**2. Observations and discussion**

#### **2.1 Possible mechanisms of how the SARS-CoV-2 can infect the testes**

As angiotensin-converting enzyme 2 receptors (ACSE2) expression is rich in testes, SARS-CoV-2 may bind these receptors to penetrate cells and initiate its intracellular replication and action (cytotoxicity) that disrupting the testicular hemostasis. Similarly, several studies reported that ACSE2 receptor expression is rich in human male gonads (spermatogonia, Leydig, Sertoli cells, and seminiferous ducts), thus SARS-CoV-2 can bind ACSE2 receptor to disrupt gonadal hemostasis and increase the risk of testicular dysfunction [19–22]. SARS-CoV-2 may cause spermatogenic failure [20]. However, **t**he detection of SARS-CoV-2 in human semen was 1 to 15 patients (6.66%) [23]. More importantly, Li et al. [24] detected the SARS-CoV-2 in the semen of patients with COVID-19 and the semen of recovering cases. However, this study was limited to 50 patients only and a short time. Previously, SARS-CoV and NL63 coronavirus (NL63-CoV) can propagate inside the host cells by binding the cell surface ACE2 [25, 26]. SARS-CoV can disrupt spermatogenesis causing orchitis [27] and infect Leydig cells and testicular epithelial cells [28]. The previous findings could be attributed to SARS-CoV-2-induced pneumonia, neutropenia, lymphopenia, and hypo-albuminemia [29], and immunosuppressive state and cytokine storm [13, 14]. This state could be illustrated by the variation in the levels of several interleukins (IL-1β, IL-10, and IL-4), interferons (interferon-inducible protein 10, and interferon-gamma (IFN-γ)), and monocyte chemoattractant protein 1 (MCP-1) [13, 14]. Alternatively, SARS-CoV can elevate the levels of lipid peroxidation (LPO) and generally reactive oxygen species (ROS), causing oxidative stress (OS) and testicular dysfunction [30].

Another possible mechanism is that in severe states, COVID-19 disease can increase body/testes temperature, which may destroy the germ cell in the long term. Concomitantly, the viral infection-induced fever disrupts the male reproductive homeostasis [22]. In similar, severe fever in SARS-CoV causes congestion and mild fibrosis in the testes, disrupting the testicular hemostasis [27]. There was a reduction in the sperm number and fragmentation in the sperm DNA in males recovering from COVID-19 disease and fever [31, 32]. This variation can deteriorate fertility, delay embryo development, and augment abortion [33]. Importantly, fever alone can damage the spermatogenesis process [34] and destruct the Sertoli and germ cells [27].

The final mechanism is that SARS-CoV-2 infection causes stress, panic, and anxiety states, causing brain disorders that may perturb the hypothalamic– pituitary-testes-axis (HPTA). Also, the disturbance in the hypothalamic–pituitary axis can vary the sex hormones and adrenaline that support sexual activities [35]. SARS-CoV might cause leukocyte infiltration in testes [36], disrupt the functions of Leydig cells and the production of testosterone, destroy the seminiferous epithelium, and damage the blood-testis barrier [27]. Interestingly, the elevation in the level of serum IgG was reported in SARS-CoV patients [37]. This elevation could degenerate the Sertoli and germ cells, causing autoimmune orchitis [27]. Mumps orchitis could be attributed to the reduction in the level of testosterone and an increase in the follicular stimulating hormone (FSH) and luteinizing hormone (LH) levels [38]. In general, the virus can cause orchitis and sterility and increase the risk of the testicular tumor [39–41]. This damage may lead to hypogonadism [42] and decrease the number of Leydig cells [43]. In similar, male infertility might initiate by several viruses such as human papillomavirus (HPV) [44], herpes simplex viruses (HSVs) [45], human immunodeficiency viruses (HIV) [46], hepatitis B virus (HBV) [47], hepatitis C virus (HCV) [48], *Mumps orthorubulavirus* virus (MuV) [49], and Bluetongue virus (BTV) (an arbovirus of ruminants) [50].

#### **2.2 Sexual transmission, sexual behavior, pregnancy, and progeny**

The SARS-CoV-2 can transfer via respiratory droplets from human-to-human [51], feces [52], blood [53], or semen [24, 54, 55]. SARS-CoV-2 can form a systemic local infection in the male reproductive system due to the disruption in the barriers between testes, blood, vas deferens, and epididymis barriers [24, 54, 55]. However, the transportation of SARS-CoV-2 through semen was absent during the sexual process [56]. This absence may be due to the defense barrier between the testes and blood [57]. Importantly, real-time polymerase chain reaction (RT-PCR) has failed to designate SARS-CoV-2 sequences in the testicular tissues [43, 58].

The infection of SARS-CoV-2 may transfer during the sexual activity between the couples who have COVID-19 disease [59]. Moreover, saliva contact (physical process) between couples can increase the risk of virus transmission [12, 60]. On the other hand, pregnant women during the last trimester of pregnancy are more vulnerable to SARS-CoV-2 infection [61]. Moreover, cerebral vasculitis [62] and maternofetal T helper 2 (Th2) disorder [63] could damage the placenta. In Iran, 7 from 9 infected pregnant women with SARS-CoV-2 were dead [64]. A few data have supported this route [64]. However, most studies neglected the risk of the vertical route of SARS-CoV-2 between dams and their offspring [65–67]. On the other hand, the infected breast milk with SARS-CoV-2 or the close contact between neonates and infected dams with COVID-19 disease can be other routes for the possibility of SARS-CoV-2 transmission [68].

More importantly, the outbreak of infectious diseases can put the dams and their neonates in a risky state [69]. Likewise, SARS-CoV 2003 might disrupt the maternofetal immune system, causing abortion [70] or intrauterine growth restriction (IUGR) [71]. This disruption may delay neonatal health and cause neurodevelopmental disorders [72]. However, the severity and duration of this disruption on offspring are not identified completely. A healthy dietary supplementation and proper awareness during the perinatal period should be followed during this epidemic period to avoid this disorder. Also, anti-inflammatory treatments will be supportive to treat fertility problems [22].

#### **3. Conclusion**

This chapter showed three possible mechanisms of how the SARS-CoV-2 can infect the testes (**Figure 1**): **(1)** SARS-CoV-2 may bind ACSE2, disrupting the

*Crosstalk between SARS-CoV-2 and Testicular Hemostasis: Perspective View DOI: http://dx.doi.org/10.5772/intechopen.98218*

#### **Figure 1.**

*Summary about the expected mechanisms of SARS-CoV-2 (COVID-19) on testicular hemostasis. Here, ACSE2 is angiotensin-converting enzyme 2, and HPTA is hypothalamic–pituitary-testes-axis.*

testicular hemostasis. **(2)** SARS-CoV-2 and its COVID disease can increase the temperature of the testes, destroying the germ cell in the long term. This severity may be age-dependent and depending on the expression and distribution of testicular ACSE2 receptors. **(3)** SARS-CoV-2 and its COVID disease may perturb the HPTA. In the future, SARS-CoV-2 may directly or indirectly change the world's demographics [73]. Thus, preserving the testicular hemostasis may play a dynamic role in a healthy life for the offspring. Additional studies are desired to explore these issues.

#### **4. Recommendations**

As there is limited information about the complications of SARS-CoV-2 on reproductive organs, the current findings warrant the risk of the occurrence of orchitis and recommend the following-up and evaluation of the testicular hemostasis (andrological health) in the infected males with SARS-CoV-2. Also, avoid sex activity between the couples who have SARS-CoV-2 infection or symptoms of COVID-19 was recommended. In cases that recovered from COVID-19, the endothelial disorder may cause erectile dysfunction as a pathophysiological condition [74, 75]. Importantly, couples should be avoided the fear of virus transmission during the sexual process because this fear can decrease the sexual desire and quality of sex activity [76]. Moreover, these severe conditions can increase abortion, menstrual disorders, and psychological problems (depression, poor mood, nervousness, or irritability) [77].

On the other hand, recovered dams from symptoms of COVID-19 should use an artificial feeding pump, wash their hands, and wear a mask before and during the breasting feeding process [78]. Evaluation of gonadal function and genital examination for patients recovered from COVID-19 should be warranted. More importantly, the American Society for Reproductive Medicine (ASRM) recommended suspending all types of assisted reproductive techniques (ART),

including intrauterine inseminations (IUIs) or in vitro fertilization (IVF) during the COVID-19 pandemic [79], particularly, for patients who have immunocompromised diseases (AIDS, cancer, or malnutrition) or chronic diseases (cardiovascular, hepatic, or renal diseases, hypertension, and diabetes mellitus) [80, 81]. Similarly, the French Biomedicine Agency (ABM) suspended ART during this period [82]. Finally, the social contact between ART professional groups and patients should be online during this period.
