Very early in the short history of the SARS-CoV-2 pandemic, it was clear that the male gender was a risk factor for severe disease and an increased mortality rate [
10,
11]. Multiple reasons could justify this finding, but realistically the causality of this association can be found in a mixture of lifestyle patterns and other intrinsic gender-related biological characteristics, including comorbidities, genetic differences, and hormonal profile [
2]. The angiotensin-converting enzyme 2 (ACE2) is exploited by SARS-CoV-2 as its receptor, through which it can invade the host cells. ACE2 is highly expressed in human tissues, including Leydig and Sertoli cells, seminiferous duct cells, and spermatogonia, allowing to postulate their potential role as a viral target [
12]. Nonetheless, SARS-CoV-2 also requires additional mediators to facilitate the virus-host cell fusion [
13]; transmembrane protease serine 2 (TMPRSS2), in particular, by cleaving the spike protein, might have a role in the male reproductive system as its expression is regulated by androgens and it is known to be expressed in human prostate epithelial cells [
14]. Although evidence of simultaneous expression of these two proteins in the male genital trait is limited [
15,
16], this theoretical background has been generally accepted to hypothesize the risk of testicular infection and, thus, of testicular COVID-related damage, further supported by post-mortem detection of viral proteins in testicular tissue [
17,
18]. In order to infect and damage testicular cells, another necessary postulation is the arrival of the virus to the blood-testis barrier and its passing. While the latter can be achieved through cytokine-induced inflammation, which may alter the tight junctions of the Sertoli cells similarly to other viruses [
19], the virus’s arrival to the testis requires the presence of viremia. Although nasopharyngeal swab samples are the reference specimens, SARS-CoV-2 has been reported in a wide range of body fluids and tissues, especially urine, feces, and blood [
20]. While viral detection and loads may differ depending upon the sample characteristics, the severity of the disease and the timing from the primary infection, a SARS-CoV-2 viremia has been an inconstant finding [
12,
20]. It should be further stressed that clinically evident orchitis in SARS-CoV-2 has been inconsistently reported [
21‐
23], and recent reports and even a metanalysis showed an overall insignificant rate of detection of SARS-CoV-2 semen samples of COVID-19 patients [
4,
12]. A relatively old study reported the chance of orchitis as a manifestation of SARS-CoV [
24], and some recent studies from SARS-CoV-2 infections reported associations with testicular discomfort [
25] or testicular pain [
21]. The only certain association between testicular histological appearance of orchitis and presence of SARS-CoV-2 comes from post-mortem studies, where however the severity of the disease could have led to multiple organ failure, damage to the blood-testis barrier; as such, the orchitis-like appearance could rather be the result of a vasculitis secondary to COVID-19 related coagulation abnormalities of the testes vascularization [
23]. In fact, the SARS-CoV-2-related testicular endothelial dysfunction may trigger inflammatory cells and leukocytes (CD3+, CD68+) in the interstitial tissue, which was found in some of these patients [
26,
27]. Therefore, it is likely that the anatomical protection of the blood-testis barrier in association with the absent/low viremia in COVID-19 patients might hinder the SARS-CoV-2 progression towards the testes [
28]. A recent paper showed results from an andrological follow-up of a cohort of SARS-CoV-2 recovered patients with no known previous andrological comorbidities, highlighting that after three months from recovery no persistent damage to testicular function could be observed [
3]. In conclusion, it is relatively safe to assume that direct damage to the seminiferous tubules and spermatogenesis is a remote and probably clinically unimportant event in the vast majority of cases, at least in absence of significant comorbidities.