Growth hormone therapy-established uses in short children

Since the first reported efficacious use of human growth hormone in 1958, numerous children have been treated with this hormone. This review discusses the five indications for use of human growth hormone in children that have been approved to date by the United States Food and Drug Administration.Conclusion: Further, long-term studies will be needed to address the optimal use of this hormone in each of these conditions.     

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.     

Twenty years of recombinant human growth hormone in children: relevance to pediatric care providers

Recombinant human growth hormone has revolutionized the management of children and adolescents with growth hormone deficiency and other growth disorders, but clinical and ethical controversies remain regarding diagnostic approach, optimal recombinant human growth hormone dose and duration, and expected outcomes. Management of pubertal and transitioning patients with growth hormone deficiency has also commanded increased attention. Recent clinical studies that demonstrate the positive health benefits of recombinant human growth hormone in children with cystic fibrosis, inflammatory bowel disease, and juvenile rheumatoid arthritis have not yet clarified issues about patient selection and appropriate long-term use. An understanding of current recombinant human growth hormone indications and controversies can facilitate patient evaluation and expedite referral for potential treatment. This review summarizes current indications for recombinant human growth hormone use, discusses clinical challenges, and provides recommendations for pediatricians caring for children who may be appropriate candidates for recombinant human growth hormone therapy.     

Growth hormone therapy of short stature

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.     

The role of recombinant insulin-like growth factor I in the treatment of the short child

PURPOSE OF REVIEW: Commercial preparations of recombinant human insulin-like growth factor I became available in 2005. Off-label use has been promoted because of the paucity of patients having approved indications; I review the background and rationale for such use. RECENT FINDINGS: Attempts to identify growth hormone unresponsiveness in children with idiopathic short stature have been nonproductive. Treatment with insulin-like growth factor I for unequivocal growth hormone insensitivity improves but does not correct growth failure, in contrast to the typical experience with growth hormone replacement of growth hormone deficiency. This emphasizes the importance of direct effects of growth hormone at the growth plate, which cannot be duplicated by administration of recombinant insulin-like growth factor I. Adverse effects testify to the more than adequate delivery of administered recombinant human insulin-like growth factor I to other tissues, including lymphoid hyperplasia, coarsening of the facies, and increased body fat. SUMMARY: In view of the risk profile, the limited ability of endocrine insulin-like growth factor I to restore normal growth, and the suppression of endogenous growth hormone (and therefore local effects on growth) that occurs with insulin-like growth factor I administration, the use of recombinant insulin-like growth factor I should be limited to those with well-documented growth hormone unresponsiveness and severe short stature.     

Growth Hormone and Insulin-Like Growth Factor I: Nutritional Pathophysiology and Therapeutic Potential

The growth hormone—insulin-like growth factor I axis has been appreciated for more than 30 years and the effects of malnutrition on this axis for more than 20 years. Over the last decade, advances in molecular biology have permitted enhanced understanding of feedback regulation between growth hormone and IGF-I at the gene level, including limited information on nutritional influences. Similarly, the availability of recombinant human growth hormone has allowed controlled clinical studies demonstrating its net anabolic actions at hypocaloric dietary energy intake levels and its ability to enhance height velocity in children with various causes of diminished growth. Although investigational use of recombinant IGF-I in humans has been limited, its actions are likely to complement those of growth hormone during periods of profound dietary energy deficit. From the information presented, two hypotheses are developed. First, recombinant IGF-I administration will enhance substrate anabolic events during the acutely malnourished state when dietary intake is severely limited. Second, administration of recombinant human growth hormone will accelerate protein anabolism and catch-up growth during the period of recovery from protein-energy malnutrition. Given current clinical investigational tools and the availability of both recombinantly-produced hormones, these are testable hypotheses.     

Do short children secrete insufficient growth hormone?

The 24-hour integrated concentration of growth hormone from 46 children of normal stature was compared with that of 90 short children. Nineteen of the short children had classic growth hormone deficiency by standard pharmacologic growth hormone stimulation tests. Seventy-one children had normal growth hormone responses to stimulation. The mean integrated concentration of growth hormone for children with normal stature (6.6 +/- 1.9 ng/mL) was greater than the mean value for those with normal stimulated growth hormone (3.8 +/- 2.3 ng/mL) and greater than the mean value for those with growth hormone deficiency (1.6 +/- 0.6 ng/mL); differences between groups were all statistically significant (P less than .0001). Forty-five percent of children with normal stimulated growth hormone responses had integrated concentration of growth hormone within the range of values for the group with growth hormone deficiency; this finding may provide the explanation for their poor growth. Thus, patients with normal growth hormone responses have a spectrum of spontaneous growth hormone secretion ranging from normal to impaired. Recent reports indicate that children with normal growth hormone responses who have very low integrated concentration of growth hormone may have the potential to improve their growth with growth hormone therapy. Therefore, use of the integrated concentration of growth hormone may be a more effective method than standard pharmacologic stimulation tests for determining which short children are potentially able to respond to growth hormone therapy.     

从循证医学证据看生长激素促生长治疗的收益及风险

基因重组人生长激素（rhGH）自1985年上市以来,已经治疗了上百万矮身材患儿,适应证不断扩大。同时,超适应证用药及单纯为增高而用药的现象也越来越严重。为此,多个学术组织出台指南或共识期望规范rhGH的诊疗。rhGH治疗生长激素缺乏症（growth hormone deficiency,GHD）终身高获益最大,其他非GHD疾病包括特发性矮小、特纳综合征等应用rhGH促生长收益有限。rhGH长期应用的安全性尚存有争议,临床医生处方rhGH时应谨慎,做到规范化使用。     

Body segments and growth hormone.

The effects of human growth hormone treatment for five years on sitting height and subischial leg length of 35 prepubertal children with isolated growth hormone deficiency were investigated. Body segments reacted equally to treatment with human growth hormone; this is important when comparing the effect of growth hormone on the growth of children with skeletal dysplasias or after spinal irradiation.     

Growth hormone treatment in children with cystic fibrosis

Children with cystic fibrosis (CF) have problems with poor linear growth and inadequate weight gain. Nutritional augmentation has been the mainstay of therapy for improving both weight and height in CF; however inadequate growth continues to be a problem. Furthermore, protein catabolism has been documented even in non-acutely ill adults and children with CF, and could adversely affect longitudinal growth. Human recombinant growth hormone (GH) has positive effects on nitrogen balance, and multiple studies have demonstrated improved height and weight in children treated with GH. The purpose of this article is to summarize studies evaluating GH use in children with CF.     

Growth hormone therapy in children with short stature: Is bigger better or achievable?

The introduction of recombinant DNA-synthesized human growth hormone in the mid-1980s, and its attendant unlimited supply, have led to wider application of growth hormone therapy in children. Over the past decade, the efficacy of growth hormone treatment in patients with Turner syndrome and chronic renal insufficiency, two conditions in which growth hormone secretion is normal, in improving growth velocity and final height, has also led to the consideration of growth hormone therapy in children with idiopathic short stature. Although thousands of patients with idiopathic short stature are currently being treated with growth hormone, the limited overall results available at this time do not show a significant improvement in final adult height despite an improvement in short-term growth velocity. Potential reasons for this outcome include 1) skeletal age advancing more rapidly than height age, 2) heterogeneity of the patient population comprising idiopathic short stature, 3) inherent inaccuracies of methodological tools, such as measurement of predicted adult height, and 4) a subset of children with idiopathic short stature who may, in fact, have partial growth hormone insensitivity. From a psychological perspective, the consensus of investigations in non-clinic-referred populations of psychosocial function in children with short stature do not indicate a disadvantage compared with children of normal height when socio-economic status is taken into consideration. These results, in conjunction with the minimal gains reported in behavioural measurements in idiopathic short children treated with growth hormone, question the traditional rationale that augmentation of growth velocity results in improvement in psychosocial well-being.     

Human growth hormone therapy of non-growth hormone deficient children

With biosynthetically derived human growth hormone (hGH) available in large quantities, attempts will be made to promote growth in short children who do not fulfill the 'classical' criteria for growth hormone deficiency (GHD). By these criteria, GHD is excluded if hGH levels to pharmacological stimuli exceed a definite level. Several studies have shown that a variety of short children, who are not growth hormone deficient by these criteria, will demonstrate an increased growth rate with hGH treatment. A subpopulation of children with clinical features of GHD, delayed bone age and low somatomedin levels, have low levels of spontaneously secreted growth hormone or 'bioinactive' growth hormone. These children increase their growth rates to substitution doses of hGH. In other children whose growth disorder is not likely to be caused by a disorder in the growth hormone-somatomedin axis, growth increments are occasionally seen on higher hGH doses. Future long-term studies--carefully considering the ethics of such approaches--will have to evaluate the relationships between hGH dose and both metabolic and growth responses and side effects in children with short stature in order to define more specifically further target groups of short children who will benefit from hGH therapy.     

Urinary growth hormone excretion as a screening test for growth hormone deficiency.

Overnight urinary growth hormone secretion was measured by an immunoradiometric assay incorporating commercially available reagents, in 41 normal prepubertal school-children from three age groups: 3-5 years, 6-7 years, and 9-10 years. There was no significant difference between the groups expressing the results as total microU/specimen and so they have been combined to provide a prepubertal reference range of 2.25-10.50 microU/night. Prepubertal children with growth hormone deficiency who had not been receiving growth hormone treatment for two days had overnight urinary growth hormone concentrations well below this range. Urinary growth hormone was assayed in 49 children undergoing investigation for short stature with conventional provocative testing, and those shown to have growth hormone deficiency had correspondingly low overnight urinary growth hormone concentrations. There was, in addition, a strong correlation between overnight urinary growth hormone concentrations and peak serum response to provocation. This simple urine assay may provide a useful screening test for growth hormone deficiency.     

Development,production and pharmacodynamics of human growth hormone

With the advent of recombinant DNA technology, it is possible to produce biosynthetic human growth hormone (B-hGH). Novo Nordisk A/S has developed a method for manufacturing B-hGH which is identical to the 22K fraction of pituitary human growth hormone (P-hGH), using a nonpathogenic strain of Escherichia coli as host. B-hGH has been investigated extensively in physical, chemical and biological studies and found to be identical to P-hGH. Pharmacological studies have revealed that B-hGH possesses the same pharmacokinetic and short-term metabolic profiles as P-hGH. Long term clinical studies have shown that B-hGH induces a significant increase in height velocity in children with growth hormone deficiency (GHD) and is characterized by a low antigenicity.     

Effects of insulin-like growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insentivity syndrome

Underwood LE, Backelijau P, Duncan V, and the GHIS Collaborative Group. Effects of insulinlike growth factor I treatment on statural growth, body composition and phenotype of children with growth hormone insensitivity syndrome. Acta Paediatr 1999; Suppl 428:182-4. Stockholm. ISSN 0803-5326
Eight children with growth hormone insensitivity syndrome (GHIS) have been treated with injections of recombinant human insulin-like growth factor I (rh1GF-I) for more than 5 years each. After good acceleration of growth in the first year of therapy, the growth rade 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. □ Growth hormone insensitivity syndrome, insulin-like growth factor I therapy, Laron syndrome     

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.     

Expanded spectrum of recombinant human growth hormone therapy

The efficacy of recombinant human growth hormone in the treatment of growth hormone deficiency is well established. In recent years, the use of recombinant human growth hormone as a therapeutic modality has greatly increased and has expanded beyond the realm of replacement for growth hormone deficiency. Recombinant human growth hormone has been employed to ameliorate growth failure in multiple other disorders. For some, like Turner syndrome, recombinant human growth hormone has become the standard of care. For others, the ultimate benefit of recombinant human growth hormone remains to be determined. Although recent investigations provide encouraging short-term data, it is important to recognize that the impact of recombinant human growth hormone therapy on adult height has not been established in a number of conditions.     

Suppression of immune function in growth hormone-deficient children during treatment with human growth hormone

Inasmuch as growth hormone is known to interact with the immune system, we studied immune functions including immunoglobulins, cell surface markers, mitogen responses, and polymorphonuclear cell function in eight children with growth hormone deficiency, ages 1 to 17 years, before and during treatment with human growth hormone for 12 to 16 months. Before treatment immune functions were normal in all children. Treatment with human growth hormone did not significantly affect serum immunoglobulins, polymorphonuclear cell function, or percent T cells. However, percent B cells decreased to subnormal levels in seven of seven patients. T helper/suppressor ratios decreased in all patients, to subnormal values in seven of eight patients; and mitogen responses decreased to below normal in all. The decline of percent B cells was transient in all patients, of T helper/suppressor ratios in seven of eight, and mitogen responses in five of eight patients. In vitro incubation of lymphocytes with growth hormone resulted in no changes in cell surface markers or mitogen responses. Although the depression of immune functions resulted in no increased rate of infections during the observation period, we do not know the possible effects of prolonged treatment and therefore caution against the indiscriminate use of human growth hormone. The effects of biosynthetically obtained growth hormone on immune function remain to be determined.     

Human insulin induces a higher glucagon response to induced hypoglycemia in short normal children, compared to porcine insulin.

After transfer of diabetic patients from porcine to human insulin, many reports emerged supporting an increased hypoglycemia unawareness. Several studies were then undertaken in both diabetic and healthy adults to investigate counterregulatory hormone responses to both porcine and human insulin-induced hypoglycemia as a possible underlying cause for this different hypoglycemia awareness. Most studies demonstrated similar neuroendocrine responses to both insulin species in adults. However, no such studies have ever been performed in healthy children. We undertook a double-blinded study of counterregulatory hormone responses to both porcine and human insulin-induced hypoglycemia in 17 short normal children randomly assigned to two groups, one receiving human and the other porcine insulin. We found similar responses of growth hormone, cortisol, epinephrine, norepinephrine and dopamine to both porcine insulin- and human insulin- induced hypoglycemia. Interestingly, we observed a significantly higher glucagon secretion when hypoglycemia was induced by human insulin. In conclusion, human insulin induces a higher glucagon secretion in healthy children than porcine insulin. Evidently, this observation cannot be extrapolated to diabetic patients. This study, however, further underlines the importance of performing investigations in children, since results found in adults differ from those observed in children.     

Endocrine function following the treatment of acute leukemia in childhood

Pituitary function has been studied in 25 children after treatment of acute leukemia. Impaired growth hormone responses both to hypoglycemia and to Bovril were found in 11 subjects. Elevated basal thyroid-stimulating hormone levels were seen in five children, three of whom had an augmented TSH response to thyrotrophin-releasing hormone. Radiation-induced damage to the hypothalamic-pituitary region is thought to be the cause of these abnormalities in growth hormone and in secretion of TSH. The peak cortisol response to hypoglycaemia is significantly decreased in the group of subjects who received the higher dose of cranial radiation therapy, but no individual child is hypothyroid or shows impaired adrenal function, clinically or biochemically. Three prepubertal girls studied have biochemical evidence of ovarian failure following the use of combination chemotherapy.