Azoospermia caused by the same molecular mechanisms as Cystic Fibrosis

A recent research article reveals that the molecular causes for Azoospermia and Cystic Fibrosis could be common!

But first, some background information…

Azoospermia in brief

Azoospermia is a male medical condition of having low or not having any measurable level of sperm in semen. This results in very low levels of fertility or even sterility. Some forms of azoospermia are susceptible to medical treatment. Azoospermia affects about 1% of the male population and is the reason for up to 20% of male infertility cases.
From medical point of view there are three types of azoospermia – pretesticular, testicular  and posttesticular azoospermia. Based on these types and the genetic causes of the disease vary:

  • Pretesticular azoospermia is associated with gonadotropin deficiency (induced by diseases like congential hypopituitarism, Kallmann syndrome, Prader-Willi syndrome).
  • Testicular azoospermia is seen in Klinefelter syndrome(XXY) and the XX male syndrome and defects of the Y chromosome (a section of the long arm of the Y chromosome has been termed Azoospermia Factor)
  • Recent studies (and the one I am referring now) demonstrates that posttesticular azoospermia can caused malfunctioning (e.g. point mutations) of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

Cystic Fibrosis main facts

Cystic fibrosis (also known as CF or mucoviscidosis) is a common inherited chronic lung disease that causes thick, sticky mucus to build up in the lungs and digestive tract.

Cystic fibrosis is caused by a mutation in a gene which encodes a regulatory protein of a transmembrane conductance – cystic fibrosis transmembrane conductance regulator (CFTR). This gene is involved in the regulation the components of sweat, digestive juices, and mucus. In the human genome there are to copies of this gene – so that if the person have a mutation just in one of the CFTR loci, the cystic fibrosis will not be developped. Therefore, CF is considered an autosomal recessive disease.

A recent research paper published in PloS ONE, reveals clear relation between the mechanisms which cause Cystic Fibrosis and Azoospermia.

As a model study organisms were used CFTR knockout mice. They showed decreased expression levels in testis for  cystic fibrosis transmembrane conductance regulator (CFTR) and cAMP-responsive element binding protein (CREB). The CFTR is involved in HCO3 transport and the expression of the HCO3 sensor – a soluble adenylyl cyclase (sAC). Inhibition of CFTR or depletion of HCO3 could reduce FSH-stimulated, sAC-dependent cAMP production and phosphorylation of CREB, the key transcription factor in spermatogenesis. The present study reveals a previously undefined role of CFTR and sAC in regulating the cAMP-CREB signaling pathway in Sertoli cells, defect of which may result in impaired spermatogenesis and azoospermia. Altered CFTR-sAC-cAMP-CREB functional loop may also underline the pathogenesis of various Cystic Fibrosis and related diseases.

The full study revealing the linkage between azoospermia and cystic fibrosis is available for free at PloS ONE.

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