Abstract
CONTEXT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry is facilitated by transmembrane protease serine 2 (TMPRSS2), which is regulated by the androgen receptor (AR). Androgen deprivation therapy (ADT), widely used in prostate cancer treatment, may potentially modulate TMPRSS2 expression, affecting SARS-CoV-2 infection susceptibility and severity. OBJECTIVE: To evaluate the impact of ADT on pulmonary TMPRSS2 expression in prostate cancer patients and analyze differences in expression patterns associated with specific ADT regimens. DESIGN: We examined TMPRSS2 immunohistochemical expression in lung tissue from 20 consecutive autopsy cases of men with prostate cancer (6 receiving ADT at time of death), compared with non-ADT prostate cancer patients and age-matched women controls. Histoscores were calculated by assessing percentage and intensity of pneumocyte TMPRSS2 expression. RESULTS: Prostate cancer patients receiving ADT showed significantly reduced pulmonary TMPRSS2 expression compared to non-ADT patients (mean histoscores: 152.7 vs. 225.0, p=0.037) and age-matched women controls (mean histoscores: 152.7 vs. 238.0, p=0.024). Direct AR antagonists (apalutamide, bicalutamide) produced more pronounced TMPRSS2 suppression than GnRH modulators or androgen biosynthesis inhibitors. No significant correlation was observed between TMPRSS2 expression and Gleason score, PSA levels, or underlying lung pathology. CONCLUSION: Our findings demonstrate that ADT significantly reduces pulmonary TMPRSS2 expression, with direct AR antagonists showing the strongest effect. This suggests a potential mechanistic explanation for differential COVID-19 susceptibility and provides rationale for investigating AR-targeted therapies as potential protective interventions against SARS-CoV-2 infection severity.