Active folate for women: essential for hormone health, fertility, and mood

Folate (vitamin B9) plays an essential role in various bodily functions and is a game changer for our overall health, hormones and mood. A lot of processes in the body rely on folate – it supports blood cell production (red, white and platelets), is involved in DNA synthesis, supports our mood, detoxification pathways and energy production. Studies back in the 90’s and early 2000’s demonstrated its impact on our immune system. Specifically, folate is involved in not only the proliferation of T and B lymphocytes of the adaptive immune response, but also natural killer cells which are part of the innate immune system. It’s also essential for fertility and methylation. Naturally found in foods like leafy greens, legumes, and citrus fruits, folate is crucial for overall health, especially during periods of rapid growth such as pregnancy. However, there’s often confusion surrounding folate and its synthetic counterpart, folic acid. Understanding the difference between these two forms is important, particularly if you have specific genetic variations like MTHFR polymorphisms.

How does folate impact our immune function?

Folate plays a crucial role in supporting the immune system. It is involved in DNA synthesis and repair, which is essential for the production and function of immune cells. Specifically, folate impacts both innate and adaptive immunity. It supports the proliferation of T and B lymphocytes, key players in adaptive immune responses, and natural killer (NK) cells, which are part of the innate immune system. Folate's role in immune function is also linked to its involvement in the one-carbon metabolism pathway, where it helps generate nucleotides necessary for DNA synthesis. This is particularly important during immune responses, as immune cells need to rapidly divide and proliferate to respond to pathogens. A deficiency in folate can impair this process, leading to weakened immune defences.

What is folic acid?

Folic acid is the synthetic version of folate and is commonly found in over-the-counter supplements (please check the quality and brand of your supplements!) and fortified foods like cereals, bread, and pasta. It’s even found in baby formula and berocca! It is added to foods to help prevent neural tube defects (NTDs) in newborns, and this has been successful in some respects. However, folic acid is not biologically active. For folic acid to be utilised by the body, it must be converted into its active form, methyl-folate, through a series of steps involving enzymes like DHFR (dihydrofolate reductase).

Why not just use the more biologically available form of folate in foods to prevent NTDs, you ask? The answer, is money. Folic acid is about $5 per kilogram, where methylated-folate is about $17,000 per kilogram. So when you next ask yourself why a better quality supplement is that much more expensive; this is part of the reason!

The problem with excess folic acid

Our bodies have a limited capacity to process folic acid. DHFR, the first step in converting folic acid to methyl-folate, can only handle around 220 mcg of folic acid per day, but the recommended daily allowance (RDA) for folic acid is 400 mcg. Given the widespread fortification of foods, many of us are consuming far more than this and therefore far more than what our bodies can convert. The excess is known as unmetabolised folic acid (UMFA), which circulates in the bloodstream and has been linked to health issues like cancer, fatty liver, mood disorders, and fertility problems(h)(i)(j).

MTHFR gene mutation and its impact

The final step in converting folic acid to its active form is controlled by the MTHFR gene. Some of you might have heard about the MTHFR gene and mutations of it? Yes, mutations in this gene are common, with 50% of the population having some form of it. BUT. Regardless of whether or not you have a mutation, folic acid slows down the activity of MTHFR.

What does the MTHFR gene do?

1. Produces the MTHFR enzyme which activates and converts folate into active forms so our bodies can use it

2. Facilitates methylation. This is a critical process our body’s do all the time, where a methyl group is transferred between molecules. This activity impacts DNA synthesis and repair, gene expression, detoxification, neurotransmitter production and energy metabolism in the cells(m)

3. Supports homocysteine metabolism. MTHFR converts homocysteine (potentially harmful amino acid) into methionine which is necessary for methylation reactions. High homocysteine levels have been associated with pregnancy complications, cardiovascular disease and neurodegenerative disorders(k)(l).

People with MTHFR mutations (heterozygous or homozygous) experience even further reduced efficiency in processing folic acid, further impacting overall health.

• Heterozygous Mutation: Up to a 30% reduction in MTHFR enzyme activity.

• Homozygous Mutation: Up to a 70% reduction in enzyme activity.

  
  

These mutations can affect fertility, mental health, and overall wellbeing, especially when unmetabolised folic acid is present. Incredibly, excess folic acid effects gene expression which is significant when you think about folic acid and pregnancy.

Folate and pregnancy: why it matters

For individuals trying to conceive, having adequate levels of natural folate is critical. Folate not only supports fertility but also influences the genetic health of the child. MTHFR mutations, coupled with excess folic acid, can block folate receptors, preventing the body from using the active form of the vitamin. Even if you don’t have an MTHFR mutation, unmetabolized folic acid can still interfere with essential processes, highlighting the importance of natural folate over synthetic folic acid.

Health indicators: testing and implications

If you have a family history of autoimmune disorders, cancer, stroke, or fertility issues, you may want to test for MTHFR mutations. Blood tests that reveal low folate levels (below 40 nmol) or abnormally high levels may indicate that your body isn’t properly metabolizing folic acid or you are over-consuming it. Addressing folate levels with natural sources, particularly in the three months leading up to conception, can improve both maternal and child health.

Folate in mental health and energy levels

Folate has significant implications for mental health and energy. Deficiencies in vitamin B9, along with vitamin B12, are often associated with mood disorders and chronic fatigue. Ensuring proper levels of natural folate can support mental clarity, energy, and mood stability.

Conclusion

While folic acid has played a role in reducing neural tube defects, better prevention methods that avoid the risks of excess synthetic folic acid should be considered. Focusing on folate from natural sources and choosing supplements with methylated folate (5-MTHF) ensures that your body can readily use the vitamin without the risk of unmetabolised folic acid buildup. Incorporating folate-rich foods like leafy greens, beans, lentils, avocados, and citrus fruits into your diet is a great way to support your body’s natural processes. For those needing supplements, look for options that contain the active form of folate to maximize health benefits.

*Side note – the term folate and folic acid are often used interchangeably, so when you read a food packet and it says folate, 9/10 times it’ll actually be folic acid. I asked Sanitarium myself about their Weetbix packaging! Also when you’re reading online, or doing some googling (come on…I know you will!), the term folate will often be used, when the article is actually referring to folic acid.

References:

a)    Gao S, Khalid A, Amini-Salehi E, et al. Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analyses. Food Sci Nutr. Published online March 8, 2024. doi:10.1002/fsn3.4073

b)    Ledowsky CJ, Schloss J, Steel A. Variations in folate prescriptions for patients with the MTHFR genetic polymorphisms: A case series study. Explor Res Clin Soc Pharm. 2023;10:100277. Published 2023 May 8. doi:10.1016/j.rcsop.2023.100277

c)    Saftić Martinović L, Mladenić T, Lovrić D, Ostojić S, Dević Pavlić S. Decoding the Epigenetics of Infertility: Mechanisms, Environmental Influences, and Therapeutic Strategies. Epigenomes. 2024; 8(3):34. https://doi.org/10.3390/epigenomes8030034

d)    Clark DF, Schmelz R, Rogers N, Smith NE, Shorter KR. Acute high folic acid treatment in SH-SY5Y cells with and without MTHFR function leads to gene expression changes in epigenetic modifying enzymes, changes in epigenetic marks, and changes in dendritic spine densities. PLoS One. 2021;16(1). doi:10.1371/journal.pone.0245005.

e)    Tu H, Dinney CP, Ye Y, Grossman HB, Lerner SP, Wu X. Is folic acid safe for non-muscle-invasive bladder cancer patients? An evidence-based cohort study. Am J Clin Nutr. 2018;107(2):208-216. doi:10.1093/ajcn/nqx019

f)     Carboni L. Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health. Integr Med (Encinitas). 2022;21(3):36-41.

g)    Yang S, Ye Z, Liu M, et al. Associations of different serum folate forms with indices of nonalcoholic fatty liver disease and advanced fibrosis. Obes Res Clin Pract. 2023;17(1):58-65. doi:10.1016/j.orcp.2023.01.004.

h)    Fardous AM, Heydari AR. Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. Nutrients. 2023; 15(21):4699. https://doi.org/10.3390/nu15214699

i)      Yang S, Ye Z, Liu M, et al. Associations of different serum folate forms with indices of nonalcoholic fatty liver disease and advanced fibrosis. Obes Res Clin Pract. 2023;17(1):58-65. doi:10.1016/j.orcp.2023.01.004

j)      Tang JS, Cait A, White RM, Arabshahi HJ, O’Sullivan D, Gasser O. MR1-dependence of unmetabolized folic acid side-effects. Front Immunol. 2022;13:946713. doi:10.3389/fimmu.2022.946713

k)     Dai C, Teng Y, Ma Z, et al. A novel review of homocysteine and pregnancy complications. Front Nutr. 2021;8:703726. doi:10.3389/fnut.2021.703726

l)      Saija C, Currò M, Ientile R, Caccamo D, Bertuccio MP. Impact of alterations in homocysteine, asymmetric dimethylarginine and vitamins-related pathways in some neurodegenerative diseases: a narrative review. Int J Mol Sci. 2025;26(8):3672. doi:10.3390/ijms26083672

m)   Baek A, Kim SY, Lee JH, et al. Modulation of DNA methylation by one‑carbon metabolism. Nutr Res Pract. 2023;17(4):597–611. doi:10.4162/nrp.2023.17.4.597