Oral Administration Of Metyrapone Research Articles

Suppressing the Morning Cortisol Rise After Memory Reactivation at 4 A.M. enhances Episodic Memory Reconsolidation in Humans.

Evidence from animal and human research shows that established memories can undergo changes after reactivation through a process called reconsolidation. Alterations of the level of the stress hormone cortisol may provide a way to manipulate reconsolidation in humans. Here, in a double-blind, within-subject design, we reactivated a 3-d-old memory at 3:55 A.M. in sixteen men and four women, immediately followed by oral administration of metyrapone versus placebo, to examine whether metyrapone-induced suppression of the morning cortisol rise may influence reconsolidation processes during and after early morning sleep. Crucially, reactivation followed by cortisol suppression versus placebo resulted in enhanced memory for the reactivated episode tested 4 d after reactivation. This enhancement after cortisol suppression was specific for the reactivated episode versus a non-reactivated episode. These findings suggest that when reactivation of memories is immediately followed by suppression of cortisol levels during early morning sleep in humans, reconsolidation processes change in a way that leads to the strengthening of episodic memory traces.SIGNIFICANCE STATEMENT How can we change formed memories? Modulation of established memories has been long debated in cognitive neuroscience and remains a crucial question to address for basic and clinical research. Stress-hormone cortisol and sleep are strong candidates for changing consolidated memories. In this double-blind, placebo-controlled, within-subject pharmacological study, we investigate the role of cortisol on the modulation of reconsolidation of episodic memories in humans. Blocking cortisol synthesis (3 g metyrapone) during early morning sleep boosts memory for a reactivated but not for a non-reactivated story. This finding contributes to our understanding of the modulatory role of cortisol and its circadian variability on reconsolidation, and moreover can critically inform clinical interventions for the case of memory dysfunctions, and trauma and stress-related disorders.

Dynamics of Adrenocorticotropin after Application of Metyrapone.

Purpose: To investigate the kinetics of adrenocorticotropin (ACTH) following oral metyrapone administration and describe differences between ACTH-deficient and non-ACTH-deficient subjects. Methods: 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. Results: 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. Conclusion: 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.

Oral pharmacokinetics and in-vitro metabolism of metyrapone in male rats.

The purpose of this study was to investigate the pharmacokinetics of a single oral administration of metyrapone (MP) and metabolites produced from it in male Wistar rats, and the major tissues and enzymes involved in the production of the MP metabolites. Furthermore, the MP metabolism in human liver subcellular fractions was compared with that in rats. High-performance liquid chromatography with ultraviolet detection (HPLC-UV) was used to determine the concentrations of MP and its metabolites in plasma and urine after administration, and the production activity of MP metabolites in subcellular fractions of various tissues. Plasma concentration of MP was rapidly increased and decreased, and the primary metabolite, metyrapol (MPOL), was immediately produced. The production activity of MPOL was substantially inhibited by an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor in the rat and human liver microsomal and mitochondrial fractions. In the liver cytosolic fraction, the activity was inhibited by a carbonyl reductase inhibitor in the humans but not rats. In this study, we elucidated the plasma pharmacokinetics of MP and its metabolites in male rats after an oral administration. MPOL is most likely to be produced by 11β-HSD1 in the male rats and humans.

Effects of suppressing cortisol following castration of bull calves on adrenocorticotropic hormone, in vitro interferon-gamma production, leukocytes, acute-phase proteins, growth, and feed intake.

The objective was to determine the effects of reducing the plasma cortisol rise in calves following castration on plasma ACTH concentrations, keyhole limpet hemocyanin (KLH)- and concanavalin A (Con A)-induced in vitro interferon (IFN)-gamma production, white blood cell (WBC) numbers, neutrophil:lymphocyte (N:L) ratio, plasma haptoglobin and fibrinogen concentrations, ADG, and ADFI. Forty 5-mo-old Friesian bull calves (169 +/- 1.7 kg) were assigned to four treatments: 1) control (CON); 2) oral metyrapone administration (MET); 3) surgical castration at 0 h on d 0 (SURG); and 4) oral metyrapone administration and surgical castration (MET+SURG). Cortisol, ACTH, IFN-gamma production, haptoglobin, fibrinogen, ADFI, and ADG were not different between CON and MET animals. The MET+SURG calves had lower (P < .001) peak and mean cortisol during .25 to 1.5 h than SURG animals, but area under the cortisol vs time curve from 0 to 12 h did not differ (P > .39) between SURG and MET+SURG calves. Peak ACTH concentrations and area under the ACTH vs time curve from 0 to 6 h were greater (P < .05) for MET+SURG than for SURG calves. There were no differences between MET+SURG and SURG animals in IFN-gamma production, WBC numbers, and ADFI. On d 1, MET+SURG and SURG animals had lower (P < .01) KLH- and Con A-induced IFN-gamma production and higher (P < .05) neutrophil numbers and N:L ratio compared with CON animals. Plasma haptoglobin on d 1 and 3 and fibrinogen concentrations on d 3 and 7 were elevated (P < .05) for MET+SURG and SURG compared with CON animals, whereas SURG animals had greater (P < .05) haptoglobin and fibrinogen concentrations than MET+SURG animals on d 7. The ADG of SURG calves was lower (P < .05) than that of MET+SURG calves during d 0 to 7. Metyrapone treatment partially suppressed cortisol and increased ACTH in castrated calves but did not alter the castration-induced suppression of IFN-gamma and increases in neutrophil numbers and the N:L ratio.

Adrenal androgen response to metyrapone, adrenocorticotropin, and corticotropin-releasing hormone stimulation in children with hypopituitarism.

We determined the adrenal steroid responses to metyrapone, ACTH, and CRH in 12 ACTH-intact and 5 ACTH-deficient hypopituitary children to determine the mechanisms that control adrenal androgen secretion. Serum adrenal androgen concentrations [dehydroepiandrosterone (DHEA) and delta 4-androstenedione (delta 4-A)] rose in response to oral administration of metyrapone (450 mg/m2 X dose, every h for 7 doses) in ACTH-intact hypopituitary children with multiple or isolated pituitary hormone deficiencies [mean postmaryrapone level: DHEA, 225 ng/dL (range, 27-566); delta 4-A, 313 ng/dL (range, 105-651)], except in 2 young children in whom DHEA did not rise. These adrenal androgens did not rise in all ACTH-deficient hypopituitary children [mean postmetyrapone level: DHEA, 11.0 ng/dL (range, 3-16); delta 4-A, 6.2 ng/dL (range, 3-10)]. The increases in both serum cortisol and adrenal androgens, including DHEA sulfate, in response to short term ACTH infusion (40 U in 6 h) in ACTH-intact hypopituitary children were normal or above normal, while these steroid responses were significantly (P less than 0.05-0.01) lower in ACTH-deficient hypopituitary children compared to normal values. However, prolonged administration of ACTH (40 U/day, or im) for 6 days to 2 ACTH-deficient hypopituitary children resulted in normal DHEA responses to the 6-h ACTH stimulation test (DHEA levels after the first test, 14 and 30 ng/dL, after priming, 80 and 50 ng/dL). Furthermore, CRH administration to 4 ACTH-deficient patients caused a rise in serum DHEA and cortisol in patients with a normal ACTH response, while those with a poor ACTH response had a lesser rise in DHEA and cortisol. These data suggest that ACTH is the major tropic hormone for adrenal androgen secretion.

Big form of γ-melanotropin-like immunoreactivity in normal human plasma

Using a radioimmunoassay for γ 3-melanotropin ( γ 3-MSH), γ-melanotropin-like immunoreactivity (γ-MSH-LI) was detected in plasma extracts of normal subjects before and after metyrapone administration. Plasma γ-MSH-LI from four normal men rose significantly after a single oral administration of metyrapone (30 mg/kg of body weight). Gel chromatographic study of plasma extract after metyrapone administration showed a single peak of γ-MSH-LI near the elution position of mouse 16K fragment, however smaller forms of γ-MSH-LI were not detected.

Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA): Gas-liquid chromatographic studies of RA patients and matched normal control women indicating decreased 11-deoxy-17-ketosteroid excretion

Using GLC, multiple adrenal corticosteroid urinary metabolites, including androgenic-anabolic, glucocorticoid, pregnanediol, and pregnanetriol, were measured in eight ambulatory female RA patients and eight matched normal control subjects on baseline, ACTH-, and metyrapone-stimulation days under carefully monitored clinical research center protocol. Neither group had been treated previously with any steroid hormones. The 11-deoxy-17-KS metabolites, derived from adrenal androgenic-anabolic steroids, and comprising androsterone, etiocholanolone, and DHA, were significantly lower in RA patients on baseline (P less than .001), ACTH (P less than .005)-, and metyrapone (P less than .02)-stimulation days. To the contrary, the 11-oxy-17-KS metabolites, derived mainly from glucocorticoids, showed some lowered excretion at baseline (P less than .05), but none on ACTH- or metyrapone-stimulation. RA patients had lower tetrahydrocortisone (P less than .001) and tetrahydro-11-deoxycortisol (P less than .01) excretion at baseline, but not during ACTH- or metyrapone-stimulation, than control subjects. Pregnanetriol excretion was lower (P less than .005) in RA patients than control subjects only during ACTH-stimulation. No difference was found between groups in tetrahydrocortisol or pregnanediol excretion on any day studied. Under conditions of oral metyrapone administration (750 mg every four hours for seven doses) each control subject increased their DHA excretion, but no RA patient showed an increase over baseline excretion (P less than .02). Except for 11-deoxy-17-KS, no difference was found in the other metabolites studied during metyrapone stimulation, ie, pregnanediol, pregnanetriol, tetrahydro-11-deoxycortisol, and tetrahydrocortisol. The 24-hour oral metyrapone test provided a greater stimulus to total 11-deoxy-17-KS excretion than an eight-hour intravenous ACTH test in control and particularly RA (P less than .01) subjects even though the DHA excretion decreased in the RA groups. Our findings of lower adrenal androgenic-anabolic metabolite excretion in female RA patients than normal matched control subjects under various conditions and other supportive androgenic hormone and metabolite studies reviewed in the English reports suggest an abnormality of adrenal androgen synthesis or metabolism in RA, whether it be a primary predisposing or secondary factor in disease. The recognized female sex preponderance and age-specific patterns of occurrence of RA are consistent with adrenal androgenic function in adrenarche, adrenopause, and later changes in aging. Metabolite excretion patterns at baseline, ACTH-, and metyrapone- stimulation indicate the greatest relative

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.

Serum cortisol and 11 deoxycortisol by liquid chromatography: clinical studies and comparison with radioimmunoassay.

We describe a liquid-chromatographic procedure for separating and measuring cortisol and 11-deoxycortisol in serum. We quantitated these steroids in patients who were undergoing various tests of pituitary and (or) adrenal function and compared the results with those obtained by two radioimmunoassays done in two different laboratories. Results of 48 tests done in 37 functionally normal humans are presented. Cortisol values for sera collected in the morning as determined by liquid chromatography were (mean +/- SD) 134 +/- 54 micrograms/L. Serum cortisol concentrations increased from 136 +/- 65 to 321 +/- 80 micrograms/L 60 min after injecting synthetic corticotropin and increased from 107 +/- 46 to 242 +/- 31 micrograms/L after insulin-induced hypoglycemia. Serum cortisol decreased from 142 +/- 49 to 26 +/- 20 micrograms/L after oral administration of metyrapone, while 11-deoxycortisol increased from less than 10 to 210 +/- 53 micrograms/L. Serum cortisol measured less than 10 micrograms/L the morning after oral ingestion of dexamethasone. Results of the dynamic tests of adrenal function correlated well with previously reported studies. However, the cortisol values obtained by our technique were generally lower than those obtained by radioimmunoassay, possibly owing to lack of specificity of the latter methods used here for comparison. In contrast, values for 11-deoxycortisol were the same by both methods. The present studies confirm the usefulness of liquid chromatography for measuring these two steroids in serum during tests of pituitary and adrenal function. Future refinements of the technique should continue to increase its clinical applications.

Hypothalamic-pituitary functions in patients with idiopathic pituitary dwarfism. Further evidence for hypophysiotropic human deficiencies.

Somatotropic, thyrotropic, gonadotropic and corticotropic functions in 10 patients with idiopathic hypopituitary dwarfism (IH) were investigated. The patients were divided into two groups: Group I (5 patients) had normal plasma T4 levels, and Group II (5 patients) had T4 levels of less than 4.6 microgram/dl. In Group I three cases had isolated growth hormone (GH) deficiency and two cases had GH and gonadotropin (Gn) deficiencies; in Group II the 5 cases showed multiple anterior pituitary hormone deficiencies. In Group II, the plasma thyroid stimulating hormone (TSH) was 4.1-9.4 muU/ml and the response to thyrotropin releasing hormone (TRH) was greatly delayed and prolonged, with a maximum after 120 min instead of 15 min. The basal prolactin (PRL) level in Group II was 12-31 ng/ml, which was significantly higher than normal (P less than 0.001). In 4 cases in Group II, the plasma cortisol level increased 120 min after the infusion of lysine-vasopressin, whereas oral administration of metyrapone and hypoglycemia induced by insulin did not increase the plasma cortisol levels. From these findings it is concluded that hypothalamic lesions caused the pituitary hormone deficiencies in 4 Group II cases, and Group I may tentatively be differentiated from Group II by T4 determinations.

Simultaneous determination of eight adrenal steroids in human serum by radioimmunoassay

A radioimmunological method for estimation of progesterone, 17-OH-progesterone, deoxycorticosterone (DOC), corticosterone, 11-deoxycortisol, 18-OH-deoxycorticosterone (18-OH-DOC), aldosterone and cortisol in one sample of human serum is described. The procedure involves separation of the steroids into four fractions by liquid-liquid partition, purification by paper chromatography and quantitation by radioimmunoassay. The parameters precision, accuracy, sensitivity and specificity of the present method are shown to be equivalent to those of single steroid radioimmunoassays. Mean serum concentrations in a series of normal males were as follows : progesterone, 17.9 ng/100 ml ; 17-OH-progesterone, 179 ng/100 ml; DOC, 6.6 ng/100 ml; corticosterone, 421 ng/100 ml; 11-deoxycortisol, 49 ng/100 ml; 18-OH-DOC, 20 ng/100 ml; aldosterone, 12.4 ng/100 ml and cortisol, 14.4 μg/100 ml. The percentage increment of steroid serum concentration after adrenocortical stimulation by ACTH or insulin induced hypoglycemia differed markedly between the individual steroids. The changes of serum steroid concentrations after oral administration of metyrapone are shown. Angiotensin II infusion caused a significant increase of serum aldosterone and a significant fall of serum cortisol, while serum concentrations of the other steroids remained unaltered.

Simultaneous Radioimmunoassay for Corticosterone and Deoxycortisol in Human Serum: Sex Differences in the Mean Serum Concentrations

A specific radioimmunoassay is described which allows the simultaneous determination of serum corticosterone and deoxycortisol. The method involves extraction with dichloromethane, purification by paper chromatography in a modified Bush-system and quantitation by radioimmunoassay. The normal serum concentration of both steroids were found to be dependent on sex and menstrual cycle. Mean concentrations (+/- S.D.) in males, females (follicular phase) and females (luteal phase) were 4210 +/- 2170 ng/1,2410 + 1480 ng/1 and 4390 +/- 2320 ng/1 for corticosterone and 499 +/- 273 ng/1, 207 +/- 152 ng/1 and 335 +/- 182 ng/1 for deoxycortisol. After adrenal stimulation by corticotropin itself or by insulin induced hypoglycemia, the serum concentrations of corticosterone became significantly higher than those of deoxycortisol. After oral administration of dexamethasone serum concentrations of both steroids were suppressed to levels below the limit of the normal range. One hour after oral metyrapone administration at midnight, serum corticosterone decreased, while serum deoxycortisol increased by a factor of about five. After eight hours serum concentrations of both steroids were increased considerably. Corticosterone attained levels slightly higher than the normal range and deoxycortisol rose to levels which were higher than the normal mean concentrations by a factor of about 500.

Circadian rhythms in adrenocortical adrenocortical activity during and after a 36 hour 4-hourly-sustained administration of metyrapone in humans

The circadian variations of plasma cortisol, plasma 11-deoxycortisol and their urinary metabolites, 17-hydroxycorticosteroids and tetrahydro-11-deoxycortisol, have been investigated on two healthy young human males before, during and after a 36 h sustained oral administration of metyrapone (total dose: 7.50 g). Circadian changes were analysed by the cosinor method. Subjects were synchronized with diurnal activities from 0715 h to 2300 h and nocturnal rest. A circadian rhythm is likely to be present for plasma cortisol before, and plasma 11-deoxycortisol after metyrapone administration. A prominent peak has been shown at a trial period of 24 h. A circadian rhythm seems to be present in 17-hydroxycorticosteroids excretion before during and after metyrapone administration. In tetrahydro-11-deoxycortisol excretion it was found only during and after, and in the estimated portion of 11-hydroxylated tetrahydrocorticosteroids before and after, but not during metyrapone administration. The acrophases of validated rhythms in urinary steroids are located between 1130 h and 1630 h.

Spontaneous and stimulated secretion of QUSO-extractable immunoassayable ACTH in man.

A factor is present in the plasma which “binds” ACTH thus disturbing the radioimmunologic system. Therefore, ACTH was extracted for radioimmunological measurement. A simple method is described to extract a representative part of the ACTH from plasma utilizing the high capacity of silicates (QUSO G-32) to adsorb free, intact ACTH. Basal values of QUSO-extractable, immunoassayable ACTH in normal persons at 8 a.m. amounted from 0 to 120 pg/ml ( $$\bar x$$ =30.3 pg/ml). In most patients with Cushing's disease basal values were clearly elevated. The highest ACTH levels (up to 6000 pg/ml) were found in untreated Addison's disease. Under normal clinical conditions there were marked fluctuations of the ACTH level during 24 hours in normal persons as well as in patients with Cushing's disease. However, a peak value during the early morning hours was not constantly recovered. Lysin-vasopressin infusion (5 I.U. LVP/60 min) induced a rapid increase in ACTH concentrations, which began to fall after the 30th minute while infusion of LVP continued. The rise in plasma ACTH following oral administration of metyrapone (750 mg every 4 hours during 24 hours) was delayed for about 12 hours from the first administration and elevated levels were demonstrable up to 12 hours after the last administration. There were remarkable differences in the temporal pattern of the ACTH levels after administration of metyrapone.

Simultaneous determination of cortisol, deoxycortisol and corticosterone in plasma and urine by competitive protein binding assay. Response of normal subjects to ACTH and metyrapone

A procedure is described for measurement of Cortisol, deoxycortisol and corticosterone in samples of plasma or urine by competitive protein binding assay. The method, involving t.l.c., is such that no “blank” value is dealt with; amounts as small as 1 ng of cortisol and 0–15 ng of deoxycortisol and corticosteronecan be reliably measured. It is therefore suitable for clinical and investigative purposes. In healthy adults the plasma levels at 9 a.m. are 16.1 μg/100 ml for cortisol, 0.11 μg/10ml for deoxycortisol and 0.70 μg/100 ml for corticosterone. The urinary excretion of unconjugated cortisol, deoxycortisol and corticosterone are respectively 34.0, 0.31 and 2.04 μg/24 h. At the end of an ACTH infusion (0.25 mg i.v. over 8 h) the plasma levels of cortisol had risen to 48.1 μg/100 ml and those of deoxycortisol and corticosterone to 0.34 and 5.90 μg/100 ml, respectively. The corresponding values for urinary excretion of unconjugated cortisol, deoxycortisol and corticosterone were 1320, 2.0 and 23.0 μg/24 h. Oral administration of metyrapone, 750 mg q. 4h, for 48 h, induces a fall of plasma cortisol to 3.6 μg/100 ml while plasma deoxycortisol level increases to 16 μg/100 ml; concomitantly urinary excretion of unconjugated cortisol decreases to 14.3 μg/24 h and that of unconjugated deoxycortisol rises to 24.8 μg/24 h, while plasma and urine corticosterone levels are left unaffected.

Simultaneous determinations of plasma ACTH and GH levels after an oral metyrapone.

The levels of plasma ACTH and GH were simultaneously measured in normal subjects every 30 min for 4 nr after an oral administration of metyrapone, either 1.0g or 1.5g. Both doses of metyrapone caused a significant decrease in plasma cortisol levels 90min later, when the mean values of plasma cortisol levels were not significantly different between both groups. An administration of 1.0g of metyrapone raised plasma ACTH levels in 2 out of 6 subjects within 90min, while an increase in plasma GH levels of 5.0ng/ml above the base line levels was observed in 2 subjects. In one of the subjects in whom the levels of plasma GH increased, plasma GH peak was preceded by that of plasma ACTH, but no rise in plasma ACTH levels was observed in another subject. When 1.5g of metyrapone was given, plasma ACTH levels increased in all 6 subjects. The response of plasma ACTH was quite different in each individual and there appeared one or two peaks within 240 min. The mean value of plasma ACTH was 69±17 pg/ml at 0 time and increased to 165±18 pg/ml at 60min (p<0.01 vs 0 time). An increment in plasma GH levels was observed in 5 out of 6 subjects. The mean peak value was reached at 90min and the difference between the values at 0 and 90 min was significant. There was also no correlation between the secretion of ACTH and that of GH. These results may indicate that a higher dose of metyrapone causes both ACTH and GH secretions within a short period not by a negative feedback mechanism of cortisol but presumably by acting directly on the pituitary and/or on the hypothalamus as a nonspecific stimulus.

PITUITARY-ADRENAL FUNCTION IN TEN PATIENTS RECEIVING MEDROXYPROGESTERONE ACETATE FOR TRUE PRECOCIOUS PUBERTY

ABSTRACT The effect of medroxyprogesterone acetate (MPA) on pituitary-adrenal function was investigated in 10 patients with true precocious puberty. Although the patients receiving MPA responded to exogenously administered ACTH by a rise in the plasma 17-hydroxycorticosteroids, the mean values of both the pre- and post-ACTH levels were statistically lower than those obtained in the controls. In 7 of the 8 patients the increase of the urinary 17-ketogenic steroids following the oral administration of metyrapone was less than 2-fold. The data suggest that MPA in the dosages tested has a suppressive effect on pituitary ACTH synthesis and/or release. Despite this inhibition, however, no clinical evidence of hypoadrenocorticism was observed in these patients even during periods of stress. When the drug was discontinued, pituitary-adrenal function rapidly returned toward normal, suggesting that the suppressive effect of MPA was a relatively mild one.

Plasma Metyrapone, Adrenocorticotropic Hormone, Cortisol, and Deoxycortisol Levels

Plasma metyrapone, adrenocorticotropic hormone (ACTH), cortisol, and deoxycortisol levels were measured sequentially in normal subjects during and after oral and intravenous metyrapone administration. Urinary 17-hydroxycorticosteroid (OHCS) values were determined before and after oral metyrapone administration. Though metyrapone levels were higher after intravenous administration, ACTH response to orally given metyrapone was greater, occurring mainly simultaneously with circadian rise of ACTH level. Plasma deoxycortisol levels paralleled those of ACTH. Urinary 17-OHCS manifested exaggerated diurnal variation especially the day after oral metyrapone administration, the changes corresponding to those of plasma ACTH and deoxycortisol levels. Concomitant hydrocortisone infusions abolished ACTH and deoxycortisol responses to orally given metyrapone only if the plasma cortisol level was above 7.5??g/100 ml. Daytime responses to metyrapone depend on the degree of inhibition of 11-??-hydroxylase. Nocturnal response is somehow related to the circadian rhythm of ACTH release.

Pituitary-adrenal function in oral contraception.

ABSTRACT 14 normally menstruating women aged 17 to 29 were treated cyclically with a daily dose of 5 mg of 6-methyl-6-dehydro-17α-acetoxyprogesterone (megestrol acetate) + 0.1 mg of 17α-ethynyl-oestradiol-3-methylether (mestranol) for a period of 3 to 74 weeks. During treatment we found a gradual decrease in the excretion of both 17-ketogenic steroids (17-KGS) and 17-ketosteroids (17-KS). After cessation of treatment, we found a rapid increase to pre-treatment levels in the excretion of both 17-KGS and 17-KS. The decrease in the output of 17-KGS and 17-KS observed during treatment with megestrol acetate + mestranol might be explained by: a suppression of the pituitary function a suppression of the adrenal cortical function a change in the metabolism of the corticosteroids. The purpose of the present investigation was to explore these hypotheses. 8 patients were treated with the above mentioned dose of megestrol acetate + mestranol until the excretion of pituitary gonadotrophins was significantly suppressed. This occurred after a treatment-period of 3 to 10 months. In all 8 patients we determined the responsive to metyrapone before the treatment started and a short time before the treatment was discontinued. During treatment all 8 patients showed a normal response to oral administration of metyrapone. Furthermore, in 6 out of the 8 patients we tested the response of the adrenal cortex to intravenous and intramuscular administration of corticotrophin (ACTH) just before the treatment was discontinued. In all patients a normal ACTH-stimulation test was found. During treatment, the concentration of plasma cortisol was significantly increased to values about 3 times the control values, whereas the concentration of plasma 11-deoxycortisol (compound S) remained unchanged. This high plasma cortisol level during treatment is probably caused by an increased protein-binding of cortisol. As both the responsive to metyrapone and to ACTH is normal during treatment with megestrol acetate + mestranol, we are of the opinion that the decrease observed in the excretion of 17-KGS and 17-KS is due to a change in the metabolism of the corticosteroids.

PITUITARY-ADRENAL FUNCTION FOLLOWING HYPOPHYSECTOMY IN MAN.

ABSTRACT The pituitary-adrenal function in hypophysectomized patients was evaluated by means of the steroid content in blood and urine prior to and following oral administration of metyrapone (Metopirone®). This method appears to be useful in revealing cases of incomplete hypophysectomy. In two out of six patients, in whom no gonadotrophin could be detected in the urine, metyrapone administration was followed by a marked increase in the plasma level of compound S and a significant increase in the urinary 17-ketogenic steroid output, indicating that the hypophysectomy was presumably incomplete.