What you need to know about folate and folic acid if you struggle with fertility, high FSH, and low AMH

If you’re struggling with fertility, your doctor may have recommended folate or folic acid supplements to improve fertility and embryo survival [1,2]. 

Fertility doctors commonly prescribe doses as high as 5 mg (5,000 micrograms) of folic acid for both prospective parents. This dose is over 12 times the dose required to prevent neural tube defects (400 micrograms). However, it’s unclear whether such high doses are safe and beneficial [3].

One of the most common questions we get is about the best form of folate for fertility and pregnancy. There are so many forms of folate on the market that it can get confusing. 

In this article, we’ll explain all the different forms of folate that are available on the market and what the research says about their effects on fertility. We’ll also cover what studies say about safe and effective doses in the context of fertility. 

What are folate and folic acid?

Folate is a water-soluble form of B vitamin (vitamin B9) that occurs naturally in certain foods. It may be added to some foods and is also available in the form of a dietary supplement [4].

The word “folate” refers to a group of substances that function as B9 vitamins, including  [5]:

• Folic acid
• 5-formyltetrahydrofolate (5-FTHF), also known as folinic acid
• 5-methyltetrahydrofolate (5-MTHF) is similar to methyl folate and [6S]-5-MTHF
• 10-formyl-tetrahydrofolate (10-formyl-THF)
• Tetrahydrofolate (THF)
• 5,10-methylene-THF
• Dihydrofolate (DHF)

Natural folate in foods may include all of the compounds mentioned above, except folic acid. In unfortified vegetables, fruits, legumes, and meat, most of the folate is in folinic acid and 5-MTHF [6,7]. These natural forms of folate may degrade over a few days or weeks.

Whereas, folic acid is the synthetic form of folate not found in nature. It is more shelf-stable and more readily absorbed than natural folate [5].

How does folate help with fertility?

Healthy folate levels, functioning of MTHFR, and methylation are essential for many aspects of fertility, including:

• Maintaining a normal hormone balance 
• Controlling homocysteine levels
• Providing building blocks for RNA and DNA, which are important for cell division. This is essential for preparing the uterine lining for pregnancy and fetal development [8]
• Providing methyl groups for DNA methylation, which is important for hormone production and breakdown, healthy preconception uterine lining, and fetal development [9]

How low folate may contribute to infertility, high follicle-stimulating hormone (FSH) and low Anti-Mullerian hormone (AMH)

There are a few ways low folate and poor methylation may contribute to low ovarian reserve or premature ovarian failure, leading to low AMH and high FSH  [10,11].

In premenopausal women, higher homocysteine is associated with anovulation (absence of ovulation) and reduced ovarian function [12].

The homocysteine may also interfere with egg ripening and ovulation. Subsequently, the corpus luteum may not produce enough progesterone during the luteal phase [12].

Conversely, a high serum folate level is associated with higher luteal phase progesterone. Therefore, folate deficiency may cause low progesterone [12].

Poor methylation can also make you less sensitive to hormones that are important for conception, especially if you’re receiving fertility treatments. Women older than 35 and those with the C677T MTHFR variant make fewer eggs than younger women and women without the variant. Additionally, their eggs are less sensitive to FSH, so they are less likely to ovulate [13].

After conception, elevated homocysteine can increase the risk of blood clots and first-trimester miscarriage [14]. 

Altogether, maintaining optimum folate and low homocysteine levels may help balance progesterone and estrogen. Also, since homocysteine can contribute to infertility and miscarriage, it is important to ensure you have enough folate. 

Given that folic acid fortification has been widespread in the past few decades, most people are eating enough folic acid. The real cause of low folate could be low absorption in the gut and poor conversion. Therefore, it is important to supplement with folate if you’re struggling with fertility.

Now that we’ve learned about the importance of folate and fertility, let’s talk about different supplementation options, along with their pros and cons. 

Different forms of folate supplements for fertility: Folic Acid vs Methylfolate

Folic Acid

Folic acid has long been recommended during preconception and prenatal periods to prevent neural tube defects. Because it has a long history of use by millions of people, doctors are more familiar with it and are more likely to prescribe it. However, it may not be the best form of folate for health and fertility.

Folic acid is a synthetic, water-soluble, and oxidized form of folate. It’s not found in nature, but it can naturally occur in cooked or stored foods [15]. Because it is very shelf-stable, folic acid is most commonly used in supplements and to fortify foods, including grain and flour products. 

However, folic acid is inactive. You need the enzyme dihydrofolate reductase (DHFR) to convert it into the active forms that your cells can take up and use, such as methylfolate  [16,17].

DHFR is a very slow enzyme. Given that many women are supplementing with folic acid and eating foods fortified with folic acid, inactive folic acid can build up in their blood (unmetabolized folic acid syndrome). In the long run, this can increase some health risks.

Does folic acid help you get pregnant and increase fertility?

Fertility doctors often prescribe extremely high doses (up to 5,000 mcg) of folic acid for both prospective parents. Some studies show this improves sperm parameters among men with abnormal sperm and MTHFR C677T, but it may not improve live birth rates [18,19].

While it may help in some cases, it can also hinder fertility by affecting epigenetics. The following are health effects of high-dose folic acid and having excessive levels of it in your blood.

May increase cancer risks

Unmetabolized folic acid syndrome is clearly associated with prostate cancers, while evidence is mixed for breast and other types of cancers [20,21]. However, while folate deficiency allows for initial cancer cell growth, too much folic acid can augment the progression of already established cancer and precancerous cells [22].

May lower folate function and increase homocysteine

Paradoxically, very high doses of folic acid can inhibit DHFR and MTHFR enzymes, causing symptoms of folate deficiency [16]. However, we still lack large clinical trials to find out how often this happens.

A case study reported by fertility doctors in Paris and London described a 41-year-old woman with a normal MTHFR enzyme. They prescribed 5,000 mcg of folic acid before her egg donation cycle. Over a few months, her homocysteine levels increased to abnormal levels. Once they switched her over to 500 mcg of methylfolate, her homocysteine levels dropped to normal within five days [23].

May cause abnormal DNA methylation in sperms and children

DNA methylation is a type of epigenetic change that typically turns genes off. The methylated DNA can also be passed on to children. 

A dose of 5,000 mcg of folic acid in men with the MTHFR C677T variant reduced sperm DNA methylation, suggesting that it may inhibit MTHFR function [24].

In another study of 30 men with infertility of unknown causes, six months of folic acid supplementation increased their blood folate but not sperm parameters. They found folic acid reduced the methylation of many genes, including that of the MTHFR gene, and genes involved in cancers and neurobehavioral disorders [25]. The men who had MTHFR C677T had even more loss of DNA methylation. 

Is 5,000 mcg of folic acid a good idea for people experiencing infertility? What’s the best dose of L-methylfolate for pregnancy?

Among women with unexplained infertility who already have good folate status and homocysteine levels, adding more folate may not be beneficial [26]. Therefore, supplementing with reasonable doses (400-500 mcg) of methylfolate is likely better for maintaining folate levels and fertility. 

Methyl Folate

Methylfolate is the active form of folate that doesn’t require MTHFR, DHFR, or the methylation pathway to activate. Also, it can readily enter your cells and cross your blood-brain barrier. Therefore, it doesn’t cause unmetabolized folic acid syndrome.

Natural methylfolate is less stable than folic acid, so supplement formulators have turned them into salt forms. Currently, there are two shelf-stable and bioavailable forms of methylfolate, Metafolin and Quatrefolic. 

Metafolin is the salt of methyl folate with calcium [27]. It is absorbed in the gut as well as folic acid.

Quatrefolic ([6S]-5-methyltetrahydrofolate glucosamine salt) is the salt of methylfolate with glucosamine. It is almost 100 times more water-soluble than Metafolin. Its absorption takes place in the intestines, so it does not need stomach acid for absorption [28,29], making it much better absorbed than methylfolate and folic acid [30]. Therefore, quatrefolic may be better and more effective for people who have malabsorption or gut problems.

In conclusion, having healthy folate levels is important for ovarian function and fertility. If you have slow MTHFR or DHFR, you may have trouble using folic acid. The leftover folic acid in the blood can increase health risks and may not be good for fertility. Therefore, it is best to get your folate from food and methylfolate supplements such as Metafolin and Quatrefolic.

Low folate may also indicate that your gut cannot effectively absorb it, so it is a good idea to also examine gut health. 

When in doubt, it is best to test rather than guess your folate, homocysteine, and gut health status. 

To learn more about our functional approach to optimize your folate based on your genes and tests, apply here. 

References:

1. Chavarro JE. International Journal of Fertility & Sterility, suppl. Tehran. 2015. p. 1.
2. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000;71: 1295S–1303S.
3. Murphy MSQ, Muldoon KA, Sheyholislami H, Behan N, Lamers Y, Rybak N, et al. Impact of high-dose folic acid supplementation in pregnancy on biomarkers of folate status and 1-carbon metabolism: An ancillary study of the Folic Acid Clinical Trial (FACT). Am J Clin Nutr. 2021;113: 1361–1371.
4. Folate. [cited 7 Oct 2021]. Available: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
5. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44: 480–488.
6. Johansson M, Jägerstad M, Frølich W. Folates in lettuce: a pilot study. Scandinavian Journal of Food & Nutrition. 2007;51: 22.
7. Delchier N, Herbig A-L, Rychlik M, Renard CMGC. Folates in Fruits and Vegetables: Contents, Processing, and Stability. Compr Rev Food Sci Food Saf. 2016;15: 506–528.
8. Forges T, Monnier-Barbarino P, Alberto JM, Guéant-Rodriguez RM, Daval JL, Guéant JL. Impact of folate and homocysteine metabolism on human reproductive health. Hum Reprod Update. 2007;13: 225–238.
9. Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet. 2001;2: 21–32.
10. T. Plowden S.L. Mumford K. Devine K.S. Richter A. DeCherney S. Beall. Discordant Antimullerian hormone (AMH) and follicle stimulating hormone (FSH) and pregnancy outcomes. Fertility and Sterility. 2015. Available: https://www.fertstert.org/article/S0015-0282(15)01179-6/fulltext
11. Jankowska K. Premature ovarian failure. Prz Menopauzalny. 2017;16: 51–56.
12. Michels KA1, Wactawski-Wende J2, Mills JL1, Schliep KC3, Gaskins AJ4, Yeung EH1, Kim K1, Plowden TC1, Sjaarda LA1, Chaljub EN1, Mumford SL. Folate, homocysteine and the ovarian cycle among healthy regularly menstruating women. Europe PMC. 2017. Available: https://europepmc.org/article/PMC/5850828
13. Thaler CJ, Budiman H, Ruebsamen H, Nagel D, Lohse P. Effects of the common 677C>T mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene on ovarian responsiveness to recombinant follicle-stimulating hormone. Am J Reprod Immunol. 2006;55: 251–258.
14. Tafuri L, J Servy E, J R Menezo Y. The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective. Clin Obstet Gynecol Reprod Med. 2018;4. doi:10.15761/cogrm.1000215
15. Forssén KM, Jägerstad MI, Wigertz K, Witthöft CM. Folates and dairy products: a critical update. J Am Coll Nutr. 2000;19: 100S–110S.
16. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci U S A. 2009;106: 15424–15429.
17. Wright AJA, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr. 2007;98: 667–675.
18. Huang W-J, Lu X-L, Li J-T, Zhang J-M. Effects of folic acid on oligozoospermia with MTHFR polymorphisms in term of seminal parameters, DNA fragmentation, and live birth rate: a double-blind, randomized, placebo-controlled trial. Andrology. 2020;8: 110–116.
19. Schisterman EF, Sjaarda LA, Clemons T, Carrell DT, Perkins NJ, Johnstone E, et al. Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. JAMA. 2020;323: 35–48.
20. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101: 432–435.
21. Koenig KL, Scarmo S, Afanasyeva Y, Clendenen TV, Ueland PM, Zeleniuch-Jacquotte A. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study. Eur J Clin Nutr. 2020;74: 1306–1315.
22. Kim Y-I. Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde? The American journal of clinical nutrition. 2018. pp. 139–142.
23. Cornet D, Clement A, Clement P, Menezo Y. High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome. SAGE Open Med Case Rep. 2019;7: 2050313X19850435.
24. Aarabi M, Christensen KE, Chan D, Leclerc D, Landry M, Ly L, et al. Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation. Hum Mol Genet. 2018;27: 1123–1135.
25. Aarabi M, San Gabriel MC, Chan D, Behan NA, Caron M, Pastinen T, et al. High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism. Hum Mol Genet. 2015;24: 6301–6313.
26. Murto T, Skoog Svanberg A, Yngve A, Nilsson TK, Altmäe S, Wånggren K, et al. Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility. Reprod Biomed Online. 2014;28: 766–772.
27. Seremak-Mrozikiewicz A. [Metafolin–alternative for folate deficiency supplementation in pregnant women]. Ginekol Pol. 2013;84: 641–646.
28. Quatrefolic® – White Paper. [cited 7 Oct 2021]. Available: https://quatrefolic.com/whitepaper.php
29. Prinz-Langenohl R, Brämswig S, Tobolski O, Smulders YM, Smith DEC, Finglas PM, et al. [6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C–>T polymorphism of methylenetetrahydrofolate reductase. Br J Pharmacol. 2009;158: 2014–2021.
30. Miraglia N, Agostinetto M, Bianchi D, Valoti E. Enhanced oral bioavailability of a novel folate salt: comparison with folic acid and a calcium folate salt in a pharmacokinetic study in rats. Minerva Ginecol. 2016;68: 99–105.