-
Frontiers in Endocrinology 2022Although surgery is considered the first-line treatment for patients with endogenous Cushing's syndrome (CS), medical therapy is often required to control severe...
BACKGROUND
Although surgery is considered the first-line treatment for patients with endogenous Cushing's syndrome (CS), medical therapy is often required to control severe hypercortisolism. Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, however, their therapeutic effectiveness has not yet been directly compared. This study aimed to evaluate metyrapone and osilodrostat in the short-term therapy of CS.
METHODS
Retrospective analysis of patients with endogenous CS treated with metyrapone or osilodrostat as monotherapy for at least 4 weeks. Main outcome measures were serum cortisol and 24h urinary free cortisol (UFC) at baseline (T0) and after 2 (T1), 4 (T2), and 12 weeks (T3) of therapy.
RESULTS
16 patients with endogenous CS were identified (pituitary n=7, adrenal n=4, ectopic CS n=5). Each 8 patients were treated with metyrapone and osilodrostat. Despite heterogeneity, both groups showed comparable mean UFC levels at T0 (metyrapone: 758 µg/24h osilodrostat: 817 µg/24h; =0.93). From T0 to T1, the decrease of UFC was less pronounced under metyrapone than osilodrostat (-21.3% -68.4%; median daily drug dose: 1000 mg vs 4 mg). This tendency persisted at T2 (-37.3% vs -50.1%; median drug dose: 1250 mg 6 mg) while at T3 a decrease in UFC from T0 was more pronounced in the metyrapone group (-71.5% -51.5%; median dose 1250 mg 7 mg). Under osilodrostat, a QTc-interval prolongation was identified at T3 (mean 432 ms vs 455 ms). From T0 to T2, the number of antihypertensive drugs remained comparable under metyrapone and decreased under osilodrostat (n= -0.3 n= -1.0).
CONCLUSION
Although both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster.
Topics: Cohort Studies; Cushing Syndrome; Humans; Hydrocortisone; Imidazoles; Metyrapone; Pyridines; Retrospective Studies
PubMed: 35769081
DOI: 10.3389/fendo.2022.903545 -
Epilepsia Jun 2023Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The...
OBJECTIVE
Stress is one of the most commonly reported triggers for seizures in patients with epilepsy, although the mechanisms that mediate this effect are not established. The clinical evidence supporting this is derived from patients' subjective experience of stress, and how this influences their own seizures. Animal models can be used to explore this phenomenon in controlled environments, free from subjective bias. Here, we used genetic absence epilepsy rats from Strasbourg (GAERS), a genetic rat model of absence epilepsy, to explore the influence of stress and stress hormones on spontaneous seizures.
METHODS
Adult male GAERS (n = 38) and nonepileptic control (NEC) rats (n = 4) were used. First, rats were subjected to 30-min restraint stress to assess hypothalamic-pituitary-adrenal axis function. Next, we assessed the effects of 30-min noise stress, and cage tilt stress, on spike-wave discharge seizures in GAERS. We then performed pharmacological experiments to assess the direct effects of stress hormones on seizures, including corticosterone, metyrapone, and deoxycorticosterone.
RESULTS
GAERS exhibited elevated baseline corticosterone levels, compared to NEC rats. Noise stress and cage tilt stress significantly enhanced seizure incidence (p < .05), but only during stress periods. Exogenous corticosterone administration also significantly increased seizure occurrence (p < .05). Metyrapone, an inhibitor of corticosterone synthesis, completely abolished seizures in GAERS, and seizures remained suppressed for >2 h. However, deoxycorticosterone, the precursor of corticosterone, increased seizures.
SIGNIFICANCE
These results suggest that GAERS exhibit elevations in stress hormones, and this may contribute to seizures. Inhibiting corticosterone synthesis with metyrapone prevents seizures in GAERS, and shows potential for repurposing this drug as a future antiseizure medication.
Topics: Humans; Rats; Male; Animals; Epilepsy, Absence; Metyrapone; Corticosterone; Hypothalamo-Hypophyseal System; Patient Discharge; Electroencephalography; Pituitary-Adrenal System; Seizures; Desoxycorticosterone; Disease Models, Animal
PubMed: 36916834
DOI: 10.1111/epi.17584 -
Experimental and Clinical Endocrinology... Jan 2017To investigate the kinetics of adrenocorticotropin (ACTH) following oral metyrapone administration and describe differences between ACTH-deficient and...
To investigate the kinetics of adrenocorticotropin (ACTH) following oral metyrapone administration and describe differences between ACTH-deficient and non-ACTH-deficient subjects. Patients from a tertiary endocrine center at a University Hospital in Munich, Germany, were tested for secondary adrenal insufficiency in a regular patient care setting. Metyrapone (Metopirone, HRA Pharma, France) was administered with a dosage of 40 mg/kg bodyweight at 8 a.m. Consecutive levels of ACTH were determined at 0, 60, 120, 180, and 240 min. Patients were categorized according to their need of glucocorticoid substitution in the follow-up phase. A significant rise in ACTH concentration compared to basal values was found at 60 and 120 min following oral metyrapone administration. ACTH concentrations at 60 and 120 min predicted patients without need for glucocorticoid substitution. ACTH concentrations determined later had no additional benefit. In contrast to previous reports, we found a significant rise in ACTH concentration as soon as one hour after oral metyrapone administration. ACTH values seem to estimate the pituitary corticotrophic function when correlating results to the further clinical course of subjects. Further studies are needed to investigate this finding as a potential basis for a ACTH-based metyrapone short test protocol.
Topics: Administration, Oral; Adrenocorticotropic Hormone; Adult; Aged; Female; Follow-Up Studies; Germany; Humans; Hypopituitarism; Male; Metyrapone; Middle Aged; Tertiary Care Centers
PubMed: 27750352
DOI: 10.1055/s-0042-117832 -
Pharmacology, Biochemistry, and Behavior Apr 2005Pre-clinical research suggests that suppression of adrenocorticosteroid synthesis might decrease susceptibility to stress-induced relapse. Metyrapone effectively... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Pre-clinical research suggests that suppression of adrenocorticosteroid synthesis might decrease susceptibility to stress-induced relapse. Metyrapone effectively suppresses cortisol synthesis and thus might have promise as a cocaine dependence treatment. The present inpatient study evaluated the interaction of metyrapone and cocaine to assess the safety of conducting an outpatient trial. Twelve nontreatment-seeking cocaine-dependent individuals completed this double-blind, placebo-controlled, crossover study with two factors: medication (750 mg of metyrapone vs. placebo) and infusion (40 mg of cocaine vs. saline). Safety measures included vital signs, adverse events, and electrocardiogram. Efficacy measures included visual analog scale (VAS) ratings of craving and drug effect. Neuroendocrine measures included cortisol and ACTH. As predicted, metyrapone was well tolerated and did not exacerbate cocaine's physiological effects. Also as predicted, metyrapone did not significantly alter cocaine's subjective effects. The results of the present study suggest that metyrapone at the dose studied can likely be used safely in an outpatient study with active cocaine users.
Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Blood Pressure; Cocaine; Cross-Over Studies; Double-Blind Method; Drug Interactions; Electrocardiography; Female; Heart Rate; Humans; Hydrocortisone; Male; Metyrapone; Middle Aged
PubMed: 15820533
DOI: 10.1016/j.pbb.2005.01.017 -
Nordisk Medicin Jul 1964
Topics: Drug Therapy; Ketones; Metyrapone; Mineralocorticoid Receptor Antagonists; Pharmacology
PubMed: 14312788
DOI: No ID Found -
Psychoneuroendocrinology Oct 2023Pharmacological manipulation of cortisol levels is instrumental in elucidating mechanisms underlying acute stress effects and for distinguishing the physiological and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pharmacological manipulation of cortisol levels is instrumental in elucidating mechanisms underlying acute stress effects and for distinguishing the physiological and behavioral effects of cortisol from those of the adrenergic system. Administration (oral or IV) of hydrocortisone is a direct and efficient method to elevate cortisol, and thus, frequently used in psychobiological stress research. However, lowering of cortisol (i.e. blockade of stress cortisol) requires a more sophisticated approach, such as the administration of the corticostatic compound metyrapone (MET). However, there is insufficient knowledge about the temporal dynamics of MET for the blocking of stress-induced cortisol reactivity. Thus, the present study aimed to build up an experimental protocol suitable to suppress acute behavioral stress-induced cortisol secretion by MET.
METHODS
50 healthy young men were randomly assigned to one of five treatment groups. They received 750 mg oral MET either 30 (n = 9), 45 (n = 11), or 60 (n = 10) minutes before exposure to a combined cold pressor and mental arithmetic test (stress induction), or were subjected to two different control treatments (placebo 60 min before stress (n = 10) or MET 30 min before non-stressful warm-water condition (n = 10)). Salivary cortisol concentration, hemodynamics, and subjective ratings were assessed.
RESULTS
Suppression of cold stress-induced cortisol release was strongest when MET intake was scheduled 30 min prior to stress onset. Cardiovascular stress-responses and subjective ratings remained unaffected by MET.
CONCLUSION
In healthy young males, 750 mg of MET efficiently block cold stress-induced cortisol release when oral administration is scheduled 30 min prior to stress onset. This finding may guide future research in improving timing of suppression of stress-induced cortisol secretion.
Topics: Male; Humans; Hydrocortisone; Metyrapone; Cold-Shock Response; Hemodynamics; Heart; Stress, Psychological; Hypothalamo-Hypophyseal System; Saliva; Pituitary-Adrenal System
PubMed: 37393800
DOI: 10.1016/j.psyneuen.2023.106328 -
The Journal of Clinical Endocrinology... Mar 1975The 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... (Comparative Study)
Comparative Study
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.
Topics: 17-Hydroxycorticosteroids; Administration, Oral; Adult; Cushing Syndrome; Evaluation Studies as Topic; Female; Humans; Male; Metyrapone; Middle Aged; Pituitary-Adrenal Function Tests; Pituitary-Adrenal System
PubMed: 1117059
DOI: 10.1210/jcem-40-3-521 -
Neuroendocrinology 2023The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in...
INTRODUCTION
The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response.
METHODS
44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 μg/L) and a pathological (11-deoxycortisol <70 μg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics.
RESULTS
At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 μg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%).
CONCLUSION
The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.
Topics: Humans; Metyrapone; Hypothalamo-Hypophyseal System; Hydrocortisone; Cortodoxone; Adrenocorticotropic Hormone; Pituitary-Adrenal System
PubMed: 36646062
DOI: 10.1159/000529146 -
Pharmacology, Biochemistry, and Behavior Aug 1994The fluid intake of male Wistar rats with simultaneous access to water and 6% ethanol was determined between 0900 and 1500 h. In high-preferring males (normally covering...
The fluid intake of male Wistar rats with simultaneous access to water and 6% ethanol was determined between 0900 and 1500 h. In high-preferring males (normally covering > 60% of their daily fluid consumption in the form of ethanol), two injections with the corticosterone synthesis inhibitor metyrapone (50 mg/kg) at 0900 h and 1200 h for 4 consecutive days significantly reduced ethanol preference such that they preferred water over alcohol. Treatment with corticosterone (0.6 mg/kg) 2 h before each metyrapone injection partially cancelled this effect of the synthesis inhibitor. By contrast, there was no significant effect of metyrapone treatment on the drinking of ethanol in low-preferring rats (normally covering < 30% of their daily fluid consumption in the form of ethanol). These results suggest that the adrenal secretion of corticosterone directly or indirectly modulates the intake of alcohol in high-preferring rats.
Topics: Alcohol Drinking; Animals; Corticosterone; Drinking; Ethanol; Male; Metyrapone; Rats; Rats, Wistar
PubMed: 7972304
DOI: 10.1016/0091-3057(94)90208-9 -
The Journal of Steroid Biochemistry and... Jun 1997The present study was designed to examine the effects of metyrapone in vitro on the activities of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, the two...
The present study was designed to examine the effects of metyrapone in vitro on the activities of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, the two intracellular enzymes responsible for the metabolism of glucocorticoids. Enzymatic activities of 11beta-HSD1 and 2 were determined by a radiometric conversion assay using cortisol and cortisone as physiological substrates. The enzyme activity assays were carried out in the absence and presence of metyrapone using sheep liver and kidney microsomes as the source of 11beta-HSD1 and 2, respectively. It was found that metyrapone inhibited the reductase activity of 11beta-HSD1 in a dose-dependent manner with an apparent Ki of 30 microM. Moreover, this inhibition was competitive because the Km for cortisone was increased in the presence of metyrapone. In contrast, metyrapone showed biphasic effects on the dehydrogenase activity of 11beta-HSD1, in that it increased the activity at concentrations lower than 100 microM but decreased it at higher concentrations. However, under similar conditions, metyrapone had little effect on the unidirectional dehydrogenase activity of 11beta-HSD2. In conclusion, the present results provide the first direct evidence that metyrapone is a competitive inhibitor of 11beta-HSD1 reductase, and that it also exerts biphasic effects on 11beta-HSD1 dehydrogenase activity. These findings indicate that metyrapone influences peripheral glucocorticoid metabolism through its regulation of 11beta-HSD1 activity, in addition to its classic inhibitory effects on adrenal steroid biosynthesis. It is therefore imperative that this novel extra-adrenal effect of metyrapone be considered when this drug is used in the diagnosis and treatment of adrenocorticoid-related diseases.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Binding, Competitive; Enzyme Inhibitors; Hydroxysteroid Dehydrogenases; Kidney; Metyrapone; Microsomes; Microsomes, Liver; Sheep
PubMed: 9393954
DOI: 10.1016/s0960-0760(97)00027-7