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AIM: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. METHODS: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. RESULTS: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). CONCLUSION: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.
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PURPOSE: To evaluate differences in clinical presentation and in surgical outcomes between growth hormone-secreting pituitary adenomas (GH-PAs) and GH and prolactin co-secreting pituitary adenomas (GH&PRL-PAs). METHODS: Multicenter retrospective study of 604 patients with acromegaly submitted to pituitary surgery. Patients were classified into two groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal and IHC for GH and PRL was positive or PRL levels were >100ng/and PRL IHC was not available (n=130) and b) GH-PAs who did not meet the previously mentioned criteria (n=474). RESULTS: GH&PRL-PAs represented 21.5% (n=130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P<0.001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs. 77.4%, P=0.001) and tended to be more invasive (33.6% vs. 24.7%, P=0.057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (OR 2.8, 95% CI 1.83-4.38). IGF-1 upper limit of normality (ULN) levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [IQR 1.73-3.29] vs. 2.7 [IQR 1.91-3.67], P=0.023). There were no differences in the immediate (41.1% vs 43.3%, P=0.659) or long-term post-surgical acromegaly biochemical cure rate (53.5% vs. 53.1%, P=0.936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs. 2.4%, P=0.011) in GH&PRL-PAs patients. CONCLUSIONS: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.
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INTRODUCTION: Intermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-fetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. METHODS: Retrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50 (P25-P75). RESULTS: 24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother's disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31â¯+â¯5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. CONCLUSIONS: Pregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and fetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.
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Aborto Espontáneo , Errores Innatos del Metabolismo de los Aminoácidos , Errores Innatos del Metabolismo , Niño , Embarazo , Adulto , Humanos , Recién Nacido , Femenino , Estudios Retrospectivos , Errores Innatos del Metabolismo/terapia , Resultado del EmbarazoRESUMEN
Introduction: Water and electrolyte disturbances are common after pituitary surgery and can generally be classified into transient hypotonic polyuria and transient or permanent diabetes insipidus (DI). The prevalence varies in the literature between 31-51% for transient hypotonic polyuria, 5.1-25.2% for transient DI, and 1-8.8% for permanent DI. Objective: The aim of this study was to identify the prevalence of water and electrolyte disturbances with polyuria and the preoperative and postoperative predictive factors in patients undergoing surgery with an extended endoscopic endonasal approach. Material and methods: This retrospective observational descriptive study included 203 patients with a diagnosis of pituitary adenoma who underwent their first transsphenoidal surgery via the extended endoscopic endonasal approach between April 2013 and February 2020. The diagnosis of water and electrolyte disturbances was based on the criterion for polyuria (>4 ml/kg/h). Postoperative polyuria was defined as those cases diagnosed during the immediate postsurgical period that resolved prior to discharge. Transient DI included all cases with a duration of less than 6 months but still present at hospital discharge, and permanent DI included cases lasting more than 6 months. Results: The overall prevalence of water and electrolyte disorders was 30.5% (62), and the prevalence of postoperative polyuria was 23.6% (48). The median number of desmopressin doses administered to patients with postoperative polyuria was one dose (interquartile range [IQR] 1-2), and thus the median duration of treatment was 0 days. The median initiation of desmopressin was the second day after surgery (IQR 1-2). The overall prevalence of DI was 6.89%. Among the patients with transient DI, the duration was less than 3 months in three patients (1.47%), and between 3 and 6 months in two (0.98%). Nine patients had permanent DI (4.43%). (4.43%). Conclusions: The prevalence of electrolyte disturbances in our study was high, although similar to that found in the literature. Most of the cases were transient hypotonic polyuria that resolved within one day. The prevalence of transient DI in our cohort was lower than that described in the literature, while permanent DI was similar.
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Neoplasias Hipofisarias , Complicaciones Posoperatorias , Desequilibrio Hidroelectrolítico , Desamino Arginina Vasopresina , Diabetes Insípida/etiología , Humanos , Neoplasias Hipofisarias/cirugía , Poliuria/etiología , Estudios Retrospectivos , Desequilibrio Hidroelectrolítico/etiologíaRESUMEN
CONTEXT: Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. OBJECTIVES: This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. METHODS: A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. RESULTS: Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (Pâ <â .001). CONCLUSION: This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.
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Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Enfermedades de la Hipófisis , Neoplasias Hipofisarias , Humanos , Hidrocortisona , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/cirugía , Hipófisis/patología , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/cirugía , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The establishment of national neonatal screening systems has resulted in improved quality of life and life expectancy in patients with phenylketonuria (PKU). This has led to the development of multidisciplinary treatment units for adult patients with PKU. We present a retrospective descriptive study of a cohort of 90 adult patients (>16 years) with PKU under active follow-up in two reference centers in Andalusia. We analyzed disease severity, treatment type, demographic variables, cardiovascular risk factors, vitamin and hormone profiles, and bone metabolism. The median (interquartile range)age was 29 (23−38) years, 47 (52.2%) were women and 43 (47.8%) were men. Eighty (88.9%) had classical PKU, five (5.6%) moderate PKU, and five (5.6%) mild PKU. Diagnosis was by neonatal screening in 62 (68.9%) of the patients. The rest had late diagnosis. Treatment with sapropterin was given to 18 (20%) patients and diet and nutrition therapy to 72 (80%). There was adequate metabolic control according to Phe levels in 43 (47.78%) patients. Body mass index was 26.61 (22.7−31.1) kg/m2. Twenty-six (29.2%) patients had obesity, 7 (7.9%) hypertension, 2 (2.2%) type 2 diabetes, 26 (28.89%) dyslipidemia, 14 (15.6%) elevated total cholesterol, 9 (15.8%) decreased high-density lipoprotein cholesterol and 16 (17.8%) hypertriglyceridemia. Seven (10.3%) patients had osteoporosis and 28 (41.17%) osteopenia. Twenty-six (30.6%) had vitamin D (25OH) deficiency and four (4.5%) vitamin B12 deficiency. Although we observed no differences with most vascular risk factors, we found a high prevalence of obesity in relation to the age of the cohort. A continued evaluation of comorbidities in these patients is therefore needed, despite adequate metabolic control.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Fenilcetonurias , Adulto , Enfermedades Cardiovasculares/epidemiología , Femenino , Humanos , Recién Nacido , Masculino , Morbilidad , Fenilcetonurias/epidemiología , Calidad de Vida , Estudios RetrospectivosRESUMEN
Craniopharyngiomas (CPs) are rare tumors of the sellar and suprasellar regions of embryonic origin. The primary treatment for CPs is surgery but it is often unsuccessful. Although CPs are considered benign tumors, they display a relatively high recurrence rate that might compromise quality of life. Previous studies have reported that CPs express sex hormone receptors, including estrogen and progesterone receptors. Here, we systematically analyzed estrogen receptor α (ERα) and progesterone receptor (PR) expression by immunohistochemistry in a well-characterized series of patients with CP (n = 41) and analyzed their potential association with tumor aggressiveness features. A substantial proportion of CPs displayed a marked expression of PR. However, most CPs expressed low levels of ERα. No major association between PR and ERα expression and clinical aggressiveness features was observed in CPs. Additionally, in our series, ß-catenin accumulation was not related to tumor recurrence.
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Somatostatin receptor subtype 5 (SST5 ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.
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Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Hipofisarias , Receptores de Somatostatina , Metilación de ADN , Epigénesis Genética , Humanos , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismoRESUMEN
OBJECTIVE: To describe the characteristics of the patients, as well as the treatment outcomes for the people treated in an Endocrinology and Nutrition unit with a diagnosis of SE-ED (> 7 years evolution despite evidence-based conventional treatment). METHODS: A descriptive observational study was conducted. Patients with a diagnosis of SE-ED (anorexia nervosa and bulimia nervosa) treated in the Endocrinology and Nutrition service of the Virgen del Rocío University Hospital between 2014 and 2019 were included. RESULTS: 67 patients were contacted and accepted to participate in the study. 95.5% were women. 67.2% were diagnosed with AN (anorexia nervosa) and 32.8% with BN (bulimia nervosa). Their median ages (years) at the onset of symptoms, beginning of follow-up and at present were 17, 32 and 42.5 respectively. Their median time of follow-up was 9 years. 73.1% had mental comorbitidy and AN patients had more osteoporosis (48.9% vs 22.7%, p = 0.04) and hypogonadotropic hypogonadism (31.1% vs. 4.5%, p = 0.014). DISCUSSION: The SE-ED patients in our sample began treatment years after the onset of symptoms, which may have led to their chronification. This emphasizes the importance of an early diagnosis in eating disorders. They presented with a high rate of physical complications and mental comorbidity. In the current sample, it was determined that patients with AN presented with higher rates of osteoporosis and hypogonadotropic hypogonadism than patients with BN. LEVEL OF EVIDENCE: Level III: Evidence obtained from well-designed cohort or case-control analytic studies. At present, the criteria for severe and enduring eating disorders (SE-ED) are not sufficiently clearly defined. It has been calculated that approximately 20% of patients with anorexia nervosa (AN) and 10% of patients with bulimia nervosa (BN) suffer a chronification. We evaluated the characteristics of the patients, as well as the treatment outcomes for the people treated in an Endocrinology and Nutrition unit with a diagnosis of SE-ED (which was made based on an evolution greater than 7 years despite conventional treatment). The SE-ED patients in our sample began treatment years after the onset of symptoms, which may have led to their chronification. They presented with a high rate of physical complications and mental comorbidity. In the current sample, it was determined that patients with AN presented with higher rates of osteoporosis (health condition that weakens bones, making them fragile and more likely to break) and hypogonadotropic hypogonadism (illness in which testes or ovaries produce little or no sex hormones due to a problem in the pituitary gland) than patients with BN.
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Nowadays, neither imaging nor pathology evaluation can accurately predict the aggressiveness or treatment resistance of pituitary tumors at diagnosis. However, histological examination can provide useful information that might alert clinicians about the nature of pituitary tumors. Here, we describe our experience with a silent corticothoph tumor with unusual pathology, aggressive local invasion and metastatic dissemination during follow-up. We present a 61-year-old man with third cranial nerve palsy at presentation due to invasive pituitary tumor. Subtotal surgical approach was performed with a diagnosis of silent corticotroph tumor but with unusual histological features (nuclear atypia, frequent multinucleation and mitotic figures, and Ki-67 labeling index up to 70%). After a rapid regrowth, a second surgical intervention achieved successful debulking. Temozolomide treatment followed by stereotactic fractionated radiotherapy associated with temozolomide successfully managed the primary tumor. However, sacral metastasis showed up 6 months after radiotherapy treatment. Due to aggressive distant behavior, a carboplatine-etoposide scheme was decided but the patient died of urinary sepsis 31 months after the first symptoms. Our case report shows how the presentation of a pituitary tumor with aggressive features should raise a suspicion of malignancy and the need of follow up by multidisciplinary team with experience in its management. Metastases may occur even if the primary tumor is well controlled.
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Adenoma/diagnóstico por imagen , Adenoma/cirugía , Corticotrofos/patología , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/cirugía , Resultado Fatal , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. AIM: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. PATIENTS AND METHODS: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. RESULTS: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65-83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57-118) months. DI at last visit was associated with a lower survival. CONCLUSION: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population.
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Envejecimiento , Craneofaringioma , Neoplasias Hipofisarias , Anciano , Anciano de 80 o más Años , Craneofaringioma/diagnóstico , Craneofaringioma/mortalidad , Craneofaringioma/patología , Craneofaringioma/terapia , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/mortalidad , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Estudios Retrospectivos , España/epidemiologíaRESUMEN
INTRODUCTION: Giant prolactinomas (tumor size larger than 40mm) are a rare entity of benign nature. Prolactinomas larger than 60mm are usually underrepresented in published studies and their clinical presentation, outcomes and management might be different from smaller giant prolactinomas. PATIENTS AND METHODS: We retrospective collected data from patients with prolactinomas larger than 60mm in maximum diameter and prolactin (PRL) serum levels higher than 21,200µIU/mL in our series of prolactinomas (283). Data were collected from January 2012 to December 2017. We included three patients with prolactinomas larger than 60mm. RESULTS: At diagnosis, two patients presented neurological symptoms and one nasal protrusion. All patients received medical treatment with dopamine agonists. No surgical procedure was performed. Median prolactin levels at diagnosis was 108,180 [52,594-514,984]µIU/mL. Medical treatment achieved a marked reduction (>99%) in prolactin levels in all cases. Tumor size reduction (higher than 33%) was observed in all cases. In one patient cerebrospinal fluid (CSF) leak was observed after tumor shrinkage. CONCLUSIONS: Dopamine agonists appear to be an effective and safe first-line treatment in prolactinomas larger than 60mm even in life-threatening situations. More studies with a higher number of patients are necessary to obtain enough data to make major recommendations.
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The primary treatment for non-functioning pituitary tumors (NFPTs) is surgery, but it is often unsuccessful. Previous studies have reported that NFPTs express receptors for somatostatin (SST1-5) and dopamine (DRDs) providing a rationale for the use of dopamine agonists and somatostatin analogues. Here, we systematically assessed SST1-5 and DRDs expression by real-time quantitative PCR (RT-qPCR) in a large group of patients with NFPTs (n = 113) and analyzed their potential association with clinical and molecular aggressiveness features. SST1-5 expression was also evaluated by immunohistochemistry. SST3 was the predominant SST subtype detected, followed by SST2, SST5, and SST1. DRD2 was the dominant DRD subtype, followed by DRD4, DRD5, and DRD1. A substantial proportion of NFPTs displayed marked expression of SST2 and SST5. No major association between SSTs and DRDs expression and clinical and molecular aggressiveness features was observed in NFPTs.
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INTRODUCTION: Central nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. PATIENTS AND METHODS: The medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. RESULTS: We found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p=0.012). CONCLUSIONS: Almost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors.
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Neoplasias Encefálicas/complicaciones , Enfermedades del Sistema Endocrino/etiología , Neoplasias de Células Germinales y Embrionarias/complicaciones , Niño , Enfermedades del Sistema Endocrino/diagnóstico , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
INTRODUCTION: Pituitary neuroendocrine tumors (PitNETs), the most abundant of all intracranial tumors, entail severe comorbidities. First-line therapy is transsphenoidal surgery, but subsequent pharmacological therapy is often required. Unfortunately, many patients are/become unresponsive to available drugs (somatostatin analogues [SSAs]/dopamine agonists), underscoring the need for new therapies. Statins are well-known drugs commonly prescribed to treat hyperlipidemia/cardiovascular diseases, but can convey additional beneficial effects, including antitumor actions. The direct effects of statins on normal human pituitary or PitNETs are poorly known. Thus, we aimed to explore the direct effects of statins, especially simvastatin, on key functional parameters in normal and tumoral pituitary cells, and to evaluate the combined effects of simvastatin with metformin (MF) or SSAs. METHODS: Effects of statins in cell proliferation/viability, hormone secretion, and signaling pathways were evaluated in normal pituitary cells from a primate model (Papio anubis), tumor cells from corticotropinomas, somatotropinomas, nonfunctioning pituitary tumors, and PitNET cell-lines (AtT20/GH3-cells). RESULTS: All statins decreased AtT20-cell proliferation, simvastatin showing stronger effects. Indeed, simvastatin reduced cell viability and/or hormone secretion in all PitNETs subtypes and cell-lines, and ACTH/GH/PRL/FSH/LH secretion (but not expression), in primate cell cultures, by modulating MAPK/PI3K/mTOR pathways and expression of key receptors (GH-releasing hormone-receptor/ghrelin-R/Kiss1-R) regulating pituitary function. Addition of MF or SSAs did not enhance simvastatin antitumor effects. CONCLUSION: Our data reveal direct antitumor effects of simvastatin on PitNET-cells, paving the way to explore these compounds as a possible tool to treat PitNETs.
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Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Tumores Neuroendocrinos/tratamiento farmacológico , Hipófisis/efectos de los fármacos , Neoplasias Hipofisarias/tratamiento farmacológico , Simvastatina/farmacología , Adulto , Anciano , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Quimioterapia Combinada , Femenino , Humanos , Hipoglucemiantes/farmacología , Masculino , Metformina/farmacología , Ratones , Persona de Mediana Edad , Papio anubis , Ratas , Somatostatina/farmacología , Adulto JovenRESUMEN
BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) represent approximately 15% of all intracranial tumors and usually are associated with severe comorbidities. Unfortunately, a relevant number of patients do not respond to currently available pharmacological treatments, that is, somatostatin analogs (SSAs) or dopamine-agonists (DA). Thus, novel, chimeric somatostatin/dopamine compounds (dopastatins) that could improve medical treatment of PitNETs have been designed. OBJECTIVE: This study aims to determine the direct therapeutic effects of a new-generation dopastatin, BIM-065, on primary cell cultures from different PitNETs subtypes. METHODS: Thirty-one PitNET-derived cell cultures (9 corticotropinomas, 9 somatotropinomas, 11 nonfunctioning pituitary adenomas [NFPAs], and 2 prolactinomas), were treated with BIM-065, and key functional endpoints were assessed (cell viability, apoptosis, hormone secretion, expression levels of key genes, free cytosolic [Ca2+]i dynamics, etc.). AtT-20 cell line was used to evaluate signaling pathways in response to BIM-065. RESULTS: This chimeric compound decreased cell viability in all corticotropinomas and somatotropinomas tested, but not in NFPAs. BIM-065 reduced ACTH, GH, chromogranin-A and PRL secretion, and increased apoptosis in corticotropinomas, somatotropinomas, and NFPAs. These effects were possibly mediated through modulation of pivotal signaling cascades like [Ca2+]i kinetic and Akt- or ERK1/2-phosphorylation. CONCLUSIONS: Our results unveil a robust antitumoral effect in vitro of the novel chimeric compound BIM-065 on the main PitNET subtypes, inform on the mechanisms involved, and suggest that BIM-065 could be an efficacious therapeutic option to be considered in the treatment of PitNETs.
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Dopaminérgicos/farmacología , Dopamina/análogos & derivados , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Hipofisarias/tratamiento farmacológico , Somatostatina/análogos & derivados , Somatostatina/farmacología , Dopamina/farmacología , Humanos , Somatostatina/análisis , Células Tumorales CultivadasRESUMEN
PURPOSE: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models. EXPERIMENTAL DESIGN: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. RESULTS: We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. CONCLUSIONS: This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
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Tumores Neuroendocrinos/tratamiento farmacológico , Péptidos/farmacología , Neoplasias Hipofisarias/tratamiento farmacológico , Receptores de Somatostatina/agonistas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Quinasas Janus/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Péptidos/química , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Transducción de Señal , Células Tumorales Cultivadas , Adulto JovenRESUMEN
Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs.
RESUMEN
OBJECTIVE: Thyrotropin (TSH)-secreting pituitary tumors are rare and typically present with hyperthyroidism. Here we report the diagnosis, treatment, and surgical outcomes in a series of patients with TSH-secreting pituitary tumors in a tertiary referral center. METHODS: Descriptive retrospective study that included all patients with TSH-secreting pituitary tumors who underwent transsphenoidal surgery in the endocrinology and nutrition unit of the Virgen del Rocío University Hospital (Seville, Spain) between 2004 and 2016. RESULTS: The mean age at diagnosis was 42.8 ± 17 years. The mean time from onset of symptoms to diagnosis was 13 ± 10 months. Four patients displayed symptoms indicating hyperthyroidism (1 suffered from tachycardia); 3 patients showed symptoms because of mass effect (visual impairment and headache) and 3 patients were diagnosed based on incidental findings after routine blood tests (high free thyroxine levels). Eight patients had macroadenomas, and 2 patients had microadenomas. Five patients underwent conventional pituitary surgery, and 5 patients underwent expanded endoscopic transsphenoidal surgery. Six patients achieved cure after surgery. The other patients received radiotherapy and/or treatment with somatostatin analogs. Analysis of somatostatin receptor (SSTR) expression by immunohistochemistry could be performed in 6 tumors. CONCLUSIONS: Our results confirm the clinical and hormonal heterogeneity caused by TSH-secreting pituitary adenomas. Surgery is considered the first choice of treatment for these tumors. We observed surgical cure rates similar to those reported in recent published series. SSTR2 and SSTR3 are highly expressed in TSH-secreting pituitary adenomas. Our results suggest that somatostatin analog treatment may be also helpful in the treatment of TSH-secreting pituitary adenomas.
Asunto(s)
Adenoma/cirugía , Hipertiroidismo/cirugía , Procedimientos Neuroquirúrgicos/métodos , Neoplasias Hipofisarias/cirugía , Tirotrofos/patología , Tirotropina/metabolismo , Adenoma/complicaciones , Adenoma/metabolismo , Adenoma/patología , Adolescente , Adulto , Anciano , Femenino , Humanos , Hipertiroidismo/etiología , Hipertiroidismo/metabolismo , Hipertiroidismo/patología , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Estudios Retrospectivos , Centros de Atención Terciaria , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Cushing disease (CD) is a rare, poorly understood entity. Our aim was to add our clinical experience of >30 years in a multidisciplinary specialized unit to the global knowledge of CD. METHODS: This descriptive retrospective study included all patients admitted to the Endocrinology and Nutrition Department of the Virgen del Rocío University Hospital, Seville, Spain, from January 1980 to May 2016. All patients had a definitive diagnosis of CD. RESULTS: Total sample included 119 patients; 100 (84%) were female. Median age at diagnosis was 37.97 years (interquartile range [IQR]: 25.89-45.07 years). Median follow-up was 88 months (IQR: 45.50-157.00 months). Most tumors were microadenomas (62/95) (5.1 mm [IQR: 4.0-7.0 mm]) without sinus invasion. Surgical procedures were conventional transsphenoidal surgery (CTSS) (101/108; cured 70 after first attempt) and expanded endoscopic transsphenoidal surgery (EETSS) (7/108; cured 5 after first attempt); 11 patients did not receive surgical treatment. Fourteen patients received radiotherapy after a first surgery and 5 patients after a second surgical removal attempt. In 13 patients (12.04%), CD relapse was demonstrated after initial CTSS (median disease-free period 65 months [IQR: 45-120 months]). Ten patients developed panhypopituitarism owing to the surgical procedure (CTSS); 8 patients developed panhypopituitarism after adjuvant radiotherapy. CONCLUSIONS: We observed slightly inferior cure rate after first surgery compared with moderately better relapse rates and time to relapse. Radiotherapy after surgery failure seemed to be more effective than CTSS; however, EETSS may be a valid alternative. Postoperative panhypopituitarism rate after first surgery was lower than expected; after radiotherapy, our results were comparable to other series.