Androgens and COVID-19.

BACKGROUND: The humans have been disproportionately affected by the coronavirus disease (COVID-19) pandemic. The novel coronavirus or the severe acute respiratory syndrome coronavirus 2 (SARS-COV2) causing coronavirus disease (COVID-19) has spread across the globe. Androgens have been suggested to have a role in COVID-19 pathogenesis. OBJECTIVE: The objective of this review article is to study the link between androgens and COVID-19. METHODOLOGY: PubMed and Google Scholar search was performed to retrieve literature related to the topic. Review articles, clinical trials, retrospective studies, observational studies, and case-control studies were considered for the review. RESULTS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected men are more inclined to be hospitalized for intensive care unit (ICU) as compared with women. This difference in the ICU admissions provides some clue for possible influence of androgens in the severity of COVID-19. The contribution of androgen and androgen receptor in COVID-19 disease and its severity, as well as the numerous medications targeting androgen and its receptor for lowering COVID-19 disease severity, are discussed in this review. Available literature suggests the role of androgen in the pathogenesis and severity of COVID-19. Sensitivity for androgen may be an important factor in regulating the severity of COVID-19 disease. CONCLUSION: There is a scope for the development of COVID-19 treatments based on androgen suppression. Clinical trials may furnish pivotal data and add more evidence-based options for the management of COVID-19.

Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients.

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), is estimated to have caused over 6.5 million deaths worldwide. The emergence of fast-evolving SARS-CoV-2 variants of concern alongside increased transmissibility and/or virulence, as well as immune and vaccine escape capabilities, highlight the urgent need for more effective antivirals to combat the disease in the long run along with regularly updated vaccine boosters. One of the early risk factors identified during the COVID-19 pandemic was that men are more likely to become infected by the virus, more likely to develop severe disease and exhibit a higher likelihood of hospitalisation and mortality rates compared to women. An association exists between SARS-CoV-2 infectiveness and disease severity with sex steroid hormones and, in particular, androgens. Several studies underlined the importance of the androgen-mediated regulation of the host protease TMPRSS2 and the cell entry protein ACE2, as well as the key role of these factors in the entry of the virus into target cells. In this context, modulating androgen signalling is a promising strategy to block viral infection, and antiandrogens could be used as a preventative measure at the pre- or early hospitalisation stage of COVID-19 disease. Different antiandrogens, including commercial drugs used to treat metastatic castration-sensitive prostate cancer and other conditions, have been tested as antivirals with varying success. In this review, we summarise the most recent updates concerning the use of antiandrogens as prophylactic and therapeutic options for COVID-19.

Sex differences in COVID-19: the role of androgens in disease severity and progression.

PURPOSE: Throughout the SARS-CoV2 pandemic, multiple reports show higher percentages of hospitalization, morbidity, and mortality among men than women, indicating that men are more affected by COVID-19. The pathophysiology of this difference is yet not established, but recent studies suggest that sex hormones may influence the viral infectivity process. Here, we review the current evidence of androgen sensitivity as a decisive factor for COVID-19 disease severity. METHODS: Relevant literature investigating the role of androgens in COVID-19 was assessed. Further, we describe several drugs suggested as beneficial for COVID-19 treatment related to androgen pathways. Lastly, we looked at androgen sensitivity as a predictor for COVID-19 progression and ongoing clinical trials on androgen suppression therapies as a line of treatment. RESULTS: SARS-COV2 virus spike proteins utilize Transmembrane protease serine 2 (TMPRSS2) for host entry. Androgen receptors are transcription promoters for TMPRSS2 and can, therefore, facilitate SARS-COV2 entry. Variants in the androgen receptor gene correlate with androgen sensitivity and are implicated in diseases like androgenetic alopecia and prostate cancer, conditions that have been associated with worse COVID-19 outcomes and hospitalization. CONCLUSION: Androgen's TMPRSS2-mediated actions might explain both the low fatalities observed in prepubertal children and the differences between sexes regarding SARS-COV2 infection. Androgen sensitivity may be a critical factor in determining COVID-19 disease severity, and sensitivity tests can, therefore, help in predicting patient outcomes.

Spironolactone may provide protection from SARS-CoV-2: Targeting androgens, angiotensin converting enzyme 2 (ACE2), and renin-angiotensin-aldosterone system (RAAS).

In coronavirus disease-19 (COVID-19), four major factors have been correlated with worse prognosis: aging, hypertension, obesity, and exposure to androgen hormones. Angiotensin-converting enzyme-2 (ACE2) receptor, regulation of the renin-angiotensin-aldosterone system (RAAS), and transmembrane serine protease 2 (TMPRSS2) action are critical for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cell entry and infectivity. ACE2 expression and RAAS are abnormal in hypertension and obesity, while TMPRSS2 is overexpressed when exposed to androgens, which may justify why these factors are overrepresented in COVID-19. Among therapeutic targets for SARS-CoV-2, we hypothesized that spironolactone, a long used and safe mineralocorticoid and androgen receptors antagonist, with effective anti-hypertensive, cardioprotective, nephroprotective, and anti-androgenic properties may offer pleiotropic actions in different sites to protect from COVID-19. Current data shows that spironolactone may concurrently mitigate abnormal ACE2 expression, correct the balances membrane-attached and free circulating ACE2 and between angiotensin II and Angiotensin-(1-7) (Ang-(1-7)), suppress androgen-mediated TMPRSS2 activity, and inhibit obesity-related RAAS dysfunctions, with consequent decrease of viral priming. Hence, spironolactone may provide protection from SARS-CoV-2, and has sufficient plausibility to be clinically tested, particularly in the early stages of COVID-19.

COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor.

COVID-19 is the pandemic that hit the world starting December 2019. Recent studies and international statistics have shown an increased prevalence, morbidity as well as mortality of this disease in male patients compared to female patients. The aim of this brief communication is to describe the pathophysiology of this sex-discrepancy, based on the infectivity mechanism of the coronavirus including the Angiotensin-Converting Enzyme 2 (ACE2), the Type II transmembrane Serine Protease (TMPRSS2), and the androgen receptor. This could help understand the susceptibility of urological patients, especially those receiving androgen deprivation therapy for prostate cancer, and testosterone replacement therapy.

COVID-19 and androgen-targeted therapy for prostate cancer patients.

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.