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Concept: Dexamethasone suppression test

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CONTEXT: Prevalence of Cushing’s syndrome (CS) in patients presenting with hirsutism is not well-known. OBJECTIVE: Screening of CS in patients with hirsutism. SETTING: Referral hospital PATIENTS AND OTHER PARTICIPANTS: This study was carried out on 105 patients who admitted to Endocrinology Department with the complaint of hirsutism. INTERVENTION: All the patients were evaluated with low dose dexamethasone suppression test (LDDST) for CS. MAIN OUTCOME MEASURE: Response to LDDST in patients presenting with hirsutism RESULTS: All the patients had suppressed cortisol levels following low dose dexamethasone administration excluding CS. The etiology of hirsutism were polycystic ovary syndrome in 79%, idiopathic hirsutism in 13%, idiopathic hyperandrogenemia in 6% and non-classical congenital hyperplasia in 2% of the patients. CONCLUSION: Routine screening for CS in patients with a referral diagnosis of hirsutism is not required. For the time being, diagnostic tests for CS in hirsute patients should be limited to patients who have accompanying clinical stigmata of hypercortisolism.

Concepts: Obesity, Glucocorticoid, Cortisol, Spironolactone, Polycystic ovary syndrome, Cushing's syndrome, Hirsutism, Dexamethasone suppression test

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Cushing’s syndrome results from chronic inappropriate exposure to excessive glucocorticoid concentrations. Low-dose dexamethasone suppression, late-night salivary cortisol, and 24-h urinary free cortisol are regarded as screening tests of first choice. Consequently, measurement of circulating cortisol (e. g., in serum, saliva, and urine) is mandatory in the diagnostic workup of suspected patients. The particular analytical procedure needs to be chosen carefully. Antibody-based immunoassays offer several potential advantages: they require small volumes and are widely available, relatively cheap, and easy to handle. Modern (ideally automated) systems also have a rapid turnaround time on a large number of samples and demonstrate high analytical accuracy. However, there are some important pitfalls. Inadequate standardization and poor interlaboratory performance remain problematic and precise reference ranges are lacking for some of the newer assays. Immunoassays are also susceptible to error due to cross-reactivity with cortisol metabolites or exogenous glucocorticoids. In contrast, steroid analysis by modern chromatographic and mass spectrometric techniques is largely independent from such interference and is therefore regarded as diagnostic gold standard. To date, however, these procedures are costly, time-consuming, and at least at present restricted to a limited number of specialized centers. This review puts special emphasis on the potential advantages of salivary cortisol analysis by immunoassays. It has been shown in numerous studies that such an approach allows excellent identification of hypercortisolemic states. In this context, use of automated systems may allow for broader use of this diagnostic tool.

Concepts: Osteoporosis, Hypertension, Greek loanwords, Corticosteroid, Glucocorticoid, Cortisol, Cushing's syndrome, Dexamethasone suppression test

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The diagnostic accuracy of dehydroepiandrosterone sulfate (DHEAS) to predict subclinical Cushing’s syndrome (sCS) has been a matter of debate. The primary objective of this study was to assess the diagnostic power of DHEAS in predicting sCS. This retrospective study was conducted in a tertiary referral center and based on subjects referred between 2004 and 2014. Data of 249 subjects with adrenal incidentalomas were evaluated. We also reviewed 604 DHEAS measurements from adults, which were performed during the same period in our laboratory (LB group). Adrenocortical function, tumor size, and clinical characteristics were assessed. We diagnosed sCS in 15.2 % of the participants in the presence of ≥2 of the following; 1 mg dexamethasone suppression test >3.0 μg/dl, urinary free cortisol >70 μg/24 h, and corticotrophin (ACTH) <10 pg/ml. DHEAS levels were significantly reduced in patients with sCS (n = 38) compared to sCS (-) (n = 141) and LB groups (n = 604) (27.95, 65.90, and 66.80 µg/dl, respectively, p < 0.001) while age was comparable. The ROC curve analysis showed that the cut-off of the DHEAS with the best diagnostic accuracy for detecting sCS was 40.0 μg/dl (SN, 68 %; SP, 75; PPV, 43 %; NPV, 90 %, AUC: 0.788, p < 0.001). Logistic regression assessed the impact of age, BMI, low DHEAS (<40 μg/dl), bilateral tumors, and tumor size on the likelihood of having sCS. The strongest predictor was low DHEAS, recording an OR of 9.41. DHEAS levels are inversely associated with the extent of cortisol excess. In subjects with intermediate laboratory findings, detection of low DHEAS could be advantageous for distinguishing sCS.

Concepts: Prediction, Futurology, Corticosteroid, Glucocorticoid, Cortisol, Cushing's syndrome, Adrenocorticotropic hormone, Dexamethasone suppression test

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Objective: To describe that Topiramate may well be a cause of false positive in Overnight 1 mg dexamethasone suppression test (DST) for hypercortisolism screening.Methods: We present a case in which topiramate induced dexamethasone metabolism showing a false positive in DST.Results: A 44 year-old woman, with an incidentally found adenoma in the right adrenal gland, underwent a DST for hypercortisolism screening. The patient was taking topiramate prescribed by a psychiatrist for an affective disorder and insufficient suppression of cortisol (11.9 mcg/dl) was observed. Free cortisol in 24-hour urine was normal and insufficient suppression was established in a second determination (9.3 mcg/dl). Finally, her psychiatrist switched her treatment from topiramate to bupropion and measures were repeated. When she was not taking topiramate correct suppression with 1 mg of dexamethasone was obtained (1.7 mcg/dl) and free cortisol in 24 hour urine was again normal, thereby excluding the presence of hypercortisolism. On reviewing the literature, topiramate was not found to have been previously described as a cause of a false positive in DST, but it was proposed as a cause of hypoadrenalism in a patient taking oral corticosteroid replacement because its capacity to induce dexamethasone metabolism.Conclusion: Topiramate treatment may well be a cause of false positive in dexamethasone suppression tests and its presence should be taken into consideration when performing DST.

Concepts: Corticosteroid, Cortisol, Cushing's syndrome, Adrenal cortex, Dexamethasone suppression test, Adrenal gland, Dexamethasone, Adrenal insufficiency

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Adrenal incidentalomas (AIs) are present in 4% of adults. As many as 30% may secrete cortisol autonomously in the absence of specific signs of overt hypercortisolism, in a phenomenon called subclinical hypercortisolism (SH). Diagnosis of SH is established by serum cortisol resistance to dexamethasone suppression.

Concepts: Cholesterol, Medical terms, Cortisol, Chromatography, Cushing's syndrome, Dexamethasone suppression test, Adrenal gland, In the Absence of Truth

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A 62-year-old woman presented with an 11-month history of worsening nasal symptoms of rhinorrhoea, anosmia, nasal congestion and intermittent epistaxis. MRI revealed a large mass in the upper nasal vault. Biopsy of the mass revealed an olfactory neuroblastoma. While waiting resection, she acutely developed severe proximal muscle weakness, lethargy and lower extremity oedema. Blood glucose was elevated, and hypokalaemic metabolic alkalosis was noted. Elevated serum cortisol level of 95.7 µg/dL (8.7-22.4 µg/dL) and markedly elevated 24-hour urinary cortisol level of 6962.3 µg/24 hours (4.0-50.0 µg/24 hours) with concurrent adrenocorticotropic hormone (ACTH) level of 171 pg/mL (6-58 pg/mL) were suggestive of an ACTH-dependent source of hypercortisolism. A subsequent positive high-dose dexamethasone suppression test was consistent with ectopic ACTH production. She underwent near-total resection of the right nasal mass followed by radiotherapy, resulting in complete resolution of signs and symptoms of cortisol excess.

Concepts: Cancer, Metabolism, Symptoms, Cortisol, Cushing's syndrome, Adrenocorticotropic hormone, Adrenal cortex, Dexamethasone suppression test

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A 10-y-old cranially implanted rhesus macaque (Macaca mulatta) involved in visual research was presented for dull mentation and weight loss. Physical examination revealed alopecia and poor body conditioning, and bloodwork revealed marked hypercortisolemia (23 μg/dL). Differential diagnoses for hypercortisolemia, weight loss, and alopecia included Cushing and pseudo-Cushing syndromes. To further evaluate hypercortisolemia, we compared the urine cortisol:creatinine ratio (UCCR) at baseline and after low-dose dexamethasone suppression (LDDS) testing in the presenting animal and healthy naïve and implanted working monkeys. At baseline, UCCR was 10 times higher in the presenting macaque (118.1 ± 7.1) than in naïve animals (12.5 ± 12.8) and 3 times higher than in healthy implanted working macaques (44.4 ± 6.9); however, levels were suppressed similarly by dexamethasone in both the presenting animal and healthy controls. In addition, healthy implanted working macaques had significantly higher baseline UCCR levels than naïve controls, suggesting chronic stress in working animals. Abdominal ultrasonography and radiographs of the presenting animal revealed marked bilateral adrenal mineralization but no overt adrenal tumor or hyperplasia. Overall, these results excluded endogenous Cushing syndrome and prompted us to evaluate different causes of pseudo-Cushing syndrome, including depression. Using videorecordings to evaluate behavior, we used published criteria for macaque models of depression models, including huddling, to make a presumptive diagnosis of depression. The macaque was treated with fluoxetine (2 mg/kg PO daily), provided increased environmental enrichment, and followed over time by regular UCCR assessment and videorecordings. The animal improved clinically and behaviorally, and UCCR returned to levels observed in working implanted macaques (44.4) after 8 wk of treatment. This case highlights the potential effect of research-related work on stress and pathologic behaviors in macaques and demonstrates the utility of UCCR and LDDS for screening behavioral and hypothalamic-pituitary-adrenal abnormalities in these animals.

Concepts: Cortisol, Macaque, Primate, Rhesus Macaque, Behavior, Human behavior, Dexamethasone suppression test, Cercopithecine monkeys

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To evaluate the cut-off value of the ratio of 24 h urinary free cortisol (24 h UFC) levels post-dexamethasone to prior-dexamethasone in dexamethasone suppression test (DST) during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome.

Concepts: Corticosteroid, Glucocorticoid, Cortisol, Ratio, Cushing's syndrome, Adrenocorticotropic hormone, Dexamethasone suppression test, Zona fasciculata

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Aldosterone-producing adenoma (APA) is sometimes accompanied with subclinical hypercortisolism. We investigated the ability of cortisol production in APA, both clinically and pathologically. A retrospective cohort study was conducted at Yokohama Rosai Hospital from 2009 to 2016. Thirty patients with APA and serum cortisol levels during the 1 mg dexamethasone suppression test (F-DST)<3.0 μg/dl were included. We evaluated the 1) difference between pre-adrenalectomy F-DST (pre-F-DST) and post-adrenalectomy F-DST (ΔF-DST), 2) correlation between ∆F-DST and pre-F-DST, tumour size determined by CT, and type of adrenalectomy (total or partial), and 3) relationship between the ratio of F-DST divided by tumour size (ΔF-DST/pre-F-DST/mm) and immunoreactivity of CYP17A1, CYP11B1, and CYP11B2. The median [interquartile range] age was 48 [38-58] years. We found a significant decrease in F-DST after adrenalectomy [before: 1.4 (1.1-1.8); after: 0.9 (0.6-1.2); p<0.001]. Additionally, a significant correlation was found for ΔF-DST and both pre-F-DST (Spearman, ρ=-0.68, p<0.001) and tumour size (ρ=-0.51, p 0.005). No significant difference was found in ΔF-DST between total and partial adrenalectomy. CYP17A1 and CYP11B1 were positive in 21 (100%) and 17 (81%) adenomas, respectively. CYP17A1 immunoreactivity in the tumour was significantly related with ΔF-DST/pre-F-DST/mm (p 0.049). F-DST significantly decreased after adrenalectomy, and most of the adenomas were immunohistochemically positive for CYP17A1 and CYP11B1 as well as CYP11B2. We should consider the possibility of autonomous cortisol production as well as hyperaldosteronism in the evaluation and treatment of APA patients.

Concepts: Cohort study, Oncology, Anatomical pathology, Cortisol, Ratio, Cushing's syndrome, Dexamethasone suppression test, Dexamethasone

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In this study, we compared the 2 mg dexamethasone suppression test (DST) with the gold-standard 1 mg DST in obese patients in order to reduce the false-positive rate for Cushing’s syndrome (CS). The primary endpoint was the comparison of serum cortisol levels after 1 mg versus 2 mg DST in patients with a BMI >30 kg/m(2) and at least one additional feature of the metabolic syndrome. Secondary endpoints were comparison of salivary cortisol and ACTH levels, respectively. Fifty-four obese patients were included. Median serum cortisol levels after 1 mg DST and 2 mg DST were similar [28 nmol/l (20; 36) vs. 28 nmol/l (20; 38), p=0.53]. Salivary cortisol was 8.2 nmol/l (4.7; 11.7) after the 1 mg DST vs. 6.7 nmol/l (4.2; 9.5) after the 2 mg test, p=0.09. ACTH levels were higher after the 1 mg DST compared to the 2 mg DST [10.0 pg/ml (7.6; 10.7) vs. 5.0 pg/ml (5.0; 5.1), p<0.0001]. The false positive rate after the 1 mg DST was 14.8% (n=8) and was reduced to 11.1% (n=6) after the 2 mg DST. All non-suppressors (n=8) had type 2 diabetes and most of them took a medication interacting with cytochrome P450 3A4 (CYP3A4). In individuals with obesity, the 2 mg DST was not superior to the 1 mg DST in regard to serum cortisol levels. However, in some patients, particularly with poorly controlled diabetes or medication interacting with CYP3A4 and without adequate suppression after the 1 mg DST, the 2 mg DST might prove helpful to reduce the false-positive rate for CS. ClinicalTrials.gov Number: NCT02227420.

Concepts: Hypertension, Diabetes mellitus, Obesity, Cortisol, Cytochrome P450, Cushing's syndrome, Dexamethasone suppression test, Dexamethasone