Obesity in children with congenital adrenal hyperplasia in the Minnesota cohort: importance of adjusting body mass index for height-age.

OBJECTIVES: To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH) and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index-for-height-age (BMIHA ) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature. DESIGN: Longitudinal. PATIENTS: One hundred and ninety-four children with CAH seen from 1970 to 2013: 124 salt wasting (SW); 70 simple virilizing (SV); 102 females. MEASUREMENTS: Body mass index (BMI) end-points were overweight (85-94 percentile) and obese (≥95 percentile). RESULTS: Approximately 50% of the children had at least one BMI measurement ≥95 percentile and about 70% had at least one ≥85 percentile. Using BMIHA percentiles, obesity incidence decreased slightly in SW children (47-43%) and markedly in SV children (50-33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (≥3 clinic visits) when BMIHA was applied, whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMIHA occurred before age 10 and there was no association with hydrocortisone (HC) or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3·3 years and in SV females by age 3·8 years, over a year earlier than the adiposity rebound for healthy children. CONCLUSION: Children with CAH are at higher risk for early onset obesity and overweight with or without using BMIHA but rates of persistent obesity were lower than previously reported. Careful HC dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.

Home Use of an Artificial Beta Cell in Type 1 Diabetes.

BACKGROUND: The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS: In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS: Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS: Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Deprivation and ethnicity impact on diabetes control and use of treatment regimen.

AIMS: Deprivation and/or ethnicity impact on care delivery. We have assessed how these factors influence diabetes care in a paediatric clinic. METHODS: We related access to care [type of insulin treatment regimen-twice daily, multiple daily injections and insulin pump therapy (continuous subcutaneous insulin infusion)], measures of care process (HbA(1c)) and an approximate measure of satisfaction with the service (clinic attendance rate) in 325 (170 male) children and young people with Type 1 diabetes (mean age 10.6 years, mean duration of diabetes of 4.5 years), with indices of deprivation and ethnicity. RESULTS: Of the 325 children and young people, 2.7% received twice-daily insulin, 48.4% multiple daily injections and 48.9% continuous subcutaneous insulin infusion. Median clinic HbA(1c) was 62 mmol/mol (7.8%) and those receiving the insulin pump therapy had the lowest HbA(1c). Four ethnic groups were represented; White British 81.6%, Asian non-Indian 6.5%, African 8.1% and Asian Indian 3.8%. Mean deprivation score was 21.06. White British and Asian Indian groups were more likely to receive insulin pump therapy (χ(2) = 50.3; P < 0.001). Attendance rates were 94.1% and did not differ across ethnic groups. Deprivation was related to ethnicity and HbA(1c) (R(2) = 0.02; P = 0.02). There was no relationship between clinic attendance and deprivation. Insulin regimen and ethnicity were associated with HbA(1c) (R(2) = 0.096; P < 0.001). Similar findings were obtained when analysis was confined to the White British population. CONCLUSIONS: These data suggest that deprivation and ethnicity influence diabetes control and how intensive insulin therapy is utilized. A better consideration of the needs of different ethnic groups is required to ensure equitable care delivery in paediatric diabetes.

The relationship between body mass index and mid-arm circumference in a pregnant population.

Our objective was to correlate body mass index (BMI) with mid-arm circumference (MAC) and also to ascertain whether maternal BMI could be calculated from MAC at booking. We approached all Caucasian women who met the inclusion criteria attending the University College Hospital, London between 1 April 1996 and 30 June 1997 and the Rotunda Hospital, Dublin, Ireland between 15 April 2003 and 19 May 2004. A total of 2,912 women agreed to participate in the research. The participants' maternal height and weight were measured. Their BMI was calculated using the formula: BMI = weight (kg) ÷ height (m(2)). The MAC was measured in cm. Statistical analysis was performed using SPSS for Windows version 11 with p < 0.05 as significant. We found that BMI is directly correlated with MAC (r = 0.836) and estimates of BMI may be calculated from the simple equation BMI = MAC ± 2. Alternatively, a MAC of ≥ 27 cm allowed for a detection rate for overweight patients of 75%, with a false positive rate of 15%.

Use of intravenous etomidate to control acute psychosis induced by the hypercortisolaemia in severe paediatric Cushing's disease.

BACKGROUND: Psychosis secondary to paediatric Cushing's disease (CD) is extremely rare and presents a significant management challenge. METHOD: We report a 14.7-year-old CD patient with acute psychosis and self-inflicted injuries following failed transsphenoidal pituitary surgery. Her mental state rapidly deteriorated precluding medical therapy. RESULTS: Emergency intravenous low-dose etomidate infusion (3-3.5 mg/h) with dose titration according to the serum cortisol combined with a hydrocortisone infusion, in an intensive care setting, was effective in controlling the hypercortisolaemia. Her mental state improved with normalisation of her cortisol levels enabling oral administration of ketoconazole and bilateral adrenalectomy to be performed. CONCLUSION: This case illustrates the safe and effective use of a low-dose etomidate infusion in an unusual case of paediatric CD.

Do centimetres matter? Self-reported versus estimated height measurements in parents.

AIM: An impressive discrepancy between reported and measured parental height is often observed. The aims of this study were: (a) to assess whether there is a significant difference between the reported and measured parental height; (b) to focus on the reported and, thereafter, measured height of the partner; (c) to analyse its impact on the calculated target height range. METHODS/RESULTS: A total of 1542 individual parents were enrolled. The parents were subdivided into three groups: normal height (3-97th Centile), short (<3%) and tall (>97%) stature. Overall, compared with men, women were far better in estimating their own height (p < 0.001). Where both partners were of normal, short or tall stature, the estimated heights of their partner were quite accurate. Women of normal stature underestimated the short partner and overestimated the tall partner, whereas male partners of normal stature overestimated both their short as well as tall partners. Women of tall stature estimated the heights of their short partners correctly, whereas heights of normal statured men were underestimated. On the other hand, tall men overestimated the heights of their female partners who are of normal and short stature. Furthermore, women of short stature estimated the partners of normal stature adequately, and the heights of their tall partners were overestimated. Interestingly, the short men significantly underestimated the normal, but overestimated tall female partners. CONCLUSION: Only measured heights should be used to perform accurate evaluations of height, particularly when diagnostic tests or treatment interventions are contemplated. For clinical trails, we suggest that only quality measured parental heights are acceptable, as the errors incurred in estimates may enhance/conceal true treatment effects.

A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency.

AIMS: To determine the effectiveness of different doses of r-hGH therapy during puberty in children with growth hormone deficiency (GHD). METHODS: Randomized controlled trial of different doses of r-hGH therapy administered during puberty in 49 children with GHD. The patients were allocated randomly using a random number table to one of two groups: group 1 (15 IU/m(2)/week) or group 2 (30 IU/m(2)/week). Patients were included if they had received r-hGH daily at a dose of 15 IU/m(2)/week (0.7 mg/m(2)/day) for at least 1 year before randomization. RESULTS: Height increase standard deviation scores (SDS) were similar between the two groups (group 1: 1.1; group 2: 1.2; p = 0.81). CONCLUSION: A higher dose of r-hGH administered during puberty does not appear to have a significant effect on final height of children with GH deficiency. Altering pubertal tempo or intensifying prepubertal r-hGH therapy may be a more promising approach to improving final height in children with GH deficiency.

A randomised study of the effect of two doses of biosynthetic human growth hormone on final height of children with familial short stature.

BACKGROUND/AIMS: The effects of biosynthetic human growth hormone (r-hGH) in children with familial short stature (FSS) are varied. We determined whether responsivity to r-hGH in FSS is dose-dependent. METHOD: Randomised trial of two doses (20 or 40 IU/m(2) body surface area/week by daily subcutaneous injection) of r-hGH in 29 (24 male, 5 female) FSS children with assessment at adult height. RESULTS: Age range at presentation was 5.1-10.5 years, height less than 1.5 standard deviation scores (SDS) below the mean, height velocity SDS greater than -1.5 and peak growth hormone response to provocative testing over 13.5 mU/l. Adult height data (SDS) at 16.5 +/- 2.1 years for the low-dose group and 16.1 +/- 1.1 years for the high-dose group (p = 0.62) were similar [low dose -1.06 (SD 0.75), high dose -1.02 (SD 0.83); p = 0.88]. The incremental effect of both doses on stature was minimal [low-dose difference in height actual-predicted 0.79 (SD 0.94), high dose 1.27 (SD 0.88); p = 0.12]. CONCLUSION: Using this r-hGH dosing schedule there were little short- or long-term effects on height in children with FSS.

Childhood body mass index (BMI), breastfeeding and risk of Type 1 diabetes: findings from a longitudinal national birth cohort.

AIMS: To perform a longitudinal analysis of the association between childhood body mass index (BMI) and later risk of Type 1 diabetes, controlling for socio-economic status, birthweight, height in early and late childhood, breastfeeding history and pubertal status. METHODS: Analysis of the 1970 British Birth Cohort, followed up at age 5, 10 and 30 years (n = 11,261). Data were available on birthweight, breastfeeding; height, weight, pubertal status, socio-economic status at age 10 years; self-report data on history of diabetes (type, age at onset) at age 30 years. Cox proportional hazards models were used to examine relations of childhood growth, socio-economic status and breastfeeding history to the incidence of Type 1 diabetes between 10 and 30 years of age. RESULTS: Sixty-one subjects (0.5%) reported Type 1 diabetes at 30 years of age; 47 (77%) reported onset >or= age 10 years. Higher BMI z-score at 10 years predicted higher risk of subsequent Type 1 diabetes (hazard ratio 1.8, 95% confidence interval 1.2 to 2.8, P = 0.01) when adjusted for birthweight, pubertal status, breastfeeding history and socio-economic status. Repeating the model for childhood obesity, the hazard ratio was 3.1 (1.0, 9.3; P = 0.05). Birthweight, breastfeeding, height growth and pubertal timing were not associated with incidence of Type 1 diabetes. CONCLUSIONS: Higher BMI in childhood independently increased the risk of later Type 1 diabetes, supporting suggestions that obesity may provide a link between Type 1 and Type 2 diabetes. This supports observations of a rise in Type 1 diabetes prevalence. Reduction in childhood obesity may reduce the incidence of Type 1 as well as Type 2 diabetes.

Plasma aldosterone response to the low-dose adrenocorticotrophin (ACTH 1-24) stimulation test.

BACKGROUND: Endocrine tests for adrenal insufficiency use pharmacological doses of stimulant such as ACTH. More physiological tests have often used high-dose protocols for sampling frequency. AIMS: To evaluate the response of plasma aldosterone concentration to low doses (125, 250 and 500 ng/m(2) body surface area) of synthetic ACTH. DESIGN: A randomised trial in six normal adult males aged 18-27 years. MATERIALS AND METHODS: Aldosterone concentration was measured by radioimmunoassay in serum from blood samples taken at 10 min intervals for 90 min. RESULTS: All three doses produced a significant rise in plasma aldosterone concentration (125 ng/m(2), P = 0.003; 250 ng/m(2), P < 0.001; 500 ng/m(2), P < 0.001) but there was no effect of dose on either the peak or incremental plasma aldosterone concentration. Mean time to peak was similar between the doses and the two higher doses were associated with a longer secretory profile (125 ng/m(2) 56 (26 SD) mins, 250 ng/m(2) 74 (19) mins, 500 ng/m(2) 77 (21) mins; F = 3.39; P = 0.04). Peaks of 100% were detected within 30 min of drug administration and peak response was associated with the prestimulation plasma aldosterone concentration (r = 0.45; P = 0.003). The between- and within-individual coefficients of variation for prestimulation concentrations were 37.0% and 32.8%, and for the peak response were 27.2% and 27.2%, respectively. CONCLUSIONS: The response of plasma aldosterone concentrations to low-dose ACTH administration requires a blood sampling protocol of 0, 10, 20 and 30 min to capture concentrations near the peak response. The high-dose protocol would have missed the response. Over the dose range studied no dose-response was observed so the selection of dose should be based on the dose effective to release steroids in the glucocorticoid pathway if this study is to be used in conjunction with such evaluation.

Management of neonatal endocrinopathies--best practice guidelines.

Neonatal emergencies are uncommon, but may lead to significant morbidity and mortality if not recognised and managed promptly. Disorders of sex development, hypoglycaemia, thyrotoxicosis and calcium balance are discussed, with emphasis on the clinical assessment, investigations and management of these disorders in the acute setting.

A method for assessing quality of control from glucose profiles.

AIM: As the practice of multiple assessments of glucose concentration throughout the day increases for people with diabetes, there is a need for an assessment of glycaemic control weighted for the clinical risks of both hypoglycaemia and hyperglycaemia. METHODS: We have developed a methodology to report the degree of risk which a glycaemic profile represents. Fifty diabetes professionals assigned risk values to a range of 40 blood glucose concentrations. Their responses were summarised and a generic function of glycaemic risk was derived. This function was applied to patient glucose profiles to generate an integrated risk score termed the Glycaemic Risk Assessment Diabetes Equation (GRADE). The GRADE score was then reported by use of the mean value and the relative percent contribution to the weighted risk score from the hypoglycaemic, euglycaemic, hyperglycaemic range, respectively, e.g. GRADE (hypoglycaemia%, euglycaemia%, hyperglycaemia%). RESULTS: The GRADE scores of indicative glucose profiles were as follows: continuous glucose monitoring profile non-diabetic subjects GRADE = 1.1, Type 1 diabetes continuous glucose monitoring GRADE = 8.09 (20%, 8%, 72%), Type 2 diabetes home blood glucose monitoring GRADE = 9.97 (2%, 7%, 91%). CONCLUSIONS: The GRADE score of a glucose profile summarises the degree of risk associated with a glucose profile. Values < 5 correspond to euglycaemia. The GRADE score is simple to generate from any blood glucose profile and can be used as an adjunct to HbA1c to report the degree of risk associated with glycaemic variability.

Polymorphisms in the angiotensin converting enzyme gene and growth in the first year of life.

Abnormal patterns of fetal and infant growth have been associated with an increased risk of cardiovascular disease in adulthood. Catch-up growth during the first year of life has been associated with a higher prevalence of type 2 diabetes mellitus, whereas a lack of catch-up growth tracks with a risk of hypertension. The role of genetic factors influencing both growth and blood pressure have not been explored. We genotyped cord blood samples from 530 singleton, Caucasian, uncomplicated pregnancies, drawn from a larger cohort of 1650 pregnancies, and related polymorphism in the angiotensin converting enzyme (ACE) gene (alleles insertion (I) or deletion (D)) with measures of size at birth and at age of 1 year. ACE genotype did not significantly influence size at birth, although there was a greater proportion of individuals with the D/D genotype born with a birth weight less than the 10th centile (P=0.004). The ACE I/I genotype was significantly associated with higher weight (p=0.001), body mass index (p=0.001) and mid arm circumference (p=0.001) at 1 year of age compared to the ACE D/D and I/D genotypes. Individuals with the I/I genotype displayed catch-up (gain from birth size of >or=0.6 Standard Deviation Score) in weight (p=0.04), body mass index (p=0.03) and mid arm circumference (p=0.03) compared to the D/D group, the majority of which showed no change or catch-down. The I/D genotype was distributed equally across the catch up/catch down/no change categories. The effect was more marked in males, but ACE genotype and sex of the infant contributed independently to mid arm circumference measurements and there was no interaction between the two. There was no effect of maternal or paternal ACE genotype on birth size. In a multiple linear regression model ACE genotype, socioeconomic status and sex of the infant explained 10.9% of the variance in body mass index SDS at 1 year of age. We conclude that the ACE I/I genotype is associated with a higher weight and body mass index SDS at 1 year of age, along with catch-up in terms of these measures from birth to 1 year. The D/D genotype is associated with a greater proportion of babies, born at term, that at small for gestational age. These results suggest that due consideration should be given to the underlying genotype of an individual when evaluating the association of early human growth with the development of risk factors for cardiovascular disease. The observation of independent effects of genotype, sex of the individual and socioeconomic status on postnatal growth suggests the need to develop methodologies for the integration of genetic and environmental factors in causality modelling.

Normal and abnormal fetal growth.

The fetal origins of adult disease hypothesis suggests that poor intrauterine growth is associated with an increased risk of cardiovascular disease. The hypothesis goes on to implicate different growth 'phenotypes', particularly disproportionate growth, in the determination of the type of cardiovascular disease that develops. Analysis of the antenatal growth of a low-risk pregnancy population does not identify such growth phenotypes within the general population. Rather, intrauterine growth is characterized by poor predictability of subsequent size, suggesting that centile crossing is a common feature of intrauterine growth. Furthermore, there is a sexually dimorphic pattern to this growth that needs to be considered in further work to test the fetal origins hypothesis.

The impact of hormone physiology on clinical practice with reference to two papers spanning 40 years of endocrinology.

Following the pioneering work of Roger Ekins in describing the methodology for radioimmunoassay of hormone concentrations in plasma a series of publications followed describing variation in plasma hormone concentrations in a number of diseases. Though fluctuations in hormonal concentrations had been suspected, it was not until Hunter and Rigal documented these for the GH axis that it became apparent that the preferred mode of signalling for many hormone systems and in particular the anterior-pituitary hormones was of a pulsatile nature.

Disturbed adrenal function in adolescents with chronic fatigue syndrome.

OBJECTIVE: To investigate adrenal function in children and adolescents with chronic fatigue syndrome (CFS) compared with age-matched controls. METHODS: Case-control study of low dose (500 ng/m2) synacthen tests (LDST) in 23 adolescents with CFS and 17 age-matched controls. Serum cortisol concentrations were measured at 5-min intervals from 10 to 45 minutes. Peak serum cortisol concentration, time to peak, rise in cortisol and area under the curve (AUC) were derived. RESULTS: Patients with CFS had significantly lower mean cortisol levels during the LDST (p <0.001), lower peak cortisol (p <0.025), reduced cortisol AUC (p <0.005) and longer time to peak cortisol (p <0.05). Abnormalities were seen in both sexes but were more pronounced in females. Unstimulated adrenal androgen and 17-hydroxyprogesterone concentrations were normal. CONCLUSIONS: Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on hypothalamic-pituitary-adrenal axis regulation between the sexes.

Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia.

BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due to PNAH. PATIENTS: Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied. RESULTS: All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based on elevation of sleeping midnight serum cortisol and urinary free cortisol excretion, and impaired suppression of cortisol on both low- and high-dose dexamethasone suppression tests (DST). All patients had undetectable plasma ACTH with absent responses of both plasma ACTH and serum cortisol to an intravenous (i.v.) corticotrophin-releasing hormone (CRH) test. Computed tomography or magnetic resonance imaging showed normal or small adrenals, with nodules in two patients. All patients underwent bilateral adrenalectomy, performed by open (n = 2) or laparoscopic surgery (n = 4) at a mean of 0.4 years (range 0.2-0.8 years) from diagnosis. Hypercortisolaemia was treated preoperatively by metyrapone alone 0.50-0.75 g/day (n = 4), metyrapone 0.75-1.50 g/day + o'p'DDD/mitotane 1-2 g/day (n = 1), or ketoconazole (n = 1). Adrenal histology showed nodular cortical hyperplasia with shrinkage of intervening cortical tissue and pigmentation, present in four patients. Molecular analysis of the type 1-alpha regulatory subunit of protein kinase A (PRKAR1A) gene revealed a novel germline mutation in one patient. Postadrenalectomy, three patients, had catch-up growth with height velocities increasing from 3.0, 3.9 and 2.5-8.9, 8.3 and 9.0 cm/years, respectively. All six are well at a follow-up (mean 4.0 years; range 0.5-10.8 years). CONCLUSIONS: PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.

Growth hormone (GH) provocation tests and the response to GH treatment in GH deficiency.

OBJECTIVE: To identify factors, particularly the growth hormone (GH) provocation test result, affecting growth response to GH treatment in children with GH deficiency (GHD). SUBJECTS: A total of 337 prepubertal GHD patients aged <10 years from the UK Pharmacia KIGS database (GH response to provocation test <20 mU/l). OUTCOME MEASURE: Annual change in height standard deviation score (SDS) (revised UK reference) in the first and second years of treatment. RESULTS: Height increased by 0.74 SDS units (SD 0.39) in the first year of treatment and 0.37 units (SD 0.27) in the second. Adjusting for age, height, weight, midparent height, and injection frequency, the strongest predictor of first year growth response was the GH provocation test result; halving the result predicted an extra height increment of 0.09 units (p<0.0001). It predicted the second year response less well (p<0.0002) and after adjusting for the first year response was not predictive at all. CONCLUSIONS: Among patients referred for possible GHD, the GH provocation test, though not a gold standard for diagnosis, is a valuable predictor of growth response in the first year of treatment. A year's treatment is recommended for cases with a marginal provocation test result, with the option to continue treatment if the response is adequate. The value of unified protocols for single or repeated provocation tests needs to be assessed.

Sexual dimorphism in the synchrony of joint growth hormone and cortisol dynamics in children with classic 21-hydroxylase deficiency.

In humans, growth hormone (GH) and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/insulin-like growth factor (IGF)-I axis and hypothalamic-pituitary-adrenal (HPA) axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female children with classic CAH. Thirty-eight children with classic 21-hydroxylase deficiency (M: 13, F: 25; age range: 6.1-18.8 yr) were studied prospectively. Serum GH and cortisol concentrations were determined at 20 min intervals for 24 hours. The irregularity of GH and cortisol pattern was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol dynamics was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol concentrations was computed at various time lags covering the 24-h period. There was no gender difference in mean 24-hour serum GH (males vs females: 5.25 +/- 4.72 vs 4.44 +/- 2.64 mIU/l) or cortisol (156.2 +/- 44.6 vs 172.0 +/- 58.5 nmol/l) concentrations. For GH, ApEn values were significantly higher in females (0.66 +/- 0.14) than in males (0.53 +/- 0.16) (p = 0.009). No difference in cortisol ApEn values was noted between sexes (0.53 +/- 0.21 vs 0.54 +/- 0.12). Cross-ApEn values of paired GH-cortisol, with cortisol leading GH, were significantly higher in females (0.94 +/- 0.14) than in males (0.83 +/- 0.20) (p = 0.03). These findings suggest that females with classic 21-hydroxylase deficiency have a more irregular pattern of GH secretion and a more asynchronous joint GH and cortisol dynamics than their male counterparts.