Evaluation of Severe Oligospermia and Non-obstructive Azoospermia (NOA)

Men with low numbers of sperm in the ejaculate (oligospermia) or no sperm in the ejaculate (azoospermia) may have genetic abnormalities.  These may involve large or small abnormalities (deletions, additions, translocations) in any of the 23 pairs of chromosomes, or small abnormalities (microdeletions) in the Y chromosome.  Men with azoospermia may have an obstruction preventing the sperm from reaching the ejaculate, or they may have abnormalities of the testicle (non-obstructive) which result in no production of sperm.  Fifteen to 20% of men with NOA have deletions of the Y chromosome or karyotypic anomalies.

Microdeletion of Genetic Regions of the Y chromosome 

Microdeletions of the Y chromosome are identified by the region that they involve (a, b, or c).  The microdeletion may involve a single region or multiple regions.  The area involved with the deletion will determine the prognosis for the patient.

AZFa:

Microdeletion of the AZFa region is found in <1% of men with NOA.  These patients are highly unlikely to have sperm found in their testicle.

AZFb:

These men will not have sperm in the ejaculate or testis tissue.

AZFc:

Microdeletion occurs in the AZFc region in 1 in 4000 men and is the most common molecular cause of NOA.  Thirteen percent of men with NOA will be AZFc microdeleted.

Approximately 70% of men with an AZFc microdeletion will possess sperm, either in the ejaculate or testis tissue.

Approximately 6% of men with severe oligospermia, < 5 million/cc, will be AZFc microdeleted.

If sperm are present in the ejaculate or testis tissue in a man with an AZFc microdeletion, their quality is normal and fertilization, embryo development, and live birth are all eminently possible.

Male offspring will inherit the AZFc microdeletion but may manifest across the spectrum of abnormality seen in the rest of the AZFc microdeleted population.

Karyotypic Anomalies in Men 

Klinefelter syndrome (47, XXY)

Approximately 50% of Klinefelter syndrome patients who present as adults will have sperm found in their testicle.  These sperm can be used for intracytoplasmic sperm injection (ICSI) with a slight risk of transmission of Klinefelter syndrome, however all babies born to date have been normal.

These men may require testosterone replacement after testicular sperm retrieval (TESE).  These men are also at greater risk of developing breast cancer and osteoporosis.

46, XX male syndrome

A small piece of the most distal aspect of the short arm of the Y chromosome is present.  The prediction for sperm production is dismal-no level of spermatogenesis has been found in the testicular tissue of these males.

Isodicentric Y chromosome

These men may or may not have sperm present depending on where the abnormality occurs in the Y chromosome.

The Role of the  Cystic Fibrosis Gene

Congenital bilateral absence of the vas deferens (CBAVD) is associated with mutations within the cystic fibrosis (CF) gene in 70% to 80% of men.  Any male with CBAVD should be tested to see if they carry any mutations within the CF gene.  Their partners should also consider testing.  If both partners are carriers of mutations in the CF gene they have a 25% chance of having a child with CF.

These men almost always have sperm in the epididymal remnant and these sperm can be used for intracytoplasmic sperm injection (ICSI).  The sperm perform equally as well in either the fresh or frozen-thawed state.