Racial variations in COVID‐19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti‐androgens a potential treatment for COVID‐19?

McCoy, J. Philip; Wambier, Carlos Gustavo; Vañó‐Galván, Sergio; Shapiro, Jerry; Sinclair, Rodney; Ramos, Paulo Müller; Washenik, Ken; Andrade, Murilo Ferreira de; Herrera, Sabina; Goren, Andy

doi:10.1111/jocd.13455

Cited by 88 publications

(94 citation statements)

References 14 publications

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“…This implies that patients with prostate cancer that are treated with anti-AR therapy could be less susceptible to viral infection. The use of anti-AR compounds could also be used as a therapeutic strategy and preventive option in these patients to avoid viral entry 38 , 39 . In the future, other cancer types expressing AR, besides prostate cancer that can be treated with anti-AR compounds as a therapeutic option, would benefit from this type of treatment and could be less susceptible to SARS-CoV-2 infection and likely to its most severe effects.…”

Section: Discussionmentioning

confidence: 99%

ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

et al. 2020

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. One open question is whether genetics could influence the severity of symptoms. Considering the limited data on cancer patients, we analyzed public data repositories limited to investigate angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) expressions and genetic variants to identify the basis of individual susceptibility to SARS-CoV-2. Gene expression and variant data were retrieved from Tissue Cancer Genome Atlas, Genotype-Tissue Expression, and gnomAD. Differences in gene expression were tested with Mann-Whitney U-test. Allele frequencies of germline variants were explored in different ethnicities, with a special focus on ACE2 variants located in the binding site to SARS-CoV-2 spike protein. The analysis of ACE2 and TMPRSS2 expressions in healthy tissues showed a higher expression in the age class 20 to 59 years (false discovery rate [FDR] < 0.0001) regardless of gender. ACE2 and TMPRSS2 were more expressed in tumors from males than females (both FDR < 0.0001) and, opposite to the regulation in tissues from healthy individuals, more expressed in elderly patients (FDR = 0.005; FDR < 0.0001, respectively). ACE2 and TMPRSS2 expressions were higher in cancers of elderly patients compared with healthy individuals (FDR < 0.0001). Variants were present at low frequency (range 0% to 3%) and among those with the highest frequency, the variant S19P belongs to the SARS-CoV-2 spike protein binding site and it was exclusively present in Africans with a frequency of 0.2%. The mechanisms of ACE2 and TMPRSS2 regulation could be targeted for preventive and therapeutic purposes in the whole population and especially in cancer patients. Further studies are needed to show a direct correlation of ACE2 and TMPRSS2 expressions in cancer patients and the incidence of COVID-19.

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Section: Discussionmentioning

confidence: 99%

ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

et al. 2020

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“…In previous micemodels,female hormones had a protective effect on mortality duetoSARS-CoV infection 3 . McCoy et al suggestedthatandrogens, which could play an important role in SARS-CoV-2entryinto the host cell, seemed to be implicated inCOVID-19mortality 4 . However, in our study, male sex wasnot anindependent risk factor for mortality, and there wasnostatistically signi cant association between HRT and theclinicaloutcomes of peri-and post-menopausal women.…”

Section: Discussionmentioning

confidence: 99%

“…Sex has already been a factor of marked importance in theshorthistory of COVID-19. According to several studies, men havehighermorbidity and mortality to COVID-19 than women 3,4 .Somestudies suggest that sex hormone may affect the susceptibilitytosevere acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection and subsequent mortality [3][4][5][6] . Basedon these ndings, a clinical trial is recruiting patientstoevaluate the effect of female sex hormone on clinical outcomesofpatients as administering oestrogen to adult men orpost-menopausalwomen who have low level of female hormone(ClinicalTrials.govIdenti er: NCT04359329).…”

Section: Introductionmentioning

confidence: 99%

The effect of sex hormone on COVID-19: analysis of laboratory-confirmed 5061 patients in South Korea

Lee

Kim

Cho

et al. 2020

Preprint

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Limited data describing the effect of sex hormone on coronavirus disease (COVID-19) is available. We evaluated the effect of sex hormone on prevalence and clinical outcomes of COVID-19. Retrospective cohort study was performed using the nationwide claims data of 5061 adult patients with laboratory-confirmed COVID-19 in South Korea, from January 20 to April 8, 2020. COVID-19 was most prevalent in women of the 20-39 age group (1250 [44.14%]). Men were more likely to receive oxygen therapy (144 [6.46%] vs 131 [4.63%], P=0.004), be admitted to the intensive care unit (60 [2.69%] vs 53 [1.87%], P=0.049), and stay longer after admission to the intensive care unit (19.70±11.80 vs 14.75±9.23, P=0.016). However, there was no significant difference in mortality rates between men and women. In multivariable Cox analysis, independent risk factors for mortality were older age and underlying co-morbidities, rather than sex. To evaluate the effect of HRT among women, subgroup analysis was implemented using age-matched case-control data with a 1:3 ratio of females receiving HRT to those who did not. HRT did not have statistically significant association with clinical outcomes. This study suggests that sex hormone may not affect prevalence and clinical outcome of COVID-19 in South Korea.

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“…The binding patterns of GR, pioneer factors and H3K27ac in lung cells, however, differ to what is seen in LNCaP cells (compare regulatory region 1 and 2). To assess if androgen response elements are present in regulatory region 2, the AR binding motif (MA0007.2, Figure 6B) from the JASPAR database, was used to detect AR target sites using methods previously described [31]. This analysis identified potential androgen response elements throughout the 5' region of the TMPRSS2 gene ( Figure 6A and 6C).…”

Section: Tmprss2 Expression In Lung Is Potentially Directly Regulatedmentioning

confidence: 99%

“…It is therefore possible that inhibition of androgen signalling, in response to antiandrogens, will reduce TMPRSS2 expression in the lung and reduce viral entry. For this reason, antiandrogens have been proposed as a treatment option for COVID-19 [31][32][33]. Here we review and reanalyse available data to investigate AR and TMPRSS2 in the lung, and provide additional pre-clinical data to support the use of antiandrogens for the treatment of COVID-19.…”

Section: Introductionmentioning

confidence: 99%

TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer therapeutic

Leach¹,

Isac²,

Bevan³

et al. 2020

Preprint

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The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, attacks various organs but most destructively the lung. It has been shown that SARS-CoV-2 entry into lung cells requires two host cell surface proteins: ACE2 and TMPRSS2. Downregulation of one or both of these is thus a potential therapeutic approach for COVID-19. TMPRSS2 is a known target of the androgen receptor, a ligand-activated transcription factor; activation of the androgen receptor increases TMPRSS2 levels in various tissues, most notably the prostate. We show here that treatment with the antiandrogen enzalutamide – a well-tolerated drug widely used in advanced prostate cancer – reduces TMPRSS2 levels in human lung cells. Further, enzalutamide treatment of mice dramatically decreased Tmprss2 levels in the lung. In support of this new experimental data, analysis of existing datasets shows striking co- expression of AR and TMPRSS2, including in specific lung cell types that are targeted by SARS- CoV-2. Together, the data presented provides strong evidence to support clinical trials to assess the efficacy of antiandrogens as a treatment option for COVID-19.

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Racial variations in COVID‐19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti‐androgens a potential treatment for COVID‐19?

Cited by 88 publications

References 14 publications

ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

ACE2 and TMPRSS2 Potential Involvement in Genetic Susceptibility to SARS-COV-2 in Cancer Patients

The effect of sex hormone on COVID-19: analysis of laboratory-confirmed 5061 patients in South Korea

TMPRSS2, required for SARS-CoV-2 entry, is downregulated in lung cells by enzalutamide, a prostate cancer therapeutic

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