RESUMO
CONTEXT: Once hypercortisolemia is confirmed, differential diagnosis between Cushing's syndrome (CS) due to neoplastic endogenous hypercortisolism and non-neoplastic hypercortisolism (NNH, pseudo-Cushing's syndrome) is crucial. Due to worldwide corticotropin-releasing hormone (CRH) unavailability, accuracy of alternative tests to dexamethasone (Dex)-CRH, is clearly needed. OBJECTIVE: Assess the diagnostic accuracy of Dex-CRH test, desmopressin stimulation test, midnight serum cortisol (MSC), and late-night salivary cortisol (LNSC) levels to distinguish CS from NNH. METHODS: Articles through March 2022 were identified from Scopus, Web of Science, MEDLINE, EMBASE, and PubMed. All steps through the systematic review were performed independently and in duplicate and strictly adhered to the updated PRISMA-DTA checklist. DATA SYNTHESIS: A total of 24 articles (1900 patients) were included. Dex-CRH had a pooled sensitivity and specificity of 91% (95%CI 87-94%; I2 0%) and 82% (73-88%; I2 50%), desmopressin test 86% (81-90%; I2 28%) and 90% (84-94%; I2 15%), MSC 91% (85-94%; I2 66%) and 81% (70-89%; I2 71%), and LNSC 80% (67-89%; I2 57%) and 90% (84-93%; I2 21%), respectively. Summary receiver operating characteristics areas under the curve were Dex-CRH 0.949, desmopressin test 0.936, MSC 0.942, and LNSC 0.950 without visual or statistical significance. The overall risk of studies bias was moderate. CONCLUSION: Dex-CRH, the desmopressin stimulation test, and MSC have similar diagnostic accuracy, with Dex-CRH and MSC having slightly higher sensitivity, and the desmopressin test being more specific. LNSC was the least accurate, probably due to high heterogeneity, intrinsic variability, different assays, and lack of consistent reported cutoffs. When facing this challenging differential diagnosis, the results presented here should increase clinicians' confidence when deciding which test to perform.
Assuntos
Síndrome de Cushing , Humanos , Síndrome de Cushing/diagnóstico , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Diagnóstico Diferencial , Hormônio Liberador da Corticotropina/metabolismo , Dexametasona , Desamino Arginina VasopressinaRESUMO
Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting pasireotide in these studies. Of patients treated with pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305), normal glucose tolerance, and no history of hypertension or dyslipidemia at baseline. Thirteen (4%) patients discontinued pasireotide because of hyperglycemia-related adverse events. Metformin alone or in combination with other oral antidiabetic medications controlled elevations in glucose levels in most pasireotide-treated patients; 78% of C2305 patients and 73 (pasireotide 40 mg) and 60% (pasireotide 60 mg) of C2402 patients achieved the ADA/EASD goal of HbA1c <7% (<53 mmol/mol) at the end of the core phase. Not all patients develop hyperglycemia, and it is reversible upon pasireotide withdrawal. Close monitoring, patient education and prompt action remain key elements in addressing hyperglycemia during pasireotide treatment.
RESUMO
Acromegaly is a chronic systemic disease with many complications and is associated with increased mortality when not adequately treated. Substantial advances in acromegaly treatment, as well as in the treatment of many of its complications, mainly diabetes mellitus, heart failure, and arterial hypertension, were achieved in the last decades. These developments allowed change in both prevalence and severity of some acromegaly complications and furthermore resulted in a reduction of mortality. Currently, mortality seems to be similar to the general population in adequately treated patients with acromegaly. In this review, we update the knowledge in complications of acromegaly and detail the effects of different acromegaly treatment options on these complications. Incidence of mortality, its correlation with GH (cumulative exposure vs last value), and IGF-I levels and the shift in the main cause of mortality in patients with acromegaly are also addressed.
Assuntos
Acromegalia , Doenças Cardiovasculares , Doenças do Sistema Endócrino , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Doenças Metabólicas , Doenças Musculoesqueléticas , Neoplasias , Transtornos Respiratórios , Acromegalia/complicações , Acromegalia/metabolismo , Acromegalia/mortalidade , Acromegalia/terapia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Doenças do Sistema Endócrino/etiologia , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/mortalidade , Doenças do Sistema Endócrino/terapia , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/mortalidade , Doenças Metabólicas/terapia , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/mortalidade , Doenças Musculoesqueléticas/terapia , Neoplasias/etiologia , Neoplasias/mortalidade , Neoplasias/terapia , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/metabolismo , Transtornos Respiratórios/mortalidade , Transtornos Respiratórios/terapiaRESUMO
BACKGROUND: Many patients with acromegaly do not achieve biochemical control with first-generation somatostatin analogues. A large, multicenter, randomized, Phase III core study demonstrated that pasireotide LAR had significantly superior efficacy over octreotide LAR. This analysis explores the efficacy and safety of switching therapeutic arms in inadequately controlled patients during a 12-month crossover extension. METHODS: Patients with inadequate biochemical control (GH ≥2.5 µg/L and/or IGF-1 > ULN) at end of core study (month 12) were eligible to switch to pasireotide LAR 40 mg/28 days (n = 81) or octreotide LAR 20 mg/28 days (n = 38). One dose escalation to pasireotide LAR 60 mg/28 days or octreotide LAR 30 mg/28 days was permitted, but not mandatory, at month 17 or 20. RESULTS: Twelve months after crossover, 17.3 % of pasireotide LAR and 0 % of octreotide LAR patients achieved GH <2.5 µg/L and normal IGF-1 (main outcome measure); 27.2 and 5.3 % of pasireotide LAR and octreotide LAR patients achieved normal IGF-1, respectively; 44.4 and 23.7 % of pasireotide LAR and octreotide LAR patients achieved GH <2.5 µg/L, respectively. Mean (±SD) tumor volume further decreased from the end of the core study by 25 % (±25) and 18 % (±28); 54.3 % of pasireotide LAR and 42.3 % of octreotide LAR patients achieved significant (≥20 %) tumor volume reduction during the extension. The safety profile of pasireotide LAR was similar to that of octreotide LAR, with the exception of the frequency and degree of hyperglycemia-related adverse events. CONCLUSIONS: Pasireotide LAR is a promising treatment option for patients with acromegaly inadequately controlled with the first-generation somatostatin analogue octreotide LAR. TRIAL REGISTRATION: clinicaltrials.gov, NCT00600886 . Registered 14 January 2008.
Assuntos
Acromegalia/tratamento farmacológico , Biomarcadores Tumorais/sangue , Substituição de Medicamentos , Octreotida/uso terapêutico , Somatostatina/análogos & derivados , Acromegalia/sangue , Adenoma/sangue , Adenoma/tratamento farmacológico , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Substituição de Medicamentos/estatística & dados numéricos , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/sangue , Adenoma Hipofisário Secretor de Hormônio do Crescimento/tratamento farmacológico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Hormônio do Crescimento Humano/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Somatostatina/uso terapêutico , Resultado do Tratamento , Carga Tumoral , Adulto JovemRESUMO
Morbidity and mortality rates in patients with active acromegaly are higher than the general population. Adequate biochemical control restores mortality to normal rates. Now, medical therapy has an increasingly important role in the treatment of patients with acromegaly. Somatostatin receptor ligands (SRLs) are considered the standard medical therapy, either after surgery or as a first-line therapy when surgery is deemed ineffective or is contraindicated. Overall, octreotide and lanreotide are first-generation SRLs and are effective in ~20%-70% of patients. Pegvisomant, a growth hormone receptor antagonist, controls insulin-like growth factor 1 in 65%-90% of cases. Consequently, a subset of patients (nonresponders) requires other treatment options. Drug combination therapy offers the potential for more efficacious disease control. However, the development of new medical therapies remains essential. Here, emphasis is placed on new medical therapies to control acromegaly. There is a focus on pasireotide long-acting release (LAR) (Signifor LAR®), which was approved in 2014 by the US Food and Drug Administration and the European Medicine Agency for the treatment of acromegaly. Pasireotide LAR is a long-acting somatostatin multireceptor ligand. In a Phase III clinical trial in patients with acromegaly (naïve to medical therapy or uncontrolled on a maximum dose of first-generation SRLs), 40 and 60 mg of intramuscular pasireotide LAR achieved better biochemical disease control than octreotide LAR, and tumor shrinkage was noted in both pasireotide groups. Pasireotide LAR tolerability was similar to other SRLs, except for a greater frequency and degree of hyperglycemia and diabetes mellitus. Baseline glucose may predict hyperglycemia occurrence after treatment, and careful monitoring of glycemic status and appropriate treatment is required. A precise definition of patients with acromegaly who will derive the greatest therapeutic benefit from pasireotide LAR remains to be established. Lastly, novel therapies and new potential delivery modalities (oral octreotide) are summarized.
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Acromegalia/tratamento farmacológico , Desenho de Fármacos , Somatostatina/análogos & derivados , Acromegalia/fisiopatologia , Animais , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Humanos , Octreotida , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/uso terapêuticoRESUMO
The definition of the etiology of hyperprolactinemia often represents a great challenge and an accurate diagnosis is paramount before treatment. Although prolactin levels > 200-250 ng/mL are highly suggestive of prolactinomas, they can occasionally be found in other conditions. Moreover, as much as 25% of patients with microprolactinomas may present prolactin levels < 100 ng/mL, which are found in most patients with pseudoprolactinomas, drug-induced hyperprolactinemia, or systemic diseases. On the other hand, some conditions may lead to falsely low PRL levels, particularly the so-called hook effect, that is an assay artifact caused by an extremely high level of PRL, and can be confirmed by repeating assay after a 1:100 serum sample dilution. The hook effect must be considered in all patients with large pituitary adenomas and PRL levels within the normal range or only modestly elevated (e.g., < 200 ng/mL). An overlooked hook effect may lead to incorrect diagnosis and unnecessary surgical intervention in patients with prolactinomas. Another important challenge is macroprolactinemia, a common finding that needs to be identified, as it usually requires no treatment. Although most macroprolactinemic patients are asymptomatic, many of them may present galactorrhea or menstrual disorders, as well as neuroradiological abnormalities, due to the concomitance of other diseases. Finally, physicians should be aware that pituitary incidentalomas are found in at least 10% of adult population.
Assuntos
Hiperprolactinemia/diagnóstico , Hiperprolactinemia/etiologia , Prolactina/sangue , Prolactinoma/complicações , Precipitação Química , Cromatografia em Gel , Feminino , Galactorreia/etiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Anamnese , Exame Físico , Prolactina/classificaçãoRESUMO
The definition of the etiology of hyperprolactinemia often represents a great challenge and an accurate diagnosis is paramount before treatment. Although prolactin levels > 200-250 ng/mL are highly suggestive of prolactinomas, they can occasionally be found in other conditions. Moreover, as much as 25% of patients with microprolactinomas may present prolactin levels < 100 ng/mL, which are found in most patients with pseudoprolactinomas, drug-induced hyperprolactinemia, or systemic diseases. On the other hand, some conditions may lead to falsely low PRL levels, particularly the so-called hook effect, that is an assay artifact caused by an extremely high level of PRL, and can be confirmed by repeating assay after a 1:100 serum sample dilution. The hook effect must be considered in all patients with large pituitary adenomas and PRL levels within the normal range or only modestly elevated (e.g., < 200 ng/mL). An overlooked hook effect may lead to incorrect diagnosis and unnecessary surgical intervention in patients with prolactinomas. Another important challenge is macroprolactinemia, a common finding that needs to be identified, as it usually requires no treatment. Although most macroprolactinemic patients are asymptomatic, many of them may present galactorrhea or menstrual disorders, as well as neuroradiological abnormalities, due to the concomitance of other diseases. Finally, physicians should be aware that pituitary incidentalomas are found in at least 10% of adult population. Arq Bras Endocrinol Metab. 2014;58(1):9-22.
A definição da etiologia da hiperprolactinemia muitas vezes representa um grande desafio e um diagnóstico preciso é fundamental antes do tratamento. Embora níveis de prolactina > 200-250 ng/mL sejam altamente sugestivos de prolactinomas, ocasionalmente podem ser encontrados em outras condições. Além disso, até 25% dos pacientes com microprolactinomas podem apresentar-se com níveis de prolactina < 100 ng/mL, os quais são evidenciados na maioria dos pacientes com pseudoprolactinomas, hiperprolactinemia induzida por drogas ou doenças sistêmicas. Por outro lado, deve-se atentar às condições que podem levar a valores de prolactina falsamente baixos, particularmente o chamado efeito gancho. Este último é um artefato causado por um nível extremamente elevado de PRL e que pode ser confirmado pela repetição do exame após diluição do soro a 1:100. O efeito gancho deve ser considerado em todo paciente com grandes adenomas hipofisários e níveis de prolactina dentro da faixa normal ou apenas moderadamente elevados (p. ex., < 200 ng/mL). Um efeito gancho não detectado pode levar a diagnóstico incorreto e intervenção cirúrgica desnecessária em pacientes com prolactinomas. Outro desafio importante é a macroprolactinemia, um achado comum que precisa ser identificado visto que geralmente não requer tratamento. Ainda que a maioria dos pacientes seja assintomática devido à concomitância de outras doenças, muitos podem apresentar galactorreia ou distúrbios menstruais, bem como anormalidades neurorradiológicas. Finalmente, os médicos devem estar cientes de que incidentalomas hipofisários são encontrados em pelo menos 10% da população adulta. Arq Bras Endocrinol Metab. 2014;58(1):9-22.