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1.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401779

RESUMO

The impairment of skeletal muscle function is one of the most debilitating least understood co-morbidity that accompanies acromegaly (ACRO). Despite being one of the major determinants of these patients' poor quality of life, there is limited evidence related to the underlying mechanisms and treatment options. Although growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels are associated, albeit not indisputable, with the presence and severity of ACRO myopathies the precise effects attributed to increased GH or IGF-1 levels are still unclear. Yet, cell lines and animal models can help us bridge these gaps. This review aims to describe the evidence regarding the role of GH and IGF-1 in muscle anabolism, from the basic to the clinical setting with special emphasis on ACRO. We also pinpoint future perspectives and research lines that should be considered for improving our knowledge in the field.


Assuntos
Acromegalia/metabolismo , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Acromegalia/fisiopatologia , Animais , Hormônio do Crescimento/deficiência , Humanos , Fator de Crescimento Insulin-Like I/deficiência , Sistema de Sinalização das MAP Quinases/genética , Músculo Esquelético/fisiopatologia , Serina-Treonina Quinases TOR/metabolismo
2.
Eur J Endocrinol ; 183(6): 597-606, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33075752

RESUMO

Objective: Neurosurgery is the first-line treatment for acromegaly. Whether metabolic disorders are reversible after neurosurgery is still debated. The meta-analysis aimed to address the following questions: (i) Does neurosurgery affect glycolipid metabolism? (ii) Are these effects related to disease control or follow-up length? Design: A meta-analysis and systematic review of the literature. Methods: Three reviewers searched databases until August 2019 for prospective trials reporting glycometabolic outcomes after neurosurgery. Three other extracted outcomes, all assessed the risk of bias. Results: Twenty studies were included. Neurosurgery significantly reduced fasting plasma glucose (FPG) (effect size (ES): -0.57 mmol/L, 95% CI: -0.82 to -0.31; P < 0.001), glucose load (ES: -1.10 mmol/L, 95% CI: -1.66 to -0.53; P < 0.001), glycosylated haemoglobin (HbA1c) (ES: -0.28%, 95% CI: -0.42 to -0.14; P < 0.001), fasting plasma insulin (FPI) (ES: -10.53 mU/L, 95% CI: -14.54 to -6.51; P < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (ES: -1.98, 95% CI: -3.24 to -0.72; P = 0.002), triglycerides (TGDs) (ES: -0.28 mmol/L, 95% CI: -0.36 to -0.20; P < 0.001) and LDL-cholesterol (LDLC) (ES: -0.23 mmol/L, 95% CI: -0.45 to -0.02 mmol/L); P = 0.030) and increased HDL-cholesterol (HDLC) (ES: 0.21 mmol/L, 95% CI: 0.14 to 0.28; P < 0.001). Meta-regression analysis showed that follow-up length - not disease control - had a significant effect on FPG, with the greatest reduction in the shortest follow-up (beta = 0.012, s.e. = 0.003; P = 0.001). Conclusions: Neurosurgery improves metabolism with a significant decrease in FPG, glucose load, HbA1c, FPI, HOMA-IR, TGDs, and LDLC and increase in HDLC. The effect on FPG seems to be more related to follow-up length than to disease control.


Assuntos
Acromegalia/metabolismo , Acromegalia/cirurgia , Procedimentos Neurocirúrgicos/tendências , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Colesterol/sangue , Seguimentos , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Procedimentos Neurocirúrgicos/efeitos adversos , Estudos Prospectivos
3.
Nat Commun ; 11(1): 4752, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958754

RESUMO

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Gigantismo/metabolismo , Hormônio do Crescimento/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Acromegalia/metabolismo , Acromegalia/patologia , Animais , Composição Corporal , Linhagem Celular , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Gigantismo/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Hipófise/metabolismo , Proteína Quinase C/metabolismo , Ratos , Receptores Acoplados a Proteínas-G/genética
4.
Expert Opin Pharmacother ; 21(15): 1883-1895, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32633582

RESUMO

INTRODUCTION: Acromegaly is a rare disease due to oversecretion of growth hormone (GH). Even though the disease is often portrayed by its most apparent clinical features, given the abundance of GH receptors throughout the body, it truly is a systemic disease leading to numerous complications and comorbidities. A distinct medical issue in the context of acromegaly is diabetes: It can be a complication as a consequence of GH excess and its mediators, but it can also result from treatment of acromegaly. AREAS COVERED: This review provides an overview of the effects of acromegaly pathophysiology on glucose homeostasis. Furthermore, it devotes an extensive section on the influence that acromegaly treatment has on glucose metabolism, including approved as well as currently investigated drugs. It also summarizes observations from the use of anti-diabetic medication in patients with acromegaly. EXPERT OPINION: Glucose imbalance is an important aspect of acromegaly comorbidity and deserves more attention. Even though numerous studies have investigated glucose homeostasis in acromegaly, there is still a clear need for more basic, translational, and also clinical research to advance the understanding of the underlying mechanisms and how to best address them.


Assuntos
Acromegalia/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Glucose/metabolismo , Somatostatina/uso terapêutico , Acromegalia/complicações , Acromegalia/epidemiologia , Acromegalia/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Prevalência , Somatostatina/análogos & derivados
5.
Eur J Endocrinol ; 182(3): 375-383, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972545

RESUMO

Context: Cardiovascular disease is one of the main causes of morbidity in active acromegaly due to the increased prevalence of risk factors and arterial consequences of increased growth hormone levels. No in vivo study has evaluated the consequences of acromegaly on the retinal microvasculature. Objective: The aim of this study was to identify in vivo the presence of morphological alterations of retinal arterioles in subjects with acromegaly. Patients and methods: Single-center retrospective study of a cohort of 60 subjects with acromegaly, matched to 60 controls, who were referred for adaptive optics camera (AOC) from September 2014 to December 2016. Of the subjects with acromegaly, 19 had an active disease (AD) and 41 a controlled disease (CD) based on the IGF1 ratio (IGF1r). Retinal arteriolar remodeling was previously assessed using adaptive optics camera (AOC) in order to measure wall-to-lumen ratio (WLR), wall thickness (WT), internal diameter (ID) and wall cross sectional area (WCSA). Results: WLR was significantly higher in AD subjects compared to CD subjects and controls (AD: 0.311 ± 0.06, CD: 0.279 ± 0.04, controls: 0.281 ± 0.04, P = 0.031). A significant positive correlation was observed between WLR and IGF-1r (R2 = 0.215, P < 0.001), even after adjustment for gender, age, systolic blood pressure (SBP) and the presence of dopamine agonist treatment (R2 = 0.406, P < 0.001). Retinal arteriolar anatomical indices were comparable between CD and controls. Conclusion: Active acromegaly is associated with the presence of small retinal arteriolar remodeling. These results provide new perspectives to better stratify cardiovascular risk and consequently optimize treatment in acromegaly.


Assuntos
Acromegalia/diagnóstico por imagem , Arteríolas/diagnóstico por imagem , Fator de Crescimento Insulin-Like I/metabolismo , Artéria Retiniana/diagnóstico por imagem , Remodelação Vascular , Acromegalia/tratamento farmacológico , Acromegalia/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Óptica , Tamanho do Órgão , Artéria Retiniana/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença
6.
Ann Endocrinol (Paris) ; 81(1): 11-17, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31982107

RESUMO

OBJECTIVE: The aim of this study was to describe endocrinological outcome in patients operated on for acromegaly. METHODS: A retrospective study included 167 patients. Patients were assessed in the early postoperative period (EPP), at 3 months (M3), at 1 year (Y1), and then annually. They were classified as grade I (IGF-1 level normal-for-age and positive GH response on oral glucose tolerance test [nadir <0.4ng/L]); grade II (discordant); or grade III or IV (acromegaly, controlled or uncontrolled under medical therapy, respectively). RESULTS: Taking all patients with all grades, 35% changed grades between EPP and M3, 26% between M3 and Y1 and 9% after Y1. In grade I, respectively 22%, 15% and 2% of patients changed grades between EPP and M3, between M3 and Y1, and after Y1, compared to 31%, 6% and 6% in grade IV. Respectively 57%, 67%, and 47% of grade II patients changed grades between EPP and M3, between M3 and Y1, and after Y1; between EPP or M3 and last follow-up (>1 year), respectively 74% and 75% of grade II patients changed grades. Knosp category, resection quality and abnormal GH response (vs. abnormal IGF-1) significantly impacted grade II patients' outcome. CONCLUSIONS: Whereas outcome in grades I and III-IV seems to be determined by 1 year, grade II discordant patients' outcome remains uncertain even after 1 year.


Assuntos
Acromegalia/metabolismo , Acromegalia/cirurgia , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Acromegalia/diagnóstico , Acromegalia/patologia , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Teste de Tolerância a Glucose , Adenoma Hipofisário Secretor de Hormônio do Crescimento/diagnóstico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , Recidiva , Estudos Retrospectivos , Via Secretória/fisiologia , Resultado do Tratamento
7.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31930294

RESUMO

CONTEXT: Metabolic disorders, especially dysregulated lipid metabolism, increase the risk of cardiovascular mortality in acromegaly. Previous studies measuring plasma macromolecular lipids have yielded conflicting results. PURPOSE: To explore the plasma lipid metabolite profiles by metabolomics analysis and identify potential metabolites associated with cardiac function in acromegaly. METHODS: Plasma was obtained from 80 newly diagnosed, untreated patients with acromegaly and 80 healthy controls. Echocardiography was performed. Based on the results of an oral glucose tolerance test (OGTT), patients were categorized into 2 groups: normal glucose tolerance (NGT, n = 28) and impaired glucose tolerance or diabetes mellitus (IGT/DM, n = 52). High-performance liquid chromatography-mass spectrometry (HPLC-MS)-based metabolomics analysis was conducted. Data were processed by principal components analysis (PCA), orthogonal partial least square-discriminant analysis (OPLS-DA), and MetaboAnalyst 4.0. Associations between metabolic substances and cardiovascular parameters were also explored. RESULTS: Metabolomics uncovered a distinct metabolic pattern between acromegaly and healthy controls, and perturbed pathways mainly include glycerophospholipid metabolism, sphingolipid metabolism, as well as linoleic acid metabolism. Collective analysis showed that phosphatidylethanolamine (PE) (22:6/16:0) was positively correlated with LV mass, while lysophosphatidylcholine (LysoPC) (16:0) was positively correlated with fractional shortening (FS) and left ventricle ejection fraction (LVEF). CONCLUSION: Patients with acromegaly have distinct lipid metabolite profiling, while PE (22:6/16:0) and LysoPC (16:0) are correlated with cardiac structure and function, which may contribute to the risk of cardiovascular complications.


Assuntos
Acromegalia/sangue , Lipídeos/sangue , Espectrometria de Massas/métodos , Metaboloma , Acromegalia/complicações , Acromegalia/diagnóstico por imagem , Acromegalia/metabolismo , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Complicações do Diabetes/sangue , Complicações do Diabetes/diagnóstico por imagem , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico por imagem , Ecocardiografia , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/complicações , Intolerância à Glucose/diagnóstico por imagem , Teste de Tolerância a Glucose , Humanos , Metabolismo dos Lipídeos , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/complicações , Transtornos do Metabolismo dos Lipídeos/diagnóstico por imagem , Lipídeos/análise , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade
8.
Eur J Endocrinol ; 182(3): 285-292, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31917681

RESUMO

Objective: To examine all-cause mortality rates in patients with acromegaly on pegvisomant and identify pertinent risk factors, including insulin-like growth factor I (IGF-I). Design: Retrospective cohort analysis of data from ACROSTUDY (global surveillance study of patients with acromegaly treated with pegvisomant). Methods: Kaplan-Meier analyses and Cox regression techniques were used to examine survival rates. Standardized mortality ratios (SMR) with reference to general population (WHO GBD 2016) were estimated. Multiplicative multiple Poisson regression models were used to characterize the association between SMR, IGF-I, and other risk factors associated with mortality risk. Results: The study consisted of 2077 subjects who were followed for a median interval of 4.1 years, contributing to 8957 patient-years. Higher on-treatment IGF-I (P = 0.0035), older attained age (P < 0.0001), and longer duration of acromegaly (>10 years) before starting pegvisomant (P = 0.05) were associated with higher mortality rates. In reference to general population rates, higher SMR (1.10, 1.42, and 2.62, at attained age 55 years) were observed with higher serum IGF-I category (SMR trend: 1.44 (44%)/per fold level of IGF-I/ULN (95% CI: 1.10, 1.87), P = 0.0075). SMR increased per year of younger attained age (1.04 (1.02-1.04), P < 0.0001) and were higher for longer disease duration (>10 years) before starting pegvisomant (1.57 (1.02, 2.43), P = 0.042). Serum IGF-I levels within the normal range during pegvisomant therapy were associated with all-cause mortality rates that were indistinguishable from the general population. Conclusions: Higher on-treatment IGF-I, older attained age, and longer duration of acromegaly before starting pegvisomant are associated with higher all-cause mortality rates. Younger patients with uncontrolled acromegaly have higher excess all-cause mortality rates in comparison with older patients.


Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Mortalidade , Receptores da Somatotropina/antagonistas & inibidores , Acromegalia/metabolismo , Adulto , Fatores Etários , Idoso , Causas de Morte , Estudos de Coortes , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Tempo para o Tratamento
9.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31544947

RESUMO

BACKGROUND: Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM: To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS: Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, ß-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Total FGF21, active FGF21 and ß-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION: 1) Circulating FGF21 and ß-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION: NCT00647179.


Assuntos
Acromegalia/metabolismo , Biomarcadores/metabolismo , Colágeno/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Gelatinases/metabolismo , Hormônio do Crescimento Humano/metabolismo , Proteínas de Membrana/metabolismo , Serina Endopeptidases/metabolismo , Acromegalia/patologia , Acromegalia/terapia , Adulto , Idoso , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
10.
Endocrinol Metab Clin North Am ; 48(4): 779-793, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31655776

RESUMO

Hypertension is one of the most frequent complications in acromegaly, with a median frequency of 33.6% (range, 11%-54.7%). Although the pathogenesis has not been fully elucidated, it probably results from concomitant factors leading to expansion of extracellular fluid volume, increase of peripheral vascular resistance, and development of sleep apnea syndrome. Because the effect of normalization of growth hormone and insulinlike growth factor 1 excess on blood pressure levels is unclear, an early diagnosis of hypertension and prompt antihypertensive treatment are eagerly recommended, regardless of the specific treatment of the acromegalic disease and the level of biochemical control attained.


Assuntos
Acromegalia , Anti-Hipertensivos/uso terapêutico , Hipertensão , Acromegalia/complicações , Acromegalia/diagnóstico , Acromegalia/metabolismo , Acromegalia/terapia , Humanos , Hipertensão/diagnóstico , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/terapia
11.
Pituitary ; 22(6): 601-606, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31556014

RESUMO

INTRODUCTION: Axial skeleton arthropathy and osteoporotic vertebral fractures are common findings in acromegalic patients and can result in severe spinal deformity. OBJECTIVE: To investigate the presence of spinal fractures and deformities, sagittal imbalances, and spinopelvic compensatory mechanisms in acromegalics. PATIENTS AND METHODS: 58 patients with acromegaly from a referral neuroendocrinology center were prospectively evaluated by panoramic spine radiographs to detect the presence of fractures and scoliosis, to measure thoracic kyphosis, lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT) and sagittal vertical axis (SVA). Sagittal imbalance criteria were considered: thoracic kyphosis > 50°, PI-LL > 10°, PT > 20° and SVA > 5 cm. Their medical records were analyzed for clinical and laboratorial data. RESULTS: The prevalence of fractures was 13.8%, predominantly in the thoracic spine, with mild and anterior wedge compressions. Scoliosis was present in 34.5% of the cases, all with degenerative lumbar curve apex. Thoracic kyphosis > 50º occurred in 36.8% of patients, PI-LL > 10° in 48.3%, PT > 20° in 41.4% and SVA > 5 cm in 12.1%. CONCLUSION: Increased number of vertebral fractures and high prevalence of spinal deformities related to sagittal imbalance were detected, indicating the importance of monitoring bone comorbidities in acromegaly, with radiological evaluation of the spine as part of the follow up.


Assuntos
Acromegalia/patologia , Acromegalia/diagnóstico por imagem , Acromegalia/metabolismo , Acromegalia/cirurgia , Adulto , Idoso , Cabergolina/uso terapêutico , Feminino , Fraturas Ósseas/diagnóstico por imagem , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/cirurgia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Lordose/diagnóstico por imagem , Lordose/tratamento farmacológico , Lordose/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Região Lombossacral/diagnóstico por imagem , Região Lombossacral/cirurgia , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêutico , Estudos Prospectivos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/tratamento farmacológico , Fraturas da Coluna Vertebral/cirurgia
12.
Clin Endocrinol (Oxf) ; 91(6): 805-809, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31520541

RESUMO

INTRODUCTION: The prevalence of gestational diabetes (GD) in women with acromegaly is rarely reported. The aims of this study were to evaluate the prevalence of GD in acromegalic women submitted to a systematic screening for GD and then to compare women with or without GD. PATIENTS AND METHODS: We studied 14 pregnancies in 11 women (34.0 ± 3.6 years) treated with somatostatin analogues after a pituitary surgery (n = 6) or as primary (n = 5) therapy, and treatment was discontinued at the time of pregnancy diagnosis for 13 pregnancies. One woman was diagnosed with acromegaly during pregnancy and was treated with octreotide LAR between 12 and 18 weeks of gestation. Before pregnancy, no women had diabetes mellitus, and GH/IGF-1 hypersecretion was uncontrolled in 6 women. RESULTS: Gestational diabetes was diagnosed during 7 pregnancies (50%) in 6 women (one woman had GD during her 2 pregnancies), according to fasting blood glucose (n = 5) or to an oral glucose tolerance test (n = 2). Before pregnancy, IGF-1 was not controlled in 4 GD+ and in 2 GD- women. Women with GD were not significantly older and had increased pregestational BMI (P = .02), with a more frequent family history of type 2 diabetes, no personal history of GD but of macrosomia for one patient. CONCLUSION: The prevalence of GD in our women is higher than that reported in the literature, probably resulting from the systematic GD screening and to the age of women. Therefore, routine screening of GD should be considered in women with acromegaly, particularly in those with risk factors for GD and with uncontrolled IGF-1 levels before pregnancy.


Assuntos
Acromegalia/diagnóstico , Diabetes Gestacional/diagnóstico , Acromegalia/sangue , Acromegalia/metabolismo , Adulto , Diabetes Gestacional/sangue , Diabetes Gestacional/metabolismo , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Gravidez , Somatostatina/uso terapêutico
13.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(5): 320-329, mayo 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-182807

RESUMO

Objectives: The ACROSTART study was intended to determine the time to achieve normalization of GH and IGF-I levels in responding patients with acromegaly administered different dosage regimens of lanreotide Autogel (Somatuline(R) Autogel(R)). Methods: From March 2013 to October 2013, clinical data from 57 patients from 17 Spanish hospitals with active acromegaly treated with lanreotide for ≥4 months who achieved hormonal control (GH levels <2.5ng/ml and/or normalized IGF-I levels in ≥2 measurements) were analyzed. The primary objective was to determine the time from start of lanreotide treatment to hormonal normalization. Results: Median patient age was 64 years, 21 patients were male, 39 patients had undergone surgery, and 14 patients had received radiotherapy. Median hormonal values at start of lanreotide treatment were: GH, 2.6ng/ml; IGF-I, 1.6×ULN. The most common starting dose of lanreotide was 120mg (29 patients). The main initial regimens were 60mg/4 weeks (n=13), 90mg/4 weeks (n=6), 120mg/4 weeks (n=13), 120mg/6 weeks (n=6), and 120mg/8 weeks (n=9). An initial treatment regimen with a long interval (≥6 weeks) was administered in 25 patients. Mean duration of lanreotide treatment was 68 months (7-205). Median time to achieve hormonal control was 4.9 months. Injections were managed without healthcare assistance in 13 patients. Median number of visits to endocrinologists until hormonal control was achieved was 3. Fifty-one patients were "satisfied"/"very satisfied" with treatment and 49 patients did not miss any dose. Conclusions: Real-life treatment with lanreotide Autogel resulted in early hormonal control in responding patients, with high treatment adherence and satisfaction despite disparity in starting doses and dosing intervals


Objetivos: El objetivo del estudio ACROSTART era determinar el período de tiempo para lograr la normalización hormonal (GH e IGF-I) en pacientes con acromegalia respondedores al tratamiento considerando los regímenes de lanreótida Autogel (Somatuline(R) Autogel(R)) utilizados en la práctica clínica. Métodos: Desde marzo de 2013 hasta octubre de 2013, en 17 hospitales españoles se analizaron los datos clínicos de 57 pacientes con acromegalia activa tratados con lanreótida durante ≥4 meses que lograron control hormonal (niveles de GH <2,5ng/ml y/o IGF-I normalizado en ≥2 evaluaciones). El objetivo principal fue determinar el período de tiempo desde el inicio del tratamiento con lanreótida hasta la normalización hormonal. Resultados: La mediana de edad de los pacientes fue 64 años, 21 pacientes eran hombres, 39 pacientes habían recibido cirugía, 14 pacientes habían recibido radioterapia. Los valores hormonales medianos al inicio del tratamiento con lanreótida fueron GH: 2,6ng/ml, IGF-I: 1,6×LSN. La dosis inicial más frecuente de lanreótida fue de 120mg (29 pacientes). Los principales regímenes iniciales fueron 60mg/4 semanas (n=13), 90mg/4 semanas (n=6), 120mg/4 semanas (n=13), 120mg/6 semanas (n=6), 120mg/8 semanas (n=9). Se administró un régimen de intervalo prolongado (≥6 semanas) en 25 pacientes. La duración media del tratamiento con lanreótida fue de 68 meses (7-205). El tiempo medio hasta lograr el control hormonal fue de 4,9 meses. Las inyecciones se manejaron sin asistencia médica en 13 pacientes. La mediana del número de visitas al endocrinólogo hasta el control hormonal fue 3. Cincuenta y un pacientes estaban "satisfechos"/"muy satisfechos" con el tratamiento y 49 pacientes no olvidaron ninguna dosis. Conclusiones: El tratamiento en la vida real con lanreótida Autogel condujo a un control hormonal temprano en pacientes que respondieron, con una alta adherencia al tratamiento y satisfacción con el tratamiento, a pesar de la disparidad de las dosis iniciales y los intervalos de dosificación


Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Adulto , Idoso , Idoso de 80 Anos ou mais , Acromegalia/tratamento farmacológico , Peptídeos Cíclicos/uso terapêutico , Hormônio do Crescimento Humano/metabolismo , Somatostatina/análogos & derivados , Acromegalia/sangue , Estudos Retrospectivos , Peptídeos Cíclicos/administração & dosagem , Acromegalia/metabolismo , Cooperação e Adesão ao Tratamento , Somatostatina/administração & dosagem
14.
EBioMedicine ; 43: 537-552, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30975543

RESUMO

BACKGROUND: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. METHODS: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized' pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. FINDINGS: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. INTERPRETATION: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. FUND: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1.


Assuntos
Acromegalia/diagnóstico , Acromegalia/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Fator de Transcrição Pit-1/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acromegalia/genética , Acromegalia/terapia , Animais , Apoptose/genética , Biomarcadores , Terapia Combinada , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Imuno-Histoquímica , Modelos Biológicos , Mutação , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Ratos , Transdução de Sinais , Fator de Transcrição Pit-1/genética , Resultado do Tratamento , Proteína Supressora de Tumor p14ARF/genética , Proteína Supressora de Tumor p53/genética
15.
Sci Rep ; 9(1): 5646, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30948746

RESUMO

Impaired insulin sensitivity (IS) and ß-cell dysfunction result in hyperglycaemia in patients of acromegaly. However, alterations in incretins and their impact on glucose-insulin homeostasis in these patients still remain elusive. Twenty patients of active acromegaly (10 each, with and without diabetes) underwent hyperinsulinemic euglycaemic clamp and mixed meal test, before and after surgery, to measure indices of IS, ß-cell function, GIP, GLP-1 and glucagon response. Immunohistochemistry (IHC) for GIP and GLP-1 was also done on intestinal biopsies of all acromegalics and healthy controls. Patients of acromegaly, irrespective of presence or absence of hyperglycaemia, had similar degree of insulin resistance, however patients with diabetes exhibited hyperglucagonemia, and compromised ß-cell function despite significantly higher GIP levels. After surgery, indices of IS improved, GIP and glucagon levels decreased significantly in both the groups, while there was no significant change in indices of ß-cell function in those with hyperglycaemia. IHC positivity for GIP, but not GLP-1, staining cells in duodenum and colon was significantly lower in acromegalics with diabetes as compared to healthy controls possibly because of high K-cell turnover. Chronic GH excess induces an equipoise insulin resistance in patients of acromegaly irrespective of their glycaemic status. Dysglycaemia in these patients is an outcome of ß-cell dysfunction consequent to GIP resistance and hyperglucagonemia.


Assuntos
Acromegalia/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Resistência à Insulina/fisiologia , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Técnica Clamp de Glucose , Humanos , Hiperglicemia/metabolismo , Incretinas/farmacologia , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Estudos Prospectivos , Receptores dos Hormônios Gastrointestinais
16.
J Clin Endocrinol Metab ; 104(7): 2770-2776, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840065

RESUMO

CONTEXT: The rapid pubertal height growth is unique to humans, but why do we have it? Although the spurt contributes 13% to 15% to the final adult height, we hypothesized that the biological significance of the high acromegalic levels of GH and IGF-I, which are behind the pubertal growth spurt, might primarily occur to stimulate the reproductive organs. EVIDENCE SYNTHESIS: Animal data have demonstrated that adult Igf1 and Igf2 gene knockout mice that survive show a dramatic reduction in the size of the reproductive organs and are infertile. In humans, case reports of mutations in the genes affecting the GH-IGF axis and growth (GH, GHRH, GH-R, STAT5b, IGF-I, IGF-II, IGF-1R, PAPPA2) are also characterized by delayed pubertal onset and micropenis. Furthermore, GH treatment will tend to normalize the penile size in patients with GH deficiency. Thus, the endocrine effects of high IGF-I levels might be needed for the transition of the sexual organs, including the secondary sex characteristics, from the "dormant" stages of childhood into fully functioning reproductive systems. The peak IGF-I levels, on average, occur 2 years after the peak height growth velocity, suggesting reasons other than longitudinal growth for the high IGF-I levels, and remain high in the years after the height spurt, when the reproductive systems become fully functional. CONCLUSION: We suggest that the serum levels of IGF-I should be monitored in children with poor development of sexual organs, although it remains to be investigated whether GH should be added to sex steroids in the management of hypogonadism for some pubertal children (e.g., boys with micropenis).


Assuntos
Desenvolvimento Infantil , Hormônio Liberador de Gonadotropina/metabolismo , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Puberdade/metabolismo , Acromegalia/metabolismo , Adolescente , Adulto , Criança , Desenvolvimento Fetal , Genitália/crescimento & desenvolvimento , Crescimento , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipogonadismo/tratamento farmacológico , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Adulto Jovem
17.
J Clin Endocrinol Metab ; 104(7): 2892-2902, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30869797

RESUMO

INTRODUCTION: Pegvisomant (PEG) in monotherapy or combined with somatostatin analogs (SSAs) is used to control acromegaly, improving metabolism. However, the metabolic changes induced by PEG have not been systematically reviewed. OBJECTIVE: To address the following questions: does PEG or the combination of PEG and SSAs affect fasting plasma glucose (FPG), glycosylated Hb (HbA1c), glucose load (2-hour oral glucose tolerance test), insulin levels [fasting plasma insulin (FPI)], homeostatic model assessment of insulin resistance (HOMA-I), homeostatic model assessment of ß-cell function, lipid profile, or body mass index? Are the effects disease-related or drug-related? DATA SOURCES: Indexed databases up to January 2019. STUDY SELECTION: Prospective interventional trials reporting glycometabolic outcomes under PEG or PEG plus SSAs for a minimum of 6 months. DATA EXTRACTION: Three reviewers screened eligible publications (7248), three others extracted the outcomes, and all assessed the risk of biases. DATA SYNTHESIS: Thirteen studies were included in the PEG and 5 in the PEG plus SSAs analysis (overall 550 subjects). PEG significantly decreased FPG [effect size (ES) -0.80 mmol/L (95% CI, -1.06 to -0.55); P = 0.000], HbA1c [ES -0.43% (95% CI, -0.56 to -0.31); P = 0.000], FPI [ES -5.31 mU/L (95% CI, -10.23 to -0.39); P = 0.034], and HOMA-I [ES -0.61 (95% CI, -1.17 to -0.04); P = 0.034]. Effects on FPG and FPI were not correlated to IGF-1 changes. The addition of PEG to SSAs mitigated the effects of SSAs on metabolism, producing an overall neutral effect. CONCLUSIONS: Independently of disease control, PEG in monotherapy or combined with SSAs seems to improve glucose metabolism, reducing FPG, HbA1c, FPI, and HOMA-I.


Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Somatostatina/análogos & derivados , Acromegalia/metabolismo , Glicemia/metabolismo , Índice de Massa Corporal , Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Quimioterapia Combinada , Teste de Tolerância a Glucose , Hemoglobina A Glicada/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Resistência à Insulina , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Receptores da Somatotropina/antagonistas & inibidores , Somatostatina/uso terapêutico , Triglicerídeos/metabolismo
18.
Sci Rep ; 9(1): 1122, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718563

RESUMO

Filamin-A (FLNA) plays a crucial role in somatostatin receptor (sst) subtype-2 signaling in somatotropinomas. Our objective was to investigate the in vivo association between FLNA and sst2 expression, sst5 expression, dopamine receptor subtype-2 (D2) expression, somatostatin receptor ligand (SRL) responsiveness and tumor invasiveness in somatotropinomas. Quantitative real-time PCR was used to evaluate the absolute mRNA copy numbers of FLNA/sst2/sst5/D2 in 96 somatotropinomas. FLNA, sst2 and sst5 protein expression levels were also evaluated using immunohistochemistry. The Knosp-Steiner criteria were used to evaluate tumor invasiveness. Median FLNA, sst2, sst5 and D2 copy numbers were 4,244, 731, 156 and 3,989, respectively. Thirty-one of the 35 available tumors (89%) were immune positive for FLNA in the cytoplasm and membrane but not in the nucleus. FLNA and sst5 expression were positively correlated at the mRNA and protein levels (p < 0.001 and p = 0.033, respectively). FLNA was positively correlated with sst2 mRNA in patients who were responsive to SRL (p = 0.014, R = 0.659). No association was found between FLNA and tumor invasiveness. Our findings show that in somatotropinomas FLNA expression positively correlated with in vivo sst5 and D2 expression. Notably, FLNA was only correlated with sst2 in patients who were controlled with SRL. FLNA was not associated with tumor invasiveness.


Assuntos
Acromegalia/genética , Adenoma/tratamento farmacológico , Antineoplásicos/administração & dosagem , Filaminas/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Receptores de Dopamina D2/genética , Receptores de Somatostatina/genética , Acromegalia/etiologia , Acromegalia/metabolismo , Adenoma/complicações , Adenoma/genética , Adenoma/metabolismo , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Membrana Celular/genética , Membrana Celular/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/genética , Citoplasma/metabolismo , Feminino , Filaminas/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/uso terapêutico , Receptores de Dopamina D2/metabolismo , Receptores de Somatostatina/metabolismo , Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Carga Tumoral , Adulto Jovem
19.
Growth Horm IGF Res ; 45: 1-5, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30731342

RESUMO

PURPOSE: Somatostatin analogues (SSAs) can slow down the growth of neuroendocrine tumors. However, the mechanism remains unclear. Recent studies on patients with acromegaly suggest that SSAs may induce apoptosis, increase autophagy, and decrease cell proliferation of pituitary adenoma. Ki-67-labeling index is a marker of cellular proliferation; therefore, decreased levels are associated with inhibition of proliferation. The aim of this study was to evaluate and compare the Ki-67-labeling index of GH-secreting pituitary adenoma tissues in patients who had undergone pituitary surgery twice due to residual or recurrent tumors and had received SSA treatment between the two surgeries. METHOD: Thirty acromegaly patients who met the above criteria were identified and evaluated for the demographic, clinical and radiological features retrospectively. Surgical pathology samples of each operation were stained for Ki-67 and evaluated blindly by a staff pathologist specialized in pituitary diseases. RESULTS: Among patients who received SSA treatment between the first and second operations, the Ki-67 index of the adenoma at the second operation was significantly lower than the Ki-67 index at the first operation. There were no differences in clinical and radiological prognostic markers between the groups with decreased and unchanged Ki-67 index. CONCLUSION: We concluded that SSA treatment appears to decrease Ki-67 proliferation index independent of tumor features, SSA type, dose and treatment duration. This result suggests that SSA treatment may decrease cellular proliferation, supporting the previous studies.


Assuntos
Acromegalia/metabolismo , Adenoma/cirurgia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/cirurgia , Hormônio do Crescimento Humano/metabolismo , Antígeno Ki-67/metabolismo , Procedimentos Neurocirúrgicos/efeitos adversos , Somatostatina/análogos & derivados , Acromegalia/tratamento farmacológico , Acromegalia/etiologia , Adenoma/patologia , Feminino , Seguimentos , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Somatostatina/administração & dosagem
20.
Expert Rev Endocrinol Metab ; 14(2): 85-96, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30696300

RESUMO

INTRODUCTION: As pregnancy is rare in women with acromegaly, only case reports and few series have been published. AREAS COVERED: All case reports and publications dealing with pregnancy in patients with acromegaly were collated. Information concerning the effects of acromegaly on pregnancy outcomes, the impact of pregnancy on GH/IGF-I measurements, acromegaly comorbidity and pituitary adenoma size, the effects of treatment of acromegaly on fetus outcomes were retrieved and analyzed. EXPERT COMMENTARY: Based on the small number of reported cases, pregnancy is generally uneventful, except for a potential increased incidence of gestational hypertension and diabetes mellitus. Medical therapy of acromegaly (dopamine agonists, somatostatin analogs, growth hormone-receptor antagonists) is generally interrupted before or at diagnosis of pregnancy. In very rare patients with a pituitary adenoma, particularly a macroadenoma that has not been surgically treated before pregnancy, or if a surgical remnant persists, or when acromegaly is revealed during pregnancy, tumor volume may increase and cause symptoms through a mass effect. Close monitoring of clinical manifestations and imaging are necessary during pregnancy in these cases. In the rare cases of symptomatic tumor enlargement during pregnancy, medical treatment with dopamine agonists or eventually somatostatin analogs may be attempted before resorting to transsphenoidal surgery.


Assuntos
Acromegalia/terapia , Complicações na Gravidez , Acromegalia/complicações , Acromegalia/metabolismo , Adenoma/complicações , Feminino , Glucose/metabolismo , Hormônio do Crescimento Humano/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Hipofisárias/complicações , Gravidez , Complicações na Gravidez/metabolismo , Resultado da Gravidez
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