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MTHFR and PCOS: Is there a Connection?

MTHFR and PCOS: Is there a Connection? | Methyl-Life

MTHFR and PCOS: Is there a Connection?

Polycystic ovary syndrome (PCOS) is the most common hormone-related disorder in women, affecting an estimated 7-10 percent (5-6 million) of women in the US. It is also the most common cause of infertility.

Although the etiology of PCOS is largely unknown, recent research has revealed that MTHFR genetic mutations may be linked due to its involvement in the regulation of homocysteine. However, there is no specific evidence to show that MTHFR directly causes PCOS. 

Methylenetetrahydrofolate reductase (MTHFR) plays a key role in the metabolism of folate and DNA methylation, and RNA synthesis.

MTHFR is required for the conversion of folic acid in plasma and tissues. However, a mutation in the MTHFR gene can result in low folate concentrations, leading to elevated homocysteine levels

Decreased efficiency of the folate/homocysteine pathway appears to be prevalent in women with PCOS, and that PCOS is often accompanied by high homocysteine levels. 

It has also been found that homocysteine levels in women with PCOS return to normal following folate supplementation, which supports the theory that MTHFR is connected.

This article will discuss what PCOS is and the links to MTHFR mutations. We will also cover the possible treatment for PCOS for those with MTHFR genetic mutations.

What is PCOS?

Polycystic ovarian syndrome (PCOS) is a complex condition characterized by hormonal imbalances, irregular menstruation, and/or small cysts on the ovaries. The increased levels of androgens in women with PCOS results can also inhibit follicular development, affecting fertility.

It is estimated that PCOS has affected 116 million women (3.4%) worldwide. The prevalence of PCOS between different countries is highly variable, ranging from 2.2% to as high as 26%.

The severity of PCOS symptoms vary between women and can change throughout life. Common symptoms include:

  • Irregular menstruation
  • Very light periods or amenorrhea
  • Enlarged ovaries due to eggs that do not ovulate
  • Multiple cysts on the ovaries
  • Difficulty becoming pregnant
  • Excess hair on the face and body (hirsutism)
  • Thinning hair or hair loss on the scalp (alopecia)
  • Acne on the face and/or body that can be severe
  • Oily skin
  • Darkened or thickened patches of skin (acanthosis nigricans) in the armpits, back of the neck, under the breasts
  • Weight gain, usually around the abdomen
  • Skin tags on the neck or armpits
  • Mood changes: depression, anxiety, low self-esteem

Risk Factors for PCOS

While the exact cause is uncertain, many factors can increase the risk of developing PCOS. Nutritional status, obesity, insulin resistance, lifestyle, and environmental factors may play a part, along with genetics. 

Increased androgen production is the main cause of PCOS symptoms, which is linked to insulin resistance. Insulin resistance and the compensatory hyperinsulinemia affect around 65–70% of women with PCOS. Of these women, 70–80% have a BMI higher than 30, which is considered obese. Another 20–25% have a BMI of less than 25. As a result, PCOS is often linked to obesity and insulin resistance. 

Excess insulin in the bloodstream causes the body to store abdominal fat, which is associated with higher levels of fasting insulin and LH (Luteinising Hormone). Hyperinsulinemia can then stimulate androgen production in the ovaries, particularly as PCOS cells are more responsive to insulin than other cells. Increased insulin is also shown to activate androgen production in PCOS theca cells.

Type 2 diabetes, glucose intolerance, dyslipidemia, and higher levels of inflammation are also more common in women with PCOS.

Conditions Related to PCOS

  • Type 2 diabetes and prediabetes
  • Cardiovascular disease
  • Metabolic syndrome
  • High blood pressure, high cholesterol, obesity, high fasting blood glucose
  • Endometrial cancer
  • Sleep apnoea
  • Infertility and pregnancy complications
  • Gestational diabetes

Could an MTHFR mutation cause PCOS or make symptoms worse

Could an MTHFR Mutation Cause PCOS or Make Symptoms Worse?

Evidence regarding the link between MTHFR and PCOS is mixed. 

A large meta-analysis in 2020 demonstrated that the C677T polymorphism contributed to an increased risk of PCOS, especially among Asian women. However, the authors noted that further studies with larger population sizes are needed to confirm these results.

A previous meta-analysis in 2017 hypothesized that the C677T would be strongly associated with the risks for PCOS in the Middle Eastern populations but found that the same polymorphism was protective in Caucasian populations. As a result, the authors suggested that the C667T variant can “increase, decrease, or have no effect” on the risks of PCOS, depending on the population’s ethnicity.

A 2010 study involving Turkish patients found the C677T variant significantly higher in women with PCOS. The authors explained that insulin resistance and hyperinsulinemia might be central roles to various hormonal and metabolic imbalances that occur in PCOS, including elevated homocysteine. They also pointed out that dietary inadequacies (such as low intake of folate and B12) may have affected the homocysteine levels in PCOS patients.

A large meta-analysis of 13 studies published in 2016 concluded that C677T does not influence the risk of PCOS and that MTHFR mutations were not clinically important in PCOS in most of the populations. They also noted that MTHFR was not correlated with obesity in PCOS.

However, a number of studies have highlighted that women with PCOS tend to have elevated homocysteine, which is a common outcome of an MTHFR mutation. Women with PCOS are also at a higher risk of developing coronary artery disease due to hyperhomocysteinemia. MTHFR deficiency is the most common cause of hyperhomocysteinemia, suggesting an association between PCOS and MTHFR C677T.

Increased levels of homocysteine in PCOS women may also play a part in several conditions that could worsen PCOS, including cardiovascular disease and infertility.

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Does Supplementation with Methylfolate Help with PCOS Symptoms?

Homocysteine levels are significantly associated with insulin resistance and hyperinsulinemia in women with PCOS. Fortunately, this can be treated with methylfolate. 

Normally, excess homocysteine is removed from the body via the methylfolate pathway. The MTHFR enzyme is required for the conversion of a form of folate to 5-methyltetrahydrofolate, the primary active form of folate involved in the conversion of homocysteine into methionine. However, a mutation on the MTHFR gene can seriously affect the ability of the MTHFR enzyme to function normally, which has severe implications for the homocysteine cycle.

Imbalances of any of the above pathways result in the accumulation of homocysteine. However, supplementation with folate, vitamins B2, B3, B12, betaine, and zinc can support the methylation cycle and improve the elimination of homocysteine.

Taking folate, B12, and B6 together has been shown to help lower homocysteine levels more effectively than taking folate alone. 

L-methylfolate is also found to increase peripheral sensitivity to insulin and maintain stable folate levels, which can help rebalance levels of homocysteine. Unlike folic acid, L-methylfolate is highly bioavailable and can bypass the MTHFR mutation. 

Studies have also highlighted the need for women with PCOS to supplement with thiamine, niacinamide, and folates with inositol in order to increase peripheral sensitivity to insulin. Myo-inositol + folate supplementation in women with PCOS may result in better fertilization rates and improved embryo quality. It also appeared to reduce the risk of hyperstimulation syndrome. 

Best Supplements for PCOS with MTHFR

Best Supplements for PCOS with MTHFR

Treatment of PCOS should be with a multi-nutrient approach aimed at supporting all areas of concern. Along with reducing the symptoms of PCOS, it is important that the risk factors of cardiovascular disease be treated. Lowering homocysteine should be a priority. 

Numerous studies have indicated that elevated homocysteine is closely linked to low levels of plasma folate. There are also links between blood levels of vitamin B12 and pyridoxal-5-phosphate (the active form of B6). Low B-vitamin status can cause homocysteine to accumulate while also reducing the availability of SAMe (S-Adenosyl methionine) for methylation processes.

One of the most effective ways to reduce elevated homocysteine is by increasing the intake of activated B vitamins, particularly L-methylfolate. Activated forms of folate, B12, and betaine may control or alleviate the risk of elevated homocysteine and can improve the efficiency of the conversion by bypassing genetic variants of MTHFR. 

L-methylfolate is more effective than folic acid in lowering homocysteine levels. Taking folate, B12, and B6 together has been shown to help lower homocysteine levels more effectively than taking folate alone. 

Some of the best methylfolate supplements for those with MTHFR mutations include Methyl-Life® products (B-Methylated II, Methylated Multivitamin, also Methylfolate 7.5+ or Methylfolate 15+). This product range has been created by a team of natural health experts and contains the purest, most stable, and most potent of the four world’s industry-leading patented L-Methylfolates. It is also suitable for vegans and those with cardiovascular risks. 

It should be noted that poor insulin management in PCOS can also lead to several health complications, including irregular menstruation, infertility, hirsutism, obesity, acne, and cardiovascular issues. A low-GI (Low-glycemic index)diet has been shown to improve glucose tolerance and menstrual regularity in women with PCOS. 

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