Arch Metab. Endocrinol 2019;63/1 andlymphoplasmacytic. xanthomatous, IgG4-related classified aslympho hypophysitisis diseases(5,6). Primary inflammatory neighboring tissuelesionsormultisystemic from hypophysitis canbeoriginated hypophysitis. Secondary and secondary gland is categorized as primary pituitary pathophysiological mechanism,theinflammationof 9 million(2-4).Basedonhistologicalappearanceand annual incidencerateofonecaseper with areported diseases, 0.24%-0.88%ofallpituitary for approximately (1). Hypophysitisisanuncommondiseaseaccounting deficiencyorpanhypopituitarism hormone pituitary inisolatedanteriorandposterior cells. Itmayalsoresult gland ofpituitary inthedestruction lesions andresult a significantcondition,which canmimictheother sellar F INTRO hypophysitis;;diabetesinsipidus hypophysitis;secondary Primary Keywords ofthedisease. be seeninthecourse radiological and endocrinological aspects. The different patterns of pituitary hormone deficiencies may should beconsideredinthedifferential diagnosisofsellarmasses.Itcanmimicpituitaryadenomasin and thickened pituitarystalkwerethemostcommonradiologicalalterations. had granulomatousandonexanthogranulomatoustypes.Contrastenhancementheterogeneous (17%) wereseenamongpatients. According tohistopathologicalforms,fourhadlymphocytic,seven nonendocrine symptoms. Anterior pituitaryhormonedeficiencies(63.7%)and/ordiabetesinsipidus pituitary operationduetoadenoma.Headache (67%)andvisualproblems(33%)werethemostfrequent Diagnosis ofhypophysitis was madeafter pituitarybiopsyinfourpatients,andeightpatientsafter were evaluated. The characteristic featuresofourpatientstendedtobepredominantlyfemaleandyoung. cases ofthepituitarydisease. Twelve patients(ninefemalesandthreemales),agesbetween17-61 years, and follow-up periodswereevaluated. Demographical data,clinicalfeatures,endocrinologicaldysfunction,imagingfindings,treatmentcourses with pituitary diseases between 2010 and 2017. Twelve patients with hypophysitis were identified. features. We aimtopresent our patientswithhypophysitis and compare clinical, laboratory and radiological Main formsarehistologicallyclassifiedaslymphocytic,granulomatous,IgG4relatedandxanthomatous. for approximately 0.24%-0.88%ofallpituitarydiseases. ofhypophysitisThe naturalcourse isvariable. Objective: ABSTRACT NasirogluNarin Imga a single-center experience different typesofhypophysitis: characteristics ofpatientswith Clinical andhormonal of the is known as hypophysitis. It is of the pituitary inflammation andcellularinfiltration ocal ordiffuse DUCTION Subjects andmethods: The inflammationofthepituitaryglandisknownas hypophysitis. Itisararediseaseaccounting cytic (autoimmune), granulomatous, cytic (autoimmune),granulomatous, 1 , Ali Erdem Yildirim,Ali We reviewedourdatabaseof1.293 retrospectively patientsdiagnosed Arch EndocrinolMetab. 2019;63(1):47-52 Results: The frequencyofhypophysitis was found0.93%inall 2 , OzdenOzdemirBaser at Ankara Numune Education and Research Hospital Hospital at AnkaraNumune EducationandResearch massdiseasefollowed patients diagnosedwithapituitary We our databaseof1.293 reviewed retrospectively SUBJECTS ANDMETHODS followed upinasingle-center. courses oftwelvepatientswithhypophysitisthat andendocrinologic data, and treatment neurologic orpanhypophysitis(7). infundibuloneurohypophysitis classifiedintoadenohypophysitis, lesions are to the anatomical location, hypophysitis According variable. hypophysitisare natural coursesofsecondary gland.Causesand histiocytes intheanteriorpituitary hypophysitis is characterized by infiltration of foamy and xanthogranulomatous hypophysitis. Xanthomatous calledlymphogranulomatous It alsohasmixedforms In thisstudy, clinicalfeatures, weaimtopresent Conclusion: 1 , DilekBerker Hypophysitis 1 Neurosurgery, Ankara, TurkeyNeurosurgery, Research Departmentof Hospital Ankara NumuneEducationand 2 Ankara, Turkey Metabolism, of Endocrinologyand Research Department Hospital Ankara NumuneEducationand 1 DOI: 10.20945/2359-3997000000102: Accepted onOct/5/2018 Received onMay/16/2017 [email protected] Ankara, Turkey– 06100 Department ofEndocrinology and Research Hospital Ankara NumuneEducation Narin NasirogluImga Correspondence to: Saglik BilimleriUniversity, Saglik BilimleriUniversity, original article article original 47

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 48 Values are expressedasmean(range), medianor number(%). LyHy: lymphocytichypophysitis;GrHy: granulomatous hypophysitis;XantgrHy: xanthogranulomatoushypophysitisBMI: bodymassindex. Table 1. level<3μg/dLanda cortisol diagnosed ifamorning insufficiency. patients withadrenal insufficiency Adrenal therapywasgivento replacement testing. Steroid the diagnosisofGHDwasmadewithoutbiochemical deficits hormone otherdocumentedpituitary and three test. Inpatientswithclear-cut characteristicsofGHD diagnosed bytheinsulintolerancetest(ITT)orglucagon deficiency(GHD)was hormone evaluated.Growth were analysesofallthesecases sodium levels.Thelaboratory osmolalityandplasma toplasmaandurinary according glandwasevaluatedwithclinicalsymptoms pituitary evaluated. Inaddition,thefunctionofposterior levels, were testosterone and estradiolortotalfree (LH) (FSH),luteinizinghormone stimulating hormone follicle- (GH),IGF-1,, hormone T3, growth T4,free (TSH),free stimulatinghormone thyrotropin gland, such as ACTH, basal cortisol, the pituitary to related plasma concentrations of hormones andpost-treatment panhypophysitis. Pretreatment or adenohypophysitis, infundibuloneurohypophysitis classifiedinto the anatomicallocation,caseswere hypophysitis.By orsecondary divided intoprimary tounderlyingdisease,theywere After that,according (H&E) stainingandimmunohistochemicalstaining. exposedtohematoxylinandeosin all specimenswere (TSS). After TSS, surgery transsphenoidal microscopic study(8).Allpatientsunderwent described inaprevious as the volume=1/2xlengthwidthheightformula, by gland volume was measured gland. Pituitary pituitary MRI images taken of their patients had initial and control allevaluated.All courses andfollow-upperiodwere gland,treatment imaging (MRI)findingsofthepituitary endocrinological dysfunction,magneticresonance data,clinicalfeatures, Demographical andlaboratory includedtothestudy. ofhypophysitiswere confirmation Out of1.293patients,12patientswhohadhistological ofEndocrinologybetween2010and2017. Department Clinical characteristics ofhypophysitis Pituitary glandvolumeafterfollow-up(mm Pituitary glandvolumebaseline(mm Pituitary BMI Gender Mean age, y Male Female Demographical dataofpatientsaccordingtothosesubgroupedwithhistological diagnosis 3 ) 3 ) 1,009 ±2,225 6,115 ±8,873 26.8 ±2.6 44 (17-61) 3 (25%) 9 (75%) All Demographical characteristics of 12 cases and pituitary Demographical characteristicsof12casesandpituitary 6to98months(median: 28months). time rangedfrom disease.Thefollow-up our 1.293caseswithpituitary ofhypophysitiswasfound 0.9%among The frequency RESULTS thestudy. Hospitalapproved Education andResearch year. The local ethical committee of Ankara Numune sixmonthsafterthesurgery, followedbyevery every follow-up inthefirstyear, evaluated thepatientswere with a low, or mildly elevated TSH (9). For the normal, rangeinconcurrence reference level belowthelaboratory T4 byfree diagnosisconfirmed Central hypothyroidism insufficiency.μ/dL at30or60minutesexcludedadrenal levels>18.1 dose ACTHstimulationtests.Peakcortisol wasassessedusingITTorstandard- insufficiency adrenal levelsbetween3-15μg/dL diagnosis. Incaseofcortisol insufficiency level > 15 μg/dL likely excluded an adrenal changes were observed radiological image pattern. radiologicalimagepattern. observed changes were to1,009±2,225mm was decreased glandvolume follow-up period,themeanpituitary was foundtobe6,115±8,873mm glandvolumeatpresentation gland. Meanpituitary pituitary andhomogeneousorheterogeneous turcica gland,athickenedstalk,expansionofsella pituitary symmetricenlargement ofthe diffuse MRI scanswere: suggestinghypophysitis onthe (27 years).Thefeatures case ofxanthogranulomatoushypophysitiswasyounger and granulomatoushypophysitis;ontheotherhand,a andfifthdecadesinlymphocytic was betweenfourth the puerperiumperiod.Themeanageatpresentation orin notpregnant of diagnosisfemalepatientswere evaluated. Atthetime 61 years(meanage:44)were males)withagesrangedbetween 17and and three summarized inTable 1.Twelve patients(ninefemales are and control gland volumeatthepresentation 4,415 ±3,867 8,169 ±7,717 LyHy (n=4) 26.2 ±2.4 40 (17-55) 1 (%25) 3 (75%) 5,564 ±10,403 GrHy (n=7) 174 ±315 26.9 ±2.9 48 (28-61) 1 (%14) 6 (%86) Arch Metab. Endocrinol 2019;63/1 3 3 . However, inthe . No other major . Noothermajor XantgrHy (n=1) 1 (100%) 1,755 40.5 29.1 27 - Arch Metab. Endocrinol 2019;63/1 LyHy: lymphocytichypophysitis; GrHy: granulomatoushypophysitis;XantgrHy: xanthogranulomatoushypophysitis; GH: growthhormone. Table 2. Panhypopituitarism wasseen seen invariabledegrees. glanddysfunctionwas inallcases.Pituitary performed identified in patients. Endocrinological evaluation was contrast enhancement (58%) were and heterogeneous stalk(41%) optic chiasm(33%)thickenedpituitary ofthe glandswelling (33%), compression Pituitary afewdaysto over fiveyears. of symptomsvariedfrom andimpotence.Theduration secondary (67%) andvisualfielddefects(33%),followedby headache non-endocrinesymptoms were predominant hypophysitis wasgiveninTable 2. tohistologicaldiagnosisof of patientsaccording characteristics, radiologicalandendocrinologicfindings = 7)andxanthogranulomatous(n1).Theclinical detected: lymphocytic(n=4),granulomatous were typesofthehypophysitis three histopathological features, Accordingstaining. immunohistochemical to the H&Estainingand diagnosis wasmadethrough TSS,andhistopathological All thepatientsunderwent biopsy, operation. whileineight patientsafterpituitary pituitary In fourpatientsdiagnosiswasmadethrough onlyforhistologicaldiagnosis. wasperformed surgery gland, adenoma cases.Incasesofasmall-sizedpituitary glandandmimicking symptoms inbig-sizedpituitary neuropathy the compressive diagnosis and to improve for histological was performed surgery Pituitary Hyperprolactinemia Hypothyroidism GH deficiency Hypogonadism Initial endocrinologicaldisturbance Contrast enhancementheterogeneous stalk Thickened pituitary Compression oftheopticchiasm glandswelling Pituitary Initial radiologicalsigns Amenorrhea/impotence Visual defects Nausea, vomiting Weight gain Headache Symptoms were foundnon-specific,but themost Symptoms were The clinicalcharacteristics, radiologicalandendocrinologicfindingsofpatientsaccordingtohistologicaldiagnosishypophysitis Symptoms andclinical signs All (n=12) 7 (58%) 9 (75%) 6 (50%) 9 (75%) 2 (17%) 7 (58%) 5 (41%) 4 (33%) 4 (33%) 5 (41%) 4 (33%) 3 (25%) 2 (16%) 8 (67%) 1 (8%) and increased infundibulum thickening were infundibulumthickening were and increased (Tablearea contrastenhancement 3).Heterogeneous toMRIfocusedonthesellar evaluated according were ofallcasesatpresentation Radiological features hypogonadismtherapy.nine onhypogonadotropic therapy,steroid therapyand sevenonlevothyroxine toreceive follow-up period,sixpatientsremained inonepatient(25%).Duringthe was observed tapering gradually(10mg/day).Completerecovery days), followed by for three day methylprednisolone (1g/ withhighdosesofglucocorticoids treated were hypophysitis therapy (75%).Fourcaseswithprimary levothyroxine therapy (58%)andninepatientsreceived steroid time ofthediagnosis,sevenpatientsreceived insipidus (DI)wasidentifiedin17%ofpatients.Atthe axis(75%).Diabetes ofpituitary-thyroid suppression gonadalaxis,followedby suppressed dysfunctions were deficiencies.Themost isolatedpituitary hormone isolated in 50%ofthecasesand25%hadoneormore idiopathic. Granulomatous hypophysitis cases were idiopathic. Granulomatoushypophysitiscaseswere found in all patients. All the lymphocytic caseswere investigated autoimmune diseases andantibodieswere hypophysitis. Etiology of thehypophysitis including one caseoflymphocyticandgranulomatous foundin were invasion andoptictractcompression sinus granulomatous hypophysitiscases.Cavernous found in50%oflymphocyticcasesand57% LyHy (n=4) 4 (100%) 1 (25%) 2 (50%) 3 (75%) 1 (25%) 2 (50%) 2 (50%) 1 (25%) 2 (50%) 1 (25%) 2 (50%) 1 (25%) 1 (25%) 2 (50%) GrHy (n=7) 1 (14%) 4 (57%) 5 (71%) 4 (57%) 6 (86%) 1 (14%) 4 (57%) 3 (43%) 3 (43%) 2 (29%) 3 (43%) 2 (29%) 2 (29%) 1 (14%) 5 (71%) Clinical characteristics ofhypophysitis XantgrHy (n=1) 1 (100%) 1 (100%) 1 (100%) 0 0 0 ------49

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 50 F: female;M: male. Table 3. or posterior lobe(infundibuloneurohypophysitis) gland,infundibulum, can involvetheanteriorpituitary findings,hypophysitis clinical andneuroradiological to deficiency(12).According and causedhormone theanterior lobe,posteriorlobeorboth system affects ofsella.Itisestimatedthattheimmune compression deficiencyand hormone anterior orposteriorpituitary to related for all types. The signs and symptoms are variable clinical manifestations of hypophysitis are and studies.Thehormonal inrecent females reported the male/femaleratioof1:3withdominance infemales(10,11).Ourstudy confirmed to bemore of hypophysitis tends studies, the frequency In previous notknownwithaccuracy.incidence ofhypophysitisare and todeath.Theprevalence spontaneousrecovery from The naturalcourseofhypophysitisisvariable,ranging DISCUSSION after thediagnosisinsomepatients. aggravated andwere notimproved deficiencies were Contrarily,had optictractcompression. thehormonal inpatientswho improved The visualfunctionswere inpatients. ofhypophysitiswasobserved recurrence therapy.antituberculous Inthefollow-upperiod,no QuantiFERON TB- Gold test. These patients received by release ofaninterferon-gamma skin testandresponse apositivetuberculin wasmadethrough tuberculosis hypophysitisandthediagnosisofpituitary tuberculosis diagnosed with hypophysitiswere cases ofsecondary idiopathic.Allthree hypophysitis andfourpatientswere granulomatous patientshadsecondary evaluated; three Clinical characteristics ofhypophysitis Case nº 12 11 10 9 8 7 6 5 4 3 2 1 The clinicopathologicalcharacteristicsandradiologicalfeaturesofthepatients includedinthisstudy Xhanthogranulomatous Granulomatous Granulomatous Granulomatous Granulomatous Granulomatous Granulomatous Granulomatous Lymphocytic Lymphocytic Lymphocytic Lymphocytic Diagnosis Age, Gender 27, M 28, M 40, M 51, F 48, F 48, F 61, F 37, F 39, F 17, F 55, F 31, F Size (mm) 15 29 11 15 11 14 28 20 15 18 36 29 Gland volume 28,910 19,656 1,755 4,959 1,073 1,568 1,200 3,000 5,148 4,872 (cm 750 495 3 ) diseases, such as autoimmune polyglandular syndrome diseases, suchasautoimmune polyglandular syndrome toother autoimmune but insomecasesitisrelated cause ofcentralDI(17,18). isa thatinfundibuloneurohypophysitis was reported it In the literature, and infundibuloneurohypophysitis. 16% ofthepatients.Thesepatientshadpanhypophysitis adenohypophysitis involvement,andDIwasseenin Mostof our patientshad in our study group. deficiencywasmostcommon This anteriorpituitary thehighest(16). deficiencywere hormone pituitary hypophysitis (15),andsymptomsduetoanterior hypophysitis wasusuallyseenintheanteriorlobeof and DI(14). hypogonadism GHdeficit,andsecondary particularly etiological diagnosisofanteriorhypopituitarism, tothe isrelated Infundibuloneurohypophysitis gland(panhypophysitis)(13). pituitary the entire is frequently unknown. Lymphocytic hypophysitisis unknown.Lymphocytic is frequently butthesource monoclonal antibodies,interferon-alfa), (anti-CTLA-4 totreatment histiocytosis) andsecondary amyloidosis, Langerhanscell (hemochromatosis, aspergillosis, coccidioidomycosis),infiltrativediseases syphilis, vasculitis), infectious diseases (tuberculosis, granulomatosis with polyangiitis, diseases (sarcoidosis, andmeningiomas),systemicinflammatory germinomas Rathke’scleftcysts, (adenomas, craniopharyngiomas, lesions variable and consist of local pituitary are hypophysitiscauses Secondary syndrome. Sjögren’s and diabetes mellitus,systemiclupuserythematosus Graves’ disease, type1 (APS), Hashimotothyroiditis, Primary hypophysitisiscommonlyidiopathic, Primary that primary In other studies, it was reported Enhancement Hetero Hetero Hetero Hetero Hetero Hetero Hetero Homo Homo Homo Homo Homo Infundibulum Thickening Yes Yes Yes Yes Yes Yes Yes No No No No No Arch Metab. Endocrinol 2019;63/1 sinus invasion Cavernous Yes Yes No No No No No No No No No No compression Optic tract Yes Yes No No No No No No No No No No Arch Metab. Endocrinol 2019;63/1 thesymptoms ofmass andresolve mass decompression can achievesellar the histologicaldiagnosis surgery Inaddition,providing replacement. missing hormone for theetiologyofunderlying diseaseandsimultaneous hypophysitismustbefocused of secondary treatment the mass andthethickenedstalk (24,25).Therewithal, reducing the volumeofthepituitary for efficient are theglucocorticoids to thelymphocytolyticfeatures, Owing themasseffect. optionstoreduce treatment or cyclosporine A are azathioprine, methotrexate suchasglucocorticoids, drugs immunosuppressant TSS,radiotherapy,hormones, with medical treatment fordeficientpituitary withreplacement Observation thedefectiveendocrinefunction. mass andreplace can both minimize the size of the pituitary treatment is usually needed. Symptomatic approach treatment hypopituitarism duetodevelopmentofemptysella. follow-upisessentialforpossible follow-up. Long-term functionsduring unchangedinpituitary remained was seenin17%ofpatients,and50%patients function ofpituitary recovery in onlyonecase.Partial (22,23). In our study,recognized was seen full recovery functionshas been ofpituitary resolution recovery orfull the partial (21). Insomecasesintheliterature, andaggressive disease coursemayberapidlydestructive andleadstohypopituitarism.The atrophy pituitary results in This byfibrosis. isreplaced the parenchyma of pituicytes,and mechanism isduetothedestruction developed.The are masseffects then thesecondary is followedbyedematousandanenlarged gland,and gland,inflammationprimarilyoccursandthen pituitary (20).Naturally, variableandunpredictable are inthe but IgG4positivitywasnotfoundinourpatients. typeofhypophysitis, hypophysitisisarare IgG4 related hypophysitis. Based on thehistopathologic features granulomatous hypophysitis and 33% had lymphocytic seen amongourpatients.Inpatients,67%had the granulomatoustypewasmostcommon is themostcommonsubtypeofhypophysitis(7),but hypophysitis gland(19).Lymphocytic in thepituitary it ischaracterizedbyinfiltrationoffoamyhistiocytes ofhypophysitis,andhistologically uncommon form and giant cells. Xanthomatous hypophysitis is a very hypophysitis is characterized by infiltration by histiocytes cells(12).Granulomatous ofthepituitary destruction gland,andfollowedby expansion ofthepituitary initially characterized by lymphocytic infiltration and In themanagementofhypophysitis,asymptomatic hypophysitis andsecondary The coursesofprimary it infrequently improved hormone deficiency. hormone improved it infrequently Itis masses, however, of pituitary achieving decompression therapyisdecreased. glucocorticoid responsiveness of stageofhypophysitis,the fibrous Afterthe treatment. and highdoseglucocorticoid surgical decompression usually didnotbenefitfrom our patients,theindividualswhohadhypopituitarism dysfunction.Asseenin hormone pituitary irreversible in glandandresulted inthepituitary cell destruction lymphocytic andgranulomatous infiltration leadsto inonepatient.We was observed considerthatthediffuse replacement withoutanyhormone Complete recovery reduction. underlying diseaseshowedsignificant mass of granulomatous hypophysitis who had treatment ofsevenpatientswhohad andthree treatment, highdoseglucocorticoid hypophysitis whoreceived of five patients who had lymphocytic three treatment, surgical Inourpatients,ofallwhounderwent effect. received antituberculous therapy at least oneyear. antituberculous received In foundnegative.Patients biopsywere tests ofpituitary of mycobacterial DNA,andZiehl-Neelsen staining fordetection fast Bacilli,andchainpolymerase reaction byacid skintest.Aconfirmation positive tuberculin by QuantiFERON TB- Gold test and gamma release of an interferon- a positive response made through was tuberculosis giant cells.Thediagnosisofpituitary glandwith ofthepituitary andnecrosis destruction of degrees phases,leadingtodifferent in different lesionsofgranulomatoustype inflammatory chronic infection. Thehistologicalstudiesshowed tuberculosis hypophysitis, withoutthe systemic manifestations of diagnosedwithtuberculosis hypophysitis were casesofsecondary hypophysitis. Allourthree incontrovertible. remains management of underlying disease still appropriate hypophysitis should begiven,forthesecondary therapy hypophysitis ismade,highdoseglucocorticoid orsecondary. If the diagnosis of primary primary After that,hypophysitisshouldbedistinguishedas mustbeperformed. ofmissinghormones replacement the tomass effect, the absenceofsymptomsrelated Consequently, ofhypophysitisin inthetreatment fluidleaks and DI (26). as bleeding, cerebrospinal alsohassomecomplications,such Surgery treatment. to medical unresponsive fields andinpatientswhoare deficits ofvisual ofcriticalandprogressive the presence in shouldgenerallybeperformed suggested thatsurgery Surgical treatment is generally appropriate for isgenerallyappropriate Surgical treatment Pituitary tuberculosis is a rare cause of a secondary causeofasecondary isarare tuberculosis Pituitary Clinical characteristics ofhypophysitis 51

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 52 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure: Funding: nothingtodeclare. up possible developmentofemptysellalong-term, hypophysitisisunderlyingdisease.Dueto secondary hypophysitis, and for for primary dose glucocorticoids is consistent with high goal of the medical treatment such asophthalmoplegiaandvisualfielddefects.The neuropathy, ofcompressive of themassanddegree shouldbedo Surgical treatment ofmissinghormones. therapy mustbethereplacement thefirst-line the absenceofsurgical decompression, most commonlyinourcasesofhypophysitis.In was seen hormones deficit of the anterior pituitary insipidus maybeseeninthecourseofdisease.The deficienciesanddiabetes hormone anterior pituitary of patterns endocrinological aspects.Thedifferent adenomasinradiologicaland It canmimicpituitary deficiencies andsellar masses. in patients with hormone poorlydefined(28). (27) butautoantigensare potential tobehelpfulinthediagnosisofhypophysitis suggested thathighpositivityofAPA andAHAhasthe availableinourlaboratory.have notbeenroutinely Itwas hypothalamus auto-antibodies (AHA) because thesetests auto-antibodies (APA) anti- andserum anti-pituitary inpatients. was observed ofhypophysitis the follow-upperiod,norecurrence Clinical characteristics ofhypophysitis

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