Genetic Causes of Male Infertility

Struggling to get pregnant as a couple? You’re not alone. The World Health Organization now estimates that almost 10% of couples worldwide are dealing with fertility issues. And the problem of infertility seems to be equally split between males and females.[ref]

Many different genetic variants can increase the risk of infertility in men. These variants impact different aspects of sperm production – from hormones to oxidative stress to DNA damage repair. My goal here is to help you understand where you are more likely to have genetic susceptibility to infertility. This can help you target the right lifestyle interventions and supplements.

Male Infertility: Getting to the root cause

Infertility is formally defined as an inability to become pregnant after 12-months of unprotected sex. There are a number of factors influencing infertility: genetic mutations, environmental exposure, physical abnormalities, and the combination of environmental factors with genetic susceptibility from common variants.

For most couples facing infertility, the first thing to do is go to a fertility specialist. The doctor can help rule out physical abnormalities or major hormone alterations.

But what happens when infertility is labeled ‘idiopathic’, which is medical-speak for ‘unknown origin’? That is when you need to dig deeper into lifestyle and genetic susceptibility.

How is sperm produced?

Men produce sperm constantly through a process called spermatogenesis. On average, hundreds of millions of precursor sperm cells are generated daily in the seminiferous tubules. From there, they go through a series of events, resulting in mature spermatozoa that are stored in the epididymis.

The whole process takes around three months. This time scale of three months is important when you are experimenting with lifestyle changes to make a difference for infertility. Patience, along with targeted interventions, are key.[ref]

Defining normal sperm concentrations:

When you start reading the research on male infertility causes, you’ll come across several technical terms for defining alterations in sperm concentration and motility.

According to the WHO:[ref]

  • oligozoospermia = decreased sperm concentration (defined as < 15 ×106 sperm/ml)
  • asthenozoospermia = decreased sperm motility (progressive motility <32% or total sperm mobility under 40%)
  • teratospermia = majorly decreased sperm motility (sperm motility of <4%)
  • oligoasthenoteratozoospermia = combination of all of the above

Essentially, this boils down to not having enough healthy sperm or not having enough sperm motility. Or both.

Oxidative Stress: Lifestyle, diet, inflammation

Research shows that one of the most significant sources of male infertility is oxidative stress, accounting for about half (somewhere between 30-80%)

Oxidative stress is defined as cells producing more reactive oxygen species (ROS) than they can balance out with antioxidants.[ref]

Sperm are particularly vulnerable to oxidative stress due to the cell membranes being rich in unsaturated fatty acids, which are more prone to oxidation when ROS is out of balance.[ref]

Excess ROS can also damage DNA in sperm, which is more of a problem than in normal cells due to a lack of enzymes to combat oxidative stress.[ref]

One research study states:

“The oxidative stress, which refers to an imbalance in levels of reactive oxygen species (ROS) and antioxidants, is one of the main causes of infertility in men.”[ref]

For motility, sperm need a lot of energy and thus have a lot of mitochondria in the flagellum. Excess oxidative stress impairs the mitochondria, leading to decreased motility.[ref]

Sources of oxidative stress:

Poor diet: A diet of fast food, junk food, and beer is a recipe for male infertility. Not only is your body fighting against the additives and oxidized fats in junk food, but the antioxidants from vegetables or organ meats are needed for fighting oxidative stress.

Cigarette smoking: Smoking is associated with reduced sperm count and decreased sperm quality.[ref] Cannabis use is also linked to reduced sperm count and an increase in abnormal sperm.[ref]

Excessive alcohol consumption: Alcohol consumption is also linked to decreased sperm function in men with infertility.[ref]

Stress/ HPA axis alterations: High levels of ROS not only leads to oxidative stress but also causes a disruption in male sex hormones via the HPA axis. Additionally, stress causes HPA axis alterations and increases inflammatory cytokines. Thus, stress can cause infertility in two ways: social/psychological stress or physical stress caused by ROS.[ref][ref]

Heat stress: Excessive heat in the testes increases oxidative stress and disrupts mitochondrial energy production. It can also decrease testosterone and luteinizing hormone levels. Heat stress also impacts the HPA axis and hormone levels.[ref]

Environmental toxicants: Exposure to mercury, cadmium, BPA, and dioxin are all linked to infertility. Endocrine-disrupting chemicals may also be a problem for some men.[ref]

 

Source: CC image, PMC6134507 – Good overview of ROS and infertility

 

Hormone alterations:

Men with infertility, on average, have higher estradiol levels. Estradiol is a type of estrogen. Essentially, higher estrogen levels lead to a decrease in spermatogenesis.[ref] Higher estrogen could be due to obesity, conversion of testosterone to estrogen, or estrogen-mimicking chemicals.

Rare mutations in the androgen receptor gene can also cause infertility.[ref]

Other Lifestyle / Environmental Causes:

Obesity “For instance, obesity is associated with male infertility, likely because of hormonal changes secondary to excess adipose tissue. In a retrospective multi-institutional cohort study, Bieniek et al. demonstrated an inverse relationship between body mass index (BMI) and testosterone, testosterone-to-estradiol ratio, ejaculate volume, sperm concentration, and morphology . The authors also reported higher rates of azoospermia and oligospermia among obese men (12.7% and 31.7%, respectively) compared with men of normal weight (9.8% and 24.5%) .”[ref]

Medications: Certain drugs, such as anabolic steroids, SSRIs, methotrexate, cannabis, and sulfasalazine, are linked to a higher risk of infertility.[ref][ref][ref] If you are on prescription medication, talk with your doctor about infertility as a side effect.

Varicoceles, the abnormally dilated and twisted veins in the pampiniform plexus, are a common cause of male infertility. Varicoceles are present in ~15 to 20% of men and 35 to 40% of infertile men, thus doubling the risk of infertility.[ref]

Hyperglycemia: High blood glucose levels reduce sperm. It is partly because of increased oxidative stress, but other changes to sperm function also are seen in men with diabetes.[ref]


Genetic Variants Linked to Male Infertility:

Understanding relative risk. Keep in mind that research studies usually report the increase in risk as relative risk.  For example, if the current odds of male infertility are 1 in 20, then a 40% increase in relative risk would increase the odds to about 1 in 12.

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CFTR mutations:

Mutations in the gene that cause cystic fibrosis (CFTR gene) also cause a mutation in how the vas deferens form and affect the formation of sperm. It is estimated that 97% of men with cystic fibrosis (two copies of CFTR mutation) are infertile.[ref][ref]

Check your genetic data for rs113993960 Delta F508 (i3000001 23andMe v4, v5; AncestryDNA):

  • D/D: cystic fibrosis (you would already know this)
  • D/I: carrier of one copy of a cystic fibrosis mutation; increased risk of male infertility
  • I/I: typical

Members: Your genotype for rs113993960 is or i3000001 is .

Related article: Cystic Fibrosis mutations

DNA damage-related variants:

DNA damage in the sperm is a cause of male infertility. During spermatogenesis, there are genes responsible for repairing any DNA damage. Variants in the DNA damage-response genes can increase the risk of male infertility.

PRM1 gene: encodes a protamine, which is important to the way that the sperm DNA gets packaged up

Check your genetic data for rs2301365 (23andMe v4):

  • G/G: typical
  • G/T: increased relative risk of male infertility (~50%)
  • T/T: increased relative risk of male infertility (~70%)[ref][ref]

Members: Your genotype for rs2301365 is .

LIG4 gene: DNA damage repair genes

Check your genetic data for rs1805388 (23andMe v4, v5; AncestryDNA):

  • A/A: increased relative risk of male infertility[ref]
  • A/G: increased relative risk of male infertility
  • G/G: typical

Members: Your genotype for rs1805388 is .

 

Chronic Inflammation (ROS) Related Variants

Excessive oxidative stress is strongly linked to idiopathic male infertility. Oxidative stress, caused by excess ROS, can be due to environmental reasons (junk food, toxicants, heavy metals) and/or a genetic propensity towards higher levels of oxidative stress.

The following variants are linked with the cellular response to oxidative stress and an increased risk of male infertility.

TGFB3 gene: transforming growth factor beta 3

Check your genetic data for rs2284792 (23andMe v4):

  • A/A: typical
  • A/G: increased relative risk of infertility
  • G/G: ~40% increased relative risk of infertility[ref]

Members: Your genotype for rs2284792 is .

GSTM1 gene: The GSTM1 (glutathione S-transferase mu 1) enzyme helps the body by detoxifying several types of carcinogens, drugs, toxins, and oxidative stress byproducts.

Check your genetic data for rs366631 (23andMe v4 only):

  • A/A: deletion (null) GSTM1 gene; increased relative risk of infertility[ref][ref]
  • A/G: GSTM1 present
  • G/G: GSTM1 present

Members: Your genotype for rs366631 is .

HSPA1L gene encodes part of the HSP70 protein, a heat-shock protein that is important in how the body reacts to certain stresses, including heat stress or cold stress.

Check your genetic data for rs2227956  T2437C (23andMe v4, v5; AncestryDNA):

  • A/A: typical genotype
  • A/G: somewhat decreased HSP70, 2-fold increased risk of male infertility
  • G/G: 2 to 3-fold increased risk of male infertility[ref]; decreased HSP70[ref]

Members: Your genotype for rs2227956 is .

NOS3 gene: encodes nitric oxide synthase, which can increase oxidative stress with upregulated

Check your genetic data for rs2070744 (23andMe v5):

  • C/C: increased risk of coronary artery disease (Asian, Caucasian)[ref] increased risk of osteoporosis[ref] decreased risk of hemorrhagic stroke, atrial fibrillation[ref][ref] increased risk of male infertility[ref]
  • C/T: increased risk of hypertension
  • T/T: typical

Members: Your genotype for rs2070744 is .

 

Methylation cycle related variants:

Methyl groups formed in the methylation cycle are key in spermatogenesis. Additionally, the methylation cycle variants are important in detoxifying some toxicants, which can increase oxidative stress.

MTHFR gene: encodes an essential enzyme in the folate cycle.

Check your genetic data for rs1801133 C677T (23andMe v4, v5; AncestryDNA):

  • G/G: typical *
  • A/G: enzyme function decreased by 40%; ~40% increased risk of male infertility.
  • A/A: enzyme function decreased by 70 – 80%; ~60% increased risk of male infertility[ref]

Members: Your genotype for rs1801133 is .

Check your genetic data for rs1801131 A1298C (23andMe v4, v5; AncestryDNA):

  • T/T: typical *
  • G/T: slightly decreased enzyme function; ~28% increased relative risk of male infertility
  • G/G: decreased enzyme by about 20%; ~28% increased relative risk of male infertility[ref][ref]

Members: Your genotype for rs1801131 is .

MTRR Gene:

Check your genetic data for rs1801394 A2756G (23andMe v4, v5; AncestryDNA):

  • A/A: typical
  • A/G: somewhat decreased enzyme efficiency, ~18% increased risk of male infertility
  • G/G: decreased enzyme efficiency, ~2-fold increased relative risk of male infertility[ref]

Members: Your genotype for rs1801394 is .

 

Hormone-related variants:

FSHR gene: Follicle-stimulating hormone receptor

Check your genetic data for rs6165 (23andMe v4; AncestryDNA):

  • C/C: less likely to have male infertility
  • C/T: typical risk of male infertility
  • T/T: greater risk of male infertility (common genotype, depending on population group)[ref]

Members: Your genotype for rs6165 is .

Check your genetic data for rs6166 Ser680Asn (23andMe v4, 5; AncestryDNA):

  • C/C: less likely to have male infertility
  • C/T: typical risk of male infertility
  • T/T: greater risk of male infertility (most common genotype)[ref]

Members: Your genotype for rs6166 is .

Immune system related variants

HLA variants: HLA-DRA gene

Check your genetic data for rs3129878 (23andMe v4, v5; AncestryDNA)

  • C/C: increased relative risk of infertility[ref][ref]
  • A/C: increased relative risk of infertility
  • A/A: typical

Members: Your genotype for rs3129878 is .

 

HFE Gene Mutations: excess iron

If you carry either of these variants, please also read through the article on Iron Overload. Not all research agrees that HFE mutations are a cause of idiopathic infertility. The age of study participants is likely important here. More iron builds up with age, causing increased ROS.

Check your genetic data for rs1800562 C282Y (23andMe v4, v5; AncestryDNA):

  • A/A: two copies of C282Y variant, most common cause of hereditary hemochromatosis, highest ferritin levels; linked to infertility due to iron toxicity in the pituitary gland and higher risk of damaged sperm DNA[ref]
  • A/G: one copy of C282Y, increased ferritin levels, hemochromatosis possible but less likely[ref]; linked to infertility due to iron toxicity in the pituitary gland and higher risk of damaged sperm DNA
  • G/G: typical

Members: Your genotype for rs1800562 is .

Check your genetic data for rs1799945  H63D (23andMe v4, v5; AncestryDNA):

  • G/G: two copies of H63D variant can cause (mild) hemochromatosis; linked to an increased relative risk of sperm motility being low[ref]
  • C/G:  one copy of H63D, linked to lower sperm motility
  • C/C: typical

Members: Your genotype for rs1799945 is .


Lifehacks:

Go to the doctor…it is the obvious first step and can help you rule out physical problems affecting sperm production. At-home sperm analysis kits are also available for men who can’t easily get to a doctor (or just won’t go).[ref] Your doctor can also do hormone testing to make sure everything is balanced. For example, there are now FSH treatments available if FSH is out of balance.[ref]

Let’s dig into the research on what else you can do to increase sperm motility and quality. Keep in mind that it can take several months to see the full effects of some of these changes.

Supplements for oxidative stress:

Antioxidant supplements have been shown to positively affect sperm quality and motility in quite a few different randomized controlled clinical trials.[ref][ref]

Clinical trials show: 

  • N-acetyl cysteine increases sperm count and motility, and it decreases DNA fragmentation and abnormal morphology.[ref] Note that N-acetyl cysteine isn’t available on Amazon, but it is available at other online retailers and health food stores.
  • Vitamin C has several solid studies showing that it can help reduce oxidative stress and increase sperm motility and sperm quality.[ref][ref][ref][ref]
  • L-carnitine and l-acetylcarnitine supplements reduced DNA fragmentation after six months.[ref]
  • Ubiquinol (CoQ10) improved sperm density, sperm motility, and sperm quality.[ref]
  • Green Tea Extract (EGCG): Green tea polyphenols, such as EGCG, act to combat oxidative stress.[ref]
  • Quercetin, another antioxidant polyphenol, has been shown to help improve sperm motility.[ref]
  • Several trials showed efficacy using mixed antioxidants, including vitamin C, zinc, lycopene, and vitamin E.[ref]

Supplements for methylation cycle variants:

A B-complex that contains methylfolate in addition to vitamin B12 may help if you have MTHFR or MTR variants. Note that methylfolate is not the same as folic acid.

Related article: MTHFR and the methylation cycle

Lifestyle and Diet:

Cut out the junk food and eat more whole foods. It may mean eating out less (or choosing better when eating out).  A recent study showed that cutting out sugar and junk food and replacing it with a healthy diet improved sperm motility in just a few weeks.[ref] A systemic review of studies showed that diets including fish, seafood, poultry, whole grains, vegetables, fruits, and dairy are associated with better sperm quality parameters.[ref]

Keep ’em cool: A study found that 30 minutes in a hot bath reduced sperm parameters. Interestingly, the results showed that intermittent baths (every three days) were worse than a hot bath every day.[ref] Additional sources of heat stress linked to infertility include fever, sauna, sitting or driving for a long time, using a laptop on the lap, and electric blankets.[ref]

Stop smoking: Cigarette smoke is bad for sperm (and your lungs and heart). Cannabis also reduces sperm count and causes abnormalities in sperm morphology.[ref]

Monitor your blood glucose levels: High blood glucose levels impair fertility. An inexpensive blood glucose monitor can help you determine if your fasting blood glucose level is consistently average. Additionally, you could use it to see your body’s response to different meals.

Avoiding environmental estrogen-mimics:  Epidemiological studies show that higher levels of endocrine disruptors are associated with lower sperm quality. Specifically, higher phthalate and BPA exposure are linked with disruption of sperm formation.[ref]

Moderate exercise: Most studies show that moderate exercise is good, but vigorous exercise may actually decrease reproductive hormone levels.[ref]


Member’s Blueprint: Where do I go from here?

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Related Articles and Genes:

Genetics, inflammatory cytokines, and recurrent miscarriage
Learn about how genetic variants in certain inflammatory cytokines can increase or decrease the risk of recurrent miscarriage.

Genetic links to infertility for women
Your genes may be playing a role in your infertility — and knowing which genetic variants you carry may help you figure out solutions to try.

Dads matter: MTHFR variants in fathers affect miscarriage risk
Dads matter – in conception, pregnancy, and throughout life. It is easy to see how prospective moms need to clean up their diets, exercise, and sleep well before getting pregnant, but recent studies show that a dad’s MTHFR variants also affect infertility and miscarriage risk.

Nrf2 Pathway: Increasing the body’s ability to get rid of toxins
The Nrf2 (Nuclear factor erythroid 2–related factor) signaling pathway regulates the expression of antioxidants and phase II detoxification enzymes. This is a fundamental pathway that is important in how well your body functions. Your genetic variants in the NFE2L2 gene impact this NRF2 pathway.

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Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.