Monitoring growth in asthmatic children treated with high dose inhaled glucocorticoids does not predict adrenal suppression

Aims: To determine whether routine outpatient monitoring of growth predicts adrenal suppression in prepubertal children treated with high dose inhaled glucocorticoid.

Methods: Observational study of 35 prepubertal children (aged 4–10 years) treated with at least 1000 µg/day of inhaled budesonide or equivalent potency glucocorticoid for at least six months. Main outcome measures were: changes in HtSDS over 6 and 12 month periods preceding adrenal function testing, and increment and peak cortisol after stimulation by low dose tetracosactrin test. Adrenal suppression was defined as a peak cortisol 500 nmol/l.

Results: The areas under the receiver operator characteristic curves for a decrease in HtSDS as a predictor of adrenal insufficiency 6 and 12 months prior to adrenal testing were 0.50 (SE 0.10) and 0.59 (SE 0.10). Prediction values of an HtSDS change of –0.5 for adrenal insufficiency at 12 months prior to testing were: sensitivity 13%, specificity 95%, and positive likelihood ratio of 2.4. Peak cortisol reached correlated poorly with change in HtSDS ( = 0.23, p = 0.19 at 6 months; = 0.33, p = 0.06 at 12 months).

Conclusions: Monitoring growth does not enable prediction of which children treated with high dose inhaled glucocorticoids are at risk of potentially serious adrenal suppression. Both growth and adrenal function should be monitored in patients on high dose inhaled glucocorticoids. Further research is required to determine the optimal frequency of monitoring adrenal function.

Validation of urinary cortisol as an indicator of hypothalamic-pituitary-adrenal function in the bearded emperor Tamarin (Saguinus imperator subgrisescens)

The use of cortisol levels as a measure of stress is often complicated by the use of invasive techniques that may increase hypothalamic-pituitary-adrenal (HPA) axis activity during sample collection. The goal of this study was to collect samples noninvasively and validate an enzyme-immunoassay (EIA) for the measurement of cortisol in urine to quantify HPA axis activity in the bearded emperor tamarin (Saguinus imperator subgrisescens). Urine samples were collected from trained subjects between 0700 and 0730 hr during a 1-month period, and were pooled for immunological validation. We validated the assay immunologically by demonstrating specificity, accuracy, precision, and sensitivity. For biological validation of the assay, we showed that levels of urinary cortisol (in samples collected between 0700 and 1700 hr) varied significantly across the day. Cortisol concentration was lowest at 0700 hr, increased to a mid-morning peak (0900 hr), and declined across the remainder of the day in a typical mammalian circadian pattern. We thus demonstrate that urinary cortisol can be used to quantify HPA activity in S. i. subgrisescens. (C) 2004 Wiley-Liss, Inc.

Structure-Phenotype Correlations of Human CYP21A2 Mutations in Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia (CAH) is a family of autosomal recessive disorders involving impaired synthesis of cortisol from cholesterol by adrenal cortex. The predominant causes of the disorder are mutations in the CYP21A2 gene that encodes a Cytochrome P450 21-hydroxylase enzyme, which is central to steroidogenesis. The severity of the disease depends upon the extent of impaired enzymatic activity and can be classified under severe Classical form or the mild Non-Classical form, Molecular characterisation of CYP21A2 mutations can be used to predict clinical phenotype and disease severity based upon changes it brings in 21-hydroxylase enzyme structure. A humanized model of CYP21A2 has been used to map and investigate the structural role of all known disease-causing mutations. A structural explanation of clinical manifestation allows us to put forward criteria that might allow the prediction of clinical severity of the disease.

Hypothalamic-pituitary-adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic-pituitary-adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown.

Growth and adrenal suppression in asthmatic children treated with high-dose fluticasone propionate

Background: Fluticasone propionate was introduced in 1993 in the UK as a potentially safer inhaled corticosteroid than those already in use. The efficacy and safety of fluticasone has been established at recommended doses of 200 µg/day, but not at the higher doses that are often used.

Methods: Growth retardation was observed in six severely asthmatic children after introduction of high-dose fluticasone propionate treatment (dry powder). Assessment of cortisol response was by insulin-induced hypoglycaemia in three cases, by short tetracosactrin test in two, and by low-dose tetracosactrin and 24-hour urinary cortisol/creatinine ratio in one.

Findings: Six children with growth retardation noted after treatment with high-dose fluticasone propionate were found to have adrenal suppression. In one case the growth rate and cortisol response returned to normal 9 months after the fluticasone dose was reduced to 500 µg/day.

Interpretation: When high doses of fluticasone propionate are used, growth may be retarded and adrenal suppression may occur.

Endocrine Surgery: Principles and Practice:adrenal chapter

The paired adrenal (suprarenal) glands are flattened retroperitoneal endocrine glands closely applied to the medial aspect of the superior pole of each kidney. The internal structure of these pale yellow glands are incongruous in that the adrenal gland is composed of two discrete parts, namely an outer cortex enveloping a central medulla. The adrenal cortex and medulla contain distinct endocrine tissues that secrete different hormones and are regulated by separate control systems.

Cyclooxygenase-2 expression correlates with phaeochromocytoma malignancy.

Abstract Aims: Phaeochromocytomas are rare but potentially life-threatening neuroendocrine tumours of the adrenal medulla or sympathetic nervous system ganglia. There are no histological features which reliably differentiate benign from malignant phaeochromocytomas. The current study evaluated cyclooxygenase-2 (Cox-2) and Bcl-2 as tissue-based biomarkers of phaeochromocytoma prognosis. Methods and Results: Cox-2 and Bcl-2 expression were examined immunohistochemically in tissue from forty-one sporadic phaeochromocytoma patients followed up for a minimum of five years after diagnosis. There was a statistically significant association between Cox-2 histoscore (intensity x porportion) and the development of tumour recurrence or metastases (p=0.006). A significant relationship between the co-expression of Cox-2 and Bcl-2 in the primary tumour and the presence of recurrent disease was observed (p=0.034). A highly significant association was observed between, (i) the tumour-associated expression of these two oncoproteins (p=0.001) and, (ii) Cox-2 histoscore and the presence of Bcl-2 expression (p=0.002). Cox regression analysis demonstrated no significant relationship between, (i) the presence or absence of either Cox-2 or Bcl-2 and patient survival or, (ii) between Cox-2 histoscore and patient survival. Conclusions: These results suggest that Cox-2 and Bcl-2 may promote phaeochromocytoma malignancy and that these oncoproteins may be valuable surrogate markers of an aggressive tumour phenotype.

Tumor Risks and Genotype-Phenotype-Proteotype Analysis in 358 Patients With Germline Mutations in SDHB and SDHD

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n = 295) and SDHD (n = 63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma, risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma. Hum Mutat 31:41-51, 2010. (C) 2009 Wiley-Liss, Inc.

An immunohistochemical study of the distribution of biotin in tissues of pigs and chickens

An optimised indirect peroxidase-anti-peroxidase immunohistochemical technique was used to detect endogenous biotin in frozen tissue sections from biotin-supplemented and biotin-depleted pigs and chickens. A monoclonal anti-biotin antibody was used as primary antibody in this technique. Immunoreactive biotin was detected in many tissues of both species including liver, kidney, pancreas, adipose tissue, adrenal gland, testis, brain, choroid plexus, cardiac and skeletal muscle, epithelium of the respiratory and digestive systems, skin and lymphoid tissues. The specificity of immunostaining for biotin was confirmed by the finding of reduced staining intensities in tissues of biotin-depleted animals compared to those of biotin-supplemented animals. The results of this study suggest that biotin has metabolic functions in a wider range of tissues than previously known. They also indicate that endogenous tissue biotin should be considered as a source of false positive staining when immunohistochemical or histochemical techniques which use avidin or streptavidin reagents or anti-biotin antibodies as components of the detection system, are applied to tissue sections.

Hair cortisol reflects socio-economic factors and hair zinc in preschoolers

This study examined the relationship between children's hair cortisol and socioeconomic status of the family, as measured by parental education and income. Low family socioeconomic status has traditionally been considered a long-term environmental stressor. Measurement of hair cortisol provides an integrated index of cumulative stress exposure across an extended period of time. The present study is the first to examine the relationship between hair cortisol and parental education as well as parental income in a representative sample of preschoolers. Data on hair cortisol, family income, and parental education were collected for a representative sample of 339 children (Mean age=4.6 years; SD=.5 years) from across 23 neighbourhoods of the city of Vancouver, Canada. As maternal education was shown previously to be associated with hair zinc level, hair zinc measurements were included as well in order to explore potential relationships between hair zinc and hair cortisol. The relationship between hair cortisol and parental education was examined using hierarchical regression, with hair zinc, gender, age, and single parenthood included as covariates. Maternal and paternal education both were correlated significantly with hair cortisol (r=-0.18; p=.001). The relationship remained statistically significant even after controlling for all demographic covariates as well as for hair zinc and after taking the neighbourhood-level clustering of the data into account. Parental income, on the other hand, was not related significantly to children's hair cortisol. This study provides evidence that lower maternal and paternal education are associated with higher hair cortisol levels. As hair cortisol provides an integrated index of cortisol exposure over an extended time period, these findings suggest a possibly stable influence of SES on the function of the hypothalamic-pituitary-adrenal (HPA) axis. Cumulative exposure to cortisol during early childhood may be greater in children from low socio-economic backgrounds, possibly through increased exposure to environmental stressors.

Cortisol levels in relation to maternal interaction and child internalizing behavior in preterm and full-term children at 18 months corrected age

Cortisol levels were compared in children born preterm at extremely low gestational age (ELGA; 24-28 weeks), very low gestational age (VGLA; 29-32 weeks), and full-term in response to cognitive assessment at 18 months corrected age (CA). Further, we investigated the relationship between maternal interactive behaviors and child internalizing behaviors (rated by the mother) in relation to child cortisol levels. EGLA children had higher "pretest" cortisol levels and a different pattern of cortisol response to cognitive assessment compared to VGLA and full-terms. Higher cortisol levels in ELGA, but not full-term, children were associated with less optimal mother interactive behavior. Moreover, the pattern of cortisol change was related to internalizing behaviors among ELGA, and to a lesser degree VLGA children. In conclusion, our findings suggest altered programming of the hypothalamic-pituitary-adrenal (HPA) axis in preterm children, as well as their greater sensitivity to environmental context such as maternal interactive behavior.