How Does MTHFR Affect Fertility?

Dealing with infertility is often a crash course in biology! You’ve discovered that this is way more complicated than just the birds and the bees.

You’ve likely gone from knowing the basics of reproduction -- to diving deep into hormones, pathways, genetics, and nutrition.

Knowing and understanding what is going on in your body is important. Infertility has many different causes. And the solutions are not one-size-fits-all!

The MTHFR gene has a couple of genetic variants that impair its function. This can impact fertility in several ways. Realizing that you carry the MTHFR variant can guide you in making diet and lifestyle choices that increase fertility.

Let’s dig into the science and research on how MTHFR could change your reproductive hormone levels and affect egg quality.

A little background on fertility hormones:

 When you began puberty, you likely had between 300,000 - 400,000 follicles, which are tiny fluid-filled sacs in the ovary.  These follicles are where the egg cell will develop.  Several follicles begin to mature each month during your menstrual cycle, but only one will completely mature and release an egg during ovulation.

Every month your body goes through cycles of rising and falling hormones that signal through your reproductive system.

These hormones include follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), estrogens, and gonadotropin-releasing hormone (GnRH).

Everything works in concert, rising and falling at the right time, to cause your body to produce an ovarian follicle that develops the egg cell released in ovulation.

Your reproductive hormones orchestrate the timing and growth of the follicle, the release of the egg cell, and then implantation of the fertilized egg in the uterus.

FSH (follicle stimulating hormone) is released by the pituitary gland. It stimulates the growth of the follicles before the egg is released in ovulation. FSH is regulated by gonadotropin-releasing hormone (GnRH).  (more info)

A surge in luteinizing hormone (LH) is what triggers ovulation to occur.

Anti-mullerian hormone (AMH) is produced in the ovarian follicles and is highest during the very first stages of follicle growth. Fertility specialists will often test AMH levels to get an idea of the size of the pool of follicles available. This is a way to determine, to some extent, the ‘ovarian reserve’.  Overall, your AMH levels were highest at puberty and then fall as you age. When you reach menopause, AMH levels will be very low. (study)

If you undergo IVF as a fertility treatment, your reproductive hormones will be manipulated to cause you to develop more mature follicles with eggs during one cycle so that they can be collected.

How does MTHFR affect your reproductive hormones?

First, let’s back up a minute and explain the MTHFR gene.

The MTHFR gene codes for an enzyme called MTHFR (methylenetetrahydrofolate reductase). This enzyme is at a critical point in the methylation cycle. It controls the final step in converting folates from food into an active form used by the body in a lot of different processes.

Some people carry genetic variants that decrease the function of the MTHFR enzyme. This impacts the body’s methylation cycle.

The methylation cycle is how the body creates the methyl groups (a carbon atom plus three hydrogens) that are needed for various biological reactions. These methyl groups are carried by the SAMe (s-adenosylmethionine) molecule. Some of the ways that the body uses methyl groups include modifying amino acids, neurotransmitters, phospholipids, and DNA.

While vital to overall health, there are also distinct ways that the methylation cycle is important in fertility. One is that it helps in the creation of glutathione, a natural antioxidant that helps protect developing egg cells. Another is that methyl groups are an integral part of DNA production and repair. Both are instrumental to the quality of the egg as it develops. (study)

Women who carry an MTHFR variant that decreases the function of the enzyme have been shown in several studies to also have altered FSH levels.

In studies of women undergoing IVF, carriers of two copies of the MTHFR C677T variant had altered FSH levels, altered AMH levels, fewer mature eggs, and lower estradiol levels. (study)(study)(study)

While this all may sound daunting, the good news is that modifying your diet (or supplements) can eliminate the negative effects of the MTHFR variant. (study)(study)

Checking your MTHFR genetic variants:

If you have done genetic testing through a direct-to-consumer test such as 23andMe or AncestryDNA, you can check the raw data file to see whether you carry the MTHFR variant referenced in the studies.

Check your genetic data for  rs1801133 (MTHFR C677T):

  • G/G: normal (wildtype)
  • A/G: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%
  • A/A: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

If your genotype say A/A, this means that you carry two copies of the MTHFR C677T variant. Read on for ways to optimize your diet to get around this problem.

MTHFR and IVF:

Women who carry two copies of the C677T variant may need different amounts of GnRH and rFSH during IVF. This is something your fertility clinic doctor will adjust to your individual needs.(study)

Supplementing with extra folate has been shown to overcome the negative effects of the MTHFR variant in fertility clinic patients. This doesn’t mean going overboard with too much folic acid. Instead, the women in the study used a combination of methylfolate and folic acid at a dose of 800 mcg, which is the amount normally found in a prenatal vitamin.(study)

MTHFR and natural pregnancy:

While most of the studies on specific hormone levels were done on fertility clinic patients, the results are valid for all women with MTHFR variants. Other studies also show that women with two copies of the variant have a reduction in egg quality, possibly due to the follicle rupturing before the oocyte is mature enough. (study)

Women who carry the MTHFR C677T variant may benefit greatly from optimizing their methylation cycle when trying to conceive.

But just taking a bunch of folic acid may not be the right approach!

Folic acid vs. natural folates vs. methylfolate:

Vitamin B9 is an essential nutrient.  It is so important that the US and Canadian governments (along with 50 other countries) mandate that it is added to foods such as bread, cereal, pasta, white rice, and cornmeal.

Vitamin B9 is most commonly known as folic acid, the synthetic (man-made) form of vitamin B9.

Vitamin B9 in its natural form is known as folate.

Folic acid differs in its chemical structure from natural folates found in foods.  This difference in the synthetic folic acid allows it to be more heat stable and pH stable, thus making it easy to add to processed foods.  It's also the form used commonly in supplements, due to its lower cost.

Natural folate is found in a variety of foods including liver, leafy green veggies, asparagus, broccoli, and legumes.

To use folic acid in the methylation cycle, the body first must convert it using an enzyme known as DHFR in a two-step process. This eventually can be used in the methylation cycle, along with the MTHFR enzyme, to create methylfolate, the active form that the body needs.

There are a couple of steps here that can go wrong with enzymes that don’t function optimally. If you carry genetic variants of the DHFR or MTHFR genes, this can impair your ability to use folic acid.

The problem with just taking a bunch of folic acid when trying to conceive is that larger doses won’t be broken down, or metabolized,  by the body. This unmetabolized folic acid can actually impair the cells ability to make methylfolate. (study)

Thus, too much folic acid can actually block the body’s methylation cycle.

How much folic acid is too much? This will vary from one person to the next.  Some studies show that 400 mcg of folic acid will cause unmetabolized folic acid in the bloodstream. (study)

Other studies show that in the US, over 95% of adults have unmetabolized folic acid due to the mandatory fortification.(study)

If you are eating foods fortified with folic acid, try tracking the amount of folic acid you eat for a few days. If your diet is heavy in rice, pasta, cereal, or bread, it may surprise you how much you are consuming.

Optimizing for fertility with an MTHFR variant:

While a lot of website and health practitioners will tell you to take some methylfolate and B12 for the MTHFR variant, that advice is a bit like slapping a bandaid on the problem. It may help in the short term, but you can do more to optimize your diet for fertility.

Instead of focusing so intently on the MTHFR variant, let’s zoom out a bit and look at the bigger picture of the methylation cycle.

The methylation cycle is creating and recycling the methyl groups needed for amino acid synthesis, neurotransmitter conversions, DNA synthesis and repair, and antioxidant creation.

The methyl group needed for the methylation cycle can come from MTHFR creating methylfolate from folate -- or it can come through other pathways in the body.

Creatine:

One way to support your methylation cycle is to look at what it is being used for...

About 40% of the methyl groups are actually being used for creatine biosynthesis. (study) Creatine is an amino acid that the body uses as a building block for proteins. Your body uses arginine and glycine (two other amino acids) along with methyl groups to create the amino acid creatine.

Instead of relying on the biosynthesis of creatine, you can also obtain it from your diet and from supplements. Adding in extra creatine then frees up methyl groups for other purposes in the body.

Creatine is found in red meat, pork, poultry, and fish. It is especially abundant in organ meats such as liver.  For vegetarians and vegans, the supplement form is best.

Glycine:

Your body uses glycine in a variety of ways, including using it for the creation of methyl groups and as a precursor for creatine and glutathione.  It is an amino acid that your body can synthesize, but generally, we also need to consume some through foods.

Adding more glycine to the diet will help to support your methylation cycle. (study)

Glycine is found in high quantities in gelatin and collagen. Good sources include broth made from chicken or beef bones. There are also collagen and gelatin supplements available that can easily be added to smoothies, soups, or coffee.

Choline:

Ensuring that you have enough choline in your diet is an excellent way of supporting your methylation cycle.  Choline can directly add methyl groups to the methylation cycle, and it also supports the synthesis of glycine in the body. (study)

Foods high in choline include egg yolks, liver, and sunflower lecithin.

Folate and B-vitamins:

Of course, you also want to ensure that you are getting the right amount of folate and B12 in your diet. Instead of adding more synthetic folic acid, supplementing with methylfolate is a better option for people with the MTHFR variant. The other B vitamins, such as riboflavin, B6, and B12 are also important in the methylation cycle. Make sure to choose a quality prenatal vitamin with methylfolate along with the other B vitamins.

Putting together the whole puzzle:

Women with MTHFR variants can be at a higher risk for infertility if their diet isn’t right.

What is the right diet for MTHFR and getting pregnant? A diet higher in choline, glycine, creatine, and B-vitamins.

  • Incorporate at least 2 eggs a day for choline.
  • Eat organ meats such as liver for creatine, folate, and B12.
  • Quality, grass-fed meats are also great for creatine.
  • Include bone broth for gelatin and collagen.
  • Green vegetables such as asparagus, broccoli, or leafy greens can add more folate.

You may notice that this is a diet that your grandmother or great-grandmother would be familiar with. In the past, people used the whole animal for food and included broths, organ meats, and other parts of the animal with higher nutritional value. Eggs have long been a source of high quality nutrition.

Today, we have shifted away from getting as much choline, creatine, and glycine in our diets. This makes it much harder for people who carry the MTHFR variant to have optimal methylation cycle function.

Fortifying processed foods with folic acid helps out a good portion of the population, but genetic differences make it harder for some people to thrive without eating an ancestral diet.