Photo: Cinemanikor/ Shutterstock
The coronavirus disease 2019 (COVID-19) pandemic outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to an unexpected global health crisis. It has adversely affected the healthcare systems of various countries and the renovation of medical procedures and protocols to curb the effects of the pandemic. These renovations include protocols and procedures in andrology laboratories to avoid negative impacts on assisted reproductive technologies outcomes.
The effect of SARS-CoV-2 infection on the quality of semen and sperm parameters that in turn reflects sperm quality and quantity is of great importance to healthcare providers and researchers worldwide. To date, more than 50 articles have been published in PubMed and Scopus databases that link SARS-CoV-2 infection with semen quality.
A new review article published in Andrologia aimed to extract, review and summarize these articles from the mentioned databases to determine the link between SARS-CoV-2 infection and semen quality.
The angiotensin-converting enzyme 2 (ACE- 2) receptor is responsible for the entry of the virus inside the cell and infection. Apart from the lungs, ACE-2 has also been detected in the testes. Therefore, testes and semen could be potential targets for SARS-CoV-2.
The presence of SARS-CoV-2 in the semen can negatively affect the sperm parameters and lead to male infertility. Additionally, it might have implications for sexually transmitted infections, congenital disease, embryonic infection, and miscarriage.
Recent studies conducted in different countries indicated that the presence of SARS-CoV-2 was not detected in the semen, and no transmission of SARS-CoV-2 was observed during assisted reproductive technologies.
Currently, seven studies have been conducted to determine the effect of SARS-CoV-2 infection on sperm parameters. Most of these studies were observational analytic. In most of these studies, the semen quality was analyzed during the recovery stage of the infection using RT-PCR.
The results indicated that out of the seven studies, six revealed a negative impact of SARS-CoV-2 infection on sperm parameters. The sperm count was found to be the most affected parameter by SARS-CoV-2 infection. However, further research needs to be done to provide more collective and robust information.
Spermatogenesis in human males is controlled by gonadal hormones such as testosterone, follicle-stimulating hormone, and luteinizing hormone. It was found that the luteinizing hormone and follicle-stimulating hormone controlled the number of Leydig cells in the testes. The Leydig cells, in turn, were responsible for the synthesis of testosterone.
It was observed that patients infected with COVID-19 had lower levels of luteinizing hormone and testosterone as compared with healthy individuals. Additionally, the patients were found to have higher levels of luteinizing and prolactin and lower levels of total testosterone compared with control. Furthermore, serious cases of COVID-19 were associated with a greater reduction in the total testosterone levels.
The increase in luteinizing hormone levels and decreased testosterone: luteinizing hormone ratio can lead to testicular dysfunction that might affect spermatogenesis.
It has been proven that the entry of SARS-CoV-2 inside the cells depends on the ACE-2 receptors and transmembrane serine protease 2. However, it has been observed that transmembrane serine protease 2 is expressed only in a subpopulation of germ cells, while ACE-2 receptors are expressed in Sertoli cells. Additionally, both ACE-2 and transmembrane serine protease 2 had limited expression in testicular tissues. This evidence supports that the entry of the virus into the testis is unlikely to occur.
However, a fever of 39 degrees centigrade or more for more than three days can lead to severe impairment of semen quality leading to azoospermia. It has been found that fever, even for a limited duration, can significantly reduce sperm parameters (e.g., count, motility, and/or vitality) and alter the integrity of sperm DNA. However, since fever is a common symptom of COVID-19, fever-induced COVID-19 can alter semen quality and reduce sperm parameters even in the absence of virus in the semen and immune responses.
Although the testes usually remain unaffected by the host response to antigens, it was found from autopsy samples of COVID-19 patients that several expressed proteins were downregulated in testicular tissues. The expression of insulin-factor-3, the most expressed protein in testicular tissue, especially Leydig cells, was found to be reduced in COVID-19 patients. This can lead to impairment of function and/or population in the Leydig cells. Another enzyme, the E3 ubiquitin-protein ligase, which is important for spermatogenesis and motility of the spermatozoa were found to be reduced in COVID-19 patients.
Additionally, the autopsied testicular samples of COVID-19 patients were found to have several histological/physiological disorders such as erythrocytes exudation in the epididymis and the testes and thinning in seminiferous tubules. Additionally, the seminiferous tubules in COVID-19 patients were found to have higher apoptotic cells than the control.
Furthermore, a study conducted on postmortem testicular specimens from eleven fatal cases of COVID-19 indicated several testicular histological changes such as vascular changes, basal membrane thickening, orchitis, Sertoli, and Leydig cell scarcity, and reduced spermatogenesis. Color Doppler ultrasound was used to diagnose testicular abnormalities in males with mild to moderate. The results from the diagnosis indicated that approximately 42 percent of men were found to have epididymitis, 19.2% had bilateralism, and 54.5 percent had enlarged epididymal head.
The immunohistochemistry of the autopsied samples obtained from COVID-19 patients showed IgG presence in the seminiferous tubules and increased macrophages and T lymphocytes in the interstitial cells. Additionally, higher concentrations of immune factors such as interleukin-6 and tumor necrosis factor-α were also found in the semen.
SARS-CoV-2 infection was also found to augment the T helper type 2 cells that disturb the level of interleukin-4 and activate several signal transcription pathways. The disturbing level of interleukin-4 ultimately reduced ACE-2 level with inflammation that negatively impacts male fertility in COVID-19 patients.
Furthermore, the multi-organ failure and tissue injury that has been associated with severe cases of COVID-19 are due to the onset of cytokine storms. Another cause for tissue damage and multi-organ dysfunction can be due to hemophagocytic lymphohistiocytosis (HLH). These multi-organ damages can lead to testicular damages that may negatively impact spermatogenesis and the quality of the semen produced.
The current study concludes that no evidence of SARS-CoV-2 was found in the semen at the symptomatic and recovery stages. However, SARS-CoV-2 infection was found to have adverse effects on sperm parameters, spermatogenesis, and semen quality. A SARS-CoV-2 infection could also lead to testicular damage and injury and alter the expression of the gonadal hormones. However, further confirmatory studies with larger populations are still desired to get the exact idea of the impact of SARS-CoV-2 infection on semen quality and spermatogenesis.