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Dutasteride Reduces Time to Remission in COVID-19: Results From a Randomized Double Blind Placebo Controlled Interventional Trial (The DUTA AndroCoV-Trial).

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Abstract and Figures

Background: SARS-CoV-2 entry into type II pneumocytes is depended on the TMPRSS2 proteolytic enzyme. The only known promoter of TMPRSS2 in humans is an androgen response element. As such, androgen sensitivity may be a risk factor for COVID-19. Previously, we have reported a retrospective cohort analysis demonstrating the protective effect of 5-alpha-reductase inhibitors (5ARis) in COVID-19. Men using 5ARis were less likely to be admitted to the ICU than men not taking 5ARis. Additionally, men using 5ARis had drastically reduced frequency of symptoms compared to men not using 5ARis in an outpatient setting. Here we aim to determine if 5ARis will be a beneficial treatment if given after SARS-CoV-2 infection. Methods: A double-blinded, randomized, prospective, investigational study of dutasteride for the treatment of COVID-19 (NCT04446429). Subjects confirmed positive for SARS-CoV-2 were treated in an outpatient setting. Endpoints for the study were remission times for a predetermined set of symptoms: fever or feeling feverish, cough, shortness of breath, sore throat, body pain or muscle pain/ache, fatigue, headache, nasal congestion, nasal discharge (runny nose), nausea or vomiting, diarrhea, loss of appetite, and loss of taste or smell (Ageusia or Anosmia). Results: The differences in the average remission times for fatigue and anosmia/ageusia were statistically different between groups (5.8 versus 10.1 days for fatigue and 7.3 versus 13.4 days for anosmia or ageusia, in dutasteride and placebo groups, respectively), however, the total remission time was significantly reduced for the men given dutasteride; 9.0 days versus 15.6 days in the placebo group (p < 0.001). Excluding loss of taste and smell the average total remission time was 7.3 days in the dutasteride group versus 11.7 in the placebo arm (p < 0.001). Conclusion: The total remission time for men using 5ARis was significantly reduced compared to men not taking 5ARis.
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Dutasteride Reduces Time to Remission in COVID-19: Results From a Randomized
Double Blind Placebo Controlled Interventional Trial (The DUTA AndroCoV-
Trial).
Flávio'Adsuara'Cadegiani,'MD,'PhD1,'John'McCoy,'PhD2*,'Carlos'Gustavo'Wambier,'
MD,'PhD3,'Andy'Goren,'MD2.'
'
1Department)of)Clinical)Endocrinology,)Federal)University)of)São)Paulo)Medical)School,)Sao)
Paulo,)Brazil.)
2Applied)Biology,)Inc.)Irvine,)CA,)USA.)
!
*Corresponding!author:!
John'McCoy,'PhD'
Applied'Biology,'Inc.'
17780'Fitch,'Suite'192'
Irvine,'CA'92614'
johnm@appliedbiology.com'
!
Funding!sources:'None'
'
Conflicts!of!Interest:'None'declared.'
!
IRB!approval!status:'The'study'was'approved'by'an'ethics'committee'and'
registered'with'clinicaltrials.gov'(NCT04446429),'and'also'approved'by'Brazilian'
National'Ethics'Committee'(Approval'number'4.173.074;''CAAE'
34110420.2.0000.0008;'Comitê'de'Ética'em'Pesquisa'(CEP)'of'the'Comitê'Nacional'
de'Ética'em'Pesquisa'(CONEP)'of'the'Ministry'of'Health'(MS))'(CEP/CONEP/MS).'''
'
Manuscript'word'count:'2025'words'
References:'12'
Tables:'2'
Figures:'1'
Supplementary'figures:'0'Tables:'0'Supplementary'tables:'0'
!
Keywords:'COVID-19;'SARS-CoV-2;'androgen'receptor;'androgenetic'alopecia;'anti-
androgen'therapy;'transmembrane'protease'serine'2;'TMPRSS2;'Dutasteride;'
Finasteride;'5-alpha'reductase;''
!
Abbreviations:!
5ARi:'5-alpha'reductase'inhibitors!
TMPRSS2:'Transmembrane'protease,'serine'2'
AGA:'Androgenetic'alopecia'
Abstract
Background:!SARS-CoV-2'entry'into'type'II'pneumocytes'is'depended'on'the'
TMPRSS2'proteolytic'enzyme.'The'only'known'promoter'of'TMPRSS2'in'humans'is'
an'androgen'response'element.'As'such,'androgen'sensitivity'may'be'a'risk'factor'
for'COVID-19.'Previously,'we'have'reported'a'retrospective'cohort'analysis'
demonstrating'the'protective'effect'of'5-alpha-reductase'inhibitors'(5ARis)'in'
COVID-19.'Men'using'5ARis'were'less'likely'to'be'admitted'to'the'ICU'than'men'not'
taking'5ARis.'''Additionally,'men'using'5ARis'had'drastically'reduced'frequency'of'
symptoms'compared'to'men'not'using'5ARis'in'an'outpatient'setting.'Here'we'aim'
to'determine'if'5ARis'will'be'a'beneficial'treatment'if'given'after'SARS-CoV-2'
infection.'
Methods:!A'double-blinded,'randomized,'prospective,'investigational'study'of'
dutasteride'for'the'treatment'of'COVID-19'(NCT04446429).''Subjects'confirmed'
positive'for'SARS-CoV-2'were'treated'in'an'outpatient'setting.''Patients'were'given'
either'dutasteride'0.5mg/day'or'placebo'for'30'days'or'until'full'COVID-19'
remission.'Nitazoxanide'was'given'500mg'twice'a'day'for'six'days'and'azithromycin'
was'given'500mg/day'for'five'days'for'all'subjects.!Endpoints'for'the'study'were'
remission'times'for'a'predetermined'set'of'symptoms:'fever'or'feeling'feverish,'
cough,'shortness'of'breath,'sore'throat,'body'pain'or'muscle'pain/ache,'fatigue,'
headache,'nasal'congestion,'nasal'discharge'(runny'nose),'nausea'or'vomiting,'
diarrhea,'loss'of'appetite,'and'loss'of'taste'or'smell'(Ageusia'or'Anosmia).'''
Results:!The'differences'in'the'average'remission'times'for'fatigue'and'
anosmia/ageusia'were'statistically'different'between'groups'(5.8'versus'10.1'days,'
or'reduction'of'43%'in'fatigue'duration,'and'7.3'versus'13.4'days,'or'reduction'of'
45%'in'anosmia'and'ageusia'duration,'in'dutasteride'and'placebo'groups,'
respectively).'The'total'time'to'remission'was'significantly'reduced'for'the'men'
given'dutasteride;'9.0'days'versus'15.6'days'(Reduction'of'42%'in'time'to'
remission)'in'the'placebo'group'(p'<'0.001).''Excluding'loss'of'taste'and'smell'the'
average'total'time'to'remission'was'7.3'days'in'the'dutasteride'group'versus'11.7'in'
the'placebo'arm'(p'<'0.001)'(Reduction'of'38%'in'time'to'remission'except'for'
anosmia'and'ageusia).''
Conclusion:!The'total'remission'time'for'men'using'5ARis'was'significantly'reduced''
compared'to'men'not'taking'5ARis.'(NCT04446429)''
!
!
Introduction!
!
Early'in'the'COVID-19'pandemic,'reports'from'Wuhan,'China'demonstrated'
that'the'infectivity'and'severity'of'the'disease'disproportionately'affects'men.''Of'
patients'sampled'in'the'early'stages'of'the'outbreak'42%'were'female'versus'58%'
male.1''Now'that'the'disease'has'progressed'to'the'majority'of'countries'across'the'
globe,'the'trend'has'been'demonstrated'many'times'over;'men'are'more'likely'to'be'
infected,'more'likely'to'have'severe'disease,'and'have'a'greater'case'fatality'rate'
compared'to'women.2'Lifestyle'differences'and'gender-biased'comorbidities,'e.g.,'
incidence'of'smoking'and'hypertension,'have'been'suggested'as'contributing'to'this'
gender'discrepancy,2'however,'definitive'proof'of'these'associations'is'lacking.''We'
have'previously'published'several'communications'suggesting'that'the'male'bias'in'
COVID-19'disease'severity'may'be'linked'to'androgens.3,4 ' '
SARS-CoV-2'entry'into'type'II'pneumocytes'is'dependent'on'modification'of'a'
viral'spike'protein'by'the'transmembrane'protease,'serine'2'(TMPRSS2)'expressed'
on'the'surface'of'human'cells.5'The'only'known'promoter'of'the'TMPRSS2'gene'in'
humans'is'an'androgen'response'element'located'in'the'5’'promoter'region.6''It'
would'follow'that'reducing'the'expression'of'TMPRSS2'by'blocking'the'androgen'
receptor'would'decrease'SARS-CoV-2'entry'into'human'cells.''Recently,'we'have'
published'several'observation'studies'linking'the'androgen-mediated'phenotype'of'
androgenetic'alopecia'(AGA)'to'COVID-19'disease'severity.3,4'In'a'cohort'of'122'men'
hospitalized'with'COVID-19,'79%'were'diagnosed'with'AGA'compared'to'the'
expected'prevalence'of'31-53%'in'aged'matched'controls'of'similar'ethnicity.3'
Additionally,'a'recent'publication'has'demonstrated'that'COVID-19'disease'severity'
was'directly'correlated'with'AGA'progression;'men'with'higher'Hamilton-Norwood'
stages'were'more'likely'to'experience'severe'disease'and'death.7''
Further'evidence'connecting'COVID-19'to'androgens'has'been'reported'in'
prostate'cancer'patients'undergoing'androgen'depravation'therapy'(ADT).'
Montopoli'et'al.'studied'a'large'population'of'COVID-19'patients'in'northern'Italy,'
observing'that'COVID-19'infection'rates'were'lower'in'prostate'cancer'patients'
receiving'ADT'compared'to'prostate'cancer'patients'not'receiving'ADT'(OR'4.05;'
95%'CI'1.55-10.59).8''Other'groups'have'suggested'that'polycystic'ovary'syndrome'
may'also'indicated'increase'risk'of'severe'COVID-19'disease'in'women,9'however,'
clinical'data'supporting'this'hypothesis'have'not'been'produced.'Finally,'we'have'
communicated'that'variations'in'the'androgen'receptor'gene'may'contribute'to'the'
racial'variations'in'case'fatality'rates'observed'in'the'United'States.10'''Taken'
together,'there'is'growing'body'of'evidence'to'support'that'SARS-CoV-2'infectivity'is'
mediated'by'the'androgen'receptor'and'may'respond'to'drugs'that'reduce'androgen'
receptor'function.''
5-alpha-reductase'inhibitors'(5ARis)'are'commonly'prescribed'for'
androgenetic'alopecia'and'benign'prostatic'hyperplasia;'they'block'the'conversion'
of'testosterone'to'the'more'potent'androgen,'dihyrotestosterone'(DHT).11''5ARis'are'
inexpensive'and'have,'compared'to'other'ADTs,'relatively'low'incidence'of'adverse'
side'effects.''As'such,'they'would'make'ideal'candidates'for'a'SARS-CoV-2'treatment.'
Recently,'we'have'reported'the'results'from'two'retrospective'cohort'analysis'
demonstrating'the'protective'effect'of'5-alpha-reductase'inhibitors'(5ARi)'for'men'
with'COVID-19.12'''In'a'study'of'77'men'hospitalized'with'COVID-19'we'found'
among'men'taking'5ARis,'8%'were'admitted'to'the'ICU'compared'to'58%'of'men'
not'taking'5ARis'(P'='0.0015).''In'the'cohort,'5ARis'were'associated'with'reduced'
risk'for'ICU'admissions'RR'0.14'(95%'CI:'0.020.94).12'Similarly,'we'have'
demonstrated'that'the'frequency'of'COVID-19'symptoms'was'drastically'reduced'
for'men'using'5ARis'in'an'outpatient'setting.''A'statistically'significant'(p<0.05)'
reduction'in'the'frequency'of'20'of'the'29'clinical'symptoms'was'observed'in'AGA'
men'using'5ARis'compared'to'AGA'men'not'using'5ARis.'For'example,'38%'and'2%'
of'men'presented'with'low-grade'fever,'60%'and'6%'with'dry'cough,'and'88%'and'
15%'reported'anosmia'in'the'non-5ARi'and'5ARi'groups,'respectively.13''In'this'
communication'we'sought'to'determine'if'5ARis'are'a'beneficial'treatment'for'
COVID-19'if'given'after'SARS-CoV-2'infection.'
'
Methods!
!
Study&Design&and&Oversight&
!
Potential'subjects'were'recruited'to'a'double-blinded,'randomized,'
prospective,'investigational'study'of'anti-androgen'treatment'of'COVID-19'
(NCT04446429).''Prospective'subjects'for'the'study'presented'with'mild'symptoms'
of'suspected'COVID-19'infection'at'one'of'five'outpatient'clinics'(Corpometria'
Institute'Brasilia,'Brazil)'and'did'not'require'admission'to'a'hospital'at'the'time'of'
their'visit.''The'study'is'registered'(clinicaltrial.gov)'and'conducted'with'the'
approval'of'the'Brazilian'National'Ethics'Committee'(Approval'number'4.173.074;''
process'number'(CAAE)'34110420.2.0000.0008;'Comitê'de'Ética'em'Pesquisa'
(CEP),'Comitê'Nacional'de'Ética'em'Pesquisa'(CONEP),'Ministry'of'Health'
(Ministério'da'Saúde'(MS))'(CEP/CONEP/MS).''All'patients'admitted'to'the'study'
gave'informed'consent.'''
'
Baseline'characteristics,'comorbidities,'test'results,'and'medications'used'
were'extracted'from'patient'records.''For'each'subject,'the'age,'BMI'(kg/m2),'
frequency'and'duration'of'medication'used'and'the'following'pre-existing'
conditions'were'extracted'from'records:'type'2'diabetes,'hypertension,'obesity'
(BMI),'hypothyroidism,'hypogonadism,'androgenetic'alopecia,'asthma,'and'chronic'
obstructive'pulmonary'disease'(COPD).''Data'were'extracted'by'the'principal'
investigator'and'managed'by'the'study'director.'''
!
Study&Population&and&Covariates&&
!
Males'being'screened'for'inclusion'in'a'double-blinded,'randomized,'
prospective,'interventional'study'of'anti-androgen'treatment'of'COVID-19'
(NCT04446429)'were'recruited'through'social'media'as'well'as'a'mailing'list'of'
10,900'men'from'the'Brazilian'health'care'system'registry.''Screening'of'potential'
subjects'was'conducted'at'five'outpatient'clinics'(Corpometria'Institute'Brasilia,'
Brazil)'at'which'nasopharyngeal'swabs'were'collected'by'trained'medical'personal.'''
SARS-CoV-2'status'was'laboratory'confirmed'by'real-time'reverse'transcription'
polymerase'reaction'testing'(Automatized'Platform,'Roche,'USA)'following'the'
Cobas'SARS-CoV-2'rtPCR'kit'test'protocol.'''
!
Procedures&
!
Patients'were'randomized'for'either'dutasteride'or'placebo'groups.'Dutasteride'was'
given'0.5mg/day'for'30'days'or'until'full'COVID-19'remission.'For'all'subjects,'
nitazoxanide'was'given'500mg'twice'a'day'after'meal'for'six'days'and'azithromycin'
was'given'500mg/day'one'hour'before'meal'for'five'days,'as'per'one'of'the'
standardized'therapies'suggested'by'the'local'Ministry'of'Health.!
!
Study&Outcomes&
!
Endpoints'for'the'study'were'remission'times'for'the'following'symptoms:'fever'or'
feeling'feverish,'cough,'shortness'of'breath,'sore'throat,'body'pain'or'muscle'
pain/ache,'fatigue,'headache,'nasal'congestion,'nasal'discharge'(runny'nose),'nausea'
or'vomiting,'diarrhea,'loss'of'appetite,'and'loss'of'taste'or'smell'(Ageusia'or'
Anosmia).'The'average'remission'time'(days)'of'each'symptom'was'tabulated'for'
each'group.'Additionally,'the'total'remission'time'was'calculated'for'each'group.''
Finally,'patients'were'asked'to'rate'their'disease'severity'at'various'times'before'
and'after'treatment'began.''The'times'used'were'Day'-7'to'-4,'Day'-3'to'-1,'Day'0'
(start'of'treatment),'Day'1,'Day'2,'Day'3,'Day'7,'Day'14,'Day'21,'Day'30,'and'Day'60.''
Subjects'were'asked'to'rate'their'health'on'a'scale'from'0'to'100,'100'being'
completely'heathy'and'0'being'their'worst'day'of'COVID-19.''
'
Statistical&Analysis&
!
Medical'history,'concomitant'medications'and'lifestyle'characteristics'of!COVID-19'
patients'were'tabulated'based'for'each'group:'age,'BMI,'hypertension,'myocardial'
infarction,'stroke,'heart'failure,'lipid'disorders,'diabeties,'pre-diabeties,'obesity,'
asthma,'COPD,'cancer,'benign'prostatic'hyperplasia,'prostate'cancer,'chronic'renal'
disease,'liver'fibrosis/cirrhosis,'clinical'depression,'anxiety,'ADHD,'insomnia,'
hypogonadism,'hypothyroidism,'and'autoimmune'disorders'as'well'as'indicated'
medications.'For'each'clinical'symptom,'the'average'remission'time'was'calculated'
for'each'group.''The'Fisher'exact'test'was'used'to'compare'the'remission'times'for'
clinical'symptoms'between'COVID-19'patients'using'5ARis'and'COVID-19'patients'
not'using'5ARis.''Statistical'significance'was'set'at'p<0.05.''XLSTAT'version'
2020.3.1.1008'(Addinsoft,'Inc.)'was'used'to'perform'all'statistical'analysis.''
!
Results!
!
)) There'were'130'SARS-CoV-2'positive'men'included'in'the'trial.''64'men'were'
assigned'to'the'investigational'arm'and'66'men'were'assigned'to'the'placebo'group.''
Average'interval'between'first'symptoms'and'beginning'of'treatment'was'4.26'and'
4.25'days'for'investigational'and'placebo'groups,'respectively'(p'='n/s).'Baseline'
characteristics'of'the'two'study'groups'are'displayed'in'Table!1.''
Table!2'reports'the'average'remission'times'for'clinical'symptoms'in'men'
taking'5ARis'versus'men'not'taking'a'5ARi.'In'most'of'the'symptoms'recorded,'the'
average'remission'time'was'not'significantly'reduced.''The'average'remission'time'
for'fatigue'was'5.8'days'in'the'dutasteride'group'versus'10.1'days'in'the'placebo'
group'(p'<'0.001),'or'43%'reduction.''The'average'remission'time'for'loss'of'taste'or'
smell'was'7.3'days'in'the'dutasteride'group'versus'13.4'days'in'the'placebo'group'(p'
<'0.001),'or'45%'reduction.''Total'time'to'remission'for'all'symptoms'was'
statistically'significantly'reduced'(9.0'days'in'the'dutasteride'group'versus'15.6'
days'in'the'placebo'group;'42%'reduction;'p'<'0.001).''After'excluding'loss'of'taste'
and'smell,'the'average'total'time'to'remission'was'7.3'days'in'the'dutasteride'group'
versus'11.7'in'the'placebo'arm'(38%'reduction;'p'<'0.001).'
Figure!1'displays'the'average'results'from'the'patient'reported'outcome'
rating'disease'severity'at'various'times'before'and'after'treatment'began.'The'level'
of'recovery'was'significantly'improved'in'the'dutasteride'group'compared'to'
placebo'group'in'Days'1,'2,'3'and'7'(p'<'0.001'for'all'days).'
No'severe'adverse'effects'were'reported'in'both'groups.'
)
Discussion!
!
Men'infected'with'SARS-CoV-2'have'an'increased'risk'of'severe'COVID-19'
disease'compared'to'women.2,14,15'A'multitude'of'factors'may'contribute'to'the'
gender'disparity,2'however,'evidence'is'mounting3,4,7,8'to'support'that'androgens,'
the'defining'male'hormones,'may'be'involved'in'the'regulation'of'COVID-19'
severity.''Concurrently,'the'mechanism'of'action'is'likely'androgen'receptor'
regulation'of'the'expression'of'the'TMPRSS2'enzyme,'one'of'the'enzymes'utilized'by'
SARS-CoV-2'to'enter'type'II'pneumocytes'in'human'lungs.5''
Androgens'are'both'circulating'and'produced'in'tissue.'Elevated'tissue'DHT'
is'implicated'in'androgenetic'alopecia'(AGA),'benign'prostatic'hyperplasia,'and'
prostate'cancer.'In'a'previous'communication,'we'reported'that'in'a'cohort'of'122'
hospitalized'COVID-19'male'patients,'79%'suffered'from'androgenetic'alopecia.3''
Similarly,'Montopoli'et'al.,8'observed'that'men'utilizing'ADT'for'prostate'cancer'
were'less'likely'to'suffer'severe'COVID-19'disease.'These'observations'led'us'to'
study'the'effect'of'anti-androgen'therapy'on'COVID-19'outcomes.''
Here'we'demonstrate'in'a'randomized,'double-blinded,'placebo'controlled'
interventional'study'that'men'treated'with'dutasteride,'commonly'used'to'treat'AGA'
and'benign'prosthetic'hyperplasia,'display'statistically'significant'improvements'in'
COVID-19'disease'remission'in'an'outpatient'setting,'compared'to'a'therapy'
standardized'by'the'local'government.''Whether'results'obtained'with'dutasteride'
can'be'observed'in'other'5ARis'is'uncertain.'We'are'currently'conducting'a'
randomized,'double-blinded,'placebo'controlled'interventional'study'with'a'novel'
anti-androgen'(proxalutamide)'in'the'treatment'of'COVID-19.'
!
Conclusion!
!
Dutasteride'demonstrated'to'reduce'COVID-19'course'duration'by'42%'in'a'
randomized,'double-blinded,'placebo'controlled'interventional'study'in'males.''
!
Funding&statements&&
'
The'funding'of'present'study'was'fully'supported'by'Corpometria'Institute'(Brasilia,'
DF,'Brazil)'and'Applied'Biology'Inc'(Irvine,'CA,'USA).'
'
Conflict&of&interest&statement&
'
Authors'declare'no'conflict'of'interest'with'any'of'the'pharmacological'interventions'
proposed'by'the'present'study.
!
!
References!
'
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'
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'
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'
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'
6.'Lucas'JM,'Heinlein'C,'Kim'T,'et'al.'The'androgen-regulated'protease'TMPRSS2'
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microenvironment'and'promotes'prostate'cancer'metastasis.'Cancer'Discov'2014;'
4(11):1310-1325.'doi:10.1158/2159-8290.CD-13-1010'
'
7.'Wambier'CG,'Vao-Galvn'S,'McCoy'J,'Pai'S,'Dhurat'R,'Goren'A,'Androgenetic'
alopecia'in'COVID-19:'compared'to'age-matched'epidemiologic'studies'and'hospital'
outcomes'with'or'without'the'Gabrin'sign.'J&Am&Acad&Dermatol.'2020,'doi:'
https://doi.org/10.1016/j.jaad.2020.07.099.'
'
8.'Montopoli'M,'Zumerle'S,'Vettor'R,'et'al.'Androgen-deprivation'therapies'for'
prostate'cancer'and'risk'of'infection'by'SARS-CoV-2:'a'population-based'study'
(n=4532)'[published'online'ahead'of'print,'2020'May'4].'Ann'Oncol'2020;'S0923-
7534(20)39797-0.'doi:10.1016/j.annonc.2020.04.479'
'
9.'Kyrou'I,'Karteris'E,'Robbins'T,'et'al.'Polycystic'ovary'syndrome'(PCOS)'and'
COVID-19:'an'overlooked'female'patient'population'at'potentially'higher'risk'during'
the'COVID-19'pandemic.'BMC'Med'2020;18(220).'https://doi.org/10.1186/s12916-
020-01697-5'
'
10.''McCoy'J,'Wambier'CG,'Vano-Galvan'S,'et'al.'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?'
J'Cosmet'Dermatol.'2020;19(7):1542-1543.'doi:10.1111/jocd.13455'
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11.'Tan,'M.,'Li,'J.,'Xu,'H.'et'al.'Androgen'receptor:'structure,'role'in'prostate'cancer'
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https://doi.org/10.1038/aps.2014.18'
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Sinclair'R.'Anti-androgens'may'protect'against'severe'COVID-19'outcomes:'results'
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'
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(SARS-CoV-2)'Induced'Acute'Respiratory'Distress'Syndrome'(ARDS)'in'COVID-19.'
Front'Med'(Lausanne).'2020'Jul'28;7:453.''
'
Spironolactone'may'provide'protection'from'SARS-CoV-2:'Targeting'androgens,'
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(RAAS).'Med'Hypotheses.'2020'Oct;143:110112.'doi:'10.1016/j.mehy.2020.110112.''
'
'
' '
Placebo
Dutasteride
AVG
STD
AVG
STD
AGE (y/o)
42.0
11.5
42.0
12.6
WEIGHT (kg)
85.5
11.6
85.5
9.8
HEIGHT (m)
1.8
0.1
1.8
0.1
BMI (Kg/m2)
26.5
2.8
26.5
3.2
N
66.0
64.0
N
%
N
%
Obesity
8
12
9
14
Married?
47
71
43
67
Live alone?
12
18
13
20
Hypertension
18
27
15
23
Mi
1
2
0
0
Stroke
0
0
0
0
Hf
0
0
1
2
Lipid disorders
14
21
16
25
Other cardiac dysfunctions
0
0
3
5
Diabetes
7
11
7
11
Pré-dm2
11
17
9
14
Asthma
1
2
0
0
COPD
0
0
0
0
Chronic renal dis.
0
0
0
0
Liver fibrosis/chirrosis
1
2
0
0
Clinical depression
5
8
4
6
Anxiety
13
20
12
19
ADHD
5
8
6
9
Insomnia
4
6
6
9
Hypothyroidism
3
5
4
6
Autoimmune disorders
1
2
0
0
Cancer
0
0
0
0
Hypogonadism
13
20
11
17
BPH
2
3
3
5
DRUGS
Beta-blocker
3
5
3
5
ECAi
4
6
1
2
ARB
14
21
14
22
Loop diur.
3
5
0
0
Thiazide diuretics
4
6
5
8
CCB
2
3
4
6
Statins
14
21
15
23
Others
0
0
1
2
Aspirin
0
0
2
3
Clopidogrel
0
0
0
0
Warfarin
0
0
0
0
Xa factor inhibitors
0
0
1
2
Direct thrombin inhibitors
0
0
0
0
Heparins
0
0
0
0
Metformin
16
24
14
22
GLP1R analogue
4
6
8
13
SGLT2 inhibitors
8
12
7
11
DPP4 inhibitors
3
5
2
3
Sylfonylureas
1
2
0
0
Glitazone
0
0
0
0
Acarbose
0
0
0
0
Insulin
0
0
0
0
Orlistat
4
6
5
8
Levothyroxine
3
5
4
6
Liothyronine
1
2
0
0
Testosterone
11
17
9
14
Aromatase inhibitors or SERMs
2
3
2
3
Hipnotics
4
6
5
8
Selective serotonin reuptaker inhibitors
(SSRI)
10
15
9
14
Other antidepressants and humor
stabilizers
7
11
6
9
Benzodiazepines
2
3
2
3
Atypical antipsychotics
4
6
3
5
CNS stimulants
5
8
8
13
Alpha-1 adren. Blockers
2
3
3
5
Gnrh analogues and inh., NSAA, others
0
0
0
0
Erectile dysfunction
2
3
1
2
Omega-3
3
5
1
2
Vitamin D
17
26
17
27
Zinc
6
9
7
11
Biotin
1
2
0
0
Vitamin C
8
12
8
13
Multivitamin
2
3
2
3
BCG
64
97
63
98
Influeza (in 2020)
20
30
21
33
Pneumococcal (since 2017)
4
6
8
13
Current smoking
4
6
6
9
Regular physical activity
41
62
42
66
ADDITIONAL COVID TREATMENTS
Ivermectin
7
11
6
9
Hydroxychlorouquine
4
6
3
5
Xa factor inhibitors
9
14
6
9
Enoxaparin
4
6
4
6
Glucocorticoids
7
11
8
13
Vitamin c
4
6
5
8
Zinc
3
5
4
6
Vitamin d
1
2
3
5
Colchicine
0
0
0
0
None!of!the!parameters!was!statistically!significant!between!groups.!!
!!
Congestive heart failure = CHF; type 2 diabetes mellitus = T2DM, chronic obstructive pulmonary disorder =
COPD, chronic kidney disease = CKD, attention deficit hyperactivity disorder = ADHD, benign prostate
hyperplasia = BPH, angiotensin converting enzyme inhibitors = ACEi; angiotensin-2 receptor blockers =
ARB; calcium channel blocker = CCB; glucagon-like peptide-1 receptor analogues = GLP1Ra; sodium-
glucose cotransporter-2 inhibitors = SGLT2i; dipeptidyl-peptidase 4 inhibitors = DPP4i; progesterone = P;
estradiol = E; gonadotropin release hormone = GnRH; selective estrogen receptor modulators = SERM; non-
steroidal antiandrogen = NSAA; selective serotonin reuptake inhibitors = SSRI; central nervous system =
CNS; Bacillus Calmette-Guérin = BCG.
!
!
Table!1.!Characteristics!of!the!study!populations.'''
Shown'are'the'characteristic'of'the'two'arms'of'the'study'
!'
''
''
'
'
Table!2.!Clinical!symptom!remission!of!the!study!populations.'
Shown'are'the'average'remission'times'for'each'clinical'symptoms'of'COVID-19''
men'using'5-alpha-reductase'inhibitors'(5ARi)'compared'to'placebo.'
'
'
'
'
'
'
!
Duration of Symptoms (Days)
Placebo
(n=66)
Dutasteride
(n=64)
Difference
compared to
placebo
p
Shortness of
Breath
0.9
0.3
¯67%
0.149
Fatigue
10.1
5.8
¯43%
< 0.001
Loss of Taste or
Smell (Ageusia or
Anosmia)
13.4
7.3
¯45%
< 0.001
Remission Minus
Loss
11.7
7.3
¯38%
< 0.001
Total Remission
15.6
9.0
¯42%
< 0.001
!
!
*'p<0.05'
!
Figure!1.''Patient'reported'disease'severity'at'various'times'before'and'after'
treatment.''Day'0'denotes'the'start'of'treatment.''Patients were'asked'to'rate'their'
health'on'a'scale'from'0'to'100,'100'being'completely'heathy'and'0'being'their'
worst'day'of'COVID-19.'
'
'
'
'
'
0
20
40
60
80
100
120
Day -7 to
-4
Day -3 ro
-1
Day 0 Day 1 Day 2 Day 3 Day 7 Day 14 Day 21 Day 30 Day 60
Patient Reported Recovery (%)
Patient Reported Disease Severity
Placebo Dutasteride
*
*
*
*
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Background: In women of reproductive age, polycystic ovary syndrome (PCOS) constitutes the most frequent endocrine disorder. Women with PCOS are considered to typically belong to an age and sex group which is at lower risk for severe COVID-19. Main body: Emerging data link the risk of severe COVID-19 with certain factors such as hyper-inflammation, ethnicity predisposition, low vitamin D levels, and hyperandrogenism, all of which have known direct associations with PCOS. Moreover, in this common female patient population, there is markedly high prevalence of multiple cardio-metabolic conditions, such as type 2 diabetes, obesity, and hypertension, which may significantly increase the risk for adverse COVID-19-related outcomes. This strong overlap of risk factors for both worse PCOS cardio-metabolic manifestations and severe COVID-19 should be highlighted for the clinical practice, particularly since women with PCOS often receive fragmented care from multiple healthcare services. Comprehensively informing women with PCOS regarding the potential risks from COVID-19 and how this may affect their management is also essential. Conclusion: Despite the immense challenges posed by the COVID-19 outbreak to the healthcare systems in affected countries, attention should be directed to maintain a high standard of care for complex patients such as many women with PCOS and provide relevant practical recommendations for optimal management in the setting of this fast moving pandemic.
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Introduction At the onset of the COVID-19 pandemic, mortality following infection of severe acute respiratory coronavirus (SARS-CoV-2) was thought to be solely associated with aging and pre-existing conditions; however, as the pandemic ensued, several large scale epidemiological observations eluded to additional atypical risk factors, particularly hypertension, obesity, and male gender (1-11). SARS-CoV-2: current knowledge on the mechanisms of action The peculiarities and complexity of SARS-CoV-2 infection patterns precluded definitive findings regarding the mechanisms of infectivity. Current literature suggests that angiotensin-converting enzyme-2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) are the key for SARS-CoV-2 cell entry (12-20). While ACE2 is the coupling site of the spike protein of SARS-CoV-2, TMPRSS2 facilitates SARS-CoV-2 spikes and ACE2 for viral cell entry. Although ACE2 expression is present diffusely, up to 80% of its expression is located in the type-2 pneumocytes (12,17), which may explain why COVID-19 is predominantly pulmonary, although SARS-COV-2 may affect any organ and system. TMPRSS2 activity is modulated by androgens, which may justify why males are overrepresented among severe COVID-19 infected patients (21). Current understanding of SARS-CoV-2 allows the division of COVID-19 into two phases (12-18). In a first, early phase, which corresponds to the period of SARS-CoV-2 cell entry, lung membrane-attached ACE2 expression seems to be positively correlated with virus infectivity, while the balance between circulating ACE2, that could protect from lung infectivity by coupling with SARS-CoV-2 and precluding from the entry into the pneumocytes (13-16)), and membrane-attached ACE2, may also be relevant. In a second phase, represented by the inflammatory and immunological responses to SARS-CoV-2 infection, ACE2 is downregulated due to the entry into cell cytoplasm when coupled with the virus. In opposition to the first phase, in the second phase, lung-attached ACE2 expression may be positively correlated with better clinical outcomes, since ACE2 may limit the cytokine storm that underlies the Acute Respiratory Distress Syndrome (ARDS) in COVID-19, while the balance between proinflammatory angiotensin II - angiotensin receptor type 1 (AT1) axis, and the anti-inflammatory angiotensin 1-7 – G-coupled Mas receptor (angiotensin 1-7 receptor) axis may also be crucial for level of severity of the second phase (13,15-20). SARS-CoV-2: the link between mechanisms of action and risk factors The Renin-Angiotensin-Aldosterone System (RAAS) has been shown to be central in COVID-19, since three of the key modulators of SARS-CoV-2 infectivity - angiotensin 1-7, ACE2, and AT1 – belong to the RAAS, in addition to the TMPRSS2 expression (12-20). Disruption of RAAS and ACE2 expression abnormalities are likely the underlying mechanism that links hypertension and obesity as important risk factors for COVID-19 (22-30). Conversely, TMPRSS2 overexpression in response to exposure to androgens may justify the higher occurrence of COVID-19 complications in males (31-34), which can be reinforced by the fact that males under androgen deprivation therapies such as for prostate cancer may experiment decreased risk for ARDS when compared to age-, sex-, and comorbidities-matched subjects (34). A pro-thrombotic state, and endothelial, hematological, kidney, hepatic, cardiovascular, gonadal, neurological and gastrointestinal manifestations in COVID-19 are at least partially mediated by ACE2 and TMPRSS2 expressions (35-61). In summary, aberrancies in ACE2 expression, unbalance between angiotensin II and angiotensin 1-7 levels, and overexpression of TMPRS22 seem to be key factors for the severity of clinical manifestations in COVID-19. Spironolactone as a candidate against COVID-19 Drugs that address ACE2, any sight of the RAAS, or TMPRSS2 expression are potential candidates for COVID-19. In this context, the use of old drugs against COVID-19 may present major potential benefits over novel drugs for some reasons, including: 1. The well-established long-term safety profile 2. Extensively described risks and contraindications, which allows to prevent its use when contraindicated and monitor for risks directedly; and 3. The lower cost of old, non-patented drugs allows its massive use in public health systems, when clinically indicated. These observations combined with our understanding of SARS-CoV-2 molecular mechanism of infectivity lead us to believe that spironolactone is an ideal candidate drug for the prophylactic treatment of SARS-CoV-2. Spironolactone is a safe and well-tolerated anti-hypertensive and anti-androgenic drug used since 1959, that is effective to maintain normal blood levels (62-64), address heart function, and provide cardio- and renoprotection (65-69). While spironolactone is a safe and unexpensive option, it may act in multiple sites against COVID-19, including: 1. Favorable patterns of ACE2 expression, including potential increase of circulating ACE2, enhancing its potential protective role in SARS-CoV-2, once plasma ACE2 may couple to SARS-CoV-2 and avoid its entry in the cells (70-76); 2. Downregulation of the androgen-mediated TMPRSS2 due to its antiandrogenic activity (77-79), without the adverse events of male sexual castration; 3. Mitigation of the deleterious effects of obesity on the RAAS, possibly reducing obesity-related COVID-19 complications (80,81); 4. Direct anti-inflammatory and anti-viral effects that could directly avoid pulmonary complications of COVID-19 (82-93). Hence, spironolactone meets corresponding epidemiological data, mechanistical plausibility, and sufficient safety profile to become a candidate against COVID-19. For the proper management of spironolactone during COVID-19, since spironolactone mostly targets the virus entry in the cells, which is the hallmark of the first phase of Covid-19, spironolactone should be preferably started during the earlier stages of the infection, prior to the complications of respiratory manifestations, but could also be employed in the second phase, when the inflammatory and immunologic responses become clinically relevant, due to its anti-inflammatory effects (94). Conclusion Abnormal ACE2 expression, angiotensin II and angiotensin 1-7 imbalance, and TMPRSS2 androgen-mediated overactivity seem to be key regulators of SARS-CoV-2 infectivity, in accordance with epidemiological observations of hypertension, obesity, and male sex as being major risk factors. Since spironolactone is a long used safe drug that exhibits concurrent actions in the modulation of ACE2 expression that could avoid SARS-CoV-2 cell entry, attenuation of the harms caused by the overexpression of angiotensin II-AT-1 axis, discloses anti-androgenic activity that can decrease viral priming through TMPRSS2 activity, and has anti-inflammatory effects in the lungs, spironolactone seems to be a plausible candidate for the prophylactic and early treatment of SARS-CoV-2
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Background: Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods: We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results: The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions: During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.).
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The COVID-19 pandemic has disproportionally affected men.1 Men infected with SARS-CoV-2 are more than twice as likely to be admitted to the intensive care unit (ICU).2 This disparity in ICU admissions suggests the important role of androgens in COVID-19 severity.3 Previously, we reported that among 122 men hospitalized due to COVID-19, 79% were diagnosed with androgenetic alopecia (AGA),4 which is commonly treated with anti-androgens. Anti-androgens commonly used in the treatment of AGA such as finasteride, dutasteride, spironolactone, and bicalutamide could improve outcomes among men infected by SARS-CoV-2.
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Background Cell entry of SARS-CoV-2 depends on binding of the viral spike (S) proteins to ACE2 and on S protein priming by TMPRSS2. Inhibition of TMPRSS2 may work to block or decrease the severity of SARS-CoV-2 infections. Intriguingly, TMPRSS2 is an androgen-regulated gene that is upregulated in prostate cancer where it supports tumor progression and is involved in a frequent genetic translocation with the ERG gene. First- or second-generation androgen-deprivation therapies (ADTs) decrease the levels of TMPRSS2. Here we put forward the hypothesis that ADTs may protect patients affected by prostate cancer from SARS-CoV-2 infections. Materials and methods We extracted data regarding 9280 patients (4532 males) with laboratory-confirmed SARS-CoV-2 infection from 68 hospitals in Veneto, one of the Italian regions that was most affected by the COVID-19 pandemic. The parameters used for each COVID-19 positive patient were gender, hospitalization, admission to intensive care unit (ICU), death, tumor diagnosis, prostate cancer diagnosis, and androgen-deprivation therapy (ADT). Results There were 9280 SARS-CoV-2 positive patients in the Veneto on April 1, 2020. Overall, males developed more severe complications, were more frequently hospitalized, and had a worse clinical outcome than females. Considering only the Veneto male population (2.4 Million men), 0.2% and 0.3% of non-cancer and cancer patients, respectively, tested positive for SARS-CoV-2. Comparing the total number of SARS-CoV-2 positive cases, prostate cancer patients receiving ADT had a significantly lower risk of SARS-CoV-2 infection compared to patients who did not receive ADT (OR 4.05; 95% CI 1.55-10.59). A greater difference was found comparing prostate cancer patients receiving ADT to patients with any other type of cancer (OR 5.17; 95% CI 2.02-13.40). Conclusion Our data suggest that cancer patients have an increased risk of SARS-CoV-2 infections than non-cancer patients. However, prostate cancer patients receiving ADT appear to be partially protected from SARS-CoV-2 infections.
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Racial disparities in COVID‐19 infection rates and disease severity are due to a multifactorial etiology that can include socioeconomic as well as other factors. Nevertheless, genetic factors in different ethnic groups often contribute to disease severity and treatment response. In particular, the frequency of genetic variations in the androgen receptor differs by ethnicity and gender. For example, the increased prevalence of prostate cancer and androgenetic alopecia among African Americans correlates with the frequency of these variants. In this communication, we propose that androgens may be implicated in COVID‐19 disease severity. As such, special attention may need to be given to African Americans infected by the SARS‐CoV‐2 virus. Finally, if a link to genetic variations in the androgen receptor and COVID‐19 disease severity can be established, it would suggest new treatment options.
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A preliminary observation of high frequency of male pattern hair loss among admitted COVID‐19 patients, and suggest that androgen expression might be a clue to COVID‐19 severity.
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The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.