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Gynecomastia

GRETCHENDICKSON,MD,MBA,UniversityofKansasSchoolofMedicine,Wichita,Kansas

Gynecomastiaisdefinedasbenignproliferationofglandularbreasttissueinmen.Physiologicgynecomastiaiscommoninnewborns,adolescents,andoldermen.Itisself-limited,butcanbetreatedtominimizeemotionaldistressandphysicaldiscomfort.Nonphysiologicgyne-comastiamaybecausedbychronicconditions(e.g.,cirrhosis,hypogonadism,renalinsuf-ficiency);useofmedications,supplements,orillicitdrugs;and,rarely,tumors.Discontinuinguseofcontributingmedicationsandtreatingunderlyingdiseasearethemainstayoftreat-ment.Medications,suchasestrogenreceptormodulators,andsurgeryhavearoleintreatinggynecomastiainselectpatients.Treatmentshouldbepursuedearlyandshouldbedirectedbythepatient.(AmFamPhysician.2012;85(7):716-722.Copyright©2012AmericanAcademyofFamilyPhysicians.)

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Patientinformation:Ahandoutonthistopicisavailableat/080.xml.

lthoughtheadultmalebreastcon-tainsminimalamountsofadiposeandglandulartissue,thereispoten-tialforproliferationifestrogenor

A

progesteronelevelsrease.Gynecomastia,whichcanbephysiologicornonphysiologic,occurswhentheestrogen-to-testosteroneratioinmenisdisrupted,leadingtoprolif-erationofglandularbreasttissue.1

PhysiologicGynecomastia

Physiologicgynecomastiahasatrimodalagedistribution,withidencepeakinginnewborns,adolescents,andmenolderthan50years.Upto90percentofnewbornboyshavepalpablebreasttissuesecondarytotranscentaltransferofmaternalestro-gens.2Newborngynecomastia,althoughconcerningtoparents,usuallyresolvesspon-taneouslywithinfourweeksofbirth.Chil-drenwithsymptomsthatpersistaftertheirfirstbirthdayshouldbeexaminedfurther;theymaybeatriskofpersistentpubertalgynecomastia.

One-halfofadolescentmaleswillexperi-encegynecomastia,withtypicalonsetat13to14yearsofage,orTannerstage3or4.3,4An reaseinestradiolconcentration,lagging testosteroneproduction,andreasedtissuesensitivitytonormalmalelevelsofestrogenarepossiblecausesofgyne-comastiainadolescents.5-7Adolescentsmayalsoexperiencenonphysiologicgynecomas-tiaastheresultofsubstance,supplement,

ormedicationuse,orfromtheunmasking

ofgicconditionswithdelayofexpectedpubertaldevelopment.Althoughadolescentphysiologicgynecomastiaoftenresolvesspontaneously,interventionmaybewar-rantedtoameliorateemotionaldistress.

Decreasing testosteronelevelsmaycontributetoafinalpeakingynecomas-tiaidenceinmenolderthan50years.Althougholdermenarelesslikelytopresentforevaluationofgynecomastiathanado-lescents,astudyofhospitalizedmenesti-matesthatapproximay65percentofmenbetween50and80yearsofageexperiencesomedegreeofgynecomastia.8

NonphysiologicGynecomastia

Nonphysiologicgynecomastiacanoccuratanyageasaresultofanumberofmedicalconditions,medicationuse,orsubstanceuse.CommoncausesofnonphysiologicgynecomastiaarelistedinTable1.1,9

PERSISTENTPUBERTALGYNECOMASTIA

Adolescentphysiologicgynecomastiashouldresolvewithinsixmonthstotwoyearsafteronset.Ifsymptomspersistaftertwoyearsorpast17yearsofage,furtherevaluationisindicated.Useofmedicationsorsub-stancesassociatedwithgynecomastiaorotherunderlyingillnessmaybeafactor.Ifnootheretiologycanbefoundandifthepatientdesirestreatment,supplementationwithtestosterone,useofestrogenreceptor–modifyingagents,orreferralforsurgerytoimprovecosmesisiswarranted.

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Table1.CausesofGynecomastia

TherightsholderdidnotgranttheAmericanAcademyofFamilyPhysicianstherighttosublicensethismaterialtoathirdparty.Forthemissingitem,seetheoriginalprintversionofthispublication.

AdaptedwithpermissionfromDerkaczM,iel-PerzynskaI,Nowa-kowskiA.Gynecomastia—adifficuiagnosticproblem.EndokrynolPol.2011;62(2):191,withadditionalinformationfromreference1.

MEDICATIONSANDSUBSTANCES

Afterpersistentpubertalgynecomastia,medicationuseandsubstanceusearethemostcommoncausesofnon-physiologicgynecomastia.Agentsassociatedwithgyne-comastiaarelistedinTable2.7,9-11Commoncontributorsludeantipsychotics,antiretrovirals,andprostatecancertherapieswithlong-termuse.12Spironolactone(Aldactone)alsohashighpropensitytocausegynecomastia,althoughothermineralocorticoidreceptorantagonists,suchaseplerenone(Inspra),havenotproducedsimilareffects.13,14Discontinuinguseofthecontributingagentoftenresults

inregressionofbreasttissuewithinthreemonths.Additionally,lavender,teatreeoil,dongquai,andTrib-ulusterrestris(aningredientinperformance-enhancing

Table2.MechanismofEffectofAgentsCommonlyAssociatedwithGynecomastia

Antiandrogenicproperties

Alkylatingagents

Cimetidine(Tagamet)Cis tin

FlutamideIsoniazidKetoconazoleMarijuanaMethotrexate

Metronidazole(Flagyl)Omeprazole(Prilosec)Penicillamine(Cuprimine)Ranitidine(Zantac)Spironolactone(Aldactone)

V aalkaloidsEstrogenicpropertiesAnabolicsteroidsDiazepam(Valium)Digoxin

EstrogenagonistsEstrogensGonadotropin-releasing

hormoneagonists

Humanchorionicgonadotropins

Induceshyperprolactinemia

HaloperidolMetoclopramide(Reglan)PhenothiazinesUnknownmechanismAmiodarone

Amlodipine(Norvasc)

Amphetamines

Angiotens

onverting

enzymeinhibitorsAntiretroviralagents

Didanosine(Videx)Diltiazem

Fenofibrate(Tricor)FinasterideFluoxetine(Prozac)

Phenytoin(Dil

Phytoestrogens

)

MethadoneMethyldopaMinocycline(Minocin)Minoxidil

Mirtazapine(Remeron)Nifedipine(Procardia)Nilutamide(Nilandron)Paroxetine(Paxil)

Reserpine

reasesmetabolism

Alcohol

reases

hormone–

Rosuvastatin(Crestor)Sulindac(Clinoril)

Theophylline

bindingglobulinconcentration

Diazepam

Phenytoin

Venlafaxine(Effexor)

Verapamil

Informationfromreferences7,and9through11.

supplements)havebeenlinkedtogynecomastia.15-17Althoughsoyconsumptionisthoughttobesafe,con-sumingmorethan300mgperdayhasbeenreportedtocausegynecomastia.18Allsupplementuseinpatientswithgynecomastiashouldbescrutinizedgiventhevari-abilityinmarketedpreparations.19

Anabolicsteroiduseoftencausesirreversiblegyne-comastia.Theinjectionofexogenoustestosteroneinhibitsnaturalproductionoftestosterone,whichcan-notrecoverrapidlyenoughbetweensteroid-injectingcyclestopreventestrogenpredominance.Attemptstopreventgynecomastiawiththeuseofconcomitant

tamoxifenorotheraromataseinhibitorsmayresultinirreversibleadverseeffects.20Useofmarijuana, ,oramphetaminesalsomaycontributetoirreversiblegynecomastia.10,11

CIRRHOSIS

Liverinjurymayimpairhepaticdegradationofestrogensandreaselevelsofhormone–bindingglobulinthatcontributetoreasedperipheralestrogens.Patientswithalcohol-relatedliverdiseaseareatparticularriskofgynecomastiabecausephytoestrogensinalcoholandthedirectinhibitionoftestosteroneproductionbyethanolfurtherdisrupttheestrogen-to-testosteroneratio.

PRIMARYHYPOGONADISM

Gynecomastiamaybetheonlypresentingsymptominmenwithprimaryhypogonadism.Forexample,one-halfofmenwithKlinefeltersyndromehavegyne-comastia.21Suspicionforprimaryhypogonadismiswarrantedinanyadolescentwithpersistentpubertalgynecomastia.

TUMORS

Althoughtesticulartumorsarerare,approximay10percentof swithtesticulartumorspresentwithgynecomastiaalone.22,23Inastudyof175menwhowerereferredtoabreastsurgeonforevaluationofgynecomastia,atesticulartumorwasdiagnosedin3percent.23Leydigcelltumors,althoughoftenbenign,arepronetocausegynecomastiabecausetheysecreteestradiol.

Adrenaltumorsmaysecreteestrogenandestrogenprecursors,causingasimilardisruptionintheestrogen-to-testosteroneratio.Thesetumorscanbedetectedbyelevatedserumdehydroepiandrosteronesulfatelevelsorreasedurinary17-ketosteroidlevels.Similarly,

Nocauseisfoundin25percentof

patientswhodevelopgynecomastia.

thepresenceofhumanchorionicgonadotro-pin(hCG)inserumcanbeusedtodetecthCG-secretingtumorsthatmayludetesticulargermcell,liver,gastric,

orbronchogeniccarcinomas.Allofthesetumorsrequiresurgicalexcision.

HYPERTHYROIDISM

Gynecomastiaoccursin10to40percentofmenwithhyperthyroidism,althoughitisrarelytheonlysymptomatpresentation.24,25Restorationofeuthyroidstatewillresolvegynecomastiainotwomonths.

CHRONICRENALINSUFFICIENCY

Hormonaldysfunctioniscommoninmenwithrenalfailurebecauseofoverallsuppressionoftestosteroneproductionanddirecttesticulardamagesecondarytouremia.26Malnutritionoccursinupto40percentofpatientswithrenalfailure;thismaycontributetogyne-comastiainmen.27Dialysisimprovesmalnutrition-associatedgynecomastia,butonlyrenaltransnteffec-tivelyresolvesnutritionalandhormonalcausesofgyne-comastiainthosewithrenalfailure.

OTHER

Conditionsthatimpairabsorption,suchasulcerativecolitisandcysticfibrosis,mayresultingynecomastia.Refeedingafterprolongedmalnutritioncsotriggerbreasttissueproliferation.Althoughmalnutritionsup-presseshormoneproduction,refeedinghelpsresumeproduction.However,theliverlagsinrecoveryandcan-notfullydegradeestrogens.9Astheliverrecovers,gyne-comastiausuallyresolveswithinotwoyearsafterresumptionofabalanceddiet.

Althoughobesitycausespseudogynecomastia(apro-liferationofadiposeratherthanglandulartissue),ele-vatedweightisalsoassociatedwithtruegynecomastia.Newresearchsuggeststhatleptinandaromataseactivityassociatedwithobesitycontributetoreasedcirculat-ingestrogens,causinggynecomastia.28

Otherrarecausesofgynecomastialudeexposuretophthalatesandlead,emotionalstress,andrepetitivemechanicalstresscausingunilalsymptoms.29-31Tes-ticularinjuryfromillnesses(e.g.,mumpsorchitis),infil-trativeprocesses(e.g.,tuberculosis,hemochromatosis),ortraumamaydecreasetestosteroneproductionandleadtogynecomastia.Additionally,patientswithhumanimmunodeficiency infectionmaydevelopgyneco-mastiafromthediseaseprocessoruseofantiretroviralmedications.Nocauseisfoundin25percentofpatientswhodevelopgynecomastia.7,30,31

Diagnosis

Somepatientswithgynecomastiamaypresentwithbreastpain,embarrassment,orfearofbreastcancer.Inotherpatients,gynecomastiaisdiscoveredonroutinephysicalexaminationandcausesnoemotionalorphysi-caldistress.Understandingthepatient’sconcernscanhelpdirecttreatment.

HISTORYANDPHYSICALEXAMINATION

Thehistoryshouldruleoutothercausesofbreastenlargement,suchasthoselistedinTable3.31-33Physiciansshouldrevietients’useofmedications,supplements,

Table3.DiagnosesinMenReferredforImagingorBiopsyBecauseofBreastEnlargement

andillicitdrugs.Symptomsthatlastlongerthanotwoyearssuggestnonphysiologiccausesthatrequireinterventionforresolu-tion.Nippledischarge;skhanges;rapidlyenlarging,firmbreastmasses;co tes-ticularmasses;orsystemicsymptomssuchasweightlossshouldraiseconcern.

Thephysicalexaminationshouldludeevaluationofheightandweight,andexami-nationofthebreasts,genitals,liver,lymphnodes,andthyroid.Assessmentofsymmetryandconsistencyofbreasttissueiscriticalonbreastexamination.Mostcommonly,gyneco-mastiaisbilal,althoughunilalsymp-tomscanoccurandareusuallyleft-sided.Palpable,firmglandulartissueinaconcentricmassaroundthenippleareolarcomplexismostconsistentwithgynecomastia.reasesinsubareolarfataremorelikelypseudogy-necomastia,whereashard,im massesshouldbeconsideredbreastcarcinomauntilprovenotherwise.Similarly,massesassoci-atedwithskinchanges,nippleretraction,nippledischarge,orenlargedlymphnodesshouldraiseconcernformalignancy.

DIAGNOSTICTESTING

Thehistoryandphysicalexaminationshoulddirectthelaboratoryandimagingworkup(Figure1).Laboratorystudiestoinvestigatetheunderlyingcauseofgyne-

Diagnosis Frequency(%) Findings

Gynecomastia 63to93 Discrete,round, mass

underareola;usuallybila l

Pseudogynecomastia 5.4 reasedadiposeratherthanglandulartissueonexamination

Breastcancer 1.4to2.9 Patientfallsoutsideofagerange

forphysiologicgynecomastiaBloodynippledischargeAxillarylymphadenopathyNonpainfulmass(painmore

commoningynecomastia)

Oftenunila l

alhistoryofmalignancy

Lipoma 0.9to2.9 AsymmetricbreastenlargementSebaceouscyst 1.4to2 Drainageofmaterialfromsite

Swellingfeelsclosertoskinthanapartofdeepertissue

Asymmetricbreastenlargement

Mastitis 0.8to1.1 Systemicsignsofinfection

Fatnecrosis 0.3to0.9 Historyofinjurytotheareamay

bepresent

Maybealocalswelling,notovernippleareolarcomplex

Asymmetricbreastenlargement

Dermoidcyst

0.9

Painlesslumpthatmayenlarge;maybeanywhereinthebreast

Hematoma

0.9

Historyofinjurytotheareamaybepresent

Asymmetricbreastenlargement

Metastaticdisease 0.8 Historyofcancer

Ductale ia 0.5 NonspecificbreasttendernessHamartoma 0.5 Solidmass;diagnosismadewith

pathologicexamination

comastiashouldludemeasurementofhepatictransaminase,serumcreatinine,andthyroid-stimulatinghormonelevelsforallpatients.LevelsofserumbetahCG,serum

Lymphosmacyticinfl tion

Postsurgicalchanges

0.5 Diagnosismadeonpathologyspecimenafterremovalofmass

0.5 Historyofsurgery

dehydroepiandrosteronesulfate,orurinary17-ketosteroidshouldbeobtainedtoruleouttesticular,adrenal,orothertumorswhenclinically ed.Likewise,totaland

Informationfromreferences31through33.

testosterone,estradiol,luteinizinghormone,andfollicle-stimulatinghormonelevelsdefinehormonalimbalancesresultingfromprimaryorsecondaryhypogonadism.Hyperprolactinemiaisnotcommoninpatientswithgyne-comastia.Laboratorystudiesmaybeorderedusingastep-wiseapproachguidedbyhistoryandphysicalexamination,butadiagnosisofphysiologicgynecomastiashouldnotbemadeuntilunderlyingetiologieshavebeenexcluded.

Recommendationsforimagingstudiesarebasedmainlyoncasereportsandexpertopinion.Somestud-ieshavesuggestedroutesticularultrasonogra-phyinmenwithgynecomastiatodetectnonpalpable

testiculartumorsthatweremissedonclinicalexamina-tion.34However,amorewidelyadvocated,conservativeapproachistoperformtesticularultrasonographyonlyinthosewithpalpabletesticularmasses,gynecomastialargerthan5cm,orotherwiseunexinedgynecomas-tia.Breastimagingshouldbeguidedbyexamination.Justasinwomen,mammographyandbreastultrasonog-raphymaybeusefulinmenifthephysicalexaminationraisessuspicionforbreastmalignancy.35

Fine-needleaspirationofmassesforcytologyshouldbepursuedonlyifmalignancyis ed.MenwithKlinefeltersyndromehaveariskofbreastcancer16to

Isthepatientanewborn?

Yes

Likelytranscental;shouldresolvewithinfourweeks

IsthepatienttakingamedicationorsubstancelistedinTable2?

Yes

Discontinueagentandmonitorforresolution

mass

Breastmassthatraisessuspicionformalignancy

Unremarkableexamination

Gynecomastia

Pseudogynecomastia

ultrasonography

Performmammographyandbreastultrasonographywithbiopsy

Recommendmeasurecreatinineandthyroid- weightlossstimulatinghormonelevels

Evidenceofchronicdisease?YesTreatunderlyingdiseaseNo

Measureserumhumanchorionicgonadotropin,dehydroepiandrosterone,luteinizinghormone,follicle-stimulatinghormone,estradiol,testosterone,andprolactinlevels

Highlevelofestradiolandlow Highlevelofprolactin Highleveloflevelofluteinizinghormone humanchorionic

gonadotropin

Lowlevelsofluteinizinghormoneandtestosterone

Highlevelofluteinizing Allhormone

hormoneandlowleveloftestosterone

normal

imaging

ultrasonography

Performtesticularultrasonographyforgermcelltumor

Secondaryhypogonadism

Idiopathic

Primary gynecomastiahypogonadism

Ultrasonographyresultsnormal

Considerexogenousestrogenuse,stress,orunderlyingchronicdiseaseaspossiblecause

Figure1.Algorithmforthediagnosisofgynecomastia.

30timeshigherthanothermen.Evenwithareassuringexamination,menwithgynecomastiaandKlinefeltersyndromemayrequireimaging.7,36

Treatment

Fetientswithgynecomastianeedtreatmentforcos-mesisorgesia.37Inastudyontreatmentforgyne-comastia,aboutone-halfofmenwerenotsignificantlybotheredbysymptoms.38Painismorecommoninpatientswithgynecomastiathatisrapidlyprogressiveorofrecentonset.Forpatientswithnonphysiologicgyne-comastia,treatmentisdirectedtowardimprovingthe

underlyingillnessordiscontinuinguseofthecontribut-ing.Watchfulwaitingwithbiannualfollow-upisappro-priateforthosewithphysiologicgynecomastiawhoareuntroubledbysymptomsandwhohavenofeaturesthatsuggestunderlyingdiseaseormalignancy.Earlytreat-mentwill izebenefitinmenwithsignificantphysicalsymptomsoremotionaldistress.Medicationsaremoreeffectiveifusedasearlyaspossibleaftersymp-tomsarefirstnoted,whereassurgerycanbeperformedatanytimewithsimilarresults.

Anumberofmedicationshavebeenusedtotreatgyne-comastia.Aretrospectivechartreviewofmenpresenting

toabreastclinicforgynecomastiafoundthatonly13of220patientsrequiredmedicationfortreatment.Patientsweretreatedwith10mgoftamoxifenperdayforthreemonths,and10ofthe13hadresolutionofpainandbreastenlargement.37Althoughtamoxifenisthoughttobeaneffectiveandsafetreatmentforphysiologic,per-sistentpubertal,oridiopathicgynecomastia,twosmalldouble-blind,crossovertrialsfoundonlymodestbenefitwhencomparedwithcebo.39,40

Gynecomastiaisacommonadverseeffectofbicalu-tamide(Casodex)therapythatmaypromptsomementodiscontinueprostatecancertreatment.Tamoxifenhasbeenrecommendedasapreventiveagentforgyne-comastiainthesepatients.Adouble-blindstudyof282menrandomizedtoreceive20mgoftamoxifenonceperdaywithbicalutamideorbicalutamidealonefoundthataftersixmonths,gynecomastiaandbreastpainweresignificantlyreducedinmenwhoreceivedtamoxifen(8.8versus96.7percentinthecontrolgroup).41AnItalianrandomizedcontrolledtrialof80participantsalsofoundthat20mgoftamoxifenonceperweekisaseffectiveas20mgonceperday.42

Inaretrospectivechartreviewof38patientsinapedi-atricendocrinologyclinic,raloxifene(Evista;60mgonceperdayforthreetoninemonths)reducedpubertalgynecomastiain91percentofpatients,whereastamoxi-fen(10to20miceperdayforthreetoninemonths)waseffectivein86percentofpatients.4However,therewasnocontrolgroup,andgiventhenaturalhistoryofpubertalgynecomastia(i.e.,self-limited),cebo-controlledtrialsarestillneeded.Dihydrotestosterone,danazol,andclomiphene(Clomid)havealsobeenusedtotreatgynecomastiawithvaryingsuccess.

Morestudiesareneededtoassesstheeffectivenessofaromataseinhibitors,suchasanastrozole(Arimidex;1mgperday).rialof42pubertalboysdemonstrated

Evidence

rating References

Discontinuinguseofspironolactone(Aldactone)oftenresultsinregressionofbreasttissuewithinthreemonths.

13,14

Routesticularultrasonographyshouldbeconsideredinmenwithgynecomastiatodetectnonpalpabletesticulartumorsthatweremissedonclinicalexamination.

Mammographyandbreastultrasonographyshouldbeperformedinmenifthephysicalexaminationraisessuspicionforbreastcancer.

4,37,42

forpreventingandtreatinggynecomastiainmenbeingtreatedforprostatecancer.

A=consistent,good-qualitypatient-orientedevidence;B=onsistentorlimited-qualitypatient-orientedevidence;C=consensus,disease-orientedevidence,usualpractice,expertopinion,orcaseseries.ForinformationabouttheSORTevidenceratingsystem,goto .

a57percentreductioninbreastvolumewithanastrozoletreatment.43However,arandomizedcontrolledtrialof80par-ticipantsdemonstratednostatisticallysignificantdifferencweenanastrozoleandcebointhepercentageofpatientswithgreaterthan50percentbreastvolumereductionatthreemonths.44

Surgerycanbeperformedatanytimetoreducebreasttissue,andanumberoftechniqueshavebeenused.32,33,45Longerdurationofsymptoms,higher-gradedis-ease,orinabilitytotoleratemedicationsmaypromptsurgeryasafirst-lineoption.

However,unilalsymptoms,high-gradedisease,andlongdurationofsymptomsarealsoassociatedwithmoresurgicalcomplications.46

Ifpseudogynecomastiais ed,noworkupisneeded,andthepatientcanbereassuredthatweightlosswillleadtoresolutionofpseudogynecomastiaandalsobemostbeneficialforoverallhealth.46Ifnecessary,lipo-suctionprocedurescanreducebreastenlargementsec-ondarytosubareolarfcumulation.

TheauthorthanksAnneWalling,MD,andScottMoser,MD,fortheirassistancewiththismanuscript.

DataSources:EssentialEvidencePlusandPubMedweresearchedforrelevantarticlesusingthefollowingsearchterms:gynecomastia,physi-ologicgynecomastia,andbreastenlargement.Eachtermwassearchedindividuallyandonjunctionwiththefollowingterms:males,men,diagnosis,treatment,andmanagement.AsearchusingthesamewordswasalsocompletedwithinandtheCochranecollection.Searchdates:December10to25,2010.

TheAuthor

GRETCHENDICKSON,MD,MBA,isdirectoroftheFamilyMedicineClerk-ship,andassistantprofessoroffamilymedicineattheUniversityofKansasSchoolofMedicineinWichita.

AddresscorrespondencetoGretchenDickson,MD,MBA,UniversityofKansasSchoolofMedicine,1010N.Kansas,Wichita,KS67214(:gdickson@).Reprintsarenotavailablefromtheauthor.

Authordisclosure:Norelevantfinancialaffiliationstodisclose.

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