Zhang-song Wu, M.D. (1,2), Jie Deng, M.D. (1,2), Song Wu, Ph.D. (1,2,3)
(1) Department of Urological Surgery, The Third Affiliated Hospital of Shenzhen University,
Shenzhen University, Shenzhen, 518000, China.
(2) Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of
Shenzhen University, Shenzhen University, Shenzhen, 518000, China.
(3) Department of Urological Surgery, The First Affiliated Hospital of Guangzhou Medical
University, Guangzhou Medical University, Guangzhou, 510120, China.
COVID-19 disease, induced by SARS-CoV-2 (also known as 2019-nCoV), typically characterized by respiratory symptoms, causes a general panic situation that is drastically changing our health and perspective. Intriguingly, the available epidemiological data across the globe have documented the higher incidence of infection, morbidity, and mortality among males1. In addition, virologic evidence has illustrated that SARS-CoV-2 mainly relies on binding to the angiotensin- converting enzyme 2 (ACE2) receptor for entry and the transmembrane protease serine 2 (TMPRSS2) for spike protein priming, both of which are known to be present in the testis2. Thus, more attention needs to be raised about the potential link between male genital system and SARS-CoV-2.
Male susceptibility and poorer prognosis
Statistically, men are more vulnerable to the COVID-19 diseases than women are, with even more poor prognoses and higher mortality. The grim figures show that males represent 73% of deaths in China, 59% in South Korea, and in 70% in Italy3. One major variable in vulnerability and severity of COVID-19 comes down to basic biological differences between men and women. Firstly, the discrepancies in vulnerability to virus infections are likely due to inherent differences in the viral transmission-and pathogenesis-associated molecular of females and males, such as TMPRSS2 and ACE2. It is reported ACE2 expression was notably up-regulated in male testes, while the very little expression of ACE2 was seen in ovarian tissue4. With regard to TMPRSS2, the transcription of TMPRSS2 gene may solely rely on androgen receptor activity as lacking other identified TMPRSS2 gene promoter in humans to date5; Secondly, women exhibit stronger innate, cellular, and humoral immune responses to all pathogens contrast to men as a result of differences in the effects of sex hormones (e.g., estrogen, progesterone, and androgens) and the gene dosage on sex chromosomes (such as IL-13, IL-4, IL-10, XIST, TLR7, FOXP3), which contribute to be less susceptible to viral infections in females in contrast to males, even when infected with lower viral load levels or higher rate of viral clearance6. Indeed, a retrospective cohort study systematically estimated the viral loads in more than 3000 samples collected from 96 admitted patients with laboratory-confirmed SARS-CoV-2 infection, and the results showed that the virus persists longer with higher load, and peaks later in the respiratory tissue of patients with severe symptoms. Among the severe disease group, the duration of the virus was significantly longer in males than in females7. The other major factor is the pre-existing conditions, particularly hypertension, cardiovascular disease, chronic lung disease, kidney disease, diabetes and cancer, which have been deemed as the reliable predictor for viral susceptibility and poor prognosis. Unfortunately, these conditions all tend to be more common among males than females, which might account for some of the bias.
Effects on the male fertility
As all we know, there is accumulative evidence that it is common for viral infections (e.g., mumps and HIV) to negatively impact the male reproductive system, including the production of sperm and the formation of sex hormones8. Indeed, a preliminary study found the first clinical evidence the COVID-19 infection could harm male gonad functions by significantly wrecking the balance of sex hormones, suggesting the serum testosterone to luteinizing hormone (as a predictor of male gonadal function) could be a potential marker of impairment of reproductive health by SARS- CoV-29. In addition, a study recently reported another interesting and novel clinical observation, namely that 17.6% (6/34) of men reported scrotal discomfort at the time of COVID-19 infection, though no detection of virus shedding or seeding in the semen. However, it is important to note the small sample size and selection bias, as patients with milder symptoms, so it is conceivable that earlier time to definitively rule out the absence of SARS-CoV-2 in the seminal fluid, especially for patients with severe COVID-19 symptoms. Bolstering the link, SARS-CoV, a distant relative of the SARS-CoV-2 , also could damage the immune homeostasis in the testis, as the consequence of leading to the orchitis subsequently10. With a healthy dose of skepticism at this juncture, it thus might add the SARS-CoV-2 to the list of things that cause infertility issues. Nevertheless, the exact mechanism of testes impairment induced by virus is unclear: a minimum of three postulated mechanisms that we hypothesize as followings. Firstly, the testicular damage might be mediated by the infection itself. More precisely, ACE2 are considered as the receptors for binding and entry into host cells by SARS-CoV-22. Theoretically, any cells expressing ACE2 may be susceptible to SARS-CoV-2 infection, while testis (e.g., sertoli cells and steroidogenic Leydig cells) show the highest expression level of ACE2 protein and mRNA in the body according to previous studies11. Secondly, sertoli cells are regarded as important cells in the establishment and maintenance of testicular immune privilege probably relied on secreted immunosuppressive or immunoregulatory factors12, whereas sertoli cells potentially show high risk to serve as the targeted cells for SARS-CoV-2 as the above and subsequently contaminate the tightly controlled anti-inflammatory immune environment for sensitive germ cells. Thus, virus-induced adaptive immune response might account for medicating the testicular damages as well. Finally, raised testicular temperature has a detrimental effect on mammalian spermatogenesis and the resultant spermatozoa. For instance, previous studies have indicated that the effect of temperature on male genital system is evident with respect to the mean scrotal temperature in fertile men being lower than infertile men and the quality of sperm further deteriorating along with growing increases in scrotal temperature13. Considering that one of the onset symptoms of COVID-19 is a high fever, it’s reasonable to assume that men infected with coronavirus will undergo infertility as well. There is a theoretical possibility of testicular damage and subsequent infertility following COVID-19 infection. Follow-up studies of reproductive function of recovered male patients is required to investigate this possibility.
Potential sexual transmission and suspending fertility programs
The testes as a potential target organ might be affected by SARS- CoV-2 directly, or SARS- CoV-2 is able to cross the blood-testis barrier and indirectly enter the male reproductive tract just like other viruses. Thus, it is theoretically reasonable to believe that the unprecedented virus could be transmitted by semen. Despite that this hypothesis still needs to be substantiated in the future, international community unanimous raised warnings to this extend. For example, the American Society for Reproductive Medicine (ASRM) recommends postponing non-urgent infertility care, including in vitro fertilization and intrauterine inseminations, until after the crisis passes to reduce your risk of getting COVID-19. Coincidentally, in Italy, authorities have mandated that all gamete donors should be interviewed regarding a recent travel history to epidemic areas and for the development of respiratory symptoms. A 2-week suspension is implemented in the case of donors showing respiratory symptoms from the end of symptoms, or for those people who have returned from high-risk areas.
The diversity in the aspect of the interplays of sex chromosomes, sex hormones and immune responses, and pre-existing conditions may determine sexual differences in the virologic fight. Therefore, acknowledging the importance of such factors during the COVID-19 pandemic may not only answer why men are more susceptible to the COVID-19, but also offer reliable precautions and interventions to mitigate host vulnerability and disease severity. Due to the possible pathogenicity of the virus to the male reproductive system, and potential testis dysfunctions induced by high temperature, it is notably significant that clinicians should raise their concern about threats posed on the inpatients' fertility and later clinical follow-ups. Moreover, it also provides a reminder of the potential risk of contact transmission by semen, which suggests deterring non-urgent infertility care, including IUIs and IVF, or requires the indispensable self-protection for healthcare workers and cleaners while imperatively treating for the urgent testicular diseases for patients infected or suspected to be invected with COVID-19. Nevertheless, due to limited data available regarding the association between COVID-19 infection and male reproductive system at present, further research data is warranted before a definitive conclusion can be reached, so that patients can be adequately counseled and treated.
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