For women in their reproductive years and perimenopause, high estrogen, or estrogen dominance, is one of the most common hormone imbalances I see in my practice. 

High estrogen symptoms include heavy periods, painful periods, breast tenderness, mood swings, weight gain, hypothyroidism and more. These signs of estrogen dominance provide a clue that we need to take a deeper look and understand the underlying hormonal imbalance as well as to support estrogen detoxification. 

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“High estrogen symptoms include heavy periods, painful periods, breast tenderness, mood swings, weight gain, hypothyroidism and more. These signs of estrogen dominance provide a clue that we need to take a deeper look and understand the underlying hormonal imbalance as well as to support estrogen detoxification.” 

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We might have high estrogen because the body is producing more than we need, or we are exposed to environmental estrogens, and many times poor estrogen detox accounts for a significant part of the issue as well. Addressing excess estrogen and estrogen balance is important for not only quality of life, but also to help prevent cancer and chronic disease. 

Today we will focus specifically on the biochemical process of estrogen detoxification, how estrogen is metabolized and cleared from the body. 

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“Today we will focus specifically on the biochemical process of estrogen detoxification, how estrogen is metabolized and cleared from the body.” 

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Keep reading to learn more about the three key phases of estrogen detox, including liver detoxification and the connection between estrogen and gut health. Let’s jump in! 

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Phase 1 - Estrogen and Metabolites 

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There are three main estrogens, estrone (E1), estradiol (E2) and estriol (E3). The body needs to break these estrogens down to clear them from the body, just like it does with medication or toxins we are exposed to. 

The main site for the detoxification of estrogen is in the liver. The goal is to turn estrogen from a fat-soluble molecule into a water-soluble molecule so it can be excreted. This happens in two phases of chemical reactions, called Phase 1 and Phase 2. 

In Phase 1, estrogens undergo hydroxylation with the help of cytochrome (CYP) enzymes. Hydroxylation adds a hydroxyl group to estrogen, like an accessory. It matters where this attachment occurs. There are three choices: 

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● 2-hydroxyestrone (2-OH-E1) 

● 4-hydroxyestrone (4-OH-E1) 

● 16-hydroxyestrone (16-OH-E1) 

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All these Phase 1 detox metabolites are considered free radicals; we want to send them to Phase 2 as quickly as possible, so they don’t enter circulation and cause damage. 

2-hydroxy estrogen metabolites (2-OH) are preferable. They are considered less carcinogenic, more stable and bind to estrogen receptors less tightly.

As the numbers go up, so does the risk. 4-OH metabolites are considered more carcinogenic and unstable and bind to receptors more tightly. 16-OH are the most problematic in this regard. 

Here is a visual of Phase 1 from the DUTCH hormone test in a patient with estrogen dominance. You can see the three estrogens along the top and then a green, red and blue arrows leading to the three Phase 1 metabolites. 

Phase 2 - Estrogen and Methylation 

Phase 2 estrogen detox relies on another chemical reaction to make the Phase 1 products fully water soluble. This reaction relies on the COMT enzyme (catechol-O-methyltransferase) and estrogen methylation. 

Methylation is the addition of a methyl group to the molecule, like another accessory. When methylation is impaired, or someone has a SNP (small change) in the gene that codes for the COMT enzyme, Phase 2 detoxification can slow down allowing estrogen metabolites to circulate rather than be excreted. 

As an example, 2-OH-E1 is methylated to 2-methoxy-E1 and is considered anti-proliferative in terms of cancer and anti-aromatase, blocking the conversion of androgens like testosterone into estrogens. 

Here is a visual from the same DUTCH test (read from right to left):

The connection between methylation and estrogen dominance is extremely important! Phase 3 - Estrogen-Gut Connection 

The third phase of estrogen detoxification happens in the gut, as a great example of the link between estrogen dominance and gut health. Once estrogen has completed Phase 1 and 2 in the liver, it is excreted either through the urine or enters bile and makes its way into the colon. 

Here, microbiome health and digestive function become important for clearing estrogen in this final phase. The estrobolome encompasses the part of the microbiome that interacts with estrogen. 

Certain types of bacteria produce an enzyme called beta-glucuronidase. This enzyme changes the estrogen byproducts, allowing them to be reabsorbed by the body and recirculated, contributing to estrogen dominance. This effect is enhanced by not having regular bowel movements, GI infections or imbalances in the estrobolome. 

The DUTCH test doesn’t look at Phase 3 detoxification but is easily accessed via a functional stool test that looks at beta-glucuronidase levels. 

Now that we’ve covered the steps required to clear excess estrogen, it is easy to see why detoxification is so important when addressing estrogen dominance. In Part 2 of this series, I will discuss the functional medicine approach to estrogen dominance detox and how to use food, supplements and other tools to support these critical pathways. 

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References 

1. Liska D. J. (1998). The detoxification enzyme systems. Alternative medicine review : a journal of clinical therapeutic, 3(3), 187–198. 

2. Grant D. M. (1991). Detoxification pathways in the liver. Journal of inherited metabolic disease, 14(4), 421–430. https://doi.org/10.1007/BF01797915 

3. Eliassen, A. H., Missmer, S. A., Tworoger, S. S., & Hankinson, S. E. (2008). Circulating 2-hydroxy- and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer epidemiology, biomarkers & prevention : a publication

of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 17(8), 2029–2035. 

4. Ervin, S. M., Li, H., Lim, L., Roberts, L. R., Liang, X., Mani, S., & Redinbo, M. R. (2019). Gut microbial β-glucuronidases reactivate estrogens as components of the estrobolome that reactivate estrogens. The Journal of biological chemistry, 294(49), 18586–18599. https://doi.org/10.1074/jbc.RA119.010950