Impact of SARS-CoV-2 on Male Reproductive Health: A Review of the Literature on Male Reproductive Involvement in COVID-19

Abstract

Coronavirus Disease 2019 (COVID-19) has created a global pandemic. Global epidemiological results show that elderly men are susceptible to infection of COVID-19. The difference in the number of cases reported by gender increases progressively in favor of male subjects up to the age group ≥60-69 (66.6%) and ≥70-79 (66.1%). Through literature search and analysis, we also found that men are more susceptible to SARS-CoV-2 infection than women. In addition, men with COVID-19 have a higher mortality rate than women. Male represents 73% of deaths in China, 59% in South Korea, and 61.8% in the United States. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the pathogen of COVID-19, which is transmitted through respiratory droplets, direct and indirect contact. Genomic analysis has shown that SARS-CoV-2 is 79% identical to SARS-CoV, and both use angiotensin-converting enzyme 2 (ACE2) as the receptor for invading cells. In addition, Transmembrane serine protease 2 (TMPRSS2) can enhance ACE2-mediated virus entry. However, SARS-CoV-2 has a high affinity with human ACE2, and its consequences are more serious than other coronaviruses. ACE2 acts as a "gate" for viruses to invade cells and is closely related to the clinical manifestations of COVID-19. Studies have found that ACE2 and TMPRSS2 are expressed in the testis and male reproductive tract and are regulated by testosterone. Mature spermatozoon even has all the machinery required to bind SARS-CoV-2, and these considerations raise the possibility that spermatozoa could act as potential vectors of this highly infectious disease. This review summarizes the gender differences in the pathogenesis and clinical manifestations of COVID-19 and proposes the possible mechanism of orchitis caused by SARS-CoV-2 and the potential transmission route of the virus. In the context of the pandemic, these data will improve the understanding of the poor clinical outcomes in male patients with COVID-19 and the design of new strategies to prevent and treat SARS-CoV-2 infection.

Keywords: ACE2; COVID-19; SARS-CoV-2; gender differences; male fertility; tmprss2.

Figure 1

The structure of coronavirus spikes includes: S1, S2, TM, IC, RBD. The RBD hidden in the spikes for immune evasion. When recognizing the ACE2 receptor, the RBD stands up to bind the receptor. The furin pre-activation of the spike can enhance the ability of the virus to enter certain cells. At the cell membrane, SARS-CoV-2 recognizes the ACE2 receptor and recruits TMPRSS2. TMPRSS2 facilitates viral entry and spreads into the host cell by cleaving ACE2 and S protein. S1, receptor-binding subunit 1; S2, membrane fusion subunit 2; TM, transmembrane anchor; IC, intracellular tail; RBD, receptor-binding domain; ACE2, angiotensin-converting enzyme 2; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; TMPRSS2, type II transmembrane serine protease.

Figure 2

Data on the proportion of males infected with SARS-CoV-2 from 33 articles.