Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 448
Filtrar
1.
Eur J Endocrinol ; 182(6): 595-605, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32375119

RESUMO

Objective: T2-signal intensity and somatostatin (SST) receptor expression are recognized predictors of therapy response in acromegaly. We investigated the relationship between these predictors and the hormonal and tumoral responses to long-acting pasireotide (PAS-LAR) therapy, which were also compared with responsiveness to first-generation somatostatin receptor ligands (SRLs). Design: The PAPE study is a cohort study. Methods: We included 45 acromegaly patients initially receiving SRLs, followed by combination therapy with pegvisomant, and finally PAS-LAR. We assessed tumor volume reduction (≥25% from baseline), IGF-1 levels (expressed as the upper limit of normal), and T2-weighted MRI signal and SST receptor expression of the adenoma. Results: Patients with significant tumor shrinkage during PAS-LAR showed higher IGF-1 levels during PAS-LAR (mean (S.D.): 1.36 (0.53) vs 0.93 (0.43), P = 0.020), less IGF-1 reduction after first-generation SRLs (mean (S.D.): 0.55 (0.71) vs 1.25 (1.07), P = 0.028), and lower SST2 receptor expression (median (IQR): 2.0 (1.0-6.0) vs 12.0 (7.5-12.0), P = 0.040). Overall, T2-signal intensity ratio was increased compared with baseline (mean (S.D.): 1.39 (0.56) vs 1.25 (0.52), P = 0.017) and a higher T2-signal was associated with lower IGF-1 levels during PAS-LAR (ß: -0.29, 95% CI: -0.56 to -0.01, P = 0.045). A subset of PAS-LAR treated patients with increased T2-signal intensity achieved greater reduction of IGF-1 (mean (S.D.): 0.80 (0.60) vs 0.45 (0.39), P = 0.016). Conclusions: Patients unresponsive to SRLs with a lower SST2 receptor expression are more prone to achieve tumor shrinkage during PAS-LAR. Surprisingly, tumor shrinkage is not accompanied by a biochemical response, which is accompanied with a higher T2-signal intensity.


Assuntos
Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Hormônios/uso terapêutico , Somatostatina/análogos & derivados , Acromegalia/sangue , Acromegalia/etiologia , Adenoma/sangue , Adenoma/complicações , Adulto , Estudos de Coortes , Preparações de Ação Retardada , Quimioterapia Combinada , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Ligantes , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Receptores de Somatostatina/sangue , Somatostatina/uso terapêutico , Resultado do Tratamento , Carga Tumoral
2.
Eur J Endocrinol ; 183(1): G17-G23, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32369770

RESUMO

Patients with pituitary tumours, ensuing hormonal abnormalities and mass effects are usually followed in multidisciplinary pituitary clinics and can represent a management challenge even during the times of non-pandemic. The COVID-19 pandemic has put on hold routine medical care for hundreds of millions of patients around the globe, while many pituitary patients' evaluations cannot be delayed for too long. Furthermore, the majority of patients with pituitary tumours have co-morbidities potentially impacting the course and management of COVID-19 (e.g. hypopituitarism, diabetes mellitus, hypertension, obesity and cardiovascular disease). Here, we summarize some of the diagnostic and management dilemmas encountered, and provide guidance on safe and as effective as possible delivery of care in the COVID-19 era. We also attempt to address how pituitary services should be remodelled in the event of similar crises, while maintaining or even improving patient outcomes. Regular review of these recommendations and further adjustments are needed, depending on the evolution of the COVID-19 pandemic status. We consider that the utilization of successful models of pituitary multidisciplinary care implemented during the COVID-19 pandemic should continue after the crisis is over by using the valuable and exceptional experience gained during these challenging times.


Assuntos
Adenoma/terapia , Antineoplásicos Hormonais/uso terapêutico , Infecções por Coronavirus , Agonistas de Dopamina/uso terapêutico , Procedimentos Neurocirúrgicos , Pandemias , Apoplexia Hipofisária/terapia , Neoplasias Hipofisárias/terapia , Pneumonia Viral , Adenoma/diagnóstico , Cabergolina/uso terapêutico , Gerenciamento Clínico , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Apoplexia Hipofisária/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Guias de Prática Clínica como Assunto , Radioterapia , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Telemedicina , Fatores de Tempo , Testes de Campo Visual
3.
Eur J Endocrinol ; 182(6): D17-D29, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234975

RESUMO

Current guidelines recommend the use of long-acting somatostatin receptor ligands (SRLs) first when surgery fails to correct GH/IGF-I hypersecretion in patients with acromegaly. In this issue of the journal, a pro- and contra debate will outline which arguments are in favour and which are against positioning pegvisomant (PEGV), a GH receptor antagonist, as the first-line treatment modality of acromegaly. The task of the pros was to promote a paradigm shift towards repositioning PEGV as first-line treatment as PEGV is safe and more effective than the first- and second-generation of SRLs. SRLs, when prescribed together with PEGV can still reduce tumour size when necessary, while they decrease the necessary dose of PEGV by around 50% in the average patient. They conclude that PEGV must move up towards the first-line treatment. For the cons, SRLs remain the first-line medical treatment. Indeed, even if, in recent studies, the remission rate is lower than initially claimed, SRLs are still effective not only for normalizing GH/IGF-I levels in half of the patients but also for inducing tumour shrinkage, improving comorbidities and headaches and reversing excess mortality. They are more convenient for use with their monthly administration and have a remarkable safety profile as demonstrated by the very prolonged experience acquired by more than 30 years of use. Finally, the cost-effectiveness of first-generation SRLs is better than that of PEGV. For all these reasons, cons consider that SRLs remain the best first medical treatment in patients requiring medical therapy.


Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Receptores da Somatotropina/uso terapêutico , Hormônio do Crescimento Humano/antagonistas & inibidores , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Resultado do Tratamento
4.
Eur J Endocrinol ; 182(5): R67-R82, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32069216

RESUMO

Gonadal steroids modulate the effects of GH, with oestrogens attenuating and androgens augmenting GH action. Whether these divergent effects influence the clinical manifestation, management and prognosis of acromegaly have not been carefully reviewed. This review examines whether there is a gender difference in epidemiology, presentation, quality of life (QoL), morbidity, treatments and mortality of acromegaly. Acromegaly is more common in women who present at an older age with longer diagnostic delay. At presentation, women have a higher GH relative to IGF-1 level than men. QoL is more adversely affected in women both before and after treatment. Prevalence of hypertension and diabetes are greater in women than in men with acromegaly. Treatment outcomes with SSAs are comparable between sexes, but women may require a higher dose of pegvisomant for equivalent response. Mortality in untreated acromegaly is more profoundly affected in women; however, improved treatments in recent decades have resulted in normalisation of standard mortality ratios in both sexes. We conclude that gender does matter in the management of acromegaly, with women presenting later in life, with greater diagnostic delay, higher prevalence of comorbidities and experiencing worse QoL.


Assuntos
Acromegalia/tratamento farmacológico , Hormônio do Crescimento Humano/análogos & derivados , Fatores Etários , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Feminino , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Qualidade de Vida , Fatores Sexuais , Resultado do Tratamento
5.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053994

RESUMO

Somapacitan is a long-acting, once-weekly, albumin-binding growth hormone (GH) derivative. The reversible albumin-binding properties leads to prolonged circulation half-life. Here, we investigated and compared somapacitan with human GH on downstream receptor signaling in primary hepatocytes and hepatocellular models and using isothermal titration calorimetry to characterize receptor binding of somapacitan in the presence or absence of human serum albumin (HSA). With non-invasive fluorescence imaging we quantitatively visualize and compare the temporal distribution and examine the tissue-specific growth hormone receptor (GHR) activation at distribution sites. We found that signaling kinetics were slightly more rapid and intense for GH compared with somapacitan. Receptor binding isotherms were characterized by a high and a low affinity interaction site with or without HSA. Using in vivo optical imaging we found prolonged systemically biodistribution of somapacitan compared with GH, which correlated with plasma pharmacokinetics. Ex vivo mouse organ analysis revealed that the temporal fluorescent intensity in livers dosed with somapacitan was significantly increased compared with GH-dosed livers and correlated with the degree of downstream GHR activation. Finally, we show that fluorescent-labeled analogs distributed to the hypertrophic zone in the epiphysis of proximal tibia of hypophysectomized rats and that somapacitan and GH activate the GHR signaling in epiphyseal tissues.


Assuntos
Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/farmacologia , Receptores da Somatotropina/metabolismo , Animais , Células Cultivadas , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hormônio do Crescimento Humano/farmacocinética , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Ratos Sprague-Dawley , Distribuição Tecidual
6.
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
7.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31612224

RESUMO

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is common in active acromegaly and negatively influences quality of life, morbidity, and mortality. This prospective study with 3 predetermined timepoints and a standardized treatment protocol investigates changes in sleep parameters during the first 2.5 years of acromegaly treatment. METHODS: Before initiation of acromegaly treatment (medical pretreatment followed by surgery), polysomnography (PSG) was performed in 27 consecutive patients with treatment-naive acromegaly. PSG was repeated after 1 year (N = 24) and 2.5 years (N = 23), and anthropometric and biochemical parameters were obtained. RESULTS: At baseline, 74.1% of the patients was diagnosed with OSAS. The respiratory disturbance index (RDI; P = 0.001), oxygen desaturation index (ODI; P = 0.001), lowest oxygen saturation (LSaO2; P = 0.007) and the Epworth Sleepiness Scale (ESS; P < 0.001) improved significantly during treatment, with the greatest improvement in the first year. After 2.5 years of treatment, all patients had controlled acromegaly. Of the 16 patients with repeated PSG and OSAS at baseline, 11 (68.8%) were cured of OSAS. Changes in RDI, ODI, LSaO2, and ESS correlated with insulin-like growth factor 1 levels. CONCLUSION: OSAS has a high prevalence in active acromegaly. There is a substantial decrease in prevalence and severity of OSAS following acromegaly treatment, with the largest improvement during the first year. Most patients recover from OSAS following surgical or biochemical control of the acromegaly. Therefore, a PSG is advised after diagnosis of acromegaly. When OSAS is present, it should be treated and PSG should be repeated during acromegaly treatment.


Assuntos
Acromegalia/complicações , Acromegalia/epidemiologia , Acromegalia/terapia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/patologia , Acromegalia/diagnóstico , Adenoma/complicações , Adenoma/epidemiologia , Adenoma/terapia , Adulto , Idoso , Estudos de Casos e Controles , Progressão da Doença , Agonistas de Dopamina/uso terapêutico , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/epidemiologia , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Polissonografia , Prevalência , Prognóstico , Apneia Obstrutiva do Sono/diagnóstico , Sonolência , Resultado do Tratamento
8.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613969

RESUMO

PURPOSE: Osteopathy is an emerging complication of acromegaly. In somatostatin receptor ligands (SRL)-resistant patients, pegvisomant (PegV) and pasireotide LAR (Pasi) are used for acromegaly treatment, but their effect on skeletal health is still not defined. METHODS: In a longitudinal retrospective international study, we evaluated incidence of radiological vertebral fractures (VFs) in 55 patients with acromegaly resistant to first-generation SRL. RESULTS: At study entry, prevalent VFs occurred in 23 patients (41.8%). Biochemical acromegaly control was reached in 66.7% of patients on PegV and in 66.7% of patients on Pasi. During the follow-up, incident VFs (iVFs) were detected in 16 patients (29.1%). Occurrence of iVFs was associated with prevalent VFs (P = .002), persistence of active acromegaly (P = .01) and higher value of insulin-like growth factor 1 (IGF-1) during follow-up (P = .03). Among patients with active disease at last visit, iVFs occurred less frequently in patients on treatment with Pasi (25%) compared to PegV (77.8% P = .04), independently of the IGF-1 values (P = .90). In patients who reached biochemical control, 22.7% on PegV and 12.5% on Pasi had iVFs (P = .40). Among both treatment groups, the presence of pre-existent VFs was the main determinant for iVFs. CONCLUSION: Our data show for the first time that patients with biochemically active disease treated with Pasi had lower risk of iVFs versus those treated with PegV. It also confirms that the presence of pre-existent VFs was the main determinant for iVFs. Additional studies on larger populations and with longer follow-up are needed to confirm our data and disclose the mechanisms underlying our findings.


Assuntos
Acromegalia/tratamento farmacológico , Resistência a Medicamentos , Hormônios/farmacologia , Hormônio do Crescimento Humano/análogos & derivados , Receptores de Somatostatina/agonistas , Somatostatina/análogos & derivados , Fraturas da Coluna Vertebral/prevenção & controle , Acromegalia/patologia , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Hormônio do Crescimento Humano/farmacologia , Humanos , Agências Internacionais , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Somatostatina/farmacologia
9.
Mol Metab ; 29: 65-75, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31668393

RESUMO

OBJECTIVE: Growth hormone (GH) stimulates lipolysis, but the underlying mechanisms remain incompletely understood. We examined the effect of GH on the expression of lipolytic regulators in adipose tissue (AT). METHODS: In a randomized, placebo-controlled, cross-over study, nine men were examined after injection of 1) a GH bolus and 2) a GH-receptor antagonist (pegvisomant) followed by four AT biopsies. In a second study, eight men were examined in a 2 × 2 factorial design including GH infusion and 36-h fasting with AT biopsies obtained during a basal period and a hyperinsulinemic-euglycemic clamp. Expression of GH-signaling intermediates and lipolytic regulators were studied by PCR and western blotting. In addition, mechanistic experiments in mouse models and 3T3-L1 adipocytes were performed. RESULTS: The GH bolus increased circulating free fatty acids (p < 0.0001) together with phosphorylation of signal transducer and activator of transcription 5 (STAT5) (p < 0.0001) and mRNA expression of the STAT5-dependent genes cytokine-inducible SH2-containing protein (CISH) and IGF-1 in AT. This was accompanied by suppressed mRNA expression of G0/G1 switch gene 2 (G0S2) (p = 0.007) and fat specific protein 27 (FSP27) (p = 0.002) and upregulation of phosphatase and tensin homolog (PTEN) mRNA expression (p = 0.03). Suppression of G0S2 was also observed in humans after GH infusion and fasting, as well as in GH transgene mice, and in vitro studies suggested MEK-PPARγ signaling to be involved. CONCLUSIONS: GH-induced lipolysis in human subjects in vivo is linked to downregulation of G0S2 and FSP27 and upregulation of PTEN in AT. Mechanistically, in vitro data suggest that GH acts via MEK to suppress PPARγ-dependent transcription of G0S2. ClinicalTrials.govNCT02782221 and NCT01209429.


Assuntos
Tecido Adiposo/metabolismo , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/administração & dosagem , Tecido Adiposo/patologia , Adulto , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Estudos Cross-Over , Regulação para Baixo/efeitos dos fármacos , Ácidos Graxos não Esterificados/sangue , Hormônio do Crescimento Humano/farmacologia , Humanos , Lipólise , Masculino , Camundongos , Camundongos Transgênicos , PPAR gama/metabolismo , Efeito Placebo , Transdução de Sinais , Adulto Jovem
10.
Arch. endocrinol. metab. (Online) ; 63(6): 646-652, Nov.-Dec. 2019.
Artigo em Inglês | LILACS | ID: biblio-1055016

RESUMO

ABSTRACT Advances in combination medical treatment have offer new perspectives for acromegaly patients with persistent disease activity despite receiving the available medical monotherapies. The outcomes of combination medical treatment may reflect both additive and synergistic effects. This review focuses on combination medical treatment and its current position in acromegaly, based on clinical studies evaluating the efficacy and safety of combined medical treatment(s) and our own experiences with combination therapy. Arch Endocrinol Metab. 2019;63(6):646-52


Assuntos
Humanos , Somatostatina/análogos & derivados , Receptores de Somatostatina/administração & dosagem , Receptores de Somatostatina/antagonistas & inibidores , Agonistas de Dopamina/administração & dosagem , Hormônio do Crescimento Humano/análogos & derivados , Qualidade de Vida , Acromegalia/tratamento farmacológico , Somatostatina/administração & dosagem , Hormônio do Crescimento Humano/administração & dosagem , Quimioterapia Combinada
11.
Pituitary ; 22(6): 581-593, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31522359

RESUMO

PURPOSE: Somatostatin analogs (SSAs) represent a mainstay of medical treatment for acromegaly, currently available as either intramuscular or deep subcutaneous injections. Patient-reported outcomes (PROs) are increasingly common as relevant outcomes in studies of acromegaly and its treatment, but there are no validated PRO measures available that focus on the disease burden and the impact of treatment, specifically designed for use in patients with acromegaly. We sought to develop a new and unique PRO measure, the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ). METHODS: Concept elicitation (CE) interviews were conducted with acromegaly patients in the United States receiving SSA injections at a stable dose for ≥ 6 months. A questionnaire was drafted based on these interviews; combined CE and cognitive debriefing (CE/CD) interviews were then conducted to confirm the content, clarity, and relevance of the questionnaire. RESULTS: Nineteen subjects completed interviews [n = 9 CE, n = 10 CE/CD; n = 15 Lanreotide Depot/Autogel (Somatuline), n = 4 Octreotide LAR (Sandostatin LAR)]. Most subjects responded positively when asked about the effectiveness of their current treatment; however, breakthrough symptoms, injection site reactions, and side effects were commonly reported and had negative impacts on social and emotional well-being and daily activities. All 10 subjects involved in debriefing interviews found the questionnaire to be relevant, easy to complete, and found the response options to be clear. The resulting 26-item Acro-TSQ covers symptoms and symptom control, gastrointestinal side effects and their impact on daily activities, the emotional impact of treatment, convenience and ease of use, and overall satisfaction. CONCLUSIONS: The Acro-TSQ is a novel PRO, focused on both disease burden and impact of treatment; it was found to be comprehensive, clear, and relevant for patients with acromegaly receiving injectable SSA treatment.


Assuntos
Acromegalia/tratamento farmacológico , Adulto , Bromocriptina/uso terapêutico , Cabergolina/uso terapêutico , Feminino , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Satisfação Pessoal , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Inquéritos e Questionários
12.
Arch Endocrinol Metab ; 63(4): 328-336, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365632

RESUMO

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


Assuntos
Acromegalia/tratamento farmacológico , Cabergolina/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Receptores de Somatostatina/uso terapêutico , Adenoma/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Brasil , Cabergolina/administração & dosagem , Criança , Quimioterapia Combinada , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores de Somatostatina/administração & dosagem , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
14.
Arch Endocrinol Metab ; 63(4): 320-327, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31460622

RESUMO

OBJECTIVE: To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. SUBJECTS AND METHODS: We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. RESULTS: Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). CONCLUSION: this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7.


Assuntos
Acromegalia/tratamento farmacológico , Cabergolina/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Somatostatina/análogos & derivados , Adulto , Idoso , Argentina , Cabergolina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Quimioterapia Combinada , Feminino , Seguimentos , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/análise , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Somatostatina/administração & dosagem , Somatostatina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
15.
Arch. endocrinol. metab. (Online) ; 63(4): 320-327, July-Aug. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1019363

RESUMO

ABSTRACT Objective To describe the long term safety and efficacy of pegvisomant (PEGV), and the predictors of treatment response in patients with acromegaly in the real life setting. Subjects and methods We retrospectively reviewed the clinical, hormonal and radiological data of acromegalic patients treated with PEGV in 17 Argentine centers. Results Seventy-five patients (age range 22-77, 51 females) with acromegaly have been treated with PEGV for up to 118 months (median 27 months). Before PEGV, 97.3% of patients had been treated with medical therapy, surgery and/or radiotherapy, two patients had no previous treatment. At that time, all patients had an IGF-1 above the upper normal limit (ULN) (mean 2.4 x ULN ± 0.98, range 1.25-7). At diagnosis of acromegaly 84% presented macroadenomas, prior to PEGV only 23,5% of patients remained with tumor remnant > 1 cm, the remaining showed normal or less than 1 cm images. Disease control (IGF-1 ≤ 1.2 x ULN) was achieved in 62.9% of patients with a mean dose of 11.8 mg/day. Thirty-four patients (45%) received PEGV monotherapy, while 41 (55%) received combined therapy with either somatostatin analogues and/or cabergoline. Adverse events related to PEGV were: local injection site reaction in 5.3%, elevated liver enzymes in 9.3%, and tumor size growth in 9.8%. Pre-PEGV IGF-I level was the only predictor of treatment response: 2.1 x ULN vs 2.8 x ULN in controlled and uncontrolled patients respectively (p < 0.001). Conclusion this long term experience indicates PEGV treatment was highly effective and safe in our series of Argentine patients with acromegaly refractory to standard therapies. Arch Endocrinol Metab. 2019;63(4):320-7


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Acromegalia/tratamento farmacológico , Somatostatina/análogos & derivados , Agonistas de Dopamina/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Cabergolina/uso terapêutico , Argentina , Fator de Crescimento Insulin-Like I/análise , Valor Preditivo dos Testes , Estudos Retrospectivos , Seguimentos , Resultado do Tratamento , Agonistas de Dopamina/administração & dosagem , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/uso terapêutico , Quimioterapia Combinada , Cabergolina/administração & dosagem
17.
Arch. endocrinol. metab. (Online) ; 63(4): 328-336, July-Aug. 2019. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1019350

RESUMO

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


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Acromegalia/tratamento farmacológico , Receptores de Somatostatina/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Cabergolina/uso terapêutico , Glicemia/análise , Brasil , Fator de Crescimento Insulin-Like I/análise , Hormônio do Crescimento/sangue , Adenoma/tratamento farmacológico , Valor Preditivo dos Testes , Resultado do Tratamento , Quimioterapia Combinada , Cabergolina/administração & dosagem
18.
J Clin Endocrinol Metab ; 104(11): 5453-5461, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361303

RESUMO

CONTEXT: GH activates agouti-related protein (AgRP) neurons, leading to orexigenic responses in mice. The relationship between serum GH and plasma AgRP, which has been shown to reflect hypothalamic AgRP, has not been evaluated in humans. OBJECTIVE: To test the hypothesis that central stimulatory actions of GH on hypothalamic AgRP could be reflected in plasma AgRP in acromegaly. METHODS: We studied 23 patients with active acromegaly before and for ≤2 years after surgical (n = 13) or GH receptor antagonist therapy with pegvisomant (n = 10), and 100 healthy subjects with morning fasting blood samples for AgRP, leptin, GH, and IGF-1 and anthropometric measurements. RESULTS: The plasma AgRP levels were higher in those with active acromegaly than in the matched healthy subjects [median, 100 pg/mL; interquartile range (IQR), 78 to 139 pg/mL vs median, 63 pg/mL; IQR, 58 to 67 pg/mL; P < 0.0001]. Plasma AgRP decreased from before to after surgery (median, 102 pg/mL; IQR, 82 to 124 pg/mL vs median, 63 pg/mL; IQR, 55.6 to 83 pg/mL; P = 0.0024) and from before to during pegvisomant therapy (median, 97 pg/mL; IQR, 77 to 175 pg/mL vs median, 63; IQR, 61 to 109 pg/mL; P = 0.006). The plasma AgRP level correlated with GH (r = 0.319; P = 0.011) and IGF-1 (r = 0.292; P = 0.002). In repeated measure analysis, AgRP was significantly associated with IGF-1. CONCLUSIONS: Our data have provided evidence of a stimulatory effect of GH on plasma AgRP in humans. The levels were greater in active acromegaly and decreased in parallel with GH and IGF-1 decreases with acromegaly treatment. Data from mice suggest that AgRP may mediate some of the known effects of GH on energy metabolism. This warrants further study in patients with acromegaly and other populations.


Assuntos
Acromegalia/sangue , Proteína Relacionada com Agouti/sangue , Antagonistas de Hormônios/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Receptores da Somatotropina/antagonistas & inibidores , Acromegalia/tratamento farmacológico , Acromegalia/cirurgia , Adenoma/sangue , Adenoma/tratamento farmacológico , Adenoma/cirurgia , Adulto , Feminino , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/cirurgia , Resultado do Tratamento , Adulto Jovem
19.
Endokrynol Pol ; 70(4): 305-312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31274183

RESUMO

INTRODUCTION: Long-acting repeatable (LAR) octreotide i.m. is a potent, synthetic somatostatin analogue (SSA) that requires less frequent dosing and offers quality of life (QoL) benefits in acromegaly patients compared to its shorter-acting predecessor. This study investigated the efficacy and safety of high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline in acromegalic patients with pituitary adenomas following previous failure of conventional SSA treatment. MATERIAL AND METHODS: After three months of high-dose Sandostatin® LAR® monotherapy (40 mg), patients who achieved biochemical control (n = 7) continued to receive the same treatment for an additional four months, whereas uncontrolled patients were randomised to receive high-dose Sandostatin® LAR® in combination with pegvisomant (n = 31) or cabergoline (n = 32). Outcomes included biochemical response at eight months, QoL, and safety. RESULTS: After three months, 3 of 68 (4.4%) evaluable patients achieved a biochemical control (BC) as assessed by levels of growth hormone and insulin-like growth factor-1. At eight months, 4 of 67 (6.0%) patients achieved BC, including one receiving monotherapy and three receiving Sandostatin® LAR® plus cabergoline. Partial response rate, improvements in acromegaly signs and symptoms, and changes in QoL were similar for all three groups. All treatments were well tolerated with a slight excess of adverse events in the combination arms. There were no deaths or serious adverse events leading to treatment discontinuation. CONCLUSION: These data demonstrate that high-dose Sandostatin® LAR® as monotherapy or in combination with pegvisomant or cabergoline is a feasible salvage option in patients with pituitary adenomas not adequately controlled on conventional SSA regimens.


Assuntos
Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Cabergolina/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Octreotida/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Acromegalia/complicações , Adenoma/complicações , Adulto , Idoso , Antineoplásicos Hormonais/uso terapêutico , Quimioterapia Combinada , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicações , Resultado do Tratamento
20.
J Clin Endocrinol Metab ; 104(11): 5478-5482, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219586

RESUMO

CONTEXT: The treatment of acromegaly resistant to first- and second-line therapies can be extremely challenging. DESIGN: We have described six patients who were successfully treated with a combination therapy of pasireotide and pegvisomant and compared them with a control group of patients resistant to conventional somatostatin analogs (SSAs), whose disease was controlled with other treatment, such as pasireotide (as monotherapy) or pegvisomant (as monotherapy or combined with conventional SSAs). RESULTS: In these six patients, acromegaly was controlled with combined pasireotide and pegvisomant treatment after failure of all other treatments. Compared with the 49 patients in the control group, these six patients had giant and invasive pituitary adenomas (at both the cavernous sinus and other structures). Although not statistically significant, higher growth hormone levels, more elevated Ki-67 expression, greater somatostatin receptor (SSTR) subtype 5 expression, and lower SSTR subtype 2 expression at the diagnosis of acromegaly were detected in patients receiving combination treatment with pasireotide and pegvisomant compared with the control group. CONCLUSION: Our data have reinforced the importance of personalized treatment of patients with acromegaly according to the clinical, biochemical, molecular, and morphological disease markers and suggest that combined treatment with pasireotide and pegvisomant can induce disease control in tumors with low SSTR2 expression, resistant to conventional SSAs (alone or combined with pegvisomant) and to new-generation SSAs alone (pasireotide).


Assuntos
Acromegalia/tratamento farmacológico , Adenoma/tratamento farmacológico , Hormônios/uso terapêutico , Hormônio do Crescimento Humano/análogos & derivados , Neoplasias Hipofisárias/tratamento farmacológico , Somatostatina/análogos & derivados , Acromegalia/etiologia , Adenoma/complicações , Adulto , Quimioterapia Combinada , Feminino , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicações , Estudos Retrospectivos , Somatostatina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...