Androgen Drives the Expression of SARS-CoV-2 Entry Proteins in Sinonasal Tissue.

Background And Objectives: Men have higher morbidity and mortality from COVID-19 than women, possibly due to androgen receptor-regulated viral entry protein expression. This led to a clinical trial of androgen deprivation therapy (ADT), which has not shown a significant benefit in the outcomes among hospitalized male COVID-19 patients. The aim of this study was to explore biological explanations for the failure of ADT to mitigate clinical outcomes in men with severe COVID-19 by assessing the role of androgen in regulating viral entry protein expression in the upper and lower respiratory tract.

Methods: Immunohistochemistry was used to assess the expression of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and how it correlated to androgen receptor expression in the sinonasal epithelium, minor salivary glands of the sinus, lacrimal glands, and lungs from mice pretreated with and without castration and ADT as well as the sinonasal epithelium obtained from healthy human donors and hospitalized COVID-19 patients.

Results: In murine models, castration and ADT treatment downregulated the expression of TMPRSS2 and ACE2 in the sinonasal epithelium, minor salivary glands of the sinus, and lacrimal glands, but not in the lungs. Correlative analyses using human tissue also showed a potential role of ADT in men during the early sinonasal phase but not in the later lung phase of SARS-CoV-2 infection.

Conclusions: Our study suggests a potential benefit of ADT in male patients with early COVID-19 when the virus enters the nasopharynx, but not in those with advanced disease. The downregulation of viral entry proteins in the upper respiratory system following androgen blockade may be a key mechanism for this effect.