Testosterone and Covid-19: An update

Abstract

There is overwhelming evidence to suggest that male gender is at a higher risk of developing more severe Covid-19 disease and thus having poorer clinical outcomes. However, the relationship between testosterone (T) and Covid-19 remains unclear with both protective and deleterious effects on different aspects of the disease suggested. Here, we review the current epidemiological and biological evidence on the role of testosterone in the process of SARS-CoV-2 infection and in mediating Covid-19 severity, its potential to serve as a biomarker for risk stratification and discuss the possibility of T supplementation as a treatment or preventative therapy for Covid-19.

Keywords: prostate; sexual medicine; testosterone.

FIGURE 1

Covid‐19 case fatality rates (CFRs) for males and females across 38 countries or regions reporting sex‐disaggregated data on Covid‐19 cases and deaths. (a) Male CFR is significantly higher than the female CFR in 37 of the 38 regions investigated, with an average male CFR 1.7 times greater than the average female CFR. (b) Covid‐19 CFR increases for both sexes with advancing age, but males have a significantly higher CFR than females at all ages from 30 years in 12 countries currently reporting sex‐ and age‐disaggregated data on Covid‐19 cases and deaths (Australia, Columbia, Denmark, Italy, Mexico, Norway, Pakistan, Philippines, Portugal, Spain, Switzerland and England). Reprinted by permission from Springer Nature© in Scully et al

FIGURE 2

SARS‐CoV‐2 structure, viral entry into host cells and the influence of testosterone. SARS‐CoV‐2 is made up of four structural proteins, including the spike (S), membrane, envelop and nucleocapsid proteins. The S protein has 2 functional domains known as S1 and S2. S1 is recognized and binds to angiotensin‐converting enzyme 2 (ACE2). Following ACE2 binding, cleavage of the viral spike protein (S) by proteases including transmembrane protease serine 2 (TMPRSS2) a crucial step to allow host cell membrane fusion and viral uptake. TMPRSS2 interacts with and primes ACE2 in this process and is considered crucial for host cell infection. TMPRSS2 transcription is exclusively regulated by the androgen receptor (AR) and ACE2 expression is increased in an androgen dependent manner (1). Mechanistically it is considered that androgen‐regulated TMPRSS2 promotes SARS‐CoV‐2 entry by two separate processes: ACE2 interaction/cleavage (2), which might promote viral uptake, and SARS‐2‐S cleavage, which enhances membrane fusion (3) via activation of the S protein. Created with BioRender.com

FIGURE 3

Hormone analysis in Covid‐19 subjects versus non‐infected controls. SARS‐Cov‐2‐infected patients were characterised by reduced total testosterone levels (a), whereas no difference in either follicular stimulating hormone (FSH) levels (b) or luteinizing hormone (LH) levels (c) was observed. Figure reproduced with permission from Corona et al