Anais
Brasileiros
de
Dermatologia
www.anaisdedermatologia.org.br
CONTINUING
MEDICAL
EDUCATION
Post-finasteride
syndrome
夽,夽夽
Ana
Francisca
Junqueira
Ribeiro
Pereira
∗,
Thaissa
Oliveira
de
Almeida
Coelho
TrichologyOutpatientClinic,DermatologyService,HospitaldasClínicas,UniversidadeFederaldeMinasGerais,BeloHorizonte, MG,Brazil
Received11February2020;accepted14February2020
Availableonline25March2020
KEYWORDS
5-Alphareductase inhibitors; Alopecia; Finasteride
Abstract Finasterideisa5␣-reductaseenzymeinhibitorthathasbeenapprovedforthe
treat-ment ofmaleandrogenicalopeciasince1997.Overtime,ithasbeenconsideredasafe and
well-tolerateddrugwithrareandreversiblesideeffects.Recentlytherehavebeenreportsof
adversedrug-relatedreactionsthatpersistedforatleastthreemonthsafterdiscontinuation
ofthisdrug,andthetermpost-finasteridesyndromearose.Itincludespersistentsexual,
neu-ropsychiatric,andphysicalsymptoms.Studiestodatecannotrefuteorconfirmthissyndrome
asanosologicalentity.Ifitactuallyexists,itseemstooccurinsusceptiblepeople,evenif
exposedtosmalldosesandforshortperiods,andsymptomsmaypersistforlongperiods.Based
oncurrently availabledata, theuseof5␣-reductase inhibitorsinpatients withahistoryof
depression,sexualdysfunction,orinfertilityshouldbecarefullyandindividuallyassessed.
©2020PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia.
ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/
by/4.0/).
Introduction
Finasterideisaninhibitoroftheenzyme5␣-reductasetypes 1and2--- withgreater affinityfortype2 ---thathasbeen approved by the Food and Drug Administration (FDA) in the United States for the treatment of benign prostatic
夽 How to cite this article: Pereira AFJR, Coelho TOA.
Post-finasteridesyndrome.AnBrasDermatol.2020;95:271---7.
夽夽StudyconductedattheTrichology OutpatientClinic,
Derma-tologyService,HospitaldasClínicas,UniversidadeFederaldeMinas Gerais,BeloHorizonte,MG,Brazil.
∗Correspondingauthor.
E-mail:[email protected](A.F.Pereira).
hyperplasia(BPH)since1992andforthetreatmentofmale androgeneticalopecia(AGA)since1997.1
Withashorthalf-liferangingfrom4.7to7.1h,1itisable
to significantly reduce serum, prostatic, and scalp levels of dihydrotestosterone (DHT), in addition toslightly rais-ing testosterone levels,2 generally without exceeding the
referencevaluesforthelatter.
Overtime,severalstudieshavedemonstratedthat finas-teride is a safe and well-tolerated drug, with rare and reversible side effects such as reduced sexual libido and ejaculatory volume, most commonly observed when pre-scribedinadailydoseof5mgforcasesofBPH.1
However,reports ofadverse reactions related to finas-teride that persisted for at least three months after its discontinuationhaveemergedinthepastdecade.Theterm https://doi.org/10.1016/j.abd.2020.02.001
0365-0596/©2020PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadeBrasileiradeDermatologia.Thisisanopenaccessarticle undertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
post-finasteridesyndrome(PFS)includespersistentsexual, neuropsychiatric,andphysicaladversereactionsinpatients whousedthisdrug.
Asaresult,regulatoryagenciesinseveralcountries gen-eratedwarningsaboutthisdrug;in2012,theFDAdemanded changesinthepackageinsertintheUnitedStates, includ-ingthepossibilityof persistentsideeffects.3 In2015,PFS
wasincludedinthelistofRareandGeneticDiseasesofthe NationalInstitutesofHealth(NIH).4
Symptoms ofPFS include decreaseor complete loss of libido,lowornoreactiontosexualstimulation,erectile dys-function,lossofpleasureorabsenceofsensationinorgasm, lossof genital sensitivity, decreasein ejaculated volume, poorsemenqualityandinfertility,penis shrinkage, abnor-mal penis curvature (Peyronie’s disease), testicular pain, testicularreduction,gynecomastia,chronicfatigue,muscle weakness,muscleatrophyand/orpain,musclespasms,joint pain,dryskin,memoryproblems,slowthinking, comprehen-sion difficulties, depression (including suicidal thoughts), anxietydisorder,panicattacks,emotionaldetachment,and insomnia.5
Finasteride
and
sexual
adverse
effects
Albeit uncommon, sexual dysfunction secondary to finas-terideuseis a knownadverse effectthatinvolves loss of libido, in addition to erectile and ejaculatory disorders. Morerecently, sexualanhedonia,changesin thestructure ofthepenis,andreducedpenilesensitivityhavealsobeen reported.However,thepersistenceofthesesymptomsafter thediscontinuationof thedrugisstilla matterof contro-versy in the scientific community; to date, there are no studiesthatadequatelyassessthisissue.
After15yearsofFDAapprovaloftheuseoffinasteride forAGA,in aretrospective study,Irwigetal. interviewed 71 menwho reportedpersistent sexualside effects after threemonthsofdiscontinuingthedrug,whichwasusedfor AGAtreatmentatadailydoseof1mg,withameanuseof 28weeksandmeansymptomdurationof40weeks.6
How-ever, these patients were selected primarily in an online discussionforumaimedatindividualswithsexualcomplaints aftertheuseof5␣-reductaseinhibitors,whichconstitutes an important selection bias. After 14 months, the same authorsre-interviewedthesepatients,and89%stillreported adversesexual effects.7Another retrospectivestudy,
con-ductedin 2016,of 79individualswhoreceivedfinasteride at a daily dose of 1mg for a mean of 27 months and developedlong-lastingadverse effects,demonstrated per-sistenceofsymptomsforalmostfouryearsaftertreatment discontinuation.8
These findings, however, are in contrast with previ-ous studies that demonstrated the safety of finasteride. In2003,alarge double-blindedplacebo-controlledclinical trialassessedtheincidenceofsexualsideeffectswiththe useoffinasterideatadailydoseof5mg.9Amongpatients
whodiscontinuedthedrugdue tosexualdysfunction,the persistenceofsymptomswasgreaterintheplacebogroup whencomparedwiththetreatment group,suggestingthat thedrugwasprobablynotinvolvedinthepersistenceofthe complaints.9
Two recent meta-analyses that assessed the incidence of sexual adverse effects did not directly address the persistenceofsymptoms.10,11Asystematicreviewand
meta-analysisconductedin2016observedasignificantlygreater riskofsexualdysfunctionamongpatientswithBPH,butnot in those undergoing AGA treatment.10 The two divergent
factors between the two groups that probably influenced thesefindingswerethemeanageandthedailydoseused for eachdisease.Moreover,persistentsymptomswerenot evaluated. Conflictingresults werefoundby another2019 meta-analysis,whichidentifiedatwo-foldincreasedriskof sexualdysfunctionwiththeuseoffinasteridetotreatAGA when comparedwithplacebo.11 However,the persistence
ofsymptomswasalsonotanalyzedintheincludedstudies, andremainsunclear.
In this sense, a randomizeddouble-blinded study with 117menassessedpersistentsexualsideeffectsinpatients allocated to dutasteride or placebo.12 Duringits use, the
incidenceofsexualadversereactions wastwiceashigh in the dutasteride group, and symptom onset occurred pri-marily in the first three months of treatment. However, mostsymptomswereresolvedduringtreatment;thosethat persisted were resolved within three to six weeks after treatmentdiscontinuation.12
Incontrast,a 2017retrospective cohort involving 4284 men aged 16 to 42 years whoused finasteride at a daily dose of lessthan 1.25mg,witha median of4 yearsafter suspension, observed a rate of 0.8% of persistent sexual symptoms.13Ofthe103menwhoexperiencedsexual
symp-toms duringtreatment, 33% reportedtheypersisted after suspension.The mainindependentpredictorwasusefor a periodlongerthansevenmonths.13 Thisfindingisin
agree-ment with data fromthe previous retrospective study by Irwigetal.,inwhichtheonsetofsymptomsinpatientswith persistentcomplaintsoccurredafteroneyearofusing finas-teride,althoughfewhadreportedadverseeffectsinthefirst monthofuse.6
Therefore,thecurrentliteraturedataarecontroversial, and it is not yet possible to establish a causal relation-shipbetween5␣-reductaseinhibitorsandthepersistenceof sexualsymptoms. Thestudies thatdemonstrated ahigher incidence of persistent side effects related to the use of finasteridehaveimportantbiasesandincludedlimited sam-ples, andareinsufficienttoconfirm theexistenceof PFS. Likewise, theyalsodo notallow distinguishingbetween a realadverseeffectoranoceboreactiontothemedication. This nocebo effect waswell documentedin a study com-paringpatientswhoreceivedcounselingpriortofinasteride treatment regarding the possibility of sexual side effects and those who had not; 43.6% of the patients who were informedpresentedsymptoms,comparedwith15.3%ofthe othergroup.14Thenoceboeffectmayalsoberelatedtothe
occurrenceofpersistentsexualcomplaints.
Menwithpersistentsexualsymptomsafter discontinua-tionoffinasterideforAGAdidnotpresentacorresponding hormonaldysfunction,withmaintenanceof normalserum levelsof testosterone and DHT,nordid theyshow loss of peripheralsensitivitytoandrogensorpermanentinhibition ofandrogenreceptors.15
InordertoelucidatethepathophysiologyofPFS,animal studies were carriedout and suggested changes in penile histology and architecture after the use of 5␣-reductase
inhibitors,withadecreaseinsmoothmuscleandanincrease incollageninthepenisaftertreatmentwithdutasteride.16
A human study compared the histological foreskin find-ings in individuals with permanent sexual symptoms six months after finasteride withdrawal and found a differ-ence in androgen receptor density when compared with thosewithout priorexposure to5␣-reductase inhibitors,17
butthedatawerenotcomparedtothoseofprevioususers without persistent symptoms. Although these were small studies, they provide histological evidence of potentially permanentpenile structural changes after theuse of 5␣-reductaseinhibitors.However,itisnotpossibletoestablish acausalrelationshipbetweenthefindingsortodraw defini-tiveconclusionsabouttheirclinicalsignificance.
Finasteride
and
infertility
The impact of 5␣-reductase inhibitorson malefertility is anothertopicofdebate.Intwodifferentanalysesby Sam-plaskietal.withpopulationsofmenwhosoughttreatment atinfertilityclinics,only0.6%and0.9%ofthemwere finas-teride users, from a total of 4400 and 4287 individuals, respectively.18,19
Researchers had previously demonstrated a negative impactoffinasterideonthespermatogenesisofrats.20
How-ever,Overstreetetal.foundthatfinasterideatadailydose of 1mgdid notalterspermatogenesis,semen production, orspermmorphologyinhealthyyoungmen.21 Thiswasthe
largestrandomized,controlled,double-blindedstudyonthe impactofusing1mgfinasterideonspermatogenesis, assess-ing79patientswithoutanyreproductivesystemalterations or history of infertility. The results showed no change in semen volume or sperm concentration and motility after 48 weeks of using the drug. Subjects were reassessed 60 weeksafterdiscontinuation,andnorelevantchangeswere observed,exceptforarecoveryinprostatevolume,which was reduced during treatment. Likewise, no changes in gonadotropinortestosteronelevelsweredetected. Testos-terone,notDHT,appearstobethemainandrogenregulating spermatogenesis.21
Glinaetal.reportedthreecasesofyoungpatientswith semenqualitydisordersduringtreatmentwithfinasteride.22
All three patients presented abnormal concentration and alteredspermmotilitywhenusingfinasterideatadailydose of1mg.Thesechangeswerecompletelyreversed(patients 1and2)orimproved(patient3)threeorfourmonthsafter treatmentinterruption.Twopatientshadvaricoceleonthe left and the other was obese,leading the researchers to suggest thatfinasteride doesnot markedlyalterthe sper-matogenesis processin healthy men, butin patients with infertility-relatedconditions,thenegativeeffectofthedrug couldbeamplified.22
Corroboratingthishypothesis,intheretrospectivestudy by Samplaski et al., conducted in 2013, the impact of the same daily dose of 1mg of finasteride on the sperm count of 14 men with a history of infertility was ana-lyzed, with a mean use of 57 months (2---120 months), and mean time from treatment interruption to repeat spermogram of 6.45 months (2---18 months).18 That study
demonstratedan11.6-foldmeanincreaseinsperm concen-trationafterfinasteridediscontinuation.Inthefirstanalysis,
seven of these patients presented critical sperm levels (below5million/mL), reachinglevelsabove20million/mL aftertreatmentinterruption.18 Therewasalsoanincrease
inspermmotility,butnotstatisticallysignificant.18Thiswas
theonlystudythatassessedtheimpactonindividualswith conditionsthatpredisposedtoinfertility.
Liu et al. and Chiba et al. reported cases of infer-tilepatientswithazoospermiaoroligospermiawhoshowed significant improvementin spermconcentration after dis-continuationoffinasterideatadoseof1mg;thoseauthors alsosuggestedthatthedrugmayaggravatecasesof subfer-tilityorinfertility.23,24
Otheraspectsthatcouldaffectspermatogenesisin finas-terideusersincludeahigherspermDNAfragmentationrate, demonstratedinacasereport,25andaneventualepididymis
dysfunction,proposedinastudyinrats26;however,noneof
theseeffectspersistedaftertreatmentwasstopped. In2007,amulticenter,randomized,double-blindedstudy with99 healthymen withnormalspermparameters com-paredtheuseoffinasterideatadoseof5mg,dutasteride 0.5mg,andplacebo, showing ameanreduction of30% in spermcountand6---12%inmotilityaftersixmonthsinthe finasteride and dutasteride groups.27 However, after one
yearofusingoneofthedrugs,animprovementwasobserved inthe spermcount; the reductiononly remained statisti-cally significant in thedutasteride group.27 Regarding the
persistentfindingsinthedutasteridegroup,thereduction inspermvolumeandcountwasmaintainedaftersixmonths ofdiscontinuationofthedrug.27Bothdrugswereassociated
withlossofspermmotilitysixmonthsaftertreatment sus-pension.Noalterationsinspermmorphologywereobserved inanygroup.Therepercussionofthefindingson spermato-genesiswasbelowthelevelpre-establishedascriticalbythe researchers,andthemeanalterationsobservedwould prob-ablynothaveclinicalsignificanceinhumanreproduction.27
Onlythreeofthesepatientsweremoresensitivetothedrug and reached counts as low as 10% of their baseline dur-ingtreatment,oneofwhomusedfinasterideandtheother two,dutasteride.Thesemoreseverecasespresented par-tialrecoverysixmonthsafterdrugsuspension.Theauthors suggestedthepossibilityofan individualvariabilityinthe responseto5␣-reductaseinhibitors.27
Finasteride
and
neuropsychiatric
adverse
effects
Neuroactivesteroidscomprisesteroidhormonessynthesized in peripheral glands acting on the central nervous sys-tem(CNS), aswell asneurosteroidsproduced inthebrain itself.28 The main neuroactive steroids are pregnenolone
(PREG), dehydroepiandrosterone (DHEA), progesterone, testosterone,and17-estradiol,whichhaveimportant phys-iologicalregulatoryactions,suchasneuroendocrinecontrol inreproductionandsexualbehavior,adjustmentofsynaptic plasticity,andcytoskeletalproteinregulation,inadditionto actinginthemorphologyofneuronsandastrocytes,inthe myelincompartment,inadultneurogenesis,andinfunctions relatedtocognition.28
The threeisoforms of 5␣-reductase have already been identified in the brain, and the physiological role of type 3 of the enzyme is the most explored so far.28
In the CNS, progesterone and testosterone are metabo-lizedbytheenzyme5␣-reductaseintodehydroprogesterone (DHP) and DHT, respectively, which are soon converted into more metabolites, such as tetrahydroprogesterone (THP), isopregnanolone, 5␣-androstane-3␣, 17-diol, and 5␣-androstane-3,17-diol, whose action occurs through classic(androgen,estrogen,andprogestogenreceptors)and non-classicreceptors(GABA-Areceptors).
In the assessment of neuropsychiatric adverse effects relatedto5␣-reductase inhibitors,randomizedcontrolled studiesarelacking.Pre-clinicalstudieshavedemonstrated a reduction in neurosteroid levels. Of the clinical stud-ies,very few are prospective;the remaining literature is restrictedtocasereports,reportingdepressionandanxiety without association withsexual dysfunction in finasteride users,withimprovementinsymptomsafterdrug discontin-uation and early recurrence of symptoms with treatment reinitiation.29 Persistent symptoms were reported in only
threeretrospectivestudies.Oneofthem,conductedin2011 without a control group, reported complaints of depres-sion,suicidalideation, and persistentsexual symptomsin formerfinasteride users.6 In 2015, Ganzer et al.assessed
131individualswithpersistentcomplaints,most ofwhom, unusually,startedtopresentsymptomsafterthemedication wasdiscontinued.5Atthesametime,apharmacovigilance
studyidentified4910reportsofpersistentsymptomsrelated tofinasterideover15years.30 Amongthem,therewere39
cases(0.79%)ofsuicidalideation,and34ofthesepatients alsohadpersistenterectiledysfunction.30 Thus,itwasnot
possible todetermine whether suicidalideation is associ-atedwith finasteride and/or withthe concomitantsexual disorders.30
Persistentchangesinneuroactivesteroidshavebeen doc-umentedinrodentbrainsafterfinasteridediscontinuation.31
Aprospectivemulticenterlongitudinalclinicalstudy con-ductedin2017observedabnormalitiesinplasmalevelsand cerebrospinalfluid(CSF)ofneuroactivesteroidsin individu-alswithpersistentsymptomsafterfinasteridesuspension.28
Thecasegroupwasformedbyhealthymenagedbetween 22 and 44 years whoused 1---1.25mg of finasteride daily, suspendedfor atleastthreemonths,andwhodidnotuse otherdrugswithpotentialsideeffects,norhadahistoryof depressionor sexualdysfunction.Atotalof 16individuals withPFS wererecruited,with14remaining atthe endof thestudy,ofwhom11hadtheirhormoneslevelsmeasured in blood and CSF (PREG, progesterone, DHEA, DHP, DHT, testosterone,THP,isopregnenolone,17-estradiol,3␣-and 3-diol),inadditionto25controls.ThelevelsofPREG,as wellasprogesteroneandDHP,weresignificantlyreducedin theCSFofpatientswithPFS,andthoseofDHEAand testos-teronesignificantlyelevated, withareductioninDHTand 17-estradiol.In plasma, an increasein DHEA and testos-teronewasalsoobserved,butPREGwasveryhigh.28 That
studypresentsasabiasthefactthatpatientswererecruited througha website aimed at men withcomplaints related tofinasteride. It was concludedthat finasteride not only affects the levels of 5␣-reduced metabolites of proges-teroneand testosterone, as would be expected,but also changesothermetabolitesandprecursors,suggestingthat thishasa widerconsequence in thelevelsof neuroactive steroids in patients withPFS.28 Of the 16 PFS patients in
thisstudy,eighthadmajordepression.Thehypothesisthat
testosteronelevels maynotbe predictiveof erectile dys-functionor depression,butratherDHTlevels,wasraised; apossibleassociationbetweenreducedprogesteronelevels anddepressivesymptomswassuggested.Thepossibilitythat erectiledysfunctionisrelatedtoperipheralneuropathywas alsoraised,sincethoseauthorsalsoobservedareductionin theevokedpotentialofthepudendalnerve.28
A2019studydetected,evenafterdrugdiscontinuation, areductioninprogesteronelevelsandtheircorresponding metabolites---DHPandTHP---andanincreaseinitsprecursor PREG,inadditiontoadrasticdropinthelevelofDHTand an increase in CSFtestosterone.32 In plasma, a reduction
inDHPand17-estradiolwasobserved.Inconclusion,the authorsindicatedthatprevioussexualand/orpsychological conditions wouldlead toa greater risk and magnitude of adversereactionstofinasteride,anditisimportanttoassess sexualdysfunctionandpsychiatricdisordersbeforestarting themedication.32
Followingthis same idea,in 2018,a study included 97 menaged18yearsorolderwhoreportedpersistentadverse effectsafterusingfinasterideatadailydoseof1mgforat leastthreemonths,excludingthosewithbasic sexual dys-functionandnon-confirmedpsychiatricdiagnosis.33 Ofthe
participants, 55% had had a psychiatricdiagnosis prior to the use of finasteride and 28.8% had a history of psychi-atric diagnosis in a first-degree relative; 11.3% hadboth. Afterdiscontinuingthedrug,34%reportedanxietyand49.3% depression; in 79.2% of thosewith depression, the condi-tion was classified as moderate to severe, and in 10.4%, assevere.33 The researchersalso reinforcedthe need for
screeningfor apreviouspsychiatrichistoryandcounseling onthepotentialpsychologicalconsequencesofusing finas-teride in predisposed individuals, weighing the risks and benefitsoftreatment.33
A retrospective study conducted in 2016 with79 men aged 18 to 50 years old demonstrated anhedonia as the most frequent non-sexualsymptom, occurring in 75.9% of patients;72.2%complainedofdifficultyinfocusing.8In
addi-tiontothesmallsample,itisimportanttonotetheselection biasofthatstudy,sincesubjectswereinvitedtoparticipate afterhavingansweredasurveyonaPFS-awarenesswebsite. In turn, it is important to remember that the studies carriedout sofar donotallow establishing acausal rela-tionshipbetweensymptomsandtheuseoffinasteride,and theprevalenceoftheseeventshasnotbeencalculated.34
Finasteride
and
metabolic
and
cardiovascular
events
Byalteringsteroidmetabolism,5␣-reductaseinhibitorsmay contributetoinsulinresistance,35---39 increasingthe
predis-position to diabetes, hepatic steatosis,38,40 alteration of
body fat distribution,37,38 metabolic syndrome, and
car-diovascular diseases, since they reduce the clearance of glucocorticoidsandmineralocorticoids.36
Inastudy ofmetabolic dysfunctioninpatients treated withfinasterideordutasteridecomparedwithcontrols, inhi-bitionofbothisoforms(1and2)oftheenzyme5␣-reductase bydutasteridewasassociatedwithhigherperipheralinsulin levels.41
A preclinical study corroborated these findings. The absence of type 1 isoenzyme 5␣-reductase was associ-ated,inrats,withhepaticsteatosis,insulinresistance,and changesinthedistributionofbodyfat.38
The metabolic implications would be more significant withdutasteride, but moreclinical studies areneeded to confirmsucheffectsinusersof5␣-reductaseinhibitors.Itis alsoimportanttodiscussscreeningformetabolicsyndrome andinsulinresistancein5␣-reductaseinhibitorscandidates over35 yearsof agewithrisk factors,whichmayaccount foroverhalfofthecandidates.35
With regard to the risk of cardiovascular damage, to datesuchhavenotbeenassessedwithoutcomesinclinical studies,37 hinderingthedeterminationofacausal
relation-shipbetweenthefindings.Todate,theinformationonthis subjectislimited,sincetherelevantvariableshavenotbeen analyzedinmoststudies.39
Even bone metabolism may be altered,37,42 and a
case---controlstudyrecentlydemonstratedanincreasedrisk ofosteoporosisinfinasterideusersatadailydoseof5mg, withevidencethatitisadose-dependentrisk.42The
asso-ciation between use of a 5␣-reductase inhibitor and loss ofbonedensityandmusclestrengthwasalsosuggestedin ananimalmodel,inastudyconductedin2011byWindahl et al.43; however, these are preliminary data, and there
is stillnostrongenough evidencetosupporta priorbone densityassessmentinfinasteridecandidates.
Final
considerations
Despite all the doubts and fears raised by the reports in the last years, finasteride is stillconsidered a safe drug. Theaforementionedpharmacovigilancestudyconductedin 2015collectedfewreportsofpersistentsideeffectsrelated tothedrugover15years;nonetheless,itisnotpossibleto establishacausalrelationshipwiththedruginmanycases, sinceotherdisorderswerepresent.30
In 2016, Arias-Santiago et al. raised the hypothesis of nocebo effect, discussing whether the cause of the adverseeffectsoffinasteridewasmorepsychologicalthan pharmacological.39 The authors also highlighted the
emo-tional impact and self-esteem problems that AGA itself would cause, and that this would serve asa confounding factor in the assessment of the occurrence of psychi-atric and sexual symptoms in finasteride users. However, thoseauthorsobservedthatlowerlevelsofcertainsteroid hormones couldexplain thesymptomsreportedinthe lit-erature,even suggesting theuse of alower dailydose of finasterideinpatientsconcernedaboutsideeffects.39
In thefuture,the measurementofdopamineand sero-tonin levels in individuals with PFS may elucidate many issues,sincethepathways of theseneurotransmitterscan bealteredinneurosteroidogenesisdisorders,whichinitself wouldaffectsexualbehaviorinthesepatients.44
Thepossibilitythatepigeneticmechanismsmayinfluence the occurrence of PFS is also discussed, as it appears to affectalimitednumberofindividualsexposedtothedrug.44
Giattietal.evenraisedthehypothesisthatPFShas mech-anisms in common withpost-selective serotonin reuptake inhibitor syndrome,giventhewiderangeofsimilar symp-tomsinthetwoclinicalentities.44
Finally,itisdifficulttodiscriminatewhichphysiological, endocrine,orneurologicalaspectsareprimaryorsecondary, anditisnecessarytoreviewthecausalityalgorithmsandto furtheranalyzespecificgroups ofpatients,assessing each historyinmoredetail,excludingtheuseofother drugsor relevantcomorbidities,forexample.45
It is noteworthy that the prevalence and incidence of persistentadverse reactionstofinasteride hasneverbeen establishedandthatPFSisnotyetfullyrecognizedbythe scientificcommunity.46,47Despiteitshomogeneousand
char-acteristicsymptoms,theliteraturetodatehaslowscientific quality,whichdoesnotallowrefutingorconfirmingPFSas anosologicalentity;however, itshouldnot beignored.If itdoes exist,itappearstooccurinsusceptibleindividuals exposedeventosmalldosesandforashortperiod,whose symptomsmaypersistforalongtime.34
Therefore,itisimportanttocreatepractical recommen-dationsinrelationtopatients’eligibilityfortreatmentwith finasteride,aswellasadvisingtheseindividualsonpossible risks,alternativedrugsforthetreatmentofAGA,andhow theyshouldproceedincaseofsideeffects.37,43
From the currently available data, the use of 5␣-reductase inhibitors in individuals with a previous history of depression, sexualdysfunction, or infertility shouldbe carefully assessed,and the decision should be individual-ized.Topicalfinasteride hasbeen widely studiedandmay becomeafuturealternativeinthetreatmentofAGA.
Financial
support
Nonedeclared.
Authors’
contributions
Ana Francisca Junqueira Ribeiro Pereira: Approval of the finalversionofthemanuscript;elaborationandwritingof the manuscript; critical review of the literature; critical reviewofthemanuscript.
ThaissaOliveiradeAlmeidaCoelho:Approvalofthefinal versionof the manuscript; elaborationand writing of the manuscript;criticalreviewoftheliterature;criticalreview ofthemanuscript.
Conflicts
of
interest
Nonedeclared.CME
Questions
1)Regardingfinasteride,itiscorrecttostatethat:
a)Ithasalonghalf-life,whichcouldjustifythereportsof
persistentadverseeffects.
b)ItisabletodramaticallyincreaseserumDHTand
testosterone.
c)Theoccurrenceofsideeffectsrelatedtothedrugisnot
dose-dependent.
d)Afewyearsago,aseriesofsymptomsthatappearedand
evenworsenedafterfinasteridediscontinuationhavebeen
2)Checktheincorrectalternativeonadversesexualeffects
inpost-finasteridesyndrome:
a)Oneofthemaincomplaintsispenilesensitivity
reduction.
b)Symptomsofthissyndromeareconsideredtobethose
thatpersistafterthreeweeksofdrugdiscontinuation.
c)Selectionbiasisthemainlimitationofstudiesthat
describeahigherincidenceofthesesymptoms.
d)Thedurationoffinasterideuseappearstobearisk
factorfortheonsetofthesyndrome.
3)Regardinglaboratoryfindingsinindividualswith
post-finasteridesyndrome,itispossibletostatethat:
a)SerumtestosteronelevelsarelowandDHTlevelsare
normal.
b)SerumDHTlevelsarelowandtestosteronelevelsare
normal.
c)SerumtestosteroneandDHTlevelsarenormal.
d)SerumtestosteroneandDHTlevelsarelow.
4)Inthepathophysiologyofthepersistentsexualeffectsof
post-finasteridesyndrome,itcanbestatedthat:
a)Thereisevidenceofperipheralinsensitivityto
androgens.
b)Humanstudiessuggestchangesinpenilehistologyand
architecture.
c)Therearesignsofpermanentinhibitionofandrogen
receptors.
d)Thenoceboeffectcannotberuledoutinsuchcases.
5)Regardingfinasterideandinfertility,itiscorrecttostate
that:
a)Thedrugisabletotemporarilyalterthesperm
morphology.
b)Thedecreaseinfertilitydoesnotappeartoberelated
tothedoseused.
c)Thereisapermanentreductionintheejaculated
volume.
d)Thereisstillinsufficientdatatostatethatfinasteride
interfereswiththespermatogenesisofhealthymen,
withoutpredisposingfactorsforinfertility.
6)Thefollowingalterationsinthespermogramsecondary
totheuseoffinasteridearepossible,except:
a)Oligospermia
b)SpermDNAfragmentation
c)Aberrationsinspermmorphology
d)Reductionofspermmotility
7)Regardingneurosteroidhormones,itcannotbesaidthat:
a)Bydefinition,thesearehormonesexclusivelyproduced
inthebrain.
b)Examplesofneurosteroidhormonesarepregnenolone,
progesterone,andtestosterone.
c)Inthecentralnervoussystem,progesteroneand
testosteronearemetabolizedbytheenzyme5␣-reductase
into,respectively,dihydroprogesteroneand
dihydrotestosterone.
d)Thelevelsofbrainmetabolitesofthe5␣-reductase
enzymearealteredindegenerativeandpsychiatric
diseases..
8)Regardingpost-finasteridesyndromeitiscorrecttostate
that:
a)Thepossibilityofanoceboeffectofthedrughasalready
beenruledout.
b)Theriskofdepressionandanxietydisorderinfinasteride
usersisindependentofthepresenceofaconcomitant
sexualdisorder.
c)Inthecaseofapersonalhistoryofunderlyingpsychiatric
illness,theuseoffinasterideisnotindicated.
d)Epigeneticmechanismsmayexplaintheoccurrenceof
thesyndromeinonlyalimitednumberofindividuals
exposedtofinasteride.
9)Regardingthemetaboliceffectsoffinasteride,itis
incorrecttostatethat:
a)Thedrugappearstocontributetoperipheralinsulin
resistanceanddiabetes.
b)Itchangesthedistributionofbodyfatandinduces
hepaticsteatosis.
c)Duetoitsinfluenceonbonemetabolism,aperiodicbone
densityassessmentinindividualsusingfinasterideis
mandatory.
d)Facedwithapossibleincreaseincardiovascularrisk,
moreelaborateclinicalstudiesthatanalyzecountless
relevantvariablesarenecessary.
10)Whenassessingapatientwithanindicationfortheuse
offinasteride,thephysicianshouldconsider:
a)Presenceofpreviouspsychiatricorsexualdisorders
b)Familyhistoryofpsychiatricillnesses
c)Familyhistoryofinfertilityorsubfertility
d)Riskfactorsformetabolicsyndrome
Answers
Useofpsychiatricdrugsindermatology.AnBras Dermatol.2020;95(2):133-143.
1.c 3.c 5.a 7.d 9.a
2.c 4.d 6.c 8.d 10.b
References
1.CatherJC,LaneD,HeaphyMRJr,NelsonBR.Finasteride---an updateandreview.Cutis.1999;64:167---72.
2.MarksLS.5␣-Reductase:history andclinicalimportance.Rev Urol.2004;6Suppl.9:S11---21.
3.Accessdata.fda.gov [Internet]. Propecia (finas-teride). Available from: https://www.accessdata.fda. gov/scripts/cder/daf/index.cfm?event=BasicSearch.process
[cited26.10.19].
4.Rarediseases.info.nih.gov [Internet]. Adverse events of 5-alpha-reductase inhibitors. Available from: https:// rarediseases.info.nih.gov/diseases/12407/post-finasteride-syndrome[cited26.10.19].
5.GanzerCA,JacobsAR,IqbalF.Persistentsexual,emotional,and cognitiveimpairmentpost-finasteride:asurveyofmen report-ingsymptoms.AmJMensHealth.2015;9:222---8.
6.IrwigMS,KolukulaS.Persistentsexualsideeffectsoffinasteride formalepatternhairloss.JSexMed.2011;8:1747---53. 7.IrwigMS.Persistentsexualsideeffectsoffinasteride:couldthey
bepermanent?JSexMed.2012;9:2927---32.
8.Chiriacò G, Cauci S, Mazzon G, Trombetta C. An observa-tionalretrospectiveevaluationof79youngmenwithlong-term adverseeffects afteruseof finasterideagainst androgenetic alopecia.Andrology.2016;4:245---50.
9.Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L, et al. Incidence and severity of sexual adverse experiencesinfinasterideandplacebo-treatedmenwithbenign prostatichyperplasia.Urology.2003;61:579---84.
10.LiuL,ZhaoS,LiF,LiE,KangR,LuoL,etal.Effectof 5alpha-reductaseinhibitorson sexualfunction:a meta-analysis and systematicreviewofrandomizedcontrolledtrials.JSexMed. 2016;13:1297---310.
11.Lee S, Lee YB,Choe SJ, Lee WS. Adverse sexualeffects of treatmentwithfinasterideordutasterideformaleandrogenetic alopecia:a systematic reviewand meta-analysis. ActaDerm Venereol.2019;99:12---7.
12.Tsai TF, ChoiGS, KimBJ, Kim MB, NgCF, Kochhar P,et al. Prospectiverandomizedstudyofsexualfunctioninmen tak-ingdutasterideforthetreatmentofandrogeneticalopecia.J Dermatol.2018;45:799---804.
13.KiguradzeT,TempsWH,YarnoldPR,CashyJ,BranniganRE, Nar-doneB,etal.Persistenterectiledysfunctioninmenexposed tothe5alpha-reductaseinhibitors,finasteride,ordutasteride. PeerJ.2017;5:e3020,eCollection2017.
14.MondainiN,GonteroP,GiubileiG,LombardiG,CaiT,Gavazzi A,etal.Finasteride5mgand sexualsideeffects:howmany of these are related to a nocebo phenomenon? J Sex Med. 2007;4:1708---12.
15.BasariaS,JasujaR, HuangG,WhartonW, PanH,PencinaK, etal.Characteristicsofmenwhoreportpersistentsexual symp-tomsafterfinasterideuseforhairloss.JClinEndocrinolMetab. 2016;101:4669---80.
16.SungHH,YuJ,KangSJ,ChaeMR,SoI,ParkJK,etal.Persistent erectiledysfunctionafterdiscontinuationof5-alphareductase inhibitortherapy inratsdepending onthedurationof treat-ment.WorldJMensHealth.2019;37:240---8.
17.DiLoretoC,LaMarraF,MazzonG, BelgranoE,TrombettaC, CauciS.Immunohistochemicalevaluationofandrogenreceptor andnervestructure densityinhumanprepucefrom patients withpersistent sexual side effects after finasteride use for androgeneticalopecia.PLOSONE.2014;9:e100237.
18.SamplaskiMK,LoK,GroberE,JarviK.Finasterideuseinthe male infertility population: effects on semen and hormone parameters.FertilSteril.2013;100:1542---6.
19.SamplaskiMK, Smith JF, Lo KC, Hotaling JM, LauS, Grober ED,etal.Reproductive endocrinologistsarethegatekeepers formaleinfertilitycare inNorthAmerica:resultsofa North Americansurvey onthereferral patternsand characteristics ofmenpresentingtomaleinfertilityspecialistsforinfertility investigations.FertilSteril.2019;112:657---62.
20.O’DonnellL, PratisK, StantonPG, RobertsonDM, McLachlan RI.Testosterone-dependentrestorationofspermatogenesisin adultratsisimpairedbya5alpha-reductaseinhibitor.JAndrol. 1999;20:109---17.
21.OverstreetJW,FuhVL,GouldJ,HowardsSS,LieberMM, Hell-stromW,etal.Chronictreatmentwithfinasteridedailydoes notaffectspermatogenesisorsemenproductioninyoungmen. JUrol.1999;162:1295---300.
22.GlinaS,NevesPA,SaadeR,NettoNRJr,SoaresJB,GaluppoAG. Finasteride-associatedmaleinfertility.RevHospClinFacMed SaoPaulo.2004;59:203---5.
23.LiuKE,BinsalehS,LoKC,JarviK.Propecia-induced spermato-genicfailure:areportoftwocases.FertilSteril.2008;90:849, e17---9.
24.ChibaK,YamaguchiK,LiF,AndoM,FujisawaM. Finasteride-associatedmaleinfertility.FertilSteril.2011;95:1786,e9---11. 25.TuHY, ZiniA. Finasteride-induced secondaryinfertility
asso-ciated with sperm DNA damage. Fertil Steril. 2011;95, 2125.e13-4.
26.RobaireB,HendersonNA.Actionsof5alpha-reductaseinhibitors ontheepididymis.MolCellEndocrinol.2006;250:190---5. 27.AmoryJK,WangC,SwerdloffRS,AnawaltBD,MatsumotoAM,
Bremner WJ, et al. The effect of 5alpha-reductase inhibi-tion with dutasteride and finasteride on semen parameters andserumhormonesinhealthymen.JClinEndocrinolMetab. 2007;92:1659---65.
28.MelcangiRC,SantiD,SpezzanoR,GrimoldiM,TabacchiT,Fusco ML,etal.Neuroactivesteroidlevelsandpsychiatricand andro-logicalfeaturesinpost-finasteridepatients.JSteroidBiochem MolBiol.2017;171:229---35.
29.Rahimi-ArdabiliB,POurandarjaniR,HabibollahiP,MualekiA. Finasterideinduceddepression:aprospectivestudy.BMCClin Pharmacol.2006;6:7.
30.Ali AK, Heran BS, Etminan M. Persistent sexual dysfunction and suicidal ideation in young men treated with low-dosefinasteride:apharmacovigilancestudy.Pharmacotherapy. 2015;35:687---95.
31.Giatti S, Foglio B, Romano S, Pesaresi M, Panzica G, Garcia-Segura LM, et al. Effects of subchronic finasteride treatmentand withdrawal onneuroactive steroid levels and their receptors in the male rat brain. Neuroendocrinology. 2016;103:746---57.
32.MotofeiIG,RowlandDL,TampaM,SarbuMI,MitranMI,Mitran CI, et al. Finasteride and androgenic alopecia; from thera-peutic options to medical implications. JDermatolog Treat. 2019;21:1---7.
33.GanzerCA,JacobsAR.Emotionalconsequencesoffinasteride: fool’sgold.AmJMensHealth.2018;12:90---5.
34.MaksymRB,KajdyA,RabijewskiM.Post-finasteridesyndrome ---doesitreallyexist?AgingMale.2019;22:250---9.
35.DuskovaM,HillM,StarkaL.Changesofmetabolicprofileinmen treatedforandrogeneticalopeciawith1mgfinasteride.Endocr Regul.2010;44:3---8.
36.TraishAM,GuayAT,ZitzmannM.5␣-Reductaseinhibitorsalter steroidmetabolism andmaycontributeto insulinresistance, diabetes,metabolicsyndromeandvasculardisease:amedical hypothesis.HormMolBiolClinInvestig.2014;20:73---80. 37.TraishAM,MelcangiRC,BortolatoM,Garcia-SeguraLM,
Zitz-mannM.Adverseeffectsof5␣-reductase inhibitors:whatdo we know,don’tknow, and needto know?Rev EndocrMetab Disord.2015;16:177---98.
38.LivingstoneDE,BaratP,DiRolloEM,ReesGA,WeldinBA, Rog-ZielinskaEA,etal.5␣-Reductasetype1deficiencyorinhibition predisposesto insulinresistance,hepaticsteatosis, andliver fibrosisinrodents.Diabetes.2015;64:447---58.
39.Arias-SantiagoS,Camacho-MartínezFM.Adverseeffectsof 5-alpha reductase inhibitor therapy in menwith androgenetic alopecia: is there cause for concern? Actas Dermosifiliogr. 2016;107:709---11.
40.HazlehurstJM,OprescuAI,NikolaouN,DiGuidaR,Grinbergs AE, Davies NP, et al. Dual-5␣-reductase inhibition promotes hepatic lipidaccumulationin man. JClinEndocrinol Metab. 2016;101:103---13.
41.UpretiR,HughesKA,LivingstoneDE,GrayCD,MinnsFC, Macfar-laneDP,etal.5␣-Reductasetype1modulatesinsulinsensitivity inmen.JClinEndocrinolMetab.2014;99:1397---406.
42.LinWL,HsiehYW,LinCL,SungFC,WuCH,KaoCH.A population-basednestedcase---controlstudy:theuseof5-alpha-reductase inhibitors and the increased risk of osteoporosis diagnosis inpatientswithbenignprostatehyperplasia.ClinEndocrinol (Oxf).2015;82:503---8.
43.WindahlSH,AnderssonN,BörjessonAE,SwansonC,Svensson J, Movérare-Skrtic S, et al. Reduced bone mass and muscle strengthinmale5␣-reductase type1 inactivatedmice.PLoS One.2011;6:e21402.
44.GiattiS,DiviccaroS,PanzicaG,MelcangiRC.Post-finasteride syndrome and post-SSRIsexualdysfunction:two sidesofthe samecoin?Endocrine.2018;61:180---93.
45.Healy D,LeNoury J, ManginD. Enduringsexualdysfunction aftertreatmentwithantidepressants,5␣-reductaseinhibitors andisotretinoin:300cases.IntJRiskSafMed.2018;29:125---34. 46.RezendeHD,DiasMFRG,Trüeb RM.Acommentonthe
post-finasteridesyndrome.IntJTrichol.2018;10:255---61.
47.Fertig R, Shapiro J, Bergfeld W, Tosti A. Investigation of theplausibilityof5-alpha-reductaseinhibitorsyndrome.Skin AppendageDisord.2017;2:120---9.
