www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Retro-
and
orthonasal
olfactory
function
in
relation
to
olfactory
bulb
volume
in
patients
with
hypogonadotrophic
hypogonadism
夽
Murat
Salihoglu
a,∗,
Onuralp
Kurt
a,
Seyid
Ahmet
Ay
b,
Kamil
Baskoy
b,
Aytug
Altundag
c,
Muzaffer
Saglam
d,
Ferhat
Deniz
b,
Hakan
Tekeli
e,
Arif
Yonem
b,
Thomas
Hummel
faGATAHaydarpasaTrainingHospital,DepartmentofOtorhinolaryngology,Istanbul,Turkey
bGATAHaydarpasaTrainingHospital,DepartmentofEndocrinologyandMetabolism,Istanbul,Turkey cIstanbulSurgicalHospital,DepartmentofOtorhinolaryngology,Istanbul,Turkey
dGATAHaydarpasaTrainingHospital,DepartmentofRadiology,Istanbul,Turkey eGATAHaydarpasaTrainingHospital,DepartmentofNeurology,Istanbul,Turkey
fUniversityofDresdenMedicalSchool,Smell&TasteInterdisciplinaCenter,DepartmentofOtorhinolaryngology,Dresden, Germany
Received26March2017;accepted31July2017 Availableonline24August2017
KEYWORDS Olfaction; Gustatoryfunction; Hypogonadotropic hypogonadism; Olfactorybulb Abstract
Introduction:Idiopathic hypogonadotrophic hypogonadism with an olfactory deficit is definedasKallmannsyndromeandisdistinctfromnormosmicidiopathichypogonadotrophic hypogonadism.
Objective:Becauseolfactoryperceptionnotonlyconsistsoforthonasallygainedimpressions butalsoinvolvesretronasalolfactoryfunction,inthisstudy wedecidedtocomprehensively evaluatebothretronasalandorthonasalolfactioninpatientswithidiopathichypogonadotrophic hypogonadism.
Methods:This case-controlstudy included31 controlsand45 idiopathichypogonadotrophic hypogonadismpatients. Allparticipantswhoseolfactoryandtastefunctions wereevaluated withorthonasalolfaction(discrimination,identificationandthreshold),retronasalolfaction, taste function and olfactory bulb volume measurement. The patients were separated into threegroupsaccordingtoorthonasalolfaction:anosmicidiopathichypogonadotrophic hypog-onadism, hyposmic idiopathic hypogonadotrophic hypogonadism and normosmic idiopathic hypogonadotrophichypogonadism.
夽 Pleasecitethisarticleas:SalihogluM,KurtO,AySA,BaskoyK,AltundagA,SaglamM,etal.Retro-andorthonasalolfactoryfunctionin
relationtoolfactorybulbvolumeinpatientswithhypogonadotrophichypogonadism.BrazJOtorhinolaryngol.2018;84:630---37.
∗Correspondingauthor.
E-mail:[email protected](M.Salihoglu).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. https://doi.org/10.1016/j.bjorl.2017.07.009
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
Results:Discrimination,identificationandthresholdscoresofpatientswithKallmannsyndrome weresignificantlylowerthancontrols.Thresholdscoresofpatientswithnormosmicidiopathic hypogonadotrophic hypogonadism. were significantlylower than thoseof controls, but dis-criminationandidentificationscoreswerenotsignificantlydifferent.Retronasalolfactionwas reducedonlyintheanosmicidiopathichypogonadotrophichypogonadismgroupcomparedto controls. Identificationofbitter,sweet, sour,andsaltytasteswasnotsignificantlydifferent whencomparedbetweentheanosmic,hyposmic,andnormosmicidiopathichypogonadotrophic hypogonadismgroupsandcontrols.Olfactorybulbvolumewaslowerbilaterallyinallpatient groups whencomparedwithcontrols.The olfactorybulbvolumeofbothsideswasfound to besignificantlycorrelatedwiththreshold,discriminationandidentificationscoresinidiopathic hypogonadotrophichypogonadismpatients.
Conclusion: 1)Therewerenosignificantdifferencesingustatoryfunctionbetweencontrolsand idiopathichypogonadotrophichypogonadismpatients;2)retronasalolfactionwasreducedonly inanosmicpatientsbutnotinorthonasallyhyposmicparticipants,possiblyindicatingpresence ofeffectivecompensatorymechanisms;3)olfactorybulbvolumeswerehighlycorrelatedwith olfactionscoresinthehypogonadotrophichypogonadismgroup.Thecurrentresultsindicatea continuumfromanosmiatonormosmiainidiopathichypogonadotrophichypogonadismpatients. © 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE
Olfato;
Func¸ãogustativa; Hipogonadismo hipogonadotrófico; Bulboolfatório
Func¸ãoolfativaretroeortonasalemrelac¸ãoaovolumedobulboolfatórioem pacientescomhipogonadismohipogonadotrófico
Resumo
Introduc¸ão: Ohipogonadismohipogonadotróficoidiopáticocomdéficitolfatórioédefinidocom síndromedeKallmanneédistintodehipogonadismohipogonadotróficoidiopáticonormósmico. Objetivo: Pelo fato de a percepc¸ão olfativa não apenas consistir em impressões obtidas ortonasalmente,mastambémenvolverafunc¸ãoolfativaretronasal,nesteestudodecidimos avaliardemaneiraabrangenteoolfatoretronasaleortonasalempacientescomhipogonadismo hipogonadotróficoidiopático.
Método: Este estudo caso-controle incluiu 31 controles e45 pacientescom hipogonadismo hipogonadotrófico idiopático. Todosos participantes tiveram asfunc¸ões olfativas ede pal-adaravaliadascomolfac¸ãoortonasal(discriminac¸ão,identificac¸ãoelimiar),olfac¸ãoretronasal, func¸ãodopaladaremedidadovolumedobulboolfatório.Ospacientesforamseparadosem três gruposde acordocomaolfac¸ãoortonasal: hipogonadismo hipogonadotrófico idiopático anósmico, hipogonadismo hipogonadotrófico idiopático hipósmico e hipogonadismo hipogo-nadotróficoidiopáticonormósmico.
Resultados: Osescores de discriminac¸ão,identificac¸ão e limiarde pacientescomsíndrome deKallmannforamsignificativamentemenoresdoqueoscontroles. Osescoresdoslimiares de pacientes com hipogonadismo hipogonadotrófico idiopático foram significativamente menores do que os dos controles, mas os escores de discriminac¸ão e identificac¸ão não foram significativamente diferentes. A olfac¸ão retronasal foi reduzida apenas no grupo hipogonadismo hipogonadotrófico idiopático anósmico em comparac¸ão comos controles. A identificac¸ãodegostosamargos,doces,azedosesalgadosnãofoisignificativamentediferente quandocomparadaentreosgruposecontrolesdehipogonadismohipogonadotróficoidiopático anósmicos,hipósmicosenormósmicos.Ovolumedobulboolfatóriofoimenorbilateralmente em todos os grupos depacientesquando comparadocom oscontroles. Ovolume do bulbo olfatório deambos os lados foisignificativamente correlacionadocomosescores delimiar, discriminac¸ão,identificac¸ãoempacientescomhipogonadismohipogonadotróficoidiopático. Conclusão:1) Não houve diferenc¸as significativas na func¸ão gustativa entre controles e pacientescomhipogonadismohipogonadotróficoidiopático;2)Aolfac¸ãoretronasalfoireduzida apenasempacientesanosmáticos,masnãoemparticipantesortonasalmentehipósmicos, pos-sivelmenteindicoupresenc¸ademecanismoscompensatóriosefetivos;3)Osvolumesdobulbo olfatórioforamaltamentecorrelacionadoscomosescoresdeolfac¸ãonogrupohipogonadismo hipogonadotrófico. Osresultados atuais indicam um contínuo da anosmia à normosmia em pacientescomhipogonadismohipogonadotróficoidiopático.
© 2017 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
Pulsatile secretion of gonadotropin releasing hormone (GnRH)fromthehypothalamuscauses releaseofthe pitu-itary gonadotropins,luteinizing hormone(LH) andfollicle stimulating hormone (FSH). Idiopathic hypogonadotrophic hypogonadism (IHH) refers to an evident hypogonadism phenotype with low levels of serum gonadotropins with-out anatomic problems in the hypothalamo-pituitary axis.1 Prevalence of IHH is estimated to be between 1/4000---1/10,000inmalesand1/40,000infemales.2
GnRH-secretingneuronsandolfactoryneurons sharean embryologicmigrationpathway. These twoneuron groups originate from the embryonic olfactory placode. Axons fromolfactory receptor neurons andGnRH-secreting neu-rons migrate through the cribriform plate, where axons from olfactory receptor neurons synapse in the olfactory bulb (OB). Further migration of GnRH-secreting neurons targets the mediobasal hypothalamus, where functional pulsatile GnRH secretion occurs.3 Abnormal development of the olfactory placode leads to improper development of the OB and olfactory sulcus aplasia or hypoplasia of the OB and olfactory tracts is frequently associated with anosmia.
Hypogonadotrophichypogonadism(HH)withanolfactory deficitisdefinedasKallmannsyndrome(KS)andisdistinct fromnormosmic HH.Howeverbothdiseases couldsharea commongeneticetiology.1 Older studies have shown that deletionoftheKAL1geneisrelatedtoKS.4,5Thisdeletion causes defectsin migrationof GnRH-secreting neurons in embryogenesis.Similarly,deletionsingenesfunctioningon the fibroblast growth factor signaling pathway (FGF8 and FGFR1)maycauseKS.KSmayalsoresultfromdeletionsin genesfunctioningonthe PROK2signalingpathway(PROK2 andPROKR2)andCHD7pathway.Thesegenedeletionscan also be seen in normosmic HH patients.3 Genes affect-ing secretion of GnRH (GNRHR, TAC3, KISS1, and KISS1R) havealsobeen foundinbothhyposmicandnormosmicHH patients.Thesestudiesindicatethatnormosmic,hyposmic, andanosmic HH have their basis in the same pathogene-sis,butdifferentexpressionsofrelatedgenescauseclinical variances.
Most previous studies on HH patients have used various psychophysiologic methods to assess olfactory function.3,6,7 Because olfactory perception not only con-sists of orthonasally gained impressions but also involves retronasal olfactory function, we decided to comprehen-sively evaluate both retronasal and orthonasal olfaction. Possible differences in gustatory function of HH patients werealsoinvestigated.
Methods
The present investigation wasdesigned as a case-control studyandwasapprovedbytheClinicalResearchEthics Com-mittee of Haydarpasa Training Hospital. All subjects gave writteninformedconsent.Hypogonadotropichypogonadism patients wererecruited from ourinstitution’s endocrinol-ogydepartmentandwereselectedconsecutivelyforfurther evaluation. Serumfree testosterone (ng/dL), serumtotal testosterone(ng/dL),serumsexhormonebindingglobulin (nmoL/L),FSH(mIU/mL),andLH(mIU/mL)weremeasured. Bilateraltestisvolumes(mL) wereevaluatedusingscrotal ultrasonography.Thestudygroupconsistedofmenwiththe following characteristics: 18 years or older, clinical signs and symptoms of hypogonadism, serum testosterone lev-elsunder100ng/dL,lowornormallevelsofgonadotropins,
normalserumlevelsof otheranteriorpituitary hormones, and absence of anatomic anomaly in the hypothalamic and pituitary areas confirmed with magnetic resonance imaging.
Orthonasalolfactorytesting
Psychophysical olfactory testing was conducted using the commerciallyavailableSniffin’Sticktestkit,inwhichodors arepresented via felt-tip pens.8---10 Afteropening the pen cap,each odorantwassmelledbythepatientfor approx-imately 3s. Olfactorytests weredividedintothreeparts. The first part was the threshold test (T), during which increasingconcentrationsofphenyl-ethylalcoholwere pre-sented. The second part wasthe odor discriminationtest (D), consisting of16 triplets withtwodifferent odorsper triplet.ThethirdpartwasanodorIdentificationtest(I)using 16 commonodors;participants wereasked tochoose one offourchoicestoidentifyeachparticularodor.Eachtest’s maximumscorewas16,andthemaximumcompositescore was48 (TDIscore: total ofthreshold, discrimination,and identification scores). Normal values for the TDI compo-sitescoreare>30.5, witha cut-offbetween anosmiaand hyposmiaat16.5.11AccordingtotheirTDIscores,study par-ticipantswerediagnosedasfunctionallyanosmic(hereafter called‘‘anosmic’’),hyposmic,ornormosmic.
Retronasalolfactorytesting
Forretronasalolfactory testing, astandardized, validated test wasused.12 The test includes 20 items and is based ontheidentificationofodorizedpowdersorgranules(e.g., groundinstantcoffee,cinnamon,ormushrooms)presented totheoralcavity.Thesubstanceswereappliedtothe mid-lineofthetonguewithdisposableplasticsticks.Participants were free to sample as much stimulant as necessary for identification.Thisapproachminimizedtheproblemof stan-dardizingtheareaofstimulationanddifferencesinsizesof participants’tonguesandoralcavities.Inatypicaltrial,the experimenterplacedapproximately0.05gofthetest sub-stance on themiddle of the tongue. Afteradministration of eachpowder,participants rinsedtheirmouthswithtap water. Theprocedure wasself-timed.Each substancewas identifiedbymeansofaforced-choiceprocedure inwhich theparticipantselectedoneoutof fourverbalitems pre-sentedtogetherwitheachodor.Thetestresultwasthesum scoreofthecorrectlyidentifiedstimuli(maximumscore20). Tastefunctiontesting
Fourbasictastantswithfourconcentrations wereusedfor tasteevaluation.Eachtastantwasadsorbedonfilterpaper stripsateachconcentration(sweet:0.4,0.2,0.1,0.05g/mL sucrose;sour:0.3,0.165,0.09,0.05g/mLcitricacid;salty: 0.25,0.1,0.04,0.016g/mLsodiumchloride;bitter:0.006, 0.0024,0.0009,0.0004g/mLquininehydrochloride).These impregnatedfilterpaperstripswereplacedontheanterior tongue.Beforeeveryadministrationthemouth wasrinsed withdistilledwater.Taste qualitieswereappliedina ran-domized fashionbut inincreasing orderofintensity. Each participantwastestedwitheachtasteatevery concentra-tionforatotalof16trials.Patientswereaskedtoidentify thetastefromalistcontaining‘‘sweet,’’‘‘sour,’’‘‘salty,’’ and ‘‘bitter’’ (forced multiple choice). Correct answers wereaddedupforatastescore‘‘(maximumscore16).13
Olfactorybulbmeasurement
Examinationswere performed using a 1.5Tmagnetic res-onance imaging(MRI) system (Avanto; Siemens,Erlangen, Germany)witha12channelheadcoil.Sectionswere angu-lated perpendicularly to theanterior base of the skullor cribriform plate. We used three-dimensional T2 sampling perfectionwithapplicationofoptimizedcontrastusing dif-ferentflipangleevolutions(SPACE)coveringtheanteriorand middlesegmentsofthebaseoftheskull.Parametersofthe three-dimensionalT2SPACEsequencewereasfollows:echo time,224ms;repetitiontime,1440ms;bandwidth,349Hz perpixel;fieldofview,190×190;matrix,520×512;slice thickness,1mm;nointerslicegap.
SyngoMMWPsoftware(SiemensMedicalSolutions, Forch-heim,Germany)wasusedtodeterminethevolumeof the rightandleftOBs.Volumemeasurementswereperformed byanexperiencedradiologistblindedtotheclinical diagno-sis.Beforevolumetricmeasurements, amidsagittalimage of the OBs was chosen and the length of both OBs was measured. Afterward,measurementsofthe right andleft olfactorybulbvolumes(OBV)wereperformedthrough man-ualsegmentationofthecoronalslicesbyplanimetricmanual contouring(surfaceinpixels),thenallpixelswereaddedand multipliedbythex,y,andzaxes(0.36×0.37×1number ofpixels)toobtainavolumeincubicmillimeters.14
Statisticalanalysis
DataanalysiswasperformedusingSPSSversion21.0(SPSS Inc.,Chicago,IL,USA). Thenormaldistributionof consid-ered variables was first evaluatedusing the Shapiro---Wilk test.Dataarepresentedasmeans±standarddeviationsfor continuous variables and asthe number of cases for cat-egorical variables. In comparingtwo independentgroups, the Student’s t-test was used if the continuous variables were normally distributed, and the Mann---WhitneyU test was used for non-normally distributed continuous varia-bles. Categorical variables (proportions) were compared usingtheChi-Squaretest.Patientsweredividedintothree groupsaccording totheirSniffin’Stickscores(normosmia,
hyposmia,andanosmia).Inaddition,toexploreretronasal olfactory sensitivity in relation to group, age, gender, cigarette smoking, and alcohol consumption, data were submittedtoanalysisof variance usingthe generallinear modelwithBonferroniposthoccomparisons.Correlational analyseswerecalculatedaccordingtoPearson’scorrelation coefficient.Thelevelofsignificancewassetatp<0.05.
Results
Ourstudy included 31 controls and 45 IHH patients. The groupsdid notdiffersignificantlyin terms ofage, sex, or educationlevel.As expected, theIHH patients hadlower levelsofserumfreetestosterone,totalserumtestosterone, FSH,LH,andlowerrightandlefttestisvolumes(Table1).
Thepatientswereseparatedintothreegroupsaccording to their TDI scores: anosmic IHH group (n=14), hypos-mic IHH group (n=12), and normosmic IHH group (nIHH,
n=19).Olfactory(orthonasalandretronasal)andtastetest resultsforpatientsandcontrolsareshowninTable2. Dis-crimination,identification,andthresholdscoresofpatients with KS were significantly lower than those of controls. Threshold scores of patients with nIHH were significan-tly lower than those of controls, but discrimination and identificationscores were notsignificantly different(odor threshold:7.82±0.42 vs.8.69±1.21, p=0.01; TDIscore: 34.24±1.41 vs. 35.66±2.09, p=0.01). Retronasal olfac-tionwasreducedonlyintheanosmicIHH groupcompared to controls (8.50±3.01 vs. 16.84±2.18, p=0.001). The orthonasally hyposmic and nIHH groups were similar in retronasal olfaction when compared with controls. Iden-tification of bitter, sweet, sour, and salty tastes was not significantly different when compared between the anos-mic,hyposmic,andnormosmicIHHgroupsandcontrols.
Olfactorybulbswerenotseeninfourpatientsinthe anos-micgroup.OBVwaslowerbilaterallyin allpatientgroups whencomparedwithcontrols.However,therightOBVwas notstatisticallydifferentbetweenthenormosmicIHHgroup andthecontrolgroup(Table3).
TheOBVofbothsideswasfoundtobesignificantly cor-relatedwithTDI scores in IHH patients (right OBV-TDI, r:
Table1 Demographic,clinicalandlaboratorycharacteristicsofpatientsandcontrols.a
Controls(n=31) IHH(n=45) p-value
Age(years) 24.19±3.89 23.64±3.46 0.581 Education (years) 10.03±2.80 9.84±2.70 0.48 Serumfree testosterone (ng/dL) 3.54±11.17 1.79±6.26 <0.001 Serumtotal testosterone (ng/dL) 113.33±310.06 69.08±176.15 <0.001 SHBG(nmoL/L) 27.93±10.82 42.82±27.23 0.018 FSH(mIU/mL) 3.53±1.56 0.84±1.24 <0.001 LH(mIU/mL) 4.28±2.01 2.41±13.82 <0.001 Right,testis volume(mL) 16.02±1.49 2.07±1.63 <0.001 Left,testis volume(mL) 16.11±1.32 1.99±1.44 <0.001
IHH,idiopathichypogonadotropichypogonadism;SHBG,sexhormonebindingglobulin;FSH,folliclestimulatinghormone;LH,luteinizing hormone;p-value,controlsvs.IHH.Thevaluesmarkedinboldarestatisticallysignificant(p<0.05).
Table2 Olfactoryandtastetestresultsofpatientsandcontrols. Test (mean±SD) Anosmia (n=14)(KS) Hyposmia (n=12)(KS) Normosmia (n=19) (nIHH) Controls (n=31) P1 P2 P3 P4 P5 P6 Threshold 2.57±0.72 6.54±0.82 7.82±0.42 8.69±1.21 <0.001 <0.001 0.01 <0.001 <0.001 <0.001 Discrimination 3.71±0.91 8±0.74 12.89±0.88 13.45±1.06 <0.001 <0.001 0.07 <0.001 <0.001 <0.001 Identification 4.93±1.14 9.42±0.67 13.58 ±0.84 13.52 ±1 <0.001 <0.001 0.75 <0.001 <0.001 <0.001 TDI 11.21±2.46 23.96±1.62 34.24±1.41 35.66±2.09 <0.001 <0.001 0.01 <0.001 <0.001 <0.001 Bitter 3.36±0.5 3.42±0.51 3.42±0.51 3.42±0.5 0.70 0.99 0.99 0.76 0.72 0.98 Sweet 3.29±0.61 3.25±0.75 3.32±0.67 3.29±0.64 0.95 0.93 0.87 0.98 0.84 0.84 Salt 3.36±0.63 3.33±0.65 3.37±0.68 3.35±0.66 0.97 0.89 0.92 0.91 0.90 0.84 Sour 3.29±0.61 3.25±0.45 3.32±0.58 3.32±0.54 0.89 0.62 1.00 0.78 0.90 0.66 Totaltaste 13.29±1.82 13.25±1.86 13.42±1.98 13.39±2.01 0.94 0.86 0.99 0.94 0.93 0.80 Retronasal 8.50±3.01 16.33±1.72 16.47±2.44 16.84±2.18 <0.001 0.21 0.62 <0.001 <0.001 0.46 KS,Kallmannsyndrome;nIHH,normosmicidiopathichypogonadotropichypogonadism;SD,standarddeviations;P1value,anosmiavs.
controls;P2 value,hyposmiavs.controls;P3 value,normosmiavs.controls; P4value,anosmiavs.hyposmia;P5value,anosmiavs.
normosmia;P6value,hyposmiavs.normosmia.Thevaluesmarkedinboldarestatisticallysignificant(p<0.05).
Table3 MRIMeasurementsaofpatientsandcontrols.
OBV (mm3) Anosmia (n=14)(KS) Hyposmia (n=12)(KS) Normosmia (n=19) (nIHH) Controls (n=31) P1 P2 P3 P4 P5 P6 Right 10.79±10.09 38.88±13.43 56.64±8.91 65.52±16.75 <0.001 <0.001 0.25 <0.001 <0.001 <0.001 Left 10.43±10.13 39.12±13.98 56.07±9.15 66.61±16.06 <0.001 <0.001 0.03 <0.001 <0.001 <0.001
MRI,magneticresonanceimaging;KS,Kallmannsyndrome;nIHH,normosmicidiopathichypogonadotropichypogonadism;SD,standard deviations;P1value,anosmiavs.controls;P2value,hyposmiavs.controls;P3value,normosmiavs.controls;P4 value,anosmiavs. hyposmia;P5value,anosmiavs.normosmia;P6value,hyposmiavs.normosmia.Thevaluesmarkedinboldarestatisticallysignificant (p<0.05).
aValuesarethemeanandSD(standarddeviations).
Table4 CorrelationsbetweenOBVandTDIscoresinIHH.
Variable IHHgroup(n=45)
ra pa
RightOBV-TDI 0.934 <0.001
LeftOBV-TDI 0.928 <0.001
OBV,olfactorybulbvolume;T,threshold;D,discrimination; I, identification;IHH,idiopathichypogonadotropichypogonadism. Thevaluesmarkedinboldarestatisticallysignificant(p<0.05).
aPearsoncorrelationanalysis.
0.934,p<0.001;leftOBV-TDI,r:0.928,p<0.001)(Table4) (Figs.1and2).Serumindicatorsofhypogonadism,suchas FSH,LH,serumfreetestosterone,serumtotaltestosterone, andTDIcorrelation,wereinvestigated;nosignificant corre-lationswerefound.
Discussion
Olfaction has been studied many times in HHpatients. A differenceinthesenseofolfactionisthekeyfindingto dis-tinguish IHH from KS.15 Only a limited number of studies investigatingtasteinIHHcouldbefoundintheliterature.6,16 Thisstudy is oneof thefirststudies evaluatingretronasal andorthonasalolfactionandtaste assessment togetherin HHpatients.Categorizationofpatientsasanosmic, hypos-mic,or normosmic wasmade according to TDI scores for the Sniffin’ Stick test.11 Each group was compared with
controlsregardingodorthreshold,odordiscrimination,and identification of odors. Normosmics had lower threshold and TDI scores. Significantly lower olfactory scores even in normosmic HH patients compared to normosmic con-trols could be due to gradual expression of related HH genes.
Identificationofbitter,salty,sweet,andsourtasteswas tested between thecontrol andstudy groups. Taste func-tion was not significantly different between controls and anyofthethreeHHsubgroups.Rosetal.investigatedsmell andtasteinTurnerSyndromepatients;theyfoundolfactory impairmentinthestudygroupbutnosignificantdifference for taste functions.17 The authors explainedthe olfactory impairmentwithgeneticreasonsandclaimedthathormonal changeshadnoeffectongustatoryfunction.Thatis possi-blyisthereasonwhytastefunctionwasverysimilarinthe groupsstudied.
Flavor is a complex function, closely related to taste and to olfactory integrity, which ultimately enables food recognition, and enjoyment of food.6,18 Retronasal olfac-tion was investigated in our study and was found to be significantly lower in theanosmic group in comparisonto controls, butnosignificant differencewasfound between the hyposmic group and controls. Landis etal. compared orthonasalandretronasalolfactionandfoundthata signifi-cantproportionoforthonasallyanosmicpatientshadnormal functionofretronasalolfaction.19Authorexplainedthe dif-ference withdifferentvulnerability levelsof anteriorand posteriorolfactory epitheliumtodamageordifferent pro-cessionoforthonasalandretronasalevocationofolfaction. Orthonasal and retronasal olfactory informationhas been shown to be differently processed on a cerebral level.20
TDI 35.00 35.00 30.00 30.00 25.00 25.00 20.00 20.00 15.00 15.00 10.00 10.00 5.00 5.00 0.00 20.00 40.00 60.00 0.00 20.00 40.00 60.00
Right OBV Left OBV
Groups: IHH Groups: IHH
TDI
Observed Linear
Figure1 ThecorrelationbetweenOBV(olfactorybulbvolume)andTDI(T,threshold;D,discrimination;I,identification)scores inIHH(idiopathichypogonadotropichypogonadism)patients.
Figure2 Coronalthree-dimensionT2STIR(shorttauinversionrecovery)SPACE(samplingperfectionwithapplication-optimized contrastsusingdifferentflipangleevolution)imagesshowolfactorybulbsofanosmia(A),hyposmia(B),normosmia(C),andcontrol (D).
Becausetheretronasaltestalsoincludedgustatory stimula-tion(e.g.,sweetvanillasugar,saltycelerysalt,andbitter coffeepowder),19,20ourresultsmayindicatethathyposmic patientswereabletoutilizetheirgustatorysystemtosuch an extent that their scores were comparableto controls. ThismayindicatethathyposmicHHpatientsdevelopsome compensatorymechanismstomakeupfortheirdecreased olfactorysensitivity.
Patientsexperiencingolfactory losscomplainmainlyof flavordistortionandinabilitytoidentifyfood.However,KS patientsgenerallydonot complainof flavordysfunctions. Itisclaimedthatcongenitalanosmics mightlearnto con-centrateonotheraspectsof foods tocompensatefor the lackofolfaction.6Hasanetal.comparedfourKSpatientsto fourcontrols usingpsychophysicalsmell tests, electrogus-tometry,andtestsforflavorperception.16Theyfoundlower smellscoreswithnormaltasteinKSpatients,asexpected. However,flavorperception is not typicallyacomplaint in KS patients. Valle etal. studied 36patients withIHH and found that 41.6% were hyposmicor anosmic.1 Hypoplasia or aplasia of theolfactory bulbs wasfound in 75% of the hyposmic/anosmicgroupbutinonly7.6%ofthenormosmic group.Independentofolfactorystatus,midlinedefectsand neurosensorialhearinglossoccuratahighfrequencyinIHH patients,supportingtheideathatKSandnormosmicHHare indifferentpositionsonthespectrumofthesame develop-mentaldisease.
Severalstudiesalreadylookedatpossiblepredictionof olfactoryfunctionbasedonOBV.21WemeasuredOBVonboth sidesandsearchedforarelationbetweenOBVandolfactory function.Olfactorybulbvolumesweresignificantlysmaller inall threestudy groups comparedwithcontrols, andwe foundgoodagreementbetweenOBVandTDIscoresinIHH patients.Theexact reasonfor thedecreased OBVin nIHH isnotknown.Jagtapetal.foundahighprevalenceofMRI abnormalities in nIHH patients, along with increased fre-quencyofOBVhypoplasia,bilateralcerebellaratrophy,cleft lip,andcleftpalate.22 Theypostulatedthatthesepatients may have subtle neuroanatomical olfactory abnormalities thatmaynotcompromiseolfactoryapparatusfunction(at leastnotatayoungerage).Geneticstudiesofthesepatients would yield valuable information and may provide some cluesregardingthereasonsforthelowerOBVinnIHH.Anik etal.studiedolfactorybulbvolumesinsixKSpatientsand claimedthatMRIimagingoftheolfactorybulbswasstrongly correlatedwitholfactometryresults.23Hudsonetal.showed thattheolfactoryfunctionscoresofapparentlynormosmic subjectslaywithinthelowerendofthenormalrangesfor controlsubjects,arguingforasubtleolfactoryabnormality withinthissubset.24Likewise,Vogletal.demonstratedthat asmallpercentageofapparentlynIHHsubjectshad abnor-malolfactorybulbs,andtheirsmelltestswereinthelower rangeofthenormaldistribution.25
Conclusion
The current study provided the following major results: 1)therewerenosignificant differencesingustatory func-tion between controls and IHH patients; 2) retronasal olfaction was reduced only in anosmic patients but not in orthonasally hyposmic participants, possibly indicat-ing presence of effective compensatory mechanisms;and 3) olfactory bulb volumes were highly correlated with olfaction scores in the HH group. The current results indicate a continuum from anosmia tonormosmia in IHH patients.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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