MTHFR Testing and Estrogen

If your provider orders this, walk out the door. Here's why.

Many naturopaths and functional medicine doctors recommend testing for variants (also called polymorphisms) of the MTHFR gene as a way to “diagnose” if women may have “toxic estrogen” or “estrogen dominance.” If someone has ordered this for you, I am sorry to tell you that you have been scammed.

Real genetics experts call the MTHFR gene the motherfucker gene (no, they really do) because some doctors, naturopaths, and influencers frequently recommend testing, leaving genetic counselors and doctors who are experts in genetic medicine the unenviable job of explaining how the test result is meaningless.

I frequently see people who have had meaningless tests ordered by naturopaths and functional medicine doctors and it is often hard for people to accept that a test done in a lab can literally mean nothing. Also, these providers spend a lot of time selling the con, so it’s hard for people to believe that someone who seemed so invested in your health would order a useless test, especially one that costs a lot of money.

MTHFR Background

This part is a little science heavy, although it isn’t really necessary to know all of this to refute the claims made by naturopaths and functional medicine doctors. The real experts, meaning the American College of Medical Genetics and Genomics, have recommended against testing for MTHFR variants since 2013. This alone speaks volumes. However, as many naturopaths, functional medicine providers, people who sell genetic tests, and makers of so-called nutraceuticals (that you buy to “support” your MTHFR variant) casually abuse the terminology in an effort to sound science-y and make you think they know something that you don’t, so therefore you should listen to them, it can be useful to learn more.  

Here is some technical background for those who want to know and for those who don’t just skip ahead to the section titled, “Deconstructing the Nonexistent MTHFR-Estrogen Connection”

The MTHFR gene produces the enzyme methylenetetrahydrofolate reductase, which converts 5,10-methylenetetrahydrofolate to the primary form of folate (5-methyltetrahydrofolate). The primary form of folate (or 5-methyltetrahydrofolate) is involved in converting homocysteine (an amino acid) into methionine (another amino acid). The body uses methionine for many biological functions, one is the production of a substance called s-adenosylmethionine (SAMe), which is important for methyl transfers (a chemical reaction vital for many biological functions). It is the MTHFR-SAMe connection that is the heart of the estrogen disinformation, so hang on to that nugget.

We all inherit two genes that code for the MTHFR enzyme, one from each parent. There are two variations in the MTHFR gene that can result in reduced activity of the MTHFR enzyme and an estimated 30-40% of people in the United States have at least one of them. The common MTHFR variants are called the C677T variant and the A1298C variant. People can inherit two copies of the regular MTHFR gene, they can inherit a regular copy of the MTHFR gene and one of the variants, they can inherit two copies of the C677T variant or two copies of the A1298C variant, or they can inherit one copy of the A1298C variant and one copy of the C677T variant. Only people who inherit two copies of the C677T variant are at risk of developing high levels of homocysteine, although risk of a negative outcome for this appears quite low.  

What we do know is that inheriting one or two copies of a MTHFR variant doesn’t impact estrogen.

A Primer in Estrogen Metabolism and Revisiting the MTHFR-SAMe Connection 

Estrogen is metabolized, meaning it is changed into other substances to render it less active and to facilitate its removal. Before menopause, the ovaries are regularly making estrogen and at times the levels in the blood are relatively high, so without ways to inactivate estrogen and remove it from the system there would be a lot of trouble as estrogen levels would just get higher and higher each month. As ovulation depends on complex signaling that includes changes in estrogen levels, systems to remove estrogen is needed. After menopause, even though the ovaries are no longer making estrogen and blood levels are low, many tissues continue to make estrogen inside their cells (for example the brain and muscles), so ways to deactivate and remove estrogen are still required.

There are several ways that estradiol and estrone (the main estrogens) are taken out of service and removed. One pathway is through the bile (if you want to learn more about that and how bowel movements do not regulate estrogen levels, read this post). Estradiol and estrone are also removed by enzymes (not MTHFR) that convert them to estriol, which is then removed in the urine. 

And another pathway for metabolism of estrogen involves converting estradiol into estrogens known as catechol estrogens. This is where the false MTHFR claim appears to originate. Catechol estrogens can be further metabolized by two pathways:

  • Conversion into methoxyestrogens by an enzyme called catechol-O-methyltransferase or COMT. This involves a chemical reaction that requires S-adenosylmethionine (SAMe), levels of which are related to MTHFR. 

  • Conversion into one of two types of quinone estrogens. One of these, the quinone estrogen called estradiol-3,4 quinone, can harm DNA and is believed to be cancer causing.

So one of the several pathways of estrogen metabolism (not all of them are discussed here) involves producing an estrogen metabolite that can damage DNA and is linked with cancer. 

So how is this related to MTHFR?

Some MTHFR truthers appear to believe low activity of MTHFR from variants leads to less SAMe, affecting the ability of the enzyme COMT to produce the safe methoxyestrogens and so the system backs up, producing more of the potentially harmful quinone estrogen.

There is no published evidence to support this hypothesis or any other naturopathic fever dream involving MTHFR and “toxic” estrogen. I guess “science” is easy when you can make it all up. 

Deconstructing the Nonexistent MTHFR-Estrogen Connection

What you should know is genetics experts don’t recommend MTHFR testing. For those of you who don’t know, doctors who specialize in medical genetics and genetic counselors are not just experts in genetic conditions that affect the risk of cancer, they are also experts in genetic conditions that affect metabolism. They got this. If MTHFR were important for hormone health, these experts would tell us. After all, this is possibly the most studied gene. Ever.

Science aside, just look at it from a common sense perspective. If 30-40% of people have a dysfunction in a key metabolic pathway involving estrogen due to a MTHFR variant, how did people manage with their abnormal estrogen pathways before the advent of “special” supplements? 

Also, if these common MTHFR variants produced issues with toxic or harmful estrogen, we’d know by now. Common problems are a lot easier to identify because, well, they’re common. For example, high levels of estrogen or “toxic” estrogen should produce cancer of the lining of the uterus (endometrial cancer), but MTHFR variants are not associated with endometrial cancer. A large, prospective study also showed no association with breast cancer. There is simply no data to link these common MTHFR variants with estrogen-related health issues. 

Elizabeth Fieg, a senior genetic counselor at Brigham and Women’s Hospital (Harvard), backs me up. She told me via email, “I am not aware of any scientific evidence that would explain or in any way support the claim that MTHFR genotype impacts estrogen levels.” 

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The MTHFR gene is perhaps one of the best studied in all of genetics. 

I said this before, but it bears repeating. If the MTHFR gene were associated with excess estrogen or harmful estrogen we’d know by now. Genetic counselors and doctors who practice genetic medicine are not shy about ordering tests. If they thought testing for MTHFR was important they would be recommending it. They have no incentive here not to test. The truth is testing for MTHFR is not indicated for estrogen-related concerns (or for most other reasons, but that is beyond the scope of this post).

It’s no wonder MTHFR testing is such a popular scam, remember that 30-40% of people have a perfectly harmless variant that you can identify on testing. So it’s a great business plan when you can be confident you will have a high “failure rate” to create a hormone health horror story that requires cash or credit to fix in the form of supplements and expensive nutritional plans.

A constant theme with naturopaths and functional medicine is simplifying complex concepts, albeit incorrectly, (like estrogen metabolism) so they still sound science-ish. As the MTHFR gene is related to one aspect of estrogen metabolism, you can see how people could be swayed. But there are multiple pathways for estrogen metabolism, which tells us the body has a fair bit of redundancy here — when one pathway isn’t working as well other metabolic pathways can often compensate.

What you need to know is there is no proof that these MTHFR variants result in any issues with excessive estrogen or a buildup of toxic estradiol-3,4 quinone. Having one of these MTHFR variants is a variation, not a problem.

Naturopaths and doctors who believe in testing for MTHFR are either MTHFR truthers or they know it’s a scam and don’t care. They provide no evidence to support their assertions. I’ve read multiple websites that recommend MTHFR testing and they are filled with bold, yet nonsensical claims, not biology. 

If a naturopath or doctor recommended MTHFR testing for estrogen for me or for any of my friends, I’d suggest they run, not walk out of their office and report that person to the state medical board. 

MTHFR testing for estrogen “dominance” or “toxicity” is bad medicine. I know it may be hard to accept if you have been victimized. I suspect the naturopath or functional medicine doctor spent a lot of time listening to you and made you feel as if they were considering you as a whole person, when what they were considering was your wallet.