Long-term outcome after bilateral adrenalectomy in Cushing's disease with focus on Nelson's syndrome

ABSTRACT Objective We analyzed the clinical, biochemical, and imaging findings of adrenalectomized patients with Cushing's disease (CD) in order to compare the characteristics of those who developed Nelson's syndrome (NS) versus those who did not develop this complication (NNS), aiming to identify possible predictive factors for its occurrence. Subjects and methods We performed a retrospective review of the clinical records of a group of patients with CD who underwent TBA between 1974 and 2011. Results Out of 179 patients with CD, 13 (7.3%) underwent TBA. NS occurred in 6 of them (46%) after a mean of 24 months from the total bilateral adrenalectomy (TBA). Age at diagnosis, duration of Cushing's syndrome (CS) until TBA, and steroid replacement doses were similar in both groups. Initial urinary cortisol levels (24-hour urinary free cortisol [UFC]) were significantly higher in the NS group than in the NNS group (p = 0.009). Four patients in the NS group and three of those in the NNS group received radiotherapy before TBA (p = 0.26). Three patients in the NS group presented residual tumors before TBA, compared with none in the NNS group (p = 0.04). At 1 year after TBA, the median ACTH level was 476 ng/L (240-1500 ng/L) in the NS group and 81 ng/L (48-330 ng/L) in the NNS group (p = 0.0007). Conclusion In conclusion, a residual tumor before TBA, higher 24-hour UFC at diagnosis, and increasing ACTH levels within 1 year after TBA emerged as predictive factors of development of NS.

Pegvisomant in acromegaly: a multicenter real-life study in Argentina

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

Prolactinomas: evolution after menopause

ABSTRACT Objetive The aim was to assess the evolution of tumor size and prolactin (PRL) levels in patients with micro and macroprolactinomas diagnosed and treated with dopamine agonists during fertile age, and the effects of suspension of drugs after menopause. Retrospective study, 29 patients with prolactinomas, 22 microadenomas and 7 macroadenomas, diagnosed during their fertile age were studied in their menopause; treatment was stopped in this period. Age at menopause was 49 ± 3.6 years. The average time of treatment was 135 ± 79 months. The time of follow-up after treatment suspension was 4 to 192 months. Results Pre-treatment PRL levels in micro and macroadenomas were 119 ± 57 ng/mL and 258 ± 225 ng/mL, respectively. During menopause after treatment suspension, and at the latest follow-up: in microadenomas PRL levels were 23 ± 13 ng/mL and 16 ± 5.7 ng/mL, respectively; in macroadenomas, PRL levels were 20 ± 6.6 ng/mL 5t5and 25 ± 18 ng/mL, respectively. In menopause after treatment suspension, the microadenomas had disappeared in 9/22 and had decreased in 13/22. In the group of patients whose tumor had decreased, in the latest follow-up, tumors disappeared in 7/13 and remained unchanged in 6/13. In macroadenomas, after treatment suspension 3/7 had disappeared, 3/7 decreased and 1/7 remained unchanged. In the latest control in the 3 patients whose tumor decreased, disappeared in 1/3, decreased in 1/3 and there was no change in the remaining. Conclusions Normal PRL levels and sustained reduction or disappearance of adenomas were achieved in most of patients, probably due to the decrease of estrogen levels. Dopamine agonists might be stopped after menopause in patients with prolactinomas.

Pseudo-tumor pituitario e hipopituitarismo secundario a un papiloma invertido del seno esfenoidal / Pseudo-pituitary tumor and hypopituitarism secondary to a sphenoid sinus inverted papilloma

El papiloma invertido (PI) es un tumor epitelial benigno, poco frecuente, que se origina mayormente de la pared nasal lateral. A pesar de ser benigno, constituye una lesión altamente invasiva de tejidos vecinos y puede sufrir una transformación maligna. El PI primario del seno esfenoidal con extensión intracraneana e invasión dural, aun sin evidencia histológica de malignidad, ha sido excepcionalmente descrito. Describimos el caso de una mujer de 59 años de edad que fue evaluada por cefaleas intensas de 5 años de evolución y anormalidades del campo visual. Una resonancia magnética nuclear (RMN) mostró una masa selar heterogénea de 1.4 por 2 cm con extensión supraselar y al seno esfenoidal, con erosión del piso selar y compresión del quiasma óptico. Recibió 16 mg/día de prednisona durante aproximadamente 3 meses con una regresión casi total de la masa en la RMN. En la evaluación hormonal se halló insuficiencia gonadal, tiroidea y adrenal central. En una nueva RMN se observó crecimiento del tumor con compromiso total del seno esfenoidal. Una biopsia endoscópica confirmó el diagnóstico de PI. Se realizó una cirugía sinusal transnasal endoscópica con una resección completa evidenciada en una RMN un año más tarde.

nverted papilloma (IP) is a benign uncommon epithelial tumor, arising mostly from the lateral nasal wall. Though benign, this lesion is highly invasive into surrounding tissues and malignant transformation may occur. Primary IP of the sphenoid sinus and intracranial extension with dural invasion, even without histological evidence of malignancy, has only rarely been described. Hypopituitarism as a complication of this lesion has never been reported. We describe the case of a 59-year-old woman who was evaluated because of a 5-year-history of severe headaches and abnormalities in the visual field. Magnetic resonance imaging (MRI) showed a 1.4 per 2.0 cm heterogeneous sellar lesion with suprasellar and sphenoid sinus extension, eroding the sellar floor with optic chiasm compression. Otolaryngologists gave her 16 mg/day of prednisone during approximately 3 months with a near total regression of the mass on MRI. The endocrine biochemical evaluation showed pituitary gonadal, thyroid and adrenal insufficiency. A new MRI showed growth of the tumor with obliteration of the sphenoid sinus. An endoscopic sinus biopsy revealed an IP, so a transnasal endoscopic sinus surgery was performed with complete resection evidenced by MRI a year later.

Análisis de un registro de adenomas pituitarios / Analysis of a pituitary adenoma registry

Dada la complejidad que reviste el enfoque diagnóstico y terapéutico de los tumores pituitarios, el registro y análisis de la experiencia clínica acumulada es de gran ayuda en la toma de decisiones. En este trabajo se informan datos clínico-terapéuticos, extraídos de un registro computarizado, sobre 519 de un total de 670 pacientes con adenomas pituitarios. Trescientos cuarenta y cinco fueron mujeres (66%) y 174 varones (34%), de 14 a 80 años de edad. El diagnóstico final fue: acromegalia en 176, enfermedad de Cushing en 153, prolactinoma en 101 y adenoma clínicamente no-funcionante (ANF) en 89. La edad media al momento del diagnóstico de acromegalia fue 43.9 ± 13.5 (16-80), para enfermedad de Cushing 35.7 ± 12.9 (14-72), para prolactinomas 30.0 ± 13.4 (15-79) y para ANF 52.1 ± 15.2 (17-79) años. La creación de un registro institucional de tumores de hipófisis es un instrumento de gran utilidad para el análisis de la experiencia adquirida y constituye una herramienta valiosa para mejorar la estrategia terapéutica, optimizar la relación costo/beneficio y mejorar el cuidado del paciente. Contribuye a la docencia médica, tanto en el pre como en el posgrado y da base a la realización de trabajos de investigación clínica, aportando a la difusión y transferencia de conocimientos.

Collection and analysis of data obtained during the clinical treatment of pituitary tumours are of great utility in the decision making process, when facing clinical situations. We report here data on 519 from 670 patients with pituitary adenomas obtained from a computerized registry. Three hundred and forty five were females (66%) and 174 males (34%), aged 14-80. Final diagnosis was acromegaly in 176, Cushing's disease in 153, prolactinoma in 101 and clinically non-functioning adenoma in 89. Mean age at diagnosis was 43.9 ± 13.5 (16-80) for acromegalics, 35.7 ± 12.9 (14-72) for Cushing's, 30.0 ± 13.4 (15-79) for prolactinoma and 52.1 ± 15.2 (17-79), for non-functioning tumours. The setup of an institutional registry on pituitary tumours constitutes a useful tool to analyze clinical experience, optimize the cost/benefit ratio of procedures used for diagnosis and to ameliorate therapeutic strategies, improving patient's care. It greatly contributes to teaching medical students as well as to post-graduate physicians and provides a basis for developing clinical research.

Enfoque terapéutico en 154 pacientes con acromegalia / Therapeutic management in 154 acromegalic patients

La acromegalia es una enfermedad poco frecuente producida en más del 95% de los casos por un tumor hipofisario secretor de hormona de crecimiento (GH). Las manifestaciones clínicas están asociadas a síntomas locales por crecimiento del tumor o a las consecuencias orgánicas y metabólicas secundarias a la hipersecreción de GH. Debido a la alta morbilidad y mortalidad asociadas a la acromegalia, un tratamiento individualizado y optimizado para cada paciente es fundamental. Informamos el enfoque terapéutico de nuestro servicio de endocrinología en la atención de 154 pacientes con acromegalia. Utilizando criterios bioquímicos estrictos, con la cirugía logramos un 32% de remisión global, tasa relativamente baja debido fundamentalmente a que la mayor parte de los pacientes presentaban macroadenomas con un alto porcentaje de invasividad local. Con radioterapia complementaria o como tratamiento inicial se logró la remisión en el 65.4% de los pacientes irradiados. El 14.0% de los pacientes controlaron la enfermedad utilizando agonistas dopaminérgicos solos o combinados con otra droga, mientras que aquellos que utilizaron análogos de la somatostatina normalizaron los parámetros bioquímicos en un 45.7% de los casos. En conclusión, con los diferentes tratamientos utilizados obtuvimos el control de la acromegalia en el 55.2% de los casos, esperando optimizar el tratamiento de estos pacientes en la medida en que contemos con y tengamos acceso a nuevas herramientas terapéuticas.

Acromegaly is a chronic, invalidating disease due in over 95% of cases to a growth hormone (GH) secreting pituitary adenoma. Its clinical manifestations are associated to local complications related to the tumor growth and/or to the metabolic consequences of GH excess. We report here our experience on 154 acromegalic patients. Surgical remission rate using stringent biochemical criteria was 32%, a figure relatively low due to the great number of patients bearing macroadenomas with invasive complications. Primary or adjuvant radiotherapy was able to obtain normalization of biochemical parameters in as much as 65.4% of treated patients. In only 14.0% of acromegalics drug therapy with dopaminergic agents was effective in controlling the disease. By contrast, somatostatinergic analogues were more effective, obtaining a clinical and biochemical remission in 45.7% of the patients. In summary, multimodal therapy of acromegaly can lead to a global safe control of the disease in 55.2% of the cases. The ongoing development of new drugs represents promising alternatives in the management of this disabling condition.

High prevalence of thyroid disorders in relatives of patients with familial papillary thyroid cancer / Elevada prevalencia de alteraciones tiroideas en familiares de pacientes con diagnóstico de carcinoma papilar familiar

In the familial form of papillary thyroid cancer (PTC), two or more members of the same family have to be affected with PTC. Prevalence is around 5% of all PTC. We performed a clinical analysis in 79 relatives of 16 patients of 7 unrelated kindred with the diagnosis of familial papillary thyroid carcinoma (FPTC). The results were compared with a control group. Thyroid palpation and TSH and TPO-Ab assessment was carried out in the relatives without a diagnosed PTC. Additionally, molecular analysis was performed in the sixteen affected patients. Clinical screening of the 79 family members showed the presence of goiter in 22/79 (29 %). This frequency was much higher than that observed in the control group (8.7%), p < 0.001. Hypothyroidism was found in 4 of the relatives (5%) vs. 2.5% observed in the control group, p < 0.01, and anti-thyroid antibodies (TPO-Ab) were positive in 14% of the relative's group vs. 10 % in the control group, (p = NS). In the molecular analysis, only a protooncogene TRK rearrangement was observed in family # 6. In conclusion, we found a higher incidence of goiter and hypothyroidism in the relatives of patients with FPTC. Nevertheless, TPO-Ab frequency was not different. No molecular abnormalities were indicative of a specific pattern in this subset of patients with FPTC.

En la forma familiar del carcinoma papilar de tiroides (CPT), dos o más miembros de la misma familia deben presentar CPT. Esta entidad ocurre en aproximadamente el 5% de todos los CPT. En este estudio, realizamos una evaluación de 79 familiares de 16 pacientes con diagnóstico de carcinoma papilar familiar (CPF) provenientes de 7 familias diferentes. Los resultados se compararon con los hallados en un grupo control. Se realizó palpación tiroidea y medición de TSH y anticuerpos anti-tiroperoxidasa (TPO-Ab) en todos los familiares. Además, se llevó a cabo el análisis molecular en los 16 sujetos que presentaban el diagnóstico de CPF. La evaluación de los 79 familiares de estos pacientes demostró la presencia de bocio en 22/79 (29%). Esta frecuencia fue mucho mayor que la observada en el grupo control (8.7%), p < 0.001. Se diagnosticó hipotirodismo en 4 familiares (5%) vs. 2.5%, observado en el grupo control, p < 0.01, y los TPO-Ab fueron positivos en 14% de los familiares vs. 10% del grupo control, (p = ns). En el análisis molecular, solamente se halló un rearreglo del protoncogen TRK en una de las 7 familias con CPF. En conclusión, hallamos una elevada prevalencia de bocio e hipotiroidismo en los familiares de pacientes con CPT. Sin embargo, la frecuencia de autoinmunidad no fue diferente. No se hallaron alteraciones moleculares distintivas en estos pacientes con CPF.

La corrección de la sustitución excesiva de cortisol mejora la morbilidad en pacientes con hipopituitarismo: un estudio piloto / Correction of Cortisol Overreplacement Ameliorates Morbidities in Patients with Hypopituitarism: A pilot study

Context: Hyporituitarism in adults is known to be associated with deleterious effects on body composition, lipid profile and quality of life (QoL). This was attributed to GH deficiency. The potential role of glucocorticoid overreplacement had never been investigated. Objective: To investigate whether reduction in glucocorticoid replacement dose to more physiological one could ameliorate the "AO-GHD"-attributed symptomatology in patients with hypopituitarism. Design: Eleven patients with panhypopituitarism taking 20-30 mg/day of hydrocortisone, but on no GH replacement were switched to 10 to 15 mg of hydrocortisone daily. Both basally and 6-12 months later, their body mass index, body composition by dual-energy x-ray absorptiometry, lipid profile, and the score of quality of life, QOL-AGHDA were measured. Results: Within 6-12 months of lower hydrocortisone dose, subjects lost an average of 7.1 kg of total body fat and 4.1 kg of abdominal fat. No changes were seen in lean body mass, bone mineral content and HOMA-IR Plasma total cholesterol and triglyceride concentrations decreased significantly (<0.05) and the QoL improved (p=0.018). Conclusions: Our pilot study suggests that decreasing the glucocorticoid replacement dose to ~ 15 mg/ day is beneficial in terms of patients' body composition, lipid profile and quality of life.

Biomarcadores de aterosclerosis e indicadores de resistencia insulínica en pacientes acromegálicos no diabéticos / Biomarkers of Atherosclerosis and Indicators of Insulin Resistance in Non-Diabetic Acromegalic Patients

Introducción En la acromegalia, las comorbilidades cardiovasculares, respiratorias y metabólicas contribuyen a un aumento significativo de la mortalidad de los pacientes afectados. Asimismo, una proporción elevada de estos pacientes presentan diabetes mellitus. Pese a que el hallazgo de un perfil lipídico y lipoproteico anormal en pacientes acromegálicos suele ser habitual, cuando se intenta identificar y/o establecer el grado de modificaciones de parámetros específicos, los resultados son controversiales. Objetivos Evaluar la presencia de biomarcadores de aterosclerosis en pacientes con acromegalia activa no diabéticos y su asociación con la hormona del crecimiento (GH) y el factor de crecimiento similar a la insulina tipo 1 (IGF-1). Material y métodos Se estudiaron 14 pacientes y 14 controles sanos pareados por sexo y edad. Se midieron las concentraciones de GH e IGF-1 por inmunoensayos. Se evaluaron indicadores de resistencia insulínica (glucosa, insulina y HOMA), perfil lipoproteico, niveles plasmáticos de lipoproteínas de baja densidad oxidadas (LDLox), moléculas de adhesión celular vascular 1 (VCAM-1), endotelina-1 y actividad de fosfolipasa A2 asociada con lipoproteínas (LpPLA2). Resultados En comparación con los controles, los pacientes presentaron aumentos de GH (p < 0,05) e IGF-1 (p < 0,001), de los indicadores de resistencia insulínica (insulina p < 0,001; HOMA p < 0,001), triglicéridos (p < 0,05), apo B (p < 0,001), LDLox (117 ± 20 versus 89 ± 23 U/ L; p < 0,05) y endotelina-1 (0,9 ± 0,2 versus 0,7 ± 0,2 pg/ml; p < 0,05). Más aún, la GH y el IGF-1 se asociaron positivamente con (r; p <) insulina (0,40; 0,05 y 0,73; 0,001), HOMA (0,39; 0,05 y 0,74; 0,001), triglicéridos (0,57; 0,05 y 0,64; 0,001), colesterol de lipoproteínas de muy baja densidad (C-VLDL) (0,54; 0,05 y 0,47; 0,05), apo B (0,40; 0,05 y 0,54; 0,05), LDLox (0,59; 0,05 y 0,66; 0,05) y endotelina-1 (0,55; 0,05 y 0,51; 0,05). Conclusiones Los pacientes con acromegalia activa no diabéticos presentaron un estado de resistencia insulínica, así como modificaciones sutiles en el perfil lipoproteico y concentraciones elevadas de LDLox y endotelina-1. Las alteraciones descriptas podrían contribuir a un estado de mayor propensión al desarrollo de enfermedad cardiovascular aterosclerótica, la cual se sumaría a la miocardiopatía específica de la acromegalia.

Background Cardiovascular, respiratory and metabolic comorbidities associated with acromegaly contribute to a significant increase in the mortality of this disease. Many of these patients are also diabetic. Although it is frequent to find abnormal lipid and lipoprotein profiles in patients with acromegaly, controversial outcomes arise in an attempt to identify and/or establish the degree of the modifications of specific parameters. Objectives To assess the presence of biomarkers of atherosclerosis in non-diabetic patients with active acromegaly and its association with growth hormone (GH) and with insulin-like growth factor type 1 (IGF-1). Material and Methods The study included 14 patients and 14 healthy controls, pared by sex and age. Serum concentration of GH and IGF- 1 were determined by immunoassays. Indicators of insulin resistance (glucose, insulin and HOMA) were measured, as well as lipoprotein profile, plasmatic levels of oxidized LDL (oxLDL), vascular cell adhesion molecule 1 (VCAM-1), endothelin-1 and lipoprotein-associated phospholipase A2 activity (LpPLA2). Results Compared to controls, non-diabetic acromegalic patients had increased levels of GH (p<0.05) and IGF-1 (p<0.001), of indicators of insulin resistance (insulin p<0.001; HOMA p<0.001), triglycerides (p<0.05), apo B (p<0.001), oxLDL (117±20 versus 89±23 U/L; p<0.05) and endothelin-1 (0.9±0.2 versus 0.7±0.2 pg/ml; p<0.05). In addition, GH and IGF-1 were positively associated with (r; p <) insulin (0.40; 0.05 and 0.73; 0.001), HOMA (0.39; 0.05 and 0.74; 0.001), triglycerides (0.57; 0.05 and 0.64; 0.001), very low density lipoprotein-cholesterol (VLDL-C) (0.54; 0.05 and 0.47; 0.05), apo B (0.40; 0.05 and 0.54; 0.05), oxLDL (0.59; 0.05 and 0.66; 0.05) and endothelin-1 (0.55; 0.05 and 0.51; 0.05). Conclusions Non-diabetic patients with active acromegaly presented an insulin-resistant status, as well as subtle modifications of lipid profile and increased levels of oxLDL and endothelin- 1. These alterations could explain why these patients are more likely to develop atherosclerotic cardiovascular disease in addition to acromegalic cardiomyopathy.