There is no obvious link between MTHFR and estrogen – they seem to be in unrelated fields in the body, affecting different spheres. Sadly, that isn’t true. While it is true that the MTHFR gene is not involved in estrogen metabolism, it is also true that the products of the MTHFR gene are. So in the end does MTHFR end up in bed with Estrogen? Yes. Yes, it does.


Why Does MTHFR Affect Estrogen? It’s Another Detox Issue.

The word “detox,” when you have an MTHFR issue, starts to trigger a nervous eye twitch pretty quickly. You just know there is some catch or some little loophole that you’re going to fall into and spend months crawling out of. Estrogen detox is no exception. But first, estrogen is a useful substance – it’s called the “Marilyn Monroe Hormone” and that sounds amazing (more on that in a minute). So, why do we even need to detoxify it?

Why Do We Need to Detoxify Estrogen In The First Place?

Estrogen is a highly useful hormone for both men and women, although women have it in larger quantities. Estrogen helps boost sex drive, thicken bones, protect your heart from cardiovascular disease, and decrease anxiety. It is responsible for the majority of female sex characteristics like breast growth and without it there would be no fertility. So why get rid of it?

Hormones are SHORT TERM Messengers

Hormones are meant to send their signal and then go away. They fluctuate day by day during the female menstrual cycle and in order for a hormone level to change, you need to be able to get rid of it. Plain and Simple.

How Do You Get Rid of Estrogen?

Remember we talked about Phase I and Phase II detox reactions? Estrogen goes through both of those. To be clear, there isn’t just one thing in the body called “estrogen.” Just like folate, there are many forms of estrogen, some better and some worse. These forms interconvert in various ways and affect tissues differently. Below, is a diagram of how estrogen changes as your body get it ready to go out with the trash.

MTHFR and estrogen - the estrogen interconversions
Red “x”s are not our friends

Ok, So I See A Few Hitches Here.

Hitches galore! I added some red “x”s where there are possible problems for MTHFR folks and that’s a lot of “x”s. The methylation cycle is plopped smack in the middle of estrogen metabolism because we methylate some metabolites into their less harmful forms in order to excrete them. If you can’t methylate at that particular moment, then your body has to convert estrogens to quinones, the worst possible pathway. Glutathione, which can be a bit shakey in MTHFR folks, is necessary to help neutralize these quinones, otherwise, they have potentially carcinogenic effects.

Not All Estrogen Is Created Equal.

Different types of estrogen have different relative impacts on body tissues (different strengths, so to speak).. Here’s the breakdown:

Estradiol (E2) is 1.5 to 5 times more active in tissues than Estrone (E1). These two forms of estrogen can interconvert. Estriol is only biologically active in pregnant women, so doesn’t factor in so much. In terms of Estrogen metabolites, 2-hydroxyestrone (2OH-E1) helps modulate the activity of more biologically active estrogens and has been shown to decrease the risk of breast cancer. 4- and 16-hydroxyestrogens have been shown to be more biologically active and also more carcinogenic (meaning they promote cancer).

What Does This Mean For Me?

The bottom line in all of this is that without good methylation in Phase II detox, estrogens are oxidized and converted to quinones, which have potential carcinogenic effects. These effects can be mitigated by glutathione, but with MTHFR issues you have the potential to be short on that, too.

MTHFR Mutants Are Prone To Estrogen Dominance

Estrogen dominance means that your estrogen levels are, relatively speaking, higher than the levels of other hormones. It doesn’t mean that they are “too high” on a lab test, it means that the ratio between estrogen and progesterone (in women) or estrogen and testosterone (in men) is out of balance.

Signs and Symptoms of MTHFR and Estrogen Dominance

In Women:

  • Fibrocystic breasts or uterine fibroids
  • PCOS, endometriosis,
  • Heavy bleeding, clotting and cramping with periods
  • Irregular periods and infertility
  • fatigue, depression, anxiety

In Men:

  • Gynecomastia (a.k.a. man boobs)
  • Loss of muscle mass and more typically female fat distribution
  • Sexual dysfunction
  • fatigue, depression, anxiety

What Can You Do About Estrogen Dominance?

  • Eat your veggies! – Cruciferous veggies including broccoli, cauliflower, kale, Brussels’s sprouts, and cabbage help shift your metabolic pathways away from the cancer-promoting 16-hydroxy metabolites. This also helps to reduce symptoms of estrogen dominance by shifting from high-activity forms to lower activity forms.
  • Eat your fiber – You are an inherently thrifty creature and even after your body eliminates something into your gut, you often go back and sort through the trash to pick it up again, because it might be useful. If you have a good amount of fiber in your system, then lots of toxins (like hormone-waste) bind to that fiber so that you can’t retrieve it.
  • Eat your lignans – lignans, which are found especially in flax seeds but to a lesser degree in sesame seeds, are estrogen modulators. They help to balance excess estrogens and are the foundation for the gentle form of hormone balancing in women called seed cycling.
  • Supplement with NAC – N-acetylcysteine is a readily available supplement that acts along with selenium as a precursor to glutathione production. This works even for MTHFR folks and it boosts the levels of glutathione so that if you are creating damaging quinones, you have the capacity to minimize the damage. If your multivitamin doesn’t have selenium in it, you can get enough by eating three Brazil nuts daily.
  • Eliminate Estrogen Mimetics – you don’t just have to worry about the effects of estrogen that your body makes, you also have to worry about environmental toxins that *look* like estrogen to your body, because if they look enough like estrogen, they can bind to estrogen receptors. These include phthalates and parabens from things like lotion, perfume, synthetic air fresheners, and body wash (the name will be long, but ‘phthalate” or “paraben” will be in there somewhere), BPA and related chemicals from plastics (don’t ever, ever microwave your food in plastic.) Plasticizers in soft plastic construction products like caulk.

What About MTHFR and Other Hormones?

Great question! No known link between MTHFR and testosterone levels has been demonstrated, but high estrogen can lead to low effective testosterone through the back door of sex hormone binding globulin. SHBH rises when estrogen levels become too high in order to bind to and therefore inactivate some of the excess estrogen. Unfortunately, SHBH prefers testosterone, so it binds to that more frequently (thereby inactivating that as well.) So high estrogen levels often lead to lower levels of free testosterone, which is the active form.

Also, stress hormones and MTHFR have not been studied, but there may be a link. A paper published in 2017 from the NURSES study, showed that MTHFR polymorphisms affect perceived occupational stress levels. This study didn’t actually test levels of cortisol, which is the major stress hormone, but it did show that people who were homozygous (two bad copies) for C677T mutations perceived higher stress levels than their heterozygous (one bad copy) or wild-type peers. The heterozygous group did perceive a higher stress level than the normal group, but the difference wasn’t great enough to be considered statistically significant.

Back to the Marilyn Monroe Hormone?

Estrogen – specifically estradiol (E2), the most potent estrogen, has been called the “Marilyn Monroe” hormone because the results of a high estradiol level are so visibly apparent in the famous actress. She had symmetrical facial features, an hourglass figure with large breasts and a low waist-to-hip ratio, and a tendency to have sex with partners outside of her relationship. Also, high levels of estradiol make it more likely that a person is considered attractive, both by themselves and by other people. Unfortunately in women it also means they are more likely to be disliked by other women.

Marilyn knows all about the glamorous MTHFR lifestyle
Marilyn knows all about the glamorous MTHFR lifestyle. Actually, if I had to place a bet, she was an MTHFR mutant too!

Next week we’ll talk about MTHFR and neurotransmitter formation, because that is the basis for so many other topics (like how MTHFR intertwines with anxiety and depression). After that, we get into the good stuff, like why your multivitamin might actually be doing more harm than good. If you want to jump right to what to do about all of this, check out our Start Here for MTHFR guide.

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