RESUMO
BACKGROUND: Congenital adrenal hyperplasia (CAH) encompassed a bunch of autosomal recessive disorders characterized by impaired cortisol levels due to an enzymatic deficiency in steroid synthesis. In adult male patients with CAH, a frequent complication related to poor disease control is the development of ectopic adrenocortical tissue in the testes, named testicular adrenal rest tumors (TART). Conversely, ovarian adrenal rest tumors (OART) in females are extremely rare and adrenal rests in sites other than gonads are so uncommon to have been described only few times in literature. CASE PRESENTATION: We report a case of a male patient with untreated CAH and oncologic history of pleomorphic sarcoma who presented with massive bilateral adrenal enlargement and adrenal rest tumors in peri-lumbar and peri-cecal sites, which mimicked metastasis from sarcoma. CONCLUSIONS: The development of massive adrenal enlargement and ectopic adrenal rest tumors in sites other than gonads, even if very uncommon, should be suspected in patients with CAH and prolonged periods of undertreatment.
Assuntos
Hiperplasia Suprarrenal Congênita , Tumor de Resto Suprarrenal , Humanos , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/patologia , Hiperplasia Suprarrenal Congênita/diagnóstico , Masculino , Tumor de Resto Suprarrenal/patologia , Tumor de Resto Suprarrenal/diagnóstico , Tumor de Resto Suprarrenal/etiologia , Diagnóstico Diferencial , Sarcoma/diagnóstico , Sarcoma/patologia , Adulto , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/secundário , PrognósticoRESUMO
Pseudohyperaldosteronism (PHA) is characterized by hypertension, hypokalemia, and a decrease in plasma renin and aldosterone levels. It can be caused by several causes, but the most frequent is due to excess intake of licorice. The effect is mediated by the active metabolite of licorice, glycyrrhetinic acid (GA), which acts by blocking the 11-hydroxysteroid dehydrogenase type 2 and binding to the mineralocorticoid receptor (MR) as an agonist. The management of licorice-induced PHA depends on several individual factors, such as age, gender, comorbidities, duration and amount of licorice intake, and metabolism. The clinical picture usually reverts upon licorice withdrawal, but sometimes mineralocorticoid-like effects can be critical and persist for several weeks, requiring treatment with MR blockers and potassium supplements. Through this case series of licorice-induced PHA, we aim to increase awareness about exogenous PHA, and the possible risk associated with excess intake of licorice. An accurate history is mandatory in patients with hypertension and hypokalemia to avoid unnecessary testing. GA is a component of several products, such as candies, breath fresheners, beverages, tobacco, cosmetics, and laxatives. In recent years, the mechanisms of action of licorice and its active compounds have been better elucidated, suggesting its benefits in several clinical settings. Nevertheless, licorice should still be consumed with caution, considering that licorice-induced PHA is still an underestimated condition, and its intake should be avoided in patients with increased risk of licorice toxicity due to concomitant comorbidities or interfering drugs.
Assuntos
Ácido Glicirretínico , Glycyrrhiza , Hiperaldosteronismo , Humanos , Glycyrrhiza/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Ácido Glicirretínico/farmacologia , Adulto , Hipopotassemia/induzido quimicamente , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Idoso , Hipertensão , Aldosterona/metabolismo , Aldosterona/sangue , Renina/sangue , Renina/metabolismoRESUMO
CONTEXT: Cushing's disease (CD) is rare condition burdened by several systemic complications correlated to higher mortality rates. The primary goal of clinicians is to achieve remission, but it is unclear if treatment can also increase life expectancy. AIM: To assess the prevalence of cortisol-related complications and mortality in a large cohort of CD patients attending a single referral centre. MATERIALS AND METHODS: The clinical charts of CD patients attending a referral hospital between 2001 and 2021 were reviewed. RESULTS: 126 CD patients (median age at diagnosis 39 years) were included. At the last examination, 78/126 (61.9%) of the patients were in remission regardless of previous treatment strategies. Patients in remission showed a significant improvement in all the cardiovascular (CV) comorbidities (p < 0.05). The CV events were more frequent in older patients (p = 0.003), smokers and persistent CD groups (p < 0.05). Most of the thromboembolic (TE) and infective events occurred during active stages of the disease. The CV events were the most frequent cause of death. The standardized mortality ratio (SMR) resulted increased in persistent cases at the last follow-up (SMR 4.99, 95%CI [2.15; 9.83], p < 0.001) whilst it was not higher in those in remission (SMR 1.66, 95%CI [0.34; 4.85], p = 0.543) regardless of the timing or number of treatments carried out. A younger age at diagnosis (p = 0.005), a microadenoma (p = 0.002), and remission status at the last follow-up (p = 0.027) all increased survival. Furthermore, an elevated number of comorbidities, in particular arterial hypertension, increased mortality rates. CONCLUSIONS: Patients with active CD presented a poor survival outcome. Remission restored the patients' life expectancy regardless of the timing or the types of treatments used to achieve it. Persistent CD-related comorbidities remained major risk factors.
Assuntos
Hipertensão , Hipersecreção Hipofisária de ACTH , Humanos , Idoso , Adulto , Hipersecreção Hipofisária de ACTH/epidemiologia , Seguimentos , Comorbidade , Encaminhamento e Consulta , Resultado do TratamentoRESUMO
Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing's disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic-pituitary-adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth.
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Adenoma Hipofisário Secretor de ACT , Adenoma , Hipersecreção Hipofisária de ACTH , Neoplasias Hipofisárias , Hormônio Adrenocorticotrópico/metabolismo , Glucocorticoides/uso terapêutico , Humanos , Hidrocortisona , Sistema Hipotálamo-Hipofisário/metabolismo , Hipersecreção Hipofisária de ACTH/patologia , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de GlucocorticoidesRESUMO
Cushing's disease (CD) causes diabetes mellitus (DM) through different mechanisms in a significant proportion of patients. Glucose metabolism has rarely been assessed with appropriate testing in CD; we aimed to evaluate hormonal response to a mixed meal tolerance test (MMTT) in CD patients and analyzed the effect of pasireotide (PAS) on glucose homeostasis. To assess gastro-entero-pancreatic hormones response in diabetic (DM+) and non-diabetic (DM−) patients, 26 patients with CD underwent an MMTT. Ten patients were submitted to a second MMTT after two months of PAS 600 µg twice daily. The DM+ group had significantly higher BMI, waist circumference, glycemia, HbA1c, ACTH levels and insulin resistance indexes than DM− (p < 0.05). Moreover, DM+ patients exhibited increased C-peptide (p = 0.004) and glucose area under the curve (AUC) (p = 0.021) during MMTT, with a blunted insulinotropic peptide (GIP) response (p = 0.035). Glucagon levels were similar in both groups, showing a quick rise after meals. No difference in estimated insulin secretion and insulin:glucagon ratio was found. After two months, PAS induced an increase in both fasting glycemia and HbA1c compared to baseline (p < 0.05). However, this glucose trend after meal did not worsen despite the blunted insulin and C-peptide response to MMTT. After PAS treatment, patients exhibited reduced insulin secretion (p = 0.005) and resistance (p = 0.007) indexes. Conversely, glucagon did not change with a consequent impairment of insulin:glucagon ratio (p = 0.009). No significant differences were observed in incretins basal and meal-induced levels. Insulin resistance confirmed its pivotal role in glucocorticoid-induced DM. A blunted GIP response to MMTT in the DM+ group might suggest a potential inhibitory role of hypercortisolism on enteropancreatic axis. As expected, PAS reduced insulin secretion but also induced an improvement in insulin sensitivity as a result of cortisol reduction. No differences in incretin response to MMTT were recorded during PAS therapy. The discrepancy between insulin and glucagon trends while on PAS may be an important pathophysiological mechanism in this iatrogenic DM; hence restoring insulin:glucagon ratio by either enhancing insulin secretion or reducing glucagon tone can be a potential therapeutic target.
Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Resistência à Insulina , Hipersecreção Hipofisária de ACTH , Glicemia/metabolismo , Peptídeo C , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico , Glucagon , Peptídeo 1 Semelhante ao Glucagon , Hemoglobinas Glicadas , Humanos , Incretinas/uso terapêutico , Insulina/metabolismo , Refeições , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Somatostatina/análogos & derivadosRESUMO
The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing high and rapid morbidity and mortality. Immune system response plays a crucial role in controlling and resolving the viral infection. Exogenous or endogenous glucocorticoid excess is characterized by increased susceptibility to infections, due to impairment of the innate and adaptive immune system. In addition, diabetes, hypertension, obesity and thromboembolism are conditions overrepresented in patients with hypercortisolism. Thus patients with chronic glucocorticoid (GC) excess may be at high risk of developing COVID-19 infection with a severe clinical course. Care and control of all comorbidities should be one of the primary goals in patients with hypercortisolism requiring immediate and aggressive treatment. The European Society of Endocrinology (ESE), has recently commissioned an urgent clinical guidance document on management of Cushing's syndrome in a COVID-19 period. In this review, we aim to discuss and expand some clinical points related to GC excess that may have an impact on COVID-19 infection, in terms of both contagion risk and clinical outcome. This document is addressed to all specialists who approach patients with endogenous or exogenous GC excess and COVID-19 infection.
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COVID-19 , Síndrome de Cushing , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/etiologia , Glucocorticoides , Humanos , Pandemias , SARS-CoV-2RESUMO
INTRODUCTION: Prolactin-secreting adenoma (PRLoma) can present as large and invasive neoplasm, with increased markers of cellular proliferation. First-line approach is Dopamine Agonists (DAs) treatment; however, DA-resistance has been reported, especially in male patients. Estrogens induce lactotroph cell replication and PRL secretion: the use of anti-estrogen treatment in patients with PRLoma have been described in few cases. We reported our experience regarding treatment with the aromatase inhibitor anastrozole (ANA) as add-on therapy for male patients with DA resistant PRLoma. MATERIALS AND METHODS: We describe four male patients (26, 38, 29 and 19 years old at diagnosis), with PRLoma (median diameter 26 mm, PRL 7730 µg/L). They were resistant to cabergoline (CAB, > 2 mg/week) in terms of PRL secretion and tumor size reduction. ANA 1 mg/day was added to the maximum tolerated dose of CAB for at least 1 year. Magnetic Resonance was performed at baseline, after 6 months of CAB + ANA combination and every 12 months afterward. RESULTS: PRL levels decreased in all patients after CAB + ANA (mean - 70%, range - 44/- 97%), achieving a normalization of PRL levels in one case. Tumor size decreased in all cases (mean - 47%, range - 24.5/- 68%). No severe adverse effects have been reported, a moderate weight gain has been observed in two cases. CONCLUSIONS: Addition of an aromatase inhibitor (ANA) to the dopamine agonist therapy improved the control of prolactin levels and induced tumour regression.
Assuntos
Neoplasias Hipofisárias , Prolactinoma , Anastrozol , Cabergolina , Agonistas de Dopamina/uso terapêutico , Ergolinas/uso terapêutico , Humanos , Masculino , Neoplasias Hipofisárias/tratamento farmacológico , Prolactina , Prolactinoma/tratamento farmacológicoRESUMO
BACKGROUND: The contribution of functional and/or structural remodeling to reduced coronary flow velocity reserve (CFVR), reflecting impaired coronary microcirculation in Cushing's syndrome (CS), has not been clearly elucidated. We aimed to identify the potential mechanisms of coronary microvascular impairment in CS. METHODS: We studied 15 CS patients (11 female, age 50⯱â¯9â¯years) without clinical evidence of cardiovascular disease. Coronary flow velocity in the left anterior descending coronary artery was measured by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. Average peak flow velocities, CFVR, and microvascular resistance in baseline (BMR) and hyperemic conditions (HMR) were assessed. CFVR ≤2.5 was considered a marker of microvascular disease (CMD). Diastolic function (E/e'), global longitudinal strain (GLS) and fractional pulse pressure (fPP), an index of arterial stiffness, were also assessed. RESULTS: CMD was present in 5 patients (33.3%). CMD was primarily driven by increased baseline peak flow velocity (29⯱â¯12 versus 19.6⯱â¯4.2â¯cm/s, pâ¯=â¯.03) in the presence of decreased BMR (3.62⯱â¯0.6 versus 5.46⯱â¯1.4â¯mmâ¯Hg·s/cm, pâ¯=â¯.03). Moreover, urinary cortisol and E/e' were higher (pâ¯=â¯.001 and pâ¯=â¯.001, respectively) and GLS was lower (pâ¯=â¯.009) in patients with CMD. fPP was higher in patients with CMD (pâ¯=â¯.01). Urinary cortisol correlated to CFVR (pâ¯=â¯.008), E/e' (pâ¯<â¯.0001) and GLS (pâ¯<â¯.0001). fPP directly correlated to average peak flow velocities at rest (pâ¯=â¯.01) and inversely to BMR (pâ¯=â¯.03). CONCLUSIONS: Functional microvascular regulatory impairment seems to be the potential mechanism of CMD in CS. CMD seems to be related to decreased myocardial contractility and diastolic dysfunction associated with cortisol excess.
Assuntos
Circulação Coronária , Vasos Coronários/diagnóstico por imagem , Síndrome de Cushing/complicações , Ecocardiografia Doppler de Pulso , Cardiopatias/diagnóstico por imagem , Microcirculação , Resistência Vascular , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Vasos Coronários/fisiopatologia , Estudos Transversais , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/urina , Feminino , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Cardiopatias/urina , Humanos , Hidrocortisona/urina , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Projetos Piloto , Valor Preditivo dos Testes , Função Ventricular EsquerdaRESUMO
The glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone produced in the gastrointestinal tract in response to nutrients. GIP has a variety of effects on different systems, including the potentiation of insulin secretion from pancreatic ß-cells after food intake (i.e. incretin effect), which is probably the most important. GIP effects are mediated by the GIP receptor (GIPR), a G protein-coupled receptor expressed in several tissues, including islet ß-cells, adipocytes, bone cells, and brain. As well as its involvement in metabolic disorders (e.g. it contributes to the impaired postprandial insulin secretion in type 2 diabetes (T2DM), and to the pathogenesis of obesity and associated insulin resistance), an inappropriate GIP/GIPR axis activation of potential diagnostic and prognostic value has been reported in several endocrine tumors in recent years. The ectopic GIPR expression seen in patients with overt Cushing syndrome and primary bilateral macronodular adrenal hyperplasia or unilateral cortisol-producing adenoma has been associated with an inverse rhythm of cortisol secretion, with low fasting morning plasma levels that increase after eating. On the other hand, most acromegalic patients with an unusual GH response to oral glucose suppression have GIPR-positive somatotropinomas, and a milder phenotype, and are more responsive to medical treatment. Neuroendocrine tumors are characterized by a strong GIPR expression that may correlate positively or inversely with the proliferative index MIB-1, and that seems an attractive target for developing novel radioligands. The main purpose of this review is to summarize the role of the GIP/GIPR axis in endocrine neoplasia, in the experimental and the clinical settings.
Assuntos
Polipeptídeo Inibidor Gástrico/metabolismo , Tumores Neuroendócrinos/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Adenoma/metabolismo , Diabetes Mellitus Tipo 2 , Regulação Neoplásica da Expressão Gênica , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Humanos , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Receptores dos Hormônios Gastrointestinais/genéticaRESUMO
Secreting pituitary adenomas are tumors for which few treatment options are available, including surgical treatment and management of hormonal imbalance due to altered pituitary secretion. In case of inoperable relapse, radiotherapy or chemotherapeutic treatment can be considered; the effectiveness of these treatments, however, remains limited. In the immunotherapy era, it is necessary to select patients who can benefit from immunotherapeutic treatment. Mismatch repair deficiency is strongly associated with responsiveness to anti-PD-1 in other cancers and can be detected using immunohistochemistry for MLH1, MSH2, MHS6, and PMS2. In this case report, we report a case of rapid disease progression to pembrolizumab in a patient with a MMRd pituitary adrenocorticotropic hormone (ACTH)-secreting adenoma. For the best of our knowledge, we described for the first time, a poor efficacy of pembrolizumab in a patient with ACTH-secreting pituitary adenoma having mismatch repair deficiency probably caused by high levels of cortisol in this patient. Prospective study should be performed to assess the activity of immune checkpoint inhibitor alone or in association with temozolomide in this subsetting of pituitary adenomas.
Assuntos
Adenoma Hipofisário Secretor de ACT/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA , Síndromes Neoplásicas Hereditárias/patologia , Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/genética , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/tratamento farmacológico , Síndromes Neoplásicas Hereditárias/genética , PrognósticoRESUMO
INTRODUCTION: Pasireotide (PAS) is an effective treatment for Cushing's disease (CD) but its use is burdened by an associated high incidence of diabetes mellitus (DM). The aim of this study was to examine the effect of a single subcutaneous injection of PAS on glucose metabolism in CD, and to identify predictors of DM onset. METHODS: Fifteen patients with CD (13 females, 2 males; median age 43 years [IQR 34-50]) were submitted to an acute PAS test (600 µg s.c.), measuring glucose, insulin, C-peptide, GIP, glucagon, GLP-1, ACTH, and cortisol at the baseline and every 30 min for 2 h. Then they were treated twice daily with PAS 600 µg, and followed up with clinical and hormone assessments for a median of 6 months [2-13]. RESULTS: PAS prompted a significant decrease in all hormonal parameters considered except for glycemia, which increased (as expected), reaching the highest value at 120' (p < 0.0001). Overall, 9/15 patients developed DM within 2 months of starting PAS therapy. There were no differences in age, weight, visceral adiposity, HOMA index, fasting glucose or severity of CD between patients who developed DM and those who did not. Baseline fasting glucagon levels were higher in the DM patients (17.95 [12.45-20.54] vs. 10.53 [8.11-12.33] pmol/L, p = 0.0256), and so were GIP and HbA1c levels (37 [5.5-39.5] vs. 29 [27-31.8] mmol/mol, p = 0.0008). Glucose at 120' was also significantly higher in the DM patients (9.5 [8.65-11.95] vs. 6.85 [4.48-9] mmol/L, p = 0.012). CONCLUSIONS: PAS was rapidly able to suppress insulin and incretin secretion, with a subsequent rise in glucose levels into the diabetic range. It also induced a significant inhibition of glucagon production. The patients at higher risk of DM during PAS therapy were those with higher glucagon levels, HbA1c > 34.5 mmol/mol, and a glucose peak after PAS administration > 9 mmol/L. CD patients with these features given PAS therapy should therefore be monitored more carefully.
Assuntos
Diabetes Mellitus/induzido quimicamente , Somatostatina/análogos & derivados , Adulto , Glicemia/metabolismo , Diabetes Mellitus/sangue , Feminino , Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Homeostase/efeitos dos fármacos , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Somatostatina/efeitos adversosRESUMO
PURPOSE: Aggressive pituitary adenomas (APAs) and pituitary carcinomas (PCs) are challenging for their invasive nature, resistance to treatment and recurrences. Temozolomide (TMZ) is used with benefit and well-tolerated toxicity profile in APAs and PCs. In most studies patients received ≤ 12 cycles but the best length of treatment is debated since other options after discontinuation are scarce and a second course is mainly unsuccessful. METHODS: We report outcomes of 8 patients with APAs and PCs treated with TMZ for more than 12 continuous cycles with a literature review. Data were retrospectively collected from Padua and Milan University Hospitals. TMZ was used as a single agent (150-200 p.o. mg/m2 daily, 5/28 days) for 14 to 45 cycles. RESULTS: Eight patients (7 M), 7 APAs and 1 PC. Previous treatments included neurosurgery and radiotherapy in all cases except two giant masses (ACTH-silent APA and prolactinoma). No patient had progression disease (PD) during long-term treatment nor toxicities. No one had complete response (CR) but four had partial response (PR). Four ACTH+ tumors maintained stable disease (SD) but the secretion pattern improved in all. After drug withdrawal, three had delayed PD (2 after 18 and one after 29 months, all ACTH+); two are still in SD. CONCLUSIONS: TMZ may be useful and well-tolerated in APAs and PCs as a long-term therapy. PR appears within the first cycles with no escape throughout the treatment; most patients achieve SD. We suggest extended protocols particularly in responsive ACTH+ PAs and PCs, when further therapies may be unsuccessful.
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Adenoma/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Carcinoma/tratamento farmacológico , Duração da Terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Temozolomida/uso terapêutico , Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma/patologia , Adulto , Idoso , Carcinoma/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/patologia , Intervalo Livre de Progressão , Prolactinoma/tratamento farmacológico , Prolactinoma/patologia , Radiocirurgia , Radioterapia AdjuvanteRESUMO
Polycystic ovary syndrome (PCOS) is characterized by elevated androgen production and subclinical changes in cardiovascular and metabolic risk markers. Total cholesterol, high-density lipoprotein (HDL) cholesterol, fasting glucose, and fasting insulin appear to increase specifically in PCOS compared with fertile women. PCOS also confers an increased risk of cardiometabolic disease in later life. Novel biomarkers such as serum's cholesterol efflux capacity and blood-derived macrophage activation profile may assist in more accurately defining the cardiometabolic risk profile in these women. Aldosterone antagonists, androgen receptor antagonists, 5α-reductase inhibitors, and synthetic progestogens are used to reduce hyperandrogenism. Because increased insulin secretion enhances ovarian androgen production, short-term treatment with metformin and other hypoglycemic agents results in significant weight loss, favorable metabolic changes, and testosterone reduction. The naturally occurring inositols display insulin-sensitizing effects and may be also used in this context because of their safety profile. Combined oral contraceptives represent the drug of choice for correction of androgen-related symptoms. Overall, PCOS management remains focused on specific targets including assessment and treatment of cardiometabolic risk, according to disease phenotypes. While new options are adding to established therapeutic approaches, a sometimes difficult balance between efficacy and safety of available medications has to be found in individual women.
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Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Quimioprevenção , Síndrome do Ovário Policístico/complicações , Adulto , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Quimioprevenção/métodos , Anticoncepcionais Orais/farmacologia , Anticoncepcionais Orais/uso terapêutico , Suscetibilidade a Doenças , Feminino , Humanos , Avaliação de Resultados em Cuidados de Saúde , Síndrome do Ovário Policístico/epidemiologia , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND AND AIM: Patients with adrenal insufficiency (AI) require lifelong glucocorticoid (GC) replacement therapy. Cortisol measurement in saliva is increasingly being used: we assessed salivary cortisol rhythm in outpatients with AI, to provide new insights regarding the management of GC treatment. MATERIALS AND METHODS: Nineteen AI outpatients collected six saliva samples from awakening (Fa , before taking the morning GC therapy), during the day (F1.5 h , F6 h before the afternoon GC dose, F8.5 h , F12 h ) until bedtime (Fb ). We measured daily cortisol exposure by calculating the area under the curve (AUCFaâFb ). Saliva samples were collected at baseline and one year after GG dose reduction (by at least 5 mg of hydrocortisone). RESULTS: Hydrocortisone equivalents decreased from median 25 mg/d (baseline, interquartile range IQR 20-27.5) to 15 mg/d (IQR 15-20, P < .01). As expected, we observed a reduction in both daily cortisol exposure (AUCFaâFb 23 982 nmol·h/L, IQR 12 635-45 369, to 14 689 nmol·h/L, IQR 7168-25 378, P < .001) and salivary cortisol levels at F6 h (24.8 nmol/L, IQR 20.1-35.7, to 21 nmol/L, IQR 8.7-29.2, P < .05) and Fb (8.7 nmol/L, IQR 3.4-20.2, to 3.7 nmol/L, IQR 3.0-5.8, P < .05). None of the patients developed signs or symptoms consistent with AI after GC reduction. Median diastolic blood pressure (DPB) values fell from baseline to the end of follow-up (87.5 mm Hg, IQR 80-90, to 80 mm Hg, IQR 80-85, P < .05). The AUCFaâFb of patients at baseline was above the reference value (90th percentile of controls) in 12 patients (60%); after the dosage reduction, 30% of patients normalized their daily cortisol exposure (AUCFaâFb ). CONCLUSIONS: The reduction in GC treatment in patients with AI resulted in better control of daily cortisol rhythm, measured with salivary cortisol, and in an improvement of DPB. Further studies are needed to ascertain if salivary cortisol could be used as a biomarker to manage GC replacement therapy.
Assuntos
Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/metabolismo , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Hidrocortisona/metabolismo , Saliva/química , Adulto , Idoso , Esquema de Medicação , Feminino , Terapia de Reposição Hormonal , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
INTRODUCTION: Central diabetes insipidus (DI) is a rare disease characterized by the excretion of excessive volumes of dilute urine due to reduced levels of the antidiuretic hormone arginine vasopressin (AVP), caused by an acquired or genetic defect in the neurohypophysis. The aim of this study was to identify any autonomic dysfunction (AD) in patients with DI as a possible cofactor responsible for their reportedly higher mortality. METHODS: The study involved 12 patients (6 females) with central idiopathic DI and a well-controlled electrolyte balance, and 12 controls matched for age, sex and cardiovascular risk factors, who were assessed using the tilt, lying-to-standing, hand grip, deep breath, Valsalva maneuver and Stroop tests. RESULTS: The tilt test showed a significantly more pronounced decrease in both systolic (- 20.67 ± 18 vs. - 1.92 ± 6.99 mmHg, p = 0.0009) and diastolic blood pressure (- 10.5 ± 14.29 vs. - 1.5 ± 5 mmHg, p = 0.012) in patients than in controls. Three patients with DI had to suspend the test due to the onset of syncope. The lying-to-standing test also revealed a marked reduction in blood pressure in patients with DI (1.05 ± 0.13 vs. 1.53 ± 0.14, p = 0.0001). Similar results emerged for the Valsalva maneuver (Valsalva ratio, 1.24 ± 0.19 vs. 1.79 ± 0.11, p < 0.0001) and deep breath test (1.08 ± 0.11 vs. 1.33 ± 0.08, p < 0.0001). CONCLUSIONS: All the principal autonomic tests performed in the study were concordant in indicating that patients with central DI have an impaired autonomic nervous system function despite a normal hydroelectrolytic balance under desmopressin therapy. This impairment may reflect damage to the autonomic system per se and/or the absence of any vasoactive effect of AVP on vascular smooth muscle. In our opinion, patients with central DI should be educated on how to prevent orthostatic hypotension, and pharmacological treatment should be considered for patients with a more marked impairment.
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Sistema Nervoso Autônomo/fisiopatologia , Sistema Cardiovascular/inervação , Diabetes Insípido Neurogênico/complicações , Hemodinâmica , Hipotensão Ortostática/etiologia , Adulto , Antidiuréticos/uso terapêutico , Estudos de Casos e Controles , Estudos Transversais , Desamino Arginina Vasopressina/uso terapêutico , Morte Súbita Cardíaca/etiologia , Diabetes Insípido Neurogênico/diagnóstico , Diabetes Insípido Neurogênico/tratamento farmacológico , Diabetes Insípido Neurogênico/fisiopatologia , Feminino , Humanos , Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Teste de Stroop , Teste da Mesa Inclinada , Manobra de ValsalvaRESUMO
BACKGROUND: Pituitary adenomas are usually considered benign tumours, although some of them can exhibit an aggressive behaviour. Patients with clinically aggressive pituitary adenomas are frequently diagnosed with larger masses, and may present an earlier recurrence (or persistence) after surgery. Our aim was to characterise the clinical, histopathological and radiological features of patients with aggressive pituitary adenoma, in order to correlate their clinical behaviour with the response to treatment plan. METHOD: We considered an aggressive pituitary adenoma on the basis of radiological features (size, local invasion), pathological reports (atypical adenoma: MIB-1 >3%, p53 immunoreactivity, increased mitotic activity) and clinical aspects (response to surgery, radiotherapy and medical treatment). RESULTS: Among our cohort of 582 patients, we considered 102 subjects with aggressive pituitary adenomas (18%, 56 male and 46 female): 14 adrenocorticotrophic hormone (ACTH)-secreting, 18 growth hormone (GH)-secreting, 23 prolactin (PRL)-secreting and 47 non-secreting, with a median follow-up of 5 years. In the whole cohort, 75% of patients with aggressive pituitary adenomas presented invasion of surrounding structure, especially GH-secreting, PRL-secreting and non-secreting. Besides invasion, their remission rate after surgery, radiotherapy or medical treatment was similar, irrespective of hormonal secretion. Surgery was the most performed treatment (overall remission rate of 24%), especially in those patients with ACTH- or GH-secreting adenoma, and 22% of patients were submitted to radiotherapy, with a remission rate of 45% after a median of 3 years. Two consecutive years of medical treatment, in patients with secreting pituitary adenoma, achieved disease control in 41% of them. Considering pathological reports, 24% of cases were defined as atypical adenomas; radiological characteristics, responses to medical treatment and remission rates were similar among patients with typical and atypical adenoma. CONCLUSIONS: We proposed a new and comprehensive definition of aggressive pituitary adenoma, based upon radiological, clinical and pathological features. In a selected cohort of patients, radiological invasion resulted in the most common marker to describe the aggressive behaviour of pituitary adenoma. Surgery, radiotherapy and medical treatment (the latter only in secreting adenoma) achieved disease control in half of the patients with aggressive adenoma, especially surgery in those with ACTH-oma and medical treatment in those with GH- and PRL-secreting adenoma. Nevertheless, radiological, clinical or atypical features did not affect the outcome.
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Adenoma/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Adenoma/patologia , Adenoma/radioterapia , Adenoma/cirurgia , Adulto , Estudos de Coortes , Detecção Precoce de Câncer , Feminino , Humanos , Antígeno Ki-67 , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/radioterapia , Neoplasias Hipofisárias/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: Differential diagnosis between Cushing's Disease (CD) and Ectopic ACTH Syndrome (EAS) may be a pitfall for endocrinologists. The increasing use in clinical practice of chromatography and mass spectrometry improves the measurement of urinary free cortisol (UFF) and cortisone (UFE). We have recently observed that cortisol to cortisone ratio (FEr) was higher in a small series of EAS; in this study we collected a larger number of ACTH-dependent Cushing's Syndrome (CS) to study the role of FEr to characterize the source of corticotropin secretion. MATERIALS AND METHODS: High-pressure liquid chromatography with UV detection (HPLC-UV, n=35) or liquid chromatography-tandem mass spectrometry (LC-MS/MS, n=72) were used to measure UFF, UFE and FEr in 83 patients with CD and 24 with EAS. RESULTS: UFF, UFE and FEr levels were higher in EAS than in CD (UFF: 6671 vs 549 nmol/24 hours; UFE: 2069 vs 464 nmol/24 hours; FEr: 4.13 vs 0.97; all P<.001). FEr >1.15 (the best ROC-based threshold) was able to distinguish CD from EAS with 75% sensitivity (SE) and 75% specificity (SP), AUC 0.811; results were similar between HPLC-UV (SE 73%, SP 79%, AUC 0.708) and LC-MS/MS (SE 77%, SP 73%, AUC 0.834; P=.727). The diagnostic accuracy of FEr was similar to that of CRH test or high-dose dexamethasone suppression test (respectively P=.171 and P=.683), also combined. Finally, FEr was able to increase the number of correct diagnosis in patients with discordant dynamic tests. CONCLUSIONS: Urinary FEr >1.15 was able to suggest EAS, with a diagnostic accuracy similar to that of other dynamic tests proposed to study ACTH-dependent CS.
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Síndrome de ACTH Ectópico/diagnóstico , Cortisona/urina , Hidrocortisona/urina , Hipersecreção Hipofisária de ACTH/diagnóstico , Adulto , Idoso , Cromatografia Líquida , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Espectrometria de Massas em TandemRESUMO
Patients with active Cushing's syndrome (CS) exhibit an increase of the visceral adipose tissue, increasing the risk of cardiovascular events. Until now, it is not yet clear whether remission of CS leads to a normalization of body composition, or if different strategies to control hypercortisolism could result in a different clinical outcome concerning adipose tissue distribution. Therefore, we analyzed body composition changes using dual-energy X-ray absorptiometry (DXA) in patients with CS in a prospective and controlled study. We considered 23 patients with CS, whose remission was achieved after surgery in 14 or gained with pharmacological treatment in 9 subjects. Clinical and DXA data (lean and fat mass in total body, trunk, and R1 box) were collected during active hypercortisolism and after sustained remission, defined as the normalization of both late night salivary and 24-h urinary cortisol levels, at least for 6 consecutive months. Healthy subjects, matched with CS for gender, age, and BMI, were considered as controls (n=25). After remission of hypercortisolism, body compositions of patients were similar to matched controls; fat mass in total body (-7.53%), trunk (-3.24%), and R1- box (-12.82%, all p<0.01) were decreased from baseline levels. Dividing patients by type of treatment, fat mass reduction was higher in those that achieved surgical remission of CS (total body -17.26%, trunk -22.73%, and R1 box -21.21%, all p<0.05). Surgical remission of hypercortisolism is characterized by improvement of body composition, particularly fat reduction, easily detectable with DXA during routine clinical practice.
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Absorciometria de Fóton , Composição Corporal , Síndrome de Cushing/diagnóstico por imagem , Síndrome de Cushing/cirurgia , Adiposidade , Antropometria , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
INTRODUCTION: Diagnosing Cushing's syndrome (CS) can be a challenge, especially in ACTH-dependent CS, when it comes to detecting the origin of ACTH secretion. MATERIALS AND METHODS: Retrospective data were collected on 170 patients with ACTH-dependent CS (149 CD, 21 EAS) referring to two endocrinology units, focusing on three non-invasive tests: dexamethasone 8 mg overnight challenge (HDDST); corticotrophin-releasing hormone (CRH) assay and the desmopressin (DDAVP) test. RESULTS: Patients with EAS were slightly older and had higher ACTH, serum and urinary cortisol levels than patients with CD (p < 0.01). CD patients had a stronger ACTH and cortisol response after CRH injection (p < 0.0001), and a more pronounced reduction in cortisol levels after HDDST (p < 0.0001). A threshold percentage ACTH increase after CRH stimulation of 72.4 % was able to identify CD with a sensitivity (SE) of 76 % (95 % CI 68-83) and a specificity (SP) of 100 % (95 % CI 83-100). As for HDDST, a cortisol suppression >52.7 % below the basal level suggested a pituitary origin with a SE of 88 % (95 % CI 81-93) and a SP of 90 % (95 % CI 68-99). There were no cases of EAS with positive responses to both these tests. Increases in ACTH and cortisol levels after the DDAVP test were also higher in CD than in EAS (p < 0.01), though the SE and SP were lower. CONCLUSIONS: Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.
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Síndrome de Cushing/diagnóstico , Técnicas de Diagnóstico Endócrino , Adolescente , Adulto , Idoso , Hormônio Liberador da Corticotropina , Desamino Arginina Vasopressina , Dexametasona , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Cushing's disease (CD) is associated with an increased risk of thrombotic events, particularly after surgery. No guidelines are available on the management of patients with CD undergoing pituitary transsphenoidal surgery (TSS). We aimed to compare the effectiveness of different prophylactic procedures on the prevention of thrombotic events after surgery in CD. METHODS: We retrospectively collected data on 78 consecutive patients who underwent TSS for CD between 2001 and 2012 at Padova's Neurosurgical Unit, recording their hemostatic, hormonal and anthropometric parameters. Patients were divided into two groups according to their perioperative management. Group A (34 patients) received fractionated heparin for a maximum of 14 days after surgery. Patients in group B (44 patients) were given no early glucocorticoid replacement therapy, and treated with subcutaneous enoxaparin 4,000-8,000 U/daily (depending on their weight) for 30 days plus graduated elastic stockings until mobilization, and early ambulation. RESULTS: The whole cohort of patients had clotting and anticoagulant factors significantly higher than the normal range. The two groups were comparable for age, BMI, ACTH, urinary free cortisol levels, outcome of surgery, and main clotting parameters. The surgical procedure did not change during the study period. Three venous thrombotic events [venous thromboembolic events (VTE), 2 associated with pulmonary embolism] were recorded in group A, none in group B (p = 0.079). No hemorrhagic events were reported. CONCLUSIONS: Provoked thrombotic events pose a major problem in the management of CD patients after surgery, regardless of the procedure's outcome. The prophylactic regimen proposed in this paper afforded an efficacy prophylaxis against postoperative VTE in patients with CD. Due to the rarity of CD, a multicenter study on a larger sample of cases would be warranted in order to collect more thrombotic events.