As a quick recap, all substances that require detoxification go through two phases. Phase one can render substances more or less toxic than they were before. Either way, it’s a setup for phase 2, which allows for final elimination.
Phase 1 Detoxification of Estrogen
In the case of estrogen (estrone and estradiol), Phase 1 is accomplished by several possible cytochrome (CYP) enzymes, depending on the tissue from which it is being eliminated: CYP1A2 or CYP3A4 from the liver, or CYP1A1 or 1B1 in tissues other than the liver. All of these add a hydroxyl (-OH) group to either estrone or estradiol. The issue is where on the molecule those enzymes add the -OH group.
You want them to add it at the 2 position (2-OH, or 2-hydroxyeone). CYP1A2 and 1A1 tend to add it here, and CYP3A4 sometimes does too. This estrogen metabolite is healthy.
You don’t want them to add a hydroxyl group at the 4 or 16 positions (4-hydroxyestrone or 4-OH, and 16-hydroxyeone or 16-OH), for the most part. These have stronger estrogenic activity, and are more associated with cancer. 4OH gets produced mostly through CYP1B1 in the peripheral tissues, while 16OH gets produced by CYP2C9, and sometimes also by CYP3A4.
At this stage, the goal is to increase production of 2-OH, and decrease production of 4-OH and 16-OH. Genetic mutations in the CYPs responsible for the latter two may be responsible for increased production of them, though other toxic chemicals may act as “inducers” of those CYPs too, even if there is no mutation. These inducers include dioxins, PCBs, and PAHs (polycyclic aromatic hydrocarbons, made from cooking at high heat like frying and grilling), cigarette smoke, and xenoestrogens, or chemicals that behave like estrogen in the body. Inhibitors include polyphenols (so dark-colored fruits and veggies).
On the flip side, one of the best ways to encourage production of 2-OH is to consume cruciferous veggies, as these produce DIM (Diindolemethane). DIM balances the estrogen metabolites in favor of 2-OH. Flax seeds also support 2-OH production, as does soy consumption—though caveat here, make sure the soy is non-GMO or organic.
Phase 2 Detoxification of Estrogen
Once estrogen has been primed for elimination by Phase 1, Phase 2 takes over. This involves the COMT (catechol oxygen methyltransferase), which adds a methyl group to the above metabolites. This is especially important for the 4-OH and any excessive amounts of 16-OH, as the addition of a methyl group renders them harmless. Those with COMT mutations may struggle with this step, though adequate levels of the COMT enzyme cofactors (magnesium or Vitamin B6) can help support a slower functioning enzyme.
COMT function also requires that the body has adequate methyl donors available to perform this step, though. Those who have either MTHFR mutations or an overworked methylation pathway (due to toxicity or low levels of methyl donors like folate, Vitamin B12, Vitamin B6, or methionine) may not be able to eliminate estrogen effectively at this stage, causing 4-OH or 16-OH levels to rise. One easy way to determine methylation function is to test homocysteine: an efficient methylation cycle should recycle homocysteine well, so levels should be relatively low (around 6-7).
Estrogen dominance can mean more than just high levels of estradiol on blood testing. There are many potential pathways for backup, depending upon enzymatic function, toxicity, and nutrient status.
If you’re struggling with estrogen dominance, consider increasing your cruciferous veggies, dark-colored berries, flax seeds, and non-GMO or organic soy, while avoiding hormone disrupting chemicals. You may also want to consider testing estrogen metabolites, homocysteine, micronutrients, or perhaps genetic testing to see which enzymes may need the most support.