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Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency.

ABSTRACT: Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resides primarily in physiological replacement of glucocorticoid secretion. Standard glucocorticoid therapy is shrouded in several controversies. Along the difficulties arising from the inability to accurately replicate the pulsatile circadian cortisol rhythm, come the uncertainties of dose adjustment and treatment monitoring (absence of reliable biomarkers). Furthermore, side effects of inadequate replacement significantly hinder the quality of life of patients. Therefore, transition to circadian hydrocortisone therapy gains prominence. Recent therapeutic advancements consist of oral hydrocortisone modified-release compounds (immediate, delayed and sustained absorption formulations) or continuous subcutaneous hydrocortisone infusion. In addition to illustrating the current knowledge on conventional glucocorticoid regimens, this review outlines the latest research outcomes. We also describe the management of pediatric patients and suggest a novel strategy for glucocorticoid replacement therapy in adults.

SUBMITTER: Oprea A

PROVIDER: S-EPMC6360643 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency.

Oprea Alina A Bonnet Nicolas C G NCG Pollé Olivier O Lysy Philippe A PA

Therapeutic advances in endocrinology and metabolism 20190202

Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resides primarily in physiological replacement of glucocorticoid secretion. Standard glucocorticoid therapy is shrouded in several controversies. Along the ...[more]

PMID: 30746120

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Project description:Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93-140/million), secondary AI (estimated prevalence, 150-280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387).Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy.Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands.EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.

Project description:ObjectivesThe aim of this systematic literature review was to summarize the current knowledge regarding the prevalence of, time to recovery from, and influence of glucocorticoid dose and duration on glucocorticoid-induced adrenal insufficiency (AI).MethodsEligible studies were original research articles, which included adult patients with an indication for glucocorticoids and measured adrenal function following exposure to systemic glucocorticoids. Searches were performed in Web of Science and MEDLINE, with further articles identified from reference lists. Screening was performed in duplicate. Data were extracted for each group of glucocorticoid-exposed patients within eligible studies. The reported proportion of patients with AI was summarized as median and inter-quartile range. Results were then stratified by daily dose, cumulative dose, duration of exposure and time since last glucocorticoid use. The risk of bias within and across studies was considered: for randomised controlled trials risk of bias was assessed using the tool developed by the Cochrane Collaboration.ResultsOverall, 73 eligible studies were identified out of 673 screened. The percentage of patients with AI ranged from 0% to 100% with a median (IQR) = 37.4% (13-63%). Studies were small-median (IQR) group size 16 (9-38)-and heterogeneous in methodology. AI persisted in 15% of patients retested 3 years after glucocorticoid withdrawal. Results remained widely distributed following stratification. AI was demonstrated at <5mg prednisolone equivalent dose/day, <4 weeks of exposure, cumulative dose <0.5g, and following tapered withdrawal.ConclusionsThe heterogeneity of studies and variability in results make it difficult to answer the research questions with confidence based on the current literature. There is evidence of AI following low doses and short durations of glucocorticoids. Hence, clinicians should be vigilant for adrenal insufficiency at all degrees of glucocorticoid exposure.

Project description:BackgroundAdjustment of daily hydrocortisone dose on clinical criteria lacks sensitivity for fine tuning. Long term hydrocortisone (HC) over-replacement may lead to increased morbidity and mortality in patients with adrenal insufficiency (AI). Biochemical criteria may help detecting over- or under-replacement but have been poorly evaluated.MethodsMulticenter, institutional, pharmacokinetic study on ACTH and cortisol plasma profiles during HC replacement in 27 AI patients compared to 29 matched controls. All AI patients were administered HC thrice daily at doses of 6, 10 and 14 mg/m2/d. Blood samples were drawn hourly from 0800h to 1900h. The main outcome measures were: i) plasma peak cortisol and cortisol area under the curve (AUC) in AI patients compared to controls, ii) correlations between cortisol AUC vs single-point cortisol or ACTH decrease from baseline (ΔACTH) and iii) the predictive value of the two latters for obtaining AI patients' cortisol AUC in the control range.ResultsCortisol peaks were observed 1h after each HC intake and a dose response was demonstrated for cortisol peak and cortisol AUC. The comparison of AI patients' cortisol AUC to controls showed that 81.5% AI patients receiving 6mg/m2/d were adequately replaced, whereas most patients receiving higher doses were over-replaced. The correlation coefficient between 1000h/1400h cortisol concentrations and 0800-1900h cortisol AUC were 0.93/0.88 respectively, whereas the 0800-1200h ΔACTH fairly correlated with 0800-1900h cortisol AUC (R = 0.57). ROC curve analysis indicated that the 1000h and 1400h cortisol concentrations best predicted over-replacement.ConclusionsPatients receiving a 6mg/m2 hydrocortisone daily dose exhibited the most physiological daytime cortisol profile. Single point plasma cortisol correlated with daytime cortisol AUC in AI patients. Although hydrocortisone dose should be currently determined on clinical grounds, our data suggest that single point plasma cortisol may be an adjunct for further hydrocortisone dose adjustment in AI patients.

Project description:ImportancePediatric pseudotumor cerebri syndrome pathophysiology is complex and not well delineated. Therefore, it is important to identify potential contributors or targets underlying the primary pathogenesis for its development.ObjectiveTo report cases highlighting the association of pediatric pseudotumor cerebri syndrome with adrenal insufficiency.Design, setting, and participantsThis noncontrolled, observational case series included pediatric patients diagnosed with pseudotumor cerebri syndrome and adrenal insufficiency at an urban academic children's hospital in Houston, Texas, from June 2015 to October 2019.Main outcomes and measuresMonitoring optic nerve edema by clinical examination, fundus photography, and optical coherence topography images of the optic nerve.ResultsData were collected from 5 pediatric patients (age range, 5-10 years) diagnosed with pseudotumor cerebri syndrome and adrenal insufficiency. One was a girl; all were White and prepubertal. Three patients had unrecognized glucocorticoid exposure. All patients had bilateral optic nerve edema that was initially treated with acetazolamide or topiramate, but cortisol functional testing by either 8 am cortisol or cosyntropin stimulation tests revealed a diagnosis of central adrenal insufficiency. Treatment with physiological doses of hydrocortisone resulted in resolution of optic nerve edema and clinical symptoms of pseudotumor cerebri syndrome, as well as a shorter time receiving medical therapy.Conclusions and relevanceIn this case series, adrenal insufficiency was associated with both primary and secondary prepubertal pediatric pseudotumor cerebri syndrome. As a potential target specific to causative mechanism, physiologic hydrocortisone therapy resolved the condition. To date, there remains a global unawareness among clinicians about the suppressive outcome that glucocorticoids may have on the developing hypothalamic-pituitary-adrenal axis, resulting in adrenal insufficiency and so-called episodic pseudotumor cerebri syndrome in young children. Ophthalmologists and pediatric subspecialists should implement cortisol testing via either 8 am cortisol or cosyntropin stimulation tests at initial evaluation of all children with pseudotumor cerebri syndrome and risk factors for adrenal insufficiency, no predisposing causes, or nonresponse to conventional treatment. Further management and treatment should be in combination with ophthalmology and endocrine services.

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Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency.

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Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency.

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