Insulin-like growth factor-I (rhIGF-I) therapy of short stature

The United States Food and Drug Administration (FDA) approved the use of subcutaneously injected rhIGF-I in late 2005 for treatment of children with severe short stature from growth hormone (GH) insensitivity due to genetic defects in the GH receptor or postreceptor mechanisms or from the development of GH inactivating antibodies. The approval was based on 15 years experience treating these rare conditions with rhIGF-I. Because of the very small numbers of children with these conditions, there has been an effort to justify and promote broader use for rhIGF-I. Attempts to identify GH unresponsiveness in children with idiopathic short stature (ISS) have yielded only a handful of patients with rare genetic disorders. IGF-I treatment for unequivocal GH insensitivity improves but does not correct growth failure, in contrast to the typical experience with GH replacement of GH deficiency. This emphasizes the importance of direct effects of GH at the growth plate, including the stimulation of maturation of cartilage precursor cells and local production of IGF-I, effects that cannot be duplicated by exogenous administration of rhIGF-I. Adverse effects testify to the more than adequate delivery of administered rhIGF-I to other tissues; these include lymphoid hyperplasia, coarsening of the facies, and increased percentage body fat. The absence of convincing evidence of GH insensitivity in a substantial number of children with ISS, the limited ability of endocrine IGF-I to restore normal growth in those with unequivocal GH unresponsiveness, the suppression of endogenous GH (and thereby, local GH effects on growth) that occurs with IGF-I administration, the risk profile, and the absence of data on efficacy in other than proven severe GH insensitivity, led the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society to conclude that rhIGF-I use is only justified in conditions approved by the FDA and that other growth promotional use should only be investigational. Nonetheless, substantial numbers of children are being treated with rhIGF-I off-label, exuberant estimates of potentially eligible patients are projected, and several uncontrolled clinical trials have been undertaken which are not based on sound preliminary data or established growth principles, and a single four-arm study begun comparing monotherapy with rhGH to combination rhGH with three dosages of rhIGF-I as a single daily injection, a means of administration of rhIGF-I that has not been tested.     

Effects of insulin-like growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insensitivity syndrome. GHIS Collaborative Group

Eight children with growth hormone insensitivity syndrome (GHIS) have been treated with injections of recombinant human insulin-like growth factor I (rhIGF-I) for more than 5 years each. After good acceleration of growth in the first year of therapy, the growth rate decreased to an average of 5-6 cm/year. In general, growth with IGF-I therapy is less exuberant than that observed with growth hormone (GH) therapy in GH-deficient children. IGF is well tolerated, though there may be overgrowth of the lymphoid tissues and the kidneys. Bone mineral density is improved by treatment. The benefits of therapy appear to exceed the risks.     

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.     

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.     

Normal stimulated growth hormone secretion but low peripheral levels of insulin-like growth factor I in prepubertal children with insulin-dependent diabetes mellitus

The hypothalamo-pituitary-insulin-like growth factor I (IGF-I) axis was studied in 24 prepubertal children with insulin-dependent diabetes mellitus (IDDM) and 12 non-diabetic children. There were no significant differences between the diabetic and control subjects in basal concentrations of immunoreactive growth hormone releasing hormone (ir-GHRH), growth hormone (GH) or stimulated GH levels, but after exercise ir-GHRH concentrations were higher in the diabetic children. Peripheral IGF-I levels were significantly lower in the diabetic children, and even lower in those with poor metabolic control. A positive correlation was found between IGF-I levels and circulating free insulin concentrations in the diabetic subjects (r = 0.49, p < 0.05). These observations suggest that the GH response to physiological stimulation is normal in prepubertal diabetic children. Exercise-induced GH response may not be mediated by GHRH. IGF-I levels were reduced in prepubertal children with IDDM and even more so in subjects with poor metabolic control. This may be a consequence of transitory hypoinsulineamia, emphasizing the importance of adequate insulinization to facilitate optimal growth in children and adolescents with IDDM.     

Growth hormone therapy improves growth in children with cystic fibrosis related liver disease

Growth impairment in cystic fibrosis (CF) is worsened by liver disease. Children with CF have serum levels of insulin-like growth factor-I (IGF-I) that are lower than expected for their normal growth hormone (GH) production. In children with CF-related liver disease (CFLD), response to endogenous GH is further reduced. We present our experience with two young children with CFLD given recombinant human GH (rhGH). The first patient was a 5 year-old female with CFLD and poor growth who responded well for 1 1/2 years to rhGH therapy during her initial course and without a significant increase in serum IGF-I, but with a substantial increase in IGF-I concentration when the GH dose was increased. The second patient was a 5 month-old male with advanced liver disease who had transient improved growth and liver function following rhGH. These patients suggest that rhGH is safe and may be effective in children with CFLD.     

Growth hormone treatment in short children with beta-thalassemia major

The effect of one year recombinant human growth hormone (rhGH) treatment on growth rate and bone age was studied in ten short prepubertal children with beta-thalassemia major (age range 7.10-12.03 yr) with normal GH response to provocative stimuli. rhGH was given subcutaneously every day in a dose of 28 IU/m2/week. In the 10 children who completed 12 months of treatment the growth velocity increased from 4.22+/-0.81 cm/yr (-1.38+/-0.80 SDS for CA) to 7.61+/-1.16 cm/yr (+2.27+/-1.64 SDS for CA). IGF-I was low before treatment, 138.3 +/-38.9 ng/ml, and rose significantly to 232.2+/-122.1, 243.2+/-98.4 and 227.5+/-86.2 at 3, 6 and 12 months post-treatment, respectively (p<0.01). Bone maturation was accelerated in proportion to the increase in chronological age. The mean pre-treatment bone age in the ten children was 8.20+/-1.97 and increased to 9.55+/-1.80 yr after one year of treatment. Our data demonstrate that GH treatment of thalassemic children with normal GH reserve and low serum IGF-I concentrations with supraphysiological doses of rhGH for one year can cause a significant increase in serum IGF-I levels and growth velocity, but it remains to be elucidated whether long-term administration will affect the final height.     

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.     

Predictors of first-year growth response to a fixed-dose growth hormone treatment in children born small for gestational age: results of an open-label, multicenter trial in the United States

BACKGROUND: Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. AIM: To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. METHODS: 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. RESULTS: Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. CONCLUSION: GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.     

Growth hormone treatment of children with Prader-Willi syndrome affects linear growth and body composition favourably

We have compared the growth and the body composition in children with Prader-Willi syndrome (PWS) with and without growth hormone treatment (recombinant GH 0.1 IU/kg/day) after a 1-y period. Twenty-nine prepubertal children with PWS, with mean body mass index (BMI) SDS of 2.2, and 10 (control) healthy obese children with mean BMI SDS of 5.6, underwent 24-h frequent blood sampling. Both PWS and control obese children had low and similar GH levels (0.7 /ng/l ± 0.4 SD). Serum IGF-I levels, however, were significantly lower in children with PWS (-1.5 SDS ± 0.8 SD vs -0.2 SDS ±0.8 SD). The 29 PWS children were randomized into 2 groups of 15 and 14 subjects for GH treatment and no treatment, respectively. Height velocity increased from -1.9 SDS to + 6.0 SDS in the treated group ( p < 0:001) and decreased from -0.1 SDS to -1.4 SDS in the control PWS group during the study year. BMI decreased significantly for the treated group (+3.0 SDS to + 2.0 SDS). Relative fat mass decreased significantly, while fat-free mass increased ( p < 0:001) for the treated group. No significant changes were noticed in body composition in the control PWS group. In conclusion, the low spontaneous 24-h GH secretion, regardless of body weight, and the exceptional response to growth hormone treatment together with the finding of low IGF-I levels suggest that growth hormone deficiency is a common feature of PWS, as a result of hypothalamic dysfunction. Treatment with growth hormone is beneficial for the majority of PWS children.     

Serum levels of insulin-like growth factor (IGF)-I, free IGF-I, IGF binding protein (IGFBP)-1, IGFBP-3 and insulin in obese children.

In simple obesity, spontaneous and stimulated growth hormone (GH) secretions are diminished. However, this diminished GH secretion does not result in decreased somatic growth in obese children. Although the increased insulin level, low insulin-like growth factor binding protein (IGFBP)-1 and the resulting increase of bioavailability of insulin-like growth factor I (IGF-I) have been suggested as being involved, the exact mechanism has not yet been established. We investigated serum IGF-I, free IGF-I, IGFBP-1, IGFBP-3 and insulin levels in 36 obese and 39 non-obese healthy children. Insulin and IGFBP-3 were significantly higher in the obese group than in the control group (p < 0.05, p = 0.001, respectively). IGF-I, free IGF-I, free IGF-I/IGF-I and IGFBP-1 levels in the obese children were not significantly different from those in the control group. A positive correlation was found between body mass index (BMI) and IGF-I in the obese children (r = 0.30, p = 0.05). IGFBP-3 levels correlated positively with IGF-I (r = 0.44, p < 0.005), and free IGF-I levels (r = 0.37, p = 0.05) in the obese children. A negative correlation was found between IGFBP-1 and insulin levels (r = -0.30, p = 0.05) in the obese children. We concluded that normal growth in obese children might be maintained through normal IGF-I and increased IGFBP-3 levels, which are stimulated by increased insulin levels or nutritional factors or by increased responsiveness to GH.     

Growth hormone, insulin-like growth factor I and sex hormones: effects on protein and calcium metabolism

The availability of non-invasive tracer technologies has greatly facilitated the study of the metabolic effects of nutrients and hormones, particularly in children. This brief review examines recent work on the effects of growth hormone (GH), insulin-like growth factor I (IGF-I), testosterone and oestrogen on rates of protein synthesis and degradation and lipolysis, as well as on body composition and bone calcium fluxes in young children and adults. GH acts indirectly on whole body protein pools via IGF-I, but GH appears to act directly on lipolysis. Testosterone stimulates protein synthesis independently of changes in GH concentrations and acts synergistically with GH to enhance whole body metabolism. Oestrogens and androgens both modulate calcium fluxes, enhancing calcium absorption and retention, and thereby underscoring the importance of both groups of hormones in bone calcium metabolism. Further understanding of the physiological role of these hormones during the critical years of adolescence will give us better tools with which to treat disorders of puberty and growth.     

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.     

Partial growth hormone insensitivity--idiopathic short stature is not always idiopathic

Heterozygous growth hormone receptor (GHR) gene defects are not a common cause of idiopathic short stature. Although some of these GHR mutations may result in relative insensitivity to growth hormone (GH) in other studies, obligate heterozygotes did not present any clinical manifestations. Although patients with GH insensitivity and elevated GH binding protein (GHBP) levels have been described, it may be a reasonable approach to screen children who have growth failure, low levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, and low levels of GHBP. Whether the sensitivity of this screening approach can be increased by administering pharmacological doses of GH for a few days and measuring the resultant increase in serum IGF-I concentration remains to be determined by ongoing studies.     

Two cases of insulin-dependent diabetes mellitus under insulin treatment with slow height velocity: Relationship of growth hormone-binding protein,metabolic control and growth

Inadequate blood sugar control in children with insulin-dependent diabetes mellitus (IDDM) sometimes results in low insulin-like growth factor-I (IGF-I) and sluggish height growth. High affinity growth hormone-binding protein (GHBP), which is identical to the extracellular domain of growth hormone (GH) receptor, is present in the human sera. We have determined GHBP activity in two cases of poorly controlled IDDM with low height velocity in relation to metabolic control in order to determine the mechanism of resistance to GH in this condition, as indicated by low levels of GH-dependent growth factor IGF-I in the face of high serum GH levels. GHBP activity was within the normal range in two cases of IDDM with slow height velocity, low IGF-I and high hemoglobin-A₁. In both cases, improved blood sugar control normalized IGF-I to result in accelerated height velocity without a major change in GHBP levels. These results may indicate either normal peripheral GH receptor or normal free portion of serum GH, and may suggest that the major defect in slow growth in poorly controlled diabetes is due to the post GH receptor.     

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children

Schwarze CP, Wollmann HA, Binder G, Ranke MB. Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children. Acta Paediatr 1999; Suppl 428:200-8. Stockholm. ISSN 0803-5326
The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from-1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGEBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS. □ Growth hormone treatment, insulin-like growth factor I, insulin-like growth factor binding protein-3, insulin-like growth factor generation test     

Interactions between the thyroid hormones and the hormones of the growth hormone axis

The normal secretion and action of the thyroid hormones and the hormones of the GH/IGF-I (growth hormone/ insulin-like growth factor I) axis are interdependent. Their interactions often differ in man from animal studies in rodents and sheep. Thus neonates with congenital hypothyroidism are of normal length in humans but IUGR (intrauterine growth retardation) in sheep. Postnatally normal GH/IGF-I secretion and action depends on an euthyroid state. Present knowledge on the interactions between the two axes is reviewed in states of hypo- and hyperthyroidism, states of GH/IGF-I deprivation and hypersecretion, as well as the relationship between IGF-I and thyroid cancer. Emphasis is given to data in children and aspects of linear growth and skeletal maturation.     

Anabolic and Tissue Repair Functions of Recombinant Insulin-Like Growth Factor I

ABSTRACT. Recombinant human insulin-like growth factor I (rhIGF-I) has been produced in yeast and purified using conventional biochemical techniques. It has been shown to have receptor-binding properties and in vitro growth-promoting activities comparable to those of plasma-derived IGF-I. The anabolic actions of IGF-I can be studied using both systemic and local administration in vivo. The growth-promoting activity and systemic anabolic actions of recombinant IGF-I were studied in mutant dwarf rats. IGF-I was infused intravenously for 9 days and resulted in a significant gain in body weight and significant bone growth, though the effects were not as great as those observed with human growth hormone (hGH). IGF-I also had selective effects on specific organs which were not observed in hGH-treated animals. The results indicate that the growth-promoting effects of IGF-I show a different pattern compared to hGH. The effects of local administration of recombinant IGF-I on tissue regeneration and maintenance were also studied in hypophysectomized and normal rats. After hypophysectomy, the regeneration processes were impaired when both peripheral nerve regeneration and incision wound healing were considered. The results indicate that local administration could have significant effects on regeneration of, for example, peripheral nerves.     

Asymmetrical closure of epiphyses in a patient with sickle cell anemia

There is a high incidence of delayed sexual development and short stature during childhood in children with sickle cell anemia (SCA). We report a 15 year-old male with SCA who presented with significant short stature after a near death event (involving seizures and prolonged hypoxia). His evaluation showed growth hormone (GH) deficiency with low insulin-like growth factor-I (IGF-I), low IGF binding protein-3, and low GH response to stimulation. He was started on GH replacement with poor response in height gain although with normal response in terms of elongation of his arm span. Further studies showed premature closure of the epiphyses of the femora and tibiae bilaterally. This report demonstrates that children with SCA may present with growth failure not only due to nutritional and GH abnormalities but also due to abnormal growth plates, probably due to local anoxic events. Children with SCA should always have their arm span measured carefully.     

Partial growth hormone insensitivity - idiopathic short stature is not always idiopathic

Saenger P. Partial growth hormone insensitivity - idiopathic short stature is not always idiopathic. Acta Pædiatr 1999; Suppl 428: 194–8. Stockholm. ISSN 0803–5326
Heterozygous growth hormone receptor (GHR) gene defects are not a common cause of idiopathic short stature. Although some of these GHR mutations may result in relative insensitivity to growth hormone (GH) in other studies, obligate heterozygotes did not present any clinical manifestations. Although patients with GH insensitivity and elevated GH binding protein (GHBP) levels have been described, it may be a reasonable approach to screen children who have growth failure, low levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, and low levels of GHBP. Whether the sensitivity of this screening approach can be increased by administering pharmacological doses of GH for a few days and measuring the resultant increase in serum IGF-I concentration remains to be determined by ongoing studies. □ Growth hormone insensitivity, growth hormone receptor, short stature