Some of the causes of infertility for women can be categorized as follows:
- hormonal issues: thyroid problems, PCOS, HPA axis dysregulation, reproductive hormone dysregulation
- structural issues: fibroids, blocked fallopian tubes, other structural abnormalities
- ovarian insufficiency or premature menopause
- recurrent miscarriages
- and more
This article highlights some of the common genetic variants that may play a role in infertility. It is just a starting point… My hope is that it gives you enough information to get started on figuring out the root cause of your problems conceiving.
Everything here is for informational purposes only, based on research studies on genetics and fertility. Please talk with your doctor for medical advice or seek help from a fertility coach or expert.
A crash course in reproduction:
A lot of people think of pregnancy in basic terms: sperm meets egg and 9 months later you have a baby. Birds do it, bees do it. Heck, even trees do it, in their own way.
But when you get down to the specific details, it gets a lot more complicated.
At puberty, women have around 300,000 to 400,000 follicles in their ovaries. These primordial follicles are tiny fluid-filled sacs that contain the oocyte (immature egg cell). Over the course of a woman’s reproductive years, only 400 – 500 eggs will reach maturity.
Hormones stimulate the development of some of the follicles each month. Usually only one will reach maturity each month, at which point ovulation occurs. (The other follicles are broken down and reabsorbed.)
That egg cell that gets released at ovulation is what can get fertilized by the sperm, resulting in pregnancy if all goes well. The egg needs to be healthy with no DNA damage.
For all of this to happen, the reproductive hormones need to be at the right levels and at the right time. Follicle stimulating hormone (FSH) rises at the right time to stimulate the immature follicles to begin to mature. Without FSH, the immature follicles will go through apoptosis (cell death).
When the follicle reaches a certain size, it will start secreting estrogen. This causes a surge in gonadotrophin-releasing hormone (GnRH).
The surge in GnRH causes a surge in luteinizing hormone (LH) secretion, which triggers ovulation.
As women age, they have fewer follicles in their ovaries eventually reaching the end of reproductive span at menopause. A hormone called AMH (anti-mullerian hormone) is often used as a marker of ‘ovarian reserve’, an estimate of available eggs.
But the ovaries aren’t like a gumball machine, spitting out good gumballs (eggs) up until the last one comes out. Oxidative damage, insults to the cells, etc. cause egg quality to decline as we age.
Conditions that can decrease fertility rates include PCOS (polycystic ovarian syndrome), hypothyroidism, diabetes, and autoimmune diseases.
The risk of recurrent miscarriages also increases with age. Blood clots can increase the risk of recurrent miscarriages, and several genetic variants cause increased clotting.
Genetic variants and pathways that impact fertility:
How does the MTHFR variant impact fertility for women?
The MTHFR gene codes for a key enzyme in the methylation cycle. It is the final step for converting folate into the form the body uses, methylfolate. While most women know that folate is important to a growing baby, the MTHFR gene can also impact other aspects of fertility.
Research shows that the MTHFR C677T and A1298C variants impact fertility in a couple of specific ways.
Carriers of two copies of the C677T variant have altered reproductive hormone levels (FSH and AMH) that impact egg number and quality. This can also alter the hormone amount needed during IVF. [ref][ref][ref]
Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):
- G/G: normal (wildtype)
- A/G: one copy of MTHFR C677T allele (heterozygous), MTHFR enzyme efficiency reduced by 40%
- A/A: two copies of MTHFR C677T (homozygous), MTHFR efficiency reduced by 70 – 80%
Check your genetic data for rs1801131 (23andMe v4, v5; AncestryDNA):
- T/T: normal (wildtype)
- G/T: one copy of A1298C allele (heterozygous), MTHFR enzyme efficiency slightly reduced
- G/G: two copies of A1298C (homozygous), MTHFR efficiency reduced
Blood clot disorders and miscarriage risk:
There are several genetic variants that increase the risk of blood clots and conditions such as deep vein thrombosis. These genetic variants also increase the risk of recurrent miscarriages due to clotting. This does NOT mean that everyone who carries these variants will have a miscarriage. It is something to talk with your doctor or fertility specialist about.
Note that the 23andMe and AncestryDNA raw data is marketed for informational purposes, not clinical testing. So if your raw data shows that you carry one of the risk factors below, you should talk with your doctor and consider possibly getting a second test done for verification before making medical decisions.
Factor V Leiden (read more here):
Check your genetic data for rs6025 (23andMe v4, v5; AncestryDNA):
Prothrombin G20210A variant (read more here):
Check your 23andMe data for i3002432 (rs1799963, G20210A):
PCOS and fertility:
PCOS is thought to be partially genetic, with about 70% of the disease risk due to genetic factors.
There are quite a few genes that contribute to the risk of PCOS. Instead of listing them all here, please read my article on PCOS.
Optimizing for fertility:
Your overall health impacts your ability to reproduce. This makes sense for all animals and especially for humans.
There are quite a few genetic variants that affect very basic aspects of health that also affect fertility. You need healthy egg cells in order to get pregnant. This list is a bit of a hodge-podge of some of those variants that affect the quality of the oocyte.[ref]
The ‘sleep hormone’ does a lot in the body. Within cells, it acts as a natural antioxidant, reducing reactive oxygen species. Melatonin receptors are found in high levels in the ovaries and in the follicle cells. Melatonin turns out to be fairly important in egg quality for IVF. [ref][ref][ref][ref] Melatonin also may play a role in keeping the mother’s body from rejecting the fetus.[ref]
How can you increase melatonin? Two free things you can do that will greatly impact melatonin levels: Block blue light at night, get out in the sunshine during the day.
Below is one common melatonin receptor variant that increases the risk for PCOS. Read more about other melatonin genetic variants here.
Check your genetic data for rs10830963 ( 23andMe v.4, v.5; AncestryDNA):
Active forms of vitamin A in the body are essential for both male and female reproduction.[ref]
Vitamin A can be obtained in the diet in retinol forms from animals sources or in beta-carotene in plants. The beta-carotene form has to be converted by the body into the retinol form — which is where genetics comes into play.
Note that while essential in the right amount, too much vitamin A, through drugs like Accutane (isotretinoin, acne medicine) or through really high levels of vitamin A supplements, can cause birth defects.
The BCMO1 enzyme converts beta-carotene into the retinal form the body uses. There are two gene variations in the BCMO1 gene that help determine a person’s ability to convert beta-carotene into the retinol a body uses. [ref]
People with a T allele on both rs12934922 and rs7501331 have a 69% decreased conversion of beta-carotene to retinol.
Check your genetic data for rs7501331 (23andMe v.4 and v.5, AncestryDNA):
- C/C: normal
- C/T: decreased beta-carotene conversion by 32%
- T/T: decreased beta-carotene conversion by 32% or more
Check your genetic data for rs12934922 (23andMe v.4 and v.5):
- A/A: normal
- A/T: decreased beta-carotene conversion
- T/T: decreased beta-carotene conversion
BPA and phthalates are two well known endocrine disruptors that are extremely prevalent in our environment today. BPA is well known as a component of plastics, but it is also found in food can linings, processed foods, thermal receipt paper, and more. Phthalates are found in fragrances (laundry detergent, air fresheners), lotions, plastics, pharmaceuticals, nail polish, and more. [ref] [ref]
Both BPA and phthalates have been clearly shown in animal studies to disrupt reproduction in multiple ways. They also may be affecting the reproduction of offspring.[ref]
In women undergoing IVF, increasing concentrations of BPA in their blood correlates linearly with decreasing number of oocytes and pregnancy.[ref] And yes, nearly everyone has BPA and phthalate metabolites in their body.
Some people can detoxify and clear out the BPA and phthalates better than other people.
Read more about the genetic variants associated with BPA detoxification.
Read more about the genetic variants associated with phthalate detoxification.
I’ve thrown a lot of information into this article, but it is just a portion of what goes into the mix for fertility.
If you are dealing with infertility, genetic variants are probably playing a role — whether through PCOS, altering your vitamin or hormone levels, or through increasing the risk for problems from toxins. But this is just a part of the picture… stress, sleep, and diet are all important also.
Obviously, the first place to go for help when trying to conceive is your OB/GYN for testing. Your OB can do ultrasounds and other tests to rule out a physical cause. Hormone testing is also available to make sure everything is normal there.
There are also fertility experts that offer online coaching and help as you go through this process. Julie Chang at Fertility Eggspurt is one that I can recommend if you are looking for information online. Or ask around for recommendations in your local area. Talking with people, getting lots of good information, and getting some emotional support are all helpful when dealing with problems trying to conceive.
MTHFR for fertility:
There is a lot of information available about MTHFR and taking methylfolate instead of folic acid. Here is my take on folic acid along with the research on it.
It is vital for women who carry the MTHFR variants to ensure that they meet their body’s needs for the methylation cycle. This can include adding more folate to the diet (liver, green leafy veggies, legumes) or taking a methylfolate supplement.
In general, a balanced diet that includes eggs (choline), organ meats (creatine, choline, folate), organic vegetables (folate), and bone broth (glycine) may cover your dietary needs for methylation cycle optimization. If you are on a diet that cuts out any major food groups, you should track your diet for a week or two to make sure you are not missing out on anything.
I’m going to mention sleep one more time as being important since I think it is undervalued in health and fertility. Melatonin is important, but that is only one aspect. There are a lot of recent studies that point to circadian rhythm and sleep as being very important in reproduction (both animal studies and human studies). A 2018 study found that sleep disorders (non-sleep apnea related) increased the risk of infertility by 3 to 5 fold.[ref] [ref][ref][ref]
There have been quite a few studies on the effects of eating more fruits and vegetables on IVF outcomes.
Some studies show that increasing amounts of fruit and veggies don’t make much difference. What does make a difference for oocyte quality and IVF outcome is avoiding pesticide residue. This could mean eating organic fruits and vegetables (or just avoiding conventional produce).[ref] I was surprised that more fruits and vegetables didn’t make a difference in fertility, but this may be due to women taking prenatal vitamins have the micronutrients covered fairly well. [ref][ref]
Other studies, though, in women trying to conceive, do show that increasing fruit consumption decreases the time to conception — and that higher fast food consumption increases the time to conception. But the effect size is fairly small here. The changes were on the scale of 0.3 to 0.9 months difference — so less than a month difference in time to conception.