Methylation and Fertility

Fertility issues affects more couples than we might think – 1 in 7 couples (15%) have difficulty conceiving a child. A diagnosis of infertility means you haven’t been able to get pregnant after a year of trying. If you’re a woman over 35, it means you haven’t been able to get pregnant after 6 months of trying. Women who are able to conceive but not carry a pregnancy to term may also be diagnosed with infertility.

But fertility (or infertility) isn’t just a woman’s problem. In fact, men and women are equally likely to have fertility problems. As the reproductive system is complex, there are many possible causes of infertility, and for a quarter of infertility cases, it is not possible to identify the cause.

Different causes of infertility

There are various reasons for a men or a women’s infertility. Infertility in men can be caused by poor quality of semen and sperm, testicles issues, ejaculation disorders, hypogonadism (a failure of the testes to produce the male sex hormone testosterone, sperm, or both) or a consequence of medication. Infertility in women can be due to ovulation issues, scarring from surgery, cervical mucus issues, fibroids, endometriosis, PCOS, pelvic inflammatory disease or again, a consequence of medicines and drugs. There are many risk factors involved in infertility issues but the main ones are

age – fertility declines with age
weight – being overweight or underweight
sexually transmitted infections (STIs)
smoking, alcohol, environmental factors
stress
genetics

All of these can affect ovulation, sperm quality and production, or sex drive and libido.

Nutrigenomics

Nutrigenomics is an area of genomics which focuses on genes that relate and respond to nutrition and lifestyle interventions. An important aspect of nutrigenomics is that it is possible to modify gene expression with nutrition. Genes are not destiny, so if your fertility issues have a nutrigenetic component, then it’s possible to do something about it.

Methylation

Methylation, also referred to as one carbon metabolism, is a process by which methyl groups are added to molecules. It is involved in almost every biochemical reaction in the body, occurring billions of times every second in our cells and contributing to numerous crucial bodily functions, including: detoxification, DNA synthesis and repair, energy production, inflammation control, immune function, gene expression, neurotransmitter balance and telomere protection (anti-ageing).

Sub-optimal methylation can impact fertility and pregnancy in different ways - egg and sperm quality, implantation, miscarriage, pre-eclampsia, neural tube defects and preterm birth. Of particular relevance to fertility and pregnancy -

the Folate cycle - provides folates for i) DNA synthesis and repair - very important for pregnancy - cell division, growth of the baby, and also red blood cell synthesis (oxygen & nutrient delivery) and ii) Methylfolate for recycling of folate and supply of Methyl to the Methionine cycle
the Methionine cycle - for i) making SAMe (the master methyl donor) - needed to make choline - very important for nerve/neural development, and cell membranes (making new cells) and ii) recycling (detoxifying) homocysteine - a toxin associated with DNA damage, oxidative stress, inflammation, coagulation issues and more
the Transsulphuration pathway is also an important route for homocysteine disposal (for which it requires SAMe), as well as synthesis of glutathione (the 'master antioxidant').

Key Genes

There are many (hundreds) of genes involved in DNA methylation but this article will focus on five genes involved in methylation and that research has shown have significant roles in fertility.

Starting with the MTHFD1 (Methylenetetrahydrofolate Dehydrogenase 1) gene. MTHFD1 helps to convert folate, from foods or supplements, to active THF (tetrahydrofolate) forms. THF is used to make nucleotides needed for DNA synthesis and repair – important for fertility. Small changes in the MTHFD1 gene code (SNPs) can alter and down-regulate its activity, and have been linked to risk of neural tube defects. MTHFD1 SNPs can be supported by choline and folate.

The second gene MTHFR (Methylenetetrahydrofolate Reductase) is quite famous, and is also associated with fertility issues. MTHFR converts folate to methylfolate (5-MTHF), which is pivotal to methylation. The folate (from methylfolate) is cycled to THF to support DNA synthesis and repair (as for MTHFD1, vital for healthy cell division), and the methyl (from methylfolate) is used to convert (methylate) homocysteine to make methionine. This second function is key as i) homocysteine is toxic and can damage DNA and ii) methionine is the precursor to make SAMe (pronounced sam-ee) the, so called, 'master methyl donor'.

SNPs on the MTHFR gene result in lower activity. The C677T SNP, which is very common (occuring in about 30% of people), can result in as much as 70% reduction in methylfolate synthesis. This can cause vulnerability to folate sensitive neural tube defects but just as with MTHFD1, you can support with it nutrition. Folate (vitamin B9), riboflavin (vitamin B2), cobalamin (vitamin B12) and zinc and particularly important.

PEMT (Phosphatidylethanolamine N-methyltransferase) converts phosphatidylethanolamine to phosphatidylcholine which is a significant source of choline relative to dietary intake. It is related to fertility because choline is an important vitamin for sperm and egg health, and neural development. A SNP on PEMT is associated with reduced activity and lower choline. Dependency on PEMT can be reduced by ensuring adequate dietary intake of choline (found in eggs, beef, chicken and fish).

A SNP on the CHDH gene, has been associated with altered sperm motility patterns and dysmorphic mitochondrial structure in sperm. The SNP is associated with decreased CHDH protein in sperm upto 73% lower ATP (energy) concentrations (in sperm). In a study carried out by Johnson et al. (2012), carriers of this SNP were supplemented with betaine-water and the result was an improvement in the motility of their sperm, implying a potential improvement in fertility.

Finally, the BHMT gene, which uses a methyl group from betaine to for convert ('methylate') homocysteine to form methionine. It is known as a ‘short route' rather than the methylfolate and B12-dependent 'long route'. The BHMT pathway is zinc-dependent and requires adequate levels of betaine (also known as TMG – trimethylglycine) to function properly. BHMT SNPs are also associated with reduced function and risk of neural tube defects. BHMT can be supported by increasing intake of co-factors including foods containing zinc – such as beef, lamb, chicken, chickpeas, pumpkin seeds, cashews, betaine – from quinoa, spinach and beetroot, and choline (substrate of betaine) – found in eggs.

Lifecode Gx® Reports

Our Methylation Report provides a comprehensive analysis of methylation related genetics. It examines over 40 genes involved in five sub-cycles:

folate cycle
methionine cycle
neurotransmitter cycle
transsulphuration cycle
urea cycle

A Lifecode Gx® Methylation DNA test can help explain how your genes can impact fertility and pregnancy, but most importantly enable you and your partner to take a personalised approach to optimise your health.