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At least 19 recordsLinked to original sources

PubMed1979

The short metyrapone test: comparison of the plasma ACTH response to metyrapone and insulin-induced hypoglycaemia.

Plasma ACTH levels in response to metyrapone and insulin hypoglycaemia were compared in subjects with normal pituitary-adrenal function. After a single dose of 2 g of metyrapone given with a snack at midnight, the ACTH level was 468 ng/l +/- 66 )SEM) at 07.30 h the next morning (mean increment approximately nine fold over normal morning values). After insulin-hypoglycaemia the peak ACTH level was 369 ng/l +/- 31 (SEM). Peak ACTH levels greater than 200 ng/l were achieved in twenty of twenty-one (95%) subjects after metyrapone and twenty of twenty-four (83%) after insulin. No major side effects were noted after metyrapone. It is concluded that the short single-dose metyrapone test produces at least as strong and consistent a stimulus to ACTH release as the standard insulin-hypoglycaemia test in normal subjects. A direct assay of ACTH avoids misinterpretations which are inherent in a judgement based on compound S increase only. The short test has significant practical advantages over the classical metyrapone test, and provides a convenient and sensitive method of assessing the negative feedback ACTH control mechanism. It may be particularly useful in detecting minor degrees of pituitary suppression. The value of this test in clinical practice for the investigation of patients with hypothalamic-pituitary diseases in comparison to the classical tests of ACTH stimulation has yet to be demonstrated.

Adolescent↗

PubMed1976

The effect of metyrapone on uterine prostaglandin output and smooth muscle activity.

Metyrapone, at low doses (0.5-1.0 mM), stimulated the output of both PGE and PGF from the isolated uterus of the pregnant rat determined following extraction of bath fluid, chromatographic separation and bioassay of the prostaglandin. At higher doses (2-4 mM), metyrapone inhibited PGF output, but had no effect on PGE output. Uterine activity was rapidly inhibited by metyrapone in a dose-related manner. This inhibition was not related to PG output as, at 1 mM metyrapone, activity was inhibited and PG output stimulated. Both metyrapone and papaverine produced dose-dependent inhibition of the activity of the isolated rabbit ileum, papaverine being 10 times more potent than metyrapone. Propranolol antagonised the response of the ileum to isoprenaline, but had no effect on the response to metyrapone. These observations confirm earlier data, suggsting that metyrapone exerts a differential effect on uterine PGE and PGF production and indicate that metyrapone has a direct inhibitory effect on smooth muscle activity.

Animals↗

PubMed1977

A comparative study on the influence of cysteamine and metyrapone on mixed-function oxygenase activities in variously pretreated liver microsomes from rats and mice.

It has been found that metyrapone can inhibit both type I and type II mixed-function oxygenase reactions, while cysteamine inhibits only type I activity in this mammalian system. Following pretreatment with phenobarbital and 3-methylcholanthrene the half-maximal inhibiting concentrations for the O-demethylation of paranitranisol are increased for cysteamine and decreased for metyrapone. Both cysteamine and metyrapone give type II binding spectra with oxidized cytochrome P-450. The negative and positive peaks are at 393 and 426 nm respectively for metyrapone, and 410 and 434 nm for cysteamine. Cysteamine showed no binding comparable to that of metyrapone for reduced cytochrome P-450. Metyrapone showed little or no inhibition of the NADH cytochrome-c reductase (EC 1.6.1.1) or NADPH (EC 1.6.2.3) cytochrome-c reductase while cysteamine had a more or less strong inhibiting effect depending on the pretreatment of animals. Neither the binding to P-450 heme nor the inhibition of NADH and NADPH cytochrome-c reductase correlates well with cysteamine inhibition of total activity. It is therefore suggested that cysteamine reacts with an intermediate electron carrier of non-heme iron or glycoprotein character thus inhibiting mixed-function oxygenase activity.

Acetanilides↗

PubMed1977

New inhibitors of steroid 11beta-hydroxylase. Structure--activity relationship studies of metyrapone-like compounds.

A series of metyrapone analogues was synthesized for study as inhibitors of steroid 11beta-hydroxylase. Racemic mixtures of the new compounds were evaluated in vitro. Preliminary results revealed several analogues to be effective inhibitors of deoxycorticosterone hydroxylation. 2-(3-pyridyl)propiophenone (13) and alpha,beta-diphenyl-3-pyridineethanol (16) were the most active new compounds. Each was 65% as potent as metyrapone; 3-Pyridyl alpha-3-pyridylbenzyl ketone (3), 2-phenyl-2-(3-pyridyl)acetophenone (4), alpha-(diphenylmethyl)-3-pyridinemethanol (17), and 1,2-di-3-pyridyl-1-propanol (26) were 52, 32, 25, and 41% as inhibitory as metyrapone, respectively. Diphenylmethyl 3-pyridyl ketone (5), benzyl 3-pyridyl ketone (10), 2-(3-pyridyl)acetophenone (12), 2-phenyl-1-(3-pyridyl)-1-propanone (11), alpha,beta-di-3-pyridylphenethyl alcohol (15), and 1,2-di-3-pyridylethanol (27) had less than 25% the activity of metyrapone. All compounds displaying a metyrapone-like inhibition contained appropriately substituted alcoholic or ketonic functions. A phenyl or methyl group alpha to the carbon bearing the oxygen was necessary for appreciable activity. A 3-phridyl group alpha to the carbonyl carbon could be replaced by a phenyl group. For optimal activity, however, the other 3-pyridyl group of metyrapone could not be exchanged for a phenyl group.

Adrenal Cortex↗

PubMed1975

The influence of metyrapone on the synthesis and release of prostaglandins from the pregnant rat uterus in vitro.

1 Metyrapone (150 mg/kg, s.c. or i.p.) an inhibitor of corticosteroid biosynthesis, significantly reduced the release of prostaglandins of the F-type from isolated preparations of pregnant rat uteri in vitro, on day 22 - the expected day of delivery. 2 Metyrapone and indomethacin administered in vitro both inhibited the conversion of 14C-arachidonic acid to prostaglandin E2 by homogenates of day 22 pregnant rat uteri. Metyrapone was approximately 150 times less potent than indomethacin. Although indomethacin also inhibited prostaglandin F2alpha production, metyrapone stimulated synthesis of this prostaglandin. The differential inhibition of prostaglandin synthesis by metyrapone may reflect sensitivity of the inhibitor to changes in experimental conditions. 3 Inhibition of prostaglandin synthesis may explain the effects of metyrapone on parturition in the rat.

Animals↗

PubMed1975

Inhibition of ACTH response to oral and intravenous metyrapone by antiserotoninergic treatment in man.

Plasma ACTH levels after oral and iv metyrapone administration were studied in 7 and 5 healthy women respectively both under basal conditions and after a 4-day treatment with metergoline, a specific antiserotoninergic agent. In 3 additional women, the effects of methysergide, another antiserotoninergic drug, on the plasma ACTH rise induced by oral metyrapone, were evaluated. A significant lowering of the plasma ACTH levels attained after either oral or iv metyrapone was observed following metergoline administration: 149+/-64.3 vs 239+/-49.1 pg/ml (mean peak values), P less than 0.05 in the oral test and 331+/-19.7 vs 221+/-19.5 pg/ml, P less than 0.02 in the iv test. The fall of plasma cortisol caused by metyrapone was comparable before and after the antiserotoninergic treatment. An interference of metergoline in the ACTH radioimmunoassay was also excluded. After metergoline administration, a slight reduction in the baseline plasma ACTH values was noted: 79+/-7.7 vs 67+/-7.7 pg/ml (NS). A decrease, however not statistically significant, of the metyrapone-induced plasma ACTH elevation occured after methysergide administration: 421+/-150.7 vs 344+/-135.1 pg/ml. These results can be interpreted as indicating that antiserotoninergic treatment caused an inhibition of hypophysial ACTH release in response to metyrapone. Caution is recommended, however, before concluding, on the basis of these findings, that serotonin as such plays a physiological stimulating role on ACTH secretion.

Administration, Oral↗

PubMed1979

[Effect of metyrapone on bile flow and bile acid excretion in Wistar rats].

The influence of metyrapone on bile flow and excretion of mono-(MBA), di-(DBA) and trihydroxy-(TBA)-bile acids was investigated in adult male Wistar rats after single and repeated pretreatment. MBA were not found in the rat bile. Metyrapone administration (200 mg/kg b.w. i.p.) 1 h before onset of a 3-hour bile collection period diminished bile flow and excretion of DBA and TBA. The relation TBA/DBA was changed towards DBA. Similar results were found after repeated administration 12 h after the last metyrapone injection (4 x 50 mg/kg b.w. i.p. per day for 4 consecutive days). But 60 h after the last metyrapone administration bile flow and the excretion of TBA were enhanced and the TBA/DBA ratio was changed towards TBA. The possible influence of metyrapone on bile acid hydroxylation is discussed and compared with metyrapone action on hydroxylation of foreign compounds.

Animals↗

PubMedDate not supplied

An acute rise in serum phosphorus after single-dose oral metyrapone.

Metyrapone, an 11 beta-hydroxylase inhibitor, is widely used as a pharmacologic test for ACTH reserve. During studies on the pharmacodynamics of metyrapone and the response of plasma 11-deoxycortisol and cortisol, we fortuitously noted a consistent change in serum phosphate but no other routine laboratory chemistry determination. For these studies 12 control subjects were given oral methyrapone (30 mg/kg) at midnight. Serum phosphate (P) concentration was measured in fasting subjects at 08:00 on the morning before and after the administration of metyrapone. In 11 of 12 subjects, serum P increased from a mean of 3.6 +/- 0.7 (SD) mg/100 ml to a mean of 4.2 +/- 0.07 (SD) mg/100 ml on the morning following the drug. No increase in P was noted following the same dose of metyrapone in four patients on acute or chronic steroid therapy or in patients with primary or secondary hypoadrenocorticism. In addition, two addisonian patients were given either a saline or a hydrocortisone infusion for four hours. While the hydrocortisone infusion resulted in a drop in serum P, there was no decrease during saline infusions. These findings suggest that an acute rise in serum P after a single dose of metyrapone might be a rapid indicator of adrenocortical blockade leading to increased ACTH secretion, and cortisol and/or ACTH might play a role in P homeostasis.

Adult↗

PubMed1976

Quantitation of the accelerating effect of metyrapone on cortisol metabolism.

Quantitation of the accelerating effect of metyrapone on cortisol metabolism has been made by determination of the metabolic clearance rate (MCR) of exogenous cortisol during a metyrapone load. Six adrenalectomized patients were studied. The slope of cortisol concentrations in plasma was determined after intravenous administration of 0-3 mg cortisol/kg b.w. with or without metyrapone 17-5 mg/kg b.w./h. In all six patients studied, the MCR of cortisol increased during metyrapone load from an average of 12-3 +/- 5-0 (SD) l/h to 29-6 +/- 15-7 (SD) l/h or corrected for body weight 3-0 +/- 1-1 (SD) ml/kg b.w./min to 7-1 +/- 2-5 (SD) ml/kg b.w./min. The discrepancy discovered in clinical practice between the relatively small rise in plasma total corticosteroid concentration and the greater increase in urinary excretion of corticosteroid metabolites during the metyrapone test may be explained by the findings in this study.

Adrenalectomy↗

PubMed1976

Potentiation of the ACTH response to metyrapone by L-dopa in the monkey.

The intravenous injection of L-Dopa (15 mg/kg) to monkeys (Macaca mulatta) failed to alter plasma concentrations of ACTH and of 11-deoxy-cortisol. When cortisol synthesis was blocked with iv metyrapone, potentiation of ACTH secretion by L-Dopa became apparent. Simultaneous injection of L-Dopa and metyrapone resulted in a marked increase in plasma ACTH from 93 +/- 18 pg/ml to 432 +/- 80 pg/ml, whereas plasma 11-deoxycortisol increased from 1.5 +/- 0.2 mug/100 ml to 14.6 +/- 1.0 mug/100 ml 90 min after treatment. Throughout the experiment the rise in ACTH and in 11-deoxycortisol following coadministration of L-Dopa and metyrapone was significantly (P less than 0.01) higher than that produced by metyrapone administration alone. The results suggest that acute administration of L-Dopa in monkeys enhances the response of ACTH to metyrapone. L-Dopa (or one of its metabolites) probably acts upon a noradrenergic or a dopaminergic system located in the hypothalamus to alter the release of hypothalamic corticotropin regulatory factor(s) and thereby enhance the release of ACTH.

Adrenocorticotropic Hormone↗

PubMed1976

Effects of norgestrel and metyrapone on pituitary-adrenal-ovarian function.

To assess the effects of d-norgestrel on pituitary-adrenal-ovarian function, basal levels and responses to metyrapone of urinary 17-ketogenic steroids (17-KGS) and 17-ketosteroids (17-KS), plasma cortisol (F), plasma delta4-androstenedione (A), plasma testosterone (T), plasma estrone (E1) and estradiol (E2), plasma and urinary LH and FSH were determined in 10 normal women before and while taking d-norgestrel 1 mg/day. Cortisol secretion rate (CSR) and binding capacities of cortisol binding globulin (CBG) and testosterone-estradiol binding globulin (TeBG) were also measured. Norgestrel did not significantly alter 17-KGS, 17-KS, F, LH, FSH, CSR, or the 17-KGS and 17-KS responses to metyrapone. Norgestrel reduced TeBG binding capacity but not CBG binding capacity. Norgestrel competitively inhibited the binding of dihydrotestosterone to TeBG under in vitro conditions. Levels of T, E2, and E1 were reduced by norgestrel. All measured hormone levels except FSH were increased following metyrapone prior to norgestrel administration. Norgestrel completely blocked the metyrapone-induced increases in LH and E2 and markedly reduced the E1 increase. Metyrapone reduced E2 during norgestrel treatment.

17-Hydroxycorticosteroids↗

PubMed1977

[Changes in plasma level of corticotropin after intravenous injection of metyrapone. Value of this test in pituitary pathology].

The Metyrapone was given, the morning, in perfusion intravenous of saline serum over 2 hours. A.C.T.H. levels were determined before and at 2, 4, 8 and 24 hours. Sixteen normal subjects adults served on controls with 1 g of Metyrapone. Sixteen other normal subjects with 2 g of Metyrapone are best responses. With this maximum dose 2 g were studied nine hypophysal adenomas with three low responses, three normal and three high responses; thirteen hypophysectomised subjects with very low peak value at 4 hours, and only two responses higher than the controls, five Cushing's syndromes with variable responses. The I.V. Metyrapone test seems to offer several advantages: it eliminates the questions about gastro-intestinal absorption of Metyrapone (oral) and the difficulties of urine collection. With the A.C.T.H. dosage on 4 hours, this is a rapid test able to put in combination other hypophysal tests.

Adrenocorticotropic Hormone↗

PubMedDate not supplied

A comparison of the adrenal responses to hypoglycemia, metyrapone and ACTH.

The adrenal responses to insulin-induced hypoglycemia and the rapid adrenocorticotropic hormone (ACTH) stimulation test were compared in 24 healthy volunteers, 18 of whom also underwent a rapid oral metyrapone test. The cortisol levels after hypoglycemia (18.0-30.0 microgram/100 ml) were similar to and directly related to the levels after ACTH (21.0-31.0 microgram/100 ml). The levels after both stimuli were independent of age, sex, height, and weight. The 11-deoxycortisol response to the metyrapone test was less than the cortisol response to hypoglycemia and metyrapone administration was associated with more unpleasant side effects. In a group of 69 control subjects, the post-ACTH cortisol levels were 15.0 to 80.0 microgram/100 ml while in seven patients with Addison's disease they were less than 1-4.5 microgram/100 ml. In 44 control subjects, the posthypoglycemia cortisol levels were 18.0 to 30.0 microgram/100 ml compared with less than 1.0-9.0 microgram/100 ml in 22 patients with hypopituitarism. The absolute poststimulation cortisol levels provided better separation of control subjects from patients with adrenal or pituitary insufficiency than either the increment in cortisol levels or the 11-deoxycortisol response to metyrapone.

17-Hydroxycorticosteroids↗

PubMed1977

Evaluation of 3 hour metyrapone test in children and adolescents.

An evaluation of a new 3 h metyrapone test is presented. The test consists of one oral dose of metyrapone given at 08.00-09.00 hours, and determination of plasma deoxycortisol from a single capillary blood sample taken 3 h later. The test has been assessed in children and adolescents in conjunction with a 5 day metyrapone test, insulin test, vasopressin test, and ACTH test in forty-five reference subjects, in thirty-six hypopituitary subjects with normal or deficient ACTH secretion, in three subjects with primary adrenocortical disease and in ten subjects prior to and after pharmacological prednisone medication. During the first hour after metyrapone the plasma cortisol level decreased to almost the low level maintained for the rest of the 3 h period. The plasma deoxycortisol concentration was basally less than or equal to 35 nmol/l and increased continuously during the 3 h period to the mean level of 299 (95% confidence interval 133-669) nmol/l in the reference subjects. The new test proved to be as accurate as the insulin test in detecting ACTH deficiency. No significant rise was observed in the plasma somatotrophin (GH) level in those children who had a normal GH response to insulin hypoglycaemia.

Adolescent↗

PubMed1976

Binding of a metyrapone spin label to microsomal cytochrome P-450.

Probing of the active site of microsomal cytochrome P-450 was carried out with a spin label derived from 2-methyl-1,2-bis(3-pyridyl)-1-propanone (metyrapone). Its optical binding spectra to cytochrome P-450 resemble the spectra with metyrapone. The electron paramagnetic resonance spectrum of the spin label in microsomes indicates binding with strong immobilization. Since the apparent optical and EPR binding constants agree very well (Ks approximately 2-10(-5) M), and metyrapone is found to displace the spin label, we conclude, that the spin label binds to the active site of cytochrome P-450. Addition of detergents or an increase in temperature mobilizes the bound spin label slightly. The EPR signal accounts for only 60% of the bound spin label due to its dipolar interaction with the low-spin ferric heme of cytochrome P-450. From this finding, the distance between nitroxide and iron is evaluated to be 11 A. This supports the model that one of the pyridine nitrogens of metyrapone is coordinated to the iron of cytochrome P-450. The bound spin label shows virtually no interaction with ferricyanide as if the active site of cytochrome P-450 is a hydrophobic pocket not accessible to ions.

Animals↗

PubMed1977

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.

Adolescent↗

PubMedDate not supplied

Circadian rhythm of urinary 17-hydroxycorticosteroids during metyrapone-induced ACTH release in normal subjects.

The circadian rhythm of urinary 17-OHCS was studied in nine normal subjects before and after oral metyrapone administration (750 mg every 4 hrs over a period of 24 hrs). The test was carried out twice in each subject with a shift of 12 hrs in the time of first administration (0800-test and 2000-test). For data from serial measurements of steroid metabolites on urine collected at 2-h intervals, the least squares fit of a 24-h cosine curve allowed the demonstration of a rhythm both in control conditions and during the 48-h span following metyrapone administration. Circadian acrophases were substantially similar. Total urinary 17-OHCS output in the first 24-h day following metyrapone was higher in the 2000-test as compared with the 0800-test (P less than .001). Conversely, in the second 24-h day, higher values were obtained in the 0800-test (P less than .025). The combined 48-h exretion, however, was identical in the two groups. The results suggest a time-limited action of metyrapone upon the pituitary-adrenal axis, since the increased excretion of 17-OHCS seems essentially accounted for by an exaggerated impulsive phase of ACTH secretion during the early morning hours.

17-Hydroxycorticosteroids↗

PubMed1979

Metyrapone test with adrenocorticotrophic levels. Separating primary from secondary adrenal insufficiency.

Basal plasma adrenocorticotrophic hormone (ACTH) and cortisol concentrations as well as plasma ACTH and 11-deoxycortisol responses to the administration of a single dose of metyrapone were evaluated in 104 patients with intact pituitary-adrenal axis, in 20 patients with secondary adrenal insufficiency, and in seven patients with primary adrenal insufficiency. In patients with primary adrenal insufficiency, baseline ACTH levels were high. Following metyrapone administration, 11-deoxycortisol concentrations were low and ACTH levels did not change. In patients with secondary adrenal insufficiency, baseline plasma ACTH levels were normal, but neither 11-deoxycortisol nor ACTH levels increased in response to metyrapone. The metyrapone test is not only useful to screen for adrenal insufficiency, it is also useful to differentiate a primary from a secondary cause.

Adrenal Insufficiency↗