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Prolactinoma gigante – 3 casos clínicos e revisão da literatura
Giant prolactinoma ‐ Three case reports and literature review
Patrícia Tavaresa,
Autor para correspondencia
patriciatavares.med@gmail.com

Autor para correspondência.
, Gustavo Rochaa, Mário Resendeb, Lino Mascarenhasb, Maria João Oliveiraa
a Serviço de Endocrinologia, Centro Hospitalar Vila Nova Gaia/Espinho, Vila Nova de Gaia, Portugal
b Serviço de Neurocirurgia, Centro Hospitalar Vila Nova Gaia/Espinho, Vila Nova de Gaia, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">Os prolactinomas s&#227;o os tumores da hip&#243;fise mais frequentes&#44; com uma preval&#234;ncia de 3&#44;5&#8208;5 por 10&#46;000 habitantes nos estudos epidemiol&#243;gicos mais recentes<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1&#8211;4</span></a>&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Os prolactinomas gigantes s&#227;o raros&#44; com uma frequ&#234;ncia estimada em estudos retrospetivos de 0&#44;5&#8208;4&#44;4&#37; entre os tumores da hip&#243;fise<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">5&#44;6</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Embora a primeira s&#233;rie que relata prolactinomas gigantes seja de 1940&#44; m&#250;ltiplas defini&#231;&#245;es e crit&#233;rios de diagn&#243;stico foram propostos&#46; Em 2014&#44; Maiter e Delgrange propuseram a seguinte defini&#231;&#227;o de prolactinoma gigante<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">1</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">i&#41;</span><p id="par0020" class="elsevierStylePara elsevierViewall">adenoma hipofis&#225;rio com maior eixo de 4<span class="elsevierStyleHsp" style=""></span>cm ou superior e extens&#227;o extrasselar&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">ii&#41;</span><p id="par0025" class="elsevierStylePara elsevierViewall">doseamento de prolactina &#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;000<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; com m&#233;todos modernos e estandardizados&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">iii&#41;</span><p id="par0030" class="elsevierStylePara elsevierViewall">exclus&#227;o de secre&#231;&#227;o concomitante de hormona de crescimento &#40;HC&#41; ou corticotrofina &#40;ACTH&#41;&#46;</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall">Na maioria dos doentes existe uma associa&#231;&#227;o entre os n&#237;veis de prolactina e o tamanho do tumor&#59; contudo&#44; esta associa&#231;&#227;o nem sempre se verifica e pode ser causada pela composi&#231;&#227;o predominantemente c&#237;stica do prolactinoma com poucos lactotrofos vi&#225;veis ou pelo efeito de <span class="elsevierStyleItalic">hook</span>&#44; que ocorre em cerca de 20&#37; dos prolactinomas gigantes<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46; Este artefacto laboratorial ocorre quando os n&#237;veis elevados de prolactina interferem com a forma&#231;&#227;o do complexo anticorpo&#8208;antig&#233;nio&#8208;anticorpo&#44; o que determina um valor falsamente reduzido de prolactina<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">7&#44;8</span></a>&#46; Em caso de d&#250;vida&#44; o doseamento de prolactina deve ser repetido numa dilui&#231;&#227;o de 1&#58;100 de forma a evitar o efeito de <span class="elsevierStyleItalic">hook</span><a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Descri&#231;&#227;o dos casos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Caso 1</span><p id="par0040" class="elsevierStylePara elsevierViewall">Homem de 33 anos&#44; com diagn&#243;stico de prolactinoma gigante em 2001&#44; ap&#243;s cefaleias persistentes&#46; Na altura&#44; com doseamento de prolactina superior a 4&#46;700<span class="elsevierStyleHsp" style=""></span>ng&#47;mL e maior eixo da les&#227;o com cerca de 6<span class="elsevierStyleHsp" style=""></span>cm&#46; Observado por neurocirurgia e submetido&#44; nesse ano&#44; a ex&#233;rese transesfenoidal que foi incompleta e posteriormente medicado com bromocriptina 5<span class="elsevierStyleHsp" style=""></span>mg&#47;dia at&#233; 2009&#44; quando teve alta da consulta de neurocirurgia de outra institui&#231;&#227;o hospitalar&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Enviado &#224; consulta de endocrinologia pelo m&#233;dico de fam&#237;lia em 2011&#44; por cefaleias persistentes e prolactina de 676<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; Negava altera&#231;&#245;es visuais ou disfun&#231;&#227;o sexual&#44; apresentava obesidade grau 3 e aspeto hipogon&#225;dico ao exame objetivo&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Foi feita reavalia&#231;&#227;o imagiol&#243;gica com resson&#226;ncia magn&#233;tica &#40;RMN&#41; cerebral&#44; que revelou volumosa les&#227;o expansiva centrada na regi&#227;o parasselar direita com cerca de 6<span class="elsevierStyleHsp" style=""></span>cm de maior di&#226;metro com invas&#227;o do seio cavernoso &#40;<a class="elsevierStyleCrossRef" href="#fig0005">fig&#46; 1</a>&#41;&#46; Analiticamente com hipogonadismo hipogonadotr&#243;fico e suspeita de hipercortisolismo &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#44; que foi exclu&#237;do por prova de frena&#231;&#227;o com baixa dose de dexametasona&#46; Campos visuais de Goldmann e Humphrey sem perda campim&#233;trica significativa&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Reiniciou tratamento m&#233;dico com bromocriptina com aumento progressivo da dose at&#233; 25<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46; Verificou&#8208;se resposta parcial do tumor com diminui&#231;&#227;o acentuada do seu volume &#40;<a class="elsevierStyleCrossRef" href="#fig0010">fig&#46; 2</a>&#41; ap&#243;s 23 meses de tratamento&#46; Houve normaliza&#231;&#227;o da hiperprolactinemia &#40;21&#44;8<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; e dos n&#237;veis de testosterona&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Na reavalia&#231;&#227;o de janeiro de 2015 deteta&#8208;se novo agravamento imagiol&#243;gico&#44; descrito como ligeiro aumento do componente direito da les&#227;o&#44; mas bom controlo bioqu&#237;mico&#46; Foi aumentada dose de bromocriptina para 15<span class="elsevierStyleHsp" style=""></span>mg&#47;bid&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Caso 2</span><p id="par0065" class="elsevierStylePara elsevierViewall">Homem de 42 anos que&#44; em outubro de 2013&#44; recorreu ao servi&#231;o de urg&#234;ncia por perda progressiva da vis&#227;o do olho esquerdo associada a cefaleias holocraneanas&#46; Realizada TAC cerebral e posteriormente RMN cerebral que confirmou volumosa les&#227;o expansiva extra&#8208;axial de 4&#44;8<span class="elsevierStyleHsp" style=""></span>cm de maior eixo&#44; com ponto de partida selar e invas&#227;o das c&#226;maras esfenoidais e dos seios cavernosos&#44; principalmente o esquerdo &#40;<a class="elsevierStyleCrossRef" href="#fig0015">fig&#46; 3</a>&#41;&#46; O n&#237;vel de prolactina era de 17&#46;847<span class="elsevierStyleHsp" style=""></span>ng&#47;mL e n&#227;o tinha altera&#231;&#227;o dos outros eixos hipofis&#225;rios&#44; exceto hipogonadismo hipogonadotr&#243;fico &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; Apresentava campos visuais de Humphrey com pontos de hipossensibilidade &#237;nferotemporais do olho esquerdo&#46; Foi submetido a ex&#233;rese transesfenoidal da les&#227;o em novembro de 2013&#44; com exame anatomopatol&#243;gico e imuno&#8208;histoqu&#237;mico compat&#237;vel com prolactinoma&#46; Posteriormente&#44; foi enviado para a consulta de endocrinologia&#46; Medicado inicialmente com cabergolina 0&#44;25<span class="elsevierStyleHsp" style=""></span>mg 2 vezes por semana&#44; mas por intoler&#226;ncia &#40;n&#225;useas e tonturas&#41; foi alterada terap&#234;utica para bromocriptina 10<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">&#218;ltima RMN cerebral de janeiro de 2015 com redu&#231;&#227;o marcada das dimens&#245;es da les&#227;o&#44; persistindo um componente lesional com cerca de 1<span class="elsevierStyleHsp" style=""></span>cm que envolve o seio cavernoso esquerdo &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; Prolactina de janeiro de 2015 igual a 5&#44;8<span class="elsevierStyleHsp" style=""></span>ng&#47;mL e testosterona normal &#40;<a class="elsevierStyleCrossRef" href="#fig0020">fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Caso 3</span><p id="par0075" class="elsevierStylePara elsevierViewall">Homem de 76 anos com diagn&#243;stico incidental de adenoma gigante em mar&#231;o de 2014&#44; ap&#243;s realiza&#231;&#227;o de imagem cerebral por queda e traumatismo de cr&#226;nio&#46; Negava cefaleias&#44; altera&#231;&#245;es da vis&#227;o&#44; ginecomastia&#44; galactorreia e disfun&#231;&#227;o sexual&#46; A les&#227;o localizada na sela turca e com extens&#227;o ao corpo do esfenoide apresentava 4<span class="elsevierStyleHsp" style=""></span>cm de maior eixo e invas&#227;o de ambos os seios cavernosos &#40;<a class="elsevierStyleCrossRef" href="#fig0025">fig&#46; 5</a>&#41;&#59; contudo&#44; a imagem descrita na RMN colocava a hip&#243;tese de diagn&#243;stico diferencial entre macroadenoma hipofis&#225;rio invasivo &#40;hip&#243;tese mais prov&#225;vel&#41;&#44; tumor de c&#233;lulas gigantes&#44; met&#225;stase ou um meningioma &#40;embora menos prov&#225;veis&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Foi doseada prolactina com valor superior a 4&#46;700<span class="elsevierStyleHsp" style=""></span>ng&#47;mL e testosterona diminu&#237;da&#44; sem outras altera&#231;&#245;es anal&#237;ticas &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">tabela 1</a>&#41;&#46; Avalia&#231;&#227;o dos campos visuais sem altera&#231;&#245;es&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Em maio de 2014&#44; realizada bi&#243;psia do seio esfenoidal&#44; orientada por neuronavega&#231;&#227;o&#46; O estudo imuno&#8208;histoqu&#237;mico foi positivo para prolactina e negativo para ACTH&#44; FSH&#44; GH e TSH&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Foi medicado com cabergolina 2<span class="elsevierStyleHsp" style=""></span>mg&#47;semana&#46; Dez meses ap&#243;s in&#237;cio do tratamento&#44; a prolactina tinha um valor s&#233;rico de 1&#46;098<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; Proposto aumento da dose do agonista dopamin&#233;rgico &#40;AD&#41;&#44; que o doente recusou por motivos econ&#243;micos&#44; no entanto&#44; 14 meses ap&#243;s o in&#237;cio do tratamento apresentava doseamento de prolactina de 44&#44;1<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; Realizou reavalia&#231;&#227;o imagiol&#243;gica nessa altura&#44; que revelou persist&#234;ncia da les&#227;o j&#225; descrita&#44; com dimens&#245;es sobrepon&#237;veis mas com hipersinal espont&#226;neo em T1&#44; que pode corresponder a eventual foco hemorr&#225;gico &#40;<a class="elsevierStyleCrossRef" href="#fig0030">fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Coment&#225;rio</span><p id="par0095" class="elsevierStylePara elsevierViewall">Assim como nos casos cl&#237;nicos descritos&#44; a maioria das s&#233;ries referidas na literatura &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41; relata os prolactinomas gigantes como sendo mais prevalentes em homens com idade m&#233;dia ao diagn&#243;stico de 40 anos e com uma raz&#227;o homens&#47;mulheres de 9&#58;1<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1&#44;9</span></a>&#46; Os sintomas mais frequente s&#227;o resultado do efeito de massa e&#47;ou hiperprolactinemia com cefaleias&#44; altera&#231;&#245;es visuais&#44; oftalmoplegia por compress&#227;o do quiasma &#243;tico ou nervos oculomotores&#44; disfun&#231;&#227;o sexual&#44; ginecomastia&#44; amenorreia e hipogonadismo hipogonadotr&#243;fico<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1&#44;7</span></a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">O mecanismo respons&#225;vel pelo hipogonadismo nos prolactinomas gigantes parece estar relacionado com a diminui&#231;&#227;o dos n&#237;veis s&#233;ricos de LH e FSH consequentes &#224; diminui&#231;&#227;o da secre&#231;&#227;o de GnRH secund&#225;ria &#224; hiperprolactinemia&#44; da compress&#227;o da haste hipofis&#225;ria e do efeito de massa pelo tumor<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">10&#44;11</span></a>&#46; Cerca de 50&#37; dos doentes do sexo masculino com prolactinomas gigantes em tratamento com AD t&#234;m hipogonadismo persistente&#44; que &#233; tratado com testosterona<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">12</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Os prolactinomas gigantes frequentemente invadem estruturas adjacentes &#224; sela turca&#44; nomeadamente a cisterna suprasselar&#44; o seio esfenoide ou os seios cavernosos<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46; Raramente podem estender&#8208;se ao lobo temporal&#44; sendo respons&#225;veis por crises convulsivas ou altera&#231;&#245;es da personalidade<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">13</span></a>&#44; assim com invadir a base do cr&#226;nio&#44; a &#243;rbita ou a nasofaringe<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">14&#44;15</span></a>&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Estes tumores s&#227;o tipicamente invasivos&#44; contudo&#44; podem apresentar simultaneamente um comportamento agressivo definido pela resist&#234;ncia ao tratamento farmacol&#243;gico e &#224; recorr&#234;ncia ap&#243;s cirurgia<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">16&#44;17</span></a>&#46; Apenas os prolactinomas com met&#225;stases &#224; dist&#226;ncia s&#227;o considerados carcinomas&#44; sendo muito raros<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a>&#46; Nos prolactinomas invasivos foram investigados marcadores de prolifera&#231;&#227;o&#44; nomeadamente o &#237;ndice Ki&#8208;67&#44; o &#237;ndice mit&#243;tico e a muta&#231;&#227;o da prote&#237;na p53&#44; de forma a identificar os tumores com potencial de crescimento&#44; invas&#227;o e metastiza&#231;&#227;o e&#44; dessa forma&#44; decidir de forma precoce uma abordagem multidisciplinar<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">18&#8211;20</span></a>&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Diferentes abordagens de tratamento como os AD&#44; a cirurgia ou a radioterapia podem ser necess&#225;rios &#40;<a class="elsevierStyleCrossRef" href="#fig0035">fig&#46; 7</a>&#41; para alcan&#231;ar os alvos terap&#234;uticos&#44; nomeadamente a diminui&#231;&#227;o do volume tumoral&#44; a normaliza&#231;&#227;o dos n&#237;veis de prolactina e a restitui&#231;&#227;o do eugonadismo<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">No passado&#44; a cirurgia era a primeira op&#231;&#227;o para al&#237;vio r&#225;pido dos sintomas neurol&#243;gicos&#44; no entanto&#44; devido &#224;s taxas de mortalidade e morbilidade&#44; &#224; persist&#234;ncia de les&#227;o tumoral e &#224; crescente demonstra&#231;&#227;o da efic&#225;cia dos AD na redu&#231;&#227;o do volume tumoral&#44; a cirurgia foi perdendo o seu lugar de destaque no tratamento desta patologia<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">1&#44;21</span></a>&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">O uso dos AD cabergolina e bromocriptina est&#225; associado a uma redu&#231;&#227;o do tumor&#44; mesmo nos de grandes dimens&#245;es e nos que causam altera&#231;&#245;es visuais&#44; hidrocefalia&#44; exoftalmia ou sintomas neurol&#243;gicos&#44; sendo atualmente recomendados como a primeira linha no tratamento dos prolactinomas gigantes<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">5&#44;17&#44;22</span></a>&#46; A melhoria dos campos visuais pode ocorrer em 1&#8208;2 dias ap&#243;s a administra&#231;&#227;o dos AD&#44; com um tempo m&#233;dio de 5 dias&#44; e pode ser observado na aus&#234;ncia de uma resposta tumoral significativa<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">23</span></a>&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">A cabergolina &#233; o AD preferido devido &#224; sua efic&#225;cia na redu&#231;&#227;o das dimens&#245;es do tumor&#44; na normaliza&#231;&#227;o dos n&#237;veis de prolactina e tamb&#233;m devido &#224; sua excelente tolerabilidade&#46; A dose m&#233;dia varia entre 1&#44;4&#8208;4&#44;5<span class="elsevierStyleHsp" style=""></span>mg&#47;semana em v&#225;rias s&#233;ries publicadas<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">5&#44;12&#44;22&#44;24&#44;25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">tabela 2</a>&#41;&#44; no entanto&#44; 2<span class="elsevierStyleHsp" style=""></span>mg&#47;semana &#233; dose suficiente para controlo tumoral e bioqu&#237;mico da maioria dos prolactinomas<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a>&#46; A efic&#225;cia da cabergolina na melhoria dos campos visuais&#44; na melhoria da disfun&#231;&#227;o sexual e na revers&#227;o do hipogonadismo foi tamb&#233;m demonstrada<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">5&#44;22</span></a>&#46; Ainda n&#227;o existem estudos conclusivos sobre o resultado da cessa&#231;&#227;o dos AD nos prolactinomas gigantes&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">A efic&#225;cia da bromocriptina &#233; vari&#225;vel nos diferentes estudos com uma dose m&#233;dia usada de 10&#8208;40<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46; &#201; menos utilizada devido &#224; menor efic&#225;cia e &#224; maior incid&#234;ncia de n&#225;useas&#44; v&#243;mitos e hipotens&#227;o postural<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Alguns artigos referem que o uso de AD nas doses usadas para o tratamento da doen&#231;a de Parkinson pode estar associado a doen&#231;a valvular card&#237;aca severa&#44; no entanto&#44; as doses usadas no tratamento dos prolactinomas s&#227;o menores&#44; n&#227;o se verificando esta associa&#231;&#227;o em estudos recentes&#46; Contudo&#44; tratamentos de longa dura&#231;&#227;o com AD podem estar associados a les&#245;es subcl&#237;nicas como calcifica&#231;&#245;es na v&#225;lvula a&#243;rtica ou regurgita&#231;&#227;o tric&#250;spide leve a moderada<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">26&#44;27</span></a>&#46; Moraes et al&#46; recomendam a realiza&#231;&#227;o de ecocardiograma previamente &#224; introdu&#231;&#227;o de cabergolina e nos 3&#8208;6 meses ap&#243;s in&#237;cio do tratamento e&#44; se for detetada doen&#231;a valvular&#44; o doente n&#227;o deve ser tratado com cabergolina<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">A dose dos AD deve ser aumentada de acordo com a resposta e at&#233; &#224; toler&#226;ncia m&#225;xima do doente antes de ser proposta a cirurgia<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a>&#46; Os doentes que apresentam resist&#234;ncia &#224; ac&#231;&#227;o da bromocriptina podem subsequentemente responder &#224; cabergolina<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">28</span></a>&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">A remo&#231;&#227;o cir&#250;rgica de um prolactinoma gigante &#233; frequentemente parcial e a cura bioqu&#237;mica &#233; rara&#44; devendo ser considerada como parte de uma abordagem multidisciplinar para os tumores resistentes aos AD ou para os doentes intolerantes a esses f&#225;rmacos<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">7&#44;29</span></a>&#46; &#201; tratamento de primeira linha para os doentes que apresentam sinais de hipertens&#227;o intracraniana ou apoplexia hipofis&#225;ria com sintomas severos&#44; como altera&#231;&#245;es visuais recentes ou progressivas ou deteriora&#231;&#227;o do estado de consci&#234;ncia&#46; A via transesfenoidal&#44; usada frequentemente&#44; pode permitir uma ex&#233;rese eficaz dos componentes esfenoidal&#44; selar e suprasselar com baixa taxa de complica&#231;&#245;es<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">A radioterapia fica reservada para os doentes em que&#44; com os AD e com a cirurgia&#44; n&#227;o &#233; alcan&#231;ado o controlo da doen&#231;a&#44; permanecendo efeito de massa<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">17</span></a>&#46; O efeito adverso mais comum deste tratamento &#233; o hipopituitarismo e&#44; em casos raros&#44; a les&#227;o de nervos cranianos ou o desenvolvimento de um tumor secund&#225;rio<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">30&#8211;32</span></a>&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">A temozolomida &#233; um agente alquilante oral que inibe o crescimento de c&#233;lulas tumorais e que demonstrou alguma efic&#225;cia nos carcinomas da hip&#243;fise e nos prolactinomas gigantes agressivos que permanecem descontrolados apesar de m&#250;ltiplas modalidades de tratamento<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">33&#8211;35</span></a>&#46; &#201; habitualmente bem tolerada&#44; as n&#225;useas e a fadiga s&#227;o frequentes&#44; a leucopenia e trombocitopenia ocorrem em 4 e 17&#37; dos doentes&#44; respetivamente<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">36</span></a>&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Nos 3 casos apresentados os doentes negam ao diagn&#243;stico sintomas de altera&#231;&#245;es end&#243;crinas&#44; provavelmente pela progress&#227;o lenta do tumor&#44; o que poder&#225; ter atrasado o diagn&#243;stico&#44; mas reconhecem a melhoria sintom&#225;tica da astenia e da fun&#231;&#227;o sexual ap&#243;s resolu&#231;&#227;o bioqu&#237;mica da hiperprolactinemia e do hipogonadismo&#46; Em nenhum dos doentes foi necess&#225;ria medica&#231;&#227;o com testosterona e tamb&#233;m n&#227;o havia evid&#234;ncia de excesso ou d&#233;fice de outras hormonas produzidas&#47;libertadas pela hip&#243;fise&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Em 2 dos 3 casos apresentados o primeiro tratamento foi cir&#250;rgico&#46; O doente do primeiro caso foi submetido a ressec&#231;&#227;o transesfenoidal em 2001 pela extens&#227;o do tumor&#46; No segundo doente a apresenta&#231;&#227;o cl&#237;nica com diminui&#231;&#227;o recente&#44; mas progressiva da vis&#227;o conduziu &#224; decis&#227;o do neurocirurgi&#227;o pelo tratamento cir&#250;rgico&#44; tendo sido posteriormente encaminhado para a consulta de endocrinologia para in&#237;cio do tratamento com AD&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Dois doentes est&#227;o medicados com bromocriptina&#58; o doente do caso 2 por intoler&#226;ncia &#224; cabergolina e o do caso 1 por raz&#245;es econ&#243;micas &#40;a cabergolina &#233; substancialmente mais cara&#41;&#44; apesar do comportamento agressivo do tumor que recidivou em 2011 para as dimens&#245;es pr&#233;&#8208;cir&#250;rgicas&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">As doses de bromocriptina usadas no caso 1 e 2 est&#227;o de acordo com o descrito na literatura&#44; sendo que a dose m&#225;xima descrita usada &#233; de 40<span class="elsevierStyleHsp" style=""></span>mg&#47;dia&#46; Os 2<span class="elsevierStyleHsp" style=""></span>mg semanais de cabergolina com que o doente 3 se encontra medicado tamb&#233;m se encontram dentro dos valores descritos&#44; sendo que o tempo m&#233;dio at&#233; &#224; resposta m&#225;xima &#233; de 12&#8208;24 meses&#46; Contudo&#44; apesar da boa resposta bioqu&#237;mica com normaliza&#231;&#227;o dos n&#237;veis de prolactina&#44; o prolactinoma apresenta as mesmas dimens&#245;es&#44; pelo que ser&#225; proposto novamente ao doente aumentar a dose de cabergolina&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Os prolactinomas gigantes apresentam um desafio diagn&#243;stico e terap&#234;utico&#44; cujo diagn&#243;stico &#233; muitas vezes tardio&#46; Na maioria dos casos os sintomas relacionados com altera&#231;&#245;es end&#243;crinas n&#227;o s&#227;o valorizados e o tumor s&#243; &#233; identificado ap&#243;s o aparecimento de sintomas neurol&#243;gicos devido ao efeito de massa&#46; Os AD s&#227;o a primeira op&#231;&#227;o de tratamento e proporcionam uma diminui&#231;&#227;o marcada do tamanho tumoral&#44; melhoria dos sintomas neurol&#243;gicos e controlo dos n&#237;veis de prolactina&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">O papel do endocrinologista &#233; essencial na abordagem inicial destes doentes&#44; devendo fazer parte da equipa multidisciplinar o neurocirurgi&#227;o&#44; o oftalmologista e&#44; em casos mais espec&#237;ficos e raros&#44; o radioterapeuta e o oncologista&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conflito de interesses</span><p id="par0195" class="elsevierStylePara elsevierViewall">Os autores declaram n&#227;o haver conflito de interesses&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Os prolactinomas gigantes s&#227;o tumores raros&#44; mais frequentes em homens&#44; cujos crit&#233;rios de diagn&#243;stico incluem adenoma hipofis&#225;rio com maior eixo igual ou superior a 4<span class="elsevierStyleHsp" style=""></span>cm e extens&#227;o extrasselar&#44; valor s&#233;rico de prolactina &#8805;<span class="elsevierStyleHsp" style=""></span>1&#46;000<span class="elsevierStyleHsp" style=""></span>ng&#47;mL e exclus&#227;o de secre&#231;&#227;o concomitante de hormona de crescimento &#40;HC&#41; ou corticotrofina &#40;ACTH&#41;&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">S&#227;o descritos 3 casos de prolactinoma gigante&#44; todos em doentes do sexo masculino com idades ao diagn&#243;stico de 20&#44; 41 e 75 anos&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">O sintoma de apresenta&#231;&#227;o foi cefaleia em 2 casos &#40;uma associada a perda de vis&#227;o do OE&#41; e o terceiro caso foi um diagn&#243;stico incidental&#46; O doseamento de prolactina era superior a 4&#46;700<span class="elsevierStyleHsp" style=""></span>ng&#47;mL em todos os casos&#44; associado a um hipogonadismo hipogonadotr&#243;fico&#46; O tamanho m&#233;dio &#40;maior eixo&#41; da les&#227;o inicial foi de 4&#44;9<span class="elsevierStyleHsp" style=""></span>cm &#40;4&#8208;6<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; sendo 2 dos casos submetidos a ressec&#231;&#227;o transesfenoidal ao diagn&#243;stico&#46; Dois doentes est&#227;o sob tratamento m&#233;dico com bromocriptina e um medicado com cabergolina&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A bibliografia atual defende a op&#231;&#227;o inicial pelo tratamento m&#233;dico com cabergolina&#44; permanecendo a indica&#231;&#227;o cir&#250;rgica para os casos resistentes&#44; com sintomas compressivos graves ou doentes intolerantes aos agonistas dopamin&#233;rgicos&#46;</p></span>"
      ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Giant prolactinomas are rare tumors&#44; more frequent in men and whose diagnostic criteria include pituitary adenomas with a diameter of 4<span class="elsevierStyleHsp" style=""></span>cm or more&#44; extrasellar extension&#44; a serum prolactin &#8805;<span class="elsevierStyleHsp" style=""></span>1&#44;000<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; and no concomitant growth hormone &#40;GH&#41; or corticotropin &#40;ACTH&#41; secretion&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">We report on three cases of giant prolactinoma&#44; all in male patients with an age at diagnosis of 20&#44; 41 and 75 years&#46;</p><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">The presenting symptom was headache in 2 cases &#40;1 associated with vision loss of left eye&#41; the third case was an incidental diagnosis&#46; The prolactin assay was greater than 4700<span class="elsevierStyleHsp" style=""></span>ng&#47;ml in all cases associated with hypogonadotrophic hypogonadism&#46; The average size &#40;major axis&#41; of the initial lesion was 4&#46;9<span class="elsevierStyleHsp" style=""></span>cm &#40;4&#8208;6<span class="elsevierStyleHsp" style=""></span>cm&#41;&#44; 2 cases underwent trans&#8208;sphenoidal resection at diagnosis&#46; Two patients are under medical treatment with bromocriptine and one was medicated with cabergoline&#46;</p><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The current literature supports the initial option for medical treatment with cabergoline&#44; with surgical indication reserved for cases resistant to medical therapy&#44; patients with severe compressive symptoms or intolerant to dopamine agonists&#46;</p></span>"
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          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Involu&#231;&#227;o das dimens&#245;es lesionais face &#224; <a class="elsevierStyleCrossRef" href="#fig0005">figura 1</a>&#46;</p>"
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          "pt" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Redu&#231;&#227;o marcada das dimens&#245;es da les&#227;o neoformativa observada na <a class="elsevierStyleCrossRef" href="#fig0015">figura 3</a>&#46;</p>"
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          "pt" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Persist&#234;ncia da les&#227;o&#46;</p>"
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        "figura" => array:1 [
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          "pt" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Tratamento dos prolactinomas gigantes&#46;</p> <p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">&#42;Preferencialmente cabergolina&#46;</p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;Apoplexia&#44; altera&#231;&#245;es da vis&#227;o recentes ou progressivas&#44; altera&#231;&#227;o do n&#237;vel de consci&#234;ncia&#46;</p> <p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;&#42; Doseamento de PRL semestral&#44; RMN cerebral e campos visuais anualmente&#46; AD&#58; agonistas dopamin&#233;rgico&#59; HIC&#58; hipertens&#227;o intracraniana&#59; PRL&#58; prolactina&#59; RT&#58; radioterapia&#59;&#59; TZM&#58; temozolomida&#46; Adaptado de&#58; Moraes et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">7</span></a>&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Valores normais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Doente 1</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Doente 2</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Doente 3</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">In&#237;cio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Atual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">In&#237;cio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Atual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">In&#237;cio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Atual&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolactina&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;04&#8208;15&#44;2<span class="elsevierStyleHsp" style=""></span><br>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">676&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#46;847&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;<span class="elsevierStyleHsp" style=""></span>4&#46;700&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Testosterona&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#44;2&#8208;23&#44;0<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#44;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">FSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;5&#8208;12&#44;4<span class="elsevierStyleHsp" style=""></span>mUI&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;66&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">LH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;7&#8208;8&#44;6<span class="elsevierStyleHsp" style=""></span>mUI&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cortisol &#40;8<span class="elsevierStyleHsp" style=""></span>h&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ACTH &#40;8<span class="elsevierStyleHsp" style=""></span>h&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#8208;46<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">31&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8208;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TSH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;27&#8208;4&#44;2<span class="elsevierStyleHsp" style=""></span>uUI&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#44;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;08&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">T4 livre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;93&#8208;1&#44;70<span class="elsevierStyleHsp" style=""></span>ng&#47;dL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#44;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#44;18&nbsp;\t\t\t\t\t\t\n
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ISSN: 16463439
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