Scientists have long considered that the world’s most common sexually transmitted infection, human papillomavirus, or HPV, may be a driver of infertility.

Most research about HPV’s potential impact on fertility has focused on women. But in recent years, researchers have increasingly expanded their focus to include the infection’s association with male fertility.

A new study from Argentinian researchers has found that the strains of HPV considered high risk because of their links to cancer were not only more common than low-risk strains in a small study population of men, they also appeared to pose a greater threat to sperm quality.

The study, published Friday in Frontiers in Cellular and Infection Microbiology, found that high-risk HPV appears to suppress key components of the immune system in the male genital tract. This could hamper the body’s ability to clear HPV, a process that typically takes about six months to a year after infection, while raising the risk of other infections that may also compromise male fertility.

“Individuals often have no symptoms or signs, yet still carry HPV in the male genital tract,” said the study’s senior author, Virginia Rivero, a professor of immunology at the National University of Córdoba in Argentina.

A 2020 systematic review of 50 studies found that 21% of infertile men had HPV-positive semen, compared with 8% in the general male population. Even after accounting for female infertility, men with HPV in their semen had three-fold greater odds of being infertile than those without the virus.

There are over 200 known strains of HPV. The riskiest handful can cause multiple cancers, including, in the U.S., about 26,000 diagnoses in women and 21,000 in men each year, according to the Centers for Disease Control and Prevention. The most common HPV-driven malignancy is cervical cancer, with about 13,800 invasive cases annually. Research suggests that most people are unaware that the virus can also cause vulval, anal, throat, vaginal and penile cancer.

A vaccine for HPV has been available since 2006, when it was initially recommended just for girls; the recommendation was expanded to boys in 2011. The current version, which is given in a two- or three-dose series, prevents nine of the riskiest HPV strains, including those that cause genital warts.

The CDC recommends routine HPV vaccination for all boys and girls at 11 or 12 years old — children can receive it at as young as age 9 — and for those through age 26 who were not previously fully vaccinated. Experts consider the vaccine exceptionally safe.

A CDC study published Thursday found that for adolescents born in 2007, about 65% were fully vaccinated for HPV by age 15, compared with 60% of those born in 2008. The CDC attributes this statistically significant difference to disruptions from the Covid pandemic, beginning when the younger group turned 12.

Vaccination at older ages typically provides less benefit, since so many people contract at least one strain of HPV after becoming sexually active. But the CDC suggests that people up to age 45 may still discuss potential vaccination with their doctors. 

High-risk HPV lowers immune cells

In her new study, Rivero and her colleagues studied the ejaculate samples of 205 men, none of whom were vaccinated for HPV. The men, who had a median age of 35, sought a fertility assessment or treatment for urinary-tract problems from 2018 to 2021 at a urology clinic in Argentina.

Thirty-nine, or 19%, of the men tested positive for HPV. Researchers were able to identify 20 men among them who had high-risk strains and seven men with low-risk HPV.  

On the surface, the investigators didn’t find any notable differences in the semen quality between the men with either type of HPV and a group of 43 men who tested negative for the virus. When they examined the semen more closely with highly sensitive tools, they found clues suggesting how high-risk HPV strains might be influencing male infertility.

The men with high-risk HPV had a lower level of certain immune cells in their semen, suggesting the virus had hampered the body’s ability to fight it off. This suppression of immune cells might also have raised the men’s risk of other infections that could further compromise their ability to conceive.

There was also evidence that the sperm of the men with high-risk HPV were sustaining damage from what’s known as oxidative stress. This could explain why these men had a higher level of dead sperm compared with those who didn’t have the virus.

Dr. Eugenio Ventimiglia, an oncologist in the unit of urology at the Università Vita-Salute San Raffaele in Milan, Italy, said the new study, which he was not involved in, “provides insight into the biological mechanisms potentially linking HPV to male reproductive health issues.” 

Nevertheless, he said its findings should be “interpreted cautiously.”

“Instead of conclusively proving a cause-effect relationship between HPV and male factor infertility, the study’s findings are more appropriately seen as generating hypotheses for further research,” Ventimiglia said.

Can vaccination protect men’s fertility?

Men’s HPV might also affect fertility in part by transmitting the virus into the woman’s reproductive tract; the virus might then harm the pregnancy at various stages, including before the fertilized egg implants in the womb. Couples receiving assisted reproductive technology have a greater chance of miscarriage if the man has HPV in his semen, researchers have found.

Research indicates that providing the HPV vaccine to men who are having trouble conceiving and who have an active HPV infection might help them clear the virus faster and potentially improve their chances of conceiving.

“Whatever other changes are thought to be associated with HPV, it should be noted that HPV infection is usually brief, as is the sperm lifespan,” said Dr. Marie-Hélène Mayrand, an epidemiologist and the chair of the obstetrics and gynecology department of University of Montreal. “This is reassuring that any effect, if found, would be brief and self-limited.” Mayrand was not involved in the new research.

Rivero advises that men struggling with fertility receive testing for HPV and other sexually transmitted infections that could affect their fertility. If positive for HPV, additional testing may be needed to identify specific strains. 

The test results, Rivero said, could help men identify a potential driver of their infertility. 

HPV vaccination rates among adolescent boys and men have been rising over the last decade. Recent research suggested that the HPV vaccine was linked to a drastically lower rate of head and neck cancers in men and adolescent boys. 

It’s not yet known if the vaccine could protect men’s fertility. 

“When a critical mass of boys and girls are vaccinated, it is likely that the transmission of the HPV genotypes covered by the vaccines will decrease.” Rivero said. “But the broader impact on fertility remains uncertain.”

Rivero said she hoped to see a larger study in the future that could lend more statistical heft to her findings. Her own lab plans to further study how simultaneous infections with HPV and other STIs might influence male fertility.