Long-term outcome of oxandrolone treatment in boys with constitutional delay of growth and puberty.
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Adolescent↗
Biomedical subjects
C G Brook
Publications and source records attributed to C G Brook.
Endocrine disorders following treatment of childhood brain tumours.
We have studied the long-term endocrine effects of treatment on 144 children treated for brain tumours. All received cranial irradiation, 86 also received spinal irradiation and 34 chemotherapy. Almost all patients (140 of 144) had evidence of growth hormone insufficiency. Treatment with growth hormone was effective in maintaining normal growth but could not restore a deficit incurred by delay in instituting treatment. The effect of spinal irradiation on spinal growth was not corrected by growth hormone. As spinal growth makes the major contribution to the pubertal growth spurt and limb length the major contribution to childhood growth, treatment with GH will have maximal effect on leg length if instituted before the onset of puberty. Primary thyroid dysfunction was found in 11 of 47 children (23%) treated with craniospinal irradiation but in none treated with cranial irradiation alone. The incidence rose to 69% of 29 children treated with spinal irradiation and chemotherapy and to 50% of four children treated with cranial irradiation and chemotherapy. This effect of chemotherapy has not previously been reported and was detected by us through measurement of serum TSH concentration. Primary thyroid dysfunction requires treatment with thyroxine to prevent increasing the risk of secondary thyroid tumours. Seven of 20 girls (35%) treated with spinal irradiation had primary ovarian dysfunction as determined by raised gonadotrophin levels. Chemotherapy increased this, but not significantly. Three of 15 boys (20%) treated with chemotherapy had primary testicular dysfunction. Gonadotrophin deficiency occurred in seven boys. Four of 90 children had deficiency of cortisol secretion in response to hypoglycaemia. These results confirm the requirement for long-term follow-up of children treated for brain tumours from the endocrine point of view. Anticipation of hormone deficiencies and replacement treatment can improve the quality of life of survivors.
Adolescent↗
The interaction between clonidine and growth hormone releasing hormone in the stimulation of growth hormone secretion in man.
Six normal adult males were given clonidine and GHRH either separately, or in combination, in random order. The peak serum GH concentrations elicited by clonidine or GHRH were variable but one factor influencing the GH response to GHRH was the GH secretory status in the hour prior to the administration of the GHRH. Peak serum GH concentrations attained were significantly greater when serum GH concentrations were rising (mean 52.9 mU/l, SD 17.2) than if they were falling (mean 27.5 mU/l, SD 13.3) or unchanged/undetectable (mean 20.6 mU/l, SD 9.8) (one-way ANOVA, F = 8.77; P = 0.004). The GH response to clonidine was not influenced by the secretory status in the hour prior to administration of clonidine. Pretreatment with clonidine did not augment the peak serum GH response to GHRH but the direction of response was more predictable than when GHRH was administered separately or repeatedly. Prior treatment with GHRH(1-29)-NH2 led to a marked attenuation of the peak serum GH response to clonidine. These results suggest that the alpha-2 adrenergic agonists probably stimulate GH secretion through pathways other than just GHRH.
Adult↗
Continuous subcutaneous GHRH(1-29)NH2 promotes growth over 1 year in short, slowly growing children.
We have treated eight pre-pubertal children with partial GH insufficiency with continuous subcutaneous infusions of GHRH(1-29)NH2 at a dose of 60 ng/kg/min for periods of up to 1 year. In five children treated for 1 year, mean growth velocity increased from 4.6 cm/year (range 4.4-5.2) to 7.0 cm/year (5.7-8.7) (P = 0.04). Three children treated for 3-6 months showed similar height velocity increases. A return to pretreatment growth rates was seen after cessation of treatment in all children. Twenty-four-hour GH profiles performed at intervals of 3 months showed sustained augmentation of pulsatile GH secretion without evidence of desensitization. The presence of pulsatile GH secretion during continuous GHRH administration provides strong evidence in man for the role of somatostatin in determining GH pulse frequency. The ability of the pituitary to respond to a supramaximal bolus of GHRH remained constant during the treatment. Continuous administration of GHRH(1-29)NH2 will become a practicable treatment when formulated into a sustained release or depot preparation. We have shown this to be an effective therapy for some short, slowly growing children. Further studies are required to establish the optimal dosage regimen.
Body Height↗
The application of deconvolution analysis to elucidate the pulsatile nature of growth hormone secretion using a variable half-life of growth hormone.
A deconvolution analysis model to calculate pituitary growth hormone (GH) secretion rate from measured serum GH concentration has been developed. This uses an iterative method of 'curve-stripping' based on an estimate of the half-life. The model has been applied to serum GH profiles and demonstrates that GH secretion occurs in discrete bursts with quiescent periods between secretory episodes, an 'on-off' phenomenon. The model can clearly dissect complicated concentration profiles such as the serum GH concentration response to growth hormone releasing hormone. The estimate was derived from calculating the half-life of serum GH in 10 subjects following an intravenous bolus injection of 50 mU of biosynthetic human growth hormone (b-hGH) and following infusions of the exogenous hormone (3 mU/kg/h) for 15, 30, 60 and 180 min. Endogenous GH secretion was suppressed by a continuous infusion of somatostatin (1-14). An asymptotic relationship between the duration of GH infusion and the GH half-life was established. A half-life of 15.3 min was achieved after exposure to GH for 60 min and a maximum half-life of 15.7 min after 180 min exposure.
Adolescent↗
A preliminary report on the role of somatostatin analogue (SMS 201-995) in the management of children with tall stature.
We have studied the effect of somatostatin analogue (SMS 201-995) given as a subcutaneous injection on the growth and growth hormone secretion in seven tall children (two male; five female). SMS 201-995 was given in doses of 37.5 or 50 micrograms on a once or twice-daily regimen. Growth velocity decreased from a pretreatment median of 8.3 cm/year (range 5.5-12.2) to 3.0 cm/year (range 0.2-4.5) after 6 months treatment (Wilcoxon, P = 0.02). In three of the children therapy was discontinued for the next 6 months with restoration of growth rate to pretreatment values in two of the three. Growth hormone secretion decreased as a result of SMS 201-995 therapy although one child needed a twice-daily regimen to achieve long-term suppression. Final height measurements were reduced in four of five patients with an overall reduction between 1.1 and 6.3 cm and no change in the other. No effects of treatment on fasting glucose and insulin, glycosylated haemoglobin or serum thyroxine concentrations were observed. These preliminary studies suggest that SMS 201-995 may have a role in the management of the growth of tall children but the optimum mode of administration remains to be established.
Adolescent↗
The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives.
Seventy-seven female patients (36 adults and 41 children aged under 16 years) with congenital adrenal hyperplasia (CAH) were assessed using pelvic ultrasound, as well as with standard endocrine tests and HLA typing. Forty-six close female relatives were also tested for ovarian morphology using ultrasound after assessment of their heterozygous state using HLA typing. The association of CAH with ultrasonically detected polycystic ovaries (PCO) was confirmed in 30/36 (83%) adult patients, 4/10 (40%) postpubertal girls and 1/31 (3%) pre and peripubertal girls: in all, 35/46 (76%) postmenarcheal patients. Six out of nine (67%) pre-menopausal mothers of patients with PCO, and 8/10 (80%) sisters of patients with PCO also had PCO. The proportions of both CAH patients and heterozygote subjects with PCO were significantly greater than that found in a normal population (P less than 0.0001). The finding, however, of two homozygous non-CAH-affected adult sisters with PCO and, conversely, of 10 heterozygous adult relatives and of 12 postmenarcheal CAH patients with normal ovaries, indicates that the ovarian morphological change may be independent of the adrenal lesion.
Adolescent↗
The management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
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Adrenal Hyperplasia, Congenital↗
Growth and growth hormone secretion in children following treatment of brain tumours with radiotherapy.
We have studied the growth of 144 children after treatment of brain tumours distant from the hypothalamo-pituitary axis. All had cranial irradiation and 87 spinal irradiation. In 56 patients observed without intervention for 3 years, height SDS in the cranial (CR) group (n = 20) declined from 0.02 to -0.44 and in the craniospinal (CS) group (n = 36) from -0.28 to -1.11. Failure of spinal growth had a marked effect in the CS group. The onset of puberty was slightly but not significantly advanced; median ages at onset of puberty were 10.3 years in girls and 12.1 years in boys. Of the total group 86.4% had clinical and biochemical evidence of growth hormone insufficiency. Fifty-two children, 33 (28 CS; 5 CR) of whom were prepubertal, received biosynthetic human growth hormone, in a dose of 15 mU/m2/week by daily injection for a period of one year. Height velocity SDS increased significantly in both groups from -2.74 to +1.90 (CS) and from -1.0 to +4.26 (CR). Spinal response to GH treatment was restricted in the craniospinal group.
Brain↗
Effects of 3 years of growth hormone therapy in short normal children.
The effect of 3 years of growth hormone (GH) treatment on growth rate, predicted height, carbohydrate and metabolic status, and thyroid function was studied in 16 short prepubertal children growing with a normal pretreatment growth rate. The height velocity SDS increased from a pretreatment value of -0.44 +/- 0.33 (mean +/- SD) to a value of +2.20 +/- 1.03 during the first year of treatment. It was maintained at a value above zero over the subsequent 2 years. By the end of the third year of treatment, the predicted final height had increased by 6.8 cm in the boys and by 4.2 cm in the girls (p less than 0.001 and p less than 0.01, respectively). Increasing the dose of GH on a body surface area basis reduced the deceleration of growth observed during the second year of treatment, leading to an improvement in height prognosis over that year. Glucose homoeostasis was achieved initially at the expense of an elevation in fasting serum insulin concentration, but this had returned to pretreatment values by the end of the second year of therapy.
Blood Glucose↗
Treatment of constitutional delay of growth and puberty with oxandrolone compared with growth hormone.
The effects of oxandrolone or biosynthetic human growth hormone (r-hGH) on the growth of 26 boys with constitutional delay of growth and puberty were studied. Both regimens increased growth rate twofold, oxandrolone to a greater extent than r-hGH. We conclude that oxandrolone is a more effective method of increasing growth rate in such children.
Adolescent↗
Non-conventional use of growth hormone: European experience.
Results from several centres in Europe using biosynthetic human growth hormone (hGH) for the promotion of growth in a variety of conditions other than classical hGH deficiency were evaluated. Significant increments in growth rates were achieved by daily administration of hGH in doses appropriate for body size without disproportionate skeletal advances in short normals, Turner syndrome, low birth weight, skeletal dysplasia, central precocious puberty (reared with gonadotrophin-releasing hormone analogue) and renal failure.
Child↗
Frequency of administration of growth hormone--an important factor in determining growth response to exogenous growth hormone.
Growth hormone (GH) secretion in man occurs in a pulsatile manner with a dominant periodicity of 200 min. Animal studies and growth hormone-releasing hormone therapeutic studies in man demonstrate the importance of the frequency of GH pulses on the growth response observed. Daily injections of GH produce effective growth. More frequent regimens may be beneficial to prevent waining of the growth spurt induced by GH therapy.
Animals↗
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.
Adolescent↗
Growth hormone increases rate of pubertal maturation.
We have performed a retrospective analysis of the pubertal parameters of 134 children with isolated GH insufficiency on GH treatment and compared them to the standards of Tanner and to a recent longitudinal study of growth and development in the United Kingdom. The age at onset of puberty (13.0 years in boys, 12.1 years in girls) was found to be significantly delayed (Mann-Whitney p less than 0.001), but duration of puberty (1.5 years in both sexes) was shortened (Kolgomarov-Smirnov p less than 0.01). Skeletal maturity at the onset of puberty was not advanced excluding this as a contributory factor. There was no association between dose of GH administered and the pubertal parameters. The results suggest that GH accelerates the pubertal process.
Adolescent↗
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.
Body Height↗
Ovarian ultrasound appearances in Turner syndrome.
We performed pelvic ultrasound assessment in 104 patients with Turner syndrome aged 0.2 to 17.4 years; 69 had the 45,X karyotype and 35 had variant karyotypes. Ovarian appearances were classified as "streak" (n = 70, including 30 patients in whom no ovary could be seen) or "nonstreak" (n = 34). The nonstreak ovaries ranged from small glands, sometimes containing minute cysts, to ovaries indistinguishable from those which are normal for age. Nonstreak ovaries retained a range of function, as evidenced in some cases by spontaneous breast development and uterine enlargement. The proportion of nonstreak ovaries followed a U-shaped pattern, with a nadir from 4 to 10 years; this follows the known biphasic pattern of luteinizing hormone and follicle-stimulating hormone secretion. Only those patients with karyotype variants in which the long arm of the X chromosome was retained fared better than those with the 45,X karyotype.
Adolescent↗