Copyright© AE&M all rights reserved. (HC-UFPR), Curitiba,PR,Brasil Universidade Federal doParaná dasClínicasda Interna, Hospital deMedicina Departamento (SEMPR), e Metabologia 562 L INTRODUCTION DOI: 10.1590/2359-3997000000192 Accepted onJan/26/2016 Received onSept/24/2015 [email protected] 80030-110 –Curitiba,PR,Brasil Av. Agostinho Leão Júnior, 285 Gisah Amaral deCarvalho Correspondence to: 2 1 LT4 reflect only pituitary euthyroidism (8).Thiscould euthyroidism LT4 onlypituitary reflect (TSH)levelsinpatientsreceiving stimulating hormone tissues simultaneously, thyroid- serum andthatnormal stateinthebloodand all aeuthyroid cannot assure Mounting evidencesuggests thatLT4 monotherapy range(7). reference TSH levelsbeingwithinthenormal despitetheir symptomsofhypothyroidism, to report and symptoms. signs inhypothyroid most patients,withimprovements achievedin T4(fT4)are blood levelsofTSHandfree normal patientswithhypothyroidism, When treating daily dose(6). an oral (T4) afteringestionof thyroxine fairlystablebloodlevelsof of sixdaysandprovide (1-5). TheLT4a half-life availablehave formulations University,Canberra, ACT, Australia National AustralianResearch, The The John CurtinSchool ofMedical original article GenomeSciencesDepartment, Serviço deEndocrinologia Serviço However, 5-10%of patientscontinue approximately for the treatment of patients with hypothyroidism ofpatientswithhypothyroidism for thetreatment ofchoice sodium(LT4)evothyroxine isthedrug Gilberto Paz-Filho Gilberto vital signs, and quality of life (QoL) were evaluated atweeks0,8and16.vital signs,andqualityoflife(QoL)were for 8moreweeks. Thyroid function,lipidprofile,plasmaglucose,bodyweight,electrocardiogram, (G1) ortostart LT4/LT3 therapy(75/15 μg/day;G2). After 8weeks,participants switched treatments on stabledosesofLT4 for≥6months (125 or150 μg/day)wererandomized tocontinueLT4 treatment double-blind, crossover study. Adults withprimaryhypothyroidism (n=32,age42.6±13.3, 30females) Objective: ABSTRACT double-blind, crossover study liothyronine: arandomized, with levothyroxine plus Treatment ofhypothyroidism Juliana KaminskiJuliana profile, bodyweightandQoLremainedunchanged. in heart rate,withnosignificant changes inelectrocardiogramorarterial bloodpressure.Lipid LT3 had T3 levelsabove theupperlimit(15% vs.3%). The combinationtherapyledtoanincrease 0.43 ng/dL;P<0.001). TSH and T3 levelswerenotaffected bytypeoftherapy. MorepatientsonLT4/ were significantlylowerwhileon LT4/LT3 (G1: 1.07 ±0.29vs. 1.65 ±0.46;G2:0.970.26vs. 1.63 ± quality oflife;randomized Clinical trial;combinedmodalitytherapy;cross-overstudies;hypothyroidism;levothyroxine;triiodothyronine;liothyronine; Keywords Endocrinol Metab. 2016;60(6):562-72 and theimpactofcombinedtherapyinselectpopulationswithgeneticpolymorphisms. of thestudiedformulationcouldbeobserved.Future trialsneedtoevaluatedifferent formulations elevated T3 levels,withnosignificantalterationsintheevaluatedoutcomes.Noclearclinicalbenefit significantly lowerfree T4levels,withno changes in TSHor T3levels.Morepatientson LT4/T3 had therapy inpatientswithprimaryhypothyroidism. To comparetheeffects ofauniquefixedcombinationlevothyroxine/liothyronine (LT4/LT3) 1 2 , Fabíola Yukiko Miasaki , HansGraf patients treated withLT4/LT3patients treated (11),andsimilarresults psychometric functionalityin well-being, moodand in In 1999,Buneviciusandcols. describedanincrease (possibly due to excessive doses ofLT4/LT3) (10). symptoms ahighincidenceofhyperthyroid revealed LT4/LT3 toward patient preference therapyand regarding in 1970.Theseshowednopositiveresults reported trialwere randomized, double-blind,crossover thefirst from and qualityoflife(QoL).Theresults symptoms andimprove hypothyroidism overt reverse whether LT4/LT3 combinationtherapywas ableto rats(9). inalltissuesofthyroidectomized euthyroidism LT4/LT3) oftriiodothyronine; synthetic form ensured (the the combinationlevothyroxine/liothyronine T3levels.Inanimalstudies,only normal to restore (T3)isnotsufficient T4totriiodothyronine from be attributedtothefactthatperipheralconversion 1 , Gisah Amaral deCarvalho In humans,severalclinicaltrialshaveevaluated Subjectsandmethods: 1 Conclusions: ,

The combinationtherapyyielded Arch Metab. Endocrinol 2016;60/6 1 Results: This isarandomized, reT levels Free T4 Arch Arch Arch Metab. Endocrinol 2016;60/6 LT3 for 8 weeksandtogoback theirusualLT4 tothecombinationtherapyLT4/therapeutic regimen randomizedtoswitchtheirusual (G2) were group includedinthesecond weeks (G1).Theparticipants by useofcombinationtherapy LT4 plusLT3 for8more their usualdoseofLT4receiving for8weeks,followed wasrandomizedtocontinue ofparticipants One group study.This wasarandomized,double-blind,crossover Study design sixmonths. for theprevious treatment antidepressant adequate theyhadbeenreceiving excluded, provided not were withdiagnosisofdepression Participants contraception. of hormonal anduse pregnancy; hormones; TSHandofthyroid ofserum and measures orsubstancesthatalterthe pharmacokinetics use ofdrugs failure); concomitant diseases(suchasliver, orheart renal diabetesmellitus orserious Exclusion criteriawere: six months(125or150μg/day). during theprevious stabledosesof LT4 whohadreceived hypothyroidism, 65 yearsold,withanestablisheddiagnosisofprimary ofanygender, participants between 15and criteria were Federal UniversityofParaná,Curitiba,Brazil.Inclusion theClinicalHospital ofthe from recruited who were allstudyparticipants, consentwasobtainedfrom informed Hospital ofParanáEthicsCommittee,andwritten bytheFederal University The studywasapproved Study subjects SUBJECTS ANDMETHODS hypothyroidism. primary signs, metabolicparameters,andQoLofpatientswith levels,bodyweight,vital hormone a day)onthyroid LT3 therapy(75µgofLT4 and15µgofLT3, once ofaunique,fixedcombination LT4/ the effects patients withhypothyroidism. therapy LT4/LT3 issuperiortoLT4 monotherapyin itisstillunclearwhetherthecombination Therefore, thattypeoftherapy(15). with LT4/LT3 andpreferred whenempiricallytreated mentioned improvements TSHandfT4levels)have (despite havingnormal symptoms some patientswhocomplainofhypothyroid (13,14).However,treatment intheclinicalsetting, ofcombination asuperioreffect evidence supporting meta-analysesofthosetrialsdidnotshowany recent byotherstudies,and replicated could notbefurther r were The aim of the present study was to compare studywastocompare The aimofthepresent eplicated by another group (12).Thosefindings eplicated byanothergroup triglycerides. and HDLcholesterol fT4, glucose,totalcholesterol, TSH,totalT3, serum tomeasure hour fastinorder aftera12- allparticipants collectedfrom samples were end ofeach8-weekperiod.Atvisit,venousblood anamnesis andphysicalexamination. evaluatedbystandard counting. Adverseeventswere questioningduringfollow-upvisitsandpill by direct tothetherapywasassessed Adherence of theresults. intheassessment This individualdidnotparticipate byoneunblindedinvestigator(G.A.C.). was performed dispensing anotherbatchofcapsules.Drug received At theendofeacheight-weekperiod,participants medication oncedaily, breakfast. halfanhourbefore advisedtotaketheir were Participants KGaA, Germany). (75 μgofLT4, plus15μgofLT3; Novothyral,Merck S/A,Brazil)orLT4/LT3 Merck 150 μg;Euthyrox, containing eithertheirusualdoseofLT4 (125μgor capsules received dose foranother8weeks.Participants the end of each treatment period. the endofeachtreatment (ECG) wasobtained at Twelve-lead electrocardiogram inthesittingposition. measured were blood pressure rateand arterial period.Restingheart each treatment atbaselineandtheendof measured were pressure Triglyceride FastColorkits,Bayer, Germany). FastColorkit,HDLAdviaandSera-Pak Cholesterol byenzymaticcolorimetricmethods(Sera-Pak measured were l andtriglycerides cholestero HDL cholesterol, total method (HexokinaseII,Bayer, Serum Germany). CV, byenzymatic 5.3%-15%).Glucosewasmeasured 19 ng/dL;intra-assayCV, 4.4%-12%;andinter-assay Corporation, CA,USA;RV, 82-179 ng/dL;sensitivity, Products kit (Diagnostic immunosorbent assay linked by Immulite CV, 4.8%-9.0%).Total induplicates T3wasmeasured 0.15 ng/dL;intra-assayCV, 4.4%-7.5%;andinter-assay Corporation, CA,USA;RV, 0.8-1.9ng/dL;sensitivity, Products kit (Diagnostic immunosorbent assay linked TSH was determined induplicatesbyImmulite TSH wasdetermined methods Laboratory by Immulite CV, induplicates T4wasmeasured 4.6-12.5%).Free ofvariation[CV],3.8-12.5%;andinter-assay coefficient mUI/L; intra-assay 0.4-4.0 mUI/L;sensitivity0.002 values[RV] Corporation,CA,USA;reference Products kit(Diagnostic chemiluminescence TSHthird-generation Participants were evaluatedatbaselineand atthe were Participants Body weight, resting heart rate and arterial blood rateandarterial heart Body weight,resting ® ® 2000chemiluminescenceenzyme- 2000chemiluminescenceenzyme- LT4 plusLT3 inhypothyroidism ® 2000 2000 563

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 564 (Figure 1). (Figure sixmonths TSH levelsduringtheprevious of increased because cause ofonsetdiabetesmellitus, andthree because ofpregnancy, twobe onebecause ofdivorce, randomization,one excludedbefore ven patientswere inclusion. Se for considered A totalof39patientswere RESULTS Prism 5.04. usingGraphPad performed test.Analyseswere Smirnov byKolmogorov- testedfornormality All variableswere coefficients. orPearson’scorrelation using Spearman’s calculated levelswere hormone andthyroid scores QoL between rank-sums test.Correlations Friedman analyzed by were was employed.Qualityoflifescores distribution. To az-test sampleproportions, compare Mann-Whitney Utestforvariableswithoutnormal signed-ranktestor distribution,andWilcoxon normal t-testforvariableswith appropriate) (where or unpaired way ANOVA, Dunn’smultiplecomparisontest,paired one- by analyzed were Clinical andbiochemicaldata Statistical analysis sessions(eitherJ.K.orF.Y.M.).miner duringallthree Each patientwasevaluatedbythesameblindedexa insex). social interaction,abilitytoworkandinterest ability toengageinphysicalactivity, abilitytoengagein (overallfeeling, five questionsin0.25-pointincrements given foreachofthe +2.5 (thebestpossiblestate)were the VAS, -2.5(theworstpossiblestate)to from scores in physicalactivities,socialinteractionsandwork.In insexandability toengage overall well-being,interest (VAS) atbaseline,8weeksand16thatassessed alsocompletedavisualanalogscale state. Participants favorable amore representing tofive,withzero zero (10 items).Scoringwasbasedonasix-pointscalefrom general well-being(11items),andmoodemotions categories: physicalcomplaints(12items),energy and intothree consistedof33itemsgrouped questionnaire andanxiety.tion, insomnia,irritability our Therefore, andaddedfouritems:palpita HRQOL questionnaire Wewith hypothyroidism. the selected29itemsfrom well-beinginsubjects was elaboratedtodetectimpaired (16),whichinturn of Life(HRQOL)questionnaire theHealthRelatedQuality adaptedfrom questionnaire At eachvisit,QoLwasassessedusingadisease-specific Quality oflifeevaluation LT4 plusLT3 inhypothyroidism - - - - patient served ashisorherown control. patient served patients in the statistical analysisbecause each crossover range.However,within normal wedecidedtokeepall Ideally, basalTSHconcentrationswouldbe serum TSHlevelsat the timeofrandomization. had increased On thecontrary, carcinoma. for thyroid some patients oftreatment TSHasaresult patients hadsuppressed 0.001to8.425mU/LinG2.Six in G1andfrom 0.001to4.5mU/L basal TSHlevelsrangedfrom (Table similarforbothgroups data were 1).Serum therapy (G2;n=15).Baselineclinicalandbiochemical (G1; n=17)ortoswitchtheLT4/LT3 combination randomized tocontinuetakingtheirusualLT4 dose 125 μgor150ofLT4 perday. were Participants witheither wasbeingtreated ofparticipants proportion 4.5 years(minimum1,maximum33years).Thesame was female. Themediandurationofhypothyroidism Mean agewas42.6±13.3yearsold,and94%were duetoGraves’ disease. induced hypothyroidism (9.4%) had radioiodine- andthree carcinoma, thyroid aftertherapyfordifferentiated acquired hypothyroidism six(18.7%)hadpost-surgical hypothyroidism, (71.9%)hadautoimmuneoridiopathic participants Twenty-three recruited. and exclusioncriteriawere Figure 1. CONSORT diagram. Allocated toLT4 (n=15) Allocated toLT4 (n=17) Lost tofollow-up(n=0) Lost tofollow-up(n=0) Thirty-two participants whofulfilled theinclusion participants Thirty-two Analyzed n =15 G1 Assessed foreligibility Randomized n =32 n =39 Excluded (n=7) G2 • Declinedtoparticipate(divorce, n=1) • Pregnancy(n=1) Diabetesmellitus(n=2) • Increased TSH (n=3) • Arch Metab. Endocrinol 2016;60/6 Allocated toLT4/LT3 (n=17) Allocated toLT4/LT3 (n=15) Lost tofollow-up(n=0) Lost tofollow-up(n=0) Analyzed n =17 Note: resultsareshownasmean±standarddeviationormedian(minimum–maximum). ± 0.26 at week 8 vs. 1.63 ± 0.43 ng/dL at week 16 in ± 0.26atweek8vs.1.630.43ng/dL16in at week16vs.1.65±0.46ng/dL8inG1;0.97 whiletakingLT4/LT3 (1.07±0.29 treatment observed withsignificantlylowerlevels 0.001 inbothgroups), onlyforfT4levels(one-wayANOVAobserved P< Arch Metab. Endocrinol 2016;60/6 G1: Group 1, onLT4 monotherapy; G2: Group2, onLT4/LT3 combination therapy. * P<0.05;**0.01;***0.001. Only statisticallysignificantcomparisons aredepicted. Figure 2. Changesinthyroidfunctiontests. Table 1. Baselineclinicalandbiochemicaldata Diastolic bloodpressure(mmHg) Systolic bloodpressure(mmHg) Resting heartrate(beatsperminute) Triglycerides (mg/dL) HDL (mg/dL) Total cholesterol(mg/dL) Glucose (mg/dL) (ng/dL) Free T4 Total(ng/dL) T3 TSH (mU/L) fT4 (ng/dL) Body massindex(kg/m Radioiodine-induced hypothyroidism(%) Post-surgical hypothyroidism(%) Autoimmune/idiopathic hypothyroidism(%) Time ofhypothyroidismdiagnosis(years) Participants onLT4 125μg/day(%) Gender (F:M) Age (years-old) 4.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 A G1 Basal Over the16-weekperiod,significantchangeswere

G2 Basal ** G1 8 Weeks 2 ) *

G2 8 Weeks fT4 *** **

G1 16 Weeks ***

G2 16 Weeks *** *** Prior torandomization (0.001 –8.425) (90.0 –150.0) 139.7 ±68.0 191.1 ±35.4 78.9 ±11.3 47.2 ±11.9 99.0 ±12.5 1.26 ±0.26 93.6 ±11.6 42.6 ±13.3 4.5 (1–33) 28.5 ±5.6 76.7 ±9.8 T3 (ng/dL) (n =32) 120.0 0.309 400 100 150 200 250 300 350 18.7 71.9 30:2 9.4 B 50 50

G1 Basal 0

G2 Basal

G1 8 Weeks

on LT4/LT3 on LT4 G2 8 Weeks T3 (100.0 –140.0) (0.001 –4.500) Group 1(G1) 144.5 ±75.0 188.8 ±36.9 77.1 ±11.2 47.5 ±12.4 97.6 ±10.6 1.26 ±0.25 93.2 ±11.6 39.5 ±14.2 0.05) or in G2 (one-way ANOVA 2C). P = 0.819; Figure notsignificantinG1(one-wayANOVAlevels were = P 2B).ChangesinTSH bytypeoftherapy (Figure affected ANOVA not P=0.247),andmedianT3levelswere in G1(one-wayANOVA P=0.662)andG2(one-way similaroverthestudy 2A).T3levelswere G2) (Figure 27.3 ±5.0 79.1 ±9.0 5 (1–33) (n =17) 120.0 0.078 17.6 23.5 58.8 52.9 15:2

G1 16 Weeks

G2 16 Weeks

(0.001 –8.425) (90.0 –150.0) Group 2(G2) 134.3 ±61.2 193.7 ±34.8 100.5 ±14.5 46.1 ±11.86 74.1 ±10.3 81.0 ±11.5 TSH (mUI/L) 46.9 ±11.8 1.26 ±0.28 94.0 ±12.0 10 C 29.8 ±6.0 4 (1–23) 0 1 2 3 4 5 6 7 8 9 G1 Basal (n=15) 120.0 0.535 13.3 86.7 46.7 15:0 0 G2 Basal

G1 8 Weeks LT4 plusLT3 inhypothyroidism

G2 8 Weeks TSH P (group1vs. group2) 0.211 0.160 0.612 0.335 0.117 0.679 0.706 0.532 0.891 0.956 0.847 0.088 0.460 0.080 0.726 0.143 G1 16 Weeks 0.595 0.170

G2 16 Weeks 565

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. Note: resultsareshownas mean±standarddeviationormedian(minimum –maximum). well-being scores andTSHlevelswhileonLT4/LT3well-being scores onlybetweenenergy/general levels showedcorrelation hormone andthyroid bysubgroups between scores LT4/LT3 analysis (r=0.4164,P0.018).Correlation whileon betweenTSHandglobalscores correlation LT3 (allP>0.05).However, wasapositive there (fT4 andT3)atbaselineorwhileonLT4 orLT4/ levels hormone andthyroid between globalscores nocorrelations were 3).There (all P>0.05)(Figure similarforbothtreatments were in eachsubgroup scores types oftherapy(P=0.888).Furthermore, whencomparingthetwo inglobalscores difference randomization (P<0.05).However, wasno there after also improved being, andmood/emotions) (physicalcomplaints,energy/general well- subgroups categorized into randomization (P<0.001).Scores after improved scores median Global questionnaire. ECG. detectedonresting were arrhythmias addition, no range.In withinthenormal LT3 itremained treatment, rate wasslightlyhigherduringthecombinationLT4/ subjects completedthestudy. heart Althoughresting when onLT4 therapy. T3levels(298.5ng/dL) hadincreased one participant only ± 57.1ng/dL,highest311.5ng/dL),whereas had T3>180ng/dLwhileonLT4/LT3 (mean239.4 fivepatients type oftherapy(Table 2).Furthermore, therapy. similar, Otheroutcomeswere of regardless takingthe combination were higher whileparticipants rate wasslightly resting heart significantly lowerand therapy (LT4 orLT4/LT3) showedthatfT4levelswere 566 Table 2. Clinicaldata, thyroidfunctiontestsandbiochemicalresultswhileonLT4 orLT4/LT3 LT4 plusLT3 inhypothyroidism Triglycerides (mg/dL) HDL (mg/dL) Total cholesterol(mg/dL) Glucose (mg/dL) (ng/dL) Free T4 T3 (ng/dL) TSH (mU/L) Diastolic bloodpressure(mmHg) Systolic bloodpressure(mmHg) Resting heartrate Body massindex(kg/m All participants responded totheadaptedHRQOL responded All participants andall reported, were No significantadverseeffects totypeof according The analysisoftheresults 2 ) 0.189 (0.004–3.495) On LT4 monotherapy 103.8 (40.0–298.5) 130.6 ±53.4 188.4 ±31.3 102.9 ±23.7 118.1 ±13.3 49.1 ±10.1 1.64 ±0.44 28.5 ±5.7 75.6 ±9.0 74.6 ±9.5

while participants were onLT4. were Conversely,while participants compared thesameforonlyoneitem remained scores whereas onLT4/LT3, were for 3itemswhileparticipants combination therapy. didnotchange Medianscores onLT4/LT3 were whenparticipants frequently more baselinewasobserved from lack ofimprovement ofeachtypetherapy withinthese15items, effect all 15ofthesespecificitems.Whenanalyzingthe for QoLimproved tothesescores, 0.05). According ofLT4/LT3to scores combination therapy(P< whenonLT4 atbaselinetoscores comparing scores when median scores items hadsignificantlydifferent individually,questionnaire that15 weobserved * P<0.05;**0.01;***0.001. Box-plots depictmedianandrange. Figure 3. Scoresofqualitylife, globalandbytypeofcomplaint. 0.4011, P=0.023). and TSHlevels,alsowhileonLT4/LT3scores (r= (r =0.4123,P0.019)andbetweenmood/emotions On LT4/LT3 combinationtherapy By analyzingthe33itemsofadaptedHRQOL Score 120 100 110 10 20 30 40 50 60 70 80 90 0 0.638 (0.013–9.500) 98.5 (44.7–311.5) 135.7 ±66.6 190.9 ±34.9 117.5 ±11.1 *** 48.2 ±10.4 1.03 ±0.28 99.0 ±14.1 28.4 ±5.7 74.1 ±8.7 77.4 ±9.2 Global *** NS complaints Physical * * NS Arch Metab. Endocrinol 2016;60/6 Energy and complaints well-being *** ** NS < 0.0001 0.212 0.286 0.742 0.540 0.191 0.623 0.493 0.875 0.446 0.046 on LT4/LT3 on LT4 Baseline P complaints Mood and emotions ** *** NS NA: notapplicable;G1: Group1, onLT4 monotherapy;G2: Group2, onLT4/LT3 combinationtherapy. Note: scoresareshownasmedian(minimum–maximum). Scoringwasbasedonasix-pointscalefrom zerotofive, withzerorepresentingamorefavorablestate. Arch Metab. Endocrinol 2016;60/6 Table 3. Itemizedscoresofqualitylife lower brittlenailswere concerning Median scores compared. were whenthetwotreatments different a In 12 itemsoftheadaptedHRQOLquestionnaire. on LT4; onLT4/LT3, obtainedin were lowerscores while improved to baseline,14itemshadtheirscores N

Mood and emotions Energy and general well-being Physical complaints significantly post hocanalysis,onlytwoitemswere No energytogetthrough Needing moretimetodo Deterioration ofmemory Needing napduringday Difficulty concentrating Slowing ofmovements Needing moretimefor Feeling needformore Losing interestinsex Tightening ofclothes Feeling discouraged Shortness ofbreath Pins andneedlesin Puffiness ofhands Feeling depressed Feeling frustrated Feeling worthless activities/hobbies Losing interestin Slower physically Slower mentally Muscle cramps Going outless Feeling tired Swollen feet Feeling cold daily chores calculations Brittle nails hands/feet Symptom Palpitation Cold skin Irritability Insomnia Dry skin Dry Dry hair Dry the day Anxiety sleep randomization 1.5 (0-5) 1.5 (0-5) 1.5 (0-5) 2.5 (0-5) 1.5 (0-5) 0.5 (0-5) 0.5 (0-5) Prior to 1 (0-5) 2 (0-5) 2 (0-5) 2 (0-5) 0 (0-5) 1 (0-5) 0 (0-5) 1 (0-5) 1 (0-5) 2 (0-5) 1 (0-5) 1 (0-5) 1 (0-5) 1 (0-5) 0 (0-5) 2 (0-5) 0 (0-5) 0 (0-3) 1 (0-5) 0 (0-4) 0 (0-4) 1 (0-5) 0 (0-5) 1 (0-3) 1 (0-5) 1 (0-4) 1.5 (0-4) 0.5 (0-5) 1.5 (0-3) On LT4 1 (0-5) 1 (0-5) 1 (0-5) 0 (0-2) 0 (0-5) 0 (0-2) 1 (0-5) 1 (0-4) 1 (0-3) 1 (0-4) 0 (0-3) 1 (0-4) 1 (0-5) 1 (0-5) 0 (0-4) 0 (0-5) 1 (0-5) 0 (0-4) 1 (0-4) 0 (0-3) 1 (0-3) 1 (0-3) 2 (0-4) 0 (0-2) 0 (0-5) 0 (0-5) 0 (0-3) 0 (0-3) 0 (0-4) 0 (0-5) On LT4/LT3 0.5 (0-3) 0.5 (0-5) 1.5 (0-4) 0 (0-3) 1 (0-5) 1 (0-5) 1 (0-4) 0 (0-5) 0 (0-5) 0 (0-3) 1 (0-4) 1 (0-5) 1 (0-4) 1 (0-5) 1 (0-4) 1 (0-5) 0 (0-3) 0 (0-5) 1 (0-5) 1 (0-4) 0 (0-5) 1 (0-3) 1 (0-4) 1 (0-5) 0 (0-4) 0 (0-3) 0 (0-5) 0 (0-5) 1 (0-5) 0 (0-3) 0 (0-3) 1 (0-5) 0 (0-5) regimens (Tableregimens 3). between thetwo observed significant changeswere andanxiety),no (palpitation, insomnia,irritability addedtotheoriginalquestionnaire items thatwere lower whileonLT4/LT3.were thefour Concerning ofbreath shortness while onLT4, regarding andscores P value (baseline vs. LT4 vs. LT4/ < 0.001 0.011 0.069 0.001 0.072 0.021 0.971 0.044 0.120 0.495 0.013 0.066 0.476 0.182 0.001 0.658 0.005 0.002 0.093 0.433 0.220 0.587 0.002 0.032 0.007 0.640 0.076 0.113 0.013 0.013 0.071 0.018 0.182 LT3) LT4) Post hoc (baseline vs. < 0.001 < 0.001 P value 0.033 0.005 0.013 0.012 0.002 0.003 0.001 0.003 0.018 0.002 0.021 0.006 0.453 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA (baseline vs. LT4 plusLT3 inhypothyroidism Post hoc LT4/LT3) < 0.001 P value 0.003 0.016 0.118 0.128 0.006 0.001 0.016 0.004 0.002 0.025 0.031 0.557 0.013 0.006 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA P value (LT4 vs. LT4/LT3) Post hoc 0.359 0.135 0.191 0.307 0.797 0.340 0.758 0.135 0.538 0.879 0.904 0.275 0.004 0.778 0.038 NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 567

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. index, arterial blood pressure or resting heart rate. heart orresting bloodpressure index, arterial VAS scores), (global andsubgroup bodymass scores, QoLscores regarding showed nosignificantdifferences withhighT3levels(T3>180ng/dL),which the group We asubanalysisfor the twotreatments. alsoperformed between scores) (globalandsubgroup orQoLscores scores in observed were disease. Nosignificantchanges VAS duetoGraves’ radioiodine-induced hypothyroidism and carcinoma thyroid after therapyfordifferentiated acquired post-surgical hypothyroidism hypothyroidism, idiopathic or autoimmune etiologies ofhypothyroidism: LT3 (0.44±1.26;one-wayANOVA P=0.5175). 0.91), whileonLT4 (0.21±0.91),andwhileonLT4/ 568 levothyroxine. In addition, there isthepossibility Inaddition,there levothyroxine. adequate nonspecific symptomsdespite apparently go unnoticed,andsome patientshavepersistent development oftheseassociated conditionsmight of developingotherautoimmune diseases.The athighrisk diseaseare with autoimmunethyroid individuals,andpatients about 70%ofhypothyroid items evaluatingqualityoflife. was significantly superiorto LT4 foronlyoneof the33 overallqualityoflife,andLT4/LT3regarding therapy observed were no differences Furthermore, observed. were ECG alterationsnorsignificantadverseeffects takingthecombinationtherapy,in participants neither rate wasslightly higher heart pite thefactthatresting Des bloodpressure. fect bodymassindexandarterial implemented didnotaf levels. Thetypeoftreatment TSH,totalT3,lipids,orfastingglucose altering serum T4levelswithoutsignificantly free mines lowerserum therapy LT4/LT3the combination deter significantly LT4/LT3 suggestthat foranother8weeks.Ourresults LT4 received alone for8weeksand which participants clinical trialin a randomized,double-blind,crossover weconducted of hypothyroidism, nine inthetreatment outcomes(15).Toimproves ofliothyro clarifytherole therapy tolevothyroxine the additionofliothyronine is conflictinganimalandhumandatasuggestingthat modality (7).There lely asanexperimentaltreatment LT3 so combinationtherapyshouldbeconsidered sodium(1-5),and LT4/ islevothyroxine thyroidism Currently, ofhypo ofchoiceforthetreatment thedrug DISCUSSION LT4 plusLT3 inhypothyroidism We performed a sub-analysis according the the We asub-analysisaccording performed Mean VAS similaratbaseline(0.47± were scores Autoimmune thyroid disease is present in diseaseispresent Autoimmune thyroid ------1 year (22). Furthermore, ameta-analysisevaluating 1 year(22).Furthermore, subsequently after which wasnotconfirmed treatment, QoL andanxietyafter3months ofthecombination inmood, aslightimprovement That studyreported double-blind designataT4:T3weightratioof5:1. inanon-crossover,initially randomizedandtreated study, were hypothyroidism 697patientswithprimary follow-up wasconductedbySaravananandcols. The studywiththelargest samplesize andlongest with aconsiderablylowerT4:T3ratioof2.5:1(12). observed andanxietyscaleswere in QoL,depression TSHlevels.Significantimprovements for stableserum other positive study, dosewastitrated to aim treatment (21).Inthe tothecauseofhypothyroidism related were cancer.thyroid Thus,itisnotclearwhethertheresults had subjectswhohadpreviously ofathyreotic a group benefit ofthecombinationtherapywasevidentonlyin results, thesignificant In thefirsttrialshowingpositive andanxiety(12). ofQoL,depression with betterscores along (11,21), being andpsychometricfunctionality inmood,well- improvements Denmark, whichreported Lithuaniaand from amongtwogroups only observed (20). Clearbenefitsofthecombinationtherapywere containing bothT3andT4 extract desiccated thyroid andcols.(15)],onestudyevaluated Morreale byEscobar- [reviewed in patientswithhypothyroidism combination therapyofLT4 plussyntheticliothyronine ofhypothyroidism. treatment of LT4/LT3 inthe human trialsassessingtheefficacy functiontests,ledtothedevelopment of thyroid withLT4 improved therapyalonedespitenormal patientsdonothavetheirsymptoms hypothyroid thatmany of evidence,alongwiththeobservation LT3 combinationtherapyisemployed(9).Thispiece plasma andtissue)maybeattainedonlywhenLT4/ state(in euthyroid (18,19).Infact,atrue is normal T4toT3 assuming thatperipheralconversionfrom andtissularT3,even 100%ofthecirculating replenish orto toleadeuthyroidism of LT4 isnotsufficient therapyintheform replacement hormone that thyroid animalandhumanstudiessuggests thyroidectomized T4(17).Evidencefrom 5’-deiodination ofthesecreted peripheral T3derivesfrom 80% ofthecirculating intheblood.Theremaining T4 and20%ofT3present function (8). to nonspecificsymptoms,independentofthyroid autoimmunityitselfmightgiverise that thyroid To date,15clinicaltrialshaveevaluatedthe allthecirculating glandsecretes The adultthyroid Arch Metab. Endocrinol 2016;60/6 In that Arch Metab. Endocrinol 2016;60/6 is an expected finding that was reported in a previous in aprevious reported is anexpectedfindingthat was plasma levelsoffT4whileon LT4/LT3 therapy. This for 8weekseach,which led tosignificantlylower LT3 twicedaily(26). dosewasadministered dose astheoneemployedinourstudy. However, the on LT4 thesamecombination 125µg/dayreceived by Clydeandcols. LT4of ours (75µg to equal + 20µgofT3).Inthestudy withadosethatwasclosebutnot treated µg/day were whosedosepriortorandomizationwas125 participants LT4;of doses daily afew patientsondifferent recruited and cols.’sstudy and significantweightloss.Nygaard rate inheart andexperiencedincreases suppression TSH underwent halfoftheparticipants overtreated, ofpatientsthatwasprobably thissubgroup Within (usual LT4 doseminus25µgofLT4 plus15µgofLT3). calculate theLT4/LT3 ofpatients doseforasubgroup of LT4, wasemployedto andasubstitutionapproach takinganydose participants (24). Thatstudyrecruited by onestudy only has beenevaluated plus 15µgofT3 criteria,andthefixeddoseof75µg of LT4 recruitment knowledge, nootherstudieshaveemployedsuchstrict andcols.(12).Toperiod, aswasdonebyNygaard our notadjustedduringthestudy (12,22-24). Doseswere evaluated in otherstudies 5:1 weightratioaspreviously oftheirinitialLT4of LT3, dose,inthesame regardless LT4/LT3 atafixeddoseof75μg LT4 plus15μg used afixedcombinationapproach. We administered limited LT4 dailydoserange(125or150μg/day)and withinavery whowere participants LT3, werecruited tocalculatethedoseofLT4/substitution approach (21).Insteadofusinga factor, observed aspreviously maybeaconfounding thisheterogeneity therefore, included in thestudy; disease. Also,bothgenderswere administration ofradioactiveiodinetherapyforGraves’ becauseofthe cancerorhadhypothyroidism thyroid for followingtreatment athyreotic some patientswere of autoimmuneoridiopathicetiology. However, mostofthem hypothyroidism, primary stable, treated thecombinationtherapy.fatigue (25)benefitedfrom with LT4 therapy (23),psychiatric symptoms (24), or (11),highdissatisfaction even patientswithdepression QoL, cognition,bodyweightorbloodlipids(13).Not inbodilypain,mood,fatigue, improvements regarding LT4/LT3the superiorityof combination therapy isnoevidencesupporting patients concludedthatthere trialswithatotalof1,216 11 randomizedcontrolled We tobothtypesoftherapy submittedparticipants In ourstudy, with we evaluated 32participants , a few participants who were initially initially whowere , afewparticipants our study, significantchangesin wedidnotobserve LT3 onbloodlipids(37).In combinationtreatment fewtrials showedabenefitofthe LT4/ However, very significantlywith improves LT4 therapy(35,36). onlipidmetabolism(34),which negative effects (11,12,22,23). changes inbodyweightafterLT4/LT3 therapy significant otherclinicaltrialsdidnotreveal results, similartoour TSH of0.07mU/L(24).Nevertheless, inmanypatients,obtainingamedian overtreatment However, thecombinationtherapyledto observed. in bodyweightafterthecombinationtherapywere study,(33). Inoneprevious significantdecreases energy expenditure body compositionandresting levels), hormone byslightvariations inthyroid affected clinical trials(10-12,22-24,32). withprevious inconcordance bloodpressure, arterial detectedin nosignificantchangeswere Furthermore, 12-leadECG. onresting we didnotdetectarrhythmias (10,32), duringthecombinationtreatment overtreated intwostudieswhichpatientswere been reported have adverse events.Eventhoughatrialarrhythmias which didnotleadto rateby3beats/minute, heart in significantincrease aborderline we observed (31).Inourstudy,manifestations ofhyperthyroidism aminotransferases(30),leadingtoclinical serum markers(24,28-30) and rate (27),boneremodeling heart LT3 inresting maycontributetoincreases Excessivedoses ofLT4/and tissulareuthyroidism. not assessedwhetherthatdoseledtobothblood Association(7)],wehave Thyroid the European by than the13:1-20:1weightratiorecommended is similartothoseusedinotherstudies[butdifferent LT3 tablets. hours afteradministrationoftheLT4/collected 24 aswellthefactthatbloodsampleswere liothyronine, half-lifeof falselylowduetotheshort are these results caused bythecombinationtherapy, itispossiblethat inT3levels Although wecouldnotidentifyincreases changes inTSHandT3levelsoverthe16-weekperiod. under LT4/LT3were therapy. no were Also,there lowerwhenparticipants also showedthatfT4levelswere at8weeksand16 baseline tothoseobserved (13). Inourstudy, at observed comparisonsofresults combination therapyonplasmaTSH,totalT3orlipids ofthe no effect meta-analysis, whichalsoreported Overt hypothyroidism isclassicallyassociatedwith hypothyroidism Overt We alsoevaluatedbodyweight(asthiscanbe Although theT4:T3ratioof5:1usedinourstudy LT4 plusLT3 inhypothyroidism 569

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 570 analysis of the scores obtained from theVAS. obtainedfrom analysis ofthescores onQoLwasalsoevident inthe LT3). Thelackofeffect on LT4/ (allwhile mood/emotions scores and levels andbetweenTSH energy/general well-beingscores, betweenTSHand between TSHandglobalscores, T3 levels,wecouldidentifyonlymoderatecorrelation therapy. withTSH,fT4and scores Whencorrelating byLT4is unclearwhythissymptomwasimproved it (42).Nevertheless, involvement inhypothyroidism symptom inpatientswithnail themostprevalent are isunclear.clinical importance Bycontrast, fragilenails unspecificandtheir complaintsare patients, breathing Inhypothyroid ofbreath. shortness reduced reported thoseonLT4/LT3“brittle nails”complaint,whereas inthe improvement onLT4 reported Participants scores. evaluated itemshadsignificantlydifferent onlytwooutofthe33 the twotreatments, between theposthoc analysis andperforming the baselinescores inatrial(6).However,participation whenexcluding inhealth simply dueto to describeimprovement orthetendencyofpatients effect, by theHawthorne Thiscouldbeexplained withbaselinescores. compared thestudyperiodwhen throughout in thescores improvement weobserved items ofthequestionnaire, being, andmoodemotions).Interestingly, in15 (physicalcomplaints,energy andwell- each category within or in scores significant changesinglobalscores no revealed our adaptedHRQOLquestionnaire and cols.intheirclinicaltrials(26).Theanalysisof and employedbyJaeschkecols.(16)Clyde developed thequestionnaire translated toPortuguese have beenemployed.Inourstudy, weadaptedand and Anxiety, SymptomQuestionnaire) andThyroid (such astheSF-36,HamiltonScalesofDepression instruments studies,anddifferent across standardized symptomsisnot of QoL,well-being,moodandthyroid QoL orcognition.Itshouldbenotedthattheevaluation inbodilypain,well-being,mood,fatigue, improvement 10 (14)and11(13)ofthesestudiesshowedno Two26,28,30-32,40,41). meta-analyses including combination therapywithLT4/LT3 (11,12,21,23- during changes inmood,cognitionfunctionandQoL assessed have studies Most (38,39). dysfunction LT4/LT3 therapyoninsulinsensitivity. fasting insulinlevels,wecouldnotassesstheimpactof fastingglucoselevels.Sincewedidnotmeasure affect (11,22). Additionally, thecombinationtherapydidnot studies withprevious or triglycerides,inconcordance total LT4 plusLT3 inhypothyroidism Hypothyroidism may induce affective andcognitive mayinduceaffective Hypothyroidism cholesterol, LDL-cholesterol, HDL-cholesterol HDL-cholesterol LDL-cholesterol, cholesterol, ) polymorphisms can benefit from combination polymorphisms canbenefitfrom (DIO2) ofpatientswithdeiodinase2 is possiblethatasubgroup LT4/LT3, individualswithcombination hypothyroid it treatment of analyses failedtofindclearbenefitsinthe did notundergo validationinPortuguese. being validatedinEnglish,ourHRQOLquestionnaire in othersimilartrials(10,11,21,28).Finally, despite combination therapyhasbeenevaluatedfor≤8weeks to detectchangesinperipheralparameters.However, of our study maynothavebeenlongenough duration power (11,21,25,28,30,32,37,41).Similarly, the withadequatestatistical evaluated ≤40participants, homogeneous, larger sample,butseveralsimilartrials inamore couldhavebeenobserved results Different (8). daily twice or preparation sustained-release orintramuscular T3 bymeansofenteric,transdermal aconstant,steady supplyof instead hadadministered ifwe results couldhavebeen observed and significant half-life, hasashorter In addition,oralliothyronine clinicalhypothyroidism. tounnecessary participants and thecombinedtherapy, toavoidsubmittingour employ awashoutperiodbetweentheLT4 treatment wedidnot (20).Furthermore, in quantitativescores (orlackthereof) LT3 toimprovements andunrelated whichmightbehigherwhentakingLT4/ preference, However,liothyronine. wedidnotassesspatient whencompounding avoidingdosingerrors thereby ofLT4/LT3presentation that can beappliedinclinics, the study. Moreover, available weusedacommercially fairlyconstant throughout and TSHlevelsremained TSH levelswhileonLT4 orLT4/LT3 similar, were that Bydoingso,weobserved effect. any carryover eachother.from However, notsignificantlydifferent were thosescores baselinewithboththerapies. from improved scores Amongthosefouritems,onlyirritability questionnaire. that wouldhavebeenmissedbytheoriginalHRQOL that LT4/LT3 therapycouldinducesomecomplaints becausewepostulated insomnia, anxietyandirritability) We (palpitation, addedfouritemstothatquestionnaire not detectedbyouradaptedHRQOLquestionnaire. symptomsthatwere acute risecancausehyperthyroid the first4hoursafteringestionof LT4/LT3 (27).This T3within free amarkedriseby42%inserum determine in the first 4hourspost-dose, LT4/LT3 therapycan T3 free monotherapy leadstonochangeinserum Despite the fact that our study and previous meta- Despite thefactthatourstudyandprevious trialtoeliminate We a16-weekcrossover performed studyshowedthatLT4 aprevious Whereas Arch Metab. Endocrinol 2016;60/6 Arch Metab. Endocrinol 2016;60/6 2. 1. REFERENCES had andhavefullaccesstothestudydata. or decisiontosubmitthemanuscriptforpublication.Allauthors ofdata,writing the manuscript, data analysisandinterpretation instudydesign, S/A,Brazil,hadnorole capsules.Merck thyrox NovothyralandEu S/A,Brazil,provided Merck Disclosure: sing themanuscript. Acknowledgments: theauthorsthankMr. AngadJoharforrevi economy. thyroid polymorphisms ingenesaffecting combination LT4/LT3 inpatientswiththe treatment tothe evaluatetheresponse tofurther required andlongertrialsare prospective Furthermore, physiologicalendogenousT3production. normal ofT3,whichmimic forms of long-acting,slow-release studiesneedtoevaluatethe effect Future secretion. humanthyroidal innormal present triiodothyronine to oflevothyroxine do notmimictheproportion containanexcessof the latterand and liothyronine thatcontainlevothyroxine preparations commercial Similarly, profile. inadequate pharmacokinetic havean preparations available oralliothyronine Currently tolevothyroxine. addition ofliothyronine the from the possibilityofadverseeventsresulting Hence,thisshouldbebalanced against background. therapy (foundinsometrials)mayhaveagenetic ofsomepatientsforcombined alone. Thepreference overadministrationoflevothyroxine that approach trials inhumanshavenotshowntheadvantagesof therapy, plusliothyronine levothyroxine clinical (45-47). therapy inpatientswithhypothyroidism to inresponse whether polymorphismsplayarole TSHlevels(7).Todespite normal date,itisstillunclear symptoms hypothyroid sustained leading to set-point, TSH geneticallydetermined may alsoalterthecarrier’s phosphodiesterase 8B(PDE8B) the polymorphisms in T3(6,44).Other T4tofree ratiooffree than-normal ofthispolymorphismcouldbeahigher-the presence feedback.Asuggestive indicationto thyroid–pituitary aswellalterationsin in skeletalmuscleandthyroid, T4toT3activation (Th92Ala) isassociatedwithreduced therapy (43).OnesuchpolymorphismintheD2gene Even though animal studies support combined Even thoughanimalstudiessupport Celi FS,etal.Guidelines forthetreatmentofhypothyroidism: Jonklaas J, Bianco AC, Bauer AJ, BurmanKD,Cappola AR, Endocrinol (Oxf).2016;84(6):799-808. by theBritish Thyroid Committee.Association Executive Clin M, etal.Managementofprimary hypothyroidism: statement Okosieme O, Gilbert J, Abraham P, Boelaert K,Dayan C,Gurnell - - 20. 19. 18. 17. 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. thyroid extractcomparedwithlevothyroxine inthetreatment of Hoang TD, OlsenCH,Mai VQ, ClydePW, ShakirMK.Desiccated all athyreotic patients.PLoS One.2011;6:e22552. 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