Unexplained infertility

Female DNA: the culprit behind some cases of male infertility?

Unexplained infertility is a frustrating diagnosis to receive.

After all the stress and upset of all the appointments and tests, couples should at least be able to expect to be given a concrete reason for why it is they’re having trouble conceiving.

But sadly, this isn’t the case. For 20-30% of couples struggling to get pregnant, their problems seem to stem from this mysterious culprit; ‘unexplained infertility’.

When we look at reproduction in a broad sense, the complexity of the whole process becomes clear. Intricate processes need to be working in perfect timing to allow for the production of healthy sperm and eggs and to allow for any chance of an embryo developing into a full term pregnancy.

So – despite the sophistication and sensitivity of modern fertility tests – it’s not really surprising that scientists are missing some of the minor indicators that tell us why a man or woman’s fertility has been thrown out of kilter.

Could DNA teach us more about unexplained infertility?

More and more, scientists are turning to DNA for answers as to what might be behind unexplained cases of infertility. Errors in DNA – known as mutations – might have catastrophic effects on fertility.

Nearly half of all cases of male infertility that are not caused by a physical obstruction in the testes are estimated to be genetic – which means they are linked to mutations in a man’s DNA.

But, strangely, a study published this month in the New England Journal of Medicine seems to have found a link between female DNA and male infertility.

The study found that some cases of male infertility can be linked back to mutations in DNA which is found in women. DNA which they will ultimately pass on to their sons.

The type of male infertility these mutations have been linked to is known as azoospermia – where a man has no sperm in the fluid he ejaculates. The condition affects about 20% of infertile men.

Whilst 20% of men with azoospermia have a detectable genetic mutation, for the other 80% of men, the cause of their azoospermia is idiopathic – i.e. unknown. Idiopathic azoospermia is therefore a type of unexplained infertility.  

DNA mapping
Photo credit: snre / Foter / CC BY

To try and delve a bit deeper into what might be behind idiopathic azoospermia, the University of Pittsburgh researchers looked closely at the DNA of 15 men with the condition.

In two patients, they found that some DNA had been deleted in an area of genetic material which forms a gene. The gene is known as the ‘testis-expressed gene 11’ (TEX11). It’s found on the X chromosome – a molecule that stores DNA and which men inherit from their mothers.

The missing DNA causes a problem known as ‘meiotic arrest’ – which means the cell division process that leads to the production of sperm cannot happen as it normally would.

The researchers then looked at the DNA of more men who had been diagnosed with idiopathic azoospermia. Similar mutations in the TEX11 gene (which caused meiotic arrest) were found in a further seven out of 289 (2.4%) infertile men who were studied in Germany and Poland.

In order to check that these TEX11 mutations were definitely linked with azoospermia, the researchers looked at the DNA of 384 men with healthy sperm concentrations. As expected, they couldn’t find any evidence of TEX11 mutations in these men.

What do these findings mean for male fertility?

The researchers speculate that – as older men are more prone to getting mutations in their sperm DNA – older fathers may be more likely to pass along TEX11 mutations to their daughters.

Also, some men with azoospermia might undergo a procedure to have a few, rare sperm removed from their testes so that they can attempt to conceive with their partner using an assisted reproduction treatment such as in vitro fertilisation (IVF). These men might also be passing along azoospermia TEX11 mutations to their daughters.

In both these cases, the men’s daughters could become ‘carriers’ of the TEX11 mutations. This would mean that any sons they might have would be unable to produce sperm.

This study is one of the first to describe such a specific X chromosome mutation that contributes to azoospermia and male infertility.

However, other studies have also identified chromosome errors that cause fertility problems; for example, deletions of DNA on the male Y chromosome and duplication of the whole X chromosome in Klinefelter syndrome.

Genetic research could be the key to understanding unexplained infertility

Even though the number of patients in the study with these TEX11 mutations seems quite low, the research brings new hope for men diagnosed with idiopathic azoospermia and unexplained infertility.

There are so many possible DNA mutations that could contribute to male infertility. But even knowing about a small selection of them might mean that some men can get answers about the cause of their idiopathic azoospermia and unexplained infertility.

What’s more, as we learn more about the specific mutations leading to male infertility, it will become easier to begin correcting these problems in the lab with special DNA altering techniques.

Although much more needs to be done to find further genetic causes of male infertility, this study is a step in the right direction when it comes to getting the answers behind the unsatisfying diagnosis that nobody wants.

Photo credit: Foter / CC BY-SA
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