Menstrual irregularities are experienced by 14-20% of cycling women. Often these irregularities show up as heavy, light, short, or long cycles or menstrual cramping. These symptoms are linked to imbalances in hormone levels, specifically estrogen. Estrogen production occurs in the ovary. But, we must also consider the organ responsible for metabolizing or breaking down estrogen, an equally important process for hormone regulation - and that is the liver.

Metabolism of estrogen is a multistep process that can affect the level of circulating estrogen. Therefore it is crucial to shed light on liver function when discussing estrogen levels.

This article will discuss the function of the liver, how it metabolizes estrogen, signs of high estrogen, and how to test for it, as well as a functional medicine approach to supporting liver estrogen metabolism.

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What is the Liver's Role in the Body?

The liver is an organ located in the upper right quadrant of the abdomen. The liver plays a vital role in the body, affecting digestion, absorption, metabolism, and hormone regulation. The liver's functions include:

• Bile production, which helps to break down fats and remove waste from the body
• Creation of proteins for the blood
• Synthesis of cholesterol and carriers for fats to help them move through the body
• Storage of blood sugar (glycogen) and utilization of glycogen when needed
• Synthesis of proteins
• Iron storage
• Metabolism/detoxification of compounds, including hormones, to water-soluble compounds for excretion in the urine and feces
• Assistance in blood clotting factors
• Creation of immune factors that aid in the protection from pathogens
• Assistance in the breakdown of red blood cells

The Role of the Liver in Estrogen Clearance

Estrogen is a collective term for estradiol, estrone, and estriol hormones. Estradiol and estrone are the most active of the estrogens, and estriol is a weak estrogen, a byproduct made from estrone. Estrogens are metabolized in the liver in two main phases: Phase I (hydroxylation) and Phase II (methylation, sulfation, and glucuronidation). The third phase of metabolism occurs in the gut and kidneys.

Phase I

Also known as hydroxylation, this is the phase where estrogens get converted into three different metabolites, all of which have different biological actions. The conversions depend on enzymes, and genes control enzyme function. This means that some people may utilize one pathway more than others depending on their genetic predispositions, which is why testing can be beneficial.

Products (metabolites) of Phase I:

• 2-hydroxy-estrone (2-OH): considered the "good" estrogen metabolite due to its weak activity. Some research suggests a protective effect on breast tissue from this metabolite.
• 16-hydroxy-estrone (16-OH): a stronger estrogen metabolite than 2-OH. It may cause tissue proliferation or growth and may be linked to estrogen-sensitive cancers. It is important to note that estriol converts only into this 16-OH metabolite.
• 4-hydroxy-estrone (4-OH): considered the "bad" estrogen metabolite as it is the most potent and causes the formation of depurinating adducts (molecules that cause DNA damage leading to the initiation of breast cancer).

Phase II

In this phase, the products of Phase I are ultimately made to be water soluble, allowing them to move into Phase III, elimination.

Methylation, controlled by the enzyme Catechol-O-methyltransferase (COMT), converts these metabolites from Phase I into methoxyestrogens, which may have anti-cancer benefits. Sulfation and/or glucuronidation will make these metabolites water soluble so they can be excreted in the urine via the kidneys or the stool via bile. The excretion is considered Phase III, or the final step, in estrogen metabolism.  

However, there's another option for these metabolites that's dependent on how COMT functions. COMT is an enzyme that is controlled by genetics. This means that COMT may run at a fast, slow, or average speed depending on an individual's predispositions. When COMT is slow, metabolites from Phase I may turn into quinones which can form depurinating adducts, molecules that cause DNA damage and have been linked to breast cancer. However, quinones can be neutralized through the antioxidant glutathione, or they can also be recycled back to the estrogen metabolites that they previously were. In addition to genetic predisposition, COMT may be affected by specific nutrients or lack thereof.

Additionally, Phase I metabolites can skip methylation and go straight into sulfation or glucuronidation, making them water soluble and ready for Phase III.

Phase III

While not occurring in the liver, briefly discussing Phase III of estrogen detoxification is essential. In our large intestine lives our gut microbiome, a collection of microbes that aid in numerous functions in our body. Within the microbiome is a specific group of microbes that scientists have referred to as the "estrobolome." They coined this term because these microbes specifically aid in removing estrogen. However, sometimes we can have a dysbiosis, or an imbalance, in the microbes of the estrobolome. When this occurs, these microbes release an enzyme, beta-glucuronidase, which frees estrogen and recirculates it in the body.  

Symptoms of High Estrogen

Common symptoms of high estrogen, also referred to as estrogen dominance, include:

• Heavy periods
• Mood swings
• Headaches
• Sleep disturbances
• Breast tenderness
• Fibroids

Testing Liver and Estrogen Levels

The DUTCH Complete test is a hormone panel that assesses urine metabolites to see how the body breaks down hormones. This in-depth test shows you the above-discussed estrogen metabolites, showing both Phases I and II estrogen metabolism. It also gives you other hormone levels and metabolites, including those involved in the stress response.

Since methylation is involved in Phase II of estrogen metabolism, a genetic methylation test can be helpful. Genes control the rate at which enzymes, such as the COMT enzyme, run. This test will give insight into whether the COMT enzyme (as well as others involved in methylation) is running fast, slow, or normal.

Beta glucuronidase is the enzyme released by the microbes in the estrobolome, part of Phase III. When beta-glucuronidase is high, it indicates that estrogen is being recirculated in the body rather than being eliminated.

A Liver Panel will show two major liver enzymes that, if high, would indicate a problem with liver functioning. This panel also shows bilirubin levels, a substance created by the liver that helps to eliminate toxins and is also responsible for carrying out estrogen in the stool.  

All biochemical pathways are dependent on enzymes. Enzymes depend on cofactors, which are often vitamins and minerals. Estrogen metabolism is no different, requiring numerous cofactors for the enzymes to run correctly. Therefore, a Micronutrient test will show levels of numerous cofactors involved in estrogen metabolism.

How to Support Optimal Liver Estrogen Detoxification

Supporting Estrogen Detoxification is usually done in three phases.

Phase I Support

I3C (Indole 3 Carbinol) and DIM (3,3’-diinolylmethane) may be useful. I3C is a compound found in the Brassica family of vegetables. I3C is converted to DIM, and both are beneficial for estrogen metabolism because I3C and DIM have been shown to increase the favorable 2-OH estrogen metabolism pathway. Eating brassica family vegetables, such as kale, cauliflower, broccoli, and Brussels sprouts, can be supportive too. In fact, eating 500g of broccoli per day has also been shown to shift estrogen pathway ratios in favor of 2-OH.

Resveratrol is a compound found in the skin of red grapes and berries and is considered an antioxidant. Resveratrol may help to reduce the adduct formation from the "bad" 4-OH estrogen metabolites. N-Acetylcysteine (NAC), a compound that our bodies make naturally, was also shown to reduce adduct formation. Another study showed that resveratrol paired with NAC was better than using each in isolation in reducing quinone formation.

Soy contains compounds called isoflavones that may be beneficial. One study compared a group of participants consuming a high soy diet (two servings per day) with another group consuming a low soy diet (less than three servings per week). After six months, the high soy group had favorable changes in the ratio between the 2-OH and 16-OH metabolites, suggesting that a diet including soy could be beneficial for Phase I estrogen metabolism.

Phase II Support

Since methylation plays a significant role in Phase II of estrogen metabolism, the following methylation cofactors and their food sources may be helpful:

• Cobalamin (B12) - found in red meat, eggs, fish, dairy products, and poultry
• Folate (B9) - found in spinach, eggs, asparagus, and cheese
• Riboflavin (B2) - found in eggs, meat, milk, and cheese
• Pyridoxine (B6) - found in fish, bananas, grains, and legumes
• Choline - found in eggs, cauliflower, peanuts, and flax seeds
• Magnesium - found in pumpkin seeds, chia seeds, cashews, and almonds

Glutathione is vital to the process of neutralizing cancer-causing quinones formed during Phase II of estrogen detoxification through its effect on the enzyme glutathione s-transferase (GSH). Asparagus, avocado, and cucumbers are all good sources of glutathione.

Another phytonutrient from the Brassica family, sulforaphane, a potent antioxidant and anti-inflammatory molecule, can help regulate COMT and can also help GSH. Broccoli sprouts are the best source of this phytonutrient, holding 10-100x more sulforaphane than mature broccoli plants.  

Phase III Support

Diets high in fibrous foods have been shown to have lower beta-glucuronidase levels, allowing Phase III detoxification to function better.

Calcium-D-glucarate can inhibit beta-glucuronidase, thus allowing estrogen to be more easily excreted.

Lifestyle changes

Since the ultimate breakdown products of estrogen are excreted in the kidneys and stool, drinking enough water and having daily bowel movements are essential to eliminate these products.

Limiting pesticide exposure can also help ensure liver enzymes function properly and can process estrogen correctly.

Summary

Menstrual irregularities affect many women, and estrogen levels may be to blame. When we discuss estrogen levels, we must give enough attention to the liver and consider liver function as a part of the equation because two out of the three steps of estrogen metabolism occur in the liver.

Knowing that we all have biochemical individuality in how our bodies function, functional medicine testing can be an important tool to help get to the root cause of estrogen dominance. A comprehensive, personalized treatment plan can be made to get to the root cause of the problem by assessing individual estrogen metabolism, genetic control of enzymes, liver function, and specific micronutrient levels.