Is It Profitable to Test Patients Being Treated for Breast Cancer for Estrogen Metabolites?

As with so many questions the answer is probably…”it depends!” We believe that 4-OH estrogens are especially problematic with respect to breast cancer risk. Should they therefore be tested when someone has active breast cancer?

First, I am not an expert in breast cancer, so I am not going to wade into the controversial waters and discuss which treatment options are best. However, there are conclusions we can pass along that may be helpful.

Read on if you’re interested in this topic, but the short story is that when on drugs like Tamoxifen, testing may be valuable and actionable. When patients are on strong aromatase inhibitors (which stop the creation of estrogens), testing may be of more limited value.

Estrogens can cause proliferation by working at the receptor level. This is inhibited by drugs like Tamoxifen, BUT there is another mechanism potentially at work in terms of increasing cancer risks – estrogen metabolites. 4-OH-estrogens are related to cancer risks by creating a quinone that can attach to DNA and actually break a piece off (guanine or adenine). This is the mechanism by which they (4-OH estrogens) are thought to increase the risk of certain cancers. My logic says that if you are “blocking” the cancer-causing action at the receptor level, you are still vulnerable to this other mechanism because overall estrogen levels have not been reduced. Testing metabolites makes sense in these people. If the patient is making an abundance of 4-OH estrogens, you might consider things like DIM (increases more protective 2-OH estrogens), products that help methylation (which gets rid of 4-OH estrogens before they can make a quinone and harm DNA) or glutathione (the last attempt to get rid of the quinone before it attaches to DNA). (Note, however, that DIM and I3C may render Taxmoxifen less effective; thus caution is advised when using these compounds).1,2

What about people on Arimidex? This is different, as I see it. Postmenopausal women with breast cancer may be put on aromatase inhibitors to block the production of estrogens from androgens. Their levels of estrogens are already pretty low, so this leaves their estrogens VERY low. This is true of estradiol and also the metabolites. Consider the following patient. If she was on Arimidex, causing VERY low estrogen levels, is it relevant that she makes more of the 4-OH-estrogens and 16-OH estrogens compared to 2-OH-estrogens? You expect about 70% 2-OH, 10% 4-OH and 20% 16-OH, but she only makes about 52% 2-OH and higher than expected percentages of the “bad” metabolites (24.5% 4-OH).


There is an opportunity to run further with these results than may be justified. The results for 4-OH-E1 is 0.0. It is actually 0.03 (16-OHE1 is 0.03 also and 2-OH-E1 0.06). These values are very near the detection limit of the assay. This will make them less precise (could be 0.02, could be 0.04…who knows?), so the ratios between the three compounds will not be as reliable as it would be at higher concentrations. Theoretically, if a patient makes almost zero estrogen (as in this case), there is hardly any of the “bad” estrogen metabolites to create any problems. It is doubtful that extremely low levels of 4-OH-estrogens will be highly problematic in damaging DNA (this is a guess!). The levels in this example are less than 1% of premenopausal levels.

When estrogen levels are EXTREMELY low it is possible the specific metabolite pattern is still relevant, but it is of significantly less value than in situations where overall estrogen levels are higher. You might keep that in mind if and when you treat patients on different therapies for estrogen-related cancers.

Melatonin levels that are lower are seen in patients who develop breast cancer and high cortisol may play a role also. There is benefit in DUTCH (Dried Urine Test for Comprehensive Hormones) testing as it relates to breast cancer, but do think through what treatment options the patient is on and what the relative value of the test might be in a particular case. Patients with breast cancer obviously are in a tough position wanting help but also some serious financial considerations. We want the testing they are doing to be as impactful as possible. If you have questions in particular cases (before or after they test), please do let me know.