MTHFR and the Menstrual Cycle

The menstrual cycle spans 21-35 days and is regulated by the complex interaction of the hypothalamus, anterior pituitary gland, ovaries, and uterus.¹ The ovarian and endometrial cycles occur within the overall menstruation process.

Day 1 to ovulation: Follicular and proliferative phase

The follicular phase begins on day 1 (onset of menstruation) and continues through to ovulation, which can take from 7-21 days.

Follicle-stimulating hormone (FSH) stimulates a group of primordial follicles to mature. The dominant follicle produces rising estradiol, which suppresses non-dominant follicles. At the same time, estrogen triggers endometrial proliferation.

Mid-cycle: Ovulation 

A surge in luteinizing hormone (LH)  triggers ovulation, briefly followed by a drop in estrogen. This marks the transition between the two primary phases (follicular and luteal).

Days ~14: Luteal and secretory phase

After ovulation, granulosa cells transform into luteal cells, which create the corpus luteum, a structure that secretes progesterone. Progesterone prepares the uterus for possible pregnancy by stimulating endometrial glandular development, glycogen accumulation, and the expansion of spiral arteries.

If pregnancy does not occur, the lining of the corpus luteum breaks down. Progesterone and estrogen decline and menstruation follows.

MTHFR is involved in the conjugation and inactivation of catechol estrogens by COMT (catechol-O-methyltransferase) and is also required for the creation of S-adenosylmethionine (SAMe). SAMe is the methyl donor for COMT-catalyzed reactions, which allow inactivation of catechol estrogens. In the case of MTHFR mutations, reduced MTHFR activity can impair the inactivation of catechol estrogens by COMT, potentially leading to estrogen accumulation. This can result in heavier or more painful periods and more severe PMS (premenstrual syndrome) symptoms.²

A 2025 study found that low folate intake (<647 mcg/day) was associated with premenstrual depression and some cognitive symptoms in women with the MTHFR C677T mutation. Women with the T‑allele carriers (particularly TT) were more likely to be affected by premenstrual depression, while women with higher folate intake did not. This suggests that folate may mitigate MTHFR‑related risk for premenstrual depression.³

A 2025 study found a higher frequency of the T allele and CT/TT genotypes of MTHFR C677T in women with endometriosis.⁴ The CT and TT genotypes were found more frequently in those with stages II-III endometriosis. The MTR A2756G variant was not found to be significantly associated with endometriosis.

Previous research suggests that the MTHFR C677T variant may raise the risk of developing endometriosis due to oxidative stress and poor methylation. Reduced methyl donor availability and higher homocysteine can lead to overall DNA hypomethylation and weaker antioxidant defences (including lower glutathione), which increases oxidative stress and epigenetic changes in genes involved in cell growth, invasion, and cell death in endometrial tissue. Elevated homocysteine in follicular fluid and the endometrial tissue may then impair oocyte quality, implantation, and local cell viability.⁵

Some studies report higher homocysteine levels in women with PCOS than in controls, suggesting homocysteine may play a part in PCOS physiology. A 2025 study found a significant correlation between hyperhomocysteinemia, MTHFR C677T and A1298C variants, and PCOS.⁶ Other studies have shown that compound heterozygous MTHFR C677T/A1298C genotypes are linked with lower enzyme activity, higher homocysteine, and infertility. Elevated homocysteine can impair microcirculation and raise thrombosis risk, which may affect ovarian and endometrial function.⁷

MTHFR mutations do not directly cause menstrual symptoms, but low folate along with impairments in methylation and higher homocysteine can contribute to conditions such as endometriosis, PMS, PMDD (premenstrual dysphoric disorder), PCOS, infertility, and miscarriage.

Reduced MTHFR activity may lead to higher homocysteine and impaired methylation, which are associated with symptoms such as fatigue, vascular symptoms, early pregnancy loss, depression, and infertility. The pathophysiology of these symptoms has been linked to reproductive disorders such as endometriosis, PMS/PMDD, PCOS, and miscarriage.

MTHFR C677T is found to be higher in women with endometriosis, with symptoms including pelvic pain, dysmenorrhea, and irregular periods. Reduced MTHFR enzyme function can lead to increased homocysteine, which increases oxidative stress. Changes in DNA methylation in endometrial tissue also appear to increase the risk of endometriosis in some women with MTHFR.⁸

Women with low folate intake and the MTHFR C677T T‑allele (CT/TT) appear to be more affected by premenstrual depression, suggesting that folate plays a key role in mood-related premenstrual symptoms.⁹

Higher homocysteine levels are found in women affected by infertility, and the MTHFR C677T TT genotype in childbearing-aged women is associated with a higher risk of infertility.¹⁰

Women with the combined 677TT/1298AA genotype were found to have the lowest MTHFR enzyme activity and also a lower oocyte maturation rate compared with those with the CC genotype. Women with intermediate MTHFR activity had poorer embryo quality, and oocyte maturation rate also decreased linearly with the decline in MTHFR enzyme activity.¹¹

Several meta‑analyses report that MTHFR C677T (especially the TT genotype) is associated with recurrent pregnancy loss. This seems to be linked to hyperhomocysteinemia from reduced MTHFR activity, which can increase endothelial damage, thrombosis, and poorer placental and endometrial blood flow, all of which can undermine implantation and early pregnancy.¹²

There is no specific ‘MTHFR treatment’ for menstrual cycle irregularities, as MTHFR is only one of many factors that may contribute. 

However, research suggests that menstrual symptoms in women with MTHFR mutations are often related to low folate and high homocysteine, so focusing on these aspects should be a priority.

• Methylfolate
  The MTHFR C677T mutation - which impairs folate metabolism - is higher in women with endometriosis. Researchers have noted folic acid may not be suitable for women with these variants, and that methylfolate may better support folate and homocysteine metabolism. Methylfolate is the main circulating form of folate and does not require conversion by MTHFR to restore folate required for homocysteine metabolism and other methylation processes.¹³
  
  
• Vitamin B12 and B6
  Vitamins B12 and B6 work alongside folate in metabolizing homocysteine and supporting the production of neurotransmitters such as serotonin, which are required for healthy mood.¹⁴ Vitamin B6 intake has been shown to reduce period pain and PMS symptoms.¹⁵
  
  
• Vitamin D
  Supplementation with vitamin D may improve systemic symptoms of dysmenorrhea, including pain intensity, the number of days with pain, and the need for pain-relief medications.¹⁶