The scope of knowledge in this area is still in its infancy, but is expanding at a rapid rate. The work of the Human Genome Project has aided in the identification of some of the DNA regions responsible for sperm production. It likely that there are thousands of DNA regions that contribute to sperm production, and as yet, only a few have been identified. It is also likely that the majority of infertile or subfertile men in whom no definite cause can be found, have a genetic defect preventing normal sperm production.
Human beings have 23 pairs of chromosomes, for a total of 46. One pair of these chromosomes determine your sex. A female will have to "X" chromosomes, designated "XX", and a male will have one "X" and one "Y" chromosome, designated "XY". It is on this "Y" chromosome that DNA responsible for sperm production is located.
Abnormal sperm production caused by abnormal DNA can generally be divided into 2 categories: 1) an abnormal number of chromosomes (or karyotype), and 2) abnormal DNA on the "Y" chromosome.
The most common condition leading to infertility that is caused by abnormal chromosomes is Klinefelter's Syndrome(KS). The karyotype of men with KS includes an extra "X" chromosome, and is designated "XXY". Other combinations of sex chromosomes leading to KS exist, but are rare. However, about 10-20% of men with Klinefelter's Syndrome are mosaics, indicating that some sperm contain "XXY" chromosomes, and some contain the normal number of chromosomes, or "XY". KS is said to occur in about 1:600 males, and is the most common known genetic cause of azospermia. Men with KS typically demonstrate short stature, small testicles, and breast enlargement (gynecomastia). Almost all have no sperm in the ejaculate (about 8% of mosaics will have sperm in their semen). Men with KS have a higher risk of breast cancer and non-Hodgkin's lymphoma. Most men with KS will be unable to conceive, but microscopic Testicular Sperm Extraction (micro TESE) can occasionally result in sperm retrieval that can be used for ICSI.
Several sites on the Y chromosome have been isolated and determined to play a role in sperm production. Loss of the DNA in these areas are known to disable sperm production. Such DNA losses are termed microdeletions. It is likely that there are many more areas that have not been discovered yet, as a microdeletion is identified only 10% of men with azospermia. Three areas that have been looked at as of 2014 are are AZFa, AZFb, and AZFc . Deletions in the AZFa and AZFb regions always result in complete lack of sperm production, and thus complete loss of fertility potential. Deletions of the AZFc region will almost always result in severe oligospermia or azosprmia, but about 70% of men will have sperm upon micro TESE. It is important to note that the genetic abnormality in microdeletions is always transferred to the offspring.
Another chromosomal abnormality worth mentioning is Congenital Bilateral Absence of the Vas Deferens (CBAVD). This can also result from mutations in different genes, but the most common is a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene., located on chromosome #7. Yes CBAVD is a form of cystic fibrosis, but patients may demonstrate a spectrum of conditions ranging from only CBAVD, to "full blown" cystic fibrosis. Men with CBAVD will have sperm, but they will be trapped in the epididymis, due to lack of a duct for them to pass into the lower genitourinary tract. Sperm can be retrieved by microsurgical aspiration of the epididymis, and used for ICSI. It should be noted that if the female partner of the affected man is a carrier of the CFTR gene mutation, their children will have a 25% chance of developing cystic fibrosis. Men with CBAVD should also undergo a screening ultrasound of their kidneys, as about 1% will be born with only one kidney. A test for the CFTR mutation is available.
Suspicion of a genetic mutation related to sperm production is raised when the semenalysis reveals either no sperm (azospermia) or very low amounts of sperm (severe oligospermia). The definition of severe oligospermia varies a little, but it is most commonly defined as less than 5 million motile sperm in the entire ejaculate. If such a situation exists, and there is no evidence of obstruction, we will order genetic tests. Typically there are two standard genetic tests performed on men with azospermia or severe oligospermia: 1) karyotype, and 2) Y-chromosome microdeletion assay (YCMD). Both are blood tests and are readily available.