Generally no treatment recommended
The bad news may be that you are making too much of the 4-hydroxyestrogens and not methylating them well. The good news is that you know this is happening and can do things to change how your body metabolizes estrogens, and in doing so decrease your breast cancer risk. Nutritional intervention (e.g., foods rich in DIM or indole-3-carbinol) can be used to shift estrogens in the direction of 2-hydroxylation, which is safer. Additionally, methylation of estrogen metabolites can be supported nutritionally (e.g., methyl donors such as vitamin B12, folic acid, SAM-e, and foods such as onions, garlic and beets). And the effectiveness of this intervention can be evaluated by measuring the ratio of 2- and 4-methoxyestrone to 2- and 4-hydroxyestrone.
- Improve methylation by adding cofactors (B12, folate) or methyl donors (betaine, dimethyl glycine)
- Consider genetic testing for COMT and CYP1B1 activity, particularly if positive family history
- Reduce stress: COMT is involved in the metabolism of epinephrine, reducing availability for estrogen metabolism
- Increase inhibitors of CYP1B1 (Grapefruit, Ginseng)
- Avoidance of CYP1B1 inducers (Polycyclic aromatic hydrocarbons)
Evaluate methylation activity:
- Serum Homocysteine
- Serum B12 or methylation
- Urinary FIGLU
- Urinary xanthurenate
Other potential protective factors:
- Glutathione (reduction of estrogen quinones)
- Resveratrol (prevents estrogen quinone formation)
- Selenium, zinc, magnesium
High levels of 4-hydroxylated estrogens (4-OH-E2 and 4-OH-E1) and/or low levels of their methylated forms are associated with increased breast cancer risk.
Lifestyle modifications help reduce excessive levels of the parent estrogens (estradiol, estrone) and their down-stream hydroxylated metabolites.
Some of these lifestyle modifications include:
- maintaining a healthy weight,
- eating green leafy vegetables
- avoiding excess red meat,
-assuring that iodine and selenium are within healthy ranges that protect the breast epithelium, using bioidentical hormones (particularly natural progesterone),
- avoiding toxic foods and chemicals as much as possible.
Try to consume 40 to 60 grams of fiber every day. Fiber helps to bind excessive hormones and metabolites that are excreted in your stool. The addition of fiber will also help to bind and excrete excessive fats.
EAT FLAX SEEDS:
Flax seeds – Flax seeds are a promoter of CYP1A1 and an inhibitor of CYP1B1. Thus, flax seeds are promoters of 2 hydroxylation (neutral estrogen), and inhibitors of 4 hydroxylation (potentially undesirable). Flax also has shown to inhibit CYP3a4 and reduce the excretion of 16OHE1, another potentially problematic estrogen.
EAT GREEN VEGGIES:
Eat raw organic broccoli, Brussels sprouts, kale, or cauliflower three times per week. A recent clinical trial found that these vegetables produce the substances indole – 3 – carbinol (I3C) and diindolymethane (DIM). They help to stimulate or make more CYP1A1, which is responsible for making more 2-OHE1. Increased ratios of 2-OHE1 to 16a-OHE1 are thought to be protective against breast cancer formation.
Numerous types of berries (blackberries, raspberries, grapes, blueberries) are a rich source of polyphenolic compounds, including ellagic acid. Ellagic acid is a promoter of glutathione transferase (GSTM) as well as NQO1 (quinone reductase). These 2 enzymes are important in the detoxification of 3,4 semi-quinones. Additionally, ellagic acid has been shown to increase DNA repair genes, as well as reduce DNA adducts that have been formed by carcinogens.
GRAPEFRUIT AND CITRUS PEEL:
Grapefruit & Citrus peel are sources of hesperidin. Hesperidin at high doses inhibits CYP1B1 and also CYP3a4. Grapefruit is notorious for inhibiting CYP3a4. Citrus peel contains a considerable amount of hesperidin, that is especially true of dried tangerine peel. An assortment of studies done on hesperidin have found an overall increase in blood flow and circulation, reduction in blood pressure, and reduction in symptoms of cell adhesion factors, which may disrupt cancer activities.
Take 600 – 800 mg of DHA omega 3 fatty acids per day. The easiest way to do this is through supplementation. This helps to prevent overall inflammation in the body.
Take a good multivitamin in order to ingest adequate amounts of nutrients necessary to convert estrogen metabolites to the protective methyl forms such as 2-MeOHE1. Specifically you want adequate amounts of methyl folic acid, methyl cobalamin, and vitamin B6. (Consult your health care practitioner prior to taking a multivitamin).
AVOID PROCESSED SUGARS:
Avoid processed sugars or excessive amounts of natural sugars. Excess sugar is stored as fat in humans. Estrogen loves to store itself in fat cells. These stored estrogens can be released or converted, causing more effects of estrogen dominance. This can increase a person’s risk of estrogen-induced cancers.
Exercise 5 times per week for 30 minutes each time, including 3 days of resistance training. This helps to control excessive body weight and increases natural regulation of sex hormones.
Avoid contact or ingestion of pesticides and/or chemical irritants. Many common chemical products cause DNA damage in cells, making them more susceptible to developing cancers.
AVOID GENETICALLY MODIFIED FOODS:
Avoid genetically modified foods or foods with chemical preservatives. Many of these types of foods have been shown to cause cellular damage.
AVOID EXCESS CONSUMPTION OF SOY PRODUCTS:
Avoid excess consumption of processed soy products as they may increase your risk of estrogen metabolite production.
LOWER STRESS LEVELS:
Keep your stress levels as low as possible.
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