Severe male factor: is there a genetic cause?

Severe male factor: is there a genetic cause?

The World Health Organization (WHO) estimates that approximately 10% of couples will experience fertility problems. Some 50% of the causes are due to a male factor. Many men with fertility problems have a very low sperm count, a condition referred to as severe male factor:

  • severe oligospermia: <1 million sperm per ml
  • azoospermia – absence of sperm in the ejaculate

Is there a genetic cause behind this problem? What tests can I perform to investigate the origin?


The karyotype is an individual’s collection of chromosomes. Humans have 23 pairs of chromosomes: 22 pairs of autosomes and one pair of sex chromosomes (X and Y) that will determine the sex of the individual.

A karyotype test allows us to detect whether there is an alteration in the normal number of chromosomes, or in their structure.

When is karyotyping recommended?

In cases of severe male factor, there is an increased chance of chromosomal abnormalities.

Klinefelter’s syndrome (XXY) is one of the most frequent disorders among the population, with a prevalence of 1 in 500. Most males affected by this disorder will not produce sperm.

However, this chromosomal abnormality may not necessarily be present in all the cells of the body (mosaicism). The prognosis for such patients will be more optimistic.

Chromosomal alterations affecting the normal chromosome structure (Robertsonian translocations, reciprocal translocations, inversions, etc.) can also lead to a decrease in sperm quality.

What can I do if I have an altered karyotype?

In order to provide appropriate genetic counselling, it is important to know what type of chromosomal alteration the male has. In the case of Klinefelter’s syndrome, despite the absence of sperm in the ejaculate, sperm can be obtained from a testicular biopsy or testicular puncture in approximately 50% of all cases.

In this syndrome and in structural chromosomal alterations, it is advisable to perform a PGT-A after fertilisation to determine the chromosomal status of the embryos, as a percentage of them will present unbalanced chromosomal alterations that will lead to miscarriages or congenital anomalies in the newborns.

Study of Y chromosome microdeletions

Despite its small size, the Y chromosome contains the information needed for sexual differentiation to occur in the foetus. It is, in other words, the chromosome that will establish the biological sex as male. In addition, within this chromosome there is a region known as AZF (azoospermia factor) which contains genes that are involved in sperm formation (spermatogenesis). Three sub-regions have been identified to date: AZFa, AZFb and AZFc.

Microdeletions of the AZF region of the Y chromosome are the second leading cause of male infertility of genetic origin.

It is estimated that 10% of males whose seminogram reveals alterations may have lost one or more of these regions.

What are the implications of carrying Y chromosome microdeletions?

The degree of severity of sperm production impairment will vary depending on the deletion region or regions:

  • Deletion of the AZFa region: small testes, azoospermia, elevated FSH and testosterone levels. This is the most severe variant.
  • Deletion of the AZFb region: affects the final maturation process of spermatozoa. It is also associated with azoospermia.
  • Deletion of the AZFc region: This is the most common variant (66% of cases) and has the best prognosis. It is associated with oligozoospermia.

A combination of AZFb and AZFc deletion occurs in 10% of cases.

What can I do if I am a carrier of Y chromosome microdeletions?

After being diagnosed as a carrier of microdeletions, and if azoospermia does not already exist, it is advisable to undergo sperm banking to preserve fertility, as this condition can rapidly deteriorate into total sperm failure.

It is also extremely important that patients with microdeletions receive appropriate genetic counselling to help guide their reproductive treatment. Moreover, due to its genetic origin, this alteration will be transmitted to male offspring.

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Genetic study of cystic fibrosis

Cystic fibrosis is a very common genetic disease in the Caucasian population, with 1 in 25 people being healthy carriers of the disease. There are more than 1400 mutations in the CFTR gene that cause cystic fibrosis.

As it is a recessive disease, when two carriers have offspring there is a 25% chance that their children will be affected by it.

95% of men with cystic fibrosis have azoospermia due to the absence of the ductus deferens, which are responsible for transporting sperm from the testicle to the ejaculate.

What can I do if I have cystic fibrosis?

Azoospermic males may undergo a testicular puncture in order to obtain sperm for fertilisation.

It is also important that they receive proper genetic counselling in order to avoid passing the same disease on to their children.

Genetic spermatogenesis test

In addition to the genes mentioned above, there are many others involved in spermatogenesis which we are now beginning to identify thanks to advances in mass sequencing. Mutations in these genes may be responsible for sperm failure in the male.

To complete the genetic study of male infertility, Instituto Bernabeu has developed an innovative test that makes it possible to study 426 genes involved in spermatogenesis.

Using massive sequencing techniques, we can determine the presence of mutations in any one of these genes. As well as allowing us to assess the patient’s reproductive prognosis, it will allow us to provide a much more personalised treatment.

It will also be very useful when it comes to preserving fertility, especially in young patients, before sperm production ceases completely.

Alba Cascales, Biochemist at Instituto Bernabeu


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