Understanding the Implications of COVID-19 on Male Reproductive Health: Comprehensive Analysis of the Effects of N Protein-Based Vaccines


COVID-19 is a global pandemic that has affected millions of people worldwide. The virus that causes COVID-19, SARS-CoV-2, can infect various organs and tissues in the human body, including the male reproductive system.

Several studies have reported that COVID-19 can cause inflammation, oxidative stress, and apoptosis in the testes, leading to impaired spermatogenesis and reduced sperm quality.

Moreover, COVID-19 can also affect the levels of sex hormones, such as testosterone and estradiol, which are essential for maintaining male fertility and sexual function.

One of the strategies to combat COVID-19 is to develop effective vaccines that can elicit protective immune responses against the virus. Several vaccines have been authorized for emergency use in different countries, and many more are under development. Most of these vaccines target the spike protein of SARS-CoV-2, which is responsible for binding to the host cell receptor and facilitating viral entry. However, some vaccines also target other viral proteins, such as the nucleocapsid (N) protein, which is involved in viral replication and assembly.

The N protein-based vaccines aim to induce both humoral and cellular immunity against SARS-CoV-2 by presenting the N protein antigens to the immune system. However, there is a potential risk that these vaccines may also trigger autoimmune reactions against the host cells that express similar or homologous proteins.

In particular, some studies have suggested that the N protein of SARS-CoV-2 shares sequence and structural similarities with several human proteins that are expressed in the male reproductive system, such as protamines, histones, and transition proteins. These proteins are essential for sperm chromatin condensation and DNA protection during spermatogenesis.

Therefore, it is possible that the N protein-based vaccines may induce cross-reactive antibodies or T cells that can recognize and attack the host sperm proteins, resulting in damage to the male reproductive system and reduced fertility.

Impact on Male Reproductive Health

SARS-CoV-2 infection has been shown to affect the male reproductive system, leading to altered spermatogenesis and endocrine production, potentially impacting fertility. The inflammatory cascade, direct cell damage, and fever have been implicated as contributing factors. However, limited research exists on the adverse effects of SARS-CoV-2 vaccines on the male reproductive tract, and clinical trials in this regard are lacking.

Previous studies on Spike protein-based vaccines have shown no significant changes in seminal patterns. Nevertheless, as the number of vaccine candidates increases, a comprehensive understanding of the impact of various viral peptides on male fertility, including spermatogenesis and the endocrine system, becomes crucial.

This study aimed to evaluate the safety of a potential vaccine based on the N protein for male reproduction. The research analyzed possible changes in the testes, epididymis, seminal vesicles, and prostate gland of rats inoculated with the isolated N protein. Additionally, the study examined the vaccine’s effect on serum levels of sex hormones, including total and free testosterone, luteinizing hormone (LH), and estradiol (E2). These findings would provide insights into the impact on male endocrine function, fertility, and the occurrence of eugonadism or hypogonadism.


Histological analysis of the male reproductive tract revealed no significant histopathological changes between the control group and the group inoculated with the N protein. Notably, there was no significant damage to Leydig cells responsible for testosterone production. Previous studies on COVID-19 patients did not find evidence of orchitis or testicular tissue damage associated with SARS-CoV-2 infection or the N protein.

The presence of the virus in testicular tissues or seminal alterations could not be confirmed. The protective role of the blood-testis barrier in preventing histopathological alterations was also questioned. Considering that only N protein epitopes were used in the study, viral aggression was excluded as a cause of the findings. Therefore, the study concluded that immunization with the N protein does not affect male reproductive tract tissues.

Regarding sex hormone levels, the study observed lower serum levels of total and free testosterone in the N protein group, while other hormones did not show statistically significant changes. Sertoli and Leydig cells play critical roles in androgen production and spermatogenesis regulation.

Previous studies have identified alterations in testicular endocrine function in COVID-19 patients, including increased LH levels and decreased testosterone/LH ratios, indicative of transient hypogonadism. Additionally, low testosterone levels have been observed in COVID-19 patients with testicular alterations.

The regulation of hormones is complex and involves multiple factors beyond the gonads. Therefore, further research is needed to better understand the impact of N protein immunization on the male endocrine system.

The study had certain limitations, including a small sample size, which may have impacted the results. Moreover, the study did not conduct comprehensive immunohistochemical analyses of the discovered histopathological tissue changes. Another potential confounding factor was the use of a control group inoculated with a protein solution similar to the production of the N protein vaccine.

Prolonged storage time of samples, both tissue and serum, could have influenced the preservation and accuracy of the measurements. Additionally, the absence of pre-inoculation measurements of sex hormones limits the interpretation of the results concerning the influence of the N protein on male endocrine function.

The study acknowledges that its findings provide initial insights into the effects of the immune response elicited by N protein inoculation on the male reproductive tract. However, further research with larger cohort studies is necessary to determine whether hormonal alterations have additional influencing factors beyond the host response. Prospective studies should explore the impact of long-term immunizations on male reproductive function, including fertility, testicular endocrine function, and the potential for male hypogonadism in the post-COVID-19 era.


In conclusion, this comprehensive study investigated the effects of N protein-based vaccination on male reproductive health. The results demonstrated no significant tissue damage in the testes, epididymis, prostate, or seminal vesicles. While there was a decrease in spermatozoa count in the control group, no histopathological changes were observed.

Serum levels of LH and E2 remained unchanged, while the N protein group showed lower levels of total and free testosterone. These findings suggest testicular involvement by a mechanism not yet understood.

Nonetheless, the study emphasizes the need for further research to better understand the impact of long-term immunizations on male reproductive function, including fertility and testicular endocrine function. The potential tendency towards hypogonadism, as observed in previous publications on the post-COVID-19 syndrome, warrants attention.

This study serves as an important foundation for future investigations and highlights the importance of considering the effects of vaccines on male reproductive health.

It contributes to the ongoing global efforts to combat the COVID-19 pandemic and provides valuable insights into the development of safe and effective vaccines for all individuals, including males. Continued research in this area will be crucial in ensuring the overall well-being of individuals and the global population in the face of this unprecedented health crisis.

reference link : https://www.frontiersin.org/articles/10.3389/fphys.2022.867444/full


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