Total Estrogen and Precision Medicine: Treating Our Patients vs. Treating the Population
Throughout the history of medicine, healthcare trends have evolved toward disease prevention instead of treating disease. Yet, the flood of lifestyle and dietary changes designed to avoid certain diseases seems to be more of a marketing strategy for food distributors, health clubs and supplement companies than realistic and actionable recommendations in practice. In recent years, a number of studies have discussed the association between genetic mutations (SNPs), estrogen sensitive cancers (breast, uterine and prostate), and estrogen hormone replacement therapies. In these studies, there seemed to be a clear association between orally administered synthetic estrogen and the development of estrogen-sensitive cancer. However, as more and more medical practitioners switched from oral administration of synthetic estrogen to bio-identical creams, patches, gels and pellets, the association between estrogen and breast cancers appeared to decrease. Those prescribing and/or marketing bioidentical hormones made the assumption that breast cancer risk was related to the synthetic make-up in oral administration of estrogen, but although the association to synthetic oral estrogen to cancer is statistically significant, this assumption may be misleading. This article will specifically discuss the pathways of estrogen metabolism, what these pathways represent in clinical practice and how to identify and, subsequently, mitigate the risks associated with developing estrogen-sensitive breast, uterine and prostate cancers in disease prevention.
Estrogen is essential in both men and women for bone health, brain health, cardiovascular health, reproductive health and has even shown positive effects in treating certain cancers. It is clear that maintaining optimal levels of estrogen is very important, because having too much or too little estrogen can present with a myriad of symptoms. Measuring Estrogen before addressing suspected hormone imbalances and monitoring estrogen levels during hormone replacement therapy are crucial in maintaining hormone balance, but the clinical science behind the risks and benefits of Estrogen relating to cancer remained a mystery until estrogen metabolism became more understood. In order to customize therapies for patients while mitigating risks associated with estrogen-sensitive cancers, all primary estrogens (Estrone, Estradiol and Estriol), as well as the downstream estrogen metabolites, must be evaluated.
Most practitioners are accustomed to evaluating serum estradiol by itself when determining if a patient is a candidate for estrogen hormone therapy, but measuring a single estrogen significantly limits practitioners in developing therapies that are precise to each individual patient. As men and women age, aromatase activity takes place at the testosterone precursor, Androstenedione, at a higher rate than the aromatase activity at Testosterone observed in younger populations. The result is a migration toward estrone production over estradiol; so simply measuring estradiol can produce an inaccurate assessment of estrogen effect at the estrogen receptors (ERs).
In addition to assessing Estrone, it is essential to look at the various stages of Estradiol, Estrone and Estrone metabolism collectively. Special attention should be paid to the amount of free hormone that is available to tissues based on the binding affinities of estrone (E1), estradiol (E2), estriol (E3) and 16-alpha-hydroxyestrone at the estrogen receptors.1,2 The Total Estrogen Effect (TEE) in urinary hormone and hormone metabolite testing is calculated based on the presence of estrone, estradiol, estriol, and their relative binding affinities at the estrogen receptors.1,2 Estradiol is considered to be the most estrogenic estrogen and is the prevalent primary estrogen produced by menstruating women. Estradiol has a strong and long-binding affinity at the estrogen receptors and is responsible for most cell proliferation at estrogen-sensitive tissues, such as breast and uterine tissues, in menstruating women.1-6 Based on receptor availability at the tissues, estradiol is converted to estrone and further converted to estriol through the 16-alpha-hydroxyestrone metabolism pathway during Phase I metabolism. Unless a female is pregnant or menopausal, most estrone and estriol is a result of conversion from estradiol. Based on this knowledge, we are able to assume the estrogen effect at the estrogen receptors. The calculation for the TEE assumes certain standard binding affinities at the estrogen receptors. Estriol is the weakest binding primary estrogen at the estrogen receptors and can compete with stronger-binding estrogens.2 Due to its competitive nature and its weaker binding affinity, estriol is considered to be a protective estrogen.1,3,10 Following estriol in binding affinity is estrone (4x more estrogenic than estriol), 16a-hydroxyestrone (9x more estrogenic than estriol), and estradiol (10x more estrogenic than estriol).2,7 These relative values are added together to establish the Total Estrogen Effect at the ERs.
Table 1: Fictitious Example (If a patient has an estriol of 2, an estrone of 2, a 16a-OHE1 of 2, and an estradiol of 2, then the Total Estrogen Effect (TEE) would be 48 based on their relative binding affinities)
|Total Estrogen Load
**Although 16a-OHE1 is a Phase I metabolite, it is included in the calculation due to its ability to contribute to estrogen dominance.
Assessing the amount of estrogen effect at the receptor is the best way to decide if a patient is a candidate for estrogen hormone replacement, but this assessment is only the beginning; assessing Phase I and Phase II metabolism of estrogen is where inflammatory responses and cancer risk are assessed and customized therapies are derived.
As shown in Figure 2, 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.
- 4-OHE1 is catalyzed predominantly through CYP1B1
- 2-OHE1 is catalyzed predominantly through CYP1A1
- 16-a-OHE1 is catalyzed predominantly through CYP3a4
Improvements in lifestyle result in a preference of metabolism down the most favorable 2-hydroxyestrone pathway. 2-hydroxyestrone does not bind to the estrogen receptors. However, COMT activity causes the methylation of 2-hydroxyestrone in Phase II metabolism. That results in stable DNA adducts and can slow estrogen-sensitive cell growth and even reverse DNA damage caused by the 4-OHE1 pathway of Phase I metabolism. 2-methoxyestrone has also been shown to reverse inflammatory responses to estrogen dominance and slow or reverse breast, uterine and prostate cancer growth. When estrogen dominance or certain mutations in the CYP1B1 gene are present, Phase I metabolism increases down the 4-hydroxyestrone pathway. 4-Hydroxyestrones are highly reactive and form 3,4 Quinones that can form unstable DNA adducts, resulting in the creation of carcinogenic mutations. The 4-hydroxyestrone pathway is additionally influenced by environmental toxins, so patients who have CYP1B1 SNPs are especially susceptible to estrogen-sensitive cancers. Because 4-OHE1 is a biomarker of CYP1B1 SNPs, patients with increased 4-OHE1 levels should avoid chemical toxins and improve methylation to drive Phase II detoxification of 4-OHE1. When 4-OHE1 is methylated in Phase II metabolism, the carcinogenic effects of 4-OHE1 are completely neutralized. Finally, the 16-alpha-hydroxyestrone pathway increases in the presence of inflammation. While most of this inflammation stems from the gut, estrogen dominance and the presence of estrogen-sensitive cancers can increase 16-a-OHE1 during Phase I metabolism as well. The best way to assess 16-a-OHE1 levels is the relative rate of metabolism of 2-OHE1 to 16-a-OHE1 via the 2:16 ratio. When the 2:16 is low, supporting Phase I metabolism and reducing gut inflammation are the primary ways to redirect Phase I metabolism down the 2-OHE1 pathway. Additionally, driving the 16-a-OHE1 pathway through 16-a-OHE1 to Estriol (via 16-hydroxylase activity) is another way to protect the tissues from estrogen dominance through weaker competitive binding of estriol at the ERs. 16-a-OHE1 covalently binds to ERs, resulting in long-standing action at the target tissues. This covalently-binding estrogen metabolite has positive effects in cell proliferation and has even been used to treat certain cancers, but it can cause an existing cancerous tumor or damaged estrogen-sensitive tissue to grow aggressively as well. This unique action of increased 16-a-OHE1 in the presence of inflammation, followed by increase cell proliferation, makes 16-a-OHE1 advantageous in the absence of free-radicals and un-repaired DNA damage. On the other hand, this action makes 16-a-OHE1detrimentally aggressive in the presence of cancer or certain genetic predispositions to increases in 4-OHE1. This is why assessing estrogen metabolism, modulating Phase I metabolism through lifestyle, and supporting Phase II metabolism through methylation and glutathione activity are essential in customizing therapies for patients and optimizing clinical outcomes.
Provided there is sufficient glutathione activity, the removal of DNA-damaging free-radicals is a regular event inside of cells. In the event of DNA mutations, insufficient DNA repair and the initiation of cancerous tissue, these mechanisms of cellular defense are likely compromised significantly. Un-repaired DNA damage is a major cause of cancer initiation. Again, the 2-hydroxy ➝ 2-methyoxyestrone pathway is the most advantageous pathway for repairing DNA damage and reversing the effect of free-radicals, as well as glutathione activity.
A number of nutrients, botanicals and nutrient compounds have been identified as having varying effects on the estrogen-metabolizing and detoxifying pathways. Implementation of many of these compounds through an individualized process affords great potential for those affected by the potentially deleterious effects of aberrant estrogen metabolism.
- 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 been 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.
- 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). 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 & 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.
- 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, zinci
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