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.

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.

Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours.

BACKGROUND: The evolution of anterior pituitary deficits after treatment for pituitary tumours has been largely attributed to local irradiation, but may be influenced as much by tumour mass or surgery. Other than growth hormone (GH) insufficiency, the late endocrinopathies after survival from non-central brain tumours have been little documented. The aim of this study was to investigate the hypothalamic-pituitary-adrenal (HPA) axis in long-term survivors of cranial irradiation for childhood posterior fossa tumours. PROCEDURE: We studied long-term data in patients treated prepubertally for posterior fossa brain tumours and systematically referred by radiation oncologists for growth and pubertal monitoring to the London Centre for Paediatric Endocrinology over the last 25 years. They must have undergone HPA axis assessment twice, first prepubertally at documentation of growth failure, and second at completion of growth and puberty. Data on sixteen patients (12 males, 4 females; median age: 5.7 years, range: 2.5-8.8 years), who had undergone excision surgery with high dose cranial irradiation and/or chemotherapy for childhood posterior fossa tumours, were examined. Patients were followed for a median of 11.0 (range: 6.8-21.4) years after radiotherapy. HPA axis assessment was undertaken with the insulin-induced hypoglycaemia test (ITT). Basal thyroid, cortisol and gonadal function tests were undertaken annually throughout the follow-up period and any deficits replaced. RESULTS: At each ITT, all patients mounted an inadequate GH response. By the end of the follow-up period all patients remained severely GH deficient, two (12.5%) had partial ACTH insufficiency, one (6.3%) had secondary hypothyroidism but none were gonadotropin deficient or hyperprolactinaemic. CONCLUSIONS: Unlike the severe, evolving multiple pituitary deficits after treatment of pituitary or central tumours in adults, these findings in children with posterior fossa tumours suggest that, with the exception of GH, neurotoxicity due to irradiation per se is associated with a low prevalence of anterior pituitary hormone deficiencies, even at a long follow-up. Since the children in this study were selected for assessment on the basis of growth failure, the high prevalence of GH insufficiency at first testing is to be expected; however, the early onset (within 1-3 years of irradiation) and permanence we have identified supports the view that GH is the most sensitive hormone to radiation injury.

Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by a defect in cortisol and often aldosterone secretion, and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenocortical androgen secretion. Anti-androgen therapy with flutamide is an option that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid. METHODS: We examined the pharmacokinetic parameters of hydrocortisone administered i.v. as a bolus at a dose of 15 mg/m2 in a 17.3 year-old female patient with classic CAH before and four weeks after institution of flutamide treatment by determining serum cortisol concentrations at 10 min intervals for 6 h following the i.v. bolus of hydrocortisone. RESULTS: Treatment with flutamide resulted in a decrease in cortisol clearance from 420 ml/l to 305 ml/l (27% reduction), and a decrease in volume of distribution from 51.61 to 451 (12.9% reduction). The half-life of cortisol increased from 85.3 min to 102.1 min. CONCLUSIONS: Flutamide treatment decreases cortisol clearance, thereby prolonging its half-life. These findings indicate that a reduction in the daily dose of glucocorticoid replacement may need to be considered when flutamide is added to the treatment regimen of patients receiving hydrocortisone.

Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty?

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-hydroxylase gene cause glucocorticoid and often mineralocorticoid deficiency. Despite optimal substitution therapy, control of classical CAH is often inadequate at puberty, and the problems encountered relate to hypocortisolism and/or hyperandrogenism. A number of physiological alterations in the endocrine milieu at puberty, which include alterations in the growth hormone/insulin-like growth factor axis, insulin sensitivity, as well as the activity of enzymes participating in cortisol metabolism and adrenal steroidogenesis, may account for the documented hypocortisolism and elevated androgen production, and may explain the difficulty in maintaining adequate adrenocortical suppression in pubertal patients with classical 21-hydroxylase deficiency.