Oś hormon wzrostu–insulinopodobny czynnik wzrostu a karcynogeneza

  The growth hormone (GH) and insulin-like growth factor (IGF) system plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. In terms of cell cycle regulation, the GH-IGF system induces signalling pathways for cell growth that compete with other signalling systems that result in cell death; thus the final effect of these opposed forces is critical for normal and abnormal cell growth. The association of the GH-IGF system with carcinogenesis has long been hypothesised, mainly based on in vitro studies and the use of a variety of animal models of human cancer, and also on epidemiological and clinical evidence in humans. While ample experimental evidence supports a role of the GH-IGF system in tumour promotion and progression, with several of its components being currently tested as central targets for cancer therapy, the strength of evidence from patients with acromegaly, GH deficiency, or treated with GH is much weaker. In this review, we will attempt to consolidate this data. (Endokrynol Pol 2016; 67 (4): 414–426)    Oś hormon wzrostu (GH)–insulinopodobny czynnik wzrostu (IGF) odgrywa istotną rolę w regulacji proliferacji i różnicowania komórek, apoptozy i angiogenezy. Oś GH–IGF wpływa na regulację cyklu komórkowego przez pobudzenie szlaku wzrostu komórki w stosunku do szlaków sygnałowych prowadzących do śmierci komórki, a ostateczny efekt oddziaływania tych dwóch sił ma podstawowe znaczenie dla prawidłowego lub nieprawidłowego wzrostu komórki. Hipotezy na temat powiązań osi GH–IGF z karcynogenezą pojawiły się wiele lat temu, głównie w oparciu o wyniki badań in vitro oraz badań z wykorzystaniem różnych zwierzęcych modeli raka występującego u ludzi. Chociaż liczne dane doświadczalne potwierdzają rolę osi GH–IGF sprzyjającą rozwojowi i progresji nowotworów, a nad kilkoma składowymi tej osi trwają obecnie badania oceniające ich przydatność jako główne cele terapii przeciwnowotworowej, to jednak siła dowodów uzyskanych u chorych z akromegalią, niedoborem GH lub osób leczonych GH jest znacznie słabsza. W niniejszej pracy przeglądowej spróbowano zebrać wszystkie te dane. (Endokrynol Pol 2016; 67 (4): 414–426)

Avaliação do tratamento supressivo com levotiroxina na doença nodular de tireoide : resultados de um estudo clinico prospectivo, randomizado, duplo-cego e controlado com placebo

Orientador: Doris RosenthalDissertação (mestrado) - Universidade Federal do Parana, Setor de Ciencias da SaudeResumo: O objetivo do presente estudo foi avaliar o efeito do tratamento supressivo com levotiroxina em reduzir o tamanho de nódulos tireoideanos clinicamente solitários. Os critérios para inclusão dos pacientes no estudo foram: nódulo frio ou morno a cintilografia, neste ultimo caso suprimível com o uso de hormônio tireoideano; nódulos sólidos ou predominantemente sólidos a ecografia; e resultado citológico da PAAF de lesão negativa para malignidade. Critérios de exclusão foram: mais do que um nódulo palpável, nódulos quentes ou mornos não suprimíveis pelo uso do hormônio tireoideano; císticos ou predominantemente císticos a ecografia, achados sugestivos ou positivos para malignidade na PAAF; gestação e qualquer contraindicação para terapia supressiva de tireoide. Um total de 48 pacientes foram randomizados para receber levotiroxina (n = 25) ou placebo (n = 23) por um período de 1 ano. A dose de levotiroxina (LT) foi de 200 (ig/dia para pacientes com menos de 70 kg e 250 [ig/dia para aqueles pesando mais do que 70 kg. Foi realizada ecografia de alta resolução antes e apos 6 e 12 meses de tratamento, para avaliar as mudanças no tamanho dos nodulos. Dosagens de TSH-sensivel (TSH-S) e prova do TRH foram realizadas para confirmar a supressão do eixo hipofisario-tireoideano, correlacionando-se os níveis basais de TSH-S com suas respostas na prova do TRH. A tireoglobulina (TG) foi dosada com intuito de verificar sua possível utilidade como um "marcador bioquímico" da eficácia do tratamento supressivo. Apos 1 ano, ocorreu diminuição do volume nodular em 44% dos pacientes do grupo levotiroxina (GT) contra 35% do grupo placebo (GP). A diferença entre os dois grupos nao foi significativa. Aos 6 meses, ocorreu uma significativa diminuição do volume nodular médio no GT (p < 0,05; teste t de Student), mas aos 12 meses a diminuição no volume nodular não foi significativa. No GP, ocorreu um aumento significativo no volume nodular médio após 6 e 12 meses de acompanhamento (p < 0,05; teste t de Student). Foram usados parâmetros clínicos e laboratoriais para identificar um possível subgrupo de nódulos mais responsivos a LT. O único parâmetro que demonstrou relação de dependência com a resposta a medicação foi a característica cintilografica: os nódulos frios responderam melhor do que os nódulos mornos. No presente estudo, o efeito da terapia supressiva com LT para nódulos solitários de tireoide não foi diferente de placebo após 1 ano de tratamento. Entretanto, e possível que exista um subgrupo de nódulos que respondam a LT. Embora se tenha atingido uma supressão adequada em todos os pacientes do GT, nenhuma correlação foi encontrada entre os níveis basais de TSH-S e suas variações na prova do TRH. De modo similar, os níveis de TG não se correlacionaram com as mudanças no volume dos nódulos em nenhum dos dois grupos do estudo.Abstract: The purpose of the present study was to evaluate the effect of thyroid suppression therapy on clinically solitary thyroid nodules. Criteria for inclusion were the following features of the nodule: "cold" or "warm" on thyroid scintigraphic scanning (in the latter case, suppressible with thyroid hormone); solid or predominantly solid on ultrasonography; and negative for malignancy by fine-needle aspiration biopsy. Exclusion criteria were: more than one palpable nodule; "hot" or "non-suppressible-warm" nodule on scintigraphic scanning; cytologic findings suggestive of a neoplasy by fine-needle aspiration biopsy; cystic or predominantly cystic nodule on ultrasonography, and pregnancy or any other contraindication for thyroid suppression therapy. A total of 48 patients were randomly assigned to receive either levothyroxine (n = 25) or placebo (n = 23), for a one-year period. The dose of levothyroxine (LT) given was 200 (ig/day for patients weighing less and 250 ug/day for those weighing more than 70 kg. High-frequency ultrasonography was performed before, at six months, and after one year of treatment, to evaluate changes in nodule size. TSH-sensitive (TSH-S) levels and TRH test were performed to confirm the suppression of thyrotropin. The TSH-S basal level and its variation with TRH test were correlated. Thyroglobulin (TG) was measured to evaluate its possible usefulness as a "biochemical marker" of thyroid suppression. After one year, nodule volume was reduced in 44% of LT-treated patients, and in 35% of patients given placebo. The difference between the two groups was not significant. At six months, there was a significant reduction in mean nodule volume in the LT-treated group (p < 0,05; Student's t test). At one year, however, this volume reduction was no longer found to be significant. In the placebo group, there was a significant increase in the mean nodule volume at both six months and one year (p < 0,05; Student's t test). Clinical and laboratory parameters were used to identify a possible subgroup of nodules more responsive to LT. The only parameter found to be relevant was the scintigraphic features of the nodule: "cold" nodules responded better than "warm" nodules. The present study shows that the effect of LT-suppressive therapy on solitary thyroid nodules is not diferent from placebo, after one year of treatment. It is possible, however, that there exists a subgroup of nodules that respond to LT. Despite the fact that adequate thyroid suppression was achieved in all patients, no correlation was found between basal levels of TSH-S and their variations on the TRH test. Similarly, TG levels did not correlate with nodule volume changes, ineither group

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions

Chronic l-menthol-induced browning of white adipose tissue hypothesis: A putative therapeutic regime for combating obesity and improving metabolic health

Obesity constitutes a serious global health concern reaching pandemic prevalence rates. The existence of functional brown adipose tissue (BAT) in adult humans has provoked intense research interest in the role of this metabolically active tissue in whole-body energy balance and body weight regulation. A number of environmental, physiological, pathological, and pharmacological stimuli have been proposed to induce BAT-mediated thermogenesis and functional thermogenic BAT-like activity in white adipose tissue (WAT), opening new avenues for therapeutic strategies based on enhancing the number of beige adipocytes in WAT

A review on the diagnosis and treatment of patients with clinically nonfunctioning pituitary adenoma by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism

Clinically nonfunctioning pituitary adenomas (NFPA) are the most common pituitary tumors after prolactinomas. The absence of clinical symptoms of hormonal hypersecretion can contribute to the late diagnosis of the disease. Thus, the majority of patients seek medical attention for signs and symptoms resulting from mass effect, such as neuro-ophthalmologic symptoms and hypopituitarism. Other presentations include pituitary apoplexy or an incidental finding on imaging studies. Mass effect and hypopituitarism impose high morbidity and mortality. However, early diagnosis and effective treatment minimizes morbidity and mortality. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism is to provide a review of the diagnosis and treatment of patients with NFPA, emphasizing that the treatment should be performed in reference centers. This review is based on data published in the literature and the authors’ experience. Arch Endocrinol Metab. 2016;60(4):374-9

Revisitando a síndrome de Nelson

A síndrome de Nelson é caracterizada pela tríade de hiperpigmentação cutânea, níveis elevados de ACTH e expansão do tumor hipofisário após adrenalectomia bilateral como terapia para Doença de Cushing. Apresenta taxas de incidência que variam de 0 a 47% e tem como principais fatores preditivos para o seu surgimento os níveis de ACTH plasmático no primeiro ano após a adrenalectomia, duração da doença de Cushing até a retirada das adrenais e tratamento prévio com radioterapia para o tratamento da doença de Cushing. Os critérios diagnósticos para essa doença consistem na adrenalectomia bilateral em pacientes com doença de Cushing associada à elevação nos níveis de ACTH (acima de 500 ng/L ou aumento de pelo menos 30% do valor em três amostras consecutivas) e/ou imagem hipofisária com lesão tumoral. O tratamento de primeira linha é a ressecção da lesão através da cirurgia transesfenoidal, porém radioterapia e tratamento farmacológico com cabergolina, pasireotide ou temozolamida podem ser necessários em alguns casos

Revisitando a síndrome de Nelson

A síndrome de Nelson é caracterizada pela tríade de hiperpigmentação cutânea, níveis elevados de ACTH e expansão do tumor hipofisário após adrenalectomia bilateral como terapia para Doença de Cushing. Apresenta taxas de incidência que variam de 0 a 47% e tem como principais fatores preditivos para o seu surgimento os níveis de ACTH plasmático no primeiro ano após a adrenalectomia, duração da doença de Cushing até a retirada das adrenais e tratamento prévio com radioterapia para o tratamento da doença de Cushing. Os critérios diagnósticos para essa doença consistem na adrenalectomia bilateral em pacientes com doença de Cushing associada à elevação nos níveis de ACTH (acima de 500 ng/L ou aumento de pelo menos 30% do valor em três amostras consecutivas) e/ou imagem hipofisária com lesão tumoral. O tratamento de primeira linha é a ressecção da lesão através da cirurgia transesfenoidal, porém radioterapia e tratamento farmacológico com cabergolina, pasireotide ou temozolamida podem ser necessários em alguns casos

Recommendations of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism for diagnosis and treatment of acromegaly in Brazil

A acromegalia é uma doença associada à elevada morbidade e à redução da expectativa de vida. Em virtude do seu caráter insidioso e do seu não reconhecimento, o diagnóstico é frequentemente realizado com atraso, o que, associado às complicações relacionadas ao excesso do GH/IGF-I, determina elevada morbimortalidade. No entanto, um diagnóstico precoce e um tratamento efetivo minimizam a morbidade e normalizam a taxa de mortalidade. Nesta publicação, o objetivo do Departamento de Neuroendocrinologia da Sociedade Brasileira de Endocrinologia e Metabologia é divulgar quando suspeitar clinicamente da acromegalia e como diagnosticá-la. Além disso, discute-se a maneira mais eficaz e segura de realizar o tratamento da acromegalia, enfatizando que este deve ser realizado em centros de referência. Assim, com base em dados publicados em periódicos de nível científico reconhecido e na experiência dos autores, são apresentadas as recomendações para o diagnóstico e tratamento da doença.Acromegaly is a disease associated with increased morbidity and reduced life expectancy. Because of its insidious character and its non-recognition, the diagnosis is often made with delay, which, along with the complications related to GH/IGF-I excess, determines high morbidity and mortality. However, an early diagnosis and an effective treatment reduce the morbidity and normalize the mortality rate. In this publication, the goal of Neuroendocrinology Department from Brazilian Society of Endocrinology and Metabolism is to disclose which clinical set should arouse the suspicious of acromegaly and how to diagnose it. Furthermore, we discuss the most effective and safe approach to perform the treatment of acromegaly, emphasizing that it must be carried out in reference centers. Therefore, based on data published in journals with recognized scientific level and authors' experience, recommendations are presented for diagnosis and treatment of the disease

Brazilian multicenter study on pegvisomant treatment in acromegaly

Objective Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. Subjects and methods Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. Results 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. Conclusions In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies

A review of Cushing’s disease treatment by the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism

The treatment objectives for a patient with Cushing’s disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails.There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition