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1.
Expert Rev Endocrinol Metab ; 16(4): 159-174, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34380370

RESUMO

Introduction: Endogenous Cushing's syndrome (CS) is a rare, life-threatening endocrine disorder that is caused by chronic exposure to cortisol overproduction. Levoketoconazole (Recorlev), a 2S, 4R stereoisomer of ketoconazole, is a steroidogenesis inhibitor under investigation for the treatment of CS.Areas covered: This review covers the pharmacology, efficacy, and safety of levoketoconazole for the treatment of patients with endogenous CS.Expert opinion: Based on the preclinical and clinical pharmacology findings, levoketoconazole appears to be the relevant enantiomer of ketoconazole for inhibition of steroidogenesis, with more potent inhibition of both cortisol and androgen synthesis relative to ketoconazole racemate and the 2R, 4S stereoisomer dextroketoconazole. Results from the phase III SONICS study showed that levoketoconazole was effective in normalizing cortisol levels and improving biomarkers of cardiovascular risk in a significant percentage of patients. In addition, treatment with levoketoconazole showed improvements in subjective clinical assessments of clinician-rated CS clinical signs and symptoms, patient-reported quality of life, and depression symptom severity. Testosterone levels decreased significantly in women. Levoketoconazole had an acceptable safety profile with no unexpected safety signals. The favorable pharmacology, efficacy, and safety profile of levoketoconazole supports its use as medical therapy for CS, if approved.

2.
Molecules ; 26(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807567

RESUMO

Catecholamines are physiological regulators of carbohydrate and lipid metabolism during stress, but their chronic influence on metabolic changes in obese patients is still not clarified. The present study aimed to establish the associations between the catecholamine metabolites and metabolic syndrome (MS) components in obese women as well as to reveal the possible hidden subgroups of patients through hierarchical cluster analysis and principal component analysis. The 24-h urine excretion of metanephrine and normetanephrine was investigated in 150 obese women (54 non diabetic without MS, 70 non-diabetic with MS and 26 with type 2 diabetes). The interrelations between carbohydrate disturbances, metabolic syndrome components and stress response hormones were studied. Exploratory data analysis was used to determine different patterns of similarities among the patients. Normetanephrine concentrations were significantly increased in postmenopausal patients and in women with morbid obesity, type 2 diabetes, and hypertension but not with prediabetes. Both metanephrine and normetanephrine levels were positively associated with glucose concentrations one hour after glucose load irrespectively of the insulin levels. The exploratory data analysis showed different risk subgroups among the investigated obese women. The development of predictive tools that include not only traditional metabolic risk factors, but also markers of stress response systems might help for specific risk estimation in obesity patients.


Assuntos
Metanefrina/urina , Análise Multivariada , Normetanefrina/urina , Obesidade/urina , Adolescente , Adulto , Idoso , Biomarcadores/urina , Análise por Conglomerados , Diabetes Mellitus Tipo 2/urina , Feminino , Humanos , Síndrome Metabólica/urina , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Circunferência da Cintura
3.
Eur J Endocrinol ; 184(3): P1-P16, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33444221

RESUMO

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.


Assuntos
Adenoma Hipofisário Secretor de ACT/cirurgia , Adenoma/cirurgia , Adrenalectomia/efeitos adversos , Síndrome de Nelson/etiologia , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/patologia , Progressão da Doença , Humanos , Síndrome de Nelson/patologia
4.
Eur J Endocrinol ; 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33320830

RESUMO

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. AIMS: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. DESIGN: On-line survey in endocrine centres throughout Europe. PATIENTS AND METHODS: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. RESULTS: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. CONCLUSION: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

5.
Endocr Relat Cancer ; 27(10): 561-570, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32698148

RESUMO

Cardiomyopathy is a frequent complication of pheochromocytoma, and echocardiography is the most accessible method for its evaluation. The objective of this study was to assess the clinical significance of classical and novel echocardiographic parameters of cardiac function in 24 patients with pheochromocytomas (PPGL) compared to 24 subjects with essential hypertension (EH). Fourteen PPGL patients were reassessed after successful surgery. Left ventricular hypertrophy was four times more prevalent in patients with PPGL vs EH (75% vs 17%; P = 0.00005). Left ventricular mass index (LVMi) significantly correlated with urine metanephrine (MN) (rs = 0.452, P = 0.00127) and normetanephrine (NMN) (rs = 0.484, P = 0.00049). Ejection fraction (EF) and endocardial fractional shortening (EFS) were normal in all participants and did not correlate with urine metanephrines. Global longitudinal strain (GLS) was significantly lower in PPGL compared to EH group (-16.54 ± 1.83 vs -19.43 ± 2.19; P < 0.00001) and revealed a moderate significant positive correlations with age (rs = 0.489; P = 0.015), LVMi (rs = 0.576, P < 0.0001), MN (rs = 0.502, P = 0.00028) and NMN (rs = 0.580, P < 0.0001). Relative wall thickness (RWT) showed a strong positive correlation with urine MN (rs = 0.559, P < 0.0001) and NMN (rs = 0.689, P < 0.00001). Markedly decreased LVMi (118.2 ± 26.9 vs 102.9 ± 22.3; P = 0.007) and significant improvement in GLS (-16.64 ± 1.49 vs -19.57 ± 1.28; P < 0.001) was observed after surgery. ΔGLS depended significantly on the follow-up duration. In conclusion, classical echocardiographic parameters usually used for assessment of systolic cardiac function are not reliable tests in pheochromocytoma patients. Instead, GLS seems to be a better predictor for the severity and the reversibility of catecholamine-induced myocardial function damage in these subjects. RWT should be measured routinely as an early indicator of cardiac remodeling.


Assuntos
Neoplasias das Glândulas Suprarrenais/fisiopatologia , Biomarcadores Tumorais/metabolismo , Feocromocitoma/fisiopatologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade
6.
Arch Endocrinol Metab ; 64(3): 269-275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555993

RESUMO

OBJECTIVE: Acromegaly is characterized by high neoplastic morbidity as a side effect of growth hormone (GH) hypersecretion. Increased incidence of goiter, thyroid carcinoma, and thyroid dysfunction is also reported. The aim of the present study was to find the prevalence of thyroid dysfunction and goiter in patients with acromegaly and determine its relationship to disease activity, disease duration, and the presence of secondary hypothyroidism. SUBJECTS AND METHODS: In a cross-sectional study of the period 2008-2012 were included 146 patients with acromegaly (56 men, 90 women) of mean age 50.3 ± 12.4 years. Acromegaly disease activity and thyroid function were evaluated in all patients. Thyroid ultrasonography was performed to calculate thyroid volume and detect the presence of nodular goiter. RESULTS: Ninety-one patients were determined to have an active disease, and 55, a controlled disease. The mean thyroid volume in patients without previous thyroid surgery was 37.6 ± 38.8 mL. According to disease activity, thyroid volume was significantly higher in patients with active disease (38.5 ± 45.4 mL vs. 27.2 ± 18.4 mL, p = 0.036). A weak positive correlation was found between thyroid volume and insulin-like growth factor 1 (IGF-1) in the whole group and in females (R = 0.218; p = 0.013, and R = 0.238; p = 0.037, respectively). There was no significant correlation of thyroid volume with disease duration and GH level in the whole group and in both sexes. The patients with secondary hypothyroidism had twofold smaller thyroid volume, relative to the rest of the group. The prevalence of thyroid dysfunction was 39%, with a female to male percentage ratio of 1.73. Goiter was diagnosed in 87% of patients, including diffuse goiter (17.1%) and nodular (69.9%), with no significant difference between patients with active and controlled disease or the presence of secondary hypothyroidism. CONCLUSIONS: Thyroid volume in patients with acromegaly depends on disease activity and the presence of secondary hypothyroidism as a complication. The increased prevalence of nodular goiter determines the need of regular ultrasound thyroid evaluation in the follow-up of patients with acromegaly. Arch Endocrinol Metab. 2020;64(3):269-75.


Assuntos
Acromegalia/complicações , Bócio Nodular/fisiopatologia , Hipotireoidismo/fisiopatologia , Glândula Tireoide/fisiopatologia , Acromegalia/fisiopatologia , Adulto , Estudos Transversais , Feminino , Bócio Nodular/diagnóstico , Humanos , Hipotireoidismo/diagnóstico por imagem , Hipotireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Testes de Função Tireóidea , Glândula Tireoide/diagnóstico por imagem , Hormônios Tireóideos/sangue , Ultrassonografia
7.
Arch. endocrinol. metab. (Online) ; 64(3): 269-275, May-June 2020. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1131093

RESUMO

ABSTRACT Objective Acromegaly is characterized by high neoplastic morbidity as a side effect of growth hormone (GH) hypersecretion. Increased incidence of goiter, thyroid carcinoma, and thyroid dysfunction is also reported. The aim of the present study was to find the prevalence of thyroid dysfunction and goiter in patients with acromegaly and determine its relationship to disease activity, disease duration, and the presence of secondary hypothyroidism. Subjects and methods In a cross-sectional study of the period 2008-2012 were included 146 patients with acromegaly (56 men, 90 women) of mean age 50.3 ± 12.4 years. Acromegaly disease activity and thyroid function were evaluated in all patients. Thyroid ultrasonography was performed to calculate thyroid volume and detect the presence of nodular goiter. Results Ninety-one patients were determined to have an active disease, and 55, a controlled disease. The mean thyroid volume in patients without previous thyroid surgery was 37.6 ± 38.8 mL. According to disease activity, thyroid volume was significantly higher in patients with active disease (38.5 ± 45.4 mL vs. 27.2 ± 18.4 mL, p = 0.036). A weak positive correlation was found between thyroid volume and insulin-like growth factor 1 (IGF-1) in the whole group and in females (R = 0.218; p = 0.013, and R = 0.238; p = 0.037, respectively). There was no significant correlation of thyroid volume with disease duration and GH level in the whole group and in both sexes. The patients with secondary hypothyroidism had twofold smaller thyroid volume, relative to the rest of the group. The prevalence of thyroid dysfunction was 39%, with a female to male percentage ratio of 1.73. Goiter was diagnosed in 87% of patients, including diffuse goiter (17.1%) and nodular (69.9%), with no significant difference between patients with active and controlled disease or the presence of secondary hypothyroidism. Conclusions Thyroid volume in patients with acromegaly depends on disease activity and the presence of secondary hypothyroidism as a complication. The increased prevalence of nodular goiter determines the need of regular ultrasound thyroid evaluation in the follow-up of patients with acromegaly. Arch Endocrinol Metab. 2020;64(3):269-75

8.
Front Public Health ; 8: 147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411649

RESUMO

Background: Acromegaly and its comorbidities affect the patients' quality of life, each healthcare system and the society. This study aimed to evaluate clinical characteristics and treatment patterns and the economic burden of acromegaly. Materials and methods: All patients with acromegaly treated with expensive medicines and regularly followed up at the main expert clinical center for acromegaly in the country were included in this nationwide, retrospective, observational, population-based study. Patient characteristics, treatment patterns, healthcare resource use, and costs were assessed for 1-year period (01.01.2018-31.12.2018). Results were processed through statistical analysis using MedCalc software version 16.4.1. Results: A total of 191 acromegaly patients were observed. Approximately 67% were female, 45.5% were between 41 and 60 years and the mean age at diagnosis was 40.73 years. Surgical treatment was preferred as a first-line therapy among almost 89% of all diagnosed patients. The level of comorbidities was very high as more than 95% suffered from at least one concomitant disease. The most frequent comorbidities were other endocrine and metabolic diseases (96.7%), followed by cardiovascular diseases (70.7%). The most common first-line pharmacotherapy was long-acting somatostatin analogs (SSA) (38%) followed by dual combination SSA + pegvisomant (21%). The total economic burden of acromegaly was estimated to be 2,674,499.90 € in 2018 as the direct costs (medication costs, hospitalization costs covered by the patients and the National Health Insurance Fund) outnumbered indirect costs (loss of productivity due to hospitalization): 2,630,568.58 € vs. 43,931.32 €. The average annual per-patient direct and indirect costs were 14,002.62 €. Conclusions: The current study demonstrates a significant clinical and socio-economic burden of acromegaly in the country. Proper diagnosing and regular follow up of acromegaly patients in a specialized pituitary center ensure appropriate innovative pharmacotherapy with achievement of disease control.


Assuntos
Acromegalia , Acromegalia/tratamento farmacológico , Bulgária/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Qualidade de Vida , Estudos Retrospectivos
9.
Horm Metab Res ; 52(8): 553-561, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32299111

RESUMO

Pituitary adenomas are benign tumors with variable functional characteristics that can have a significant impact on patients. The majority arise sporadically, but an inherited genetic susceptibility is increasingly being recognized. Recent advances in genetics have widened the scope of our understanding of pituitary tumorigenesis. The clinical and genetic characteristics of pituitary adenomas that develop in the setting of germline-mosaic and somatic GNAS mutations (McCune-Albright syndrome and sporadic acromegaly), germline MEN1 mutations (multiple endocrine neoplasia type 1), and germline PRKAR1A mutations (Carney complex) have been well described. Non-syndromic familial cases of isolated pituitary tumors can occur as familial isolated pituitary adenomas (FIPA); mutations/deletions of the AIP gene have been found in a minority of these. Genetic alterations in GPR101 have been identified recently as causing X-linked acro-gigantism (X-LAG) leading to very early-onset pediatric gigantism. Associations of pituitary adenomas with other tumors have been described in syndromes like multiple endocrine neoplasia type 4, pheochromocytoma-paraganglioma with pituitary adenoma association (3PAs) syndrome and some of their genetic causes have been elucidated. The genetic etiologies of a significant proportions of sporadic corticotropinomas have recently been identified with the discovery of USP8 and USP48 mutations. The elucidation of genetic and molecular pathophysiology in pituitary adenomas is a key factor for better patient management and effective follow-up.


Assuntos
Adenoma/patologia , Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Mutação , Neoplasias Hipofisárias/patologia , Adenoma/etiologia , Adenoma/genética , Humanos , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/genética , Prognóstico
10.
Ann Endocrinol (Paris) ; 81(1): 3-10, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32067697

RESUMO

BACKGROUND: Carbohydrate disorders are the most frequent metabolic disorders, affecting a significant proportion of patients with pheochromocytoma. OBJECTIVE: A retrospective study assessed the prevalence and progression of carbohydrate disorders in 204 patients (92 men, 112 women) with histologically proven pheochromocytoma diagnosed in a single specialized tertiary center during a 40-year period (1978-2017). One hundred were followed-up after tumor removal. RESULTS: Carbohydrate disorders were diagnosed in 49.5% of cases: 30.4% with diabetes and, 19.1% prediabetes. Subjects with carbohydrate disorders had significantly greater age at diagnosis and higher 24-hour urine metanephrine and normetanephrine concentrations than those with normal glucose tolerance. One-third of patients with diabetes achieved good glycemic control under oral treatment (54% on metformin monotherapy). One-third of patients overall required preoperative insulin treatment. Postoperative follow-up (100 patients; 5-year mean duration) showed reduced prevalence of diabetes (13% vs. 33%; P=0.0007) and prediabetes (12% vs. 24%; P=0.027). Almost 60% of subjects initially diagnosed with carbohydrate disorders recovered normal glucose tolerance after surgery; these subjects had significantly higher preoperative urine metanephrine/normetanephrine levels than those with persistent diabetes/prediabetes. Correlation analysis revealed a moderate negative relationship between urine metanephrine/normetanephrine concentration and the outcome of the carbohydrate disorders (Spearmen's Rho=-0.507; P=0.013). There was no significant difference according to pre- or postoperative prevalence of obesity (15% vs. 16%; P=0.845) or dyslipidemia (46% vs. 39%; P=0.316). CONCLUSIONS: Carbohydrate disorders affect approximately 50% of pheochromocytoma patients; 30% develop overt diabetes, which may be the only clinical manifestation in some rare cases. Pheochromocytoma-related diabetes is more likely to affect patients with predominant adrenaline secretion. It is often easy to control and usually requires oral antidiabetic treatment. Reversibility of carbohydrate disorders depend on severity, preoperative metanephrine level, age and weight.


Assuntos
Neoplasias das Glândulas Suprarrenais/epidemiologia , Transtornos do Metabolismo de Glucose/epidemiologia , Transtornos do Metabolismo de Glucose/patologia , Paraganglioma/epidemiologia , Feocromocitoma/epidemiologia , Adolescente , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/metabolismo , Adulto , Idoso , Glicemia/metabolismo , Criança , Progressão da Doença , Feminino , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/patologia , Transtornos do Metabolismo de Glucose/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/complicações , Paraganglioma/metabolismo , Feocromocitoma/complicações , Feocromocitoma/metabolismo , Prevalência , Estudos Retrospectivos , Adulto Jovem
11.
Endocr Relat Cancer ; 27(8): T77-T86, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32083999

RESUMO

Familial isolated pituitary adenoma (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.


Assuntos
Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Masculino
12.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665382

RESUMO

CONTEXT: Signs and symptoms of Cushing's syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. OBJECTIVE: The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. DATA SOURCES: A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. STUDY SELECTION: Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. DATA EXTRACTION: Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included. DATA SYNTHESIS: Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere. CONCLUSIONS: Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.


Assuntos
Síndrome de Cushing/diagnóstico , Diagnóstico Tardio/estatística & dados numéricos , Fatores Etários , Diagnóstico Precoce , Humanos , Fatores Sexuais , Fatores de Tempo
13.
Int J Endocrinol ; 2019: 6718761, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687020

RESUMO

Background: Gynecomastia (GM) is a benign enlargement of male breast due to glandular tissue proliferation. GM is a symptom of systemic or local hormonal disturbances, which could be associated with functional changes or pathological conditions. However, the long-lasting steroid imbalance in men with GM might exert negative influence on their metabolic health. Methods: A total of 110 adult men with symptomatic GM were included in the present retrospective cross-sectional study. Anthropometric, metabolic, and hormonal data of the patients were collected. Results: In almost 64% of GM patients, the underlying pathological condition was identified. Moreover, the development of GM was among the primary symptoms leading to the proper diagnosis in more than 40% of hypogonadal patients. The prevalence of metabolic syndrome (MS) was 53%; the highest prevalence of MS was found in patients with medication-induced GM and in the hypogonadal patients, whereas the lowest prevalence was observed in men with idiopathic postpubertal GM despite the similar degree of obesity. The lower testosterone levels were associated with more unfavorable lipid profile in the GM patients. Conclusion: The development of GM in adults might be an important symptom of an underlying gonadal disease. Moreover, it could be associated with an increased risk of metabolic disturbances. Our results support the need of detailed laboratory and hormonal investigations in patients with GM including targeted screening for metabolic disturbances. Further longitudinal studies are needed to evaluate the long-term consequences of sex hormones imbalance on cardiovascular morbidity and mortality in adults with GM.

14.
Eur J Endocrinol ; 181(6): R235-R254, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31658440

RESUMO

Pituitary adenomas are frequently occurring neoplasms that produce clinically significant disease in 1:1000 of the general population. The pathogenesis of pituitary tumors is a matter of interest as it could help to improve diagnosis and treatment. Until recently, however, disruptions in relatively few genes were known to predispose to pituitary tumor formation. In the last decade, several more genes and pathways have been described. Germline pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene were found in familial or sporadic pituitary adenomas, usually with an aggressive clinical course. Cyclin-dependent kinase inhibitor 1B (CDKN1B) pathogenic variants lead to multiple endocrine neoplasia type 4 (MEN4) syndrome, in which pituitary adenomas can occur. Xq26.3 duplications involving the gene GPR101 cause X-linked acrogigantism. The pheochomocytoma and/or paraganglioma with pituitary adenoma association (3PAs) syndrome suggests that pathogenic variants in the genes of the succinate dehydrogenase complex or MYC-associated factor X (MAX) might be involved in pituitary tumorigenesis. New recurrent somatic alterations were also discovered in pituitary adenomas, such as, ubiquitin-specific protease 8 (USP8) and USP48 pathogenic variants in corticotropinomas. The aim of the present review is to provide an overview of the genetic pathophysiology of pituitary adenomas and their clinical relevance.


Assuntos
Mutação em Linhagem Germinativa/genética , Neoplasias Hipofisárias/genética , Animais , Inibidor de Quinase Dependente de Ciclina p27/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasia Endócrina Múltipla/genética
15.
Eur J Endocrinol ; 181(5): 461-472, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31480014

RESUMO

Objective: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. Methods: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years. Results: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. Conclusion: Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.


Assuntos
Síndrome de Cushing/mortalidade , Doenças das Glândulas Suprarrenais/etiologia , Doenças das Glândulas Suprarrenais/mortalidade , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Estudos de Coortes , Comorbidade , Síndrome de Cushing/complicações , Complicações do Diabetes/mortalidade , Europa (Continente)/epidemiologia , Feminino , França/epidemiologia , Humanos , Infecções/complicações , Infecções/mortalidade , Masculino , Pessoa de Meia-Idade , Doenças da Hipófise/etiologia , Doenças da Hipófise/mortalidade , Sistema de Registros , Fatores Sexuais , Adulto Jovem
16.
Gynecol Endocrinol ; 35(1): 23-27, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29909741

RESUMO

11ß-Hydroxylase deficiency is the second most common enzyme disorder after 21-hydroxylase deficiency causing congenital adrenal hyperplasia (CAH11ß). In females, the clinical phenotype of CAH11ß classic forms is associated with ambiguous genitalia, virilization and hypertension, while most common complaints in milder non-classic forms include hirsutism, acne, menstrual disturbances, and infertility. Herein, we present clinical and genetic characteristics of an adult woman with 11ß-hydroxylase deficiency, hypertension and infertility; she has been followed up from her first pregnancy to her early menopause. Genetic analyses of the patient revealed a compound-heterozygosity due to two variants in the CYP11B1 gene p.Val316Met and p.Asp480ThrfsTer2. Both mutations have not been previously reported as pathogenic in the literature. Emerging questions concerning the clinical management, fertility potential, mineral corticoid abnormalities and perimenopausal transition in patients with non-classic CAH11ß have also been briefly discussed. The presented case of an adult woman with CAH11ß shows that the proper diagnosis and close monitoring of patients with different CAH forms might ensure good therapy adherence and successful fertility.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Infertilidade Feminina/genética , Mutação , Esteroide 11-beta-Hidroxilase/genética , Acne Vulgar/genética , Adulto , Feminino , Seguimentos , Hirsutismo/genética , Humanos , Distúrbios Menstruais/genética , Pessoa de Meia-Idade
17.
Horm Metab Res ; 50(4): 280-289, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29621813

RESUMO

Cushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients - the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.


Assuntos
Adrenalectomia , Hormônio Adrenocorticotrópico/metabolismo , Terapia Combinada/história , Hipersecreção Hipofisária de ACTH/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Feminino , História do Século XX , História do Século XXI , Humanos , Hidrocortisona , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/metabolismo , Hipersecreção Hipofisária de ACTH/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
18.
Endocr Relat Cancer ; 24(10): 505-518, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28733467

RESUMO

Acromegaly is a rare disorder caused by chronic growth hormone (GH) hypersecretion. While diagnostic and therapeutic methods have advanced, little information exists on trends in acromegaly characteristics over time. The Liège Acromegaly Survey (LAS) Database, a relational database, is designed to assess the profile of acromegaly patients at diagnosis and during long-term follow-up at multiple treatment centers. The following results were obtained at diagnosis. The study population consisted of 3173 acromegaly patients from ten countries; 54.5% were female. Males were significantly younger at diagnosis than females (43.5 vs 46.4 years; P < 0.001). The median delay from first symptoms to diagnosis was 2 years longer in females (P = 0.015). Ages at diagnosis and first symptoms increased significantly over time (P < 0.001). Tumors were larger in males than females (P < 0.001); tumor size and invasion were inversely related to patient age (P < 0.001). Random GH at diagnosis correlated with nadir GH levels during OGTT (P < 0.001). GH was inversely related to age in both sexes (P < 0.001). Diabetes mellitus was present in 27.5%, hypertension in 28.8%, sleep apnea syndrome in 25.5% and cardiac hypertrophy in 15.5%. Serious cardiovascular outcomes like stroke, heart failure and myocardial infarction were present in <5% at diagnosis. Erythrocyte levels were increased and correlated with IGF-1 values. Thyroid nodules were frequent (34.0%); 820 patients had colonoscopy at diagnosis and 13% had polyps. Osteoporosis was present at diagnosis in 12.3% and 0.6-4.4% had experienced a fracture. In conclusion, this study of >3100 patients is the largest international acromegaly database and shows clinically relevant trends in the characteristics of acromegaly at diagnosis.


Assuntos
Acromegalia/diagnóstico , Hormônio do Crescimento Humano/efeitos adversos , Acromegalia/patologia , Bases de Dados Factuais , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
19.
Endocrine ; 57(3): 486-493, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28726182

RESUMO

BACKGROUND: The potent immunomodulatory action of prolactin has been demonstrated in many experimental in vitro studies. In accordance with these data, our retrospective analyses revealed higher prevalence of autoimmune thyroid diseases in prolactinoma patients compared to general population. PURPOSE: A cross-sectional case-control study was carried out in a single tertiary referral centre. The main aim was to assess the frequency of newly diagnosed autoimmune thyroid diseases in female patients with prolactinomas. METHODS: The study population consisted of 260 females (154 patients and 106 sex-matched, ethnicity-matched, and age-matched healthy controls) enroled in a prospective manner. Physical exam, thyroid ultrasound, and laboratory testing (measurement of antibodies to thyroglobulin, thyroid peroxidase, TSH-receptor, serum TSH and FT4 levels) were performed in all study participants. RESULTS: Autoimmune thyroid diseases were diagnosed in 29.9% of the patients and 10.4% of the healthy subjects (p = 0.0002). Subclinical hypothyroidism was found in 9.7% of the patients versus 2.8% of the controls (p = 0.044). Autoimmune hyperthyroidism was observed in 1.3% of all patients. CONCLUSIONS: The prevalence of newly diagnosed autoimmune thyroid diseases, and especially the subclinical hypothyroidism, was significantly higher in our female prolactinoma patients in comparison to age-matched healthy women. Based on our results, we suggest routine screening for autoimmune thyroid diseases (thyroid function, immunology and ultrasound examination) in all female patients with prolactinoma at the time of diagnosis. We also recommend a close follow-up of thyroid function in these women in case of pregnancy and after delivery.


Assuntos
Doença de Hashimoto/etiologia , Neoplasias Hipofisárias/fisiopatologia , Prolactinoma/fisiopatologia , Glândula Tireoide/fisiopatologia , Tireoidite Autoimune/etiologia , Adulto , Doenças Assintomáticas/epidemiologia , Bulgária/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Doença de Hashimoto/diagnóstico por imagem , Doença de Hashimoto/epidemiologia , Doença de Hashimoto/imunologia , Hospitais Universitários , Humanos , Hipotireoidismo/diagnóstico por imagem , Hipotireoidismo/epidemiologia , Hipotireoidismo/etiologia , Hipotireoidismo/imunologia , Tamanho do Órgão , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/imunologia , Neoplasias Hipofisárias/patologia , Prevalência , Prolactinoma/sangue , Prolactinoma/imunologia , Prolactinoma/patologia , Estudos Prospectivos , Encaminhamento e Consulta , Risco , Centros de Atenção Terciária , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/imunologia , Glândula Tireoide/patologia , Tireoidite Autoimune/diagnóstico por imagem , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/imunologia , Ultrassonografia
20.
Horm Metab Res ; 49(7): 499-506, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28493240

RESUMO

Apart from being individually associated with cardiometabolic health, 25(OH)D and IGF-1 interplay with a positive correlation between them, which raises questions about the role of vitamin D for the adverse cardiovascular (CV) risk profile in hyposomatotropism. Thus, we aimed to investigate vitamin D status in GH deficiency (GHD) and the association between 25(OH)D and metabolic syndrome (MetS), its components, and other surrogate markers of CV risk. A total of 129 GHD adults (childhood-onset GHD, 41.9%) underwent blood testing (glucose, insulin, lipid profile, uric acid); blood pressure, anthropometric and bioelectrical-impedance measurements. Other CV risk markers were examined in a subsample of the initial population - hsCRP, adiponectin, and asymmetric dimethylarginine (n=88); carotid intima-media thickness (n=44). Total serum 25(OH)D, measured by electro-chemiluminescence binding assay, was used for vitamin D status assessment (adequate,≥30 ng/ml; insufficient, 20-29.9 ng/ml; deficient,<20 ng/ml). Data demonstrated high prevalence of hypovitaminosis D in GHD (deficiency 79.1%; insufficiency 14.7%), with lower 25(OH)D among adult-onset GHD subjects (14.0±7.2 vs. 16.8±8.0 ng/ml, p=0.039) and patients with MetS (11.8±4.5 vs. 16.3±8.1 ng/ml, p<0.0001). 25(OH)D correlated negatively and weakly with BMI, waist circumference, percent body fat, visceral fat area, and systolic BP. Regardless of whether vitamin D is a cause or a consequence of these metabolic abnormalities, 25(OH)D testing in hyposomatotropism is advisable. Normalization of vitamin D status is not proven to improve CV outcomes in general population, but it might have favorable effects in GHD, as its benefits might be restricted to patients with both low 25(OH)D and certain risk factors.


Assuntos
25-Hidroxivitamina D 2/sangue , Hormônio do Crescimento Humano/deficiência , Síndrome Metabólica/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Arginina/análogos & derivados , Arginina/sangue , Glicemia/metabolismo , Proteína C-Reativa/metabolismo , Feminino , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Ácido Úrico/sangue
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