Daily subcutaneous administration of human growth hormone in growth hormone deficient children

Sixteen children (10 boys, 6 girls) on treatment for some years with i.m. injections twice or thrice weekly of human growth hormone (hGH; Crescormon Kabi Vitrum), participated in a prospective study. The weekly amount of hGH (8, 12, or 16 IU) was kept the same in each child, but divided into daily (7) s.c. injections at bedtime. The growth rate increased in all children during the first year on s.c. daily hGH (5.3 to 7.4 cm/year; 1.95 to 4.27 SDS). This increased growth rate did not persist during the second year on daily s.c. hGH, but an increased growth rate did not persist during the second year on daily s.c. hGH, but an increased predicted final height was found. The plasma profile of hGH was followed: i.m. injected hGH gave mostly a high (200 mU/l) plasma level of some hours (wide intra- and interpatient variation), and s.c. injected hGH a lower max level of longer duration (wide inter patient variation). The daily s.c. regimen of hGH was extremely well accepted by the children and their parents and no GH-antibodies or other adverse effects were found. We recommend daily s.c. injection of hGH as an alternative in the treatment of GH-deficient children.     

The Effect of Human Growth Hormone Injection Frequency on Linear Growth Rate

Albertsson-Wikland, K. (Departments of Paediatrics II and Physiology, University of Gothenburg, Gothenburg, Sweden). The effect of injection frequency on linear growth rate. Acta Paediatr Scand [Suppl] 337:110, 1987.
hGH has been used in the treatment of hGH deficient children for nearly 30 years. The optimum treatment regimen is, however, still unknown. Generally, administration has been by 2 or 3 intramuscular injectiodweek and the total weekly dose has been 0.3–0.5 IU/kg. Many factors are known to influence the effect of treatment, such as the dose and the age of the child. In animal studies, the optimum growth rate occurs when the physiological pulse frequency of growth hormone is simulated (i.e. intravenous infusions of growth hormone every 3 hours in the rat). In humans, optimal growth rates occur in children in whom the spontaneous secretion of hGH is associated with many peaks (pulses) of high amplitude. In hGH deficient children, growth rate increases when the weekly dose of hGH is administered daily rather than 2–3 times/week, thereby optimizing the body's utilization of the hormone. The hGH plasma profile after daily subcutaneous hGH injections is, however, different from the hGH plasma profiles of children growing normally, in whom hGH secretion is episodic with many sharp pulses during the day and night. Whether simulation of normal hGH plasma profiles will increase the growth rate in hGH deficient children and normalize their adult height requires further investigation.     

Immunological and Endocrinological Response to Growth Hormone Therapy in Short Children

ABSTRACT. We investigated the influence of human growth hormone (hGH) on mitogen-stimulated lymphoproliferation, in vitro IgM production, serum levels of immunoglobulins, somatomedin-C (Sm-C) values and serum growth-promoting activity (Thymidine Activity, TA) in 18 short children, aged between 6.6–14.5 years, undergoing a 3-month course of hGH therapy. Blood was collected the day before treatment (Group A), on the 5th day after patients were administered hGH daily (0.1 U/kg) i.m. for 4 days (Group B), after a 3-month course of hGH injected three times weekly, and finally before (Group C) and 24 h after an extra injection (Group D). In vitro IgM production from the patients' unstimulated lymphocytes decreased from 277±41 (Group A) to 168±38 (Group B), to 119±43 (Group C) and then to 119±28 ng/ml (Group D) ( p <0.05). Using PWM-stimulated lymphocytes in vitro IgM production decreased from 2015±464 (Group A) to 1116±316 (Group B), then to 511±170 (Group C) and 968±295 ng/ml (Group D) ( p <0.02). The variation of this decrease could be correlated with the variation of growth velocity during treatment ( r =0.619, p <0.05). In contrast, no significant changes were found following therapy either in serum levels of IgA, IgE, IgG, IgM, Sm-C and TA, or in phytohemagglutinin, concanavalin A and pokeweed mitogen-stimulated lymphoproliferation. Our data suggest that there is some relationship between growth hormone, growth and immunity.     

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.     

Who is Treated with Growth Hormone Today?

ABSTRACT. The present demographic data from the Kabi International Growth Study (KIGS) database are summarized. Of the 2580 patients included, 85% have growth hormone deficiency (GHD) and 15% have other causes of growth failure. Idiopathic GHD is present in 78.5% of the patients, the remaining 21.5% have organic GHD. Isolated GHD is common in idiopathic GHD whereas multiple pituitary hormone deficiencies occur in at least 50% of the organic GHD patients. A preponderance of boys is observed in most groups of patients. Median chronological age (CA) at start of treatment is 10 years and median duration of therapy is 2.3 years. However, a wide range is observed. In most cases growth retardation is severe. In most patients with GHD height SDS for chronological age at start of therapy is at or below -3. The median difference between idiopathic and organic GHD is 1 SDS. Most patients have 6 or 7 injections of growth hormone (GH) per week. The median total weekly dose is approximately 0.5 IU/kg/week, but it is lower in older patients. It is concluded that steadily increasing numbers of patients with idiopathic and organic GHD are being treated with human GH (hGH). In addition, many patients with other growth disorders not necessarily associated with GHD receive hGH therapy. Chronological age at start of treatment still appears to be (too) high in most patients and growth retardation severe. The frequency of hGH injections has been increased to nearly daily administration. However, the total weekly dose appears to be low, especially in the older patients. It is hoped that KIGS will contribute to improving the efficacy of treatment and hence the quality of life for all patients with growth disorders.     

Growth Hormone Releasing Hormone in the Assessment and Long-term Treatment of Growth Hormone Deficiency

The secretion of hGH after the administration of the analogue of growth hormone releasing hormone, GHRH (1–29)NH₂, to 8 normal adults and 41 short children has been studied. The children were classified on the basis of their hGH response to insulin-induced hypoglycaemia; 28 had severe hGH deficiency (peak serum hGH less than 7 mIU/litre) and 13 had simple short stature (peak serum hGH greater than 15 mIU/litre). The hGH response to GHRH was similar in normal adults and short stature children, but significantly lower in the hGH deficient children. In 23 (82%) of the hGH deficient children the peak serum hGH in response to GHRH was greater than 7 mIU/litre (the maximum value seen during hypoglycaemia), and in 14 (50%) the peak serum hGH in response to GHRH was greater than 15 mIU/litre. This suggests that in the majority of hGH deficient children the defect in hGH secretion results from hypothalamic GHRH deficiency. The hGH responses of the short stature children to insulin-induced hypoglycaemia were mainly in the low range of normal, and the majority showed normal hGH responses to GHRH. Eighteen prepubertal children with definite hGH deficiency have been treated for 3–18 months with twice daily, subcutaneous injections of GHRH. This has promoted linear growth in 12 children, of whom 8 showed an increment in height velocity of 2–11 cm/year. GHRH provides a valuable method for the assessment of hGH secretion, but by itself it cannot be used to establish deficient hGH secretion; this requires a stimulation test that promotes hypothalamic GHRH secretion, such as insulin-induced hypoglycaemia. GHRH is a practical alternative therapy to hGH for some hGH-deficient children.     

A Controlled Trial of Methionyl Growth Hormone Therapy in Prepubertal Children with Short Stature, Subnormal Growth Rate and Normal Growth Hormone Response to Secretagogues

ABSTRACT. Thirty short and slowly growing children with normal plasma growth hormone (GH) responses to standard provocation tests were randomly assigned to either a group ( n = 20) undergoing treatment with methionyl GH (somatrem), 2IU per m² body surface s.c. daily, or a control group ( n = 10). Twelve out of 18 children who completed the first year of treatment showed a height velocity increment of more than 2 cm/year. The mean (SD) growth velocity of the treatment group increased by 3.0 (1.9) cm/year over the first year, compared with -0.2 (0.7) cm/year in the control group. Neither parameters of endogenous GH secretion nor plasma IGF-I levels showed a significant correlation with the growth response. Of the auxological variables studied, pre-treatment growth velocity ( r = 0.8) and the short-term height velocity increment ( r = 0.7–0.9) showed significant correlations with the growth response in the first year of treatment. Somatrem therapy was without side effects, except in one child who developed anti-GH antibodies in combination with a poor growth response.     

Growth Hormone Treatment in Turner's Syndrome

ABSTRACT. A total of 21 patients with Turner's syndrome were treated with pituitary hGH and/or somatrem for 1–2 years. Plasma non-esterified fatty acid increased significantly from 0.52 ± 0.06 to 1.30 ± 0.09 mEq/litre at 4 hours after injection of hGH, 4 IU (mean ± SEM, p < 0.001). Basal plasma IGF-1 levels were within the normal range; however, they increased significantly at 24 hours after the first three daily injections of hGH, 4 IU (basal, 0.92 ± 0.14 units/ml; 24 hours, 1.39 ± 0.16 units/ml; 48 hours, 1.68 ± 0.19 units/ml; 72 hours, 1.91 ± 0.22 units/ml; p < 0.001). For long-term treatment, patients were given hGH, 4–16 IU for 1–2 years. Their height velocity increased to 5.5 ± 1.2 cm/year and 5.1 ± 0.6 cm/year in the first and second year of the treatment, respectively. These values were greater than the pretreatment value of 3.6 ± 0.8 cm/year (p < 0.001). Antibody against hGH was observed in 60% of the patients at the end of 12 months of somatrem treatment. Otherwise there were no significant changes in physical, blood or urine examinations. These results indicate that hGH treatment is useful for the acceleration of growth velocity in patients with Turner's syndrome.     

Growth Hormone Treatment in Short Children

ABSTRACT. A study of 31 children with short stature was initiated in 1982. They received subcutaneous injections of pituitary hGH, 0.1 IU/kg/day; no adverse effects were seen and none of the patients acquired antibodies. Only the results of the first year are presented, as final height has not yet been attained. A high growth response was seen in 29 of the 31 children; they experienced an initial rise of IGF-1, IGF-2, alkaline phosphatase and procollagen III. The best response was obtained in the child with the lowest levels of endogenous pulsatile hGH secretion.     

Growth hormone therapy with a new delivery system

Until recently the general regimen for treatment of growth hormone deficient (GHD) children consisted of 2 to 3 intramuscular (i.m.) injections per week using conventional syringes and vials. However, studies within the last 5–10 year have shown that by dividing the same total weekly dosage into daily subcutaneous (s.c.) injections it is possible to achieve a significantly increased growth rate. To make it more feasible for the patients and the parents to cope with this increased number of injections, an injection pen system (Nordiject) for administration of B-hGH has been developed. The Nordiject pen has been investigated both with respect to patient acceptance and bioavailablity of the B-hGH (Norditropin) injected with the device. Twenty-seven children with growth retardation were included in a study. The patients had no problems with the handling of the pen and approximately 2/3 of them experienced less injection pain with the pen compared to the syringe. Those patients who had previously been using conventional syringes strongly preferred the pen, and all wished to continue using the device.Fourteen adult GHD patients were included in a randomized cross-over study for investigation of bioavailability. Two separate s.c. injections of 4 IU of B-hGH (Norditropin) each were administered in random order by means of either syringe (4IU/ml) or injection pen (Nordiject) (12 IU/ml). On the basis of this study it was concluded that the bioavailability of B-hGH, measured as AUC, C _max′ and t _max′ is equal following injection with the pen to that of injection by syringe.     

Growth Response to Daily Subcutaneous Administration of Growth Hormone

The effect on growth rate of daily subcutaneous (sc) administration of growth hormone (GH) was studied in seven GH-deficient children. All patients had been receiving conventional GH treatment (intramuscularly, twice or thrice weekly) for three to six years. The growth-promoting effect of conventional treatment gradually decreased in these seven patients [4.0 ± 0.3 (mean ± SD) cm%sol;year during the last preceding year of conventional treatment]. Following transfer to daily sc GH treatment without increase in weekly dosage, all seven patients showed an increase in growth rate (7.5 ±1.1 cm%sol;year, P>0.001). During the period of daily sc GH treatment, the pubertal stage did not advance in six of the seven patients. An increase in Δheight age%sol;Δbone age ratio was observed in six patients. None of the patients developed antibodies against GH. Local reactions were not observed at the injection site. Daily sc GH injections were tolerated without complaint. In conclusion, daily sc GH treatment is recommended for patients whose growth response to conventional GH treatment is poor.     

重组人生长激素替代治疗对生长激素缺乏症患儿糖代谢的影响

目的观察国产重组人生长激素(r-hGH)替代治疗对生长激素缺乏症(GHD)患儿糖代谢的影响。方法用国产r-hGH对GHD 15例患儿治疗3个月。治疗前后行口服葡萄糖耐量试验(OGTT)及胰岛素(INS)释放试验(IRT)。分别于0、30 mun,1、2 h采静脉血行血浆葡萄糖(PG)及胰岛素(INS)测定。结果治疗前患儿糖耐量均正常,治疗3个月后OGTT空腹PG 无明显增加,但PG 30min(P<0.01)、1 h(P<0.05)、2 h(P<0.05)、血糖曲线下面积(AUCglu)(P<0.01)均明显增加;虽葡萄糖耐量曲线上移,但均未出现糖耐量损伤(IGT)或糖尿病(DM)。IRT空腹INS(P<0.05)、30 min(P<0.05)、1 h(P<0.01)、2 h(P<0.01)、INS曲线下面积(AUCins)(P<0.01)均显著增加,稳态模型胰岛素抵抗指数(Homa IR)明显上升(P<0.05)。结论GHD患儿r-hGH替代治疗3个月后INS敏感性下降,糖耐量降低,提示应用r-hGH替代治疗患儿应监测PG、INS水平     

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.     

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.     

Antigenic Epitope Mapping of the Human Growth Hormone Molecule: A Strategy to Standardize Growth Hormone Immunoassays

ABSTRACT. The antigenic surface of the human growth hormone (hGH) molecule has been characterized by means of monoclonal antibodies (MAbs) and their specific binding sites. From a panel of MAbs raised against the 22 kDa variant of hGH, ten distinct antigenic entities could be identified as binding sites for specific MAbs in an epitope mapping experiment. The experiment was based on combinations of the MAbs in two-site assays. By investigating the cross-reactivity of the MAbs with growth hormone (GH) variants and fragments of hGH, the underlying protein structure of some of the partially overlapping epitopes could be identified. By using antibodies of known epitope specificity as competitors in receptor binding assays of hGH, it was demonstrated that the lactogenic and somatogenic biological effects of hGH are mediated through different portions of the hormone. These observations may explain some of the differences between the various immunoassays for hGH. A strategy for selecting antibodies of known epitope specificity and biological relevance for the design of plasma GH immunoassays is outlined. The results of such an immunoassay should closely reflect the biological activity of circulating plasma hGH.     

Growth Response in the First Year of Growth Hormone Treatment in Prepubertal Children with Organic Growth Hormone Deficiency: a Comparison with Idiopathic Growth Hormone Deficiency

ABSTRACT. Patients in the Kabi International Growth Study (KIGS) up to 1st January 1990 who had organic growth hormone deficiency (OGHD) were identified. They accounted for 21% of all patients with growth hormone deficiency (GHD). Diagnostic categories within the OGHD group included septo-optic dysplasia, postnatal trauma, craniopharyngioma, other cranial tumours, and following acute leukaemia. Features at presentation and during the first year of hGH treatment were compared with those of children with idiopathic growth hormone deficiency (IGHD). Ninety prepubertal children with OGHD were selected for comparison of observed first-year height velocity (HV) with predicted values based on those observed in 257 children with IGHD. Those with septo-optic dysplasia, postnatal trauma and craniopharyngioma responded as predicted, whereas those with other cranial tumours appeared to grow less well than predicted. Glucocorticoid treatment did not affect response, but previous cranial or craniospinal irradiation was found to be associated with an observed HV which was significantly less than predicted.     

Comparison of dose frequency of human growth hormone in treatment of organic and idiopathic hypopituitarism

Two weekly (biw) injections of pituitary human growth hormone (hGH) were compared with three weekly (tiw) injections of hGH (0.24 IU hGH/kg body weight/wk for both groups) for effect on growth rate in children with idiopathic and organic hypopituitarism. Both dosage schedules resulted in increased growth rate during the first 12 months of therapy; the tiw dosage was more effective in the first 6 months in patients with organic hypopituitarism, and in the second 6 months in patients with idiopathic hypopituitarism. There was no advantage to tiw therapy during the second year of therapy in either group. The additional increment in height after 1 year of therapy using tiw compared with biw therapy was 2 cm and 1 cm for the patients with organic and idiopathic hypopituitarism, respectively. This increment should be weighed against the cost, pain, and inconvenience of tiw versus biw doses of hGH in the treatment of hGH deficiency. With the dosages used in this study, tiw therapy was more effective during the first year, when patients are more responsive, and should be recommended. Twice weekly therapy could be considered for the second and possibly subsequent years of therapy. Other schedules of treatment may be more effective than either of these schedules.     

A controlled trial of methionyl growth hormone therapy in prepubertal children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group

Thirty short and slowly growing children with normal plasma growth hormone (GH) responses to standard provocation tests were randomly assigned to either a group (n = 20) undergoing treatment with methionyl GH (somatrem), 2 IU per m2 body surface s.c. daily, or a control group (n = 10). Twelve out of 18 children who completed the first year of treatment showed a height velocity increment of more than 2 cm/year. The mean (SD) growth velocity of the treatment group increased by 3.0 (1.9) cm/year over the first year, compared with -0.2 (0.7) cm/year in the control group. Neither parameters of endogenous GH secretion nor plasma IGF-I levels showed a significant correlation with the growth response. Of the auxological variables studied, pre-treatment growth velocity (r = -0.8) and the short-term height velocity increment (r = 0.7-0.9) showed significant correlations with the growth response in the first year of treatment. Somatrem therapy was without side effects, except in one child who developed anti-GH antibodies in combination with a poor growth response.     

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-Promoting Effect of Human Growth Hormone on Patients with Achondroplasia

To evaluate the effect of human growth hormone (hGH) on the growth of children with achondroplasia, three patients with achondroplasia and one patient with hypochondroplasia were treated with 0.5 IU/kg/W of pituitary-extracted hGH for 6–12 months. Mean height velocity was significantly increased from 4.0 0.4 to 7.5 0.7 cm/year (P0.05) by hGH. The tibial index, defined as the length/width ratio of left tibia, did not change during the treatment, indicating that hGH promotes growth without exaggeration of tubular bone deformity. Case 2, who had atlantoaxial dislocation, developed sleep apnea and neurological deficits during the second hGH treatment, but these were cured by operation. Thus, hGH therapy is effective in promoting growth in patients with achondroplasia, but the complication of atlantoaxial dislocation should be explored and corrected before the treatment.