Academic literature on the topic 'Cushing's syndrome'

Exophthalmos is typically associated with Graves' ophthalmopathy. Although originally described by Harvey Cushing, exophthalmos is an underappreciated sign of Cushing's syndrome. We present a case of a 38-year-old female who presented with severe bilateral proptosis and was subsequently diagnosed with Cushings disease. We discuss the possible mechanisms causing exophthalmos in patients with either endogenous or exogenous hypercortisolemia.

Drug-induced (iatrogenic) Cushing's syndrome results from excessive or prolonged exposure to glucocorticoids, commonly prescribed for autoimmune, inflammatory, and hematological disorders due to their anti-inflammatory, immunosuppressive, and proapoptotic effects. Despite their therapeutic benefits, these medications can lead to a range of multisystemic symptoms mirroring those of endogenous Cushing’s syndrome. This review aims to elucidate the causes, clinical presentation, diagnosis, and management of iatrogenic Cushing's syndrome, emphasizing awareness of medications that can trigger its onset. The following review covers cortisol physiology, Cushing's syndrome etiology and subtypes, hypercortisolism complications and prognosis, and strategies for glucocorticoid withdrawal. This article synthesizes key findings and recommendations, highlighting challenges and controversies in the diagnosis and treatment of iatrogenic Cushing's syndrome.

We report outcomes from laparoscopic adrenalectomy (LA) comparing patients with Cushing's syndrome with those with other adrenal pathology with respect to length of stay (LOS), overall complications, and financial implications. We conducted a retrospective review of 80 continuous patients (103 glands) undergoing LA. The clinical diagnoses were: hypercortisolism (Cushing’ syndrome; n = 33), hyperaldosteronism (Conn's syndrome; n = 20), phaeochromocytoma (n = 16), and neoplasm (others; n = 11). Advanced care in the intermediate or intensive care unit was necessary in 27 patients, most frequently in our Cushing's population (16 of 33 [48%]). Six patients sustained major complications, including death in two patients; seven patients sustained minor complications. LOS was longer for patients with Cushing's syndrome (mean, 5.5 vs 3.3 days; P = 0.024). Financially, patients with Cushing's syndrome had statistically higher total hospital ( P = 0.009), advanced care ( P = 0.002), and anesthetic costs ( P = 0.005). LA in patients with Cushing's syndrome is associated with longer hospitalizations, more frequent major complications, and higher advanced care requirements, especially for patients undergoing bilateral adrenalectomy Minor complications were infrequent and median LOS was brief regardless of diagnosis. Patients with Cushing's syndrome had higher costs for overall hospital charges, advanced care, and anesthesia.

Paraneoplastic syndromes can serve as initial indicators of malignancy, with small cell lung cancer accounting for 13% of new lung cancer diagnoses. The most prevalent paraneoplastic syndrome associated with small cell lung cancer is inappropriate antidiuretic hormone syndrome, followed by ectopic adrenocorticotropic hormone-mediated Cushing’s syndrome. Cushing’s syndrome manifests as hypercortisolemia and presents with diverse symptoms, including central obesity, plethora, menstrual irregularities, hypertension/diabetes mellitus, ecchymoses, osteoporosis, muscle weakness, virilization/hirsutism, skin atrophy, decreased libido, and infertility. This case report details the uncommon presentation of small cell lung carcinoma manifesting with ectopic adrenocorticotropic hormone secretion (EAS), leading to resistant hypokalemia and rhabdomyolysis. This case emphasizes the importance of considering EAS in severe cases of Cushing's syndrome and highlights the diagnostic and therapeutic challenges associated with this condition.

From the very beginning of his career, Harvey Williams Cushing (1869–1939) harbored a deep interest in a complex group of neoplasms that usually developed at the infundibulum. These were initially known as “interpeduncular” or “suprasellar” cysts. Cushing introduced the term “craniopharyngioma” for these lesions, which he believed represented one of the most baffling problems faced by neurosurgeons. The patient who most influenced Cushing's thinking was a 16-year-old seamstress named “Mary D.,” whom he attended in December 1901, exactly the same month that Alfred Fröhlich published his seminal article describing an adiposogenital syndrome in a young boy with a pituitary cyst. Both Cushing's and Fröhlich's patients showed similar symptoms caused by the same type of tumor. Notably, Cushing and Fröhlich had met one another and became good friends in Liverpool the summer before these events took place. Their fortunate relationship led Cushing to realize that Fröhlich's syndrome represented a state of hypopituitarism and provided a useful method of diagnosing interpeduncular cysts. It is noteworthy that Cushing's very first neurosurgical procedure on a pituitary tumor was performed in the case of Mary D.'s “interpeduncular cyst,” on February 21, 1902. Cushing failed to remove this lesion, which was later found during the patient's autopsy. This case was documented as Pituitary Case Number 3 in Cushing's masterpiece, The Pituitary Body and Its Disorders, published in 1912. This tumor was considered “a teratoma”; however, multiple sources of evidence suggest that this lesion actually corresponded to an adamantinomatous craniopharyngioma. Unfortunately, the pathological specimens of this lesion were misplaced, and this prompted Cushing's decision to retain all specimens and documents of the cases he would operate on throughout his career. Accordingly, Mary D.'s case crystallized the genesis of the Cushing Brain Tumor Registry, one of Cushing's major legacies to neurosurgery. In this paper the authors analyze the case of Mary D. and the great influence it had on Cushing's conceptions of the pituitary gland and its afflictions, and on the history of pituitary surgery.

Patients with Cushing’s syndrome often complain about sleep disruption and excessive day time sleepiness, which could contribute to worsening quality of life and metabolic comorbidities (obesity, hypertension, diabetes mellitus, dyslipidaemia) associated with hypercortisolism. Sleep disorders have been shown to increase the risk of developing cardiovascular disease and that the risk of cardiovascular disease in patients with hypercortisolism may be worsened by impaired sleep. Cushing’s syndrome patients may also be at increased risk for obstructive sleep apnea due to their obesity.
Dissertation (MSc)--University of Pretoria, 2020.
Physiology
MSc
Restricted

Cyclic-AMP dependent protein kinase (PKA) is a key intracellular signal transduction kinase that is modulated by Gs- and Gi-coupled GPCRs. Under normal physiological conditions, PKA exists as an inactive holoenzyme made up of two catalytic subunits and two regulatory subunits. Upon cAMP binding to the regulatory subunits, the catalytic subunits (PKACa) are released to perform various downstream phosphorylation events. However, aberrant PKA activation can cause various diseases including Cushing’s Syndrome, which is an endocrine disorder caused by the overproduction of cortisol by the hypothalamus-pituitary-adrenal hormone system. This disorder can be caused by pituitary adenomas that release unregulated amounts of ACTH, adrenal adenomas that release unregulated amounts of cortisol without ACTH stimulation, and ectopic tumors outside the hypothalamus-pituitary-adrenal axis that produce ACTH. In recent genomic studies of patients with ACTH-independent Cushing’s Syndrome, the L205R-PKACamutant has been discovered. Through various studies on the mutant enzyme multiple research groups learned that the single point mutation causes a loss in sensitivity to cAMP signaling, a loss in binding to PKA regulatory subunits, and unregulated phosphorylation of PKACasubstrates, which ultimately leads to the increased cortisol biosynthesis in these patients. The first part of this work describes the enzymology and inhibition studies of known inhibitors against both wt- and L205R-PKACa. Early in the enzymology studies we developed at medium throughput endpoint assay that used Rhodamine-kemptide as the substrate and as a chromophore separating substrate and phosphorylated product using a reverse-phase HPLC method. The analysis of the substrate peptide against both wild-type and mutant enzyme showed a 6-fold decrease in the KMand a 2-fold decrease in kcat, and a similar but lower order of magnitude effect was observed for the studies with ATP. The inhibition studies were performed using the substrate competitive inhibitor PKI(5-24), which showed a 253-fold higher potency towards the wild-type enzyme over the mutant while the ATP-competitive inhibitor was determined to be equipotent. Using this information we used modeling studies to aid in the development of mutant selective functional inhibitors for the substrate-binding pocket. Additionally, we begun to explore the use of Proteolysis Targeting Chimeras, or PROTACs, as another means for targeting the L205R mutant enzyme.

Los estudios descritos en esta tesis se centran en las consecuencias neuropsicológicas de quienes han sufrido síndrome de Cushing (SC, debido al exceso de glucocorticoides) y acromegalia (debido al exceso de hormona de crecimiento -GH-). Las evidencias muestran que la exposición prolongada a glucocorticoides puede tener efectos adversos en pacientes con SC, los cuales no recuperan el nivel de funcionamiento y la calidad de vida después de años de curación. Por otro lado, en los pacientes con acromegalia, los potenciales efectos negativos de la GH sobre la personalidad, la cognición y el comportamiento apenas han sido considerados hasta hace poco. Tomar decisiones es un comportamiento habitual de la vida diaria y requiere seleccionar una opción entre varias posibilidades. El Iowas gambling Task (IGT) es una medida de toma de decisiones que pretende imitar situaciones de la vida real que implican incertidumbre, recompensas y sanciones. La corteza frontal tiene un rol clave en el IGT porque posee la habilidad de coordinar el procesamiento de millones de neuronas para dirigirlas a conseguir metas futuras y tomar decisiones ventajosas. Los objetivos de estos estudios son evaluar la toma de decisiones y la memoria en pacientes con SC y acromegalia, y explorar sus relaciones con la corteza frontal y los problemas afectivos. Se evaluaron 35 pacientes con SC y 35 controles sanos usando el IGT y una resonancia magnética 3Tesla para medir la corteza frontal. Treinta y un pacientes con acromegalia y 31 controles sanos fueron evaluados con el IGT, el RAVLT (Rey Auditory Verbal Learning Test), el STAI (State-Trait Anxiety Inventory) y el BDI-II (Beck Depression Inventory-II). En el primer estudio, los pacientes con SC presentaron estrategias de toma de decisiones alteradas, elegían menos cartas seguras y más cartas de riesgo. Mostraron más dificultades que los controles en aprender los perfiles correctos de ganancias y pérdidas de cada grupo de cartas. En el análisis cerebral completo, los pacientes con SC mostraron adelgazamiento del grosor cortical en la corteza frontal superior izquierda, la corteza precentral izquierda, la corteza insular izquierda, la corteza cingulada anterior izquierda y derecha y la corteza frontal medial caudal derecha, en comparación con los controles sanos. En el segundo estudio, los pacientes acromegálicos mostraron peor memoria verbal a largo plazo y más síntomas de depresión y ansiedad que los controles sanos. Respecto al IGT, los pacientes con acromegalia presentaron una alteración en la estrategia de toma de decisiones en comparación con los controles, elegían menos cartas seguras y más cartas de riesgo. Múltiples correlaciones fueron encontradas entre los síntomas depresivos y ansiosos y la ejecución en memoria y toma de decisiones. Estos estudios muestran una peor toma de decisiones en pacientes con SC y acromegalia. Los pacientes seleccionaban más opciones desfavorables que ventajosas. Mientras los controles sanos aprendían gradualmente a favor de las opciones ventajosas, los pacientes con SC y acromegalia continuaban obteniendo sanciones a lo largo de la tarea. No obtuvimos relación directa entre mala toma de decisiones y adelgazamiento de la corteza frontal, a diferencia de estudios previos en otras patologías. Los déficits en el IGT correlacionaron con los problemas de memoria en pacientes con CS y acromegalia. Además, los pacientes con acromegalia mostraron alteraciones emocionales (ansiedad y síntomas depresivos) que influenciaron la memoria a largo plazo y la toma de decisiones.
The studies described in this thesis focus on the neuropsychological consequences in patients who have suffered Cushing’s syndrome (CS, due to glucocorticoid excess) and acromegaly (due to excess of growth hormone -GH-). It is known that prolonged exposure to glucocorticoids may have long-lasting adverse effects in CS patients who do not completely return to premorbid level of functioning and quality of life despite long-term cure. On the other hand, in acromegalic patients, potential long-lasting effects of GH on the brain affecting personality, cognition and behaviour have not been considered until recently. Making a choice is a common behavior in daily life and requires selecting one option among several alternative possibilities. The Iowa Gambling Task (IGT) is a measurement of decision making that mimics real-life risk taking situations since it involves uncertainty, reward and punishment. Frontal cortex has a key role in the IGT because it has the ability to coordinate processing among its millions of neurons in order to direct them towards future goals and advantageous decisions. The aims of these studies were to evaluate memory and decision making in patients with CS and acromegaly, and explore their relationship with frontal cortex and affective disorders. Thirty-five CS patients and thirty-five matched controls were evaluated using the IGT and 3Tesla magnetic resonance imaging (MRI) to assess frontal cortical thickness. Thirty-one patients with acromegaly and thirty-one healthy controls were evaluated using the IGT, Rey Auditory Verbal Learning Test (RAVLT), State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory-II (BDI-II). In the first study, CS patients presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards and higher number of riskier cards. They showed more difficulties than controls to learn the correct profiles of wins and losses for each card group. In whole brain analysis, CS patients showed decreased cortical thickness in the left superior frontal cortex, left precentral cortex, left insular cortex, left and right rostral anterior cingulate cortex, and right caudal middle frontal cortex compared to controls. In the second study, acromegalic patients showed impairments in delayed verbal memory and more anxiety and depressive symptoms than controls. Regarding the IGT, acromegalic patients presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards and higher number of the riskier cards. Multiple correlations between anxiety and depressive symptoms and performance in memory and decision making were found. These studies show impaired decision making in both CS and acromegalic patients. They selected more disadvantageous choices than advantageous choices. Whereas healthy controls gradually learned to favor the advantageous decks, patients with acromegaly and CS continued to experience large punishment throughout training. We have not found a direct relationship between poor decision making and frontal cortical thinning in CS patients, opposite to previous studies on other clinical conditions. Decision deficits on the IGT were correlated with memory deficits in CS and acromegalic patients. Moreover, acromegalic patients show affective alterations (anxiety and depressive symptoms) that influenced delayed memory and decision making.

El Síndrome de Cushing (SC) es una enfermedad endocrina rara, causada por una larga exposición a la hormona cortisol. Este hipercortisolismo endógeno determina síntomas endocrinos, cognitivos y psiquiátricos. Algunos estudios de neurorradiología han investigado la estructura cerebral en pacientes con SC encontrando alteraciones. Los objetivos de los estudios de esta tesis se centran en investigar la microestructura de la Sustancia Blanca cerebral (SB), un área que hasta ahora apenas ha sido estudiada en el SC, en evaluar los síntomas neuropsiquiátricos (depresión y ansiedad) y neuropsicológicos (velocidad de procesamiento de la información) y su relación con la SB. La Imagen con Tensor de Difusión (DTI) es una técnica de resonancia magnética (RM) que permite el estudio no-invasivo in vivo del cerebro evaluando el movimiento de las moléculas de agua a través de los axones. Existen diferentes mapas de DTI que permiten estudiar la arquitectura de la SB y mostrar anomalías microestructurales de la SB. La anisotropía fraccional (FA) refleja la integridad de la SB, mientras que los incrementos en la difusividad media (MD) pueden ser debidos ​​a desmielinización y/o edema. La disminución de la difusividad axial (AD) indica la pérdida axonal, mientras que el aumento de la difusividad radial (RD) se relaciona más con la desmielinización. En este trabajo se incluyeron 35 pacientes con SC y 35 voluntarios control sanos. En un primer estudio, se realizó un análisis de DTI comparando a los pacientes con SC con los controles sanos, seguido de un segundo análisis en el cual los pacientes fueron separados en SC activo, SC controlado y SC curado. Los resultados revelaron reducciones generalizadas de la FA, aumentos de MD y RD y un aumento parcial de la AD en pacientes con SC en comparación con los controles sanos. El análisis de subgrupos demostró este mismo patrón en la SB en pacientes con SC activo, controlado y curado, lo que sugiere un inicio temprano y duradero de las alteraciones en la microestructura de la SB. Las alteraciones de la SB fueron independientes del hipercortisolismo concomitante y de la presencia o ausencia de otros factores de riesgo cardiovascular incluidos en el análisis, como fueron la hipertensión, dislipidemia y la obesidad. Nuestro objetivo en un segundo estudio fue el investigar los trastornos del estado de ánimo y neuropsicológicos en los pacientes con SC y su relación con las alteraciones que habíamos visto en la SB. Planteamos la hipótesis de que los trastornos del estado de ánimo, utilizando el Beck Depression Inventory II (BDI-II) y el State-Trait Anxiety Inventory (STAI), serían mayores en los pacientes con SC que en los controles, y que se relacionarían con las alteraciones de la SB. Además, hipotetizamos que los pacientes con SC podrían mostrar anomalías en la velocidad de procesamiento de información, utilizando el Symbol Digit Modalities Test (SDMT), posiblemente vinculadas a las alteraciones de la SB, lo que sería debido a la conectividad funcional. Los resultados mostraron mayores trastornos del estado de ánimo (síntomas de depresión y de ansiedad), sin diferencias en las puntuaciones de velocidad de procesamiento de la información, en los pacientes con SC comparados con los controles sanos. En el estudio caso-control con DTI, los síntomas depresivos se correlacionaron negativa y positivamente, respectivamente con FA y RD, lo que refleja un patrón de alteraciones funcionales en estos pacientes que está vinculado a la pérdida de mielina y de la integridad axonal. FA y AD se correlacionaron positivamente con la velocidad de procesamiento de la información. Esto parece implicar que el estado/integridad de la SB determina una mejor ejecución en el procesamiento de la información tanto en pacientes con SC como en controles.
Cushing’s syndrome (CS) is an endocrine disorder due to prolonged exposure to cortisol. This endogenous hypercortisolism determines endocrine, cognitive and psychiatric symptoms. A few imaging studies have investigated brain structures in patients with CS and have observed brain damage. The aims of the studies described in this thesis were to explore the microstructure of cerebral white matter (WM), a topic hardly investigated up to now in CS, and to evaluate neuropsychiatric symptoms (depression and anxiety) and cognitive impairment (information processing speed) and their relationship with the WM. Diffusion Tensor Imaging (DTI) is a Magnetic Resonance (MR) imaging technique that allows noninvasive, in vivo study of the brain by assessing the motion of water molecules along and across neural axons. Different DTI maps show WM architecture and can depict microstructural WM abnormalities. Fractional anisotropy (FA) reflects WM integrity, while increases in mean diffusivity (MD) may be caused by demyelination or edema. Decreases in axial diffusivity (AD) indicate axonal loss, while increased radial diffusivity (RD) is related to demyelination. Thirty-five patients with CS and 35 healthy control volunteers were included in these studies. In the first study, a DTI analysis was performed comparing patients with CS with healthy controls, followed by a second analysis in which patients were separated into active CS, remitted CS, and cured CS. Results revealed widespread reductions in whole brain FA, increases in MD and RD and partially also of AD in patients with CS compared to healthy controls. The subgroup analysis demonstrated this same pattern of WM damage in patients with active, remitted and cured CS, suggesting an early onset and persistent damage of brain WM microstructure. DTI alterations seemed to be independent of concomitant hypercortisolism and the presence or absence of other cardiovascular risk factors included into the analysis like hypertension, dyslipidemia, and obesity. Our aim in the second study was to investigate mood disturbances and cognitive impairment in CS patients, and their relationship to WM alterations on DTI. We hypothesized that mood disturbances, evaluated using the Beck Depression Inventory II (BDI-II) and State-Trait Anxiety Inventory (STAI), would be greater in CS patients than in controls, and related to widespread WM alterations on DTI. We additionally hypothesized that CS patients would show abnormalities in information processing speed, evaluated using the Symbol Digit Modalities Test (SDMT), possibly related to WM alterations, since WM state has been related to connectivity function. Results showed greater mood disturbances (depression and anxiety symptoms), but no differences in information processing speed scores, in CS patients compared to healthy controls. In the case-control DTI study, depressive symptoms correlated negatively with FA and positively with RD, a pattern which is linked to loss of myelin and axonal integrity. FA and AD correlated positively with information processing speed. These results indicate that WM integrity are associated with better information processing in CS patients and controls.

Cushing's syndrome and glucocorticoid therapy lead to central obesity, insulin resistance, and symptoms of altered energy regulation similar to those observed in the metabolic syndrome. We hypothesized that excess glucocorticoids alter energy sensing/signaling in skeletal muscle through mediation of the LKB1/AMPK signaling pathway. To test this hypothesis, three 100 mg pellets of corticosterone were implanted subcutaneously in each of nine rats for two weeks. Responses were compared with sham operated controls fed ad libitum or food restricted to produce the body weights similar to the treatment group rats. After the treatment period, animals were anesthetized and the right gastrocnemius-plantaris and soleus were removed for analysis. After tibial nerve stimulation for 5 min, the left gastrocnemius-plantaris and soleus were also removed. We assessed AMPK activity and subunit expression, as well as several metabolic indicators including ATP, creatine phosphate, creatine, glycogen, and malonyl-CoA levels in rested and stimulated gastrocnemius-plantaris and soleus muscles. We found that high levels of glucocorticoids decreased AMPKγ3 subunit expression in the gastrocnemius-plantaris. We also observed reduced AMPKα2 activity in the stimulated gastrocnemius-plantaris, but not the soleus; and that this decreased activity corresponded to a significant reduction in phosphorylated TBC1D1, a protein involved in signaling GLUT-4 translocation. Finally, in the gastrocnemius-plantaris, we also noted an increase in glycogen stores in the hypercorticosteronemic rats. Our data suggest that altered energy sensing/signaling associated with high levels of glucocorticoids may be due in part to inhibition of AMPKα2 activity and the high energy state produced by increased glycogen stores. We also conclude that high levels of glucocorticoids decrease the levels of AMPKγ3 and diminish insulin/contraction signaling through phosphorylated TBC1D1.

Appropriate regulation of gene expression is necessary for correct development and homeostasis of organisms. Epigenetic mechanisms represent an additional layer of information, besides the genetic sequence, crucial for the correct functioning of each cell. Histone modifications, which modulate and are associated to transcriptional activation or repression, are a major epigenetic feature. Thanks to predictive modelling, we have studied which histone modifications relate better to enhancer or promoter function in mouse embryonic stem cells, during differentiation and in animal development. We have found that different histone modifications relate better to enhancers or promoters, respectively. We have studied the role of poised enhancers during differentiation and development. We have seen that poised enhancer activation is not exclusive of the neural lineage, but a general mechanism implicated in differentiation of every cell type. We have characterized the epigenetic landscape of Cushing’s syndrome. We have found persistent epigenetic and transcriptional alterations after long-term remission of the disease, related to a deep alteration of the circadian rhythm. These findings promise to be relevant for future therapeutic advances.
Una regulació apropiada de l’expressió gènica és necessària per a un correcte desenvolupament i homeòstasi dels organismes. Els mecanismes epigenètics representen una informació addicional, a més de la seqüència genètica, crucial per al correcte funcionament de cada cèl·lula. Les modificacions d’histones, que modulen i s’associen a activació o repressió transcripcionals, són una característica epigenètica important. Gràcies al modelatge predictiu, hem estudiat quines modificacions d’histones es relacionen millor amb la funció dels enhancers o promotors en cèl·lules mare embrionàries de ratolí, durant la diferenciació i en el desenvolupament animal. Hem trobat que modificacions d’histones diferents es relacionen millor amb enhancers o promotors, respectivament. Hem estudiat el rol dels poised enhancers durant la diferenciació i el desenvolupament. Hem vist que l’activació dels poised enhancers no és exclusiva del llinatge neural, sinó un mecanisme implicat en la diferenciació de tot tipus cel·lular. Hem caracteritzat el paisatge epigenètic de la síndrome de Cushing. Hem trobat alteracions epigenètiques i transcripcionals després d’una remissió de la malaltia a llarg termini, relacionades amb una profunda alteració del ritme circadiari. Aquestes troballes prometen ser rellevants per a futurs avenços terapèutics.

INTRODUÇÃO: A hiperplasia adrenal macronodular independente de ACTH (AIMAH) é uma doença rara, caracterizada pela presença de macronódulos funcionantes nas adrenais e por uma produção aumentada, autônoma e sustentada de cortisol. Constitui uma causa incomum de síndrome de Cushing (SC). A forma esporádica da doença parece ser a mais frequente, no entanto, se desconhece a real prevalência de sua forma familial. Apesar de ser uma entidade clínica conhecida há quase 50 anos, o processo fisiopatológico que culminaria com a AIMAH, as alterações genéticas predisponentes e aspectos clínicos, laboratoriais e radiológicos relevantes da doença ainda não foram elucidados de forma clara. O diagnóstico recente de uma grande família portadora da doença viabilizou a realização do presente trabalho. OBJETIVOS: 1) Caracterizar a evolução da AIMAH em sua forma familial, correlacionando as manifestações clínicas, os dados laboratoriais e os achados radiológicos; 2) investigar a possível associação entre a AIMAH e a ocorrência de meningiomas intracranianos; 3) avaliar a atividade metabólica das adrenais hiperplasiadas na AIMAH; 4) definir o padrão de herança genética da doença na família estudada; e 5) mapear regiões cromossômicas e loci potencialmente relacionados à etiologia genética da AIMAH familial. MÉTODOS: 96 membros da família estudada foram inicialmente submetidos a uma avaliação clínica e laboratorial pormenorizada. Em seguida, foram realizados exames de tomografia computadorizada para a caracterização radiológica das adrenais. Exames de ressonância magnética e de tomografia por emissão de pósitrons com fluordesoxiglicose marcada, acoplada à tomografia computadorizada (18F-FDGPET/CT) foram realizados em pacientes com as formas familial e esporádica da doença para, respectivamente, investigar a presença de meningiomas intracranianos e caracterizar a atividade metabólica das adrenais hiperplasiadas. Foram também realizados testes in vivo para a pesquisa de receptores hormonais aberrantes nos pacientes com a forma familial da doença. Em uma outra etapa do estudo, diferentes técnicas de biologia molecular foram empregadas para a investigação da etiologia genética da AIMAH familial. Desta forma, realizou-se: o sequenciamento do gene do receptor do ACTH (MC2R), um estudo de ligação genética utilizando microssatélites específicos, um estudo de ligação genética em escala genômica utilizando polimorfismos de nucleotídeo único (SNPs) e o sequenciamento de genes suspeitos. RESULTADOS: A avaliação dos indivíduos pertencentes à genealogia permitiu o diagnóstico de 15 casos da doença (7 mulheres e 8 homens) em três gerações consecutivas. A AIMAH era transmitida para as gerações subsequentes tanto pelo sexo masculino como feminino e acometia cerca de metade dos irmãos em alguns segmentos da família. A idade média ao diagnóstico da doença foi de 52,8 +-11,3 anos (32 a 74 anos) e cerca de 86% (12/14) desses pacientes apresentavam SC subclínica. As dosagens do cortisol salivar à meia-noite e do cortisol em urina de 24 horas demonstraram baixa sensibilidade (21% e 14%, respectivamente) para o diagnóstico da doença em sua forma familial. O valor do ACTH plasmático encontrava-se baixo ( < 10 pg/mL) em 46% (5/11) dos pacientes doentes. Em cerca de 62% (8/13) dos casos, foi demonstrada uma redução do valor sérico do sulfato de desidroepiandrosterona (SDHEA). Por regressão logística simples, foi observado que a probabilidade (odds ratio) de um indivíduo apresentar a doença na família era maior diante da presença de pletora, após o diagnóstico de diabetes ou pré-diabetes ou diante do relato de ganho ponderal progressivo. O espessamento de ambas as adrenais associado à presença de nódulos bilaterais foi o achado radiológico mais frequente na forma familial da doença. No entanto, em um terço dos pacientes (5/15) foram encontradas alterações radiológicas em somente uma das adrenais. Durante os testes in vivo para pesquisa de receptores hormonais aberrantes, foram observadas, com frequência, respostas distintas entre os indivíduos doentes pertencentes à família. Nos pacientes submetidos ao exame de ressonância magnética, foram demonstradas imagens típicas de meningiomas intracranianos em um terço (5/15) dos casos. No exame 18F-FDG-PET/CT, foi observado um aumento da atividade metabólica das adrenais hiperplasiadas, tanto nos pacientes com SC manifesta como naqueles com a forma subclínica da doença. O estudo molecular permitiu delimitar nos cromossomos 16 e 11 algumas regiões genômicas potencialmente relacionadas à etiologia genética da AIMAH familial. O sequenciamento de alguns genes suspeitos (GPR56, GPR97 e GPR114), localizados nessas regiões, não demonstrou a presença de mutações. CONCLUSÕES: Na genealogia estudada, o padrão de transmissão da AIMAH foi autossômico dominante, e a SC subclínica foi a forma mais frequente de manifestação da doença. O teste de supressão com 1 mg de dexametasona via oral à meia-noite demonstrou ser o exame laboratorial de escolha para a avaliação inicial dos pacientes suspeitos de apresentarem AIMAH familial, em função, sobretudo, da baixa sensibilidade do cortisol salivar à meia-noite e do cortisol urinário para o diagnóstico da doença. Valores normais do ACTH plasmático foram um achado laboratorial frequente na AIMAH familial e valores baixos do SDHEA sérico demonstraram ser um indício relativamente precoce da SC subclínica associada à doença. Diferentes padrões radiológicos foram demonstrados nas tomografias das adrenais dos pacientes com AIMAH familial, não sendo infrequente a presença de assimetria entre as duas glândulas. Os resultados dos testes in vivo para a pesquisa de receptores hormonais aberrantes foram mais condizentes com a hipótese de que a expressão desses receptores seria um epifenômeno do processo fisiopatológico, resultante da proliferação e desdiferenciação celular. Uma alta prevalência de meningiomas intracranianos foi observada nos pacientes com AIMAH, tanto na forma familial da doença como na forma esporádica. Demonstrou-se também, pela primeira vez, que as adrenais na AIMAH podem exibir uma captação aumentada de 18F-FDG no exame de PET/CT, de forma semelhante às metástases e aos carcinomas da glândula. Por fim, foram delimitadas no cromossomo 16 (16p12.1, 16p11.2, 16q12.1, 16q13 e 16q21) e no cromossomo 11 (11q23.1) as principais regiões do genoma suspeitas de estarem ligadas à etiologia genética da AIMAH familial (genoma de referência: NCBI36/hg18)
INTRODUCTION: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disease characterized by functioning adrenal macronodules and increased, autonomous and sustained cortisol production. This condition is an uncommon cause of Cushing\'s syndrome (CS). While the sporadic form of the disease appears to be the most frequent, the true prevalence of its familial form is unknown. Despite being a known clinical entity for almost 50 years, the pathophysiological process that leads to AIMAH, the predisposing genetic alterations and important clinical, laboratory and radiological aspects of the disease have not been fully clarified. The recent identification of a large group of relatives with familial AIMAH allowed the accomplishment of the present study. OBJECTIVES: The following were the aims of this study: 1) characterize the development of familial AIMAH through correlations between clinical manifestations, laboratory data and radiological findings; 2) investigate the possible association between AIMAH and the occurrence of intracranial meningioma; 3) characterize the metabolic activity of the adrenal glands in this disease; 4) define the inheritance pattern of the disease in the family studied; and 5) map chromosomal regions and loci potentially related to the genetic etiology of familial AIMAH. METHODS: 96 members of the family studied were initially subjected to a detailed clinical and laboratory evaluation. Computed tomography (CT) scans were performed for the radiological characterization of the adrenal glands. Magnetic resonance imaging scans and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were performed on patients with both forms of the disease (familial and sporadic) to investigate the presence of intracranial meningioma and characterize the metabolic activity of the adrenal glands, respectively. In vivo studies for aberrant hormone receptors were also conducted on those patients with familial AIMAH. In another phase of the study, different molecular biology techniques were employed to investigate the genetic etiology of familial AIMAH. For such, sequencing of the ACTH receptor gene (MC2R), a linkage study using specific microsatellite markers, a single nucleotide polymorphism (SNP)-based genome-wide linkage study and the sequencing of suspect genes were performed. RESULTS: The evaluation of the family revealed the diagnosis of 15 cases of the disease (7 women and 8 men) in three consecutive generations. AIMAH was transmitted to subsequent generations by both genders and half of the siblings were affected in some segments of the family. Mean age at diagnosis was 52.8 +-11.3 years (range: 32 to 74 years) and about 86% (12/14) of the patients exhibited subclinical CS. Both midnight salivary cortisol and 24-hour urinary cortisol demonstrated low sensitivity (21% and 14%, respectively) for the diagnosis of familial AIMAH. Plasma ACTH levels were low ( < 10 pg/ml) in 46% (5/11) of patients with the disease. In about 62% (8/13) of cases, serum dehydroepiandrosterone sulphate (DHEAS) levels were below the normal range. Simple logistic regression models revealed that the probability (odds ratio) of an individual having the disease in the family was greater in the presence of plethora, progressive weight gain or after the diagnosis of diabetes or prediabetes. Adrenal thickening associated with the presence of bilateral nodules was the most common radiological finding in familial AIMAH. However, radiological abnormalities were found in only one of the adrenal glands in one third of the patients (5/15). Throughout the in vivo studies for aberrant hormone receptors, distinct responses were frequently observed among the individuals with familial AIMAH. One third (5/15) of the patients who underwent magnetic resonance imaging scans had typical images of intracranial meningiomas. The 18F-FDG-PET/CT scan revealed increased metabolic activity of the hyperplastic adrenals in patients with both overt and subclinical CS. The molecular studies delimited genomic regions on chromosomes 16 and 11 potentially related to the genetic cause of familial AIMAH. Some suspected genes (GPR56, GPR97 and GPR114), located in these genomic regions, were sequenced, but no mutations were found. CONCLUSIONS: In the extended family studied, AIMAH followed an autosomal dominant pattern of inheritance and subclinical CS was the most common presentation of the disease. The 1 mg overnight dexamethasone suppression test proved to be the screening test of choice for the initial evaluation of patients suspected to have familial AIMAH, due mainly to the low sensitivity of midnight salivary cortisol and 24-hour urinary cortisol as screening tests. A normal level of plasma ACTH was a common laboratory finding in familial AIMAH. Low serum levels of DHEAS proved to be a relatively early finding associated with the subclinical CS determined by the disease. Adrenal CT scans revealed different radiological patterns among patients with familial AIMAH, with a fairly frequent rate of asymmetry between glands. The distinct responses observed throughout the in vivo studies for aberrant hormone receptors, among family members, favor the hypothesis that these receptors may be an epiphenomenon resulting from cell proliferation and dedifferentiation. An increased prevalence of intracranial meningioma was demonstrated in both the familial and sporadic forms of AIMAH. For the first time, it was shown that AIMAH may exhibit increased 18FFDG uptake on the PET/CT scan, similarly to adrenal carcinoma and metastasis. The main genomic regions potentially associated with familial AIMAH were delimited on chromosome 16 (16p12.1, 16p11.2, 16q12.1, 16q13 and 16q21) and chromosome 11 (11q23.1) (reference genome: NCBI36/hg18)

La síndrome de Cushing (SC), una malaltia minoritària per secreció excessiva de cortisol, s'associa a augment de morbi-mortalitat, inclús després del tractament, comparat amb població de referència i s'associa a processos d'envelliment prematur. Per altra banda, els telòmers són seqüències de DNA essencials per mantenir l'estabilitat genòmica. Sense telòmers, el material genètic es perdria després de cada divisió cel·lular; quan aquests són críticament curts, es paren les divisions cel·lulars, s'indueix la senescència i apoptosi. Per evitar l'escurçament de la longitud telomèrica (LT) es produeix un complex enzimàtic anomenat telomerasa, regulada per factors genètics, epigènetics i hormonals, com el cortisol. L'hipercortisolisme també passa en trastorns depressius majors i estrés psicosocial, on la LT és més curta que els controls. A més, l'escurçament de la LT s'ha associat a malaltia cardiovascular, factors de risc cardiovasculars (FRCV) i inflamació crónica. L'escurçament telomèric és considerat un nou marcador de risc cardiovascular i s'ha associat a biomarcadors d'inflamació. Basats en aquestes evidències, hipotetitzem que l'hipercortisolisme contribuiria a envelliment prematur induint escurçament telomèric accelerat i estaria implicat en la morbiditat persistent i conseqüències clíniques de la SC inclús anys després de la remissió bioquímica. Així mateix, l'escurçament de la LT, estaria involucrat en l'estat inflamatori de “baix grau” i l'elevada prevalença de FRCV en la SC. Per tant, aquesta recerca ha estat dissenyada per contestar aquestes hipòtesis, essent els principals objectius investigar LT a la SC comparat amb controls, i evaluar relacions entre LT, FRCV i marcadors d'inflamació. És la primera recerca que avalua LT en la SC amb una sèrie relativament llarga, una oportunitat única per explorar els efectes de l'hipercortisolisme en el manteniment telomèric. Setanta-set pacients amb SC són comparats amb 77 controls aparellats per sexe, edat i tabac. Quinze SC, també són avaluats longitudinalment, durant la malaltia activa i després de remissió de l'hipercortisolisme. S'han recollit dades clíniques i analítiques (lípids, funció adrenal...). Adiponectina, interleukina-6(IL6) i proteïna-C reactiva (PCR) foren disponibles en 32 pacients. La LT leucocitària s'ha mesurat per fragment de restricció telomèrica-Southern. La LT mitjana entre SC i controls fou similar, no obstant, en l'avaluació longitudinal després d'ajustar per l'edat, la LT fou més curta en la malaltia activa que en remissió. No s'han trobat correlacions entre altres paràmetres del cortisol, duració d'exposició a l'hipercortisolisme o curació bioquímica amb la LT. Els SC dislipidèmics tenien la LT més curta que els no dislipidèmics. Després d'ajustar per edat i índex de massa corporal, SC actius i curats amb dislipidèmia tenien la LT més curta que els no dislipidèmics. A més, major escurçament telomèric s'ha observat en pacients obesos dislipidèmics que també tenien hipertensió, comparat amb aquells amb 2 o menys FRCV. El colesterol total i els triglicèrids es correlacionaren negativament amb la LT, així com la PCR i la IL6. No s'han observat diferències en la LT segons la presència d'altres FRCV en SC i controls. Les principals conclusions són que els pacients amb SC amb hipercortisolisme controlat després d'un tractament eficaç, la LT augmenta malgat ser de mitjana tres anys més grans. Per tant, podria haver-hi una inducció de l'activitat telomerasa al desaparèixer l'hipercortisolisme, i ser un dels mecanismes pels quals aquest augment de morbi-mortalitat i envelliment biològic millorin quan la malaltia està controlada. Aquests resultats suggereixen que l'hipercortisolisme podria tenir impacte negatiu en el manteniment telomèric. A més, la LT és més curta en les SC amb dislipidèmia i menor si coexisteixen hipertensió i/o obesitat; i es correlaciona negativament amb l'elevació dels marcadors d'inflamació. Pertant, l'augment dels lípids i un estat inflamatori de “baix grau” contribuirien a escurçament telomèric, a l'envelliment prematur i augment de la morbiditat de la SC.
Cushing's syndrome (CS), a rare disease due to excessive cortisol secretion, is associated with increased morbidity and mortality, even after therapy compared to background population and is associated with premature aging processes. On the other hand, telomeres are repetitive DNA sequences, essential to maintain genomic stability. Without telomeres, genetic material could be lost after every cell division; thus, when telomeres are critically short, cell division stops and senescence and apoptosis are induced. To avoid telomere length (TL) attrition an enzymatic complex called telomerase is produced. Telomerase can be regulated by genetic, epigenetic and hormonal factors such as cortisol. Hypercortisolism also occurs in chronic depressive disorders and psychosocial stress, where TL is shorter than in controls. Moreover, TL shortening has also been associated with cardiovascular disease, cardiovascular risk factors (CVRF) and chronic inflammation processes. TL shortening is considered a novel cardiovascular risk marker, and is associated with inflammation biomarkers. Based on these previous evidences, we hypothesized that hypercortisolemia could contribute to premature ageing by inducing accelerated telomere shortening, which in turn could be implied in the persistent morbidity and clinical consequences associated with CS, even years after biochemical remission. Additionally, TL shortening, might be involved in the “low grade” inflammatory state and higher prevalence of CVRF observed in CS. Therefore, this research was designed to answer our hypothesis, being the main aims of this project to investigate TL in CS patients compared to controls, and to evaluate relationships between TL, CVRF and inflammation markers in CS. This is the first research to evaluate TL in this rare disease with a relatively large series of CS patients, which could provide a unique opportunity to examine the effects of hypercortisolism on telomere maintenance. Seventy-seven CS patients were compared with 77 gender-, age-, and smoking-matched controls. Fifteen CS were also evaluated longitudinally, during active disease and after remission of hypercortisolism. Clinical data and blood samples were collected (lipids, adrenal function...). Adiponectin, interleukin-6 (IL6) and C-reactive protein (CRP) were available in a subgroup of patients (n=32). Leukocyte TL was measured by telomere restriction fragment-Southern technique. Mean TL in CS and controls was similar, however in the longitudinal evaluation after adjustment for age, TL was shorter in active disease than after remission. No correlation was found between other circulating cortisol parameters, duration of exposure to hypercortisolism or biochemical cure and TL. We observed that dyslipidemic CS had shorter TL than non-dyslipidemic subjects. After adjustment for age and body mass index, cured and active CS dyslipidemic patients had shorter TL than non-dyslipidemic subjects. Additionally, higher TL shortening was observed in dyslipidemic obese patients who were also hypertensive, compared to those with two or less CVRF. Total-cholesterol and triglycerides negatively correlated with TL, as well as CRP and IL6. No differences in TL according the presence of other CVRF were observed in CS or the control group. The main conclusions are that individual CS patients in whom hypercortisolism is controlled after successful treatment, TL increases despite being on average 3 years older. It would appear therefore that telomerase activity would be induced once hypercortisolism disappears, and this could be one of the mechanisms by which increased morbidity, mortality and biological aging improve when disease is controlled. These preliminary results suggest that hypercortisolism might negatively impact telomere maintenance. Moreover, TL is shortened in dyslipidemic CS patients, further worsened if hypertension and/or obesity coexist and is negatively correlated with increased inflammation markers. Therefore, increased lipids and a “low-grade” inflammation may contribute to TL shortening and consequently to premature ageing and increased morbidity in CS.

Anxiety disorders represent one of the most common psychiatric conditions in children and adolescents, significantly affecting their quality of life, social functioning, and academic performance. These disorders are characterized by the presence of excessive fear, persistent worry, and physical manifestations of anxiety, such as tachycardia, sweating, and muscle tension. Anxiety in children and adolescents can be even more complex when it is associated with endocrine disorders such as type 1 diabetes, thyroid disorders, and Cushing's syndrome.