Evaluation of adrenal function using the human corticotrophin-releasing hormone test, low dose Synacthen test and 9am cortisol level in children and adolescents with central adrenal insufficiency.

BACKGROUND: The insulin tolerance test (ITT) has become less popular in paediatrics because of the risks associated with hypoglycaemia. Human corticotrophin-releasing hormone (hCRH) test results correlate with the ITT and may be an acceptable method to test for central adrenal insufficiency (CAI). Simpler tests, such as the low dose Synacthen test (LDST) and 9am cortisol, have also been proposed. OBJECTIVE: To compare the ability of the hCRH test, LDST, 9am cortisol level and 24-h cortisol profiles to diagnose CAI in a paediatric population. DESIGN AND SETTING: A cross-sectional study in a tertiary paediatric endocrine clinic. PARTICIPANTS: Thirty-one children and adolescents (aged 2.3-18.3 years) with CAI risk factors had an hCRH test, LDST, 9am cortisol and 24-h cortisol profile performed. RESULTS: Of 23 patients with confirmed CAI (hCRH peak cortisol < 400 nmol/), 19 failed the LDST (peak cortisol < 267 nmol/l, i.e. 10th percentile for controls). Nineteen would have failed based on the 10th percentile cut point for 9am cortisol (< 140 nmol/l). Using receiver operating characteristic (ROC) curve coordinates, a 9am cortisol < 108 nmol/l was sensitive (83%) and specific (99%) for CAI. The 9am cortisol levels measured on two occasions were repeatable (94%) and correlated (r = 0.83, P = 0.01). All eight adrenally sufficient patients (hCRH peak cortisol > or = 400 nmol/l) passed the LDST. Seven had normal 9am cortisol (> or = 140 nmol/l). The 24-h cortisol area under the curve (AUC) for these patients was within the 10th-90th percentiles for control subjects' AUC. The peak cortisol to hCRH and LDST were correlated (r = 0.88, P = 0.01), with no difference between the peaks (mean difference -5.3 nmol/l, P = 0.69). CONCLUSIONS: In children with CAI risk factors, the diagnosis can be made if unstressed 9am cortisol is < 108 nmol/l. As cortisol levels > 381 nmol/l are highly suggestive of normal hypothalamic-pituitary-adrenal (HPA) function, stimulation testing need only be performed if 9am cortisol is 108-381 nmol/l. The LDST should be interpreted cautiously because mild CAI may be missed. When stimulation results are marginal, 24-h cortisol profiles can provide reassurance of normal cortisol status.

The clinical utility of alternative, less invasive sampling techniques in the assessment of oral hydrocortisone therapy in children and adolescents with hypopituitarism.

OBJECTIVE: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol). DESIGN: Cross-sectional study in a paediatric teaching hospital. METHODS: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings. RESULTS: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%). CONCLUSION: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.

Effect of growth hormone therapy and puberty on bone and body composition in children with idiopathic short stature and growth hormone deficiency.

The state of bone health and the effect of growth hormone (GH) therapy on bone and body composition in children with idiopathic short stature (ISS) are largely unknown. A direct role of GH deficiency (GHD) on bone density is controversial. Using dual-energy X-ray absorptiometry, this study measured total body bone mineral content (TB BMC), body composition, and volumetric bone mineral density (vBMD) at the lumbar spine (LS) and femoral neck (FN) in 77 children (aged 3-17 years) with ISS (n = 57) and GHD (n = 20). Fifty-five children (GHD = 13) receiving GH were followed over 24 months including measurement of bone turnover. At diagnosis, size-corrected TB BMC SDS was greater (P

Importance of estrogen on bone health in Turner syndrome: a cross-sectional and longitudinal study using dual-energy X-ray absorptiometry.

Osteoporosis and fractures are features in adults with Turner syndrome (TS). Using dual-energy x-ray absorptiometry, correcting bone mineral content (BMC) for height and lean mass (LTM) avoids misclassification of short children as osteopenic. Total body (TB), lumbar spine (LS), and femoral neck (FN) dual-energy x-ray absorptiometry scans were performed on 83 patients with TS (aged 4-24 yr). A prepubertal subgroup (n = 17) receiving GH was followed for 24 months. Age z-scores for height, TB BMC, LTM, the BMC/LTM ratio, and LS volumetric bone mineral density (vBMD) decreased significantly (P < 0.001) with age in prepubertal subjects (n = 51) but were constant in the combined pubertal and postmenarchal group (n = 32). Osteopenia was found in 14.5% (TB), 15.8% (LS), and 28.4% (FN) of patients. In the longitudinal subgroup, TB BMC z-scores decreased by -0.28 (0.31) in subjects remaining prepubertal (n = 11) but increased by 0.71 (0.56) in subjects entering puberty (n = 6; P = 0.007). The z-scores for height and LTM increased in both groups. Our results show a height-independent prepubertal decrease in bone mass accrual, which ceased with puberty. Optimizing bone mass in TS may require earlier induction of puberty than currently recommended. However, reduced FN volumetric bone mineral density and a dissociation of bone and muscle measures were age independent, suggesting an additional intrinsic bone defect.

The skeletal phenotype of men with previous constitutional delay of puberty.

It is presently unclear whether men with a history of constitutional delay (CD) of puberty are osteopenic. This study compares auxology, bone mass, size, and density of 32 men (age, 21-33 yr) with previous CD with 45 controls. Using dual-energy x-ray absorptiometry, areal bone mineral density (aBMD) and volumetric bone mineral density at the lumbar spine (LS) and femoral neck (FN), hip strength analysis, and total-body and body segment (arms, legs, trunk) measurements were determined. Auxological variables, body composition, the muscle-bone relation, and the effect of prior androgen treatment were studied. Men with previous CD were shorter (P < 0.001) and had shorter height-adjusted arms compared with controls. Height-adjusted total-body bone mineral content (BMC) (P = 0.004), aBMD (P = 0.016), and bone area (P = 0.006) but not lean tissue mass (P = 0.507) were lower in CD men compared with controls; consequently, their BMC to lean tissue mass ratio was reduced (P < 0.001). Segment length-adjusted BMC and bone area of arms (P < 0.001) and legs (P < 0.03), but not trunk were lower in CD men than in controls. They had lower LS aBMD (P = 0.044) but normal LS and FN volumetric bone mineral density. Size-adjusted LS width and the hip cross-sectional area were lower than in controls. There was no difference in anthropometric or dual-energy x-ray absorptiometry results between untreated (n = 15) and androgen-treated (n = 17) CD men.We conclude that men with previous CD have normal LS and FN volumetric density but reduced total-body bone mass, which was explained by reduced limb bone mass and size. Together with the reduced LS bone width and hip crosssectional area, these skeletal characteristics suggest impaired periosteal expansion during puberty. The skeletal phenotype of CD males may be altered by their late onset of puberty.

Prolonged hypocortisolemia in hydrocortisone replacement regimens in adrenocorticotrophic hormone deficiency.

OBJECTIVES: Studies of adults have shown that thrice-daily hydrocortisone dosing results in more physiologic cortisol profiles than twice-daily dosing. There are no data on thrice-daily dosing and only limited data on twice-daily dosing in children despite the possible adverse effects of glucocorticoid underreplacement or overreplacement. METHODS: Using 24-hour cortisol and glucose profiles, along with computerized cognitive testing, our aim was to assess prescribed hydrocortisone regimens in children and adolescents with hypopituitarism. RESULTS: Twenty patients with adrenocorticotrophic hormone deficiency participated. The hydrocortisone dosing regimen was thrice daily in 9 patients and twice daily in 11 patients (mean total daily dose: 8.3 +/- 2.6 and 7.6 +/- 2.1 mg/m2 per day, respectively). Those on twice-daily dosing had more waking hours (between 8:00 am and 8:00 pm) below the reference range than those on thrice-daily dosing (5.5 vs 2.1) and more daytime prolonged hypocortisolemia, defined as plasma cortisol level of < 50 nmol/L for > or = 4 hours (64% vs 0%). Morning doses > 4 mg/m2 caused larger postdose peaks than < 4 mg/m2 (151 vs 47 nmol/L, above the 97.5th percentile). However, there was no difference in the length of time taken to reach nadir below the 2.5th percentile (5.2 vs 4.8 hours). This was true for evening doses of > 2.5 mg/m2 and < 2.5 mg/m2. No hypoglycemia or hyperglycemia was detected in association with low or high cortisol levels. On predose and postdose cognitive testing (34 paired tests), no significant change in reaction speed was detected (453.3 vs 438.8 milliseconds) or in subgroup analysis of those who had symptoms of lethargy, predose cortisol levels of < 50 nmol/L, or prolonged hypocortisolemia. CONCLUSIONS: Thrice-daily dosing resulted in less frequent and prolonged hypocortisolemia than twice-daily regimens, but we were unable to relate either regimen to acute clinical end points of glycemia, lethargy, or cognitive function.