cortodoxone and Cushing-Syndrome

Topics: Adrenal Cortex Diseases; Adrenal Hyperplasia, Congenital; Biomarkers; Cortodoxone; Cushing Syndrome; Humans; Hyperaldosteronism; Radioimmunoassay; Reference Values; Specimen Handling

Topics: Addison Disease; Adrenal Gland Diseases; Adrenocorticotropic Hormone; Biomarkers; Chromatography, Paper; Colorimetry; Cortodoxone; Cushing Syndrome; Dexamethasone; Gas Chromatography-Mass Spectrometry; Humans; Metyrapone; Radioimmunoassay; Reference Values; Specimen Handling; Thyroid Diseases

Topics: 17-Hydroxycorticosteroids; Adenoma; Adrenal Gland Neoplasms; Adrenal Glands; Adrenocorticotropic Hormone; Blood Specimen Collection; Circadian Rhythm; Corticotropin-Releasing Hormone; Cortodoxone; Cushing Syndrome; Dexamethasone; Diagnosis, Differential; Female; Humans; Hydrocortisone; Metyrapone; Peptides; Pituitary Gland; Pituitary Neoplasms; Potassium; Pregnancy; Tomography, X-Ray Computed

Osilodrostat is a new 11β-hydroxylase inhibitor with a mode of action analogous to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated with either Osilodrostat or Metyrapone for adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome (CS).. Patients followed up at Cochin hospital Endocrinology department between March 2019 and December 2021 for an ACTH-dependent CS, controlled by either Osilodrostat or Metyrapone, were included. A serum profile of five steroids (cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione and testosterone) was determined using UPLC- tandem mass spectrometry (UPLC-MS/MS).. Nineteen patients treated with Osilodrostat, eight patients treated with Metyrapone and six patients treated with consecutive Metyrapone then Osilodrostat were included. Hypocortisolism (basal cortisol <100 nmol/L) was found in 48% of patients treated with Osilodrostat and 7% of patients treated with Metyrapone. 11-deoxycortisol and androstenedione levels were higher in patients treated with Metyrapone (80.9 (2.2-688.4) and 14.9 (2.5-54.3) nmol/L, respectively) than in patients treated with Osilodrostat (10.3 (0.5-71.9) and 4.0 (0.3-13.3) nmol/L) (P = 0.0009 and P = 0.0005). Testosterone level in women was also higher in Metyrapone group (3.3 (0.93-4.82) nmol/L vs 1.31(0.13-5.09) nmol/L, P = 0.0146). CYP11B1 activity (11-deoxycortisol/cortisol) was not significantly different between the two groups. CYP21A2 activity (17OHprogesterone/11-deoxycortisol) and CYP17A1 activity (17OHprogesterone/androstenedione) were significantly decreased in Osilodrostat group (P < 0.0001).. In patients with ACTH-dependent CS, the use of CYP11B1 inhibitors in routine care suggests that Osilodrostat has a less specific effect on the inhibition of steroidogenic enzymes than Metyrapone. This might explain a smaller increase in 11-deoxycortisol and androgen levels in patients treated with Osilodrostat.

Topics: Adrenocorticotropic Hormone; Androstenedione; Chromatography, Liquid; Cortodoxone; Cushing Syndrome; Female; Humans; Hydrocortisone; Imidazoles; Metyrapone; Pyridines; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase; Tandem Mass Spectrometry; Testosterone

The metabolomics of urinary steroids was studied by gas chromatography-mass spectrometry in 25 patients with Cushing's syndrome without malignant potential and in 12 patients with malignant potential of adrenal neoplasms (Weiss score 1-3). Patients with adrenocortical adenoma (N=24) constituted the control group. In patients with Cushing's syndrome and malignant potential, increased urinary excretion of 16-oxo-androstendiol, tetrahydro-11-deoxycortisol, and 16-hydroxypregnendiol, which had 100% specificity and sensitivity >90% for the diagnosis of malignant potential. Additionally, non-classical 5-ene-pregnenes (16-OHpregnenolone, 21-OH-pregnenolone, 3β,16,20-pregnentriol, and 3β,17,20-pregnentriol) were identified. The revealed changes in the metabolomics of steroids can be early signs of malignant potential in patients with Cushing's syndrome. In patients with malignant potential, three signs of reduced activity of 11β-hydroxysteroid dehydrogenase type 2 were detected and in patients without malignant potential, one sign was found. In patients with and without malignant potential, three signs increased activity of 5β-reductase were found.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Adrenal Gland Neoplasms; Adrenocortical Adenoma; Adult; Androstenediols; Biomarkers, Tumor; Cortodoxone; Cushing Syndrome; Early Detection of Cancer; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Metabolomics; Middle Aged; Neoplasm Grading; Oxidoreductases; Pregnenediones; Pregnenes; Pregnenolone

Metyrapone and ketoconazole, frequently used steroidogenesis inhibitors for treatment of Cushing syndrome, can be associated with side effects and limited efficacy. Osilodrostat is a CYP11B1 and CYP11B2 inhibitor, with unknown effects on other steroidogenic enzymes.. To compare the effects of osilodrostat, metyrapone, and ketoconazole on adrenal steroidogenesis, and pituitary adenoma cells in vitro.. HAC15 cells, 17 primary human adrenocortical cell cultures, and pituitary adenoma cells were incubated with osilodrostat, metyrapone, or ketoconazole (0.01 to 10 µM). Cortisol and ACTH were measured using chemiluminescence immunoassays, and steroid profiles by liquid chromatography-mass spectrometry.. In HAC15 cells, osilodrostat inhibited cortisol production more potently (IC50: 0.035 µM) than metyrapone (0.068 µM; P < 0.0001), and ketoconazole (0.621 µM; P < 0.0001). IC50 values of osilodrostat and metyrapone for basal cortisol production varied with a 25- and 18-fold difference, respectively, with comparable potency. Aldosterone production was inhibited more potently by osilodrostat vs metyrapone and ketoconazole. Osilodrostat and metyrapone treatment resulted in strong inhibition of corticosterone and cortisol, 11-deoxycortisol accumulation, and modest effects on adrenal androgens. No pituitary-directed effects of osilodrostat were observed.. Under our study conditions, osilodrostat is a potent cortisol production inhibitor in human adrenocortical cells, comparable with metyrapone. All steroidogenesis inhibitors showed large variability in sensitivity between primary adrenocortical cultures. Osilodrostat might inhibit CYP11B1 and CYP11B2, in some conditions to a lesser extent CYP17A1 activity, and a proximal step in the steroidogenesis. Osilodrostat is a promising treatment option for Cushing syndrome, and in vivo differences with metyrapone are potentially driven by pharmacokinetic differences.

Topics: Aldosterone; Cell Culture Techniques; Cortodoxone; Cushing Syndrome; Cytochrome P-450 CYP11B2; Enzyme Inhibitors; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Pyridines; Steroid 11-beta-Hydroxylase

Urinary steroid profiling (USP) was studied using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) methods in 108 patients with adrenocortical adenoma (ACA) and in 31 patients with adrenocortical carcinoma (ACC). Thirteen ACC and Cushing's syndrome (ACC-CS) patients had two types of USP as well as 18 ACC patients without hypercortisolism. These four types differed by androgen and glucocorticoid secretion of the adrenal cortex. Fifteen main ACC features were observed by GC-MS. Urinary excretion of dehydroepiandrosterone (DHEA) was increased in 67.7 % of ACC patients and tetrahydro-11-deoxycortisol (THS) in 74.2 %. By combination of the following parameters: THS >900 μg/24 h and/or DHEA >1500 μg/24 h with ratios of 3α,16,20-pregnentriol/3β,16,20-pregnentriol (3α,16,20dP3/3β,16,20dP3) less than 6.0 and 3α,17,20dP3/3β,17,20dP3 less than 9.0 and the detection of "non-classical" 5-en-pregnens, not found in ACA and healthy persons, 100 % sensitivity and specificity of ACC and ACA differential diagnosis were achieved. Features of 21-hydroxylase and 11β-hydroxylase deficiency were observed by GC-MS in 32.2 and 61.3 % of the ACC patients, respectively. Additional features for ACC-CS diagnostic were increased urinary excretion of 6β-hydroxycortisol, 18-hydroxycorticosterone, the sum (UFF + UFE) obtained by HPLC, tetrahydrocorticosterone, and the sum (THF + THE + allo-THF) obtained by GC-MS.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Adrenocortical Carcinoma; Adult; Chromatography, High Pressure Liquid; Cortodoxone; Cushing Syndrome; Dehydroepiandrosterone; Diagnosis, Differential; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase; Steroids; Young Adult

The serum concentrations of cortisol, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, 21-deoxycortisol and 11-deoxycortisol were measured in 19 healthy dogs, 15 dogs with pituitary-dependent hypercortisolism (pdh) and eight dogs with other diseases before and one hour after an injection of synthetic adrenocorticotrophic hormone (acth). At both times the dogs with pdh had significantly higher concentrations of cortisol, 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone and 21-deoxycortisol than the healthy dogs. Basal 11-deoxycortisol concentrations were also significantly higher in dogs with pdh compared with healthy dogs. When compared with the dogs with other diseases, the dogs with pdh had significantly higher basal and post-acth cortisol and basal 21-deoxycortisol, and significantly lower post-acth 11-deoxycortisol concentrations. The dogs with other diseases had significantly higher post-acth cortisol, 17alpha-hydroxyprogesterone and 11-deoxycortisol concentrations than the healthy dogs. In general, the post-acth concentrations of 17alpha-hydroxypregnenolone, 17alpha-hydroxyprogesterone, 11-deoxycortisol and 21-deoxycortisol were more variable than the post-acth concentrations of cortisol, resulting in large overlaps of the concentrations of these hormones between the three groups. A two-graph receiver operating characteristic (ROC) analysis was used to maximise the sensitivity and specificity of each hormone for diagnosing hypercortisolism; it showed that the post-acth concentration of cortisol had the highest sensitivity and specificity. The overlaps between the healthy dogs, the dogs with pdh and the dogs with other diseases suggested that the individual precursor hormones would not be useful as a screening test for hypercortisolism.

Topics: 17-alpha-Hydroxypregnenolone; 17-alpha-Hydroxyprogesterone; Adrenocorticotropic Hormone; Animals; Case-Control Studies; Cortodoxone; Cushing Syndrome; Dog Diseases; Dogs; Female; Hormones; Hydrocortisone; Male; Pregnenediones; Radioimmunoassay; ROC Curve; Sensitivity and Specificity

The prevalence of steroid secretion abnormalities was studied by evaluating the 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (S) responses to adrenocorticotropic hormone (ACTH) stimulation in 48 patients with 'nonfunctioning' incidentalomas and in 10 patients with 'subclinical' Cushing's syndrome.. In all patients the cortisol, 17-OHP, and S levels were measured after ACTH test. Eight patients were reinvestigated after surgery.. In patients with nonfunctioning lesions, the ACTH test induced 17-OHP and S peaks higher than in normals (p < 0.005). In 10 cases an augmented rise of 17-OHP and S was observed. In patients with subclinical Cushing's syndrome, the 17-OHP peak after ACTH was greater than in patients with nonfunctioning lesions and in normals (p < 0.005); the S peak was also higher than in controls (p < 0.005). In 7 of 8 operated patients, the exaggerated 17-OHP peak was normalized.. A combined impairment of different enzyme activities is frequently present in adrenal incidentalomas; the alteration of enzymatic pathways can also coexist with the presence of partial cortisol autonomy.

Topics: 17-alpha-Hydroxyprogesterone; Adenoma; Adrenal Gland Neoplasms; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Aged; Cortodoxone; Cushing Syndrome; Female; Humans; Hydrocortisone; Male; Middle Aged

Topics: Adrenocorticotropic Hormone; Adult; Cortodoxone; Cushing Syndrome; Dexamethasone; Female; Humans; Hydrocortisone; Infant, Newborn; Male; Pregnancy; Pregnancy Complications; Pregnancy, Multiple; Twins, Dizygotic

Topics: Adrenocorticotropic Hormone; Chromatography, Gas; Corticotropin-Releasing Hormone; Cortodoxone; Cushing Syndrome; Humans; Hydrocortisone

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

ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) is a rare cause of Cushing's syndrome in which adrenal glands become very enlarged, occupied and distorted by multiple cortical nodules. We report on such two patients, a 44-year-old man and a 40-year-old woman. Physical examination revealed in both cases a classic cushingoid habit. Laboratory studies showed overt hypercortisolism with high urinary free cortisol excretion and elevated serum cortisol with loss of the circadian rhythm. Serum cortisol levels were not modified after high dose dexamethasone. ACTH levels were undetectable both in baseline conditions and following CRH or metyrapone. In both cases, abdominal CT demonstrated bilaterally enlarged adrenal glands which were distorted by multiple bumps. 131I-Norcholesterol scintiscan showed bilateral uptake of the radionuclide. Pituitary region was normal at neuroradiologic imaging. Bilateral adrenalectomy was performed in both cases. In patient I, adrenal glands weighted 77 and 90 g, respectively, while in patient II they were of 90 and 55 g, respectively. At histological examination, the adrenal cortex was occupied by multiple nodular lesions composed mostly of clear cells. In the internodular regions, no evidence of cortical architecture was observed. At the immunohistochemical evaluation, both cases displayed KI-67 staining comparable with that of ACTH-dependent diffuse hyperplasia. Postoperative course was uneventful and signs of Cushing's syndrome resolved in about three months. At the last follow up, the patients are going well on glucocorticoid and mineralocorticoid supplementation. Plasma ACTH levels are 65 and 107 pg/ml, respectively.

Topics: Adrenal Cortex; Adrenal Cortex Function Tests; Adrenalectomy; Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Cortodoxone; Cushing Syndrome; Female; Follow-Up Studies; Humans; Hydrocortisone; Hyperplasia; Male; Radionuclide Imaging; Tomography, X-Ray Computed

The prediction of relapse during the early months after transsphenoidal surgery for Cushing's disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation.. From a retrospective series of 77 consecutive primary pituitary operations for Cushing's disease 29 patients, who also had a metyrapone test at 14 days postoperatively, were selected. Median follow-up was 35 months (range: 8-118 months).. Early postoperative: fasting morning serum cortisol, 24-hour urinary cortisol excretion, serum 11-deoxycortisol after 6 x 750 mg metyrapone. Remission was defined as a fasting morning serum cortisol < 140 nmol/l and/or 24-hour urinary cortisol excretion < 250 nmol. During follow-up: serum cortisol, as well as serum cortisol in the 1 mg overnight dexamethasone-suppression test was measured in order to detect relapse of Cushing's disease.. Twelve of 29 patients were not in remission after surgery. These patients all had serum 11-deoxycortisol levels > 350 nmol/l after metyrapone. Seventeen patients met the criteria for early remission. Four of these patients had serum 11-deoxycortisol levels between 150 nmol/l and 350 nmol/l after metyrapone. Three of these 4 patient's experienced a relapse of Cushing's disease during follow-up. In the 13 patients with a serum 11-deoxycortisol < 150 nmol/l after metyrapone, no relapse occurred.. The metyrapone test is a useful test in the assessment of outcome of pituitary surgery for Cushing's disease, with a sensitivity of 100% and a specificity of 75% for the early detection of patients at risk of a relapse. Patients in whom a serum 11-deoxycortisol > 150 nmol/L is found after metyrapone are at a high risk for relapse of Cushing's disease.

Topics: Adolescent; Adult; Cortodoxone; Cushing Syndrome; Dexamethasone; Female; Glucocorticoids; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged; Pituitary Gland; Postoperative Period; Predictive Value of Tests; Recurrence; Retrospective Studies; Sensitivity and Specificity; Treatment Outcome

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

A 28-year old female patient with virilization due to left adrenocortical adenoma was studied. The patient had clinical features of hyperandrogenism such as hirsutism and a low pitched voice, but not of hypercorticoidism. Plasma testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were high. Although the basal plasma cortisol concentration and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were within the normal range, the absence of diurnal variation in plasma cortisol and loss of suppressibility by dexamethasone suggested constitutive secretion of cortisol by the tumor. Inappropriate cortisol secretion was also supported by blunted ACTH response to provocative stimuli. After successful removal of the left adrenal tumor, such endocrinological abnormalities were all normalized. Immunohistochemical analysis revealed that tumor cells were positively stained for C21 hydroxylase cytochrome P-450 (P-450C21) and P-450(11) beta which convert 17-hydroxy (OH) progesterone to cortisol as well as P-450SCC, 3 beta-hydroxysteroid dehydrogenase and P-450(17) alpha which are involved in testosterone biosynthesis. These findings suggest that adrenocortical adenoma secretes predominantly testosterone and constitutively cortisol in a young woman patient with virilization.

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adenoma; Adrenal Cortex Neoplasms; Adult; Circadian Rhythm; Cortodoxone; Cushing Syndrome; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Dexamethasone; Female; Humans; Hydrocortisone; Immunohistochemistry; Japan; Testosterone

To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test.. Retrospective cohort study.. Inpatient research ward.. 186 patients believed to have the ACTH-dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH.. The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used.. 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively.. The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone.

Topics: Adrenocorticotropic Hormone; Cortodoxone; Cushing Syndrome; Decision Trees; Dexamethasone; Diagnosis, Differential; Humans; Hydrocortisone; Hydroxysteroids; Likelihood Functions; Metyrapone; Pilot Projects; Pituitary Function Tests; Retrospective Studies; ROC Curve; Sensitivity and Specificity

We report a patient with Cushing's syndrome in whom the etiology of the hypercortisolemia could not be definitely established despite extensive biochemical investigations. Results included raised basal serum cortisol, plasma ACTH, and urinary free cortisol; failure to suppress even a paradoxical rise in serum cortisol after dexamethasone (1 mg overnight, 2, 8, and 16 mg/day); and a definite but not exaggerated rise in 11-deoxycortisol after metyrapone. After iv CRF, plasma ACTH rose from 22 to 30 pmol/L. Abdominal computed tomographic scanning showed adrenal hyperplasia; the presence of an adrenal adenoma, although suspected, was not established. An unusual finding was the presence in the urine of large amounts of 21-deoxycortisol metabolites, including 3 alpha,11 beta,17 alpha-trihydroxy-5 beta-pregnan-20-one and 5 beta-pregnane 3 alpha,11 beta,17 alpha,20 alpha-tetrol. On the basis of preoperative biochemical/radiological findings, a provisional diagnosis of ACTH-dependent Cushing's syndrome associated with autonomous bilateral adrenal hyperplasia was made. Incomplete bilateral adrenalectomy was performed; adrenal hyperplasia was histologically confirmed, but no tumor was found. However, ACTH was measured 1) just before operation when the patient was receiving treatment with metyrapone, and 2) postoperatively when the patient was receiving steroid replacement only, and on these occasions ACTH levels were lower than during the initial investigations. Pituitary scans before and after adrenalectomy were similar, offering no evidence of pituitary infarction. We propose that abnormal production of 21-deoxycortisol contributed to the aberrant regulation of ACTH and cortisol in this case, providing an example of a previously unreported cause of hypercortisolemia.

Topics: Adrenal Glands; Adrenocorticotropic Hormone; Adult; Cortodoxone; Cushing Syndrome; Dimethyl Sulfoxide; Female; Humans; Hydrocortisone; Hyperplasia

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

We measured cortisol and precursor steroid production in response to ACTH, cholera toxin, and forskolin by the dispersed adrenocortical cells prepared from the adrenal glands of 10 patients with different forms of Cushing's syndrome. The cells prepared from the hyperplastic adrenal glands from 4 patients with Cushing's disease responded in a dose-dependent manner to ACTH, cholera toxin, and forskolin. The adrenal cells prepared from 4 encapsulated adrenal adenomas showed no (n = 2), a lowered (n = 1), or a clear (n = 1) response of cortisol release to ACTH. The cells prepared from the adrenal glands of 1 patient with dysplastic micronodular adrenal glands showed a limited response to ACTH, while the cells from an adrenocortical carcinoma, which secreted very little cortisol per cell, were unresponsive to ACTH, cholera toxin, and forskolin. The reaction of the dispersed adrenal cells from these 10 patients to ACTH, cholera toxin, and forskolin showed a close correlation (P less than 0.001 in all instances). This suggests that the defect in autonomous glands is not located at the level of the ACTH receptor, but, rather, involves the adenylate cyclase complex as a whole or its coupling to cAMP-dependent protein kinase. The release into the medium of the cortisol precursors deoxycortisol, 17-hydroxyprogesterone, and progesterone showed that the four autonomous nodules were characterized by a significantly higher deoxycortisol/cortisol ratio in the medium (P less than 0.01), suggesting a relative blockade of 11 beta-hydroxylase in these adrenal adenomas. This was further substantiated in cells from several adrenals by a significant increase in the release of these precursors in response to ACTH in the absence of a cortisol response. We conclude the following. 1) Adrenal adenoma formation in patients with Cushing's syndrome is accompanied by a parallel decrease in the stimulation of the release of steroid hormones in response to ACTH, cholera toxin, and forskolin. This points to a defect in the adenoma cells beyond the ACTH receptor. 2) Adrenal adenoma formation in patients with Cushing's syndrome is accompanied by a relative blockade of 11 beta-hydroxylase activity. 3) By comparing the preoperative dynamic tests of the pituitary-adrenal axis, the plasma ACTH concentration, the morphology of the adrenal glands, and their in vitro responsiveness, a gradual transition from pituitary to (partial) adrenal autonomy could be recognized in several patients.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Cholera Toxin; Colforsin; Cortodoxone; Culture Media; Cushing Syndrome; Dose-Response Relationship, Drug; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Male; Middle Aged; Pituitary-Adrenal System; Progesterone

We present nine cases of primary adrenocortical carcinoma, collected in our department of medicine and endocrinology over 25 years. In our patients, the most dependable tumor marker was urinary excretion of tetra-hydro-ll-deoxycortisol (THS), and elevated values were found in all cases where it was determined. In addition to surgical treatment, medication with o,p'-DDD was found to be of value for some of the patients. Median tumor weight was 487 g (118-2,085 g). Prognosis is difficult to predict. Median survival time after diagnosis was 34 months, but varied from three to 266 months.

Topics: 17-Ketosteroids; Adrenal Cortex Neoplasms; Adult; Aged; Biomarkers, Tumor; Cortodoxone; Cushing Syndrome; Female; Humans; Hydrocortisone; Male; Middle Aged; Mitotane; Neoplasm Metastasis; Prognosis

We have investigated the combined use of metyrapone and sodium valproate in the treatment of five cases of dexamethasone-suppressible Cushing's disease and one case with dexamethasone non-suppressible disease. Metyrapone alone reduced 24 h urinary free cortisol (UFC) and plasma cortisol concentrations. Addition of sodium valproate to metyrapone produced a further reduction in these values in five of six patients with a reduction in plasma ACTH in three of five patients who had dexamethasone-suppressible disease. Plasma 11-deoxycortisol increased markedly on metyrapone. However, addition of valproate produced a further rise in 11-deoxycortisol values in four of five patients including the patient with dexamethasone non-suppressible disease. The results suggest that valproate may be a useful addition to metyrapone in the medical treatment of some patients with Cushing's syndrome and that it may have an action both at the hypothalamus and peripherally.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Cortodoxone; Cushing Syndrome; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Male; Middle Aged; Pyridines; Valproic Acid

Selective adrenal vein catheterization was done preoperatively in 11 patients with Cushing's syndrome owing to either an adrenal adenoma (6) or an adrenal carcinoma (5). Peripheral and adrenal venous blood (tumor side) was analyzed for progesterone, 17-hydroxyprogesterone, testosterone, delta-4-androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol and 11-deoxycortisol. Comparisons were made of the ratios of precursors to products in the androgen and cortisol production pathways. In adrenal vein samples, cortisol levels were higher in the adenoma patients (p equals 0.06). These patients had a higher ratio of 17-hydroxyprogesterone to delta-4-androstenedione (p less than 0.04). The ratio of 11-deoxycortisol to cortisol was higher in the carcinoma patients (p less than 0.02). In the peripheral samples, the carcinoma patients had higher levels of testosterone and 11-deoxycortisol (p less than 0.02) and progesterone (p equals 0.05). The most striking differences were in the peripheral levels of 17-hydroxyprogesterone, delta-4-androstenedione and dehydroepiandrosterone, which were 10 to 20 times higher in the carcinoma group (p less than 0.005). The ratios of progesterone to 17-hydroxyprogesterone and 17-hydroxyprogesterone to 11-deoxycortisol were higher in the adenoma group (p less than 0.005 and p equals 0.06, respectively). The peripheral blood ratio of 11-deoxycortisol to cortisol was higher in the carcinoma group (p less than 0.03). These data indicate that peripheral and adrenal venous steroid levels and ratios of precursors to products are significantly different in the 2 groups. The carcinomas have a block in the conversion of 11-deoxycortisol to cortisol with a subsequent accumulation in androgen and cortisol precursors. The elevations in 17-hydroxyprogesterone, delta-4-androstenedione and dehydroepiandrosterone, and in the ratio of 11-deoxycortisol to cortisol in the carcinoma group are most striking in the periphery. Peripheral blood steroid measurement in patients with Cushing's syndrome and an adrenal mass aids in the preoperative differentiation of carcinoma from adenoma.

Topics: 17-alpha-Hydroxyprogesterone; Adenoma; Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Androstenedione; Carcinoma; Cortodoxone; Cushing Syndrome; Dehydroepiandrosterone; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Male; Progesterone; Testosterone

Eleven beta-hydroxylase activity was assessed by measuring the cortisol to 11-deoxycortisol ratio in 20 control subjects, 38 patients with major depression, and five patients with Cushing's disease before and after 1 mg of dexamethasone. The mean levels of 11 beta-hydroxylase activity did not differ among groups before dexamethasone. After dexamethasone patients with Cushing's disease showed a nonsignificant increase in 11 beta-hydroxylase activity while patients with major depression and controls subjects both showed a decrease. Endogenous depressive patients were no more likely to show high 11 beta-hydroxylase activity than neurotic depressive patients; however, depressed patients with cortisol nonsuppression after dexamethasone were. Post-dexamethasone 11 beta-hydroxylase activity is positively correlated with age in both control subjects and patients with depression.

Topics: Adult; Cortodoxone; Cushing Syndrome; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

Eleven-beta-hydroxylase activity was measured before and after acute adrenocorticotrophic hormone (ACTH) stimulation in 28 controls, 25 depressed Dexamethasone Suppression Test (DST) suppressors, 13 DST nonsuppressor patients, and 8 patients with Cushing's syndrome to investigate changes in states of cortisol hypersecretion. Eleven-beta-hydroxylase activity was equivalent among groups both before and after stimulation. Such 11-beta-hydroxylase stability, however, resulted in higher cortisol and 11-deoxycortisol poststimulation levels in both depressed DST nonsuppressors and Cushing's patients than in controls. Basal 11-beta-hydroxylase activity is positively correlated and 11-deoxycortisol is negatively correlated with age in controls and DST suppressors, but not in the patients tested with evidence of cortisol hypersecretion. These findings suggest that in vivo basal 11-beta-hydroxylase activity rises gradually with age, but does not rise after acute administration of exogenous ACTH. The age relationship is lost in states of cortisol hypersecretion, but the lack of response to acute exogenous ACTH is not affected.

Topics: Adrenocorticotropic Hormone; Adult; Aging; Cortodoxone; Cushing Syndrome; Depressive Disorder; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Sex Factors; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

The direct effects of etomidate, ketoconazole, miconazole and metyrapone were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of a normal individual and four patients with Cushing's syndrome. The drugs interfered with adrenocorticotropic hormone-stimulated cortisol secretion in a dose-dependent way. Desoxycortisol concentrations in the medium were increased after the addition of metyrapone and low doses of etomidate but were suppressed with higher doses of etomidate. The production of 17-hydroxy-progesterone was stimulated by miconazole and metyrapone but was strongly suppressed by the high doses of etomidate. Ketoconazole caused a stimulation of progesterone release, whereas the release of 17-hydroxyprogesterone was suppressed. Finally, the concentration of progesterone was strongly enhanced with high doses of miconazole, whereas etomidate suppressed progesterone production. It is concluded that etomidate at a low concentration (IC50, 10(-8) M) inhibits 11 beta-hydroxylase, whereas, at higher concentrations (10(-7)-10(-6) M), the side-chain cleavage enzyme system is also inhibited; metyrapone is a weaker (IC50, 10(-7) M) but pure 11 beta-hydroxylase inhibitor; miconazole inhibits adrenal 21-hydroxylase at 10(-6) M; and ketoconazole inhibits 17-hydroxylase. Etomidate, ketoconazole, miconazole and metyrapone inhibit cortisol biosynthesis in the human adrenal gland in different manners, which appear to involve the four cytochrome P-450-dependent monooxygenase reactions. Interestingly, these drugs affect corticosteroidogenesis by normal, hyperplastic and adenomatous adrenal cells in a similar manner.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Cortex; Adrenocorticotropic Hormone; Cortodoxone; Cushing Syndrome; Etomidate; Humans; Hydrocortisone; Hydroxyprogesterones; In Vitro Techniques; Ketoconazole; Metyrapone; Miconazole; Progesterone

A 13-year-old boy was diagnosed as suffering from pituitary-dependent Cushing's syndrome. He was treated with 2.0 g of metyrapone daily as the sole treatment for four years. All clinical and biochemical stigmata of Cushing's disease disappeared within a few months. The patient grew 23.0 cm in four years and regained normal health. No significant side effects of metyrapone were noticed. Administering the medication at 2 PM and 8 PM allowed higher cortisol levels in the morning and noon hours than in the evening and night, approximating the normal diurnal variation in cortisol production. We conclude that metyrapone may be considered the sole treatment in patients with Cushing's disease.

Topics: Adolescent; Adrenocorticotropic Hormone; Circadian Rhythm; Cortodoxone; Cushing Syndrome; Drug Administration Schedule; Humans; Hydrocortisone; Male; Metyrapone; Radioimmunoassay

A 77-year old woman with pituitary-driven Cushing's disease is described. The condition was completely controlled on long-term treatment with metyrapone.

Topics: Adrenocorticotropic Hormone; Age Factors; Aged; Cortodoxone; Cushing Syndrome; Female; Humans; Hydrocortisone; Metyrapone

Unstimulated plasma ACTH concentrations remain at or below the detection limit of conventional immunoassays. Grossly elevated ACTH concentrations are diagnostic in suspected adrenal insufficiency, remain elevated well above 200 ng/l during substitution therapy and obviate the need of further tests. For the diagnosis of secondary adrenal failure, plasma ACTH, cortisol and 11-desoxycortisol response to a single midnight dose of metyrapone (1.2 g/m2 = 30 mg/kg) discriminates between a normal (morning ACTH above 100 ng/l), diminished (morning ACTH detectable, but below 100 ng/l), and an absent (ACTH below 20 - 40 ng/l) ACTH reserve. In congenital adrenal hyperplasia, plasma ACTH concentrations mirror, together with 17-alpha-hydroxyprogesterone, the extent of ACTH suppression. Elevated ACTH concentrations were suppressed by prednisolone (25%), dexamethasone (2% of the hydrocortisone dose) or by addition of cyproterone acetate (100 mg/m2/day). Using selective venous catheterisation in clinically and biochemically proven Cushing's syndromes, a pituitary adenoma could be identified and localized in 6 of 8 patients by measuring ACTH concentrations in the left and right petrosal sinus before and after stimulation with corticotrophin releasing hormone.

Topics: 17-alpha-Hydroxyprogesterone; Adenoma; Adrenal Gland Diseases; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Adrenocorticotropic Hormone; Adult; Child; Cortodoxone; Cushing Syndrome; Humans; Hydrocortisone; Hydroxyprogesterones; Metyrapone; Pituitary Neoplasms

Topics: 17-alpha-Hydroxyprogesterone; Addison Disease; Adrenal Cortex Hormones; Adrenal Hyperplasia, Congenital; Child; Chromatography, High Pressure Liquid; Cortodoxone; Cushing Syndrome; Endocrine System Diseases; Humans; Hydrocortisone; Hydroxyprogesterones; Radioimmunoassay; Spectrophotometry, Ultraviolet

An enzyme-linked immunosorbent assay (ELISA) for 11-deoxycortisol is described for the first time. 11-Deoxycortisol-thyroglobulin conjugate is adsorbed onto the wells of a 96-well ELISA plate and competes with 11-deoxycortisol in the standards or plasma extract for antibody binding sites. After washing, immobilized primary antibody is probed with peroxidase-labeled goat anti-rabbit IgG. The ELISA plate is further washed and o-phenylenediamine added, color developed and the absorbance read at 492 nm. The ELISA shows good agreement with our existing 11-deoxycortisol radioimmunoassay (RIA) and has similar specificity and performance which allow its use in the routine steroid laboratory for assessing pituitary adrenal function by the metyrapone test.

Topics: 17-Hydroxycorticosteroids; Animals; Cortodoxone; Cushing Syndrome; Enzyme-Linked Immunosorbent Assay; Humans; Metyrapone; Radioimmunoassay

Seventeen patients with well-proven Cushing's syndrome (13 with Cushing's disease, 3 with adrenal tumour and 1 presenting ectopic ACTH syndrome caused by bronchial carcinoid) were investigated by using a single-dose 8 mg dexamethasone nocturnal test. The results obtained were compared with those of the classical 8 mg Liddle's test, metyrapone stimulation, plasma ACTH concentration and with the final diagnosis reached through surgery, pathologic anatomy, and/or clinical and biochemical follow-up of the patients after treatment. The diagnostic efficacy or the predictive power of the test (defined as the ratio between the number of cases in which the diagnosis was correctly predicted and the total number of cases), was at least 82.4% vs 84.6% for the classical 8 mg Liddle's test. This percentage increased to 94.1% when the results of repeated tests on three patients with conflicting data were included. It is concluded that the nocturnal high-dose dexamethasone suppression test is a valuable tool in the aetiological diagnosis of Cushing's syndrome.

Topics: 17-Hydroxycorticosteroids; Adrenocorticotropic Hormone; Adult; Circadian Rhythm; Cortodoxone; Cushing Syndrome; Dexamethasone; Dose-Response Relationship, Drug; Female; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged; Pituitary-Adrenal Function Tests

We investigated basal and ACTH stimulated levels of cortisol, corticosterone, 17 alpha-hydroxyprogesterone, 11-deoxycortisol and 11-deoxycorticosterone as well as plasma levels of ACTH before and during the oral administration of ketoconazole in five patients with Cushing's syndrome (3 with bilateral adrenal hyperplasia, 1 with adrenal adenoma and 1 with adrenal carcinoma) and in three controls. The influence of ketoconazole on the transformation of 3H-17 alpha-hydroxyprogesterone to 3H-11-deoxycortisol and 3H-cortisol and of 3H-11-deoxycortisol to 3H-cortisol as well as of 3H-11-deoxycorticosterone to 3H-corticosterone was also examined in slices or homogenates of normal and hyperplastic adrenal tissue from four patients. Ketoconazole induced a rise of 11-deoxycortisol and 11-deoxycorticosterone, but not of cortisol and inconsistently of corticosterone which were increased by ACTH. Thus the ratio 11-deoxycortisol/cortisol rose more after ketoconazole than after ACTH and the ratio 11-deoxycorticosterone/corticosterone rose after ketoconazole but fell after ACTH. Plasma ACTH levels were stimulated 2-50 fold by ketoconazole. Incubation studies of adrenal tissue slices with 3H-17 alpha-hydroxyprogesterone showed that ketoconazole inhibited the transformation of 3H-17 alpha-hydroxyprogesterone to 3H-cortisol but not to 3H-11-deoxycortisol so that the ratio 3H-11-deoxycortisol/3H-cortisol increased 15-80 fold. After incubation of adrenal slices with 3H-11-deoxycortisol or 3H-11-deoxycorticosterone and ketoconazole, a 2-260 fold increase of the ratios 3H-11-deoxycortisol/3H-cortisol and 3H-11-deoxycorticosterone/3H-corticosterone were also found.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Glands; Adrenocorticotropic Hormone; Corticosterone; Cortodoxone; Cushing Syndrome; Desoxycorticosterone; Humans; Hydrocortisone; Hydroxyprogesterones; Ketoconazole; Steroid 11-beta-Hydroxylase; Steroid Hydroxylases

A case of adrenal carcinoma with Cushing's syndrome was presented. Endocrinological and morphological investigations disclosed the presence of a functional adrenal carcinoma. This case was characterized by its unusual urinary 17-ketosteroid (17-KS) fractionation, i.e. a marked elevation of 17-KS was accompanied by the increments of etiocholanolone, but not of dehydroepiandrosterone (DHEA) or androsterone. Measurements of the plasma adrenocorticosteroids revealed normal DHEA and DHEA-S (sulfate) levels, moderately increased 17-OH-pregnenolone, and markedly increased (less than 100 times the normal) 11-deoxycortisol (cpd S). Therefore, it seems plausible that the normal urinary DHEA level in this patient would have occurred as a result of remarkably low C17-20 lyase activity sufficient to hamper DHEA production, and that markedly increased etiocholanolone might possibly have been converted from cpd S as well as from DHEA and androstenedione through 5 beta-reduction.

Topics: 17-alpha-Hydroxypregnenolone; 17-Ketosteroids; Adrenal Cortex Neoplasms; Adult; Androstenedione; Androsterone; Cortodoxone; Cushing Syndrome; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Etiocholanolone; Humans; Male; Tomography, X-Ray Computed

o,p'-DDD is an inhibitor of adrenal steroid synthesis currently used for therapy of Cushing's syndrome. Conflicting data have been published on the relationship between the plasma level of the drug and its clinical and biological effects. The levels of o,p'-DDD and o,p'-DDE in various tissues obtained from treated patients have been measured and are compared with data on in vitro steroidogenesis in adrenal tissues from the same patients. o,p'-DDD was found in all samples and o,p'-DDE in half of them, both levels being high when the tissue lipid concentration was high. There was considerable variability in lipid content from one tissue to another and within a tissue from one sample to another; only the drug to lipid ratio seems able to provide a reproducible index of drug entry into a tissue. No relationship was found between the tissue concentration of the drug and the total dose administered or inhibition of the steroid biosynthetic step studied.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Gland Neoplasms; Adrenal Glands; Adult; Carcinoma; Child; Cortodoxone; Cushing Syndrome; Desoxycorticosterone; Dichlorodiphenyl Dichloroethylene; Female; Humans; Hydroxyprogesterones; Hyperplasia; In Vitro Techniques; Male; Middle Aged; Mitotane; Steroids

Serum 11-deoxycortisol (S) determination has been used to evaluate the pituitary adrenal response to the short metyrapone (MTP) test. The validity of this indirect evaluation of corticotrophin ACTH reserve has been questioned since the MTP-induced S elevation may reflect a passive accumulation rather than an ACTH activated adrenal response. The purpose of this study was to evaluate the usefulness of serum beta-lipotrophin (beta-LPH) measurement during the short midnight MTP test (30 mg/kg body weight) in patients with pituitary diseases (n = 36) and in patients with Cushing's syndrome (n = 8). In 28/36 patients with pituitary diseases both S and beta-LPH concentrations were increased normally by MTP. In 8/36 patients the beta-LPH response was lacking, while their serum S concentrations increased significantly. The absence of beta-LPH response to MTP in these 8 patients was in good agreement with the diagnosis of ACTH insufficiency because in 7 of them the cortisol response to insulin induced hypoglycaemia was also insufficient. In the 8 patients with Cushing's syndrome serum S concentration increased following MTP administration in all the cases. In 2 with adrenal adenoma the increase of S level was an ACTH-independent phenomenon, since beta-LPH level was undetectable both before and after MTP administration. In 2 patients with ectopic ACTH secretion, the basal beta-LPH concentrations were high and remained unmodified by MTP administration. In the 4 patients with Cushing's disease, MTP administration resulted in a dramatic increase of beta-LPH concentration. We conclude that beta-LPH measurement improves the utility of the short MTP test for investigation of pituitary adrenal function.

Topics: Adrenocorticotropic Hormone; Adult; beta-Lipotropin; Cortodoxone; Cushing Syndrome; Female; Humans; Insulin; Male; Metyrapone; Middle Aged; Pituitary Diseases; Pituitary-Adrenal System

Differentiating the cause of Cushing's syndrome traditionally has depended upon measuring the response of 24-hour urine samples of cortisol or glucocorticoid metabolites to the high-dose (8 mg per day) dexamethasone test. The metyrapone test, however, is more convenient because it is a shorter test and requires the obtainment of serum samples, which can be collected more simply and more reliably than 24-hour urine samples. The usefulness of these two tests has not been adequately evaluated in a large series of patients with Cushing's syndrome. This study prospectively evaluated the accuracy of the dexamethasone and metyrapone tests in determining the cause of Cushing's syndrome in a series of 25 unselected patients. The diagnostic accuracy of these tests was calculated as follows: diagnostic accuracy = true positives and true negatives/study population X 100. Results of this study demonstrated that the metyrapone test was more accurate than the dexamethasone test in differentiating Cushing's disease from adrenocortical neoplasm (diagnostic accuracy, 100 percent versus 81 percent). All patients with Cushing's disease had a normal postmetyrapone 11-deoxycortisol concentration (greater than 10 micrograms/dl), while all patients with adrenocortical neoplasm had a suppressed 11-deoxycortisol concentration (less than 10 micrograms/dl). Thus, this study demonstrates that the metyrapone test is superior to the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.

Topics: Adolescent; Adrenal Cortex Neoplasms; Adult; Aged; Cortodoxone; Cushing Syndrome; Dexamethasone; Diagnosis, Differential; Female; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged; Prospective Studies

An adrenal tumor was discovered fortuitously in a patient with no clinical features of Cushing's syndrome. On adrenal imaging, there was good uptake in the nodule but no visualization of the contralateral adrenal. The latter was seen, however, in a second scan performed under ACTH treatment. In the hormone assessment, basal cortisol and 17-hydroxycorticoids were normal and cortisol diurnal variation was near normal, but a dexamethasone suppression test and ACTH responses to metyrapone and insulin hypoglycemia were abnormal. Eight months after excision of a spongiocytic-type adenoma, the remaining adrenal was visible on scintigram and the hormonal tests were normal. This pattern suggests that the clinical Cushing's syndrome but enough to suppress partially ACTH and, consequently, visualization of the contralateral gland.

Topics: 17-Hydroxycorticosteroids; Adenoma; Adrenal Cortex Neoplasms; Adrenocorticotropic Hormone; Cholesterol; Cortodoxone; Cushing Syndrome; Humans; Hydrocortisone; Male; Middle Aged; Radioisotopes; Radionuclide Imaging; Selenium

Four post-menopausal women had Cushing's syndrome due to adrenal cortical carcinomas. Comprehensive analyses of blood and urinary steroids showed that although the steroid profiles differed between patients, the pattern in each patient remained almost constant as the disease progressed, or remitted due to therapy. Elevations of serum testosterone and oestradiol were commensurate with the extent of virilisation, and the urinary output of aldosterone was associated with the severity of hypertension. A new finding was that all had substantially increased urinary free deoxycorticosterone. Complete surgical removal of the primary tumours was impossible but when most of the tumour tissue was removed, full clinical and biochemical remissions were obtained for a short time in 2 patients. One patient obtained a clinical and biochemical remission from op'DDD. In another patient the drug caused reduction both in blood pressure and in urinary aldosterone excretion, but there were unpleasant side effects. A third patient could not tolerate op'DDD. Metyrapone therapy produced neither clinical nor biochemical improvement in 3 patients. The mean duration of survival was 17 months after the first symptoms and 10 months from the date of operation. Despite advances in drug therapy, adrenal cortical carcinoma remains a lethal disease. Biochemical screening of multiple steroids offers a means of early diagnosis and disease monitoring. Extensive surgical removal of the tumour offers the best chance of a clinical and biochemical remission.

Topics: 17-Ketosteroids; Adrenal Cortex Neoplasms; Adrenocorticotropic Hormone; Aldosterone; Carcinoma; Cortodoxone; Cushing Syndrome; Desoxycorticosterone; Electrolytes; Estradiol; Female; Humans; Hydrocortisone; Luteinizing Hormone; Metyrapone; Middle Aged; Mitotane; Pregnanetriol; Testosterone

Topics: Adrenal Cortex; Adrenal Cortex Hormones; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Corticosterone; Cortodoxone; Cushing Syndrome; Cyclic AMP; Humans; Hydrocortisone

In this study we evaluated the role of ACTH and angiotensin on regulation of activities of 11beta-hydroxylases of the adrenal cortex. The ratio of the plasma concentrations of 11 deoxycorticosterone (DOC) to plasma corticosterone (B) reflected the activity of the enzyme of the B and/or aldosterone pathways, and the ratio of plasma 11-deoxycortisol (S) to plasma cortisol (F) as the activity of the enzyme in the F pathway. In normal subjects, both ratios were significantly lower at 0800-0900 h (Doc to B, .01+/-.004, mean+/-SE, n=10; and S to F, .01+/-.003) than at 2000 h (DOC to B, .028+/-.024 and S to F, .015+/-.005). The plasma levels of DOC, B, S and F were all significantly lower at 2000-2100 h than at 0800-0900 h. In contrast 9 patients with Cushing's syndrome exhibited no diurnal change in the ratios. The ratios increased substantially following dexamethasone or metyrapone administration. A high or low salt diet and an angiotensin infusion produced no significant effect on the ratios. The plasma concentration of all four steroids was increased by more than 50% by an infusion of angiotensin. Four hours after administration of 80 mg of Lasix at 0800 h to 10 normal subjects, the ratios of DOC to B and S to F increased significantly (P less than .02), an effect possibly related to a decreased secretion of ACTH.. 1) 11beta-hydroxylase activity of the B and/or aldosterone and F pathways appears to change in parallel with ACTH secretion, and 2) although angiotensin stimulates steroidogenesis of the pathways, it has no apparent effect on 11beta-hydroxylase activity.

Topics: 17-Hydroxycorticosteroids; Adrenal Cortex; Adrenocorticotropic Hormone; Aldosterone; Angiotensin II; Circadian Rhythm; Corticosterone; Cortodoxone; Cushing Syndrome; Desoxycorticosterone; Dexamethasone; Diet, Sodium-Restricted; Furosemide; Humans; Hydrocortisone; Metyrapone; Posture; Renin; Steroid Hydroxylases

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.

Topics: Adenoma, Chromophobe; Adult; Cortodoxone; Cushing Syndrome; Dexamethasone; Female; Humans; Hydrocortisone; Metyrapone; Pituitary Neoplasms