Estrogen Detoxification and Liver Support

Each step of estrogen metabolism and detoxification, with multiple possible enzymatic reactions, can influence a person’s degree of estrogen-related health risks, including that of gynecological and breast health complications and endometriosis. Phase I and II detoxification reactions can create multiple different types of estrogen metabolites, and the proportion of each produced can have major implications on the resulting risk of oxidative stress and DNA damage. The actions of these active metabolites can prompt or exacerbate estrogen-related disorders such as endometriosis, while the production of other metabolites can reduce risks or even provide protection.

During the first phase of estrogen detoxification, estradiol undergoes hydroxylation, which creates 2-OHE (2-hydroxyestrogens), 4-OHE (4-hydroxyestrogens), and 16-OHE (16a-hydroxyestrones). The 2-OHE form is the most protective and least likely to cause cellular and DNA damage. It also has anti-proliferative effects which helps protect against sickness.

Having a low 2-OHE:16-OHE ratio (ie. higher amounts of 16-OHE) can promote HPV (human papilloma virus) proliferation in strains 16 and 18 and is associated with an increased risk of cervical dysplasia,¹ as well as breast health complications.²

When 2-, 4- and 16-OHE metabolites are further transformed by phase II detoxification, the function of liver enzymes COMT, SULT1A1, UGT1A1, and GST enzymes then affect the proportion and ratio of new metabolites which will either be excreted from the body or will recirculate and potentially cause damage.

Both 2-OHE and 4-OHE metabolites undergo methylation before they’re released. Proper COMT activity can make 4-OHE less active (less dangerous), while poor COMT function can increase the risk of quinone production, increasing oxidative stress and DNA damage. Most of the resulting estrogen metabolites from phase II detoxification will be secreted into the gut via bile, though some may be bound for blood flow to then be excreted in urine.

Once in the gut, these estrogen metabolites should follow the GI tract and be eliminated from the body. However, the presence of the enzyme beta-glucuronidase, made by specific gut bacteria, can reactivate these metabolites, turning their estrogen functions back on and allowing them to be reabsorbed into circulation.

We can influence the generation of protective 2-OHE, and reduce 16-OHE and 4-OHE by promoting the activity of the specific enzymes that drive those more ideal pathways. We can also use substances and foods to inhibit beta-glucuronidase activity to prevent the re-activation and uptake of these metabolites to ensure they’re excreted properly.

Phase 1 Detox

Phase 1 detoxification in the liver is called hydroxylation and relies on cytochrome P450 (CYP450) enzymes. CYP450 enzymes such as CYP1A1 and 1A2, CYP1B1, and CYP3A4 add a hydroxyl group onto estradiol converting it into 2-OHE, 4-OHE and 16-OHE, respectively. Altered gene expression and function of each of these enzymes can affect the production and proportion of each type of metabolite.

Cruciferous vegetables, such as broccoli and Brussels sprouts, have been shown to induce CYP1A1 and 1A2 activity, as has DIM (3’3-Diindolylmethane), a constituent in crucifers.³ Meanwhile resveratrol has also been shown to enhance CYP1A1 activity.⁴ The substances that get produced as a result of these transformations can increase or decrease health risks. For example, low CYP1A2 activity can increase health risks, but that risk is also dependent on what the liver does with those next metabolites. That is, phase I detoxification often creates more toxic metabolites and requires they go through a second transformation to make them less reactive and dangerous. 

Phase II Detoxification

The process of Phase II detoxification is characterized by conjugation: When hydrophilic compounds such as glucuronic acid, sulfate, glutathione, amino acids, acetyl and methyl groups are transferred onto and transform estrogen metabolites. This transformation makes metabolites more hydrophilic so they can be excreted in bile and/or urine.³

The enzyme UGT1A1, which facilitates glucuronidation of 2-OHE, is a UGT (UDP-glucuronosyltransferase) enzyme. Its activity is supported by compounds such as resveratrol, those in cruciferous vegetables, and calcium d-glucarate.³

The enzyme SULT1A1, a SULT (sulfotransferase) enzyme, facilitates the sulfation of 2-OHE. Similar to glucuronidation, sulfation makes 2-OHE less reactive and less toxic. In addition to affecting estrogen metabolite levels, low SULT activity can affect androgens and thyroid hormones.³

If 2-OHE is methylated by COMT (instead of undergoing glucuronidation or sulfation) then GST (Glutathione S-transferase) enzymes finish phase II detoxification. GSTs help render these metabolites safer, catalyzing a reaction that allows glutathione (GSH) to stop these metabolites from causing damage.

GST activity can be enhanced by cruciferous vegetables, N-acetyl cysteine (NAC), and by resveratrol when baseline GST levels or activity is low.⁴ However, if an individual’s genetic SNP (single nucleotide polymorphisms) testing reveals a GSTM1-null genotype, cruciferous vegetable intake may not have the same benefit since this genotype favours rapid excretion of the isothiocyanate compounds found in these foods.³

GST enzymes require glutathione, which can be obtained via supplementation of liposomal glutathione, or by consuming or supplementing with NAC, glycine, glutamate, magnesium, selenium and vitamin B6 so the body make its own glutathione. Curcumin, milk thistle, and alpha-lipoid acid can also help recover glutathione levels.

In phase II detoxification, methylation of 2-OHE and 4-OHE via COMT is important for decreasing the toxicity of these metabolites and overall health risk. Methylation can be supported with methyl donors such as methionine, vitamin B6, vitamin B12, folate, betaine, choline and magnesium. Other dietary factors may also play a role: One animal study found that a high-sugar diet actually decreased gene expression of COMT.⁵

The function and activity of Phase I and II enzymes are affected by the combination of an individual’s genetics and environment. Dietary components and supplementation can affect their activity, but the efficacy of dietary constituents to do so may depend on a person’s individual genetic polymorphisms. Polymorphisms in CYP450’s, COMT, GST, as well as those involved in antioxidant production, can all influence these detoxification pathways by increasing or decreasing the activity of each enzyme, influencing the composition of end metabolites. 

An example of a disorder associated with polymorphisms in estrogen metabolism is endometriosis. Polymorphisms of GST-M1 and GST-P1 have been identified as being significantly associated with endometriosis.⁶

DIM – Phase I

As mentioned earlier, DIM promotes the phase I hydroxylation of estradiol, favouring the 2-OHE pathway, and shunting metabolism away from the 16-OHE pathway. DIM helps increase the 2-OHE:16-OHE ratio while having beneficial actions. In particular, it has been shown prevent the development of cervical dysplasia and inhibit cell adhesion.¹ It also has been shown to affect the secretion of estradiol in endometriotic cells, leading to decreased pelvic pain and bleeding in women with endometriosis.⁷

In those with cervical dysplasia, 2mg/kg of DIM per day has been shown to significantly improve cervical health, taking five months on average to see significant improvements in CIN grading.⁸ Of those given DIM, 72% had a decrease in lesion number, and by six-month follow up, 85% of patients no longer required the LEEP procedure they had originally been scheduled for at baseline.

Hops – Phase I

Hops contains multiple active constituents that affect the action of estrogen and its metabolites. 8-PN (8-prenylnarigenin) promotes the 2-OHE pathway by inducing CYP1A1 gene expression.⁹ Meanwhile XH (xanthohumol) helps increase the production of GST via Nrf2 activity.⁹

Broccoli and Sulforaphane Glucosinolate (SGS) – Phase II

Many studies have reported links between dietary crucifers and beneficial outcomes of estrogen metabolism and detoxification.^3,10,11 Using dietary measurements, consuming a greater number of cruciferous vegetables has been shown to increase the 2-OHE:16-OHE ratio in postmenopausal women.¹⁰

The SGS (sulforaphane) found in these vegetables, such as broccoli sprouts, has demonstrated beneficial activities and supports the activity of phase II enzymes and the antioxidant glutathione.¹² SGS can induce apoptosis, inhibit cell cycles and prevent the spread of abnormal cells. It even activates Nrf2, a transcription factor that induces many other antioxidant enzymes and activities.¹³

In a model of endometriosis, supplementing with SGS led to decreased lesion volume and lower adhesion scores.¹¹ It also decreased IL-6, IL-10, TNF-alpha and VEGF in both peritoneal fluid and plasma. A similar result was found in another animal model of endometriosis, where treatment with SGS decreased the size of lesions and led to decreased pain.¹⁴

Calcium D-glucarate – Phase III

Once transformed, estrogen metabolites can enter the gastrointestinal tract via bile secretion. From here, these metabolites can be excreted, or they can be transformed again while in the gut.

The presence of beta-glucuronidase from gut microorganisms can reverse the detoxifying transformation of estrogens, liberating them and basically reactivating the harmful metabolites. These can be reabsorbed in the intestines and re-enter circulation, increasing health complications.¹⁵ Calcium d-glucarate stops this from happening. It prevents estrogens from being liberated and reactivated, which could have positive implications for calcium d-glucarate in endometriosis, PCOS, and gynecological health.

There are many dietary and botanical substances that promote protective estrogen metabolism and detoxification pathways. Urine testing for estrogen metabolites can help identify which pathways (and therefore enzymes) are currently more or less active. Meanwhile, genetic SNP testing, available as direct-to-consumer testing, can be used to identify polymorphisms in genes that code for these liver detoxification enzymes. Understanding these pathways, and an individual’s genetic predisposition can help drive the use of specific substances that correlate to specific enzymatic activity.

Lastly, it’s important that in addition to altering these metabolites, that they also be removed promptly from the body. Staying well hydrated and having regular urination and bowel movements will help ensure they are flushed out of the body.

References

1. Hodges RE, Minich DM. (2015). Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab. 2015:760689
2. Busserolles J, Zimowska W, Rock E, et al. (2002). Rats fed a high sucrose diet have altered heart antioxidant enzyme activity and gene expression. Life Sci. 71(11):1303-12
3. Méar L, Herr M, Fauconnier A, et al. (2020). Polymorphisms and endometriosis: a systematic review and meta-analyses. Hum Reprod Update. 26(1):73-102
4. Morales-Prieto D, Herrmann J, Osterwald H, et al. (2018). Comparison of dienogest effects upon 3,3’-diindolylmethane supplementation in models of endometriosis and clinical cases. Reprod Biol. 18(3): 252-8
5. Del Priore G, Gudipudi DK, Montemarano N, et al. (2010). Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia. Gynecol Oncol. 116(3): 464-7
6. Bolton JL, Dunlap TL, Hajirahimkhan A, et al. (2019). The Multiple Biological Targets of Hops and Bioactive Compounds. Chem Res Toxicol. 32(2):222-233
7. Zhou A, Hong Y, Lv Y. (2019). Sulforaphane attenuates endometriosis in rat models through inhibiting PI3K/Akt signalling pathway. Dose Response. 17(2): 1559325819855538
8. Xu X, Dai M, Lao F, et al. (2020). Effect of glucoraphanin from broccoli seeds on lipid levels and gut microbiota in high-fat diet-fed mice. J Functional Foods. 68: 103858
9. Liu Y, Zhang Z, Lu X, et al. (2020). Anti-nociceptive and anti-inflammatory effects of sulforaphane on sciatic endometriosis in a rat model. Neurosci Lett. 723: 134858