cortodoxone and ACTH-Syndrome--Ectopic

Inferior petrosal sinus sampling (IPSS) is a useful investigative technique in the differential diagnosis of ACTH-dependent Cushing's syndrome. Diagnostic accuracy is improved by the administration of corticotrophin releasing-factor (CRF) during the procedure to stimulate ACTH secretion. We hypothesized that, given the unavailability of CRF in Australia, stimulation of ACTH secretion from tumorous corticotrophs with metyrapone treatment before IPSS may be useful.. To describe our clinical experience with a novel diagnostic test, and to compare results between IPSS with and without metyrapone pre-treatment.. Metropolitan, Australian university teaching hospital.. 18 patients were studied on 21 occasions: three with Cushing's disease without metyrapone treatment prior to IPSS (M-), 11 with Cushing's disease with metyrapone pretreatment (M+), three with ectopic ACTH syndrome, and one with pseudo-Cushing's syndrome.. Patients received oral metyrapone, median dose 750 mg 6 hourly, for 24 h before IPSS.. No major side effects were noted. Metyrapone increased serum 11-deoxycortisol concentration to a median of 400 nmol/l (range 36-1310) on the morning of the test. Radiological confirmation of correct catheter placement was shown in 36/42 inferior petrosal sinuses (86%). Median peak central: peripheral ACTH ratios were 9.8 for M- pituitary adenomas (range 5.7-13.6), 12.9 for the technically successful M+ pituitary adenomas (range 8-54.1), and 1.6 for M+ ectopic ACTH syndrome cases (range 1.2-3.4). Repeat studies in unoperated patients with ectopic ACTH syndrome showed ratios < 1.6. IPSS showed median peak ACTH concentrations of 190 ng/l for M- pituitary adenomas (range 83-205), 595 ng/l for the technically successful M+ pituitary adenomas (range 80-7630; P = 0.035 compared to M-), and 62 ng/l for M+ ectopic ACTH syndrome cases (range 47-220). IPSS correctly identified the pituitary source of ACTH production in all cases of Cushing's disease (except one technical failure where MRI revealed a lesion). MRI scanning correctly identified a lesion in 3/14 operated Cushing's disease cases. IPSS correctly lateralized 1/3 M- and 7/8 M+ Cushing's disease cases where the procedure was technically successful and surgical descriptions adequate. Pituitary exploration revealed a visible lesion in 75% of cases corresponding to the side predicted by IPSS; 'blind' hemi-hypophysectomy was performed on the side predicted from IPSS in the remainder. All cases of Cushing's disease were cured or improved following surgery, with a median follow-up of 2.8 years (range 0.7-5.9).. Metyrapone pre-treated inferior petrosal sinus sampling is safe, and appears to induce high ACTH output from pituitary corticotroph adenomas. The technique has allowed accurate localization and treatment of pituitary corticotroph microadenomas.

Topics: ACTH Syndrome, Ectopic; Adenoma; Adolescent; Adrenocorticotropic Hormone; Adult; Cortodoxone; Cushing Syndrome; Diagnosis, Differential; Female; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged; Petrosal Sinus Sampling; Pituitary Neoplasms; Stimulation, Chemical

We wished to develop optimal criteria for interpreting the single-dose overnight metyrapone test and to compare the diagnostic efficiency of the overnight and the standard 6-dose metyrapone tests for the differential diagnosis of ACTH-dependent Cushing's syndrome.. Retrospective pilot study based on all patients who completed both metyrapone tests and whose diagnoses were subsequently confirmed surgically.. Sixty-three patients, 57 with pituitary tumours and 6 with ectopic ACTH syndrome, were studied.. The sensitivity and specificity were determined using stimulation of plasma 11-deoxycortisol and suppression of plasma cortisol as endpoints for the overnight test and stimulation of urine 17-hydroxysteroid and plasma 11-deoxycortisol as endpoints for the standard test. The lest response that gave the highest sensitivity for the diagnosis of Cushing's disease, with 100% specificity, was determined for each test endpoint.. Both the stimulation of plasma 11-deoxycortisol and the suppression of plasma cortisol were expressed as the ratio of the post-metyrapone value to baseline. A plasma 11-deoxycortisol ratio > than 220 or a plasma cortisol ratio > 0.6 was associated with 100% specificity for diagnosis of Cushing's disease by the overnight test. When these two criteria were combined, the sensitivity was 65%, which was significantly higher than that obtained using either steroid alone: 42% for both plasma 11-deoxycortisol and plasma cortisol. The sensitivity of 65% for the overnight test, at 100% specificity, was nearly identical to that of the standard test in the same patients: 67% for the combined criterion of > 70% stimulation of urine 17-hydroxysteroid or > 480-fold increase of plasma 11-deoxycortisol. When the criteria for both the overnight and standard tests were combined, the sensitivity increased to 84%, which was higher than that obtained using the criteria for either test alone (P < 0.02).. The single-dose overnight metyrapone test, which can be performed in 24 hours and which avoids the disadvantages associated with timed urine collections, has a nearly identical sensitivity (for a specificity of 100%) as the 6-dose standard metyrapone test for the diagnosis of Cushing's disease. Furthermore, the diagnostic performance of a criterion that combines the results of both tests is significantly better than the best criterion for either test alone.

Topics: ACTH Syndrome, Ectopic; Cortodoxone; Cushing Syndrome; Humans; Hydrocortisone; Metyrapone; Pilot Projects; Pituitary Neoplasms; Retrospective Studies; Sensitivity and Specificity

To analyse the clinical and biochemical effects of metyrapone in the treatment of Cushing's syndrome.. An evaluation of the standard clinical practice at one institution.. Ninety-one patients with Cushing's syndrome: 57 pituitary-dependent Cushing's disease, 10 adrenocortical adenomas, six adrenocortical carcinomas and 18 ectopic ACTH syndrome.. The acute response to metyrapone was assessed by measuring cortisol, 11-desoxycortisol and ACTH at 0, 1, 2, 3, 4 hours after a test dose of 750 mg of metyrapone. The longer-term effect of metyrapone was judged by measuring serum cortisol at 0900, 1200, 1500, 1800, 2100 and sometimes 2400 h and calculating a mean.. A test dose of 750 mg of metyrapone decreased serum cortisol levels within 2 hours in all groups of patients and this effect was sustained at 4 hours. At the same time, serum 11-desoxycortisol levels increased in all patients, while plasma ACTH increased in patients with pituitary Cushing's disease and the ectopic ACTH-syndrome. Fifty-three patients with Cushing's disease were followed on short-term metyrapone therapy (1 to 16 weeks) before other more definitive therapy. Their mean cortisol levels (median 654 nmol/l, range 408-2240) dropped to the target range of less than 400 nmol/l in 40 patients (75%) on a median metyrapone dose of 2250 mg/day (range 750-6000). Metyrapone was given long term in 24 patients with Cushing's disease who had been given pituitary irradiation, for a median of 27 months (range 3-140) with adequate control of hypercortisolaemia in 20 (83%). In 10 patients with adrenocortical adenomas and six with adrenocortical carcinomas, metyrapone in a median dose of 1750 mg/day (range 750-6000) reduced their mean cortisol levels (median 847 nmol/l, range 408-2000) to less than 400 nmol/l in 13 patients (81%). In 18 patients with the ectopic ACTH-syndrome the 'mean cortisol levels', obtained from five or six samples on the test day (median 1023 nmol/l, range 823-6354) were reduced to less than 400 nmol/l in 13 patients (70%), on a median dose of 4000 mg/day (range 1000-6000). Reduction of cortisol levels was clearly associated with clinical and biochemical improvement. The medication was well tolerated. Transient hypoadrenalism and hirsutism were unusual but were the most common side-effects.. In our experience metyrapone remains a most useful agent for controlling cortisol levels in the management of Cushing's syndrome of all types.

Topics: ACTH Syndrome, Ectopic; Adenoma; Adolescent; Adrenal Cortex Neoplasms; Adrenocorticotropic Hormone; Adult; Aged; Carcinoma; Cortodoxone; Cushing Syndrome; Depression, Chemical; Female; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged; Time Factors