Androgen sensitivity gateway to COVID‐19 disease severity

Abstract

In this communication, we present arguments for androgen sensitivity as a likely determinant of COVID-19 disease severity. The androgen sensitivity model explains why males are more likely to develop severe symptoms while children are ostensibly resistant to infection. Further, the model explains the difference in COVID-19 mortality rates among different ethnicities. Androgen sensitivity is determined by genetic variants of the androgen receptor. The androgen receptor regulates transcription of the transmembrane protease, serine 2 (TMPRSS2), which is required for SARS-CoV-2 infectivity. TMPRSS2 primes the Spike protein of the virus, which has two consequences: diminishing viral recognition by neutralizing antibodies and activating SARS-CoV-2 for virus-cell fusion. Genetic variants that have been associated with androgenetic alopecia, prostate cancer, benign prostatic hyperplasia and polycystic ovary syndrome could be associated with host susceptibility. In addition to theoretical epidemiological and molecular mechanisms, there are reports of high rates of androgenetic alopecia of from hospitalized COVID-19 patients due to severe symptoms. Androgen sensitivity is a likely determinant of COVID-19 disease severity. We believe that the evidence presented in this communication warrants the initiation of trials using anti-androgen agents.

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

“…A proposed androgen sensitivity model provides a link between increased disease severity in men and the role of androgens in COVID-19 ( 101 ). Androgen sensitivity is primarily determined by genetic variants of the AR.…”

“…While men are generally predisposed to these effects due to higher testosterone levels compared to women, individuals with hyperandrogenism and other conditions may similarly be impacted. For example, women with hirsutism and polycystic ovarian syndrome (PCOS), as well as women taking progesterone-based birth control, may be at greater risk for more severe COVID-19 symptoms ( 101 ). Markers of androgen sensitivity such as PCOS, androgenetic alopecia, and prostatic hyperplasia may thus be used as clinical signs of vulnerability.…”

Global dynamics of SARS-CoV-2 clades and their relation to COVID-19 epidemiology

“…32 Wambier and colleagues assumed androgen receptor genetic variation as a likely reason. 33 The receptor is thought to regulate transcription of the transmembrane protease serine 2 (TMPRSS2), responsible for S protein priming that allows viral fusion to host cell membranes. 32 To explain the role of genomic variation of SARS-CoV-2, the distribution of SARS-CoV-2 clades in viral genomes from male versus female patients was analyzed.…”

Structure of human steroid 5α-reductase 2 with anti-androgen drug finasteride

“…In particular, finasteride is among the top-100 most-prescribed drugs in the United States, which is associated with an irreversible action on SRD5α2 16,17 . Interestingly, androgen receptor signaling has recently been linked to COVID-19 disease severity, explaining why males are more prone to severe COVID-19 symptoms 18 . The 5ARI drugs have thus been suggested to hold the repurposing potential for treating COVID-19 18,19 .…”

“…Interestingly, androgen receptor signaling has recently been linked to COVID-19 disease severity, explaining why males are more prone to severe COVID-19 symptoms 18 . The 5ARI drugs have thus been suggested to hold the repurposing potential for treating COVID-19 18,19 .…”