Diagnostic, therapeutic, and prognostic characteristics of patients with acromegaly according to tumor size at diagnosis.

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.

Activated AMP-protein kinase (pAMPK) is overexpressed in human somatotroph pituitary adenomas.

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.

Genetic diagnosis in acromegaly and gigantism: From research to clinical practice.

It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.

Surgical outcomes in patients with acromegaly: Microscopic vs. endoscopic transsphenoidal surgery.

Transsphenoidal resection of growth hormone-secreting pituitary neuroendocrine tumors remains the first-line treatment for acromegaly. This can be performed through microsurgery or endoscopic surgery. For the past decades, endoscopic surgery has become the preferred technique in an increasing number of centers worldwide. However, whether it offers superior clinical outcomes has yet to be determined. In this paper, we performed a narrative review of the literature comparing both techniques in the treatment of acromegaly. We critically assessed available comparative studies from an objective perspective to determine their suitability for defining superiority of either technique. Available evidence displays substantial methodological variations and reports conflicting findings. Although endoscopic surgery provides a wider exposure and enhanced visibility of the surgical field, this does not consistently translate into better clinical outcomes, as most tumors are equally accessible through both techniques. Postoperative outcomes such as remission and complication rates are similar between both techniques. The management of acromegaly should be performed by experienced pituitary neurosurgeons, regardless of the approach. The involvement of a multidisciplinary team in a dedicated pituitary center is critical to ensure optimal outcomes.

Acromegalia e hipertensão arterial: casualidade ou causalidade? Insights a partir de relato de caso / Acromegaly and arterial hypertension: causality or causality? Insights from case report

INTRODUÇÃO E/OU FUNDAMENTO: A acromegalia é uma doença endócrina rara causada por adenoma hipofisário secretor de Hormônio do Crescimento (GH), cursando com aumento dos níveis plasmáticos de GH e, consequentemente, do Fator de Crescimento Semelhante à Insulina-1 (IGF-1). Ambos os hormônios exercem importantes atividades regulatórias no sistema cardiovascular (CV) que é o principal responsável pelas complicações clínicas da síndrome. O relato de caso a seguir expõe diversas dessas complicações. MÉTODOS: Relatamos caso de paciente do sexo feminino, 47 anos, branca, tabagista, sem outras comorbidades, que procurou atendimento por cansaço progressivo, associado à dispneia aos esforços e edema de membros inferiores. RESULTADOS: O ecocardiograma transtorácico confirmou dupla lesão mitral grave, com predomínio de estenose, tratada cirurgicamente com implante de prótese mitral biológica. Cinco anos após, a paciente desenvolveu hipertensão arterial (HA) estágio 1, tratada com Hidroclorotiazida. Concomitantemente relatou cefaleia, perda visual bitemporal, separação dos dentes, aumento de extremidades (com necessidade de aumentar numeração dos sapatos) e língua. Com suspeita clínica de acromegalia, foi submetida a investigação que evidenciou elevação de níveis plasmáticos de GH e IGF1 e lesão expansiva intrasselar identificada por ressonância magnética nuclear. Iniciou-se tratamento com Bromocriptina. Nesse período a paciente interrompeu o uso da medicação anti-hipertensiva, mantendo controle adequado da pressão arterial. No entanto, três anos depois, foi constatado novo aumento dos níveis de IGF-1 para 785mcg/L (VR 2,5 segundos, sendo indicado e realizado implante de marcapasso definitivo. CONCLUSÕES: A doença CV é a comorbidade mais frequente e a principal causa de morte relacionada a acromegalia. O caso apresentado reúne e ilustra as principais manifestações CV da acromegalia: doença valvar; hipertrofia ventricular esquerda; bradiarritmias e HA, muito embora não tenha sido possível afastar doença reumática como etiologia da dupla lesão mitral. A prevalência de HA varia de 13 a 60% e contribui significativamente com o excesso de morbimortalidade observado. A alta prevalência de HA na população geral faz com que seja árduo discernir na prática clínica em que medida a HA é secundária a acromegalia, essencial ou mista. O controle pressórico obtido concomitantemente com a redução dos níveis plasmáticos de GH e IGF-1 indica uma associação direta destes hormônios com a HA em função do aumento da resistência insulínica, da reabsorção renal de sódio e da atividade simpática. Por outro lado, a persistência da HA após o controle hormonal obtido com o Octreotide sugere que nessa fase mais tardia, o remodelamento arteriolar tenha levado a instalação de HA primária.

Endoscopic endonasal approach for acromegaly: surgical outcomes using 2018 consensus criteria for remission.

Objective: The primary aim is to analyze the endoscopic endonasal surgical results in short-term and two-year follow-ups according to the 11th Acromegaly Consensus statement (2018). Indeed, prognostic factors and complications were analyzed. Subjects and methods: 40 patients who underwent endoscopic endonasal surgery by acromegaly between 2013 to 2020 was analyzed. Patients were considered in remission if an upper limit of normal (ULN) IGF-1 was less than 1.0 at the six-month and two-year follow-ups. Moreover, we assessed the Knosp grade, tumor volumetry, ULN, T2 signal in MRI, reoperation, and complications. Results: The mean age of admission was 46.7 years. Thirty-two patients were in remission after six months of surgery (80%), decreasing to 76.32% at the two-year follow-up. All microadenomas presented remission (n = 6). Regarding the complications, three patients had permanent panhypopituitarism (7.5%); postoperative cerebrospinal fluid (CSF) leaks did not occur in this series. The hyperintense signal on the T2 MRI and a higher tumor volumetry were the single predictor's factors of non-emission in a multivariate regression logistic analysis (p < 0.05). Preoperative hormone levels (GH and IGF-1) were not a prognostic factor for remission. The re-operated patients who presented hypersignal already had a high predictor of clinical-operative failure. Conclusion: The endoscopic endonasal surgery promotes high short-term and two-year remission rates in acromegaly; the tumor's volumetry and the T2 hypersignal were statistically significant prognostic factors in non-remission - the complications presented at similar rates in comparison to the literature. In invasive GH-secreting tumors, we should offer these patients a multi-disciplinary approach to improve acromegalic patients' remission rates.

Refractory somatotroph adenomas.

Somatotroph adenomas are usually controlled with standard therapy, which can include surgery, medical treatment and radiotherapy. Some tumors have a more aggressive behavior and are refractory to standard therapy. In this review, we summarize the phenotype of these tumors and the current options for their management.

Clinical and molecular features of four Brazilian families with multiple endocrine neoplasia type 1.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. Methods: From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Results: Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. Conclusions: The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.

The Future of Somatostatin Receptor Ligands in Acromegaly.

Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

[Acromegaly and it's cardiovascular implications]. / Acromegalia y sus implicaciones cardiovasculares.

Acromegaly is a chronic and slowly progressive disease that results from the hypersecretion of growth hormone (GH) and consequently insulin-like growth factor type 1 (IGF-1), due to a GH-secreting pituitary adenoma in 95-98% of cases. There are several complications or co-morbidities associated with acromegaly, the most frequent being cardiovascular, metabolic and neoplastic. The cardiovascular complications of acromegaly go from arterial hypertension to a peculiar form of cardiomyopathy and are the result of the long-standing exposure to high GH and IGF-1 levels. The pathophysiology of these complications is complex and includes an increased tubular reabsorption of sodium and the direct effects of GH and IGF-1 on the endothelium and the cardiac tissue itself. Frequently, the cardiovascular comorbidities of acromegaly occur concomitantly with metabolic complications such as diabetes and respiratory abnormalities such as the sleep apnea syndrome. In this brief review we analyze the pathophysiology, the clinical manifestations and the management of the cardiovascular complications of acromegaly.

La acromegalia es una enfermedad crónica lentamente progresiva causada por la hipersecreción de hormona de crecimiento (GH) y consecuentemente de factor de crecimiento insulinoide tipo 1 (IGF-1), originada en el 95-98% de las ocasiones por un adenoma hipofisario secretor de GH. Existen diversas complicaciones o comorbilidad asociadas a la acromegalia, de las cuales destacan las enfermedades cardiovasculares, metabólicas y neoplásicas. Las complicaciones cardiovasculares van desde la hipertensión arterial hasta la cardiomiopatía acromegálica, y resultan de la exposición crónica a valores elevados de GH y de IGF-1. La fisiopatología de estas complicaciones es compleja e incluye tanto un aumento en la reabsorción tubular de sodio como efectos directos de la GH y del IGF-1 sobre el endotelio vascular y las células cardiacas. Con frecuencia estas alteraciones cardiovasculares ocurren simultáneamente con trastornos metabólicos como la diabetes y trastornos respiratorios como la apnea del sueño, y son agravadas por ellos. En esta breve revisión se analizan la fisiopatología, las manifestaciones clínicas y el manejo de las complicaciones cardiovasculares de la acromegalia.

[Surgical treatment in acromegaly: experience in Córdoba]. / Tratamiento quirúrgico en acromegalia: experiencia en Córdoba

Introduction: Acromegaly prevalence is 35-70 / million. Transsphenoidal surgery is the first-line treatment, with a remission rate of 80% for microadenomas and 50% for macroadenomas. Our aim was to evaluate the surgical results in Córdoba and determine predictive remission factors due to the lack of records. Methods: Retrospective-descriptive study of patients with surgery as the first therapeutic line. Remission criteria: IGF1 normalization for age/sex, with GH ≤1.0 g/L. Test X2 and Fisher's exact test with p<0.05. Results: 38 patients were included: 61% women and 39% men; Average age 45 years. Most frequent chief complaint: headache and acral growth (26%), visual disturbances (20%). Macroadenomas were the 84% of the tumors. Of 37 patients, 54% underwent microscopic surgery, 38% endoscopic and 8% transcranial. The 29% of patients showed post-operative complications and diabetes insipidus was the most frequent (10%). The percentage of them was: 33% transcranial surgery, 29% endoscopic and 25% microscopic (p = 0.557). The biochemical remission at 6 months was 34% and at 12 months 55% (p= 0.0001). No significant differences between the endoscopic and microscopic approach (p = 0.071). Of 36 patients, 31% showed complete tumor resection. The subjective clinical improvement was 88%. There weren´t predictive remission factors with significant differences. Conclusion: The surgical biochemical remission was similar to the bibliography. We didn´t find predictive remission factors but a larger number of patients could modify these results.

Introducción: La acromegalia tiene una prevalencia de 35-70/millón. La cirugía transesfenoidal es el tratamiento de elección, siendo la tasa de remisión del 80% en microadenomas y 50% en macroadenomas. Debido a la falta de registros, nos propusimos evaluar los resultados quirúrgicos en Córdoba y determinar factores predictivos de remisión. Métodos: Estudio retrospectivo-descriptivo de pacientes con cirugía como primera línea terapéutica. Criterios de remisión: normalización de IGF1 para edad/sexo, con GH ≤1,0 g/L.Test X2 y test exacto de Fisher y p<0,05. Resultados: Se incluyeron 38 pacientes: 61% mujeres y 39% hombres; edad promedio 45 años. Motivos de consulta más frecuentes: cefalea y crecimiento acral (26%), alteraciones visuales (20%). El 84% de los tumores fueron macroadenomas. De 37 pacientes, 54% se sometieron a cirugía microscópica, 38% endoscópica y 8% transcraneal. El 29% evidenció complicaciones postquirúrgicas, siendo la diabetes insípida la más frecuente (10%). El porcentaje de las mismas fue: cirugía transcraneal el 33%, endoscópica 29% y microscópica 25% (p= 0,557). La remisión bioquímica a los 6 meses fue de 34% y a los 12 meses 55% (p=0,0001). Sin diferencias significativas entre la vía endoscópica y microscópica (p=0,071). De 36 pacientes el 31% evidenció resección tumoral completa. La mejoría clínica subjetiva fue del 88%. No hubo factores predictivos de remisión bioquímica estadísticamente significativos. Conclusión: La remisión bioquímica con la cirugía fue similar a la bibliografía. No encontramos factores predictivos de remisión pero un número mayor de casos podría modificar estos resultados.

Surgical and Pharmacological Outcomes in Acromegaly: Real-Life Data From the Mexican Acromegaly Registry.

CONTEXT: Acromegaly registries constitute a valuable source of therapeutic outcome information in real-life. OBJECTIVE: The objective of this work is to analyze surgical and pharmacological outcomes in the Mexican Acromegaly Registry (MAR). DESIGN AND METHODS: Data were extracted from the MAR informatic platform. Surgical remission was defined by a postoperative postglucose (GH) of less than 1 ng/mL and an insulin-like growth factor 1 (IGF-1) of less than 1.2 × upper limit of normal (ULN). Pharmacological remission was defined by a basal GH of less than 1 ng/mL and an IGF-1 of less than 1.2 × ULN. RESULTS: A total of 650 surgical outcomes were analyzed (94.6% transsphenoidal). Surgical remission was achieved in 40.15%, whereas 44.15% remained biochemically active. Persistently active disease after surgery was significantly associated with harboring an invasive macroadenoma, a basal GH of greater than 10 ng/mL, and/or an IGF-1 of greater than 2 × ULN at diagnosis on bivariate and multivariate analysis. The outcome of monotherapy with first-generation somatostatin analogs (SSAs) was evaluated in 267 patients (adjunctive in 65%), of whom 28.4% achieved remission. Persistently active disease was significantly associated with harboring an invasive macroadenoma as well as with pretreatment basal GH and IGF-1 levels of greater than 10 ng/mL and greater than 2 × ULN, respectively, on bivariate and multivariate analysis. Combined therapy with SSA and cabergoline was analyzed in 100 patients, of whom 19% achieved remission and 44% remained active; in this subset of patients, only a pretreatment IGF-1 of greater than 2 × ULN was significantly associated with persistent disease activity. CONCLUSION: Surgical and pharmacological outcomes in acromegaly are highly dependent on tumor size/invasiveness as well as on the degree of hypersomatotropinemia.

Differentiated thyroid carcinoma in sporadic and familial presentations of acromegaly: A case series.

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.

[Clinical and genetic studies of a three-member familial isolated pituitary adenoma with homogeneous prolactinomas]. / Estudios clínicos y genéticos en tres miembros de una familia afectados con adenomas hipofisarios aislados con prolactinomas homogéneos.

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.

La mayoría de los adenomas hipofisarios son esporádicos, pero un 3-5% puede ocurrir en un contexto familiar y hereditario. Este es el caso de la neoplasia endocrina múltiple de tipo 1 (NEM1), complejo de Carney (CNC) y adenomas hipofisarios aislados familiares (FIPA). El FIPA es una condición infrecuente, que ocurre en un contexto familiar, no asociada a NEM t ipo1 ni CNC. Los FIPA pueden ser homogéneos (todos los adenomas tienen el mismo fenotipo) o heterogéneos (diferente fenotipo tumoral). Describimos una familia congolesa en la que dos hermanas y una prima fueron diagnosticadas a los 29, 32 y 40 años, respectivamente, con un prolactinoma (FIPA homogéneo). Las pacientes presentaron macroadenomas no invasivos al momento del diagnóstico, con buena respuesta biológica y tumoral al tratamiento con cabergolina hasta una dosis máxima de 1.5 mg/semanal. De las dos hermanas, una cursó un embarazo sin complicaciones. Durante el seguimiento de 12 años, ninguna de ellas presentó elementos clínicos o biológicos compatibles con NEM1 o CNC, por lo que dichos genes no se estudiaron. El análisis genético en dos de las pacientes permitió descartar la posibilidad de una mutación germinal del gen aryl hydrocarbon receptor interacting protein (AIP). Se considera que el 80% de los pacientes con FIPA no presentan mutación del gen AIP, por lo que se requieren futuros estudios en este tipo de familias, para poder determinar otros genes afectados involucrados en su fisiopatología.

Estudios clínicos y genéticos en tres miembros de una familia afectados con adenomas hipofisarios aislados con prolactinomas homogéneos / Clinical and genetic studies of a three-member familial isolated pituitary adenoma with homogeneous prolactinomas

La mayoría de los adenomas hipofisarios son esporádicos, pero un 3-5% puede ocurrir en un contexto familiar y hereditario. Este es el caso de la neoplasia endocrina múltiple de tipo 1 (NEM1), complejo de Carney (CNC) y adenomas hipofisarios aislados familiares (FIPA). El FIPA es una condición infrecuente, que ocurre en un contexto familiar, no asociada a NEM t ipo1 ni CNC. Los FIPA pueden ser homogéneos (todos los adenomas tienen el mismo fenotipo) o heterogéneos (diferente fenotipo tumoral). Describimos una familia congolesa en la que dos hermanas y una prima fueron diagnosticadas a los 29, 32 y 40 años, respectivamente, con un prolactinoma (FIPA homogéneo). Las pacientes presentaron macroadenomas no invasivos al momento del diagnóstico, con buena respuesta biológica y tumoral al tratamiento con cabergolina hasta una dosis máxima de 1.5 mg/semanal. De las dos hermanas, una cursó un embarazo sin complicaciones. Durante el seguimiento de 12 años, ninguna de ellas presentó elementos clínicos o biológicos compatibles con NEM1 o CNC, por lo que dichos genes no se estudiaron. El análisis genético en dos de las pacientes permitió descartar la posibilidad de una mutación germinal del gen aryl hydrocarbon receptor interacting protein (AIP). Se considera que el 80% de los pacientes con FIPA no presentan mutación del gen AIP, por lo que se requieren futuros estudios en este tipo de familias, para poder determinar otros genes afectados involucrados en su fisiopatología.

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.

[Prognostic value of granular pattern of growth hormone secreting tumors]. / Caracterización de tumores secretores de hormona de crecimiento de acuerdo al patrón granular y su rol en el pronóstico.

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.

Pituitary gigantism: a case series from Hospital de San José (Bogotá, Colombia).

INTRODUCTION: Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. MATERIALS AND METHODS: Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. RESULTS: All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. CONCLUSIONS: This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.

Pituitary gigantism: a case series from Hospital de San José (Bogotá, Colombia)

ABSTRACT Introduction Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. Materials and methods Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. Results All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. Conclusions This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.

Caracterización de tumores secretores de hormona de crecimiento de acuerdo al patrón granular y su rol en el pronóstico / Prognostic value of granular pattern of growth hormone secreting tumors

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.

Silent pituitary plurihormonal adenoma: clinical relevance of immunohistochemical analysis / Adenoma hipofisario silente plurihormonal: relevancia clínica de la inmunohistoquímica

Background: Non-functional pituitary adenomas (NFPAs) present low growth rates; however, some are aggressive and invasive. In 2017 the World Health Organization recognized clinically aggressive adenomas as "high-risk pituitary adenomas". These include the sparsely granulated somatotroph adenoma, the Crooke's cell adenoma, the silent corticotroph adenoma and the plurihormonal Pit-1-positive adenoma (subtype 3). Clinical case: 25-year-old woman who presented oligomenorrhea, increased weight, decreased visual acuity and chronic headache. Biochemical and imaging evaluation showed a NFPA. Transsphenoidal surgery was performed with complete resection of lesion, and during short-term follow-up it was observed recurrence, which is why the patient needed two more interventions. The immunohistochemistry reported: ACTH ++ 90%, prolactin ++ 20%, GH ++ 5%, CKAE1-AE3 +++ 90%, Ki-67 10%. The final diagnosis was plurihormonal adenoma, since the immunohistochemical analysis was positive for more than one pituitary hormone and suggested two distinct cell lineages: Pit-1 and Tpit, both recognized as aggressive adenomas. Conclusions: This case report highlights the significance of a comprehensive immunohistochemical study, which includes transcriptional factors to classify cell lineage, in order to predict aggressiveness and provide personalized treatment.

Introducción: los adenomas hipofisarios no funcionantes (AHNF) presentan una baja tasa de crecimiento; sin embargo, algunos son agresivos e invasivos. En 2017 la Organización Mundial de la Salud denominó los adenomas de comportamiento clínico agresivo como "tumores hipofisarios de alto riesgo", incluyendo los adenomas del somatotropo escasamente granulados, los adenomas de células de Crooke, los silentes de corticotropo y los adenomas plurihormonal Pit-1 positivo (subtipo 3). Caso clínico: mujer de 25 años de edad con oligoamenorrea, aumento de peso, disminución del campo visual y cefalea crónica. La evaluación bioquímica y de imagen correspondió a un AHNF. Se realizó cirugía transesfenoidal con resección completa de la lesión y durante el seguimiento a corto plazo se observó recurrencia tumoral, por lo que ameritó dos intervenciones más. La inmunohistoquímica reportó: ACTH ++ 90%, prolactina ++ 20%, GH ++ 5%, CKAE1-AE3 +++ 90%, Ki-67 10%. El diagnóstico definitivo correspondió a un adenoma plurihormonal, debido a que la inmunohistoquímica fue positiva para la expresión de más de una hormona hipofisaria, con sugerencia de contenido celular con dos linajes distintos, tanto de Pit-1 como de Tpit, ambos reportados como adenomas agresivos. Conclusiones: este caso resalta la importancia de una inmunohistoquímica completa que incluya factores de transcripción que permitan clasificar el linaje celular para predecir agresividad y proporcionar un tratamiento individualizado.