G. M. Addison

A novel variant of growth hormone (GH) insufficiency following low dose cranial irradiation

objective We aimed to Investigate the effect of low dose (1800 cGy) prophylactic cranial Irradiation on physiological growth hormone secretion.

Urinary IGF and IGF binding protein‐3 in children with disordered growth

OBJECTIVE Both IGF‐l and IGFBP‐3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF‐I and IGFBP‐3 measurements in the diagnosis of children with disordered growth.

Insulin-like growth factor binding protein-3 generation : an index of growth hormone insensitivity

GH insensitivity may be an inherited condition or may arise as a consequence of disease or malnutrition. Laron syndrome is the most severe form of GH insensitivity, arising from an absent or defective GH receptor. Less severe forms of GH insensitivity, however, may exist, resulting in short stature but in few other features of Laron syndrome. We have identified a heterogeneous group of children with short stature and either high basal(>10 mU/L) or high peak GH levels (>40 mU/L) on GH provocation testing, to examine biochemical markers of GH sensitivity. These children received 4 d of GH (0.1 U/kg) and the increment in IGF-I, IGF binding protein (BP)-3, and GHBP was determined. Eight GHD children, commencing GH therapy, were recruited as positive controls. The two groups could not be differentiated by age, height SDS (SD score), height velocity SDS, or body mass index. IGF-I and IGFBP-3 generation were correlated in all children (ΔSDS IGF-Iversus ΔSDS IGFBP-3, r = 0.49, p = 0.03). Neither basal GHBP levels or the increment in GHBP were predictive of the IGF-I or IGFBP-3 response to GH. The GHI group had a significantly reduced IGFBP-3 response to stimulation with 4 d of GH (median percent increment in IGFBP-3, 26%, versus 72% in the GHD group, p = 0.03); their IGF-I response to GH was also reduced (median% increment in IGF-I 75%versus 144% in the GH deficient group), but this did not achieve significance, p = 0.06. In all children, the percentage rise orΔSDS in both IGF-I and IGFBP-3 inversely correlated with the GH peak obtained on provocation testing, the latter being the most significant determinant of GH peak. We propose that the “IGF generation test,” in particular IGFBP-3 generation, can be used in the investigation of partial GH insensitivity. Further work, however, is required to establish diagnostic criteria for partial GH insensitivity.

Changes in the urinary excretion of creatinine, albumin and N-acetyl-β-D-glucosaminidase with increasing age and maturity in healthy schoolchildren

Raised urinary levels of albumin and N-acetyl-β-D-glucosaminidase (NAG) are predictive of abnormal renal function and excretion of these substances is often expressed as a creatinine ratio. However, it is important to establish normal reference limits of albumin and NAG excretion for comparison of values from patients. For this reason, overnight excretion rates of creatinine, albumin and NAG were determined in timed overnight urine samples from 528 healthy schoolchildren (260 boys, 268 girls; 4–16 years) of normal size. There was a significant correlation with age and puberty for all substances in both sexes (P<0.01). Peak creatinine excretion occurred at 16 year in boys, at 15 years in grils and at pubertal stage 5 in both sexes. Maximum albumin excretion was seen at 15 years and genital stage 5 in boys and at 16 years and breast stage 4 in girls. Peak NAG excretion occurred earlier, at 14 years and genital stage 4 in boys and at 13 years and breast stage 3 in girls. Boys excreted significantly more creatinine compared with girls before and during puberty (reflecting greater muscle mass) (P<0.01) while excretion rates for albumin and NAG were similiar in both sexes. Height and weight combined accounted for 58% and 29% of the variation in creatinine and NAG excretion respectively, while height alone predicted 20% of variation in albumin excretion.

Linear growth in prepubertal children with atopic dermatitis

OBJECTIVE To define the evolution of prepubertal growth in atopic dermatitis and the factors influencing that growth pattern. METHODS Height and height velocity over two years, weight, triceps and subscapular skin fold thickness, and bone age were assessed in 80 prepubertal patients with atopic dermatitis and a control group of 71 healthy prepubertal school children. RESULTS Height standard deviation scores (SDS) and height velocity SDS did not differ between patients and controls, and were not influenced by body surface area affected by atopic dermatitis, topical glucocorticoid potency, or coexisting asthma. However, height SDS (r = −0.37) and height velocity SDS (r = −0.31) correlated inversely to age in patients but not in controls. A greater proportion (z = 2.84) of patients than controls had year 2 height velocity SDS less than −1.96. Patients had a mean delay in bone age of 0.22 years and 0.41 years at the beginning of year 1 and year 2 of the study, respectively. The delay in bone age correlated positively with age (r = 0.39) and duration of atopic dermatitis (r = 0.39), and negatively with height SDS (r = −0.51) and height velocity SDS (r = −0.38). CONCLUSIONS Prepubertal children with atopic dermatitis are not short compared with controls. However, as they approach the teenage years their height velocity decreases, the proportion of children with extremely low height velocity increases, and the delay in bone age increases. These features are consistent with the pattern of growth seen in people with constitutional growth delay.

Growth and growth hormone responses to oxandrolone in boys with constitutional delay of growth and puberty (CDGP)

Thirteen boys with constitutional delay in growth and/or development aged 7.6 to 16 years received 2.5mg/day of oxandrolone for 3 months. Their growth response on treatment and in the subsequent 3 months was compared to that of 14 age‐matched untreated controls. Growth rates were analysed in groups arbitrarily defined by testicular volume at entry (>4ml prepubertal, >4ml pubertal). Growth velocities increased on oxandrolone (prepubertal, mean 4.4 to 7.5cm/year, P = 0.05: pubertal, mean 4.7 to 8cm/year, p>0.05). Over the next 3 months, the pubertal boys grew at 9.3cm/year, while the prepubertal group decelerated to 6.2cm/year. Both control groups showed no significant change in velocity over 6 months. GH responses to arginine and GRF, and to sleep in prepubertal boys, were unchanged throughout the study. However, in pubertal boys the mean GH levels (‘area under the curve’) during sleep at 3 and 6 months, had increased over baseline values, associated with a significant increase at 6 months in basal somatomedin‐C (140 to 214ng/ml, p>0.05). Oxandrolone does not alter the GH status of prepubertal boys, and thus probably promotes growth by a direct action at the growth plate. In contrast, the persistent growth acceleration of pubertal boys may be associated with increased GH and somatomedin‐C levels: in this group, oxandrolone has proved a useful stimulus to growth.

Urinary growth hormone excretion in the assessment of children with disorders of growth.

OBJECTIVE We wished to evaluate the use of urinary GH measurements when compared to conventional GH provocation tests in the assessment of short children.

Relationship between urinary and serum growth hormone and pubertal status.

Urinary growth hormone (uGH) excretion and serum growth hormone concentrations have been compared in three groups of children. Group 1 consisted of 21 children who had had cranial irradiation as part of their treatment for acute lymphoblastic leukaemia; group 2, 18 normal children; and group 3, 12 boys with constitutional delay in growth and puberty who were in early puberty. Children in groups 1 and 2 each had a 24 hour serum growth hormone profile (sampling every 20 minutes) and concurrent urine collection. The 12 boys in group 3 had a total of 21 profiles (sampling every 15 minutes for 12 hours) and concurrent urine collections. In the prepubertal children (n = 17), in both groups 1 and 2, there was a significant correlation between mean serum growth hormone and total uGHng/g creatinine. There were also significant correlations between total uGHng/g creatinine and both peak serum growth hormone and mean amplitude of the pulses in the growth hormone profile. In the pubertal children (n = 22), in groups 1 and 2, whether combined or in separate groups, there was no significant correlation between total uGHng/g creatinine and mean serum growth hormone, peak serum growth hormone, or mean amplitude of the pulses in the growth hormone profile. In group 3 there were significant correlations between total uGHng/g creatinine and both the mean serum growth hormone and mean amplitude of the pulses in the profile. Therefore uGH estimations appear to correlate well with serum growth hormone profiles in children who are prepubertal or in early puberty, but not in those further advanced in pubertal development. These results may reflect a variation in the renal handling of growth hormone during pubertal development. uGH estimation may be an unreliable screening investigation for growth hormone sufficiency in mid to late puberty.

VARIABILITY IN THE URINARY EXCRETION OF GROWTH HORMONE (GH) AND CREATININE IN CHILDHOOD

As a basis for assessment of the clinical validity of urinary GH measurements in children, the variability in renal handling of GH was compared to that of creatinine in 93 healthy children (aged 4-16 years), 20 of normal stature and 73 with growth disorders. 10 were classified as GH deficient (GHD), 48 as short normal (SN) and 15 had Turner syndrome (TS). 5 overnight urine samples were collected over 2 weeks, and the variability of excretion expressed as a coefficient of variation (CV) of the total overnight amount of GH or creatinine. There was considerable night to night variability in the excretion of both substances:* p<0.05 compared to Normal + SN, #p<0.05 compared to Normal.Assay variation rather than a change in renal protein handling accounted for the large variation in low uGH concentrations, thus contributing to the high uGH CV of the GHD group. Increasing the number of samples collected (upto 5) decreased the expected sample variation (error) for uGH but not significantly in all groups, and reduced the convenience and practicality of the test. These results indicate that variation in GH and creatinine excretion is considerable in both normal children and those with growth disorders. The use of multiple samples (upto 5) does not significantly reduce the variability inherent in uGH measurement.

LOW DOSE OXANDROL ONE THERAPY IN CONSTITUTIONALLY DELAYED GROWTH

27 boys (aged 7.6-16yrs) with delayed growth were subdivided by testicular size into prepubertal (<4mls) and pubertal (≥4mls). 13 received 2.5mg/d oxandrolone (Ox) for 3 months, and 14 acted as controls. Each group grew at a velocity below the 25th centile over the preceding 0.3-1.4yrs. The controls continued to grow poorly over the next 6 months. Ox promoted an increase in velocity in prepubertal (4.4 to 7.5cm/yr, p=0.05) and pubertal buys (4.7 to 8cm/yr, p<0.05) during therapy, maintained over the subsequent 3 months only in the pubertal group (to 9.3cm/yr). The prepubertal decelerated after treatment (to 5.4cm/yr).GH secretion (arginine, GRF and during the first 90mins of sleep) was assessed at entry and 6 months in prepubertal controls, and at entry, 3 and 6 months in treated boys. No change in peak GH response or “areas under curve” (AUC) were seen in the prepubertal groups. At 3 and 6 months, treated pubertal boys had significantly greater AUC and GH peaks during sleep than the prepubertal, associated at 6 months with increases in basal testosterone (3.7nmol/l at entry to 18.2nmol/l, p<0.01) and somatomedin-C ( 140 to 2l4ng/ml, p<0.05). These changes were not seen in the prepubertal boys.Ox does not. alter the GH status of prepubertal boys, but enhances growth probably through a direct action on cartilage. Persistent, growth acceleration in the pubertal boy is associated with increased GH and somatomedin levels.