Glucocorticoid replacement regimens in the treatment of 21-hydroxylase deficiency congenital adrenal hyperplasia

Ng, Sze May; Stępień, Karolina M.

doi:10.1002/14651858.cd012517

Cited by 2 publications

(2 citation statements)

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“…Further prospective clinical studies are obviously required to further explore to what extent 21DF and 21DB directly impact sodium and water balance. In addition to that, the need of a new paradigm for HC therapy in 21OHD is now well established (34,42). Recent development of extended-/dual-release, or continuous subcutaneous forms of HC that mimic the physiological cortisol rhythm (4,22) may improve compliance and should probably contribute significantly toward achieving adrenocortical suppression and better control of upstream enzymatic defect steroids.…”

Section: -Hydroxylase Deficiency (21ohdmentioning

confidence: 99%

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency

Travers

Bouvattier

Fagart

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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21-Hydroxylase deficiency (21OHD) is a rare genetic disorder in which salt-wasting syndrome occurs in 75% of cases, due to inability to synthesize cortisol and aldosterone. Recent mass spectrometry progress allowed identification of 21-deoxysteroids, i.e., 17-hydroxyprogesterone (17OHP), 21-deoxycortisol (21DF), and 21-deoxycorticosterone (21DB). We hypothesized that they may interfere with mineralocorticoid signaling and fludrocortisone therapy in patients with congenital adrenal hyperplasia (CAH) without effective glucocorticoid replacement and ACTH suppression. Our goal was to quantify circulating 21-deoxysteroids in a pediatric cohort with CAH related to 21OHD and to examine their impact on mineralocorticoid receptor (MR) activation. Twenty-nine patients with salt-wasting phenotype were classified in two groups according to their therapeutic control. During routine follow-up, 17OHP, 21DF, 21DB, and cortisol levels were quantified by liquid chromatography with tandem mass spectrometry before hydrocortisone intake and 1 and 2.5 h following treatment administration. Luciferase reporter gene assays were performed on transfected HEK293T cells while in silico modeling examined structural interactions between these steroids within ligand-binding domain of MR. Plasma 17OHP, 21DF, and 21DB accumulate in uncontrolled patients reaching micromolar concentrations even after hydrocortisone intake. 21DF and 21DB act as partial MR agonists with antagonist features similar to 17OHP, consistent with altered anchoring to Asn770 and unfavorable contact with Ala773 in ligand-binding pocket of MR. Our results demonstrate a complex interaction between all accumulating 21-deoxysteroids in uncontrolled 21OHD patients and mineralocorticoid signaling and suggest that appropriate steroid profiling should optimize management and follow-up of such patients, as keeping those steroids to low plasma levels should attest therapeutic efficacy and prevent interference with MR signaling.

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Section: -Hydroxylase Deficiency (21ohdmentioning

confidence: 99%

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency

Travers

Bouvattier

Fagart

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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“…Hydrocortisone replacement therapy is essential in children with CAH and adrenal insufficiency to control androgen excess and optimise their growth and development. Hydrocortisone is used to mimic glucocorticoid levels of a healthy child and the best therapy will be one that matches the circadian rhythm of cortisol (Ng and Stepien, 2017). The rapid half-life of hydrocortisone means that frequent administration of low doses best matches the normal physiological endogenous cortisol levels.…”

Section: Introductionmentioning

confidence: 99%

How close is the dose? Manipulation of 10 mg hydrocortisone tablets to provide appropriate doses to children

Webb

Kerr

Davies

et al. 2018

International Journal of Pharmaceutics

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This study explores the methodology advised by healthcare professionals and the methods used by parents/carers to identify whether there is a best practice method for manipulation of 10 mg hydrocortisone tablets to provide an accurate dose to children. Bespoke surveys were used to identify methods recommended and used in manipulation of tablets. Hydrocortisone tablets were manipulated to provide a specified dose by both naïve participants and parents/carers. The accuracy of manipulation was assessed using HPLC analysis. Competed surveys were received from 159 parent/carers reporting doses that ranged from 0.25 to 15 mg. Parents/carers most commonly reported splitting the tablet and administering the solid fraction; however more than 30% of those reporting physically splitting tablets were preparing doses that were not simply halving or quartering tablets. In a naïve population the dose accuracy, defined as percent of doses within 20% of the theoretical dose ranged from 57 to 58% depending on the tablet brand and the method of manipulation used. Almost three-quarters (74.1%) of parent/carers (n = 27) were able to produce a dose within 20% of the theoretical value and the most accurate method was to split tablets and administer the solid fraction. This study shows that a lack of age-appropriate medicines results in children being at risk of sub-optimal dosing.

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Glucocorticoid replacement regimens in the treatment of 21-hydroxylase deficiency congenital adrenal hyperplasia

Cited by 2 publications

References 20 publications

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency

How close is the dose? Manipulation of 10 mg hydrocortisone tablets to provide appropriate doses to children

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Glucocorticoid replacement regimens in the treatment of 21-hydroxylase deficiency congenital adrenal hyperplasia

Cited by 2 publications

References 20 publications

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency

Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency

How close is the dose? Manipulation of 10 mg hydrocortisone tablets to provide appropriate doses to children

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How close is the dose? Manipulation of 10 mg hydrocortisone tablets to provide appropriate doses to children