High accuracy of bilateral and simultaneous petrosal sinus sampling with desmopressin for the differential diagnosis of pediatric ACTH-dependent Cushing's syndrome.

PURPOSE: To analyze the bilateral and simultaneous petrosal sinus sampling (BIPSS) in a subgroup of children and adolescents with ACTH-dependent Cushing's syndrome (ADCS) METHODS: Retrospective study in a tertiary reference center. From 1993 and 2017, 19 children and adolescents (PED) were submitted to the BIPSS, median age of 14 years (range 9-19 years), 53% were males, 18 had Cushing's disease (CD) and one had ectopic ACTH syndrome (EAS). All procedures were performed with 10 µg of intravenous desmopressin. RESULTS: The catheter positioning was successful in all cases. The central ACTH gradient was met in 17/19 cases. At baseline, central gradient occurred in 16/19 (84%) with gradient values of 7.2 ± 6.0. After stimulation, there was an increase in the center-periphery gradient values (33.6 ± 44.3). In one case, central gradient was defined only after stimulation. Two cases presented without a central gradient; one case of CD with a false-negative and one EAS case. Lateralization occurred in all cases with a central gradient. Confirmation of the tumor location presumed by the procedure with the surgical description occurred in 60% of the cases. The BIPSS in this PED subgroup of ADCS presented a sensitivity of 94.4% and specificity of 100%. There were no complications of the procedure. CONCLUSION: In a series of children and adolescents with ADCS, BIPSS was safe and highly accurate in defining the central to peripheral ACTH gradient using desmopressin as secretagogue. Nevertheless, there was a limited value of the ACTH-gradient between the petrosal sinuses for the tumor location.

Cushing's disease due to somatic USP8 mutations: a systematic review and meta-analysis.

PURPOSE: Cushing's disease (CD) is a severe illness generally caused by microcorticotropinomas (MICs) and in approximately 7-20% of patients by macrocorticotropinomas (MACs). USP8-mutations have been identified as a major genetic cause of CD (~ 50%). Few studies have reported the distribution between MICs-MACs related to USP8-mutations and their genotype-phenotype correlations. Therefore, we aimed to evaluate USP8-mutations in a cohort of MICs-MACs from a unique center and to perform a systematic review and meta-analysis. METHODS: DNA-tumor-tissues from 47 corticotropinomas (16 MICs and 31 MACs) were sequenced. Clinical-biochemical data, radiological imaging data and remission/recurrence rates were evaluated. In addition, we performed a meta-analysis of nine published series (n = 630). RESULTS: We identified four different USP8-mutations previously described, in 11 out of 47 (23.4%) corticotropinomas; 8 out of 11 were MACs. The urinary cortisol levels of our patients with corticotrophin USP8-mutated-alleles were lower than those of patients with wild-type (WT) alleles (p ≤ 0.017). The frequency of USP8-mutated-alleles among the series was approximately 30% with a higher prevalence in female-patients (p < 0.1 × 10-4). Among the 5 series, the remission rates were higher in patients with USP8-mutated-alleles than in those with the USP8-WT-alleles (p < 0.1 × 10-4). CONCLUSION: Our data, as well as the retrospective review of CD series associated with USP8-mutated alleles, show heterogeneous findings among the series. Several drawbacks included the lack of a systematic protocol to evaluate these patients before surgery and follow-up. Further prospective studies using a systematic protocol will provide more consistent information about the influence of the corticotropinomas with USP8-mutated alleles on the phenotype, responses to treatment and outcome of patients with CD.

Filamin A and DRD2 expression in corticotrophinomas.

PURPOSE: Filamin A (FLNA) expression is related to dopamine receptor type 2 (DRD2) expression in prolactinomas. Nevertheless, in corticotrophinomas, there are few studies about DRD2 expression and no data on FLNA. Therefore, we evaluated FLNA and DRD2 expression in corticotrophinomas and their association with tumor characteristics. METHODS: DRD2 and FLNA expression by immunohistochemistry, using H-score, based on the percentage of positive cells in a continuous scale of 0-300, were evaluated in 23 corticotrophinomas samples from patients submitted to neurosurgery. In six patients, treatment with cabergoline was indicated after non curative surgery. RESULTS: Twenty-two patients were female and one male. Regarding tumor size, 10 were micro and 12 were macroadenomas. DRD2 expression was found in 89% of cases and did not correlate with FLNA expression. Moreover, the response to cabergoline, observed in 33% of the cases, did not correlate with DRD2 nor FLNA expression. FLNA expression was not associated with clinical and tumor characteristics, except for sphenoid sinus invasion. CONCLUSIONS: In our cohort of corticotrophinomas, DRD2 expression was not associated with FLNA expression nor to the response to CAB. Nonetheless, FLNA expression could be related to tumor invasiveness.

Accuracy of the 10 µg desmopressin test for differential diagnosis of Cushing syndrome: a systematic review and meta-analysis.

We evaluated the accuracy of the 10 µg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering ΔACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Δcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of ΔACTH > 35% and Δcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering ΔACTH, Δcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=85634, identifier CRD42018085634; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=68317, identifier CRD42017068317.

Pregnancy after pituitary surgery does not influence the recurrence of Cushing's disease.

PURPOSE: Pregnancy is associated with the activation of the hypothalamus-pituitary-adrenal axis, which can cause a misdiagnosis of Cushing's syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence rate in Cushing's disease (CD) patients. METHODS: This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14-45), PS remission, a follow-up of ≥6 months (median of 122 months, 6-402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing's syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA). RESULTS: Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses. CONCLUSIONS: There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data.

Resolution of Cyclicity After Pasireotide LAR in a Patient With Cushing Disease.

OBJECTIVE: The cyclicity (CIC) of cortisol spontaneously occurs in a minority of patients with Cushing syndrome (CS). When it arises, diagnostic and therapeutic approaches become more challenging. This study aimed to report a patient with Cushing disease (CD) who achieved normalization of cortisol and CIC pattern with pasireotide long-acting release (pasi/LAR). METHODS: A 43-year-old female patient related an 8-month history of CS. An 8-mm pituitary nodule depicted by magnetic resonance imaging, serum cortisol suppression of >50% after 8 mg of dexamethasone therapy, and the absence of other lesions were compatible with a CD diagnosis. The patient presented with a CIC pattern with 1 episode before and 17 episodes after an unsuccessful pituitary surgery. RESULTS: Medical treatment with cabergoline alone up to 3.5 mg/wk and a combined treatment with ketoconazole 400 mg/d did not improve CIC CS. Pasi/LAR was initiated at a dose of 20 mg/mo. A few days after the first dose, the patient experienced symptoms suggestive of adrenal insufficiency. The medication and dose were maintained for 24 months. During this period, there was a normalization of UFC levels and progressive clinical improvement. Additionally, new episodes of CIC were not observed. CONCLUSION: A CD patient with a challenging issue of CIC was reported. The condition was not controlled after pituitary surgery and by the combined treatment with cabergoline and ketoconazole, although hypercortisolism was abated by the continuous use of pasi/LAR. To our knowledge, this is the first report as regards the use of this medication to control CIC in a patient with CD.

Time to Diagnosis in Cushing's Syndrome: A Meta-Analysis Based on 5367 Patients.

CONTEXT: Signs and symptoms of Cushing's syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. OBJECTIVE: The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. DATA SOURCES: A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. STUDY SELECTION: Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. DATA EXTRACTION: Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included. DATA SYNTHESIS: Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere. CONCLUSIONS: Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.

Corrigendum: Transcriptome Analysis Showed a Differential Signature Between Invasive and Non-invasive Corticotrophinomas.

[This corrects the article DOI: 10.3389/fendo.2017.00055.].

Role for postoperative cortisol response to desmopressin in predicting the risk for recurrent Cushing's disease.

UNLABELLED: In the early postoperative period of Cushing's disease patients, desmopressin may stimulate ACTH secretion in the remnant corticotrophic tumour, but not in nontumour suppressed cells. OBJECTIVE: The aim of this study is to evaluate the serum cortisol responses to desmopressin after pituitary surgery, establishing an optimal cut-off for absolute increment (Delta) of serum cortisol (F) suitable to predict recurrence risk. DESIGN: Retrospective case record study. PATIENTS: Fifty-seven Cushing's disease patients submitted to pituitary surgery and desmopressin stimulation in the early postoperative with a long-term follow-up (20-161 months) were studied. METHODS AND MEASUREMENTS: Serum cortisol levels after desmopressin test (10 microg i.v.) 15-30 days after adenomectomy were used to determine DeltaF (absolute increment of F: F peak - F baseline). Sensitivity and specificity of DeltaF were calculated and a ROC curve was performed to establish an optimal cut-off for DeltaF to predict recurrence risk. RESULTS: Fifteen patients had immediate postoperative failure (basal F > 165 nmol/l; 6 microg/dl) and one patient was lost during the follow-up. Forty-one patients achieved initial remission and were followed-up. Five of 11 patients who recurred had DeltaF > 193 nmol/l (7 microg/dl), but none of 30 patients who remained in prolonged remission showed DeltaF > 193 nmol/l after postoperative desmopressin stimulation. CONCLUSIONS: Persistence of cortisol response (DeltaF > 193 nmol/l) to desmopressin in the early postoperative period can help to identify Cushing's disease patients with initial remission who present risk for later recurrence.

Serpin peptidase inhibitor clade A member 1 as a potential marker for malignancy in insulinomas.

PURPOSE: The biological behavior of insulinomas cannot be predicted based on histopathologic criteria in which the diagnosis of malignancy is confirmed by the presence of metastases. In this study, microarray and quantitative real-time reverse transcription-PCR were applied to identify differentially expressed genes between malignant and nonmalignant insulinomas to search for useful biomarkers to recognize the metastatic potential of insulinomas. EXPERIMENTAL DESIGN: Code Link human bioarrays were used to analyze differences in approximately 20,000 genes between six well-differentiated endocrine tumors of benign behavior compared with one well-differentiated endocrine carcinoma (WDEC) and three metastases of endocrine carcinomas (MEC). Quantitative real-time reverse transcription-PCR was used to validate differential expressions of five genes in a series of 35 sporadic insulinomas. Serpin peptidase inhibitor clade A member 1 (SERPINA1; alpha-1-antitrypsin) expression, identified as up-regulated in malignant insulinomas, was also evaluated by immunohistochemistry. RESULTS: Analysis of microarray data resulted in 230 differentially expressed genes. Gene Ontology analysis identified serine-type endopeptidase activity and serine-type endopeptidase inhibitor activity as pathways presenting significant differential expression. Protease serine 2 and complement factor B (from serine-type endopeptidase activity pathway) were respectively confirmed as up-regulated in well-differentiated endocrine tumors of benign behavior (WDET) and in WDEC/MEC. Angiotensinogen and SERPINA1 (from serine-type endopeptidase inhibitor activity pathway) were confirmed as up-regulated in WDEC/MEC. SERPINA1 was shown to be expressed in 85.7% of malignant versus 14.3% of nonmalignant insulinomas by immunohistochemistry. CONCLUSIONS: Our data are consistent to the possibility that SERPINA1 is a marker of malignancy in insulinomas. Given the widespread availability of antibody anti-alpha-1-antitrypsin in pathology services, SERPINA1 expression evaluation might be of clinical utility in recognizing patients more likely to develop an aggressive presentation.

Pregnancy in Patients with Cushing's Syndrome.

Progress in diagnosis and treatment of endocrine diseases has made pregnancy possible for women with endocrinopathies, including Cushing's syndrome (CS). The risk of maternal-fetal complications in patients who are not biochemically controlled, however, is substantial. Therefore, the surgical and/or medical control of hypercortisolism is mandatory prior to conceiving. A diagnosis of de novo CS during gestation is difficult due to changes in the hypothalamic-pituitary-adrenal axis during pregnancy, which may lead to some clinical features suggestive of CS along with abnormal laboratory tests. This review presents the diagnosis and management of CS during pregnancy.

A review of Cushing's disease treatment by the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism.

The treatment objectives for a patient with Cushing's disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails. There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition.

Transcriptome Analysis Showed a Differential Signature between Invasive and Non-invasive Corticotrophinomas.

ACTH-dependent hypercortisolism caused by a pituitary adenoma [Cushing's disease (CD)] is the most common cause of endogenous Cushing's syndrome. CD is often associated with several morbidities, including hypertension, diabetes, osteoporosis/bone fractures, secondary infections, and increased cardiovascular mortality. While the majority (≈80%) of the corticotrophinomas visible on pituitary magnetic resonance imaging are microadenomas (MICs, <10 mm of diameter), some tumors are macroadenomas (MACs, ≥10 mm) with increased growth potential and invasiveness, exceptionally exhibiting malignant demeanor. In addition, larger and invasive MACs are associated with a significant increased risk of local complications, such as hypopituitarism and visual defects. Given the clinical and molecular heterogeneity of corticotrophinomas, the aim of this study was to investigate the pattern of genetic differential expression between MIC and MAC, including the invasiveness grade as a criterion for categorizing these tumors. In this study, were included tumor samples from patients with clinical, laboratorial, radiological, and histopathological diagnosis of hypercortisolism due to an ACTH-producing pituitary adenoma. Differential gene expression was studied using an Affymetrix microarray platform in 12 corticotrophinomas, classified as non-invasive MIC (n = 4) and MAC (n = 5), and invasive MAC (n = 3), according to modified Hardy criteria. Somatic mutations in USP8 were also investigated, but none of the patients exhibited USP8 variants. Differential expression analysis demonstrated that non-invasive MIC and MAC have a similar genetic signature, while invasive MACs exhibited a differential expression profile. Among the genes differentially expressed, we highlighted CCND2, ZNF676, DAPK1, and TIMP2, and their differential expression was validated through quantitative real-time PCR in another cohort of 15 non-invasive and 3 invasive cortocotrophinomas. We also identified potential biological pathways associated with growth and invasiveness, TGF-ß and G protein signaling pathways, DNA damage response pathway, and pathways associated with focal adhesion. Our study revealed a differential pattern of genetic signature in a subgroup of MAC, supporting a genetic influence on corticotrophinomas in patients with CD.

Somatostatin receptor subtype 5 (SSTR5) mRNA expression is related to histopathological features of cell proliferation in insulinomas.

Insulinomas are rare endocrine neoplasias that constitute the most frequent islet cell tumours. Somatostatin (SST) analogs are tentatively used to inhibit insulin secretion and control tumour growth in patients with local invasion or inoperative metastasis, but variable responses have been reported. Data regarding somatostatin receptor (SSTR) subtypes expression in insulinomas are conflicting. In this study, we evaluated 16 cases of primary insulinomas (including four primary plurihormonal tumours) and two hepatic metastases. Histopathological and immunohistochemical analysis for some features associated with tumour aggressiveness and semi-quantitative RT-PCR for SSTR1-5 and real-time qPCR for SSTR5 were performed. SSTR subtypes 1, 3, and 5 were expressed in 100%, SSTR2 in 89%, and SSTR4 only in 22% of the insulinomas. SSTR5 mRNA was positively correlated with histopathological features related to tumour aggressiveness (large tumour diameter, well-differentiated endocrine tumour with uncertain behaviour and higher number of cells with nuclear atypia). SSTR5 mRNA expression in primary insulinomas was lower than in primary plurihormonal tumours (P < 0.05). The observed positive correlation between SSTR5 expression and tumour size suggests that the use of SST analogues more specific to SSTR5 in the treatment of insulinomas deserves attention.

Ectopic ACTH syndrome: our experience with 25 cases.

OBJECTIVE: Ectopic ACTH syndrome (EAS) occurs in about 5-10% of all patients with ACTH-dependent hypercortisolism with most of them caused by intrathoracic neoplasms. It may be associated with overt malignancies or with occult and indolent tumors. We assessed the accuracy of dynamic tests, inferior petrosal sinus sampling (IPSS) using desmopressin, and imaging in the work-up diagnosis of EAS. DESIGN AND SUBJECTS: Tumor markers, imaging, and outcome data from 25 patients (13F/12M) aged 18-72 years. High dexamethasone suppression test (HDDST), desmopressin test, GHRP-6 test, corticotropin-releasing hormone (CRH) test, IPSS, computed tomography (CT), magnetic resonance imaging (MRI), and (111)In-pentetreotide scintigraphy were revised. RESULTS: In 5 out of 20 patients HDDST was positive. In 13 patients who underwent desmopressin test, ACTH- and cortisol-positive responses were seen in six and five patients respectively. GHRP-6 test was positive in two out of three cases. Two patients underwent CRH test with negative response. In the seven patients submitted to IPSS using desmopressin in six of them, none had ACTH gradients. CT was positive in 15 out of 21 patients and MRI in 8 out of 17 cases. (111)In-pentetreotide scintigraphy was positive in three out of five patients. Fourteen patients had intrathoracic tumors, five had pheochromocytomas, three had pancreatic tumors, one had a glomic tumor, and had three occult tumors. Six out of 11 patients with metastasis died and 3 others without metastasis died. CONCLUSIONS: IPSS with desmopressin was helpful for differential diagnosis. Patients initially harboring occult carcinoids may also exhibit severe hypercortisolism and those harboring tymic carcinoids had poor prognoses when compared with bronchial carcinoids and pheocromocytomas.

Thymus hyperplasia after resolution of hypercortisolism in ACTH-dependent Cushing's syndrome: the importance of thymic vein catheterization.

Thymic hyperplasia has been described after the resolution of hypercortisolism from several etiologies, causing great diagnostic dilemmas. We describe a case where the catheterization of the thymic vein was essential for the differential diagnosis of a thymic enlargement in an adrenalectomized patient with ACTH-dependent Cushing's syndrome. The patient was a 48-year-old female with clinical and laboratorial data suggesting Cushing's disease. She underwent a transsphenoidal surgery with no tumor visualization and no remission of the syndrome. Histopathological studies disclosed a normal pituitary. She underwent a bilateral adrenalectomy and 8 months later a chest CT showed an increase of left thymic lobe, which was previously non-existent. After a negative (111)In-pentetreotide scintigraphy, the patient underwent simultaneous and bilateral catheterism of the petrosus sinuses and catheterization of the thymic and inominate veins and no ACTH gradient was shown among the sites of collection. She did not undergo thoracotomy and a follow-up was established. During the evolution, there was a spontaneous regression of the thymic lesion 38 months after the diagnosis. The ACTH gradient during the catheterization of thymic vein was essential for the differential diagnosis of the thymic enlargement tumor after hypercortisolism resolution in ACTH-dependent Cushing's syndrome, especially in this case, where the ACTH source was occult, thus avoiding an invasive surgical procedure for a benign entity with spontaneous resolution.

Cushing's disease arising from a clinically nonfunctioning pituitary adenoma.

A 49-yr-old woman with a large pituitary tumor leading to visual loss and galactorrhea- amenorrhea was submitted to transcranial pituitary surgery, when a clinically nonfunctioning pituitary adenoma was partially removed. Histopathology and immunohistochemistry confirmed the diagnosis of "non-secreting atypical adenoma." At that time, serum and urinary free cortisol were normal, with low T4 levels and hyperprolactinemia. The patient was discharged on thyroxine and bromocriptine and treated with conventional radiotherapy. Two years later, she presented high free urinary cortisol levels and a positive ACTH response to desmopressin testing on dexametasone 2 mg overnight. A pituitary biopsy confirmed aggressive growth as well as positive immunoreactivity for ACTH, p53, Ki-67, and c-erb-B2. The patient was then treated with radiosurgery on ketoconazole therapy. The overall clinical, laboratory, and pathological data suggest a transition from a clinically nonfunctioning to a hypersecreting ACTH-producing tumor. Putative mechanisms of tumor transformation and the possibility of a silent corticotropinoma evolving into clinical Cushing s syndrome are discussed.

Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing's disease in Brazil.

Although it is a rare condition, the accurate diagnosis and treatment of Cushing's disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing's syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing's syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing's disease, recommending follow-up of these patients at experienced referral centers. Arch Endocrinol Metab. 2016;60(3):267-86.

Choroidal and Retinal Abnormalities by Optical Coherence Tomography in Endogenous Cushing's Syndrome.

CONTEXT: Cortisol has been suggested as a risk factor for choroidal thickening, which may lead to retinal changes. OBJECTIVE: To compare choroidal thickness measurements using optical coherence tomography (OCT) in patients with endogenous active Cushing's syndrome (CS) and to evaluate the occurrence of retinal abnormalities in the same group of patients. DESIGN: Cross-sectional study. SETTING: Outpatient clinic. PATIENTS: Eleven female patients with CS in hypercortisolism state as determined by the presence of at least two abnormal measurements from urinary cortisol 24 h, no suppression of cortisol with low dose dexamethasone suppression test, and nocturnal salivary cortisol levels and 12 healthy controls. METHODS: Choroidal and retinal morphology was assessed using OCT. MAIN OUTCOME MEASURES: Choroidal thickness measurements and the presence of retinal changes. RESULTS: The mean subfoveal choroidal thickness was 372.96 ± 73.14 µm in the patients with CS and 255.63 ± 50.70 µm in the control group (p < 0.001). One patient (9.09%) presented with central serous chorioretinopathy and one patient (9.09%) with pachychoroid pigment epitheliopathy. CONCLUSION: Choroidal thickness is increased in the eyes of patients with active CS compared to healthy and matched control. Also, 18.18% of patients presented with macular changes, possibly secondary to choroidal thickening. While further studies are necessary to confirm our findings, excess corticosteroid levels seem to have a significant effect on the choroid and might be associated with secondary retinal diseases.

Retraction Note: Fatal factitious Cushing syndrome (Münchhausen's syndrome) in a patient with macroprolactinoma and silent corticotrophinoma: case report and literature review.

[This retracts the article DOI: 10.1186/s40842-015-0002-8.].