Let's talk about sex in the context of COVID-19

Abstract

In recent months, the coronavirus disease 2019 (COVID-19) pandemic has sent many countries into crisis. Studies have shown that this virus causes worse outcomes and a higher mortality in men than in women. It has been recognized that sex can affect the immune response to a pathogenic agent, as well as the susceptibility for some respiratory diseases. These different responses in males and females may be related to the actions of sex hormones. Angiotensin-converting enzyme 2 (ACE2) acts as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. The expression of ACE2 is influenced by sex hormones; therefore, we discuss in this article that this could be one of the reasons why COVID-19 is more prevalent in men than in women.

Keywords: ACE2; SARS-CoV; hormones; pandemic; sex difference.

Fig. 1.

Graphs of data from 35 countries who provided information on the number of COVID-19-related deaths by sex. Death rate expressed in % of data using only number of confirmed deaths. Represented are the data acquired on or before April 30, 2020.

Fig. 2.

Schematic illustration showing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binding of the spike protein with angiotensin-converting enzyme 2 (ACE2), which acts as a receptor for the virus. Viral S glycoproteins are activated by transmembrane serine protease 2 (TMPRSS2), which facilitates virus-cell membrane fusion. TMPRSS2 transcription is upregulated by the androgen receptor. This leads to viral entry into the cell by endocytosis.

Fig. 3.

Schematic illustration showing the classic renin-angiotensin system (RAS) and the sequential cleavage of protein substrates by specific proteases. The primary substrate for the RAS is angiotensinogen, which is converted by renin into angiotensin (Ang)-[1–10]. In a sequential reaction, the dicarboxyl-peptidase angiotensin-converting enzyme (ACE) cleaves Ang-[1–10] to form Ang-[1–8]. Angiotensin-[1–8] could bind to angiotensin AT₁ and AT₂ receptors, each with distinct functions, or could be degraded by angiotensin-converting enzyme 2 (ACE2) into a heptapeptide, Ang-[1–7]. ACE2 also can degrade Ang-[1–10] into a nonapeptide, Ang-[1–9]. ACE2 expression is regulated by hypoxia, IL-1β, and estradiol (E2) via histone deacetylase sirtuin 1 (SIRT1), which binds to the promoter region and facilitates ACE2 mRNA expression. Hypoxia and IL-1β can also be modulated by E2.