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 109 records · Page 6Linked to original sources
PubMed2005

Inhibition of cortisol production with metyrapone prevents mental stress-induced endothelial dysfunction and baroreflex impairment.

OBJECTIVES: This study was designed to investigate the role of cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (BRS) by blocking cortisol production with metyrapone before subjecting healthy volunteers to mental stress. BACKGROUND: Mental stress raises cortisol levels and is associated with increased coronary heart disease (CHD) morbidity and mortality, especially from sudden cardiac death. It also causes endothelial dysfunction and impaired BRS. METHODS: We measured brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and BRS in 36 subjects without CHD risk factors who were then randomized in a double-blind fashion to oral metyrapone 750 mg x 2 or placebo. Five hours later we subjected subjects to mental stress and then remeasured endothelial function and BRS. RESULTS: Prestress cortisol levels were significantly higher in the placebo group at 270.5 (30.9) nmol/l versus 89.1 (11.8) nmol/l (p = 0.01), and the increase with stress was higher at 57.9 (17.9) nmol/l versus 11.2 (2.2) nmol/l (p < 0.001). In the placebo group, compared to baseline, FMD and BRS fell significantly from 4.5% (0.7%) to 1.4% (1.1%) (p = 0.02) and 21.4 (2.3) ms/mmHg to 16.3 (1.5) ms/mmHg (p = 0.04), respectively. In the metyrapone group, FMD and BRS were unchanged from baseline: 4.3% (0.9%) versus 5.1% (0.8%) (p = 0.48) and 26.4 (2.9) ms/mmHg versus 24.9 (2.6) ms/mmHg (p = 0.62), respectively. Analysis of covariation showed a significant effect of metyrapone on change in both FMD (p = 0.009) and BRS (p = 0.024). CONCLUSIONS: Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.

Adult↗
PubMed1998

Neuroactive steroid concentrations following metyrapone administration in depressed patients and healthy volunteers.

BACKGROUND: There is evidence that treatment with the 11 beta-hydroxylase inhibitor metyrapone may represent an alternative treatment strategy in major depression. As a consequence of inhibition of cortisol synthesis the overdrive of corticotropin leads to an accumulation of precursor steroids. However, the effects of metyrapone on the concentrations of endogenous neuroactive steroids that modulate ion channels, e.g., the GABAA receptor, have not yet been studied systematically. METHODS: Therefore, we quantified the concentrations of an array of neuroactive steroids following administration of 1.5 g metyrapone before and after pretreatment with 1 mg dexamethasone in 19 patients suffering from severe depression in comparison to 13 healthy controls by means of a highly sensitive gas chromatography/mass spectrometry analysis. RESULTS: The administration of metyrapone induced a pronounced increase in all neuroactive steroids studied both in patients and controls that was prevented by dexamethasone pretreatment. CONCLUSIONS: Thus, the psychotropic properties of endogenous neuroactive steroids may contribute to the antidepressant properties of metyrapone in the treatment of major depression.

Adrenocorticotropic Hormone↗
PubMed1983

Structural studies of metyrapone: a potent inhibitor of cytochrome P-450.

The crystal and molecular structure of metyrapone, a powerful inhibitor of certain cytochromes P-450, is described. Cytochrome P-450 enzymes are involved in metabolic processes, including those activating insecticides, drugs, and carcinogens. Metyrapone inhibits both the adrenal cytochrome P-450 catalyzing 11-beta-hydroxylation in steroid biosynthesis and most microsomal cytochromes P-450 induced by phenobarbital pretreatment. Crystal data are as follows: a = 11.828 (1), b = 6.268 (6), c = 18.269 (3) A, beta = 115.27 (1) degree, V = 1224.9 (3) A3, space group P21/c, dcalcd = 1.227 g cm-3, Z = 4. No intermolecular interactions are apparent in the solid state other than van der Waals forces. The torsion angle about the C(7)-C(10) bond to which the two 3-pyridyl groups are attached is 59.4 (1) degree. The three negatively charged heteroatoms form a triangle; the nitrogen atoms are anti to the exocyclic oxygen and are 4.347 (1) A apart. The N5-O11 distance is 5.850 (1) A; the N14-O11 intramolecular distance is 4.750 (1) A. The "twisted butterfly" conformation found for metyrapone is found in other molecules that are substrates and inducers of the specific cytochrome P-450 inhibited by metyrapone. The availability of nucleophilic functional groups is a feature common to most directly acting inhibitors of cytochrome P-450 enzymes and is manifested in metyrapone by the presence of the basic nitrogens. These factors may be necessary for interaction with the protein.

Computers↗
PubMed1984

Structure-activity relationship study of the inhibition of adrenal cortical 11 beta-hydroxylase by new metyrapone analogues.

Metyrapone, 2-methyl-1,2-di-3-pyridyl-1-propanone (1a), is a potent reversible inhibitor of the cytochrome P-450 11 beta-hydroxylase enzyme system (P-450(11) beta) of the adrenal cortex. The structural features of the metyrapone molecule have been systemically altered to determine the requirements necessary for inhibition of P-450(11) beta activity. Metyrapone and 14 analogues have been obtained or synthesized and evaluated as inhibitors using a crude, defatted bovine adrenal cortical mitochondrial preparation. The inhibition of P-450(11) beta activity with these derivatives demonstrated that (1) the A-ring phenyl derivatives 2a-d were better inhibitors than the respective dipyridyl analogues, (2) the ketone in the 1-position can be replaced by various functionalities without markedly reducing inhibition, and (3) at least one methyl group should be present in the 2-position to maintain inhibition. The observed inhibition of P450(11) beta activity with the metyrapone analogues suggest that A-ring phenyl metyrapone analogues 2a-d would be candidates for radioiodination and subsequently used as adrenal cortical imaging agents.

Adrenal Cortex↗
PubMed1988

Enhancement of the adrenocortical response to metyrapone by L-dopa in the chicken (Gallus domesticus).

1. Eight-week-old chickens were treated with a single intravenous injection of saline, L-dopa (20 mg/kg body weight), metyrapone (60 mg/kg) or a combined dose of L-dopa and metyrapone. Serum corticosterone was measured by radioimmunoassay at 30, 60 and 90 min after the treatment. 2. L-dopa did not alter the corticosterone concentration during the experiment, whereas metyrapone increased it at 60 and 90 min. 3. When L-dopa and metyrapone were given together there was a gradual increase in corticosterone and the hormone concentrations were significantly greater than control values at all times. 4. It was concluded that L-dopa is not a potent stimulator of adrenocortical cells in chickens, but it enhances the response to metyrapone. This may be achieved through the release of endogenous ACTH by stimulating central dopamine receptors.

Adrenal Cortex↗
PubMed2004

Metyrapone infusion stimulates adrenal growth without activating the cell cycle or the IGF system in the late gestation fetal sheep.

Recently, we have demonstrated that administration of metyrapone, to suppress cortisol synthesis and decrease negative feedback at the pituitary, results in an increase in circulating ACTH and adrenal growth in the late gestation sheep fetus. In these studies, we demonstrated a 2-fold increase in adrenocortical growth using morphometric techniques. To elucidate the potential molecular mechanisms leading to the increase in adrenal growth, we examined adrenal expression of the cell cycle regulatory proteins (cyclin D1) and cyclin-kinase inhibitory proteins (p16ink, p21Cip), and insulin-like growth factor-II (IGF-II), IGF-binding protein 2 (IGFBP-2) and IGF-I type 1 Receptor (IGF1R) from fetuses infused with metyrapone or vehicle for 15 days. There was a significant decrease in adrenal expression of cyclin D1 in metyrapone-(472.0 +/- 29.7) compared with vehicle-infused (662.7 +/- 29.2) fetuses. There was no significant difference, however, in the adrenal expression of the cyclin-kinase inhibitory proteins (p16ink or p21Cip) or in the IGF system (IGF-II, IGFBP-2 or IGF1R) mRNA between metyrapone- and vehicle-infused. In summary, in this model of metyrapone-activated adrenal cortical hypertrophy, growth occurs with a suppression of the rate-limiting cell cycle protein and without activation of the IGF system.

Adrenal Glands↗
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↗
PubMed1999

Corticotropin-releasing effect of hexarelin, a peptidyl GH secretagogue, in normal subjects pretreated with metyrapone or RU-486, a glucocorticoid receptor antagonist, and in patients with Addison's disease.

GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules which possess strong GH-releasing activity but also stimulatory effect on hypothalamo-pituitary-adrenal axis. The ACTH and cortisol responses to Hexarelin (HEX), a peptidyl GHS, are abolished by low-dose dexamethasone pretreatment in normal subjects but are exaggerated and higher than those after hCRH in patients with pituitary ACTH-dependent Cushing's disease, in spite of their hypercortisolism. Based on the foregoing, we studied the ACTH, cortisol and GH responses to HEX (2.0 microgram/kg i.v. at 0 min) alone and after metyrapone (2 g p.o. at 23:00 h the night before) or RU-486 (400 mg p.o. at 02:00 h), a glucocorticoid receptor antagonist, in 6 normal women (NS, age 26-34 years). The endocrine responses (mean +/- SEM) to HEX alone were also studied in 8 patients with Addison's disease (AD, 6 males, 2 females, age 30-77 years; last hydrocortisone administration the day before testing). In NS, HEX stimulated basal ACTH (peak, mean +/- SEM: 26.0 +/- 7.8 vs. 10.7 +/- 2.0 pg/ml, p < 0. 05), cortisol (163.2 +/- 18.3 vs. 137.4 +/- 15.4 microgram/l, p < 0.05) and GH (72.6 +/- 23.5 vs. 3.7 +/- 1.3 microgram/l, p < 0.01) levels. Metyrapone markedly increased basal ACTH (294.4 +/- 61.6 pg/ml, p < 0.05), reduced basal cortisol (19.6 +/- 7.2 microgram/l, p < 0.05), while it did not modify GH levels. After metyrapone pretreatment the ACTH response to HEX was clearly increased (DeltaAUC: 2,857.4 +/- 901.9 vs. 367.3 +/- 274.0 pg/ml/h, p < 0.05), while the GH response was not modified. HEX did not stimulate the low cortisol levels after metyrapone pretreatment. RU-486 significantly increased basal ACTH (76.6 +/- 12.5 pg/ml, p < 0.05) and cortisol (312.7 +/- 22.2 microgram/l, p < 0.05), while it did not modify basal GH levels. RU-486 pretreatment did not modify the ACTH, cortisol and GH responses to HEX. In AD, HEX elicited a marked ACTH response (6,619.4 +/- 3,365.8 pg/ml/h; p < 0.01), which was clearly higher (p < 0.01) than that in NS after HEX alone but not significantly different from that after HEX+MET. The GH response to HEX in AD (1,325.6 +/- 284.1 microgram/l/h) was similar to that in NS (1,519.7 +/- 483.8 microgram/l/h). In conclusion, our present data demonstrate that the ACTH-releasing activity of HEX is increased in primary hypoadrenalism as well as in normal subjects after metyrapone but not after RU-486 pretreatment. These findings indicate that in normal subjects as well as in hypocortisolemic patients the ACTH-releasing activity of GHS is enhanced by the lack of negative glucocorticoid feedback.

Addison Disease↗
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↗
PubMed2000

The corticosterone synthesis inhibitor metyrapone prevents hypoxia/ischemia-induced loss of synaptic function in the rat hippocampus.

BACKGROUND AND PURPOSE: Ischemia is accompanied by abundant corticosterone secretion, which could potentially exacerbate brain damage via activation of glucocorticoid receptors. We addressed whether manipulating steroid levels during ischemia affects hippocampal synaptic function along with neuronal structure. Moreover, we established whether pretreatment with the glucocorticoid receptor antagonist RU38486 is as effective in preventing deleterious effects after ischemia as is the steroid synthesis inhibitor metyrapone. METHODS: Rats underwent 20 minutes of unilateral hypoxia/ischemia (HI). Convulsions were monitored after HI, and 24 hours later, field potentials were recorded in vitro in the hippocampal CA1 area in response to stimulation of the Schaffer collateral/commissural fibers. Morphological alterations were determined in brain slices from the same animals. Data were correlated with steroid treatment before HI. RESULTS: Metyrapone suppressed plasma corticosteroid levels during HI, whereas corticosterone treatment significantly elevated plasma steroid levels. These treatments affected the incidence of visible seizures after HI: corticosterone treatment resulted in the highest incidence, whereas metyrapone attenuated the occurrence of seizures. Moreover, the HI-induced impairment in synaptic transmission in the CA1 area in vitro was exacerbated by concomitant corticosteroid treatment and alleviated by pretreatment with metyrapone. In parallel, degenerative changes in the hippocampus after HI were most pronounced after corticosterone treatment, whereas metyrapone reduced these alterations. RU38486 was effective only in reducing the incidence of seizures shortly after ischemia. CONCLUSIONS: We tentatively conclude that synaptic function along with cellular integrity is preserved after HI by preventing the ischemia-evoked rise in corticosteroid levels rather than blocking the glucocorticoid receptor.

Animals↗
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↗
PubMed1981

[Plasma 11-deoxycortisol response to single dose metyrapone in prostatic cancer patients (author's transl)].

A radioimmunoassay procedure for plasma 11-deoxycortisol (S) was developed using an antiserum prepared by immunizing rabbits with S-21-hemisuccinate bovine serum albumin and S-3-oxime-bovine serum albumin. Thereafter plasma S, cortisol (F) and adrenocorticotropic hormone (ACTH) responses to metyrapone were investigated in 13 normal adult males and 39 patients with prostatic cancer. The results were as follows: 1) The antiserum against S-3-oxime-bovine serum albumin had less cross reactivity (less than 10%) with other steroids than that against S-21-hemisuccinate bovine serum albumin and obtained a good standard curve. The intra-assay variance and interassay variance of this method using the former antiserum (N = 10) were 12.4% asd 14.9% respectively, and the blank value was 3.7 +/- 1.6 pg. 2) Basal levels of S. F and ACTH in plasma from 13 normal adult males, ranged 21 approximately 80 years, old, were 98.4 +/- 15.7 ng/dl (mean value +/- S.E.), 12.7 +/- 0.78 micrograms/dl and 30.6 +/- 3.02 pg/ml respectively. Those level increased to 7060 +/- 598 ng/dl, 24.3 +/- 1.69 micrograms/dl and 24.3 +/- 1.6 pg/ml at 9 a.m. following oral administration of metyrapone (30 mg/kg b.w.) at midnight. 3) Both basal levels and responses of plasma S and F to metyrapone increased remarkably, while those of ACTH were within the normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and AC normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and AC normal range in prostatic cancer patients during the estrogen therapy. It was considered that protein-bound S and F increased following elevation of corticosteroid binding globulin but returned to the normal range about 2 weeks after discontinuation of the therapy. 4) In case treated wih estrogens, plasma, S, F and ACTH responses to metyrapone were unchanged compared to normal adult males 2 approximately 4 weeks after discontinuation of the therapy, and this data suggested that estrogens had no inhibitory effect on the pituitary-adrenal axis. However, in cases treated with progestational agents over a long-term period, plasma S and ACTH responses to metyrapone decreased slightly but returned to the normal range 2 approximately 4 weeks after discontinuation of the therapy. This suggested that the inhibitory effect of these agents on the pituitary-adrenal axis was mild and reversible.

17-Hydroxycorticosteroids↗
PubMed2001

Rational, effective metyrapone treatment of ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH).

Standard therapy for ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH), a rare form of Cushing's syndrome, is bilateral adrenalectomy. Patients with AIMAH are usually elderly, with a variety of complications, and at risk for surgery. Postoperatively, they must receive lifelong corticosteroids and spend the remainder of their lives avoiding adrenal crisis. Therapy using metyrapone, a potent inhibitor of steroidogenesis, provides the advantages of avoiding the surgery. Its effectiveness is further anticipated because adrenal steroidogenic enzymes are reportedly weak in AIMAH. Treatment with metyrapone thus appears a good therapy for AIMAH, but its effectiveness has not, to our knowledge, been studied. We treated a 59-year-old man with AIMAH with metyrapone. At a low dose of metyrapone (500 to 750 mg/day), his plasma cortisol levels decreased to the normal range, and hypertension and diabetes mellitus were ameliorated. Therapy using metyrapone thus appears effective in treating AIMAH, and can be recommended for high risk AIMAH patients as an alternative therapy.

Adrenal Glands↗
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↗
PubMed1987

Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells.

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.

17-alpha-Hydroxyprogesterone↗