Genetic Factors Cause Low Sperm Counts in Some Otherwise Healthy Males

CAMBRIDGE, Mass. — Scientists have found that a specific defect in the male sex (Y) chromosome, known to cause azoospermia, or the inability to make sperm, can also cause the most common form of male infertility-low sperm production, or oligozoospermia. This study is the first to definitively show that genetic defects can cause low sperm counts in some males and suggests that intracytoplasmic sperm injection (ICSI)—the now popular technology of injecting a single sperm into an egg to circumvent low sperm counts—may cause the sons of these men to inherit infertility.

The scientists recommend that infertile couples who are contemplating ICSI should be offered genetic counseling and the option of a DNA test for the mutation before they begin assisted reproductive procedures. The study, published in the May 11 issue of the British journal Lancet, was conducted by Dr. David Page, Dr. Renee Reijo, and Ms. Raaji Alaggappan at the Whitehead Institute for Biomedical Research and the Howard Hughes Medical Institute (HHMI) using DNA samples from their collaborator, Dr. Pasquale Patrizio at the Fertility Center of San Antonio, TX.

In the study, the Whitehead/HHMI researchers examined the Y chromosomes of 35 men who had extremely low sperm counts and found that two of these men were missing a tiny fragment of the long arm of the Y chromosome. The Y chromosomes of their fathers (who obviously had no fertility problems) were intact in this region, proving that the mutation was in fact the cause of oligozoospermia. More, the scientists found this mutation was also present in the sperm of one oligozoospermic man they tested, confirming that the mutation is likely to be transmitted by ICSI.

Last year, the Whitehead/HHMI scientists had found similar mutations in 12 of 89 men who produced no sperm. The fathers of these men also had intact Y chromosomes as did 90 fertile men, who were studied for comparison. Based on these findings researchers believe that a gene or genes located in this fragment of the Y chromosome are involved in proper sperm production.

"Low sperm counts are much more common in men—1 in 30 men have low sperm counts—than the complete absence of sperm, which affects 1 in 1,000 men. Our finding of the Y chromosome defect in men with low sperm counts suggests that this defect is more common that we previously estimated," says Dr. Page.

About 1 in 6 American couples is infertile, and each year as many as 20,000 couples seek assisted reproductive technologies to help them conceive. In a fifth of the infertile couples, a key factor is a defect in sperm production, which could result from a variety of reasons, including infections and other illnesses. Scientists are only now beginning to understand the role of genetic factors in infertility. The Whitehead/HHMI studies provide the first clear cut indication that genetic defects are the underlying problems in some men with genetic defects in sperm production. They suggest that some "unexplained" cases of male infertility can be traced to genetic defects in the Y chromosome and that these genetic defects can be transmitted to male offspring.

"Normally, these men would not be able to have children, and people thought of genetically transmitted infertility as an oxymoron," says Dr. Page. "However, the explosion in assisted reproductive technologies is now making it possible for these men and their wives to have children and raises the possibility that they will pass on their infertility to their sons. It is for these cases that we recommend genetic counseling."

Physicians consider sperm counts of 50 million or more sperm per mL of semen as being in the normal range. In the most common form of male infertility, men have less than 10-15 million sperm per mL of semen. Some men produce even fewer sperm-a million or less per mL of semen. Men with such severely low sperm production were the subject of the Whitehead/HHMI study. The researchers say that further studies will be needed to ascertain the role, if any, of Y chromosome mutations in less severe cases of oligozoospermia.

This work was funded in part by grants from the National Institutes of Health and the Damon Runyan/Walter Winchell Foundation.