Madison K.W. Sobarzo

Background: Human Papilloma Virus (HPV) is the most common sexually transmitted STI in the world, with an estimated 6.2 million new cases annually.³ HPV is spread through direct skin to skin contact, specifically sexual contact of any sort.^2,3 There is currently no cure for HPV, but vaccines exist that protect against HPV infection. Initial HPV vaccine campaigns were aimed at women, promoting the reduction of cervical cancer, leading to disproportionate rates of vaccination between men and women.² One study found that HPV vaccination coverage is less than 11% in eligible males.⁵ Current studies have started to investigate possible correlations between HPV infection in men and negative fertility outcomes. One study found that the prevalence of HPV DNA in semen was found to be significantly higher in infertile males when compared to a control group.⁵ Another study found that HPV DNA detected in seminal fluid was associated with a reduction in pregnancy rate and an increase in miscarriage rate.⁴ This highlights the possible association between HPV infection and negative fertility outcomes for males.

Objectives: We hypothesize that HPV infection leads to reactive oxygen species (ROS) mediated damage to sperm cells, leading to negative sperm parameters and possibly infertility in males.

Search Methods: Using the PubMed database, an online search was conducted from 2018 to 2024 using the following keywords: “HPV infection”, “male infertility”, “negative sperm parameters”.

Results: One study found that the L1 protein of HPV selectively binds to Aquaporin-8, a peroxiporin which facilitates H₂O₂ membrane permeation, in the midpiece of the sperm, resulting in a reduced clearance of H₂O₂.⁶ The same study also found a significant decrease in osmotic permeability of sperm cells infected with HPV when compared to uninfected control groups.⁶ Another study found an overexpression of CYP2E1 and downregulation of antioxidants, Catalase and Superoxide Dismutase, in HPV infected sperm samples when compared to uninfected control groups.⁷ Overexpression of CYP2E1 and downregulation of antioxidants suggests increased concentration of ROS in HPV infected sperm samples.⁷ This study also found that levels of lipoperoxidation in seminal plasma were significantly higher in HPV infected sperm samples, suggesting that increased levels of ROS leads to increase in lipoperoxidation damage.⁷ Moreover, one study found that increased ROS in HPV infected sperm samples led to a statistically significant decline in sperm concentration and sperm motility.⁸ One study found that prophylactic vaccination with Gardasil in infertile, HPV infected men led to a statistically significant improvement in sperm motility when compared to motility before vaccination and compared to control groups of infertile HPV infected men who were not vaccinated.⁵ This study also found a significant difference in the number of successful pregnancies in the vaccine group when compared to the control group. Lastly, one study found that daily administration of antioxidants, Ellagic Acid and Annona Muricata, for three months led to a significant improvement in sperm motility.⁹

Conclusion: Studies have found that HPV infected sperm are subject to lipoperoxidation damage by increased levels of reactive oxygen species, leading to worse sperm concentration and motility. Poor sperm parameters worsen fertility outcomes, emphasizing the significance of HPV vaccination in males. Both prophylactic vaccination and antioxidants should be considered for treatment options in HPV infected infertile males.

Works Cited:

1. Isaguliants M, Krasnyak SS, Smirnova OA, Colonna V, Аполихин ОИ, Buonaguro FM. Genetic instability and anti-HPV immune response as drivers of infertility associated with HPV infection. Infectious Agents and Cancer. 2021;16(1). doi:10.1186/s13027-021-00368-1
2. Sucato A, Buttà M, Bosco L, Di Gregorio L, Perino A, Capra G. Human papillomavirus and male infertility: What do we know? International Journal of Molecular Sciences. 2023;24(24):17562. doi:10.3390/ijms242417562
3. Muscianisi F, Foresta C, Garolla A. Role of HPV vaccination for prevention of male infertility. Minerva Endocrinology. 2022;47(1). doi:10.23736/s2724-6507.22.03667-3
4. Muscianisi F, De Toni L, Giorato G, Carosso A, Foresta C, Garolla A. Is HPV the novel target in male idiopathic infertility? A Systematic Review of the literature. Frontiers in Endocrinology. 2021;12. doi:10.3389/fendo.2021.643539
5. Garolla A, De Toni L, Bottacin A, et al. Human Papillomavirus Prophylactic Vaccination improves reproductive outcome in infertile patients with HPV semen infection: a retrospective study. Scientific Reports. 2018;8(1). doi:10.1038/s41598-018-19369-z
6. Pellavio G, Todaro F, Alberizzi P, et al. HPV infection affects human sperm functionality by inhibition of aquaporin-8. Cells. 2020;9(5):1241. doi:10.3390/cells9051241
7. Pérez-Soto E, Medel-Flores MO, Fernández-Martínez E, Oros‐Pantoja R, Miranda-Covarrubias JC, Sánchez-Monroy V. High-Risk HPV with Multiple Infections Promotes CYP2E1, Lipoperoxidation and Pro-Inflammatory Cytokines in Semen of Asymptomatic Infertile Men. Antioxidants. 2022;11(6):1051. doi:10.3390/antiox11061051
8. Kato Y, Shigehara K, Nakagawa T, et al. Human papillomavirus detected in sperm of Japanese infertile males affects reproductive parameters. International Journal of Infectious Diseases. 2021;112:294-299. doi:10.1016/j.ijid.2021.09.029
9. La Vignera S, Basile L, Aversa A, et al. The Use of Ellagic Acid and Annona Muricata Improves Semen Quality in Men with High-Risk Papillomavirus Infection. Journal of Clinical Medicine. 2022;11(16):4691. doi:10.3390/jcm11164691