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Garry L Warne - One of the best experts on this subject based on the ideXlab platform.
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a possible defect in the inter conversion between Cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving Cortisone Acetate therapy
The Journal of Steroid Biochemistry and Molecular Biology, 1991Co-Authors: C B Whorwood, Garry L WarneAbstract:Oral administration of Cortisone Acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient ‘first pass’ hepatic conversion of the biologically inactive Cortisone (E) to cortisol (F) by the 11-reductase component of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system is required for suppression of the hypothalamic—pituitary—adrenal (HPA) axis. 11-β-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydroCortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving Cortisone Acetate therapy. In this paper, we describe THE and THF concentrations in 24 h urine samples collected every 3–6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving Cortisone Acetate and 9α-fluorohydroCortisone since diagnosis and were investigated for 2–4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5β,17α-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime—trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean ± SD) was significantly higher in patients during periods of poor control (6.56 ± 2.51, P 40 mg/day compared with doses <15 mg/day. A significant linear correlation could be drawn between THE excretion and total daily dose during periods of both poor (r = 0.67, P < 0.05) and good (r = 0.68, P < 0.005) control. Excretion of 5α-THF, cortols and the cortolones, unlike that for normal subjects, was very low in Cortisone Acetate treated CAH patients. In contrast, the ratios of 5α5β C19 steroid metabolites were no different from normal. The results from this study suggest that poor therapeutic control is unlikely to be due to: (i) failure of compliance with therapy; (ii) inefficient absorption from the intestine; or (iii) inefficient Acetate group removal. The data are consistent with a hypothesis of rapid tetrahydroderivitization of E, present in excess of the capacity of 11β-HSD to form F; i.e. a preferential reduction of the A ring rather than the 11-keto group as a consequence of hepatic ‘first pass’ uptake of the exogenously administered E. The ability of prednisolone and dexamethasone, both of which are bioactive and not subject to significant A ring reduction, to suppress the HPA axis of patients poorly suppressed by Cortisone Acetate, lends support to this hypothesis.
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A possible defect in the inter-conversion between Cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving Cortisone Acetate therapy.
The Journal of Steroid Biochemistry and Molecular Biology, 1991Co-Authors: C B Whorwood, Garry L WarneAbstract:Oral administration of Cortisone Acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient ‘first pass’ hepatic conversion of the biologically inactive Cortisone (E) to cortisol (F) by the 11-reductase component of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system is required for suppression of the hypothalamic—pituitary—adrenal (HPA) axis. 11-β-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydroCortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving Cortisone Acetate therapy. In this paper, we describe THE and THF concentrations in 24 h urine samples collected every 3–6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving Cortisone Acetate and 9α-fluorohydroCortisone since diagnosis and were investigated for 2–4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5β,17α-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime—trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean ± SD) was significantly higher in patients during periods of poor control (6.56 ± 2.51, P 40 mg/day compared with doses
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A possible defect in the inter-conversion between Cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving Cortisone Acetate therapy.
The Journal of steroid biochemistry and molecular biology, 1991Co-Authors: C B Whorwood, Garry L WarneAbstract:Oral administration of Cortisone Acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient 'first pass' hepatic conversion of the biologically inactive Cortisone (E) to cortisol (F) by the 11-reductase component of the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) system is required for suppression of the hypothalamic-pituitary-adrenal (HPA) axis. 11-beta-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydroCortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving Cortisone Acetate therapy. In this paper, we describe THE and THF concentration in 24 h urine samples collected every 3-6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving Cortisone Acetate and 9 alpha-fluorohydroCortisone since diagnosis and were investigated for 2-4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5 beta, 17 alpha-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime-trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean +/- SD) was significantly higher in patients during periods of poor control (6.56 +/- 2.51, P less than 0.001) compared with periods of good control (3.73 +/- 0.96) in the same patients. THE/THF levels were also significantly (P less than 0.001) higher in CAH patients, irrespective of the level of control, than those for the normal subjects (1.79 +/- 0.20). Furthermore, THE excretion was significantly higher during periods of poor control compared with good control at all doses of Cortisone Acetate administered (10-50 mg/day). There were no significant differences in THF excretion. THE levels also rose significantly (P less than 0.001) in response to increasing total dose during periods of poor control. The increase in THF excretion was slight and significant only at doses greater than 40 mg/day compared with doses less than 15 mg/day.(ABSTRACT TRUNCATED AT 400 WORDS)
C B Whorwood - One of the best experts on this subject based on the ideXlab platform.
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a possible defect in the inter conversion between Cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving Cortisone Acetate therapy
The Journal of Steroid Biochemistry and Molecular Biology, 1991Co-Authors: C B Whorwood, Garry L WarneAbstract:Oral administration of Cortisone Acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient ‘first pass’ hepatic conversion of the biologically inactive Cortisone (E) to cortisol (F) by the 11-reductase component of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system is required for suppression of the hypothalamic—pituitary—adrenal (HPA) axis. 11-β-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydroCortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving Cortisone Acetate therapy. In this paper, we describe THE and THF concentrations in 24 h urine samples collected every 3–6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving Cortisone Acetate and 9α-fluorohydroCortisone since diagnosis and were investigated for 2–4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5β,17α-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime—trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean ± SD) was significantly higher in patients during periods of poor control (6.56 ± 2.51, P 40 mg/day compared with doses <15 mg/day. A significant linear correlation could be drawn between THE excretion and total daily dose during periods of both poor (r = 0.67, P < 0.05) and good (r = 0.68, P < 0.005) control. Excretion of 5α-THF, cortols and the cortolones, unlike that for normal subjects, was very low in Cortisone Acetate treated CAH patients. In contrast, the ratios of 5α5β C19 steroid metabolites were no different from normal. The results from this study suggest that poor therapeutic control is unlikely to be due to: (i) failure of compliance with therapy; (ii) inefficient absorption from the intestine; or (iii) inefficient Acetate group removal. The data are consistent with a hypothesis of rapid tetrahydroderivitization of E, present in excess of the capacity of 11β-HSD to form F; i.e. a preferential reduction of the A ring rather than the 11-keto group as a consequence of hepatic ‘first pass’ uptake of the exogenously administered E. The ability of prednisolone and dexamethasone, both of which are bioactive and not subject to significant A ring reduction, to suppress the HPA axis of patients poorly suppressed by Cortisone Acetate, lends support to this hypothesis.
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A possible defect in the inter-conversion between Cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving Cortisone Acetate therapy.
The Journal of Steroid Biochemistry and Molecular Biology, 1991Co-Authors: C B Whorwood, Garry L WarneAbstract:Oral administration of Cortisone Acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient ‘first pass’ hepatic conversion of the biologically inactive Cortisone (E) to cortisol (F) by the 11-reductase component of the 11β-hydroxysteroid dehydrogenase (11β-HSD) system is required for suppression of the hypothalamic—pituitary—adrenal (HPA) axis. 11-β-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydroCortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving Cortisone Acetate therapy. In this paper, we describe THE and THF concentrations in 24 h urine samples collected every 3–6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving Cortisone Acetate and 9α-fluorohydroCortisone since diagnosis and were investigated for 2–4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5β,17α-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime—trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean ± SD) was significantly higher in patients during periods of poor control (6.56 ± 2.51, P 40 mg/day compared with doses
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A possible defect in the inter-conversion between Cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving Cortisone Acetate therapy.
The Journal of steroid biochemistry and molecular biology, 1991Co-Authors: C B Whorwood, Garry L WarneAbstract:Oral administration of Cortisone Acetate is widely used to treat prepubertal patients with congenital adrenal hyperplasia (CAH). However, efficient 'first pass' hepatic conversion of the biologically inactive Cortisone (E) to cortisol (F) by the 11-reductase component of the 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) system is required for suppression of the hypothalamic-pituitary-adrenal (HPA) axis. 11-beta-HSD activity can be assessed by measurement of urinary tetrahydroderivatives of E (tetrahydroCortisone, THE) and F (tetrahydrocortisol, THF), formed in separate hepatic compartments by reduction of the A ring. Inadequate HPA axis suppression is frequently encountered in peripubertal CAH patients receiving Cortisone Acetate therapy. In this paper, we describe THE and THF concentration in 24 h urine samples collected every 3-6 months from 14 prepubertal patients with simple virilizing CAH. The patients had been receiving Cortisone Acetate and 9 alpha-fluorohydroCortisone since diagnosis and were investigated for 2-4 years during which there was marked intra- and inter-individual variation in the level of suppression. Good and poor control of HPA axis suppression were defined on the basis of a profile of early morning serum 17-hydroxyprogesterone, androstenedione, plasma renin activity and 24 h urinary excretion of pregnanetriol, pregnanetriolone and 5 beta, 17 alpha-hydroxypregnanolone. Serum steroids were measured by RIA and urinary metabolites quantitated as methyloxime-trimethylsilylimidazole derivatives by gas chromatography and GC-mass spectrometry. There were no significant differences in the THE/THF ratio between male (n = 9) and female (n = 5) patients during either good or poor therapeutic control. The data were therefore analyzed without consideration of patient sex. Urinary THE/THF (mean +/- SD) was significantly higher in patients during periods of poor control (6.56 +/- 2.51, P less than 0.001) compared with periods of good control (3.73 +/- 0.96) in the same patients. THE/THF levels were also significantly (P less than 0.001) higher in CAH patients, irrespective of the level of control, than those for the normal subjects (1.79 +/- 0.20). Furthermore, THE excretion was significantly higher during periods of poor control compared with good control at all doses of Cortisone Acetate administered (10-50 mg/day). There were no significant differences in THF excretion. THE levels also rose significantly (P less than 0.001) in response to increasing total dose during periods of poor control. The increase in THF excretion was slight and significant only at doses greater than 40 mg/day compared with doses less than 15 mg/day.(ABSTRACT TRUNCATED AT 400 WORDS)
Tsunekazu Yamano - One of the best experts on this subject based on the ideXlab platform.
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Poor Response to Substitution Therapy with Cortisone Acetate in Patients with Congenital Adrenal Hyperplasia
Clinical Pediatric Endocrinology, 2004Co-Authors: Hiroshi Inada, Takuji Imamura, Ryoichi Nakajima, Tsunekazu YamanoAbstract:Although Cortisone Acetate is approved worldwide as corticosteroid substitution therapy in congenital adrenal hyperplasia (21-hydroxylase deficiency), its effectiveness is uncertain since its biologic activity depends on activation by 11β-hydroxysteroid dehydrogenase (11β-HSD). We sought to compare the effect of Cortisone Acetate with that of hydroCortisone. In 10 patients with congenital adrenal hyperplasia, Cortisone Acetate was replaced with hydroCortisone in substitution therapy. During this change, blood concentrations of 17-hydroxy-progesterone, adrenocorticotropin (ACTH), and requirements for each drug were monitored. Concentrations of 17-hydroxyprogesterone decreased (mean 10.1 vs. 48.6 ng/ml), as did those of ACTH. Cortisone Acetate dose requirements averaged 33.9 mg/m2, while hydroCortisone dose requirements averaged only 20.3 mg/m2. In one of the patients resistant to Cortisone Acetate therapy, DNA sequences in the coding regions and promoter of the 11β-HSD gene were analyzed, detecting no genetic abnormalities. Cortisone Acetate is inferior to hydroCortisone as substitution therapy in patients with congenital adrenal hyperplasia.
Hiroshi Inada - One of the best experts on this subject based on the ideXlab platform.
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Poor Response to Substitution Therapy with Cortisone Acetate in Patients with Congenital Adrenal Hyperplasia
Clinical Pediatric Endocrinology, 2004Co-Authors: Hiroshi Inada, Takuji Imamura, Ryoichi Nakajima, Tsunekazu YamanoAbstract:Although Cortisone Acetate is approved worldwide as corticosteroid substitution therapy in congenital adrenal hyperplasia (21-hydroxylase deficiency), its effectiveness is uncertain since its biologic activity depends on activation by 11β-hydroxysteroid dehydrogenase (11β-HSD). We sought to compare the effect of Cortisone Acetate with that of hydroCortisone. In 10 patients with congenital adrenal hyperplasia, Cortisone Acetate was replaced with hydroCortisone in substitution therapy. During this change, blood concentrations of 17-hydroxy-progesterone, adrenocorticotropin (ACTH), and requirements for each drug were monitored. Concentrations of 17-hydroxyprogesterone decreased (mean 10.1 vs. 48.6 ng/ml), as did those of ACTH. Cortisone Acetate dose requirements averaged 33.9 mg/m2, while hydroCortisone dose requirements averaged only 20.3 mg/m2. In one of the patients resistant to Cortisone Acetate therapy, DNA sequences in the coding regions and promoter of the 11β-HSD gene were analyzed, detecting no genetic abnormalities. Cortisone Acetate is inferior to hydroCortisone as substitution therapy in patients with congenital adrenal hyperplasia.
Ryoichi Nakajima - One of the best experts on this subject based on the ideXlab platform.
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Poor Response to Substitution Therapy with Cortisone Acetate in Patients with Congenital Adrenal Hyperplasia
Clinical Pediatric Endocrinology, 2004Co-Authors: Hiroshi Inada, Takuji Imamura, Ryoichi Nakajima, Tsunekazu YamanoAbstract:Although Cortisone Acetate is approved worldwide as corticosteroid substitution therapy in congenital adrenal hyperplasia (21-hydroxylase deficiency), its effectiveness is uncertain since its biologic activity depends on activation by 11β-hydroxysteroid dehydrogenase (11β-HSD). We sought to compare the effect of Cortisone Acetate with that of hydroCortisone. In 10 patients with congenital adrenal hyperplasia, Cortisone Acetate was replaced with hydroCortisone in substitution therapy. During this change, blood concentrations of 17-hydroxy-progesterone, adrenocorticotropin (ACTH), and requirements for each drug were monitored. Concentrations of 17-hydroxyprogesterone decreased (mean 10.1 vs. 48.6 ng/ml), as did those of ACTH. Cortisone Acetate dose requirements averaged 33.9 mg/m2, while hydroCortisone dose requirements averaged only 20.3 mg/m2. In one of the patients resistant to Cortisone Acetate therapy, DNA sequences in the coding regions and promoter of the 11β-HSD gene were analyzed, detecting no genetic abnormalities. Cortisone Acetate is inferior to hydroCortisone as substitution therapy in patients with congenital adrenal hyperplasia.
