A new generation IRMA for ACTH with improved specificity: validation in various physiological and pathological conditions.
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OBJECTIVE: Measurement of plasma ACTH is a key step for the exploration of hypothalamic-pituitary-adrenal disorders. To further improve ACTH recognition a new generation of ACTH IRMA was developed using antibodies directed towards succinylated ACTH (sACTH IRMA). DESIGN: The usefulness of this assay was compared with that of another commercially available ACTH IRMA assay using intact ACTH (ELSA-ACTH) in various pathophysiological situations: patients with low ACTH plasma levels, high ACTH plasma levels with normal or tumoural pituitaries, or ectopic ACTH syndrome, and pregnant women with high proopiomelanocortin (POMC) plasma levels. METHODS: All plasma samples were assayed simultaneously with the two different IRMAs. Comparisons were assessed by plotting the results along the theoretical line of identical values, and by the graphical method of Bland and Altman. RESULTS: In the ELSA-ACTH IRMA, CLIP (or ACTH18-39) showed true cross-reactivity, and alpha-melanocyte-stimulating hormone and purified POMC both interfered and induced falsely lower ACTH results; in the sACTH IRMA no peptide showed any cross-reactivity, and only extremely high values of CLIP (50 000 pg/ml) interfered and induced falsely lower ACTH results. In ACTH hypersecretory syndromes, of tumoural (Cushing's disease, ectopic ACTH secretion) or non-tumoural (Addison's disease, congenital adrenal hyperplasia) origins a good agreement between the two assays was observed except for very high ACTH plasma values (above 1000 pg/ml) and in some tumours where the sACTH IRMA yielded lower results; in some cases, the presence of circulating CLIP, demonstrated by HPLC studies, may contribute to this discrepancy. It is also likely that the calibration of the ELSA-ACTH kit itself generates higher ACTH values. In normal pregnant women both IRMAs gave highly correlated values, yet lower results were obtained with the sACTH IRMA. CONCLUSION: These data show that the sACTH IRMA has improved qualities of specificity and usefulness for rapid assessment of ACTH plasma levels. (+info)
Inferior petrosal sinus sampling in the differential diagnosis of Cushing's syndrome: results of an Italian multicenter study.
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OBJECTIVE: To evaluate the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) in the differential diagnosis of ACTH-dependent Cushing's syndrome as compared with pituitary imaging techniques. DESIGN AND METHODS: We retrospectively studied the diagnostic accuracy of basal and post corticotropin-releasing hormone (CRH) IPSS, magnetic resonance imaging and computed tomography in distinguishing pituitary from ectopic ACTH secretion in 97 Cushing's syndrome patients: 74 with Cushing's disease (CD) and 10 with ectopic ACTH secretion (EAS). Thirteen patients were excluded because of unconfirmed diagnosis. The difference between IPSS and pituitary imaging techniques in the correctly localized pituitary adenoma in the patients with CD was also investigated. RESULTS: The basal ACTH inferior petrosal sinus:periphery (IPS:P) ratio was > or = 2 in 63/74 patients with CD (85%), and in 1/10 EAS patients (10%); after stimulation with CRH, the ratio was > or = 3 in 60/68 patients with CD (88%) and < 3 in all patients with EAS. The basal and post-CRH ACTH IPS:P ratios had a diagnostic accuracy of 86% and 90% respectively. The diagnostic accuracy of IPSS with both ratios was significantly higher than magnetic resonance imaging (50%) and computed tomography (40%). The IPS:P ratio suggested by receiver-operator characteristic (ROC) analysis that better distinguished CD from EAS was 2.10 for the basal and 2.15 for the post-CRH ratios. Using these cut-offs, the specificity of basal ratio and the sensitivity of the post-CRH test rose to 100% and 93% respectively. Diagnostic accuracy remained substantially unchanged for the basal ratio (87% vs 86%), while it rose from 90% to 94% for the post-CRH ratio. The sensitivity of IPSS was significantly higher than that of magnetic resonance and computerized tomography. IPSS was less reliable in identifying the adenoma site found at surgery than magnetic resonance imaging or computed tomography (65% vs 75% and 79% respectively). CONCLUSION: In conclusion, IPSS improved the diagnostic performance of imaging techniques. It can help in excluding transsphenoidal surgery in EAS patients. More striking results were obtained when a > or = 2.1:1 basal ratio or a > or = 2.15:1 post-CRH ratio were considered as criteria to distinguish between patients with CD and EAS. To establish correctly the location of the pituitary adenoma, IPSS is less reliable than imaging techniques. (+info)
A case of aldosterone-producing adrenocortical adenoma associated with preclinical Cushing's syndrome and hypersecretion of parathyroid hormone.
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A rare case of aldosterone-producing adrenocortical adenoma with preclinical Cushing's syndrome and hypersecretion of parathyroid hormone (PTH) is described. A 64-year-old male patient had a history of hypertension for two decades and hypokalemia for 4 years. He suffered from left hemiparesis and aphasia due to cerebral hemorrhage, but his appearance was not Cushingoid. His plasma renin activity was below the normal range, while plasma aldosterone concentration was high. They did not respond to furosemide-upright test. His plasma cortisol level in the morning was at the upper limit of the normal range, but it did not show a diurnal rhythm nor was it suppressed by 1 mg and 8 mg of dexamethasone. Computed tomography showed a low density tumor in the right adrenal gland. An adrenal scintigram under dexamethasone treatment revealed an uptake of the tracer on the right side, and plasma aldosterone and cortisol concentrations in the adrenal vein were higher on the right side than on the opposite. The diagnosis of right aldosterone-producing adrenal adenoma with an autonomous production of cortisol was confirmed by right adrenalectomy. Histological findings showed an adenoma consisting mostly of clear cells, but that the nests of compact cells were scattered. Analysis of an extract from the adenoma revealed that the adenoma contained an excess amount of aldosterone and that the cortisol/corticosterone ratio was higher than that of aldosterone-producing adenoma. Both serum calcium and PTH levels remained high one year after adrenalectomy. Ultrasonography revealed the swelling of a parathyroid gland on the left side, indicating the coexistence of an autonomous hyperparathyroidism. (+info)
Postoperative plasma cortisol levels predict long-term outcome in patients with Cushing's disease and determine which patients should be treated with pituitary irradiation after surgery.
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Transsphenoidal surgery is the treatment of choice for ACTH-producing pituitary adenoma (Cushing's disease) and pituitary irradiation is widely considered the most appropriate treatment for patients with Cushing's disease for whom transsphenoidal surgery has been unsuccessful. We studied 49 consecutive patients who underwent transsphenoidal surgery for the treatment of Cushing's disease at Tokyo Women's Medical University from 1977-1997 with a mean follow-up duration of 87.6 months (range, 24-253 months). We examined the relationship between postoperative endocrinological data, assessed between 3 and 8 weeks after surgery, and long-term outcome and efficacy of pituitary irradiation after surgery. Long-term remission was defined as the regression of the symptom and signs of Cushing's syndrome, and restoration of normal levels of plasma ACTH, cortisol and urinary free cortisol, together with adequate suppression of morning plasma cortisol levels following the administration of low dose (1 mg) of dexamethasone. Thirty patients had no additional treatment after pituitary surgery. Only 1 of 25 patients (4%) whose postoperative plasma cortisol level was less than 2 microg/dl developed recurrent disease whereas 3 out of 5 patients with postoperative plasma cortisol levels higher than 2 microg/dl relapsed. Postoperative external pituitary radiation was used to treat the remaining 19 patients. Four patients who received radiation therapy had a low or undetectable postoperative plasma cortisol level (<2 microg/dl, 56 nmol/L) and all of these patients developed hypopituitarism whereas 5 patients with subnormal plasma cortisol levels (2.0-10.0 microg/dl) remained in remission. Among 10 patients with persistent disease after surgery, 6 entered remission 6-47 months after irradiation but one of them subsequently relapsed after 108 months. These results suggest that 1) additional therapy should be avoided in patients with a postoperative plasma cortisol less than 2 microg/dl because relapse is very rare and radiotherapy will frequently induce hypopituitarism, 2) patients with a subnormal cortisol level following surgery should be treated with pituitary irradiation, because the relapse rate is reportedly high and radiotherapy is effective in preventing relapse, 3) radiotherapy in patients with persistent disease after surgery is effective only in 50% (5/10) of the patients. (+info)
Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing syndrome: possible contribution for the autonomous production of cortisol.
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OBJECTIVE: To examine whether inhibition of endogenous adrenocorticotropin (ACTH) secretion in patients with Cushing syndrome affects the expression of the ACTH receptor (ACTH-R) gene in adrenocortical adenoma and attached atrophic normal gland. SUMMARY BACKGROUND DATA: ACTH increases adrenal cell growth and steroidogenesis by means of ACTH-R. In vivo and in vitro studies have shown that expression of ACTH-R is upregulated by its own ligand ACTH in several species. In patients with Cushing syndrome resulting from adrenocortical adenoma, there is autonomous production of cortisol from the adenoma. This strongly inhibits endogenous ACTH secretion, giving rise to the speculation that the expression of the ACTH-R gene in these patients is also suppressed. However, previous studies have shown that administration of exogenous ACTH to these patients leads to a further increase in the production of cortisol, suggesting the expression of functional ACTH-R in the adenoma. The authors, therefore, examined the expression of the ACTH-R gene in these patients. METHODS: Fourteen patients with Cushing syndrome were studied. Glucocorticoid excess resulting from autonomous production from the adenomas was ascertained, and unilateral adrenalectomy was performed. The levels of ACTH-R and cytochrome P450 side chain cleavage enzyme (P450scc) mRNAs were determined by Northern blot analysis. The entire coding region of the ACTH-R gene in these patients was sequenced. RESULTS: ACTH-R mRNA abundance in the attached atrophic normal adrenals was suppressed and invariably less than that in the normal gland obtained from a patient with renal cancer. However, the expression of ACTH-R mRNA was not suppressed in any of the adenomas. Expression of ACTH-R mRNA in the adenomas was four- to sixfold greater than that in the attached atrophic gland. No mutation in the coding sequence of the ACTH-R gene in the adenoma was detected in any of the patients. The mRNA in the adenomas appeared to be translated into functionally active receptor because intramuscular administration of ACTH resulted in significant increases in plasma cortisol before surgery but not 3 months after surgery. In addition, there was a positive linear correlation between the expressions of ACTH-R and P450scc mRNAs in the adenoma tissue. CONCLUSIONS: Suppressed ACTH secretion in patients with Cushing syndrome results in reduction of the ACTH-R mRNA expression in nonneoplastic adrenocortical cells. However, the regulatory mechanism of ACTH-R expression might be different in adenoma. Persistent expression in the adenoma of ACTH-R alone, even in the absence of ACTH, might result in increased basal adenyl cyclase activity, as observed in the case of thyroid-stimulating hormone receptor, and thereby might play a role in the autonomous production of cortisol. (+info)
Lung carcinoid related Cushing's syndrome: report of three cases and review of the literature.
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Three patients with lung carcinoid related Cushing's syndrome (LCRCS) treated at Frenchay Hospital, Bristol between 1984 and 1994 are described. The first patient presented with hyperpigmentation 13 years after bilateral adrenalectomy. The second patient had no recurrence or metastases 14 years after removal of a typical carcinoid tumour. The last patient survived nine years after diagnosis of liver metastasis. The possibility of LCRCS should be considered in every patient proved to have Cushing's disease and bilateral adrenal enlargement on abdominal computed tomography. Biochemical sets of investigation (for example, adrenocorticotrophic hormone (ACTH) stimulation, dexamethasone suppression, and metyrapone response) could be misleading and should not be relied upon solely. Search for an ectopic ACTH source should be called off only when ACTH has been demonstrated in the surgically removed specimen, and most importantly, when the serum ACTH concentration returns to normal after surgery. Lung carcinoid tumours are compatible with long survival, and liver metastasis could prove indolent and slowly growing. (+info)
Cushing's syndrome presenting as disseminated cutaneous Mycobacterium chelonae infection.
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Mycobacterium chelonae infection has not to our knowledge been reported as a complication of endogenous Cushing's syndrome. We describe a patient who presented with sporotrichoid M. chelonae infection and olecranon bursitis whose symptoms did not completely resolve until after bilateral adrenalectomy. (+info)
Bone loss determined by quantitative ultrasonometry correlates inversely with disease activity in patients with endogenous glucocorticoid excess due to adrenal mass.
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OBJECTIVE: Glucocorticoid excess is widely recognized as one of the most important causes of bone loss. The mechanism of glucocorticoid-induced osteoporosis is presumably multifactorial, and consists of the loss of organic and non-organic compounds. Efforts have been made to develop simple physical methods for the assessment of bone tissue for the screening of subjects at high risk of osteoporosis, without the use of radioactive sources or ionizing radiation. Quantitative ultrasonometry (QUS) has been suggested as a useful method for monitoring patients undergoing glucocorticoid therapy, which is the most common cause of glucocorticoid excess. QUS appears to detect more structural bone changes than the traditional methods and allows assessment of bone density and elasticity, both characteristics influenced by organic and non-organic bone compounds. However, the use of QUS has not yet been extensively investigated in subjects with endogenous cortisol excess. The aim of this study was to evaluate the usefulness and predictive power of QUS in assessing bone loss in subjects with differing degrees of endogenous cortisol excess due to adrenal mass. DESIGN: Thirty-four patients (20 women and 14 men) aged between 21 and 59 years were evaluated; fifteen (9 women and 6 men; median age, 42 years) were affected by overt Cushing's syndrome (CS) and nineteen (11 women and 8 men; median age, 44 years) by subclinical CS, defined as lacking clinical signs of hormone excess despite the presence of at least two abnormalities in hypothalamic-pituitary-adrenal axis function, as assessed by routine endocrine tests. All women included were eumenorrhoic. METHODS: QUS measurement of amplitude-dependent speed of sound was performed on the 2nd to 5th proximal phalanges of the non-dominant hand using a DBM Sonic 1200R bone profiler (Igea S.r.l, Italy). The results were compared with bone density assessed on lumbar vertebrae (L1-L4) and femoral neck sites by dual-energy X-ray absorptiometry (DEXA). RESULTS: A strongly significant bone loss was detected by finger QUS measurement when the patients were considered either all together or as two subgroups (P<0.001, all). The bone density decrease in the fingers was similar to that found at the lumbar spine and femoral neck by the DEXA technique. Lumbar and finger Z-scores correlated inversely with 24 h urinary free cortisol (UFF) excretion (P<0.01, both). Finger Z-scores also correlated inversely with the estimated duration of subclinical CS (P<0.05). Concerning disease activity, only UFF was confirmed by multivariate analysis to be an independent factor influencing bone loss (P<0.05). A positive correlation between the results of the two techniques was found in controls (P<0.05) but not in patients. The lack of correlation between the two techniques in patients can probably be attributed to the different parameters of bone alteration measured by the techniques. CONCLUSIONS: The detection of bone loss in subclinical CS similar to that in overt CS suggests that all subjects with endogenous cortisol excess should be evaluated for bone mass. QUS measurement appears to be a reliable, radiation-free, simple and fast tool for the identification of bone alteration in subjects with endogenous cortisol excess. (+info)