Prolactin-producing pituitary carcinoma, hypopituitarism, and graves' disease-Report of a challenging case and literature review

June 2018 | Volume 9 | A icle 3121 Case RepoR published: 06 June 2018 doi: 10.3389/ endo.2018.00312 F on ie s in Endoc inology | www. on ie sin.o g Edi ed by: Ma ia Flese iu, O egon Heal h & Science Uni e si y, Uni ed S a es Re iewed by: Aki a Shima su, Na ional Hospi al O ganiza ion (NHO), Japan Leand o Kasuki, Ins i u o Es adual do Cé eb o Paulo Niemeye , B azil *Co espondence: Ri a Be encou -Sil a [email p o ec ed] Special y sec ion: This a icle was submi ed o Pi ui a y Endoc inology, a sec ion o he jou nal F on ie s in Endoc inology Recei ed: 10Janua y2018 Accep ed: 24May2018 Published: 06June2018 Ci a ion: Be encou -Sil aR, Pe ei aJ, BeloS, MagalhãesD, Quei ósJ and Ca alhoD (2018) P olac in- P oducing Pi ui a y Ca cinoma, Hypopi ui a ism, and G a es’ Disease—Repo o a Challenging Case and Li e a u e Re iew. F on . Endoc inol. 9:312. doi: 10.3389/ endo.2018.00312 p olac in-p oducing pi ui a y Ca cinoma, Hypopi ui a ism, and G a es’ Disease—Repo o a Challenging Case and Li e a u e Re iew Ri a Be encou -Sil a1,2,3*, Josué Pe ei a2,4, Sand a Belo1,2,3, Daniela Magalhães1,2,3, Joana Quei ós1 and Da ide Ca alho1,2,3 1 Depa men o Endoc inology, Diabe es and Me abolism, Cen o Hospi ala São João, Po o, Po ugal, 2 Facul y o Medicine, Uni e si y o Po o, Po o, Po ugal, 3 Ins i u o de In es igação e Ino ação em Saúde (i3S), Uni e si y o Po o, Po o, Po ugal, 4 Depa men o Neu osu ge y, Cen o Hospi ala São João, Po o, Po ugal In oduc ion: The diagnosis o pi ui a y ca cinoma is e y a e, equi es he e idence o me as a ic disease, and has a poo o e all su i al. Malignan p olac inoma e- quen ly equi es dopamine agonis he apy, pi ui a y su ge y, adio he apy, and e en chemo he apy. Case desc ip ion: A 19-yea -old emale p esen ed wi h galac o hea, p ima y ameno - hea, and le hemianopsia. Complemen a y s udy de ec ed hype p olac inemia and a pi ui a y mac oadenoma wi h ca e nous sinus in asion and sup asella g ow h. She was ea ed wi h cabe goline and b omoc ip ine wi hou clinical o analy ical imp o emen . Resec ion o he pi ui a y lesion was p og ammed and a non-con iguous lesion o he nasal mucosa was de ec ed du ing he app oach. This me as asis led o he diagnosis o p olac in-p oducing pi ui a y ca cinoma. A e pa ial esec ion, he pa ien was submi ed o adio he apy o esidual disease wi h pe sis en symp oms. She de eloped g ow h ho mone de iciency, cen al hypo hy oidism, hypogonadism, and pe manen diabe es insipidus. Six yea s la e she was admi ed o he suspicion o seconda y ad enal insu i- ciency and hy o oxicosis. Physical indings, labo a o y da a, hy oid ul asound, and scin ig aphy achie ed he diagnosis o G a es’ disease and hypoco isolism. She was ea ed wi h hyd oco isone and me himazole, bu cen al hypo hy oidism ecu ed a e an i hy oid d ug wi hd awal. Nine yea s a e he diagnosis o a pi ui a y ca cinoma, she main ains ea men wi h b omoc ip ine, has a locally s able disease, wi h no me as ases. Conclusion: This epo highligh s an unusual p esen a ion o a p olac in-p oducing pi ui a y ca cinoma in a young emale. The pa ien had mul iple ho mone de iciencies due o a pi ui a y lesion and ea men s. The pos e io de elopmen o hype hy oidism and ad enal insu iciency b ough an addi ional di icul y o he app oach. Keywo ds: pi ui a y ca cinoma, p olac inoma, G a es’ disease, hypopi ui a ism, ad enal insu iciency, pi ui a y su ge y Abb e ia ions: ACTH, ad enoco ico opic ho mone; FT3, ee iiodo hy onine; FT4, ee hy oxine; GD, G a es’ disease; LI, labeling index; LT4, le o hy oxine; MMI, me himazole; MRI, magne ic esonance imaging; RAIU, adioac i e iodine up ake; Tg, hy oglobulin; TgAb, hy oglobulin an ibody; TPOAb, pe oxidase an ibody; TRAb, TSH- ecep o an ibody; TSH, hy oid- s imula ing ho mone. 2 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 IN RoDUC IoN P olac inomas a e he mos common unc ioning pi ui a y umo s. They a e gene ally benign umo s wi h a a o able p og- nosis and symp oms a e mos ly ela ed o hype p olac inemia and a ely o umo mass e ec (1). Howe e , ce ain pi ui a y umo s may exhibi an agg essi e beha io in ading su ound- ing s uc u es and can cause li e- h ea ening complica ions (2). I s managemen is a challenge o heal hca e p o essionals and should be pe o med by a mul idisciplina y eam. Pi ui a y ca ci- noma is a e and he diagnosis equi es he e idence o me as a ic disease (1–5). Indeed, exhibi ing me as a ic sp ead is he unique c i e ion o diagnose a pi ui a y ca cinoma. Di e en ia ing a ypical om malignan pi ui a y umo s can be e y di icul because me as ases a ini ial p esen a ion a e e y uncommon (3). Cu en ly, he e a e no eliable ma ke s o umo -speci ic ea u es sa ely p edic ing he po en ial malignancy o a p olac inoma. Inc eased Ki-67 labeling index (LI), mi o ic ac i i y, o e exp ession o he oncop o ein p53, and gene ic backg ound ha e been s udied (3, 6–8). T ea men o pi ui a y ca cinoma commonly equi es medical managemen , pi ui a y su ge y, adio he apy, and e en chemo he apy (1–4). Pa ien s wi h pi ui a y ca cinoma ha e an expec ed poo o e all su i al (9). Hypopi ui a ism wi h mul iple ho mone de ici s (including cen al hypo hy oidism) can occu due o p ima y pi ui a y lesions o jus a e su gical esec ion o adia ion he apy (3, 10, 11). Hype hy oidism has a p e alence o 0.75% in Eu ope and G a es’ disease (GD) is he mos common cause (12). Cen al hypo hy- oidism and p ima y hype hy oidism can coexis . Heal hca e p o essionals equi e a high index o suspicion o make he co ec diagnosis and ea men o se e al concomi an ho mone diso de s. This case epo is an unusual p olac in-sec e ing pi ui a y umo . The pa ien p esen ed a a e pi ui a y ca cinoma and was ea ed wi h mul iple he apies. We also desc ibe and discuss he challenge o managing GD in he backg ound o cen al hypo hy- oidism, complica ed by he concomi an de elopmen o cen al ad enal insu iciency. Case DesCRIp IoN A 19-yea -old emale p esen ed wi h p ima y ameno hea, unin- en ional weigh loss (10kg in 6mon hs), bila e al galac o hea o 4mon hs, headache, and le hemianopsia in he p e ious mon h. He pas medical his o y was signi ican o Henoch–Schönlein pu pu a and obesi y (body mass index o 32kg/m2). The e was no usual medica ion o amily his o y o endoc ine o au oimmune diseases. A an endoc inology consul a ion in 2008, physical examina ion highligh ed bila e al spon aneous galac o hea and le homonymous hemianopsia (con i med wi h isual ields). Vi al signs and emaining physical and neu ological examina ion we e no mal. Complemen a y s udy de ec ed hype p olac inemia pe sis- en ly abo e 200ng/mL ( e e ence: 1.2–29.9). The samples we e no dilu ed, so i was impossible o ob ain he absolu e alue o p olac in. Renal ailu e, hypo hy oidism, and d ug-induced hype - p olac inemia we e excluded. Endoc ine assessmen e ealed concomi an g ow h ho mone de iciency and hypogonado opic hypogonadism. A no mal esponse o insulin-induced hypogly- cemia (basal co isol o 18.0µg/dL and peak se um co isol o 26.3µg/dL a e a hypoglycemia o 33mg/dL) excluded seconda y ad enal insu iciency. She unde wen a pi ui a y magne ic eso- nance imaging (MRI) ha e ealed a pi ui a y mac oadenoma wi h igh ca e nous sinus in asion, sphenoid sinus in asion, and sup asella g ow h (Figu es1A,B). The diagnosis o mac op ol- ac inoma was made. She was ea ed o 8 mon hs wi h wo dopamine agonis s a he maximum ole a ed doses (cabe goline 5 mg/week and b omoc ip ine 20mg/day). The combined ea men was made because he pa ien had side e ec s wi h highe doses o b o- moc ip ine, mono he apy wi h cabe goline was oo expensi e o he pa ien and in an a emp o a oid high doses o cabe goline in o de o p e en i s ad e se ca diac e ec s (in 2008, he sa e y o cabe goline ega ding al ula hea disease in pa ien s wi h p olac inomas was no gua an eed). Howe e , she had no clinical, analy ical, o imaging imp o emen and was conside ed esis an o dopamine agonis s. The pa ien unde wen anssphenoidal esec ion o he pi ui a y lesion in 2009, bu comple e emo al was no easible. Du ing he su gical app oach, an independen mucosa lesion loca ed in he le nasal ossa, nea he sphenoid os um, was de ec ed and emo ed. A e eassessing he MRI images pe o med 5mon hs be o e he su ge y, a millime ic a ea o di icul isualiza ion was iden i ied in he le nasal ossa ha could co espond o he excised nasal me as asis (Figu es1A,B). His ology o he su gical specimen (Figu e2) e ealed an adenoma wi h p olac in exp ession, di use g ow h pa e n, and Ki-67 LI o 4%. The esec ed nasal lesion also had p olac in exp ession, con- i ming he diagnosis o umo me as asis. Despi e he ela i ely low Ki-67 LI, he de ec ion o a nasal me as asis non-con inuous wi h he pi ui a y gland was consis en wi h a pi ui a y ca cinoma. A e su ge y, she main ained hypogonado opic hypogonadism and de eloped pe manen cen al diabe es insipidus and cen al hypo hy oidism wi h hy oid-s imula ing ho mone (TSH) le els o 0.06μUI/mL ( e e ence: 0.35–5.0) and ee hy oxine (FT4) le els o 0.76 ng/dL ( e e ence: 0.88–1.58). Desmop essin and le o hy oxine we e p omp ly ini ia ed. Es adiol and p oges ogen we e ini ia ed 2yea s la e due o loss o libido and dyspa eunia wi h signi ican educ ion in quali y o li e and sexual sa is ac ion. Se um p olac in le els and umo size did no change a e his ea men . The pos ope a i e pi ui a y MRI e ealed a pe sis en expansi e lesion wi h cys ic ans o ma ion and nec o ic a eas (Figu es1C,D). The whole-body bone scin ig aphy wi h echne ium-99m hyd ox- yme hane diphosphona e showed no ocal bone pa hology. She also unde wen ce ical- ho acic-abdominal-pel ic compu ed omog aphy, wi h no addi ional lesions disclosed. Six mon hs a e su ge y, she unde wen adia ion he apy (1.8Gy/day, 45Gy in o al) o esidual expansi e lesion and pe sis en hype p olac ine- mia. The lesion became ma kedly educed and no maliza ion o hype p olac inemia was achie ed 3yea s a e adia ion he apy, leading o cabe goline wi hd awal and ea men only wi h b o- moc ip ine (b omoc ip ine was p e e ed o economic easons). In 2015, 6yea s a e pi ui a y su ge y and adio he apy, he pa ien p esen ed wi h nausea, as henia, muscle weakness, FIGURe 1 | Sagi al (a) and co onal (B) plane o he i s pi ui a y magne ic esonance imaging (MRI) wi h an in asi e mac oadenoma wi h gadolinium enhancemen . The pi ui a y umo measu ed 32mm×30mm×25.5mm in an e opos e io , c aniocaudal, and ans e se dimensions, espec i ely. The lesion had in asion o he igh ca e nous sinus, supe io de ia ion o he le in e nal ca o id a e y, sphenoid sinus in asion, and comp ession and s e ching o he op ical chiasm. The umo was isossignal a ea in T1 and T2 wi h small cys s and had ma ked con as enhancemen . The possible nasal me as asis was localized nea he sphenoid os um in he le nasal ossa (a ows). The pos ope a i e MRI (C,D) e ealed a pe sis en expansi e pi ui a y lesion wi h igh ca e nous sinus in asion. The las pi ui a y MRI (e,F) pe o med in Oc obe 2017 showed a pi ui a y umo wi h ma kedly educed dimensions. 3 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 palpi a ions, emo , and unin en ional weigh loss (15kg in 2mon hs). She was admi ed o he suspicion o ad enal c isis and hy o oxicosis. The pa ien denied excessi e in ake o le o hy ox- ine; indeed, she sel wi hd ew i weeks be o e admission. Physical examina ion highligh ed a high- equency emo o he hands, sinus achyca dia ( es ing hea a es abo e 100–110/min), and a hy oid b ui . She p esen ed no mal blood p essu e, no e e , and no signs o endoc ine oph halmopa hy o de mopa hy. The pa ien did no mee he diagnos ic c i e ia o hy oid s o m (13). Plasma sampling e ealed TSH le el o 0.001μUI/mL ( e e - ence: 0.35–4.94), FT4 o 2.42ng/dL ( e e ence: 0.70–1.48), ee iiodo hy onine (FT3) o 16.74 pg/mL ( e e ence: 1.71–3.71), and hy oglobulin (Tg) o 7.81ng/mL ( e e ence: 0–55). Se um FT3 was inc eased o e ou old while se um FT4 exhibi ed only FIGURe 2 | His ology o a p olac in-p oducing pi ui a y umo . Tumo wi h di use g ow h pa e n o cells wi h elonga ed nuclei and inconspicuous nucleoli and mode a e amoun o sligh ly acidophilic cy oplasm [(a)—HE 400×]. P olac in exp ession in neoplas ic cells [(B)—400×]. 4 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 a wo old inc eased, a o ing he assump ion o p ima y hype - hy oidism. She had posi i e hy oglobulin an ibody (TgAb) 67.2IU/mL ( e e ence: <4.11), nega i e pe oxidase an ibody (TPOAb) 0.5 IU/mL ( e e ence: <5.61), and TSH- ecep o an ibody (TRAb) a he uppe no mal ange 1.8U/L ( e e ence: 0–1.8). He baseline se um co isol and ad enoco ico opic ho mone (ACTH) le els we e low (5.4 µg/dL and 7.2 ng/L, espec i ely), sugges ing seconda y ad enal ailu e. She had mild mic ocy ic anemia and mild leukocy osis, no mal enal unc ion, ionog am, and li e p o ile. Me himazole 20mg/day, p op anolol, in a enous luids, and hyd oco isone we e ini ia ed leading o symp oma ic and analy ical imp o emen . To con i m he e iol- ogy o hy o oxicosis, he pa ien unde wen a hy oid ul asound and scin ig aphy (Figu e3). Ul asonog aphy (Figu e3A) sug- ges ed hy oidi is and e ealed inc eased ascula i y wi h di use homogeneous dis ibu ion. Scin ig aphy (Figu e 3B) e ealed a ma kedly hype unc ioning hy oid wi h a adioac i e iodine up ake (RAIU) ma kedly ele a ed. These esul s allowed he diagnosis o GD. An insulin-induced hypoglycemia es was pe o med a e clinical s abiliza ion o e alua e o ad enal insu iciency. Se um co isol alues below 4 µg/dL secu ed he diagnosis o long- s anding seconda y ad enal insu iciency. The pa ien unde wen a p og essi e me himazole dose educ ion and wi hd ew he d ug a e 6mon hs o ea men . A ha ime, she was medica ed wi h me himazole 5 mg/day and had FT4 le els in he lowe no mal ange. Since she had nega i e TRAb le els (0.8U/L) be o e me himazole wi hd awal, he emission was mo e p obable (13). Wi hou any hy oid ea men , she expe ienced ede elopmen o seconda y hypo hy oidism (low FT4 0.52ng/dL) and had o esume he ea men wi h exogenous hy oid ho mone. Figu e3C shows he hy oid unc ion e olu ion since he diag- nosis o cen al hypo hy oidism a e pi ui a y su ge y. Cu en ly, he pa ien main ains ea men wi h le o hy oxine and has a no mal FT4. She is also unde hyd oco isone 20mg/ day, wi h no symp oms sugges i e o ad enal insu iciency o elec oly e dis u bances. Conce ning he p olac in-sec e ing pi ui a y ca cinoma, she has no mal se um p olac in le els unde b omoc ip ine 20mg/day and a pi ui a y lesion wi h ma kedly educed dimensions on MRI compa ed o p e- adio he apy pe iod (Figu es1E,F). The e olu ion o se um p olac in le els since he diagnosis is showed in Figu e4. The e was no u he e idence o me as a ic disease du ing his 9 yea s ollow-up pe iod. DIsCUssIoN Diagnosis o Hype p olac inemia and Managemen o p olac inomas P olac inomas a e he mos equen ly sec e o y pi ui a y umo s, accoun o 40% o all pi ui a y umo s (4). Pa ien s can p esen signs and symp oms ela ed o umo mass, like isual ield abno mali ies, hypopi ui a ism, headache, and seizu es, bu also associa ed wi h hype p olac inemia pe se, like ameno hea, in e ili y, and galac o hea. A single measu emen o se um p o- lac in is enough o con i m hype p olac inemia and he umo size usually co ela es wi h se um p olac in le els (1). Pa ien s need o be e alua ed o o he concomi an ho mone hype sec e- ion o hypopi ui a ism. Dopamine agonis s a e cu en ly he gold s anda d ea - men o bo h mic o and mac op olac inomas (1). Cabe goline has highe e icacy and be e ole abili y, being p e e ed o b omoc ip ine (14, 15). Al hough mos pa ien s p esen good esponse o dopamine ecep o agonis s, in a dose- ela ed man- ne , o he s ail o achie e no mal p olac in le els and a 50% educ ion in umo size, e en a he maximal ole able doses. Almos 10% o pa ien s a e esis an o cabe goline and 25% o b omoc ip ine (1, 15). T anssphenoidal pi ui a y su ge y is gene ally ese ed o medically esis an p olac inomas o o pa ien s who canno ole a e high doses o hese d ugs (1, 11, 16). A sys ema ic e iew ocused on emission and ecu ence o bo h unc ioning and non- unc ioning pi ui a y adenomas a e anssphenoidal su ge y (11). Rega ding p olac inoma pa ien s, he e was a mean emis- sion a e o 68.8% a e su ge y (simila o hose wi h ac omegaly o Cushing’s disease), bu a highe ecu ence a e was highligh ed. A low basal pos ope a i e p olac in and no maliza ion o he FIGURe 3 | Thy oid ul asonog aphy (a) showed a no mal size gland, wi h he e ogeneous ex u e and pseudonodula a eas, wi hou nodula lesions, sugges ing hy oidi is. The colo low Dopple signal showed signi ican ly inc eased ascula i y wi h di use homogeneous dis ibu ion ( hy oid in e no). The e was a ma kedly hype unc ioning hy oid in scin ig aphy (B), wi h homogeneous ac i i y dis ibu ion and no ocal a eas sugges i e o hype - o hypoac i e nodula o ma ions. The adioac i e iodine up ake was 70.2% a he end o 24h, ma kedly ele a ed compa ed o no mal ange (10–30%). Panel (C) shows he e olu ion o hy oid unc ion. A e pi ui a y su ge y in 2009 he pa ien de eloped seconda y hypo hy oidism and ini ia ed LT4. She was admi ed wi h p ima y hype hy oidism in Ap il 2015 and ini ia ed MMI. Du ing an i hy oid d ug wi hd awal be o e scin ig aphy, FT4 and FT3 e-inc eased abo e he e e ence ange. MMI was p og essi ely educed a e 6mon hs o ea men , bu a e wi hd awal in Oc obe 2015, cen al hypo hy oidism ecu ed and she esumed LT4 since Ma ch 2016. Abb e ia ions: LT4, le o hy oxine; MMI, me himazole; FT4, ee hy oxine; FT3, ee iiodo hy onine. 5 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 hy o opin eleasing ho mone es we e p edic i e ac o s o cu e, while age, gende , umo in asion, and umo size did no appea o be signi ican . Su ge y- ela ed hypopi ui a ism de eloped in less han 10% o pa ien s wi h p olac inomas (11, 17). In pa ien s wi h mac op olac inomas, a ca e ul endoc ine ollow-up emains necessa y i es ogen eplacemen is ini ia ed. The es ogen ecep o is exp essed in p olac inomas and es o- gens ha e been implica ed in he de elopmen and p og ession o lac o oph umo s, especially du ing p egnancy (1, 18). Howe e , in pa ien s ea ed wi h es ogen/p oges e one eplacemen o 2yea s, a apid g ow h o an unde lying pi ui a y adenoma was no con i med (19). FIGURe 4 | E olu ion o se um p olac in le els o e ime and i s ela ion wi h medical, su gical, and adia ion he apy. *Samples no dilu ed. 6 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 In he case he e desc ibed, he pa ien exhibi ed hype p ol- ac inemia, g ow h ho mone de iciency, and hypogonado opic hypogonadism a i s endoc ine assessmen . A e su ge y, she de eloped o he pi ui a y ho mone de ici s, namely hy o ophic and asop essin. In e es ingly, co ico oph ailu e was excluded pos ope a i ely wi h a dynamic es (insulin-induced hypoglyce- mia es ) and was only p esen 6yea s a e he pi ui a y su ge y. pi ui a y adenomas and Ca cinomas Pi ui a y adenomas can exhibi agg essi e biological beha io and can in il a e sphenoid sinus, du a ma e , and c anial bone (1–5, 8). Pi ui a y ca cinomas a e exceedingly a e, making up only 0.2% o all pi ui a y umo s. Ce eb ospinal o sys emic me as ases a e equi ed o diagnosis, bu a e e y uncommon ab ini io (2, 3, 6). Me as ases may be ound inciden ally o may become symp oma ic (3, 20). Pa ien s wi h pi ui a y ca cinomas ha e a wo se o e all su i al han hose wi h in asi e adenoma (9); once me as ases de elop, he mean su i al is less han 5yea s (3). The Wo ld Heal h O ganiza ion classi ica ion o Tumo s o he Pi ui a y Gland has been ecen ly e ised (21, 22). In he new classi ica ion, he p e ious e m “a ypical adenoma” is no longe u ilized (5). Clinical, biochemical, his ological, o umo -speci ic adiological ea u es canno eliably di e en ia e be ween locally agg essi e adenomas and pi ui a y umo s (2–6, 8, 20–24). Tumo in asion, highe Ki-67 LI, and ele a ed mi o ic index we e co ela ed wi h a mo e agg essi e beha io (2, 21). The bes ma ke seems o be he Ki-67 LI, bu he bes cu o alue a ies among s udies. In one se ies (23), malignan umo s exhibi ed signi ican ly highe mean Ki-67 (11.91%) compa ed o in asi e adenomas (4.66%), sugges ing ha a Ki-67 LI g ea e han 10% should aise he conce n o malignancy. Howe e , compa ing a ypical adenomas and pi ui a y ca cinomas iden i ied om he Ge man Regis y, he e we e no signi ican di e ences ega d- ing his ea u e (6). Mo e s udies a e needed o enable a be e iden i ica ion o inc eased isk o malignancy, allowing modi i- ca ion o ea men acco ding o agg essi eness, imely manage- men o agg essi e umo s, p e en ion o neoplas ic p og ession, and imp o emen o ou comes. Radio he apy may be equi ed in pa ien s wi h ele an umo g ow h despi e su ge y and medical ea men in unc ioning umo s (2). Radio he apy may equi e up o 20 yea s o he maximal e ec and is associa ed wi h possible hypopi ui a ism, c anial ne e damage, o second umo o ma ion (2, 10, 25). Chemo he apy wi h emozolomide is ecommended o pi ui a y ca cinomas a e ailu e o s anda d he apies (1, 2, 26). Ou pa ien had a p olac in-p oducing pi ui a y ca cinoma esis an o cabe goline and b omoc ip ine. He nasal me as asis was ound and emo ed du ing anssphenoidal su ge y, bu pi ui a y su ge y ailed o con ol disease p og ession. Radia ion he apy led o educed umo olume and no mal p olac in le els. e iology, Wo kup, and Di e en ial Diagnosis o GD G a es’ disease is he mos common cause o hype hy oidism (12). TRAb a e GD-speci ic and an indica o o disease ac i i y (13). Despi e being a hallma k in he diagnos ic, a signi ican p opo ion o pa ien s a e TRAb nega i e. TgAb and TPOAb a e de ec able in many pa ien s wi h GD, which ends o de elop in a backg ound au oimmune hy oidi is (4). Labo a o y and imag- ing da a a e c ucial in he di e en ial diagnosis o hy o oxicosis (4, 13). We quickly excluded ac i ious hy o oxicosis in ou pa ien because se um Tg would be low o e en unmeasu able (4). She had a hy oid b ui and se um FT3 was highe han FT4, a o ing he diagnosis o p ima y hype hy oidism, because a hype ac i e gland p oduces ela i ely mo e T3 han T4 (13). Despi e TRAb le els a he uppe no mal ange, TgAb posi i i y sugges ed an au oimmune e iology. Thy oid ul asound was impo an o con i m he inc eased ascula i y and o exclude nodula lesions. 7 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 Scin ig aphy was help ul o con i m he hype unc ioning hy oid issue and o exclude hy oidi is o ac i ious hy o oxicosis. E en in he hy o oxic s age o hy oidi is, RAIU would be low (4, 13); ou pa ien had an unequi ocal inc eased RAIU. O e all, hese esul s led o diagnosis o GD. Cu en li e a u e suppo s he associa ion be ween hype - p olac inemia and au oimmuni y. P olac in in e e es wi h B and Tlymphocy e p oli e a ion and has been associa ed wi h au oim- mune diseases such as sys emic lupus e y hema osus, heuma oid a h i is, pso iasis a h i is, ype 1 diabe es melli us, Addison’s dis- ease, and au oimmune hy oid diseases (27). A ecen case-con ol s udy ound a signi ican ly highe p e alence o au oimmuni y, namely hy oid disease, in pa ien s wi h p olac inomas compa ed wi h hose wi h non- unc ioning adenomas (28). The e o e, ch onic hype p olac inemia may ha e played a ole in igge ing au oimmuni y in his case. The mos common e ec in hy oid unc ion a e adia ion he apy is o e hypo hy oidism, bu GD may be a a e adia ion- induced diso de (29). The la ency ime be ween adio he apy and hy oid dys unc ion is highly a iable among s udies. In his case epo , GD occu ed 6 yea s a e adia ion he apy. Al hough unlikely, we canno exclude he possible ela ionship be ween hese en i ies. Managemen o GD in a pa ien Wi h Cen al Hypo hy oidism The p esence o cen al hypo hy oidism does no p eclude he de elopmen o p ima y hype hy oidism and hese wo en i ies can coexis . In li e a u e, we ound some case epo s ega d- ing he associa ion be ween GD and cen al hypo hy oidism. The e iology o cen al hypo hy oidism in he epo ed cases was c aniopha yngioma (30, 31), Sheehan’s synd ome (32, 33), hypo halamic umo (34), pi ui a y mac oadenoma (35), su gi- cal esec ion o a pi ui a y lesion (36), and adia ion he apy o a nasopha yngeal umo wi h pi ui a y in asion (37). The e ec o an i hy oid d ugs in GD is a iable among pa ien s. Usually, ea men wi h me himazole should be con- inued o 12–18mon hs and hen discon inued when TSH and TRAb le els no malize (13). Howe e , TSH measu emen is no help ul in cen al hypo hy oidism, since TSH le els may be low, no mal, o e en ele a ed (4). Fu he mo e, in pa ien s wi h low o nega i e TRAb i e s, i s measu emen is less help ul o p edic hype hy oidism elapse a e an i hy oid d ugs wi hd awal (13). Hype hy oidism and ad enal Insu iciency Thy oid ho mones accele a e he co isol u no e a e by a ec ing hepa ic 11β-hid oxys e oid dehyd ogenase ype 1 and 5α/5β- educ ases (38). Hype hy oidism o eplacemen o hy o- xine can exace ba e ad enal insu iciency o e en p ecipi a e li e- h ea ening ad enal c isis (39). In pa ien s wi h known hypo- co isolism, hyd oco isone eplacemen he apy may need o be inc eased in hose who de elop hype hy oidism and high dosages o glucoco icoids will acu ely block con e sion o T4 o T3 (4). On he o he hand, physiological concen a ions o glucoco icoids exe an i-in lamma o y and immunosupp es- si e ac ions (40) and hypoco isolism may igge au oimmuni y. Fu he mo e, some clinical ea u es o bo h ad enal insu iciency and hy o oxicosis a e simila and a high index o suspicion is equi ed o imely diagnosis. In s ess condi ions, ACTH and co isol le els a e expec ed o inc ease; a no mal co isol le el can be in e p e ed as ela i e ad enal insu iciency. A ecen s udy in es iga ed he sec e ion o co isol du ing hype hy oidism and eu hy oidism (41). ACTH- s imula ed peak co isol was dec eased du ing hype hy oidism s a e and highe se um hy oid ho mones we e ound o be an independen p edic o o his lowe co isol esponse. In 10% o hype hy oid pa ien s, he ACTH-s imula ed co isol alues we e lowe han 18µg/dL ( he cu o gene ally conside ed as ad enal insu iciency), bu no malized a e a ainmen o eu hy oidism. These esul s ale o he inc eased possibili y o ad enal insu - iciency du ing hype hy oidism. CoNCLUsIoN We p esen he case o a young emale wi h a a e p olac in- p oducing pi ui a y ca cinoma wi h a non-con inuous nasal me as asis, submi ed o medical, su gical, and adia ion he apy. The pa ien had g ow h ho mone de iciency, hypogonado opic hypogonadism, cen al diabe es insipidus, and cen al hypo hy- oidism ela ed o p ima y pi ui a y lesion and ea men s. Six yea s la e , she de eloped ad enal insu iciency and GD. The mul iple hypo halamic–pi ui a y–end o gan axis dys unc ions we e a challenge in e ms o he apeu ic app oach. To ou bes knowledge, his p olac in-p oducing pi ui a y ca cinoma is he only one wi h a nasal me as asis and has one o he longes su i - als a e me as ases de elopmen . e HICs s a eMeN The case epo was w i en wi h he ecommenda ions o he Decla a ion o Helsinki. The pa ien is desc ibed anonymously and ga e w i en in o med consen o he publica ion o his case epo and any accompanying images. A copy o he w i en con- sen is a ailable o e iew by he Edi o -in-Chie o his jou nal. aU HoR CoN RIBU IoNs RB-S pa icipa ed in he clinical ea men , collec ed and in e - p e ed he da a, and w o e he manusc ip . SB, DM, JQ, and DC pa icipa ed in he clinical ea men and e ised he manusc ip . JP pe o med he pi ui a y su ge y, pa icipa ed in he clinical managemen , and e ised he manusc ip . All au ho s ead and app o ed he inal manusc ip . aCKNoWLeDGMeN s The au ho s exp ess hei g a i ude o I ene Be na des, MD (Depa men o Neu o adiology), Robe o Sil a, MD (Depa men o Pa hology), Olinda Fa ia, MD (Depa men o Oph halmology), Edua do Vinha, MD (Depa men o Endoc inology, Diabe es and Me abolism), and Paula F ei as, PhD (Depa men o Endo- c inology, Diabe es and Me abolism), o hei inpu and eedback on his case epo , and o José Cos a Maia, MD (Depa men o Su ge y) o his w i ing assis ance and language edi ing. 8 Be encou -Sil a e al. Pi ui a y Ca cinoma, Hypopi ui a ism, G a es’ Disease F on ie s in Endoc inology | www. on ie sin.o g June 2018 | Volume 9 | A icle 312 ReFeReNCes 1. Melmed S, Casanue a FF, Ho man AR, Kleinbe g DL, Mon o i VM, Schlech e JA, e al. Diagnosis and ea men o hype p olac inemia: an Endoc ine Socie y clinical p ac ice guideline. J Clin Endoc inol Me ab (2011) 96(2):273–88. doi:10.1210/jc.2010-1692 2. 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Copy igh © 2018 Be encou -Sil a, Pe ei a, Belo, Magalhães, Quei ós and Ca alho. This is an open-access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion License (CC BY). The use, dis ibu ion o ep oduc ion in o he o ums is pe - mi ed, p o ided he o iginal au ho (s) and he copy igh owne a e c edi ed and ha he o iginal publica ion in his jou nal is ci ed, in acco dance wi h accep ed academic p ac ice. No use, dis ibu ion o ep oduc ion is pe mi ed which does no comply wi h hese e ms.