Can male infertility be genetic?

Yes, it can. Usually male infertility that’s related to the Y chromosome are the biggest issue that we see with male infertility and it can be passed on from the father to the son.

TESE is essentially a testicular biopsy where you with a scalpel cut directly into the testicles and remove tissue directly from it. Sometimes it’s done with the use of a microscope so they look for what look to be the best tubules in the testicles.

A significant proportion of male fertility could be due to genetic reasons and the most common one is single gene, so basically the difference between males and females is the Y chromosome, so females have 46 XX whereas males have 46 XY chromosomes. So Y chromosome is the main chromosome which controls testicular function and gives you male features, the Y chromosome has thousands of genes within it and if there is some problem and some genetic material is missing we call it Y chromosome microdeletion and there are certain specific reasons that could be missed and we could pick them and it could lead to a severely low count of sperm or the total absence of sperm so we call it severe oligospermia or azoospermia. Micro deletion of some genes or some portions of the Y chromosome is one of the causes, the other one is that the whole X chromosome is extra so rather than 46 XY the male has 47 XY and this is called Kleinfelter syndrome which has very typical features as it is a whole extra chromosome which can affect the testicular function. So the testes become very small in size and their function reduces starting from puberty but it is a variable spectrum as not all aspects of Kleinfelter syndrome are the same. But this is the common genetic cause as well. The other genetic reason could lead to obstructive azoospermia which means that the tube which brings the sperm from the site of production in the testes to the outside through ejaculation, that you are either completely missing or a major part of it is missing and this is related to a disease called cystic fibrosis which is due to a single gene. So there are certain genetic diseases which are called single gene disorders. So one of the common single gene disorders which may lead to male infertility is cystic fibrosis and it is common in Caucasian populations compared to non Caucasian populations.

Apparently it seems that in more cases than not male infertility is linked to the genetic background of the male. Nowadays, in 25% of the azoospermic cases and male infertility cases, a genetic condition is acknowledged and identified. Most frequent conditions may relate to chromosomal abnormalities such as Robertsonian, inversion or on medical conditions such as the Kleinfelter syndrome or a gene mutation such as Y microdeletion or CF mutations. In the remaining male infertility cases, at the moment, we do not have a linked genetic factor. However, our data show that in most of the cases there’s still a genetic factor involved and this is the huge challenge of this era because thanks to the new genetic tools and these bioinformatic platforms we are able for the first time to massively study huge number of genes and for the first time, we have gained access to the whole genome information of males suffering from male infertility and it is quite promising and that we will be able soon to identify the genetic profile of the different male infertility conditions and once we are able to identify the genetic conditions that relate and are involved in main fertility, we will pave the way for new treatment options and new therapeutic regimes that may eventually be able to achieve restoration of the fertility.

Well it’s a very interesting area and certainly there are some causes that have been identified now. Normally, in the clinics. you’ll be tested for three things: you’ll be tested for the number of chromosomes (make sure the chromosomes you’ve got are all kind of intact), it’s called a karyotype test, it also might be tested for the cystic fibrosis gene which can be associated with absent vas deferens (the pipes that carry the sperms in some men) and also the Y chromosome microdeletion is another test that can be used to look for bits that are missing from part of the Y chromosome which contains the sperm making genes but beyond that, there are perhaps many many more genes associated with male fertility to varying degrees of strength which aren’t currently being tested for. In Newcastle, here we are based, we’re leading a big international study looking at new types of mutations using very advanced genetic testing to see if men who’ve got noninvasive azoospermia, have got anything else to explain the situation they’re in because we do think a lot more genetic is the significant ones. The severe ones aren’t lifestyle related, something profound has gone on here and it’s awful that we can’t tell the patients what the problem is because obviously not all patients are going to have come to terms with all this and it’s very important to get as much help as much information as you can about the process to come to terms with it.

Yes, indeed male infertility can be from genetic factors as well.
We know today there are certain genetic conditions, genetic variants of specific genes that can cause infertility such as for example Cystic fibrosis or Klinefelter syndrome. Klinefelter syndrome is where the males instead of having the classic X and Y chromosome they have an extra X chromosome so these patients have the phenotype as we say as XXY in which cases they can be quite tricky and then the specialists they need to discuss options with those patients.
They see other cases where we have for example Cystic fibrosis. Cystic fibrosis we have seen across the population – it can have approximately around 50 different variants when we say variance we mean different mutations on one of the CFTR genes and it can cause different phenotypes on that patients in which cases Cystic fibrosis for example is known to cause in some cases the bilateral absence of the vas deferens in the males in which cases these patients then need to explore the options with one of the specialists again to see what can be done: if they have to use donor sperm if there is not a possibility to retrieve sperm from that patients or if there is another medical intervention so we can in the lab isolate sperm.

Male infertility can have a genetic physiology in around 15 to 30 percent of cases. This may be due to numerical chromosomal errors for example Klinefelter syndrome which is characterised by karyotype of 47 XX and Y. This means there is an additional X chromosome, resulting in male infertility . Or there is a genetic condition called 46 XX males, where the gene responsible for the male phenotype is translocated on a X chromosome. So technically there are two X chromosomes if a person is female but there is the gene responsible for being male so the phenotype is male. Other types of genetic conditions could be Robertsonian translocation, chromosomal inversions, even microdeletion of chromosomal Y or mutation in mitochondrial DNA. We also must not forget clinical conditions such as cystic fibrosis. In cystic fibrosis, there is an absence  of vas deferens, the man in this case is azoospermic. Therefore it is important to identify the genetic condition where it is present, leading to male infertility.

Genetics has come into the investigation of the male because they are part of the causes of infertility. Approximately 5% of male infertility is estimated to be due to genetic factors. In severe oligospermia and azoospermia, we have the most frequent syndrome is that of Klinefelter, whereby the chromosomal abnormalities cause an inability of the sperm to produce first an adequate number of spermatozoa, and secondly an adequate amount of the male hormone. Another frequent cause is known as the chromosome Y deletions at the AZF region. This sounds very complicated but it is the second most interesting genetic test. AZF is a big subject and depending on which region on the chromosome the abnormality is located, we can predict the prognosis in this patient. A and B are very bad prognoses, C has a better prognosis but this alteration is transmissible to sons that are produced after pregnancy. Various other genetic causes with mutations, deletions, translocations, and so on are known to be less frequent causes of male infertility. So overall, depending on the clinical picture and the test analysis we get in a couple we may proceed indeed to investigate the genetic causes of infertility.