Why does COVID‐19 kill more elderly men than women? Is there a role for testosterone?

Abstract

Background Recent epidemiological data indicate that there may be a gender predisposition to COVID‐19, with men predisposed to being most severely affected, and older men accounting for most deaths. Objectives Provide a review of the research literature, propose hypotheses and therapies based on the potential link between testosterone (T) and COVID‐19 induced mortality in elderly men. Materials and Methods A search of publications in academic electronic databases, and government and public health organization web sites on T, aging, inflammation, severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS‐CoV‐2) infection, and COVID‐19 disease state and outcomes was performed. Results The link between T, the immune system and male aging is well‐established, as is the progressive decline in T levels with aging. In women, T levels drop before menopause and variably increase with advanced age. Elevated IL‐6 is a characteristic biomarker of patients infected with COVID‐19 and has been linked to the development of the acute respiratory distress syndrome (ARDS). Thus far, half of the admitted COVID‐19 patients developed ARDS, half of these patients died, and elderly male patients have been more likely to develop ARDS and die. Low T is associated with ARDS. These data suggest that low T levels may exacerbate the severity of COVID‐19 infection in elderly men. It may also stand to reason that normal T levels may offer some protection against COVID‐19. SARS‐CoV‐2 binds to the angiotensin‐converting enzyme 2, present in high levels in the testis. Conclusion At present, it is not known whether low T levels in aging hypogonadal males create a permissive environment for severe responses to COVID‐19 infection or if the virus inhibits androgen formation. Given the preponderance of COVID‐19 related mortality in elderly males, additional testing for gonadal function and treatment with T may be merited.

What’s Testosterone Got to Do with It? A Critical Assessment of the Contribution of Testosterone to Gender Disparities in COVID-19 Infections and Deaths

“…Several studies have indeed reported androgendependent upregulation of ACE2 and TMPRSS2 proteins in normal prostate tissue, prostate cancer cell lines, and lung cancer cell lines. [18][19][20][21][22][23][41][42][43] However, multiple studies have shown no differences between males and females in ACE2 and TMPRSS2 mRNA or protein expression in human or murine lung tissue, indicating that T is unlikely to upregulate these gene products in lung, [44][45][46][47][48][49] using a microarray gene expression data set generated from bronchial brushings of 504 healthy subjects reported that gender did not correlate with gene expression of any candidate host molecule involved in COVID-19 infection, and that ACE2 and TMPRSS2 were the lowest expressed genes of interest among those examined. 49 The authors suggested that alternative mechanisms in the respiratory mucosa may become important during COVID-19 infection, perhaps including other coreceptors.…”

ACE2, COVID-19 Infection, Inflammation, and Coagulopathy: Missing Pieces in the Puzzle

“…First, chronic airway disease, smoking, and pollution are associated with expansion of the population of alveolar macrophages expressing ACE2 ( Abassi et al, 2020d ). Furthermore, ACE2 expression is increased in males ( La Vignera et al, 2020 ; Papadopoulos et al, 2020 ). Indeed, bioinformatics analyses revealed higher abundance of ACE2-expressing AT2 cells in men than women ( Wei et al, 2020 ), potentially enhancing viral susceptibility among men.…”

“…In addition, testosterone enhances AT1R expression in male, whereas estrogen preferentially upregulates AT2R expression in females ( Chanana et al, 2020 ). Finally, hypogonadal males are characterized by low T cell count which may provide unrestrained environment for severe responses to SARS-CoV-2 infection ( Papadopoulos et al, 2020 ). In sum, it is tempting to assume that enhanced expression of ACE2 in target organs and also of other molecules permissive to viral binding to ACE2 facilitate viral invasion and augment viral load ( Figure 3 ), although the details of this formulation require validation in further studies.…”

Why COVID-19 Transmission Is More Efficient and Aggressive Than Viral Transmission in Previous Coronavirus Epidemics?

“…Importantly, this ACE2 and TMPRSS2 up-regulation was also associated with the up-regulation of the androgen pathway, suggesting that the smoking-mediated increased activity of the androgen signaling pathway itself and up-regulation of the central regulators of androgen pathways (e.g., HDAC6, CTNNB1, and SMARCA4) paired with the increased ACE2 and TMPRSS2 expression could represent a mechanism for the increased susceptibility of smokers to SARS-CoV-2 [ 295 ]. Importantly, the opportunity for SARS-CoV-2 infection of being androgen-mediated [ 296 ] via the androgen receptor-TMPRSS2 link, where the transcription of the TMPRSS2 is controlled by the androgen receptor activity [ 297 ], can represent a mechanistic explanation for the known sex-related differences in the COVID-19 vulnerability and lethality, with males typically being more susceptible to the infection [ 298 , 299 , 300 ]. This also suggests that androgen deprivation therapy, leading to the reduction of the TMPRSS2 expression, thereby limiting SARS-CoV-2 cellular entry, could potentially protect against severe complications from COVID-19 [ 301 , 302 , 303 ].…”