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The effect of altered prednisolone kinetics in patients with the nephrotic syndrome and in women taking oral contraceptive steroids on human mixed lymphocyte cultures.

The purpose of this study was to examine the influence of altered prednisolone kinetics in patients with the nephrotic syndrome and women taking oral contraceptive steroids on mixed lymphocyte cultures (MLC). After oral and iv prednisolone treatment, blood samples were collected over 24 h. The area under the plasma concentration vs. time curve (AUC) of unbound, transcortin- bound, and albumin-bound prednisolone was determined. All plasma samples were incubated with MLCs, and the area under the inhibition vs. time curve of the MLC (AUIC), a measure of the effect over time, was calculated. The steroid concentrations required to produce half-maximal inhibition (EC50) were calculated. The 10 women taking oral contraceptives had higher AUCs of unbound and transcortin-bound prednisolone than the 10 normal subjects. The mean biological effect (AUIC value) was more pronounced in women taking contraceptive steroids. An analysis of the concentration-response curves revealed that the EC50 values of total, but not unbound, prednisolone were higher in women taking contraceptives. Compared with the normal subjects, the 9 nephrotic patients had lower total and comparable unbound AUCs of prednisolone. The AUIC values were higher whereas the EC50 values of unbound and total prednisolone were lower in the nephrotic patients. These findings indicate that the increased steroid effect in women taking oral contraceptives is explained by higher concentrations of prednisolone, while the increased effect in nephrotic patients is not attributable to the abnormal kinetics or protein binding of prednisolone.

Adult↗

Specific interaction of corticosteroids with binding sites in the plasma membranes of the rat anterior pituitary gland.

The binding of glucocorticoids to a crude fraction of rat pituitary plasma membranes and to solubilized membrane proteins was measured. The binding characteristics were similar to those exhibited by transcortin: radioactive corticosterone was bound to a greater extent than radioactive dexamethasone and labelled corticosterone, but not labelled dexamethasone, was displaced by unlabelled corticosterone, deoxycorticosterone and progesterone. A Scatchard plot of the binding data revealed the presence of a binding material with a dissociation constant of about 3.2 nmol/l, which sedimented at 4S after sucrose density-gradient centrifugation. It was found that the number of binding sites was inversely related to the concentration of corticosterone in the circulation and was increased after long-term adrenalectomy. These data suggest that a material similar to transcortin is complexed to the plasma membrane of rat pituitary cells.

Adrenalectomy↗

[The endocrine status of clinically conspicuous mares during the peripartum period].

The aim of the present investigations was to characterize the endocrine changes in the peripheral plasma during the periparturient phase of mares with a known history of obstetrical disorders. Blood plasma samples from 9 mares (8 mares during parturition, 1 mare during abortion) were collected and the following steroid hormones were radioimmunologically determined: progesterone (P4), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), estrone (E1), estrone sulfate (E1-S), estradiol-17 beta (E2), estriol (E3), cortisol and transcortin. In general, with the exception of cortisol, DHEA and transcortin, all steroid hormone levels declined significantly after parturition. Mean plasma concentrations of DHEA-S, the direct fetal precursor of estrone, were 6 times higher than DHEA. However, DHEA-S levels varied considerably between all mares as well as between daily values of the same mare. Levels of E1-S were found to be about thousand times higher than those of E1, E2, and E3. The rather low concentrations of E3 suggest that this hormone is mainly produced by peripheral conversion and that in the horse fetus the 16 alpha-hydroxylation of DHEA-S is lacking. Despite the fact that most of the examined mares showed signs of severe disease none of the investigated steroid hormones indicated any disturbances of gestation. It is concluded that, from the clinical point of view, serial determinations of E1-S plasma levels are the best way to prove the fetal well-being. However, it should be stressed, that even the E1-S values are no indicators for the onset of parturition or abortion.

Abortion, Veterinary↗

[Age-related characteristics of corticosteroid interactions with blood transport proteins].

In blood of old rats the content of corticosteroid transport proteins was decreased, as a result of which their balance was distorted and negative cooperativity between transcortin-binding sites developed. Values of Hill coefficient were below 1 in the hormone-protein interactions, which appears to occur due to polymerization of the protein or to appearance of unknown factors(s) in blood of old animals. After treatment of the old rats blood serum with activated charcoal the steroid-binding transcortin capacity and its affinity to hormone was increased and the negative cooperativity was not observed.

Adrenal Cortex Hormones↗

Hirsutism due to the treatment with L-thyroxine in patients with thyroid pathology.

There are many factors involved in the aetiology of hirsutism. It is well known that some drugs may cause hirsutism as a side effect, such as phenytoin, diazoxide, minoxidil etc. In Turkey, where the endemic goiter constitutes an important health problem, the value of suppression therapy with thyroid hormone still carries a special importance. We established the increasing tendency of hirsutism in patients treated with L-thyroxine (L-T4) for various thyroid pathology. That is why we decided to evaluate the role of thyroid hormones in the aetiology of hirsutism observed in patients treated with L-T4. We determined the total and free T3, T4, TSH, TBG, Plasma Cortisol transcortin, delta-4-androstenedione, FSH, LH, prolactin, total and free testosterone, estradiol, progesterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS) and 17 hydroxyprogesterone (17 OH Pg) levels in serum or plasma in a group of female patients who were taking L-T4 daily, regularly at least for 6 months and complaining of the occurrence of hirsutism. We demonstrated in these patients SHBG, transcortin and estradiol levels significantly lower than controls (p less than 0.001, p less than 0.05 and p less than 0.05, respectively) and DHEAS level significantly higher than controls (p less than 0.001). An important correlation was found between TBG and SHBG levels (r:0.536, p less than 0.05) and also between total and free testosterone levels (r:0.952, p less than 0.001).

Adolescent↗

[Primary response mechanisms of the adrenal cortex in dogs to pain stress].

The adrenal cortex of dogs shows a drop in the glucocorticoid content 10--15 sec after the pain action in the presence of the free cholesterol level increase and its esterified form drop. The concentrations of hormones in the blood falls chiefly at the expense of protein bound hydrocortisone. The subsequent phase of the reaction (after 30--60 sec) is characterized by a considerable accumulation of the hormones by the gland. The level of free glucocorticoids significantly increases, the initial ratio of hydrocortisone and cortisone restores, and transcortin depot is filled up. The role of the adrenal and transcortine depot in realization of feedback mechanisms under stress is discussed.

Adrenal Cortex↗

Influence of dexamethasone on peripheral metabolic parameters of cortisol in the adult male conscious guinea-pig.

The influence of dexamethasone on distribution, metabolism and protein binding of cortisol was studied in conscious adult male guinea-pigs, under chronic cannulation, by a single injection technique for cortisol metabolic parameters and Sephadex equilibrium dialysis procedure for protein binding. The results showed that biological half-life of cortisol (51-55 min) was identical in control and in dexamethasone-treated guinea-pigs (low plasma cortisol level). The apparent volume of distribution of cortisol, which was higher in control (550 +/- 20 ml) than in dexamethasone-treated animals (380 +/- 30 ml), was related to the higher plasma cortisol level in controls (0.96 +/- 0.07 mumole/l) as compared to dexamethasone-treated animals (0.12 +/- 0.02 mole/l). When a high cortisol concentration was infused in dexamethasone-treated guinea-pigs in order to produce hig plasma cortisol level, plasma cortisol MCR increased by 80% (P less than 0.001) reflecting increases of 50% (P less than 0.001) in the apparent volume of distribution and decreases of 19% (0.01 less than P less 0.02) in the half-life cortisol compared to dexamethasone-treated animals (low plasma cortisol level). Although the plasma cortisol level was higher (P less than 0.001) in dexamethasone-treated animals infused with non-labelled cortisol (2.9 +/- 0.02 mumol/l) than in controls (0.96 +/- 0.07 mumol/l), the identical values of the apparent volume of distribution in dexamethasone-treated animals infused with non-labelled cortisol and in controls suggested that dexamethasone could alter the distribution of cortisol, and therefore its metabolism. Dexamethasone did not modify the transcortin-binding capacity and did not complete with cortisol on transcortin sites in guinea-pig plasma.

Animals↗

[Radioimmunologic methods for determining cortisol binding globulin-CBG in human serum].

The authors described double antibodies radioimmunoassay of human cortisol binding globulin serum level in support of previous isolated and purified trancortin and anti-transcortin antibodies produced by rabbit immunization. Antigen was iodinated by chloraminet method and purification on Ultragel AcA 54 column. Standard curve had specific Bx/Box100%. Using described method investigation of transcortin globulin serum level is precise and repetitive.

Carrier Proteins↗

Diurnal variation of prednisolone binding to serum corticosteroid-binding globulin in man.

Serum corticosteroid-binding globulin (CBG, transcortin) binding capacity for prednisolone and for cortisol, and levels of the circulating cortisol were evaluated in healthy adult subjects and in patients under long-term treatment with prednisone. Blood samples were drawn at 4-hr intervals throughout at least 24 hr; the prednisone administration was discontinued 24 hr before starting examination. Circadian fluctuations in the CBG-binding capacity for prednisolone occurred in healthy subjects: maximum binding was at 12 midnight and minimum binding at 8 a.m. The diurnal pattern of prednisolone-binding capacity was characterized by phase shifts of approximately 12 hr and 8 hr compared with those of serum cortisol and cortisol-binding capacity, respectively. There were no diurnal variations of prednisolone- and cortisol-binding capacity in the prednisone-treated patients. Moreover, the levels of both capacities, expressed as micrograms bound steroid/100 ml, were significantly reduced with respect to normal control subjects. Cyclic variations in serum CBG-binding capacity may represent an additional factor accounting for temporal differences in the action of synthetic corticoids which are bound by the transport protein. Synthetic derivatives when chronically administered may interfere not only with the adrenal secretion but also with the serum transport of glucocorticoids.

Adult↗

Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone.

The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n = 10) had higher mean (+/- SD) area under the plasma concentration versus time curves of total (428 +/- 67 micrograms/ml/min vs 188 +/- 28 micrograms/ml/min, p less than 0.001) and unbound prednisolone (64 +/- 10 micrograms/ml/min vs 41 +/- 10 micrograms/ml/min, p less than 0.001) than women not taking oral contraceptive steroids (n = 10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p less than 0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.

Adult↗

Corticosteroid-binding globulin. A review of some recent aspects.

Among the numerous corticosteroid-binding proteins that have been demonstrated to exist throughout the vertebrates, the corticosteroid-binding globulins (CBG or transcortin) of man and guinea pig have been most thoroughly investigated. Both are glycoproteins that contain one binding site for corticosteroid hormones and other steroids. The binding forces are predominantly of a hydrophilic nature, in addition to hydrophobic interaction. Human CBG forms a reversible dimer that maintains full binding affinity and capacity. The monomeric form is composed of two electrophoretic variants that appear indistinguishable in their chemical, immunological, and steroid binding properties. Thermodynamic analysis indicates different binding mechanisms for human and cavian CBG at the lower and higher temperature range. Entrance of hydroxy groups into the steroid molecule increases the affinity to CBG; the contributions to the free energy of complex formation, resulting from individual substitutions or other alterations in the steroid molecule, are additive. Determination of binding specificity leads to a conceptual image of the steroid binding site with respect to the nature of the various binding domains.

Animals↗

Increased plasma corticosteroid-binding globulin in insulin-dependent pubertal diabetics: relationships with other glycoproteins, growth hormone and prolactin.

A selected group of 13 juvenile-onset insulin-dependent diabetics in mid-late puberty (stages 3-4) and under comparable conditions of metabolic control was studied in order to evaluate the plasma levels of corticosteroid-binding globulin (CBG, transcortin: expressed as the binding capacity for cortisol) in relation to the levels of other glycoproteins and to growth hormone (GH) and prolactin (PRL) responsiveness to provocative tests (arginine infusion and TRH injection, respectively). Further evidence was provided that juvenile-onset diabetics show most frequently enhanced plasma CBG binding capacity; statistical significance with p-values less than 0.01 was attained in comparison to 25 age-matched controls. Among other variables examined, only hemoglobin A1c amd alpha 2-macroglobulin were significantly raised in the diabetic group (p less than 0.01 and less than 0.02, respectively). In our patients growth hormone response to arginine infusion was in the normal range, whereas PRL response to TRH was slightly but significantly supranormal in terms of maximum value and maximum increment above baseline value. No correlation was found between CBG binding capacity and other variables examined. We conclude that raised levels of CBG may occur as an additional alteration of the plasma glycoprotein pattern in juvenile-onset insulin-dependent diabetics. Specific regulatory factors conceivably subserve plasma concentrations of different glycoproteins.

Adolescent↗

Maternal and fetal serum levels of total cortisol and cortisone, unbound cortisol, and corticosteroid-binding globulin in vaginal delivery and cesarean section.

The levels of corticosteroid-binding globulin (CBG, transcortin), total cortisol, and unbound cortisol were measured in maternal and fetal serum at the time of cesarean section or vaginal delivery. While the total cortisol levels in maternal serum do not differ significantly in vaginal delivery as compared to cesarean section, cord serum cortisol levels are significantly higher after vaginal delivery. There are no differences associated with the route of delivery between the mean levels of CBG in cord and maternal blood. However, after the vaginal delivery the unbound cortisol level in maternal serum is more than twice as high as that at cesarean section and in cord serum it is seven times as high. These changes reflect changes in total cortisol and may represent a prelabor surge of fetal cortisol production, or a stress response associated with labor, or a combination of both.

Cesarean Section↗

Methylation analysis in glycoprotein chemistry: a comparative study of the carbohydrate structures of three hormone-binding glycoproteins from human serum.

The structures of the carbohydrate moieties of three hormone-binding glycoproteins from human serum, namely, thyroxine-binding globulin, transcortin, and sex hormone-binding globulin, have been characterised using quantitative g.l.c. of the methylated monosaccharide derivatives obtained after methanolysis of the methylated glycoproteins.

Carbohydrate Conformation↗

Relative competition of corticosterone, cortisol, cortisone, 11-dexycortisol and prednisolone with (1,2-3H)-cortisol in various protein-binding radioassay systems.

The relative influence of some endogenous corticosteroids and of synthetic prednisolone on competitive protein-binding radioassay was compared with that of cortisol, using as a source of transcortin pooled plasmas from various species and at different dilutions. Human (different clinical situations), cow, dog, sheep, hog, rabbit and chicken plasma were examined. The ability of corticosterone, cortisone, 11-deoxycortisol and prednisolone to displace [1,2-3-H] cortisol from corticosteroid-binding globulin (CBG) was measured: (1) by assessing the amounts (ng/tube) which produce a displacement equal to 10 ng/tube of cortisol, and (2) by calculating the integrated areas of displacement defined by the binding curves and by expressing them as a percentage of the cortisol curve area. While corticosterone, 11-deoxycortisol and prednisolone have a binding potency not very different from that of cortisol in almost the entire set of competitive protein-binding assays tested, the binding ability of cortisone was found to be particularly dependent upon the species of diluted plasma. Differences in the relative specificity of binding are apparent also within the human species, depending on the source of diluted plasma, whereas the concentration of endogenous steroids does not seem to significantly affect binding curves under the conditions examined. It is suggested that binding proteins in various conditions differ from those of healthy adults not only quantitatively but also qualitatively.

Addison Disease↗

Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel.

The changes in plasma hormone levels were evaluated in matched healthy female volunteers investigated before and after 6 months' use of three new oral contraceptives (OCs): TrigynonR (n = 13), a triphasic OC containing low doses of ethinylestradiol (EE) + levonorgestrel (LNg); MarvelonR (n = 14), a monophasic OC containing low doses of EE + desogestrel (DOG, a new progestogen derived from LNg); and OvidolR (n = 10), a sequential OC containing higher doses (50 micrograms) of EE + DOG. Serum levels of FSH, LH, estradiol and progesterone were decreased in all cases to levels incompatible with ovulation. Prolactin concentrations were unchanged. Sex hormone binding globulin (SHBG) and Transcortin (CBG) levels were significantly increased by all three OCs (Ovidol greater than Marvelon greater than Trigynon); free testosterone levels decreased significantly while free cortisol concentrations remained unchanged. Collectively, these data indicate that (a) all three OCs are effective ovulation inhibitors, (b) Ovidol and Marvelon have greater estrogenic effects than Trigynon, (c) LNg is more effective than DOG in reducing the EE-induced increase in SHBG levels, and (d) free testosterone levels are equally well suppressed by all three Ocs.

Adult↗

An open prospective study on the effects on carbohydrate metabolism of an oral monophasic contraceptive containing gestodene (WL-70).

The effects of a monophasic oral contraceptive (gestodene 75mcg + ethinylestradiol 30 mcg) on plasma glucose (PG) and insulin (IRI) responses to an oral glucose load (OGTT) and on glycosylated haemoglobin Alc (HbAlc), fructosamine (Fr), total cortisol (FT) and transcortin (CBG) were studied in 30 healthy women. Blood samples were taken before treatment and after 6 and 12 cycles. After 6 and 12 months, OGTT-PG and IRI levels showed substantially unchanged values; for HbAlc and Fr the same behaviour was seen with the exception of the latter between 6 and 12 months; FT and CBG showed significant rises. All recorded values were in the normal range. The basal and dynamic PG and IRI behaviour failed to show any significant variations between pre-treatment values and those after 6 and 12 months of OC administration. Other data showed a substantial neutrality for this oral contraceptive containing gestodene.

Adolescent↗

Hemostasis profile and lipid metabolism with long-interval use of a desogestrel-containing oral contraceptive.

Thirty healthy women, aged 18 to 37, were randomly allocated to treatment with a desogestrel-containing oral contraceptive, with 20 women using a nine-week on, one-week off regimen, and 10 women using the traditional regimen. At 0, 3 and 12 months, blood samples were drawn for liver proteins, lipoproteins and hemostatic variables. No significant changes were observed between the two regimens. Sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG, transcortin) were increased two- to four-fold, as a measure of estrogenicity. Minimal changes occurred within the lipoprotein cholesterol fractions, whereas there were some increases within the lipoprotein triglyceride fractions. Among the hemostatic variables, there were significant increases of fibrinogen, factor VII and thrombin/antithrombin III (TAT) complex. The coagulation inhibitors, antithrombin III, protein C and protein S, were essentially unchanged. A decrease of both tissue plasminogen activator antigen (t-PA) and tissue plasminogen activator inhibitor activity (PAI activity) of the fibrinolytic system was observed. A nine-week regimen does not seem to alter lipid metabolism and coagulation more than a three-week regimen.

Adolescent↗