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Primary pigmented nodular adrenocortical disease (PPNAD), whether in the context of Carney complex (CNC) or isolated, leads to ACTH-independent Cushing's syndrome (CS). CNC and PPNAD are caused typically by inactivating mutations of PRKAR1A, a gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). Mice lacking Prkar1a, specifically in the adrenal cortex (AdKO) developed CS caused by bilateral adrenal hyperplasia (BAH), which is formed from the abnormal proliferation of fetal-like adrenocortical cells. Celecoxib is a cyclooxygenase 2 (COX2) inhibitor. In bone, Prkar1a inhibition is associated with COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of bone stromal cells. We hypothesized that COX2 inhibition may have an effect in PPNAD. In vitro treatment of human cell lines, including one from a patient with PPNAD, with celecoxib resulted in decreased cell viability. We then treated AdKO and control mice with 1500 mg/kg celecoxib or vehicle. Celecoxib treatment led to decreased PGE2 and corticosterone levels, reduced proliferation and increased apoptosis of adrenocortical cells, and decreased steroidogenic gene expression. We conclude that, in vitro and in vivo, celecoxib led to decreased steroidogenesis. In a mouse model of PPNAD, celecoxib caused histological changes that, at least in part, reversed BAH and this was associated with a reduction of corticosterone levels., (© 2016 Society for Endocrinology.)

Objective: Cushing's syndrome (CS) is associated with high cardiovascular risk. White matter lesions (WML) are common on brain magnetic resonance imaging (MRI) in patients with increased cardiovascular risk., Aim: To investigate the relationship between cardiovascular risk, WML, neuropsychological performance and brain volume in CS., Design/methods: Thirty-eight patients with CS (23 in remission, 15 active) and 38 controls sex-, age- and education-level matched underwent a neuropsychological and clinical evaluation, blood and urine tests and 3Tesla brain MRI. WML were analysed with the Scheltens scale. Ten-year cardiovascular risk (10CVR) and vascular age (VA) were calculated according to an algorithm based on the Framingham heart study., Results: Patients in remission had a higher degree of WML than controls and active patients (P<0.001 and P=0.008 respectively), which did not correlate with cognitive performance in any group. WML severity positively correlated with diastolic blood pressure (r=0.659, P=0.001) and duration of hypertension (r=0.478, P=0.021) in patients in remission. Both patient groups (active and in remission) had higher 10CVR (P=0.030, P=0.041) and VA than controls (P=0.013, P=0.039). Neither the 10CVR nor the VA correlated with WML, although both negatively correlated with cognitive function and brain volume in patients in remission (P<0.05). Total brain volume and grey matter volume in both CS patient groups were reduced compared to controls (total volume: active P=0.006, in remission P=0.012; grey matter: active P=0.001, in remission P=0.003), with no differences in white matter volume between groups., Conclusions: Patients in remission of Cushing's syndrome (but not active patients) have more severe white matter lesions than controls, positively correlated with diastolic pressure and duration of hypertension. Ten-year cardiovascular risk and vascular age appear to be negatively correlated with the cognitive function and brain volume in patients in remission of Cushing's syndrome., (© 2015 European Society of Endocrinology.)

Context: Bilateral adrenalectomy is the reference treatment for Cushing's syndrome (CS) related to primary bilateral macronodular adrenal hyperplasia (PBMAH). It is, however, responsible for definitive adrenal insufficiency., Objective: The objective of the study was to evaluate the clinical interest of unilateral adrenalectomy (UA) of the larger gland for the treatment of CS related to PBMAH., Design, Setting, Patients, and Intervention: This was a retrospective study in four tertiary French centers including all 15 patients with PBMAH and CS who underwent UA of the larger gland between 2001 and 2015., Main Outcome Measures: Urinary free cortisol, plasma cortisol, ACTH, body mass index, blood pressure, plasma glucose, and lipids were registered pre- and postoperatively and on follow-up. Median follow-up was 60 months (interquartile range 39-105), including 8 of 15 patients followed up for at least 5 years., Results: A normal or low urinary free cortisol was obtained in 15 of 15 patients (100%) postoperatively. Six patients (40%) became adrenal insufficient, of whom three of six recovered a quantitatively normal cortisol secretion on follow-up. Decrease of both body mass index and blood pressure were observed at 1 year, and decrease of blood pressure was persistent 5 years postoperatively. Diabetes was cured in four of six patients. Two patients experienced a recurrence of hypercortisolism, and one was treated with mitotane, whereas the other underwent a second adrenal surgery 9 years after initial UA., Conclusion: UA induced remission of hypercortisolism in all patients, with sustained significant clinical improvement. The rates of both definitive adrenal insufficiency and 5-year recurrence were low. UA appears an interesting alternative to bilateral adrenalectomy as a first-line treatment in PBMAH responsible for overt CS.

Background: Laparoscopic bilateral adrenalectomy (LBA) is recommended for patients with bilateral adrenal disease and occult or unresectable ectopic Cushing's syndrome (CS). There are limited data on long-term outcomes after LBA, partly due to the lack of disease-specific tools for the measurement of impact on patients' health and quality of life., Methods: We used a disease-specific questionnaire covering all major clinicopathologic characteristics of CS. We compared the outcome from LBA to a control group of 60 patients who had thyroidectomy (matched for age, gender, and time of surgery, 2:1 control-to-CS)., Results: Twenty-eight patients (20 women and 8 men) underwent LBA for CS. Of them, 24 patients (86 %) provided responses to our questionnaire. Ninety-two percent of patients' responses indicated a significant improvement of general Cushing's physical features with complete resolution reported in 59 % of responses. Significant improvement of associated biochemical abnormalities and comorbidities was reported in 83 % of patients' responses including complete reversal in 58 %. Significant improvement in emotional-behavioral symptoms was reported in 84 % of patients' responses with complete recovery in 53 %. All patients expressed satisfaction with LBA and significant improvement in their general health and self-reported quality of life. All of the improvements after LBA were statistically significant compared with the control group., Conclusions: Our disease-specific questionnaire enables a clearer understanding of the association between the clinical, metabolic, and emotional-behavioral features of CS, its treatment with LBA, and long-term impact on patient-reported quality of life. This disease-specific questionnaire may be useful for future studies in patients with CS.

Context: Cortisol-producing adenomas (CPAs), primary pigmented nodular adrenocortical disease (PPNAD), and primary macronodular adrenocortical hyperplasia (PMAH) cause ACTH-independent Cushing syndrome (CS). Investigation of their pathogenesis has demonstrated their integral link to the cAMP-dependent protein kinase signaling pathway., Objective: The aim of this study was to identify differences in cholesterol biosynthesis among different CS-causing adrenocortical tumors. Because of the concomitant associations of cAMP levels with cholesterol and with steroid biosynthesis, we hypothesized that benign cortisol-producing tumors would display aberration of these pathways., Design and Setting: Twenty-three patients with CPA, PPNAD, or PMAH who underwent adrenalectomy for CS were included in the study. Preoperative biochemical analyses were performed, and excised adrenal tissues were studied., Main Outcome Measures: Serum, urinary hormone levels, serum lipid profiles, and anthropometric data were obtained preoperatively. Adrenal tissues were analyzed for total protein, cholesterol, and neutral sterol content by mass spectrometry and expression of HMGCR, LDLR, ABCA1, DHCR24, and STAR genes., Results: There were differences in cholesterol content and markers of cholesterol biosynthesis and metabolism that distinguished CPAs from PMAH and PPNAD; cholesterol, lathosterol, and lathosterol/cholesterol ratio were significantly higher in CPAs. ABCA1 mRNA was lower among CPAs compared to tissues from bilateral adrenocortical hyperplasia (PMAH and PPNAD), and mRNA expression of LDL-R, DCHR24, and HMGCR tended to be higher in CPA tumor tissues., Conclusion: CPAs displayed characteristics of "cholesterol-starved" tissues when compared to PPNAD and PMAH and appeared to have increased intrinsic cholesterol production and uptake from the periphery, as well as decreased cholesterol efflux. This has implications for a potential new way of treating these tumors.

Cushing's syndrome (CS) due to a corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH) co-secreting tumor is very rare, and diagnosis can be difficult. We describe a case of CS caused by ectopic CRH and ACTH production from a pancreatic neuroendocrine tumor (pNET) and discuss possible pitfalls in the diagnosis. A 48-year-old woman presented with gradual increase in body weight, muscle weakness, and difficult to control hypertension. Laboratory and imaging investigations revealed ACTH-dependent hypercortisolemia and a 3-cm mass at the head of the pancreas. The patient underwent partial pancreatoduodenectomy. Histological examination revealed a well-differentiated pNET, expressing both CRH and ACTH. After a follow-up period of 18 months, she remains asymptomatic with no metastatic disease. This is the fourth case report of CS in adults due to an ectopic ACTH- and CRH-secreting pNET. Co-secretion of ACTH and CRH by the same tumor may cause diagnostic problems since investigation depends on which of the two hormones is secreted in greater amounts. Measurement of plasma CRH may help in establishing the diagnosis, especially in patients in whom endocrine tests are indicative of ectopic CS, whereas imaging findings are suggestive of pituitary hyperplasia.

Context: Although Crooke's changes in the pituitary corticotrophs were initially described in 1935, the prevalence in which the changes occur in patients with Cushing's syndrome (CS) has not been established., Objective: This study aimed to determine the prevalence and assess clinical features associated with the presence or absence of Crooke's changes in a large set of patients with CS., Design: Information from a prospective computer database and retrospective chart review was analyzed., Setting: The setting was an academic medical center., Patients: Consecutive patients (N = 213) who received surgery with a preoperative diagnosis of Cushing's disease are included., Intervention: The patients received pituitary surgery and specimens obtained underwent pathological analysis., Main Outcome Measure: The presence or absence of Crooke's changes was determined by histopathological analysis of the normal pituitary tissue included with the specimen obtained at surgery. Cortisol production was measured by 24-hour urine cortisol production., Results: Crooke's changes occurred in 144 of 177 patients (81%) with a histologically demonstrated ACTH-staining tumor and in 74% of 213 patients diagnosed with CS who had pituitary surgery. The presence of Crooke's changes correlated with the finding of an ACTH-staining tumor removed at surgery and with the degree of hypercortisolism. Among patients with histologically established ACTH-staining tumors the prevalence of Crooke's changes was particularly high in patients with a 24-h urinary free cortisol (UFC) of at least 4-fold the upper limit of normal, in which 91% of patients had Crooke's changes, compared with 74% of patients whose maximum UFC was less than 4-fold the upper limit of normal (P = .008)., Conclusions: Crooke's changes occur in 75-80% of patients with CS, and depend on the degree of hypercortisolism and individual variability. Almost all patients with UFC at least 4-fold the upper limit of normal have them, whereas with less severe hypercortisolism the expression of Crooke's changes varies from person to person.

Background: Cushing's syndrome (CS) is characterized by excessive exposure to cortisol, and is associated with both metabolic and behavioral abnormalities. Symptoms improve substantially after biochemical cure, but may persist during long-term remission. The causes for persistent morbidity are probably multi-factorial, including a profound effect of cortisol excess on the brain, a major target area for glucocorticoids., Objective: To review publications evaluating brain characteristics in patients with CS using magnetic resonance imaging (MRI)., Methods: Systematic review of literature published in PubMed, Embase, Web of Knowledge, and Cochrane databases., Results: Nineteen studies using MRI in patients with CS were selected, including studies in patients with active disease, patients in long-term remission, and longitudinal studies, covering a total of 339 unique patients. Patients with active disease showed smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy as well as alterations in neurochemical concentrations and functional activity. After abrogation of cortisol excess, the reversibility of structural and neurochemical alterations was incomplete after long-term remission. MRI findings were related to clinical characteristics (i.e., cortisol levels, duration of exposure to hypercortisolism, current age, age at diagnosis, and triglyceride levels) and behavioral outcome (i.e., cognitive and emotional functioning, mood, and quality of life)., Conclusion: Patients with active CS demonstrate brain abnormalities, which only partly recover after biochemical cure, because these still occur even after long-term remission. CS might be considered as a human model of nature that provides a keyhole perspective of the neurotoxic effects of exogenous glucocorticoids on the brain., (© 2015 European Society of Endocrinology.)

The primary bilateral macronodular adrenal hyperplasia or the independent adrenocorticotropic hormone bilateral nodular adrenal hyperplasia is a rare cause hypercortisolism, its diagnosis is challenging and there is no clear way to decide the best therapeutic approach. Adrenal venous sampling is commonly used to distinguish the source of hormonal production in patients with primary hyperaldosteronism. It could be a useful tool in this context because it might provide information to guide the treatment. We report the case of a patient with ACTH independent Cushing syndrome in whom the use of adrenal venous sampling with some modifications radically modified the treatment and allowed the diagnosis of a macronodular adrenal hyperplasia.

Background: Subclinical hypercortisolism (SH) has been associated with metabolic complications such as type 2 diabetes mellitus, obesity and dyslipidemia. Scarce data are available regarding the lipid pattern abnormalities in SH, in relation to insulin resistance and impaired glucose metabolism (IGM). We aimed to evaluate the possible influence of SH on lipid pattern in relation to the presence/absence of impaired glucose metabolism., Methods: In 338 patients with adrenal incidentaloma, the presence of SH, hypertension, dyslipidemia and IGM was evaluated. According to the presence of SH and IGM the patients were divided into 4 groups (IGM+SH+, IGM+SH-, IGM-SH+, IGM-SH-). We recruited 98 subjects without IGM (IGM-) and 100 with IGM (IGM+) as control groups., Results: The prevalence of dyslipidemia was comparable among Group IGM+SH+, Group IGM+SH- and IGM+ controls (57.9, 58.4, 56%, P = NS). No difference in dyslipidemia prevalence among IGM- patients and IGM- controls was observed. The IGM+SH+ patients had a higher prevalence of dyslipidemia (57.9%) than IGM-SH+ ones (29.1%, P < 0.01). The IGM+SH- patients showed an increased prevalence of hypertension (76.6 vs 54.8%, P < 0.01) and dyslipidemia (58.4 vs 23.8%, P < 0.0001) as compared with IGM-SH- patients. Logistic regression analysis showed that only IGM was associated to dyslipidemia (OR 4.31, 95% CI 2.61-7.12, P = 0.0001) regardless of age, SH and gender., Conclusions: In the absence of alterations of glucose metabolism the presence of a subtle cortisol excess has no effect on lipid pattern. IGM seems to influence the lipid metabolism regardless of the presence of SH.

Background and Purpose: Cushing syndrome appears after chronic exposure to elevated glucocorticoid levels. Cortisol excess may alter white matter microstructure. Our purpose was to study WM changes in patients with Cushing syndrome compared with controls by using DTI and the influence of hypercortisolism., Materials and Methods: Thirty-five patients with Cushing syndrome and 35 healthy controls, matched for age, education, and sex, were analyzed through DTI (tract-based spatial statistics) for fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity (general linear model, family-wise error, and threshold-free cluster enhancement corrections, P < .05). Furthermore, the influence of hypercortisolism on WM DTI changes was studied by comparing 4 subgroups: 8 patients with Cushing syndrome with active hypercortisolism, 7 with Cushing syndrome with medication-remitted cortisol, 20 surgically cured, and 35 controls. Cardiovascular risk factors were used as covariates. In addition, correlations were analyzed among DTI values, concomitant 24-hour urinary free cortisol levels, and disease duration., Results: There were widespread alterations (reduced fractional anisotropy, and increased mean diffusivity, axial diffusivity, and radial diffusivity values; P < .05) in patients with Cushing syndrome compared with controls, independent of the cardiovascular risk factors present. Both active and cured Cushing syndrome subgroups showed similar changes compared with controls. Patients with medically remitted Cushing syndrome also had reduced fractional anisotropy and increased mean diffusivity and radial diffusivity values, compared with controls. No correlations were found between DTI maps and 24-hour urinary free cortisol levels or with disease duration., Conclusions: Diffuse WM alterations in patients with Cushing syndrome suggest underlying loss of WM integrity and demyelination. Once present, they seem to be independent of concomitant hypercortisolism, persisting after remission/cure., (© 2015 by American Journal of Neuroradiology.)

Objective: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing's syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification., Design: This study is a case series., Methods: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS., Results: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype., Conclusions: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification., (© 2015 European Society of Endocrinology.)

Thymic neuroendocrine carcinomas are the most common mediastinal neuroendocrine tumor. These malignancies are not often diagnosed by fine-needle aspiration (FNA), as they are more commonly diagnosed by biopsy or excision. We describe a case of a FNA of a paratracheal mass from a 38-year-old man who presented with Cushing syndrome. A low-grade neuroendocrine carcinoma with oncocytic features was diagnosed, which was later confirmed by excision of the thymus, anterior mediastinal and paratracheal soft tissue, and lymph nodes. Oncocytic features in these tumors are a rare finding and bring metastatic medullary thyroid carcinomas as well as other metastases into the differential diagnosis. The prognosis of neuroendocrine carcinomas in this location is worse than neuroendocrine carcinomas in other areas, and close follow-up is recommended., (© 2014 Wiley Periodicals, Inc.)

Objective: Cardiovascular events are the most common cause of mortality in Cushing syndrome (CS). This study aimed to evaluate the impact of novel factors on atherosclerosis in endogenous CS., Methods: A total of 22 female patients with CS and 33 normal female controls underwent evaluation of fibrinogen, high-sensitivity C-reactive protein (hsCRP), inflammatory cytokines (interleukin [IL]-6, IL-1β, soluble tumor necrosis factor receptor [sTNFR]-1, and sTNFR2), glutathione peroxidase (GPx; measure of oxidative stress), carotid intima media thickness (CIMT; a measure of atherosclerosis), and percent change in flow-mediated vasodilation (%FMV) of the brachial artery, a measure of endothelial dysfunction. Stepwise multiple linear regressions were done after adjusting for variables in models 1 through 3 to evaluate their role in predicting CIMT and %FMV. Model 1 consisted of age and body mass index (BMI). Model 2 consisted of model 1 plus blood pressure (BP), fasting blood glucose (FBG), and 2-hour postglucose blood glucose (2hPGBG). Model 3 consisted of model 2 plus triglycerides and low- and high-density lipoprotein., Results: Females with CS had significantly higher BMI, BP, FBG, 2hPGBG, total cholesterol, triglycerides, fibrinogen, IL-6, IL-1β, sTNFR1, and GPx. CIMT and %FMV were significantly higher and lower, respectively, in CS patients. Regression analyses revealed sTNFR1 to be a consistent predictor of CIMT after adjusting for model 1 (β = 0.656; P = .004), model 2 (β = 0.571; P = .047), and model 3 (β = 0.683; P =.026). GPx was a predictor of CIMT after adjusting for model 1 (β = 0.565; P = .033) and model 3 (β = 0.756; P= .038)., Conclusion: This study highlights increased CIMT and endothelial dysfunction in CS, associated with an altered inflammatory milieu. sTNFR1 and GPx may predict CIMT in females with CS.

Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein-coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Cushing's disease is the most common cause of endogenous hypercortisolemia, in 90% of cases due to microadenoma. Macroadenoma can lead to atypical hormonal test results and complete removal of the tumour is unlikely., Case Report: A 77-year-old woman with diabetes and hypertension was admitted because of fatigue, proximal muscles weakness, lower extremities oedema, and worsening of glycaemic and hypertension control. Physical examination revealed central obesity, 'moon'-like face, supraclavicular pads, proximal muscle atrophy, and skin hyperpigmentation. Biochemical and hormonal results were as follows: K 2.3 mmol/L (3.6-5), cortisol 8.00 86 μg/dL (6.2-19.4) 23.00 76 μg/dL, ACTH 8.00 194 pg/mL (7.2-63.3) 23.00 200 pg/mL, DHEAS 330 μg/dL (12-154). CRH stimulation test showed lack of ACTH stimulation > 35%, overnight high dose DST revealed no suppression of cortisol. Chest and abdominal CT as well as somatostatin receptor scan didn't show ectopic tumour responsible for ACTH oversecretion. MRI revealed a pituitary macroadenoma (28 × 20 × 17 mm) extending towards the left cavernous sinus. After partial transsphenoidal adenomectomy, serum cortisol of 40 μg/dL was obtained. The patient's condition was still very poor, so unilateral adrenalectomy was performed. After surgery, serum morning cortisol level dropped to 20 μg/dL and the patient's condition improved significantly. 26 months after the operations, the patient remains in remission. Because her life expectancy exceeds the prognosed duration of remission with the presence of pituitary tumour remnants and intact left adrenal gland, the patient was qualified to radiosurgery with a Gamma Knife., Conclusion: In selected cases, unilateral, laparascopic adrenalectomy may serve as a life-saving procedure in a patient with ACTHdependent Cushing's syndrome.

We describe the pathology of 5 patients with germline PRKACA copy number gain and Cushing syndrome: 4 males and 1 female, aged 2 to 43 years, including a mother and son. Imaging showed normal or slightly enlarged adrenal glands in 4 patients and a unilateral mass in the fifth. Biochemically, the patients had corticotropin-independent hypercortisolism. Four underwent bilateral adrenalectomy; unilateral adrenalectomy was performed in the patient with the adrenal mass. Pathologically, 3 patients, including the 1 with the tumor (adenoma), had primary pigmented nodular adrenocortical disease with extranodular cortical atrophy and mild intracapsular and extracapsular extension of cortical cells. The other 2 patients had cortical hyperplasia and prominent capsular and extracapsular micronodular cortical hyperplasia. Immunoperoxidase staining revealed differences for synaptophysin, inhibin-A, and Ki-67 (nuclei) in the atrophic cortices (patients 1, 2, and 3) and hyperplastic cortices (patients 4 and 5) and for Ki-67 (nuclei) and vimentin in the extracortical nodules in the 2 groups of patients. β-Catenin stained the cell membrane, cytoplasm, and nuclei of the adenoma. The patients were well at follow-up (1-23 years); 24-hour urinary cortisol excretion was elevated in the patient who had unilateral adrenalectomy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear., Objective: The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias., Patients and Methods: Whole-genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analyzed for accompanying somatic mutations in the identified target genes., Results: PMAH presenting either as overt or subclinical Cushing's syndrome was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) located on chromosome 16. Analysis of tumor tissue showed different somatic ARMC5 mutations in adrenal nodules supporting a second hit hypothesis with inactivation of a tumor suppressor gene. A damaging somatic ARMC5 mutation was also found in a concomitant meningioma (p.R502fs) but not in a pancreatic tumor, suggesting biallelic inactivation of ARMC5 as causal also for the intracranial meningioma., Conclusions: Our analysis further confirms inherited inactivating ARMC5 mutations as a cause of familial PMAH and suggests an additional role for the development of concomitant intracranial meningiomas.

We recently identified a high prevalence of mutations affecting the catalytic (Cα) subunit of protein kinase A (PKA) in cortisol-secreting adrenocortical adenomas. The two identified mutations (Leu206Arg and Leu199&#95;Cys200insTrp) are associated with increased PKA catalytic activity, but the underlying mechanisms are highly controversial. Here we utilize a combination of biochemical and optical assays, including fluorescence resonance energy transfer in living cells, to analyze the consequences of the two mutations with respect to the formation of the PKA holoenzyme and its regulation by cAMP. Our results indicate that neither mutant can form a stable PKA complex, due to the location of the mutations at the interface between the catalytic and the regulatory subunits. We conclude that the two mutations cause high basal catalytic activity and lack of regulation by cAMP through interference of complex formation between the regulatory and the catalytic subunits of PKA.

Context and Objective: Cushing's syndrome (CS) is caused by a glucocorticoid excess. This hypercortisolism can damage the prefrontal cortex, known to be important in decision-making. Our aim was to evaluate decision-making in CS and to explore cortical thickness., Subjects and Methods: Thirty-five patients with CS (27 cured, eight medically treated) and thirty-five matched controls were evaluated using Iowa gambling task (IGT) and 3 Tesla magnetic resonance imaging (MRI) to assess cortical thickness. The IGT evaluates decision-making, including strategy and learning during the test. Cortical thickness was determined on MRI using freesurfer software tools, including a whole-brain analysis., Results: There were no differences between medically treated and cured CS patients. They presented an altered decision-making strategy compared to controls, choosing a lower number of the safer cards (P < 0·05). They showed more difficulties than controls to learn the correct profiles of wins and losses for each card group (P < 0·05). In whole-brain analysis, patients with CS 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 (P < 0·001)., Conclusions: Patients with CS failed to learn advantageous strategies and their behaviour was driven by short-term reward and long-term punishment, indicating learning problems because they did not use previous experience as a feedback factor to regulate their choices. These alterations in decision-making and the decreased cortical thickness in frontal areas suggest that chronic hypercortisolism promotes brain changes which are not completely reversible after endocrine remission., (© 2014 John Wiley & Sons Ltd.)

The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias (BAHs), which are often associated with ACTH-independent Cushing syndrome (CS). Although CS is invariably associated with obesity and is frequently associated with PKA signaling defects, we recently reported that its different forms appear to also present with variable weight gain and adiposity. The present study was aimed at characterizing further the phenotypic and molecular differences in periadrenal adipose tissue (PAT) among patients with subtypes of CS, by anthropometric/biochemical analyses and quantification of PKA expression and activity in BAHs in comparison to a non-CS group with aldosterone producing adenomas (APAs). Glucocorticoid levels, serum parameters, and BMI were analyzed among a larger patient cohort including those with different forms of CS, APAs, and Cushing disease. Abdominal CT scans were available for a small subset of patients examined for fat distribution. PAT collected during adrenalectomy was assayed for PKA activity, cAMP, and PKA expression. BMI and BMI z-score were lower in adults with PPNAD with PRKAR1A mutations and in pediatric patients with PPNAD with and without PRKAR1A mutations, respectively. Patients with PPNAD had higher cAMP levels in PAT and different fat distribution. Thus, PKA activity in PAT differed between CS diagnostic groups. Increased cAMP and PKA activity may have contributed to phenotypic differences among subtypes of CS. In agreement with the known roles of cAMP signaling in the regulation of adiposity, patients with PPNAD were less obese than other patients with CS., (© Georg Thieme Verlag KG Stuttgart · New York.)

Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing's syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing's syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Patients with Cushing's syndrome have left ventricular (LV) hypertrophy and dysfunction on echocardiography, but echo-based measurements may have limited accuracy in obese patients. No data are available on right ventricular (RV) and left atrial (LA) size and function in these patients., Objectives: The objective of the study was to evaluate LV, RV, and LA structure and function in patients with Cushing's syndrome by means of cardiac magnetic resonance, currently the reference modality in assessment of cardiac geometry and function., Methods: Eighteen patients with active Cushing's syndrome and 18 volunteers matched for age, sex, and body mass index were studied by cardiac magnetic resonance. The imaging was repeated in the patients 6 months (range 2-12 mo) after the treatment of hypercortisolism., Results: Compared with controls, patients with Cushing's syndrome had lower LV, RV, and LA ejection fractions (P < .001 for all) and increased end-diastolic LV segmental thickness (P < .001). Treatment of hypercortisolism was associated with an improvement in ventricular and atrial systolic performance, as reflected by a 15% increase in the LV ejection fraction (P = .029), a 45% increase in the LA ejection fraction (P < .001), and an 11% increase in the RV ejection fraction (P = NS). After treatment, the LV mass index and end-diastolic LV mass to volume ratio decreased by 17% (P < .001) and 10% (P = .002), respectively. None of the patients had late gadolinium myocardial enhancement., Conclusion: Cushing's syndrome is associated with subclinical biventricular and LA systolic dysfunctions that are reversible after treatment. Despite skeletal muscle atrophy, Cushing's syndrome patients have an increased LV mass, reversible upon correction of hypercortisolism.

Objective: Cushing's syndrome (CS) is associated with neuropsychological deficits. As the cerebellum plays a key role in neuropsychological functions it may be affected in CS. The aim of this study was to investigate whether patients with CS have a smaller cerebellar volume than healthy controls, and to analyse whether cerebellar volume is associated with neuropsychological performance and clinical parameters., Design: A cross-sectional study was performed., Methods: Thirty-six CS patients (15 with active CS and 21 with CS in remission) and 36 controls matched for age, sex, and education underwent neuropsychological testing, quality of life assessment, clinical evaluation, and magnetic resonance imaging brain scan. Cerebellar volumes (white matter and cortex, bilateral) were calculated using FreeSurfer Software., Results: Patients with active CS showed smaller bilateral cerebellar cortex volumes than controls (left, P=0.035 and right, P=0.034), as well as a trend toward smaller right cerebellar cortex volumes than patients in remission CS (P=0.051). No differences were observed in the volume of cerebellar white matter between the three groups. Both right and left cerebellar cortex volumes correlated negatively with triglyceride levels (right: r=-0.358, P=0.002 and left: r=-0.317, P=0.005) and age at diagnosis (right: r=-0.433, P=0.008 and left: r=-0.457, P=0.005). Left cerebellar cortex volume also correlated positively with visual memory performance (r=0.245, P=0.038). Right cerebellar cortex volume positively correlated with quality-of-life scores (r=0.468, P=0.004)., Conclusions: The cerebellar cortex volume is smaller in active CS patients than in controls. This finding is associated with poor visual memory and quality of life and is mostly pronounced in patients with higher triglyceride levels and older age at diagnosis., (© 2014 European Society of Endocrinology.)

Context: Distinguishing between pituitary [Cushing's disease (CD)] and ectopic causes [ectopic ACTH syndrome (EAS)] of ACTH-dependent Cushing's syndrome can be challenging. Inferior petrosal sinus sampling (IPSS) best discriminates between CD and occult EAS but is a specialized procedure that is not widely available. Identifying adjunctive diagnostic tests may prove useful. In EAS, abnormal processing of the ACTH precursor proopiomelanocortin (POMC) and the accumulation of POMC-derived peptides might be expected and abnormal levels of other neuropeptides may be detected., Objective: The objective of the study was to evaluate the diagnostic utility of POMC measurements for distinguishing between CD and occult EAS in patients referred for IPSS. Another objective of the study was to evaluate in parallel the diagnostic utility of another neuropeptide, agouti-related protein (AgRP), because we have observed a 10-fold elevation of AgRP in plasma in a patient with EAS from small-cell lung cancer., Design and Participants: Plasma POMC and AgRP were measured in 38 Cushing's syndrome patients presenting for IPSS, with either no pituitary lesion or a microadenoma on magnetic resonance imaging, and in 38 healthy controls., Results: Twenty-seven of 38 patients had CD; 11 of 38 had EAS. The mean POMC was higher in EAS vs CD [54.5 ± 13.0 (SEM) vs 17.2 ± 1.5 fmol/mL; P < .05]. Mean AgRP was higher in EAS vs CD (280 ± 76 vs 120 ± 16 pg/mL; P = .01). Although there was an overlap in POMC and AgRP levels between the groups, the POMC levels greater than 36 fmol/mL (n = 7) and AgRP levels greater than 280 pg/mL (n = 3) were specific for EAS. When used together, POMC greater than 36 fmol/mL and/or AgRP greater than 280 pg/mL detected 9 of 11 cases of EAS, indicating that elevations in these peptides have a high positive predictive value for occult EAS., Conclusions: Expanding upon previous observations of high POMC in EAS, this study specifically demonstrates elevated POMC levels can identify occult ectopic tumors. Elevations in AgRP also favor the diagnosis of EAS, suggesting AgRP should be further evaluated as a potential neuroendocrine tumor marker.

The original 4 patients with Cushing syndrome who underwent bilateral adrenalectomy for primary pigmented nodular adrenocortical disease were followed up for an average of 31 years to determine whether they or any of their primary relatives had developed Carney complex or its components. None had. Three of the patients were alive and well; the fourth had died of an unrelated condition. All the adrenal glands contained multiple small, black or brown cortical nodules, up to 4 mm in diameter. The extracapsular extension of the micronodules was limited to the immediate pericapsular adipose tissue and was not considered evidence of low-grade malignancy. Immunocytochemically, the nodules were positive for synaptophysin, inhibin-A, and melan A and negative for vimentin and CD56. Ki-67 antibody stained the cytoplasm of cells in the micronodules but not that of the atrophic cortical cells. The 4 patients had the PRKAR1A deletion that has been associated with the isolated form of primary pigmented nodular adrenocortical disease.

Background: We report the case of a patient who had a non-functional metastatic pancreatic neuroendocrine tumour (pNET), which changed in functionality during the course of the disease. This case demonstrates the effectiveness of conventional cytotoxic chemotherapy in the management of select group of patients with this rare, challenging condition., Case Presentation: Our patient was a 34 year old man under oncology follow up, diagnosed with a non-functional metastatic pancreatic neuroendocrine tumour treated with a Whipple's procedure two years ago. Despite treatment with somatostatin analogues and sunitinib, a tyrosine kinase inhibitor, he had demonstrated radiological progression of his metastatic disease. He now presented with a short history of Cushing's syndrome. A presumptive diagnosis of a rapidly progressive, metastatic, functional pNET with ectopic ACTH production was made, confirmed biochemically and with liver biopsy. The proliferative index, Ki-67 of 20% of the liver biopsy prompted us to treat him with conventional cytotoxic chemotherapy using streptozocin, 5-fluorouracil and doxorubicin. Prior to its administration clinical and biochemical control of the hypercortisolemic state was achieved with metyrapone. However the clinical, biochemical and radiological response to chemotherapy was so dramatic obviating the need for metyrapone therapy., Conclusions: Non-functional pNETs may evolve in their clinical and biologic behaviour producing functional hormonal syndromes. Chemotherapy may be an effective therapeutic modality in such circumstances.

Background: Kaposi sarcoma (KS) is a malignant disease most commonly diagnosed in the setting of a human immunodeficiency virus (HIV) infection and in patients receiving immunosuppressive treatment. Pulmonary KS has never been reported in association with endogenous Cushing's syndrome (CS)., Case Presentation: A 60-year-old woman presented with symptoms and signs of CS. Adrenal CS was confirmed by standard biochemical evaluation. Imaging revealed a right adrenal lesion (diameter 3.5 cm) and multiple pulmonary nodules, suggesting a cortisol-secreting adrenal carcinoma with pulmonary metastases. The patient underwent right adrenalectomy with a pathohistological diagnosis of an adrenal adenoma. Subsequent thoracoscopic wedge resection of one lung lesion revealed pulmonary KS with positive immunostaining for human herpes virus 8 (HHV-8). HIV-serology was negative. Hydrocortisone replacement was initiated for secondary adrenal insufficiency after surgery. Post-operative follow up imaging showed complete remission of all KS-related pulmonary nodules solely after resolution of hypercortisolism., Conclusion: KS may occur in the setting of endogenous CS and may go into remission after cure of hypercortisolism without further specific treatment.

Objective: Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls., Design: A retrospective study of 75 patients with CS followed at an academic center., Methods: Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population., Results: In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001)., Conclusions: Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission., (© 2014 European Society of Endocrinology.)

Background: Cushing's syndrome results from exposure to excess glucocorticoids. Ectopic Cushings is endogenous ACTH dependant form of Cushing's associated with markedly raised ACTH and cortisol levels. This leads to an impaired immune response, setting the stage for occurrence of opportunistic infections. Nocardiosis is a gram positive bacterial infection caused by aerobic actinomycetes in genus Nocardia. We report a series of patients diagnosed with ectopic Cushings, having pneumonia with Nocardia spp. In one of these cases, the manifestations of Cushing's disappeared with treatment for Nocardia., Case Presentation: Two middle aged men of Asian descent presented to the Endocrine clinic: the first with history of exertional shortness of breath, and weight loss for 1 year, the other with facial swelling, disturbed sleep and lethargy for a month. The third case was a young Asian male who presented with progressive weakness & weight loss for 2 months. All three patients had uncontrolled hypertension, high blood sugars & were hypokalemic (K: 2.52, 2.9, 1.5 mmol/l); 24 hour urine cortisol was elevated at 2000, 27216 and 9088 (32-243 ug/24 hours); ACTH 68.5, 159, 255 [0-48 pg/ml), respectively. Their MRI pituitary was normal, inferior petrosal sinus sampling revealed no central peripheral gradient. CT chest of these subjects demonstrated cavitatory lung lesions; microscopic analysis of respiratory samples was suggestive of infection with Nocardia spp. Histopathology of bronchoscopic-guided biopsy revealed no malignancy. Antihypertensives, insulin, potassium replacement, ketoconazole & trimethoprim-sulphamethoxazole (TS) were initiated. The patients' symptomatology improved & cavitatory lesions resolved with treatment. The primary source for the ectopic cushings remained unknown. The first case required bilateral adrenalectomy. The second case followed a progressively downhill course leading to death. In the third case, we were able to completely taper off ketoconazole, potassium, insulin & antihypertensives, after starting TS., Conclusion: Opportunistic infections are known to be associated with Cushing's syndrome, and higher levels of glucocorticoid secretion are found in patients with ectopically produced ACTH. Pulmonary nocardiosis is important differential to consider. This series includes the first case reported in which signs and symptoms of cushings subsided after treatment of Nocardia.

Background: Management of subclinical Cushing's syndrome (SCS) remains controversial; it is not possible to predict which patients would benefit from adrenalectomy. In the present study we aimed to evaluate the role of adrenocortical scintigraphy (ACS) in the management of patients with SCS., Methods: The medical records of 33 consecutive patients with adrenal "incidentaloma" and proven or suspected SCS who underwent (131)I-19-iodocholesterol ACS between 2004 and 2010 were reviewed. Sixteen underwent laparoscopic adrenalectomy (surgical group-S-group) and 17 were medically managed (medical group-M-group). Follow-up evaluation was obtained by outpatient consultation., Results: Overall 25 patients (15 in the S-group and 10 in the M-group) had concordant unilateral uptake at ACS (ACS+). In the S-group, the mean follow-up duration was 30.9 ± 16.1 months and, irrespective of the presence of hormonal diagnosis of SCS, in patients who were ACS+ adrenalectomy resulted in a significant increase in HDL cholesterol and decreases in body mass index, glycemia, and blood pressure (BP). One patient reduced antihypertensive medication and three others were able to discontinue it altogether. Prolonged postoperative hypoadrenalism (PH) occurred in 14 patients in the S-group. The overall accuracy in predicting PH was 93.7 % for ACS and 68.7 % for laboratory findings. In the M-group, the mean follow-up duration was 31.5 ± 26.3 months and no patient developed overt Cushing's syndrome, although ACS+ patients experienced a worsening in glycemia and diastolic BP., Conclusions: Adrenal scintigraphy seems the most accurate diagnostic test for SCS. It is able to predict the metabolic outcome and the occurrence of PH, identifying the patients who could benefit from adrenalectomy irrespective of hormonal diagnosis.

Adrenal diseases in pregnant women are diagnosed relatively rarely. The main cause of hypercortisolemia during pregnancy is Cushing's syndrome related to adrenal adenoma. It is important to diagnose Cushing's syndrome in pregnant women because it can lead to significant maternal and foetal complications and morbidity. However, due to physiological endocrine changes and symptoms in pregnant women the diagnosis of this disorder can be a challenge. One current case describes a 38-year-old pregnant woman with hypertension, oedema and an adrenal tumour. At the beginning, Conn syndrome was suspected, but after careful analysis Cushing's syndrome (with an adenoma of the right adrenal gland) was diagnosed. After delivery and 5 weeks of pharmacological treatment the patient underwent right side adrenalectomy by laparoscopy.

Background: Little information is available about the risk of progression of seemingly benign adrenocortical hyperplasias to carcinomatous conditions. Using in silico approaches of digitally archived tissue sections, the nuclear morphometric parameters were compared to assess nuclear asymmetry as an index for nuclear atypia., Methods: Four groups of nuclei were used for the current study: spongiocytes and compact cells obtained from adrenocorticotropic hormone (ACTH)-independent macronodular hyperplasia, which were hypothesized to be high risk for nuclear asymmetry, and primary pigmented nodular adrenocortical disease and micronodular adrenocortical hyperplasia samples were used as internal controls., Results: Analyses reveal high nuclear irregularity index of spongiocytes and shape factor abnormalities of both spongiocytes and compact cells of ACTH-independent macronodular adrenal hyperplasia compared with the other 2 groups (high F values and very low P values after analyses of variances), thus confirming the hypothesis that ACTH-independent macronodular adrenal hyperplasia present with subtle morphometric features of nuclear atypia., Conclusions: This probably puts this class of adrenocortical tumors at risk of dysplastic progression, and more studies are needed to test the hypothesis.

Introduction: Paraneoplastic Cushing's syndrome (CushingPS) in small-cell lung cancer is rare but severe., Methods: We studied 383 patients with small-cell lung cancer diagnosed between 1998 and 2012. Among them, 23 patients had CushingPS, 56 had other paraneoplastic syndrome (OtherPS), and 304 had no paraneoplastic syndrome (NoPS)., Results: After comparison of the three groups, we observed that CushingPS patients had more extensive disease: 82.6% versus 67.8% versus 53.3% (p = 0.005), respectively, with more than two metastatic sites: 63.2% versus 15.8% and 24.1% (p ≤ 0.001), a higher World Health Organization performance status (2-4): 73.9% versus 57.1% versus 43.7% (p = 0.006), greater weight loss (≥10%): 47.8% versus 33.9% versus 16.4% (p ≤ 0.001), reduced objective response to first-line treatment: 47.6% versus 74.1% versus 71.1% (p = 0.04), and poorer sensitivity to first-line treatment: 19% versus 38.9% versus 48.6% (p = 0.01). NoPS patients, with World Health Organization performance status of 3-4, had extensive disease at diagnosis, with response, sensitivity to first-line treatment, and survival similar to the CushingPS group. At relapse, the CushingPS group had no objective response to second-line treatment versus 25% versus 42.8% in OtherPS and NoPS groups, respectively (p = 0.005). The median survival of CushingPS patients was 6.6 months versus 9.2 months for OtherPS and 13.1 months for NoPS patients (p ≤ 0.001). CushingPS is a prognostic factor of death (hazard ratio, 2.31; p ≤ 0.001)., Conclusion: CushingPS is the worst form of the paraneoplastic syndromes with particularly extensive tumors. Reduced objective response and sensitivity to first-line treatment and no response to second-line treatment suggest starting palliative care early at first line and exclusively at relapse.

Central obesity is associated with insulin resistance and dyslipidemia. Thus, the mechanisms that control fat distribution and its impact on systemic metabolism have importance for understanding the risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushing's syndrome) or local levels (due to adipose-specific overproduction via 11β-hydroxysteroid dehydrogenase 1) results in the preferential expansion of central, especially visceral fat depots. At the same time, peripheral subcutaneous depots can become depleted. The biochemical and molecular mechanisms underlying the depot-specific actions of glucocorticoids (GCs) on adipose tissue function remain poorly understood. GCs exert pleiotropic effects on adipocyte metabolic, endocrine and immune functions, and dampen adipose tissue inflammation. GCs also regulate multiple steps in the process of adipogenesis. Acting synergistically with insulin, GCs increase the expression of numerous genes involved in fat deposition. Variable effects of GC on lipolysis are reported, and GC can improve or impair insulin action depending on the experimental conditions. Thus, the net effect of GC on fat storage appears to depend on the physiologic context. The preferential effects of GC on visceral adipose tissue have been linked to higher cortisol production and glucocorticoid receptor expression, but the molecular details of the depot-dependent actions of GCs are only beginning to be understood. In addition, increasing evidence underlines the importance of circadian variations in GCs in relationship to the timing of meals for determining their anabolic actions on the adipocyte. In summary, although the molecular mechanisms remain to be fully elucidated, there is increasing evidence that GCs have multiple, depot-dependent effects on adipocyte gene expression and metabolism that promote central fat deposition. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Hypercortisolism leads to various physical, psychological and cognitive symptoms, which may partly persist after the treatment of Cushing's disease. The aim of the present study was to investigate abnormalities in white matter integrity in patients with long-term remission of Cushing's disease, and their relation with psychological symptoms, cognitive impairment and clinical characteristics., Methods: In patients with long-term remission of Cushing's disease (n = 22) and matched healthy controls (n = 22) we examined fractional anisotropy (FA) values of white matter in a region-of-interest (ROI; bilateral cingulate cingulum, bilateral hippocampal cingulum, bilateral uncinate fasciculus and corpus callosum) and the whole brain, using 3 T diffusion tensor imaging (DTI) and a tract-based spatial statistics (TBSS) approach. Psychological and cognitive functioning were assessed with validated questionnaires and clinical severity was assessed using the Cushing's syndrome Severity Index., Results: The ROI analysis showed FA reductions in all of the hypothesized regions, with the exception of the bilateral hippocampal cingulum, in patients when compared to controls. The exploratory whole brain analysis showed multiple regions with lower FA values throughout the brain. Patients reported more apathy (p = .003) and more depressive symptoms (p < .001), whereas depression symptom severity in the patient group was negatively associated with FA in the left uncinate fasciculus (p < 0.05). Post-hoc analyses showed increased radial and mean diffusivity in the patient group., Conclusion: Patients with a history of endogenous hypercortisolism in present remission show widespread changes of white matter integrity in the brain, with abnormalities in the integrity of the uncinate fasciculus being related to the severity of depressive symptoms, suggesting persistent structural effects of hypercortisolism.

Objective: Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data., Design: Observational study (enrolment phase of Phase III study)., Methods: Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks., Results: Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism., Conclusions: There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity., (© 2013 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Although Cushing's syndrome has been described in association with various neuroendocrine tumors producing ectopic adrenocorticotropin (ACTH), primary ovarian carcinoma rarely causes this syndrome. We hereby report the case of a 61-year-old woman presented with abdominal distension, facial swelling and skin pigmentation. Clinical and diagnostic evaluation revealed a right ovarian tumor with hypercortisolemia, high plasma ACTH, extremely high plasma ACTH precursors and lack of dexamethasone suppression. Removal of the tumor led to normalization of ACTH, ACTH precursors and cortisol levels. In addition, hypokalemia, hyperglycemia and elevated serum CA 125 were noted, which were also normalized after resection of the tumor. Histopathological examination indicated a primary ovarian carcinoma with a mixed pattern of differentiation. Immunohistochemistry showed immunoreactivity for chromogranin A, synaptophysin and ACTH. Hence, the diagnosis of Cushing's syndrome arising from an ovarian carcinoma secreting ectopic ACTH was made. The case was managed successfully, with subsequent good recovery and no evidence of recurrence at 4 years of follow-up.

We hereby describe the rare case of a 59-year-old patient presenting with marked hyperamylasaemia mimicking acute pancreatitis upon admission. Investigation of co-existent hypokalemia revealed the presence of ectopic adrenocorticotropic hormone secretion, leading to the final diagnosis of small cell lung cancer, exhibiting dual paraneoplastic syndromes including Cushing Syndrome and hyperamylasaemia. Although, paraneoplastic syndromes occur commonly, paraneoplastic hyperamylasaemia especially in the context of dual paraneoplastic syndromes occurring simultaneously, is extremely rare. Such misleading manifestations require a high index of suspicion on behalf of the physician, so that an underlying malignancy is not missed, and a final diagnosis combining all clinical and laboratory findings is reached. In turn, in rare cases common biochemical markers such as amylase can be used as a useful follow up index driving further management.

Feline pituitary tumors are rare. An 8-year-old male Japanese domestic cat presented with anorexia and emaciation. The cat died 17 days after admission from progressive neurological symptoms. At necropsy, a pituitary tumor measuring 25 × 18 × 15 mm was found. Microscopically, the tumor was divided into multiple lobules and had grown invasively into the adjacent brain tissue and sphenoid bone. Tumor cells had pleomorphic nuclei with prominent centrally located nucleoli and abundant amphophilic polygonal cytoplasm. Immunohistochemically, the tumor cells stained with anti-adrenocorticotropic hormone (ACTH), α-melanin-stimulating hormone (MSH) and β-endorphin antibodies. Ultrastructurally, the cytoplasm of the tumor cells contained various sized secretory granules. Based on these pathological findings, this tumor was diagnosed as pituitary carcinoma originated from pars intermedia cells.

Purpose of Review: Glucocorticoids have a negative impact on bone through direct effects on bone cells and indirect effects on calcium absorption. Here, recent findings regarding glucocorticoid-induced osteoporosis, bone changes in patients with endogenous glucocorticoid derangements, and treatment of steroid-induced bone disease are reviewed., Recent Findings: Although the majority of our understanding arises from the outcomes of patients treated with exogenous steroids, endogenous overproduction appears to be similarly destructive to bone, but these effects are reversible with cure of the underlying disease process. Additionally, there are bone changes that occur in diseases that interrupt adrenal glucocorticoid production, both in response to our inability to perfectly match glucocorticoid replacement and also related to the underlying disease process. More investigation is required to understand which patients with endogenous overproduction or underproduction of glucocorticoid would benefit from osteoporosis treatment. Better understood is the benefit that can be achieved with currently approved treatments for glucocorticoid-induced osteoporosis from exogenous steroids. With growing concern of long-term use of bisphosphonates, however, further investigation into the duration of use and use in certain populations, such as children and premenopausal women, is essential., Summary: Glucocorticoid-induced osteoporosis is a complex disease that is becoming better understood through advances in the study of exogenous and endogenous glucocorticoid exposure. Further advancement of proper treatment and prevention is on the horizon.

ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production with subclinical or overt Cushing's syndrome. Although the family clustering of AIMAH is infrequent, we have tried our best to find such a familial affected pedigree with complete clinical information and successfully collect adrenalectomy tissue samples from two members of this family. Using whole exome sequencing and several variant prioritization strategies based on disease network analysis, we identified Endothelin receptor type A (EDNRA) Ser420Thr mutation as a causative mutation of AIMAH. EDNRA is a member of G protein coupled receptor family and is involved in cardiovascular or polycystic kidney disease. Our findings indicate that the mutation of EDNRA at S420T site should be regard as a potential AIMAH causative variation in familial and sporadic affected patients.

Background: Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands., Methods: We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients., Results: The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion., Conclusions: Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.).

Background: Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition., Methods: We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models., Results: The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival., Conclusions: Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.).