Use of Antiandrogens as Therapeutic Agents in COVID-19 Patients

Abstract

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.

COVID-19 and metabolic syndrome

“…Benefits and risks of common medications used in metabolic syndrome management in the setting of COVID-19 are an area of intense research and discussion and have been reviewed in detail elsewhere [68] , [69] , [70] , [71*] , [72] , [73] . Data from meta-analyses [74] , [75] , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , observational studies [25] and randomized controlled trials [84] , [85*] , [86] , [87] , [88*] , [89] have emerged while several studies are on-going.…”

The antiviral potential of the antiandrogen enzalutamide and the viral‐androgen signaling interplay in seasonal coronaviruses

“…8 The sex discordance in COVID-19 outcomes, with males generally faring worse than females, has been associated with androgens, the steroid hormones predominant in males, fueling interest in antiandrogens (androgen receptor antagonists) as potential antivirals. 8 We previously demonstrated that enzalutamide, an antiandrogen typically used to prevent the androgen receptor-mediated growth of castrateresistant prostate cancers, reduces the expression in the lungs and other target cells of the transmembrane serine protease TMPRSS2, a key protease for SARS-CoV-2 cell entry, and thus holds potential as antiviral. 9 TMPRSS2 is part of the type 2 transmembrane serine protease family and has been extensively studied in the context of prostate cancer metastasis.…”

“…The reasons are not entirely clear, but several explanations have been proposed, including immunological, genetic, hormonal, and sociobehavioral factors 8 . The sex discordance in COVID‐19 outcomes, with males generally faring worse than females, has been associated with androgens, the steroid hormones predominant in males, fueling interest in antiandrogens (androgen receptor antagonists) as potential antivirals 8 . We previously demonstrated that enzalutamide, an antiandrogen typically used to prevent the androgen receptor‐mediated growth of castrate‐resistant prostate cancers, reduces the expression in the lungs and other target cells of the transmembrane serine protease TMPRSS2, a key protease for SARS‐CoV‐2 cell entry, and thus holds potential as antiviral 9 .…”

“…While there is no explicit report of sexual discordance in HCoV prevalence, it is becoming more evident that males of both younger and older ages are more susceptible to respiratory viruses in general and are also at a higher risk of severe disease outcomes when compared to females 2 . The reasons are not entirely clear, but several explanations have been proposed, including immunological, genetic, hormonal, and sociobehavioral factors 8 . The sex discordance in COVID‐19 outcomes, with males generally faring worse than females, has been associated with androgens, the steroid hormones predominant in males, fueling interest in antiandrogens (androgen receptor antagonists) as potential antivirals 8 .…”

The antiviral potential of the antiandrogen enzalutamide and the viral-androgen interplay in seasonal coronaviruses

“…8 The sex discordance in COVID-19 outcomes with males generally faring worse than females has been associated with the primarily male hormones androgens and fueled interest in antiandrogens as potential antivirals. 8 We previously demonstrated that enzalutamide, an antiandrogen typically used to prevent the androgen-mediated growth of castrate-resistant prostate cancers, reduces the expression of the transmembrane serine protease TMPRSS2, a key protease for SARS-CoV-2 cell entry, and thus holds potential as antiviral. 9 TMPRSS2 is part of the type 2 transmembrane serine protease family and has been extensively studied in the context of prostate cancer metastasis.…”