Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Abstract

SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.

Expression of concern: potential risk for developing severe COVID-19 disease among anabolic steroid users

“… 12 DHT is known to promote the expression of transmembrane serine protease 2 (TMPRSS2), and androgen signalling regulates SARS-CoV-2 infectivity. 13 TMPRSS2 plays a crucial role in COVID-19 infectivity and pathogenesis since COVID-19 employs it for spike protein priming before it is internalised in an ACE2-facilitated fashion. 14 DHT significantly increases ACE2 levels and internalisation of recombinant SARS-CoV-2 spike protein, and antiandrogens reduced SARS-CoV-2 infection in human embryonic cell-derived lung organoids.…”

Androgen-deprivation therapy and SARS-CoV-2 in men with prostate cancer: findings from the University of California Health System registry

“… 1 , 2 SARS-CoV-2 entry into host cells is facilitated by the transmembrane protease TMPRSS2, whose expression can be modulated by the androgen receptor. 3 Pre-clinical data suggests that ADT may protect from SARS-CoV-2 infection and decrease COVID-19 severity. 3 A registry study reported by Montopoli et al 1 demonstrated that ADT was associated with decreased COVID-19 incidence in Venetian men with prostate cancer.…”

“… 3 Pre-clinical data suggests that ADT may protect from SARS-CoV-2 infection and decrease COVID-19 severity. 3 A registry study reported by Montopoli et al 1 demonstrated that ADT was associated with decreased COVID-19 incidence in Venetian men with prostate cancer. However, this relationship was not observed by Koskinen et al 2 in a study of Finnish men.…”

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities

“…Recently, it was reported that an elevated androgen level increases the risk of SARS-CoV-2 susceptibility and severity in males. Androgen signaling inhibition reduces infectivity of SARS-CoV-2 in human embryonic stem cell (hESC)-derived lung organoids via decreasing the expression of ACE2 and TMPRSS2 levels [ 51 ].…”