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.     

Diagnosis of corticotropin-producing bronchial carcinoid tumors causing Cushing's syndrome

Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (corticotropin) has been recognized for many years. Traditionally, clinicians have thought that most cases were due to lung carcinomas and that the clinical manifestations differed from those for pituitary-dependent Cushing's syndrome. We report two cases of corticotropin-producing bronchial carcinoid tumors that were clinically and biochemically indistinguishable from pituitary-dependent Cushing's syndrome. Review of the literature revealed that bronchial carcinoid tumors are the most common cause of Cushing's syndrome due to ectopic secretion of corticotropin. On biochemical and anatomic studies, they are frequently indistinguishable from pituitary-dependent Cushing's syndrome and thus may be difficult to diagnose. Inferior petrosal sinus sampling for corticotropin and computerized imaging of the chest may be the best aids in making the diagnosis.     

Steroid 21-hydroxylase and 17 alpha-hydroxylase in microsomal fraction of functioning adrenocortical tumors

In order to survey the enzymic activities of steroidogenesis in functioning adrenocortical tumors, we investigated the activities of steroid 21-hydroxylase and 17 alpha-hydroxylase in microsomal fractions of 12 surgically resected adrenocortical tumors associated with Cushing's syndrome (5 adenomas and one carcinoma), primary aldosteronism (5 adenomas) and adrenogenital syndrome (AGS) (one carcinoma), and one adrenocortical hyperplasia resulting from Cushing's disease. Seven adrenal cortices from the patients with mammary carcinoma, renal cell carcinoma or pheochromocytoma were used for normal control. In normal controls 21-hydroxylase activities with progesterone as a substrate were 1.61 +/- 0.25 nmole/min/mg protein and those with 17 alpha-hydroxyprogesterone were 5.22 +/- 1.06 nmole/min/mg protein. The activity of 21-hydroxylase was higher in four cases of 5 aldosteronomas than in normal controls. Those activities in Cushing's adenomas were in the range of normal controls in this study. 17 alpha-hydroxylase activities were much variable from case to case even though in normal controls (4.50 +/- 2.40 nmole/min/mg protein), and in most cases of adenomas 17 alpha-hydroxylase activities were in the range of normal controls. Activities of both hydroxylase in carcinomas were lower than in normal controls. The present paper showed the abnormal steroidogenic enzyme activities in aldosteronomas and adrenocortical carcinomas.     

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.     

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.     

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.     

Evaluation and treatment of women with hirsutism

Hirsutism is a common disorder, often resulting from conditions that are not life-threatening. It may signal more serious clinical pathology, and clinical evaluation should differentiate benign causes from tumors or other conditions such as polycystic ovary syndrome, late-onset adrenal hyperplasia, and Cushing's syndrome. Laboratory testing should be based on the patient's history and physical findings, but screening for levels of serum testosterone and 17alpha-hydroxyprogesterone is sufficient in most cases. Women with irregular menses and hirsutism should be screened for thyroid dysfunction and prolactin disorders. Pharmacologic and/or nonpharmacologic treatments may be used. Advances in laser hair removal methods and topical hair growth retardants offer new options. The use of insulin-sensitizing agents may be useful in women with polycystic ovary syndrome.     

Cushing's syndrome due to primary multinodular corticotrope hyperplasia

In this report, a case of Cushing's syndrome due to primary multinodular corticotrope hyperplasia is described. The patient had typical features of Cushing's syndrome and dynamic pituitary-adrenal testing, which suggested an ectopic adrenocorticotropic hormone (ACTH) syndrome. Results of petrosal sinus catheterization indicated that the pituitary gland was the source of excess ACTH. Total hypophysectomy resulted in complete remission of Cushing's syndrome. Light microscopic and immunohistochemical studies revealed multinodular corticotrope hyperplasia. Plasma corticotropin releasing hormone (CRH) was undetectable, and computed tomography of the chest and abdomen disclosed no neoplastic source of CRH. We speculate that either an abnormality in hypothalamic CRH secretion or corticotrope hypersensitivity to CRH might have been responsible for Cushing's syndrome in this patient.     

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.     

B超对柯兴氏综合征的诊断研究

本文对７６例柯兴氏综合征患者的超声诊断进行了分析研究，在７６例中有７９个有肾上腺经外科手术检查，其中超声检出肿瘤４６个，手术探出肿瘤５１个，均经病理证实，超声无假阳性。但有假阴性。本组的敏感性、特异性和诊断正确率分别为９０．１９％、１００％和９３．８２％。阳和阴性预期值分别为１００％和８５．７１％。本文对柯兴氏综合征超声诊断的临床意义及漏诊原因进行了较为详细的讨论。     

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.     

Cushing's syndrome. How to pinpoint and treat the underlying cause

In addition to prolonged glucocorticoid therapy (not discussed here), at least five other conditions cause Cushing's syndrome. They are excessive corticotropin secretion by the pituitary gland (which results in Cushing's disease), ectopic production of corticotropin by malignant nonpituitary tumors, benign adrenal adenoma, adrenal carcinoma, and primary adrenocortical nodular dysplasia. Each can be distinguished by a specific pathophysiologic process that triggers the adrenal glands to overproduce glucocorticoids. At present, diagnosis of Cushing's syndrome or disease relies heavily on the dexamethasone (Decadron, Hexadrol) suppression test. After diagnosis, other studies, including computed tomography, magnetic resonance imaging, and corticotropin radioimmunoassay, can be used to localize the site of the lesion. Treatment, of course, depends on the underlying cause.     

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).     

Sarcoidosis emerging after adrenalectomy for Cushing's syndrome

Cushing's syndrome is characterised by circulating steroid excess; the mainstay of treatment of systemic sarcoidosis is steroid therapy. We describe a case of sarcoidosis emerging after treatment for Cushing's syndrome.     

Fatal pulmonary thromboembolism after successful transsphenoidal hypophysectomy for Cushing's disease

We have reported the case of a 30-year-old woman with Cushing's disease who died of massive pulmonary thromboembolism 5 weeks after successful transsphenoidal hypophysectomy. Glucocorticoid excess appears to cause a hypercoagulable state, and consideration of this thromboembolic propensity and its potential duration after cure is indicated in all patients with Cushing's syndrome during the perioperative period. At the present time, we recommend the routine perioperative use of intermittent pneumatic compression in all patients with Cushing's disease or Cushing's syndrome.     

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.     

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.     

Diagnosis and pathophysiology of Cushing's syndrome

Cushing's syndrome is the consequence of a sustained overproduction of cortisol (hydrocortisone) by the adrenal cortex. This may be due to excessive secretion of cortisol by functioning adrenocortical tumors or to "nontumorous" adrenocortical hyperfunction. The latter may be a result of stimulation of the adrenal cortex by increased release of corticotropin (ACTH) from a small pituitary tumor or from nonpituitary nonadrenal tumor. Carcinoids or carcinomas of the lung or pancreas, and even pheochromocytomas have caused the syndrome of ectopic ACTH production. The problems involved in the diagnosis of Cushing's syndrome are establishing its presence and determining the underlying cause. Treatment is then dependent upon the underlying pathogenetic lesion.     

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.     

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.