Ectopic ACTH-producing Tumors Research Articles

Processing of high-molecular-weight form adrenocorticotropin in human adrenocorticotropin-secreting tumor cell line (DMS-79) after transfection of prohormone convertase 1/3 gene

Ectopic ACTH-producing tumors preferentially secrete biologically inactive ACTH precursors and ACTH-related fragments. DMS-79 is known to secrete unprocessed high-molecular-weight (HMW) form ACTH. To determine whether prohormone convertase (PC) 1/3 is involved in the abnormal processing of proopiomelanocortin (POMC), we studied whether PC1/3 and 2 genes are expressed in DMS-79, and whether overexpression of PC1/3 gene affects POMC processing pattern. Steady-state mRNA levels of PC1/3 and 2 were determined by real-time RT-PCR. Molecular weights of ACTH-related peptides were determined by chromatographical analyses coupled with ACTH and beta-endorphin (beta-END) radioimmunoassays. PC1/3 gene was transfected into DMS-79 by retrovirus transduction using pMX-IP vector encoding PC1/3 cDNA. The steady-state mRNA levels of PC1/3 and 2 in DMS-79 were lower than those in ACTH-secreting and nonfunctioning pituitary tumors. DMS-79 predominantly secreted HMW form with both ACTH and beta-END immunoreactivities by size-exclusion chromatography. After purification by immunoaffinity chromatography with anti-ACTH antibody, the apparent molecular weight of HMW form ACTH was estimated to be 16 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with silver staining. After retroviral transfection of PC1/3 cDNA into DMS-79 and puromycin selection, PC1/3 stably-expressing cell line (DMS-79T) secreted two immunoreactive ACTH components, a major one coeluting with ACTH(1-39) and a minor one as a HMW form as well as two beta- END immunoreactive components coeluting with beta-lipotropic hormone and beta-END, respectively. Thus, we have established PC1/3 stably-expressing cell line (DMS-79T) capable of proteolytically processing ACTH precursor molecule(s) into mature ACTH and beta-END.

Simultaneous bilateral catheterization of the inferior petrosal sinus in Cushing's syndrome. ACTH determination for the diagnosis and location of the side of a hypophyseal microadenoma before and after administration of corticotropin-releasing hormone

ACTH concentration was measured in simultaneously drawn blood samples from the left and right inferior petrosal sinuses before and after administration of corticotropin-releasing hormone (CRH). Such samples were successfully obtained in 20 of 21 patients with ACTH-dependent Cushing's syndrome on whom it was attempted. In 11 of the 20 patients there was no concentration difference between petrosal sinus and peripheral blood. But 13 of 19 patients had a unilateral central to peripheral concentration gradient greater than 1.4 after CRH administration. In the other six patients no ipsi- to contralateral gradient was demonstrable. Two of these patients had a proven ectopic ACTH-producing tumor; no adenoma was found at operation in three; on patient is awaiting operation. In 10 of 13 patients with unilateral gradient a microadenoma was found on the same side at operation. One patient had a hemi-hypophysectomy on the side of the higher gradient: hypocortisolemia developed in her postoperatively. Two other patients are awaiting operation. The results indicate that simultaneous bilateral catheterization of the inferior petrosal sinus with CRH stimulation is a highly informative examination with few side-effects and will contribute to better diagnosis and treatment of Cushing's syndrome.

Cyclic Cushing’s syndrome: a clinical challenge

Cyclic Cushing's syndrome (CS) is a rare disorder, characterized by repeated episodes of cortisol excess interspersed by periods of normal cortisol secretion. The so-called cycles of hypercortisolism can occur regularly or irregularly with intercyclic phases ranging from days to years. To formally diagnose cyclic CS, three peaks and two troughs of cortisol production should be demonstrated. Our review of 65 reported cases demonstrates that cyclic CS originates in 54% of cases from a pituitary corticotroph adenoma, in 26% from an ectopic ACTH-producing tumour and in about 11% from an adrenal tumour, the remainder being unclassified. The pathophysiology of cyclic CS is largely unknown. The majority of patients with cyclic CS have clinical signs of CS, which can be either fluctuating or permanent. In a minority of patients, clinical signs of CS are absent. The fluctuating clinical picture and discrepant biochemical findings make cyclic CS extremely hard to diagnose. Clinicians should therefore be aware of this clinical entity and actively search for it in all patients with suspected CS but normal biochemistry or vice versa. Frequent measurements of urinary cortisol or salivary cortisol levels are a reliable and convenient screening tool for suspected cyclic CS. Cortisol stimulation or suppression tests may give spurious results owing to spontaneous falls or rises in serum cortisol at the time of testing. When cyclic CS is biochemically confirmed, further imaging and laboratory studies are guided by the presence or absence of ACTH dependency. In cases of suspected ectopic ACTH production, specific biochemical testing for carcinoids or neuroendocrine tumours is required, including measurements of serotonin in platelets and/or urine, chromogranin A and calcitonin.

The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH‐dependent Cushing's syndrome

Bilateral inferior petrosal sinus sampling (BIPSS) with corticotrophin-releasing hormone (CRH) stimulation is currently the gold standard test for the differential diagnosis of ACTH-dependent Cushing's syndrome. Reports on the use of desmopressin in this approach are limited. The aim of this study was to evaluate the use of desmopressin during BIPSS in a cohort of patients with ACTH-dependent Cushing's syndrome. A retrospective case-record study. Fifty-six patients with confirmed ACTH-dependent Cushing's syndrome underwent BIPSS with desmopressin stimulation when presenting negative pituitary tumour imaging. Central to peripheral (CEN:PER) ACTH gradient, lateralization of the ACTH source and surgical tumour confirmation were evaluated. A CEN:PER ACTH gradient was found in 40 patients under basal conditions (CEN:PER >or= 2) and in 47 patients after desmopressin stimulation (CEN:PER >or= 3). Ectopic ACTH-producing tumours (three lung carcinoid tumour, one thymus carcinoid tumour and one thymus hyperplasia) were confirmed in five out of nine patients without the CEN:PER ACTH gradient, and four cases were false negative for Cushing's disease. Lateralization (IPS:IPS >or= 1.4) was observed in 80.8% of patients under basal conditions (38/47) and in 97.8% after desmopressin (46/47), and it was surgically confirmed in 78.7%. There were no false-positive cases. Sensitivity and specificity were 92.1% and 100%, respectively. Desmopressin improves the differential diagnosis of ACTH-dependent Cushing's syndrome by amplifying the CEN:PER and IPS:IPS ACTH gradients, and is therefore a useful ACTH secretagogue in BIPSS.

Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery

BackgroundACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed.Case presentationA 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled 111In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results.ConclusionThis case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical locations may benefit from explorative radioguided surgery using 111In-pentetreotide and a gamma probe.

Usefulness of FDG-PET in detecting an ADH-secreting tumor: a case report

We report a case of a 41-year-old woman who was diagnosed as having the syndrome of inappropriate secretion of ADH (SIADH). There was no evidence of any disorders of the central nervous system, lung diseases, or drugs causing SIADH. Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) was performed and indicated a tumor of the uterine cervix. After resection of the tumor, both serum sodium level and serum osmolarity were normalized concomitantly with a decrease in serum ADH level. This is the first case report suggesting the usefulness of a FDG-PET scan to detect an occult cancer responsible for SIADH. It seems plausible that FDG-PET may be helpful in the diagnosis of other ectopic hormone-producing tumors such as ectopic ACTH-producing tumors that cause Cushing's syndrome.

Papel da terapia medicamentosa na síndrome de Cushing

A terapêutica cirúrgica continua, até o momento, a ser considerada a principal, para a síndrome de Cushing endógena, qualquer que seja a causa. Entretanto em certas circunstâncias, como preparo pré-cirúrgico, ausência de cura após a cirurgia ou impossibilidade cirúrgica, a terapêutica medicamentosa tem papel importante. As drogas que inibem a esteroidogênese, como mitotane, metirapona, cetoconazol e aminoglutetimida são as drogas de escolha qualquer que seja a causa da síndrome de Cushing. Cetoconazol constitui-se em nosso meio na droga de escolha entre os inibidores da síntese de cortisol. É uma medicação que pode ser usada a longo prazo e freqüentemente não ocasiona efeitos colaterais importantes. Os chamados neuromoduladores, como ciproheptadina, bromocriptina e ácido valpróico em nossa experiência tem pouco efeito na doença de Cushing. Somatostatina de ação prolongada como Sandostatin e Sandostatin-LAR podem ter papel importante na terapêutica da síndrome de secreção ectópica de ACTH/CRH. Quimioterapia e radioterapia têm indicações especificas nas diversas causas da síndrome de Cushing.

Pathophysiology and diagnosis of Cushing's syndrome

Prolonged exposure of every tissue in the body to an excess of cortisol produces Cushing's syndrome. Endogenous causes of Cushing's syndrome are ACTH-dependent, including Cushing's disease, ectopic ACTH-producing tumors. CRH-producing tumors, and ACTH-independent Cushing's syndrome, including cortisol-producing adrenal benign or malignant tumors, and rare micronodular adrenal hyperplasia. In Japan the incidence of ACTH-dependent Cushing's syndrome due to endogenous causes is about 60%, in which autonomous pituitary ACTH secretion is responsible for 95%, and the rest are ectopic ACTH-producing tumors. Cortisol-secreting tumors are responsible for about 40% of endogenous causes, in which benign adenoma is 90% and adrenocortical carcinoma is 10%. The first step for the diagnosis of Cushing's syndrome is to demonstrate the presence of hypercortisolism biochemically by determining 24-hour urinary free cortisol excretion and low-dose dexamethasone suppression test. The next step is to identify the precise etiologic causes. To differentiate Cushing's syndrome, the most important procedures are dynamic endocrine tests to check the integrity of hypothalamic-pituitary-adrenal function by high dose dexamethasone suppression test, CRH test arid measurement of steroid hormone profile. Imaging techniques can help to determine the etiology of Cushing's syndrome.

Whole-Body PET with [ 11C]-5-Hydroxytryptophan for Localization of Neuroendocrine Tumors

Purpose: [11C]-5-Hydroxytryptophan (5-HTP) has previously been shown to be an excellent tracer for localization of neuroendocrine tumors, especially hormone-producing midgut carcinoids. To improve the clinical usefulness of 5-HTP PET in a diagnostic setting, we wanted to develop a whole-body scanning approach.Methods: The patients received 200 mg carbidopa orally as premedication to block physiological decarboxylation, thereby improving tumor/background contrast. Two hundred to 800 MBq of 5-HTP was injected in a forearm vein. Ten minutes post-injection emission scanning was performed, covering thorax and abdomen in whole-body mode. In a GE4096 scanner (10 cm FOV), a protocol of up to 6 bed positions with timeframes of 5, 7, 10, 10, 15, and 20 minutes was used. In a Siemens CTI Ecat HR+ scanner (15.5 cm FOV), 4 bed positions with timeframes of 7, 10, 15, and 20 minutes was used. Transmission scans were performed for 2–4 minutes for each bed position and segmented for attenuation correction. Comparison with CT, octreotide scintigraphy, and surgical end points were made.Results: So far 50 patients referred for staging of carcinoid tumors, localization of ectopic ACTH-producing tumors or endocrine pancreatic tumors have been investigated. 5-HTP generally shows more lesions than CT and in some cases more lesions and lesions at an earlier stage than octreotide scintigraphy. Clinical trials have been set up to define the role of 5-HTP whole-body scans in routine clinical use.Conclusions: Whole-body PET with 5-HTP is a promising new approach in diagnostic imaging of neoplasias of neuroendocrine origin, evidently changing treatment planning in selected patient groups. (Clin Pos Imag 1999;2:338) All rights reserved.

Primary Localization of an Ectopic ACTH-Producing Bronchial Carcinoid Tumor by Indium111Pentetreotide Scintigraphy—Authors’ Response

Primary Localization of an Ectopic ACTH-Producing Bronchial Carcinoid Tumor by Indium¹¹¹Pentetreotide Scintigraphy—Authors’ Response

Lack of utility of (111)In-pentetreotide scintigraphy in localizing ectopic ACTH producing tumors: follow-up of 18 patients.

Octreotide scintigraphy has been advocated as the principal imaging modality for localizing ectopic ACTH-secreting tumors in Cushing's syndrome. To assess its usefulness we reviewed the course of 18 consecutive patients with ectopic ACTH-producing tumor. Imaging included (111)In-pentetreotide scintigraphy, computed tomography (CT), and/or magnetic resonance imaging (MRI). Tumor was detected initially in 7/18 patients, and in 3/18 during follow-up. No ACTH-secreting tumor was detected by octreotide scintigraphy when CT/ MRI were negative. Seventeen of forty octreotide scintigrams were abnormal. CT and/or MRI confirmed tumors in 10, but demonstrated nonendocrine lesions in association with 6 false positive octreotide scintigrams. Hepatic venous sampling for ACTH refuted one lesion detected by octreotide and CT scans. Twenty-three of forty octreotide scintigrams were normal. Of these, 8 were false negative, as CT and/or MRI detected tumor; 10 agreed with negative CT and MRI, and 5 correctly refuted false positive CT and/or MRI scans. Repeated CT/ MR, but not octreotide scintigraphy, led to tumor resection in 2 patients. We conclude that octreotide scintigraphy does not offer greater sensitivity than CT/MRI and that false positive scans are common. Although octreotide scintigraphy may be helpful in selected cases, it is not a significant advance over conventional imaging for ectopic ACTH-secreting tumors.

An ACTH-producing small cell lung cancer expresses aberrant glucocorticoid receptor transcripts from a normal gene

ACTH production by non-pituitary tumors is generally not suppressible by exogenous glucocorticoid administration. We had postulated that defects in the glucocorticoid receptor (GR) signaling system might be responsible for this apparent glucocorticoid resistance and had previously demonstrated that DMS-79 cells, derived from an ectopic ACTH-producing tumor, express an abnormal GR mRNA. In this DMS-79 cell GR the sequence normally derived from exons 8 and 9 is replaced by sequence unmatched in the DNA databases. The protein encoded by this mRNA lacks the steroid-binding domain and does not function as a ligand-activated transcription factor. In the present work, we sought to identify the origin of the novel GR mRNA sequence. Southern blot analysis of DMS-79 genomic DNA showed no major structural alteration of the GR gene. Southern blotting of cosmid clones of the normal GR gene revealed that the novel DMS-79 GR mRNA sequence is derived from intron G, between exons 7 and 8. No splice site mutations were found in PCR-amplified DMS-79 DNA fragments surrounding the downstream splice junctions. Further sequencing indicated that the aberrant GR transcript appears to be generated by use of a consensus cleavage/polyadenylation signal found 3650 base pairs into the normal intron G. We conclude that abnormal GR pre-mRNA processing rather than a GR gene mutation confers glucocorticoid resistance on DMS-79 cells.

Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.

The molecular basis of Cushing's disease is not known. One of the most characteristic features of such tumors is their resistance to corticosteroid feedback at the pituitary level. We have hypothesized that abnormalities of the glucocorticoid receptor (GR) gene might play a role in the development of Cushing's disease via an increase in the relative production of the nonligand-binding splice variant of the GR, GR beta, known to exert dominant negative effects over the ligand-binding isoform, GR alpha. Alternatively, a change in overall GR expression, or mutations of some functional domains of the GR gene, might be involved in the pathogenesis of corticotroph tumors. We studied 22 tumors (17 pituitary ACTH-secreting tumors, 2 ectopic ACTH-producing tumors, 2 prolactinomas, and 1 nonfunctioning adenoma) and three normal pituitaries. RT-PCR was performed with primers specific to GR alpha and GR beta complementary DNA, followed by Southern blotting using an internal probe, and the ratio of the two bands quantitated by densitometry. We also assessed the overall expression of GR relative to the message of both the POMC gene and a housekeeping gene. Single-strand conformation polymorphism analysis of the DNA-binding domain and splice junction region of the gene was also performed. GR alpha messenger RNA was expressed at 37.3-fold +/- 5.7 (range, 32 to 46) excess, as compared with the GR beta subform. This pattern was observed both in the tumor samples and in the normal pituitaries used as controls. A majority of the ACTH-secreting tumors (16/19), including the ectopic secretors, showed variable but increased overall GR expression, whereas 3 tumors showed an expression approximately equivalent to the normal controls; however, no correlation was found between these two groups and the response to the high-dose dexamethasone test, nor was there any correlation with tumor histology. No mutations were found in any of the tumors by PCR-single-strand conformation polymorphism analysis. In conclusion, although both pituitary and ectopic ACTH-secreting tumors are at least partially glucocorticoid-resistant, no significant abnormalities in the relative expression of the two main GR subforms were observed in a series of such tumors. Additionally, mutations of regions critical to normal function of the receptor do not seem to be a frequent event in these tumors.

Expression of prohormone convertase, PC2, in adrenocorticotropin-producing thymic carcinoid with elevated plasma corticotropin-releasing hormone.

An autopsy case of ACTH-producing thymic carcinoid with Cushing's syndrome is reported. The patient was a 63-yr-old man with multiple bone metastases from an undetermined primary site. Hyperpigmentation was observed at the terminal stage. The plasma levels of ACTH, cortisol, chromogranin A, and urinary 17-hydroxy-corticosteroids were extremely high, and ectopic ACTH-producing neuroendocrine tumor was diagnosed. In addition, plasma CRH was high. Autopsy revealed that the patient had primary thymic carcinoid with extensive metastases. Remarkable hyperplasia of the adrenal cortexes and Crooke's hyaline degeneration of the pituitary gland were consistent with Cushing's syndrome by ectopic ACTH production. There were multiple CRH-producing cells without degenerative changes in the hypothalamus. The tumor cells were immunoreactive to ACTH, CRH, and the cleavage enzyme PC2. POMC messenger ribonucleic acid and PC2 messenger ribonucleic acid were detected in the tumor cells by an in situ hybridization method. Expression of PC2 was considered to induce hyperpigmentation by producing alpha MSH. Despite hypercortisolism and ectopic production of CRH by the tumor cells, hypothalamic CRH cells were not atrophic. This case is a good example to demonstrate the correlation between CRH and the hypothalamo-pituitary-adrenal axis as well as hyperpigmentation in Cushing's syndrome.

Clinical and analytical evaluation of an immunoradiometric assay for corticotropin

We evaluated a new IRMA developed commercially for the measurement of corticotropin (ACTH) in human plasma. The assay involves purified polyclonal goat capture antibodies specific for ACTH 26-39 and an 125I-labeled monoclonal signal antibody specific for ACTH 1-17. CVs for intraassay and total precision at ACTH concentrations between 9 and 801 ng/L ranged from 2.5% to 4.7% and from 3.3% to 9.3%, respectively, with an assay detection limit of 1.7 ng/L. The reference interval determined for adults with the new method (16-52 ng/L) differed significantly (P < 0.05) from that for an established ACTH IRMA (9-54 ng/L). Method comparison with clinical samples (n = 179) revealed a correlation coefficient of 0.970 and a best-fit equation of y (new IRMA) = (1.011 +/- 0.019)x + (4.17 +/- 3.31) with Sylx = 40.2. Both methods showed equivalent clinical sensitivity in evaluating Cushing disease, adrenal tumors, ectopic ACTH-producing tumors, hypopituitarism, steroid suppression, surgical adrenalectomy, Nelson syndrome, Addison disease, and corticotropin-releasing hormone stimulation. We conclude that the new IRMA is technically simple to perform and provides a specific and sensitive method for evaluating of adrenocortical function.

Ectopic ACTH syndrome.

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.

Technetium-99m methoxyisobutylisonitrile localizes an ectopic ACTH-producing tumour: case report and review of the literature

Extensive investigation including whole-body examinations with computed tomography and magnetic resonance imaging did not detect the suspected ectopic ACTH-producing tumour in a patient with advanced Cushing's syndrome and hypokalemic alkalosis. Gamma camera examination with technetium-99m methoxyisobutylisonitrile (MIBI) depicted the tumour, which was localized in the anterior neck and mediastinum. This was later verified by surgery. 99mTc-MIBI is normally used for myocardial scintigraphy. Its accumulation is unspecific and merely reflects metabolic activity. Despite this, the present case shows that examination with this agent can provide important information with regard to tumour localization in a given situation, thereby serving as a complement to other imaging modalities. The current literature on 99mTc-MIBI for tumour diagnosis is reviewed.

Corticotropin-releasing hormone, proopiomelanocortin, and glucocorticoid receptor gene expression in adrenocorticotropin-producing tumors in vitro.

To differentiate between ectopic ACTH syndrome and Cushing's disease, gene expression of corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), and glucocorticoid receptor was examined in 10 pituitary adenomas (Cushing's disease) and in 10 ectopic ACTH-producing tumors. CRH increased plasma ACTH levels in all patients with Cushing's disease and in five patients with ectopic ACTH syndrome whose tumors contained CRH and CRH mRNA. In five CRH nonresponders, CRH was not detected in tumors that contained no CRH mRNA or that contained only long-size CRH mRNA. Dexamethasone (Dex) decreased plasma ACTH levels in all patients with Cushing's disease and in three patients with ectopic ACTH-producing bronchial carcinoid. These tumors contained glucocorticoid receptor mRNA. CRH increased and Dex decreased ACTH release and POMC mRNA levels in pituitary adenoma and bronchial carcinoid cells. PMA increased POMC mRNA levels only in carcinoid cells. These results reveal characteristics of ectopic ACTH-producing tumors: long-size CRH mRNA and PMA-induced POMC gene expression. In addition, there are two ectopic ACTH syndrome subtypes: tumors containing ACTH with CRH (CRH responder) and tumors without CRH. Dex decreases ACTH release and POMC mRNA levels in some bronchial carcinoids. Therefore, CRH and Dex tests have limited usefulness in differentiating between Cushing's disease and ectopic ACTH syndrome.

Unidentified steroid hormone of Cushing's syndrome and disease

A previously unknown HPLC peak was recently observed in urine samples from patients with Cushing's syndrome and disease. We analysed dansylated derivatives of 17keto steroid glucuronides in urine samples from patients with Cushing's syndrome, Cushing disease and from healthy subjects using high-performance liquid chromatography (HPLC) on reversed-phase Cap Cell PakC8. All urine samples from patients with Cushing's syndrome caused by adrenal adenoma and Cushing's disease showed an unknown large peak at the point between [110HE-G] and [110HA-G] peaks and at a retention time of 25.4 min. The same unknown peak was also observed in urine samples from a patient with asymptomatic cortisol-producing adrenal adenoma and two patients with ectopic ACTH-producing tumor, though the peak height was low for the former and one of the latter but high for the second of the two patients. In contrast, healthy male and female urine only showed a very small peak at the same retention time. Urine samples from a Cushing disease treated with op'DDD and Cushing's syndrome bilaterally adrenalectomized and treating with cortisol showed no such peak. The retention time of this unknown peak is clearly different from that of seven 17keto steroid standard glucuronide conjugates. The structure of this substance may be closely related to [110HE-G] or [110HA-G].

Somatostatin Analogue(SMS 201-995) Decreases Plasma Levels of Corticotropin(ACTH) and Corticotropin-Releasing Hormone in a Patient with Ectopic ACTH-Producing Tumors.

Effects of long-acting somatostain analogue (SMS 201-995) on plasma corticotropin (ACTH) and corticotropin-releasing hormone (CRH) levels were studied in a patient (63-year-old woman) with ectopic ACTH-producing tumors associated with type I multiple endocrine neoplasia (MEN-I). The patient had undergone bilateral adrenalectomy. Plasma CRH, as well as plasma ACTH, beta-endorphin and alpha-MSH, increased. The hormone levels were dramatically decreased by acute administration of SMS 201-995. Moderately higher doses of dexamethasone (0.05 or 0.1 mg/kg a day) did not decrease plasma CRH or ACTH. An extremely high dose of dexamethasone (0.2 mg/kg a day), however, decreased plasma ACTH, but failed to decrease plasma CRH. Acute administration of SMS 201-995 further lowered the level of plasma ACTH even in this condition. In addition to the decrease in ACTH, SMS 201-995 decreased plasma CRH. Chronic administration of SMS 201-995 continuously decreased plasma CRH, ACTH and beta-endorphin. The decrease in these hormone concentrations accompanied the disappearance of hyperpigmentation. These results suggested that SMS 201-995 inhibits hypersecretion not only of ACTH but also of CRH, and that the agent is therapeutically useful in normalizing the hypersecretion of these hormones.