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Central hypothyroidism (CH) is characterized by decreased thyroid hormone production due to insufficient stimulation of an otherwise normal thyroid gland by TSH. In patients with established hypothalamic-pituitary disease, a low FT4 concentration is considered highly specific, although poorly sensitive, for the diagnosis of CH. That would be comparable to diagnosing primary hypothyroidism in patients at risk only when serum FT4 concentrations are below the reference range, missing all patients with subclinical primary hypothyroidism and preventing proper therapy in patients in which thyroxine replacement is clearly beneficial. Cardiac time intervals, especially the isovolumic contraction time (ICT), have been considered the gold standard of peripheral thyroid hormone action. Using Doppler echocardiography, we have previously shown a very high proportion of prolonged ICT in patients with hypothalamic-pituitary disease and serum FT4 levels indistinguishable from controls. As ICT decreased/normalized after thyroxine-induced increases in FT4 concentrations within the normal reference range, prolonged ICT was considered a bona fide diagnostic biomarker of subclinical CH. Those findings challenge the usual interpretation that FT4 concentrations in the mid-reference range exclude hypothyroidism in patients with hypothalamic-pituitary disease. Rather, subclinical central hypothyroidism, a state analogous to subclinical primary hypothyroidism, seems to be frequent in patients with hypothalamic-pituitary disease and normal FT4 levels. They also challenge the notion that thyroid function is usually the least or the last affected in acquired hypopituitarism. The relevance of Doppler echocardiography to correctly diagnose and monitor replacement therapy in both clinical and subclinical forms of CH should improve quality of life and decrease cardiovascular risk, as already demonstrated in patients with clinical and subclinical primary hypothyroidism.
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Enfermedades Hipotalámicas , Hipotiroidismo , Humanos , Enfermedades Hipotalámicas/diagnóstico , Enfermedades de la Hipófisis/diagnóstico , Tiroxina/uso terapéutico , Tiroxina/sangreRESUMEN
INTRODUCTION: Cabergoline is the treatment of choice for prolactinomas. However, 10-20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. SUBJECTS AND METHODS: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26-61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38-386 ng/mL) under cabergoline treatment (2-7 mg/week) for at least 6 months (6-108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0-2.5 g v.o./day) was given according to patients' tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30-60 days) and long-term (120-180 days) metformin treatment. RESULTS: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30-60 days, and at 120-180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0-2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. CONCLUSION: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.
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Cabergolina/farmacología , Agonistas de Dopamina/farmacología , Hiperprolactinemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Síndrome Metabólico/tratamiento farmacológico , Metformina/farmacología , Prolactina/efectos de los fármacos , Prolactinoma/tratamiento farmacológico , Adulto , Cabergolina/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Resistencia a Medicamentos/fisiología , Quimioterapia Combinada , Femenino , Humanos , Hiperprolactinemia/sangre , Hipoglucemiantes/administración & dosificación , Síndrome Metabólico/sangre , Metformina/administración & dosificación , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Proyectos Piloto , Prolactina/sangre , Prolactinoma/sangre , Estudios ProspectivosRESUMEN
BACKGROUND: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months). METHODS: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal. RESULTS: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found. CONCLUSION: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients.
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Acromegalia/tratamiento farmacológico , Antineoplásicos Hormonales/uso terapéutico , Octreótido/uso terapéutico , Acromegalia/sangre , Adulto , Anciano , Femenino , Hormona del Crecimiento/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Estudios Retrospectivos , Síndrome de Abstinencia a Sustancias/etiología , Factores de Tiempo , Adulto JovenRESUMEN
INTRODUCTION: Acromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life. METHODS: We conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment. FINDINGS AND CONCLUSIONS: Successful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.
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Adenoma/diagnóstico , Adenoma Hipofisario Secretor de Hormona del Crecimiento/diagnóstico , Adenoma/complicaciones , Adenoma/epidemiología , Adenoma/terapia , Enfermedades Cardiovasculares/epidemiología , Síndrome del Túnel Carpiano/epidemiología , Comorbilidad , Diabetes Mellitus/epidemiología , Manejo de la Enfermedad , Adenoma Hipofisario Secretor de Hormona del Crecimiento/complicaciones , Adenoma Hipofisario Secretor de Hormona del Crecimiento/epidemiología , Adenoma Hipofisario Secretor de Hormona del Crecimiento/terapia , Cefalea/etiología , Insuficiencia Cardíaca/epidemiología , Humanos , Hipertensión/epidemiología , Hipertrofia Ventricular Izquierda/epidemiología , Macroglosia/epidemiología , Osteoartritis/epidemiología , Pronóstico , Síndromes de la Apnea del Sueño/epidemiología , Trastornos de la Visión/etiologíaRESUMEN
Objective: To evaluate the cumulative incidence, risk factors, and outcomes of COVID-19 in patients with Cushing's disease (CD). Subjects and methods: In all, 60 patients with CD following up in our outpatient clinic answered via phone interview a questionnaire about the occurrence of COVID-19 infection documented by RT-PCR (including the diagnosis date and clinical outcome) and vaccination status. Clinical and biochemical data on disease activity (hypercortisolism) and comorbidities (obesity, diabetes mellitus, and hypertension) were obtained from the patients' electronic medical records. Risk ratios (RRs) of risk factors were obtained using univariate and multivariate analyses. Results: The cumulative incidence of COVID-19 in patients with CD during the observation period was 31.7%, which was higher than that in the general reference population (9.5%). The cumulative incidence of COVID-19 was significantly higher in patients with hypercortisolism (57% versus 17% in those without hypercortisolism, p = 0.012) and obesity (54% versus 9% in those without obesity, p < 0.001) but not in patients with hypertension or diabetes mellitus. On multivariate analysis, hypercortisolism and obesity were each independent risk factors for COVID-19 (RR 2.18, 95% CI 1.06-4.46, p = 0.033 and RR 5.19, 95% CI 1.61-16.74, p = 0.006, respectively). Conclusion: The incidence of COVID-19 in patients with CD was associated with hypercortisolism, as expected, and obesity, a novel and unexpected finding. Thus, correction of hypercortisolism and obesity should be implemented in patients with CD during the current and future COVID-19 outbreaks.
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COVID-19 , Síndrome de Cushing , Diabetes Mellitus , Hipertensión , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/complicaciones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/epidemiología , Síndrome de Cushing/complicaciones , Síndrome de Cushing/epidemiología , COVID-19/epidemiología , Obesidad/complicaciones , Obesidad/epidemiología , Hipertensión/epidemiología , Diabetes Mellitus/epidemiologíaRESUMEN
Abnormal hypothalamic/posterior pituitary development appears to be a major determinant of pituitary stalk interruption syndrome (PSIS). The observation of familial cases and associated congenital abnormalities suggests a genetic basis. Single-gene mutations explain less than 5% of the cases, and whole exome sequencing has shown heterogeneous results. The present study aimed to assess copy number variation (CNV) using array-based comparative genomic hybridization (aCGH) in patients with non-syndromic PSIS and comprehensively review data from the literature on CNV analysis in congenital hypopituitarism (CH) patients. Twenty-one patients with sporadic CH from our outpatient clinics presented with ectopic posterior pituitary (EPP) and no central nervous system abnormalities on magnetic resonance image (MRI) or any other malformations on physical examination at presentation were enrolled in the study. aCGH using a whole-genome customized 400K oligonucleotide platform was performed in our patients. For the literature review, we searched for case reports of patients with CH and CNV detected by either karyotype or aCGH reported in PubMed up to November 2021. Thirty-five distinct rare CNVs were observed in 18 patients (86%) and two of them (6%) were classified as pathogenic: one deletion of 1.8 Mb in chromosome 17 (17q12) and one deletion of 15 Mb in chromosome 18 (18p11.32p11.21), each one in a distinct patient. In the literature review, 67 pathogenic CNVs were published in 83 patients with CH, including the present study. Most of these patients had EPP (78% out of the 45 evaluated by sellar MRI) and were syndromic (70%). The most frequently affected chromosomes were X, 18, 20 and 1. Our study has found that CNV can be a mechanism of genetic abnormality in non-syndromic patients with CH and EPP. In future studies, one or more genes in those CNVs, both pathogenic and variant of uncertain significance, may be considered as good candidate genes.
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Hipopituitarismo , Enfermedades de la Hipófisis , Humanos , Variaciones en el Número de Copia de ADN/genética , Hibridación Genómica Comparativa/métodos , Enfermedades de la Hipófisis/genética , Hipopituitarismo/genética , Hipopituitarismo/diagnóstico , Hipopituitarismo/patología , Síndrome , Hipófisis/diagnóstico por imagen , Hipófisis/patologíaRESUMEN
Primary Pigmented Nodular Adrenocortical Disease (PPNAD) is a rare form of bilateral adrenocortical hyperplasia that is inherited in an autosomal dominant manner and leads to ACTH-independent Cushing's syndrome (CS). PPNAD may be isolated or associated with Carney Complex (CNC). For the diagnosis of PPNAD and CNC, in addition to the hormonal and imaging tests, searching for PRKAR1A mutations may be recommended. The aims of the present study are to discuss the clinical and molecular findings of two Brazilian patients with ACTH-independent CS due to PPNAD and to show the diagnostic challenge CS represents in childhood. Description of two patients with CS and the many sequential steps for the diagnosis of PPNAD is provided. Sequencing analysis of all coding exons of PRKAR1A in the blood, frozen adrenal nodules (patients 1 and 2) and testicular tumor (patient 1) is performed. After several clinical and laboratory drawbacks that misled the diagnostic investigation in both patients, the diagnosis of PPNAD was finally established and confirmed through pathology and molecular studies. In patient 1, sequencing of PRKAR1A gene revealed a novel heterozygous 10-bp deletion in exon 3, present in his blood, adrenal gland and testicular tumor. The etiologic diagnosis of endogenous CS in children is a challenge that requires expertise and a multidisciplinary collaboration for its prompt and correct management. Although rare, PPNAD should always be considered among the possible etiologies of CS, due to the high prevalence of this disease in this age group.
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Enfermedades de la Corteza Suprarrenal/diagnóstico , Enfermedades de la Corteza Suprarrenal/etiología , Complejo de Carney/genética , Síndrome de Cushing/complicaciones , Enfermedades de la Corteza Suprarrenal/genética , Adulto , Síndrome de Cushing/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Femenino , Humanos , Masculino , Mutación , Adulto JovenRESUMEN
Hypopituitarism is a disorder characterized by insufficient secretion of one or more pituitary hormones. New etiologies of hypopituitarism have been recently described, including head trauma, cerebral hemorrhage, and drug-induced hypophysitis. The investigation of patients with these new disorders, in addition to advances in diagnosis and treatment of hypopituitarism, has increased the prevalence of this condition. Pituitary hormone deficiencies can induce significant clinical changes with consequent increased morbidity and mortality rates, while hormone replacement based on current guidelines protects these patients. In this review, we will first discuss the different etiologies of hypopituitarism and then address one by one the clinical aspects, diagnostic evaluation, and therapeutic options for deficiencies of TSH, ACTH, gonadotropin, and GH. Finally, we will detail the hormonal interactions that occur during replacement of pituitary hormones.
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Endocrinología , Hipopituitarismo , Brasil , Terapia de Reemplazo de Hormonas , Humanos , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/etiología , Hormonas HipofisariasRESUMEN
BACKGROUND: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. METHODS: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. RESULTS: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. CONCLUSIONS: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.
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CONTEXT: Artificial intelligence (AI), in particular machine learning (ML), may be used to deeply analyze biomarkers of response to first-generation somatostatin receptor ligands (fg-SRLs) in the treatment of acromegaly. OBJECTIVE: To develop a prediction model of therapeutic response of acromegaly to fg-SRL. METHODS: Patients with acromegaly not cured by primary surgical treatment and who had adjuvant therapy with fg-SRL for at least 6 months after surgery were included. Patients were considered controlled if they presented growth hormone (GH) <1.0 ng/mL and normal age-adjusted insulin-like growth factor (IGF)-I levels. Six AI models were evaluated: logistic regression, k-nearest neighbor classifier, support vector machine, gradient-boosted classifier, random forest, and multilayer perceptron. The features included in the analysis were age at diagnosis, sex, GH, and IGF-I levels at diagnosis and at pretreatment, somatostatin receptor subtype 2 and 5 (SST2 and SST5) protein expression and cytokeratin granulation pattern (GP). RESULTS: A total of 153 patients were analyzed. Controlled patients were older (Pâ =â .002), had lower GH at diagnosis (Pâ =â .01), had lower pretreatment GH and IGF-I (Pâ <â .001), and more frequently harbored tumors that were densely granulated (Pâ =â .014) or highly expressed SST2 (Pâ <â .001). The model that performed best was the support vector machine with the features SST2, SST5, GP, sex, age, and pretreatment GH and IGF-I levels. It had an accuracy of 86.3%, positive predictive value of 83.3% and negative predictive value of 87.5%. CONCLUSION: We developed a ML-based prediction model with high accuracy that has the potential to improve medical management of acromegaly, optimize biochemical control, decrease long-term morbidities and mortality, and reduce health services costs.
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Acromegalia/tratamiento farmacológico , Reglas de Decisión Clínica , Monitoreo de Drogas/métodos , Aprendizaje Automático , Receptores de Somatostatina/administración & dosificación , Acromegalia/sangre , Adulto , Anciano , Biomarcadores/sangre , Femenino , Hormona de Crecimiento Humana/sangre , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Queratinas , Ligandos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores de Somatostatina/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Nearly 40% of acromegalic patients fail to control GH/IGF-I levels with somatostatin analogues (SA). Dopaminergic agonists (DA) are even less effective, but combination therapy with SA and DA normalizes IGF-I levels in 33-56% of patients not controlled by octreotide alone in short-term studies. This study was designed to evaluate short- and long-term efficacy of cabergoline in controlling IGF-I levels in acromegalic patients receiving octreotide. DESIGN: Open-label, single arm, prospective trial. Nineteen patients (14 females, 29-78 years of age) with high IGF-I on octreotide-LAR (30 mg/month IM) for > or =6 months were enrolled. Study I: Cabergoline (PO) was started at 1.0, increased to 2.0 and 3.5 mg/week, and withdrawn at 6-week intervals. IGF-I, GH, and PRL were measured at baseline and at 6-week intervals. Study II: Responder patients (IGF-I < or =1 ULN) resumed cabergoline at individual lowest effective doses and were evaluated at 6-month intervals for > or =12 months. Study III: Responders were withdrawn from octreotide and hormonally evaluated at 3-month intervals. METHODS: Serum IGF-I (IRMA), GH (ICMA) and PRL (ICMA) levels were determined by commercially available kits. RESULTS: Addition of cabergoline to octreotide-LAR normalized IGF-I levels in 7 of 19 patients (37%) during both short- and long-term follow-up (12-27 months, mean: 18 months). Octreotide withdrawal increased IGF-I levels in only 2 of 6 responder patients. Normalization of IGF-I levels by cabergoline was strongly associated with IGF-I < or =2.2 ULNR and/or GH < or =4.0 ng/ml under octreotide treatment. CONCLUSION: Addition of cabergoline to octreotide was effective in both short- and long-term control of IGF-I in acromegaly, especially in patients with mild/moderately elevated GH/IGF-I levels during octreotide.
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Acromegalia/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Ergolinas/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Octreótido/uso terapéutico , Acromegalia/sangre , Adulto , Anciano , Cabergolina , Quimioterapia Combinada , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Persona de Mediana Edad , Somatostatina/análogos & derivadosRESUMEN
ABSTRACT Objective: To evaluate the cumulative incidence, risk factors, and outcomes of COVID-19 in patients with Cushing's disease (CD). Subjects and methods: In all, 60 patients with CD following up in our outpatient clinic answered via phone interview a questionnaire about the occurrence of COVID-19 infection documented by RT-PCR (including the diagnosis date and clinical outcome) and vaccination status. Clinical and biochemical data on disease activity (hypercortisolism) and comorbidities (obesity, diabetes mellitus, and hypertension) were obtained from the patients' electronic medical records. Risk ratios (RRs) of risk factors were obtained using univariate and multivariate analyses. Results: The cumulative incidence of COVID-19 in patients with CD during the observation period was 31.7%, which was higher than that in the general reference population (9.5%). The cumulative incidence of COVID-19 was significantly higher in patients with hypercortisolism (57% versus 17% in those without hypercortisolism, p = 0.012) and obesity (54% versus 9% in those without obesity, p < 0.001) but not in patients with hypertension or diabetes mellitus. On multivariate analysis, hypercortisolism and obesity were each independent risk factors for COVID-19 (RR 2.18, 95% CI 1.06-4.46, p = 0.033 and RR 5.19, 95% CI 1.61-16.74, p = 0.006, respectively). Conclusion: The incidence of COVID-19 in patients with CD was associated with hypercortisolism, as expected, and obesity, a novel and unexpected finding. Thus, correction of hypercortisolism and obesity should be implemented in patients with CD during the current and future COVID-19 outbreaks.
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OBJECTIVE: Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. SUBJECTS AND METHODS: Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. RESULTS: 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. CONCLUSIONS: In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies.
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Acromegalia/tratamiento farmacológico , Cabergolina/uso terapéutico , Hormona de Crecimiento Humana/análogos & derivados , Receptores de Somatostatina/uso terapéutico , Adenoma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Glucemia/análisis , Brasil , Cabergolina/administración & dosificación , Niño , Quimioterapia Combinada , Femenino , Hormona del Crecimiento/sangre , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptores de Somatostatina/administración & dosificación , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Kallmann syndrome (KS), the association of hypogonadotropic hypogonadism and anosmia, was described by Maestre de San Juan in 1856 and characterized as a hereditary condition by Franz Josef Kallmann in 1944. Many aspects such as pathogeny, phenotype and genotype in KS were described in the last fifteen years. The knowledge of this condition has grown fast, making it difficult to update. Here we review historical aspects of this condition and its discoverers and describe new findings regarding the embryogenesis of the olfactory bulb and GnRH secreting neuronal tracts that are important for understanding the association of hypogonadism and anosmia. Additionally, we describe the phenotypic and genotypic heterogeneity of KS, including five related genes (KAL-1, FGFR1, PROKR2, PROK2 e NELF), and discuss the function of each codified protein in migration and maturation of the olfactory and GnRH neurons, with data from in vitro and in vivo studies. Finally we describe the clinical phenotype of patients carrying these mutations.
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Heterogeneidad Genética , Síndrome de Kallmann/genética , Mutación/genética , Vías Olfatorias/fisiología , Proteínas de la Matriz Extracelular/genética , Hormonas Gastrointestinales/genética , Genotipo , Hormona Liberadora de Gonadotropina/genética , Humanos , Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/fisiopatología , Proteínas del Tejido Nervioso/genética , Neuropéptidos/genética , Trastornos del Olfato/genética , Bulbo Olfatorio/fisiología , Percepción Olfatoria , Fenotipo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genéticaRESUMEN
BACKGROUND: Human morbid obesity is increasing worldwide in an alarming way. The hypothalamus is known to mediate its mechanisms. Deep brain stimulation (DBS) of the ventromedial hypothalamus (VMH) may be an alternative to treat patients refractory to standard medical and surgical therapies. OBJECTIVE: To assess the safety, identify possible side effects, and to optimize stimulation parameters of continuous VMH-DBS. Additionally, this study aims to determine if continuous VMH-DBS will lead to weight loss by causing changes in body composition, basal metabolism, or food intake control. METHODS: The BLESS study is a feasibility study, single-center open-label trial. Six patients (body mass index > 40) will undergo low-frequency VMH-DBS. Data concerning timing, duration, frequency, severity, causal relationships, and associated electrical stimulation patterns regarding side effects or weight changes will be recorded. EXPECTED OUTCOMES: We expect to demonstrate the safety, identify possible side effects, and to optimize electrophysiological parameters related to VMH-DBS. No clinical or behavioral adverse changes are expected. Weight loss ≥ 3% of the basal weight after 3 mo of electrical stimulation will be considered adequate. Changes in body composition and increase in basal metabolism are expected. The amount of food intake is likely to remain unchanged. DISCUSSION: The design of this study protocol is to define the safety of the procedure, the surgical parameters important for target localization, and additionally the safety of long-term stimulation of the VMH in morbidly obese patients. Novel neurosurgical approaches to treat metabolic and autonomic diseases can be developed based on the data made available by this investigation.
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Índice de Masa Corporal , Estimulación Encefálica Profunda/métodos , Obesidad Mórbida/fisiopatología , Obesidad Mórbida/terapia , Núcleo Hipotalámico Ventromedial/fisiología , Adulto , Estudios de Factibilidad , Femenino , Humanos , MasculinoRESUMEN
Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.
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Hiperprolactinemia/diagnóstico , Hiperprolactinemia/terapia , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/terapia , Guías de Práctica Clínica como Asunto , Prolactinoma/diagnóstico , Prolactinoma/terapia , Antineoplásicos/uso terapéutico , Brasil , Bromocriptina/uso terapéutico , Cabergolina , Agonistas de Dopamina/uso terapéutico , Ergolinas/uso terapéutico , Femenino , Humanos , Masculino , Prolactina/sangreRESUMEN
CONTEXT: The regulation of TSH bioactivity in humans is not completely understood. OBJECTIVE: The aim of the study was to investigate the role of serum thyroid hormones in regulating the bioactivity of TSH. DESIGN: We determined in vitro TSH bioactivity and glycosylation in nine patients (six females and three males, age 41.3 yr) with primary hypothyroidism before and after L-T(4) replacement, in 11 age- and sex-comparable controls (seven females and four males, age 37.6 yr), and in two thyroidectomized patients with TSH-secreting adenomas during and after L-T(4) withdrawal. METHODS: In vitro TSH bioactivity was measured by a sensitive and specific bioassay based on cAMP generation by Chinese hamster ovary cells transfected with human TSH receptor. TSH glycosylation was assessed by concanavalin A lectin and ricin column affinity chromatography. RESULTS: In vitro TSH bioactivity in hypothyroid patients was low as compared with controls (0.48 +/- 0.1 vs. 1.1 +/- 0.2; P = 0.004) and increased during L-T(4) (0.48 +/- 0.1 vs. 0.8 +/- 0.1; P = 0.01). A strong significant correlation (r = +0.80; P = 0.004, Spearman) was observed between the absolute increments of serum TSH bioactivity and T(3) during L-T(4) replacement. The degree of sialylation was elevated in hypothyroid patients before treatment (47 +/- 2.4% vs. 29 +/- 4.3%; P = 0.002) and decreased significantly after L-T(4) (47 +/- 2.4% vs. 33 +/- 4.3%; P = 0.02). The mannose content of serum TSH in hypothyroid patients was similar to controls and did not change during L-T(4). In vitro TSH bioactivity also decreased in patients with TSH-secreting adenomas during L-T(4) withdrawal. CONCLUSION: These data indicate that serum thyroid hormone level is a positive regulator of TSH bioactivity.
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Hormonas Tiroideas/fisiología , Tirotropina/sangre , Adenoma/metabolismo , Adulto , Animales , Células CHO , Cromatografía de Afinidad , Concanavalina A/química , Cricetinae , Cricetulus , AMP Cíclico/biosíntesis , Femenino , Glicosilación , Terapia de Reemplazo de Hormonas , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Inmunoensayo , Masculino , Manosa/sangre , Persona de Mediana Edad , Neuraminidasa/química , Receptores de Tirotropina/genética , Receptores de Tirotropina/metabolismo , Ricina/química , Hormonas Tiroideas/metabolismo , Tiroidectomía , Tiroxina/uso terapéutico , TransfecciónRESUMEN
CONTEXT: The biological significance of GH-induced changes in serum TH concentrations is unknown. It has been suggested that serum free T(4) (FT(4)) should be targeted at the high-normal range during GH replacement. OBJECTIVE: Our objective was to evaluate the effects of GH replacement on T(4) biological effects. HYPOTHESIS: If GH modulates thyroxine biological effects, serum FT(4) should be targeted accordingly. DESIGN AND SETTING: We conducted observational (study 1) and interventional (studies 2 and 3)/outpatient studies. PATIENTS: Thirty-two GH-deficient patients (13 off GH; 22 on l-T(4)) participated in the study. INTERVENTIONS: In study 2, levothyroxine was administered to increase FT(4) (>1.0 ng/dl). In study 3, GH was administered or withdrawn. MAIN OUTCOME MEASURES: We measured FT(4), total T(3) (TT(3)), myocardial isovolumic contraction time (ICT), and resting energy expenditure (REE). RESULTS: In study 1, off-GH and on-GH groups had similar FT(4), but off GH showed lower TT(3) (P < 0.01) and REE (P = 0.02), higher ICT (P < 0.05) than on-GH and controls. On GH, ICT and REE correlated only with TT(3) (r = -0.48; r = 0.58; P < 0.05). Off GH, ICT correlated only with FT(4) (P < 0.01). In study 2, off GH, levothyroxine intervention increased FT(4) (P = 0.005) and TT(3) (P = 0.012), decreased ICT (P = 0.006), and increased REE (P = 0.013); ICT and FT(4) changes correlated (r = -0.72; P = 0.06). On GH, levothyroxine increased FT(4) (P = 0.0002), TT(3) (P = 0.014), and REE (P = 0.10) and decreased ICT (P = 0.049); REE and TT(3) changes correlated (r = 0.60; P = 0.05). In study 3, GH decreased FT(4), increased TT(3), decreased ICT, and increased REE (P < 0.05). REE correlated (P < 0.05) with IGF-I (r = 0.57) and TT(3) (r = 0.64). ICT correlated only with TT(3) (r = -0.46). CONCLUSIONS: GH replacement improves the biological effects of T(4). Serum FT(4) should be targeted at the high-normal range in GH-deficient patients only off GH replacement.
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Hormona del Crecimiento/uso terapéutico , Hipotiroidismo/tratamiento farmacológico , Tiroxina/uso terapéutico , Adolescente , Adulto , Niño , Quimioterapia Combinada , Ecocardiografía , Metabolismo Energético/efectos de los fármacos , Femenino , Terapia de Reemplazo de Hormonas , Hormona de Crecimiento Humana/deficiencia , Humanos , Masculino , Contracción Miocárdica/efectos de los fármacos , Hormonas Tiroideas/sangre , Triyodotironina/sangreRESUMEN
Kallmann syndrome (KS) describes the association of isolated hypogonadotropic hypogonadism with hypo/anosmia. A few KS patients may reverse hypogonadism after testosterone withdrawal, a variant known as reversible KS. Herein, we describe the first mutation in KAL1 in a patient with reversible KS and review the literature. The proband was first seen at 22 years complaining of anosmia and lack of puberty. His brother had puberty at 30 years and a maternal granduncle had anosmia and delayed puberty. On physical examination, he was P(2)G(1), testes were 3 ml and bone age was 14 years. During 20 years of irregular testosterone replacement, he developed secondary sexual characteristics and testicular enlargement. At the age of 41 years, after stopping testosterone replacement for 5 months, his testes were 15 ml, serum testosterone, LH, and FSH responses to GnRH were normal, and his wife was pregnant. The molecular study revealed a cytosine insertion in exon 2 of KAL1, generating a frameshift at codon 75 and a premature stop at codon 85. The expected gene product is a truncated peptide with 85 of the 680 [corrected] amino acids present in the wild-type protein. Fourteen cases of reversible KS have been described but the genotype was only studied in a single case showing a heterozygous fibroblast growth factor receptor type 1 (FGFR1) mutation. Considering the low prevalence of mutations in KAL1 or FGFR1 in KS, it is possible that these genotypes are more prevalent in reversible KS than in other KS patients, but additional studies are necessary to confirm this hypothesis.