Thèse-Bern. / "Litérature": p. 24.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2016. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-12-08T19:23:49Z No. of bitstreams: 1 2016_MariadeFátimadeMagalhãesGonzaga.pdf: 5144127 bytes, checksum: cb59574d03a568889d6d7b757bf394f8 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2017-01-13T17:59:45Z (GMT) No. of bitstreams: 1 2016_MariadeFátimadeMagalhãesGonzaga.pdf: 5144127 bytes, checksum: cb59574d03a568889d6d7b757bf394f8 (MD5) / Made available in DSpace on 2017-01-13T17:59:45Z (GMT). No. of bitstreams: 1 2016_MariadeFátimadeMagalhãesGonzaga.pdf: 5144127 bytes, checksum: cb59574d03a568889d6d7b757bf394f8 (MD5) / Introdução. O tratamento preferencial dos prolactinomas é realizado com agonistas da dopamina porque eles oferecem melhores resultados em controlar a doença do que a cirurgia de exérese do tumor. Contudo, alguns poucos adenomas apresentam resistência ao tratamento com os agonistas da dopamina. Objetivo. Avaliar o comportamento de pacientes portadores de prolactinoma resistentes ao tratamento com os agonistas da dopamina, em acompanhamento a longo prazo. Métodos. Estudo retrospectivo de estudo de série de casos. Foram considerados resistentes aos agonistas da dopamina, os pacientes que não normalizaram as concentrações sanguíneas de prolactina e não obtiveram redução de mais de 50% do volume tumoral, com a dose de no mínimo 2,0 mg de cabergolina por semana. Dez pacientes com diagnóstico de prolactinoma resistente à agonista de dopamina, sendo nove deles acompanhados na Clínica de Neurologia e Endocrinologia (CLINEN) e um no Hospital Universitário de Brasília. Resultados. Três pacientes receberam tratamento com a bromocriptina antes de iniciar a cabergolina. Sete pacientes receberam tratamento com cabergolina exclusivamente. Na época do diagnóstico, as idades variaram de 11 a 62 anos. A prolactina inicial variou de 128 ng/mL a 14.992 ng/mL e na última avaliação variou de 4,1 ng/mL a 2169 ng/mL. As doses máximas por semana da cabergolina variaram de 2,5 mg a 4,5 mg. O tempo de acompanhamento variou de 3 anos a 17 anos. A normalização da prolactina aconteceu em duas mulheres e em dois homens. A regressão tumoral ocorreu em todos pacientes, mas o desaparecimento total do adenoma com a formação de sela vazia ocorreu em três pacientes. Três pacientes foram submetidos à cirurgia, mas somente uma mulher teve cura da doença. Conclusão. Este estudo de série de casos sugere que os tumores com resistência aos agonistas da dopamina podem ser mais agressivos em homens do que em mulheres; que o tumor a longo prazo pode regredir com o continuar do tratamento com dose baixa ou alta de cabergolina, mesmo nos macroprolactinomas e o controle efetivo da prolactina ocorre em poucos pacientes. ________________________________________________________________________________________________________ ABSTRACT / Introduction.The preferential treatment of prolactinoma is with dopamine agonists because they have better results in controlling the disease than the tumor excision surgery. However, some few adenomas show resistance to treatment with dopamine agonists. Objective.To evaluate the behavior of patients with prolactinoma resistant to treatment with dopamine agonists in long-term follow-up. Methods.Retrospective study of case series study. Patients who did not normalize blood concentrations of prolactin and had no more than 50% reduction of tumoral volume, with the dose of at least 2.0 mg of cabergoline per week, were considered resistant to agonists. Ten patients with diagnosis of prolactinoma resistant to dopamine agonist, nine of them followed in the Clinic of Neurology and Endocrinology (CLINEN) and one at the University Hospital of Brasilia. Results. Three patients received treatment with bromocriptine before starting the cabergoline. Seven patients received treatment with cabergoline exclusively. At the time of diagnosis, the ages ranged from 11 to 62 years old. The initial prolactin ranged from 128 ng/mL to 14.992 ng/mL and that last evaluation ranged from 4.1 ng/mL to 2.169 ng/mL. The maximum weekly doses of cabergoline ranged from 2.5 mg to 4.5 mg. The follow-up time ranged from 3 years to 17 years. The normalization of prolactin happened in two women and two men. The tumoral regression occurred in all patients, but the complete disappearance of the adenoma with empty sella formation occurred in three patients.Three patients were also submitted to a surgery, but only one woman had cure of the disease. Conclusion. This case series study suggests that tumors resistant to dopamine agonists can be more aggressive in men than women; that the long-term tumor, even the macroprolactinomas, can regress with the continue treatment with low or high doses of cabergoline,and that the control of prolactin can occur in a fraction of patients.

Submitted by Alexandra Feitosa (alexandra.feitosa@ufpe.br) on 2017-07-25T14:27:48Z No. of bitstreams: 1 2011-dissertação-joséLucianoFrançaAlbuquerque.pdf: 1044823 bytes, checksum: 4092919a43a1c83613d188603b5d5457 (MD5) / Made available in DSpace on 2017-07-25T14:27:49Z (GMT). No. of bitstreams: 1 2011-dissertação-joséLucianoFrançaAlbuquerque.pdf: 1044823 bytes, checksum: 4092919a43a1c83613d188603b5d5457 (MD5) Previous issue date: 2011-08-15 / A hiperprolactinemia é o distúrbio endócrino mais comum do eixo hipotálamo-hipofisário. Caracteriza-se pela elevação consistente dos valores plasmáticos desse hormônio. As características clínicas clássicas são distúrbios do ciclo menstrual, amenorréia, galactorréia, infertilidade e diminuição da libido. Distúrbios psiquiátricos, particularmente a ansiedade e a depressão, têm sido associados à hiperprolactinemia há mais de três décadas. Para avaliar a presença de sintomas depressivos, foram submetidos à entrevista através do Inventário de Depressão de Beck (IDB), 60 pacientes portadores de prolactinoma, sendo 30 pacientes com hiperprolactinemia e 30 pacientes normoprolactinêmicos em uso de Cabergolina (prolactina (PRL) média: 241,08 vs 25,92 ng/ml, p<0,001). A pontuação do IDB foi significativamente maior entre os hiperprolactinêmicos (15,07 ± 7,89 vs 7,53 ± 8,20, p<0,001). Foi verificada correlação positiva entre o nível sérico de PRL e a pontuação do IDB (r = 0,573 p<0,001).Entre oshiperprolactinêmicos, 14 pacientes apresentaram pontuação do IDB correspondente a transtornos do humor. Tais pacientes foram tratados com cabergolina por 2 meses. Houve redução significativa nos valores da PRL (média 241,08 vs 25,92, p<0,001) e da pontuação do IDB (média 22,15 vs 11,54, p<0,001). Encontramos correlação positiva entre as variações da prolactina e da pontuação do IDB (r = 0,557, p = 0,048). No presente estudo, observamos maior frequência de sintomas depressivos entre hiperprolactinêmicos, com correlação positiva entre o nível sérico de PRL e a presença de sintomas, além de encontrarmos melhora da sintomatologia com o tratamento da hiperprolactinemia. / Hyperprolactinemia is the most common disorder of the hypothalamus-hypophysis axis. It is characterized by elevated serum prolactin levels. The classic clinical features are menstrual cycle disorders, amenorrhea, galactorrhea, infertility and libido decrease. Psychyatric disturbances, particularlyanxiety and depression,have been associated to hyperprolactinemia for more than three decades. Toevaluate the presence ofdepressive symptoms, 60 patients with prolactinoma, divided into two groups: 30 patients with hyperprolactinemia and 30 patients with normal levels of prolactin (PRL), underwent interview through Beck Depression Inventory (BDI).The BDI score was significantly higher in hyperprolactinemic patients (15.07 ± 7.89 vs. 7.53 ± 8.20, p <0,001). Positive correlation was found between serum PRL and BDI score (r = 0,573, p<0,001).Among the hyperprolactinemic, 14 patients had BDI scores corresponding to mood disorders. These patients were treated with cabergoline for 2months. There was significant reduction in PRL values (mean 241.08 vs. 25.92, p <0.001) and BDI scores (mean 22.15 vs. 11.54, p <0.001). We found a positive correlation between changes in prolactin and the BDI score (r = 0.557, p = 0.048). In conclusion, we observed a higher frequency of depressive symptoms in hyperprolactinemic patients with a positive correlation between serum PRL and symptoms, and find relief of symptoms with treatment of hyperprolactinemia.

Background: Prolactin-secreting tumours( prolactinomas) are the commonest type of pituitary tumour, accounting for approximately 30 to 40 %% of all pituitary adenomas. Although there is ample epidemiologic and clinic data from Industrialised countries there remains sparse data from Africa. Specifically, the clinical presentation, and hormonal deficiencies and treatment outcomes in the South Africa have not been described. Methods: A retrospective study of all patients with a diagnosis of prolactinoma attending the Endocrine and Pituitary Clinics at Groote Schuur Hospital over a 12-month period, between March 2019-March 2020. Patients folders were reviewed to retrieve the following information: demographic data, clinical presentation, clinical signs, prolactinoma phenotype, hormonal deficiencies, treatment modalities and clinical outcomes. Results: Over a 12-month period 52 patients were included in this study, females 73% (n=38), mean age of all participants was 46.1 ± 14.6 years. A macroprolactinoma was present in 67.3% (n=35) of patients and 32.7% (n=17) of patients had a microprolactinoma. In the macroprolactinoma group: the common presenting symptoms were headache 88.6% (n=33), altered vision 40% (n=14) and , in females, amenorrhoea 63.6% (n=14) but a cranial nerve palsy 17.1% (n=6) and apoplexy 5.7% (n=2) were uncommon. . In the microprolactinoma group the common presenting symptoms included amenorrhoea 75% (n=12), galactorrhoea 70.6% (n=12), headache 64.7% (n=11). On presentation the majority of patients with a macroadenoma had at least one hormonal abnormality with hypogonadism 73.1% (n=19) being most common, followed by hypothyroidism 53.8% (n=14) and hypoadrenalism 30% (n=8). Over 50% of patients with a giant adenoma had panhypopituitarism with hypogonadism in 100%, hypothyroidism in 77.8% (n=7) and hypoadrenalism in 66.7% (n=6). Hormonal deficiencies in the microadenoma group on presentation included hypogonadism 64.7% (n=11), hypothyroidism 35.3 (n=6) and one patient had hypoadrenalism. All patients received medical treatment, however, in the macroadenoma group 4 patients required surgical debulking of the tumour, 3 patients required a ventriculo-peritoneal (VP) shunt for hydrocephalus and 2 patients required radiation. After a median follow-up of 46.5 months, the median prolactin level decreased from 322.5 ug/l (94.0-4282.0) at presentation to 17.5 ug/l (8.6-82.5) at follow-up. In parallel there was a reduction of 12.2 ±9.7 mm in tumour size after a mean of 59.8 ±53.3 months. There was resolution of hypogonadism in 56.4% (n=22), of hypothyroidism in 2.7% (n=2) and hypoadrenalism only resolved in 1 patient. Conclusions: Most patients with a prolactinoma are symptomatic and have at least one hormone deficiency on presentation. With medical management most patients experienced a reduction in prolactin levels and tumour size. . This was associated with the resolution of hypogonadism in the majority, however, hypothyroidism and hypoadrenalism are unlikely to resolve despite a reduction in tumour size.

INTRODUCTION: Idiopathic granulomatous mastitis (IGM) is becoming more commonly recognized and reported more often. Currently, many recommend corticosteroids in its management. PRESENTATION OF CASE: A 34-year-old G3P2 Hispanic female, 28 weeks pregnant, presented with a 19 cm right breast mass. She had a known prolactinoma treated with bromocriptine which was discontinued during her pregnancy. Ultrasound guided core biopsy procedure revealed granulomatous mastitis. The patient was told that the mass would resolve with observation. The patient seen at another institution by an infectious disease specialist who started treatment with amphotericin for presumptive disseminated coccidioidomycosis. Repeated titers were negative for coccidioides antibody. Repeat cultures were negative as well. Due to the persistence of the infectious disease specialist, tissue cultures were performed on fresh tissue specimens, which did not grow bacterial, fungal, nor acid fast organisms. The amphotericin regimen resulted in no improvement of her breast mass after 10 weeks. Within two weeks of stopping the antifungal therapy, however, the mass diminished to 6 cm. The patient delivered at 39 weeks. Bromocriptine was restarted, and within 4 weeks, the lesion was no longer palpable. She had not shown signs of recurrence for 32 months. DISCUSSION: Treatment recommendations for IGM vary widely but antibiotics and antifungal medications are not recommended. Corticosteroid treatment is most commonly recommended, however, outcomes may not be different from management with observation. Prolactin may be involved in the pathophysiology of the process. CONCLUSION: IGM is becoming recognized more frequently. Observation and patience with natural history can be an effective management. (C) 2015 The Authors. Published by Elsevier Ltd. on behalf of Surgical Associates Ltd.

De nombreux modèles ont été proposés pour expliquer les mécanismes de développement et de progression tumorale, néanmoins certains aspects comme la nature et la hiérarchie des altérations primaires et secondaires sont encore discutés. Pour répondre à ces questions, nous nous sommes intéressés à la progression tumorale des tumeurs hypophysaires à prolactine humaines. Ces tumeurs d'origine monoclonale sont souvent bénignes mais certaines présentent un phénotype agressif voire malin. Afin d'identifier les mécanismes impliqués dans la progression vers le phénotype agressif nous avons utilisé des techniques de génomique intégrative (puces à ADN, séquençage haut débit) couplant l'étude du transcriptome, du génome (variation du nombre de copie chromosomique, polymorphismes) et du miRNome à partir des mêmes échantillons tumoraux. Par cette stratégie nous avons identifié et hierarchisé des altérations spécifiques des tumeurs agressives et / ou malignes dans un modèle expliquant la progression tumorale des tumeurs hypophysaires à prolactine humaines. Nous avons montré que la sous-expression des microARNs miR-183, miR-744 et miR-98 stimule la prolifération via la surexpression de leurs cibles KIAA0101, TGFB1 et E2F2 spécifiquement dans les tumeurs agressives. Ceci entraine l'acquisition d'altérations chromosomiques (perte du chromosome 11 et le gain du chromosome 1q) permettant l'activation de la dissémination métastatique. Enfin, ce travail montre que l'approche de génomique intégrative multidimensionnelle permet d'apporter de nouveaux éléments pour la caractérisation des phénotypes tumoraux, le diagnostic des tumeurs agressives et la prédiction du comportement tumoral / Numerous models have been proposed to explain the mechanisms of tumor development and progression. Nevertheless some aspects such as the nature and hierarchy of primary and secondary alterations are still debated. To answer these questions, we decided to focus on the tumoral progression of human prolactin pituitary tumors. These monoclonal tumors are usually benign but some present an aggressive or malignant phenotype. To identify the molecular events involved in tumoral progression of human PRL towards aggressive phenotype we used an integrative genomics approach (microarrays, high-throughput sequencing) coupling analysis of transcriptome, genome (variation in the number of chromosomal copy polymorphisms) and miRNome from the same human tumor. Using this strategy we identified and prioritized specific alterations of aggressive and / or malignant tumors in a model explaining the tumor progression of human prolactin pituitary tumors. We have shown that under-expression of micro-RNA miR-183, miR-744 and miR-98 stimulates proliferation through overexpression of their targets KIAA0101, TGFB1 and E2F2 specifically in aggressive tumors. This leads to the acquisition of chromosomal damage (loss of chromosome 11 and gain of chromosome 1q) which allowed the activation of the metastatic processes. Finally, this work shows that the integrative genomic multi-dimensional approach can provide new clues for the characterization of tumor phenotypes, diagnosis of aggressive tumors and prediction of tumor behavior

Introduction: Dopamine agonists (DA) constitute primary treatment for prolactinomas.Recent international guidelines on prolactinoma management recommend use of cabergolineover other DAs and suggest attempting withdrawal after two years given certain criteria. Thelocal data on adherence to guidelines are scarce. Aim: This study aimed to compare local clinical practice to regional and internationalguidelines for prolactinomas and investigate management and outcome of patients with thisdiagnosis in a clinical setting in Örebro county. Methods: Medical records of patients with prolactinoma visiting the unit of endocrinology atÖrebro University Hospital between 2015-2019 were reviewed. Data on initial investigations,monitoring, treatment, and outcome were collected. Results: 91 patients with a median follow-up time of 69 months, were included. All patientshad initial investigations according to regional guidelines. 98.9% were ever treated with DA,and overall use of bromocriptine was higher than that of cabergoline. DA-withdrawal wasattempted in 40% of patients after a median treatment time of 6 years and was often successful.9.9% of patients had pituitary surgery. At last follow-up 37.4% of the patients were cured while20.9% had hypopituitarism. Treatment outcome differed significantly with adenoma size;microadenomas dominated among patients cured and macroadenomas among patients withremaining hypopituitarism (p&lt;0.001). Conclusions:Local diagnostic prolactinoma care is in line with regional guidelines and patients are monitoredregularly. However, it is feasible that local practice concerning the choice of dopamine agonistand routines for its withdrawal could be revised and adjusted to international guidelines.

A macroprolactinemia é condição freqüente na hiperprolactinemia e em geral, sem impacto clínico. Os dados sobre a atividade biológica da macroprolactina (bbPRL) são controversos e baseados em bioensaio heterólogo com células de rato Nb2. A atividade biológica da bbPRL é observada in vitro e não in vivo, provavelmente porque seu alto peso molecular evita sua passagem pelos capilares. A bioatividade da bbPRL talvez varie de acordo com a especificidade do receptor de prolactina (PRLR). Avaliamos a bioatividade da bbPRL de indivíduos macroprolactinêmicos (Grupo I, n = 18) e da PRL monomérica (mPRL) de pacientes hiperprolactinêmicos sem bbPRL (Grupo II, n = 5) em Nb2 e em células Ba/F-LLP, transfectadas com o PRLR humano. Enquanto ambos ensaios apresentam resultados similares para a atividade de mPRL, nossos resultados indicam que a atividade da bbPRL é presente em ensaio heterólogo e não em ensaio homólogo. O ensaio Ba/F-LLP é sensível e apresenta melhor correlação com a atividade in vivo da bbPRL / Macroprolactinemia is a frequent finding in hyperprolactinemic individuals, usually without clinical impact. Data on biological activity of macroprolactin (bbPRL) is mostly based on a heterologous bioassay (Nb2 cell). Biological activity of bbPRL observed in vitro but not in vivo maybe due to its high molecular weight preventing its passage through capillary barrier. Alternatively, bbPRL bioactivity may differ depending on the PRL receptor species specificity. BbPRL from macroprolactinemic individuals and monomeric PRL (mPRL) from hyperprolactinemic patients without macroprolactinemia were tested in two bioassays: Nb2 and in Ba/F-LLP, which expresses human prolactin receptor. While both bioassays achieve similar results considering mPRL activity, our results indicate that bbPRL displays activity in a heterologous but not in a homologous bioassay, consistently with the apparent absence of bbPRL bioactivity in vivo

A macroprolactinemia é condição freqüente na hiperprolactinemia e em geral, sem impacto clínico. Os dados sobre a atividade biológica da macroprolactina (bbPRL) são controversos e baseados em bioensaio heterólogo com células de rato Nb2. A atividade biológica da bbPRL é observada in vitro e não in vivo, provavelmente porque seu alto peso molecular evita sua passagem pelos capilares. A bioatividade da bbPRL talvez varie de acordo com a especificidade do receptor de prolactina (PRLR). Avaliamos a bioatividade da bbPRL de indivíduos macroprolactinêmicos (Grupo I, n = 18) e da PRL monomérica (mPRL) de pacientes hiperprolactinêmicos sem bbPRL (Grupo II, n = 5) em Nb2 e em células Ba/F-LLP, transfectadas com o PRLR humano. Enquanto ambos ensaios apresentam resultados similares para a atividade de mPRL, nossos resultados indicam que a atividade da bbPRL é presente em ensaio heterólogo e não em ensaio homólogo. O ensaio Ba/F-LLP é sensível e apresenta melhor correlação com a atividade in vivo da bbPRL / Macroprolactinemia is a frequent finding in hyperprolactinemic individuals, usually without clinical impact. Data on biological activity of macroprolactin (bbPRL) is mostly based on a heterologous bioassay (Nb2 cell). Biological activity of bbPRL observed in vitro but not in vivo maybe due to its high molecular weight preventing its passage through capillary barrier. Alternatively, bbPRL bioactivity may differ depending on the PRL receptor species specificity. BbPRL from macroprolactinemic individuals and monomeric PRL (mPRL) from hyperprolactinemic patients without macroprolactinemia were tested in two bioassays: Nb2 and in Ba/F-LLP, which expresses human prolactin receptor. While both bioassays achieve similar results considering mPRL activity, our results indicate that bbPRL displays activity in a heterologous but not in a homologous bioassay, consistently with the apparent absence of bbPRL bioactivity in vivo

The purpose of these studies was to determine whether the inhibitory effects of short photoperiod exposure on prolactin cell activity in male Syrian hamsters and/or the inhibitory effects of melatonin treatment on the growth and activity of diethylstilbestrol- (DES) induced prolactinomas in Fisher 344 (F344) rats were possibly mediated through alterations in dopaminergic regulatory mechanisms. In both the hamster and the rat, changes in hypothalamic dopamine neuronal activity and changes in pituitary responsiveness to dopamine have been suggested as possible mechanisms in the prolactin-inhibitory effects of light deprivation or melatonin administration. The present studies in the male Syrian hamster addressed two issues. First, it was of interest to determine if anterior pituitaries of long photoperiod-exposed male hamsters possess dopamine receptors, which are presumably necessary for responsiveness to dopamine. This was accomplished by analysis of ³H-spiperone binding to anterior pituitary membranes. Second, possible changes in pituitary sensitivity to dopamine were assessed by comparison of dose response curves for the inhibition by dopamine of prolactin release from hemipituitaries incubated in vitro from both long and short photoperiod-exposed animals over a series of time points from three to fifteen weeks. In the second series of experiments, adult female F344 rats received daily injection of melatonin or saline vehicle. After two weeks, half of the animals were sacrificed for analysis of ³H-spiperone binding to anterior pituitary membranes, measurement of hypothalamic dopamine turnover and analysis of in vitro pituitary sensitivity to dopamine. The remaining animals received subcutaneous implants containing DES and injections were continued on the same schedule until sacrifice four weeks later for measurement of the same parameters. In both the hamster and rat models, treatments exerted profound inhibitory effects on indices of prolactin cell activity. However, these studies provide no evidence for the involvement of altered dopaminergic regulation in the production of such effects. Neither pituitary sensitivity to dopamine in vitro nor hypothalamic dopamine neuronal activity was enhanced by short photoperiod exposure or melatonin treatment. Prolactin-inhibitory effects of these treatments appear to be mediated through as yet unidentified dopamine-independent mechanisms.