Tracing the Genetic Causes of Male Infertility

July 28, 2000 -- A man's role in creating a baby may seem simple and straightforward. Yet, it's widely reported that up to 60% of pregnancy failures are due at least partially to male infertility. While research on male fertility problems in the past decade has focused on poor habits, structural problems, even a man's style of underwear, experts predict that future research will center on genetics, along with other new developments.

Larry Lipshultz, MD, a professor of urology at Baylor College of Medicine in Houston, tells WebMD that identifying genetic abnormalities in men might one day enable researchers to develop gene therapy as a treatment for some types of infertility. "Things are changing rapidly, and new discoveries in the lab to diagnose and to treat the infertile male happen much quicker than they did just 10 years ago," he says.

Researchers have uncovered the genetic causes for a flood of diseases as more DNA data have become available. But the study of infertility has lagged. "The very idea that infertility could be genetic seemed not all that logical," says David Page, PhD. "Most people didn't get beyond the idea of what genetics is the study of disease passed on in families, and the definition of infertility is the inability to have families." Page is with the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology.

Writing in the journal Current Opinion in Urology, Lipshultz, who is the former president of the American Society for Reproductive Medicine, summarizes the areas of current research and discusses those that are likely to bring treatment advances in the future. Here's a brief summary:

Y chromosome problems:

Normal males carry both an X and a Y chromosome, whereas females have two X chromosomes. Researchers have discovered that about 20% of male infertility can be traced either to the loss of a large chunk of the male Y chromosome, or to some other major chromosome abnormality, such as the presence of a second X chromosome. Just recently, Page from Whitehead found the first mutation on the Y chromosome known to prevent sperm production and, thus, cause male infertility. The finding eventually may help in the design of treatments for infertile men.

For this reason, Lipshultz routinely screens most patients who have very low sperm counts for these so-called Y-chromosome deletions. "When we find large segments missing, it's obvious why the patient is infertile," he says.

The genetic analysis is important for two reasons, he says. If the man wants to use assisted reproductive technology to conceive a child, he and his spouse need to be counseled about the possibility of passing the genetic defect to their male offspring. And the test results can be used to identify other areas of the Y chromosome that might be associated with severe infertility.

In addition to looking within the Y chromosome for causes of infertility, researchers are hunting for clues on the autosomes -- any of the non-sex-determining, or sex-neutral, chromosomes. Human cells each have 22 pairs of autosomes. "Deletions on some of the autosomes have been linked to infertility, so deletions of the Y chromosome are not the sole genetic culprit," Lipshultz says.

Microassisted or micromanipulation reproduction:

In addition to genetic defects, infertility can be caused by physical flaws, such as an obstruction in the tubes through which sperm flows, or varicose veins in the scrotum. Also, some men may lack a vas deferens -- the tube that transports sperm from the testicles. If surgery cannot solve such problems, techniques like ICSI (inctra-cytoplasmic sperm injection), in which a single sperm is removed from the man and inserted into the woman's egg, may help infertile men. "Sperm of virtually any quality and from any level of the male reproductive tract may be used, with the only criterion for use being that the sperm is alive," says Mark Perloe, MD, of Georgia Reproductive Specialists.

Perloe says that while ICSI may solve an infertility problem, it does not address the cause, which could be genetic. "Sub-fertility in men can be related to certain ... defects of the chromosomes," he says, "and, therefore, there is a strong recommendation for all couples that achieve pregnancies from ICSI to undergo prenatal screening."

Stem cell research:

Stem cells, which are cultured human cells that have the potential to develop into almost any of the body's different tissues, including bone, heart, or brain tissue, hold tremendous promise for tissue replacement and for treatment of a variety of diseases. They usually are derived from embryos left over from in vitro, or test tube, fertilization.

Stem cells could lead to a number of breakthrough therapies. Already, stem cells derived from the reproductive system of mice have grown into new testicles when transplanted. "Maybe in the future, a similar technique can be used in humans to restore fertility in some males," Lipschultz says.

Some of the areas of research Lipschultz discusses are the subject of much controversy and will undergo much scrutiny and debate before -- if ever -- they become mainstream. They include:

  • Cloning. The idea is simple: Extract the genetic code from a human cell to create a replica of the donor. It's been done with animals, but there's a ban in the U.S. on performing the feat with humans, at least for researchers using funds from the National Institutes of Health. "It is likely that private laboratories will achieve the feat in the near future," Lipschultz writes.
  • Sex selection. A technique to distinguish and separate the X and Y chromosomes recently has been developed. Researchers also can tell whether an embryo with as few as eight cells is male or female.

Lipshultz says these two techniques may be valid for couples whose transmission of a genetic disease to a son, due to a problem with the man's X chromosome, is a serious medical concern. "There are numerous ethical questions if these techniques are used for preferential selection," he warns.

For now, a solution has yet to be discovered for men who lack the genetic programming to produce healthy sperm, Lipschultz says. "The main direction of infertility research is headed toward isolating and sequencing the specific genes that control production of sperm," he says. "Ultimately, we hope to be able to develop gene therapy to replace the missing genes that cause infertility."