This is an Open Access document downloaded from ORCA, Cardiff University's institutional

repository: http://orca.cf.ac.uk/119659/

This is the author’s version of a work that was submitted to / accepted for publication.

Citation for final published version:

Gupta, Aditya K., Mays, Rachel R., Versteeg, Sarah G., Shear, Neil H., Piguet, Vincent and

Piraccini, Bianca Maria 2019. Efficacy of off-label topical treatments for the management of

androgenetic alopecia: a review. Clinical Drug Investigation 39 (3) , pp. 233-239. 10.1007/s40261-

018-00743-8 file

Publishers page: http://dx.doi.org/10.1007/s40261-018-00743-8 <http://dx.doi.org/10.1007/s40261-

018-00743-8>

Please note:

Changes made as a result of publishing processes such as copy-editing, formatting and page

numbers may not be reflected in this version. For the definitive version of this publication, please

refer to the published source. You are advised to consult the publisher’s version if you wish to cite

this paper.

This version is being made available in accordance with publisher policies. See

http://orca.cf.ac.uk/policies.html for usage policies. Copyright and moral rights for publications

made available in ORCA are retained by the copyright holders.

1

EfficacyofOff-LabelTopicalTreatmentsfortheManagementofAndrogeneticAlopecia:a

SystematicReview

AdityaK.GuptaM.D.,Ph.D.1,2,RachelR.MaysB.Sc.

1,SarahGVersteegM.Sc.

1,NeilH.ShearM.D.

2,3,

VincentPiguetM.D.,Ph.D.2,4,5

andBiancaMariaPiracciniM.D.6

1MediprobeResearchInc.,London,Canada

2DivisionofDermatology,DepartmentofMedicine,UniversityofTorontoSchoolofMedicine,Toronto,Canada

3DivisionofDermatology,SunnybrookHealthSciencesCentre,Toronto,Canada

4DivisionofDermatology,Women'sCollegeHospital,Toronto,Canada

5DivisionofInfectionandImmunity,CardiffUniversitySchoolofMedicine,Cardiff,UnitedKingdom

6Dermatology,DepartmentofExperimental,DiagnosticandSpecialtyMedicine,UniversityofBologna,Italy

CorrespondingAuthor:

A.K.Gupta

MediprobeResearchInc.

645WindermereRoad

London,Ontario,CanadaN5X2P1

Phone:519-851-9715

Fax:519-657-4233

Email:agupta@mediproberesearch.com

CompliancewithEthicalStandards

Funding:Thispaperwasnotfunded.

Conflictofinterest:Dr.PiguetreportsreceivingeducationalgrantsinhisroleasDepartmentDivision

Director,Dermatology,UniversityofToronto(onbehalfoftheDivisionofDermatologyResidency

Program)fromAbbvie,Celgene,Janssen,Naos,Lilly,Sanofi,Valeant,andnon-financialsupportfromLa

Roche-Posay,outsidethesubmittedwork.

2

Abstract

Androgeneticalopecia(AGA)ischaracterizedbynon-scarringfollicleminiaturization.Despitethe

successofapprovedtherapies,commonlyreportedsideeffectsandtheneedforcontinualusehasled

totheinvestigationofalternativetherapies.Theaimofthispaperistocriticallyreviewthesuccessof

off-label,topicalmonotherapiesfortreatmentofAGAinmen.Aliteraturesearchwasconductedto

obtainrandomized,controlledandblindedstudiesthatinvestigatedoff-label,topical,monotherapiesin

malepatients.Hairdensity,hairdiameterandhairgrowthwereusedtoevaluatetreatmentsuccess.

Fourteenoff-labeltopicaltherapieswereinvestigatedamongthe16studiesthatmetinclusioncriteria.

Nineoff-labeltherapieswerereportedtoproduceasignificantlygreaterimprovementinhair

restorationparameters(e.g.,meanchangefromhaircountandhairdiameter)ascomparedtoplacebo

(p<0.05foralltreatments).Intwostudies,procyanidinoligomersexhibitedgreaterefficacyovervehicle

withresponsetomeanchangeinhairdensity(hairs/cm2)(ps<0.0001atweek24).Inconclusion,

prostaglandinanalogsandpolyphenols,suchaslatanoprostandprocyanidinoligomers,canimprove

hairrestorationparametersinmaleAGApatients,possiblythroughtargetingmechanismsproposedin

theetiologyofAGA.Thecurrentevidencesuggestsshortterm(24weeks)usemayprovidebenefitfor

hairlosspatients;however,long-termefficacyandsafetydataarerequired.

KeyPoints

• Duetothepotentialsideeffectsandtheneedforcontinualuseofapprovedtherapies,thereisa

needtoexploretheefficacyofoff-labeloptions.

• Eightoff-labeltopicaltherapies,includingprostaglandinanalogsandpolyphenols,werefoundto

improvehairdensity,whileoneadditionaltherapyimprovedhairdiameter.

Keywords:androgeneticalopecia,off-labeltherapies,prostaglandinanalogs,polyphenols

3

1.0Introduction

Androgeneticalopecia(AGA)isacommonhairlossdisordercharacterizedbynon-scarring

follicleminiaturization1.TheetiologyofAGAismultifactorialandpolygenetic,withandrogensplaying

apivotalrole2,3.Finasteride,anoral5-αreductaseinhibitor,andminoxidil,atopicalvasodilator,are

FDAandHealthCanadaapprovedfortreatmentofAGA4–7.Despitetheirsuccess,theseapproved

therapieshaveseveraldrawbacks.Theirimprovementinhairrestorationparameterstendstoplateau

afterafewyearsofcontinueduse.Inaddition,theseapprovedtherapieshavebeenassociatedwithside

effectssuchasskinirritationandsexualdysfunction4–7.Thus,thereisaneedfornew,safeandeffective

treatmentsforAGA.Theaimofthispaperistocriticallyreviewthesuccessofoff-label,topical

therapiesfortreatmentofandrogeneticalopeciainmen.

2.0MethodsofLiteratureSearch

AliteraturesearchinPubMed,MEDLINE(Ovid),Embase(Ovid),andCINAHLwasconducted

usingthefollowingsearchterms:‘androgeneticalopecia’,‘malepatternbaldness’,‘AGA’and

‘randomizedcontrolledtrial’(February2018).Randomized,controlled(placeboorvehicle)andblinded

(single,doubleortriple)trialsthatinvestigatedtopicaloff-labelmonotherapiesforthetreatmentof

androgeneticalopeciainmalepatientswereincluded.Studiesthatinvestigatedoralorcombination

therapies,includedonlyfemalepatients,and/orincludedalopeciaconditionsotherthanandrogenetic

alopeciawereexcluded.Eligiblestudieswererequiredtoevaluatetreatmentsuccessusinghairdensity

(hair/cm2),hairdiameter(mm)orhairgrowth(mm/cm

2).Clinicaloutcomesvarywidelyamongstudies;

weselectedarangeofquantitativemeasurementstobeasinclusiveandobjectiveaspossible.

3.0ResultsofLiteratureSearch

Sixteenstudiesmetinclusioncriteria(Figure1)8–23

.Atotalof1,709maleparticipantswere

includedwithanaverageageof40years.Fourteenoff-labeltopicaltherapieswereinvestigated:a

4

penta-peptide(Gly-Pro-Iie-Gly-Ser),adenosine,bimatoprost,Curcumaaeruginosaextract,dabao,

fulvestrant,aherbalextract,latanoprost,anon-steroidalanabolichormonegel,procyanidinoligomers,

pyrithionezinc,roxithromycin,sodiumvalproateandviprostol(Tables1-3)8–23

.Treatmentduration

rangedfrom4weeks23to52weeks

21with24weeksthemostcommonduration(10/16=63%)

9,12,15–19,21–

23.Investigatedtherapieswereadministeredinawidearrayofformulationsincludingcream(herbal

extract11),gel(non-steroidalanabolichormones

18),lotion(adenosine,penta-peptide,dabao,

roxithromycin12-14,17

),shampoo(pyrithionezinc8),solution(bimatoprost

22-23,latanoprost

9,Curcuma

aeruginosaextract20,fulvestrant

10,procyanidin

16,21,viprostal

19),andspray(sodiumvalproate

15).

3.1HairDensity

Fifteenincludedstudiesusedhairdensitytoevaluatetreatmentsuccessofoff-labeltherapiesin

AGApatients8–11,13,15-23

.Themeanchangeinhairdensity(hairs/cm2)frombaselinetoendoftreatment

foroff-labeltherapiesrangedfrom-4hairs/cm2to54hairs/cm

2(Table1).Eightoff-labeltherapies

(pyrithionezincshampoo,latanoprost,aherbalextract,adenosine,sodiumvalproatespray,procyanidin

oligomers,dabao,andanon-steroidalanabolichormonesolution)hadasignificantlyhighermean

changefrombaselineascomparedtoplacebo(p<0.05foralltreatments)8,9,11,13,15–18,21

.Thehighestmean

changeinhairdensity(hairs/cm2)after24weeksoftreatmentwasfoundwithlatanoprost(Figure2)

9.

Twostudiesreportedprocyanidinoligomertreatmentexhibitedgreaterefficacyovervehiclewith

responsetomeanchangeinhairdensity(hairs/cm2)byendof24weeksoftreatment(ps<0.001)

16,21.

3.2HairDiameter

Twoincludedstudiesusedchangesinhairdiametertoevaluatetreatmentsuccessofoff-label

therapiesinAGApatients(Table2)8,12

.Meanchangeinhairdiameter(mm)ascomparedtobaselinewas

significantlyhigherwithroxithromycinascomparedtovehicleafter24weeksoftreatment(p<0.01)12,

whereas,26weeksofpyrithionezinctreatmentwasnotsignificantlydifferentfromplacebotreatment8.

5

3.3HairGrowth

Threestudiesmeasuredtheimpactofoff-labeltopicaltherapyonmeanchangeinhairgrowth,

asdefinedasmm/cm2frombaseline,comparedtovehicletreatedpatients(Table3)

10,22,23.Bimatoprost

treatmentonceortwiceadayproducedameanchangeinhairgrowthafter24weeksoftreatmentof

0.76mm/cm2and0.92mm/cm

2,respectively

22,23.Asignificantlylowermeanchangeinhairgrowthwas

foundwithfulvestrantascomparedtominoxidilafter16weeksoftreatment(p<0.001)10.

4.0Discussion

Inrecentyears,manynoveltreatmentsfortreatingAGAandotherhairlosshavebeen

investigated.Theobjectiveofthisreviewwastoevaluatetherapeutic,off-labeloptionsavailabletotreat

AGA.TheexistingpharmaceuticaltherapiesforAGAareoralfinasterideandtopicalminoxidil;someof

theoff-labeltreatmentsdiscussedinthisreviewworkviasimilarmechanisms.Eightoff-labeltherapies

(pyrithionezincshampoo,latanoprost,aherbalextract,adenosine,sodiumvalproatespray,procyanidin

oligomers,dabao,anon-steroidalanabolichormonesolution)producedsignificantincreasesinhair

density,whileroxithromycinsignificantlyincreasedhairdiameter8,9,11-13,15–18,21

.Apartfrom

placebo/vehicle,minoxidil5%wasusedasanactivecomparatorinthreestudies,whereitwas

significantlybetterthanfulvestrant10,numericallysimilartopyrithionezincshampoo

8andC.aeruginosa

extract20,andnumericallybetterthanbimatoprostformulations

22.Althoughsafetywasnotafocusof

thisreview,allbutfourstudies8,17-19

monitoredadverseevents.Therewerenoadverseeventsor

adverseeventsrelatedtotreatmentforherbalextract,adenosine,procyanidinoligomers,and

roxithromycin.Studiesofbimatoprost,latanoprost,fulvestrant,herbalextract,valproate,andCurcuma

aeruginosareportedmildskin-relatedadverseeventssuchaserythema,pruritus,urticarial,or

dermatitis.Mostofthetreatmentsappeartobewell-toleratedandsafeintheshort-term.

6

Ofthe24weektreatments,latanoprost,aprostaglandinanalogantagonist,wasfoundtohave

thehighestmeanchangeinhairdensity(hairs/cm2)9.Prostaglandinanalogs,whichincludelatanoprost,

bimatoprostandviprostol,canstimulatekeratinocyteandmelanocyteactivity,enhancinghairgrowth

andpigmentation24.Interestingly,viprostol,asyntheticprostaglandininhibitor,wasnotaneffective

treatment19.Thisfindingcouldbeduetothesyntheticnatureofviprostol,thehairlossseverityof

includedpatients(IIIvtoV)orthedosageused.

Intwostudies,procyanidinoligomersexhibitedagreaterefficacyovervehiclebyendof

treatmentwithresponsetomeanchangeinhairdensity(hairs/cm2)16,21

.Procyanidinoligomers,and

otherpolyphenols,mostlikelypromotehairgrowthvianitricoxide,agasproducedintheliningofveins

whichpromotesvasodilationandreducescholesterolbuild-up.Polyphenolshavealsobeenshownto

inhibit5α-reductaseactivitywhichhasbeentheorizedtoplayaroleinthepathogenesisofAGA25.

Regardlessofthesepromisingeffects,moreclinicaltrialsneedtobeconductedbeforetheuse

oftheseoff-labeltreatmentsissanctioned.Ofparticularnoteisthatthecurrentevidenceforoff-label

treatmentsisfromclinicalstudiesthatareshortinduration,with24weeksthemostcommon.Long-

termefficacyandsafetydataarenotavailableandwearethusunabletodrawcomparisonswith

approvedtherapies.Whileimprovementcanplateauovertimewithfinasterideandminoxidil,thelong-

termefficacyofoff-labeltreatmentsisunknown.Thepatientsintheincludedstudieswere

predominantlymaleanddifferencesintreatmentefficacybetweenmalesandfemalesshouldbekeptin

mind.Therapieswithmulti-factorialcapabilitiesmaybemoreappropriatefortreatingfemalepattern

hairloss,whereas,malepatternhairlosspatientsbenefitmorefromadirectanageneffect2.

Additionally,animportantlimitationwhenevaluatingefficacyofhairlosstreatmentsisthe

varietyofoutcomemeasuresusedtomeasuresuccessfulhairgrowth;thereisnoacceptedindustry

standard.Assessmentofglobalphotographsbyanexpert,haircountsusingphototrichogram,and

7

manualhaircountsusingclippingsorhairdensityinatargetareawereallreportedinstudies.Global

assessmentsbasedonphotographs,forexample,canofferusefulinsight,buttheyarenotthesameas

blindedquantitativemeasurement.Haircountcanbeconvertedintohairdensitywhenatargetareais

providedbytheauthors,butnotallauthorsdisclosedthisinformation.Thisshouldbeapointof

considerationinthedevelopmentofnewtrialsasaconsistentquantitativeoutcomemeasurecanaidin

comparingdifferenttreatments.Patient-centredoutcomessuchassatisfactionarealsoimportant.

Whilethereporteddata(Tables1-3)certainlyshowanincreaseinhairparameters,increasesmaynot

benoticeableorsatisfactoryforpatientstojustifytreatmentor,patientsmayexpresssatisfaction

despitelittletonoclinicalimprovement.Evenifpatientsbelieveatreatmentisbeneficial,acasecanbe

madethatcliniciansshouldnotencourageuseoftreatmentsthatdonotobjectivelyimprovehairloss.

5.0Conclusion

Preliminaryevidencesuggeststhat,intheshort-term,eightoff-labeltherapiessuchas

prostaglandinanalogsandpolyphenolscansignificantlyimprovehairdensity8,9,11,13,15–18,21

.Furtherstudy

ofhairlosspatientsenrolledinrandomized,controlledandblindedstudiesisneededtoexpandonthe

efficacyandsafetydatathathasbeencollectedtodate.Inthemeantime,cliniciansmaywishtouse

off-labeltherapiesastheymayprovidebenefittopatients.Hairlossneedsshouldbeaddressed

individuallyasbothoff-labelandapprovedtreatmentthatworksforonepersonmaynotworkfor

another.

8

6.0References

1. CrabtreeJS,KilbourneEJ,PeanoBJ,ChippariS,KenneyT,McNallyC,etal.Amousemodelof

androgeneticalopecia.Endocrinology.2010;151(5):2373–80.

2. SadickNS,CallenderVD,KircikLH,KoganS.NewInsightIntothePathophysiologyofHairLoss

TriggeraParadigmShiftintheTreatmentApproach.JournalofDrugsinDermatology.2017;16(11):135–

40.

3. ChristophT,Müller-RöverS,AudringH,TobinDJ,HermesB,CotsarelisG,etal.Thehumanhair

follicleimmunesystem:cellularcompositionandimmuneprivilege.BritishJournalofDermatology.

2000;142(5):862–73.

4. ROGAINE®MINOXIDILTOPICAL2%SOLUTION[Internet].GovernmentofCanada.2017[cited

2018Sep18].Availablefrom:https://pdf.hres.ca/dpd_pm/00040937.PDF

5. Men’sRogaine[Internet].Drugs@FDA:FDAApprovedDrugProducts.2006[cited2018Sept18].

Availablefrom:https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021812s000LBL.pdf

6. PROPECIA®(finasteride)tabletsfororaluse[Internet].FDAU.S.FoodandDrugAdministration.

2016[cited2018Sep18].Availablefrom:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020788s024lbl.pdf

7. PROPECIA®Finasteridetablets,USPFilm-coatedTablets1mgTypeII5α-reductaseinhibitor

[Internet].GovernmentofCanada.2018[cited2018Sep18].Availablefrom:

https://pdf.hres.ca/dpd_pm/00043972.PDF

8. BergerRS,FuJL,SmilesKA,TurnerCB,SchnellBM,WerchowskiKM,etal.Theeffectsof

minoxidil,1%pyrithionezincandacombinationofbothonhairdensity:arandomizedcontrolledtrial.

BritishJournalofDermatology.2003;149(2):354–62.

9. Blume-PeytaviU,LönnforsS,HillmannK,GarciaBartelsN.Arandomizeddouble-blindplacebo-

controlledpilotstudytoassesstheefficacyofa24-weektopicaltreatmentbylatanoprost0.1%onhair

growthandpigmentationinhealthyvolunteerswithandrogeneticalopecia.JournaloftheAmerican

AcademyofDermatology.2012;66(5):794–800.

10. GassmuellerJ,HoffmannR,WebsterA.Topicalfulvestrantsolutionhasnoeffectonmaleand

postmenopausalfemaleandrogeneticalopecia:resultsfromtworandomized,proof-of-conceptstudies.

BritishJournalofDermatology.2008;158(1):109–15.

11. GreenbergJH,KatzM.Treatmentofandrogeneticalopeciawitha7.5%herbalpreparation:

JournalofDermatologicalTreatment.1996;7(3):159–62.

9

12. ItoT,FukamizuH,ItoN,SeoN,YagiH,TakigawaM,etal.Roxithromycinantagonizescatagen

inductioninmurineandhumanhairfollicles:implicationoftopicalroxithromycinashairrestoration

reagent.ArchivesofDermatologicalResearch.2009;301(5):347–55.

13. IwabuchiT,IdetaR,EhamaR,YamanishiH,IinoM,NakazawaY,etal.Topicaladenosine

increasestheproportionofthickhairinCaucasianmenwithandrogeneticalopecia.Journalof

Dermatology.2016;43(5):567–70.

14. IwabuchiT,TakedaS,YamanishiH,IdetaR,EhamaR,TsurudaA,etal.Thetopicalpenta-peptide

Gly-Pro-Ile-Gly-SerincreasestheproportionofthickhairinJapanesemenwithandrogeneticalopecia.

JournalofCosmeticDermatology.2016;15(2):176–84.

15. JoSJ,ShinH,ParkYW,PaikSH,ParkWS,JeongYS,etal.Topicalvalproicacidincreasesthehair

countinmalepatientswithandrogeneticalopecia:arandomized,comparative,clinicalfeasibilitystudy

usingphototrichogramanalysis.JournalofDermatology.2014;41(4):285–91.

16. KamimuraA,TakahashiT,WatanabeY.InvestigationoftopicalapplicationofprocyanidinB-2

fromappletoidentifyitspotentialuseasahairgrowingagent.PhytomedicineInternationalJournalof

PhytotherapyandPhytopharmacology.2000;7(6):529–36.

17. KesselsAG,CardynaalsRL,BorgerRL,GoMJ,LambersJC,KnottnerusJA,etal.Theeffectiveness

ofthehair-restorer‘Dabao’inmaleswithalopeciaandrogenetica.Aclinicalexperiment.Journalof

ClinicalEpidemiology.1991;44(4–5):439–47.

18. LindenbaumES,FeitelbergAL,TendlerM,BeachD,Gamliel-LazarovichA,Har-ShaiY,etal.Pilot

studyofanoveltreatmentforandrogeneticalopeciausingenrichedcellculturemedium:clinicaltrials.

DermatologyOnlineJournal.2003;9(1):4.

19. OlsenEA,DeLongE.Transdermalviprostolinthetreatmentofmalepatternbaldness.Journalof

theAmericanAcademyofDermatology.1990;23(3):470–2.

20. PumthongG,AsawanondaP,VarothaiS,JariyasethavongV,TriwongwaranatD,Suthipinittharm

P,etal.Curcumaaeruginosa,anovelbotanicallyderived5α-reductaseinhibitorinthetreatmentof

male-patternbaldness:amulticenter,randomized,double-blind,placebo-controlledstudy.Journalof

DermatologicalTreatment.2012;23(5):385–92.

21. TakahashiT,KamimuraA,KagouraM,ToyodaM,MorohashiM.Investigationofthetopical

applicationofprocyanidinoligomersfromapplestoidentifytheirpotentialuseasahair-growingagent.

JournalofCosmeticDermatology.2005;4(4):245–9.

22. SafetyandEfficacyStudyofBimatoprostintheTreatmentofMenWithAndrogenicAlopecia-

StudyResults-ClinicalTrials.gov[Internet].[cited2018Sept18].Availablefrom:

https://clinicaltrials.gov/ct2/show/results/NCT01325337

10

23. ASafetyandEfficacyStudyofBimatoprostinMenWithAndrogenicAlopecia(AGA)-Study

Results-ClinicalTrials.gov[Internet].[cited2018Sept18].Availablefrom:

https://clinicaltrials.gov/ct2/show/results/NCT01904721

24. JohnstoneM,AlbertD.Prostaglandin-InducedHairGrowth.SurveyofOphthalmology.

2002;47(1):S185–202.

25. HiipakkaRA,ZhangH-Z,DaiW,DaiQ,LiaoS.Structure-activityrelationshipsforinhibitionof

human5alpha-reductasesbypolyphenols.BiochemicalPharmacology.2002;63(6):1165–76.

11

FigureCaptions:

Figure1:StudySelectionProcess

Figure2:MeanChangeinHairDensity(hairs/cm2)after24weeksofOff-LabelTopicalTherapy

8,9,13–22.

BimatoprostA,B,andC:Detailsonthesetreatmentgroups(e.g.,percentageofbimatoprost)notyet

releasedonclinicaltrials.gov;Dabao:50%ethanol,42%water,8%Chineseherbalextracts(saffron

flowers,mulberryleaves,stemonaroot,fruitsofthepepperplant,sesameleaves,theskinofthefruitof

Sichuanpepper,gingerroot,Chineseangelicaroot,barkofthePseudolarix,fruitsofthehawthorn);

Latanoprost:50%ethanol,20%propyleneglycolwater;Non-steroidalanabolichormones(NSAH):

CMM,madeofinsulin,thyroxinandgrowthhormonegelledin1.5%hydroxyethylcellulose;Procyanidin

B-2:70%ethanol,10%1,3-butyleneglycol,0.5%N-acetylglutamine-isostearylester,

0.25%polyoxyethyleneglycerylmonopyroglutamatemonoisosterate,0.1%dl-α-tocopherol,0.05%d-

biotin,0.1%ascorbylpalmitate,0.001%β-carotene,0.1%sodiumcitrateand17.899%purifiedwater;

ProcyanidinMix:7.3%procyanidinB-1,26.2%procyanidinB-2,7.7%procyanidinC-1,40%other

oligomericprocyanidins,70%ethanol,3%1,3-butyleneglycol,0.15%N-acetylglutamineisostearylester,

0.067%citrate-sodiumcitratebuffer,0.05%sodiumbisulfite,purifiedwater;SodiumValproate:8.3%

sodiumvalproateusinga27%ethanolsolutionasthevehicle.

12

Table1:ImpactofOff-LabelTopicalTherapyonHairDensity(hairs/cm2)byEndofTreatment

Study Characteristics TreatmentDetails MeanChangeFromBaseline

Bergeretal.20038

N:200

Age:40

Severity:IIIvtoIV

Duration:26wks

PlaceboShampoo(1xday) -1hairs/cm2

PyrithioneZincShampoo(1%,1xday) 6hairs/cm2*

PyrithioneZincShampoo(1%,1xday)+Minoxidil(5%,2xday) 6hairs/cm2*

Minoxidil(5%,2xday)+PlaceboShampoo(1xday) 12hairs/cm2*

Blume-Peytavietal.20129

N:16

Age:(23-35)

Severity:IItoIII

Duration:24wks

Placebo(50µL/day) 8hairs/cm2

Latanoprost(0.1%,50µL/day) 51hairs/cm2*

Gassmuelleretal.200810

N:102

Age:38

Severity:IIItoVa

Duration:16wks

Vehicle(2xday) 8hairs/cm2

Fulvestrant(70mg/mL,42mg/day) 8hairs/cm2

Minoxidil(20mg/mL,12mg/day) 25hairs/cm2**

Greenberg&Katz199611

N:24

Age:43

Severity:IIItoIV

Duration:40wks

Vehicle(1xday) 6hairs/cm2

HerbalExtract(1xday) 54hairs/cm2*

Iwabuchietal.2016a13

N:38

Age:42

Duration:24wks

Vehicle -10hairs/cm2

Adenosine(0.75%) 12hairs/cm2*

Joetal.201415

N:40

Age:38

Severity:IIIvtoV

Duration:24wks

Vehicle(0.8mL/dose,2xday) -1hairs/cm2a

SodiumValproateSpray(0.8mL/dose,2xday) 23hairs/cm2a*

Kamimuraetal.200016

N:30

Age:47

Duration:24wks

Placebo(1%,1.8mL2xday) 4hairs/cm2

ProcyanidinB-2(1%,1.8mL2xday) 28hairs/cm2*

Kesselsetal.199117

N:396

Duration:24wks

Placebo(1.7mL,2xday) 22hairs/cm2

Dabao(1.7mL,2xday) 27hairs/cm2*

Lindenbaumetal.200318

N:56

Age:28

Severity:IItoIV

Duration:24wks

Placebo(1-3mL/day) 16hairs/cm2

Non-SteroidalAnabolicHormones(1-3mL/day) 30hairs/cm2*

NCT0132533722

N:307

Duration:24wks

Vehicle(1xday) 4hairs/cm2b

BimatoprostFormulationB(1xday) 6hairs/cm2b

BimatoprostFormulationC(1xday) 6hairs/cm2b

BimatoprostFormulationA(1xday) 13hairs/cm2b

Minoxidil(5%,1xday) 22hairs/cm2b

NCT0190472123

N:244

Duration:7-24wks

BimatoprostSolution1(2xday) 13hairs/cm2b

BimatoprostSolution2(2xday) 9hairs/cm2b

Vehicle(2xday) 6hairs/cm2b

Olsen&DeLongetal.

199019

N:72

Age:38

Severity:IIIvtoV

Duration:24wks

Vehicle(0.3mL/dose,2xday) -8hairs/cm2

Viprostol(120µg,0.3mL/dose,2xday) -4hairs/cm2

Placebo(0.3mL/dose,2xday) -3hairs/cm2

Pumthongetal.201220

N:89

Age:39

Severity:II-VII

Duration:24wks

Vehicle(2xday) 20hairs/cm2

Curcumaaeruginosaextract(5%,2xday) 31hairs/cm2

Minoxidil(5%,2xday) 31hairs/cm2

Minoxidil(5%,2xday)+Curcumaaeruginosaextract(5%,2x

day)33hairs/cm

2

Takahashietal.200521

N:49

Age:(27-58)

Duration:24-52wks

Vehicle(2mL2xday) -8hairs/cm2

Procyanidin(0.7%,2mL2xday) 6hairs/cm2*

*p<0.05ascomparedtoplacebo/vehicle;**p<0.05ascomparedtocomparator;a:medianchange;b:terminalhairswereused;Age(years):Mean(range);Severity:

BasedonHamilton-NorwoodScaleandeligibilitycriteria;Wks:weeks;Latanoprost:50%ethanol,20%propyleneglycolwater;Herbalextract:7.5%extractoffennel,

13

polygonum,mentha,chamomile,thujaandhibiscusinawater-basedcream;SodiumValproateSpray:8.3%sodiumvalproateusinga27%ethanolsolutionasthevehicle;

ProcyanidinB-2:70%ethanol,10%1,3-butyleneglycol,0.5%N-acetylglutamine-isostearylester,0.25%polyoxyethyleneglycerylmonopyroglutamatemonoisosterate,

0.1%dl-α-tocopherol,0.05%d-biotin,0.1%ascorbylpalmitate,0.001%β-carotene,0.1%sodiumcitrateand17.899%purifiedwater;Procyanidin:7.3%procyanidinB-1,

26.2%procyanidinB-2,7.7%procyanidinC-1,40%otheroligomericprocyanidins,70%ethanol,3%1,3-butyleneglycol,0.15%N-acetylglutamineisostearylester,0.067%

citrate-sodiumcitratebuffer,0.05%sodiumbisulfite,purifiedwater;Dabao:50%ethanol,42%water,8%Chineseherbalextracts(saffronflowers,mulberryleaves,

stemonaroot,fruitsofthepepperplant,sesameleaves,theskinofthefruitofSichuanpepper,gingerroot,Chineseangelicaroot,barkofthePseudolarix,fruitsofthe

hawthorn);Non-steroidalanabolichormones:CMM,madeofinsulin,thyroxinandgrowthhormonegelledin1.5%hydroxyethylcellulose;BimatoprostA,B,C,1and2:

Detailsonthesetreatmentgroups(e.g.,percentageofbimatoprost)notyetreleasedonclinicaltrials.gov

14

Table2:ImpactofOff-LabelTopicalTherapyonHairDiameter(mm)byEndofTreatment8,14

Study Characteristics TreatmentDetails MeanChangefromBaseline

Bergeretal.20038

N:200

Age:40

Severity:IIIvtoIV

Duration:26wks

PlaceboShampoo(1xday) -0.04mm

PyrithioneZincShampoo(1%,1xday) -0.04mm

PyrithioneZincShampoo(1%,1xday)+Minoxidil(5%,2xday) -0.01mm

Minoxidil(5%,2xday)+PlaceboShampoo(1xday) -0.01mm

Itoetal.200912

N:24

Age:48

Severity:IItoIIIV

Duration:24wks

Vehicle 0.0004mm

Roxithromycin 0.309mm*

*p<0.01ascomparedtobaseline;Age(years):Mean(range);Severity:BasedonHamilton-NorwoodScaleandeligibilitycriteria;Wks:weeks;Roxithromycin:0.5%

Roxithromycin,65%ethylalcohol,5%propyleneglycol,39.5%distilledwater

15

Table3:ImpactofOff-LabelTopicalTherapyonHairGrowth(mm/cm2)byEndofTreatment

10,24,25

Study Characteristics TreatmentDetails MeanChangefromBaseline

Gassmuelleretal.200810

N:102

Age:38

Severity:IIItoVa

Duration:16wks

Vehicle(2xday) 0.7mm/cm2

Fulvestrant(70mg/mL,42mg/day) 0.84mm/cm2

Minoxidil(20mg/mL,12mg/day) 2.9mm/cm2*,^

NCT0132533722 N:307

Duration:24wks

BimatoprostFormulationC(1xday) 0.12mm/cm2

Vehicle(1xday) 0.13mm/cm2

BimatoprostFormulationB(1xday) 0.25mm/cm2

BimatoprostFormulationA(1xday) 0.76mm/cm2

Minoxidil(5%,1xday) 1.29mm/cm2

NCT0190472123 N:244

Duration:7-24wks

Vehicle(2xday) 0.05mm/cm2

BimatoprostSolution2(2xday) 0.67mm/cm2

BimatoprostSolution1(2xday) 0.92mm/cm2

*p<0.05ascomparedtoplacebo/vehicle;^p<0.05ascomparedtoinvestigatedoff-labeltopicaltherapy;Age(years):Mean;Severity:BasedonHamilton-NorwoodScale

andeligibilitycriteria;Wks:weeks;BimatoprostA,B,C,solution1andsolution2:Detailsonthesetreatmentgroups(e.g.,percentageofbimatoprost)notyetreleasedon

clinicaltrials.gov

16

Figure1.

Recordsidentifiedthroughdatabases

(N=1004)

Recordsaftertitleandabstractexclusion

(N=113)

Recordsafterfulltextexclusion

(N=42)

Recordsincludedinreview

(N=16)

Titleandabstract

exclusion

(N=891)

Fulltextexclusion

(N=71)

Exclusionduring

dataextraction

(N=26)

17

Figure2

-4

6 6 68

12 13

23

27 2830 31

51

-10

0

10

20

30

40

50

60

MeanChangeinHairDensity(hairs/cm

2)