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The cardiometabolic implications of Non-Functioning Adrenal Incidentaloma (NFAI) is still matter of debate. This study takes a novel approach to analyze this association, accounting for the influence of various confounding factors. We present the findings of a retrospective, cross-sectional, and case-control study. Data from all NFAI patients in primary prevention, referred to the University of Turin between 2000 and 2023, were collected and compared with subjects without adrenal disease, using propensity score matching analysis. A total of 1997 patients were included (906 patients with NFAI; 1091 controls). Adrenal tumor group was associated with high levels of cardiovascular risk scores in both univariate and multiple linear regression analyses (Progetto CUORE: EC 11.00, 95% CI 2.72-44.46, p = 0.001; SCORE: EC 1.97, 95% CI 1.01-3.81, p = 0.046). Regarding cardiometabolic complications, multivariable logistic regression revealed an independent association between NFAI and ascending aorta dilation (OR 4.64, 95% CI 2.24-9.63, p = 0.000), after adjusting for age, sex, smoking status, metabolic syndrome, number of antihypertensive drugs, estimated glomerular filtration rate (eGFR), and normetanephrine levels. Propensity score matching analysis (1:1 matching ratio), based on the same logistic regression model, confirmed the association of NFAI with aortic dilation (ß = 0.083, 95% CI 0.008-0.157, p = 0.030). No significant associations were found with metabolic syndrome, type II diabetes, eGFR <60 mL/min/1.73 m2, microalbuminuria, atrial fibrillation, or hypertensive heart disease. This study suggests that patients with NFAI face increased cardiometabolic risk and high prevalence of ascending aorta dilation. Routine evaluation of NFAI patients should include thorough cardiovascular assessment and consideration of treatments aimed at reducing cardiovascular risk.
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PURPOSE: To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process. METHODS: A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes. RESULTS: A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM. CONCLUSION: This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.
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OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.
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Síndrome de Cushing , Síndrome do QT Longo , Humanos , Estudos Cross-Over , Síndrome de Cushing/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia , Voluntários Saudáveis , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/tratamento farmacológico , Moxifloxacina , Receptores de Glucocorticoides , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
Background: Conventional glucocorticoids (C-GC) replacement regimens have a detrimental effect on skeletal health in patients with adrenal insufficiency (AI), ultimately leading to an increased fracture risk. The novel dual-release hydrocortisone (DR-HC) formulations are characterized by a more favourable safety profile on various clinical endpoints. Data comparing the impact of C-GC and DR-HC on bone, however, are scarce. Methods: Twenty-seven patients with autoimmune primary AI (PAI; 13 treated with C-GC and 14 treated with DR-HC) were evaluated to compare bone-related parameters between the two treatment groups. Results: No significant differences between the two treatments groups were observed with respect to bone turnover markers. Patients treated with C-GC showed a lower bone mineral density (BMD) at lumbar spine (LS; 0.791 ± 0.195 vs. 0.942 ± 0.124 g/cm2, p=0.025) and at femoral neck (FN; 0.633 ± 0.114 vs. 0.716 ± 0.088 g/cm2, p=0.045). Moreover, they were characterized by a lower trabecular bone score (TBS; 1.236 ± 0.035 vs. 1.383 ± 0.030, p=0.004) and by a higher mean number of vertebral fractures per patient (0.75 vs. 0 fractures, p=0.002). TBS was the best predictor of fracture risk, with a pseudo-R2 of 0.593; moreover, at mediation analysis, it was able to fully explain the observed detrimental effect of C-GC, compared to DR-HC, on fracture risk. Conclusions: These results suggest that DR-HC is associated with less bone-related complications compared to C-GC in patients with PAI. Moreover, TBS seems to play a pivotal role in the mediation of the relationship between glucocorticoid treatment regimens and fracture risk.
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BACKGROUND: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. METHODS: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I-III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14-20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. FINDINGS: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67-94) in the mitotane group and 75% (63-90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30-1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89-100] in the mitotane group and 86% [74-100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. FUNDING: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Mitotano/uso terapêutico , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/cirurgia , Intervalo Livre de Doença , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/cirurgiaRESUMO
Background: Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce. Methods: A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing's syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021. Results: Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison's disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission. Conclusion: This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.
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Several studies argued that cardiovascular evaluation of patients with nonfunctioning adrenal incidentaloma is of particular importance. Therefore, we aimed to evaluate the possibility of stratifying the cardiometabolic risk using metanephrine levels in this setting of patients. A retrospective cross-sectional study was designed, collecting data of metanephrine values in 828 patients with nonfunctioning adrenal incidentaloma, referred to our Division within the University of Turin between 2007 and 2021. The univariate analysis showed associations between urine metanephrines and cardiometabolic variables/parameters, particularly considering the noradrenaline metabolite. At the univariate regression, normetanephrine was associated with metabolic syndrome (OR = 1.13, p = 0.002), hypertensive cardiomyopathy (OR = 1.09, p = 0.026), microalbuminuria (OR = 1.14, p = 0.024), and eGFR < 60 mL/min/1.73 m2 (OR = 1.11, p = 0.013), while metanephrine was associated with microalbuminuria (OR = 1.50, p = 0.008). At multivariate regression, considering all major cardiovascular risk factors as possible confounders, normetanephrine retained a significant association with metabolic syndrome (OR = 1.10, p = 0.037). Moreover, metanephrine retained a significant association with the presence of microalbuminuria (OR = 1.66, p = 0.003). The present study showed a further role for metanephrines in the cardiovascular risk stratification of patients with nonfunctioning adrenal incidentaloma. Individuals with high levels of these indirect markers of sympathetic activity should be carefully monitored and may benefit from an aggressive treatment to reduce their additional cardiometabolic burden.
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Neoplasias das Glândulas Suprarrenais , Hipertensão , Síndrome Metabólica , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/epidemiologia , Estudos Transversais , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Síndrome Metabólica/complicações , Síndrome Metabólica/epidemiologia , Metanefrina , Normetanefrina , Feocromocitoma/complicações , Feocromocitoma/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: In recent years, scientific research has increasingly focused on Endocrine Disrupting Chemicals (EDCs) and demonstrated their relevant role in the functional impairment of endocrine glands. This induced regulatory authorities to ban some of these compounds and to carefully investigate others in order to prevent EDCs-related conditions. As a result, we witnessed a growing awareness and interest on this topic. AIMS: This paper aims to summarize current evidence regarding the detrimental effects of EDCs on pivotal endocrine glands like pituitary, thyroid and adrenal ones. Particularly, we directed our attention on the known and the hypothesized mechanisms of endocrine dysfunction brought by EDCs. We also gave a glimpse on recent findings from pioneering studies that could in the future shed a light on the pathophysiology of well-known, but poorly understood, endocrine diseases like hormone-producing adenomas. CONCLUSIONS: Although intriguing, studies on endocrine dysfunctions brought by EDCs are challenging, in particular when investigating long-term effects of EDCs on humans. However, undoubtedly, it represents a new intriguing field of science research.
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Disruptores Endócrinos , Doenças do Sistema Endócrino , Doenças da Hipófise , Humanos , Disruptores Endócrinos/toxicidade , Glândula Tireoide , Hipófise , Glândulas SuprarrenaisRESUMO
Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
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Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/tratamento farmacológico , Dexametasona/uso terapêutico , Europa (Continente)/epidemiologia , Feminino , Humanos , Gravidez , Estudos ProspectivosRESUMO
The simultaneous measurement of dexamethasone and cortisol has proven the ability to increase the diagnostic performance of the overnight dexamethasone-suppression test. Furthermore, the therapeutic drug monitoring of administered corticosteroid drugs could represent a crucial tool for investigating unexpected variations of steroid hormones' circulating levels. In this work, an LC-MS/MS method for the quantification of cortisol, cortisone, dexamethasone and six additional exogenous corticosteroids in the serum/plasma matrix was developed and validated in compliance with the ISO/IEC requirements. To assess the efficiency of the validated method, serum samples of 75 patients undergoing the dexamethasone-suppression test and 21 plasma samples of patients under immunosuppressive treatment after kidney transplant were analyzed. In all dexamethasone-suppression test samples, it was possible to measure the circulating levels of cortisol, cortisone and dexamethasone. Concentrations of the latter were for all tested patients above the proposed cutoff for the dexamethasone-suppression test's results, and the cortisol concentrations showed good correlation with the ones measured by routine immunometric analysis, therefore confirming the screening outcome for all enrolled patients. Prednisone was detected and quantified in all enrolled patients, confirming the use of such a corticosteroid for immunosuppressive therapy. Thanks to these two applications, we proved the overall performance of the developed LC-MS/MS method for four target analytes. The future implementation of such an analytical tool in the clinical biochemistry laboratory's routine will guarantee a single and versatile tool for simultaneously monitoring dexamethasone-suppression-test results and corticosteroid drugs' administration.
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Cortisona , Hidrocortisona , Humanos , Cromatografia Líquida , Dexametasona , Espectrometria de Massas em TandemRESUMO
Background: Hypercortisolism accounts for relevant morbidity and mortality and is often a diagnostic challenge for clinicians. A prompt diagnosis is necessary to treat Cushing's syndrome as early as possible. Objective: The aim of this study was to develop and validate a clinical model for the estimation of pre-test probability of hypercortisolism in an at-risk population. Design: We conducted a retrospective multicenter case-control study, involving five Italian referral centers for Endocrinology (Turin, Messina, Naples, Padua and Rome). One hundred and fifty patients affected by Cushing's syndrome and 300 patients in which hypercortisolism was excluded were enrolled. All patients were evaluated, according to current guidelines, for the suspicion of hypercortisolism. Results: The Cushing score was built by multivariable logistic regression, considering all main features associated with a clinical suspicion of hypercortisolism as possible predictors. A stepwise backward selection algorithm was used (final model AUC=0.873), then an internal validation was performed through ten-fold cross-validation. Final estimation of the model performance showed an average AUC=0.841, thus reassuring about a small overfitting effect. The retrieved score was structured on a 17.5-point scale: low-risk class (score value: ≤5.5, probability of disease=0.8%); intermediate-low-risk class (score value: 6-8.5, probability of disease=2.7%); intermediate-high-risk class (score value: 9-11.5, probability of disease=18.5%) and finally, high-risk class (score value: ≥12, probability of disease=72.5%). Conclusions: We developed and internally validated a simple tool to determine pre-test probability of hypercortisolism, the Cushing score, that showed a remarkable predictive power for the discrimination between subjects with and without a final diagnosis of Cushing's syndrome.
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Síndrome de Cushing/diagnóstico , Modelos Estatísticos , Adulto , Idoso , Estudos de Casos e Controles , Síndrome de Cushing/etiologia , Técnicas de Diagnóstico Endócrino , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estatística como Assunto/métodosRESUMO
Primary adrenal insufficiency (PAI) occurs in ~1/5000-1/7000 individuals and is in most cases caused by autoimmune Addison's disease (AAD). Around 10-20% of women with AAD develop premature ovarian insufficiency (POI) before the age of 40 years. 21-Hydroxylase autoantibodies (21OHAb) are the best single immune marker to classify AAD among PAI patients and autoimmune POI in hypergonadotropic hypogonadic women. In AAD, detection of steroid-cell autoantibodies (StCA) predicts future development of POI. AAD-related autoimmune POI is characterized by a selective destruction of theca cells with preservation of primary follicles and granulosa cells of secondary and tertiary follicles. Women with AAD show reduced fertility and parity. Patients with well-managed disease are generally expected to have uneventful pregnancies with favorable outcome, but increased risk of maternal and neonatal complications has been reported. Hence, AAD pregnant women must be carefully monitored by skilled staff which is familiar with the disorder and specific attention must be given to the substitutive therapy.
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Doença de Addison , Insuficiência Adrenal , Insuficiência Ovariana Primária , Insuficiência Adrenal/etiologia , Adulto , Autoanticorpos , Feminino , Fertilidade , Humanos , Recém-Nascido , Gravidez , Insuficiência Ovariana Primária/etiologiaRESUMO
The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44-9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95-0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00-1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00-11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94-0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00-1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03-1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4-15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2-16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06-1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.
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Neoplasias das Glândulas Suprarrenais/diagnóstico , Mutação , Recidiva Local de Neoplasia/diagnóstico , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/genética , Feocromocitoma/patologia , Prognóstico , Carga TumoralRESUMO
Pituitary autoimmunity, considered a synonym of autoimmune hypophysitis, defines a wide spectrum of conditions (neoplastic, functional, and iatrogenic pituitary disorders; and extra-pituitary autoimmune and non-autoimmune diseases), and is characterized by the presence of antipituitary antibodies (APAs) at various titer and prevalence. These conditions have been increasingly recognized not only in adults, but also in children. The autoimmune pathogenesis, histological features of the primary (i.e. lymphocytic, granulomatous, xanthomatous, IgG-4 related lymphoplasmacytic, and necrotizing) forms, and the pathognomonic association of lymphocytic hypophysitis with pregnancy and CTLA-4 antibody therapy, have been clearly demonstrated. Meanwhile, non-invasive differential diagnosis remains extremely challenging since none of the suggested clinical, radiological or laboratory criteria are pathognomonic. In this context, the demonstration of APA is not sufficient, because of the lack of specificity, and associated methodological and theoretical issues (i.e. disease marker vs. pathogen; antigen target(s); and diagnostic/prognostic significance). This chapter aims at providing a comprehensive overview of the pituitary autoimmunity panorama for epidemiological, clinical radiological, and histological aspects, while discussing the main diagnostic limitations and issues associated with disease management.
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Doenças Autoimunes , Autoimunidade , Doenças da Hipófise , Hipófise , HumanosRESUMO
Since the mid 1900s, a significant increase of infectious, hematological, and autoimmune diseases has been reported in patients with Down's syndrome (DS), independent of sex, age, family history, and exposure to other risk factors, suggesting an intrinsic alteration of the immune system. Several in vitro and in vivo studies have demonstrated alterations of both cellular and humoral immunological response mainly, although not exclusively, secondary to alterations of the expression of autoimmune regulator gene (located on chromosome 21), leading to thymic structural and functional impairments. Autoimmune thyroid disorders (i.e. Hashimoto's thyroiditis and Graves' disease) and type 1 diabetes mellitus are the most common autoimmune endocrine disorders associated with DS, and present with some peculiar features. The underlying etiopathogenic mechanisms and clinical significance of some mild laboratory alterations are still poorly understood. For these aspects, together with the associated multiple comorbidities and intellectual impairment - that make DS patients dependent on care givers - and in the absence of definite guidelines, disease management is very challenging and should be patient-tailored.
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Diabetes Mellitus Tipo 1 , Síndrome de Down , Tireoidite Autoimune , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Síndrome de Down/imunologia , Síndrome de Down/metabolismo , Humanos , Tireoidite Autoimune/imunologia , Tireoidite Autoimune/metabolismoRESUMO
Adrenal failure secondary to hypothalamic-pituitary disease is a common although underestimated and underdiagnosed condition, with serious consequences. Corticotropin deficiency can be isolated or more frequently occur in association with other pituitary hormones deficiencies. The most frequent endogenous cause of secondary adrenal insufficiency (SAI) is a tumor of the hypothalamic-pituitary region, usually associated with panhypopituitarism secondary to tumor growth or to its treatment with surgery or irradiation. Less commonly, SAI is due to nontumoral disorders including infiltrative lesions, infective processes, vascular alterations, traumatic brain injury, empty sella or genetic disorders. Finally, long-term administration of exogenous glucocorticoids can determine secondary and/or tertiary hypoadrenalism acting at the hypothalamic level and leading to prolonged suppression of the hypothalamic-pituitary-adrenal axis. It is essential to perform validated diagnostic procedures in order to promptly diagnose hypoadrenalism so as to prevent an adrenal crisis. At the same time, diagnosis is complex as no single test has sufficient sensitivity to identify all patients with SAI. Therefore, clinical judgment and follow-up are crucial for the assessment of corticotropin deficiency. Patients with persisting suggestive symptoms and/or a clinical history of higher risk for adrenal insufficiency deserve careful subsequent reassessments.
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Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/etiologia , HumanosRESUMO
In patients with Addison's disease (AD), a dual-release preparation of hydrocortisone (Plenadren, PLEN) has been demonstrated to maintain cortisol levels in a more physiological range than conventional glucocorticoid therapy, and to exert positive effects. This study aimed to assess variations of anthropometric, metabolic, and hormonal parameters in patients with AD after switching from conventional hydrocortisone (HC) treatment to PLEN. In nineteen AD patients (15 F and 4 M, age 27-65 years) treated with HC 20 mg/day thrice daily, body weight, BMI, waist circumference, fasting glucose, HbA1c, serum lipids, plasma renin activity, electrolytes, and blood pressure were evaluated at baseline, and 1, 3, 6, and 12 months after switching from HC to PLEN. At baseline, and after 1 and 12 months of PLEN, blood ACTH and cortisol (at 0800 h at fasting, and 30, 60, 90, 120, and 240 min after drug ingestion), and health-related quality of life (HRQoL), using 30-AddiQoL questionnaire, were evaluated. During PLEN, waist and serum lipid progressively decreased. After 12 months of PLEN, a significant difference was observed in waist circumference (P = 0.007), HbA1c (P = 0.002), total and LDL-cholesterol levels (P < 0.05). ACTH levels at 240 min and the area under the curve (AUC) were lower (P < 0.05) during PLEN than HC, while cortisol peaks and AUC were similar. 30-AddiQoL total score also improved (P = 0.04) during PLEN. In AD patients, PLEN reduces central adiposity, and improves glucose and metabolism parameters and HRQoL.
Assuntos
Doença de Addison/tratamento farmacológico , Pressão Sanguínea/fisiologia , Glucocorticoides/uso terapêutico , Terapia de Reposição Hormonal , Hidrocortisona/uso terapêutico , Qualidade de Vida , Doença de Addison/metabolismo , Adulto , Idoso , Índice de Massa Corporal , Preparações de Ação Retardada , Feminino , Glucocorticoides/administração & dosagem , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Circunferência da Cintura/efeitos dos fármacosRESUMO
BACKGROUND: The association between the hypothalamic-pituitary-adrenal (HPA) axis and sleep is well described. It is also known that HPA axis disturbances have an effect on sleep. In fact, patients affected by Cushing's syndrome (CS) often complain about poor sleep quality. Our aim was to evaluate objective sleep quality and duration in patients with Cushing's syndrome in active phase, using wrist actigraphy. PATIENTS AND METHODS: In 12 patients with active CS without ongoing specific therapy (11 F, 1 M; age 40.0 ± 10.9 years; BMI 28.4 ± 6.7 kg/m(2)) and 12 healthy control subjects (HS) (11 F, 1 M; age 44.0 ± 11.0 years; BMI 23.9 ± 4.2 kg/m(2)) an actigraphic evaluation was performed on 3 consecutive days under free living conditions. Objective measurement of sleep duration and quality was estimated by an actiwatch, which is a wristwatch-like device used to detect motor activity. RESULTS: In CS patients, wrist actigraphy showed higher fragmented sleep (fragmentation index CS 16.2 ± 4.2, HS 13.0 ± 3.6; p = 0.034) and increased nocturnal motor activity (total activity score CS 8318 ± 4308, HS 4971 ± 2372; p = 0.020; mean activity score CS 8.7 ± 4.2, HS 5.4 ± 2.2; p = 0.030; mean score in active time CS 104.8 ± 39.2, HS 74.8 ± 23.1; p = 0.030). On the contrary, actual sleep time resulted similar in CS and HS. No correlation was found between sleep alterations and urinary free cortisol in patients. CONCLUSIONS: The impaired actigraphic parameters described in our study suggest that hypercortisolism is associated with sleep alterations, which could contribute to the worsening of life quality and metabolic comorbidities associated with CS. These results have to be confirmed in a larger cohort of patients, using more accurate instruments for sleep assessment.
Assuntos
Actigrafia , Síndrome de Cushing/diagnóstico , Sono/fisiologia , Adulto , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/patologia , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/patologia , PunhoRESUMO
CONTEXT: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. OBJECTIVES: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. METHODS: Autoantibodies against NALP5/MATER and inhibin chains-α and -ßA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. RESULTS: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/ßA autoantibodies. CONCLUSIONS: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.