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April 12, 2021

Is male infertility genetic?

The journey to parenthood isn't always as clear-cut as it's made out to be. Approximately 9% of men in the U.S. have reported seeking advice, testing, or treatment for infertility. While many cases of male-factor infertility can be treated with simple lifestyle interventions, in some cases, the cause is deeper—your genes. Read on to learn about the types of genetic male infertility.

How common is genetic male infertility? 

Studies show that 10–15% of male infertility cases are caused by genetics. So while age, diet, lifestyle, and hormones may be more common causes of infertility, genetics is sometimes a factor or even the sole cause of trouble conceiving.

There is some evidence that men who are infertile are more likely to have sons who are infertile, as well. One study found that the male children of men who used intracytoplasmic sperm injection (ICSI) to conceive were significantly more likely to experience poor semen quality parameters—including lower sperm concentration, sperm count, and motility—compared to male children who were naturally conceived.

There wasn't conclusive evidence to pinpoint exactly what caused the low quality semen parameters. They did find that the difference wasn’t cut across lines of BMI, smoking, alcohol consumption, or drug use, so lifestyle factors that may be carried from father to son weren’t relevant to this study. The most likely reason for this correlation is underlying genetics, and not necessarily the ICSI procedure itself. Since ICSI is a treatment that helps overcome fertility issues, such as oligospermia (when a man produces low sperm count), it's possible that those same fertility issues may be genetically passed down to male offspring.

This evidence is backed up by a larger study from 2007 of male children conceived through any type of fertility treatment. Nearly 2,000 young men submitted semen analyses for study, and it was found that offspring conceived through fertility treatment had, on average, lower sperm concentration and fewer motile and morphologically normal sperm. Researchers again concluded that the findings did not “necessarily indicate that female infertility treatment induces a risk of reproductive problems for the next generation,” but “could, in fact, be due to genetic factors inherited through the mother or even the father.”

Genetic causes for male infertility

While genetic factors for lower semen parameters are still research-in-progress, in some rare cases, we can identify a clear genetic cause for infertility.

Y-chromosome microdeletions

Everyone is born with a pair of sex chromosomes; females have two x-chromosomes and males have one x-chromosome and one y-chromosome. The Y-chromosome has anywhere between 50 and 60 genes, and since it's the male-determining chromosome, many of those genes are specific to the male sex. For instance, there's the SRY gene which causes testes to form in the embryo and results in the development of male genitalia. There are other genes, such as DAZ, RBMY, BDY, and more, that relate to male fertility.

As the name "Y-chromosome microdeletion" suggests, this is a chromosomal abnormality that involves small deletions of genes on the Y-chromosome within a man’s sperm. Since the Y-chromosome is passed from father to son, this microdeletion, and potential fertility issue, is passed on genetically. Microdeletions of pertinent fertility genes are one possible cause of azoospermia, a condition where sperm is absent in semen. 

In a study that observed 200 infertile men and 200 fertile men, it was found that Y-chromosome microdeletions were present in 7% of infertile men and 2% of fertile men. Of the infertile men with Y-chromosome microdeletions, 9 had azoospermia or severe oligospermia, 4 had oligospermia, and 1 had normal sperm count. 

This study also found that the size and location of the deletions did not correlate with the severity of sperm production failure. And another study that observed 38 infertile men with microdeletions found that 21% of those men had another possible cause of male infertility. This data suggests that while the occurrence of Y-chromosome microdeletions tends to be more significant in infertile men, it may not be the only factor at play, and it doesn't rule out the possibility of conception.

Sperm DNA fragmentation-why the genetic health of sperm is important

Cystic fibrosis

Cystic fibrosis (CF) is what’s known as a “single gene disorder,” a condition that’s caused by one specific gene. In the case of CF, a mutation in the CTFR gene changes the expression of a protein that regulates the movement of salt in and out of cells, causing the lungs to fill up with mucus, trouble breathing, and digestive issues. CF typically also causes congenital absence of the vas deferens, the tube that connects the epididymis (where sperm is stored) to the ejaculatory ducts. This means that men with CF may produce healthy, strong sperm, but lack the connection that carries that sperm to the semen.

Nearly 98% of men with cystic fibrosis (CF) are infertile, but can still have biological children with the help of assisted reproductive technology. In fact, 90% of men with CF have normal, healthy sperm production. Procedures like testicular sperm extraction (TESE), paired with IVF, can make fathering biological children possible for patients with CF.

Interestingly, recent studies have revealed that it’s not only those with full-blown cystic fibrosis that can experience the effects on their fertility. Cystic fibrosis carriers, those who have inherited the CF gene from one parent, are also at a significantly higher risk for male infertility.

Many CF patients, carriers, and those with CF in their family will choose to utilize embryo genetic screening, known as preimplantation genetic diagnosis, to ensure their embryos are healthy before using them for pregnancy. This is another benefit of using IVF for carriers of the cystic fibrosis gene.

Klinefelter syndrome

Klinefelter syndrome (KFS) is one of the most common chromosomal abnormalities, and is also known as one of the most common causes of azoospermia. In fact, KFS is found in 11% of cases of azoospermia. In KFS, instead of having the typical XY chromosome pair, a male is born with an extra X chromosome (KFS is sometimes referred to as XXY syndrome). Since this condition doesn’t affect day-to-day life, it's not uncommon for a male to go undiagnosed for most of his life.

However, nearly 50% of men with KFS experience low testosterone levels, and approximately 95–99% of men with KFS experience infertility due to low sperm count. However, this doesn't necessarily mean that sperm production is absent altogether, as sperm is found in more than 50% of men diagnosed with KFS.

There are a variety of treatment options available for men with KFS. Ad

vancements in reproductive technology, like TESE and ISCI, have shown a promising 50% pregnancy and live birth rate for men with KFS. Studies have also found benefits to sperm freezing for men with KFS and recommend this as an option to young males diagnosed with KFS.

Learn more about sperm freezing.

46 XX syndrome

46 XX is a rare condition in which a person is born with the XX chromosome typically found in females, but is also born with external male genitalia. This condition occurs in 1 out of every 20,000–25,000 newborns assigned male at birth, and is an intersex condition.

While the physical manifestation of this condition varies, people with 46 XX will typically experience underdeveloped genitalia and azoospermia. Chances of biological parenthood with this condition are incredibly slim. Since 46 XX is such a rare condition, patients with 46 XX currently make up less than 1% of male infertility cases.

Primary ciliary dyskinesia/Kartagener’s syndrome

Primary Ciliary Dyskinesia (PCD), also sometimes referred to as Kartagener's syndrome, is a rare inherited disease that impacts the cilia (tiny, hair-like structures) that lines internal airways. As a result, the most common symptoms are chronic respiratory infections, abnormally positioned internal organs, and even infertility.

The epididymis, a series of tubes where sperm is stored, is lined with cilia-like structures that help sperm cells move. Since PCD affects cilia and cilia-like structures, sperm cells may not be able to effectively travel. In addition, motile cilia and sperm flagella (tails) share common structures, so many men with PCD experience severe or total aesthenozoospermia (sperm with reduced or no motility).

Approximately 75% of men with Kartagener’s syndrome experience infertility. Unfortunately, reproductive technologies like ICSI and have not shown much promise for males with PCD. Studies suggest that procedures like TESE-ICSI can improve fertilization rates, but have not been shown to improve pregnancy outcome.

Kallmann syndrome

Kallmann syndrome is a rare condition affecting 1 out of every 30,000 males, and causes delayed or absent puberty. Kallman syndrome causes a lack of hormones that direct sexual development, which is why it is most commonly diagnosed during adolescence. Although other symptoms like impaired sense of smell are prevalent in those with Kallmann syndrome, it is delayed puberty that usually alerts a doctor's attention, provoking testing and diagnosis.

Most males with this condition experience absent sperm production and infertility. In some cases, sperm production can be induced by long-term administration of GnRH, which is a hormone that causes the pituitary gland in the brain to make and secrete male fertility hormones like luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to stimulate testosterone and sperm production.

When testing for male fertility, genetic testing is typically performed after frontline tests like semen analysis and sperm DNA fragmentation analysis. If you've gone through rounds of fertility testing or have a unique family medical history, genetic testing may be your next step.

Genetic male infertility versus sperm DNA fragmentation

Sperm DNA fragmentation may sound like it’s related to genetics, but inherited infertility and sperm DNA fragmentation are two very different things.

Genetic infertility is inherent at birth (or “congenital”), such as in the above cases, where an aspect of your chromosomal genetic makeup experienced a mutation. Sperm DNA fragmentation, on the other hand, is damage specifically to the DNA inside the sperm cells, usually brought on by age, smoking, illness, infection, or environmental toxin exposure. This damage can occur at multiple points in the sperm's lifecycle, from production in the testes to when it's in “storage” in the epididymis or even post-ejaculation.

While genetic testing will typically require on-site clinic visits, there is an at-home sperm DNA fragmentation analysis kit that makes fertility testing easier.

What are other causes of male infertility?

While male fertility can be impacted by genetics, there are other, much more common factors that influence fertility. These include:

  • Age. Although men can continue producing sperm throughout their entire lifetime, that doesn't mean that the quality of sperm remains constant. Sperm quality parameters naturally decline with age, and most men see a significant decline in sperm motility after the age of 40. Studies also show that DNA fragmentation becomes more common as a man ages.
  • Diet and exercise. Research shows that there's an association between poor male fertility and obesity. Diets high in fried foods, refined grains, added sugars, and processed meats correlate with poor sperm quality factors, like reduced sperm count, motility, and morphology. And finally, exercise regimens such as walking and jogging have been shown to improve fertility markers. Learn more about sperm improvement.

  • Alcohol and tobacco consumption. Smoking cigarettes and excessive alcohol consumption can affect all aspects of male fertility, from sperm concentration to count, motility, and morphology. Reducing your alcohol intake to less than five drinks per week and quitting smoking are both great ways to improve your fertility.

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