madman
Super Moderator
Coronavirus disease 2019 (COVID-19) has emerged as a new public health crisis, threatening almost all aspects of human life. Originating in bats, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted to humans through unknown intermediate hosts, where it is primarily known to cause pneumonia-like complications in the respiratory system.Organ-to-organ transmission has not been ruled out, thereby raising the possibility of the impact of SARS-CoV-2 infection on multiple organ systems. The male reproductive system has been hypothesized to be a potential target of SARS-CoV-2 infection, which is supported by some preliminary evidence. This may pose a global threat to male fertility potential, as men are more prone to SARS-CoV-2 infection than women, especially those of reproductive age.Preliminary reports have also indicated the possibility of sexual transmission of SARS-CoV-2. It may cause severe complications in infected couples. This review focuses on the pathophysiology of potential SARS-CoV-2 infection in the reproductive organs of males along with their invasion mechanisms. The risks of COVID-19 on male fertility as well as the differences in vulnerability to SARS-CoV-2 infection compared with females have also been highlighted.
1. Introduction
In early December 2019, several pneumonia cases of unknown etiology were reported in Wuhan, China. Genome sequencing studies confirmed these to be the result of a novel viral infection named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID19) [1]. As of 22 December 2020, the viral outbreak has spread globally across as many as 222 countries, thereby infecting more than 76 million people and causing over 1.6 million deaths [2].SARS-CoV-2 mainly enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), a receptor found predominantly on the surface of epithelial cells in the lungs [3]. This is believed to be the main reason behind the vulnerability of the respiratory system to SARS-CoV-2 infection. However, ACE2 is also expressed in various other tissues of the body, and as a result, there is a high probability of SARS-CoV-2 infection of other organ systems, including the digestive, urogenital, circulatory, central nervous, and reproductive systems [4].
Due to the high expression of the ACE2 receptor in testicular tissue in both somatic and germ cells, such as seminiferous duct cells, Leydig cells, Sertoli cells, and spermatogonia, there is increasing concern about the possible impact of SARS-CoV-2 infection on male fertility [5,6]. Moreover, ACE2-mediated SARS-CoV-2 invasion may lead to viral infection, which may also cause damage to testicular tissues [7]. This indicates that the testis is a potential target of SARS-CoV-2 invasion and that damage to testicular cells may severely hamper the process of spermatogenesis. A recent study reported significant impairment of sperm quality in a COVID-19 patient [8]. Moreover, young men, if infected, may be at a greater risk of testicular damage due to higher expression of the ACE2 receptor in comparison to patients more than 60 years of age, who show comparatively lower levels of expression and are hence less prone to such testicular damage [9]. Single-cell RNA sequencing data of adult human testes indicated a higher positive rate of ACE2 in infertile men. The authors further suggested that such men with reproductive disorders may be susceptible to SARS-CoV-2 infection through a pathway activated by ACE2 [9]. However, infection in testicular organs does not necessarily mean direct damage to sperm cells. In a recent study, a semen sample of only 15.8% of COVID-19 patients under surveillance was found to be positive for SARS-CoV-2 particles, even in recovering patients [10]. By contrast, in situ hybridization studies could not confirm the presence of any viral genetic material in testicular tissues, and the damage was attributed to the infiltration of inflammatory molecules in the testicular tissue during the immunological response of the virus [11]. Recently, another group of researchers has also reported the absence of SARS-CoV-2 in the semen and testis of men in the acute infection and recovery phases [12]. This review discusses the origin of SARS-CoV-2 and its mechanism of invasion along with potential infection of the reproductive system of the affected male.
2. SARS-CoV-2: history, origin and transmission
3. Possible mechanism of SARS-CoV-2 invasion into host cells and immune pattern of infection
4. Effect on the male reproductive system
5. SARS-CoV-2 and male fertility
6. Gender-based susceptibility
7. Conclusion
Preliminary findings so far suggest the possibility of both direct and indirect infection of SARS-CoV-2 in the reproductive system of males and possible impact on general health and well-being potentially leading to infertility. Evidence indicates a possible long-term effect of the pathogenicity of SARS-CoV-2 infection on testicular tissue, which may further impact reproductive performance. Moreover, the possibility of sexual transmission of SARS-CoV-2 cannot be ruled out.
8. Future perspective
The presence of SARS-CoV-2 nuclei has been confirmed in the testicular tissue of infected men using RT-qPCR technique, which is indicative of the direct viral invasion on the male reproductive system [101]. However, the evidence is not yet considered to be conclusive enough to definitely determine as to whether there are asymptomatic patients who need to avoid sexual intercourse with their female partners in order to prevent possible viral transmission[102]. SARS-CoV-2-infected men should be provided with psychological consultation in time to avoid irrational fear and excessive stress, as these may indirectly affect their reproductive health and well-being [71]. The effects of SARS-CoV-2 on the reproductive system of such men may also be elicited by viral infection-mediated immunomodulation and progressive inflammation [103]. Further research is also needed to develop specific treatment strategies for men with an impaired male reproductive system resulting from SARS-CoV-2 infection. In this regard, several therapeutic methods have been developed recently for the treatment of COVID-19 patients, such as mesenchymal stem cells [104], miRNA-based therapy (responsible for changing ACE-2 expression) [105] and hormone therapy [106]. Therefore, treatment regimens should also consider the androgen levels of men, as SARS-CoV-2 infection is believed to be associated with androgen secretion[9]. Management strategies such as cryopreservation and ART may be considered vital approaches in tackling specific clinical conditions of male infertility. To employ these strategies for COVID-19 patients, extra precautionary measures should be undertaken during the handling of semen to reduce the chances of viral transmission [85]. Accordingly, clinical trials should be conducted on SARS-CoV-2-infected male subjects of reproductive age, along with longitudinal studies in pediatric patients to understand the long-term effects of SARS-CoV-2 infection on testicular functions and spermatogenesis in such men [85]. In summary, existing evidence on the impairment of the reproductive system in men who have suffered and/or are suffering from COVID-19 is still preliminary in nature and further research can only reveal the exact mechanisms and impacts of SARS-CoV-2 infection clearly together with specific short- and long-term approaches for the management of these men.
1. Introduction
In early December 2019, several pneumonia cases of unknown etiology were reported in Wuhan, China. Genome sequencing studies confirmed these to be the result of a novel viral infection named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID19) [1]. As of 22 December 2020, the viral outbreak has spread globally across as many as 222 countries, thereby infecting more than 76 million people and causing over 1.6 million deaths [2].SARS-CoV-2 mainly enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), a receptor found predominantly on the surface of epithelial cells in the lungs [3]. This is believed to be the main reason behind the vulnerability of the respiratory system to SARS-CoV-2 infection. However, ACE2 is also expressed in various other tissues of the body, and as a result, there is a high probability of SARS-CoV-2 infection of other organ systems, including the digestive, urogenital, circulatory, central nervous, and reproductive systems [4].
Due to the high expression of the ACE2 receptor in testicular tissue in both somatic and germ cells, such as seminiferous duct cells, Leydig cells, Sertoli cells, and spermatogonia, there is increasing concern about the possible impact of SARS-CoV-2 infection on male fertility [5,6]. Moreover, ACE2-mediated SARS-CoV-2 invasion may lead to viral infection, which may also cause damage to testicular tissues [7]. This indicates that the testis is a potential target of SARS-CoV-2 invasion and that damage to testicular cells may severely hamper the process of spermatogenesis. A recent study reported significant impairment of sperm quality in a COVID-19 patient [8]. Moreover, young men, if infected, may be at a greater risk of testicular damage due to higher expression of the ACE2 receptor in comparison to patients more than 60 years of age, who show comparatively lower levels of expression and are hence less prone to such testicular damage [9]. Single-cell RNA sequencing data of adult human testes indicated a higher positive rate of ACE2 in infertile men. The authors further suggested that such men with reproductive disorders may be susceptible to SARS-CoV-2 infection through a pathway activated by ACE2 [9]. However, infection in testicular organs does not necessarily mean direct damage to sperm cells. In a recent study, a semen sample of only 15.8% of COVID-19 patients under surveillance was found to be positive for SARS-CoV-2 particles, even in recovering patients [10]. By contrast, in situ hybridization studies could not confirm the presence of any viral genetic material in testicular tissues, and the damage was attributed to the infiltration of inflammatory molecules in the testicular tissue during the immunological response of the virus [11]. Recently, another group of researchers has also reported the absence of SARS-CoV-2 in the semen and testis of men in the acute infection and recovery phases [12]. This review discusses the origin of SARS-CoV-2 and its mechanism of invasion along with potential infection of the reproductive system of the affected male.
2. SARS-CoV-2: history, origin and transmission
3. Possible mechanism of SARS-CoV-2 invasion into host cells and immune pattern of infection
4. Effect on the male reproductive system
5. SARS-CoV-2 and male fertility
6. Gender-based susceptibility
7. Conclusion
Preliminary findings so far suggest the possibility of both direct and indirect infection of SARS-CoV-2 in the reproductive system of males and possible impact on general health and well-being potentially leading to infertility. Evidence indicates a possible long-term effect of the pathogenicity of SARS-CoV-2 infection on testicular tissue, which may further impact reproductive performance. Moreover, the possibility of sexual transmission of SARS-CoV-2 cannot be ruled out.
8. Future perspective
The presence of SARS-CoV-2 nuclei has been confirmed in the testicular tissue of infected men using RT-qPCR technique, which is indicative of the direct viral invasion on the male reproductive system [101]. However, the evidence is not yet considered to be conclusive enough to definitely determine as to whether there are asymptomatic patients who need to avoid sexual intercourse with their female partners in order to prevent possible viral transmission[102]. SARS-CoV-2-infected men should be provided with psychological consultation in time to avoid irrational fear and excessive stress, as these may indirectly affect their reproductive health and well-being [71]. The effects of SARS-CoV-2 on the reproductive system of such men may also be elicited by viral infection-mediated immunomodulation and progressive inflammation [103]. Further research is also needed to develop specific treatment strategies for men with an impaired male reproductive system resulting from SARS-CoV-2 infection. In this regard, several therapeutic methods have been developed recently for the treatment of COVID-19 patients, such as mesenchymal stem cells [104], miRNA-based therapy (responsible for changing ACE-2 expression) [105] and hormone therapy [106]. Therefore, treatment regimens should also consider the androgen levels of men, as SARS-CoV-2 infection is believed to be associated with androgen secretion[9]. Management strategies such as cryopreservation and ART may be considered vital approaches in tackling specific clinical conditions of male infertility. To employ these strategies for COVID-19 patients, extra precautionary measures should be undertaken during the handling of semen to reduce the chances of viral transmission [85]. Accordingly, clinical trials should be conducted on SARS-CoV-2-infected male subjects of reproductive age, along with longitudinal studies in pediatric patients to understand the long-term effects of SARS-CoV-2 infection on testicular functions and spermatogenesis in such men [85]. In summary, existing evidence on the impairment of the reproductive system in men who have suffered and/or are suffering from COVID-19 is still preliminary in nature and further research can only reveal the exact mechanisms and impacts of SARS-CoV-2 infection clearly together with specific short- and long-term approaches for the management of these men.
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