Some estrogen hormone metabolites are known to bind to DNA, increasing the risk of cancer [1]. Research has shown that there are ways to promote the healthy pathway of metabolism and discourage the pathway that leads to carcinogenic metabolites. The undesirable pathway can further be nullified through methylation.
A combination of SAMe, 5-MTHF, and vitamin B12 (methylcobalamin) helps the body to methylate estrogen metabolites. Furthermore, DIM helps shunt estrogen metabolites down a safer pathway by modifying the active cytochrome P450 enzymes. Lastly, using glutathione or NAC can help detoxify quinones and semiquinones to mitigate DNA damage.
This article will describe the major pathways concerned in order to show why estrogen metabolism may be a concern for some people. Additionally, each of the above recommendations will be covered in greater detail.
Estrogen Metabolism Pathways
To start, the two major estrogen hormones estradiol and estrone can easily convert into each other. Estrone is metabolized further into intermediate compounds 2-hydroxyestradiol (2-OH-E1) and 4-hydroxyestradiol (4-OH-E1). This is accomplished through the cytochrome P450 enzymes CYP1A1 and CYP1B1 respectively [2]. The 2-OH-E1 route catalyzed by CYP1A1 is a stable route, and it can be easily metabolized further through methylation, which is accomplished by catechol-O-methyltransferase (COMT). The resulting product is 2-methoxyestradiol.
The major concern is the 4-OH-E1 route catalyzed by CYP1B1. Ideally, it will quickly be methylated with COMT. Unfortunately, it can be converted into quinones and semiquinones, which in turn can covalently bond with DNA [2]. This causes DNA damage and increases the risk of cancer.
Therefore, it is important to encourage the body to use the 2-OH-E1 pathway. The 4-OH-E1 pathway can further be managed by supplying the body with everything it needs for methylation. Lastly, the quinones and semiquinones can be detoxed from the body by ensuring that glutathione detoxification is active.
16-OH-E1 is a precursor to estriol, a weak estrogen hormone. It also plays a role in maintaining bone density.
We can check these pathways by using a simple urine test. If you need help balancing your hormone health, contact us to set up an appointment.
DIM for Healthy Estrogen Metabolism Pathways
Indole-3-carbinol (I3C) is a phytochemical found in cruciferous vegetables. 3,3’-diindolymethane (DIM) is its more stable product. I3C and DIM have antitumor properties [3,4]. Further research shows that consuming cruciferous vegetables, specifically white cabbage, is associated with promotion of the 2-OH-E1 pathway [5].
Consuming cruciferous vegetables is a natural way to promote the preferred pathway for estrogen metabolism. DIM may also be taken as a supplement to achieve this same effect.
Methylation
The COMT enzyme renders the estrogen metabolite ready for elimination from the body. It does this by converting a hydroxyl group into a methoxy group. This requires the donation of a methyl group from S-adenosylmethionine (SAMe) [6,7]. Upstream of this methyl donation, 5-methyltetrahydrofolate (5-MTHF) passes a methyl group to B12 to form methylcobalamin, which in turn converts homocysteine into methionine. The methionine can then be converted into SAMe.
Thus, supplementation of SAMe, 5-MTHF, and B12 promotes the methylation process to help the body eliminate estrogens and avoid the conversion of 4-OH-E1 into reactive quinones and semiquinones.
When supplementing with folate or B12, be sure that it is the methylated version of those vitamins. Folate should come in the form of 5-MTHF, and B12 should come in the form of methylcobalamin.
Glutathione Detoxification
DIM promotes the healthy oxidative pathway. SAMe, 5-MTHF, and B12 promote methylation. This doesn’t completely eliminate the quinones and semiquinones coming from 4-OH-E1. To help reduce the risk of these compounds even further, the body turns to glutathione. Glutathione is the chief detoxification molecule of the body. Supplementation with glutathione directly can aid the body in detoxification. It’s also common to use N-acetylcysteine (NAC), which will get converted into glutathione later. The main benefit of NAC is the cost. Glutathione is more expensive that NAC. Thus, many people elect to use NAC over glutathione.
SAMe not only plays a role in methylation. It also is required to make glutathione.
A diet that includes cruciferous vegetables provides sulforaphane, a necessary precursor to make glutathione [8]. A natural way to increase glutathione production is by eating cruciferous vegetables.
Estrogen Abundance
In some cases, women have an overall high level of estrogens in the body. This can most commonly be seen in polycystic ovarian syndrome (PCOS) or endometriosis. It’s important to eliminate excess estrogens as much as possible to avoid their conversion into harmful metabolites.
Fiber
Fiber binds to estrogen metabolites, including the carcinogenic metabolites, in the gut to eliminate them from the body [9]. Make sure you are getting at least 35 grams of fiber every day.
βeta-Glucuronidase
β-glucuronidase is an enzyme produced by bacteria in the gut. It cleaves glucuronic acid from estrogen molecules that have been prepared for elimination from the body. In doing this, it frees up estrogen to be absorbed back into the body in its active form [10]. Therefore, elevated levels of β-glucuronidase are of concern for people at risk of ovarian and breast cancer, PCOS, or endometriosis. Levels of β-glucuronidase can be assessed by taking a stool test.
Estrogen Metabolism Disruptors
Several other factors may disrupt estrogen metabolism and produce carcinogenic estrogen metabolites. Major contributing factors include:
- Alcohol
- Insulin Resistance
- Obesity
- Oral Contraceptives
- Hormone Replacement Therapy (HRT)
Summary
- Carcinogenic estrogen metabolites are created from 4-OH-E1.
- Healthy estrogen metabolism relies on the formation of 2-OH-E1 as the dominant detoxification pathway.
- Methylation and glutathione detox play important roles in estrogen detoxification.
- Supplements for healthy estrogen metabolism include: SAMe, 5-MTHF, B12 (methylcobalamin), DIM, and NAC (or glutathione).
- The inclusion of cruciferous vegetables in the diet promotes the 2-OH-E1 pathway and provides sulforaphane to create glutathione.
- Dietary fiber binds estrogen metabolites to excrete them from the body.
- Elevated β-glucuronidase in the gut reactivates estrogen hormones that should be excreted from the body.
- Factors that may disrupt healthy estrogen detoxification include alcohol, insulin resistance, obesity, oral contraceptives, and HRT.
In our practice, we help people balance their hormones. If you need help, feel free to book an online consultation.
Disclaimer: This website does not provide medical advice. The information contained on this website is for informational purposes only. No material on this site is intended to be a substitute for medical advice, diagnosis, or treatment. Always seek the advice of a healthcare professional with any questions you may have regarding a medical condition and treatment before undertaking a new healthcare regimen.
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