Racial variations in COVID‐19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti‐androgens a potential treatment for COVID‐19?

Abstract

As the SARS-CoV-2 (COVID-19) pandemic continues to infect many more Americans, a racial disparity in the number of deaths from infection has emerged. On April 7, 2020, the Washington Post reported that counties with census demographics indicating a majority black population had almost six times the rate of death from COVID-19 as counties where the majority of residents were white.1 In the report, the deaths per hundred thousand residences for counties consisting of a majority white, Asian, black, and Hispanic populations was 1.1, 0.4, 6.3, and 0.6, respectively. There is undoubtedly a multifactorial etiology to this racial disparity that can include socioeconomic as well as other factors. However, a similar racial bifurcation is evident in conditions influenced by sensitivity to androgens, for example, prostate cancer and androgenetic alopecia.2, 3 Further, gender and age differences in the severity of COVID-19 disease and mortality rates have also been reported4 and might also be explained by an androgen-mediated mechanism. We have recently published two communications offering an explanation for a gender disparity in COVID-19 disease severity.5, 6 SARS-CoV-2 enters type II pneumocytes by binding to angiotensin-converting enzyme 2 (ACE2). Binding of SARS-CoV-2 to ACE2 is mediated by proteolytic cleavage of a viral surface protein by transmembrane protease, serine 2 (TMPRSS2).7-9 As such, concentrations and activity of both ACE2 and TMPRSS2 in host pneumocytes are crucial to SARS-CoV-2 ability to infect a host. Both ACE2 and TMPRSS2 are regulated by the androgen receptor; in fact, the 15-base-pair androgen response element is the only known transcription promoter for the TMPRSS2 gene.10-13 Androgen-mediated expression of ACE2 and TMPRSS2 may explain the gender difference in COVID-19 disease severity and mortality. Racial variations in other androgen-mediated conditions have been noted. For example, it has been reported that African American men are at higher risk for aggressive prostate cancer.2 Polymorphisms in the length of CAG repeat in exon 1 of the androgen receptor have been shown to correlate with incidence of prostate cancer.14 In a study of men without prostate cancer, Sator et al reported that the average CAG repeat length for non-Hispanic white men (n = 130) was 21.0, while the average CAG repeat length for African American men (n = 65) was 19.0. 15 In a study of men with prostate cancer, Bennett et al reported a CAG length of 21.9 in non-Hispanic white men (n = 168) and 19.8 in African American men (n = 151). Additionally, it was found that the occurrence of stage D prostate cancer (currently classified as High Risk) was highest in men with shorter CAG repeats.16 Racial variations in androgenetic alopecia (AGA) have also been reported to correlate with CAG length polymorphisms in the androgen receptor.3 Finally, while no direct association between CAG repeat length in the AR gene and SARS-CoV-2 viral infectivity has been reported, studies in animal models demonstrated the effect of androgens (testosterone) on influenza disease severity.17 In males, testosterone's biological action is dependent on the length of the CAG repeat of the AR gene. Currently, our group is planning a clinical study to measure CAG length polymorphisms in patients hospitalized with COVID-19 infection. While a direct link between polymorphisms in the androgen receptor and COVID-19 disease severity has not been established, we believe that the similarities in racial and gender bias to other androgen-mediated conditions are noteworthy. If androgen sensitivity can be confirmed as a predisposition to SARS-CoV-2 disease severity, it could suggest the use of anti-androgens or androgen-modulating drugs as a means of treatment, either alone or combined with TMPRSS2 inhibitors. For example, anti-androgens like bicalutamide and enzalutamide or androgen modulators like finasteride and dutasteride may be beneficial. There is no conflict of interest.

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