MTHFR and PCOS

MTHFR and PCOS

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

May 25, 2025

What is PCOS?

Polycystic ovary syndrome (PCOS) is one of the most common endocrine system conditions affecting women of reproductive age. Women with PCOS have excess levels of androgens (male hormones), which can cause acne, excess hair growth (hirsutism), and irregular or absent menstrual periods. Other symptoms may include metabolic dysfunction, obesity, infertility, and an increased risk of pregnancy complications and long-term cardiovascular disease.1


PCOS affects an estimated 6-13% of reproductive-aged women.2

What causes PCOS?

The exact cause of PCOS is unclear. It is a multifactorial condition that can vary between individuals. However, research suggests that contributing factors may include:

  • Environmental pollutants (heavy metals, insecticides, and endocrine-disrupting chemicals)
  • Diet
  • Lifestyle
  • Genetic factors
  • Obesity
  • Gut dysbiosis


These factors can lead to excessive androgen secretion from the ovaries, increased insulin resistance, partial folliculogenesis arrest, and chronic low-grade inflammation, potentially triggering metabolic syndrome.3

Symptoms of PCOS

According to the Rotterdam criteria, PCOS can be classified into four types:4

Type A: irregular or absent ovulation + high androgen levels + polycystic ovaries
Type B: irregular or absent ovulation + polycystic ovaries
Type C: high androgen levels + polycystic ovaries
Type D: irregular or absent ovulation + high androgen levels


Depending on these types, typical symptoms of PCOS can include:5

  • Irregular menstrual cycles that can fluctuate throughout life
  • Hirsutism (excess hair growth)
  • Darkening of the skin
  • Fatigue
  • Acne
  • Difficulty sleeping
  • Female-pattern alopecia (overall thinning with maintenance of hairline)
  • Insulin resistance
  • Infertility due to irregular or absent ovulation
  • Hyperandrogenism
  • Weight gain and/or obesity, difficulty losing weight
  • Depression and/or anxiety

PCOS and infertility

PCOS is one of the leading causes of infertility because it causes hormonal imbalances and disrupts menstrual cycles.

It is also the most common cause of anovulation in infertility, in which ovaries fail to release a mature egg during a menstrual cycle, making it more difficult to get pregnant.

PCOS is also associated with a higher risk of miscarriage, poor quality oocytes, insulin resistance leading to hyperinsulinemia, and prolonged intimal hyperplasia (abnormal thickening of the inner layer of a blood vessel), which can reduce implantation.6

It is also linked to chronic low-grade inflammation and metabolic disorders.

If PCOS progresses without treatment, it can affect more bodily systems and organs, potentially leading to diabetes, obesity, and high cholesterol. All of these conditions can also affect fertility.7


Pregnancy complications are also more likely. Research suggests that women with PCOS have a significantly higher BMI and an increased risk of gestational diabetes. The risk of pre-term birth is also significantly higher.8

The connection between low folate levels and PCOS

Low folate does not cause PCOS directly. However, women with PCOS often have elevated homocysteine, which is closely linked to folate levels. Low folate levels also tend to be correlated with raised homocysteine levels as it is a cofactor in the re-methylation of homocysteine.


Women with PCOS are found to have significantly higher homocysteine levels than those without.10


A 2024 study found that 60% of women with PCOS had low B12 levels and high homocysteine levels. It also found that their RBC folate (folate stored inside red blood cells) correlated with fasting glucose, triglycerides, and androgen markers, suggesting that folate levels could be tied to both metabolic and hormonal imbalances in PCOS.11

How does MTHFR affect PCOS?

MTHFR gene mutations can reduce the body’s ability to process folate from food and supplements, sometimes leading to low folate levels and high homocysteine. MTHFR mutations are also the most common genetic cause of homocysteine-related metabolic disorders.12

MTHFR may contribute to PCOS by increasing homocysteine levels, which is shown to impair microcirculation and increase the risk of thrombosis. High homocysteine in PCOS may then impair implantation by interfering with endometrial blood flow, as well as increasing the risk of complications in pregnancy.13

A 2017 meta-analysis showed that MTHFR C677T can have different effects on PCOS risk depending on ethnicity. The risk was higher in Asian, but there was little to no effect in Middle Eastern and Caucasian women.14

However, a 2025 study found that women with PCOS had higher homocysteine levels, a greater frequency of hyperhomocysteinemia compared to controls, and were also more likely to have MTHFR C677T + A1298C, and compound heterozygous variants.15 This is especially more common in women affected by recurrent miscarriage.

Treating PCOS: Folate, folic acid or methylfolate

Studies consistently show that PCOS and high homocysteine are linked to poor outcomes in conception and pregnancy.

The American Heart Association recommends folic acid to lower homocysteine. But in people with MTHFR mutations, folic acid is not well metabolized. In these cases, L-methylfolate (the active form of folate) is recommended instead, as it bypasses the MTHFR pathway.

L-methylfolate is shown to be safer and more effective for lowering homocysteine than folic acid, especially when combined with active forms of vitamin B12 and B6 (P5P).16

Supplementing with a combination of methylfolate, P5P, and methylcobalamin (active B12) has been shown to effectively reduce homocysteine and LDL-cholesterol levels in patients with specific MTHFR mutations: all of which are common in women with PCOS.17

NAC and PCOS

N-acetylcysteine (NAC) has been highlighted as a possible treatment for PCOS due to its antioxidant, anti-inflammatory, and insulin-sensitizing properties. NAC is a precursor of glutathione, the most potent endogenous antioxidant in the body, and studies suggest that NAC may reduce total testosterone levels, enhance FSH secretion, and improve metabolic and reproductive outcomes in PCOS.18

A 2023 meta-analysis found that NAC improved several aspects of reproductive function in women with PCOS, including increasing progesterone levels and endometrial thickness.19

In addition, NAC can be effective in reducing high homocysteine levels. Most homocysteine in the blood binds to albumin (a protein in the blood). NAC can break this bond, freeing homocysteine so it can be excreted through the kidneys.

Clinical studies show NAC can reduce homocysteine by 10-45%, depending on dosage and baseline levels.20

MTHFR and PCOS

Key takeaways

  • Icon PCOS is a common hormonal disorder in women that can cause irregular menstrual cycles, excess hair growth, and insulin imbalances.
  • Icon MTHFR is not directly linked to PCOS but many women with PCOS have high homocysteine levels.
  • Icon Methylfolate and NAC may help to reduce homocysteine in PCOS and improve fertility.

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Frequently Asked Questions about MTHFR and PCOS

Is MTHFR linked to PCOS?

While a MTHFR mutation is not a direct cause of PCOS, it can cause high homocysteine levels which are common in women with PCOS and MTHFR. Some studies have also shown a high incidence of MTHFR mutations in women with PCOS, as well as high homocysteine.

Which hormone triggers PCOS?

PCOS is linked to an imbalance of several hormones, including androgens (male sex hormones), luteinizing hormone (LH), estrogen, and prolactin. High levels of androgens are common, but high levels of LH and low levels of Sex Hormone-Binding Globulin (SHBG) can also occur. Insulin is also often elevated in PCOS, which can stimulate the ovaries to overproduce androgens, interfering with ovulation.21

Can PCOS cause folate deficiency?

While PCOS does not directly cause folate deficiency, studies show that women with PCOS are more likely to have elevated homocysteine, which has been linked to low folate levels.22 It has also been found that women with PCOS are more likely to have a MTHFR mutation - which is linked to high homocysteine.23

What hormone makes PCOS worse?

High levels of androgens (male sex hormones) can make PCOS worse by causing symptoms such as irregular menstrual cycles, excess hair growth, and acne. Insulin is another hormone that can worsen PCOS if levels are too high, as this can lead to insulin resistance, diabetes, and weight gain.

Can I take folic acid everyday if I have PCOS?

Folic acid is the synthetic form of folate. While it is considered safe, it is not absorbed well in the body as it must first undergo a lengthy conversion process. Folic acid is also not recommended for people with MTHFR mutations as they cannot metabolize it properly.
If you have PCOS and high homocysteine, methylfolate is more suitable. Methylfolate is the active form of folate that is shown to be more effective in reducing high homocysteine than folic acid, and can be safely taken by those with MTHFR.

Which gene mutation causes PCOS?

There is no specific gene mutation that causes PCOS. While genetics may contribute, this usually includes genes related to hormonal balances, such as insulin function and/or diabetes; androgen production and ovarian function, and other factors linked to gonadotropin.24 Studies have also shown that women with PCOS are more likely to have some form of MTHFR mutation, which can lead to high homocysteine levels.25

Does NAC help with PCOS?

NAC may help with PCOS, but more research is pending. Recent studies show that NAC can be effective in reducing homocysteine levels, which are common in PCOS. NAC is also shown to improve many aspects of reproductive function in women with PCOS, including increasing progesterone levels and endometrial thickness.26

References

  1. Jacob P Christ, Marcelle I Cedars; "Current Guidelines for Diagnosing PCOS?"; Diagnostics (Basel); 2023 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10047373/

  2. World Health Organization; "Polycystic ovary syndrome"; 2025 Feb

    https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome

  3. Samradhi Singh, Namrata Pal, Swasti Shubham, Devojit Kumar Sarma, Vinod Verma, Francesco Marotta, Manoj Kumar; "Polycystic Ovary Syndrome: Etiology, Current Management, and Future Therapeutics"; Journal of clinical medicine; 2023 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9964744

  4. Sulian Zhuang, Chunxia Jing, Lei Yu, Liwei Ji, Weiwei Liu, Xingpo Hu; "The relationship between polycystic ovary syndrome and infertility: a bibliometric analysis"; Annals of translational medicine; 2022 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9011246/

  5. Ebernella Shirin Dason, Olexandra Koshkina, Crystal Chan, Mara Sobel; "Diagnosis and management of polycystic ovarian syndrome"; CMAJ : Canadian Medical Association journal; 2024 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC10833093

  6. Sulian Zhuang, Chunxia Jing, Lei Yu, Liwei Ji, Weiwei Liu, Xingpo Hu; "The relationship between polycystic ovary syndrome and infertility: a bibliometric analysis"; Annals of translational medicine; 2022 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9011246/

  7. Hye Jin Kim, Eui Hyeok Kim, Eungil Ko, Sojung Park, Yaelim Lee; "The Impact of Polycystic Ovary Syndrome on Gestational Diabetes Mellitus, Disease Knowledge, and Health Behaviors"; Healthcare (Basel). 2025 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11988315

  8. Hye Jin Kim, Eui Hyeok Kim, Eungil Ko, Sojung Park, Yaelim Lee; "The Impact of Polycystic Ovary Syndrome on Gestational Diabetes Mellitus, Disease Knowledge, and Health Behaviors"; Healthcare (Basel). 2025 Mar

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11988315

  9. Juan R Ulloque-Badaracco, Ali Al-kassab-Córdova, Enrique A Hernández-Bustamante, Esteban A Alarcón-Braga, Juan C Cabrera-Guzmán, Andres A Horruitiner-Mendoza, Pamela Robles-Valcárcel, Vicente A Benites-Zapata, Faustino R Pérez-López; "Homocysteine, vitamin B12, and folate circulating levels in women with and without polycystic ovary syndrome: A systematic review and meta-analysis"; Women's health; 2024 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11437568/

  10. Francesco Orio Jr, Stefano Palomba, Sebastiano Di Biase, Annamaria Colao, Libuse Tauchmanova, Silvia Savastano, Donato Labella, Tiziana Russo, Fulvio Zullo, Gaetano Lombardi; "Homocysteine levels and C677T polymorphism of methylenetetrahydrofolate reductase in women with polycystic ovary syndrome"; The Journal of clinical endocrinology and metabolism; 2003 Feb

    https://pubmed.ncbi.nlm.nih.gov/12574198/

  11. Matías Carrasco-Cabezas, Taís Silveira Assmann, Paz Martínez, Leslie Cerpa, Susan Calfunao, Bárbara Echiburú, Manuel Maliqueo, Nicolás Crisosto, Francisca Salas-Pérez; "Folate and Vitamin B12 Levels in Chilean Women with PCOS and Their Association with Metabolic Outcomes"; Nutrients; 2024 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11206694/

  12. Elene Asanidze, Zurab R Tsetskhladze, Jenaro Kristesashvili, Marina Pirtskhalava, Manana Urjumelashvili, Shorena Tchiokadze, Malkhaz Vakhania, Nino Parunashvili, Aleksandre Asanidze; "The Relationship between Homocysteine Levels, MTHFR C677T and A1298C Polymorphism, and Pregnancy Outcomes in Georgian Women with Polycystic Ovary Syndrome: A Case-Control Study"; International journal of fertility & sterility; 2025 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11744196/

  13. Amita Diwaker, Dhiraj Kishore; "Evaluation of Plasma Homocysteine Levels in Patients of PCOS"; The Journal of the Association of Physicians of India; 20118 Oct

    https://pubmed.ncbi.nlm.nih.gov/31317701/

  14. Lihong Wang, Wenting Xu, Caihong Wang, Mengyu Tang, Yujia Zhou; "Methylenetetrahydrofolate reductase C677T polymorphism and the risks of polycystic ovary syndrome: an updated meta-analysis of 14 studies"; Oncotarget; 2017 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC5601750/

  15. Elene Asanidze, Zurab R Tsetskhladze, Jenaro Kristesashvili, Marina Pirtskhalava, Manana Urjumelashvili, Shorena Tchiokadze, Malkhaz Vakhania, Nino Parunashvili, Aleksandre Asanidze; "The Relationship between Homocysteine Levels, MTHFR C677T and A1298C Polymorphism, and Pregnancy Outcomes in Georgian Women with Polycystic Ovary Syndrome: A Case-Control Study"; International journal of fertility & sterility; 2025 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11744196/

  16. Merrill F Elias, Craig J Brown; "Medical foods for lowering homocysteine in hypertensive patients"; The journal of clinical hypertension; 2022 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9832224/

  17. Evgeny Pokushalov, Andrey Ponomarenko, Sevda Bayramova, Claire Garcia, Inessa Pak, Evgenya Shrainer, Marina Ermolaeva, Dmitry Kudlay, Michael Johnson, Richard Miller; "Effect of Methylfolate, Pyridoxal-5′-Phosphate, and Methylcobalamin (SolowaysTM) Supplementation on Homocysteine and Low-Density Lipoprotein Cholesterol Levels in Patients with Methylenetetrahydrofolate Reductase, Methionine Synthase, and Methionine Synthase Reductase Polymorphisms: A Randomized Controlled Trial"; Nutrients; 2024 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11173557/

  18. Carmen Pingarrón Santofímia, Silvia Poyo Torcal, Helena López Verdú, Alexandra Henríquez Linares, Virginia Calvente Aguilar, Pablo Terol Sánchez, María Sol Martínez García, Pilar Lafuente González; "Evaluation of the efficacy of an antioxidant combination for the modulation of metabolic, endocrine, and clinical parameters in patients with polycystic ovary syndrome"; Gynecological Endocrinology; 2023

    https://www.tandfonline.com/doi/full/10.1080/09513590.2023.2227277

  19. Isabel Viña, Juan R. Viña, Macarena Carranza, Gonzalo Mariscal; "Efficacy of N-Acetylcysteine in Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis"; Nutrients; 2025

    https://www.mdpi.com/2072-6643/17/2/284

  20. Karin Elgar; "N-acetylcysteine: A Review of Clinical Use and Efficacy"; Nutritional Medicine Journal; 2022

    https://www.nmi.health/wp-content/uploads/2023/01/NMJ_NAC_A-Review-of-Clinical-Use-and-Efficacy.pdf

  21. Kursad Unluhizarci, Zuleyha Karaca, Fahrettin Kelestimur; "Role of insulin and insulin resistance in androgen excess disorders"; World journal of diabetes; 2021 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC8107978/

  22. Francesco Orio Jr, Stefano Palomba, Sebastiano Di Biase, Annamaria Colao, Libuse Tauchmanova, Silvia Savastano, Donato Labella, Tiziana Russo, Fulvio Zullo, Gaetano Lombardi; "Homocysteine levels and C677T polymorphism of methylenetetrahydrofolate reductase in women with polycystic ovary syndrome"; The Journal of clinical endocrinology and metabolism; 2003 Feb

    https://pubmed.ncbi.nlm.nih.gov/12574198/

  23. Elene Asanidze, Zurab R Tsetskhladze, Jenaro Kristesashvili, Marina Pirtskhalava, Manana Urjumelashvili, Shorena Tchiokadze, Malkhaz Vakhania, Nino Parunashvili, Aleksandre Asanidze; "The Relationship between Homocysteine Levels, MTHFR C677T and A1298C Polymorphism, and Pregnancy Outcomes in Georgian Women with Polycystic Ovary Syndrome: A Case-Control Study"; International journal of fertility & sterility; 2025 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11744196/

  24. Nida Ajmal, Sanam Zeib Khan, Rozeena Shaikh; "Polycystic ovary syndrome (PCOS) and genetic predisposition: A review article"; European journal of obstetrics & gynecology and reproductive biology; 2019 Jun

    https://pmc.ncbi.nlm.nih.gov/articles/PMC6687436

  25. Elene Asanidze, Zurab R Tsetskhladze, Jenaro Kristesashvili, Marina Pirtskhalava, Manana Urjumelashvili, Shorena Tchiokadze, Malkhaz Vakhania, Nino Parunashvili, Aleksandre Asanidze; "The Relationship between Homocysteine Levels, MTHFR C677T and A1298C Polymorphism, and Pregnancy Outcomes in Georgian Women with Polycystic Ovary Syndrome: A Case-Control Study"; International journal of fertility & sterility; 2025 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11744196/

  26. Isabel Viña, Juan R. Viña, Macarena Carranza, Gonzalo Mariscal; "Efficacy of N-Acetylcysteine in Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis"; Nutrients; 2025

    https://www.mdpi.com/2072-6643/17/2/284

Katie Stone - Naturopath

About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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