Single Dose Metyrapone Test Research Articles

Testing the hypothalamic-pituitary-adrenal axis in survivors of childhood brain and skull-based tumors.

The objective of this study was to determine whether a low dose of ACTH (0.2 microg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors. Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-microg i.v. bolus), a low dose ACTH test (0.2 microg/kg i.v. bolus), an insulin tolerance test, and a single dose metyrapone test. Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion. In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.

Assessment of hypothalamic-pituitary-adrenocortical axis function in dexamethasone treated very low birth weight infants by a single dose metyrapone test and gas chromatographic mass spectrometric determination of urinary steroids.

In order to assess hypothalamic-pituitary-adrenocortical axis function, we conducted low and single oral dose metyrapone tests (35 mg/kg) in dexamethasone treated very low birth weight infants with bronchopulmonary dysplasia (n = 12). The responses to metyrapone of tetrahydro-11-deoxycortisol (THS) and cortisol metabolites were analyzed by gas chromatography and mass spectrometry in 24-h urinary specimens. For comparative reasons, morning plasma 11-deoxy-cortisol and cortisol were measured by radioimmunoassay before and after metyrapone. No side effects of metyrapone were observed in our patients. In 5 of 12 patients, no urinary THS could be stimulated after metyrapone and most of the other patients had small increases in urinary THS. These findings suggest suppressed or strongly impaired hypothalamic-pituitary-adrenocortical axis function in most patients. While the concentrations of plasma 11-deoxycortisol showed little variation, those of plasma cortisol were grossly different from the respective urinary values. We recommend steroid analysis in 24-h urinary specimens by gas chromatography and mass spectrometry, because urinary steroids provide more information and the highly specific analytical technique is independent of phenomena such as cross reactivity or matrix effects. The low and single oral dose metyrapone test in combination with urinary steroid analysis by gas chromatography and mass spectrometry therefore provides a noninvasive, convenient and safe means of evaluating the integrity of the hypothalamic-pituitary-adrenocortical axis in very low birth weight infants.

Prednisolone metasulphobenzoate foam retention enemas suppress the hypothalamo-pituitary-adrenal axis.

Corticosteroid enemas represent effective treatment for ulcerative proctitis, but absorption into the systemic circulation may have undesirable metabolic consequences. Prednisolone metasulphobenzoate, a lipophobic corticosteroid derivative, is designed to be absorbed poorly through the recto-sigmoid mucosa, but the effects of foam enema preparations upon the hypothalamo-pituitary-adrenal axis have not been examined. Nine patients suffering from active ulcerative proctitis underwent four weeks of therapy with prednisolone metasulphobenzoate foam enemas. The hypothalamo-pituitary-adrenal axis, defined using the modified single-dose metyrapone test, glucose homeostasis and lipid profiles were studied before and after treatment. The hypothalamo-pituitary-adrenal axis was significantly depressed after the treatment period; mean stimulated plasma cortisol concentration fell from 384 +/- 244 (s.d.) to 288 +/- 252 nmol/L, P < 0.02; stimulated mean plasma 11-deoxycortisol concentration fell from 677 +/- 333 to 407 +/- 326 nmol/L, P < 0.01. Mean fasting plasma glucose, insulin, C-peptide, fructosamine and triglyceride concentration were unchanged, whilst the mean serum cholesterol concentrations rose from 5.6 +/- 1.1 to 6.0 +/- 1.2 mmol/L (not significant). Prednisolone metasulphobenzoate foam enemas have significant systemic and endocrine metabolic effects, which could assume importance with long-term therapy.

Beta-endorphin responses to metyrapone and dexamethasone in depressed patients

Controversy continues over the characteristics of beta-endorphin secretion in depression. Beta-endorphin plasma levels were measured in 30 drug-free male patients with a DSM-III-R major depressive disorder and 21 healthy controls. Depressed patients displayed significantly lower beta-endorphin plasma levels in baseline conditions, after the single dose metyrapone test, and after the dexamethasone suppression test. The activation of hypothalamic-pituitary-adrenal (HPA) axis in depression might be due, at least in part, to low levels of beta-endorphin. These results suggest that HPA axis dysregulation in depression may involve peptides other than ACTH.

The effect of an inhaled steroid on the hypothalamic‐pituitary‐adrenal axis‐which tests should be used?

Inhaled corticosteroids may produce systemic effects which include decreased hypothalamic-pituitary-adrenal (HPA) axis activity. Four tests of HPA axis function were assessed in 12 healthy volunteers, during inhalation of two actuations of beclomethasone dipropionate (250 micrograms) aerosol four times daily for 15 days, to determine the most appropriate test for this effect of inhaled corticosteroids. Measurement of basal adrenal activity showed that both 24-hr urinary free cortisol and 0900 hr plasma cortisol were decreased by the fourth day of steroid treatment. All 12 subjects had decreases in basal adrenal activity. Overall the 24-hr urinary free cortisol showed the greater change, with mean pre-steroid baseline values of 497 and 515 nmol/24 hr reduced to 167 nmol/24 hr on the ninth day of treatment (P less than 0.001). The single-dose metyrapone test showed marked changes in each of the six subjects tested. The mean 11-deoxycortisol response was 96 nmol/l on the eleventh day of treatment, compared to baseline and eight-day post-treatment values of 439 and 407 nmol/l respectively (P less than 0.001). In contrast, no consistent treatment-related changes were observed with the short tetracosactrin test. Only two out of six subjects had an abnormal short tetracosactrin test, although all showed a decrease in basal adrenal activity. From these results, the 24-hr urinary free cortisol and single-dose metyrapone test at 0600 hr are recommended to assess the effect of inhaled glucocorticoids on the HPA axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose metyrapone test at 06.00 h: an accurate method for assessment of pituitary-adrenal reserve.

One dose of metyrapone (1.5g) administered at 06.00 h, with subsequent measurement of 11-deoxycortisol and 17-hydroxycorticosteroid (17-OHCS) levels in plasma at 12.00 and 14.00 h, allowed accurate assessment of the pituitary-adrenal reserve. Normal response was defined as achieving a serum 17-OHCS level of more than 10.0 micrograms/100 ml and a 11-deoxycortisol level of more than 6.0 micrograms/100 ml at either 12.00 or 14.00 h. These criteria are based on a group of 18 persons with normal pituitary-adrenal axis, and 86 additional cases responded in this normal range. In this group of 104 subjects, 11-deoxycortisol levels rose to 9.2 +/- 3.5 micrograms/100 ml at noon and 17-OHCS levels to 15.4 +/- 4.7 micrograms/100 ml at 14.00 h. Post-metyrapone 17-OHCS levels were significantly higher than normal cortisol levels at these times (P less than 0.001) and than those observed at 08.00 h on the day of the test, demonstrating stimulation of adrenal corticoid production in addition to blockade of cortisol production by metyrapone. Thirty-one patients found to suffer from secondary adrenal failure showed impaired response. All these patients had limited pituitary-adrenal reserve, either proven by other pituitary-adrenal tests or implicated by severe pituitary disease.

Effect of metoclopramide and L-dopa on a single dose metyrapone test in normal men.

Effect of metoclopramide and L-dopa on a single dose metyrapone test in normal men.

The Discrepancy Between ACTH and 11-Deoxycortisol Levels in a Single Dose Metyrapone Test

Five healthy men were given 1.0 gr of metyrapone p.o. (MTP test) with and without 0.5 gr of 1- dopa p.o. (DOPA-MTP test) or 10 mg of metoclopramide p.o. (MTC-MTP test) and plasma 11-deoxycortisol, cortisol, ACTH and pregnenolone (only in MTP test) were determined before and hourly after the drug administrating for 6 hrs. In the MTP test, plasma 11-deoxycortisol increased significantly at 1 hr with peak at 5 hrs, whereas the significant increases of pregnenolone and ACTH were not seen until 2 hrs, although plasma cortisol levels were reduced definitely at 1 hr. Thus, the increase of 11-deoxycortisol in the MTP test should be divided into two phases; the increase in the phase II (later than 3 hrs) is due to pituitary ACTH reserve, and that in the phase I (until 2 hrs) is due to unknown mechanism other than pituitary reserve. In the DOPA-MTP test, the 11-deoxycortisol rise was significantly larger than that in the MTP test. The increases in 11-deoxycortisol at 4 hrs and 5 hrs in the MTC-MTP test were significantly smaller than those in the MTP test. The cortisol/(cortisol + 11-deoxycortisol) ratio reached its lowest point at 3 hrs in the MTP test and at 2 hrs (a 1 hr advance) in the DOPA-MTP and MTC-MTP tests. However, there were no significant differences in the responses of cortisol and ACTH to metyrapone in these tests. This provides evidence for a discrepancy between plasma 11-deoxycortisol and ACTH responses in a single dose metyrapone test, as disclosed by the simultaneous administration of dopamine agonist or antagonist with metyrapone.

The discrepancy between plasma 11-deoxycortisol and ACTH concentrations in a single dose metyrapone test in normal men.

A single dose methyrapone test (MTP test) was carried out on 6 normal men by administering 1.0 g of metyrapone at 08.00-09.00 h with and without dexamethasone (DXM-MTP test) pre-treatment. Plasma 11-deoxycortisol, pregnenolone, ACTH and cortisol were measured before administration of the drug, and at hourly intervals for 6 h. In the MTP test, 11-deoxycortisol increased significantly at 1 h with a peak at 5 h, whereas significant increases in pregnenolone and ACTH were not seen until 3 h. There was a definite decrease in the cortisol level at 1 h with the lowest level measured at 2 h. Thus, a time discrepancy between plasma 11-deoxycortisol and ACTH concentrations was observed. The increase in 11-deoxycortisol after metyrapone should be divided into two phases: the increase in phase II (after 3 h) is due to the pituitary ACTH reserve, and that in phase I (the first 2 h) is due to some mechanism other than the pituitary ACTH reserve. The increased amount of 11-dexoycortisol in phase II (218.1 nmol) occupied 60.5% of the total increased amount in phases I and II (360.6 nmol). The cortisol/(cortisol + 11-deoxycortisol) ratio reached its lowest point 3 h after metyrapone treatment. This might be due to the initiation of an additional surge in 11-deoxycortisol by the ACTH reserve at 3 h.

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.

Plasma ACTH and compound S response to a single oral dose of metgrapone

Plasma ACTH (direct radioimmunoassay), cortisol (R.I.A.) and compound S (R.I.A.) were measured during insulin induced hypoglycemia or 3 to 7 h after a single oral dose (1 g/m2) of metyrapone taken at 7 a.m. or at midnight. The mean maximum ACTH concentration after hypoglycemia (316 ± 196 pg/ml) was comparable to the mean maximum 7 h (507 ± 344 pg/ml) and 3 h (416 ± 366 pg/ml) after metyrapone. Compound S rose to 6, 2 ± 3, 9 ng/ml, plasma cortisol was suppressed (6, 2 ± 2, 8 μg%) 3 h after metyrapone and stimulated (17, 4 ± 6, 6 μg%) 7 h after the midnight dose. Within 70 children tested a diminished or absent response was observed in patients under cyproterone acetate after steroid therapy (2), in hypothalamo-pit. insufficiency (4) and anorexia nervosa (1). The single dose metyrapone test is a safe and reliable procedure for the assessment of the hypothalamo-pituitary adrenal system. If the test is based on the compound S and cortisol response alone, it does not require venipuncture.

Single-dose metyrapone test: review of a four-year experience

Single-dose metyrapone test: review of a four-year experience

Single-Dose Metyrapone Test

Subnormal plasma 11-deoxycortisol (compound S) responses to metyrapone were found in patients with adrenal insufficiency or with Cushing syndrome caused by adrenal tumors and in those receiving long-term glucocorticoid or diphenylhydantoin sodium therapy. High normal or exaggerated responses were seen in women receiving oral contraceptives, patients with Cushing syndrome caused by adrenal hyperplasia, and those with untreated hypothyroidism. Diabetes mellitus, hypoglycemia, congestive failure, and obesity also were associated with exaggerated responses. Subnormal plasma S responses were observed in 15 patients who responded normally to a repeat test or to the standard metyrapone test. The abnormal response resulted from insufficient metyrapone, administration at the wrong time, or delay in obtaining the blood sample. The single-dose metyrapone test may be the procedure of choice in screening for adrenal insufficiency.

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.

Single-Dose Metyrapone Test

For a single-dose metyrapone test, from 2 to 3 gm of the drug were given at midnight. Blood for plasma deoxycortisol and adrenocorticotropic hormone determination was obtained at 8 AM the next morning. Urine for assay of 11-deoxycorticosteroids was also collected from midnight to midnight before and after metyrapone administration. Using any of the three determinations, we found no overlap between 30 normal subjects and 11 patients with pituitary insufficiency. The results are comparable to those obtained with the standard metyrapone test (750 mg every four hours, six times). We conclude that the single-dose metyrapone test is a simple and reliable test of pituitary function.