USC Health Now

In the United States, some 4 million married couples of child-bearing age are infertile; up to 50 percent of the time, a male factor is involved. Here, USC experts explore the causes, diagnosis and treatment of male infertility and share findings from their recent study that points to an epigenetic explanation for some forms of male infertility.

by Carrie St. Michel

It would come as no newsflash to any adult that contributions from both a man and a woman are required to create a baby. Beyond such birds-and-bees basics, however, are some surprising procreation facts. Consider this: For couples experiencing infertility—with infertility being defined as the inability to achieve pregnancy after one year of unprotected intercourse—a male factor is involved in up to 50 percent of the cases.

Diagnosis and Treatment

“People tend to associate infertility with women when, in actuality, infertility is equally prevalent across both genders,” says Rebecca Sokol, M.D., M.P.H., professor of obstetrics and gynecology and medicine at the Keck School of Medicine of USC. Sokol, who also has a clinical practice specializing in male infertility, notes that if a couple is having trouble conceiving it makes sense to simultaneously evaluate the man and the woman.

For a man, such an evaluation will include a thorough physical exam, semen analysis and hormone testing.

“If tests indicate male-factor infertility, the cause will likely fall into one of three categories,” Sokol explains. “First, there could be a hormonal imbalance.” If pituitary hormones are absent or at insufficient levels, the testes will not maximally produce sperm. “Certain types of hormonal imbalances,” adds Sokol, “can be effectively treated through hormone replacement therapy.”

Male-factor infertility also is often traced to an anatomic abnormality, such as sperm-carrying ducts that are missing or blocked. “Many anatomic abnormalities, although not all, can be surgically repaired,” Sokol says.

Many Causes Unknown

“One of the most challenging aspects of male-factor infertility,” observes Sokol, “is that some 50 percent of cases are categorized as idiopathic infertility. Simply put, this means we just don’t know what the root cause is.”

As Sokol points out, “While we can’t treat idiopathic infertility—since we don’t know what the actual problem is—that doesn’t mean the couple can’t conceive. In fact, in-vitro-fertilization (IVF) techniques have advanced to the point where up to 30 to 40 percent of couples, where the man is diagnosed with idiopathic infertility, will have successful pregnancies.” Through a process called intracytoplasmic sperm injection, for example, one sperm can be injected into each egg. Consequently, fertilization does not require a large number of sperm.

Epigenetics and Infertility

While in vitro fertilization can sometimes serve as a solution to idiopathic infertility, Sokol notes, “IVF is just a way around the problem. The underlying cause of infertility still goes unanswered.” Adding, “We launched this study in an effort to start filling in this knowledge gap.”

Sokol is referring to a study she spearheaded with co-lead author Victoria K. Cortessis, Ph.D., assistant professor in the Department of Preventive Medicine at the Keck School of Medicine of USC. Published recently in Public Library of Science One, the study was designed to explore if epigenetics could be an underlying cause of idiopathic male infertility.

Cortessis explains, “Epigenetics looks at how environmental factors can change gene function without altering DNA. Epigenetics,” she adds, “helps determine which genes are activated to enable a cell to perform its specific function in the body.” An international leader in the field of epigenetics, USC recently opened the Epigenome Center – one of the nation’s first facilities dedicated to the study of epigenetics.

Study Findings

Sokol, Cortessis and several other USC researchers studied semen samples from male members of couples attending an infertility clinic. Using highly specialized molecular biology techniques, the researchers examined the epigenetic state of DNA from each man’s sperm. They found that sperm DNA from men with various sperm abnormalities had high levels of methylation. Methylation can prevent a gene from properly performing its cell function; in this case, producing sperm free of abnormalities.

“If we can identify what causes these changes to the sperm DNA, then we might be able to prevent certain types of male infertility,” explains Sokol. “This is particularly important because recent animal sutides have suggested that epigenetics may have broader implications. Exposures to chemicals as a fetus,” she says, “could lead to adult diseases. Perhaps such exposures may be causing the changes in the sperm DNA that we have identified.”

Cortessis adds, “If we can pinpoint when these changes happen, then we can develop prevention strategies. For example, if our follow-up studies show that changes in sperm DNA happen in-utero, then we would focus on prevention strategies during the early stages of fetal development.”

XY Focus

Sokol is encouraged that increasing research focus is being placed on male-factor infertility. “We already are making significant strides is diagnosing and treating male infertility and now, with attention turning to epigenetics, I’m confident that our options for treating male infertility are going to grow tremendously.”

As part of a follow-up study, USC is currently looking for men – who have not been diagnosed with male infertility – who have fathered an infant aged 1 year or younger. Study participants will be financially compensated. Those interested are asked to call (323) 865-0558.