How MTHFR and methylation affect fertility with high FSH and low AMH

MTHFR variants are found in over 60-80% of the population and many people with the variants conceive normally. So reproductive specialists disagree on whether you should address it [1]. However, having the variants may compound with other hormonal imbalances and lifestyle issues, leading to fertility problems. In short, it’s not just MTHFR but how it interacts with your nutrition and lifestyle.

This article will cover: 

• the basics behind MTHFR and fertility in both males and females
• why you should be concerned about it if you have premature ovarian failure, diminished ovarian reserve, or struggle with egg or sperm health
• what you can do with MTHFR

MTHFR and its variants

MTHFR stands for methylenetetrahydrofolate reductase, an enzyme that activates folate into methyl folate and produces methyl donors for methylation reactions. Because MTHFR is the slowest enzyme in these pathways, variants that reduce MTHFR function can compromise the whole pathways [2]. 

Methylation is a very important biochemical reaction, where the methyl group is used to:

• Deactivate or activate a hormone or neurotransmitter, such as during their production or detoxification processes
• Silent genes from being read off
• Tag an enzyme or protein

MTHFR is an enzyme that produces a key methyl donor, S-adenosylmethionine. In this process, it also converts the toxic amino acid homocysteine into methionine. 

How does MTHFR affect fertility?

MTHFR variants (C677T and A1298C) are associated with difficulties conceiving as well as birth defects and pregnancy complications. In many cases, folate supplementation improves fertility and IVF outcomes [3].

The C677T variant is clearly associated with male infertility, whereas for A1298C, the association is less clear [4]. 

Keep in mind, also, that most MTHFR studies are association studies. These studies find the co-existence of MTHFR and certain traits. However, co-existence may not prove that MTHFR causes the problem. Given that folate supplementation is a low-risk intervention and tends to improve pregnancy outcomes across the board, many doctors simply recommend supplementation rather than testing it. 

Folate activation and methylation are essential for the following processes. 

Cell division and development

Methylation coordinates cell division and development, which is important for the following processes in fertility, conception, and embryonic development. 

Endometrial development – MTHFR variants are associated with difficult conception and early pregnancy loss due to problems with the endometrium and implantation [5]. IVF studies have shown that women with MTHFR mutation are more likely to experience recurrent implantation failure [6]. 

Sperm development – Some men with fertility problems have low MTHFR function in their sperm. Folate supplementation improves sperm count and fertility treatment success rates [7-9].

Egg development – In an IVF study, the C677T variant is associated with premature oocyte retrieval, whereas the A1298C variant is associated with fewer oocytes retrieved [10].

Embryonic development – Folate provides a backbone for some DNA building blocks, so folate deficiency can affect cell division and cause birth defects. 

Hormonal balance and response

MTHFR C677T is associated with higher basal FSH levels and requiring more FSH stimulation during fertility treatment, suggesting poorer ovarian responsiveness [11]. Women with C677T produced fewer follicles and had lower AMH after ovarian stimulation, although they may have higher baseline AMH [12]. They also needed more HCG to stimulate oocyte release [13].

The MTHFR C677T variant was also associated with premature ovarian failure [14], whereas the A1298C variant is associated with lower odds of successful pregnancy after IVF [13].

Reducing Homocysteine

Homocysteine is a toxic and inflammatory amino acid that can increase the risk of blood clots, which can hinder conception and cause pregnancy complications [15]. The methylation pathway takes the methyl group from folate and adds it to homocysteine, converting it to methionine. Therefore, blood homocysteine is a measure of methylation, although it’s possible to have methylation problems with normal homocysteine.

High blood homocysteine correlates with  [16]:

• Lower estradiol and luteal phase progesterone
• 33% increased risk of anovulation in both women with and without PCOS 
• Autoimmunity, which may cause pregnancy complications [17]

Interestingly, it is not a standard of care to test for homocysteine among women with fertility problems and pregnancy complications. Low folate is not the only factor that increases homocysteine, as kidney and thyroid problems can also increase it [18,19].

What can you do about MTHFR mutation to optimize your chances of conception? 

You can’t change your genes, but there is a lot you can do to support your nutrient levels, bypassing the MTHFR enzyme. These include lifestyle changes, dietary habits, and supplementation.

Supplementation to improve fertility with MTHFR

The most obvious choice for MTHFR is to add methylfolate. However, you want to keep in mind that B vitamins work together, so it’s a good idea to eat foods high in these nutrients and supplement with B complex instead of just folate.

Folate (vitamin B9) – MTHFR C677T reduces enzyme activity by 70% and A1298C by about 40% [20,21]. Therefore, supplementation with methylfolate helps bypass this enzyme and makes available methylfolate for other needs in the body. 

Why methylfolate instead of folic acid? – Folic acid is a synthetic and shelf-stable form of folate. Because folic acid has had a long history of use, many doctors prefer folic acid. However, some case reports and biochemical studies suggest that prolonged and high-dose folic acid use (>5 mg for >6 months) may eventually inhibit MTHFR function [32]. High levels of folic acid can inhibit DHFR, the slow enzyme that converts it into usable forms [22]. The leftover unconverted folic acid in the blood is also associated with some cancers, although folate deficiency is also associated with cancers [23]. With MTHFR variants, your ability to metabolite folic acid reduces even further, increasing the risk of side effects from folic acid [24].

Because these side effects are not observed with methylfolate, methylfolate appears to be a safer and superior choice, especially for those with MTHFR variants [25]. Keep in mind, also, that many processed food products, grains, and flours are fortified with folic acid. So, if you have MTHFR variants, you want to also avoid these fortified foods. 

Riboflavin (vitamin B2) is a cofactor of MTHFR, and B2 deficiency can increase homocysteine. Riboflavin supplementation can reduce homocysteine in people with the C677T variant [26].

Pyridoxal-5-phosphate or pyridoxine (vitamin B6) is another important cofactor for an enzyme that breaks down homocysteine independently of MTHFR. Also, high-dose B6 supplementation is often prescribed for morning sickness [27,28]. 

Creatine – The creation of creatine consumes enormous amounts of methyl groups so creatine supplementation may reduce the need for methylation resources. However, there is no evidence about creatine safety for pregnant women, so it is not recommended for pregnancy [29]. 

Choline and betaine are molecules that can provide methyl groups independently of the folate pathway, therefore compensating for low activity MTHFR enzymes [30].  Higher intakes of choline and betaine through foods are associated with lower homocysteine levels independent of folate and other B vitamins [31].

Lifestyle changes for MTHFR

Stress and toxicity increase the need for methylation. Therefore, if you have MTHFR variants, it is important to manage stress through exercise, meditation, yoga, and other mind-body techniques.

Alcohol, cigarette smoking, and toxic exposure burden your detoxification system, which also requires methylation and MTHFR. Therefore, you want to minimize your toxic load by addressing these factors during preconception. 

Some medications can also deplete your folate and B vitamin levels, so it may be beneficial to test for your micronutrient levels if you have been using multiple medications. The following medications are contraindicated for pregnancy but are commonly prescribed for TTC women and those who struggle with fertility and miscarriage. We are listing these here because they deplete folate. 

• Methotrexate 
• Hormonal birth control pills
• Metformin  (for polycystic ovarian syndrome and diabetes)
• Stomach acid-lowering drugs 

Lab tests for MTHFR and methylation problems

You can get MTHFR tests from your doctor or direct-to-consumer companies such as 23andme. But genetics load the gun, your environment pulls the trigger, so it’s important to also test to see if you have healthy methylation, folate, and other B vitamin levels. The following lab tests can help identify methylation problems, relevant nutrient deficiencies, and whether your folate levels are healthy.

• Blood folate
• Blood B12
• Blood homocysteine
• Urine methylmalonate, as a test for vitamin B12
• The dried Urine Test for Comprehensive Hormones (DUTCH) test also measures different estrogen metabolites, which can indicate how well your methylation is working for estrogen detoxification.

Conclusion

If you have diminished ovarian reserve and elevated FSH, you should pay attention to your MTHFR genotype. Because MTHFR variants interact with your lifestyle and other genes, they manifest differently for everyone, so it’s important to run functional tests to see where you are at. Successfully getting pregnant with MTHFR requires both correcting folate deficiency and addressing lifestyle factors. To learn more about addressing MTHFR and improving your chance of getting pregnant holistically, book a consultation here.

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