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      Peak cortisol response to corticotropin-releasing hormone is associated with age and body size in children referred for clinical testing: a retrospective review

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          Abstract

          Background

          Corticotropin-Releasing Hormone (CRH) testing is used to evaluate suspected adrenocorticotropic hormone (ACTH) deficiency, but the clinical characteristics that affect response in young children are incompletely understood. Our objective was to determine the effect of age and body size on cortisol response to CRH in children at risk for ACTH deficiency referred for clinical testing.

          Methods

          Retrospective, observational study of 297 children, ages 30 days – 18 years, undergoing initial, clinically indicated outpatient CRH stimulation testing at a tertiary referral center. All subjects received 1mcg/kg corticorelin per institutional protocol. Serial, timed ACTH and cortisol measurements were obtained. Patient demographic and clinical factors were abstracted from the medical record. Patients without full recorded anthropometric data, pubertal assessment, ACTH measurements, or clear indication for testing were excluded (number remaining = 222). Outcomes of interest were maximum cortisol after stimulation (peak) and cortisol rise from baseline (delta). Bivariable and multivariable linear regression analyses were used to assess the effects of age and size (weight, height, body mass index (BMI), body surface area (BSA), BMI z-score, and height z-score) on cortisol response while accounting for clinical covariates including sex, race/ethnicity, pubertal status, indication for testing, and time of testing.

          Results

          Subjects were 27 % female, with mean age of 8.9 years (SD 4.5); 75 % were pre-pubertal. Mean peak cortisol was 609.2 nmol/L (SD 213.0); mean delta cortisol was 404.2 nmol/L (SD 200.2). In separate multivariable models, weight, height, BSA and height z-score each remained independently negatively associated ( p < 0.05) with peak and delta cortisol, controlling for indication of testing, baseline cortisol, and peak or delta ACTH, respectively. Age was negatively associated with peak but not delta cortisol in multivariable analysis.

          Conclusions

          Despite the use of a weight-based dosing protocol, both peak and delta cortisol response to CRH are negatively associated with several measures of body size in children referred for clinical testing, raising the question of whether alternate CRH dosing strategies or age- or size-based thresholds for adequate cortisol response should be considered in pediatric patients, or, alternatively, whether this finding reflects practice patterns followed when referring children for clinical testing.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13633-015-0018-y) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          Effect of inhaled glucocorticoids in childhood on adult height.

          The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height. We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry. Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants. The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).
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            Adrenal insufficiency: still a cause of morbidity and death in childhood.

            Adrenal insufficiency is relatively rare in childhood and adolescence. Signs and symptoms may be nonspecific; therefore, the diagnosis may not be suspected early in the course. If unrecognized, adrenal insufficiency may present with life-threatening cardiovascular collapse. Adrenal crisis continues to occur in children with known primary or secondary adrenal insufficiency during intercurrent illness because of failure to increase glucocorticoid dosage. In this article, current knowledge of the incidence, diagnosis, and treatment of adrenal insufficiency in children and factors precipitating adrenal crisis are summarized. Suggestions for prevention of adrenal crisis in patients at risk are provided for health care professionals and families.
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              The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone.

              Suppression of pituitary-adrenal function is a well-known consequence of glucocorticoid therapy, manifested principally by decreased corticotropin secretion. To determine the degree of suppression of pituitary-adrenal function in patients treated with different doses of synthetic glucocorticoid medication for different periods, we measured the pituitary-adrenal response to the administration of exogenous human corticotropin-releasing hormone (CRH). We studied 279 patients who were receiving daily therapy with 5 to 30 mg of prednisone or its equivalent to treat various chronic diseases, principally collagen vascular disorders, and 50 normal subjects. Therapy ranged in duration from 1 week to 15 years. Stimulation tests using 100 micrograms of CRH as a bolus injection were performed in the morning, 24 hours after the most recent dose of glucocorticoids. In 61 patients an insulin hypoglycemia test, thought by many to be the reference standard, was also performed to assess the reliability of the CRH results. After the administration of CRH, 43 patients had no increase in plasma concentrations of corticotropin and cortisol. The response was blunted in 133 patients and normal in 103. There was poor correlation between the plasma cortisol response after the administration of CRH and the dose or duration of therapy or the basal plasma cortisol concentration. Although plasma cortisol concentrations after stimulation with CRH were generally lower than those after insulin administration, there was a significant correlation between the plasma cortisol responses to the two stimuli (r = 0.82). Pituitary-adrenal function in patients treated with synthetic glucocorticoids cannot be reliably estimated from the dose of glucocorticoid, the duration of therapy, or the basal plasma cortisol concentration. In such patients, testing with CRH is nearly as useful as insulin hypoglycemia testing in the assessment of pituitary-adrenal function.
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                Author and article information

                Contributors
                vajravelum@email.chop.edu
                Jtt46@drexel.edu
                burrowse@email.chop.edu
                chiluttim@email.chop.edu
                rxiao@mail.med.upenn.edu
                bamba@email.chop.edu
                willi@email.chop.edu
                Andrew.palladino@pfizer.com
                burnhams@email.chop.edu
                (215) 590-3174 , mccormacks1@email.chop.edu
                Journal
                Int J Pediatr Endocrinol
                Int J Pediatr Endocrinol
                International Journal of Pediatric Endocrinology
                BioMed Central (London )
                1687-9848
                1687-9856
                22 October 2015
                22 October 2015
                2015
                : 2015
                : 22
                Affiliations
                [ ]Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Suite 11NW, Philadelphia, USA
                [ ]Center for Biomedical Informatics, The Children’s Hospital of Philadelphia, 3535 Market St, Philadelphia, PA 19104 USA
                [ ]Department of Biostatistics and Epidemiology, University of Pennsylvania, 635 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021 USA
                [ ]Global Innovative Pharma, Pfizer, Inc, 500 Arcola Road, Collegeville, PA 19426 USA
                [ ]The Children’s Hospital of Philadelphia, Division of Rheumatology, 10103 Colket Building, 34th & Civic Center Blvd, Philadelphia, PA 19104 USA
                Article
                18
                10.1186/s13633-015-0018-y
                4618529
                acd7be5e-6223-4e3b-9393-90b42bd39757
                © Vajravelu et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 26 June 2015
                : 1 October 2015
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Pediatrics
                adrenal insufficiency,corticotropin-releasing hormone (crh) stimulation test,exogenous glucocorticoid exposure,adrenal stimulation testing,cortisol

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