A Review of the Impact of Covid-19 on the Male Genito-Urinary Tract

Introduction and Objectives: Since its advent in 2019, Corona Virus Disease 19 (Covid-19) has changed everyday life in many unprecedented ways. With the availability of Covid-19 vaccines, clinical practice has stepped gradually towards its everyday routine. The clinician, however, needs to address such concerns as “Can Covid-19 present with urinary tract symptoms predominantly?”, “Can the urinary tract develop long-term Covid-19 symptoms?”, “Can Covid-19 vaccines/drug therapy cause male infertility?” Methods: This mini-review of the current literature has been carried out by searching the Pubmed database. Results and Conclusions: Our literature review suggests that there is insufficient evidence to conclude a significant impact on the urinary tract from Covid-19 infection. There is supporting evidence that mRNA anti-SARS-CoV-2 vaccines are safe for male gonads. Research to further support these conclusions is required.

ACE2 is highly expressed in Sertoli, Leydig cells as well as spermatogonia in human males [9]. There is also evidence that SARS-CoV-2 could be transmitted through the reproductive system [10] [11]. This review aims to summarize the literature on Covid-19 related male genitourinary tract symptoms.

Materials and Methods
We reviewed the current literature regarding Covid-19 related, male genitourinary tract symptoms, and signs as well as associated findings by searching the Pubmed database. Although this is not a systematic review, compliance with PRISMA criteria has been maintained wherever possible.

Research Inclusion Criteria
A spectrum of meta-analyses, systematic reviews, and clinical trial as well as clinical reports has been included.

Types of Patients
Adolescents that have evidently been through the Covid-19 infection from the beginning of pandemic until March 2022 as well as men that have been vaccinated with the mRNA type of vaccine against SARS-CoV-2.

Complications
All complications are from the urinary tract as well as the male genital system that required either hospitalisation or review from a specialist. Such complications have been divided into 3 main arms: 1) presenting symptoms; 2) "long-term Covid" complications; 3) the impact of mRNA vaccines on male fertility.

SARS CoV-2 and Urinary Tract
It has been broadly documented that SARS-CoV-2 viral RNA can be detected in human urine, the duration of viral shedding though remains unclear [12]. However, there have only been scarce reports that the main onset of Covid-19 infection's symptoms could be the excretory urinary tract (Table 1). In a publication from Luciani et al. [13] three patients had hematuria as a presenting symptom of Covid-19 infection. Sighinolfi et al. [14] expressed concern that symptoms of Covid-19 infection may overlap those of urosepsis. In another study, 7/57 male Covid-19 patients had increased urinary frequency as a presenting symptom [15].
The concentration of proinflammatory cytokines in the urine of patients who Luciani et al. [13] Increased urinary frequency 7 Mumm et al. [15] complain of high urinary frequency appears to be higher than that of controls [16]. On the other hand, acute kidney injury (AKI) turns out to be one of the common pathologies of Covid-19 the extremely high mortality of which should make it an alarming sign for the clinician. The link between AKI and SARS-CoV-2 is believed to be ACE receptors [17] [18] because of C5b-9 deposition through CD68+macrophage mediation [19]. A special subcategory is renal-transplant patients. In a review paper published in 2021 regarding patients before the vaccines era [20], 31.6% of the patients required non-invasive ventilation while mortality rate was 15.4%, both appeared to be higher than that of the general population [21].

SARS CoV-2 and Male Reproductive System
According to "the human protein atlas" [24] ACE 2 receptors are expressed in testis, epididymis, seminal vesicles and prostate (Table 2). In addition, orchitis has been reported as a consequence of SARS-Co-V-1 infection [25]. Given the fact that SARS-CoV-2 clings to the ACE2 receptors, it could be hypothesized that male reproductive tissue damage could be an event of the Covid-19.
In 12 studies reviewed by Sengupta et al. [20] the presence of SARS-CoV-2 has been detected in only 2/12 studies. Li et al. [26] detected the virus in 6/38 patients 2 in acute stage, and 4 in recovery stage. Gacci et al. [27] found that in a sample of 43 men who have recovered from Covid-19, only one's semen tested positive for the presence of SARS-CoV-2. Similarly, Ma et al. [28] recorded that viral RNA has been detected in 1/12 patients who have moderately been compared to healthy individuals. The severity of the infection could play a role as in a study from Holtmann et al. [34], patients who underwent a moderate infection, had significantly lower total number of sperm per ejaculate, total number of motile sperm and progressively motile sperm compared to those who underwent a mild infection.

RNA Vaccines and Sperm Parameters
Unfortunately, toxicity on the male reproductive system has not been evaluated in the clinical trials of both RNA vaccines BNT162b2 (Pfizer-BioNtech) and mRNA-1273 (Moderna) no matter the association of SARS-CoV-2 with decreases in sperm parameters [41]. A small-sample-based, single-center, prospective study at the University of Miami concluded that sperm parameters in men who have received any of the 2 RNA vaccines, actually improved approximately 75 days after the second dose of any of these two vaccines [42]. In the same study, 8/45 men were oligospermic before vaccination, surprisingly 7/8 of these men became "normospermic" after the second dose while parameters like semen volume and sperm motility also significantly improved.

Conclusion
Although our impression is that Covid-19 primary manifestations from the male genitourinary tract are rare and not disease-specific, while long-term complications are relatively mild and RNA vaccines appear to be safe on the male genital and urinary systems, further research is required to either support or reject these hypotheses.

Consent for Publication
All authors consent for publication.

Author Contributions
All authors contributed in writing, editing, and finalizing the manuscript. Geor-