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Diseases of the Nervous System
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Analysis of the human brain reveals the presence of cortisol, tetrahydrocortisol and l1β,17α,20β,21-tetrahydroxy-pregn-4-ene-3-one. The concentration of cortisol in the brain is about 25 to 30 times higher than that in the blood, indicating that cortisol readily enters the organ. Blood levels of this steroid are about 15 to 40 times higher than in the cerebrospinal fluid. Intrathecally administered cortisol also disappears very quickly. These data indicate that the steroid is removed from the cerebrospinal fluid by a process of bulk flow in order to maintain a balance between the low and high level in the cerebrospinal fluid and blood respectively. The increased concentration of cortisol and corticosterone in the brain as compared to plasma is probably the result of active transport and subsequent selective bindingto proteins in nuclear and cytoplasmic fractions of brain cells. The nervous tissue contains various enzyme systems which metabolize steroids. Cortisol is converted to cortisone to a marked extent, but only minimal amounts of tetrahydrocortisol and tetrahydrocortisone are produced. NADP-dependent oxidation reactions are common. These enzymes are bound to subcellular particles and the activity of some of them changes with maturation suggesting some roles of these processes in the maturation process.
The adrenal cortex
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
In 11-β-hydroxylase deficiency there is a raised concentration of 24-h urinary tetrahydrocortisol, a metabolite of 11-deoxycortisol, and raised deoxycorticosterone concentration. In the salt-losing forms, plasma renin and aldosterone concentrations may assist diagnosis.
Steroid Δ4-Reductases: their Physiological Role and Significance
Published in Ronald Hobkirk, Steroid Biochemistry, 1979
The urine 3α-hydroxy-5β-metabolites of both cortisol and cortisone, i.e., tetrahydrocortisol and tetrahydrocortisone, have been considered unique metabolites of cortisol; that is, they are derived solely from cortisol. Using this assumption, the specific activity of one of these urine metabolites following an injection of 3H- or 14C-labeled hormone has been utilized to calculate the cortisol production rate.10 Results must at times be interpreted with caution because of some possible irreversible metabolism leading to tetrahydro metabolites occurring prior to mixing of injected with endogenous cortisol.11 As critically reviewed,12 production rates based on the use of specific activities of urine tetrahydrocortisol and tetrahydrocortisone following the intravenous administration of labeled cortisol may differ; the reasons for this are not clear, but the irreversible metabolism prior to mixing and liver compartmentation may be involved.
Hydrocortisone granules in capsules for opening (Alkindi) as replacement therapy in pediatric patients with adrenal insufficiency
Published in Expert Opinion on Orphan Drugs, 2021
Helen Coope, Lotta Parviainen, Mike Withe, John Porter, Richard J Ross
Hydrocortisone has been used in humans for more than 60 years and is identical to the innate hormone cortisol. Like other steroids, cortisol binds to an intracellular receptor which, after migrating to the nucleus of the cell, upregulates or downregulates gene expression. Hydrocortisone also acts through non-genomic mechanisms [42]. Hydrocortisone is rapidly and virtually completely absorbed from the fasted alimentary system (bioavailability is ~100%) with Tmax reached about 60 minutes [43]. Cortisol is highly protein bound mostly by cortisol binding globulin, with a smaller amount of albumin binding. This leads to non-linear pharmacokinetics as higher doses of hydrocortisone are more rapidly cleared due to saturation of the protein binding [43,44]. Metabolism of cortisol is by renal 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) to inactive cortisone whilst hepatic and adipose 11β-HSD1 converts cortisone to cortisol. Cortisol, cortisone and downstream metabolites allo-tetrahydrocortisol, tetrahydrocortisol and tetrahydrocortisone, are all renally excreted [45].
Glucocorticoid-induced ocular hypertension: origins and new approaches to minimize
Published in Expert Review of Ophthalmology, 2020
Thomas Yorio, Gaurang C. Patel, Abbot F. Clark
There have been three major experimental approaches to inhibit or block IOP elevation in animal models of GC-OHT (Table 4). The first approach has used concomitant administration of ocular steroid analogs along with the anti-inflammatory GC. Topical ocular administration of the natural cortisol metabolite tetrahydrocortisol reversed DEX-induced ocular hypertension in rabbits [114]. It is interesting to note that this compound also blocked DEX-induced CLAN formation in cultured human TM cells [115], suggesting a potential mechanism by which this metabolite may work. Another cortisol analog, anecortave acetate, was designed as an IOP lowering cortisone. In an open-label clinical trial, subTenon’s injection of an anecortave acetate suspension lowered IOP in GC-induced OHT patients [116]. The average starting IOP was over 31 mmHg, and anecortave acetate provided a sustained (up to 6 months) 30% IOP lowering. It is important to note that these two steroid analogs are not GC receptor antagonists, so they should not interfere with the anti-inflammatory effects of GCs [117].