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

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Progrèsenurologie(2020)30,484—487

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SHORT COMMUNICATION

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

COVID-19 et la susceptibilité du sexe masculin: le rôle de l’ACE2, la TMPRSS2 et le récepteur aux androgènes

G. Mjaess

^a^,^b

, A. Karam

^b

, F. Aoun

^b^,^c

, S. Albisinni

^a

, T. Roumeguère

^a^,^c^,∗

aUrologyDepartment,UniversityClinicsofBrussels,ErasmeHospital,UniversitéLibrede Bruxelles,Brussels,Belgium

bHotel-DieudeFrance,UniversityofSaint-Joseph,Beirut,Lebanon

cUrologyDepartment,InstitutJules-Bordet,Brussels,Belgium

Received28April2020;accepted17May2020 Availableonline22May2020

KEYWORDS COVID-19;

Angiotensin-

ConvertingEnzyme2;

TypeII

Transmembrane SerineProtease;

androgenreceptor

Summary COVID-19isthepandemicthathittheworldstartingDecember2019.Recentstudies andinternationalstatisticshaveshownanincreasedprevalence,morbidityaswellasmortality ofthisdiseaseinmalepatients comparedtofemalepatients.Theaimofthisbriefcommu- nicationistodescribethe pathophysiologyofthissex-discrepancy, basedontheinfectivity mechanismofthecoronavirusincludingtheAngiotensin-ConvertingEnzyme2(ACE2),theType IItransmembraneSerineProtease(TMPRSS2),andtheandrogenreceptor.Thiscouldhelpunder- standthesusceptibilityofurologicalpatients,especiallythosereceivingandrogendeprivation therapyforprostatecancer,andtestosteronereplacementtherapy.

∗Correspondingauthorat:UrologyDepartment,ErasmeHospital,UniversitéLibredeBruxelles,Brussels,Belgium.

E-mailaddress:thierry.roumeguere@erasme.ulb.ac.be(T.Roumeguère).

https://doi.org/10.1016/j.purol.2020.05.007

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COVID-19andthemalesusceptibility 485

MOTSCLÉS COVID-19; Enzymede conversionde l’angiotensine2; Sérineprotéase transmembranaire2; Récepteuraux androgènes

Résumé La COVID-19 est la pandémie mondiale apparue en décembre 2019. Les études récentesetlesstatistiquesinternationalesontmontréunenetteprédominancedela préva- lencedecettemaladieainsiquedesamorbiditéetmortalitéchezleshommes,comparésaux femmes.Lebutdecettecommunicationbrèveestd’exposerlaphysiopathologiedecettepossi- bledifférencedesexe,ensebasantsurlemécanismedel’infectivitéduvirusincluantl’enzyme deconversiondel’angiotensinedetype2(ACE2),lasérineprotéasetransmembranairedetype II(TMPRSS2),etlerécepteurauxandrogènes.Cecipourraitjustiﬁeruneétudedelasusceptibil- itédespatientsurologiques,surtoutceuxrecevantunedéprivationandrogéniquepourcancer deprostate,ouunesupplémentationentestostérone.

TheSevereAcuteRespiratorySyndromeCoronavirus2(SARS- CoV2)isthevirusresponsibleforthecoronavirusdiseaseof 2019(COVID-19),declaredapandemicbytheWorldHealth Organization (WHO). International efforts are converging intodepictingthepandemic’sclinicalcourse,epidemiology, prevention and treatment. Recent studies have reported that men aremore affected by the disease than women, and a higher percentage of COVID-19—related morbidity, intensivecareadmissionandmortalityisfoundamongmen comparedtowomen[1].Thebasisforthisdiscrepancyhas notbeenestablishedyet.

In general, differences in lifestyle and behavior exist betweensexes.Femaleshavealowerprevalenceofsmok- ingandcardiovasculardiseases,whichareassociatedwitha worseprognosisforCOVID-19patients.Moreover,literature hasuncoveredafemalepredominanceofanxietydisorders, especiallyillnessandhealthanxiety[2],thusmayberesul- ting in more restrictive activities and social distancing in women.

Speciﬁc mechanisms explaining this discrepancy exist for thecoronavirusfamily, sincethissex-differenceis not foundinothervirusfamilies.SevereAcuteRespiratorySyn- drome(SARS)andMiddleEastRespiratorySyndrome(MERS) outbreaks have also shown a male predominance in dis- easesusceptibility [3].Malemiceinfected experimentally with SARS-CoV were more susceptible than female mice, andovariectomyorestrogenreceptorantagonistsincreased female mice mortality, thereby concluding that estrogen might haveprotective effectagainstcoronavirus infection [4].

Yet,theviralpathogenicityitselfcouldbeaccountable forthismale-femaledifferenceinsusceptibilityforCOVID- 19.Coronavirusinfectivitydependsonitsentryviabinding of its viral spike (S) protein to Angiotensin-Converting Enzyme2(ACE2)receptor,andonSproteinprimingbythe TypeIITransmembraneSerineProtease(TMPRSS2)(Fig.1).

First,ACE2,whichisknowntobeabloodpressureregu- latorthroughthe renin-angiotensin-aldosteronesystem,is a functional receptor for SARS-CoV2 allowing human cell entry and viral infectivity. ACE2 is not only found in the lungsresultinginrespiratorysymptomsandlunginjuryofthe SARS-CoV2,butalsoinmanyotherorgansincludingkidneys,

prostateandintestines,suggestingotherpossibleroutesof viral transmission,and testes, hence possiblyrequiring a long-termfollow-upofthereproductivefunctioninmales.

Whilesome authorsreportedtheabsenceofSARS-CoV2in thesemenof males recoveringfromCOVID-19 [5],others haveshownitspresenceinthesemenofactiveandrecov- eringpatients.[6].

The virussusceptibilityis affectedbyACE2 expression, whichcouldbeinfluencedbyseveralfactorssuchassmok- ing[7]andrenin-angiotensin-aldosteronesysteminhibitors [8].Someauthorssuggestthattheincreasedmorbidityand mortalityfromthevirusinmalepatientsisattributedtoan increasedexpressionof ACE2in males[9],especiallythat theACE2geneislocatedontheXchromosome.Othersdid notfindasignificantdifferenceinACE2expressionbetween malesandfemales,makingthishypothesislessprobable[7].

Morestudiesareneededtodetermineanyincriminatedrole ofACE2overexpressioninCOVID-19susceptibilityinmen.

Second,theroleofTMPRSS2istoactivatethespikepro- teinandfacilitate viral entry.Notably, theTMPRSS2gene hasbeen reportedin thepathophysiologyofprostatecan- cer,whenfusedwiththeoncogenictranscriptionfactorERG.

ERGisnormallyregulatedbyandrogens,andthegenefusion juxtaposes the androgen receptor elements of these two genes;ERGgeneisthereforecontrolledbyandrogenrecep- torsignaling[10].

Since SARS-CoV and SARS-CoV-2 have a similar molec- ular structure, their viral pathogenesis is likely similar.

Interestingly,TMPRSS2geneexpressionispromotedthrough androgenreceptoronly(sincenootherregulatoryelements havebeenreportedtodate),andincreasesuponexposureto androgens[11].Severalandrogenreceptorelements(ARE) arelocatedupstreamofthetranscriptionstartsiteandthe ﬁrstintronofTMPRSS2gene[12].

ThisupregulationofTMPRSS2byandrogenscouldexplain theincreasedsusceptibilitytoCOVID-19inmen.Thispatho- physiologycouldalsoexplainthelesssymptomaticdiseasein childrenwhohavelowexpressionoftheandrogenreceptor.

However,arecentstudyhasshownthattheconstitutive TMPRSS2expressioninlungtissuedoesnotdifferbetween menandwomen[13],andlowlevelsofandrogensinwomen couldbeenoughtosustainthisTMPRSS2expressioninlungs.

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486 G.Mjaessetal.

Figure1. PathwayforSARS-CoV-2virusinfectionmediatedbyandrogenactivity

Songetal.havereportedasmallpercentageofTMPRSS2and ACE2co-expressioninprostate,andahigherco-expression inpneumocytesinmalescomparedtofemales[14].

Giventhat TMPRSS2levelsareinfluencedbyandrogens not only in the prostate but also in the lung, Montopoli etal.haveshownrecentlythatasignificantlylowerriskof COVID-19wasfoundinpatientswithprostatecancerreceiv- ingandrogendeprivationtherapy(ADT)comparedtothose whodid notreceive ADT [15]. Therefore,ADT could give partialprotectionfromSARS-CoV2infections,whiletaking intoaccountthatcanceritselfisanegativeprognosticator inCOVID-19[15].Morestudiesareneededtoconfirmthese findings.

Studying prevalenceof COVID-19and itsmorbidityand mortality,aswellasTMPRSS2proteinexpressioninlungtis- sueofpatientswithprostatecancerreceivingADT,females withpolycysticovarysyndrome(abaselineincreasedandro- gen status), patients with congenital adrenal hyperplasia (21-hydroxylase deﬁciency), and patients ontestosterone therapy,mightleadtoabetterunderstandingofthismecha- nism.TMPRSS2inhibitorsarenowbeingtestedonSARS-CoV2 (ClinicalTrials.gov,NCT04321096).

All these assumptions could help us depict underlying explanations for the difference found for morbidity and mortalityof the novel COVID-19 pandemic between male andfemalepatients.Understandingthisdiscrepancycould helpdepictthediseasepathophysiologyinordertodevelop promising targeted therapies or vaccines. Future studies must further assess the speciﬁc susceptibility of urologi- calpatients,especiallyprostate cancer patientsreceiving

androgendeprivationtherapy,andpatientsreceivingtestos- teronereplacementtherapy.

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

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