Transmitting Infertility from Father to Son

CAMBRIDGE, Mass. — Genetic studies at the Whitehead Institute for Biomedical Research have shown that some boys will be infertile as adults because they have inherited a genetic defect from their fathers through a commonly used method of assisted reproduction known as intracytoplasmic sperm injection (ICSI).

Scientists now know that many cases of male infertility have genetic origins. Deletions on the Y chromosome are the most common known cause of little or no sperm production. One particular region of the Y chromosome, known as AZFc, appears to account for infertility in about 10% of those men who produce inadequate amounts of sperm.

Since it was pioneered in the early 1990s, ICSI has become the preferred method for circumventing severe male infertility. The technique involves injecting single sperm into individual eggs and transferring the resulting embryos into the fallopian tube. ICSI is ideal for men with Y chromosome deletions because it requires only a few sperm, which usually can be retrieved from the patient's semen or testes.

"Once only an experimental procedure, ICSI is now a standard part of the repertoire of assisted reproduction," explains David Page, a member of the Whitehead Institute. "For many couples who would have had little chance of having a biological child, ICSI provides the real prospect of having a son or daughter."

Physicians speculated, however, that ICSI boys fathered by men with Y chromosome deletions might inherit the deletion and therefore also be infertile as adults. But until recently, they had no proof to support this concern. (Daughters receive an X chromosome from their fathers rather than a Y chromosome and thus are not at risk for inheriting a Y chromosome deletion.)

In a study published in the July issue of Human Reproduction, Dr. Page and his colleagues at the Whitehead Institute and St. Luke's Hospital in St. Louis, examined the sons of three men who had a deletion in the AZFc region and who together with their wives had undergone ICSI. In all three cases, the sons possessed the same Y chromosome deletion as their fathers. "In all likelihood, the adult sons will be infertile as well," says Dr. Page, also an associate investigator with the Howard Hughes Medical Institute. "Although assisted-reproductive physicians had considered this consequence of ICSI, this study is the first to demonstrate that ICSI does result in some men passing the genetic defect responsible for their infertility directly on to their sons."

The findings raise a host of ethical issues involving how physicians and infertile couples should handle the knowledge that infertility can be transmitted, explains Dr. Page. Should men with low sperm counts be encouraged to undergo testing prior to ICSI to determine whether they could have a son with a Y deletion? What options should be presented to the couple if a deletion is found? For couples concerned about having an infertile son, one possibility is that physicians can determine the sex of the embryos before they are returned to the mother and then return only the females.

Other questions revolve around boys born with Y deletions. "When is the right time to tell them about their condition? Should physicians suggest anything special medically for these boys?" asks Dr. Page.

"The bottom line is that there's a strong need for genetic counseling to be a prominent part of assisted reproduction," he stresses.

When the boys in this study reach puberty, physicians may evaluate them again„this time to determine whether they are, in fact, infertile. Dr. Page thinks it's possible that men with AZFc deletions may produce normal amounts of sperm during puberty and early adulthood, but less than normal amounts as they age. "In that case, the physician might consider harvesting the boy's sperm when he's younger and saving it until he's ready to start a family," he says. "But of course that's another ethical dilemma with consequences to consider."

The National Institutes of Health supported the Y-DNA studies for this paper, but did not fund any of the assisted reproductive services.

The Whitehead Institute is a non-profit, independent basic research and teaching institution recognized worldwide for outstanding contributions to cancer and AIDS research, developmental biology, infectious disease, basic molecular and cell biology, and the new field of genomics. The Whitehead Institute is affiliated with the Massachusetts Institute of Technology in its teaching activities, but wholly responsible for its own research programs, governance, and finance.