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1.
World Neurosurg ; 126: e41-e47, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30716503

RESUMO

OBJECTIVE: Long-term effects of endoscopic endonasal transsphenoidal intracapsular debulking and adjuvant somatostatin analogs (SSAs) were evaluated in patients with growth hormone- (GH) secreting pituitary macroadenomas. METHODS: We retrospectively reviewed the medical records of 45 patients with acromegalic macroadenoma who underwent endonasal endoscopic transsphenoidal intracapsular debulking and received adjuvant SSAs (octreotide) between 2006 and 2015 who had >1 year of follow-up. To evaluate the predictive factors for 1 year and long-term biochemical outcomes, univariate and multivariate analyses were performed. RESULTS: Biochemical remission was achieved in 1 year in 20 of the 45 (44.4%) patients, and in 31 of the 45 patients after long-term adjuvant SSA treatment. Tumor control was achieved in 43 of the 45 (93.3%) patients. The univariate analysis showed age (≥55 years), tumor size (diameter ≤1.5 cm), premedication GH levels (≤2.8 ng/mL), premedication insulin-like growth factor 1 levels (≤2-fold of upper limit of normal range), cavernous sinus invasion (Knops grades 2, 3, and 4), and near-total tumor resection were associated with long-term outcomes. The multivariate analysis showed near-total resection was a significant predictor for long-term outcomes (P = 0.019). There were no new pituitary dysfunctions. The observed complications included one case of cerebrospinal fluid leakage and one case of epistaxis requiring intervention. CONCLUSIONS: Intracapsular debulking and adjuvant SSAs are a safe and viable treatment for patients with GH secreting pituitary macroadenoma to achieve biochemical remission and tumor control. Although adjuvant SSA treatment enhances residual tumor control, cavernous sinus invasion impedes the remission of endocrine tumors.


Assuntos
Procedimentos Cirúrgicos de Citorredução/métodos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Antagonistas de Hormônios/uso terapêutico , Octreotida/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/cirurgia , Acromegalia/etiologia , Acromegalia/cirurgia , Adulto , Terapia Combinada , Endoscopia/métodos , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Cavidade Nasal/cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
2.
Minerva Endocrinol ; 44(2): 109-128, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30650942

RESUMO

Acromegaly is a chronic systemic disease mainly caused by a growth hormone (GH)-secreting pituitary neuroendocrine tumor (PitNETs), which is associated with many health complications and increased mortality when not adequately treated. Transsphenoidal surgery is considered the treatment of choice in GH-secreting PitNETs, but patients in whom surgery cannot be considered or with persistent disease after surgery require medical therapy. Treatment with available synthetic somatostatin analogues (SSAs) is considered the mainstay in the medical management of acromegaly which exert their beneficial effects through the binding to a family of G-protein coupled receptors encoded by 5 genes (SSTR1-5). However, although it has been demonstrated that the SST1-5 receptors are physically present in tumor cells, SSAs are in many cases ineffective (i.e. approximately 10-30% of patients with GH-secreting PitNET are unresponsive to SSAs), suggesting that other cellular/molecular determinants could be essential for the response to the pharmacological treatment in patients with GH-secreting PitNETs. Therefore, the scrutiny of these determinants might be used for the identification of subgroups of patients in whom an appropriate pharmacological treatment can be successfully employed (responders vs. non-responders). In this review, we will describe some of the existing, classical and novel, genetic and molecular determinants involved in the response of patients with GH-secreting PitNETs to the available therapeutic treatments, as well as new molecular/therapeutic approaches that could be potentially useful for the treatment of GH-secreting PitNETs.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/genética , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Humanos , Neoplasias Hipofisárias/complicações
3.
Minerva Endocrinol ; 44(2): 129-136, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30531694

RESUMO

Acromegaly is mainly due to the somatotroph pituitary neuroendocrine tumors (PitNET)s. These have been subtyped into densely granulated (DG) and sparsely granulated (SG) tumors, which differ in clinical, histological and biological characteristics and in response to somatostatin analogs (SA)s. The variable remission rate after surgical resection, as first line treatment, has increased interest in identifying pathological markers to better predict the response to medical treatment. Several techniques have shown somatotroph tumors to express somatostatin receptors (SSTR)s, and mainly SSTR2 and SSTR5. The molecular methods appear to give contradictory results, are expansive and cannot be routinely performed. Immunohistochemistry, while being the most powerful technique, requires optimal fixation and the use of monoclonal antibodies against at least SSTR2 and SSTR5. Almost all somatotroph tumors express SSTR2 or SSTR5, and, in great majority, at a high level. More importantly, the type of SSTR, the level of expression, and the response to SA treatment appear well correlated. Indeed, a significantly higher expression of SSTR2 in DG compared to in SG tumors likely explains the better response of DG tumors to the normalization of growth hormone and insulin-like growth factor-1 under SA. However, a reproducible scoring and a cut-off from which the SA efficacy can be reliably predicted, remain to be found. In conclusion, the SSTR expression profile and morphological subtypes of the somatotroph tumor may help predict the response to medical treatment. Such pathological profiling could become a useful decision-making tool for clinicians in the context of a multidisciplinary approach, after surgery failure.


Assuntos
Adenoma/tratamento farmacológico , Adenoma/patologia , Biomarcadores/análise , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Acromegalia/tratamento farmacológico , Acromegalia/patologia , Animais , Humanos , Valor Preditivo dos Testes , Prognóstico , Receptores de Somatostatina/genética
4.
Minerva Endocrinol ; 44(2): 169-175, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30531695

RESUMO

Acromegaly is a chronic disorder usually diagnosed late in the disease evolution, leading to substantial morbidity and mortality related to this long period of undiagnosed state as well as the difficulty in achieving normalization of GH hypersecretion and controlling tumor mass. First generation somatostatin analogues (SSA) are accepted as the first-line medical therapy or as second-line therapy in patients undergoing unsuccessful surgery. However, because a high percentage of patients experience SSA treatment failure, the inclusion of biomarkers associated with a successful or non-successful response to these drug (as well as to all classes of medical therapy) is necessary to better guide the choice of treatment, potentially allowing for a quicker achievement of disease control. The current treatment algorithms for acromegaly are based upon a "trial and error" approach with additional treatment options provided when disease is not controlled. In many other diseases, their therapeutic algorithms have been evolving towards personalizing treatment with medication that best matches individual disease characteristics, using biomarkers that identify therapeutic response, thus allowing the personalization of the therapy. It is time to introduce this approach to acromegaly treatment algorithms. This paper reviews the potential tools for doing so.


Assuntos
Acromegalia/tratamento farmacológico , Medicina de Precisão , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Humanos , Padrões de Prática Médica
5.
Minerva Endocrinol ; 44(2): 159-168, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30482010

RESUMO

Acromegaly is a rare disease characterized by high levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). The excess of GH leads to the development of different manifestations in different organs, from subtle signs in the bones and soft tissues to the development of respiratory and cardiac insufficiency. In the cardiovascular system, the GH/IGF-1 axis exerts its influence on three major aspects: myocyte growth and structure, cardiac contractility and vascular function. In this article, we review the different cardiovascular and respiratory complications as well as the effects of the different treatments on these complications. Cardiovascular complications that occur in acromegaly are known as "acromegalic cardiomyopathy," and include ventricular hypertrophy, impaired diastolic and systolic function, valve diseases, coronary artery disease, and arrhythmias. Acromegaly is also associated with relevant complications of the respiratory system, mainly sleep apnea and respiratory insufficiency. Regarding treatment, there are different therapeutic strategies. Surgery is the first-choice treatment, but in general, half of patients will require adjuvant treatments, such as medical treatment (somatostatin analogues, dopamine agonists and GH receptor antagonists) or radiotherapy. The treatment can improve some complications of acromegaly, such as left ventricular hypertrophy, hypertension, or obstructive sleep apnea. On the other hand, when strict control of the disease is achieved, a reduction in mortality and cardiovascular morbidity is assured, reaching rates similar to those of the general population.


Assuntos
Acromegalia/complicações , Acromegalia/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Síndromes da Apneia do Sono/tratamento farmacológico , Síndromes da Apneia do Sono/etiologia , Acromegalia/mortalidade , Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Humanos , Resultado do Tratamento
6.
Artigo em Inglês | MEDLINE | ID: mdl-30088454

RESUMO

BACKGROUND AND OBJECTIVE: Giant pituitary adenomas (GPAs) are benign tumours with a diameter ≥ 4 cm [1]. They can cause symptoms and signs due to the possible hyper-secretion of one or more pituitary hormones, and involvement of the surrounding structures whereas the compression of the pituitary itself can lead to hypopituitarism. METHODS: We report on a young woman with acromegaly due to an inoperable giant GH-secreting pituitary adenoma extending to right cavernous sinus, right orbital cavity, ethmoid, right maxillary sinus, sphenoid sinus, clivus and right temporal fossa, in which medical treatment with Octreotide- LAR was able to promptly relieve headache and bilateral hemianopsia due to optic chiasm involvement, improve acromegaly symptoms and, over the time, control tumor expansion, improving fertility and therefore allowing the patient to become pregnant. RESULTS: Octreotide-LAR therapy was withdrawn during pregnancy and the patient did not experience complications and gave birth to a healthy son. On magnetic resonance, the size of the tumor at the end of pregnancy and in the subsequent follow up was not increased. CONCLUSION: The history we report, therefore, confirms previous experiences reporting a possible favourable outcome of pregnancy in patients affected by acromegaly and adds further information about the behaviour of giant pituitary tumors in patients underwent pregnancy.


Assuntos
Adenoma/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Octreotida/uso terapêutico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Acromegalia/etiologia , Acromegalia/patologia , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/patologia , Adulto , Antineoplásicos Hormonais/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Hemianopsia/diagnóstico , Hemianopsia/tratamento farmacológico , Hemianopsia/etiologia , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Síndromes de Compressão Nervosa/diagnóstico , Síndromes de Compressão Nervosa/tratamento farmacológico , Síndromes de Compressão Nervosa/etiologia , Gravidez , Complicações Neoplásicas na Gravidez/diagnóstico , Complicações Neoplásicas na Gravidez/patologia , Resultado da Gravidez , Carga Tumoral
7.
J Endocrinol Invest ; 42(4): 443-451, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30171531

RESUMO

PURPOSE: Somatostatin analogs (SSAs) are considered one of the most effective medical treatments for patients with growth hormone-secreting pituitary adenomas (GH-PAs). The postoperative electron microscopy (EM) pathological subtype and SSTR2 expression in the tumor are the most established predictors of patient response to SSA therapy. The aim of this study was to evaluate how will magnetic resonance spectroscopy (MRS) measurements before surgery predict the EM pathological subtypes and SSTR2 expression of tumors, and thereby serve as an indicator for the therapeutic sensitivity to SSAs of patients with GH-PAs. METHODS: Eighteen patients with GH pituitary macroadenomas who underwent transsphenoidal surgery were included in this retrospective study. The preoperative MRS data and T2 signal intensity were obtained from patients by 1.5 T MR spectroscopy of the sellar mass. The EM pathological subtypes of tumors were determined after surgery through examination of cell granulations. The expressions of somatostatin receptor 2 (SSTR2), SSTR5, P21, P27, and Ki-67 were evaluated by immunohistochemistry. RESULTS: The MRS parameters that were found to significantly predict the EM pathological subtypes of tumors, as calculated by the receiver operating characteristic curve, were the choline (Ch) value at 3140.5 MR units (sensitivity 69.2%, specificity 100%) and the choline/creatine (Ch/Cr) ratio at 1.27 (sensitivity 92.3%, specificity 100%). Further, the Ch/Cr ratio, but not other MRS data, was shown to negatively correlate with the expression of SSTR2 (P = 0.02). The Ch/Cr ratio was also found to positively correlate with the Ki-67 value (P < 0.05) and T2 signal (P < 0.05), but not with other factors that were examined in this study. Moreover, the Ch/Cr ratio could predict the EM pathological subtypes of tumors with an accuracy of 83.3% (5/6) for patients with an isointense T2 signal. CONCLUSION: The Ch/Cr ratio by MRS could effectively predict the tumor subtype and was significantly correlated with the expression of SSTR2, which was consistent with other predictors. It was also able to distinguish the patients with isointense T2 signals. Our results provide a potentially new and non-invasive method to predict the response to SSAs in patients with GH pituitary macroadenomas.


Assuntos
Adenoma/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Antagonistas de Hormônios/farmacologia , Espectroscopia de Ressonância Magnética/métodos , Cuidados Pré-Operatórios , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adenoma/cirurgia , Adulto , Idoso , Biomarcadores/análise , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
8.
J Clin Endocrinol Metab ; 104(3): 915-924, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30346538

RESUMO

Background: The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression. Aim: To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment. Methods: We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS). Results: The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9). Conclusions: In a cohort of patients partially responsive to SRLs, the IGF-I-lowering effects of PAS-LAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.


Assuntos
Acromegalia/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Antagonistas de Hormônios/farmacologia , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/patologia , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Resultado do Tratamento
10.
Endocrine ; 62(2): 448-455, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30051198

RESUMO

INTRODUCTION: Pasireotide, a multi-somatostatin receptor (SSTR)-ligand with high affinity for SSTR5 was recently approved for acromegaly treatment. PATIENTS AND METHODS: A retrospective multicenter study investigating the efficacy and safety of long-acting (LAR) pasireotide treatment in 35 patients (20 males) with active acromegaly (28 macroadenomas). RESULTS: Mean baseline insulin-like growth factor-1 (IGF-1) at diagnosis was 3.1 ± 1.3 × ULN. All but five patients have undergone pituitary surgery and six received sellar radiotherapy. All remained with active acromegaly despite first-generation somatostatin analogue (SSA) treatment. Immediately before pasireotide-LAR initiation, eighteen patients were under SSA monotherapy and one with pegvisomant. The remaining patients received combination therapy with SSA and pegvisomant, n = 9 (two received cabergoline also); SSA and cabergoline, n = 4; pegvisomant and cabergoline, n = 1. Two were untreated. Mean IGF-1 was 1.76 ± 0.9 ULN before pasireotide. Pasireotide-LAR starting dose was 40 mg/4 weeks in most patients. IGF-1 normalized in 19 patients, IGF-1 between 1-1.2 × ULN was reached in five, and in additional two patients IGF-1 was significantly suppressed. No effect was seen in nine patients. Pasireotide dose was reduced by 20 mg in six patients with excellent response, with preserved IGF-1 control in five. Severe headaches in six patients disappeared or improved with pasireotide. Side effects consisted of symptomatic cholelithiasis in one patient and deterioration of glucose control in 22 patients, requiring initiation or intensification of antidiabetic treatment in seventeen. One patient developed diabetic ketoacidosis. CONCLUSIONS: In the real-life scenario ~54% of patients with acromegaly resistant to first-generation SSA, may normalize IGF-1 with pasireotide; however, 63% experienced glucose control deterioration.


Assuntos
Acromegalia/tratamento farmacológico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Acromegalia/etiologia , Adenoma/complicações , Adenoma/tratamento farmacológico , Adulto , Preparações de Ação Retardada/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento
11.
Horm Res Paediatr ; 90(3): 196-202, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953972

RESUMO

BACKGROUND: Somatotropinomas are rare in childhood and frequently associated with genetic mutations. AIP mutations are found in 20-25% cases and cause aggressive somatotropinomas, often resistant to somatostatin analogues. AIMS: To assess responses to multimodal therapy including pegvisomant in 2 children with sporadic somatotropinomas due to AIP mutations. CASE DESCRIPTION: We report 2 children, a boy aged 13 and a girl aged 10, with rapid growth, visual impairment, and growth hormone hypersecretion. Magnetic resonance imaging confirmed a pituitary macroadenoma with parasellar extension in both. Despite multiple surgical attempts to debulk tumour mass, residual tumour persisted. Genetic analysis showed two different AIP mutations (patient 1: c.562delC [p.Arg188Glyfs*8]; patient 2: c.140_ 163del24 [p.Gly47_Arg54del8]). They were initially treated with a long-acting somatostatin analogue (octreotide LAR 30 mg/month) and cabergoline as a dopamine agonist, with the later addition of pegvisomant titrated up to 20 mg/day and with radiotherapy for long-term control. Somatostatin analogue was ceased due to patient intolerance and lack of control. Patient 1 had normalization of insulin-like growth factor-1 (IGF-1) after 5 months of combined therapy with pegvisomant and cabergoline. For patient 2, normalization of IGF-1 was achieved after 2 months of cabergoline and pegvisomant. CONCLUSION: AIP-associated tumours can be resistant to management with somatostatin analogues. Pegvisomant can safely be used, to normalize IGF-1 levels and help control disease.


Assuntos
Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Hormônio do Crescimento Humano/análogos & derivados , Peptídeos e Proteínas de Sinalização Intracelular/genética , Acromegalia/diagnóstico , Acromegalia/tratamento farmacológico , Acromegalia/genética , Acromegalia/metabolismo , Adenoma/diagnóstico , Adenoma/metabolismo , Adolescente , Criança , Feminino , Gráficos de Crescimento , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Imagem por Ressonância Magnética , Masculino
12.
Endocrinology ; 159(8): 2953-2965, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29931263

RESUMO

The cytoskeletal protein filamin A (FLNA) has been suggested to play an important role in the responsiveness of GH-secreting pituitary tumors to somatostatin receptor subtype 2 (SSTR2) agonists by regulating SSTR2 expression and signaling. However, the underlying mechanisms are unknown. In this study, we use fast multicolor single-molecule microscopy to image individual SSTR2 and FLNA molecules at the surface of living cells with unprecedented spatiotemporal resolution. We find that SSTR2 and FLNA undergo transient interactions, which occur preferentially along actin fibers and contribute to restraining SSTR2 diffusion. Agonist stimulation increases the localization of SSTR2 along actin fibers and, subsequently, SSTR2 clustering and recruitment to clathrin-coated pits (CCPs). Interfering with FLNA-SSTR2 binding with a dominant-negative FLNA fragment increases SSTR2 mobility, hampers the formation and alignment of SSTR2 clusters along actin fibers, and impairs both SSTR2 recruitment to CCPs and SSTR2 internalization. These findings indicate that dynamic SSTR2-FLNA interactions critically control the nanoscale localization of SSTR2 at the plasma membrane and are required for coupling SSTR2 clustering to internalization. These mechanisms explain the critical role of FLNA in the control of SSTR2 expression and signaling and suggest the possibility of targeting SSTR2-FLNA interactions for the therapy of pharmacologically resistant GH-secreting pituitary tumors.


Assuntos
Filaminas/metabolismo , Regulação Neoplásica da Expressão Gênica , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Citoesqueleto de Actina/metabolismo , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma/metabolismo , Animais , Células CHO , Invaginações Revestidas da Membrana Celular/metabolismo , Cricetulus , Filaminas/ultraestrutura , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Células HEK293 , Humanos , Ligação Proteica , Transporte Proteico , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/ultraestrutura , Imagem Individual de Molécula
13.
Pituitary ; 21(4): 347-354, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29460202

RESUMO

PURPOSE: To assess baseline T2-weighted signal intensity (T2-WSI) of functional pituitary adenomas (FPA), and to investigate the relationship of baseline T2-WSI with clinical features, histopathological granulation patterns, and response to treatment in patients with acromegaly, prolactinoma and Cushing's disease (CD). METHODS: Somatotroph adenomas (n = 87), prolactinomas (n = 78) and corticotroph adenomas (n = 29) were included in the study. Baseline T2-WSI findings (grouped as hypo-, iso- and hyperintense) were compared with hormone levels, tumor diameter, granulation patterns and response to treatment. RESULTS: Somatotroph adenomas were mostly hypointense (53%), prolactinomas were dominantly hyperintense (55%), and corticotroph adenomas were generally hyperintense (45%). Hyperintense somatotroph adenomas were larger in size with sparsely granulated pattern and tumor shrinkage rate was lower after somatostatin analogues (SSA) (p = 0.007, p = 0.035, p = 0.029, respectively). T2 hypointensity was related with higher baseline IGF-1% ULN (upper limit of normal) levels and a better response to SSA treatment (p = 0.02, p = 0.045, respectively). In female prolactinomas, hyperintensity was correlated with a smaller adenoma diameter (p = 0.001). Hypointense female prolactinomas were related to younger age at diagnosis, higher baseline PRL levels and dopamine agonist (DA) resistance (p = 0.009, p = 0.022, p < 0.001, respectively). Hyperintense corticotroph adenomas were related to larger adenoma size and sparsely granulated pattern (p = 0.04, p = 0.017, respectively). There was no significant difference in the recurrence with T2WSI in CD. CONCLUSION: Baseline hypointense somatotroph adenomas show a better response to SSA, whereas hypointensity was related to DA resistance in female prolactinomas.


Assuntos
Adenoma/patologia , Neoplasias Hipofisárias/patologia , Acromegalia/complicações , Adenoma/tratamento farmacológico , Adulto , Agonistas de Dopamina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Hipersecreção Hipofisária de ACTH/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/complicações , Estudos Retrospectivos , Fatores Sexuais , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Resultado do Tratamento
14.
Eur J Endocrinol ; 178(3): R89-R100, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29339530

RESUMO

Acromegaly is associated with high morbidity and elevated mortality when not adequately treated. Surgery is the first-line treatment for most patients as it is the only one that can lead to immediate cure. In patients who are not cured by surgery, treatment is currently based on a trial-and-error approach. First-generation somatostatin receptor ligands (fg-SRL) are initiated for most patients, although approximately 25% of patients present resistance to this drug class. Some biomarkers of treatment outcome are described in the literature, with the aim of categorizing patients into different groups to individualize their treatments using a personalized approach. In this review, we will discuss the current status of precision medicine for the treatment of acromegaly and future perspectives on the use of personalized medicine for this purpose.


Assuntos
Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Agonistas de Dopamina/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Medicina de Precisão , Receptores da Somatotropina/antagonistas & inibidores , Somatostatina/análogos & derivados , Humanos , Resultado do Tratamento
15.
Endocr J ; 65(1): 33-41, 2018 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-28931779

RESUMO

Although somatostatin analogues (SSAs) are recommended as the first-line medical therapy for acromegaly, dopamine agonists (DAs) are also a therapeutic option for treatment. We aimed to assess and compare the efficacies of DAs and SSAs in treating acromegaly in clinical practice. We included 89 patients with acromegaly who took DAs (bromocriptine [BCT], n = 63; cabergoline [CAB], n = 11) or SSAs (n = 15) as a primary medical therapy for more than 3 months in the Seoul National University Hospital. The CAB (45.5%) and SSA (33.3%) groups achieved random GH levels of <2.5 ng/mL and the normal IGF-1 levels were significantly higher than in the BCT group (11.1%) (p = 0.009). We further included all the patients with acromegaly (n = 132) who had taken CAB, BCT, and SSAs as first- or second-line medical therapy. The CAB group showed similar efficacy as the SSA group in terms of the GH and insulin-like growth factor-1 (IGF-1) levels (57.6% for random GH level <2.5 ng/mL, 42.4% for normal IGF-1 levels, 36.4% for both). Logistic regression analysis revealed that medications, age, GH level, or IGF-1 level before medication, hyperprolactinemia, and prior gamma-knife surgery or radiation therapy, did not affect the therapeutic response. High pretreatment GH levels predicted poor treatment outcomes (odds ratio [95% confidence interval] = 0.95 [0.90-0.99]). CAB was effective in treating acromegaly at a relatively lower cost in patients with low pretreatment GH levels.


Assuntos
Acromegalia/prevenção & controle , Adenoma/tratamento farmacológico , Bromocriptina/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Ergolinas/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Somatostatina/análogos & derivados , Acromegalia/etiologia , Adenoma/sangue , Adenoma/patologia , Adenoma/fisiopatologia , Adulto , Antineoplásicos/uso terapêutico , Cabergolina , Estudos de Coortes , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/fisiopatologia , Hospitais Universitários , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , República da Coreia , Estudos Retrospectivos , Somatostatina/uso terapêutico , Carga Tumoral/efeitos dos fármacos
16.
Exp Clin Endocrinol Diabetes ; 126(3): 168-175, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-27322826

RESUMO

OBJECTIVE: To evaluate the effect of preoperative somatostatin analog (SRL) treatment on proteins associated with apoptosis and autophagy in patients with acromegaly and to determine factors correlating with these parameters. METHODS: Ex-vivo tumor samples of 11 SRL-treated and 9 SRL-untreated patients were retrospectively included in the study. Apoptotic and autophagic proteins were determined via immunohistochemical staining and apoptosis was evaluated via in situ DNA end labeling (TUNEL). RESULTS: TUNEL, caspase-3, and ATG-5 immunopositivity was significantly increased (p<0.01, p=0.01, p=0.01, respectively), survivin and beclin-1 immunopositivity was significantly decreased (p=0.03, p=0.02, respectively) in SRL-treated patients as compared with SRL-untreated controls. Ki-67 index was decreased significantly in the SRL-treated group (p=0.01). Significant positive correlations were detected between TUNEL and caspase-3 immunopositivity (r=0.577, p<0.01), and between survivin and beclin-1 immunopositivity (r=0.503, p=0.03). Age at diagnosis, preoperative GH, IGF-1 levels, tumor size, and invasion status were not found to affect TUNEL positivity nor did they correlate with caspase-3, survivin, beclin-1, ATG-5 immunopositivity (p>0.05 for all). Preoperative SRL treatment was the only factor that had a significant effect on TUNEL positivity (adjusted R2=0.39, p=0.02). Preoperative treatment duration was positively correlated with TUNEL and caspase-3 immunopositivity (r=0.526, p=0.02; r=0.475, p=0.04, respectively) and negatively correlated with survivin immunopositivity (r=-0.533, p=0.01). CONCLUSIONS: Somatostatin analog treatment might induce apoptosis, increase autophagy, and decrease cell proliferation in GH-secreting adenomas. Also, proteins related to cross-talk between autophagy and apoptosis are upregulated after SRL treatment.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/metabolismo , Adenoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Cuidados Pré-Operatórios , Somatostatina/farmacologia , Acromegalia/patologia , Acromegalia/cirurgia , Adenoma/metabolismo , Adenoma/patologia , Adenoma/cirurgia , Adulto , Proliferação de Células/efeitos dos fármacos , Estudos Transversais , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Retrospectivos , Somatostatina/administração & dosagem , Somatostatina/análise
17.
J Cell Mol Med ; 22(3): 1640-1649, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29266696

RESUMO

Acromegaly is a hormonal disorder resulting from excessive growth hormone (GH) secretion frequently produced by pituitary adenomas and consequent increase in insulin-like growth factor 1 (IGF-I). Elevated GH and IGF-I levels result in a wide range of somatic, cardiovascular, endocrine, metabolic and gastrointestinal morbidities. Somatostatin analogues (SSAs) form the basis of medical therapy for acromegaly and are currently used as first-line treatment or as second-line therapy in patients undergoing unsuccessful surgery. However, a considerable percentage of patients do not respond to SSAs treatment. Somatostatin receptors (SSTR1-5) and dopamine receptors (DRD1-5) subtypes play critical roles in the regulation of hormone secretion. These receptors are considered important pharmacological targets to inhibit hormone oversecretion. It has been proposed that decreased expression of SSTRs may be associated with poor response to SSAs. Here, we systematically examine SSTRs and DRDs expression in human somatotroph adenomas by quantitative PCR. We observed an association between the response to SSAs treatment and DRD4, DRD5, SSTR1 and SSTR2 expression. We also examined SSTR expression by immunohistochemistry and found that the immunohistochemical detection of SSTR2 in particular might be a good predictor of response to SSAs.


Assuntos
Adenoma/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Receptores Dopaminérgicos/genética , Receptores de Somatostatina/genética , Somatostatina/farmacologia , Adenoma/tratamento farmacológico , Adenoma/metabolismo , Adulto , Feminino , Expressão Gênica/efeitos dos fármacos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de Somatostatina/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Trends Endocrinol Metab ; 28(8): 587-596, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28622965

RESUMO

The growth hormone (GH) and insulin-like growth factor-1 (IGF1) axis is the key regulator of longitudinal growth, promoting postnatal bone and muscle growth. The available data suggest that GH expression by tumour cells is associated with the aetiology and progression of various cancers such as endometrial, breast, liver, prostate, and colon cancer. Accordingly there has been increased interest in targeting GH-mediated signal transduction in a therapeutic setting. Because GH has endocrine, autocrine, and paracrine actions, therapeutic strategies will need to take into account systemic and local functions. Activation of related hormone receptors and crosstalk with other signalling pathways are also key considerations.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/metabolismo , Terapia de Alvo Molecular , Adenoma/epidemiologia , Adenoma/metabolismo , Animais , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
19.
Hormones (Athens) ; 16(1): 84-91, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28500831

RESUMO

OBJECTIVE: To present two female patients with acromegaly inadequately controlled with long-acting octreotide who were subsequently treated with the multireceptor-targeted somatostatin analogue pasireotide that over-suppressed IGF-1 levels. METHODS: We report two patients who failed surgery and received long-acting octreotide 20-30 mg/month as part of two double-blind, Phase III clinical trials. After 6-12 months of octreotide treatment, both patients remained inadequately controlled and were switched to long-acting pasireotide 40 mg/month as part of a crossover extension phase. RESULTS: During the core phase of the studies the patients received octreotide 20-30 mg/month, but GH and IGF-1 levels remained above normal. They were switched to pasireotide 40 mg/month after 6 and 12 months, according to the study protocols. After crossover, GH and IGF-1 decreased and normalized, but continued treatment led to further reduction of IGF-1 to below the normal; these reduced levels mildly increased following pasireotide dose reduction to 20 mg/month. Tumour volume was reduced and the clinical signs and symptoms of acromegaly also improved. CONCLUSION: These patients achieved long-term biochemical control, tumour volume reduction and improvement of clinical signs/symptoms after switching from octreotide to pasireotide. IGF-1 over-suppression is observed in a few patients and requires dose adjustment of pasireotide.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Hormônios/uso terapêutico , Octreotida/uso terapêutico , Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Adenoma/patologia , Adulto , Antineoplásicos Hormonais/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Hormônios/administração & dosagem , Humanos , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Somatostatina/administração & dosagem , Somatostatina/uso terapêutico
20.
J Clin Endocrinol Metab ; 102(6): 2044-2050, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28323966

RESUMO

Context: Acromegaly is a systemic disease characterized by persistent bone pathology and excess cardiovascular mortality. Despite multiple concomitant risk factors, atherosclerosis does not seem to be accelerated in acromegaly. Objective: To compare the levels of circulating myeloid calcifying cells (MCCs), which promote ectopic calcification and inhibit angiogenesis, in individuals with and without acromegaly. Design: Cross-sectional case-control study. Setting: Tertiary ambulatory referral endocrinology center. Patients: 44 acromegalic patients (25 active; 19 inactive), 44 control subjects matched by age, sex, risk factors, and medications, and 8 patients cured of acromegaly. Intervention: MCCs were measured using flow cytometry based on the expression of osteocalcin (OC) and bone alkaline phosphatase (BAP) on monocytes and circulating CD34+ stem cells. Main Outcome Measure: Differences in MCCs between patients and controls. Results: OC+BAP+ MCCs were severely reduced in acromegalic compared with control patients (0.17% ± 0.02% vs 1.00% ± 0.24%; P < 0.001), as were the total OC+ and BAP+ monocytic cells. Patients with inactive acromegaly and those cured of acromegaly displayed persistently reduced levels of MCCs. In the controls, but not acromegalic patients, MCCs were increased in the presence of diabetes or cardiovascular disease. A direct correlation was noted between MCCs and parathyroid hormone (r = 0.61; P < 0.0001), supporting a link between bone biology and MCCs. Conclusions: In patients with acromegaly, the levels of MCCs are reduced and remain low, even years after a complete cure. This finding might be related to low atherosclerotic calcification and the persistence of bone pathology after acromegaly remission or cure.


Assuntos
Adenoma/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Monócitos/citologia , Células Mieloides/citologia , Células-Tronco/citologia , Adenoma/tratamento farmacológico , Fosfatase Alcalina/metabolismo , Antígenos CD34/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Calcinose , Estudos de Casos e Controles , Estudos Transversais , Feminino , Citometria de Fluxo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Células Mieloides/metabolismo , Neovascularização Fisiológica , Osteocalcina/metabolismo , Somatostatina/análogos & derivados , Células-Tronco/metabolismo
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