Predictive criteria for successful growth promotion in growth hormone therapy of short stature: a comparison between common endocrine parameters and knemometry

Due to increased availability of growth hormone (GH) for the treatment of short stature, its use has been proposed for a number of conditions besides classic GH deficiency. We have studied growth response during a one year treatment period with 14 IU/m2/week of GH in a heterogenous group of 24 short children with various conditions associated with short stature (SDS for body height ranging between -2.2 and -4.4). Thirteen children could be classified as "responders" with growth rate increments of 2 cm/yr or more above pretreatment growth rates, and 11 children as "non-responders". The children were measured regularly both by stadiometry and knemometry at weekly intervals. GH stimulation by insulin, arginine and spontaneous overnight secretion of GH, and SM-C generation were evaluated in the children and found to be of no predictive value for the individual responsiveness to GH administration except in one boy with classic GH deficiency. However, serial measurements of the lower leg length provided useful information for individual predictions in 21 out of the 24 children as early as 10 weeks after the start of the GH treatment.     

Growth Response to Human Growth Hormone Treatment in Children with Partial and Total Growth Hormone Deficiency

ABSTRACT. The growth response during the first and second years of human growth hormone (hGH) treatment was studied in 14 prepubertal children with so-called "partial" GH deficiency (peak GH between 8 and 15 mU/1) and compared to 28 prepubertal children with "total" GH deficiency (peak GH less than 8 mU/1). There was no difference in growth acceleration between children with partial and total GH deficiency, when initial covariables were taken into account. In a stepwise multiple regression analysis initial stature, pre-treatment growth velocity and skinfold thickness were shown to be most related to growth response, but after exclusion of 3 children with a genetic form of total GH deficiency and partial TSH deficiency this relationship was lost. GH levels during provocation tests and auxological criteria have a poor predictive value for growth response to hGH therapy.     

Clinical Usefulness of Urinary Growth Hormone Measurement in Short Children

Growth hormone GH) levels in nocturnal urine were measured in 96 short children and 73 children of normal height in order to investigate whether urinary CH levels reflect spontaneous GH secretion and whether they might be used to screen short children for GH treatment. GH levels in 24-hour urine samples were significantly correlated with urinary albumin and β₂-microglobulin levels in normal children, demonstrating an influence of renal function on urinary GH measurements. Nocturnal urinary GH levels showed significant positive correlations with mean serum GH levels during 3 hours of sleep ( r = 0.26. p < 0.05) and plasma insulin-like growth factor 1 (IGF-I) levels, reflecting physiological GH secretion. Urinary GH levels were significantly lower in the eight children with complete GH deficiency (3.1 ± 2.3 ng/g creatinine) than in the normal children (13.8 ± 11.2 ng/g creatinine). Urinary GH levels in three other groups of short children, partial CH deficiency (11.1 ± 16.9 ng/g creatinine), impaired GH secretion during sleep (10.4 ± 12.6 ng/g creatinine) and non-endocrine short stature (18.8 ± 19.5 ng/g creatinine), were not significantly different from those in the normal children. However, when the cut-off point for defining GH insufficiency was set at 5 ng/g creatinine, 87.5% (21 out of 24) of the short children with low urinary GH levels were suitable subjects for GH treatment (i.e. had complete GH deficiency, partial GH deficiency or impaired GH secretion during sleep). It is concluded that urinary GH measurement, though influenced by renal function, is potentially a simple, non-invasive and clinically useful method for screening short children for GH insufficiency. Further refinements of the technique are required before it can be widely applied.     

Growth hormone treatment in Noonan syndrome

Growth responses to growth hormone (GH) treatment in Noonan syndrome are compared with those in short children with the other growth disorders. The responses in Noonan syndrome are much less than those in children with GH deficiency, a little less than those in children with non-endocrine short stature and almost the same as those in children with Turner syndrome. As it is speculated that GH induces puberty earlier that expected in Noonan Syndrome, the efficiency of GH treatment for final height in Noonan syndrome is not promising.     

An Overview of the Diagnoses in the Kabi Pharmacia International Growth Study

This paper provides an overview of the diagnoses of patients entered in the Kabi Pharmacia International Growth Study (KIGS). By May 1991, data from a total of 5377 children treated with growth hormone (GH) were included in the main database. Of these children, 2691 were classified as having idiopathic GH deficiency (GHD), 866 as having GHD of known origin, and 1820 as having other causes of short stature. The majority of patients with idiopathic GHD have no history of perinatal trauma. In the patients with GHD of known origin, 137 were congenital cases and 729 acquired GHD. The largest number of congenital cases (114) belonged to the group of central malformations (e.g. septo-optic dysplasia and empty sella syndrome). Of the cases with acquired GHD, 73% were associated with tumours or leukaemia. Other causes of short stature include 12 groups of diagnoses, with more than 150 cases in four of them (idiopathic short stature, 635; defined syndromes with chromosomal aberrations, 337, of which 304 were Turner's syndrome; defined syndromes without chromosomal aberrations, 157; intrauterine growth retardation without stigmata, 366). Analysis of the KIGS data allows modern GH therapy for GHD to be compared with older treatment modalities. The study offers the advantage of larger numbers of cases than can be achieved in individual trials and allows assessment of the use of GH therapy for GHD of comparatively uncommon causes.     

Physiological Growth Hormone Secretion and Response to Growth Hormone Treatment in Children with Short Stature and Intrauterine Growth Retardation

Stanhope, R., Ackland, F., Hamill, G., Clayton, J., Jones, J. and Preece, M.A. (Department of Growth and Development, Institute of Child Health, London and Serono Laboratories, UK). Physiological growth hormone secretion and response to growth hormone treatment in children with short stature and intrauterine growth retardation. Acta Paediatr Scand [Suppl] 349: 47, 1989.
Physiological growth hormone (GH) secretion was examined in 31 children (8 girls, 23 boys) with short stature secondary to intrauterine growth retardation (IUGR). Seventeen (4 girls, 13 boys) had dysmorphic features of Russell-Silver syndrome. Four of the 31 children had GH insufficiency with peak GH levels of < 20 mU/I during the night. Nine of the patients (8 of whom had Russell-Silver syndrome) had a single nocturnal GH pulse. Twenty-three children (6 girls, 17 boys) were randomized into two groups treated with either 15 or 30 U/m²/week of GH by daily subcutaneous injections. Age, sex distribution, pretreatment height velocity SD score (SDS), and distribution of dysmorphic and non-dysmorphic children were similar in both groups. The group treated with 15 U/m2/week for a mean of 0.82 years showed an increase in mean height velocity SDS from - 0.61 to +1.09, and the group treated with 30 U/m²/week for a mean of 0.92 years showed an increase in mean height velocity SDS from -0.69 to +3.48. The results suggest that physiological GH insufficiency is probably common in children with Russell-Silver syndrome and that both dysmorphic and non-dysmorphic children with short stature secondary to IUGR will respond to GH treatment. Initial evidence suggests that the increase in short-term growth velocity does not result in an improved final height prognosis.     

Diagnostic Value of Growth Hormone-Releasing Hormone Tests in Short Children

Butenandt O. (Department of Paediatric Endocrinology, Children's Hospital, University of Munich, Munich, West Germany). Diagnostic value of growth hormone-releasing hormone tests in short children. Acta Paediatr Scand [Suppl] 349 93, 1989.
The growth hormone-releasing hormone (GHRH) test was applied to more than 230 children. Twenty-five out of 61 patients with proven growth hormone (GH) deficiency responded to GHRH with a GH increase of greater than 10 ng/ml. In most of the patients with idiopathic GH deficiency, a priming procedure using daily injections of GHRH improved the secretory response to GHRH. Nearly all children with familial shortness of stature showed a prompt increase in GH levels, with a mean peak level of 34.9 ng/ml (range 0.5–144 ng/ml). A second test was performed in five children with familial short stature because of failure to respond to the first test. Children with constitutional delay of growth and development did not differ in their GH response from patients with familial shortness of stature. Ten girls with Ullrich-Turner's syndrome responded with a mean increase of 22 ng/ml GH (range 10.1–34.0 nglml). Therapy with glucocorticoids, as well as endogenous hypersecretion of cortisol, suppressed the responsiveness of the pituitary gland to GHRH. Suppression was also observed following a single dose of dexamethasone during the steroid-suppression test in eight obese children. Low responsiveness of the pituitary gland was also seen in patients with thalassaemia and transfusion-induced haemosiderosis. It is concluded that it is not possible to detect GH deficiency with a single GHRH test. A full endo-crinological evaluation is necessary to prove the diagnosis.     

Growth hormone therapy in short stature

Unlimited availability of growth hormone (GH), and the demonstration of increased growth velocity (GV) during GH treatment in non-GH-deficient children have suggested new indications for GH therapy in short stature. There are two principle conditions with GH-related short stature: classical growth hormone deficiency (CGHD) and growth hormone neurosecretory dysfunction (GHND). Present knowledge about the effects of GH treatment in these and other disorders of short stature are reviewed. In non-CGHD, it is not possible to predict the short-term effect on growth during GH therapy, and even if GV increases, the effect on final adult height remains to be documented. This, together with potential side effects and the high expense of GH treatment, exhort to a restricted attitude towards routine GH treatment of short children without GH deficiency.     

Growth Response in Prepubertal Children with Idiopathic Growth Hormone Deficiency during the First Year of Treatment with Human Growth Hormone. Analysis of the Kabi International Growth Study.

ABSTRACT. In order that children with growth hormone deficiency (GHD) reach the goal of normal adult stature, treatment modalities need to be optimized. From the large database of patients enrolled in the Kabi International Growth Study (KIGS), 257 prepubertal patients with idiopathic GHD undergoing their first year of growth hormone (GH) substitution therapy were selected. A multiple regression analysis was performed to determine both auxiological factors characterizing the patients and the factors related to the chosen treatment modalities which are of significance for the observed magnitude of the growth response. Due to the structure of the data, pretreatment height velocity and bone age-derived auxiological data were not considered. It was observed that the magnitude of the growth response was inversely correlated with chronological age and relative height (HT SDS) at the start of GH treatment but was positively correlated with mid-parental height. The growth response was also positively correlated with the GH dose (IU/kg/week) and the frequency of GH injections per week. A regression equation using these five parameters was derived, allowing the growth response of these patients to be predicted. The extension of this analytical approach in the future will allow the treatment of patients with GHD to be tailored to individual requirements.     

Effects of Short-Term Growth Hormone Therapy in Short Children without Growth Hormone Deficiency

ABSTRACT. Evaluation of 24-hour endogenous growth hormone (GH) secretion was carried out in 62 children, aged 7-16 years, who did not have classic GH deficiency (GHD). The mean 24-hour GH concentration, determined at 20-minute intervals over 24 hours, was variable, ranging from 1.28 to 11.39 μg/l with a mean of 4.95 ± 2.55 μl (± SD). There was a positive correlation between mean 24-hour GH concentration and plasma insulin-like growth factor I (IGF-I) values ( r = 0.54; p < 0.01). Recombinant human GH, 0.1 IU/kg/day was administered to 30 of the 62 children for 6 months followed by 6 months'observation without treatment. Thereafter, GH was administered at the same dose for a further 6 months to 16 children. The mean height velocities before, during, and after the first treatment period were 4.3 ± 0.9, 7.3 ± 1.9 and 4.9 ± 2.0 cm/year (mean ± SD), respectively. The height velocity during treatment was greater than pre- and post-treatment values ( p < 0.001). The height velocity Increased again during the second treatment period to a mean of 8.5 ± 2.0 cm/year ( p < 0.001). Nine other children were treated continuously in a similar manner for 1 year and their height velocity increased significantly from 4.1 ± 1.4 to 6.0 ± 1.9 cm/year ( p < 0.001). According to our criteria, 29 of the 39 children (74.4%) who were treated for 6-12 months showed a GH-dependent height increase during therapy. There were no differences between the children who responded to GH treatment and those who did not in terms of Chronological age, bone age, plasma IGF-I level, maximal GH level to insulin-induced hypoglycaemia, or mean 24-hour plasma GH concentration. These data indicate that some short children without GHD respond to GH treatment with an increased height velocity. Further investigations are required to determine the effect of GH on final height.     

Growth Hormone Response to Growth Hormone-Releasing Hormone (hp GHRH-1-44) as an Index of Growth Hormone Secretory Dysfunction after Prophylactic Cranial Irradiation for Acute Lymphoblastic Leukemia (24 Grays)

ABSTRACT. The growth hormone response to growth hormone releasing hormone hp GHRH_1-14 (2 μg/kg i.v.) was studied in 19 prepubertal children who had been irradiated with 24 Gy for acute lymphoblastic leukemia (ALL) or lymphosarcoma (LS) at a mean chronological age of 410/12 years (limits 10/12 to 9 years). They were evaluated after a mean time interval of 4 8/12±3/12 years and compared to 14 prepubertal children with constitutional short stature (CSS). The individual responses to GHRH were decreased in all but three of the irradiated children. The mean GH response was 16.7±2.5 ng/ml as compared to 52.6±8.5 ng/ml in the control group ( p <0.001). The GH response to GHRH was not correlated with the GH response to arginine-insulin tolerance test (AITT). A decreased response to GHRH with values between 12.5 and 19.4 ng/ml was observed in four cases with normal growth rates and normal GH responses to AITT. These results suggest that an impaired GH response to GHRH is a frequent finding after cranial irradiation for ALL or LS and may be the only sign of GH secretory dysfunction. It is probably indicative of early hypothalamic impairment of GH secretion.     

Noonan's Syndrome: Abnormalities of the Growth Hormone/IGF-I Axis and the Response to Treatment with Human Biosynthetic Growth Hormone

ABSTRACT. 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.     

Update on the Kabi International Growth Study, April 1989

International Board, Kahi International Growth Study (Kahi, Stockholm, Sweden). Update on the Kahi International Growth Study, April 1989. Acta Paediatr Scand [Supp] 356: 173, 1989.
The efficacy and safety of recombinant human growth hormone (rhGH) treatment is under prospective evaluation in children with various short stature conditions. Of the 987 children enrolled up to April 1989, 836 (84.7%) had classic growth hormone deficiency (GHD) and 151 (15.3%) non-GHD. There was a predominance of idiopathic growth hormone deficiency (IGHD), with a ratio of IGHD to secondary or organic GHD (OGHD) of 2.2:l. There were more boys than girls in both the IGHD and OGHD groups. Isolated GHD was more common than multiple pituitary hormone deficiency except in some of the groups with OGHD. About half of the OGHD patients had GHD secondary to treatment for CNS tumours. Idiopathic short stature and Turner's syndrome were the most common diagnoses in the non-GHD group. The median age at onset of treatment in IGHD was 8.2 years for boys and 8.6 years for girls. The corresponding figures for OGHD were 14.0 years and 12.2 years, respectively. The height SDS for chronological age at the start of treatment was -3.0 for IGHD and slightly less for children with OGHD. Approximately one-third of the children had already reached puberty at the start of hGH treatment.     

Growth hormone deficiency in Dubowitz syndrome

Severe short stature as a result of intra-uterine growth retardation is one of the characteristics of Dubowitz syndrome. There have been few reports elaborating growth hormone secretory status in this syndrome. A child with Dubowitz syndrome, who was found to have complete growth hormone (GH) deficiency and who responded to growth hormone therapy, is described. This appears to be the first documentation of GH deficiency in this syndrome.     

Modification of 24-Hour Growth Hormone Secretion after Continuous Subcutaneous Infusion of Growth Hormone-Releasing Hormone (GHRH (1–29)NH2) in Short Children with Low 24-Hour Growth Hormone Secretion

Tauber, M.T., Pienkowski, C., Landier, F., Gunnarsson, R. and Rochiccioli, P. (Department of Paediatric Endocrinology, CHU Rangueil, Toulouse Cedex, and Kabi Laboratory, Paris, France and Kabi Peptide Hormones, Stockholm, Sweden). Modification of 24-hour growth hormone secretion after continuous subcutaneous infusion of growth hormone-releasing hormone (GHRH (1–29)NH₂) in short children with low 24-hour growth hormone secretion. Acta Paediatr Scand [Suppl] 349: 117, 1989.
Six short children with low 24-hour growth hormone (GH) secretion were treated with continuous subcutaneous infusion of GHRH (1–29)NH₂ for 3 weeks using a portable infusion pump. Restoration of pulsatile GH secretion was observed in all three children treated with 40 pg/kg/day of GHRH, but in only one of the three children treated with 20 pg/kg/day. All parameters of 24-hour GH secretion increased, but in five children the magnitude of the GH response was greater on day 1 than on day 21 of CHRH treatment. This decrease was not observed in the single child who responded to a low dose of GHRH (20 pg/kg/day); on the contrary, the response in this patient was greater after 21 days of GHRH treatment. Plasma levels of GHRH (1–29)NH₂ were significantly higher on day 21 than on day 1 of treatment, suggesting altered pharmacokinetics over time. The effect of GHRH treatment on growth could not be determined because of the short duration of the study, but the data obtained on 24-hour GH secretion and GHRH metabolism suggest that a long-acting analogue of GHRH could be useful for the treatment of GH deficient or insufficient children.     

Synchronization of Growth Hormone Therapy

Based on the hypothesis of periodical refractoriness of the growing tissue to exogenous administration of GH, an experimental approach is presented in which the dosage of GH was adjusted to the natural occurrence of periodical changes of the lower leg growth velocity in five children with short stature. Two 6-month periods were compared, during which the children received an identical cumulative dose of GH of 224 IU/m². During the first period, the children received a constant GH dose of 14 IU/m²/week by daily subcutaneous injection, whereas a low/high dose alternation was administered at approximately 3-week intervals synchronously with the occurrence of mini growth spurts during the second 6-month period. In all the children, mean linear growth of the lower leg accelerated during the period of synchronization by 595% compared to the previous growth rate during constant GH administration.     

Growth Hormone Secretion and Growth Hormone Treatment in Children with Intrauterine Growth Retardation

Albertsson-Wikland, K. (Departments of Paediatrics II and Physiology, University of Gothenburg, Gothenburg, Sweden). Growth hormone secretion and growth hormone treatment in children with intrauterine growth retardation. Acta Paediatr Scand [Suppl] 349: 35, 1989.
Few children with intrauterine growth retardation (IUGR) fail to show catch-up growth during the first year of life. There may he many reasons for this, ranging from disturbances of hormone production to hormonal unresponsiveness of target cells. This report presents preliminary data on growth hormone (GH) secretion and responses to GH treatment in 16 children with IUGR and poor catch-up growth, six of whom had Silver-Russell stigmata. GH secretion was assessed by measurement of the GH response to an arginine-insulin test and determination of spontaneous GH secretion over 24 hours. GH production was heterogeneous hut, more often than expected, children showed both a low response to GH provocation and low spontaneous secretion of GH. Five out of six of the children with Silver-Russell syndrome and seven out of 10 of the children with non-Silver-Russell IUGR gained more than 2 cm in height during 1 year of treatment with GH at a dose of 0.1 IU/kg/day. These results clearly demonstrate that some children with IUGR and poor catch-up growth secrete insufficient amounts of GH, and that many of these very short children show an improvement in growth rate during treatment with physiological doses of GH.     

Growth Hormone Treatment in Non-Growth Hormone-Deficient Children: Effects of Stopping Treatment

ABSTRACT. Overnight physiological growth hormone (GH) secretion was evaluated in 95 short, prepubertal children (73 boys, 22 girls). All the children were below the 3rd centile for height and achieved CH levels greater than 15 mU/1 following pharmacological stimulation. The mean average GH level was 7.1 mU/l and the mean sum of pulse amplitudes 80.4 mU/l. No relationship was found between age, height or height velocity and any of the parameters of GH secretion. The group was randomized to receive placebo, GH or remain under observation for the first 6 months and then all patients received GH treatment for a further 6 months. Those treated with GH, 0.27 IU/kg (0.1 mg/kg) three times weekly, in the first phase. demonstrated a mean increase in height velocity SDS of 3.24. There was no difference in growth response between the placebo or observation groups. In the second 6-month period. all children received GH according to the same dose regimen: they were then observed for a further 6 months following its discontinuation. In the 6 months following withdrawal of GH, all groups showed a significant fall in height velocity SDS, which returned to pretreatment levels, without demonstrating'catch-down'growth. Repeat sampling of overnight GH secretion within 3 days of discontinuing GH showed normal secretory patterns with a small reduction in mean peak amplitude. These results suggest that short children without classic GH insufficiency respond well to exogenous GH in the short term and return to pretreatment height velocities afterwards. Consequently, it may be possible to increase final adult height in such children by GH treatment.     

Growth hormone treatment of short children born small-for-gestational-age: the Nordic Multicentre Trial

The aims of this study were to evaluate the efficacy and safety of different doses of growth hormone (GH) treatment in prepubertal short children born small-for-gestational-age (SGA). Forty-eight children born SGA from Sweden, Finland, Denmark and Norway were randomly allocated to three groups: a control group of 12 children received no treatment for 2 y, one group was treated with GH at 0.1 IU/kg/d (n = 16), and one group was treated with GH at 0.2 IU/kg/d (n = 20). In total 42 children completed 2 y of follow-up, and 24 children from the treated groups completed 3 y of treatment. Their mean (SD) age at the start of the study was 4.69 (1.61) y and their mean (SD) height was -3.16 (0.70) standard deviation scores (SDS). The children remained prepubertal during the course of the study. No catch-up growth was observed in the untreated group, but a clear dose-dependent growth response was found in the treated children. After the third year of treatment, the group receiving the higher dose of GH, achieved their target height. The major determinants of the growth response were the dose of GH used, the age at the start of treatment (the younger the child, the better the growth response) and the family-corrected individual height deficit (the higher the deficit, the better the growth response). Concentration of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 increased during treatment. An increase in insulin levels was found without negative effects on fasting glucose levels or glycosylated haemoglobin levels. GH treatment was well tolerated. In conclusion, short prepubertal children born SGA show a dose-dependent growth response to GH therapy, and their target height SDS can be achieved within 3 y of treatment given GH at 0.2 IU/kg/d. However, the long-term benefit of different regimens of GH treatment in children born SGA remains to be established.     

Growth Hormone Therapy of Short Stature1

ABSTRACT. Considerable progress has been made in the diagnosis and treatment of growth hormone-related short stature. Knowledge about growth hormone releasing factor (GRF) and somatomedin C has provided the possibility of distinguishing between hypothalamic and pituitary growth hormone deficiency and growth hormone resistance. It has been shown that treatment with GRF may stimulate growth in certain cases of growth hormone deficiency. Recombinant DNA techniques may, in the near future, provide sufficient amounts of GRF, growth hormone and possibly somatomedin C for clinical use. At present, many countries have prohibited the use of human pituitary growth hormone due to a possible risk of transmission of Creutzfeldt-Jakob disease. It has become increasingly clear that several short children without classical growth hormone deficiency, may increase their growth velocity during growth hormone treatment. There are many medical, psychological, ethical and economical implications involved in the extended treatment of children with short stature. It is necessary to maintain a restricted approach towards the treatment of children with short stature, and such treatment should be prescribed and controlled by a limited number of well-trained paediatric endocrinologists. This article reviews some of the present knowledge in this rapid developing field of paediatric endocrinology.