key: cord-0920187-jqsaez0s
authors: Mauvais-Jarvis, Franck
title: Do anti-androgens have potential as therapeutics for COVID-19?
date: 2021-06-05
journal: Endocrinology
DOI: 10.1210/endocr/bqab114
sha: c93a5ce456e5abb8ecc17b29958f730c53822d0f
doc_id: 920187
cord_uid: jqsaez0s

COVID-19 is characterized by a gender disparity in severity, with men exhibiting higher hospitalization and mortality rates than women. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, infects cells following recognition and attachment of the viral spike (S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) transmembrane protein, followed by spike protein cleavage and activation by cell surface transmembrane protease serine 2 (TMPRSS2). In prostate cancer cells, androgen acting on the androgen receptor (AR) increases TMPRSS2 expression, which has led to the hypothesis that androgen-dependent expression of TMPRSS2 in the lung, may increase men’s susceptibility to severe COVID-19 and that, accordingly, suppressing androgen production or action may mitigate COVID-19 severity by reducing SARS-CoV-2 amplification. Several ongoing clinical trials are testing the ability of androgen deprivation therapies (ADT) or anti-androgens to mitigate COVID-19.This perspective discusses clinical and molecular advances on the rapidly evolving field of AR action on TMPRSS2 expression and SARS-COV-2 infection, and the potential effect of anti-androgens on COVID-19 severity in male patients. It discusses limitations of current studies and offer insight for future directions.

(S) glycoprotein to the angiotensin-converting enzyme 2 (ACE2) transmembrane protein on host cells, followed by spike protein cleavage and activation by cell surface transmembrane protease serine 2 (TMPRSS2), which facilitates membrane fusion and entry. In the prostate, TMPRSS2 expression is upregulated by androgens via the androgen receptor (AR), which has led to the hypothesis that androgen-dependent expression of TMPRSS2 in non-prostatic tissues, especially the lung, may be instrumental to men's increased susceptibility to COVID-19 severity and mortality. Accordingly, investigators have examined the relationship between androgen depletion and COVID-19 in patients with prostate cancer, as androgen deprivation therapy (ADT) consisting of luteinizing hormonereleasing hormone (LHRH) agonist/antagonists (blocking testosterone production) or AR inhibitors/antagonists (blocking testosterone action), is the standard of prostate cancer treatment.

The first population-based study of the Italian region of Veneto, which was severely affected by the COVID-19 pandemic, looked at patients with prostate cancer and confirmed SARS-CoV-2 infection. The clinical and biological characteristics of the patient populations with and without   ADT were not described and were likely to be different, and the analysis was not corrected for   multiple variables. A second study examined 58 patients with confirmed SARS-CoV-2 infection and   prostate cancer at Mount Sinai Health System in New York City (22 patients were on ADT and 36 were not) (3). After controlling for multiple variables, they concluded that ADT was associated with reduced odds of hospitalization (OR 0.23, 95% CI 0.06-0.79, p < 0.02), supplemental oxygen requirements (OR 0.26, 95% CI 0.07-0.92, p = 0.036), need for intubation (OR 0.31, 95% CI 0.05-1.81, p = 0.192) and mortality (OR 0.37, 95% CI 0.08-1.80, p = 0.22). However, the study lacked power, and two outcomes (intubation and mortality) were not significant. Another Italian study focusing on 36 SARS-CoV-2-positive patients with metastatic prostate cancer and receiving ADT did not find any increased mortality rate compared to the Italian SARS-CoV-2-positive male population of the same age (4) . A retrospective analysis compared male subjects with confirmed SARS-CoV-2 infection, and androgenetic alopecia (AGA), treated with 5-alpha-reductase inhibitors (5AIs, that block testosterone conversion to the potent AR agonist dihydrotestosterone) to men with AGA nonusers of 5AIs. They observed a significant reduction in the frequency of clinical symptoms in men with AGA using 5AIs compared to men with AGA not using 5AIs (5) . Based on these discordant observational studies, and the absence of randomized trial, no definitive clinical evidence indicates that ADT prevents COVID-19 infection or mitigates COVID-19 severity. Thus, several randomized clinical trials (RCTs) have begun to test the efficacy of ADT in the general population of male COVID-19 patients. The most interesting to date, a RCT of proxalutamide (a novel generation AR antagonist; NCT04446429) in Brazilian outpatients with COVID-19, concluded that subjects assigned to the drug (0/134) benefited from a reduced rate of hospitalization compared to those assigned to placebo (35/128). The study has not been peer reviewed yet. A second RCT in 107 men and 128 women, with mild to moderate COVID-19, reported that proxalutamide accelerates viral clearance, with 82% of subjects testing negative for SARS-CoV-2 in the treatment group at day 7 compared to only 31% in the placebo group (P<0.01) (6) . In addition, the time to clinical remission was improved with a five-fold decrease in the average number of days required to be COVID-19 symptoms free in the proxalutamide group versus the placebo. Additional ongoing RCTs, include degarelix (GnRH A c c e p t e d M a n u s c r i p t 6 antagonist; NCT04397718, completion date July 2021), bicalutamide (first-generation anti-androgen; NCT04374279; completion date January 2022), and enzalutamide (second-generation anti-androgen; NCT04475601, completion date July 2021).

In parallel to these clinical studies, investigators have begun to explore the molecular underpinnings of AR antagonism regarding TMPRSS2 expression and SARS-CoV-2 infection, using prostate and lung cell models. Two studies identified co-expression of ACE2, TMPRSS2 and AR in human alveolar and bronchial epithelial cells, suggesting that AR drives ACE2 and TMPRSS2 expression in the lung (7, 8) . Indeed, in male C57 mice, Tmprss2 is upregulated by testosterone in bronchial cells. In human prostate LNCaP cancer cells, treatment with AR antagonists approved for the treatment of prostate cancer (apalutamide, darolutamide, and enzalutamide), all inhibited SARS-CoV-2 infection (7) . Unfortunately, the effect of AR antagonists was not tested in lung cells, as the authors were unable to identify a lung epithelial cell line susceptible to SARS-CoV-2 infection that also had adequate AR signaling (7) . Still, in male human AR-expressing lung carcinoma cells (H460), treatment with androgens increased, and the anti-androgen enzalutamide or the AR degrader ARD-69 decreased TMPRSS2 and ACE2 mRNA and protein levels (9) . Using a replication-defective SARS-CoV-2 pseudovirus they found that androgen-deprivation, enzalutamide, and ARD-69, all reduced SARS-CoV-2 pseudo-virus entry into LNCaP prostate and H460 lung cells (9) . However, although Enzalutamide reduced the entry of authentic SARS-CoV-2 into LNCaP prostate cells, surprisingly, the authors did not test the effects of anti-androgens on the SARS-CoV-2 entry in lung cells (9) .

Another more translational study used human lung organoids derived from normal human lung tissues and expressing AR and TMPRSS2. They used a similar SARS-CoV-2 pseudovirus as described above. However, in contrast to the previous study, in these human lung organoids, enzalutamide showed no effect on TMPRSS2 expression, or on infection by RCTs of proxalutamide in outpatients with COVID-19 suggest that AR antagonism accelerates viral clearance and reduces rate of hospitalization (6) . However, if androgens enhance TMPRSS2 expression in lung cells to promote higher infection of male compared to female cells, one would expect men to be more susceptible to SARS-CoV-2 infection than women. Infection rates are similar between sexes globally. In the initial Veneto study reporting that men receiving ADT exhibited a low risk of SARS-CoV-2 infection, surprisingly women exhibited higher prevalence of infection than men (44% men vs 56% women) (2) . In the near future, results from the RCTs using GnRH antagonist and Finally, testosterone seems to play a bidirectional role in COVID-19 pathogenesis. Most men with COVID-19 exhibit testosterone deficiency, and low testosterone at admission was associated with intensive care admission and death in multivariate analysis. Evidence suggests that low testosterone levels actually worsen COVID-19 severe outcomes, as lower testosterone concentrations during hospitalization are associated with increased inflammation and mortality in men (12, 13) . The Xlinked AR gene contains a highly polymorphic N-terminal polyQ tract, ranging from 9 to 36 polyglutamine coding CAG repeats, with the polyQ tract-length being inversely correlated to AR functionality. A case-control study examined the genotypes of 638 male and female Italian COVID-19 patients, comparing those with severe COVID-19 with those who were oligo-asymptomatic.

Among males, they found an association between length of the AR polyQ tract and disease severity, with shorter alleles (predicted to increase AR action) appearing to protect against worse clinical outcomes independent of age (14) . In contrast, men with long polyQ repeats (predicted to decrease A c c e p t e d M a n u s c r i p t 9 AR action) exhibited increased biomarkers of inflammation. They suggest using testosterone as adjuvant therapy for patients with severe COVID-19 exhibiting low levels of circulating androgens and defective AR action, defined in this study as > 23 PolyQ repeats . Therefore, the potential bidirectional modulation of COVID-19 severity by testosterone and AR action require further investigation.

In conclusion, to what extent antiandrogens mitigate COVID-19 severity in men requires further demonstration and mechanistic study. While we wait for the results of clinical trials testing the efficacy of ADT and anti-androgens in COVID-19 outcomes, studies are also needed to assess the effect of AR action in endothelial and immune cells in preventing or mitigating SARS-CoV-2 infection.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Estradiol, Progesterone, Immunomodulation, and COVID-19 Outcomes

Androgendeprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532)

Does androgen deprivation therapy protect against severe complications from COVID-19?

On the relationship between androgen-deprivation therapy for prostate cancer and risk of infection by SARS-CoV-2

5-alpha-reductase inhibitors are associated with reduced frequency of COVID-19 symptoms in males with androgenetic alopecia

Proxalutamide Significantly Accelerates Viral Clearance and Reduces Time to Clinical Remission in Patients with Mild to Moderate COVID-19: Results from a Randomized, Double-Blinded, Placebo-Controlled Trial

Targeting transcriptional regulation of SARS-CoV-2 entry factors <em>ACE2</em> and <em>TMPRSS2</em>

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide

Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19. iScience

Endothelial cell, myeloid, and adaptive immune responses in SARS-CoV-2 infection

Androgen-Induced Immunosuppression

Low testosterone levels predict clinical adverse outcomes in SARS-CoV-2 pneumonia patients

Association of circulating sex hormones with inflammation and disease severity in patients with COVID-19

Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

A c c e p t e d M a n u s c r i p t 10 A c c e p t e d M a n u s c r i p t 11