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Purpose The differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome remains a challenge in clinical practice. The present study was aimed at assessing the diagnostic performance of pituitary dynamic contrast-enhanced magnetic resonance imaging (dMRI), high-dose dexamethasone suppression test (HDDST), and a combination of both tests for patients with ACTH-dependent Cushing's syndrome. Methods A total of 119 consecutive patients with ACTH-dependent Cushing's syndrome confirmed surgically were enrolled: 101 with proven Cushing's disease and 18 with proven ectopic ACTH syndrome. All patients underwent pituitary dMRI and HDDST. The sensitivity and specificity of pituitary dMRI, HDDST, and a combination of both tests were determined. Results The sensitivity and specificity of pituitary dMRI for diagnosing Cushing's disease were 80.2 and 83.3%, respectively, with a positive predictive value of 96.4%. The sensitivity and specificity of HDDST were 70.3 and 77.8%, respectively, with positive predictive value of 94.7%. A combination of both tests showed that the combined criteria of more than 50% suppression of serum cortisol on HDDST and a positive pituitary dMRI finding yielded a high specificity of 94.4 and sensitivity of 59.4%. The combined criteria of more than 68% suppression on HDDST and/or a positive pituitary dMRI finding yielded a sensitivity of 86.1% and specificity of 83.3%. Conclusions Pituitary dMRI was superior to HDDST in the differential diagnosis of ACTH-dependent Cushing's syndrome. HDDST is recommended in combination with pituitary dMRI to establish a diagnosis process because of the significantly increased specificity with the combination.

Aims: To determine whether the use of an octreotide suppression test will reliably distinguish pituitary from ectopic ACTH overproduction. Somatostatin receptors are expressed in NETs, but are downgraded in the pituitary as the result of hypercortisolaemia. Octreotide should therefore lower ACTH and cortisol levels in patients with NETs but not in patients with Cushing’s disease and pituitary tumors. Methodology: A cross sectional study was performed in 13 patents with ACTH dependent Cushing’s (8 women, 5 men) with ages ranging between 21 to 40 years were studied. Serum cortisol concentrations were measured at 0800 hrs before and during the administration of. Octreotide at a dosage of 100 mcg subcutaneously every 8 hours for 72 hours. Results: The serum cortisol concentrations returned to normal in 4 patients who were later documented to have ectopic disease, two with typical bronchial carcinoids and two with pancreatic NETs and metastatic disease. The other 9 patients had no suppression in serum cortisol concentrations and were documented later to have pituitary tumours. Conclusion: These results indicate that a short trial of octreotide will identify patients with ectopic disease as evidenced by a fall in serum cortisol levels whereas in those with Cushing’s disease and pituitary tumours serum cortisol levels remains unchanged. Recommendation: We recommend all patients with ACTH dependent Cushing’s syndrome have an octreotide suppression test, even if the MRI shows an adenoma, so as to exclude the possibility of a pituitary incidentaloma in a patient with ectopic disease, or false localization from IPSS to the pituitary gland due to ectopic CRH secretion.

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.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.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.

Ectopic ACTH syndrome (EAS) accounts for 10–20% of endogenous Cushing’s syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing’s syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing’s syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.

Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD).Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome.Among CD patients, negative MRI/lesion 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78).CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Objective To analyze the clinical presentations of patients with endogenous Cushing’s syndrome (CS) affected by Coronavirus disease-19 (COVID-19). Materials and methods Patients who were referred to our clinic with active CS from 31st March to 15th May 2020 were screened for COVID-19 using real-time reverse transcriptase–polymerase chain reaction (RT-PCR). Late-night serum cortisol (64–327 nmol/L), late-night salivary cortisol (LNSC) (0.5–9.4 nmol/L), or 24-h urinary free cortisol (24 hUFC) (100–379 nmol/24 h) were measured by electrochemiluminescence immunoassay. Results Among 22 patients with active CS we found three cases affected by COVID-19. Nonspecific inflammation markers were within the reference range or slightly elevated in these patients. A 71-year-old woman with newly diagnosed CS (late-night serum cortisol >1750 nmol/L, LNSC 908.6 nmol/L) developed dyspnea as an only symptom and died from bilateral polysegmantal hemorrhagic pneumonia 7 days later. A 38-year-old woman with a 5-year medical history of active Cushing’s disease (CD) (late-night serum cortisol 581.3 nmol/L, 24 hUFC 959.7 nmol/24-h) suffered from dyspnea, cough, fever (39.3 °C) and chest pain. Oxygen therapy, antibiotics and symptomatic treatments lead to full recovery 24 days later. A 66-year-old woman with a 4-year medical history of mild CD (late-night serum cortisol 603.4 nmol/L, LNSC 10.03 nmol/L) tested positive for COVID-19 in routine screening and remained asymptomatic. Conclusions The outcome of COVID-19 in patients with CS depends on the severity of hypercortisolism. Thus, severe hypercortisolism is a warning sign that CS affected by COVID-19 could require emergency care despite a lack of clinical presentations and low inflammation biomarkers.

Background: Bilateral inferior petrosal sinus sampling (BIPSS) has been the gold standard in differentiating a pituitary vs. an ectopic source of ACTH in Cushing’s syndrome however, it has many limitations. The ON-HDDST being simple to perform and the tests of choice in resource poor setting. The primary aim of our study was to consolidate the present knowledge regarding the diagnostic utility of ON-HDDST in localizing the source of ACTH. Method: We retrospectively studied 88 patients with ACTH dependent Cushing syndrome who underwent ONHDDST. Patient were considered as Cushing disease (CD) if either of the 3 criteria were met a) histopathological confirmed b) a central to peripheral gradient >2 was seen in BIPSS or c) pituitary adenoma ≥ 6mm seen in MRI of pituitary. Patient were considered as ectopic ACTH syndrome if the tumor was localized at any peripheral location by imaging or histopathological confirmed after surgery or if BIPSS shown a central to peripheral gradient of Result: Out of total 88 ACTH dependent Cushing syndrome patients, 68 (77.3%) were proven CD and 20 (22.7%) were ectopic. There was no difference in basal serum cortisol however, S. Cortisol after ONHDDST was significantly different between the two with a median of 547.7 nmol/l (341-770) in ectopic vs 273.5 nmol/l (142-689) in CD (p=0.02). A positive response to ONHDDST (≥50% suppression) was seen in about 44 (65%) patients with CD and 5 (25%) patients with ectopic disease (p = 0.002). Among CD patient, 35 (76.1%) of those with microadenoma, 7 (43.8%) amongst macroadenoma and 2 (33%) patient with no visible tumor on MRI shown positive response to ONHDDST. In ectopic group, cortisol suppressibility was seen in 3 (50%) patient with occult tumor but only in 2(14.3%) patient with. ROC curve plotted for percentage suppression of cortisol after ONHDDST shown as AUC equal to 0.68 (p = 0.01). The best test parameters with sensitivity (65%), specificity (85%) and Accuracy (69%) were seen at 50% cutoff level as were the likelihood ratio for positive test (4.3), AUC (0.75), PPV (93.6%), NPV (41.4%). Conclusion: Our study has shown that ONHDDST has poor diagnostic value in differentiating between CD and ectopic ACTH syndrome whatever be the cutoff level of the cortisol suppression. However, this can still be utilized in setups where no alternative is available. For etiologic confirmation, another test with better sensitivity and specificity is preferable.

Background: Sex differences in clinical picture of ACTH-dependent Cushing’s syndrome are controversial, except for the known higher prevalence in females. We compared a broad range of potential differences to enable a more accurate understanding of the clinical picture of sex-specific ACTH-dependent Cushing’s syndrome. Methods: Cohort study including consecutive patients with ACTH-dependent Cushing’s syndrome from Leiden and Berlin diagnosed between 2000-2016. We compared clinical presentation, biochemical parameters, diagnostic tests, surgical outcome, and comorbidities between men and women. Results: We included 130 patients: 37 males and 93 females. With similar cortisol concentrations, ACTH concentrations were higher in males than females at time of diagnosis (median: 116 ng/L versus 57 ng/L). The prevalence of osteoporosis was higher in males than in females (48.6% versus 25.0%), persisting after surgery, with more vertebral fractures (16.2% versus 5.4%) before surgery. Males showed more anemia (75.9% versus 36.8%) after surgery. There were no differences in etiology, pituitary tumor size, diagnostic and therapeutic strategy, or surgical outcome between sexes. Conclusions: Based on this study, males and females with ACTH-dependent Cushing’s syndrome present different clinical patterns. However, these differences do not justify different diagnostic strategies or treatment based on sex, considering the similar surgical outcome. Clinicians should be alert to diagnose accompanying osteoporosis (with fractures) in male patients with ACTH-dependent Cushing’s syndrome.

A 77-year-old female with rheumatoid arthritis on etanercept, depression on venlafaxine, and treated hypothyroidism presented with easy bruising and muscle weakness. She denied any steroid use. She had normal BP and BMI, but appeared mildly Cushingoid with round facies, and increased dorsocervical and supraclavicular fat. Laboratory evaluation showed: ACTH 70.8 pg/mL (< 63.3), cortisol 24.3 ug/dL, 24 h urine free cortisol 223 ug (< 50), salivary cortisol 0.428 ug/dL, DHEA-S 165.7 ug/dL (< 142.8), LH 0.1 mIU/mL, FSH 2.7 mIU/mL, and hgbA1C 6.1 % (< 5.6 %). All other hormonal testing was normal. MRI of the pituitary showed a 4 x 2 x 3 mm hypoenhancing defect of the anterior pituitary. CT of the chest and abdomen showed a 1.1 cm left adrenal nodule, and a 1 cm non-specific right middle lobe lung nodule. Inferior petrosal sinus sampling (IPSS) with CRH did not show a central ACTH step-up. PET/CT with DOTATATE showed mildly increased tracer uptake in the right middle lobe measuring 1 cm with SUV max 3.7, and a 0.6 cm left apical subpleural nodule with SUV max 1.9. The patient underwent a right middle lobectomy and pathology was positive for typical carcinoid. Post-operatively, she needed hydrocortisone replacement for 9 months. ACTH was 19.7 pg/dL, cortisol 9.5 ug/dL, DHEA-S 31.3 ug/dL, LH 61.8 mIU/mL, and FSH 112.4 mIU/mL. Her Cushingoid features and myopathy resolved. This case highlights several challenges in the diagnosis and source localization in patients with ACTH-dependent Cushing’s Syndrome (CS). In this slim, elderly female, the typical features of CS were subtle. In addition, dynamic biochemical testing with high dose dexamethasone does not reliably distinguish eutopic from ectopic ACTH-dependent CS, as the sensitivity and specificity range from 60–80%. Thus, the diagnosis largely depends on sophisticated imaging and IPSS. The patient had pituitary, adrenal, and lung lesions. The pituitary lesion initially pointed towards a central ACTH source, but IPSS was negative. The prevalence of pituitary incidentalomas is high, at 10.6% based on autopsy data, with an increasing proportion being recognized in the elderly. Adrenal incidentalomas are also often noted in older individuals, but that was clearly not the cause of CS in this patient with a non-suppressed DHEA-S and elevated ACTH. PET/CT with DOTATATE has emerged as a sensitive test for the detection of often small tumors producing ectopic ACTH and was positive in the lung lesion. In spite of newer localization techniques, the source of ectopic ACTH often remains unidentified (12.5% in a large retrospective case-record study). False negatives on PET/CT with DOTATATE imaging may be due to cortisol’s suppressive effect on the somatostatin receptor expression in neuroendocrine tumors. Thus, in cases of ACTH-dependent CS with negative IPSS, ectopic ACTH must remain as a likely source, and be re-explored after medical treatment of the hypercortisolism.

A case of a 50-year-old woman who was referred for the evaluation of possible ACTH-dependent Cushing’s syndrome (CS) is described. The localisation of ACTH-dependent CS remains difficult despite many advances in diagnostic approaches. No single test can accurately determine the location of ACTH excess and therefore a combination of non-invasive imaging, stimulation and suppression tests are advised. The recent advances, current utility and pitfalls of each of these tests are reviewed. If non-invasive tests fail to confidently localise the source of ACTH excess, inferior petrosal sinus sampling (IPSS) should follow. Recent advances improving the diagnostic accuracy of IPSS, such as DDAVP stimulation and simultaneous sampling for prolactin is discussed. Where ectopic ACTH production is suspected, newer nuclear medicine techniques, such as somatostatin receptor imaging that recently became available in South Africa, can be utilised. The role of nuclear medicine imaging in identifying ectopic ACTH production is discussed briefly.Keywords: ACTH, cushing’s disease, pituitary

Diagnosing Cushing's syndrome (CS) can be a challenge, especially in ACTH-dependent CS, when it comes to detecting the origin of ACTH secretion.Retrospective data were collected on 170 patients with ACTH-dependent CS (149 CD, 21 EAS) referring to two endocrinology units, focusing on three non-invasive tests: dexamethasone 8 mg overnight challenge (HDDST); corticotrophin-releasing hormone (CRH) assay and the desmopressin (DDAVP) test.Patients with EAS were slightly older and had higher ACTH, serum and urinary cortisol levels than patients with CD (p 0.01). CD patients had a stronger ACTH and cortisol response after CRH injection (p 0.0001), and a more pronounced reduction in cortisol levels after HDDST (p 0.0001). A threshold percentage ACTH increase after CRH stimulation of 72.4 % was able to identify CD with a sensitivity (SE) of 76 % (95 % CI 68-83) and a specificity (SP) of 100 % (95 % CI 83-100). As for HDDST, a cortisol suppression52.7 % below the basal level suggested a pituitary origin with a SE of 88 % (95 % CI 81-93) and a SP of 90 % (95 % CI 68-99). There were no cases of EAS with positive responses to both these tests. Increases in ACTH and cortisol levels after the DDAVP test were also higher in CD than in EAS (p 0.01), though the SE and SP were lower.Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.

We report the case of a 61 year old woman with a typical clinical picture of ACTH dependent Cushing’s syndrome. Diagnostic tests confirmed ACTH dependent Cushing’s syndrome, which is caused by corticomedullary mixed tumor. ACTH-secreting pheochromocytoma are rarely described in accessible literature, there is no one case report about ACTH-secreting corticomedullary mixed tumor. Due to the rarity of the disease, we believe it appropriate to share our experience and consider all variants of interaction in hypothalamic-pituitary-adrenal axis, which could lead to morphology and clinical changes uncovered in this case.

Актуальність. АКТГ-залежний синдром Кушинга (СК) — тяжке ендокринне захворювання, що характеризується хронічним надлишком кортизолу внаслідок АКТГ-секретуючої аденоми гіпофіза. Метою роботи є оцінка ефективності проведеного хірурічного лікування АКТГ-залежного СК в ранньому і пізньому післяопераційному періоді. Матеріали та методи. Під спостереженням перебувало 234 пацієнти, середній вік чоловіків становив 26,38 ± 3,40 року, жінок — 27,58 ± 3,40 року. Усім хворим виконувався комплекс досліджень, що містив загальноклінічні, біохімічні, гормональні аналізи, а також магнітно-резонансна томографія головного мозку, рентгенографія органів грудної клітки, денситометрія. Результати. Трансназальна аденомектомія гіпофіза (ТАГ) була виконана первинно у 200 пацієнтів, з них повторно — у 34. При цьому ремісія у пацієнтів, які зазнали ТАГ з приводу АКТГ-залежного СК, настала у 42 %, рецидив розвинувся у 5 %, ремісія не досягнута у 46 %. Визначена вірогідність відмінностей між такими параметрами, як число пацієнтів в період ремісії і число рецидивів після ТАГ, рівень вільного кортизолу плазми і глікемії натще у хворих в період ремісії і рецидиву. Вивчений кореляційний зв’язок між рівнем вільного кортизолу плазми в ранньому постопераційному періоді після ТАГ і частотою рецидивів. Висновки. Найбільш вірогідним, інформативним прогностичним маркером рецидиву пухлини є рівень кортизолу плазми в ранньому післяопераційному періоді: чим нижче рівень кортизолу, тим стійкішою спостерігається ремісія. Безпосередні результати хірургічного лікування СК залежать від розмірів пухлини, ступеня тяжкості загального стану пацієнта, наявності нейроендокринних і кістково-метаболічних ускладнень., Актуальность. АКТГ-зависимый синдром Кушинга (СК) — тяжелое эндокринное заболевание, характеризующееся хроническим избытком кортизола из-за АКТГ-секретирующей аденомы гипофиза. Целью работы является оценка эффективности проводимого лечения АКТГ-зависимого СК в раннем и позднем послеоперационном периоде. Материалы и методы. Под наблюдением находилось 234 пациента, средний возраст мужчин составил 26,38 ± 3,40 года, женщин — 27,58 ± 3,40 года. Всем больным выполнялся комплекс исследований, включавший общеклинические, биохимические, гормональные анализы, а также магнитно-резонансная томография головного мозга, рентгенография органов грудной клетки, денситометрия. Результаты. Трансназальная аденомэктомия гипофиза (ТАГ) была выполнена первично у 200 пациентов, из них вторично — у 34. При этом ремиссия у пациентов, подвергнутых ТАГ по поводу АКТГ-зависимого СК, наступила у 42 %, рецидив развился у 5 %, ремиссия не достигнута у 46 %. Определена достоверность различий между такими параметрами, как число пациентов в период ремиссии и число рецидивов после ТАГ, уровень свободного кортизола плазмы и гликемии натощак у больных в период ремиссии и рецидива. Изучена корреляционная связь между уровнем свободного кортизола плазмы в раннем постоперационном периоде после ТАГ и частотой рецидивов. Выводы. Наиболее достоверным, информативным прогностическим маркером рецидива опухоли является уровень кортизола плазмы в раннем постоперационном периоде: чем ниже уровень кортизола, тем более стойкой наблюдается ремиссия. Непосредственные результаты хирургического лечения СК зависят от размеров опухоли, степени тяжести общего состояния пациента, наличия нейроэндокринных и костно-метаболических осложнений., Background. Adrenocorticotropic hormone-dependent Cushing’s syndrome (ACTH-dependent CS) is a form of endogenous CS caused by abnormal production of ACTH, in 80 % of cases — due to ACTH oversecretion by a pituitary adenoma (Cushing’s disease), and in 20 % of cases — as a result of ectopic ACTH secretion by an extrapituitary tumor or, very rarely, due to a tumor secreting both ACTH and corticotropin-releasing hormone. The purpose of our study was to evaluate the efficiency of the treatment for ACTH-dependent CS in the postoperative period. Materials and methods. Under supervision, there were 234 patients, out of them 160 women and 74 men aged 26.38 ± 3.40 years. The set of researches included clinical, biochemical, hormonal studies and also magnetic resonance imaging. Results. Transnasal transsphenoidal adenomectomies were performed initially for 200 patients, out of them for the second time — in 34 persons. The significance of differences was certain between such parameters, as a number of patients in the period of remission and number of relapses after transnasal transsphenoidal adenomectomy, level of free plasma cortisol and glycemia in the period of remission. After analyzing the data on the remissions and relapses, the correlation between free plasma cortisol level in the early postoperative period after transnasal transsphenoidal adenomectomy and the incidence of relapses was selectively studied in patients. Conclusions. The most significant, informing prognostic marker of tumor relapse is the level of plasma cortisol in the early postoperative period.

Objectives To describe the possible pitfalls in correctly interpreting clinical, radiological and biochemical findings in ACTH-dependent Cushing’s syndrome. Methods We describe a case of a pituitary adenoma visualized at MRI not correlated with an ACTH-dependent Cushing’s syndrome. Results Radiological imaging and hormonal testing can be misleading in suspected pituitary ACTH-related Cushing’s syndrome. Conclusion Correct interpretation of the initial clinical presentation can help in the proper diagnosis and treatment of ACTH-dependent Cushing’s syndrome. LEARNING POINTS Occult neoplasia should always be excluded in cases of severe ACTH-dependent Cushing’s syndrome. A positive MRI result can be misleading. Ectopic ACTH-dependent syndrome is generally associated with a peculiar phenotype.