COMT and Menopause Hormone Therapy

What they aren't telling you

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Ask Dr. Jen

“I have a double COMT gene mutation and can’t take estrogen; what are my options for menopause?”

-Via Instagram

Short Take

A COMT variation has nothing to do with the safety of menopause hormone therapy. What “they,” the people recommending this test, aren’t telling you is there is no reason to test for COMT variations—in my opinion, recommending this is a red flag for bad medical care.

Tell Me More

Catechol-O-methyltransferase, or COMT, is an enzyme involved in the metabolism of catecholamines, neurotransmitters such as adrenaline and dopamine. It is also involved in the metabolism of estrogens.

There are several ways that estrogens are metabolized or broken down and removed from the body. One pathway for estradiol involves conversion into catechol estrogens, which are then further metabolized by one of two pathways:

• Conversion into methoxyestrogens by COMT. Methoxyestrogens are believed to inhibit cancer growth.

• Conversion into semiquinone and quinone estrogens, which are carcinogenic. Don’t worry; they are quickly removed.

The concern that is apparently raised by those who think COMT testing is important is that people with less active variations of the COMT enzyme will have what amounts to a backup in the system, leading to more catechol estrogens being shunted to the semiquinone/quinone pathway, producing more cancer-causing estrogen metabolites. Hence, if someone takes estrogen in menopause hormone therapy, they could end up at higher risk for cancer because they will accumulate “toxic estrogen metabolites.”

First of all, estrogen metabolism isn’t a conveyor belt in a factory where poor management causes Lucille Ball-like mayhem.

Estrogen metabolism is highly complex, involving multiple pathways, but there is no data to support the idea that a COMT variation can result in more “toxic” or cancer-causing estrogen. In fact, this has actually been looked at regarding breast cancer risk. Researchers wondered if women with COMT variations with less activity might lead to a higher risk of breast cancer. A meta-analysis of 56 shows no association between COMT variants and breast cancer risk.

But I am a gynecologist, and while I can read and interpret many studies, even those not in my field, and I can learn more about estrogen metabolism than I ever thought possible (talk about a rabbit hole), I am not an expert in genetics. Fortunately, I know people who are! I contacted two geneticists by email, both of whom work at major academic centers. They both said that there is no known useful reason for COMT testing. It can’t tell you about your risk of developing a disease, give you a diagnosis, or help you understand how you might respond to medication.

One of my geneticist pals is even an expert in pharmacogenomics, which is the impact of genetic variants on medication response. Bingo, this is exactly her field. She explained via email that there are “no actionable gene-drug guidelines for the COMT gene (either related to estrogen or anything else).” Translation: don’t do the test to see if you can safely take menopause hormone therapy or any medication!

I’m sorry to hear that people are being misled by this kind of testing. Unfortunately, there is more than a cottage industry in methylation testing (MTHFR is part of that), and it’s not cheap! You can even get a test on Amazon with Prime one-day delivery, which seems to lend it a certain validity. If it’s on Amazon, it must be a thing, right?

Wrong.

Actual genetic experts say testing for COMT variations (and MTHFR variations, for that matter) is not indicated, useful, or necessary. Not only is it a waste of money, but as you can see from the question above, it can mislead people into bad care. If you want to read more about the futility of MTHFR testing, here’s a primer.

If anyone suggests that you should be tested for a COMT (or an MTHFR variation, for that matter), that is a red flag. Do not pass GO, do not collect $200, and I would tell any family members of mine that they should not return to anyone recommending that testing for any health care needs. I imagine testing for COMT variations is highly profitable for those who order it because, of course, they can then charge for supplements to help you balance your methylation and then for repeat testing to check your pathways (whatever that means). Hey, when you make things up, the sky is really the limit.

Don’t worry about a COMT variation, and avoid anyone who says otherwise.

References

Samavat H, Kurzur MS. Estrogen Metabolism and Breast Cancer. Cancer Lett 2015;28:231-243.

Qin X, Peng Q, Qin A, Chen Z, Lin L, Deng Y, Xie L, Xu J, Li H, Li T, Li S, Zhao J. Association of COMT Val158Met polymorphism and breast cancer risk: an updated meta-analysis. Diagnostic Pathology. 2012; 7:136

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As always, this post is not medical advice.

Also, this week, I am planning a series of shorter posts as Wednesday is Menopause Awareness Day. One day seems too short, so I’m trying to give you a post a day for a week. If you have a topic you’d like to see addressed in shorter format, hit me up in the comments.