Metabolic Clearance Rate Of Cortisol Research Articles

ADRENOCORTICAL FUNCTION IN A PROTOTHERIAN MAMMAL, TACHYGLOSSUS ACULEATUS (SHAW)

The peripheral plasma concentrations and production rates of corticosterone and cortisol were measured in the conscious, unrestrained echidna (Tachyglossus aculeatus) under basal conditions and during maximal ACTH stimulation. Using Sephadex LH-20 column chromatography and radioligand assay, only cortisol and corticosterone could be detected in the peripheral blood plasma at very low concentrations of 0-07 +/- 0-03 (S.E.M.) mug/100 ml and 0-14 +/- 0-07 mug/100 ml respectively. Two-hourly sampling over periods of 36-48 h disclosed a diurnal periodicity in the combined plasma concentration of these corticosteroids, the high concentrations corresponding to periods of behavioural activity. Marked, short-term fluctuations in plasma corticosteroid concentration were also observed during periods of more frequent (20 min) sampling. Constant rate i.v. infusion of synthetic ACTH increased the plasma concentrations of both steroids to maximal values of 0-42 +/- 0-23 mug cortisol/100 ml and 1-06 +/- 0-56 mug corticosterone/100 ml at infusion rates of 1 i.u. ACTH/kg/h. This is approximately 1/160 of the potency of this ACTH in man. The production rates of corticosterone and cortisol, measured by isotope dilution during constant rate i.v. infusion of 3H-labelled tracers, were only 0-35 +/- 0-21 and 0-56 +/- 0-26 mug/kg/h respectively during saline infusion, and increased to 2-86 +/- 3-47 and 2-74 +/- 2-07 mug/kg/h during the infusion of 1 i.u. ACTH/kg/h. The metabolic clearance rate of cortisol was greater than that of corticosterone and both were depressed by ACTH. Plasma corticosteroid concentrations were increased after surgery during ether anaesthesia and in sick animals with heavy worm infestation. It is concluded that the adrenal cortex of echidnas responds to ACTH stimulation and stress in a similar way to eutherians, but the level of activity is much lower.

Méthode de mesure des vitesses d'épuration métabolique et de sécrétion du cortisol chez l'anguille (Anguilla anguilla L.)

Classical methods for the analysis of steroid dynamics were adapted to measure the metabolic clearance rate and the secretion rate of cortisol in the European eel using (1, 2-3H) cortisol as a tracer. 1. Measurements were made whilst the eels were in the steady state; stresses which usually result from anaesthesia and handling were avoided by chronic catheterization of the blood vessels of the swim bladder. In this way, the plasma cortisol level were constant; thus, it was possible to obtain valid measurements of the cortisol secretion rate knowing the metabolic clearance rate and the plasma cortisol level. 2. In the eel, cortisol and cortisone together form a chemical compartment', derived originally from cortisol secreted by the interrenal gland and subsequently transformed partially into cortisone in the plasma and maintained thenceforth in dynamic reversible equilibrium. Consequently, the metabolic clearance rate of cortisol has been calculated from the known changes in concentration of both (1, 2-3H) cortisol and (1, 2-3H)cortisone in the plasma deduced from dichloromethane-extractable plasma radioactivity, 72% of which is always attributable to these two steroids from the moment that the radioactivity begins to decline regularly as a function of time (15-30 min after the injection). 3. After a single injection of (1,2-3H) cortisol, the interpretation of the disappearance curve by compartmental analysis is complicated by the delay of tracer distribution and by the evident variability in the initial portion of the curve. Disappearance curves have accordingly been analysed in a more rigorous fashion either by integrating the area under each curve which allows one to calculate individually the metabolic clearance rates, or by integrating according to Normand, M., and Fortier, C. (1970. Can. J. Physiol. Pharmacol. 48, 274-281) which allows one statistical treatment of data. 4. Estimates of the metabolic clearance rate of cortisol were made in a satisfactory manner by either one of the two integration methods. They were also very similar to estimates obtained by prolonged infusion of (1, 2-3H) cortisol to constant specific activity into eels maintained under identical experimental conditions.

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.

Estrogen and the metabolism of progesterone in vivo

The effect of estrogen administration on the metabolism of progesterone was studied in ovariectomized, hysterectomized women. Estrogen was withheld from each subject for at least 4 weeks, then 200 μg of ethinyl estradiol were administered orally each day for 3 weeks and then no estrogen was given for 3 weeks. The subjects were studied before estrogen was started, on the third day of estrogen, after 3 weeks of daily estrogen and after the estrogen was withdrawn for 3 weeks. In 5 women plasma transcortin concentrations, measured by equilibrium dialysis, were 0.82 ± 0.06, 1.5 ± 0.16, 2.1 ± 0.13, and 0.90 ± 0.09 (S.E.) μM before starting estrogen (control), on the third day of estrogen treatment, after 3 weeks of estrogen, and after having stopped estrogen for 3 weeks, respectively. Corresponding values for the metabolic clearance rates (MCR) of cortisol (by the continuous infusion method) were 306 ± 33, 172 ± 18, 136 ± 14, and 258 ± 23 (S.E.) L. per day. Although estrogen administration caused a significant elevation of the plasma transcortin concentrations and a significant decrease in the MCR of cortisol, it had no significant effect on the MCR of progesterone or of cortisone. The estrogen administration did cause a decrease in the peripheral conversion of progesterone to 20α-hydroxy-pregn-4-en-3-one (20α-OHP) and of cortisol to cortisone but an increase in the conversion of 20α-OHP to progesterone and of cortisone to cortisol.

Studies on the production and metabolic clearance rates of cortisol in the European eel. Anguilla anguilla (L.)

Aspects of cortisol metabolism have been studied in the eel, Anguilla anguilla L., adapted to fresh water and sea water environments. The effects of hypophysectomy and removal of the corpuscles of Stannius on cortisol dynamics were assessed. High specific activity tritiated cortisol reached a steady state in plasma 7 h after beginning a constant intravenous infusion. Plasma cortisol concentrations were determined in hourly blood specimens during the steady state situation. Plasma cortisol concentration, its metabolic clearance and production rates were obtained for the various experimental groups. Plasma electrolytes were also determined. Similar cortisol concentrations occur in fresh water and sea water eels. Sea water adapted eels had higher metabolic clearance and production rates than fresh water animals. After hypophysectomy both fresh water and sea water adapted eels had reduced plasma cortisol concentrations and cortisol production rates, although the metabolic clearance rates were significantly elevated. These alterations in cortisol dynamics following hypophysectomy were returned to normal by infusion of mammalian ACTH in a group of sea water adapted eels. In fresh water eels removal of the corpuscles of Stannius produced almost twofold increases in the metabolic clearance and production rates of cortisol without there being any change in plasma cortisol concentration. Removal of the corpuscles of Stannius from sea water adapted eels induced a slight decrement in plasma cortisol concentration.

Influence de l'adaptation à l'eau de mer sur la fonction interrénalienne de l'anguille ( Anguilla anguilla

The metabolic clearance rate of cortisol and its secretion rate were measured in vivo in freshwater silver eels (Anguilla anguilla) kept: for 4 wk in the laboratory in freshwater or seawater. The rates and their errors were calculated by integration of the area under the disappearance curve of the plasma dichloromethane-extractable radioactivity after a single rapid intravenous injection of [1,2 3H]cortisol. All the tested fish were in osmotic equilibrium with the medium and were not stressed by the experimental procedures. The previous catheterization of pneumatic vessels (the ones of the gas bladder) permitted the injection of the tracer without handling the fish and also allowed blood samples to be taken at different times after injection. In both freshwater and seawater eels, the plasma cortisol concentration was approximately 2 μg/100 ml and the proportions of protein bound cortisol were similar. However, the cortisol metabolic rate in seawater was elevated twofold resulting in a calculated cortisol metabolic rate in seawater which was twice that in freshwater. In the eel, some observations suggest that the production rate of the cortisole metolite, cortisone, regulates the cellular penetration rate of plasma cortisol. If this is the case, then the increased rate of cortisol metabolism seen in seawater would result in an increase in the supply of cortisol to tissues including those involved in osmoregulation.

Cortisol metabolism in glucose-6-phosphate dehydrogenase deficiency

Ten subjects with glucose-6-phosphate dehydrogenase deficiency (G6PD Canton) and ten G6PD normal subjects matched for sex and age distribution were studied with respect to their plasma cortisol levels and 24-hr urinary total 17-oxogenic steroids excretion before and after maximal stimulation with B 1–24 corticotrophin (Synacthen depot). In five patients and five controls, the study included the metabolic clearance rate of cortisol which increased twofold after B 1–24 corticotrophin administration. No significant differences were found in these two groups of individuals. This indicates that in G6PD-deficient subjects, under basal conditions and with maximal stimulation, both cortisol production and metabolism proceed at a normal rate.

Diurnal variation of the metabolic clearance rate of cortisol. Effect on measurement of cortisol production rate.

The effects of changes in plasma concentration of cortisol (F) on the metabolic clearance rate (MCR) of this hormone were investigated in 11 normal adult males as follows: constant blood withdrawal was carried out using a portable pump attached to a non-thrombogenic catheter which itself was placed in the antecubital vein. Two pulse-injections of radioactive F were administered, first 14C-F at 8 pm and then 3H-F at 5 am. Six-hr blood collections were started immediately before each of these injections. The integrated plasma concentrations (I.C.) of endogenous and radioactive F were determined in each 6-hr pool. The MCR was calculated as radioactive F injected/I.C. of radioactive F. The MCR values of the 5 am-11 am period (149 ± 28 l/M2/24 hr) were significantly (p < 0.005) higher than those obtained during the 8 pm-2 am period (91 ± 19 l/M2/24 hr). The I.C. of endogenous F were 10.9 ± 1.7 (SD) μg/100 ml and 3.3 ± 1.0 μg/100 ml for the 2 periods of study respectively. The marked changes in MCR invalidate t...

The Progressive Increase in Estrogen Production in Human Pregnancy: An Appraisal of the Factors Responsible

This chapter focuses on progressive increase in estrogen production in human pregnancy. Estrogens are synthesized in the placenta largely from androgen sulfates secreted by the fetal zone of the fetal adrenal. The level of supply of these precursors determines the quantity of estrogen produced. This chapter considers factors that modify the concentration of cortisol in the fetal circulation. These are discussed in terms of synthesis, metabolism, transport from the maternal system, and transport to the maternal system. It is concluded that the increasing production of estrogens in the second half of gestation arises from an increasing production of androgen sulfates by the fetal adrenal associated with progressive growth of and stimulation of steroid biosynthesis in this gland, which, in turn, are provoked by an elevated secretion of ACTH from the fetal pituitary. The secretion of ACTH in increased quantities is a response to an increased metabolic clearance rate of cortisol from the fetal plasma. A major factor concerned in the increased clearance of cortisol is the disparity in the number of available binding sites for cortisol in fetal and maternal plasma.

Effect of Sexual Maturation and Gonadectomy at Sexual Maturity on Cortisol Secretion Rate in Sockeye Salmon (Oncorhynchus nerka)

Changes in cortisol dynamics in male and female sockeye salmon (Oncorhynchus nerka) have been investigated at various stages during sexual maturation, after spawning, and after gonadectomy just prior to their reaching sexual maturity. The metabolic clearance rate of cortisol was determined by the single injection technique and calculated using the formula for a two-pool system. The volume of distribution of cortisol in the inner pool and the outer pool, metabolic clearance rate, and cortisol secretion rate increased in both male and female salmon during sexual maturation. These changes were reversed in fish that were gonadectomized just before reaching functional maturity and allowed to recuperate for 2 or 8 weeks.There was a decrease in the amount of red carotenoid pigment in the flesh of salmon held in the laboratory during sexual maturation. This loss of pigment was reversed in salmon that were gonadectomized and fed marine zooplankton for 8 weeks.

Cortisol Secretion Rate in Gonadectomized Female Sockeye Salmon (Oncorhynchus nerka): Effects of Estrogen and Cortisol Treatment

Gonadectomized female sockeye salmon (Oncorhynchus nerka) were injected intramuscularly with cortisol, estradiol, estradiol cypionate, or peanut oil for 8 weeks. The metabolic clearance rate of cortisol was determined by the single injection technique and calculated from the formula for a two pool system. The cortisol secretion rate was determined from the metabolic clearance rate and the plasma cortisol concentration.The volume of distribution of cortisol in the inner compartment (V1) and the outer compartment (V2), the metabolic clearance rate (MCR), the resting secretion rate (S), and the resting plasma cortisol concentration were all significantly higher in the estradiol-injected group than in the peanut oil-injected control group, and the plasma cortisol concentration at the end of the experiment was lower. V1, MCR, and S were also significantly higher in the estradiol cypionate-injected group. There were no significant differences between the cortisol-injected group and the peanut oil-injected control group or in the biological half life of cortisol between any groups.There were no significant changes in the red colour of the flesh or in body weight during the experiment. However, the cortisol-injected group did show the largest weight loss.

The effect of androgens on the distribution and secretion of cortisol in gonadectomized male sockeye salmon ( Oncorhynchus nerka)

Gonadectomized male sockeye salmon ( Oncorhynchus nerka) were injected twice a week with peanut oil alone or with 2.5 mg of cortisol, 11-ketotestosterone or 17α-methyltestosterone in peanut oil for 4 or 7 weeks. After 7 weeks of treatment, androgen-injected fish had lost most of the red flesh color characteristic of sexually immature salmon, while the skin developed the red color typical of mature and spawned salmon. Changes in body weight were not significant. A single dose of [ 14C] cortisol was injected intraarterially at the end of the injection period and the clearance of radioactive cortisol was followed in consecutive blood samples taken during a 6-hr interval. The apparent volume of distribution in the inner and outer pools and metabolic clearance rate of cortisol were significantly higher in androgen-treated fish than in controls after 7 weeks of treatment, while half-lives were similar. Cortisol concentrations in plasma during anaesthetic stress were significantly lower in the groups receiving androgens than in control fish. Cortisol secretion rates were significantly higher in 17α-methyltestosterone-treated fish than in control fish both while resting and during anaesthesia. Cortisol injected either for 4 or 7 weeks produced only minor changes in the parameters under study compared to the effects of equal amounts of androgens.

A study of cortisol metabolism in patients with chronic asthma.

SUMMARYThe mortality rate in asthma is rising and, in our hospital, the majority of deaths occur during episodes of status asthmaticus in steroid‐treated patients. Clinical observations have indicated that relatively large doses of cortisol are necessary to treat acute episodes of asthma in the long‐term‐steroid‐treated patient. Studies on 10 patients indicate that the plasma cortisol response to the intravenous injection of cortisol is less than normal in steroid‐treated patients, and that this reduced response is associated with a lack of clinical improvement.A good clinical response in steroid‐treated patients does not occur until the plasma cortisol level is at least 100 µg. per 100 ml. Studies of cortisol metabolism in the case of these 10 patients demonstrate an increased rate of removal of cortisol. The metabolic clearance rate of cortisol is higher than in normal subjects and in non‐steroid‐treated asthmatic patients. The metabolic clearance rate of cortisol is not affected by the administration of ACTH, but is reduced in steroid‐treated patients who are simultaneously receiving æstrogen therapy. These studies indicate the need to administer an initial relatively large dose of cortisol to steroid‐treated asthmatic patients in status asthmaticus.

Effects of epinephrine on the production and metabolic clearance of cortisol in normal men and women and in women with idiopathic hirsutism.

ABSTRACT The influence of epinephrine on the metabolic clearance rate (MCR) and production rate (PR) of cortisol was determined in normal men and women and in women with idiopathic hirsutism. MCR was measured using a constant infusion of 3H-cortisol and PR calculated as the product of MCR and plasma cortisol concentration according to the model of Tait. After control observations 0.5 μg/kg epinephrine was injected intravenously in one minute followed by a constant infusion at a rate of 0.5 mg/h. The mean cortisol MCR was 10.3 litres/h in males and 7.9 litres/h in females. In neither sex was it altered by epinephrine. The mean baseline cortisol PR in males was 568 μg/h; it increased to 940 μg/h with epinephrine (P &lt; .025 &gt; .01). In hirsute females the mean baseline cortisol PR was 697 μg/h with an increase to 1067 μg/h with epinephrine. In normal females, the increase in cortisol PR was less (515 μg/h to 638 μg/h). Adrenal responsiveness to epinephrine, as measured by the production of cortisol, appears greater in hirsute than in normal women. Possible relationships between this difference and the development of hirsutism are discussed.

The effect of 2, 2-Bis (2-chlorophenyl-4-chlorophenyl)-1, 1-dighloroethane (o, p'-DDD) on the metabolism of infused cortisol-7- 3H

o, p'-DDD was administered to a subject with Cushing' s syndrome and to an adrenalectomized castrated subject maintained on a constant cortisol intake. Measurements of the secretion, metabolism and metabolic clearance rate of cortisol were made before and during the administration of the drug. In the adrenalectomized subject the “cortisol secretion rate” was an estimate of the administered cortisol. The results of this study indicated that o, p'-DDD affected both the adrenal secretion and the extraadrenal metabolism of cortisol. During the early phase of drug administration however, the extra-adrenal effect predominated. In addition, it was shown than an increased circulating level of cortisol, whether due to exogenous administration or Cushing's syndrome, was associated with an increased plasma clearance of the steroid.

Clinical Studies on the Secretion and Metabolism of Cortisol and Aldosterone

The studies on the secretion and metabolism of cortisol and aldosterone in humans were made by the use of radioactive steroid hormones. One to 3.0 μc of 7-H3- aldosterone, 7-H3-cortisol or 4-C3-cortisol were injected intravenously into normal subjects and patients with various endocrine disorders. Urine was collected for 24 hours after the injection of radioactive hormones. The daily secretion rate of cortisol and aldosterone was calculated from the injected radioactivities and specific activities of these urinary metabolites. To determine the specific activity of urinay metabolite of aldosterone, urinary aldosterone released by acid hydrolysis was purified by the use of column chromatography (florisil) and paper chromatographies (chloroform formamide system, butylacetate formamide water system and benzene methanol water system). In the case of cortisol, tetrahydrocortisol hydrolyzed by bacterial β-glucuronidase was isolated by the same paper chromatographic systems as for aldosterone.Heparinized blood samples were withdrawn at 10 to 30 minute intervals after the injection of radioactive hormones. The disappearance curves of labeled hormones were analysed mathematically and volumes of distribution space, metabolic clearance rate and speed of metabolism were calculated using two compartmental models of the human body as discribed by Tait et al.The mean values of secretion and metabolism for cortisol in three cases of normal subjects were as follow : The secretion rate of cortisol ; 20.9±3.7 mg/day, mean plasma concentration ; 5.02 ±0.62 mg/100 ml, speed of metabolism (K2) ; 39.1±1.6 units/day, volume of distribution space (V1 + V2); 14.0±0.6 L, metabolic clearance rate (M2) ; 415±39.5 L/day, and miscible pool ; 701.2±98.6μg.The mean values of secretion and metabolism for aldosterone in normal men under sodium unrestricted diets were as follow : secretion rate ; 128±22 pg/day, mean plasma concentration ; 0.0085±0004 μg/100 ml, speed of metabolism ; 57.6±3.8 units/day, volume of distribution space ; 34.5±6.7 L, metabolic clearance rate ; 1385±158 L/day, and miscible pool ; 2.94±0.58 μg.In patients with Cushing's syndrome, daily secretion rate, mean plasma concentration and miscible pool of cortisol were markedly increased, especially higher valueswere obtained in the cases due to adrenal hyperplasia than those due to adrenal adenoma. The speed of metabolism and metabolic clearance rate of cortisol was lower than normal controls. Daily secretion rate of aldosterone was slightly increased in some cases of Cushing's syndrome.In patients with Addison's disease, daily secretion rate, mean plasma concentration, and miscible pool of cortisol and aldosterone were markedly decreased or not detectable, while the speed of metabolism of these hormones was within normal range.A patient with primary aldosteronism showed high values of daily secretion rate and mean plasma concentration of aldosterone. These values were reduced to normal range after the extirpation of adrenocortical adenoma, while the speed of metabolism of aldosterone in this case did not change by operation.