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Introduction Acromegaly is an endocrine disorder characterized by excessive growth hormone production.The most common cause is a benign pituitary adenoma, which can be an isolated tumor or part of a group of concomitant endocrine neoplasms. We present a case of a middle aged woman with sleep apnea and a newly diagnosed acromegaly secondary to a pituitary macroadenoma. Case presentation A 51-year-old woman was seen in the endocrinology clinic for evaluation of hyperparathyroidism and mild hypercalcemia. She had no symptoms related to hypercalcemia. However, she complained of enlargement of her fingers and toes. She also reported galactorrhea and breast engorgement. There was no hyperhidrosis or frontal bossing present and she denied headaches or vision symptoms. Past medical history was significant for obstructive sleep apnea. Insulin like growth factor level was 630 ng/ml (reference 53 - 190 ng/ml), prolactin level was 109 ng/ml (reference 1.9- 25 ng/ml), and Follicular stimulating hormone was 0.4mIU/ml (reference 1.2 - 21.0 mIU/ml). TSH, free T4, ACTH, and cortisol were normal. The labs were consistent with pituitary macroadenoma secreting growth hormone (GH) and prolactin. MRI pituitary showed a 1.9 cm macroadenoma with no evidence of optic nerve compression. Due to the coexisting diagnoses of hyperparathyroidism and pituitary adenoma, CT abdomen was done to evaluate for neuroendocrine tumor and to rule out Multiple Endocrine Neoplasia (MEN) Type 1. She then underwent transsphenoidal resection of the pituitary, with immunostaining reflecting diffuse prolactin and patchy GH expression. Post-surgery IGF, prolactin, thyroid function tests were normal. She was started on hydrocortisone replacement due to abnormal ACTH and cortisol. Her calcium levels normalized, and further genetic testing for MEN was abandoned. Her repeat sleep study also showed resolution of sleep apnea. She did not suffer from further symptoms of acromegaly and was scheduled for periodic surveillance for thyroid axis dysfunction. Discussion Dysregulated growth hormone production seen in acromegaly leads to increased GH and IGF-1 levels. It has many ramifications including debilitating arthritis from osteoarthropathy, glucose intolerance due to insulin resistance, higher propensity for GI neoplasms, and macroglossia with prognathism causing sleep apnea. Average lifespan is decreased by 30% due to cardiovascular and pulmonary dysfunction. Treatment is aimed at decreasing IGF levels and controlling any mass effect or metabolic abnormalities caused by the tumor. Treatment options include invasive procedures for good surgical candidates and medical therapy via somatostatin analogue for patients who are not. Residual or unresectable tumors can be treated with medical therapy or radiation therapy if there is no response to medication.

A 69-year-old man was referred for elevated thyroid hormone levels. He had no symptoms apart from mild hyperhidrosis and heat intolerance with occasional headaches. Past medical history included a right hemithyroidectomy for a multinodular goiter and Hashimoto's disease. At presentation the patient had a firm, slightly enlarged left thyroid lobe. There were no visual abnormalities, and the rest of the physical findings were unremarkable. Laboratory findings included elevated values of free T4, free T3, total T 3, thyrotropin-secreting hormone (TSH), antithyroglobulin, and antimicrosomal antibodies. Normal values were found for cortisol, prolactin, testosterone, follicle-stimulating hormone, luteinizing hormone, a-subunit, and thyroid-stimulating immunoglobulin. Thyroid 123I scan showed an increased 5-hour uptake of 23% and a 24-hour uptake of 53% with a diffuse uniform enlargement of the left side. TSH level did not increase after a thyrotropin-releasing hormone stimulation test. Serum sex hormone binding globulin was elevated. Magnetic resonance imaging of the pituitary revealed a pituitary macroadenoma with suprasellar extension to the optic chiasm. Histologic examination of the adenoma after transsphenoidal hypophysectomy showed cells that stained positive for TSH. TSH-secreting pituitary adenomas account for 1% of functioning pituitary tumors and are an exceedingly rare cause of hyperthyroidism. To our knowledge, this is the first report of pituitary tumor inducing hyperthyroidism in the setting of Hashimoto's disease. There is a possibility that TSH elevation related to Hashimoto's disease might have contributed to the development of a TSH-secreting pituitary adenoma.

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-05-17T21:24:47Z No. of bitstreams: 1 NadjaCruzGaido.pdf: 2766927 bytes, checksum: 6fdfd1a4a2beb11f1da8d3669b11750a (MD5) / Made available in DSpace on 2017-05-17T21:24:47Z (GMT). No. of bitstreams: 1 NadjaCruzGaido.pdf: 2766927 bytes, checksum: 6fdfd1a4a2beb11f1da8d3669b11750a (MD5) Previous issue date: 2016-09-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA) / The pituitary adenomas represent about 10 to 15% of intracranial tumors and are usually benign, comprising a cell population of monoclonal origin. They are classified as macroscopic and radiological aspects, functional status, dyeing, immunohistochemistry and microscopic. About 70% of human cancers have mainly a deficiency in the function gene. The p53 gene is extensively studied in tumors, showing that patients with mutations have a worse prognosis, as well, the p53 protein is critical in preventing tumor development performing change detection function in DNA and thereby fix or apoptosis. It is possible that the increase in expression of this protein is the result of an attempt to stop the cell cycle in response to deregulation by a stimulus from another source. This way, the study seeks to determine the expression of p53 protein in pituitary adenomas. an analytical study, with crosssectional was held in which were included 62 patients older than 16 years of both sexes, who were diagnosed with pituitary adenoma, from 2008 to 2016, arising from the Endocrinology Service University hospital of the Federal University of Maranhão - HUUFMA. These patients underwent surgical resection of the tumor, obtaining the samples of tumor tissue. After conventional histopathology, they were embedded in paraffin, for carrying out the immuno-histoqumico study aimed to identify the expression of p53 protein and implications correlated with biological behavior of pituitary adenomas. The analysis for p53 protein expression in adenomas was obtained by immunoenzymatic of streptoavidin-biotin or immunohistochemistry. The p53 protein immunostaining revealed no statistically significant correlation, as the clinical and demographic characteristics such as gender, age, p53 expression in tumor subtypes and tumor volume. It is necessary to obtain greater numbers of patients, so that p53 expression is effective when the real prognostic value in pituitary adenomas. / Os adenomas hipófisários representam cerca de 10 a 15% das neoplasias intracranianas e são geralmente benignos e compostos por uma população celular de origem monoclonal. São classificados conforme aspectos macroscópicos e radiológicos, status funcional, tintoriais, imuno-histoquímica e microscópicas. Cerca de 70% dos cânceres humanos possuem principalmente uma deficiência na função do gene. O gene p53 é extensivamente estudado nas neoplasias mostrando que pacientes com mutações apresentam um pior prognóstico, assim, a proteína p53 é fundamental na prevenção do desenvolvimento de tumores exercendo a função de detecção de alterações no DNA e, consequentemente, correção ou apoptose. É possível que o aumento na expressão desta proteína seja decorrente de uma tentativa de frear o ciclo celular como resposta à desregulação por um estímulo de outra origem. Dessa forma, o estudo busca avaliar a imunoexpressão da proteína p53 em adenomas hipofisários. Foi realizado um estudo analítico com delineamento do tipo transversal, no qual foram incluídos 62 pacientes com idade superior 16 anos de ambos os sexos, que apresentaram diagnóstico de adenoma hipofisário no período de 2008 a 2016, oriundos do Serviço de Endocrinologia do Hospital Universitário da Universidade Federal do Maranhão – HUUFMA. Esses pacientes foram submetidos à ressecção cirúrgica do tumor, com obtenção das amostras do tecido tumoral. Após diagnóstico histopatológico convencional, foram emblocadas em parafina, para realização do estudo imuno-histoqumico com o objetivo de identificar a imunoexpressão para proteína p53 e implicações correlacionadas ao comportamento biológico dos adenomas hipofisários. A análise para expressão da proteína p53 em adenomas hipofisários foi obtida através da reação imunoenzimática da streptoavidina-biotina-peroxidase ou imuno-histoquimica. A imunoexpressão da proteína p53 não revelou correlação estatisticamente significante, quanto aos achados clínicos e características demográficas, tais como sexo, idade, imunoexpressão da p53 para os subtipos tumorais e volume tumoral. Torna-se necessário obter números mais expressivos de pacientes para que a imunoexpressão da p53 seja efetiva, quanto ao real valor prognóstico em adenomas hipofisários.

Hipofizės adenoma yra biologiškai gerybinis navikas, augantis iš priekinės hipofizės dalies – adenohipofizės ląstelių, galinčių produkuoti įvairius hipofizės hormonus. Jos paplitimas yra 20 atvejų 100000 gyventojų, kasmet nustatomi 1,5 – 2 atvejai 100000 gyventojų. Pagrindiniu priėjimu prie hipofizės šiuo metu tapo transsfenoidinis priėjimas, transkranijinį naudojant tik labai retais atvejais. Nors hipofizės adenomos diagnostikos ir gydymo galimybės tobulėja, vis dar išlieka nemaža neišspręstų problemų. Šio darbo tikslas buvo nustatyti veiksnius, turinčius reikšmės hipofizės adenomų chirurginio gydymo rezultatams. Darbo uždaviniai: 1. Įvertinti intraoperacinių ir pooperacinių komplikacijų dažnį naudojant skirtingus priėjimo prie turkiabalnio metodus. 2. Nustatyti intraoperacinį smegenų skysčio tekėjimą įtakojančius veiksnius. 3. Įvertinti naujo daugiasluoksnio turkiabalnio uždarymo metodo efektyvumą, palyginti su anksčiau naudotais metodais, esant intraoperaciniam smegenų skysčio tekėjimui. 4. Išnagrinėti prolaktinomų chirurginio gydymo baigtį lemiančius veiksnius. 5. Nustatyti veiksnius, leidžiančius prognozuoti gerą somatotropinį hormoną sekretuojančių adenomų chirurginio gydymo baigtį. 6. Įvertinti regos atsistatymo po transsfenoidinio hipofizės adenomos pašalinimo rezultatus ir nustatyti prognozinius veiksnius, leidžiančius tikėtis regos atsistatymo po operacijos. 7. Įvertinti Farnsword – Munsell spalvų skyrimo ir spalvų juslės slenksčio kompiuterinio testo jautrumą ir... [toliau žr. visą tekstą] / Pituitary adenoma is a biologically benign tumour growing from the anterior part of pituitary gland - adenopituitary cells that can produce different hormones. Its incidence rate is 20 cases per 100 000 population and each year 1.5 - 2 cases per 100 000 population are diagnosed. Transsphenoidal approach has become the major approach to the pituitary gland, with transcranial approach being applied in extremely rare cases. Although the possibilities of pituitary adenoma diagnosis and treatment have been improving, a number of problems remain unsolved. Aim of the study - to identify the factors that have an effect on the results of surgery for pituitary adenomas. Objectives: 1. To assess the incidence of intraoperative and postoperative complications by using different approach to sella turcica. 2. To identify the factors that have an effect on intraoperative cerebrospinal fluid leak. 3. To assess the efficiency of the new multi-layer sella turcica closure technique as compared to the previously used techniques in the presence of intraoperative cerebrospinal fluid flow. 4. To analyse the factors determining the outcome of surgery for prolactinomas. 5. To identify the factors enabling to prognosticate a favourable outcome of surgery for adenomas secreting the somatotropic hormone. 6. To assess the vision recovery results after transsphenoidal removal of pituitary adenoma and to establish prognostic criteria enabling to expect vision recovery after surgery. 7. To assess the... [to full text]

Made available in DSpace on 2014-06-11T19:32:12Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-07Bitstream added on 2014-06-13T18:43:12Z : No. of bitstreams: 1 nunes_vs_dr_botfm.pdf: 1297313 bytes, checksum: 470ba33e35f9a75851e361e40639894a (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A Neoplasia Endócrina Múltipla tipo 1 (MEN1; OMIM 131100) é uma doença genética, herdada de forma autossômica dominante, caracterizada pela presença de tumores em pelo menos dois dos seguintes tecidos endócrinos: paratireóide, enteropancreático e adenohipófise. Além destes componentes maiores, tumores adrenocorticais, carcinóides, lipomatose, angiofibroma e colagenoma facial têm sido associados. Trata-se de uma síndrome rara com uma prevalência estimada de 2-3/100000 indivíduos, causada por mutações inativadoras no gene MEN1. Este, por sua vez, codifica uma proteína chamada menin, que tem demonstrado interagir com diversas proteínas envolvidas em processos celulares essenciais, como controle do crescimento e ciclo celular, reparo de DNA, regulação da transcrição gênica, regulação estabilidade genômica, e controle da apoptose. A identificação do gene MEN1 possibilitou a detecção de mutações causadoras da doença e, com isto, a confirmação do diagnóstico clínico em pacientes acometidos, bem como o diagnóstico precoce em familiares assintomáticos. É preconizada a pesquisa dos principais tumores associados a MEN1 em pacientes já com o diagnóstico da síndrome ou nos portadores da mutação, mas a abordagem inversa que é a investigação da MEN1 em pacientes com diagnóstico inicial apenas de um dos principais tumores associados tem sido pouco explorada. Por isto, esta pesquisa consistiu em... / Multiple endocrine neoplasia type 1 (MEN1; OMIM 131100) is a genetic disease, inherited in the dominant autosomal form and characterized by the presence of tumors in at least two of the following endocrine tissues: parathyroid, enteropancreatic and adenopituitary. Besides the aforementioned major components, adrenocortical and carcinoid tumors, lipomas, collagenomas and facial angiofibromas have been associated with the disease. MEN1 is a rare disease, with an estimated prevalence of 2-3/100000 individuals; it is caused by inactivated mutations of the MEN1 gene. This gene encodes one protein called menin, which has been shown to interact with a number of proteins that are involved in essential cell processes such as cell division and proliferation, DNA repair, transcriptional regulation, genome stability, and apoptosis control. The MEN1 gene identification has enabled the detection of MEN1 mutations and the confirmation of the disease’s clinical diagnosis as well as its early diagnosis in asymptomatic relatives. The screening of these principal tumors associated with MEN1 has been recommended in patients with MEN1 syndrome or MEN1 mutation. However, the inverse approach (i.e., the investigation of MEN1 in patients with an initial diagnosis of only one of the principal tumors) has been little explored. For this reason, the present study aimed to evaluate the frequency of MEN1 in a group the patients with pituitary adenoma (PA), and to identify, in these individuals, variables... (Complete abstract click electronic access below)

Orientador: Célia Regina Nogueira / Banca: Cesar Luiz Boguszewski / Banca: Fernando Rodrigues Pimentel Filho / Banca: Glaucia M. F. S. Mazeto / Banca: Evandro de Souza Portes / Resumo: A Neoplasia Endócrina Múltipla tipo 1 (MEN1; OMIM 131100) é uma doença genética, herdada de forma autossômica dominante, caracterizada pela presença de tumores em pelo menos dois dos seguintes tecidos endócrinos: paratireóide, enteropancreático e adenohipófise. Além destes componentes maiores, tumores adrenocorticais, carcinóides, lipomatose, angiofibroma e colagenoma facial têm sido associados. Trata-se de uma síndrome rara com uma prevalência estimada de 2-3/100000 indivíduos, causada por mutações inativadoras no gene MEN1. Este, por sua vez, codifica uma proteína chamada menin, que tem demonstrado interagir com diversas proteínas envolvidas em processos celulares essenciais, como controle do crescimento e ciclo celular, reparo de DNA, regulação da transcrição gênica, regulação estabilidade genômica, e controle da apoptose. A identificação do gene MEN1 possibilitou a detecção de mutações causadoras da doença e, com isto, a confirmação do diagnóstico clínico em pacientes acometidos, bem como o diagnóstico precoce em familiares assintomáticos. É preconizada a pesquisa dos principais tumores associados a MEN1 em pacientes já com o diagnóstico da síndrome ou nos portadores da mutação, mas a abordagem inversa que é a investigação da MEN1 em pacientes com diagnóstico inicial apenas de um dos principais tumores associados tem sido pouco explorada. Por isto, esta pesquisa consistiu em... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Multiple endocrine neoplasia type 1 (MEN1; OMIM 131100) is a genetic disease, inherited in the dominant autosomal form and characterized by the presence of tumors in at least two of the following endocrine tissues: parathyroid, enteropancreatic and adenopituitary. Besides the aforementioned major components, adrenocortical and carcinoid tumors, lipomas, collagenomas and facial angiofibromas have been associated with the disease. MEN1 is a rare disease, with an estimated prevalence of 2-3/100000 individuals; it is caused by inactivated mutations of the MEN1 gene. This gene encodes one protein called menin, which has been shown to interact with a number of proteins that are involved in essential cell processes such as cell division and proliferation, DNA repair, transcriptional regulation, genome stability, and apoptosis control. The MEN1 gene identification has enabled the detection of MEN1 mutations and the confirmation of the disease's clinical diagnosis as well as its early diagnosis in asymptomatic relatives. The screening of these principal tumors associated with MEN1 has been recommended in patients with MEN1 syndrome or MEN1 mutation. However, the inverse approach (i.e., the investigation of MEN1 in patients with an initial diagnosis of only one of the principal tumors) has been little explored. For this reason, the present study aimed to evaluate the frequency of MEN1 in a group the patients with pituitary adenoma (PA), and to identify, in these individuals, variables... (Complete abstract click electronic access below) / Doutor

nÃo hà / IntroduÃÃo: MutaÃÃes nos genes GNAS e AIP estÃo presentes em 35% e 3%, respectivamente, dos somatotrofinomas esporÃdicos. Recentemente, observa-se importÃncia biolÃgica crescente dos microRNAs (miRNAs) na tumorigÃnese hipofisÃria. Entretanto, mecanismos moleculares envolvidos na patogÃnese de 60% desses tumores permanecem nÃo elucidados. Objetivos: Identificar a prevalÃncia de mutaÃÃes nos genes GNAS e AIP em um grupo de somatotrofinomas esporÃdicos. Comparar parÃmetros clÃnicos e bioquÃmicos ao diagnÃstico como idade, tamanho tumoral e agressividade (escore Hardy), hormÃnio do crescimento (GH), prolactina (PRL) e Fator de Crescimento Insulin-Like I (IGF-1) e resposta as terapÃuticas entre os grupos com (gsp+) e sem (gsp-) mutaÃÃo no GNAS. Analisar a expressÃo dos genes GNAS e BTG2 e miRNAs entre somatotrofinomas e hipÃfises normais (HN) e a associaÃÃo entre a expressÃo com agressividade, a resposta à cirurgia e a todas as terapÃuticas adjuvantes disponÃveis. Material e MÃtodos: 26 pacientes com diagnÃstico de acromegalia. Tamanho tumoral foi avaliado por RNM/CT e o grau de invasibilidade pelo escore de Hardy (I a IV). GH basal ≤2.5μg/L ou nadir de GH apÃs o GTT≤1μg/L e IGF-1 normal para idade e sexo foram utilizados como critÃrio de cura apÃs cirurgia transesfenoidal (CTE). Como controle com o anÃlogo da somatostatina (AS), adotamos a normalizaÃÃo dos nÃveis de IGF-1 para idade e sexo. As amostras tumorais (n=26) foram obtidas durante a CTE, realizado histopatolÃgico e armazenadas a -70 ÂC, para estudos moleculares. HN (07) foram obtidas durante autÃpsias. RNA e DNA total foram extraÃdos pelo TRIzolÂ. Os cÃdons 201 e 227 do gene GNAS e o AIP completo foram sequenciados. ExpressÃo relativa dos genes GNAS e BTG2 e dos miRNAs let-7a, miR-16a, miR-21, miR-141, miR-143, miR-15a, miR-145, miR-23a, miR-23b e miR-24-2 foi avaliada por qPCR (sondas TaqMan), pelo mÃtodo 2-ΔΔCt. Resultados: A frequÃncia de mutaÃÃes no GNAS foi de 35% e no AIP 3,8%. NÃo houve diferenÃa entre as mÃdias de idade (39,0Â11,5 vs 43,6Â9,0 anos; p=0,32), nas concentraÃÃes plasmÃticas basais de GH (62,4Â128,1 vs 39,9Â48,3Âg/L; p=0,39), IGF-1 (435,5Â230,8 vs 556,9 238,3 %ULNR; p=0,32), PRL (25,7Â29,8 vs 30,9Â32,8 ng/L; p=0,69) e agressividade tumoral entre os gsp+ e gsp-(p=1,00). Ao analisar o uso do AS como terapÃutica adjuvante à CTE, observamos que 04/05 (80%) dos indivÃduos com somatotrofinoma gsp+ obtiveram controle da doenÃa, enquanto que no grupo gsp- 02/06 (33%) obtiveram controle (p=0,08). Quando associamos ao AS, os agonistas dopaminÃrgicos e/ou radioterapia externa, observamos que 05/05 (100%) dos pacientes gsp+ tiveram critÃrio de controle da doenÃa, contra (04/09) 44% no grupo gsp- (p=0,09). NÃo houve diferenÃa na expressÃo de GNAS entre os somatotrofinomas e as HN (1,07Â0,55 vs 0,98Â0,28; p=0,97), e entre os gsp+ e gsp- (1,04Â0,59 vs 1,10Â0,55; p=0,97, respectivamente). Os tumores Hardy I / II apresentaram maior expressÃo do GNAS do que os tumores classificados como III / IV (p=0,02). NÃo houve associaÃÃo entre a expressÃo do GNAS e o controle da doenÃa com cirurgia isolada ou com o uso de todas as terapÃuticas adjuvantes. Observamos hipoexpressÃo do BTG2 e dos miR-16a e miR-141 em somatotrofinomas quando foram comparados com as HN (p=0,002, fold=-6,63; p=0,01, fold=-10,00; p=0,0003, fold=-50,00, respectivamente) sem diferenÃas entre os gsp+ e gsp-. Houve hiperexpressÃo do miR-21 (p=0,02;fold=10,18) em somatotrofinomas (20,16Â18,48) quando comparado com as HN (2,52 Â3,56), sem diferenÃa entre os gsp + e gsp-. NÃo houve diferenÃa na expressÃo entre os grupos gsp+ e gsp- para os miRNAs let-7a, miR-21, miR-143, miR-15a, miR-23a e miR-24-2. Entretanto, miR-145 e miR-23b foram mais hipoexpressos no grupo gsp+ quando comparados ao gsp- (p=0,03, fold=-4,83 e p=0,02, fold=-2,77, respectivamente). NÃo houve associaÃÃo entre a expressÃo do BTG2 e o painel de miRNAs com agressividade e com o controle da doenÃa. ConclusÃo: Na presente sÃrie de somatotrofinomas, assumidos como esporÃdicos, a frequÃncia de mutaÃÃes nos genes GNAS (35%) e AIP (3,8%) foram semelhantes aos relatados na literatura. NÃo houve diferenÃas nas caracterÃsticas clÃnicas e bioquÃmicas, agressividade, resposta Ãs terapÃuticas, e na expressÃo diferencial do GNAS entre os pacientes com tumores gsp+ e gsp-. HipoexpressÃo de BTG2 (gene supressor tumoral relacionado Ãs vias de sinalizaÃÃo do p53 e do Rb), baixa expressÃo de miRNAs (supressores tumorais) e alta expressÃo de oncomirs em somatotrofinomas sugerem um papel desses na tumorigÃnese somatotrÃfica. / Introduction: Mutations in GNAS and AIP genes are present in 35% and 3%, respectively, of the sporadic somatotropinomas. Recently, increased biological importance of microRNAs (miRNAs) has been observed in pituitary tumorigenesis. However, the molecular mechanisms involved in the pathogenesis of 60% of these tumors remain to be elucidated. Objectives: To identify the prevalence of mutations in GNAS and AIP genes in a series of sporadic somatotropinomas. Compare clinical, bioquimical parametrer at diagnosis as age, tumor size and theirs aggressiveness, pre-operative growth hormone (GH), prolactin (PRL) and insulin-like growth factor-I (IGF-1) levels and treatment responsiveness between somatotropinomas with (gsp+) and without (gsp-) GNAS mutation.To analyze the expression of GNAS and BTG2 genes and a panel of miRNAs between somatotrofinomas and normal pituitaries (NP) and the association between the expression of these genes and miRNAs with aggressiveness, as well as disease control with surgery or control with all adjuvant therapeutic approaches. Material and Methods: 26 patients with acromegaly. GH basal ≤2.5μg/L or nadir after OGTT ≤1μg/L and normal IGF-I matched for age and sex were used as diagnosis and for cure criteria after transsphenoidal surgery (TS). As control after somatostatin analogues (SA), we adopted the normalization of IGF-I matched for age and sex. Tumor size was evaluated by MRI/CT and the degree of invasiveness by Hardy score (I to IV).Tumor samples (26) were obtained during TS, processed for histopathology and stored at -70ÂC for molecular studies. NP (07) were obtained during autopsy. Total DNA and RNA were extracted by TRIzolÂ. Codons 201 and 227 of the GNAS gene and the whole AIP gene were sequenced. Relative expression of BTG2 and GNAS genes and miRNAs let-7a, miR-16a, miR-21, miR-141, miR-143, miR-15a, miR-145, miR-23a, miR-23b, and miR-24-2 was measured by qPCR (TaqMan probes) using 2-ΔΔCt method. Results: Frequencies of GNAS and AIP mutations were 35% and 3.8%, respectively. There was no difference between the mean age (39.0  11.5 vs 43.6  9.0 years, p=0.32), basal GH (62.4Â128.1 vs 39.9  48.3 μg/L; p=0.39), IGF-I (435.5  230.8 vs. 556.9  238.3; p=0.32) and PRL (25.7  29.8 vs. 30.9  32.8 ng/L, p=0.69) in plasma concentration, and tumor aggressiveness (p=1.00) between (gsp+) and (gsp-) groups. We observed that 80% (04/05) of gsp+ whereas 33% (02/06) of the gsp- achieved control (p=0.07) after SA therapy adjuvant to TS. When SA, dopamine agonists and/or external radiotherapy were associated 100% (05/05) of gsp+ group and 44% (04/09) of gsp- group (p=0.08) showed disease control.There was no difference in GNAS expression between somatotropinomas and NP (1.07  0.55 vs 0.98  0.28, p=0.97) as well as between somatotropinomasgsp+ and gsp- (1.04  0.59 vs 1.10  0.55, p=0.97, respectively). Hardy I/II tumors showed higher GNAS expression than Hardy III/IV (p=0.02), but there was no association between GNAS expression and disease control with surgery alone or associated with other adjuvant therapies. We observed hypoexpression of BTG2 and miR-16a and miR-141 in somatotropinomas compared with NP (-6.6 fold, p=0.002; -10.0 fold, p=0.01; and -50.0 fold, p=0.0003, respectively) with no difference between gsp+ and gsp- somatotropinomas. There was miR-21 overexpression in somatotropinomas compared with NP (20.2  18.5 vs 2.5  3.6; 10.2 fold, p=0.02), with no difference between gsp+ and gsp- somatotropinomas. However, miR-145 and miR-23b were more hipoexpressed in gsp+ compared to gsp- (-4.8fold, p=0.03 and-2.7 fold, p=0.02). There was no association between the expression of BTG2 and a panel of miRNAs with aggressiveness or disease control. Conclusion: In this series of assumed sporadic somatotopinomas, the frequencies of mutations in GNAS (35%) and AIP (3.8%) were similar to the literature. There were no differences in clinical and biochemical characteristics, aggressiveness, response to therapy, and GNAS expression in patients with gsp+ and gsp- somatotropinomas. Hypoexpression of BTG2, a tumor suppressor gene related to p53 and Rb signaling pathways, low expression of tumor suppressor miRNAs and high expression of oncomirs in somatotropinomas suggest a role in the somatotrophic tumorigenesis.

Abstract Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome characterized by parathyroid, gastroenteropancreatic and pituitary neuroendocrine tumours. In Northern Finland, two founder mutations of the MEN1 gene (1466del12, 1657insC) accounting for the majority of the MEN1 cases, have common ancestors born in the 18th and 19th centuries, respectively. Three small clusters of familial pituitary adenoma have also been detected, two of which could be linked by genealogy to a common ancestral couple born in the 18th century. Clinical evaluation of 82 MEN1 mutation carriers showed that age was a risk factor for most of the MEN1-related manifestations. In the whole group, nonfunctional pancreatic tumour (NFPT) was more common in the frameshift/nonsense mutation carriers (odds ratio 3.26; 95% confidence interval 1.27–8.33, P = 0.014), whereas gastrinoma was more common in the in-frame/missense mutation carriers (OR 6.77, CI 1.31–35.0, P = 0.022). In the founder mutation carriers, the 1657insC mutation predicted the risk for NFPT (OR 3.56, CI 1.29–9.83, P = 0.015), while the 1466del12 mutation was associated with the risk for gastrinoma (OR 15.1, CI 1.73–131.9, P = 0.014). The mean ages at death of the 32 obligatory MEN1 founder mutation carriers born between 1728 and 1929 were compared to those of the 29 spouses and sex-matched life expectancy estimates derived from Finnish national statistics. The ages at death of the mutation carrier males (61.1 ± 12.0 years) and females (67.2 ± 10.7 years) did not differ from the control groups. PAP (pituitary adenoma predisposition) locus was mapped in the chromosome region 11q12–11q13 by whole-genome single-nucleotide polymorphism genotyping. Combining the linkage and the gene expression array data, AIP (aryl hydrocarbon receptor interacting protein) was chosen for sequencing. The nonsense mutation Q14X was identified in the affected (acromegaly, gigantism, prolactinoma) family members and in four other patients. Loss of heterozygosity was detected in pituitary adenomas of AIP mutation carriers. Mutation analysis of MEN1, HRPT2 (hyperparathyroidism 2), CASR (calcium-sensing receptor), CDKN1B (cyclin-dependent kinase inhibitor 1B) and AIP genes was performed in primary hyperparathyroidism patients with features of inherited predisposition. One out of 29 patients was found to have the 1466del12 mutation, while no mutations were detected in other genes.

Nous avons souhaité, dans ce travail de Thèse, préciser l'impact de l'invalidation d'AIP sur la fonction sécrétoire et la prolifération des cellules somatotropes in vivo et explorer in vitro les voies de signalisation potentiellement impliquées dans la tumorigenèse hypophysaire AIP-dépendante. L'analyse du phénotype des souris Aip+/-, en particulier de la sécrétion pulsatile de GH, montre que, contrairement à l'Homme, les animaux mutés ne développent pas de gigantisme ni d'hypersécrétion de GH et que la pénétrance de la pathologie tumorale hypophysaire est beaucoup plus faible qu'initialement décrit. Les études réalisées sur les fibroblastes de patients mutés pour AIP et porteurs d'un adénome hypophysaire ainsi que sur les cellules somatolactotropes de rat GH3 révèlent que les mutations d'AIP altèrent l'activité transcriptionnelle d'AhR (Aryl hydrocarbon Receptor), mais affectent également la voie de signalisation de l'AMPc. Enfin, des mutations germinales du gène GPR101, récemment identifiées dans des cas d'acromégalie sporadique, ont aussi été trouvées chez des patients porteurs d'un adénome hypophysaire sporadique non somatotrope, sans association avec les mutations d'AIP. Ce travail a ainsi permis de préciser les conséquences des mutations d'AIP sur la fonction somatotrope et la signalisation d'AhR. Le rôle de l'AMPc dans la tumorigenèse hypophysaire AIP-dépendante sera évalué dans un nouveau modèle de souris transgénique. / In this work, we investigated the effects of AIP deficiency in vivo on somatotroph cells, both at the secretory and proliferative levels and explored in vitro the signaling pathways potentially involved in AIP-dependent pituitary tumorigenesis. Phenotype analyzes of Aip+/- mice, especially of GH pulsatility, show that, unlike humans, mutant mice do not develop gigantism nor GH hypersecretion and present with a much lower penetrance of pituitary adenomas than initially described. In vitro studies in fibroblasts of AIP-mutation positive patients with pituitary adenomas and in somatolactotroph GH3 cells demonstrate that AIP mutations alter AhR (Aryl hydrocarbon Receptor) transcriptional activity and modify the cAMP pathway. Finally, GPR101 mutations, recently reported in patients with sporadic acromegaly, have also been identified in a small portion of patients with sporadic non-somatotroph pituitary adenomas, without any association with AIP mutations. This research work defines the consequences of AIP mutations on somatotroph cell function and AhR transcriptional activity. The role of cAMP signaling in AIP-related pituitary tumorigenesis will be further evaluated in a new transgenic mouse model.