Reply to the Letter to the Editor "Androgen deprivation therapy may constitute a more effective prophylactic than therapeutic strategy in COVID-19 patients" by N. Bennani and I. M. Bennani-Baiti.

We read with interest the correspondence by Bennani and Bennani-Baiti on our publication. The authors express concerns that our data do not support the hypothesis that androgen-deprivation therapy (ADT) is an effective therapy in patients with coronavirus disease 2019 (COVID-19) but may instead be used for prophylactic treatment.

Our observational study using data from the Veneto Cancer Registry indicates that ADT in patients with prostate cancer is associated with a reduced probability of developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. However, as highlighted by Bennani and Bennani-Baiti, the small sample size of patients with prostate cancer infected by SARS-CoV-2 under ADT in our study (N = 4 patients) did not allow us to evaluate whether ADT ameliorates the disease outcomes in infected patients. Thus, the results of validation analysis on larger patient cohorts, as well as of currently ongoing clinical trials investigating the contribution of androgen-suppression therapies for COVID-19 treatment, will be important to answer to this clinically relevant question.

Interestingly, a recent study from the United States involving 58 patients with prostate cancer infected by SARS-CoV-2 showed that the use of ADT was associated with lower rates of hospitalization and oxygen requirement, thus suggesting that ADT may limit severe COVID-19 complications.

Concerning the mechanism of action, the androgen-dependent regulation of TMPRSS2 expression in the lung represents one possible explanation for the increased susceptibility of men to the development of more severe SARS-CoV-2 infections. We agree with Bennani and Bennani-Baiti that data supporting this link are still controversial. Several studies have previously demonstrated that TMPRSS2 is regulated at the transcriptional and post-translational levels by androgens, mostly in the context of prostate tissue and prostate cancer. Moreover, androgen administration increases TMPRSS2 expression in human lung epithelial cells. However, in contrast to these findings, recent studies showed that the expression levels of TMPRSS2 and ACE2 in the human lung are lower when compared with other tissues such as the nasal cavity, the gallbladder, and the prostate. Finally, one recent paper showed that ADT has no effect on TMPRSS2 messenger RNA expression in mouse lungs.

Thus, clear evidence demonstrating that androgen receptor-dependent TMPRSS2 overexpression in the context of SARS-CoV-2 infections is still missing, and androgens might affect the severity of SARS-CoV-2 infection in men by other mechanisms, such as by modulating the immune response, as suggested in our article and further stressed by Bennani and Bennani-Baiti. Sex differences have been observed, both in the innate and in the adaptive immune responses, and sex hormones have been shown to play a fundamental role. For instance, androgens can increase the production of interleukin (IL)-1β, IL-10, IL-2, and transforming growth factor-β (TGF-β) by immune cells, decrease the antibody response to viral infections, and increase the number and function of circulating neutrophils. In this respect, recent evidence demonstrates that neutrophils are responsible for the cytokine storm syndrome, observed in patients with severe COVID-19.

Understanding the key role of androgens in the context of COVID-19 pathology may allow for the identification of high-risk patients, as well as the definition of potential treatment and/or prophylaxis strategies.