Author: Michael McEvoy
Estrogen dominance is a term used to describe the amount of estrogen in the body. There are a number of reasons that estrogen overload can be problematic. Excess estrogen activity can alter the menstrual cycle for women, leading to problems such as PMS. Excess estradiol can lead to conditions such as cancer and abnormal cell proliferation in more extreme scenarios. Abnormal estrogen is implicated in a number of autoimmune diseases.
The term “estrogen dominance” is outdated because not all estrogens are the same. 2 methoxy estradiol can be protective and anti-cell proliferative. Estradiol, estriol or E3 is very weak, and has a number of therapeutic benefits. Other estrogens such as 2 hydroxy yield no cell proliferation or cancer-inducing effects, and may actually prevent abnormal endometrial growth (9). The 4OH and 16 OH’s are powerful hydroxy estrogens. The cell proliferative effects of the 4 and 16 hydroxy estrogens are very strong.
Estradiol and 4 hydroxy estrone are estrogens that are very reactive. They are prone to the formation of catechol estrogen-derived 3,4 semi-quinones, which are potent, free radical-generating molecules that have been shown to lead to DNA mutagenesis. The most potent and potentially cancer-causing estrogens are 4 hydroxy E1 and E2.
Testing For Estrogenic Activity
It is now well understood that certain estrogens increase cell growth and proliferation more than others. With the advent of genetic test analysis it is now possible to identify inherited strengths and weaknesses of certain gene variants that are encoded in certain estrogen-specific biochemical pathways. This data can be used clinically for the purpose of constructing meaningful and evidence-based protocols, which aim to positively influence the pathways of estrogen metabolism. One section in the Metabolic Healing Nutrigenomics report features estrogen metabolism genetics.
Genetics testing alone is not enough to understand what the problems are. One should pair a genetics test with a urinary sex hormone test. It is our opinion that urinary sex hormone testing is the industry standard because it provides an evaluation of estrogen metabolites. It’s useful to measure the sex hormone binding globulin in order to find out the level of bound versus unbound sex hormones. The availability of sex hormones to cells will be reduced by the elevation of the SHBG.
It’s very useful to pair the major genes of estrogen metabolism with the actual products of the enzymes, side by side.
Estrogen Metabolism: Phase I and II
The addition of a hydroxy group onto a molecule is known as Hydroxylation. The cytochrome P450 is made up of the hydroxylate and the others. The addition of hydroxy groups can make the molecule more active. Phase one metabolism is the function of these processes of estrogen hydroxylation.
Estrogens are formed from testosterone and androstenedione through the process known as aromatization. The aromatase is produced by the CYP19A1 enzyme. Once aromatized, estradiol and estrone undergo hydroxylation through 3 primary enzymes to generate their respective end products.
- The majority of 4OH is catalyzed through the CYP1B1
- The majority of 2OH is catalyzed through the CYP1A1
- The majority of 16OH is catalyzed through the CYP3a4.
The 4OH molecule is highly reactive according to the literature. It is accepted as a carcinogen because of its propensity to form the 3, 4 semi quinone free radical, which can form unstable DNA adducts. A DNA adduct is when a molecule sticks to a piece of the genetic material. If left un-repaired, these adducts can cause mutagenesis, which can cause changes in genomic activity.
CYP1B1 is the main enzyme that catalyses the formation of 4OH molecules. The genetic risk allele for CYP1B1 appears to encode for an increased function of the CYP1B1 enzyme. In addition to the hydroxylation of E1 and E2, CYP1B1 also hydroxylates a number of environmental chemicals into volatile, carcinogenic intermediates. This fact complicates the matter of estrogen carcinogenicity, especially in light of the fact that carriers of the risk allele for CYP1B1 already tend to have increased enzymatic function. Epidemiological studies have found increased colon cancer risk among carriers of the CYP1B1 risk allele, who consume well done meat. The reasoning for this is very likely due to the fact that high temperature cooking of meat increases the formation of polycyclic aromatic hydrocarbons, which are metabolized into carcinogenic intermediates via CYP1B1.
Many environmental chemicals are converted into cancer-causing intermediates via the same major estrogen hydroxylation enzymes. This includes CYP1A1, CYP1B1, CYP3a4 and CYP19A1. The toxic metal cadmium will bind to the estrogen alpha receptor. The implications of toxic metals and chemicals on the function of the enzyme are several-fold. There are many toxic compounds that are mutagenic and DNA- damaging. Their avoidance is essential, but so is the activation of the phase 2 detoxification processes, which is necessary to eliminate them.
Phase 2 Detoxification of Estrogen
The COMT is involved in the local regulation of Phase II methylation of estrogen. The volatile 4OH molecule is effectively neutered by the methylation of 4OH E1 and E2. catechol estrogens are one of the central processes in the inactivation and detoxification of a number of molecules.
The COMT genetic risk is related to a downregulation of enzymatic function. You can see the problem when an individual has risk alleles for both COMT and upregulation. The activation of a volatile molecule is higher than the inactivation. The other remaining gatekeepers protect from DNA adduct formation function to detoxify the volatile catechol estrogens.
NQO1 and GSTM1 are important enzymes that remove the semi quinone radical. NQO1 is a quinone reductase, whereas GSTM1 and GSTP1 are glutathione transferases. 3,4 semi quinones are unstable free radicals that can set off chain reactions of other free radicals and oxidants. Hydroxy radicals, peroxynitrite, hydrogen peroxide and superoxides are included in this. Problems may arise if these oxidants and radicals are not quenched and/or detoxified.
The expression of the Glutathione transferase is reduced by the genetic risk alleles for it. There are a number of other factors that affect the integrity and function of our glutathione system.
The ability to synthesise glutathione and cysteine is dependent on the function of the one carbon cycle and the transsulfuration pathway. MTHFR and CBS are important components of these pathways. Glutathione function is dependent on the presence of mineral cofactors such as selenium and magnesium, which are involved in the formation of glutathione peroxidase. Several B-vitamins play a central role in the synthesis and utilization of glutathione, including B6 and B-2. The ability to maintain sufficient reduced glutathione is dependent on the redox cofactor NADPH.
The removal of free radicals is a regular event inside of cells if there is sufficient glutathione activity. The mechanisms of cellular defense are likely to be compromised significantly in the event of mutagenesis, insufficient DNA repair and the initiation of tumorogenesis. A major cause of cancer initiation is un-repaired DNA damage.
Nutritional Therapeutic Potential For Estrogen-Related Pathways
There are a number of compounds that have different effects on the estrogen metabolism and the detoxifying pathways. Many of these compounds can be implemented through an individualized process, which affords great potential for those affected by the potentially deleterious effects of estrogen metabolism.
Let’s take a closer look at a few of these supplements.
- DIM (diindolylmethane) – DIM is used to stimulate 2 hydroxylation (neutral estrogen pathway) via CYP1A1 and reduce expression of 16 hydroxylation (potential harmful estrogen pathway) through inhibiting CYP3a4. There is far more potential therapeutic action to DIM, however. DIM has shown to reduce DNA hypermethylation of CpG islands (hallmark feature of cancer activity), reduce intestinal inflammation, function to mildly inhibit aromatase, and enhance DNA repair mechanisms.
- 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 (1, 2).
- Berries – 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) (3). 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 (4,5).
- Grapefruit & Citrus peel– Are sources of hesperidin. Hesperidin at high doses inhibits CYP1B1 and also CYP3a4. Grapefruit is notorious for inhibiting CYP3a4 (6, 7). 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 (8).
- Calcium D-glucarate – is a form of calcium that promotes phase 2 glucuronidation. This phase 2 reaction makes molecules more water soluble. Additionally, it is believed that calcium d-glucarate is a beta glucuronidase inhibitor, which acts to prevent the reabsorption of detoxified estrogens through 2nd pass metabolism.
- Glutathione promoters and/or cofactors: NAC, lipoic acid, selenium, B-2, B-6, zinc