Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Metyrapone”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1975

Single dose metyrapone test: 11 beta-hydroxylase inhibition by metyrapone and reduced metyrapone assayed by radioimmunoassay.

To assess the effects of metyrapone and reduced metyrapone on 11 beta-hydroxylase inhibition, the plasma levels of cortisol, 11-deoxycortisol, and the inhibitors were measured by radioimmunoassays in 34 normal subjects 8 h after they received a single oral dose of metyrapone at midnight. The ratio of 11-deoxycortisol to cortisol, as an index of 11 beta-hydroxylase inhibition, was compared to plasma levels of metyrapone and reduced metyrapone. One subject received an infusion of metyrapone ditartrate in order to study the sequential conversion of metyrapone to reduced metyrapone. A new radioimmunoassay was developed for measurement of plasma concentrations of metyrapone and reduced metyrapone. Following intravenous administration of metyrapone, it is rapidly converted to an active metabolite, reduced metyrapone. At 8 h after a dose was given, the average reduced metyrapone level was 1.5 times higher than the average metyrapone level. Following oral administration of the drug, we found a high correlation when plasma levels of metyrapone were compared to reduced metyrapone and when the ratio of 11-deoxycortisol to cortisol was related to metyrapone or to total metyrapone levels. In conclusion, the conversion of metyrapone to reduced metyrapone is such that by 8 hours after a single oral dose, more than one-half of the inhibitory effect on 11 beta-hydroxylase appears to be produced by reduced metyrapone. The inhibitory action of metyrapone and reduced metyrapone on the enzyme system is reflected by their concentration in plasma.

Humans↗
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

Dual sites of inhibition by metyrapone of human adrenal steroidogenesis: correlation of in vivo and in vitro studies.

In a patient with pituitary ACTH-dependent adrenal hyperplasia (AH), the standard oral metyrapone test resulted in a decrease in "apparent 11beta-hydroxylase activity" (-48%) accompanied by an increase in "apparent cholesterol cleavage activity" (+318%). When incubated adrenal mitochondria from this patient were studied, metyrapone inhibited both 11beta-hydroxylation of labeled 11-deoxycorticosterone and cleavage of labeled cholesterol, although at 0.1 and 1.0 mM metyrapone concentrations, depression of cholesterol cleavage (23 and 54%, respectively) was less than that of 11beta-hydroxylation (62 and 84%, respectively). The inhibition of cholesterol cleavage by metyrapone (26 and 62%, at 0.1 and 1.0 mM concentrations, respectively) was also demonstrable in adrenal mitochondria from a patient with hypercorticism resulting from an ACTH-independent adrenal adenoman (AA). Metyrapone administration to AA resulted in a significant depression of both 11beta-hydroxylase (-62%) and cholesterol cleavage (-36%) "apparent activities"; when metyrapone and ACTH were given together to this patient, however, only 11beta-hydroxylase "apparent activity" diminished (-26%), while cholesterol cleavage "apparent activity" was greatly augmented (+231%), thereby simulating the results of the standard metyrapone test in AH. These data demonstrate that metyrapone inhibits both mitochondrial reactions involved in cortisol synthesis--initial cholesterol cleavage and final 11beta-hydroxylation; these effects probably result from interference by this agent with the interaction between substrate and related cytochrome P - 450. Since ACTH has a major stimulatory effect on cholesterol cleavage but not on 11beta-hydroxylation, the outcome of metyrapone administration is thus determined by whether a change in ACTH level ensues: while 11beta-hydroxylation is inhibited by metyrapone under any circumstances, total steroid output rises when a compensatory ACTH increase overcomes metyrapone inhibition of cholesterol conversion into pregnenolone and falls when metyrapone inhibition of this reaction is unopposed.

Adenoma↗
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↗
PubMed1976

Evaluation of single oral dose metyrapone tests in children with hypopituitarism.

Evaluation of single-dose metyrapone tests in children with hypopituitarism; comparison with the prolonged metyrapone and insulin induced hypoglycaemia tests and their relationship with the etiology of hypopituitarism. Acta Paediatr Scand, 65:177, 1976.--Pituitary-adrenal reserve was evaluated in control and hypopituitary subjects by comparing the 8 a.m. plasma 11-deoxycorticoid response (11-DOCS) to a single midnight oral dose of metyrapone (short test) with 1) the 8 a.m. 11-DOCS increase under repeated oral doses of metyrapone (prolonged test) and 2) with the plasma corticoid response during arginine-insulin test. In the short and the prolonged metyrapone tests, the same response was obtained in 25 out of 27 patients. The short test was repeated in 22 patients and the 11-DOCS response did not show a significant difference. In 34 of 40 patients, the response to the short test was comparable to the response during the arginine-insulin test; only 3 patients with a normal 11-DOCS rise to the short test had a low response to insulin and vice versa. Among the low responders to the short test, the mean 11-DOCS value was significantly lower in subjects with operated craniopharyngiomas than in idiopathic hypopituitary patients (p less than 0.001). In the short test, the 8 a.m. baseline cortisol value was positively correlated with the 8 a.m. 11-DOCS response (p less than 0.001), the cortisol level allowing to predict the 11-DOCS response in 28 out of 53 patients. Thus, the short oral metyrapone stimulation was found to be a reliable test in hypopituitary children.

17-Hydroxycorticosteroids↗
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↗
PubMed1992

Effect of metyrapone on the pituitary-adrenal axis in depression: relation to dexamethasone suppressor status.

It has been suggested that the well-documented hypercortisolaemia found in a proportion of patients with severe depression occurs either in response to excessive secretion of corticotrophin-releasing hormone-41 (CRH-41) from the hypothalamus, or as a consequence of up-regulation of pituitary CRH-41 receptors. The attenuation of the normal ACTH response to CRH-41 in these subjects is thought to result from inhibition of corticotrophin secretion by elevated cortisol levels. We tested these hypotheses by examining ACTH responses to metyrapone, an 11 beta-hydroxylase inhibitor which blocks the formation of cortisol, followed by CRH-41 in 15 severely depressed in-patients diagnosed according to DSM-IIIR criteria. Patients were assigned to two groups according to their response to overnight administration of 1 mg dexamethasone: suppressors (8) and nonsuppressors (7). A third group consisted of 6 healthy matched controls. Metyrapone 750 mg was given 4-hourly for 24 h and samples were taken for cortisol and ACTH. Six of the original 15 patients (3 from each group) were given a bolus dose of 100 micrograms human CRH-41 intravenously after 24 h of metyrapone, and ACTH levels were measured over 2 h. Falls in circulating cortisol in response to metyrapone were similar in all three groups. However, we found exaggerated rises in ACTH amongst the nonsuppressors, as compared to the suppressors and the control group, after metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
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↗
PubMed1975

Metyrapone test in Cushing's disease.

The urinary 17-hydroxycorticosteroid response to 2 g of metyrapone given orally at 10 PM was compared with that following the standard test in which 750 mg of metyrapone was given at 4 hourly intervals for 6 doses. Both tests were performed on four occasions in 3 patients with Cushing's disease. Increments in urinary 17-hydroxycorticosteroid excretion during the modified test were 7.0, 7.5, 8.4 and 23.3 mg/day, whereas with the standard test, increments ranged from 29.5 to 56.8 mg/day. The urinary 17-hydroxycorticosteroid response to the 2 g dose of metyrapone at 10 PM was marginal in 3 of the 4 studies. Urinary 17-hydroxycorticosteroid excretion with the modified metyrapone test varied from 10.7 to 44% of that found with the standard test. Since urinary steroid excretion may vary considerably in patients with Cushing's syndrome as was evident in 2 of the 3 patients studied, the data suggest that the modified metyrapone test should not be used in preference to the standard test in evaluating Cushing's syndrome. It appears that the modified test could lead to erroneous conclusions.

17-Hydroxycorticosteroids↗
PubMed1975

Effects of metyrapone on reproductive organs of house mice (38533).

The effects of chronic administration of metyrapone, a specific adrenal 11beta-hydroxylase inhibitor, were examined on the reproductive organs of house mice. In one experiment, immature (30 days old) mice of both sexes received daily injections of either metyrapone (100 mg/kg) or saline ip for 30 days. In a second experiment, mature mice (90 days old) were treated in like manner either with metyrapone (100 mg/kg) or saline for 21 days. Twenty-four hours after the last injection, mice were killed, fixed in formalin, and organs were weighed and examined by light microscopy. There was significant impairment of ovarian and uterine development in the young female metyrapone-treated mice with the incidence of corpora lutea being reduced 82%. Seminal vesicle and body weights were significantly reduced in juvenile males. Among mature animals, a 14% decrease in adrenal gland weight from adult females was the only signigicant effect of prolonged treatment with metyrapone. These data support the hypothesis that increases in pituitary-adrenocortical function may impair development of reproductive organs in small rodents.

Adrenal Glands↗
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↗