The risk of COVID-19 in Cushing's disease is independently related to disease activity (hypercortisolism) and obesity.

Objective: To evaluate the cumulative incidence, risk factors, and outcomes of COVID-19 in patients with Cushing's disease (CD). Subjects and methods: In all, 60 patients with CD following up in our outpatient clinic answered via phone interview a questionnaire about the occurrence of COVID-19 infection documented by RT-PCR (including the diagnosis date and clinical outcome) and vaccination status. Clinical and biochemical data on disease activity (hypercortisolism) and comorbidities (obesity, diabetes mellitus, and hypertension) were obtained from the patients' electronic medical records. Risk ratios (RRs) of risk factors were obtained using univariate and multivariate analyses. Results: The cumulative incidence of COVID-19 in patients with CD during the observation period was 31.7%, which was higher than that in the general reference population (9.5%). The cumulative incidence of COVID-19 was significantly higher in patients with hypercortisolism (57% versus 17% in those without hypercortisolism, p = 0.012) and obesity (54% versus 9% in those without obesity, p < 0.001) but not in patients with hypertension or diabetes mellitus. On multivariate analysis, hypercortisolism and obesity were each independent risk factors for COVID-19 (RR 2.18, 95% CI 1.06-4.46, p = 0.033 and RR 5.19, 95% CI 1.61-16.74, p = 0.006, respectively). Conclusion: The incidence of COVID-19 in patients with CD was associated with hypercortisolism, as expected, and obesity, a novel and unexpected finding. Thus, correction of hypercortisolism and obesity should be implemented in patients with CD during the current and future COVID-19 outbreaks.

Severe osteoporosis in a young man with bilateral Cushing's syndrome: a case report.

BACKGROUND: The diagnosis of Cushing's syndrome is challenging; however, through the clinical picture and the search for secondary causes of osteoporosis, it was possible to reach the diagnosis of the case reported. There was an independent, symptomatic ACTH hypercortisolism manifested by typical phenotypic changes, severe secondary osteoporosis and arterial hypertension in a young patient. CASE PRESENTATION: A 20-year-old Brazilian man with low back pain for 8 months. Radiographs showed fragility fractures in the thoracolumbar spine, and bone densitometry showed osteoporosis, especially when evaluating the Z Score (- 5.6 in the lumbar spine). On physical examination, there were wide violaceous streaks on the upper limbs and abdomen, plethora and fat increase in the temporal facial region, hump, ecchymosis on limbs, hypotrophy of arms and thighs, central obesity and kyphoscoliosis. His blood pressure was 150 × 90 mmHg. Cortisol after 1 mg of dexamethasone (24.1 µg/dL) and after Liddle 1 (28 µg/dL) were not suppressed, despite normal cortisoluria. Tomography showed bilateral adrenal nodules with more severe characteristics. Unfortunately, through the catheterization of adrenal veins, it was not possible to differentiate the nodules due to the achievement of cortisol levels that exceeded the upper limit of the dilution method. Among the hypotheses for the differential diagnosis of bilateral adrenal hyperplasia are primary bilateral macronodular adrenal hyperplasia, McCune-Albright syndrome and isolated bilateral primary pigmented nodular hyperplasia or associated with Carney's complex. In this case, primary pigmented nodular hyperplasia or carcinoma became important etiological hypotheses when comparing the epidemiology in a young man and the clinical-laboratory-imaging findings of the differential diagnoses. After 6 months of drug inhibition of steroidogenesis, blood pressure control and anti-osteoporotic therapy, the levels and deleterious metabolic effects of hypercortisolism, which could also impair adrenalectomy in the short and long term, were reduced. Left adrenalectomy was chosen, given the possibility of malignancy in a young patient and to avoid unnecessary definitive surgical adrenal insufficiency if the adrenalectomy was bilateral. Anatomopathology of the left gland revealed expansion of the zona fasciculate with multiple nonencapsulated nodules. CONCLUSION: The early identification of Cushing's syndrome, with measures based on the assessment of risks and benefits, remains the best way to prevent its progression and reduce the morbidity of the condition. Despite the unavailability of genetic analysis for a precise etiological definition, it is possible to take efficient measures to avoid future damage.

QT interval instability and variability in dogs with naturally-occurring hypercortisolism.

Hypercortisolism is one of the most common endocrine diseases in dogs. In humans, it is clearly associated with a higher risk of cardiovascular events, but studies in dogs are scarce. To investigate the arrhythmogenic risk of dogs with naturally-occurring hypercortisolism (NOHC), indices of variability and instability of the QT interval were retrospectively studied in 38 dogs with NOHC and prospectively studied in 12 healthy dogs: variance (QTv), total instability (TI), short-term (STI) and long-term (LTI), and mean (QTm). Except for QTm, all parameters studied were higher in the NOHC group than in the control group. In addition, STI and QTv showed moderate positive correlation with left ventricle wall thickness. The NOHC group was subdivided according to cortisol suppression pattern in the low-dose dexamethasone suppression test. All electrocardiographic indices of partial and absent suppression patterns were numerically higher than healthy dogs. QTv and TI were lower in the control group than in both NOHC subgroups. LTI and STI were lower in the CG than in the group with the partial suppression pattern. There was no statistical difference between sex groups in any of the electrocardiographic parameters studied. This result might indicate that the etiology of NOHC, and its consequent influence on hypothalamus-pituitary-adrenal axis could interfere on the heterogeneity of ventricular repolarization parameters in different ways, especially in the short-term and the long-term stability; however further studies are necessary to understand the role of cortisol on electrical instability in dogs.

Enfermedad de Cushing recurrente con hipercortisolismo catastrófico: reporte de caso y revisión de literatura / Catastrophic hypercortisolism and recurrence in Cushing´s disease: a case report and literature review / Doença de Cushing recorrente com hipercortisolismo catastrófico: relato de caso e revisão da literatura

Resumen: Presentamos un caso de una paciente femenina de 27 años, con síndrome de Cushing ACTH dependiente con hipercortisolismo severo, causado por un macroadenoma hipofisario recurrente y resistente pese a dos cirugías transesfenoidales, radioterapia y terapia médica. Dada la falla en las diferentes terapias se realiza una adrenalectomía bilateral como tratamiento definitivo. La paciente fallece en el posoperatorio por causa no clara. Si bien la adrenalectomía bilateral ha sido reportada como un tratamiento efectivo en pacientes con enfermedad de Cushing, se ha relacionado con una mortalidad significativa vinculada con la severidad del hipercortisolismo y las comorbilidades presentes. En este caso la adrenalectomía izquierda se tuvo que convertir a cielo abierto, asociada con mayor morbimortalidad.

Abstract: The study presents the case of a 27-year-old female patient with adrenocorticotropic hormone (ACTH) dependent Cushing's disease and severe hypercortisolism caused by recurrent pituitary macroadenoma that was resistant to treatment despite two transsphenoidal surgeries, radiotherapy and medical treatment. Upon failure of the different therapies a bilateral adrenalectomy was performed as the final treatment. The patient died in after surgery although the case of death was not clear. Despite bilateral adrenalectomy having been reports as an effective treatment in patients with Cushing's disease, it has been related to significant mortality rates in connection with the severity of hypercortisolism and existing comorbilities. In this case the left adrenalectomy ended up being an open surgery, which is associated to a higher mortality rate.

Resumo: Apresentamos o caso de uma paciente de 27 anos com síndrome de Cushing ACTH-dependente com hipercortisolismo grave causado por macroadenoma hipofisário, recorrente e resistente, apesar de haver sido submetida a duas cirurgias transesfenoidal, radioterapia e terapia medicamentosa. Diante do fracasso das diferentes terapias, foi realizada adrenalectomia bilateral como tratamento definitivo. A paciente faleceu no pós-operatório por causa não esclarecida. Embora a adrenalectomia bilateral tenha sido relatada como tratamento eficaz em pacientes com doença de Cushing, ela tem sido associada a mortalidade significativa relacionada à gravidade do hipercortisolismo e às comorbidades presentes. Neste caso, a adrenalectomia esquerda teve que ser convertida para cirurgia aberta, associada a maior morbimortalidade.

Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.

Manic Episodes Due to Medical Illnesses: A Literature Review.

The body of evidence for mania as a secondary syndrome due to organic diseases is small. The clinical diagnosis and management of these patients are mainly based on clinical experience and on some case reports. Treatment should be focused on both the underlying medical illness and the control of acute symptoms. Mania due to a medical condition is relevant in the clinical setting, and thus more research is needed to add evidence-based recommendations to the currently available clinical knowledge. In this review, we summarize the latest information on the etiology, epidemiology, diagnostic aspects, and management of secondary mania.

Coagulation Profile Dynamics in Pediatric Patients with Cushing Syndrome: A Prospective, Observational Comparative Study.

OBJECTIVE: To evaluate the association between Cushing syndrome and hypercoagulability in children. STUDY DESIGN: A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 ± 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with18 normocortisolemic children, 13.7 ± 3.6 years. RESULTS: At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL ± 84 vs 99 ± 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 ± 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic α2-antiplasmin, 96 ± 17% vs 82 ± 26%, P = .015. After surgery, antifibrinolytic α2-antiplasmin levels decreased to 82 ± 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 ± 41% vs 84 ± 25%, P < .001), protein S (94 ± 19% vs 74 ± 19%, P = .001), and antithrombin III (96 ± 18% vs 77 ± 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004. CONCLUSION: Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00001595.

Bone density and microarchitecture in endogenous hypercortisolism.

OBJECTIVE: Osteoporosis is a serious and underestimated complication of endogenous hypercortisolism that results in an increased risk of fractures, even in patients with normal or slightly decreased bone mineral density (BMD). Alterations in bone microarchitecture, a very important component of bone quality, may explain bone fragility. The aim of this study was to investigate bone density and microarchitecture in a cohort of patients with endogenous Cushing's syndrome (CS). DESIGN: Cross-sectional study. PATIENTS: Thirty patients with endogenous active CS and fifty-one age-, sex- and body mass index-matched controls were included. MEASUREMENTS: Participants were studied for areal BMD (dual-energy X-ray absorptiometry) of the lumbar spine (LS), femoral neck (FN), total femur (TF) and radius (33%), and for volumetric bone density (vBMD) and structure using high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius and distal tibia. RESULTS: Patients with active CS exhibited lower areal BMD and Z-score values in the LS, FN and TF (P < 0·003 for all comparisons). At HR-pQCT, the patients with CS also had lower cortical area (P = 0·009 at the radius and P = 0·002 at the tibia), lower cortical thickness (P = 0·02 at the radius and P = 0·002 at the tibia), lower cortical density (P = 0·008 at the tibia) and lower total vBMD (P = 0·002 at the tibia). After the exclusion of hypogonadal individuals, the patients with CS maintained the same microarchitectural and densitometric alterations described above. CONCLUSIONS: Endogenous hypercortisolism has deleterious effects on bone, especially on cortical bone microstructure. These effects seem to be a more important determinant of bone impairment than gonadal status.

Hipertensión arterial secundaria en el adulto: evaluación diagnóstica y manejo / Secondary arterial hypertension in adults: diagnostic assesment and management

La Hipertensión arterial (HTA) es un grave problema de salud pública mundial. En efecto, sus complicaciones causan anualmente 9,4 millones de muertes. La HTA también es un problema de salud de alto impacto en Chile. De hecho, la Encuesta Nacional de Salud (ENS) 2009-2010 del Ministerio de Salud, reportó una prevalencia del 26,9%. La HTA se define como una Presión arterial sistólica (PAS) 140mmHg y/o una Presión arterial diastólica (PAD) 90mmHg. Tradicionalmente, se ha clasificado la HTA en primaria o esencial, que agrupa a más del 90% de los hipertensos adultos; y en secundaria, que reúne a menos del 10% de los hipertensos. En la evaluación inicial de un paciente con HTA, se debe: Confirmar el diagnóstico; 2) Detectar causas de HTA secundaria, y 3) Evaluar riesgo cardiovascular (CV), daño orgánico y comorbilidades. Para ello, se necesita determinar la Presión Arterial (PA) y la historia clínica, que incluya antecedentes familiares, examen físico, pruebas de laboratorio y pruebas diagnósticas adicionales. En un pequeño porcentaje de adultos con HTA, se puede identificar una causa específica y potencialmente reversible; no obstante, debido a su elevada prevalencia, las formas secundarias pueden afectar a millones de pacientes en todo el mundo. Se puede sospechar una forma secundaria de HTA por un alza marcada de la PA, la aparición o empeoramiento repentinos de una HTA, una mala respuesta de la PA al tratamiento farmacológico y por un daño orgánico desproporcionado para la duración de la HTA. Si la evaluación inicial hace pensar que el paciente tiene una HTA secundaria, entonces se debe tener en consideración las causas más relevantes, que se describen en este artículo.

Arterial hypertension is a serious public health problem worldwide. Indeed, its complications cause 9.4 million deaths annually. Hypertension is also a health problem with high impact in Chile. In fact, the National Health Survey 2009-2010, conducted by the Ministry of Health, showed a prevalence of 26.9%. Arterial hypertension is defined as systolic blood pressure (SBP) 140mmHg and/or diastolic blood pressure (DBP) 90mmHg. Traditionally, hypertension has been classified into primary or essential, which represents over 90% of adults with hypertension; and secondary, which includes less than 10% of hypertensive patients. The initial evaluation of a patient with hypertension should: 1) Confirm the diagnosis of hypertension; 2) Detect causes of secondary hypertension; and 3) Assess cardiovascular risk, organ damage (OD) and concomitant clinical conditions. This calls for blood pressure (BP) measurement, medical history including family history, physical examination, laboratory investigations and further diagnostic tests. A specific, potentially reversible cause of BP elevation can be identified in a relatively small proportion of adult patients with hypertension. However, because of the overall high prevalence of hypertension, secondary forms can affect millions of patients worldwide. A secondary form of hypertension can be indicated by a severe elevation in BP, sudden onset or worsening of hypertension, poor BP response to drug therapy and OD disproportionate to the duration of hypertension. If the initial assessment suggests that the patient has a secondary hypertension, then you should take into consideration the relevant causes, which are described in this article.

Riesgo cardiovascular en el síndrome de Cushing / Cardiovascular risk found in Cushing syndrome

El síndrome de Cushing se caracteriza por un estado de hipercortisolismo endógeno, que produce múltiples y variadas alteraciones metabólicas que aumentan el riesgo cardiovascular en la fase activa de la enfermedad y aún después de la curación. La presencia de la obesidad central, la dislipidemia, la hipertensión arterial, la resistencia a la insulina y los trastornos en la tolerancia a la glucosa (componentes del síndrome metabólico), aceleran el proceso de la aterosclerosis sistémica. El exceso de glucocorticoides genera además, un estado protrombótico que se acompaña de disfunción endotelial. Esto se traduce en un mayor riesgo de infarto del miocardio, insuficiencia cardiaca, ictus y eventos tromboembólicos venosos. Se ha estimado un incremento de la mortalidad hasta 4 veces mayor cuando se compara a estos pacientes con la población general, de ahí que pueda considerarse una enfermedad potencialmente letal. Asociado a la necesidad de eliminar la causa del exceso de glucocorticoides, se recomienda la evaluación del riesgo cardiovascular global y el tratamiento intensivo de cada uno de los factores de riesgo durante la fase activa, en el periodo de remisión y luego de la curación. Teniendo en cuenta lo mencionado anteriormente y la importancia del tema, se realiza una actualización de la repercusión cardiovascular del hipercortislismo en los pacientes que lo padecen(AU)

Cushing's syndrome is characterized by endogenous hypercortisolism that causes many different metabolic alterations increasing the cardiovascular risk at the active phase of disease and even after recovery. Central obesity, dyslipidemia, blood hypertension, insulin resistance, and glucose tolerance disorders (components of the metabolic syndrome) accelerate the process of systemic atherosclerosis. Excessive glucocorticoids also generate a prothrombotic condition with endothelial dysfunction. This leads to higher risk of myocardial infarction, heart failure, ictus and vein thromboembolic events. A fourfold increase of mortality has been estimated in these patients when compared to the general population; hence this disease may be considered a lethal one. In addition to the need of eliminating the cause of excessive glucocorticoids, it is recommended to evaluate the global cardiovascular risk and the intensive treatment for each of the risk factors during the active phase, in the remission period and after recovery. Taking into account the above-mentioned and the importance of this topic, an update on the cardiovascular impact of hypercortisolism was presented(AU)

Riesgo cardiovascular en el síndrome de Cushing / Cardiovascular risk found in Cushing syndrome

El síndrome de Cushing se caracteriza por un estado de hipercortisolismo endógeno, que produce múltiples y variadas alteraciones metabólicas que aumentan el riesgo cardiovascular en la fase activa de la enfermedad y aún después de la curación. La presencia de la obesidad central, la dislipidemia, la hipertensión arterial, la resistencia a la insulina y los trastornos en la tolerancia a la glucosa (componentes del síndrome metabólico), aceleran el proceso de la aterosclerosis sistémica. El exceso de glucocorticoides genera además, un estado protrombótico que se acompaña de disfunción endotelial. Esto se traduce en un mayor riesgo de infarto del miocardio, insuficiencia cardiaca, ictus y eventos tromboembólicos venosos. Se ha estimado un incremento de la mortalidad hasta 4 veces mayor cuando se compara a estos pacientes con la población general, de ahí que pueda considerarse una enfermedad potencialmente letal. Asociado a la necesidad de eliminar la causa del exceso de glucocorticoides, se recomienda la evaluación del riesgo cardiovascular global y el tratamiento intensivo de cada uno de los factores de riesgo durante la fase activa, en el periodo de remisión y luego de la curación. Teniendo en cuenta lo mencionado anteriormente y la importancia del tema, se realiza una actualización de la repercusión cardiovascular del hipercortislismo en los pacientes que lo padecen(AU)

Cushing's syndrome is characterized by endogenous hypercortisolism that causes many different metabolic alterations increasing the cardiovascular risk at the active phase of disease and even after recovery. Central obesity, dyslipidemia, blood hypertension, insulin resistance, and glucose tolerance disorders (components of the metabolic syndrome) accelerate the process of systemic atherosclerosis. Excessive glucocorticoids also generate a prothrombotic condition with endothelial dysfunction. This leads to higher risk of myocardial infarction, heart failure, ictus and vein thromboembolic events. A fourfold increase of mortality has been estimated in these patients when compared to the general population; hence this disease may be considered a lethal one. In addition to the need of eliminating the cause of excessive glucocorticoids, it is recommended to evaluate the global cardiovascular risk and the intensive treatment for each of the risk factors during the active phase, in the remission period and after recovery. Taking into account the above-mentioned and the importance of this topic, an update on the cardiovascular impact of hypercortisolism was presented(AU)

Rotation thromboelastometry and the hypercoagulable state in Cushing's syndrome.

INTRODUCTION: Rotation thromboelastometry (ROTEM®) can be used for hypercoagulability evaluation. Cushing's syndrome (CS) is associated with hypercoagulability; however, ROTEM® has never been evaluated in this setting. OBJECTIVE: To evaluate hypercoagulability in CS using ROTEM® and to correlate these parameters with coagulation markers and with the presence of deep vein thrombosis. DESIGN AND METHODS: Thirty patients with active CS (26 women) and 30 controls matched for age, sex, body mass index, diabetes mellitus, arterial hypertension, ABO blood group and smoking were included. We measured levels of activated partial thromboplastin time (aPTT), platelets, fibrinogen, D-dimer, factor VIII (FVIII), von Willebrand factor (vWF) and C-reactive protein. ROTEM® was used to evaluate the intrinsic (INTEM), extrinsic (EXTEM) and fibrinogen (FIBTEM) pathways. Doppler ultrasonography was performed to search for lower limbs deep vein thrombosis. RESULTS: INTEM clotting time using ROTEM® was shorter in patients than in controls (P = 0·04). Other ROTEM® parameters were not different. Mean aPTT was shorter in patients than in controls (P = 0·001). The FVIII, vWF and D-dimer levels were higher in patients than in controls (P = 0·001, 0·001 and 0·02, respectively). Obese CS patients presented higher levels of platelets and alterations in maximum clot formation (MCF), alpha angle and maximum speed of clot formation of INTEM (P = 0·03, 0·02 and 0·02, respectively) and an increase in the MCF of FIBTEM (P = 0·02). No deep vein thrombosis was found. CONCLUSIONS: Although FVIII and vWF were abnormal in CS patients, only the initiation clot formation was different in the ROTEM® methodology and no deep vein thrombosis was found.

Skeletal maturation in children with Cushing syndrome is not consistently delayed: the role of corticotropin, obesity, and steroid hormones, and the effect of surgical cure.

OBJECTIVE: To assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1-year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements. STUDY DESIGN: This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone-independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years). BA was obtained before surgery and at follow-up. Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA. RESULTS: Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA. The majority of children (76%) had normal BA. The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865). Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA. Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001). CONCLUSION: Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

Activation of PPARγ by restores mast cell numbers and reactivity in alloxan-diabetic rats by reducing the systemic glucocorticoid levels.

Mast cell function and survival have been shown to be down-regulated under diabetic conditions. This study investigates the role of the peroxisome proliferator-activated receptor (PPAR)-γ in reducing mast cell number and reactivity in diabetic rats. The effect of rosiglitazone on mast cell apoptosis was also evaluated. Diabetes was induced by intravenous injection of alloxan into fasted rats and PPARγ agonist rosiglitazone and/or specific antagonist 2-chloro-5-nitrobenzanilide (GW9662) were administered 3 day after diabetes induction, once daily for 18 consecutive days. Mast cell apoptosis and plasma corticosterone levels were evaluated by TUNEL and radioimmunoassay, respectively. Treatment with rosiglitazone restored mast cell numbers in the pleural cavity and mesenteric tissue of diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced reduction of histamine release by mast cells, as measured by fluorescence, following activation with the antigen in vitro. Increased apoptosis in mast cells from diabetic rats were inhibited by rosiglitazone. Moreover, we noted that the increase in plasma corticosterone levels in diabetic rats was inhibited by rosiglitazone. In addition, GW9662 blocked the ability of rosiglitazone to restore baseline numbers of mast cells and plasma corticosterone in diabetic rats. In conclusion, our findings showed that rosiglitazone restored the number and reactivity of mast cells in diabetic rats, accompanied with a suppression of apoptosis, in parallel with impairment of diabetes hypercorticolism, indicating that PPARγ has an important role in these phenomena.

Prevalence and associated factors of subclinical hypercortisolism in patients with resistant hypertension.

BACKGROUND: Subclinical hypercortisolism is a secondary cause of hypertension that had never been evaluated in resistant hypertensive patients, a subgroup of general hypertensive individuals with an expected high prevalence of secondary hypertension. METHODS: Four hundred and twenty-three patients with resistant hypertension and ages up to 80 years were screened for the presence of subclinical hypercortisolism by morning serum cortisol after a midnight 1 mg dexamethasone suppression test (DST). Those with morning cortisol of at least 50  nmol/l had hypercortisolism confirmed by two salivary cortisol of at least 3.6  nmol/l collected at 2300  h. Statistical analysis included bivariate tests between those with positive and negative screening test and with and without confirmed hypercortisolism, and logistic regressions to assess their independent correlates. RESULTS: One hundred and twelve patients (prevalence 26.5%, 95% confidence interval 22.0-31.9%) had the screening test positive for suspected hypercortisolism. None had overt Cushing syndrome. Patients with positive screening were older, more frequently males, had higher prevalences of diabetes and target-organ damage and higher nighttime SBPs than patients with normal screening test results. Thirty-four patients (total prevalence 8.0%, 95% confidence interval: 5.7-11.2%) had confirmed hypercortisolism. Independent correlates of a positive DST were older age (P = 0.007), male sex (P = 0.012) and presence of cardiovascular diseases (P = 0.002) and chronic kidney disease (P = 0.016). Correlates of confirmed subclinical hypercortisolism were older age (P = 0.020), diabetes (P = 0.06) and a nondipping pattern on ambulatory blood pressure monitoring (P = 0.04). CONCLUSION: Patients with resistant hypertension had a relatively high prevalence of subclinical hypercortisolism, and its presence is associated with several markers of worse cardiovascular prognosis.

Síntomas psicóticos, paranoides y catatónicos como debut de enfermedad de Cushing en una paciente con síndrome de Turner: reporte de caso y revisión de la literatura / Psicotic, paranoid and catatonic symptoms as Cushing disease onset in a Turner syndrome patient: case report and literature revision

It is known that hipercortisolism and overactivity of the Hypotalamus pituitary adrenal axis are associated to psiquiatric diseases presentation. In patients with Cushing syndrome, mood disorders are common, also psicosis cases also are present during the disease. But, the presence and mostly the onset with a episode of catatonic psicosis is unusual. The cortisol excess produce structural damage in the Central Nervous System, reversible and irreversible, specially in the hypocampus. We show the case of a young woman with previous diagnostic of Turner syndrome, karyotype 45 X0, who presented a psychiatric episode caracterized for depresive psicotic symptoms and posteriorly a catatonic state as an unusual form of Cushing disease onset. This patient presented health improvement after pituitary resection. There is not evidencia that Turner syndrome influes over this unusual form of presentation.

Se conoce que el hipercortisolismo y la sobreactividad del eje hipotálamo pituitario adrenal están asociados a la presentación de enfermedades psiquiátricas. En pacientes con síndrome de Cushing son frecuentes los trastornos del ánimo aunque también se presentan casos de psicosis durante el curso de la enfermedad. Sin embargo es inusual la presencia y más aún el debut con un cuadro de psicosis catatónica. El exceso de cortisol produce daño estructural en el sistema nervioso central tanto reversible como irreversible, especialmente en el hipocampo. Presentamos el caso de una paciente mujer joven con diagnóstico previo de síndrome de Turner, cariotipo 45 X0, quien presentó un cuadro psiquiátrico caracterizado por síntomas depresivos psicóticos y posteriormente catatonia como forma inusual de debut de enfermedad de Cushing y presentó mejoría posterior a la resección de la pituitaria. No se tiene evidencia que el síndrome de Turner influya sobre esta rara forma de presentación.

Overexpression of 11ß-hydroxysteroid dehydrogenase type 1 in visceral adipose tissue and portal hypercortisolism in non-alcoholic fatty liver disease.

BACKGROUND: The enzyme 11ß-hydroxysteroid-dehydrogenase type 1 (11ß-HSD1) catalyses the reactivation of intracellular cortisol. We explored the potential role of 11ß-HSD1 overexpression in visceral adipose tissue (VAT) in non-alcoholic fatty liver disease (NAFLD) assessing sequential changes of enzyme expression, in hepatic and adipose tissue, and the occurrence of portal hypercortisolism in obese mice. 11ß-HSD1 expression was also assessed in tissues from obese patients undergoing bariatric surgery. METHODS: Peripheral and portal corticosterone levels and liver histology were assessed in ob/ob mice at two time points (8-12 weeks of age). 11ß-HSD1 tissue expression was assessed in by RT-pcr in ob/ob mice and in 49 morbidly obese patients. RESULTS: Portal corticosterone serum levels were higher in obese mice with a 26% decrease between 8 and 12 weeks of age (controls: 78.3 ± 19.7 ng/ml, 8-week-old ob/ob: 167.5 ± 14.5 ng/ml and 12-week-old ob/ob: 124.3 ± 28 ng/ml, P < 0.05). No significant differences were found in peripheral corticosterone serum levels. Expression of 11ß-HSD1 was lower in the liver [-45% at 8 weeks and -35% at 12-weeks (P = 0.0001)] and highly overexpressed in VAT in obese mice, compared to controls (128-fold higher in 8-week-old ob/ob and 41-fold higher in 12-week-old ob/ob, P < 0.01). No significant differences were seen in the expression of 11ß-HSD1 in subcutaneous adipose tissue. In multivariate analysis, human 11ß-HSD1 expression in VAT (OR: 1.385 ± 1.010-1.910) was associated with NAFLD. CONCLUSION: Murine NAFLD is associated with portal hypercortisolism and11ß-HSD1 overexpression in VAT. In humans, 11ß-HSD1 VAT expression was associated with the presence of NAFLD. Thus, local corticosteroid production in VAT may contribute to NAFLD pathogenesis.