Human papillomavirus can cause cancer and also negatively affect male fertility, as a new study reveals that men infected with high-risk HPV genotypes could suffer sperm damage.
Cervical cancer is the fourth most common type of cancer in women and is responsible for around 350,000 deaths each year, mainly in low- and middle-income countries. Infection with the human papillomavirus (HPV) is known to be responsible for 95% of these cases, a pathogen that is also linked to an increased risk of genital warts and cancers of the penis, anus, mouth and throat in infected men, leading the World Health Organization (WHO) and the US Centers for Disease Control (CDC) to recommend that boys should also be routinely vaccinated against this virus.
However, the full potential effects of HPV on men and boys are still unknown. Now, new research published in Frontiers in Cellular and Infection Microbiology has found that men who become infected with high-risk HPV types may experience fertility problems.
“In our study we show that genital HPV infection is very common in men, with variable effects on semen inflammation and sperm quality, depending on the viral genotype present,” explained Dr. Virginia Rivero, professor at the National University of Córdoba, Argentina, and lead author of the study. “Specifically, infections caused by high-risk HPV genotypes seem to have a more negative impact on male fertility and on the ability of the immune system to clear the infection,” she added.
More than 200 different HPV genotypes have been identified, which are generally classified into high-risk (AR-HPV) and low-risk (BR-HPV) genotypes. AR-HPV is detected in almost 100% of cervical cancer cases in women and in a high percentage of anal, genital, and mouth and throat cancers in both sexes. BR-HPV, on the other hand, is typically found in abnormal but benign cervical cells in women and in warts on the larynx and genitals in both sexes, without causing cancer.
Rivero and his team studied the effects of HPV in a sample of the male population in Argentina: 205 adult volunteers who attended a urology and andrology clinic for an initial evaluation of fertility or urinary tract problems between 2018 and 2021. None of them had been vaccinated against HPV.
More dead sperm in men infected with AR-HPV
Volunteers donated a sample of their ejaculate, and the presence or absence of HPV and other sexually transmitted infections was determined by PCR. Of the 205 individuals tested, 19% were HPV positive. Specifically, 20 men were classified as AR-HPV positive, while 7 were BR-HPV positive. These HPV-positive individuals were compared to 43 men with no detected infections. In addition, 12 men were found to be HPV positive, but their genotype could not be determined due to low viral loads.
Most of the HPV-positive men were infected with only one genotype, although three men carried two genotypes simultaneously. First, the researchers analyzed the semen samples using routine analysis methods recommended by the WHO. Based on these criteria, they found no evidence of differences in semen quality between the three groups.
However, this apparent indication of normal fertility in HPV-infected men turned out to be misleading. When Rivero and his colleagues examined the samples using more detailed, high-resolution methods, they were surprised to find that the AR-HPV-positive men had significantly fewer CD45+ white blood cells (leukocytes) in their semen. They also found evidence that these men’s sperm may be frequently damaged by oxidative stress, as evidenced by their elevated production of reactive oxygen species (ROS).
While low levels of ROS are a normal byproduct of sperm function, elevated levels can lead to cell membrane disruption, DNA breaks, and uncontrolled cell death. In fact, researchers showed that AR-HPV-positive men had a higher percentage of dead sperm.
Rivero explained that they concluded that men infected with AR-HPV, but not those infected with BR-HPV, show an increase in sperm death due to oxidative stress and a weakened local immune response in the urogenital tract. “These results suggest that AR-HPV-positive men may have compromised fertility,” she said.
AR-HPV positive men had significantly lower numbers of CD45+ white blood cells (leukocytes) in their semen and their sperm could suffer frequent damage from oxidative stress.
The researchers explained the lower immune cell count in the semen of AR-HPV-positive men by the known ability of HPV to evade the immune response. This could lead to reduced mobilization of leukocytes to the site of HPV infection and a reduced ability to clear this infection.
“Our study raises important questions about how AR-HPV affects sperm DNA quality and what implications this has for reproduction and offspring health. It is crucial to understand the biological mechanisms underlying these effects. And, since sexually transmitted co-infections are quite common, we plan to explore whether the presence of an HPV infection alongside other STIs influences these outcomes,” Rivero concludes.
Yolanda Cabello, an independent clinical embryologist and consultant in assisted reproduction and professor of the Master’s in Healthcare and Clinical Management at the International University of Valencia, who was not involved in the study, explained in statements to SMC Spain that “the general population, especially men, are largely unaware of the consequences that can result from the transmission of this virus and these men, even though they are carriers, do not undergo check-ups and are vectors of the virus, unconsciously infecting all their sexual partners, since the possible consequences are long-term and not immediate. Fortunately, in 2008, girls began to be vaccinated free of charge at the age of 12, and since last year, too late in my opinion, the vaccine has also been administered to boys of that age.”
“The published study links infertility to men with high-risk HPV. These men showed significantly higher levels of sperm necrosis and a higher proportion of sperm with free oxygen radicals, responsible for the oxidation and fragmentation of sperm DNA, responsible for blocking cell division and, therefore, embryos, and also for miscarriages during the first trimester. Likewise, a reduction in semen leukocytes and inflammatory cytokines (IL-6 and IL-1β) was observed in this group of men. It should be noted that these adverse effects are not detected in routine semen analyses performed when a couple goes to assisted reproduction consultations,” adds the expert.
“The authors suggest comprehensive HPV screening in men, including genotyping, in urology and fertility clinics, which I agree with, as more conclusive conclusions could be obtained to corroborate the data from this study, which still has a low number of samples to understand the importance of this infection in male infertility,” he concludes.
