The value of corticotropin-releasing hormone (CRH) test for differential diagnosis of Cushing’s syndrome

Introduction: Diagnosis and differential diagnosis of Cushing?s syndrome (CS) remain considerable challenge in endocrinology. For more than 20 years, CRH has been widely used as differential diagnostic test. Following the CRH administration, the majority of patients with ACTH secreting pituitary adenoma show a significant rise of plasma cortisol and ACTH, whereas those with ectopic ACTH secretion characteristically do not. Objective The aim of our study was to assess the value of CRF test for differential diagnosis of CS using the ROC (receiver operating characteristic) curve method. Method A total of 30 patients with CS verified by pathological examination and postoperative testing were evaluated. CRH test was performed within diagnostic procedures. ACTH secreting pituitary adenoma was found in 18, ectopic ACTH secretion in 3 and cortisol secreting adrenal adenoma in 9 of all patients with CS. Cortisol and ACTH were determined -15, 0, 15, 30, 45, 60, 90 and 120 min. after i.v. administration of 100?g of ovine CRH. Cortisol and ACTH were determined by commercial RIA. Statistical data processing was done by ROC curve analysis. Due to small number, the patients with ectopic ACTH secretion were excluded from test evaluation by ROC curve method. Results In evaluated subgroups, basal cortisol was (1147.3?464.3 vs. 1589.8?296.3 vs. 839.2?405.6 nmol/L); maximal stimulated cortisol (1680.3?735.5 vs. 1749.0?386.6 vs. 906.1?335.0 nmol/L); and maximal increase as a percent of basal cortisol (49.1?36.9 vs. 9.0?7.6 vs. 16.7?37.3 %). Consequently, basal ACTH was (100.9 ?85.0 vs. 138.0?123.7 vs. 4.8?4.3 pg/mL) and maximal stimulated ACTH (203.8 ?160.1 vs. 288.0?189.5 vs. 7.4?9.2 pg/mL). For cortisol, determination area under ROC curve was 0.815?0.083 (CI 95% 0.652-0.978). For cortisol increase cut-off level of 20%, test sensitivity was 83%, with specificity of 78%. For ACTH, determination area under ROC curve was 0.637?0.142 (CI 95% 0.359-0.916). For ACTH increase cut-off level of 30%, test sensitivity was 70%, with specificity of 57%. Conclusion Determination of cortisol and ACTH levels in CRH test remains reliable tool in differential diagnosis of Cushing?s syndrome.

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The Desmopressin and Combined CRH-Desmopressin Tests in the Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome: Constraints Imposed by the Expression of V2 Vasopressin Receptors in Tumors with Ectopic ACTH Secretion

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.87.4.8358 ◽

2002 ◽

Vol 87 (4) ◽

pp. 1646-1653

Author(s):

S. Tsagarakis ◽

C. Tsigos ◽

V. Vasiliou ◽

P. Tsiotra ◽

J. Kaskarelis ◽

...

Keyword(s):

Differential Diagnosis ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Vasopressin Receptors ◽

V2 Vasopressin Receptors

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SUN-938 Rare Case of Ectopic Cushing Syndrome Caused by ACTH Secreting Thymic Neuroendocrine Tumor in a Patient with Multiple Endocrine Neoplasia Type 1

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1068 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Yamuna Gorantla ◽

Jorge Soria Moncada ◽

Juan Sarmiento ◽

Ambika Amblee ◽

Malini Ganesh

Keyword(s):

Neuroendocrine Tumor ◽

Poor Prognosis ◽

Rare Case ◽

Cushing Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Multiple Tumors ◽

Men 1 ◽

Acth Secreting

Abstract Introduction Cushing syndrome (CS) represents an uncommon manifestation of MEN1 and can be caused by both ACTH dependent or independent etiologies. Among them, ectopic ACTH secretion from a Thymic neuroendocrine tumor (TNET) in MEN1 is rare, with very few cases reported so far in literature. We report a case of Ectopic Cushing syndrome (ECS) in a MEN1 patient (pt) with multiple tumors, secondary to ACTH-secreting TNET. Case description: A 44 year old male presented to our institution for nausea, vomiting, dizziness. He had initial workup which revealed multiple tumors (papillary thyroid cancer, thymic mass, parathyroid adenomas, bilateral adrenal nodules, macroprolactinoma, peripancreatic nodules). Given concern for MEN 1, genetic testing was performed which was confirmative. Hormonal workup at this time for adrenal nodules was negative including low dose dexamethasone suppression test(DST). The immobile thymic mass was found to be poorly differentiated NET on biopsy with Ki-67 >50% with vascular invasion and adhesions to lung/chest wall on VATS, not amenable to surgery. The pt declined chemotherapy and radiotherapy due to poor social support. Six months later, he presented with complaints of shortness of breath, proximal muscle weakness, anasarca. Evaluation revealed AM cortisol >60 ug/dL(range 6.7-22), high-dose DST Cortisol >60 ug/dL, 24hr urine free cortisol: 8511mcg (range 4-50) and ACTH level: 278pg/mL(range 6-50) confirming ACTH-dependent CS. Special stains from the previous TNET biopsy demonstrated positive staining for ACTH confirming ectopic ACTH secretion. Ketoconazole and chemotherapy with Etoposide and Carboplatin was started, however he clinically deteriorated and expired a few weeks after diagnosed of ECS. Discussion: TNET in MEN 1 is rare, with a prevalence of 3-8%. TNET are unusual neoplasms that account for 2% to 7% of all mediastinal tumors. TNET in MEN1 rarely secrete functional hormones with very few reported Ectopic ACTH secretion. MEN1 associated ECS from TNET is an aggressive disease with local invasion of adjacent mediastinal structures or metastasis being common, resulting in poor prognosis as demonstrated in few case reports including our case. Radical surgery of involved adjacent structures and adjuvant local RT can provide local disease control. Conclusion: Our pt is a rare case of ECS from TNET in MEN1 with poor prognosis. A special feature of this case is that the patient had initial negative evaluation for hypercortisolemia, however 6 months later he presented with signs and symptoms of severe hypercortisolism, with evaluation confirming transformation into ACTH producing TNET. This conversion is very rarely found in literature and adds to the unique presentation of the case.

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The Desmopressin and Combined CRH-Desmopressin Tests in the Differential Diagnosis of ACTH-Dependent Cushing's Syndrome: Constraints Imposed by the Expression of V2 Vasopressin Receptors in Tumors with Ectopic ACTH Secretion

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.87.4.1646 ◽

2002 ◽

Vol 87 (4) ◽

pp. 1646-1653 ◽

Cited By ~ 12

Author(s):

S. Tsagarakis

Keyword(s):

Differential Diagnosis ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Vasopressin Receptors ◽

V2 Vasopressin Receptors

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MANAGEMENT OF ENDOCRINE DISEASE: Differential diagnosis, investigation and therapy of bilateral adrenal incidentalomas

Acta Endocrinologica ◽

10.1530/eje-18-0296 ◽

2018 ◽

Vol 179 (2) ◽

pp. R57-R67 ◽

Cited By ~ 17

Author(s):

Isabelle Bourdeau ◽

Nada El Ghorayeb ◽

Nadia Gagnon ◽

André Lacroix

Keyword(s):

Differential Diagnosis ◽

Hormone Secretion ◽

Adrenal Incidentalomas ◽

Adrenal Hyperplasia ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Endocrine Disease ◽

Bilateral Adrenal Hyperplasia ◽

Hormonal Evaluation

The investigation and management of unilateral adrenal incidentalomas have been extensively considered in the last decades. While bilateral adrenal incidentalomas represent about 15% of adrenal incidentalomas (AIs), they have been less frequently discussed. The differential diagnosis of bilateral incidentalomas includes metastasis, primary bilateral macronodular adrenal hyperplasia and bilateral cortical adenomas. Less frequent etiologies are bilateral pheochromocytomas, congenital adrenal hyperplasia (CAH), Cushing’s disease or ectopic ACTH secretion with secondary bilateral adrenal hyperplasia, primary malignancies, myelolipomas, infections or hemorrhage. The investigation of bilateral incidentalomas includes the same hormonal evaluation to exclude excess hormone secretion as recommended in unilateral AI, but diagnosis of CAH and adrenal insufficiency should also be excluded. This review is focused on the differential diagnosis, investigation and treatment of bilateral AIs.

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MON-178 Cyclical Cushing’s Syndrome in 12 Patients with Ectopic ACTH Secretion

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1277 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Anna Zenno ◽

Raven McGlotten ◽

Atil Kargi ◽

Lynnette Nieman

Keyword(s):

Medical Treatment ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Inferior Petrosal Sinus ◽

Acth Secretion ◽

Diagnostic Challenge ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Inferior Petrosal Sinus Sampling ◽

Acth Secreting

Abstract Background: Cyclical Cushing’s syndrome (CCS) is characterized by alternating periods of endogenous hypercortisolism and eucortisolism. A literature survey of 60 adult patients with CCS found 15 to have ectopic ACTH secretion (EAS) (1). The duration and frequency of hypercortisolemia are unpredictable, creating a diagnostic challenge. Objective: Describe biochemical and clinical characteristics of patients with CCS due to occult or histologically proven ectopic ACTH-secreting neuroendocrine tumor (NET). Methods: We conducted a retrospective medical record review of 12 adults with EAS admitted to our institution. Inclusion required 1) evidence of ectopic ACTH tumor from biochemical testing (CRH stimulation, 8 mg dexamethasone suppression [DST], and/or inferior petrosal sinus sampling [IPSS]) or pathology results and 2) cycles of hypercortisolism (Hi-F) to eucortisolism (Eu-F) off medical treatment. Results: Average age on admission was 61 (46-79) years; 58% were women. All 12 had biochemical evidence of ACTH-dependent Hi-F. IPSS results suggested EAS in 9 patients, 8 of whom had Hi-F for more than two months, and 1 whose cycles occurred every 5 - 7 days. IPSS was consistent with Cushing’s disease (CD) in 2 patients after Hi-F of only 6 -7 weeks and one with Eu-F on admission, estimated duration < 4 weeks. DST suggested EAS in 9 patients, and CD in the one with recent Eu-F. CRH was consistent with EAS in 10 patients, but suggested CD in 2 with marginal increases in ACTH (34.5%, 38%) but not cortisol. 7 patients had ACTH-secreting tumor on pathology (5 pulmonary, 1 pancreas, 1 appendix NET), and 5 had occult presumed EAS. Time from one Hi-F episode to the next ranged from 1 week to 6 years with Hi-F duration of 3 days to 5 years. 24-hour urine free cortisol (UFC) levels were 17 - 301 times the upper reference range (RR) during Hi-F periods. During Eu-F, lowest UFCs were within RR in 9 patients and subnormal in 3. Hypokalemia occurred in 11 patients with Hi-F; increasing values paralleled movement to Eu-F. Conclusion: Patients with possible ectopic ACTH-secretion and CCS may pose a diagnostic challenge: clinical and biochemical evidence of hypercortisolemia may not be present, depending on the timing and/or duration of hypercortisolism. Furthermore, test results may inappropriately suggest Cushing’s disease if performed after less than 8 weeks of hypercortisolism, or with recent eucortisolism. Thus, weekly UFC measurement may facilitate diagnosis of cyclical Cushing’s syndrome and determine appropriate timing of dynamic testing such as inferior petrosal sinus sampling. Potassium may be a useful marker to determine when medical treatment can be tapered or stopped. 1. Meinardi JR, et al. Eur J Endocrinol. 157:245, 2007.

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Cushing's syndrome due to intermittent ectopic ACTH production showing a temporary remission during a pulmonary infection

Acta Endocrinologica ◽

10.1530/eje.0.1450605 ◽

2001 ◽

pp. 605-611 ◽

Cited By ~ 16

Author(s):

A Peri ◽

D Bemporad ◽

G Parenti ◽

P Luciani ◽

M Serio ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Pulmonary Infection ◽

Wide Spectrum ◽

Acute Infection ◽

Unknown Origin ◽

Cushing's Syndrome ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Acth Secreting

OBJECTIVES: In about 15-20% of patients with ACTH-dependent Cushing's syndrome the source of ACTH is outside the pituitary gland. Pulmonary tumours are the most frequent, yet not unique, source of ectopic ACTH. In some instances the localisation of an ACTH-secreting tumour may be problematic. Occult ectopic ACTH secretion indicates the occurrence of ACTH-dependent hypercortisolism with an unknown origin. Another peculiarity of Cushing's syndrome may reside in the episodic cortisol hypersecretion, which can determine a pattern characterised by hypercortisolism together with periods of remission (cyclic Cushing's syndrome). We describe a very challenging case of Cushing's syndrome due to ectopic ACTH hypersecretion, showing virtually all of the most unusual features of the disease. DESIGN: A 55-year-old woman affected by Cushing's syndrome, presenting with biochemical features of ectopic ACTH secretion, has been followed for 7 years. METHODS: Thorough basal and dynamic hormonal assessment through the past 7 years is reported. In addition, the results of extensive imaging studies are presented. RESULTS: The source of ACTH secretion has not been identified so far, and hypercortisolism has been controlled by octreotide treatment. In addition, the patient showed a cyclic pattern of hypercortisolism with a long-term remission period. A unique feature of this case is represented by the fact that we observed a temporary, yet dramatic, short-lasting remission of ACTH and cortisol hypersecretion during a pulmonary infection, which occurred while the patient was hospitalised for a periodic hormonal assessment. CONCLUSIONS: This case well represents the wide spectrum of clinical variability of Cushing's syndrome. Most interestingly, to our knowledge, this is the first report of a case of Cushing's syndrome showing a remission during an acute infection.

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