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.     

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. 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.     

Free urinary cortisol radioimmunoassay

Summary The availability of a specific antiserum has made it possible to develop in our laboratory a radioimmunoassay for free urinary cortisol which is quite simple and rapid to perform. No preliminary procedures of chromatographic purification are necessary, and no correction for losses is required. Precision and accuracy tests are satisfactory. Seventeen normal subjects, 10 obese subjects, 18 patients with Cushing's syndrome, 4 hypopituitaric patients and 4 with Addison's disease were studied. The values of free urinary cortisol were compared with those of urinary 17-OHCS, plasma cortisol and, in some cases, the cortisol secretion rate. In normal subjects, the mean free urinary cortisol was 77.22±7.74 μg/24 h, in obese subjects it was 112.05±13.64 μg/24 h, and in patients with Cushing's syndrome it was at significantly higher levels, with a mean value of 488.06±64.39 μg/24 h. There was no overlap between the values obtained in the first two groups and those of subjects with adrenal hyperfunction, and the tesults were similar to those shown by the cortisol secretion rate. The same was not true for urinary 17-OHCS and plasma cortisol. Thus, the assay of free urinary cortisol, that is the free biologically active circulating fraction, may provide a relatively simple alternative to measurement of the cortisol secretion rate, as a single differential test for the diagnosis of conditions with adrenal hyperfunction. Less satisfactory were the results obtained in patients with primary and secondary adrenal hypofunction. Another limitation of the method is its relative non-specificity, since the results of 16 urinary samples measured without preliminary chromatography were 29.6% higher than those after previous chromatographic purification. However, in our experience, this overestimation does not affect the value of the method as a screening test for the diagnosis of Cushing's syndrome.     

Cushing's syndrome with cranial and pulmonary lesions: necessity for tissue diagnosis.

This report describes two cases of Cushing's syndrome associated with radiologic abnormalities in the lung and brain. In both cases, the pathologic diagnosis of the intracranial lesion was unsuspected and prompted changes in management. These cases illustrate that the etiology of pulmonary and central nervous system mass lesions in patients with Cushing's syndrome may not be predicted on clinical grounds or by conventional radiologic methods. A tissue diagnosis is essential as a guide to appropriate management, and biopsies of such lesions are indicated.     

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.     

Salivary cortisol for the evaluation of Cushing's syndrome

Cortisol concentrations were measured in matched plasma and salivary samples from 8 healthy controls, 8 patients with Cushing's syndrome and 4 patients suspected of having spontaneous hypercortisolism. In healthy subjects, the circadian rhythm in salivary cortisol paralleled that in plasma. Absence of the diurnal rhythm in Cushing's syndrome was seen in saliva as well as in plasma. After ACTH stimulation, mean peak cortisol in saliva showed a 3-fold increase while in plasma there was a 2.5-fold increment above baseline. Cushing's syndrome, due to pituitary or adrenal adenoma was diagnosed equally well by measuring the cortisol response to cosyntropin in either plasma or saliva. Finally, the low- and high-dose dexamethasone suppression test was reflected equally well in both plasma and saliva. In patients suspected of having Cushing's syndrome dynamic tests can be performed in both plasma and saliva. However, in some samples, the salivary cortisol measurement appears advantageous over plasma cortisol determination.     

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.     

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.     

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.     

Biochemical evaluation of adrenal dysfunction: the laboratory perspective.

In this study, we reviewed the diagnostic efficiency of laboratory tests that are performed for assessment of patients with Cushing's syndrome or adrenal insufficiency. Baseline laboratory data from patients subsequently diagnosed with adrenal dysfunction were analyzed for tests performed between 1987 and 1989 at our institution. Results were analyzed for 36 patients diagnosed with pituitary-dependent Cushing's syndrome, 15 with ectopic Cushing's syndrome, 12 with adrenal-dependent Cushing's syndrome, 20 with primary adrenal insufficiency, and 7 with secondary adrenal insufficiency. Tests reviewed were plasma cortisol, plasma corticotropin, urinary free cortisol, urinary 17-ketosteroids, urinary ketogenic steroids, low-dose and high-dose dexamethasone suppression, and metyrapone stimulation. Our findings suggest that a substantial proportion of diagnoses could be based on the results of three tests--plasma corticotropin, plasma cortisol, and urinary free cortisol. We present a nomogram that combines the results of plasma corticotropin and plasma cortisol testing to enhance the diagnostic efficiency of these tests.     

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.     

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.     

Nelson's syndrome: case report and review of the literature.

A patient who developed a pituitary tumor after adrenalectomy for Cushing's disease (Nelson's syndrome) is presented. The literature reviewed shows less than a 10 percent incidence of this disorder for which extremely elevated plasma ACTH levels are diagnostic. Special radiologic technics may be required to detect small pituitary tumors, but pituitary hormone levels may be elevated in the cerebrospinal fluid if there is suprasellar tumor extension. The different modalities available for treatment of Nelson's syndrome are discussed.     

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.     

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.     

Normal menstruation and pregnancy in a patient with Nelson's syndrome

The patient with Nelson's syndrome in this report represents an unusual case in which regular cyclic menstruation was preserved even though a large ACTH-producing pituitary adenoma was present. Despite normal menses and pregnancy, the radiologic findings of an enlarged sella turcica and an enhanced lesion on CAT scan were identified. This case demonstrates that patients with normal menstruation can have significant pituitary disease, and it exemplifies the need for regular follow-up examination to look for radiologic abnormalities in patients who have had adrenalectomy for treatment of Cushing's disease.     

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.     

'Not Cushing's syndrome'.

Cushing's syndrome is characterized by protein wasting secondary to hypergluconeogenesis, which produces thin skin, poor muscle tone, osteoporosis and capillary fragility. These features distinguish patients with true Cushing's syndrome from those who have some of the clinical findings often associated with the syndrome, such as obesity, hypertension, striae and hirsutism. The dexamethasone suppression test helps identify patients with pseudo-Cushing's 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.