Writing in British Journal of Nutrition, researchers from the University of Toronto investigated the association between folate and the MTHFR genotype, which is involved in the folate metabolic pathway. The study findings indicate that folate or its metabolites could be related to the risk of premenstrual depression.

”In our study population, roughly 50% had the version of the gene that is not associated with premenstrual depression, 40% had one copy of the version associated with a slight increase, and 10% had two copies of the version that increased their risk by more than two-fold when their folate intake was low,” said study co-author Dr. Ahmed El-Sohemy, PhD.

Complex absorption

Women of reproductive age can experience numerous symptoms associated with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), which usually occur between five to 12 days before menstruation during the luteal phase of the menstrual cycle.

“PMS is defined as having at least one moderate/severe psychological and one somatic symptom and affects approximately 30% of women, whereas PMDD is characterized by having at least five symptoms, one of which must be psychological, and is seen in up to 8% of women,” the researchers wrote.

Although research on some B vitamins suggests that they may reduce premenstrual symptom severity, there have been few studies examining folate’s association with symptoms. This may partly be due to shortcomings associated with dietary assessment methods for micronutrients that have complex absorption like folate.

Efficiently being able to metabolize dietary folate depends on the MTHFR gene which codes for methylenetetrahydrofolatereductase (MTHFR), a crucial enzyme in folate metabolism.

“MTHFR converts 5,10-methylenetetrahydrofolate from the diet to 5-methyl-tetrahydrofolate, which is the active form of folate used at the cellular level,” the researchers explained.

Folate, an essential water-soluble B vitamin, is used as a co-factor for neurotransmitters. Folate deficiency is often attributed to psychiatric symptoms including depression.

Study details

The researchers selected 678 women between the ages of 20 to 29 who had participated in the Toronto Nutrigenomics and Health (TNH) trial, a cross-sectional study exploring the effects of genetic variation and dietary consumption on biomarkers of health.

Participants’ food consumption was monitored, and they completed a general health and lifestyle questionnaire to assess the severity and presence of 15 commonly reported premenstrual symptoms five days prior to menstruation and up to four days post-onset. Researchers collected blood samples, examining DNA from white blood cells and genotyping for the C677T MTHFR (rs1801133) polymorphism.

The odds of experiencing premenstrual symptoms were compared between total folate consumption below and above 647 mcg/d and between MTHFR genotypes. Among women with low folate intake, there was an additional association shown between the T allele genetic variant of MTHFR and premenstrual depression. Depression occurred to a lesser extent om participants with other genotypes assessed. There were no associations between the MTHFR genotype and premenstrual depression for participants with regular folate consumption.

“Previous research had shown that a version of the MTHFR gene was associated with depression, but this was the first study to show that it was also associated with premenstrual depression,” Dr. El-Sohemy said.

“This gene plays an important role in folate metabolism. What stood out even more was that the risk increased with each additional copy of the genetic variant we examined. Importantly, the effect of this genetic variant was only observed among women with lower intakes of folate. This suggests that increasing folate intake might reduce the risk of premenstrual depression in women who have this genetic susceptibility.”

Companies should not rush to develop folate-based products for women with premenstrual depression just yet, Dr. El-Sohemy noted. Randomized controlled trials are still needed to establish whether folate supplementation is therapeutically effective.

“Nevertheless, our findings highlight the possibility of tailoring nutrition interventions based on genetic profiles,” he said.

“If someone knows they carry a version of this gene that reduces the efficiency of folate metabolism, it could guide them (and product developers) toward more targeted micronutrient strategies. In the future, this kind of research could contribute to more personalized supplements that take both genetics and symptom profiles into account—especially for something as under-researched as premenstrual symptoms.”

Source: British Journal of Nutrition. doi: 10.1017/S0007114525103620. “Folate intake, MTHFR genotype and premenstrual symptoms”. Authors: Tara Zeitoun and Ahmed El-Sohemy.