[Pituitary metastases: a diagnostic and therapeutic challenge]. / Metástasis hipofisarias: un desafío diagnóstico y terapéutico.

INTRODUCTION: Sellar metastases (SM) are rare manifestations of malignancy. Breast and lung cancer are the most common primary tumors. Most cases are diagnosed in patients with advanced malignant disease; however, symptoms of pituitary involvement can precede the diagnosis of the primary tumor. METHODS: Retrospective analysis of symptoms at presentation, hormonal, radiological and histological findings, management, and outcome of patients with SM from 2009 to 2020. RESULTS: Eighteen patients'cases were included, 11 with histological confirmation. Median (m) age was 53 years (range 35-75), 53% male. Primary malignant tumors: 8 lungs, 6 breast, 1 follicular thyroid carcinoma, 1 Hodgkin lymphoma, and 2 clear cell renal carcinomas. The m time between the diagnosis of the primary neoplasm and the occurrence of the SM was 108 months (range: 11-180). In 8 patients the diagnosis of the primary neoplasm was made after the finding of the symptomatic sellar mass. Insipidus diabetes, adenohypophysis deficit, visual disorders, headache, and cranial nerve deficits were evident in 78, 77, 61, 39 and 39% of the cases, respectively. Fifteen patients harbored supra / parasellar masses, in three a lesion was limited to the pituitary gland, and stalk. Eleven out of 18 (61.1%) of the patients were operated on by the trans-sphenoidal approach, for diagnostic and / or decompressive purposes. Eighteen died, with a median survival time of 6 months (1-36). DISCUSSION: In the presence of a pituitary lesion with diffuse gadolinium uptake, associated with insipidus diabetes and / or visual disorder SM should be suspected even in patients without a history of oncological disease.

Introducción: La región selar es un sitio infrecuente de metástasis, encontrándose en el 1% de las cirugías hipofisarias. Los tumores primarios más habituales son mama y pulmón. En general son diagnosticadas en pacientes con enfermedad avanzada, aunque pueden ser el debut de la enfermedad oncológica. Métodos: Análisis retrospectivo de las características clínicas, bioquímicas, radiológicas de pacientes con metástasis selares o hipofisarias (MS) durante el periodo 2009-2020. Resultados: Se reportaron 18 casos de pacientes, 11 de ellos con confirmación histológica. La mediana de edad fue 53 años (rango: 35-75), 53% hombres. La localización del tumor primario fue: 8 pulmón, 6 mama, 1 carcinoma folicular de tiroides, 1 linfoma Hodgkin y 2 carcinomas renales de células claras. La media de tiempo entre el diagnóstico del tumor primario y la aparición de la MS -en los casos de presentación metacrónica- fue 108 meses (rango: 11-180). En 8 pacientes (44.4%), el diagnóstico de la neoplasia primaria se hizo a partir del hallazgo de la masa selar. Diabetes insípida, hipopituitarismo, trastornos visuales, oftalmoplejía y cefalea se presentaron en el 78, 77, 61, 39 y 39%, respectivamente. Quince pacientes presentaron masas con extensión supra/paraselar; y 3 lesión limitada a la hipófisis y tallo. Fueron operados 11/18 por vía transesfenoidal, para diagnóstico y/o descompresión. Fallecieron 17, con una mediana de sobrevida de 6 meses (1- 36). Discusión: La sospecha de MS debe estar presente ante una masa selar y supraselar con captación difusa del gadolinio, diabetes insípida, hipopituitarismo y/o disfunción visual, aun en pacientes sin antecedentes oncológicos.

Hipofisitis primaria: diagnóstico y tratamiento. estudio multicéntrico / Primary hypophysitis: diagnosis and treatment multi-center study

Resumen Introducción : La hipofisitis es una enfermedad in frecuente que plantea un desafío en el diagnóstico y tratamiento. El objetivo de este estudio multicéntrico y retrospectivo fue describir: a) características de pa cientes con hipofisitis primaria (HP), b) métodos diag nósticos, y c) tratamientos realizados. Además, evaluar: a) presentación clínica, b) bioquímica, c) radiológica, d) oftalmológica al diagnóstico y evolución según el tratamiento recibido. Métodos : Estudio retrospectivo donde se estudiaron 28 pacientes (23 mujeres/5 varones) con HP, edad pro medio de 38±11.1 años. Resultados . Los síntomas fueron: cefalea: 68%, po liuria-polidipsia: 50% y alteraciones visuales: 48%. El examen de laboratorio inicial informó disfunción ade nohipofisaria en 71% de los pacientes, siendo el eje gonadal el más afectado. Los hallazgos radiológicos más frecuentes fueron: lesión simétrica:78.5%, aumento homogéneo post contraste: 78.5% y engrosamiento de tallo:70%. En 4/23 mujeres (17%) se relacionó con em barazos o puerperio La conducta inicial fue expectante (CE) en 14 pacientes, cirugía de resección/descompresión en 8 y tratamiento con inmunosupresores en 6. Quince pacientes tuvieron confirmación histológica, 9 resulta ron hipofisitis linfocitaria, 5 hipofisitis por IgG4 y una xantomatosa. Trece fueron diagnosticados por criterios clínicos establecidos. El tamaño de la lesión disminuyó en 43% de pacientes con CE, 62.5% con cirugía y 50% con inmunosupresores. Los síntomas compresivos mejora ron en los 3 grupos, con escaso efecto sobre la función adenohipofisaria, sin resolución de la diabetes insípida. Discusión : En pacientes sin síntomas compresivos adoptamos CE. En aquellos pacientes sin certeza diag nóstica o con síntomas compresivos graves, se optó por cirugía transesfenoidal.

Abstract Introduction : Primary hypophysitis (PH) is a rare disease that represents a challenge among differential diagnosis and management. Our aim was to describe clinical characteristics, diagnostic criteria and different treatment outcomes in patients with PH. Multicentric, retrospective study. Clinical presentation, endocrine function, magnetic resonance imaging findings, visual field defects at diagnosis and treatment outcomes were recorded. Methods : Twenty-eight patients (23 women), with PH were included. Median age: 37. Results : The most frequent symptoms: headache: 68%, polyuria-polydipsia: 50% and visual disturbances: 48%. At diagnosis, anterior pituitary deficiency was present in 71%, being hypogonadotrophic hypogonad ism the most frequent manifestation. The radiological findings: symmetric lesion: 78.5%, homogeneous en hancement: 78.5% and pituitary stalk thickening: 70%. Association with pregnancy or puerperium was found in 4/23 women (17%). Fourteen patients did not receive any treatment ("wait and see" group), 8 underwent surgery for mass reduction or resection and 6 were treated with immunosuppression therapy. Among 15 patients with histopathological diagnosis, 9 were lymphocytic hypophysitis, 5 IgG4 related hypophysitis and 1 xanthomatous hypophysitis. Thirteen were di agnosed by established clinical criteria. Mass reduction was observed in 43% of "wait and see group" patients, 62.5% of operated patients and 50% with immuno suppression therapy. Compressive symptoms showed improvement in the 3 groups, with modest effect on anterior pituitary function, diabetes insipidus did not resolve in any patients. Discussion : In patients without severe compressive symptoms, we adopted a "wait and see" approach. In patients with uncertain diagnosis of PH or severe com pressive symptoms, transsphenoidal surgery was the best option.

[Primary hypophysitis: diagnosis and treatment multicenter study]. / Hipofisitis primaria: diagnóstico y tratamiento. Estudio multicéntrico.

INTRODUCTION: Primary hypophysitis (PH) is a rare disease that represents a challenge among differential diagnosis and management. Our aim was to describe clinical characteristics, diagnostic criteria and different treatment outcomes in patients with PH. Multicentric, retrospective study. Clinical presentation, endocrine function, magnetic resonance imaging findings, visual field defects at diagnosis and treatment outcomes were recorded. METHODS: Twenty-eight patients (23 women), with PH were included. Median age: 37. RESULTS: The most frequent symptoms: headache: 68%, polyuria-polydipsia: 50% and visual disturbances: 48%. At diagnosis, anterior pituitary deficiency was present in 71%, being hypogonadotrophic hypogonadism the most frequent manifestation. The radiological findings: symmetric lesion: 78.5%, homogeneous enhancement: 78.5% and pituitary stalk thickening: 70%. Association with pregnancy or puerperium was found in 4/23 women (17%). Fourteen patients did not receive any treatment ("wait and see" group), 8 underwent surgery for mass reduction or resection and 6 were treated with immunosuppression therapy. Among 15 patients with histopathological diagnosis, 9 were lymphocytic hypophysitis, 5 IgG4 related hypophysitis and 1 xanthomatous hypophysitis. Thirteen were diagnosed by established clinical criteria. Mass reduction was observed in 43% of "wait and see group" patients, 62.5% of operated patients and 50% with immunosuppression therapy. Compressive symptoms showed improvement in the 3 groups, with modest effect on anterior pituitary function, diabetes insipidus did not resolve in any patients. DISCUSSION: In patients without severe compressive symptoms, we adopted a "wait and see" approach. In patients with uncertain diagnosis of PH or severe compressive symptoms, transsphenoidal surgery was the best option.

Introducción: La hipofisitis es una enfermedad infrecuente que plantea un desafío en el diagnóstico y tratamiento. El objetivo de este estudio multicéntrico y retrospectivo fue describir: a) características de pacientes con hipofisitis primaria (HP), b) métodos diagnósticos, y c) tratamientos realizados. Además, evaluar: a) presentación clínica, b) bioquímica, c) radiológica, d) oftalmológica al diagnóstico y evolución según el tratamiento recibido. Métodos: Estudio retrospectivo donde se estudiaron 28 pacientes (23 mujeres/5 varones) con HP, edad promedio de 38±11.1 años. Resultados. Los síntomas fueron: cefalea: 68%, poliuria- polidipsia: 50% y alteraciones visuales: 48%. El examen de laboratorio inicial informó disfunción adenohipofisaria en 71% de los pacientes, siendo el eje gonadal el más afectado. Los hallazgos radiológicos más frecuentes fueron: lesión simétrica:78.5%, aumento homogéneo post contraste: 78.5% y engrosamiento de tallo:70%. En 4/23 mujeres (17%) se relacionó con embarazos o puerperio La conducta inicial fue expectante (CE) en 14 pacientes, cirugía de resección/descompresión en 8 y tratamiento con inmunosupresores en 6. Quince pacientes tuvieron confirmación histológica, 9 resultaron hipofisitis linfocitaria, 5 hipofisitis por IgG4 y una xantomatosa. Trece fueron diagnosticados por criterios clínicos establecidos. El tamaño de la lesión disminuyó en 43% de pacientes con CE, 62.5% con cirugía y 50% con inmunosupresores. Los síntomas compresivos mejoraron en los 3 grupos, con escaso efecto sobre la función adenohipofisaria, sin resolución de la diabetes insípida. Discusión: En pacientes sin síntomas compresivos adoptamos CE. En aquellos pacientes sin certeza diagnóstica o con síntomas compresivos graves, se optó por cirugía transesfenoidal.

Cabergoline treatment in cats with diabetes mellitus and hypersomatotropism.

OBJECTIVES: The aim of this study was to evaluate the safety and efficacy of cabergoline to control hypersomatotropism (HST) and diabetes mellitus (DM) in cats. METHODS: This was a prospective cohort study. Twenty-three cats with HST and concurrent DM were enrolled. Cats received a dose of 10 µg/kg cabergoline q48h PO for 6 months. Serum insulin-like growth factor 1 (IGF-1) and fructosamine concentrations, insulin dose and Insulin Resistance Index (IRI) were measured at the time of diagnosis of HST and at the start of cabergoline treatment (t0), and 3 months (t1) and 6 months (t2) during cabergoline treatment. RESULTS: A decrease and normalization of serum IGF-1 concentration was observed in 35% and 26% of cats, respectively. Median IGF-1 (t0: 1350 ng/ml [range 832-1501]; t1: 1284 ng/ml [range 365-1501]; t2: 1240 ng/ml [range 263-1501]; P = 0.016) decreased significantly. Twelve cats underwent diagnostic imaging of the pituitary area. The median pituitary height at t0 of cats that experienced an IGF-1 reduction (n = 5/12) was significantly lower compared with those that did not experience an IGF-1 reduction (n = 7/12) (3.2 mm [range 3.1-3.7] vs 6 mm [range 3.5-9.5]; P = 0.011). Median fructosamine (t0: 628 µmol/l [range 400-963]; t1: 404 µmol/l [range 249-780]; t2: 400 µmol/l [range 260-815]; P <0.0001), insulin dose (t0: 1.3 IU/kg [range 0.5-4.6]; t0: 0.5 IU/kg [range 0-2.3]; t2: 0.4 IU/kg [range 0-2.1]; P <0.0001) and IRI (t0: 800 µmolIU/kgl [range 257-2700]; t1: 300 µmolIU/kgl [range 0-1498]; t2: 250 µmolIU/kgl [range 0-1498]; P <0.0001) decreased significantly during cabergoline treatment. Eight cats achieved diabetic remission between months 1 and 6 of cabergoline treatment (median time to achieve remission: 3 months [range 1-6]). Three cats experienced asymptomatic hypoglycemia. CONCLUSIONS AND RELEVANCE: Cabergoline was effective in normalizing IGF-1 concentration in 26% of cats. Cabergoline improved diabetes control and was associated with remission of DM in 35% of cases. Cabergoline could be a treatment option for cats with HST and DM, especially in those cases with a relatively small pituitary tumor.

Non-functioning pituitary adenomas and pregnancy: one-center experience and review of the literature.

The usual clinical presentation of non-functioning pituitary adenoma (NFPA) consists of symptoms of mass effect and hypopituitarism. NFPA is a rare condition in young women and an uncommon complication during pregnancy. We present the outcome of three patients with NFPA during pregnancy. Case 1: a 38-year-old woman was referred at 32nd week of spontaneous pregnancy because of diagnosis of a pituitary macroadenoma discovered in the context of progressive visual loss. Hormonal deficiency and hypersecretion were ruled out. Prolactin levels were high as expected. She developed diplopia and severe headache despite the use of dopamine agonists and corticosteroids, so pregnancy was interrupted at 34th week. After an uncomplicated delivery of a healthy newborn, transsphenoidal surgery was performed. The pathology was consistent with a gonadotroph adenoma. She recovered visual field, and remained with normal pituitary function. Postsurgical tumor remnant increased in size during the follow-up. Case 2: a 34-year-old woman was referred due to secondary amenorrhea and galactorrhea. A macroadenoma with suprasellar extension was discovered. Transsphenoidal surgery confirmed a gonadotroph adenoma. Two years after surgery she had a normal pregnancy. Six years after surgery a small tumor recurrence occurred. Case 3: a 23-year-old woman was referred due to a microincidental pituitary adenoma. Laboratory testing was normal. No findings on physical examination. A wait and see approach was decided. Two years after diagnosis, the patient got pregnant without complications. Image remained stable. This article may contribute new cases and provides an extensive review of NFPA during pregnancy.

Increased risk of preneoplastic colonic lesions and colorectal carcinoma in acromegaly: multicenter case-control study.

PURPOSE: Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group. METHODS: This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas. RESULTS: Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps. CONCLUSIONS: Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.

Acromegaly and thyroid cancer: analysis of evolution in a series of patients.

BACKGROUND: Acromegaly is associated with higher morbidity and mortality mainly due to cardiovascular disease. Data on the incidence and evolution of thyroid cancer in acromegaly are controversial. Our objective was to describe the characteristics of a group of acromegalic patients with differentiated thyroid carcinoma (DTC) and analyze their evolution. METHODS: This is a retrospective multicenter study of 24 acromegalic patients with DTC. The AJCC Staging System 8th Edition was used for TNM staging, and the initial risk of recurrence (RR), initial response and response at the end of follow-up (RFU) were defined according to the 2015 ATA Guidelines. As a control group, 92 patients with DTC without acromegaly were randomly included. Statistical analyses were done using SPSS Statistics 20.0. RESULTS: Median age of patients at diagnosis of acromegaly was 49.5 years (range 12-69). The median delay in diagnosis of acromegaly was 3 years (range 0.5-23). Mean baseline IGF-1 level was 2.9 ± 1.1 ULN. Median age at DTC diagnosis was 51.5 years (18-69). At the moment of diagnosis of DTC, 58.3% of the patients had active acromegaly. Median time from DTC diagnosis to acromegaly control was 1.25 years (0.5-7). Mean DTC tumor diameter of the biggest lesion was 14.6 ± 9.2 mm, being multifocal in 37.5%. All tumors were papillary carcinomas, two cases being of an aggressive variety. Lymph node dissection was performed in 8 out of 24 patients and 62.5% had metastases. Only one patient had distant metastases. Radioiodine ablation was given to 87.5% of patients. Nineteen patients (79%) were stage I, four (17%) stage II and one (4%) stage IVb. Initial RR was low in 87% (21/24), intermediate in 9% (2/24) and high in 4% (1/24) patient. RFU was: 83% (19/23) patients with no evidence of disease, 9% (2/23) with indeterminate response, 4% (1/23) with biochemical incomplete response and 4% (1/23) with structural incomplete response, at a median time of FU of 36.5 months. When comparing RFU between acromegalics and controls no statistically significant differences were found. CONCLUSIONS: Patients with acromegaly and DTC mostly had a low initial RR. When compared with the control group, we found that DTC patients with acromegaly did not have a worse evolution.

Non-functioning pituitary adenomas and pregnancy: one-center experience and review of the literature

SUMMARY The usual clinical presentation of non-functioning pituitary adenoma (NFPA) consists of symptoms of mass effect and hypopituitarism. NFPA is a rare condition in young women and an uncommon complication during pregnancy. We present the outcome of three patients with NFPA during pregnancy. Case 1: a 38-year-old woman was referred at 32nd week of spontaneous pregnancy because of diagnosis of a pituitary macroadenoma discovered in the context of progressive visual loss. Hormonal deficiency and hypersecretion were ruled out. Prolactin levels were high as expected. She developed diplopia and severe headache despite the use of dopamine agonists and corticosteroids, so pregnancy was interrupted at 34th week. After an uncomplicated delivery of a healthy newborn, transsphenoidal surgery was performed. The pathology was consistent with a gonadotroph adenoma. She recovered visual field, and remained with normal pituitary function. Postsurgical tumor remnant increased in size during the follow-up. Case 2: a 34-year-old woman was referred due to secondary amenorrhea and galactorrhea. A macroadenoma with suprasellar extension was discovered. Transsphenoidal surgery confirmed a gonadotroph adenoma. Two years after surgery she had a normal pregnancy. Six years after surgery a small tumor recurrence occurred. Case 3: a 23-year-old woman was referred due to a microincidental pituitary adenoma. Laboratory testing was normal. No findings on physical examination. A wait and see approach was decided. Two years after diagnosis, the patient got pregnant without complications. Image remained stable. This article may contribute new cases and provides an extensive review of NFPA during pregnancy.

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

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.

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

New Insights in Cushing Disease Treatment With Focus on a Derivative of Vitamin A.

Cushing's disease (CD) is an endocrine disorder originated by a corticotroph tumor. It is linked with high mortality and morbidity due to chronic hypercortisolism. Treatment goals are to control cortisol excess and achieve long-term remission, therefore, reducing both complications and patient's mortality. First-line of treatment for CD is pituitary's surgery. However, 30% of patients who undergo surgery experience recurrence in long-term follow-up. Persistent or recurrent CD demands second-line treatments, such as pituitary radiotherapy, adrenal surgery, and/or pharmacological therapy. The latter plays a key role in cortisol excess control. Its targets are inhibition of adrenocorticotropic hormone (ACTH) production, inhibition of adrenal steroidogenesis, or antagonism of cortisol action at its peripheral receptor. Retinoic acid (RA) is a metabolic product of vitamin A (retinol) and has been studied for its antiproliferative effects on corticotroph tumor cells. It has been shown that this drug regulates the expression of pro-opiomelanocortin (POMC), ACTH secretion, and tumor growth in corticotroph tumor mouse cell lines and in the nude mice experimental model, via inhibition of POMC transcription. It has been shown to result in tumor reduction, normalization of cortisol levels and clinical improvement in dogs treated with RA for 6 months. The orphan nuclear receptor COUP-TFI is expressed in normal corticotroph cells, but not in corticotroph tumoral cells, and inhibits RA pathways. A first clinical human study demonstrated clinical and biochemical effectiveness in 5/7 patients treated with RA for a period of up to 12 months. In a recent second clinical trial, 25% of 16 patients achieved eucortisolemia, and all achieved a cortisol reduction after 6- to 12-month treatment. The goal of this review is to discuss in the context of the available and future pharmacological treatments of CD, RA mechanisms of action on corticotroph tumor cells, and future perspectives, focusing on potential clinical implementation.

Riesgo aumentado de lesiones colónicas preneoplásicas en acromegalia: estudio multicéntrico caso control. Resultados preliminares / Increased risk of pre-cancerous bowel lesions in acromegaly: Multicentre case-control study. Preliminary results

Introducción: El riesgo de desarrollar neoplasias colónicas en pacientes acromegálicos y su relación directa con los niveles elevados de GH/IGF-1 no están bien establecidos y continúan siendo motivo de controversia en la literatura mundial. El objetivo de este trabajo fue evaluar el riesgo de desarrollar lesiones neoplásicas avanzadas (LNA) (adenomas mayores a 1 cm, componente velloso mayor del 75% y/o displasia de alto grado), en pacientes con acromegalia, comparado con un grupo control. Materiales y métodos: Estudio multicéntrico caso-control retrospectivo. Ciento treinta y siete pacientes con acromegalia que realizaron videocolonoscopia (VCC) fueron incluidos inicialmente, aunque solo 69 cumplieron criterios de inclusión. Sesenta y dos controles fueron obtenidos: por cada caso (paciente con acromegalia) 2 «controles¼ fueron seleccionados aleatorizadamente e igualados por edad y sexo. El riesgo se expresó en odds ratio (OR) y su correspondiente intervalo de confianza (IC) del 95%. La significación estadística fue considerada una p < 0,05. Resultados: De los 69 pacientes con VCC completa y datos adecuados para su análisis, 28 presentaron VCC positiva con hallazgos de pólipos (40%) y 41 VCC negativa o normal (60%). Dentro del grupo con VCC positiva, 14 presentaron LNA (20%) y solo un paciente presentó diagnóstico de cáncer colorrectal. Para el análisis caso-control se incluyó a 31 pacientes frente al grupo control (n = 62) que cumplieron con los criterios de inclusión. La presencia de pólipos colónicos, adenomas y LNA en los pacientes con acromegalia fue de 19/31 (61,9%), 14/31 (45,16%) y 10/31 (32,25%), y en el grupo control de 18/62 (29,03%), 11/62 (17,74%) y 4/62 (6,45%), respectivamente. El riesgo de adenomas y LNA fue mayor en el grupo de acromegalia en comparación con el grupo control, siendo ambos resultados estadísticamente significativos: adenomas OR 2,54 (IC 1,22-5,25) p = 0,005, LNA OR: 7,3 (2,4-25), p = 0,00. Conclusión: La acromegalia se asocia a un mayor riesgo de lesiones colónicas preneoplásicas. Este hallazgo justifica el cribado con VCC al diagnóstico en pacientes con acromegalia.

Background: The risk of developing cancerous lesions in the colon of acromegaly patients and their direct relationship with elevated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels is not well established, and is still controversial in the international literature. The objective of this study was to evaluate the risk of developing advanced neoplastic lesions (ALN: greater than 1 cm adenomas, villous component greater than 75% and/or high grade dysplasia) in patients with acromegaly compared to a control group. Materials and methods: A multicentre, retrospective case-control study was conducted initially on 137 patients with acromegaly (cases) who underwent videocolonoscopy (VCC), although only 69 met inclusion criteria. Sixty-two controls were obtained, and for each case two "controls" were randomly selected and matched by age and gender. Risk was expressed as odds ratio (OR) and its corresponding 95% con"dence interval (CI). P values < .05 were considered statistical significantly. Results: Of the 69 acromegaly patients with a completed VCC and adequate data for their analysis, 28 had a positive VCC with findings of polyps (40%), and 41 VCC negative with no lesions (60%). Within the group with positive VCC, 14 were ALN (20%) and one a colorectal cancer. In the case-control analysis, 31 cases were to be analysed against the control group (n = 62). The presence of colonic polyps, adenomas, and ALN in patients with acromegaly was 19/31 (61.9%), 14/31 (45.16%), and 10/31 (32.25%), respectively, and in the control group, it was 18/62 (29.03%), 11/62 (17.74%), and 4/62 (6.45%), respectively. The risk of adenomas and ALN was higher in the acromegaly group compared to the control group: adenomas OR: 2.54 (95% CI 1.22-5.25) P=.005, ALN OR: 7.3 (2.4-25) P=.00. Conclusion: This preliminary case control study showed an increased risk of pre-cancerous colprectal lesions in patients with acromegaly, supporting the VCC screening at diagnosis.

Prolactinomas: evolution after menopause.

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. SUBJECTS AND METHODS: 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.

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.

Patient-focussed outcomes in acromegaly.

BACKGROUND: Health-related quality of life (QoL) is severely impaired in acromegaly due to the physical and psychological consequences of the disease. Pharmacological and surgical treatments, when available, can improve QoL and life expectancy. CASE DESCRIPTION: A 34-year-old male with uncontrolled acromegaly due to a large and invasive macroadenoma, which could not be resected by transsphenoidal surgery. Over 9 years, he had limited access to pharmacological interventions and persisted with clinically and biochemically active disease, with severe co-morbidities and a poor QoL, which eventually lead to a premature sudden death. CONCLUSION: This case highlights the impact that active acromegaly has when treatment resources are limited. We review the factors contributing to poor QoL in this disease, with special reference to the Latin American scenario.

Cyclin-dependent kinase inhibitor 1B (CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds.

Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A>C (p.K96Q) and c.356T>C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27(I119T) shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C>T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

Comparison of two immunoassays in the determination of IGF-I levels and its correlation with oral glucose tolerance test (OGTT) and with clinical symptoms in acromegalic patients.

The aim of our study was to evaluate two different methodologies in IGF-I levels determination, its correlation with GH nadir in OGTT <1 and <0.4 ng/ml and with clinical symptoms in acromegalic patients. We analyzed 37 patients. Sixteen patients had not undergone any kind of treatment (Group 1). Twenty-one patients underwent surgery as primary treatment, and after that, some of them another kind of treatment (except pegvisomant) (Group 2). Serum IGF-I levels were measured by Immulite-1000 (IMM) and by an immunoradiometric assay (DSL) and, GH by immunochemiluminometric assay. IGF-I levels by IMM and by DSL showed a significant difference. When we analyzed in both groups the concordance by crosstabs-Kappa coefficients, between different parameters, GH nadir <1 and <0.4 ng/ml with IGF-I by DSL and IMM showed concordance in group 1, but in group 2 only GH nadir <1 and <0.4 ng/ml had a weak concordance with IGF-I by IMM. When we analyzed clinical symptoms in the patients and, GH nadir <1 and <0.4 ng/ml and IGF-I levels by both methodologies, more than 90% of clinically active patients had abnormal GH response or/and elevated IGF-I levels in group 1, but less than 70% in group 2. In the 8 patients under medical treatment, GH nadir was higher than 0.4 ng/ml in all patients, and IGF-I levels were elevated in 8/8 by DSL and in 6/8 by IMM. In conclusion, discrepant GH and IGF-I levels in the diagnosis and follow-up of patients with acromegaly requires consideration of many factors that influence these parameters.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Management of acromegaly in Latin America: expert panel recommendations.

Although there are international guidelines orienting physicians on how to manage patients with acromegaly, such guidelines should be adapted for use in distinct regions of the world. A panel of neuroendocrinologists convened in Mexico City in August of 2007 to discuss specific considerations in Latin America. Of major discussion was the laboratory evaluation of acromegaly, which requires the use of appropriate tests and the adoption of local institutional standards. As a general rule to ensure diagnosis, the patient's GH level during an oral glucose tolerance test and IGF-1 level should be evaluated. Furthermore, to guide treatment decisions, both GH and IGF-1 assessments are required. The treatment of patients with acromegaly in Latin America is influenced by local issues of cost, availability and expertise of pituitary neurosurgeons, which should dictate therapeutic choices. Such treatment has undergone profound changes because of the introduction of effective medical interventions that may be used after surgical debulking or as first-line medical therapy in selected cases. Surgical resection remains the mainstay of therapy for small pituitary adenomas (microadenomas), potentially resectable macroadenomas and invasive adenomas causing visual defects. Radiotherapy may be indicated in selected cases when no disease control is achieved despite optimal surgical debulking and medical therapy, when there is no access to somatostatin analogues, or when local issues of cost preclude other therapies. Since not all the diagnostic tools and treatment options are available in all Latin American countries, physicians need to adapt their clinical management decisions to the available local resources and therapeutic options.