Serum cortisol concentrations during low dose dexamethasone suppression test to screen for Cushing's syndrome.

Forty four subjects (23 obese controls, 11 patients with possible Cushing''s syndrome, and 10 patients with definite Cushing''s syndrome) underwent low dose (0 X 5 mg every six hours for two days) dexamethasone suppression tests during which serum cortisol concentration at 0800 and excretion of urinary free cortisol over 24 hours were measured. Serum cortisol concentration fell to below 60 nmol/1 (2 X 2 micrograms/100 ml) in 31 subjects and remained above 250 nmol/1 (9 X 1 micrograms/100 ml) in the 13 others. Excretion of urinary free cortisol showed a similar response, falling to below 110 nmol (40 micrograms)/24 h in 31 and remaining above 180 nmol (65 micrograms)/24 h in the 13 others. There was complete concordance between the two variables in terms of the pattern of response. Serum cortisol concentration fell to below 60 nmol/1 (2 X 2 micrograms/100 ml) in at least 97% (31 of a possible 32) of subjects without Cushing''s syndrome. On the other hand, a serum cortisol concentration of above 250 nmol/1 (9 X 1 micrograms/100 ml) after low dose dexamethasone gave a false positive diagnosis of Cushing''s syndrome in at most only one of 13 patients (7 X 7%). Measurement of serum cortisol concentration during the low dose dexamethasone test is simpler than, and as accurate and reliable as, measurements of urinary steroids.     

Cushing's syndrome in childhood

A patient with Cushing''s syndrome whose clinical manifestations began at approximately 9 years of age was followed for a period of four years. Initial laboratory studies revealed urinary 170HCS and 17 KS levels which were elevated for her age, with a normal diurnal variation of plasma cortisol and normal suppression of urinary 170HCS by 1.5 mg. of dexamethasone daily. It was not until four years after the onset of the disease that laboratory studies unequivocally supported the diagnosis of Cushing''s syndrome resulting in definitive therapy. Clinical features consisted primarily of cessation of growth, obesity, and hirsutism, with no evidence of protein depletion. It is suggested that the clinical and laboratory features of Cushing''s syndrome in childhood may present differences from those found in the adult. Failure to recognize these differences may result in delay in therapy with subsequent persisting stigmata of the disorder.     

Overnight Dexamethasone Suppression Test: A Reliable Screen for Cushing's Syndrome in the Obese

Objective: Reevaluation of the validity of the 1-mg overnight dexamethasone suppression test (ODST) as a screening test for Cushing's syndrome in obese patients. Research Methods and Procedures: Eighty-six obese patients (body mass index, 30 to 53 kg/m²) that were referred to a general endocrine outpatient clinic for evaluation of simple obesity, diabetes mellitus, hypertension, polycystic ovary disease, or pituitary tumor. One milligram dexamethasone was administered orally at 11:00 pm , and serum cortisol levels were measured the following morning between 8:00 am and 9:00 am . Suppression of serum cortisol to <80 nM (3 μg/dL) was chosen as the cut-off point for normal suppression. Patients with serum cortisol levels ≥80 nM were evaluated for Cushing's syndrome. Results: Suppression of morning cortisol levels to <80 nM occurred in 79 of the 86 obese patients. Seven patients had serum cortisol levels higher than 80 nM; five were eventually diagnosed with Cushing's syndrome and two were considered false positive results in view of normal 24-hour free urinary cortisol and normal suppression on a low dose dexamethasone suppression test (0.5 mg of dexamethasone every 6 hours for 2 days). We found a false positive rate of 2.3% for the ODST using a cut-off serum cortisol of 80 nM. Discussion: The ODST is a valid screening test for Cushing's syndrome in the obese population. The false positive rate was 2.3%, even when using a strict cut-off serum cortisol of 80 nM. Abnormal cortisol suppression in obese patients should be investigated and not be considered false positive results.     

Five cases of cyclical Cushing's syndrome.

Reported cases of cyclical Cushing''s syndrome are rare. Of 14 successive patients with Cushing''s syndrome nine collected sequential urine samples for the estimation of cortisol:creatinine ratio. Five had cyclical Cushing''s syndrome while two had considerable variation in urinary cortisol excretion without a cyclical pattern being established. Two of the five patients with a cyclical syndrome had paradoxical responses to dexamethasone. In only one patient with a cyclical pattern did the cortisol:creatinine ratio fall after treatment with bromocriptine or cyproheptadine, or both. The high incidence of the cyclical form of Cushing''s syndrome has important clinical implications. A high index of suspicion of the syndrome is required in patients with symptoms or signs of Cushing''s syndrome but with normal cortisol values, in patients with fluctuating cortisol values, and in patients with anomalous responses to dexamethasone. Because of possible variations in steroidogenesis the results of drug studies in Cushing''s syndrome must be interpreted cautiously.     

Variation in response to dexamethasone of a patient with Cushing's syndrome.

A patient with Cushing''s syndrome due to a nonresectable chromophobe adenoma underwent external irradiation of the hypothalamic-pituitary area. The signs of Cushing''s syndrome ameliorated subsequently but recurred eventually, necessitating bilateral adrenalectomy 30 months after initial presentation. Response to dexamethasone suppression testing on four occasions varied greatly. These results may reflect alterations in sensitivity of the tumour or the hypothalamic-pituitary axis to feedback inhibition by glucocorticoids.     

Islet-cell Carcinoma (Zollinger—Ellison Syndrome) with Fulminating Adrenocortical Hyperfunction and Hypokalemia

The production of ACTH-like material by tumours arising in non-endocrine tissue may initiate severe adrenocortical hyperfunction. The pathogenesis and clinical and laboratory features of Cushing''s syndrome associated with such tumours are characteristic. The autonomous production by the tumour of ACTH-like material cannot be suppressed by exogenous corticoids. The onset of clinical symptoms is rapid; muscle wasting, general weakness, thirst and peripheral edema predominate, and the classical signs of Cushing''s syndrome may be absent. High levels of plasma 17-hydroxycorticosteroids and urinary 17-hydroxycorticosteroids and 17-ketosteroids, usually with normal levels of urinary aldosterone, commonly occur. Hypokalemic alkalosis unresponsive to replacement therapy may cause death. In the case reported herein, the intriguing possibility exists that two hormone-like substances were produced by the primary growth and its metastases: one, ACTH-like, to account for the adrenal hyperplasia and Cushing''s syndrome; and another, gastrin-like, giving rise to the ulcerogenic diathesis.     

Hypertension,Increased Aldosterone Secretion and Low Plasma Renin Activity Relieved by Dexamethasone

A father and son are described with a condition characterized by benign hypertension, potassium deficiency, increased aldosterone secretion rate (ASR), raised plasma volume and suppressed plasma renin activity (PRA). There were intermittent elevations of urine 17-ketosteroids and 17-hydroxycorticoids (17-OHCS) but no increase in urine THS, normal circadian rhythm of plasma 17-OHCS, and normal urine 17-OHCS response to dexamethasone and intravenous ACTH. Plasma ACTH and corticosterone secretion were not elevated. Pregnanetriol excretion was normal but urine pregnanediol was increased. At operation on the father no adrenal tumour was found; the excised left adrenal weighed 7 g. and showed nodular cortical hyperplasia; juxtaglomerular cells showed only occasional granules. Following operation hypertension persisted and ASR was half the preoperative value. All abnormalities in father and son were relieved by dexamethasone (DM) 2 mg. daily. The condition recurred following cessation of DM but was relieved by a second course of treatment. No such response to DM was seen in a normal subject or in a patient with Conn''s syndrome. For a number of reasons it is suggested that patients with hypertension, increased ASR and low PRA be given a trial of dexamethasone treatment before undergoing adrenal surgery.     

Diagnostic value of 9 am plasma adrenocorticotrophic hormone concentrations in Cushing's disease.

Morning plasma adrenocorticotrophic hormone (ACTH) concentrations were measured in 58 normal subjects and seven patients with pituitary-dependent Cushing''s syndrome (Cushing''s disease). Particular note was taken of the time of venepuncture. The range of values for the normal subjects irrespective of timing was 9-77 ng/l. The range between 9 0 am and 9 30 am was 9-24 ng/l. In the patients with Cushing''s disease the ACTH concentrations were in the range 39-109 ng/l. To distinguish patients with Cushing''s disease from normal subjects it is therefore important to define accurately the 9 am normal range, since these results show no overlap.     

Plasma Levels of Immunoreactive Corticotrophin in Patients with Cushing's Syndrome

Plasma levels of immunoreactive corticotrophin (A.C.T.H.) have been determined in 56 patients with Cushing''s syndrome by means of a homologous radioimmunoassay. In untreated Cushing''s disease (bilateral adrenal hyperplasia due to excessive A.C.T.H. secretion from the pituitary) plasma values ranged from 40 to 200 μμg./ml., between 8 and 10 a.m., compared with a range in normal subjects of 12 to 60 μμg./ml. Considerably raised levels, often above 2,000 μμg./ml., were found in patients with Cushing''s disease after bilateral adrenalectomy. A.C.T.H. concentrations were usually higher in patients with bilateral adrenal hyperplasia associated with ectopic A.C.T.H. production than in patients with untreated Cushing''s disease; whereas plasma A.C.T.H. was undetectable in the presence of an adrenocortical tumour. All patients with Cushing''s syndrome failed to show the normal circadian rhythm of circulating A.C.T.H. levels.     

Single-dose four hour dexamethasone suppression test in normal men and its application for the diagnosis of cushing's syndrome

As a four hour morning test, plasma cortisol levels were radioimmunoassayed before and at two and four hours after dexamethasone (0, 0.5 mg, 1.0 mg or 2.0 mg) was administered at 8–9 a.m. in 20 normal subjects. The 1.0 mg four hour test was most effective in suppression of cortisol and it showed the same suppressibility as the widely used single-dose overnight test. With the 1.0 mg four hour test, 2 patients with Cushing's syndrome due to adrenal hyperplasia could be differentiated from normal and obese subjects.The four hour morning test would be more useful than the widely used overnight test from the reasons; i) it shows the same suppressibility as the overnight test, ii) it obviates the need for bothersome midnight administration of dexamethasone, iii) because it takes only one morning to perform, it can save a day, iv) and it might be applicable for the differential diagnosis of Cushing's syndrome because 4.0 mg morning test resulted in complete suppression of plasma cortisol in a tested Cushing's syndrome, whereas with even 8.0 mg, plasma cortisol was not suppressed in the overnight test in 2 such patients examined.     

CUSHING'S SYNDROME

Sixteen cases of verified Cushing''s syndrome, and twelve cases of probable Cushing''s syndrome were reviewed and data on them were compared with various reports on Cushing''s syndrome in the literature.The diagnosis hinges upon a high index of suspicion, and one or several of the major criteria may be lacking.Ultimate establishment of correct diagnosis should be based largely on the clinical features, although stimulation and suppression tests may help to confirm a clinical diagnosis.In well-established clinical cases, with borderline laboratory confirmation, exploration may be justified, especially if tests fail to identify a specific cause.In cases of adrenal cortical tumor, all pathological tissue should be removed if possible, with great care to support and stimulate the remaining atrophic adrenal gland during and following operation.In cases of bilateral adrenal cortical hyperplasia, the problem is one of how much to remove. At present most investigators advocate radical subtotal resection, leaving less than 10 per cent of one side.     

Resistance to Suppression by Dexamethasone of Plasma 11-O.H.C.S. Levels in Severe Depressive Illness

Use of the midnight dexamethasone suppression test showed that the plasma 11-hydroxycorticosteroid (11-O.H.C.S.) level did not undergo its normal reduction in 14 out of 27 patients with severe depression. Resistance to dexamethasone suppression correlated with the clinical rating of the severity of depression, while recovery from depression was associated with return of normal responsiveness to dexamethasone. The explanation of these findings is unknown.     

Effect of an oral serotonin antagonist,ketanserin, on plasma ACTH concentrations in Nelson's syndrome.

A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson''s syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing''s disease and who had Nelson''s syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson''s syndrome. These results show that it is not indicated in these patients.     

Desmopressin test in the diagnosis and follow-up of cyclical Cushing's disease

ObjectiveTo assess the utility of the desmopressin (DDAVP) test in the diagnosis and follow-up of a cyclical Cushing's disease (CCS) case.Material and methodsLaboratory tests included morning and midnight serum cortisol levels, 24 h urine free cortisol excretion, midnight salivary cortisol levels, serum cortisol levels after low (1 mg) and high (8 mg) dexamethasone, plasma ACTH and serum cortisol levels after DDAVP. Magnetic resonance imaging (MRI) was used to assess the presence of a pituitary adenoma. The resected tumor specimen was studied by histological, immunohistochemical and cell biology techniques.ResultsA patient was referred to our unit with a diagnosis of Cushing's syndrome (CS) for further evaluation and treatment. However, no biochemical evidence of hypercortisolism was observed in the follow-up evaluations. Furthermore, the typical features of CS fluctuated throughout this period. A consistent positive response to the DDAVP stimulation test was observed during the diagnostic work-up, even when overt clinical features of CS were not apparent, raising suspicion for CCS. After two years of follow-up a definitive diagnosis of hypercortisolism was established. An MRI scan revealed a pituitary adenoma, as the source of ACTH production. After transphenoidal surgery, clinical signs of CS resolved and the response to DDAVP became negative. DDAVP induced a significant increase in ACTH levels in cultured pituitary adenoma cells, consistent with the in vivo DDAVP test results.ConclusionsOur case illustrates the utility of the DDAVP test in the evaluation of patients with suspected CCS. The DDAVP test could facilitate the management of CCS by shortening the time of diagnosis.     

Adrenocortical Hyperfunction Associated with Bronchogenic Carcinoma: Report of Five Cases

Five patients with bronchogenic carcinoma associated with adrenocortical hyperfunction are described. The clinical features, laboratory studies and autopsy findings are discussed and compared with previously reported cases. Four patients presented most of the typical features of this disorder as previously described, whereas the fifth was atypical in some respects. Typical features included: acute onset of adrenocortical hyperfunction in a middle-aged male, rapid downhill course, slight or absent physical signs of Cushing''s syndrome, frequently impaired glucose tolerance, markedly elevated plasma and urinary 17-hydroxycorticosteroids not suppressed by exogenous steroids, absent diurnal variation of plasma corticoids, hypokalemic alkalosis with normal aldosterone excretion, and tumour histology of the oat cell variety. The adrenal glands of two patients were of normal or slightly increased weight, and mean 17-ketosteroid excretion values were normal in three; this contrasts with the marked increase in adrenal weight and 17-ketosteroid excretion in most reported cases.     

Overnight (1 mg) dexamethasone suppression testing reliably distinguishes non-cushingoid obesity from Cushing's syndrome.

To determine the sensitivity of the overnight 1-mg dexamethasone suppression test in diagnosing Cushing's syndrome, we evaluated the cortisol responses of 55 subjects (25 non-obese individuals with body mass index less than 25 kg/m2, 20 obese individuals with body mass index greater than 30 kg/m2, and 10 patients with surgically proven Cushing's syndrome) following ingestion of 1 mg dexamethasone at midnight. The basal 8 AM plasma cortisol levels among non-obese and obese individuals and patients with Cushing's syndrome were 310 +/- 85, 377 +/- 91, and 813 +/- 270 nmol/L, respectively. Following 1 mg of dexamethasone, Cushing's syndrome patients showed minimal suppression of cortisol to 609 +/- 180 nmol/L (P = 0.79). Non-obese and obese individuals suppressed to 18.7 +/- 6.0 nmol/L (P less than 0.001) and 22 +/- 7.1 nmol/L (P = 0.003), respectively. The results demonstrated similar cortisol responses to overnight dexamethasone suppression in obese and non-obese groups, and clearly distinguished these subjects from those with Cushing's syndrome. Obesity is not a confounding factor in the 1-mg dexamethasone suppression test.     

Value of computed tomography of the abdomen and chest in investigation of Cushing's syndrome.

Computed tomography (CT) scans were performed on 37 patients with biochemically proved Cushing''s syndrome to evaluate the role of CT in the investigation of this condition. CT rapidly and correctly identified all 15 adrenocortical tumours, distinguishing five carcinomas from the 10 adenomas. In ACTH-dependent Cushing''s syndrome appreciable bilateral adrenal enlargement was common in patients with an ectopic source (6 of 10 cases), while those with a pituitary source usually had normal sized adrenals (9 of 10). Two patients with a history of over seven years had bilateral adrenal nodules. CT was more accurate in locating a primary ectopic source of ACTH (5 of 12 cases) than any other technique and was particularly valuable in detecting small (less than 1.5 cm) peripheral lung carcinoid tumours which may be undetectable by conventional x-ray techniques. Its speed, accuracy, and simplicity make CT the technique of choice both to show the adrenal anatomy and to locate a suspected ectopic ACTH-secreting tumour in patients with proved Cushing''s syndrome.     

Aportaciones de los tests de supresión de cortisol al conocimiento de los trastornos psiquiátricos: revisión narrativa de la literatura

Activity of the hypothalamic-pituitary-adrenal axis had been studied for the past half century, when some researchers noted that some patients with Cushing's syndrome and severe mood disorders had high baseline cortisol levels, which resulted in an inhibited response in the 1 mg dexamethasone suppression test. Altered dexamethasone suppression test results were subsequently found in many psychiatric diseases, including anorexia nervosa, obsessive-compulsive disorder, degenerative dementia, bipolar disorders, and schizophrenia. The relationship between high baseline cortisol levels and stress has also been studied. Some researches on the genesis of borderline personality disorder focused on traumatic childhood backgrounds. Other investigations aimed at elucidating the relationship between traumatic backgrounds and some psychiatric disorders noted that patients with post-traumatic stress disorder and borderline personality disorder showed an enhanced cortisol suppression with low cortisol doses (0.5 mg). Recent studies showed that use of an ultra-low dose of cortisol during the dexamethasone suppression test may be helpful for deteting disorders with hyperactivity of the hypothalamic-pituitary-adrenal axis.Recent advances in neuroimaging support the existence of hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with borderline personality disorder, relating a decreased pituitary gland volume to major traumatic backgrounds and suicidal attempts. The purpose of this paper is to make a narrative review of research using dexamethasone suppression test in psychiatric disorders, in order to ascertain its value as a supplemental diagnostic test or as a prognostic marker.     

Experience of Ectopic Adrenocorticotropin Syndrome: 88 Cases With Identified Causes

ObjectiveEctopic adrenocorticotropic hormone syndrome (EAS) is a rare cause of Cushing's syndrome and diagnosis and management remain challenging. The aim of this study was to present the clinical spectrum of a group of EAS cases in a single center to explore better management strategies.MethodsA retrospective study was conducted to identify 88 confirmed EAS cases at our hospital from 1984 to 2019. The clinical, biochemical, imaging, and pathological features were analyzed.ResultsOf the 88 eligible patients with EAS, 38 (43.2%) cases of pulmonary neuroendocrine tumors (NETs) and a larger number of thymic/mediastinal NETs (29 cases, 33%) were identified. The clinical and biological features of EAS and Cushing's disease overlapped but were more severe in EAS. Inferior petrosal sinus sampling (97.4%) and computed tomography (85.4%) provided the highest positive diagnostic accuracy. Computed tomography is also a useful tool to identify tumors in chest cavity compared with nonchest lesions (91.2% vs 57.1%). Although a greater tumor size (4.54 cm vs 1.44 cm) and higher rate of insuppressible high-dose dexamethasone suppression test (83.3% vs 51.5%) were found in thymic/mediastinum NETs than in pulmonary NETs, the level of hormone production had no difference.ConclusionEAS had more common and severe clinical presentations than Cushing's disease, and multiple imaging approaches are required for reliable diagnosis. A higher proportion of thymic/mediastinal NETs was found in our study. For patients without a certain tumor source, long-term follow-up and further evaluations are needed.     

Metyrapone in long-term management of Cushing's disease.

Metyrapone was used in the long-term management of 13 patients with pituitary-dependent bilateral adrenal hyperplasia (Cushing''s disease). The total length of treatment ranged from two to 66 months, with a mean of 21 months. The clinical features of the disease rapidly improved on metyrapone and this improvement was maintained. Although plasma ACTH concentrations rose in all patients, the increase was insufficient to overcome the adrenal blockade induced by the drug. Eight of the 13 patients had additional external pituitary irradiation as definitive treatment of their disease and one underwent a transfrontal hypophysectomy. Radiotherapy cured one patient, and after three years metyrapone was withdrawn. Slight hirsuties was noted in four of the seven women who received the drug for six months or more. A fifth woman had more severe hirsuties and this led to bilateral adrenalectomy. Other than hirsuties, side effects were few and the routine use of metyrapone is recommended as an adjunct to more definitive treatment in all patients who present with Cushing''s syndrome, irrespective of aetiology.