RESUMEN
PURPOSE: To evaluate clinical, laboratory, radiological, therapeutic, and prognostic characteristics of patients with acromegaly according to the size of the growth hormone (GH)-secreting pituitary adenoma at diagnosis. METHODS: Observational, retrospective, single-center study of patients with acromegaly followed at a tertiary center. Data were collected regarding clinical presentation, characteristics of the adenoma in the magnetic resonance imaging, GH and IGF-1 levels, and disease control after surgery or adjuvant treatment (normal IGF-1 levels). Patients were divided according to the adenoma size at diagnosis in: group I < 10 mm; II 10-19 mm; III 20-29 mm; IV 30-39 mm; and V ≥ 40 mm. Comparisons were made between the groups, and correlations of tumor size with disease parameters, ROC curves, and logistic regression analyses were performed to investigate tumor size and confounding factors that could impact the outcomes. RESULTS: 117 patients were studied [59 women, age at diagnosis 43 ± 13 years; group I = 11 patients (9%); group II 54 (46%); group III 34 (29%); group IV 10 (9%); group V 8 (7%)]. Hypopituitarism, cavernous sinus invasion, GH levels, and use of somatostatin receptor ligands had their prevalence increased according to the adenoma size. Age showed a negative correlation with tumor size. A tumor diameter around 20 mm was the best predictor for the presence of hypopituitarism, invasiveness, need of adjuvant therapies, and poorer disease control. CONCLUSION: Adenomas < 20 mm showed lower morbidity and better therapeutic response in acromegaly, while those ≥ 20 mm had similar clinical, therapeutic, and prognostic behavior.
Asunto(s)
Acromegalia , Humanos , Acromegalia/patología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , Pronóstico , Hormona de Crecimiento Humana/metabolismo , Imagen por Resonancia Magnética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Adenoma/patología , Adenoma/terapia , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapiaRESUMEN
INTRODUCTION: AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland. METHODS: We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269_H275dup) and autopsy from normal pituitary glands without structural alterations. RESULTS: Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly. CONCLUSION: Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations.
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Proteínas Quinasas Activadas por AMP , Adenoma , Adenoma Hipofisario Secretor de Hormona del Crecimiento , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Masculino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Femenino , Persona de Mediana Edad , Adulto , Adenoma/genética , Adenoma/patología , Adenoma/metabolismo , Adenoma/enzimología , Acromegalia/genética , Acromegalia/patología , Acromegalia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Anciano , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/enzimología , Fosforilación , Hipófisis/metabolismo , Hipófisis/patología , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: In acromegaly, chronic growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exacerbate comorbidities in multiple organs. Differentiated thyroid carcinoma (DTC) has been reported as being a comorbid condition in acromegaly. Acromegaly is usuallysporadic, but 5% of cases may be genetic. The most frequent inheritable form of acromegaly is related to germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Epidemiological data on the relationship between active acromegaly, its familial forms and DTC are sparse. We present the investigation of a FIPA family (familial isolated pituitary adenoma) with homogeneous acromegaly and 6 sporadic acromegaly patients with DTC. PATIENTS AND METHODS: A study of 59 acromegaly patients assessed thyroid nodules on ultrasound and fine-needle aspiration biopsy following the ATA 2015 criteria. We diagnosed 7 differentiated thyroid carcinomas. Resected thyroid carcinoma tissues were stained using an anti-AIP antibody. Analysis of germline and tumor-derived DNA for variants in the AIP and MEN1 genes were performed in the FIPA kindred. RESULTS: We describe one FIPA patient and 6 sporadic acromegaly cases with DTC. The FIPA family (AIP mutation negative) consisted of two sisters, one of whom had a DTC with intermediate risk and incomplete structural response to therapy. In our study, DTC in sporadic acromegaly had a low recurrence rate (6/6), and excellent response to therapy (6/6). Immunohistochemistry for AIP showed similar or increased staining intensity in DTC versus normal thyroid tissue. CONCLUSION: In our cohort of sporadic and familial forms of acromegaly with DTC, AIP did not appear to influence thyroid cancer progression.
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Acromegalia/epidemiología , Adenocarcinoma/epidemiología , Adenoma/epidemiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Neoplasias de la Tiroides/epidemiología , Acromegalia/diagnóstico por imagen , Acromegalia/etiología , Acromegalia/patología , Adenocarcinoma/complicaciones , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenoma/complicaciones , Adenoma/diagnóstico por imagen , Adenoma/patología , Adulto , Anciano , Argentina/epidemiología , Biopsia con Aguja Fina , Estudios de Cohortes , Comorbilidad , Progresión de la Enfermedad , Femenino , Mutación de Línea Germinal , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico por imagen , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , UltrasonografíaRESUMEN
BACKGROUND: Classification of growth hormone (GH) - secreting tumors by the granular pattern might predict their clinical behavior in acromegalic patients. There are several other prognostic factors. AIM: To compare the features at presentation and cure rates of patients with GH secreting tumors according to the granular pattern, and to define independent prognostic factors for surgical treatment in these patients. MATERIAL AND METHODS: A retrospective, observational study of 85 active acromegalic patients surgically treated in two medical centers. RESULTS: Seventy-four patients (87%) were classified as having densely granulated (DG) and 11 (13%) as sparsely granulated (SG) tumors. The latter were less active biochemically, had a higher rate of macroadenoma and cavernous sinus invasion and had a lower rate of biochemical cure than the DG group. Several characteristics were associated with disease persistence but only age (Odds ratio (OR) = 0.93) and cavernous sinus invasion (OR = 21.7) were independently associated in the logistic regression model. CONCLUSIONS: The sparsely granulated pattern is associated with a more aggressive behavior, but the main determinants of prognosis are age and cavernous sinus invasion.
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Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Adulto , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico por imagen , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
Background: Classification of growth hormone (GH) - secreting tumors by the granular pattern might predict their clinical behavior in acromegalic patients. There are several other prognostic factors. Aim: To compare the features at presentation and cure rates of patients with GH secreting tumors according to the granular pattern, and to define independent prognostic factors for surgical treatment in these patients. Material and Methods: A retrospective, observational study of 85 active acromegalic patients surgically treated in two medical centers. Results: Seventy-four patients (87%) were classified as having densely granulated (DG) and 11 (13%) as sparsely granulated (SG) tumors. The latter were less active biochemically, had a higher rate of macroadenoma and cavernous sinus invasion and had a lower rate of biochemical cure than the DG group. Several characteristics were associated with disease persistence but only age (Odds ratio (OR) = 0.93) and cavernous sinus invasion (OR = 21.7) were independently associated in the logistic regression model. Conclusions: The sparsely granulated pattern is associated with a more aggressive behavior, but the main determinants of prognosis are age and cavernous sinus invasion.
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Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Pronóstico , Inmunohistoquímica , Imagen por Resonancia Magnética , Estudios Retrospectivos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico por imagenRESUMEN
OBJECTIVES: This study analyzed the KISS1 c.-145delA (rs5780218) promoter polymorphism in a cohort of patients with growth hormone secreting pituitary adenoma (somatotropinoma) and controls, to investigate its role in the incidence of acromegaly and to assess patient/tumor characteristics. Material and methods rs5780218 allelic and genotypic distributions were compared between 49 somatotropinoma patients and 167 healthy controls. rs5780218 was also assessed in relation to patient characteristics and tumor aggressiveness, as characterized by tumor invasion and resistance to conventional therapy. The relationship between KISS1 mRNA expression and the rs5780218 genotype was also assessed in available pituitary tumor samples. RESULTS: The homozygous -/- variant genotype was associated with high rates of somatotropinoma (P<0.01), but not with tumor invasiveness, patient characteristics or hormonal remission. KISS1 mRNA expression was much lower in somatotropinomas carrying the deleted allele than in homozygous wild type AA. CONCLUSIONS: In this pilot study, the rs5780218 promoter polymorphism was evaluated in pituitary adenoma, and showed a possible association with the incidence of somatotropinoma but not with tumor progression.
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Adenoma/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Kisspeptinas/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Adenoma/epidemiología , Adenoma/patología , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Polimorfismo de Nucleótido Simple/fisiología , Factores de Riesgo , Adulto JovenRESUMEN
Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.
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Adenoma/genética , Mutación de Línea Germinal/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Neoplasias Hipofisarias/genética , Adenoma/patología , Adulto , Brasil , Carcinogénesis , Transformación Celular Neoplásica , Estudios de Cohortes , ADN de Neoplasias , Femenino , Marcadores Genéticos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Hipófisis/patología , Neoplasias Hipofisarias/patologíaRESUMEN
Sirtuins 1-7 (SIRT) are a highly conserved family of histone deacetylases involved in the regulation of longevity that have a considerable impact in transcription, DNA repair regulation, telomeric stability, cell senescence and apoptosis. In the present study, SIRT1-7 mRNA levels were evaluated in 37 somatotropinomas and 31 nonfunctioning pituitary adenomas (NFPAs) using qPCR and relation to tumor size, invasiveness and Ki-67 proliferative index was made. Overexpression of SIRT1 was observed in 86.5% of somatotropinomas versus 41.9% of NFPAs (P < 0.01). SIRT3 was more underexpressed in NFPAs than somatotropinomas (77.4 and 40.5%, respectively, P < 0.01) as well as SIRT4 and SIRT7. Despite the lack of association between sirtuins and invasiveness or Ki-67 index, SIRT1 and SIRT3 expressions were related to tumor size. Mean of the largest diameter was smaller in adenomas with SIRT1 overexpression than with normal expression (P < 0.01) and SIRT3 underexpression was associated with larger tumors (P < 0.01). In conclusion, a pronounced difference in sirtuins expression was identified between pituitary adenomas, suggesting that these genes are potential markers of pituitary adenomas and could be employed in the characterization of somatotropinomas and NFPAs. The role of sirtuins in pathogenesis of pituitary tumors merits further investigation and possibly will provide new molecular insight about their progression.
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Adenoma/metabolismo , Neoplasias Hipofisarias/metabolismo , Sirtuinas/metabolismo , Adenoma/genética , Adenoma/patología , Adulto , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Sirtuina 1/genética , Sirtuina 1/metabolismo , Sirtuina 2/genética , Sirtuina 2/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Sirtuinas/genéticaRESUMEN
Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Neoplasias Hipofisarias/genética , Adenoma/genética , Mutación de Línea Germinal/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Hipófisis/patología , Neoplasias Hipofisarias/patología , Brasil , ADN de Neoplasias , Marcadores Genéticos , Adenoma/patología , Transformación Celular Neoplásica , Estudios de Cohortes , Péptidos y Proteínas de Señalización Intracelular , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , CarcinogénesisRESUMEN
INTRODUCTION: Pituitary adenomas (PA) occur mainly as sporadic disease, but familial syndromes are found in approximately 5% of cases. Identification of these syndromes is important in order to diagnose individuals at risk at an earlier stage. AIMS: To evaluate the frequency of familial PA in a reference outpatient clinic devoted to PA treatment and to identify family members suspected to have pituitary disease. METHODS: Patients with PA were interviewed with respect to the presence of family members with diagnosis of PA or with signs or symptoms suggestive of them. The family members who had a clinical picture suggestive of pituitary disease were further evaluated in an attempt to identify new PA cases. In families with familial disease, the AIP gene was sequenced. RESULTS: 262 patients were evaluated and familial syndrome was found in 13 (5%). Ten (3.8%) patients had familial isolated PA (FIPA) and three (1.2%) had multiple endocrine neoplasia type 1. After evaluation of family members' symptomatology, 110 were considered suspected of having pituitary disease, but only 24 participated in the study. Of these 24, 1 was diagnosed with a corticotropinoma. AIP mutations were found in 20% of FIPA families. CONCLUSION: We found a frequency of familial PA similar to that previously described, as well as a similar frequency of AIP mutations among FIPA families. An active search of the affected family members was able to identify one case of Cushing´s disease. Patients should be aware of pituitary disease's clinical picture to identify possibly affected family members.
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Predisposición Genética a la Enfermedad , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/epidemiología , Neoplasias Hipofisarias/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Instituciones de Atención Ambulatoria , Estudios Transversales , Femenino , Estudios de Seguimiento , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Patrón de Herencia , Masculino , Persona de Mediana Edad , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/patología , Pronóstico , Estándares de Referencia , Síndrome , Adulto JovenRESUMEN
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.
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Acromegalia/tratamiento farmacológico , Biomarcadores de Tumor/sangre , Sustitución de Medicamentos , Octreótido/uso terapéutico , Somatostatina/análogos & derivados , Acromegalia/sangre , Adenoma/sangre , Adenoma/tratamiento farmacológico , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Cruzados , Sustitución de Medicamentos/estadística & datos numéricos , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Persona de Mediana Edad , Somatostatina/uso terapéutico , Resultado del Tratamiento , Carga Tumoral , Adulto JovenRESUMEN
PURPOSE: The current article looks at some of the factors associated with pituitary adenomas displaying unusually aggressive biological and clinical behaviour in patients with acromegaly. METHODS: This was a retrospective, narrative review of previously published evidence chosen at the authors' discretion and presented from the perspective of a Latin American case study. FINDINGS AND CONCLUSIONS: Although most pituitary tumors in acromegalic patients are benign and non-aggressive many can behave more aggressively, compromising local surrounding structures. These lesions tend to respond poorly to somatostatin analogs, have a higher risk of recurrence after surgery and, thus, a worse prognosis. Patients with more aggressive tumors constitute a particular challenge, as they often require several therapeutic approaches and may be difficult to manage, especially when options are restricted due to limited resources.
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Acromegalia/patología , Adenoma/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Acromegalia/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Hormona de Crecimiento Humana/metabolismo , Humanos , Masculino , Invasividad Neoplásica , Estudios Retrospectivos , Somatostatina/análogos & derivados , Somatostatina/economía , Somatostatina/uso terapéuticoRESUMEN
AIMS: The current article provides a brief overview of the criteria for defining disease control in acromegaly. METHODS: This was a retrospective, narrative review of previously published evidence chosen at the author's discretion along with an illustrative case study from Latin America. FINDINGS AND CONCLUSIONS: In the strictest sense, "cure" in acromegaly is defined as complete restoration of normal pulsatile growth hormone secretion, although this is rarely achieved. Rather than "cure", as such, it is more appropriate to refer to disease control and remission, which is defined mainly in terms of specific biochemical targets (for growth hormone and insulin-like growth factor-1) that predict or correlate with symptoms, comorbidities and mortality. However, optimal management of acromegaly goes beyond biochemical control to include control of tumour growth (which may be independent of biochemical control) and comprehensive management of the symptoms and comorbidities typically associated with the disease, as these may not be adequately managed with acromegaly-specific therapy alone.
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Acromegalia/terapia , Acromegalia/diagnóstico , Adenoma/patología , Adulto , Comorbilidad , Diabetes Mellitus/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Dislipidemias/terapia , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Hormona de Crecimiento Humana/metabolismo , Humanos , Hipertensión/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estudios Retrospectivos , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Neoplasias de la Tiroides/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: In more than 98% of cases, acromegaly is due to a GH-secreting pituitary adenoma. The term "ectopic acromegaly" includes neuroendocrine tumors secreting GH releasing hormone (GHRH), usually located in the lungs, thymus and endocrine pancreas. Considerably less frequent are cases of ectopic acromegaly due to GH-secreting tumors located out of the pituitary fossa; except for one isolated case of a well-documented GH-secreting lymphoma, the majority of these lesions are located in the sphenoid sinus. CASE PRESENTATION: We present the case of a 45 year old woman with acromegaly whose MRI showed an empty sella without evidence of a pituitary adenoma but revealed a large mass within the sphenoid sinus. She underwent transsphenoidal surgery and the excised sphenoid sinus mass, proved to be a GH-secreting adenoma; the sellar floor was intact and no other lesions were found in the pituitary fossa. She required postoperative treatment with somatostatin analogs and cabergoline for clinical and biochemical control. CONCLUSIONS: This case highlights the importance of carefully evaluating the structures surrounding the sellar area when a pituitary adenoma is not found with currently available imaging techniques. The finding of an intact sellar floor and duramater lead us to conclude that the patient's tumor originated de novo from embryological pituitary remnants. Upon a careful review of the literature and a critical evaluation of our case we found neither clinical nor biochemical features that would distinguish an ectopic from the more common eutopically located somatotrophinoma.
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Acromegalia/etiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Seno Esfenoidal/patología , Acromegalia/diagnóstico por imagen , Acromegalia/cirugía , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico por imagen , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/cirugía , Hormona de Crecimiento Humana/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Imagen por Resonancia Magnética , Persona de Mediana Edad , Octreótido/análogos & derivados , Cuidados Posoperatorios , Cuidados Preoperatorios , Cintigrafía , Seno Esfenoidal/diagnóstico por imagen , Seno Esfenoidal/cirugíaRESUMEN
INTRODUCTION: There are few data regarding ZAC1 expression in clinically non-functioning pituitary adenomas (NFPA). Because somatotropinomas and NFPA behave differently with respect to tumor shrinkage during somatostatin analogs (SA) therapy, we sought to compare the ZAC1 and somatostatin receptor (sstr) types 1, 2, 3 and 5 mRNA expression in these two pituitary adenoma subtypes and in normal human pituitaries. METHODS: ZAC1 and SSTR mRNA expression levels were evaluated using real-time RT-PCR (TaqMan) in 20 NFPA and compared with the expression levels in 23 somatotropinomas and five normal pituitaries. The NFPA invasiveness was evaluated using magnetic resonance imaging with Hardy's modified criteria. Ki-67 and p53 were evaluated using immunohistochemistry. RESULTS: A total of 20 patients with NFPA [6 males, median age 56 years (range: 30-78)], 23 with acromegaly [12 males, median age 43 years (range: 24-57)] and five normal pituitaries [4 males, median age 48 years (range: 36-54)] were included. Four of the patients (20%) had Hardy's grade 2 tumors; all of the others had Hardy's grade 3 tumors. The Ki-67 median expression was 2.35 (range: 0.2-9.23), and only four of the tumors (20%) were positive for p53. The ZAC1 mRNA expression was significantly lower in NFPA than in somatotropinomas and in normal pituitaries (p<0.001 for both), as well as the SSTR2 (p=0.001 and 0.01, respectively). The SSTR3 expression was higher in the NFPA than in the somatotropinomas and in the normal pituitaries (p=0.03 and 0.02, respectively). No correlation was found between the ZAC1 mRNA expression and the tumor invasiveness, Ki-67 and p53. CONCLUSION: ZAC1 and SSTR2 are underexpressed and SSTR3 is overexpressed in NFPA compared to those in somatotropinomas and in normal pituitaries, which might explain the lack of tumor shrinkage that is observed in response to commercially available SA therapy in patients with NFPA.
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Adenoma/genética , Proteínas de Ciclo Celular/genética , Regulación Neoplásica de la Expresión Génica , Adenoma Hipofisario Secretor de Hormona del Crecimiento/genética , Neoplasias Hipofisarias/genética , Receptores de Somatostatina/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Adenoma/tratamiento farmacológico , Adenoma/metabolismo , Adenoma/patología , Adulto , Anciano , Estudios de Casos y Controles , Proteínas de Ciclo Celular/metabolismo , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/metabolismo , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Hipófisis/patología , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Receptores de Somatostatina/metabolismo , Somatostatina/análogos & derivados , Somatostatina/uso terapéutico , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Acromegaly is an excessive GH secretion, which in most cases, is caused by a pituitary GH-secreting adenoma. Traditional treatment of acromegaly consists of surgery, drug therapy, and eventually radiotherapy. The aim of this retrospective study is to evaluate the results of transsphenoidal endoscopic surgery in a group of patients with intrasellar GH adenoma who were operated by a pituitary specialist surgeon. We shall then argue about the economical advantages, for the NHS of a developing country, between surgical and medical treatment. METHODS: We have analyzed data from 33 patients with intrasellar GH tumor who had been referred to the neuroendocrine department of the HGF, Brazil. The patients underwent a transsphenoidal endoscopic adenomectomy for acromegaly between 2000 and 2005. Their ages were between 20 and 67 years (mean, 44 years) at the moment of surgery. No cavernous sinus invasion was present. Follow-up was a median of 2 years (range, 12 months-6 years). RESULTS: All 33 patients had intrasellar adenoma, 84.84% of patients achieved remission by surgery. One patient was operated twice and reached hormonal normalization. Five patients still had the disease and refused a second surgery. A treatment with octreotide was started for these 5 patients and resulted in an adequate control of GH and IGF-1 levels. No patients had radiotherapy. CONCLUSION: Our patients, with intrasellar GH tumor, operated by a pituitary specialist neurosurgeon had remission rates approaching those obtained by most specialized neurosurgical centers worldwide. For equal results, our study shows that the surgical treatment is the best issue for the patient and for the NHS.
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Adenoma/cirugía , Endoscopía/estadística & datos numéricos , Adenoma Hipofisario Secretor de Hormona del Crecimiento/cirugía , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Silla Turca/cirugía , Hueso Esfenoides/cirugía , Adenoma/patología , Adenoma/fisiopatología , Adulto , Anciano , Antineoplásicos Hormonales/uso terapéutico , Brasil , Análisis Costo-Beneficio , Países en Desarrollo , Endoscopía/economía , Endoscopía/métodos , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Programas Nacionales de Salud/economía , Procedimientos Neuroquirúrgicos/instrumentación , Procedimientos Neuroquirúrgicos/métodos , Octreótido/uso terapéutico , Evaluación de Resultado en la Atención de Salud/métodos , Radiografía , Reoperación/estadística & datos numéricos , Estudios Retrospectivos , Silla Turca/diagnóstico por imagen , Silla Turca/patología , Especialización/economía , Especialización/estadística & datos numéricos , Hueso Esfenoides/diagnóstico por imagen , Hueso Esfenoides/patología , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To present 2 cases of patients with acromegaly and severe hyperprolactinemia whose primary therapy with cabergoline resulted in hormonal normalization and a considerable reduction in the size of their somatotroph macroadenomas. METHODS: We summarize the clinical presentation and the pertinent laboratory findings in 2 patients with acromegaly, as well as their clinical response to the therapy with cabergoline. A review of the literature regarding the use of cabergoline in acromegaly is also presented. RESULTS: A 48-year-old man (case 1) and a 26-year-old woman (case 2) were found to have acromegaly associated with very high levels of serum prolactin (2,700 and 5,250 ng/mL, respectively). These patients received first line therapy with cabergoline that resulted not only in clinical improvement and normalization of growth hormone, prolactin, and insulin-like growth factor-I levels but also in a substantial reduction in the size of their somatotroph macroadenomas. By 6 months after the patients began to take cabergoline, tumor shrinkage of 94% (in case 1) and of 70% (in case 2) was demonstrated by magnetic resonance imaging. CONCLUSION: Our findings demonstrate that cabergoline should be considered for medical treatment of adenomas cosecreting growth hormone and prolactin, even in the presence of large tumors with appreciable suprasellar extension, because substantial tumor shrinkage is possible with this therapy.
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Adenoma/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Ergolinas/administración & dosificación , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Neoplasias Hipofisarias/tratamiento farmacológico , Prolactinoma/tratamiento farmacológico , Acromegalia/etiología , Adenoma/complicaciones , Adenoma/patología , Adulto , Cabergolina , Femenino , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/patología , Prolactinoma/complicaciones , Prolactinoma/patologíaRESUMEN
OBJECTIVE: To compare the intrapatient response to the same dose of slow-release octreotide (OCT-LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT-LAR. DESIGN: Prospective clinical study. PATIENTS: Eleven acromegalic patients (eight men, aged 42.45 +/- 11.15 years, 10 macroadenomas) received OCT-LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT-LAR) for 11.3 +/- 4.2 months, without IGF-I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT-LAR for 8.0 +/- 6.5 months (2ndOCT-LAR). MEASUREMENTS: GH and IGF-I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF-I was also expressed as a percentage of the upper limit of the normal age- and sex-matched range (%ULNR IGF-I). RESULTS: After 1stOCT-LAR, there was a decrease in GH levels (P = 0.003) and %ULNR IGF-I (P = 0.009) compared to baseline (B), but no IGF-I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63.7%, range 24.5-75.5%). After surgery, mean levels of GH and %ULNR IGF-I were lower than those at baseline (P = 0.0004 and P = 0.003, respectively), but not when compared to values during 1stOCT-LAR (P = 1.000 and P = 0.957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4.9-96.6%) in eight of the 10 patients. Comparing the 2ndOCT-LAR results with postsurgical results, there were no significant decrease in %ULNR IGF-I (P = 0.061) and GH levels (P = 0.414). Nine patients (82%) achieved IGF-I normalization. The degree of surgical tumour reduction did not correlate with IGF-I normalization (P = 0.794). When comparing the results between 1stOCT-LAR and 2ndOCT-LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0.059) and a significant decrease in %ULNR IGF-I (P = 0.011). CONCLUSIONS: Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT-LAR treatment in acromegalic patients resistant to primary therapy with SA.
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Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/cirugía , Octreótido/uso terapéutico , Neoplasias Hipofisarias/cirugía , Somatostatina/metabolismo , Acromegalia/metabolismo , Acromegalia/patología , Adulto , Anciano , Preparaciones de Acción Retardada , Resistencia a Antineoplásicos , Femenino , Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Hipofisarias/sangre , Neoplasias Hipofisarias/patología , Estudios Prospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the efficacy, safety and tolerability of octreotide LAR (long-acting repeatable octreotide) in the primary therapy of acromegaly. DESIGN AND PATIENTS: Ninety-eight previously untreated acromegalics were recruited into this prospective multicentre study. A total of 68 patients successfully completed 48 weeks of the study period, received 12 doses of octreotide LAR 10-30 mg every 4 weeks, and constituted the population used for this analysis. MEASUREMENTS AND RESULTS: A clinically relevant reduction (i.e. to < or = 5 microg/l) in mean GH (mGH) was recorded in 72% of patients after 24 weeks of treatment, and 42% reached a 'safe' GH value (< or = 2.5 microg/l). At week 48, 16 more patients were considered partial GH responders (GH > 2.5 microg/l and < or = 5 microg/l) and 44% had reached a GH level < or = 2.5 microg/l. IGF-1 levels normalized in 38% and 34% of patients after 24 and 48 weeks of treatment, respectively. At study completion, 10 patients (14.7%) who had not normalized their IGF-1 levels had achieved at least a 50% decrement in this marker. In eight microadenoma patients, tumour volume decreased from a mean baseline level of 298 +/- 145 mm3 to 139 +/- 94 mm3 after 24 weeks and to 99 +/- 70 mm3 after 48 weeks of therapy. In 60 patients with macroadenoma, the corresponding values were 3885 +/- 5077 mm3 at baseline and 2723 +/- 3435 and 2406 +/- 3207 mm3 after 24 and 48 weeks, respectively. At weeks 24 and 48, a significant (> 20%) tumour volume reduction was reported in 63% and 75% of patients, respectively. A reduction in the severity of symptoms of acromegaly was observed early in treatment and was maintained throughout the study period. CONCLUSION: Octreotide LAR represents a viable alternative to surgery for primary treatment of acromegaly leading to a progressive regression of tumour volume, a sustained control of biochemical abnormalities and an adequate relief of symptoms of the disease.
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Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Octreótido/uso terapéutico , Acromegalia/sangre , Acromegalia/patología , Adulto , Anciano , Anciano de 80 o más Años , Preparaciones de Acción Retardada , Esquema de Medicación , Estudios de Factibilidad , Femenino , Vesícula Biliar/diagnóstico por imagen , Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/sangre , Adenoma Hipofisario Secretor de Hormona del Crecimiento/tratamiento farmacológico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/patología , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/sangre , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/patología , Estudios Prospectivos , Resultado del Tratamiento , UltrasonografíaRESUMEN
The aim of this retrospective study was to evaluate the results of transsphenoidal surgery in a group of patients with acromegaly who were operated by the same neurosurgeon. Our results were compared to those from a cumulative meta-analysis of 10 series (1,632 patients) published between 1992 and 2005. We followed 28 patients (17M/11F; 44.1 +/- 12.7 yr; 27 with macroadenomas; 86% being invasive) during 21.4 +/- 17.6 months after treatment. Patients were classified according to disease activity as follows: 1) controlled (CD): basal or mean GH < 2.5 ng/ml or nadir GH (OGTT) < 1 ng/ml and normal IGF-1; 2) uncontrolled (UCD): basal or mean GH > 2.5 ng/ml or nadir GH > 1 ng/ml and elevated IGF-1; 3) inadequately controlled (ICD): normal GH and elevated IGF-1 or elevated GH and normal IGF-1. After surgery, GH levels decreased from 61.7 +/- 101.1 ng/ml to 7.2 +/- 13.7 ng/ml (p< 0.001) and mean IGF-1 from 673.1 +/- 257.7 ng/ml to 471.2 +/- 285 ng/ml (p= 0.01). Biochemical remission rate was 57% [10 (35.5%) patients with CD and 6 (21.5%) with ICD], similar to the mean remission rate observed in the meta-analysis of surgical outcome of macroadenomas. Seven of 28 patients were submitted to surgical re-intervention (4 had been previously operated elsewhere and 3 by our neurosurgeon), with CD observed in 5 (71.5%) on follow-up. Cavernous sinuses invasion was more prevalent in UCD and ICD, whereas infundibular stalk deviation occurred only in patients with UCD. Remission rate was significantly higher in series where all surgical procedures were performed by the same surgeon (66% vs. 49%; p< 0.05). Thus, the surgeon's experience significantly improves the surgical outcome in acromegaly, especially in patients harboring large and invasive tumors, and re-intervention performed by an experienced surgeon should be considered in the algorithms for clinical management of this disease.