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Serum prolactin (PRL) levels exhibit a gradual rise both in male and female rats from birth to adulthood, with females consistently displaying higher levels compared to age-matched males. This pattern has traditionally been attributed to the development and maturation of endocrine and neuroendocrine networks responsible for regulating PRL synthesis and secretion. However, the effect of dopamine (DA), which acts as an inhibitory factor on lactotroph function, also increases from birth to puberty, particularly in females. Nonetheless, the secretion of PRL remains higher in females compared to males. On the other hand, the observed sex differences in serum PRL levels during early postnatal development cannot be attributed to the influence of estradiol (E2). While serum E2 levels gradually increase after birth, only after 45 days of life do the disparities in E2 levels between females and males become evident. These observations collectively suggest that neither the maturation of hypothalamic DA regulation nor the rise in E2 levels can account for the progressive and sustained elevation in serum PRL levels and the observed sexual dimorphism during postnatal development. This review highlights the importance of recent discoveries in animal models that shed light on inhibitory mechanisms in the control of PRL secretion within the pituitary gland itself, that is intrapituitary mechanisms, with a specific emphasis on the role of transforming growth factor ß1 and activins in PRL secretion.
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INTRODUCTION: Prolactinomas are the most frequent pituitary tumor subtype. Despite most of them respond to medical treatment, a proportion are resistant and become a challenge in clinical management. Wnt/ß-Catenin pathway has been implicated in several cancers including pituitary tumors and other sellar region malignancies. Interestingly, Wnt/ß-Catenin inhibition augments the cytotoxicity of the chemotherapeutic agent Temozolomide (TMZ) in different cancers. TMZ is now being implemented as rescue therapy for aggressive pituitary adenoma treatment. However, the molecular mechanisms associated with TMZ action in pituitary tumors remain unclear. OBJECTIVES: Our aims in the present study were to evaluate differential ß-Catenin expression in human resistant prolactinomas and Wnt/ß-Catenin signaling activation and involvement in Prolactin (PRL) secreting experimental models treated with TMZ. RESULTS: We first evaluated by immunohistochemistry ß-Catenin localization in human resistant prolactinomas in which we demonstrated reduced membrane ß-Catenin in prolactinoma cells compared to normal pituitaries, independently of the Ki-67 proliferation indexes. In turn, in vivo 15âmg/kg of orally administered TMZ markedly reduced PRL production and increased prolactinoma cell apoptosis in mice bearing xenografted prolactinomas. Intratumoral ß-Catenin strongly correlated with Prl and Cyclin D1, and importantly, TMZ downregulated both ß-Catenin and Cyclin D1, supporting their significance in prolactinoma growth and as candidates of therapeutic targets. When tested in vitro, TMZ directly reduced MMQ cell viability, increased apoptosis and produced G2/M cell cycle arrest. Remarkably, ß-Catenin activation and VEGF secretion were inhibited by TMZ in vitro. CONCLUSIONS: We concluded that dopamine resistant prolactinomas undergo a ß-Catenin relocalization in relation to normal pituitaries and that TMZ restrains experimental prolactinoma tumorigenicity by reducing PRL production and ß-Catenin activation. Together, our findings contribute to the understanding of Wnt/ß-Catenin implication in prolactinoma maintenance and TMZ therapy, opening the opportunity of new treatment strategies for aggressive and resistant pituitary tumors.
Assuntos
Neoplasias Hipofisárias , Prolactinoma , Animais , Ciclina D1 , Humanos , Camundongos , Modelos Teóricos , Neoplasias Hipofisárias/patologia , Prolactina/metabolismo , Prolactina/uso terapêutico , Prolactinoma/tratamento farmacológico , Prolactinoma/metabolismo , Prolactinoma/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , beta CateninaRESUMO
Among pituitary adenomas, prolactinomas are the most frequently diagnosed (about 50%). Dopamine agonists are generally effective in the treatment of prolactinomas. However, a subset of about 25% of patients does not respond to these agents. The management of drug-resistant prolactinomas remains a challenge for endocrinologists and new inhibitory treatments are needed. Pituitary activins inhibit lactotroph function. Its expression and action were found reduced in animal models of lactotroph hyperplasia (female mice overexpressing the B subunit of the human chorionic gonadotrophin and female mice knockout for dopamine receptor type 2). In these models, an oophorectomy avoids prolactinoma development. Hormonal replacement with oestradiol and/or progesterone is not enough to reach the tumor size observed in transgenic females. We postulated that the loss of gonadal inhibins after an oophorectomy contributes to prevent hyperplasia development. Here, we demonstrated that an oophorectomy at 2 months age recovers the following in adulthood: (i) pituitary activin expression, (ii) activin receptor expression specifically in lactotroph population, (iii) activin biological activity in lactotrophs with a concomitant reduction of Pit-1 expression. To summarize, when an oophorectomy is performed, inhibins are lost and the inhibitory action of pituitary activins on lactotroph population is recovered, helping to prevent lactotroph hyperplasia development. These results emphasize the importance of the inhibitory action of activins on lactotroph function, positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.
Assuntos
Lactotrofos , Neoplasias Hipofisárias , Prolactinoma , Ativinas/metabolismo , Adulto , Animais , Feminino , Humanos , Hiperplasia , Inibinas/metabolismo , Inibinas/uso terapêutico , Lactotrofos/metabolismo , Lactotrofos/patologia , Camundongos , Ovariectomia , Neoplasias Hipofisárias/metabolismo , Prolactina/metabolismo , Prolactinoma/metabolismo , Prolactinoma/prevenção & controleRESUMO
INTRODUCTION: Cabergoline is the treatment of choice for prolactinomas. However, 10-20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. SUBJECTS AND METHODS: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26-61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38-386 ng/mL) under cabergoline treatment (2-7 mg/week) for at least 6 months (6-108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0-2.5 g v.o./day) was given according to patients' tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30-60 days) and long-term (120-180 days) metformin treatment. RESULTS: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30-60 days, and at 120-180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0-2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. CONCLUSION: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.
Assuntos
Cabergolina/farmacologia , Agonistas de Dopamina/farmacologia , Hiperprolactinemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Síndrome Metabólica/tratamento farmacológico , Metformina/farmacologia , Prolactina/efeitos dos fármacos , Prolactinoma/tratamento farmacológico , Adulto , Cabergolina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Resistência a Medicamentos/fisiologia , Quimioterapia Combinada , Feminino , Humanos , Hiperprolactinemia/sangue , Hipoglicemiantes/administração & dosagem , Síndrome Metabólica/sangue , Metformina/administração & dosagem , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Projetos Piloto , Prolactina/sangue , Prolactinoma/sangue , Estudos ProspectivosRESUMO
Hyperprolactinemia, defined by a level of serum prolactin above the standard upper limit of normal range, is a common finding in clinical practice and prolactinomas are the main pathological cause. Prolactinomas lead to signs and symptoms of hormone oversecretion, such as galactorrhea and hypogonadism, as well as symptoms of mass effect, including visual impairment, headaches and intracranial hypertension. Diagnosis involves prolactin measurement and sellar imaging, but several pitfalls are involved in this evaluation, which may difficult the proper management. Treatment is medical in the majority of cases, consisting of dopamine agonists, which present high response rates, with a very favorable safety profile. Major adverse effects that should be monitored consist of cardiac valvulopathy and impulse control disorders. Other treatment options include surgery and radiotherapy. Temozolomide may be used for aggressive or malignant carcinomas. Finally, pregnancy outcomes are similar to general population even when dopamine agonist treatment is maintained.
Assuntos
Neoplasias Hipofisárias , Prolactinoma , Antineoplásicos Alquilantes/uso terapêutico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico , Transtornos Disruptivos, de Controle do Impulso e da Conduta/etiologia , Agonistas de Dopamina/uso terapêutico , Feminino , Galactorreia/etiologia , Humanos , Hiperprolactinemia/etiologia , Hipogonadismo/etiologia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/terapia , Gravidez , Prolactina/sangue , Prolactinoma/complicações , Prolactinoma/diagnóstico , Prolactinoma/epidemiologia , Prolactinoma/terapia , Sela Túrcica/diagnóstico por imagem , Temozolomida/uso terapêuticoRESUMO
Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRß was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/ß, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.
Assuntos
Neoplasias Hipofisárias/prevenção & controle , Progesterona/farmacologia , Prolactina/metabolismo , Prolactinoma/prevenção & controle , Receptores de Dopamina D2/fisiologia , Receptores de Progesterona/agonistas , Animais , Gonadotropina Coriônica Humana Subunidade beta/genética , Gonadotropina Coriônica Humana Subunidade beta/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/patologia , Prolactinoma/etiologia , Prolactinoma/patologia , Ratos , Transdução de SinaisRESUMO
ABSTRACT Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.
Assuntos
Humanos , Masculino , Feminino , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/terapia , Hiperprolactinemia/diagnóstico , Hiperprolactinemia/terapia , Prolactinoma/diagnóstico , Guias de Prática Clínica como Assunto , Prolactina/sangue , Brasil , Prolactinoma/terapia , Bromocriptina/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Ergolinas/uso terapêutico , Cabergolina , Antineoplásicos/uso terapêuticoRESUMO
Os prolactinomas são o tipo mais comum de tumores secretores da hipófise. Todos os pacientes portadores de prolactinoma sintomáticos ou com crescimento evidente requerem tratamento; sendo a principal terapia o uso de agonistas dopaminérgicos. O aumento da impulsividade e o surgimento de transtornos de controle de impulsos têm sido descritos na terapia com fármacos desta classe. O objetivo primário desse estudo é avaliar a frequência de TCI em pacientes portadores de prolactinoma em tratamento com agonistas dopaminérgicos e identificar possíveis fatores associados a patologia. Materiais e métodos: Trata se de um estudo transversal em que um questionário foi aplicado durante as consultas ambulatoriais, a fim de fazer rastreio de TCIs, e foram obtidos ainda informações médicas relativas a história e tratamento do tumor durante seguimento. Resultados: no grupo em uso de cabergolina tivemos prevalência de 12,5% de TCIs relacionado ao sexo e 12,5% relacionados a compras. No grupo controle não houveram casos de TCIs relacionados ao sexo e tivemos 66,66% de rastreio positivo para TCI para compras. Conclusão: Não foi possível caracterizar completamente o uso de AD com desenvolvimento de ambos os TCI. Há possibilidade de que os próprios tumores pituitários possam contribuir com um risco independente adicional para o desenvolvimento do TCI. Os médicos que prescrevem agonistas de dopamina devem ficar atentos a esses efeitos colaterais potenciais no início do tratamento e nas consultas subsequentes da clínica
Assuntos
Prolactinoma , Transtornos Disruptivos, de Controle do Impulso e da CondutaRESUMO
The improved management of pituitary adenomas has led to an increasing number of pregnancies in patients harboring pituitary adenomas. Therefore, adequate management of pregnant women with pituitary adenomas is of growing importance. Because pregnancy produces several physiologic changes to the endocrine system, especially to the pituitary gland, endocrinologists must be knowledgeable and skilled to effectively manage pregnant women with pituitary adenomas and to guarantee the wellbeing of the fetus.
Assuntos
Síndrome de Cushing/terapia , Hiperpituitarismo/terapia , Neoplasias Hipofisárias/terapia , Complicações Neoplásicas na Gravidez/terapia , Feminino , Humanos , GravidezRESUMO
Introdução: Os prolactinomas são os adenomas hipofisários mais comuns, representando 60% dos casos. Tratam-se de tumores geralmente benignos da hipófise, secretores de prolactina (PRL), que ocorrem sobretudo em mulheres com menos de 50 anos. O tratamento medicamentoso dos prolactinomas com agonistas dopaminéricos (AD) é muito eficaz e bem tolerado, levando à redução dos níveis séricos de PRL e até mesmo diminuição do tamanho do tumor, até mesmo com o seu desaparecimento em alguns casos. Atualmente, os AD utilizados para o tratamento de prolactinomas são representados pela bromocriptina (BC) e pela cabergolina (CAB), sendo este último o mais utilizado devido à maior tolerância e eficácia. O uso desta classe de medicação na doença do Parkinson ocasionou lesões valvulares cardíacas fibróticas. Objetivos: Avaliar o risco de lesão em válvulas cardíacas nos pacientes com prolactinomas e que fizeram o tratamento com CAB.Métodos: Estudo tipo caso-controle com análise comparativa de 20 casos do ambulatório e neuroendocrinologia da clínica de endocrinologia HSPM-SP e 20 controles do ambulatório de ecocardiograma do HSPM-SP, sendo avaliados os ecocardiogramas de ambos os grupos e analisados a morfologia e funcionalidade das válvulas cardíacas. Resultados: Em relação aos 20 ecocardiogramas dos casos, 6 estavam alterados, apresentando refluxos mitral e/ou tricúspide leves. Dos 20 ecocardiogramas dos controles, 12 apresentaram alterações, desde 1 com calcificação mitral e os demais com refluxo mitral e/ou tricúspides leves. Conclusão: Nosso trabalho não mostrou aumento da incidência de valvulopatia cardíaca em pacientes com prolactinomas tratados sob regimes habituais de CAB quando comparado com controles. Devemos usar a menor dose eficaz de cabergolina e solicitar ecocardiogramas se tratamentos longos e/ou com doses elevadas para farmacovigilância, como proposto pela agência européia de medicações
Assuntos
Humanos , Prolactinoma , Agonistas de Dopamina , Bromocriptina , Valvas CardíacasRESUMO
Introducción y Objetivos: La angiogénesis es un proceso fundamental en el desarrollo tumoral. Sin embargo, se han encontrado discrepancias en el patrón angiogénico de los tumores hipofisarios. Nos propusimos estudiar la expresión de VEGF y FGF2 y su importancia en la vascularización de los adenomas hipofisarios, cuantificar los vasos con los marcadores CD31 y CD34 y determinar el índice de proliferación con PCNA y Ki67. Materiales y Métodos: Se estudiaron 76 macroadenomas hipofisarios que fueron intervenidos quirúrgicamente. Los adenomas se clasificaron según su secreción hormonal. A partir de cortes histológicos se realizó inmunohistoquímica para los marcadores de endotelio CD31 y CD34; y Ki-67 para estudio de proliferación celular. Por western blot se midieron VEGF, CD31 y PCNA. Se efectuaron comparaciones con glándulas normales. Resultados: El nivel de expresión de VEGF, hallado en todas las muestras analizadas, resultó mayor en los prolactinomas resistentes respecto a los demás tipos de adenomas hipofisarios. Esta proteína localizó en las células endoteliales de los vasos como así también en citoplasmas y núcleos de células tumorales. El 56 % de las muestras resultaron positivas para FGF2, mostrando localización citoplasmática y en matriz extracelular. Obtuvimos una fuerte correlación positiva entre VEGF y CD31 en las muestras tumorales, sin encontrar correlación lineal entre PCNA y VEGF, ni Ki-67 y VEGF en las muestras estudiadas. El área vascular resultó mayor en los tejidos normales que en los tumores utilizando CD34 como marcador de vasos. Conclusión: La importancia del estudio de la angiogénesis en los adenomas hipofisarios radica en la necesidad de hallar marcadores moleculares que predigan el comportamiento tumoral. Pudimos demostrar la expresión de los factores angiogénicos VEGF y FGF2 en estos adenomas, y la existencia de correlación lineal entre VEGF y CD31. Nuestros resultados son indicativos de existencia de angiogénesis en los adenomas hipofisarios por lo que su bloqueo podría plantearse como una estrategia alternativa para los casos resistentes a las terapias convencionales.
Introduction and objectives: Angiogenesis is an essential process in tumor development. Nevertheless, discrepancies in the angiogenic pattern of pituitary tumors, in terms of hormonal phenotype, size or invasiveness have been found. Our aim was to study the expression of VEGF and FGF2 growth factors, and their importance in the vascularization of pituitary adenomas. We also quantified blood vessels with the endothelial cell markers CD31 and CD34 determining the vascular area, and the proliferation rate through PCNA and Ki67 index. Materials and Methods: We studied 76 pituitary macroadenomas that were surgically resected in the period between 2006 and 2010 from a total of 276 patients with this pathology. Adenomas were classified into prolactinomas (PRL), somatotropinomas (GH), corticotropinomas (ACTH), non-functioning (NF) and plurihormonal (Ph) according to their hormonal secretion. Samples were collected in formalin, embedded in paraffin, and immunohistochemistry was performed from histological sections for endothelial markers CD31 and CD34; and for Ki-67 to study cell proliferation. VEGF, CD31 and PCNA were measured by Western blot. We compared results with normal glands (N=6). Results: VEGF expression levels, found in all of the samples analyzed, were higher in resistant prolactinomas than in other pituitary adenomas. This protein was detected in endothelial cells of blood vessels and in tumor cells cytoplasms and nuclei. Fifty-six percent of samples were positive for FGF2, the other potent angiogenic factor studied, showing cytoplasmatic and extracellular matrix localization. We obtained a strong positive correlation between VEGF and CD31 in tumor samples, but we did not find lineal correlation between PCNA and VEGF, or between Ki-67 and VEGF in the samples studied. The vascular area was higher in normal tissues than in tumors when CD34 was used as endothelial cell marker. Conclussion: The importance of studying angiogenesis in pituitary adenomas lies in the need to find molecular markers that can predict tumor behavior. We could demonstrate the expression of VEGF and FGF2, two potent angiogenic factors, and the existence of linear correlation between VEGF and CD31. Our results are indicative of the existence of angiogenesis in pituitary adenomas; therefore the blockage of angiogenesis might be proposed as an alternative strategy for cases of resistance to standard therapy.
RESUMO
Introducción y Objetivos: La angiogénesis es un proceso fundamental en el desarrollo tumoral. Sin embargo, se han encontrado discrepancias en el patrón angiogénico de los tumores hipofisarios. Nos propusimos estudiar la expresión de VEGF y FGF2 y su importancia en la vascularización de los adenomas hipofisarios, cuantificar los vasos con los marcadores CD31 y CD34 y determinar el índice de proliferación con PCNA y Ki67. Materiales y Métodos: Se estudiaron 76 macroadenomas hipofisarios que fueron intervenidos quirúrgicamente. Los adenomas se clasificaron según su secreción hormonal. A partir de cortes histológicos se realizó inmunohistoquímica para los marcadores de endotelio CD31 y CD34; y Ki-67 para estudio de proliferación celular. Por western blot se midieron VEGF, CD31 y PCNA. Se efectuaron comparaciones con glándulas normales. Resultados: El nivel de expresión de VEGF, hallado en todas las muestras analizadas, resultó mayor en los prolactinomas resistentes respecto a los demás tipos de adenomas hipofisarios. Esta proteína localizó en las células endoteliales de los vasos como así también en citoplasmas y núcleos de células tumorales. El 56 % de las muestras resultaron positivas para FGF2, mostrando localización citoplasmática y en matriz extracelular. Obtuvimos una fuerte correlación positiva entre VEGF y CD31 en las muestras tumorales, sin encontrar correlación lineal entre PCNA y VEGF, ni Ki-67 y VEGF en las muestras estudiadas. El área vascular resultó mayor en los tejidos normales que en los tumores utilizando CD34 como marcador de vasos. Conclusión: La importancia del estudio de la angiogénesis en los adenomas hipofisarios radica en la necesidad de hallar marcadores moleculares que predigan el comportamiento tumoral. Pudimos demostrar la expresión de los factores angiogénicos VEGF y FGF2 en estos adenomas, y la existencia de correlación lineal entre VEGF y CD31. Nuestros resultados son indicativos de existencia de angiogénesis en los adenomas hipofisarios por lo que su bloqueo podría plantearse como una estrategia alternativa para los casos resistentes a las terapias convencionales.(AU)
Introduction and objectives: Angiogenesis is an essential process in tumor development. Nevertheless, discrepancies in the angiogenic pattern of pituitary tumors, in terms of hormonal phenotype, size or invasiveness have been found. Our aim was to study the expression of VEGF and FGF2 growth factors, and their importance in the vascularization of pituitary adenomas. We also quantified blood vessels with the endothelial cell markers CD31 and CD34 determining the vascular area, and the proliferation rate through PCNA and Ki67 index. Materials and Methods: We studied 76 pituitary macroadenomas that were surgically resected in the period between 2006 and 2010 from a total of 276 patients with this pathology. Adenomas were classified into prolactinomas (PRL), somatotropinomas (GH), corticotropinomas (ACTH), non-functioning (NF) and plurihormonal (Ph) according to their hormonal secretion. Samples were collected in formalin, embedded in paraffin, and immunohistochemistry was performed from histological sections for endothelial markers CD31 and CD34; and for Ki-67 to study cell proliferation. VEGF, CD31 and PCNA were measured by Western blot. We compared results with normal glands (N=6). Results: VEGF expression levels, found in all of the samples analyzed, were higher in resistant prolactinomas than in other pituitary adenomas. This protein was detected in endothelial cells of blood vessels and in tumor cells cytoplasms and nuclei. Fifty-six percent of samples were positive for FGF2, the other potent angiogenic factor studied, showing cytoplasmatic and extracellular matrix localization. We obtained a strong positive correlation between VEGF and CD31 in tumor samples, but we did not find lineal correlation between PCNA and VEGF, or between Ki-67 and VEGF in the samples studied. The vascular area was higher in normal tissues than in tumors when CD34 was used as endothelial cell marker. Conclussion: The importance of studying angiogenesis in pituitary adenomas lies in the need to find molecular markers that can predict tumor behavior. We could demonstrate the expression of VEGF and FGF2, two potent angiogenic factors, and the existence of linear correlation between VEGF and CD31. Our results are indicative of the existence of angiogenesis in pituitary adenomas; therefore the blockage of angiogenesis might be proposed as an alternative strategy for cases of resistance to standard therapy.(AU)
RESUMO
Os prolactinomas são os tumores hipofisários mais comuns e sua frequência varia de acordo com a idade e sexo. É uma importante causa de hipogonadismo e infertilidade e dependendo do tamanho e da extensão tumoral, pode levar a sintomas compressivos, como cefaléia, perda visual e comprometimento de pares cranianos. Os agonistas dopaminérgicos (ADs) são o tratamento de escolha para os pacientes com prolactinomas. Atualmente, a dúvida não é mais se o AD deve ou não ser interrompido, e sim qual seria o momento ideal para sua retirada.Objetivos: Analisar os resultados do tratamento clínico dos pacientes com prolactinomas do nosso serviço de Endocrinologia do Hospital do Servidor Público Municipal (HSPM) e realizar revisão bibliográfica sobre o tema. O estudo também teve como objetivo caracterizar, na população estudada, apresentação clínico-laboratorial e radiológica no momento do diagnóstico e sua evolução durante e após a suspensão do tratamento.Materiais e métodos: Foram analisados 24 prontuários de pacientes com diagnóstico de prolactinoma do nosso ambulatório de Neuroendocrinologia do Hospital do Servidor Público Municipal que receberam tratamento medicamentoso, e 12 preencheram critérios de inclusão. Resultados: Dos 12 pacientes analisados, 7 obtiveram normoprolactinemia após 6 meses da interrupção do tratamento e 5 pacientes a mantiveram após 1 ano. Dos 7 pacientes, 100% eram do sexo feminino, a média de idade dos pacientes foi de 37,4 ± 9,4 anos e os sinais e sintomas encontrados foram galactorréia, oligoamenorréia, diminuição de libido e hirsutismo. A mediana encontrada do nível de prolactina (PRL) inicial nos 7 pacientes foi de 178 pg/mL. O microprolactinoma foi mais prevalente. Dos pacientes com remissão após 1 ano da interrupção do tratamento, o tempo médio de uso dos ADs foi de 74,7 ±43,2 meses; enquanto que nos pacientes que recidivaram antes de 1 ano, o tempo médio de uso foi de 15,5 ± 0,7 meses. Conclusão: O tratamento com AD é muito eficaz e bem tolerado nos pacientes com prolactinomas. A suspensão pode ser tentada, mas acompanhamento é necessário pela possibilidade de recidiva. Mais longo tempo de tratamento parece ter maior impacto no sucesso da remissão. Com esses dados esperamos conseguir desenvolver um protocolo de tratamento e retirada dos ADs em pacientes com prolactinomas no nosso serviço de endocrinologia.
Assuntos
Dopaminérgicos , ProlactinomaRESUMO
Introducción: La terapia de elección de los prolactinomas son los agonistas dopaminérgicos, cuyo principal exponente es la bromocriptina, sin embargo, hay pacientes que no responden o presentan severos efectos secundarios (resistentes o intolerantes a bromocriptina, respectivamente). El objetivo en este estudio fue valorar la respuesta al uso de cabergolina en pacientes con prolactinomas, intolerantes o resistentes a bromocriptina Material y métodos: Se estudiaron 27 pacientes (25 mujeres y dos varones) en quienes se realizó determinación basal de prolactina y cada mes hasta completar tres meses, registrando los datos asociados a hiperprolactinemia y los efectos secundarios. La dosis inicial fue de 0.25 mg los lunes y jueves durante la primera semana, y 0.5 mg a partir de la segunda. El análisis estadístico incluyó la prueba de Shapiro-Wilk, Kruskal-Wallis y Anova. Resultados: 22 pacientes presentaron microadenomas y cinco macroadenomas. En los intolerantes (n = 11) el valor inicial de prolactina de 61.45 ± 19.82 disminuyó al tercer mes a 4.94 ± 1.79 (p < 0.024). En los resistentes (n = 16), el valor basal fue 119.53 ± 11.52; 15 pacientes redujeron significativamente a 12.95 ± 3.66 (p < 0.005) al tercer mes de tratamiento. En ambos, los signos atribuibles a la hiperprolactinemia mejoraron significativamente, con poca incidencia de efectos secundarios. Conclusiones: La cabergolina es útil en la mayoría de los pacientes considerados intolerantes o resistentes a la bromocriptina.
BACKGROUND: Dopaminergic agonists are the treatment of choice for prolactinomas with bromocriptine (BCE) being the primary agent used. There is a group of patients who are not responders to such therapy or have severe side effects (resistant or intolerant to BCE, respectively). We undertook this study to evaluate the response to the administration of cabergoline (CBG) in patients intolerant or resistant to BCE. METHODS: Twenty seven patients (25 females and 2 males) were recruited with prolactin-pituitary tumors, obtaining basal serum prolactin (PRL) samples and again each month up to 3 months. We recorded signs associated with hyperprolactinemia and secondary effects of CBG. The initial dose was 0.25 mg twice weekly during the first week, with an increase to 0.5 mg twice weekly from the second week until the conclusion of the study. Statistical analysis included Shapiro-Wilk, Kruskal-Wallis and ANOVA tests. RESULTS: Twenty two patients had microadenomas and five had macroadenomas. In the intolerant group (n= 11), the initial PRL value (61.45 +/- 19.82) decreased by the third month to 4.94 +/- 1.79 (p<0.024). In the resistant group (n= 16), basal PRL values were 119.53 +/- 11.52. In 15 of these patients, the PRL value significantly decreased to 12.95 +/- 3.66 ng/ml (p<0.005) by the third month of treatment. In both groups the signs related to hyperprolactinemia significantly improved, with a low incidence of secondary effects due to CBG. CONCLUSIONS: CBG is useful in most patients considered as intolerant or resistant to BCE.