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.

Enhancement of growth hormone bioactivity by zinc in the eluted stain assay system.

The effects of ionic zinc (Zn2+) on human (h) GH bioactivity have been examined using a lactogenic bioassay. The potencies of pituitary-derived hGH (IRP 80/505), recombinant 22K hGH (IRP 88/624), pituitary-derived human PRL (IRP 84/500), and a recombinant methionyl 20-kilodalton variant of hGH in the presence of selected concentrations of ZnCl2 were investigated with an eluted stain assay that uses Nb2 rat lymphoma cells. This precise colorimetric bioassay is based upon the reduction of a yellow tetrazolium salt, 3-[4,5-dimethyl-thiazol-2-yl]2,5-di-phenyl-tetrazolium bromide, to its purple formazan by lactogen-activated Nb2 cells. Zinc (6-100 microM) enhanced the bioactivity of low doses (< 0.045 nM) of both pituitary-derived and recombinant 22K hGH, although the magnitude of enhancement was considerably less than might have been anticipated from previous binding studies (13). Higher concentrations of pituitary-derived hGH (> 0.045 nM) were inhibited by Zn2+. The bioactivity of recombinant methionyl 20K hGH was greatly enhanced by zinc (3-100 microM). In contrast to hGH, the bioactivity of hPRL was not potentiated by Zn2+. These discriminatory effects of Zn2+ when stimulating via the lactogenic receptor are in concordance with the results of previous radioligand binding studies (13). The striking enhancement of 20K hGH lactogenic bioactivity was observed at Zn2+ concentrations within the physiological range for normal human serum (5-20 microM).

Hexarelin-induced growth hormone, cortisol, and prolactin release: a dose-response study.

Dose-response data for GH-releasing peptides are limited. We studied the effects of varying doses (0-1.0 microgram/kg) of hexarelin, a novel GH-releasing peptide, administered iv to healthy adult males on GH, PRL, and cortisol release. In addition, we studied the effect of administration of a single dose of GHRH-(1-29)-NH2 (1.0 microgram/kg), alone or in combination with a low dose of hexarelin (0.125 microgram/kg). Dose-response curves for the maximum GH response and maximum percent change in serum PRL and cortisol concentrations from baseline were constructed. The GH dose-response curve reached a plateau of 140 mU/L, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.48 +/- 0.02 microgram/kg (mean +/- SEM). The PRL dose-response curve reached a plateau of 180% for the maximum percent rise from baseline, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.39 +/- 0.02 microgram/kg. The cortisol dose-response curve showed a step increase to approximately 40% at a hexarelin dose of 0.5 microgram/kg. The coadministration of GHRH-(1-29)-NH2 (1.0 microgram/kg) and low dose hexarelin (0.125 microgram/kg) resulted in massive GH release (115 +/- 32.8 mU/L), a moderate rise in serum PRL (84.9 +/- 27.5%), and no rise in serum cortisol. These data show that iv hexarelin was capable of inducing GH, PRL, and cortisol release in a dose-dependent manner. Low dose hexarelin was synergistic with GHRH and potent for GH release with a minimal effect on other hormones.

Isolated growth hormone deficiency: analysis of the growth hormone (GH)-releasing hormone gene and the GH gene cluster.

Isolated GH deficiency (IGHD) cannot be distinguished on the grounds of anti-human (h) GH antibodies and stunted growth response to exogenous hGH. DNA analysis was proposed to classify children with IGHD. Genomic DNA was extracted and studied by restriction endonuclease analysis after extraction from the circulating lymphocytes of 53 children with IGHD. These children included 5 pairs of siblings and 5 individuals from 10 families, whose parents (n = 20) and brothers and sisters (n = 5) were also analyzed. Twenty-five adults, including individuals from 3 families of normal height, were studied as controls. No deletion within the hGH gene cluster was identified using a [32P]hGH cDNA clone as a probe. A compound heterozygosity for a hGH-1 deletion or a mutation have not been found. The allelic frequencies for 5 common restriction fragment length polymorphisms were similar in patients and controls. The distribution and frequency of the distinct haplotypes in the hGH gene family revealed no differences between IGHD (n = 30 chromosomes) and controls (n = 48 chromosomes). No deletion or restriction fragment length polymorphisms could be found using a hGH-releasing hormone cDNA clone as a probe in patients or controls. This large volume of data gathered from a caucasian population indicates that the great majority of patients with IGHD has no structural abnormalities of the hGH gene cluster, particularly no hGH-1 gene deletion. In addition, they have no gross deletions within the hGH-releasing hormone gene.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty.

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis. We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m(2) body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1--10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6--16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2--20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9 alpha-fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA. The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; SD, 133.4) compared with the prepubertal (mean, 248.7 mL/min; SD, 100.6) and postpubertal (mean, 292.4 mL/min; SD, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; SD, 12.2) than the prepubertal (mean, 27.1 L; SD, 8.4) patients but not in the postpubertal (mean, 40.8 L; SD, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; SD, 19.4), pubertal (mean, 84.4 min; SD, 24.9), and postpubertal (mean, 96.7 min; SD, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04). These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.

The effect of changing gonadotropin-releasing hormone pulse frequency on puberty.

We have examined the effect of using different pulse frequencies of exogenous GnRH to induce puberty and the time relationship among LH, FSH, sex steroids, and GH in these individuals. Five girls and three boys with delayed puberty received exogenous GnRH at either 3-h frequency (slow) or every 45 min (fast). Treatment was initially given overnight and increased to 24 h when breast stage 3 in girls or testicular volume of 10 mL in boys was attained. Twenty-four-hour gonadotropin profiles were performed after 5 days, 1 month, 3 months, 6 months, and 1 yr of treatment. Temporal relationships among LH, FSH, and estradiol; LH and testosterone; GH and estradiol; and GH and testosterone were examined by cross-correlation. There was no difference in the rate of pubertal progress between the groups. Mean serum gonadotropin and sex steroid levels did not differ. LH was correlated with estradiol for both groups at 240 min (slow group, r = 0.54; fast group, r = 0.50). Estradiol correlated with LH at 300 min in the slow group (r = -0.41) and 200 min in the fast group (r = -0.37). FSH correlated with estradiol at 140 min in the slow group (r = 0.62) and 160 min in the fast group (r = 0.50). A rise in estradiol occurred 140-160 min after a rise in FSH and 240 min after a rise in LH. A rise in estradiol was followed 200-300 min later by a fall in LH. LH was correlated with testosterone at 60 min in the slow group (r = 0.73) and at 40 min in the fast group (r = 0.55). Testosterone correlated with LH at 420 min in the slow (r = -0.67) and 460 min in the fast group (r = -0.40). A rise in LH was followed 40-60 min later by a rise in testosterone. A rise in testosterone was followed by fall in LH 420-460 min later. GH correlated with estradiol at 320 min in the slow group (r = 0.37) and 380 min in the fast group (r = 0.38). A rise in GH was followed, after 320-380 min, by a rise in estradiol. There was a correlation between GH and testosterone in the slow group after 280 min (r = 0.44). A rise in GH was followed by a rise in testosterone after 280 min. The pituitary-gonadal axis is sufficiently robust to allow puberty to progress with different fixed pulse frequencies. There is a temporal relationship among LH, FSH, and estradiol secretion and between LH and testosterone secretion. We have demonstrated the feedback effect of sex steroids at the level of the pituitary and the time course of the effect of GH on gonadal function.

The measurement of growth hormone bioactivity in patient serum using an eluted stain assay.

We have adapted the MTT-ESTA bioassay for human GH (hGH) to measure the lactogenic bioactivity of the hormone in human serum. This highly quantitative in vitro colorimetric bioassay is based upon the reduction of a tetrazolium salt, 3-[4,5-dimethyl-thiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT), to its formazan by lactogen-activated Nb2 cells. Relatively high concentrations of human serum (1-10%) modified responses to the hormone in a complex manner. As the serum effects varied between samples, it proved impossible to adapt the bioassay by the conventional approach of using a lactogen-depleted serum as a representative matrix. However, as the Nb2 cells were exceptionally sensitive to hGH, the serum effects could be diluted out. We adopted a dilution strategy by which all samples of human serum were included in the bioassay at a concentration of 0.625% or less. A valid assay was obtained, as judged by the criteria of parallelism between diluted samples and hGH standards, and recoveries of spiked samples that were close to 100%. Hormonal specificity was achieved with the use of a highly specific anti-PRL antiserum. A within-assay precision of between 2-5% over the dose range of 0.03-0.96 microgram hGH/L was attained. As only highly diluted samples could be used, the sensitivity of the clinical bioassay was 1.2-2.4 micrograms hGH/L. The between-assay precision was estimated to be 11% and 9% at initial hGH concentrations in serum of 4.8 and 19.2 micrograms hGH/L, respectively. By exploiting the high sample capacity of the eluted stain bioassay system, we followed the changes in bioactivity and immunoactivity of hGH in multiple timed samples after stimulation of hGH secretion in an adult by GHRH. Systematic and progressive changes were observed in the bioactive/immunoactive ratios. Analogous changes were observed after insulin-induced hypoglycemia in a child with short stature. We speculate that the changes in the bioactive/immunoactive ratios reflect alterations in the proportions of the isoforms of hGH in the circulation after acute stimulation.

The effect of changing somatostatin tone on the pituitary growth hormone and thyroid-stimulating hormone responses to their respective releasing factor stimuli.

Somatostatin (SS) inhibits GH and TSH secretion, but its role in modulating their pulsatility is unclear. We studied GH and TSH responses to GH-releasing hormone (GHRH) and TRH stimulation upon a variable background infusion of saline, SS-(1-14) at 20 and 100 micrograms/m2.h, and oral pyridostigmine (30 and 60 mg) in six adult males. Basal GH levels were unaffected by SS-(1-14). Deconvolution analysis of serum GH values demonstrated that the pituitary responded to two GHRH stimuli 90 min apart without attenuation of the second response. The higher dose of SS-(1-14) significantly blunted the first GH response; second GH responses were further attenuated by both SS-(1-14) doses. Maximum GH release and "switch-off" rates for both stimuli were reduced without changes in the 50% secretion time. Pyridostigmine enhanced the first GH response to GHRH with an increase in the GH release rate; second GH responses were not augmented. GH secretion was prolonged by pyridostigmine, although the 50% secretion time remained unchanged. Peak stimulated serum TSH was attenuated by both SS-(1-14) doses, but pyridostigmine had no effect. All other TSH parameters examined were unaffected. We conclude that the GH response to GHRH is dependent on SS tone, but that the thyrotroph is not tonically inhibited by SS. SS attenuates the rate of GH release without changing the duration of secretion and appears important in terminating GH secretion.

Peak and trough growth hormone concentrations have different associations with the insulin-like growth factor axis, body composition, and metabolic parameters.

GH is secreted in a pulsatile fashion, promoting growth and anabolism. The components of the pulsatile signal involved in these diverse effects are unclear. We constructed (20-min sampling interval) and analyzed 24-h serum GH profiles in 45 adult male volunteers, 59.4-69.9 yr old, body mass index (BMI) 21.9-36.5 Kg/m2, using Fourier transformation and a concentration distribution analysis that determines the concentration at or below which the serum GH concentrations in the 24-h profile spend a percentage of the total time. The observed concentrations (OC) below which 95% and 5% of the values in the time series lie [lsb]OC95 (peaks) and OC5 (troughs)] and mean 24-h serum GH concentrations were related to measures of the insulin-like growth factor (IGF) family, parameters of body composition, fasting insulin and cholesterol measures, and GH-binding protein concentrations. Mean 24-h serum GH concentrations ranged between 0.19 and 2.15 mU/L (1 microgram/L = 2.6 mU/L). Pulse periodicity was between 180 and 200 min. There was a positive relationship between peak GH levels and serum IGF-1 and IGFBP-3 levels (r = 0.39; P = 0.009 and r = 0.32; P = 0.03, respectively). GH trough levels were unrelated to these measures of the IGF family. In contrast, GH troughs were related inversely to BMI (r = -0.31; P = 0.04) and waist-hip ratio (r = -0.4; P = 0.006). Peak GH levels were not related to these measures. Factors known to influence these measures, fasting insulin concentration, or cortisol secretion did not alter the trough GH relationship in multiple regression analysis. All GH parameters were related inversely to fasting insulin concentration. Although GH parameters were related inversely to cholesterol and low-density lipoprotein-cholesterol, this effect disappeared when age and fasting insulin levels were introduced into the regression. GH-binding protein levels related most strongly to BMI (r = 0.60; P < 0.001), with no effect of any GH parameter observed in multiple regression analysis. These results suggest that the peak values of a GH concentration profile may influence the IGF axis, whereas trough values may influence body composition and metabolic parameters of GH action.

Cortisol, androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS) and 17 hydroxyprogesterone (17OHP) responses to low doses of (1-24)ACTH.

The dose of 250 microg used in the standard short synacthen test is supraphysiological and lower doses may provide a more sensitive test. We examined steroid responses to 125ng/m2, 250ng/m2 and 500 ng/m2 (1-24)ACTH in 6 normal males, looking at effects of dose and the within- and between-subject coefficients of variation (CV). Subjects were given each dose 3 times, blood samples were taken at 10 minute intervals. There was a dose response relationship between dose of (1-24)ACTH and peak values for cortisol and 17OHP (p<0.05). There was no difference between peaks of A4 at different doses and no clear peaks were reached for DHEAS. 86% of the peaks for 17OHP, 63% for A4 and 25% for cortisol were at 10 minutes and 14%, 29% and 65% respectively at 20 mins (p=0.001). Within-subject CV for cortisol was 12.6% and between subject 10.1%. Tests of adrenal function using low doses of (1-24)ACTH have acceptable between- and within-subject CV for peak values with a dose as low as 125 ng/m2 (1-24)ACTH. Protocols for low dose synacthen tests, with traditional sampling at zero, 30 and 60 minutes or even as shown here at 10 minute intervals, fail to fully define the changes in steroid levels following adrenal stimulation. More frequent blood sampling will be needed to accurately detect peak levels in particular of 17OHP and A4.

Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.

A sexually dimorphic pattern of growth hormone secretion in the elderly.

In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4-73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio. Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn). There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/ mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = -0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = 0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = -0.40; P = 0.006; females: r = -0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = -0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.

Growth hormone treatment of children with brain tumors and risk of tumor recurrence.

GH is increasingly used for treatment of children and adults. It is mitogenic, however, and there is therefore concern about its safety, especially when used to treat cancer patients who have become GH deficient after cranial radiotherapy. We followed 180 children with brain tumors attending three large hospitals in the United Kingdom and treated with GH during 1965-1996, and 891 children with brain tumors at these hospitals who received radiotherapy but not GH. Thirty-five first recurrences occurred in the GH-treated children and 434 in the untreated children. The relative risk of first recurrence in GH-treated compared with untreated patients, adjusted for potentially confounding prognostic variables, was decreased (0. 6; 95% confidence interval, 0.4-0.9) as was the relative risk of mortality (0.5; 95% confidence interval, 0.3-0.8). There was no significant trend in relative risk of recurrence with cumulative time for which GH treatment had been given or with time elapsed since this treatment started. The relative risk of mortality increased significantly with time since first GH treatment. The results, based on much larger numbers than previous studies, suggest that GH does not increase the risk of recurrence of childhood brain tumors, although the rising trend in mortality relative risks with longer follow-up indicates the need for continued surveillance.

The somatotropic axis in puberty.

Sex steroids markedly affect GH pulsatility by altering GH pulse amplitude without affecting GH pulse frequency. The type of sex steroid (testosterone or estrogen) appears to determine the timing of the pubertal growth spurt although both steroids appear to influence the amount of GH released from the pituitary. GH levels also affect gonadal secretion of sex steroids. The effects of the two are synergistic, but there is a real therapeutic dilemma of what to increase and when in children who are deficient in either GH or gonadotrophin secretion. Augmented GH pulsatility, particularly during the day, may alter markedly the interpretation of standard endocrine tests. Finally, the insulin resistance arising from an increased circulating concentration of GH may have important implications for the management of insulin-dependent diabetes during puberty.

Birth weight influences the initial response to growth hormone treatment in growth hormone-insufficient children.

OBJECTIVE: To determine the influence of birth weight on the first year response to growth hormone (GH) replacement in children with isolated GH insufficiency. STUDY DESIGN: A longitudinal study of response to daily GH treatment (15-26 IU/m2/week) was performed in 16 singleton Caucasian prepubertal children (11 boys, 5 girls) with isolated GH insufficiency (peak GH response to insulin tolerance test <13.5 mU/L) attending a pediatric endocrinology clinic. Change in height velocity standard deviation scores, during the 6 to 12 months before starting GH and the 12 months after, were used to reflect responsivity to GH treatment. Potential influencing variables considered by regression analysis were birth weight standard deviation score (BWSDS), peak GH response to insulin tolerance testing, midparental height standard deviation score, age at treatment, and dose of GH administered. RESULTS: Mean BWSDS was -0.51 (SD, 1.0). Change in height velocity standard deviation score was correlated positively with BWSDS (r = 0.64) and negatively with peak GH (r = -0.59). Stepwise linear regression analysis confirmed the influence of BWSDS on response to GH treatment. CONCLUSIONS: The continuum of birth weight influences initial responsivity to GH treatment in GH-insufficient children. This may reflect relative insensitivity in the growth hormone or insulin-like growth factor axis. The influence of birth weight on final height and benefit of using higher doses of GH in these children remains to be seen.

An evaluation of hormonal changes at puberty in man.

The pulsatile nature of the secretion of gonadotrophins, sex steroids and growth hormone are important in both the onset and maintenance of sexual maturation. The night-time is intimately related to the endocrine events which result in puberty, such that hormone measurements during the daytime have little meaning. This relationship between the night-time and gonadal function is not restricted to puberty but continues in adult life; the onset of the preovulatory LH surge occurs in the early hours of the morning. Girls seem more sensitive to small changes in GnRH concentrations than boys, which is why the physical signs of puberty appear slightly earlier in them. Low levels of oestradiol appear to assist growth hormone secretion, whereas higher levels of testosterone are required for the same effect. This probably explains the sex differences in the timing of the pubertal growth spurts.

Growth and growth hormone secretion.

Growth hormone pulse amplitude is intimately connected with growth in childhood. Its effects are most clear in middle childhood, although the influence of adrenal androgens is probably also important. In infancy, nutrition plays an important part and, in the adolescent growth spurt, the synergism with sex steroids is important. Detailed attention needs now to be focussed on the mechanisms by which growth hormone is secreted and has its action; these include the effects of GHRH, somatostatin, insulin and IGF-I.

Dose-response curves for treatment with biosynthetic human growth hormone.

We have studied the effect of varying doses of biosynthetic human GH on the growth response over the first year of therapy in 90 short prepubertal children (67 males and 23 females, aged 3.1-12.9 years). As pretreatment height velocity was the predominant determinant of response, the children were divided into three groups on the basis of their pretreatment height velocity standard deviation scores (SDS). Group A (n = 27) had pretreatment height velocity SDS between +1.3 and -0.8 (short normal growing children), group B (n = 35) between -0.9 and -2.0 (moderate GH insufficiency) and group C (n = 28) less than -2 (severe GH insufficiency). Within each group, the dose of GH administered was the dominant factor in the regression. At a mean dose of 16 units/m2 body surface area per week, the change in height velocity SDS over the first year of therapy was +2.9 (95% confidence interval (CI) 2.4, 3.5) in group A, +4.3 (95% CI 3.9, 4.6) in group B and +7.0 (95% CI 6.0, 8.0) in group C. These values translate into increases in growth rate of 2.2, 3.4 and 5.5 cm/year for an 8-year-old in each group respectively. These results have important implications in planning the treatment of children with GH insufficiency.

Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.