Relationship between urinary and serum growth hormone and pubertal status.
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Creatinine↗
Biomedical subjects
J A Edge
Publications and source records attributed to J A Edge.
Impact of increased growth hormone secretion on carbohydrate metabolism in adolescents with diabetes.
Growth hormone (GH) and fasting insulin concentrations rise during puberty in normal subjects. Any increase in GH secretion in adolescents with insulin-dependent diabetes mellitus (IDDM) might be expected to lead to further insulin resistance and metabolic disturbance. Despite the high incidence of delayed growth in IDDM, the relationship between GH, insulin-like growth factor I (IGF-I) and IGF binding protein 1 (IGFBP-1) has not been clearly established. Twenty-six adolescents with IDDM and 34 healthy siblings underwent measurement of their overnight GH secretory profiles (20.00-08.00 hours, 15-minute sampling). The diabetic subjects were studied either on their normal insulin regimen (n = 15) or during a euglycaemic clamp (n = 26). A second clamp study was undertaken (n = 7) with addition of pirenzepine to suppress GH secretion. GH profiles in the diabetic subjects were characterized by increases in both pulse amplitude and baseline GH concentrations. Deconvolution analysis also revealed an increase in the frequency of GH secretory episodes. In the subjects with diabetes, a direct link between the dawn rise in insulin requirements, increased concentrations of beta-hydroxybutyrate and the elevated concentrations of GH was established. These abnormalities were reversed by the suppression of GH pulse amplitude following pirenzepine. Serum IGF-I concentrations and IGF-I bioactivity in the diabetic subjects were low and were positively correlated with mean GH concentrations. In conclusion, well controlled adolescents with IDDM show persisting abnormalities of GH, beta-hydroxybutyrate and IGF-I despite normoglycaemia. The role of inappropriate insulin delivery in the development of these abnormalities is discussed.
3-Hydroxybutyric Acid↗
Pattern of secretion of bioactive and immunoreactive gonadotrophins in normal pubertal children.
OBJECTIVE: The aim was to investigate the relationship between the nocturnal pulsatile secretory patterns of immunoreactive and bioactive luteinizing hormone in normal children at various stages of puberty. DESIGN: Blood samples were taken at 15-minute intervals from 2000 hours to 0800 hours. Pubertal stage was assessed by the method of Tanner (1962). PATIENTS: Thirty-four healthy siblings (17 males, 17 females) of diabetic children were recruited (median age 13.1, range 9.1-20.9 years). They were of normal height, non-obese, and covered the range of puberty. MEASUREMENTS: Follicle stimulating and luteinizing hormone levels were measured by radioimmunoassay in all 34 subjects; bioactive LH (B-LH) was assayed in a subgroup of 13 subjects selected to encompass the range of normal puberty. Oestradiol (girls) and testosterone (boys) were also measured at hourly intervals. RESULTS: Immunoreactive luteinizing and follicle stimulating hormone concentrations showed a progressive rise during puberty in both sexes. FSH concentrations were significantly higher in females than in males at all stages of puberty. Overnight mean bioactive luteinizing hormone concentrations were higher than immunoreactive luteinizing hormone levels in all the girls studied (n = 7). Although the number of bioactive luteinizing hormone pulses (31) was greater than immunoreactive pulses (27), the profiles were generally very similar. In the early pubertal girls an increase in the bioactive: immunoreactive ratio was observed during the middle of the night with the onset of pulsatility. Oestrogen was detected in the girls in breast stage 4-5 but not in two of the early pubertal girls, despite pulses of immunoreactive and bioactive luteinizing hormone. The boys had higher mean bioactive than immunoreactive luteinizing hormone levels and overall bioactive and immunoreactive luteinizing hormone and testosterone concentrations increased with puberty stage. Concordance between bioactive and immunoreactive hormone pulses was good although more immunoreactive pulses (16) were seen than bioactive pulses (14). As in the girls, an increase in the bioactive: immunoreactive ratio was observed in the middle of the night with the onset of pulsatility at genital stage 2 but, in contrast to the oestrogen data in the girls, testosterone secretion always followed luteinizing hormone pulsatility overnight. CONCLUSION: We conclude that mean overnight immunoreactive luteinizing and follicle stimulating hormone concentrations increase during puberty in both sexes. Bioactive luteinizing hormone levels are two to three times higher than immunoreactive luteinizing hormone in both sexes, but there is very little discordance between immunoreactive and bioactive luteinizing hormone pulsatility. The bioactive: immunoreactive ratio increases with the occurrence of pulsatility overnight in early pubertal children. The relationship between these changes in bioactive and immunoreactive luteinizing hormone and sex steroids is clearest in boys where the nocturnal testosterone rise always follows pulsatile LH secretion.
Adolescent↗
Urinary growth hormone excretion during puberty in type 1 (insulin-dependent) diabetes mellitus.
The excretion of urinary growth hormone was measured by a highly sensitive direct immunoradiometric assay in a cross-sectional study during puberty in 70 children with Type 1 (insulin-dependent) diabetes mellitus and 94 normal children. In normal children (n = 24) and diabetic children (n = 17) overnight urinary growth hormone excretion correlated significantly with the mean overnight plasma concentration (r = 0.70, p less than 0.001, and r = 0.70, p less than 0.001), indicating that urinary GH excretion reflects the circulating endogenous GH level. Overnight urinary growth hormone excretion increased during puberty. In normal and in diabetic children there was a peak in boys at genital stage 4 (both p less than 0.01), and in girls at breast stage 2 (both p less than 0.02). The diabetic children excreted more urinary growth hormone than the normal children at every pubertal stage. Excretion of albumin, retinol binding protein and N-acetyl-beta-D-glucosaminidase was measured in urine from 38 diabetic children. Urinary growth hormone correlated weakly with urinary albumin (r = 0.49, p less than 0.01), retinol binding protein (r = 0.42, p less than 0.01), and N-acetyl-beta-D-glucosaminidase (r = 0.43, p less than 0.01). Urinary GH excretion was not related to blood glucose control (HbA1) in boys (n = 31) or girls (n = 39). The measurement of urinary growth hormone provides an assessment of endogenous growth hormone during puberty in normal and diabetic children. However, caution must be exercised in interpreting urinary growth hormone data from diabetic patients with increased excretion of albumin and retinol binding protein.
Acetylglucosaminidase↗
Noonan's syndrome: abnormalities of the growth hormone/IGF-I axis and the response to treatment with human biosynthetic growth hormone.
Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5-12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.
Age Determination by Skeleton↗
Evidence for temporal coupling of growth hormone, prolactin, LH and FSH pulsatility overnight during normal puberty.
The patterns of secretion of GH, LH, FSH and prolactin were determined over a single night (20.00-08.00 h; 15-min sampling) in 34 normal subjects (17 male, 17 female, aged 9.1-20.9 years). Plasma GH was measured by an immunoradiometric assay and LH, FSH and prolactin by radioimmunoassay in all samples. Data were analysed by Fourier transformation and cross-correlation after stationarization. The highest mean GH levels were noted in girls at Tanner stage 2/3 and in boys at stages 4/5. Prolactin levels were highest in girls at stage 4/5 and in boys at stage 2/3. LH and FSH showed a progressive rise by puberty stage in both sexes. The dominant pulse periodicities of GH and prolactin were 150-180 min in girls and 180 min in boys. LH and FSH pulse periodicity was around 90 min in early puberty and 180 min in later puberty in both sexes. LH and prolactin pulses showed a phase relationship with GH with a lag of 30-75 min (r = 0.32; P less than 0.001) and 30 min (r = 0.47; P less than 0.0001) respectively. Generally, LH and prolactin pulses were in phase (r = 0.42; P less than 0.0001) and there was a highly significant correlation (r = 0.64; P less than 0.0001) between FSH and LH pulsatility. Whereas mean overnight concentrations and pulse periodicity of the principal pituitary hormones varied between the sexes during early puberty, by the end of puberty a dominant pulse periodicity of around 150-180 min was established and there was remarkable temporal coupling of pulsatility.
Adolescent↗
The growth hormone releasing hormone (GHRH) response to a mixed meal is blunted in young adults with insulin-dependent diabetes mellitus whereas the somatostatin response is normal.
Following a standard mixed meal, plasma concentrations of growth hormone releasing hormone (GHRH), somatostatin (SMS) and growth hormone (GH) were measured every 30 min for 300 min in six young adults with type I insulin-dependent diabetes mellitus (IDDM) and five normal controls. Mean blood glucose concentrations were higher and mean free insulin levels lower in the diabetics compared with controls both in fasting specimens and at all times following the mixed meal. Basal concentrations (mean +/- SEM) of GHRH were similar in diabetic (12.7 +/- 1.8 pg/ml) and control subjects (11.8 +/- 1.1 pg/ml). Following ingestion of the mixed meal, a rise in GHRH was observed in the control subjects maximal between 30 and 240 min (P less than 0.025) but the response was blunted in the diabetics. Mean GHRH concentrations were greater in the controls than in the diabetic subjects at all stages during the test, the maximum difference being noted at 120 mins (P less than 0.04). Basal SMS concentrations and those observed after the mixed meal were similar in diabetic and control subjects. These results indicate that glucose and insulin may play a role in the regulation of GHRH release following a mixed meal but circulating levels of GHRH and SMS are unlikely to be relevant to the abnormal regulation of GH in IDDM.
Adolescent↗
The dawn phenomenon is related to overnight growth hormone release in adolescent diabetics.
We have investigated the relation between nocturnal insulin requirements and nocturnal growth hormone (GH) release in 26 diabetic adolescents at various puberty stages and have examined the effect of nocturnal GH suppression on pre-breakfast insulin requirement. In all the studies, euglycaemia was maintained overnight using a computer-calculated variable-rate insulin infusion, and 15-min blood samples were collected for GH assay. During initial clamp studies, insulin infusion rates were greater from 0500-0800 h (15.22 +/- 0.95 mU/kg/h, mean +/- SEM) than from 0100-0400 h (12.42 +/- 0.84 mU/kg/h, P less than 0.001). The increase in insulin infusion rate correlated with mean overnight GH concentration (r = 0.68, P less than 0.001), and was maximal at puberty stage 3 in both sexes. In seven of the subjects, a second identical clamp was performed following administration of 100 mg oral pirenzepine. During these studies, mean overnight GH levels were reduced by 11-85%, from 17.6 +/- 1.6 to 7.5 +/- 2.2 mU/l; P less than 0.01. Insulin requirements were not significantly different between the periods 0100-0400 and 0500-0800 h during these studies, and the reduction in pre-breakfast (0500-0800 h) insulin requirement when compared with the baseline studies correlated with the fall in GH secretion (rs = 0.82, P less than 0.01). The dawn increase in insulin requirement in adolescents with IDDM is related to the overnight GH secretion during puberty, and pre-breakfast insulin requirement can be reduced by suppressing nocturnal GH release.
Adolescent↗
Insulin-like growth factor binding protein-1 levels in diabetic adolescents and their relationship to metabolic control.
Circulating levels of the low molecular weight insulin-like growth factor binding protein-1 (IGFBP-1) are insulin dependent and vary markedly throughout the day. IGFBP-1 levels are abnormally high in diabetes but the relationship between this and the metabolic status of the patient has not been defined. We have therefore measured fasting IGFBP-1 levels at 0800 h in 32 diabetic adolescents. IGFBP-1 was measured in 19 of these patients after a normal night and in 27 after a night of euglycaemia, maintained with a glucose clamp. In 13 patients both studies were performed and could be compared. Puberty-matched control data were obtained from 69 normal children. In normal prepubertal children IGFBP-1 levels were high; lower levels were found with advancing pubertal development. This fall in IGFBP-1 correlated with pubertal stage (r= 0.68, p less than 0.001) and with fasting insulin levels (r = 0.60, p less than 0.001) which rose with pubertal advancement. In the diabetic children IGFBP-1 levels also correlated inversely with the 0800 h free insulin level but there was no clear relationship with pubertal development. However, when measured after overnight euglycaemia IGFBP-1 levels correlated inversely with pubertal development (r = 0.67, p less than 0.001) as in the normal children. In the patients studied on two comparable occasions the IGFBP-1 level measured after a normal night relative to that measured under standardized euglycaemic conditions was found to correlate closely with the glycosylated haemoglobin level (r = 0.71, p less than 0.005).
Adolescent↗
Increased overnight growth hormone concentrations in diabetic compared with normal adolescents.
To determine the extent to which spontaneous plasma GH concentrations are abnormal in adolescents with insulin-dependent diabetes mellitus we performed 12-h overnight plasma GH profiles in 21 diabetic adolescents (11 males and 10 females; aged 9.8-16.5 yr; median, 13.6 yr) and 34 healthy adolescent controls (17 males and 17 females; aged 9.1-20.9 yr; median, 13.1 yr). Data were analyzed using the pulse detection program Pulsar and time series analysis, and are presented with respect to age and puberty stage. Mean and maximum GH concentrations, sum of the peak amplitudes, and mean calculated baseline concentrations in the normal children were higher during puberty; highest levels were seen in girls at puberty stages 2-3, and in boys at stages 4-5. A similar pattern was observed in the diabetic adolescents, but all measures of pulse height and mean calculated baseline concentrations were significantly greater than those in the normal subjects (multivariate analysis, P less than 0.001). Pulse frequency did not change during puberty in the normal or diabetic subjects, and the dominant pulse periodicity in both groups was about 180 min. We conclude that the predominant change in GH release during puberty is in pulse amplitude, and that this is increased in diabetes, whereas pulse frequency remains constant in both normal and diabetic adolescents.
Adolescent↗
Failure of current insulin regimes to meet the overnight requirements of adolescents with insulin-dependent diabetes.
The study was undertaken to determine whether overnight insulin requirements were being met during conventional insulin therapy in adolescents with IDDM. Overnight glucose and insulin profiles were compared when the subjects were on their usual insulin regime (baseline) and when the blood glucose was clamped using a variable rate insulin infusion (clamp). Thirteen adolescents (5 boys and 8 girls, median age 12.2 yr; range 10.5-15.4 yr; Median HBA1 11.4%; range 8.4-15.6) took part in the study. Three were on twice daily, two on multiple injection therapy and two on once daily insulin therapy. During the baseline studies, blood glucose concentrations fell to a nadir at 0200-0400 hr and then rose during the early hours of the morning. The clamp studies confirmed that the insulin requirement for euglycaemia was higher between 0500 and 0800 hr (15.4 +/- 0.9 mU/kg/hr) than between 0100 and 0400 (12.1 +/- 1.1 mU/kg/hr; p = 0.002). Comparison of the free insulin concentrations between the baseline and clamp nights, indicated that during the baseline study subjects were relatively over-insulinized during the early part of the night and under-insulinized during the latter part of the night irrespective of what insulin regime they were receiving. We conclude that current insulin regimes do not provide appropriate insulin delivery for the control of blood glucose during puberty.
Adolescent↗
Spontaneous growth hormone (GH) pulsatility is the major determinant of GH release after thyrotrophin-releasing hormone in adolescent diabetics.
GH release is abnormally regulated in insulin-dependent diabetes (IDDM), and paradoxical stimulation of GH release after TRH has been reported. However, overnight GH pulsatility is increased in IDDM, and it may be difficult to distinguish TRH-stimulated release from spontaneous secretory episodes. To resolve this question, we carried out two overnight GH profiles followed by either TRH or saline control tests in six adolescents with IDDM; ages 11.4-14.7 years, duration IDDM 2.4-6.7 years. A rise in GH was seen in four of six following TRH, but with no consistent pattern. A rise was also seen in four of six following saline. Peak GH levels were similar after TRH and saline (19.3 +/- 4.4 vs 25.8 +/- 5.5 mU/l; mean +/- SEM). Mean blood glucose was no different during TRH and saline tests (9.5 +/- 1.6 vs 7.5 +/- 0.6 mmol/l). The two subjects who had an early GH peak after TRH were those in whom GH levels had already begun to rise, suggesting the coincident occurrence of a spontaneous GH pulse. The timing of the next GH pulse could be predicted equally well after TRH and saline from the overnight secretory profile using autocorrelation. Paradoxical GH stimulation after TRH is not seen in adolescents with IDDM, but apparent responses may be due to timing coincident with the increased spontaneous pulsatility.
Adolescent↗
Urinary growth hormone during puberty in normal and diabetic children.
The measurement of GH in urine may have many clinical applications, particularly in childhood. We have used a highly sensitive direct immunoradiometric assay to examine urinary GH excretion in children during puberty. Fifty-five healthy schoolchildren collected timed overnight urine samples. A further 36 children (15 normal, six of short stature and 15 diabetic) collected urine samples during a total of 50 overnight plasma GH secretory profiles (15-min sampling). Overnight urinary GH excretion increased during puberty, with a peak at breast stage 2 in girls, and genital stage 4 in boys, before declining at stage 5. There was a positive correlation (r = 0.57, p = 0.003) with height velocity in girls, but not in boys. At each puberty stage except 2, the diabetics excreted more urinary GH than the normal children. There was a highly significant correlation (r = 0.79, p less than 0.001) between mean overnight plasma GH concentrations and urinary GH excretion, suggesting that the latter accurately reflects physiological GH secretion.
Adolescent↗
Terbutaline and ketotifen in cold urticaria in a child.
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Child↗
Levels of the small insulin-like growth factor-binding protein are strongly related to those of insulin in prepubertal and pubertal children but only weakly so after puberty.
We have looked at the relationship between fasting levels of insulin and a small insulin-like growth factor (IGF)-binding protein (IBP-1) in a cross-sectional study of 116 normal subjects aged 5-48 years. The relationship between IBP-1 and insulin was also examined within individual normal children in overnight profiles of IBP-1 and insulin obtained from two children at each stage of puberty (Tanner stages 1-5). In the cross-sectional study high levels of IBP-1 were found in early childhood and these fell throughout puberty as fasting levels of insulin rose. Multiple regression analysis revealed that both these changes were predominantly due to pubertal development rather than to age. After the age of 16 IBP-1 levels remained low despite fasting insulin levels returning to prepubertal levels. A strong negative correlation was obtained between IBP-1 and insulin in children of 5-16 years (r = -0.63; n = 60; P less than 0.001), no such relationship being found after the age of 16. In the second study, IBP-1 underwent a marked circadian variation in all cases and an inverse correlation with insulin, measured at the same time, was obtained at pubertal stages 1 to 4, but not at stage 5 (pooled data stages 1-4, r = -0.69; n = 53; P less than 0.001). We have demonstrated that a potential inhibitor of IGF-activity is inversely related to insulin throughout the period of active GH-related growth and that this relationship weakens after puberty.
Adolescent↗
Circadian variation of GH-independent IGF-binding protein in diabetes mellitus and its relationship to insulin. A new role for insulin?
Evidence is accumulating that a non-GH dependent insulin-like growth factor-binding protein (IGF-BP) is not only a carrier protein but also has an active role in the growth process. We have measured levels of this IGF-BP, using a specific RIA, over 12 or 24-h periods in 11 adolescents with diabetes mellitus and five normal adults. In each of the normal the IGF-BP was undetectable for most of the day but with a broad nocturnal peak observed, with levels up to 50 micrograms/l. The levels of IGF-BP were unrelated to the secretory pattern for GH but correlated inversely with the concentration of circulating insulin. In the diabetics a very similar pattern was observed, but with detectable levels throughout the day and much higher peak levels seen at night. Peak levels were up to 120 micrograms/l if a long-acting insulin preparation was administered in the evening but were 400-500 micrograms/l if the long-acting preparation was administered in the morning. The IGF-BP was strongly correlated with plasma glucose in this latter group. In a further group of diabetics overnight profiles were obtained on two separate nights, a normal night and a night with euglycaemia maintained with a glucose clamp technique. Euglycaemia failed to affect peak levels of the binding protein, although the shape of the nocturnal peak was altered consistent with the altered pattern of circulating free insulin. In this group a strong inverse correlation was obtained between the IGF-BP and free insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Cerebral oedema during treatment of diabetic ketoacidosis: are we any nearer finding a cause?
Cerebral oedema remains the leading cause of death and morbidity in children with Type 1 diabetes mellitus. Around seven per thousand episodes of diabetic ketoacidosis (DKA) are complicated by cerebral oedema, and one-quarter of those children will die from it. The cause or causes of cerebral oedema are still very poorly understood, but lawyers are already keen to implicate various aspects of the management of DKA. There have been many theories as to the pathophysiology of cerebral oedema, and possible contributing factors may be excessive rate of rehydration, falling plasma osmolality (particularly that due to a reduction in plasma sodium concentration), hypoxia and insulin dosage. There is some supportive evidence for all of these factors in some cases, but there have been no sizeable case-control studies, in part because of the rarity of the condition. Furthermore, cerebral oedema can still occur even when the management of DKA follows current 'best practice' guidelines. As the mechanisms of cell volume regulation within the brain are increasingly understood, different questions may provide greater insights. For example, what is it about children that makes them so much more susceptible to cerebral oedema than adults? And why does one child treated in a certain way develop cerebral oedema whereas another does not? The anxiety over causing cerebral oedema has driven most of the changes in the management of DKA over recent decades, yet there is no evidence that the incidence has reduced. Until the causes are understood, we cannot be dogmatic about treatment recommendations.
Adult↗
An unbiased glucose clamp method using a variable insulin infusion: its application in diabetic adolescents.
A simple, unbiased insulin-varying glucose clamp program is described. The aim of the program was to utilize a continuously updated array of data to predict insulin requirements for normoglycaemia. In assessing Type 1 diabetes the quantity of insulin required for maintenance of basal euglycaemia can be more clinically informative than other clamp methods. We present a method which uses an iterative computer program to predict changes in insulin infusion rate required for glucose clamping. After initial parameter estimation, the program uses no fixed algorithm but makes predictions according to previous blood glucose responses to infusion rates. The program has flexible data entry, graphic display, and running statistics including mean infusion data, mean glucose levels, and their respective standard deviations. Data for 26 consecutive overnight clamp studies have been analysed. The median coefficient of variation of glucose values at the end of the clamp was 4.1% (range 1.4-12.0%). The mean bias during the last 2 h was 0.20 +/- 0.24 mmol l-1. Cross-correlation showed that insulin had its maximal effect on the rate of decline of glucose after 15 min, and the nadir of glucose occurred 45 min after a change in insulin infusion rate.
Adolescent↗