[Cortodoxone (cortexolone) from hyodesoxycholic acid methyl ester].
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17-Hydroxycorticosteroids↗
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Topical corticosteroid therapy and pituitary-adrenal function.
Systemic absorption has been reported after the use of corticosteroid eye drops. Prolonged use could result in adrenocortical insufficiency and an associated adrenal crisis under stressful situations. For that reason, we studied the hypothalamic-pituitary-adrenal axis of patients receiving corticosteroid eye drope. Fifteen patients were given 0.1% dexamethasone sodium phosphate eye drops, one drop (approximately 1/30 ml) to each eye four times a day for six weeks. This dosage resulted in partial adrenal suppression, manifested by reduced levels of plasma cortisol. However, in each case, the hypothalamic-pituitary-adrenal axis, as evaluated with the use of the oral metyrapone tartrate test, was intact.
Administration, Topical↗
Decrease of ocular pressure with oral metyrapone. A double-masked crossover trial.
To examine the effect of a decrease in plasma cortisol level on intraocular pressure, 14 subjects with elevated ocular pressure were given oral metyrapone tartrate (an inhibitor of adrenal cortisol biosynthesis) and a placebo in a double-masked, two-period, crossover trial. Ocular pressure and the adrenal response were monitored over a seven-hour period. The decrease in ocular pressure after metyrapone administration was significantly greater than that after placebo. The 14 subjects could be designated as responders or nonresponders by decline of ocular pressure after metyrapone administration compared with response after placebo. The responders could be further differentiated from the nonresponders by a smaller decrease in ocular pressure over time in response to the placebo and by a smaller decrease over time of plasma cortisol level in response to metyrapone. These results provide further evidence that plasma glucocorticoids may play a role in the regulation of ocular pressure.
Administration, Oral↗
Augmented pituitary corticotropin response to a threshold dosage of human corticotropin-releasing hormone in depressives pretreated with metyrapone.
We studied pituitary corticotropin response to exogenous corticotropin-releasing hormone infusion and attempted to control for the confounding effect of variable serum cortisol levels between depressed and control subjects. If metyrapone was given during the time of day when hypothalamic pituitary adrenal activity was otherwise low, the relative increase in the corticotropin concentration was small. Pituitary response to exogenous corticotropin-releasing hormone can be defined under conditions in which the amount of glucocorticoid-mediated negative feedback present at the level of the pituitary gland is equal in all subjects. When the ambient cortisol level was equalized (and suppressed) in all subjects at the time of study with a threshold dosage of corticotropin-releasing hormone, we found an augmented response to corticotropin-releasing hormone in depressives. This raises the possibility that either increased pituitary sensitivity to corticotropin-releasing hormone or an increased intracellular pool of corticotropin is available for release in subjects with major depressive illness.
Adrenocorticotropic Hormone↗
Evidence of 11 beta-hydroxylase deficiency in childhood adrenocortical tumors. The plasma corticosterone/11-deoxycorticosterone ratio as a possible marker for malignancy.
In search for a biochemical marker to differentiate between adrenocortical carcinoma (AC) and adenoma (AA), plasma levels of the following steroids were studied preoperatively and postoperatively: 11-deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), and cortisol (F). Levels were measured by Sephadex LH-20 chromatography and specific radioimmunoassays. The subjects included eight children ages 2 years, 5 months to 9 years, 10 months. There were three girls and 5 boys with pseudoprecocious puberty due to adrenocortical tumors (histologically, four were AC and four, AA). The preoperative showed that DOC and S levels were elevated in all patients, F levels were elevated in four of eight children when compared with age-matched controls, whereas B was normal. Postoperatively, all levels returned to normal. The ratios of B/DOC and F/S as an index of adrenal 11 beta-hydroxylase activity were calculated. The preoperative ratios of B/DOC were markedly decreased in all patients with AC compared to controls (7.7,4.1,5.9,1.9 versus 23.5, median), but normal in three of four patients with AA (16.2, 29.6, 16.1). The F/S ratios were significantly lower in AC and AA when compared with controls. The data indicate a deficiency in 11 beta-hydroxylation in cases of adrenocortical tumors. Despite a still limited number of patients, the decreased B/DOC ratios may possibly indicate malignancy and could be helpful in distinguishing by biochemical means between benign and malignant adrenocortical tumors.
Adenoma↗
Continuous dehydrogenation of a steroid with immobilized microbial cells: effect of an exogenous electron acceptor.
Whole cells of Pseudomonas testosteroni, induced to synthesize steroid-transforming enzymes beforehand, have been immobilized by entrapment in polyacrylamide gel. The immobilized cells have been used to catalyze the continuous delta1-dehydrogenation of Reichstein's substance S under various conditions in the presence of phenazine methosulfate (PMS), an electron acceptor for the cell-free delta1-dehydrogenase. The presence of PMS substantially increases the rate of reaction when fed with the steroid substrate to a continuous stirred tank reactor containing the immobilized cells. The operational half-life of the delta1-dehydrogenase activity of the cells, about 103 hr under the best operating conditions, is essentially unaffected by the presence of PMS. Though the acceleration of the reaction may be due to PMS-mediated passage of electrons from some component in the electron transport chain to molecular oxygen, the lack of a similar effect with methylene blue is consistent with the conclusion that PMS functions directly as the electron acceptor for the delta1-dehydrogenase.
17-Hydroxycorticosteroids↗
[Contribution toward partial synthesis of 18-oxygenated cortexones I. Synthesis of 18-hydroxy-cortexone].
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17-Hydroxycorticosteroids↗
[Contribution toward partial synthesis of 18-oxygenated cortexones II. Synthesis of 18-oxo-cortexone].
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17-Hydroxycorticosteroids↗
Interaction of steroids with the transport system of glucose in human erythrocytes.
Steroids inhibit the exchange transport of glucose in human erythrocytes. The extent of inhibition is roughly correlated to the affinity of the steroids to the membrane lipids. All C-21-steroids tested show a competitive inhibition while the C-19-steriods show different types of inhibition. 5Beta-androstane-3,17-dione acts as a competitive inhibitor. The inhibition by testosterone is of mixed type, while with androst-4-ene-3,17-dione and 5alpha-androstane-3,17-dione a non-competitive inhibition is observed. In this case two inhibitor molecules can be bound per transport molecule. The "non-competitive" inhibitors compete also to some extent with the glucose binding. This effect, however, is at high inhibitor concentrations masked by the more powerful non-competitive inhibition. Competitive and non-competitive inhibitors compete with each other. The structural requirements for the different types of inhibition are discussed.
17-Ketosteroids↗
Induction of maturation of Atlantic croaker oocytes by 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one in vitro: consideration of some biological and experimental variables.
We characterized the in vitro control of germinal vesicle breakdown (GVBD) by 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one (20 beta-S) in intact ovarian follicles of gonadotropin-primed Atlantic croaker. 20 beta-S-induced GVBD was determined in relation to ovarian (oocyte) morphology, duration of incubation, steroid metabolism, and interaction with other steroids. The rate of GVBD in vitro in the absence of exogenous steroid was positively correlated with initial stage of ovarian morphological development. Maximal responsiveness to 20 beta-S was seen in ovaries with oocytes showing the first signs of morphological maturation. Dose-response experiments with 20 beta-S and 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17 alpha,20 beta-P) over a range of incubation times yielded similar results for both steroids, suggesting that conversion of 17 alpha,20 beta-P to 20 beta-S is not required for 17 alpha,20 beta-P-induced GVBD. The ED50 of these steroids markedly decreased with increasing incubation times. Comparisons between patterns of follicular transformation of various radiolabelled steroids to 20 beta-S and their respective activities (using unlabelled steroids) in the GVBD bioassay suggested that, in addition to 17 alpha,20 beta-P, progesterone has some intrinsic maturational activity. However, the maturational effects of 11-deoxycortisol and pregnenolone may be explained by their conversion to 20 beta-S. For the first time in any vertebrate, we showed that the proposed maturation-inducing steroid (20 beta-S) is not significantly transformed to any extractable, potentially active metabolite by intact, maturing ovarian follicles. These findings strongly suggest that 20 beta-S is the terminal product of the MIS biosynthetic pathway in Atlantic croaker ovaries. Estradiol had no acute effects on 20 beta-S-induced GVBD. However, testosterone decreased and cortisol augmented the maturational activity of 20 beta-S. Excess progesterone reduced the activity of a maximally effective dose of 20 beta-S, but pregnenolone was without effect. The effects of these steroids on 20 beta-S-induced GVBD are discussed in relation to their possible interactions with 20 beta-S at the MIS receptor level.
17-Hydroxycorticosteroids↗
Common biochemical pathway of dysmorphogenesis in murine embryos: use of the glucocorticoid pathway by phenytoin.
Phenytoin (5,5-diphenylhydantoin), a common anticonvulsant drug, is known to produce anomalies in the craniofacial region of animals and humans. Furthermore, recent evidence suggests that phenytoin disrupts craniofacial and neural tube morphogenesis by inhibiting the arachidonic acid cascade, a pathogenesis already implicated for glucocorticoids and hyperglycemia in the palate. This study tested the hypothesis that phenytoin interferes with the arachidonic acid cascade via the same biochemical pathway demonstrated for glucocorticoids. The proposed pathway was tested at two levels. First, indomethacin, an inhibitor of the enzyme cyclooxygenase, was used in culture to block the correction of phenytoin-induced defects by arachidonic acid. Second, cortexolone, an anti-glucocorticoid that binds at the glucocorticoid receptor binding site, was tested for its ability to prevent phenytoin-induced teratogenicity. Eighty-four percent of the embryos cultured in phenytoin and 93% of those cultured in phenytoin plus arachidonic acid and indomethacin had neural tube and/or craniofacial deformities. In contrast, only 14% of the embryos cultured in phenytoin plus cortexolone were affected. Indomethacin itself produced anomalies in 83% of the exposed embryos. These data are consistent with the hypothesis that the teratogenic action of phenytoin in murine embryo cultures occurs via the glucocorticoid anti-inflammatory pathway. Thus, the glucocorticoid receptor appears to be responsible for mediating phenytoin-induced teratogenicity.
Animals↗
Glucocorticoid receptors and actions in rat thymocytes and immunologically stimulated human peripheral lymphocytes.
After reviewing briefly our earlier studies on glucocorticoid receptors and mechanisms in thymus cells, we have outlined results from the following two areas of current interest in our laboratories: the "life-cycle" of glucocorticoid receptors and complexes in thymus cells, and the levels of glucocorticoid receptors and sensitivity in immunologically stimulated human peripheral lymphocytes. Several of our results on energetics and kinetics of hormone binding to glucocorticoid receptors in rat thymus cells seem to require extension of the simplest model of hormone-receptor transformations in intact cells. ATP-depletion experiments suggest the existence of a nonbinding form of the receptor; "chase" experiments suggest reaction of hormone directly with nuclear-bound receptor; experiments on depletion and replenishment of cytoplasmic receptor using cortisol and dexamethasone suggest the existence of at least two subpopulations of nuclear-bound hormone-receptor complex. We have found that mitogen or immunologic stimulation of human peripheral lymphocytes in culture leads within 24 h or so to a striking increase in the number of glucocorticoid receptor sites per cell. We believe this increase may be due to partial synchronization of the cell population in a phase of the cell cycle in which receptor content is high. Contrary to the widely held view that mitogen-stimulated cells become insensitive to glucocorticoids, our experiments show that with respect to inhibition of thymidine and uridine incorporation and glucose uptake, the cells are highly sensitive to dexamethasone at 24, 48, and 72 h after stimulation with concanavalin A.
Animals↗
Autoradiographic studies of a glucocorticoid agonist and antagonist: localization of 3H-corticosterone and 3H-cortexolone in mouse brain.
The localization in the mouse brain of corticosterone, the natural glucocorticoid in the mouse, and cortexolone, reported to be a glucocorticoid antagonist, was studied by autoradiography 30 min after in vivo administration of the tritiated compounds. After 3H-corticosterone (3HB) injection, radioactivity was preferentially concentrated in cell nuclei of several structures within the limbic system, and in nuclei of certain neurones of the cerebral cortex and medullar oblongata. This nuclear concentration was abolished after injection of 3H-corticosterone with an excess of unlabelled corticosterone. After 3H-cortexolone (3HS) injection, a diffuse radioactivity was observed throughout the brain. However, a higher concentration of grains was present in the ventral nucleus arcuatus and in the infundibulum. When excess unlabelled cortexolone was administered with 3H-cortexolone this preferential accumulation of grains was abolished. The accumulation of 3H-cortexolone in the medial basal hypothalamic region suggests that cortexolone concentrates preferentially in dexamethasone (DM) target regions, and in addition the autoradiographic results show that the cortexolone-receptor complex does not accumulate in the cell nucleus.
17-Hydroxycorticosteroids↗
Autoradiographic localization of 3H-glucocorticoids and 3H-cortexolone in mouse pituitary.
Autoradiograms of mouse pituitaries were prepared 30 min after injection of 3H-dexamethasone (3HDM), 3H-corticosterone (3HB) and 3H-cortexolone (3HS) either alone or in the presence of competing unlabelled steroids. 3H-dexamethasone accumulated in cell nuclei of both the pars distalis and the pars nervosa but not in those of the pars intermedia. This preferential accumulation (nuclear/cytoplasmic grain density, 4 : 1) was abolished by the concurrent administration of excess dexamethasone. 3H-corticosterone, to a much less marked extent than 3H-dexamethasone, accumulated in cell nuclei of the pars distalis but not in those of the pars intermedia and the pars nervosa. Excess unlabelled corticosterone diminished nuclear grain density in the pars distalis. After 3-h-cortexolone injection, preferential nuclear uptake was not observed. In a second series of experiments, excess dexamethasone (10 x, 100 x), corticosterone (100 x, 300 x) and cortexolone (100 x, 300 x) administered with 3H-dexamethasone were without effect on cytoplasmic grain density but totally abolished preferential nuclear accumulation. Parallel biochemical studies on kidney cytoplasmic preparations from the same animals showed no differences in total cytoplasmic radioactivity between treatments but marked differences in cytoplasmic bound 3H-dexamethasone. The results demonstrate: i) that dexamethasone binds specifically to cell nuclei of the pars distalis and the pars nervosa and that this nuclear concentration is abolished by competing corticosterone and cortexolone as well as dexamethasone; ii) that corticosterone localizes in cell nuclei of the pars distalis but much less markedly than dexamethasone; iii) that cortexolone fullfils the criteria of a glucocorticoid antagonist at the pituitary cell level.
17-Hydroxycorticosteroids↗
Elimination of by-products in 11 beta-hydroxylation of substance S using Curvularia lunata clones regenerated from NTG-treated protoplasts.
Stable mutants showing improved 11-hydroxylation of Substance S were isolated, following treatment with N-methyl-N'-nitro-N-nitrosoguanidine (NTG) and regeneration of uninucleate protoplasts of the appropriate fungal strains. This procedure was especially suitable for obtaining more directed 11 beta-hydroxylation of Substance S with Curvularia lunata IM 2901. Apart from producing cortisol (11 beta-hydroxy-S), the parent strain formed several by-products that significantly lowered the yield of the desired 11 beta-hydroxyderivative. Isolated mutants of this microorganism carried out directed 11 beta-hydroxylation with only a small amount of one of the by-products, which resulted in a much higher yield of cortisol.
Biotransformation↗
Cortexolone antagonizes development of alcohol tolerance in mice.
Mice treated with cortexolone during a period of chronic ethanol feeding displayed significantly less tolerance to a challenge dose of ethanol than mice fed ethanol but not given cortexolone. This glucocorticoid receptor blocker did not alter the hypnotic effects of ethanol in animals not previously given ethanol and no differences were found in ethanol consumption or blood ethanol levels between ethanol-fed mice receiving daily injections of cortexolone and the vehicle-injected controls. It was concluded that cortexolone interferes with the development of tolerance to ethanol.
17-Hydroxycorticosteroids↗
Postnatal course of plasma levels of adrenocortical steroids in premature infants with and without NaCl supplementation.
To assess the adrenocortical response of premature infants to alterations in sodium balance, the postnatal course of plasma progesterone, 11-deoxycorticosterone, corticosteronoe, aldosterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol and cortisone was compared in healthy premature infants kept on low (1-2 mEq/kg per day) or high (3-5 mEq/kg per day) sodium diet. The mean birthweight (1470 g, range: 1210-1670 g vs 1410 g, range: 1130-1750 g) and mean gestational age (30.5 weeks, range: 29-32 weeks vs 30.2 weeks, range: 28-32 weeks) in the low and high sodium groups, respectively, were similar. Simultaneous steroid hormone measurements were made weekly up to the 5th week of life using mechanized Sephadex LH-20 multicolumn chromatography and standardized radioimmunoassays. It was demonstrated that in response to renal salt wasting and negative sodium balance there was a significant rise in plasma aldosterone concentration. The plasma levels of other individual corticosteroids generally declined with advancing age, the initial fall, however, was followed by a transient and insignificant but simultaneous increase in 11-deoxycortisol, cortisol, cortisone and corticosterone in prematures on low a sodium diet. This effect could be prevented by giving NaCl supplement. The NaCl-suppressible increase in adrenocortical activity may be the result of the combined effect of stress or angiotensin 11-induced adrenocorticotropic hormone (ACTH) release and/or prolactin-mediated enhanced adrenal response to ACTH.
17-alpha-Hydroxyprogesterone↗
Compounds in the urinary pH 1 extract reacting with corticosteroid and tetrahydrocorticosteroid antisera. Separation of a nonpolar substance with affinity to a tetrahydroaldosterone antiserum.
In human urinary pH 1 extracts prepared for the aldosterone-18-glucuronide estimation, several other substances are present, crossreacting not only with aldosterone antisera, but also with various corticosteroid and tetrahydrocorticosteroid antisera. Aldosterone was measured before and after chromatographic purification. Further characterization of the non-aldosterone immunoreactive material was made by immunological analysis of paper chromatogram eluats. Pregnancy, and administration of ACTH, dexamethasone, and metopirone led to a change of excretion in the antigenic equivalents. A method for the separation of the antigenic material is described. For structural elucidation the gaschromatography-mass spectrometry (GC-MS) method was applied.
Adrenal Cortex Hormones↗