A large portion of genetic causes of infertility in men are attributed to tiny deletions in the Y chromosome. Why the Y? The Y chromosome is the thing that makes you a man. It turns on the switch for all things manly — the ability to identify aircraft, the love of sports, a childhood fascination with bugs and a healthy admiration for Chuck Norris all stem from the Y chromosome. It also controls testicular development and sperm production. Sometimes however, in the natural shuffling of our genetic decks tiny pieces of the Y chromosome get lost which can in turn affect a man’s sperm quality.
Getting to know the Y
As mentioned above, the Y chromosome is the piece of DNA that makes men, men. For the most part, women have a sex chromosome that is XX, while men have an XY. The Y chromosome is made up of nearly 60 million base pairs of DNA which are divided into two sections a short arm (called p) and a long arm (called q). Some of this DNA is a record of your genealogical history – sequences that tell who your father is and his father and his father, some are duplicates from the X chromosome and finally mixed in are critical genes that switch on your your manhood. Among these are the SRY gene which tells the body that you are a man so that each cell is tuned to be more masculine and several other genes responsible for the development of sperm and testicular tissue. Read more about other genetic conditions that can cause infertility.
How do sections of the Y Chromosome get deleted?
As each sperm cell is formed, the DNA gets chopped up in to tiny sections, is duplicated and slightly rearranged. These slight, random variations make each person unique with DNA never seen before. Because changes to the Y chromosome are only passed through sperm and because men make millions of sperm, it is more prone to genetic variation than all the other chromosomes. The advantage of this is that scientists can use the Y chromosome to study genealogy, the disadvantage is that men are at risk for having microdeletions on the Y chromosomes which can impact their fertility.
Is it common?
It’s hard to estimate how common Y chromosome microdeletions (YCM) are. In some cases very small deletions will have only marginal impacts on fertility. Another issues is that genetic tests are still limited and not all deletions are detectable. But, studies show that approximately 1 in every 2,000 men have detectable deletions on the Y chromosome which impact fertility. Of men diagnosed with infertility about 7.4% will have YCM. This means there are currently between 100,000 to 200,000 men in the United States who are infertile due to YCM.
Most of the time, the only thing impacted by YCM is sperm production. Sometimes, the body will try to compensate for poor testicular function by increasing sex hormones which support sperm production. Elevated hormone levels are usually undetectable but can impact mood, metabolism and sex drive.
The first tool in diagnosing male infertility is the semen analysis which is a test where semen is analyzed under a microscope to determine how many sperm are present, what they look like and how many of them can swim. If the semen analysis shows very low sperm production (oligozoospermia) or no sperm (azoospermia), doctors will perform a physical exam, take a medical history and some times order additional blood tests to analyze hormone levels and look for genetic abnormalities. Because men who have Y Chromosome Microdeletions have no other symptoms, genetic screening is commonly recommended for patients who have azoospermia but do not have any abnormal findings during the physical exam or in their medical history.
There are couple techniques that can be used to diagnose genetic abnormalities:
Cytogenetics: The oldest and and most common techniques are called cytogenetics. These tests look at white blood cells under a microscope to determine any genetic abnormalities. Karotypes are done when the cell is reproducing and the DNA forms a second copy of each chromosome. Technicians are easily able to see if there are missing or extra copies of the X chromosome which is how they are able to diagnose Klinefelter syndrome. To look for microdeletions in the Y chromosome, technicians will “FISH” for genes by adding probes that will glow if certain genes are present or missing. Again, looking under the microscope, they can see exactly where on the Y chromosome the probes stick and identify if any key genes responsible for sperm production are missing.
PCR: PCR is a more automated method that also uses probes to look for certain genes. Many labs have started using it because it is quicker, uses smaller amounts of blood and does not rely on a technician.
Chromosome Microarrays: These chips provide an automated way to look for multiple chromosomal abnormalities. They are becoming an increasingly common way to screen for genetic abnormalities in babies but can also be used to diagnose genetic causes of infertility in men.
Even though genetics are the “hand you are dealt,” there are treatment options for men diagnosed with Y chromosome microdeletions. Which course you pursue should be informed by a detailed understanding of exactly which genes are deleted. The general rule of thumb is that the larger the deletion, the more severe the effect. Also, the closer the deletion is to the center of the gene, the more severe the effect.
Scientists have identified 3 major regions of the Y chromosome responsible for sperm production AZFa, AZFb and AZFc, each of which have different roles.
AZFa is the closest to the center of the gene. Only about 6% of men with microdeletions will have deletions in the A region. Deletions in the A region lead to a condition known as Sertoli-cell only syndrome. This means that the testicle is lined with cells to help support and feed baby sperm cells, but the actual germ cells responsible for dividing and forming sperm are completely missing. In this case, there aren’t any treatment options available and men with this condition should pursue alternative options for building a family.
AZFb is fairly close to the A region and accounts for about 14% of cases of YCM. These patients often have germ cells in the testicle but they are unable to divide correctly and sperm do not mature. Currently, there are not any treatment options available for men with complete AZFb deletions because testicular extractions show an absence of sperm. There are a number of scientists working on germ cells and looking for ways to develop sperm from healthy germ cells. This research could lead to future treatment options in men where germ cells are found in testicular biopsies. In some cases, a man may have a partial rather than complete b deletion. In these circumstances, there may be some hope of finding sperm in a testicular extraction but it would depend on which exactly genes were missing from the region.
Around 66% of microdeletions are complete deletions of the AZFc region. This region is much further away from the center of the Y chromosome and therefore have a much less severe impact on sperm production. Some men with AZFc deletions will show low numbers of sperm in the ejaculate, most others will present as azoospermic but will have viable sperm present in the testicle. Studies report that sperm extraction from the testicle using microTESE have about a 75% success rate. Men with C region deletions may also benefit from lifestyle changes intended to boost testicular health to maximize sperm production.
Multiple region deletions
Rarely men will have full or partial deletions from multiple regions A,B, and C. The prognosis of finding sperm in ejaculate or using testicular extraction will depend on exactly which genes are missing. As mentioned above – A and B region deletions have the most severe impact, while C deletions usually have better chances of producing minimal levels of viable sperm.
Not all labs are able to test for partial deletions. Studies show that there are significant numbers of men with partial deletions particularly in the AZFc region. One particular partial deletion known as the gr/gr deletion has been shown to be a risk factor for infertility but may not necessarily cause it. Men with a gr/gr deletion are missing 2 out of 4 copies of the DAZ gene which is responsible for a key protein for sperm production while men with complete AZFc region deletions are missing all 4 copies. Because the most common partial deletions do not necessarily cause infertility, they are not routinely assessed.
Stories and Blogs
A few pieces missing from normalcy: This blog chronicles the journey of a man following a diagnosis of complete deletion of both AZFb and AZFc regions. In his blog, he shares his desires with fatherhood, his frustration with infertility and things he does to build up a support system.
Success in the Midwest: After 3 years, 4 doctors, countless tests, several misdiagnosis and a lot of frustration, this couple was able to overcome a rare genetic condition known as Y Chromosome Microdeletion which is when tiny parts of the Y chromosome are deleted impairing sperm production, often leading to azoospermia. With the help of FertilAid, they were able to boost his count from around 100,000 to something closer to 1 million which they were able to use with IVF where they successfully conceived a little girl. Here’s their story