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

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

Outcome Disparities Among Men and Women With COVID-19: An Analysis of the New York City Population Cohort

“…One study implied that 5-alpha reductase inhibitors, which prevent the conversion of testosterone to dihydrotesterone, might reduce ACE2 levels and thereby blunt viral infectivity, suggesting a potential differential impact of testosterone and dihydrotesterone levels. 21 Similarly, research suggests that spironolactone may have a protective effect with regard to COVID-19 given a weakly anti-androgenic activity as well as some cardio-and reno-protective effects. 22 Our data suggest that the differences in risk of adverse outcomes diminish as men and women age; men older than 75 had the least magnitude difference in relative risk of hospitalization and death compared to age matched women.…”

Repurposing existing drugs for COVID-19: an endocrinology perspective

“…The rationale for their use is based on the blockage of conversion of testosterone into 5alplha-DHT and mitigation of TMPRSS2 expression [128][129][130], eventually hampering the overrepresentation of males, particularly bald ones, in severe COVID-19. Their benefits may be exhibited if used as a preventive strategy or during the first stage of COVID-19, and has demonstrated correlations with lower severity, although causality could not be established [131,132]. There is one clinical trial currently testing dutasteride in COVID- 19 [133].…”

SARS-CoV-2 infections with emphasis on pediatric patients: a narrative review

“…Estrogens seem to participate in the upregulation of ACE2 receptors activity leading to higher amounts of circulating ACE2 in women. A recent report has shown that inhibitors of the 5 alpha reductases, a class of drugs commonly prescribed for prostatic disorders, dampen the androgen signaling and can reduce the expression of ACE2 receptors and of the transmembrane serine protease TMPRSS2, theoretically leading to a decrement in SARS-CoV-2 binding with ACE2 receptors 18 .…”