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1.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32424397

RESUMO

CONTEXT: Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. OBJECTIVE: Multicenter survey on current clinical approaches in managing AI during pregnancy. DESIGN: Retrospective anonymized data collection from 19 international centers from 2013 to 2019. SETTING AND PATIENTS: 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). RESULTS: Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. CONCLUSIONS: This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

2.
Orphanet J Rare Dis ; 15(1): 99, 2020 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-32306986

RESUMO

BACKGROUND: Glycogen storage disease type I (GSDI) is an inborn error of carbohydrate metabolism caused by mutations of either the G6PC gene (GSDIa) or the SLC37A4 gene (GSDIb). Glucose 6-phosphate (G6P) availability has been shown to modulate 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1), an ER-bound enzyme catalyzing the local conversion of inactive cortisone into active cortisol. Adrenal cortex assessment has never been performed in GSDI. The aim of the current study was to evaluate the adrenal cortex hormones levels in GSDI patients. METHODS: Seventeen GSDI (10 GSDIa and 7 GSDIb) patients and thirty-four age and sex-matched controls were enrolled. Baseline adrenal cortex hormones and biochemical markers of metabolic control serum levels were analyzed. Low dose ACTH stimulation test was also performed. RESULTS: Baseline cortisol serum levels were higher in GSDIa patients (p = 0.042) and lower in GSDIb patients (p = 0.041) than controls. GSDIa patients also showed higher peak cortisol response (p = 0.000) and Cortisol AUC (p = 0.029). In GSDIa patients, serum cholesterol (p = 0.000), triglycerides (p = 0.000), lactate (p = 0.000) and uric acid (p = 0.008) levels were higher and bicarbonate (p = 0.000) levels were lower than controls. In GSDIb patients, serum cholesterol levels (p = 0.016) were lower and lactate (p = 0.000) and uric acid (p = 0.000) levels were higher than controls. Baseline cortisol serum levels directly correlated with cholesterol (ρ = 0.65, p = 0.005) and triglycerides (ρ = 0.60, p = 0.012) serum levels in GSDI patients. CONCLUSIONS: The present study showed impaired cortisol levels in GSDI patients, with opposite trend between GSDIa and GSDIb. The otherwise preserved adrenal cortex function suggests that this finding might be secondary to local deregulation rather than hypothalamo-pituitary-adrenal axis dysfunction in GSDI patients. We hypothesize that 11ßHSD1 might represent the link between endocrine regulation and metabolic derangement in GSDI, constituting new potential therapeutic target in GSDI patients.

3.
J Clin Med ; 8(11)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684071

RESUMO

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

4.
Sci Rep ; 9(1): 11695, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406139

RESUMO

Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.

5.
Endocr Connect ; 8(9): R144-R156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31398711

RESUMO

Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.

6.
Lancet Diabetes Endocrinol ; 6(3): 173-185, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29229498

RESUMO

BACKGROUND: Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment. The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency. METHODS: We did a single-blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients (aged 18-80 years) with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment. Patients were randomly assigned (1:1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation. The primary outcome was bodyweight change from baseline to 24 weeks. Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02277587. FINDINGS: Between March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46). At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (-2·1 kg [95% CI -4·0 to -0·3] vs 1·9 kg [-0·1 to 3·9]; treatment difference -4·0 kg, 95% CI -6·9 to -1·1; p=0·008). Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group. We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0·016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related. INTERPRETATION: Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency. FUNDING: Italian Ministry of University and Research.


Assuntos
Insuficiência Adrenal/imunologia , Insuficiência Adrenal/metabolismo , Anti-Inflamatórios/uso terapêutico , Biomarcadores/metabolismo , Glucocorticoides/uso terapêutico , Hidrocortisona/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Adolescente , Insuficiência Adrenal/tratamento farmacológico , Adulto , Idoso , Peso Corporal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Qualidade de Vida , Método Simples-Cego , Adulto Jovem
7.
Endocrinology ; 158(6): 1527-1532, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28368448

RESUMO

Adrenal mass (AM) is a common incidental finding detected during radiological investigations with an estimated incidence of 4%. Subjects with AM do not show any physical signs of adrenal hormonal excess, although they are often insulin resistant. Interestingly, apparently nonfunctioning AMs are often associated with a high prevalence of insulin resistance (IR) and metabolic syndrome. However, it is unclear whether AM develops from a primary IR and compensatory hyperinsulinemia or whether IR is only secondary to the slight cortisol hypersecretion by AM. Further, the degree of IR has been directly reported to correlate to the size of AM, thus allowing one to hypothesize that compensatory hyperinsulinemia to IR could be mitogenic on the adrenal cortex acting through the activation of insulin and insulinlike growth factor 1 receptors. Thus, the aim of the present article is to review the current evidence on the link between AM and compensatory hyperinsulinemia to IR.


Assuntos
Glândulas Suprarrenais/anatomia & histologia , Resistência à Insulina/fisiologia , Síndrome Metabólica/etiologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Humanos , Hiperinsulinismo/etiologia , Hiperinsulinismo/patologia , Insulina/metabolismo , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Tamanho do Órgão
8.
Pituitary ; 20(1): 46-62, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28224405

RESUMO

Acromegaly is associated with an enhanced mortality, with cardiovascular and respiratory complications representing not only the most frequent comorbidities but also two of the main causes of deaths, whereas a minor role is played by metabolic complications, and particularly diabetes mellitus. The most prevalent cardiovascular complications of acromegaly include a cardiomyopathy, characterized by cardiac hypertrophy and diastolic and systolic dysfunction together with arterial hypertension, cardiac rhythm disorders and valve diseases, as well as vascular endothelial dysfunction. Biochemical control of acromegaly significantly improves cardiovascular disease, albeit completely recovering to normal mainly in young patients with short disease duration. Respiratory complications, represented mainly by sleep-breathing disorders, particularly sleep apnea, and respiratory insufficiency, frequently occur at the early stage of the disease and, although their severity decreases with disease control, this improvement does not often change the indication for a specific therapy directed to improve respiratory function. Metabolic complications, including glucose and lipid disorders, are variably reported in acromegaly. Treatments of acromegaly may influence glucose metabolism, and the presence of diabetes mellitus in acromegaly may affect the choice of treatments, so that glucose homeostasis is worth being monitored during the entire course of the disease. Early diagnosis and prompt treatment of acromegaly, aimed at obtaining a strict control of hormone excess, are the best strategy to limit the development or reverse the complications and prevent the premature mortality.


Assuntos
Acromegalia/complicações , Acromegalia/mortalidade , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Comorbidade , Hormônio do Crescimento Humano/metabolismo , Humanos , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndromes da Apneia do Sono/etiologia , Síndromes da Apneia do Sono/metabolismo
9.
Endocrine ; 55(3): 691-696, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27435590

RESUMO

Adrenocorticotropin-secreting pituitary tumor represents about 10 % of pituitary adenomas and at the time of diagnosis most of them are microadenomas. Transsphenoidal surgery is the first-line treatment of Cushing's disease and accurate localization of the tumor within the gland is essential for selectively removing the lesion and preserving normal pituitary function. Magnetic resonance imaging is the best imaging modality for the detection of pituitary tumors, but adrenocorticotropin-secreting pituitary microadenomas are not correctly identified in 30-50 % of cases, because of their size, location, and enhancing characteristics. Several recent studies were performed with the purpose of better localizing the adrenocorticotropin-secreting microadenomas through the use in magnetic resonance imaging of specific sequences, reduced contrast medium dose and high-field technology. Therefore, an improved imaging technique for pituitary disease is mandatory in the suspect of Cushing's disease. The aims of this paper are to present an overview of pituitary magnetic resonance imaging in the diagnosis of Cushing's disease and to provide a magnetic resonance imaging protocol to be followed in case of suspicion adrenocorticotropin-secreting pituitary adenoma.


Assuntos
Adenoma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Hipersecreção Hipofisária de ACTH/diagnóstico por imagem , Hipófise/diagnóstico por imagem , Neoplasias Hipofisárias/diagnóstico por imagem , Humanos
10.
Endocrine ; 55(2): 564-572, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26965912

RESUMO

Cushing syndrome (CS) is characterized by increased morbidity and mortality compared to the general population. However, there are patients who have more clinical aggressive forms than others. Aim of the study is to evaluate whether the degree of hypercortisolism, defined by the number of times urinary free cortisol (UFC) levels exceed the upper limit of the normal range (ULN), is related to the worsening of phenotypic features, as well as metabolic and cardiovascular parameters, in a cohort of CS patients. A cross-sectional study was conducted on 192 patients with active CS, consecutively presenting at the outpatients' clinic of the University Hospitals of Ancona, Naples, and Palermo. Patients were grouped into mild (UFC not exceeding twice the ULN), moderate (2-5 times the ULN), and severe (more than 5 times the ULN) hypercortisolism. Thirty-seven patients (19.3 %) had mild, 115 (59.8 %) moderate, and 40 (20.9 %) severe hypercortisolism. A significant trend of increase among the three groups was demonstrated for 8-, 16-, and 24-h serum cortisol levels (p < 0.001) and serum cortisol after low dose of dexamethasone suppression test (p = 0.001). No significant trend of increase was found regarding phenotype and comorbidities. The degree of hypercortisolism by itself does not appear to be a sufficient parameter to express the severity of CS. Therefore, estimating the severity of CS according to biochemical parameters remains a challenge, while the clinical phenotype and the associated comorbidities might be more useful to assessing the severity of the CS.


Assuntos
Síndrome de Cushing/diagnóstico , Hidrocortisona/urina , Adulto , Estudos Transversais , Síndrome de Cushing/sangue , Síndrome de Cushing/urina , Dexametasona , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
11.
Endocrine ; 56(1): 10-18, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27189147

RESUMO

Cushing's syndrome is caused by prolonged exposure to elevated cortisol levels. The most common form of endogenous Cushing's syndrome is Cushing's disease, which results from an adrenocorticotropic hormone-secreting pituitary tumour. Cushing's disease is associated with increased mortality, mostly attributable to cardiovascular complications, and a host of comorbidities such as metabolic and skeletal disorders, infections and neuropsychiatric disturbances. As a consequence, Cushing's disease substantially impairs health-related quality of life. It is crucial that the condition is diagnosed as early as possible, and that rapid and effective treatment is initiated in order to limit long-term morbidity and mortality. The initial treatment of choice for Cushing's disease is selective transsphenoidal pituitary surgery; however, the risk of recurrence after initial surgery is high and remains so for many decades after surgery. A particular concern is the growing body of evidence indicating that the negative physical and psychosocial sequelae of chronic hypercortisolism may persist in patients with Cushing's disease even after long-term surgical 'cure'. Current treatment options for post-surgical patients with persistent or recurrent Cushing's disease include second surgery, radiotherapy, bilateral adrenalectomy and medical therapy; however, each approach has its limitations and there is an unmet need for more efficacious treatments. The current review provides an overview of the burden of illness of Cushing's disease, underscoring the need for prompt diagnosis and effective treatment, as well as highlighting the need for better therapies.


Assuntos
Efeitos Psicossociais da Doença , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/terapia , Qualidade de Vida , Adrenalectomia , Humanos , Hidrocortisona/sangue , Hipersecreção Hipofisária de ACTH/sangue , Hipersecreção Hipofisária de ACTH/psicologia , Hipófise/cirurgia , Resultado do Tratamento
12.
Endocrine ; 55(3): 872-884, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27295183

RESUMO

To date, no data are available on the effects of long-term combined treatment with somatostatin analogues (SA) and pegvisomant (PEG) on cardiovascular complications in acromegaly. The current study aimed at investigating the effects of long-term SA + PEG on cardiac structure and performance. Thirty-six patients (14 M, 22 F, aged 52.3 ± 10.2 years) entered this study. Weight, BMI, systolic (SBP) and diastolic (DBP) blood pressure, IGF-I, fasting glucose (FG), fasting insulin (FI), HOMA-IR, HbA1c, and lipids were evaluated at baseline (T0), after long-term (median 36 months) SA (T1), after 12 (T12) and 60 (T60) months of SA + PEG, and at last follow-up (LFU, median 78 months). At each time point, all patients underwent echocardiography. At T1, induced a slight but not significant decrease in IGF-I (p = 0.077), whereas FI (p = 0.004), HOMA-IR (p = 0.013), ejection fraction (EF, p = 0.013), early (E) to late (A) ventricular filling velocities (E/A, p = 0.001), and isovolumetric relaxation time (IVRT, p = 0.000) significantly improved. At T12, IGF-I (p = 0.000) significantly reduced compared to T0, and FI (p = 0.001), HOMA-IR (p = 0.000), LVMI (p = 0.000), and E/A (p = 0.006) further improved compared to T1. At T60, FI (p = 0.027), HOMA-IR (p = 0.049), and E/A (p = 0.005) significantly improved as compared to T1. At LFU IGF-I normalized in 83.3 %, FI (p = 0.000), HOMA-IR (p = 0.000), LVMi (p = 0.000), and E/A (p = 0.005) further improved as compared to T1. PEG dose significantly correlated with LVMi at T12 (r = 0.575, p = 0.000) and T60 (r = 0.403, p = 0.037). Long-term PEG addition to SA improves cardiac structure and performance, particularly diastolic dysfunction, in acromegalic patients resistant to SA.


Assuntos
Acromegalia/tratamento farmacológico , Coração/efeitos dos fármacos , Hormônio do Crescimento Humano/análogos & derivados , Miocárdio/patologia , Somatostatina/análogos & derivados , Acromegalia/diagnóstico por imagem , Acromegalia/patologia , Adulto , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Quimioterapia Combinada , Ecocardiografia , Feminino , Coração/diagnóstico por imagem , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade
13.
Artigo em Inglês | MEDLINE | ID: mdl-27782064

RESUMO

Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies.


Assuntos
Poluentes Ocupacionais do Ar/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/induzido quimicamente , Fenóis/efeitos adversos , Compostos Benzidrílicos/farmacologia , Feminino , Glucagon/efeitos dos fármacos , Humanos , Antagonistas da Insulina , Masculino , Fenóis/farmacologia , Plásticos , Cimento de Policarboxilato
15.
Front Horm Res ; 46: 54-65, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27212264

RESUMO

Cushing's syndrome (CS) is a severe chronic and systemic condition caused by endogenous or exogenous excess of glucocorticoids, associated with increased morbidity and mortality. Patients with active CS suffer from many metabolic alterations, including visceral obesity, systemic arterial hypertension, impairment of glucose metabolism and dyslipidemia. Additionally, in these patients several cardiovascular abnormalities, i.e. atherosclerosis, clotting disorders, left ventricular hypertrophy, concentric remodeling and diastolic dysfunction have been documented. These alterations, which persist even long after hypercortisolism remission, account for the increased cardiovascular risk and greatly contribute to the increased mortality observed in patients with CS. The current review aims to discuss the main adverse effects of CS on metabolism and cardiovascular risk, focusing on the active and remission phases of disease, and underlining the importance of long-term monitoring and treatment of these complications during active disease, as well as in the long-term follow-up after CS remission.


Assuntos
Doenças Cardiovasculares/etiologia , Síndrome de Cushing/complicações , Síndrome Metabólica/etiologia , Humanos
17.
Oncotarget ; 7(9): 9718-31, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26756219

RESUMO

Deregulation of mTOR and IGF pathways is frequent in hepatocellular carcinoma (HCC), thus mTOR and IGF1R represent suitable therapeutic targets in HCC. The aim of this study was to evaluate the effects of mTOR inhibitors (mTORi) and OSI-906, blocker of IGF1R/IR, on HCC cell proliferation, viability, migration and invasion, and alpha-fetoprotein (α-FP) secretion. In HepG2 and HuH-7 we evaluated, the expression of mTOR and IGF pathway components; the effects of Sirolimus, Everolimus, Temsirolimus and OSI-906 on cell proliferation; the effects of Sirolimus, OSI-906, and their combination, on cell secretion, proliferation, viability, cell cycle, apoptosis, invasion and migration. Moreover, intracellular mechanisms underlying these cell functions were evaluated in both cell lines. Our results show that HepG2 and HuH-7 present with the same mRNA expression profile with high levels of IGF2. OSI-906 inhibited cell proliferation at high concentration, while mTORi suppressed cell proliferation in a dose-time dependent manner in both cell lines. The co-treatment showed an additive inhibitory effect on cell proliferation and viability. This effect was not related to induction of apoptosis, but to G0/G1 phase block. Moreover, the co-treatment prevented the Sirolimus-induced AKT activation as escape mechanism. Both agents demonstrated to be differently effective in inhibiting α-FP secretion. Sirolimus, OSI-906, and their combination, blocked cell migration and invasion in HuH-7. These findings indicate that, co-targeting of IGF1R/IR and mTOR pathways could be a novel therapeutic approach in the management of HCC, in order to maximize antitumoral effect and to prevent the early development of resistance mechanisms.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Somatomedina/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , alfa-Fetoproteínas/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Everolimo/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Imidazóis/farmacologia , Insulina/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/farmacologia , RNA Mensageiro/biossíntese , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/análogos & derivados , Sirolimo/farmacologia
18.
Front Neurosci ; 9: 129, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25941467

RESUMO

Endogenous Cushing's syndrome (CS), a rare endocrine disorder characterized by cortisol hypersecretion, is associated with psychiatric and neurocognitive disorders. Major depression, mania, anxiety, and neurocognitive impairment are the most important clinical abnormalities. Moreover, patients most often complain of impairment in quality of life, interference with family life, social, and work performance. Surprisingly, after hypercortisolism resolution, despite the improvement of the overall prevalence of psychiatric and neurocognitive disorders, the brain volume loss at least partially persists and it should be noted that some patients may still display depression, anxiety, panic disorders, and neurocognitive impairment. This brief review aimed at describing the prevalence of psychiatric and neurocognitive disorders and their characterization both during the active and remission phases of CS. The last section of this review is dedicated to quality of life, impaired during active CS and only partially resolved after resolution of hypercortisolism.

19.
Endocrine ; 50(3): 725-40, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25743263

RESUMO

Pasireotide is the first medical therapy officially approved for the treatment of adult patients with Cushing's disease (CD) who experienced a failure of pituitary surgery or are not candidates for surgery and require medical therapeutic intervention. The current study aimed at investigating the effects of long-term treatment with pasireotide (up to 24 months) on tumor mass in a group of patients with CD, participating to a phase III study. Fourteen CD patients entered the phase III clinical trial CSOM230B2305 at Naples Center, and eight (seven women, one man, aged 38.9 ± 17.6 years), including seven with a microadenoma and one with a macroadenoma, received treatment with pasireotide at the dose of 600-1200 µg bid for at least 6 months, and were considered for the analysis of the study. These eight patients were subjected to the evaluation of pituitary tumor volume by pituitary MRI, together with the evaluation of urinary cortisol levels, at baseline and every 6 months for the entire period of treatment. Pasireotide treatment induced full disease control in 37.5 % and partial disease control in 37.5 % after 6 months, whereas full and partial disease control after 12 months was obtained in 28.6 % and in 57.1 % of patients, respectively. A significant (>25 %) reduction in tumor volume was found in 62.5 % and in 100 % of patients, after 6 and 12 months, respectively. In particular, after 6 months, a slight tumor shrinkage (between 25.1 and 50 %) was observed in 25 %, moderate (50.1-75 %) in 25 %, and marked (>75 %) in 12.5 % of patients, whereas after 12 months, a slight tumor shrinkage was observed in 43 %, moderate in 14 %, and marked in 43 % of patients. In 25 % of patients (two patients), a marked tumor shrinkage was recorded, with tumor mass disappearance in one case; this tumor shrinkage was associated to rapid and sustained biochemical remission up to 24 months of continuous pasireotide treatment. These two cases represent the first cases with a documentation of such a notable effect of pasireotide on tumor mass. Pasireotide induces significant tumor shrinkage in 62.5 % of patients after 6 months and in 100 % of patients after 12 months, and occasionally induces a radiological disappearance of the tumor. This evidence supports and strengthens the role of pasireotide as medical treatment specifically addressed to patients with CD, particularly in those who had unsuccessful pituitary surgery, or are not candidates for surgery.


Assuntos
Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Somatostatina/análogos & derivados , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Somatostatina/uso terapêutico , Resultado do Tratamento , Adulto Jovem
20.
Eur J Endocrinol ; 170(2): 311-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24255133

RESUMO

OBJECTIVE: Diabetes mellitus (DM) is one of the most frequent complications of Cushing's syndrome (CS). The aim of this study was to define the changes in insulin sensitivity and/or secretion in relation to glucose tolerance categories in newly diagnosed CS patients. DESIGN: Cross-sectional study on 140 patients with CS. METHODS: A total of 113 women (80 with pituitary disease and 33 with adrenal disease, aged 41.7±15.7 years) and 27 men (19 with pituitary disease and eight with adrenal disease, aged 38.1±20.01 years) at diagnosis were divided according to glucose tolerance into normal glucose tolerance (CS/NGT), impaired fasting glucose and/or impaired glucose tolerance (CS/prediabetes), and diabetes (CS/DM) groups. RESULTS: Seventy-one patients had CS/NGT (49.3%), 26 (18.5%) had CS/prediabetes and 43 (30.8%) had CS/DM. Significant increasing trends in the prevalence of family history of diabetes (P<0.001), metabolic syndrome (P<0.001), age (P<0.001) and waist circumference (P=0.043) and decreasing trends in HOMA-ß (P<0.001) and oral disposition index (DIo) (P<0.002) were observed among the groups. No significant trends in fasting insulin levels, area under the curve for insulin (AUCINS), Matsuda index of insulin sensitivity (ISI-Matsuda) and visceral adiposity index were detected. CONCLUSIONS: Impairment of glucose tolerance is characterized by the inability of ß-cells to adequately compensate for insulin resistance through increased insulin secretion. Age, genetic predisposition and lifestyle, in combination with the duration and degree of hypercortisolism, strongly contribute to the impairment of glucose tolerance in patients with a natural history of CS. A careful phenotypic evaluation of glucose tolerance defects in patients with CS proves useful for the identification of those at a high risk of metabolic complications.


Assuntos
Síndrome de Cushing/complicações , Diabetes Mellitus Tipo 2/etiologia , Intolerância à Glucose/etiologia , Hidrocortisona/urina , Adulto , Estudos Transversais , Feminino , Teste de Tolerância a Glucose , Humanos , Hidrocortisona/sangue , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Fenótipo , Estado Pré-Diabético , Estudos Retrospectivos
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