Estrogen Detoxification: Know the Flow

Estrogen Detoxification: Know the Flow
Scott Resnick MD 2023

I wanted to do a piece to clarify the estrogen detoxification process. We all know that estrogen needs to be detoxified, but what does this really mean? When does it become “toxic” and what can we do about it?


The best place to start is by defining a toxin. In short, a toxin is any substance that works against our body’s normal biological functioning. But what’s interesting, is that while we are awash in a sea of synthetic molecules, our primary source of detoxification comes from within our biological processes. I will give you a couple of examples.


People don’t know that water in incorrect doses is lethal. Overhydration is a good way of ensuring that all of your cells literally swell and explode. Along these lines, carbon dioxide is another horrible toxin that we are making continually. But we detoxify this very effectively through our lungs. We breathe down our CO2 with a big sigh when it gets too high.


Our mitochondria are continually making reactive oxygen species, ROS, which are a byproduct of making energy with oxygen. Glutathione is required to buffer these highly reactive and destructive molecules. These are just a few of the ways we need to buffer internal toxins.

Detoxification Pathways: Phase I and Phase II


The primary way that we detoxify is through Phase I and Phase II detox. In Phase I detox, fat-soluble molecules (for example estrogen) first have a hydroxyl molecule added to them. This is a tiny molecule made with a single oxygen and hydrogen atom, -OH. This makes the fats more water-soluble. This is guided by the cytochrome P450 system, a set of enzymes that degrades different toxins. Herbs, smoking, alcohol, vegetables, fruits, and common medications all induce (increase activity of) or inhibit (decrease) enzyme activity.


Here’s a quick story to illustrate enzyme inhibition that you’ll remember. Grapefruit juice inhibits the CYP-450 enzyme 3A4 and makes it not work so well. So should a man take Viagra along with a big glass of grapefruit juice, the Viagra won’t be metabolized properly, and he could wind up with “too much of a good thing” as the drug fails to be metabolized out of his system. The enzyme is inhibited and unable to metabolize the drug; the drug’s levels remain high for an unplanned (and frequently unpleasant) amount of time.


In Phase II detox, the hydroxylated molecule, now more “reactive”, is then conjugated with another molecule for final excretion in the bowel, sweat, and urine. You’ll recognize the names of some of these conjugates; glutathione, methyl groups (methylation), amino acids, glucuronide, and sulfate. This larger molecule is unable to re-enter the cells and is excreted from the body.


What’s interesting about the detoxification of estradiol is that the hormone has a multi-modal relationship with the body. Its risk/benefit relationship isn’t linear, as it exerts different effects at different times throughout a woman’s life.

Estrogen Detoxification Enzymes


But we know that a cumulatively high estrogen and its metabolites, particularly if unbalanced with progesterone, put several tissues at risk, namely the breast and the uterus. The primary detox enzymes for estrogen are the cytochromes P-450 1A1, 1B1, and COMT (catechol-O-methyl transferase, methylation again).


The 16-pathway is guided by CYP 3A4– there’s that 3A4 enzyme again I discussed with the Viagra example. Many of us will have a genetic twist that favors one of the enzymatic pathways over another. This is why there’s such a wide variety of results on something like a DUTCH test— we’re all a little different.


I want to quickly editorialize a bit about the 2,4 and 16 hydroxy estrones. A decade ago, there was a lot of research looking at all of these ratios. And the jury is still out. Having followed the discussion for years, I believe that the best thing to look at is the methylation status. Getting that last methyl group added on seems to bring the estrogen molecule to a “safe haven”. Recall that methylation is a phase II conjugate.

The Bad Estrogens… and the Good


Here’s what we know to be more dangerous. A 4-OH (hydroxy) estrone, if not methylated, can become a 3,4 quinone, a molecule that binds and disrupts DNA. Seeing a urinary 4-Methoxy at higher levels on a DUTCH test is a favorable marker.


A homocysteine test is a really good way to know your methylation status. Be sure to check this at some point in your life to ensure that it isn’t too high. Elevated homocysteine is unquestionably associated with cardiovascular disease and Alzheimer’s.


So, what can we do to best drive these pathways? Here are a few practical detox tips:

Estrogen Detox Tips:


  • Don’t amass too much estrogen to start! We know that estrogen is made in the fat cells. The more over an ideal weight a woman is, the more estrogen she’ll have.
  • Fiber is your friend. In addition to your healthy meals and carrots, I often recommend fiber. I’m a big fan of the Whole Foods psyllium husk. 2 stools a day will lower your estrogen and ‘enterohepatic’ recycling of estrogen.
  • Avoid toxins. Seems so simple, right? But we can all choose to eat more healthy foods. One way not to overwhelm or distract your detox is to not expose it to additional foreign substances that it needs to reconcile. Like pesticides, dyes and preservatives, and tobacco.
  • Eat more cruciferous vegetables. This way you can get your DIM naturally. This phytonutrient works in part on the 1A1 pathway, pushing it to the probably healthier 2-OH (hydroxy) pathway. It additionally works on any number of anti-inflammatory and epigenetic effects. Resveratrol induces 1A1, as does curcumin.
  • One more point. Don’t let thyroid-based fears keep you from eating these healthy vegetables. Current data shows that these veggies don’t influence thyroid function strongly or negatively.

Detoxification is a complex process. Some simple steps with avoiding toxins, minimizing risk factors, and driving our detox pathways favorably with diet and supplementation can set us on a path to effective detoxification and whole-body health.













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