An evaluation of the distinction of ectopic and pituitary ACTH dependent Cushing's syndrome by clinical features, biochemical tests and radiological findings

The efficiency of various laboratory and radiological investigations in the differentiation of ectopic from pituitary dependent Cushing's syndrome was studied, based on findings in 23 patients with verified Cushing's disease and seven patients with the ectopic ACTH syndrome. Clinical features strongly favouring the ectopic type were male sex and history for less than 18 months. Basal biochemical features strongly indicating the ectopic syndrome included plasma K+ less than 3.0 mmol/l and HCO3 greater than 30 mmol/l; serum cortisol at 9 a.m. or midnight of greater than 800 nmol/l; urine free cortisol greater than 1300 nmol/24 hours; plasma ACTH greater than 100 ng/l. In the high-dose dexamethasone suppression test, suppression by less than 50 per cent of 9 a.m. serum cortisol, urine free cortisol or 17-oxogenic steroids was usually indicative of an ectopic source of ACTH. A mean suppressed value of greater than 450 nmol/l for the 9 a.m. and midnight cortisol combined occurred in all of those with the ectopic syndrome, but in none of the 23 patients with Cushing's disease. For urine free cortisol, a mean suppressed value of less than 1000 nmol/24 hours was found in all patients with Cushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of less than or equal to 3-fold in 11-deoxycortisol at 24 hours in patients with ectopic ACTH; the increase was greater than 3-fold in all but one of the patients with Cushing's disease. Failure to respond to either dexamethasone or metyrapone was found in only one of the patients with Cushing's disease (Patient 16); in the ectopic group, all patients except Patient D failed to respond to either test. It is concluded that patients presenting with clinically obvious Cushing's syndrome along with measurable plasma ACTH can be reliably divided by conventional tests into those that are driven from the pituitary and those driven by ectopic ACTH.     

Parallel assays of beta-endorphin and ACTH in Cushing's patients undergoing petrosal sinus sampling

This study explores the possibility of improving endocrinologic testing during petrosal sinus catheterization by determining both beta-endorphin and corticotropin (ACTH). We studied 14 patients with Cushing's disease, two with adrenal tumor, and three with ectopic tumors secreting ACTH. In patients with Cushing's disease, beta-endorphin concentrations paralleled those of ACTH in all basal plasma samples collected either from petrosal sinuses or peripheral veins. Individual responses of beta-endorphin and ACTH to corticotropin releasing hormone (CRH) were closely related to the presence of a corticotroph adenoma. In such patients, a consistently higher concentration of beta-endorphin over ACTH was observed in all samples collected either from petrosal sinuses or peripheral veins; the ratios were unchanged after the administration of CRH. In patients with ectopic ACTH secretion, the mean ratio of beta-endorphin over ACTH (with both values expressed in pmol/L) was significantly higher (3.5) than that of patients with Cushing's disease (2.9) or Cushing's syndrome due to adrenal tumor (2.7).     

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.     

Hepatotoxicity of a synthetic cortisol antagonist: OP'DDD (mitotane)

The adrenolytic agent, Op'DDD (Mitotane) has been employed for almost 50 years for treatment of Cushing's syndrome. Despite clinical observations of elevation of hepatic enzymes encountered in patients taking the drug, there are few published data regarding the frequency, time course and factors that might influence hepatic toxicity of Mitotane. We analysed 10 patients consecutively treated with Mitotane for Cushing's syndrome. We measured hepatic transaminase and gamma glutamyl transferase before, during and after treatment. The study population included 6 women and 4 males, with a mean age of 41 years. Seven patients presented Cushing's disease while two had adrenal tumours and one had an undetermined origin of Cushing's syndrome. After a progressive increase, patients were being treated with a mean dosage of 9 g per day. All patients had elevation of either GGT or ALAT and all but one had elevation of transaminase (the maximum increase was sixfold the basal value). The only variable correlated with hepatic increase was the body mass index. In contrast, the severity of the disease, alcohol intake, and other biological characteristics were not correlated with transaminase elevations. We conclude that transaminase increase is encountered in the vast majority of patients treated with Mitotane. Levels at which the drug should be withdrawn remain to be established.     

Psychiatric aspects of Cushing's syndrome

Patients with Cushing's syndrome were studied (n=209, 78% females). Control patients had pituitary adenomas secreting growth hormone or prolactin. Age at diagnosis of Cushing's syndrome was 8-74 (mean 39) years. Duration of symptoms was 0.2-9 (median 2.0) years. Adverse life events within the 2 years preceding the onset of Cushing's syndrome were not significantly commoner than in controls. Depressive illnesses were associated with the presence of adverse life events (p<0.001). Depressive illness was more common in females (p<0.01). There were no significant differences in the severity of depression in the different types of Cushing's syndrome. Pathological anxiety had been diagnosed in 26 patients (12%), mania or hypomania in six patients (3%) and confusion in three patients (1%). Psychotic illness had been diagnosed in 16 patients (8%) and was more common in adrenal carcinomas (p<0.01). Significant psychiatric illness, usually depressive preceded the onset of all symptoms and signs of Cushing's syndrome in 25 patients (12%); 23 of these developed pituitary Cushing's disease, and two adrenal adenomas. When Cushing's syndrome was diagnosed, significant psychiatric illness, usually depression, was present or had been a feature of Cushing's syndrome in 120 (57%) patients.      

Cushing's Disease: TREATMENT BY PITUITARY IMPLANTATION OF RADIOACTIVE GOLD OR YTTRIUM SEEDS

Fifty-seven patients with Cushing's disease (pituitary-dependentCushing's syndrome), and four with Nelson's syndrome followingadrenalectomy, have been treated by implantation of ¹⁹⁸Au or⁹⁰Y seeds into the pituitary gland. Fifty-five of the Cushing'sdisease patients have been fully followed up with steroid testsfor 1 to 12 years after implant. They have been categorizedaccording to the X-ray appearance of the fossa before implant,which was the most important factor in predicting the outcome.The results were as follows: 1. Cushing's disease without evidence of pituitary tumour onX-ray (31 patients). One year after implant, 65 per cent ofthese patients were in complete remission and a further 16 percent in partial remission—a total of 81 per cent improved,without any other treatment. Only 34 per cent required replacementcorticosteroids, and 30 per cent replacement thyroxine. 52 percent needed no replacement hormone treatment. Only one patienthad relapsed more than 2 years after implant. 2. Cushing's disease with possible pituitary tumour on X-ray(10 patients). One year after implant, five of these were incomplete and one in partial remission. These remissions weremaintained. 60 per cent required replacement steroids or thyroxine. 3. Cushing's disease with definite X-ray evidence of pituitarytumour (14 cases). In only two of these was permanent remissionobtained by implant alone, despite the use of higher radiationdoses in most of them. In four the tumour showed X-ray or clinicalevidence of local invasion after implant, and three subsequentlyneeded surgical hypophysectomy. A combination of implant, adrenalectomy,hypophysectomy, or external irradiation was needed to controlthe disease in most of these patients; 10 required surgery ofpituitary or adrenals. Some degree of hypopituitarism occurredin them all and 64 per cent required replacement hormones asa result of pituitary or adrenal ablation. In the whole series of 61 patients implanted for either Cushing'sor Nelson's syndrome, there were six who developed serious problemsfrom local invasion by pituitary tumours despite various formsof treatment of the pituitary. This invasion contributed tothe deaths of four. 4. In all four cases of Nelson's syndrome, clinical remissionof pigmentation was evident within a year of implant. One patientlater required external pituitary irradiation and craniotomyto control his pituitary tumour, but survived 13 years. Theothers have been followed for three, four, and nine years withoutrecurrence. 5. Pituitary implant for Cushing's disease appears to be atleast as effective in producing remission as other treatmentsdirected at the pituitary, and is as effective in restraininggrowth of pituitary tumours. It is much more effective thanexternal irradiation. Though the cure of the Cushing's syndromeis not as certain as with adrenalectomy, the proportion of patientsrequiring replacement hormone therapy is approximately half,and the procedure of implant is a smaller surgical undertaking.The technical complications of implants, particularly cerebrospinalfluid rhinorrhoea, are minimal (5 per cent) and readily treatable.     

Avascular necrosis of bone: a manifestation of Cushing's disease

Cushing's disease is endogenous hypercortisolism due to a pituitary adenoma. Although exogenous hypercortisolism is a well known cause of avascular necrosis and although there have been many reports of avascular necrosis associated with endogenous Cushing's syndrome, there has only been a single well documented case report associating avascular necrosis of bone with Cushing's disease. We report four new cases of avascular necrosis of bone in patients with well documented Cushing's disease.     

Cushing's disease: clinical manifestations and diagnostic evaluation

The most common endogenous cause of Cushing's syndrome is Cushing's disease. Frequent clinical findings include weight gain, truncal obesity, striae, hypertension, glucose intolerance and infections. Cranial nerve II may be affected by enlarging pituitary adenomas in Cushing's disease; cranial nerves III, IV and VI may also be affected. The evaluation of patients with suspected Cushing's disease and syndrome requires an understanding of the proper use and limitations of the tests commonly included in the diagnostic work-up. The best screening test for Cushing's syndrome is a 24-hour urine collection with analysis for urinary free cortisol excretion. Low-dose and high-dose dexamethasone suppression tests, corticotropin assays, a corticotropin-releasing hormone stimulation test and inferior petrosal sinus catheterization may be required for a definitive diagnosis. Magnetic resonance imaging is useful in localizing the lesion. Surgical removal of the lesion by a transphenoidal approach is usually successful, but long-term follow-up is required. Some patients require lifetime glucocorticoid replacement therapy.     

Decreased dehydroepiandrosterone sulfate in pigmented nodular adrenal dysplasia

Previous reports on patients with endogenous Cushing's syndrome describe low concentrations of the adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) in adrenal adenoma and in a case of feminizing macronodular hyperplasia. Here we present hormonal data from two adult sisters with Cushing's syndrome as a result of pigmented nodular adrenal dysplasia. Corticotropin concentrations were in the mid-normal range, cortisol production was unaffected by administration of dexamethasone (8 mg/24 h), and baseline concentrations of DHEA-S were less than 0.5 mumol/L. A low concentration of DHEA-S in these and other previously reported patients with Cushing's syndrome correctly predicts the results of dynamic testing. Decreased DHEA-S in a patient with endogenous Cushing's syndrome can be ascertained by assay of a single sample and should prompt consideration of the diagnosis of autonomous bilateral nodular disease as well as adrenal adenoma.     

Normal and abnormal regulation of β-MSH in man

The regulation of plasma beta-melanocyte-stimulating hormone (beta-MSH) in man has been studied utilizing a radioimmunoassay previously described (1). In normal subjects plasma beta-MSH values ranged from 20 to 110 pg/ml. Metyrapone increased and dexamethasone decreased plasma beta-MSH levels. Surgical stress stimulated beta-MSH secretion. Plasma beta-MSH levels were elevated in patients with untreated Addison's disease and untreated congenital adrenal hyperplasia, and these levels fell to normal during glucocorticoid therapy. In patients with Cushing's syndrome due to pituitary adrenocorticotropic hormone (ACTH) excess, plasma beta-MSH was slightly elevated before treatment. In those patients who developed pituitary tumors and hyperpigmentation after bilateral adrenalectomy, plasma beta-MSH was greatly elevated. In patients with Cushing's syndrome due to adrenal tumor, plasma beta-MSH was subnormal. In patients with the ectopic ACTH syndrome, the levels of plasma beta-MSH were high. Plasma beta-MSH had a diurnal variation in normal subjects, patients with Addison's disease, and patients with congenital adrenal hyperplasia; but the normal diurnal variation was lost in patients with Cushing's disease. In patients with high plasma beta-MSH, simultaneous determinations of plasma ACTH showed close correlation between the degree of elevation of ACTH and that of beta-MSH. In extracts of tumors from patients with the ectopic ACTH-MSH syndrome the quantities of the two hormones were roughly equivalent. In patients with hyperpigmentation due to a variety of disorders other than pituitary-adrenal abnormalities, plasma beta-MSH was normal. It is concluded that the secretion of beta-MSH is regulated by the same factors that regulate ACTH.     

Medical treatment for Cushing's syndrome

Systemic cortisol plays an important role in the metabolism of glucose, lipids and proteins, as well as in the regulation of electrolyte balance. It is well known that the development of the microvascular disease of various organs such as the heart and kidney, in patients with diabetes mellitus, hyperlipidemia and hypertension of which disorders are frequently associated with Cushing's syndrome. Thus, we should treat Cushing's syndrome as soon as possible, since many complications, including cardiovascular diseases and infections, will soon occur when the definite diagnosis is delayed. Adrenalectomy is essential for treatment for Cushing's syndrome even in the patients with pituitary or ectopic ACTH-producing tumor. Some case can not be treated with surgical procedures because of worsened conditions with several complications of infection and diabetes. Then we choose medical treatment. Medical adrenalectomy is achieved by using with mitotane which is usually used for adrenocortical cancer. We commonly treat the patients with Cushing's syndrome due to adrenal tumor and pituitary or ectopic ACTH producing tumor by using metyrapone which mainly inhibits 11-hydroxylase. Metyrapone is also recommended to treat the patients who are not well differentiated Cushing's disease from ectopic ACTH syndrome. We rarely use trilostane which is an inhibitor against 3beta-hydroxysteroid dehydrogenase (3beta-HSD). Replacement therapy with hydrocortisone should be considered if adrenal failure will occur during treatment with those drugs.     

An unusual cause of Cushing's syndrome: primary pigmented nodular adrenal dysplasia

We report a case of Cushing's syndrome due to primary pigmented nodular adrenal dysplasia (PPNAD) and discuss the diagnostic process and management of this rare case. The diagnosis of PPNAD is discussed in the context of other causes of Cushing's syndrome. Eighty-five per cent of cases of Cushing's syndrome are due to a pituitary corticotrophic tumour (Cushing's disease). Rarer causes include cortisol secreting adrenal adenoma and ectopic ACTH secretion. In the routine investigation of Cushing's disease it is not unusual to find bilateral adrenal nodules on the CT scan. We present a case of Cushing's syndrome in which this radiographic finding was present and yet the biochemical diagnosis was one of ACTH independent disease. Histology revealed PPNAD.     

Single determination of plasma ACTH using an immunoradiometric assay with high detectability differentiates between ACTH-dependent and -independent Cushing's syndrome

The purpose of this retrospective study was to elucidate the value of an ACTH assay with high detectability to differentiate between ACTH-dependent and -independent Cushing's syndrome. The study was based on the case records of 56 patients with Cushing's syndrome comprising 34 patients with ACTH-dependent Cushing's syndrome and 22 patients with ACTH-independent Cushing's syndrome. Basal morning plasma 1-39 ACTH was measured using an immunoradiometric assay (IRMA) with a normal range of 1.8-11 pmol/L. Peripheral corticotrophin-releasing hormone (CRH) tests were performed in 24 and 17 patients with ACTH-dependent and -independent Cushing's syndrome, respectively. Using a single ACTH measurement, a complete separation was observed between the two defined groups, with a cut-off value of 2.4 pmol/L. Mean ACTH concentration was 14.4 pmol L (range 2.5-47.7 pmol/L) in ACTH-dependent Cushing's syndrome and 0.6 pmol/L (range 0.2-2.2 pmol/L) in ACTH-independent Cushing's syndrome. The range of separation between the two groups was further increased by using two ACTH measurements in each patient or peripheral stimulation with CRH. It is concluded that in the majority of patients with Cushing's syndrome a single basal morning ACTH determination is sufficient to discriminate between ACTH-dependent and ACTH-independent Cushing's syndrome. In borderline cases with ACTH in the range 2-3 pmol/L, repeated measurements might be necessary. The peripheral CRH test was not superior to repeated ACTH measurements.     

Cushing's syndrome: update of diagnosis and management

Although considerable advances have been made in the understanding of Cushing's syndrome in the recent past, many difficulties persist in the diagnosis and management of patients with hypercortisolism. Precision in the diagnosis of Cushing's syndrome and the differentiation of its various forms have gradually improved, but a substantial number of cases have laboratory or radiologic findings that can be misleading or at least difficult to interpret. Furthermore, other conditions may mimic Cushing's syndrome and add to the diagnostic difficulties. Surgical extirpation of primary adrenal lesions that cause the hypercortisolism or of the neoplasms responsible for the ectopic production of adrenocorticotropic hormone remains the treatment of choice for these problems. Currently, transsphenoidal surgical exploration is the treatment of choice for Cushing's disease.     

Daily variation of blood pressure in patients with Cushing's syndrome

The circadian rhythm of blood pressure (BP) was compared between patients with Cushing's syndrome and those with essential hypertension. In patients with essential hypertension, clear nocturnal falls in systolic and diastolic BP and heart rate (HR) were observed, and there was a positive correlation between HR and systolic or diastolic BP. On the other hand, in patients with Cushing's syndrome, there was no nocturnal fall in BP and instead a rise in some cases. In all cases with Cushing's syndrome there was a nocturnal fall in HR, and consequently no significant correlation between HR and BP in these patients. The present results imply that the normal circadian rhythm of blood pressure may be regulated at least in part by the hypothalamo-pituitary-adrenal system.     

Changes of platelets, serum lactic dehydrogenase, gamma-glutamyltranspeptidase, choline esterase and creatine phosphokinase levels in patients with Cushing's syndrome

In order to identify non-endocrine laboratory tests of diagnostic value in Cushing's syndrome, we measured platelet counts and serum myogenic and hepatic enzyme levels in 10 patients with Cushing's syndrome and compared the findings with those of 15 obese patients without Cushing's syndrome. Patients with Cushing's syndrome had increased numbers of platelets, moderately elevated serum lactic dehydrogenase and gamma-glutamyltranspeptidase levels, and significantly lower creatine phosphokinase and choline esterase activities compared with those of obese control patients. We concluded that when several of these abnormal values were seen in obese patients the levels of suspicion for Cushing's syndrome should be high.     

腹腔镜下手术治疗肾上腺皮质醇增多症18例护理配合

目的:探讨腹腔镜下手术治疗肾上腺皮质醇增多症患者的护理配合方法.方法:对18例肾上腺皮质醇增多症患者行手术治疗,并给予密切护理配合.结果:本组均于腹腔镜下行手术治疗,经腹腔途径3例,经后腹腔途径15例(其中2例中转开放手术).术后1例出现肾上腺危象,经及时处理,恢复良好;其余患者无严重并发症发生.随访12～30个月,复查B超、CT未见复发.结论:充分的术前准备、默契的术中配合是手术顺利进行及患者早日康复的关键.     

原发性色素性结节状肾上腺皮质病的临床病理特征:附5例报道

目的:回顾性研究5例原发性色素性结节状肾上腺皮质病(PPNAD)的临床病理特征。方法:分析临床和实验室资料,对病变组织行HE染色和免疫组化标记。结果:本组5例患者临床诊断为库欣综合征,其中4例合并Carney综合征;1例为特发性。病理学表现为多发性色素性皮质结节伴结节间皮质萎缩;镜检观察到两种细胞,一种为含有嗜酸性细胞质和脂褐素的大细胞,另一种为细胞质富含脂质,空泡状。这些细胞免疫组化标记神经元特异性烯醇化酶阳性(++)。结论:PPNAD可造成促肾上腺皮质激素(ACTH)非依赖性皮质醇增多症。且多数患有Carney综合征。     

The Treatment of Cushing's Disease by Trans-sphenoidal Hypophysectomy

Thirteen patients aged 24 to 65 with Cushing's disease havebeen treated by tranfssphenoidal hypophysectomy. There was oneincident of meningitis and one late death from myocarditis.No radiotherapy was given. In 12 patients pituitary histologyshowed Crooke's changes and an adenoma was present in seven.On review of the 12 survivors two to 11 years later, 11 arein complete remission. One patient still showed some clinicalfeatures of Cushing's syndrome but steroid levels were normal.In five of the seven premenopausal women normal menstruationhas returned and pregnancy has occurred in three. In four patientsreplacement hormone therapy is no longer required and a furtherfour take only partial treatment. We conclude that transsphenoidalhypophysectomy is an effective treatment for Cushing's disease.     

An Evaluation of the Distinction of Ectopic and Pituitary ACTH Dependent Cushing's Syndrome by Clinical Features, Biochemical Tests and Radiological Findings

The efficiency of various laboratory and radiological investigationsin the differentiation of ectopic from pituitary dependent Cushing'ssyndrome was studied, based on findings in 23 patients withverified Cushing's disease and seven patients with the ectopicACTH syndrome. Clinical features strongly favouring the ectopic type were malesex and history for less than 18 months. Basal biochemical featuresstrongly indicating the ectopic syndrome included plasma K⁺<3.0 mmol/l and HCO₃ >30 mmol/l; serum cortisol at 9 a.m.or midnight of > 800 nmol/l; urine free cortisol > 1300nmol/24 hours; plasma ACTH > 100 ng/1. In the high-dose dexamethasone suppression test, suppressionby < 50 per cent of 9 a. m. serum cortisol, urine free cortisolor 17-oxogenic steroids was usually indicative of an ectopicsource of ACTH. A mean suppressed value of > 450nmol/l forthe 9 a.m. and midnight cortisol combined occurred in all ofthose with the ectopic syndrome, but in none of the 23 patientswith Cushing's disease. For urine free cortisol, a mean suppressedvalue of < 1000 nmol/24 hours was found in all patients withCushing's disease, but in none of those in the ectopic group. In the metyrapone test, there was an increase of