- Email: [email protected]
Indications for growth hormone therapy
symposium: endocrinology
Indications for growth hormone therapy
continues to monitor the outcomes of the 1900 patients treated with these preparations of GH, which were extracted from post mortem samples of human pituitary tissue. With the subsequent introduction of biosynthetic GH, public reassurance was required that this episode would not be repeated, and postmarketing safety surveillance was established in conjunction with the pharmaceutical industry. The largest and most extensive of these programmes, the Pfizer International Growth Study (KIGS), has been running for 20 years and has shown that GH is a very safe and effective replacement therapy.1 It has also been demonstrated that, when GH is given in supraphysiological amounts to over-drive growth in conditions such as Turner’s syndrome, no excess of side effects Is seen. In addition, no excess of relapses is seen in children treated for growth failure arising from treatment for cancer. This venture has been a remarkable success and is a testimony to the success of good joint working relationships between the pharmaceutical industry and the health-care professions.
Gary Butler
Abstract Treatment with biosynthetic growth hormone (GH) has been extended in the last 20 years to a wide range of indications. Hormone replacement in GH deficiency, congenital or acquired, can allow children to grow to a normal adult height, though treatment regimen refinements are still required. Extensive post-marketing surveillance has revealed an impressive safety record. Other successful indications include Turner’s syndrome and growth failure associated with chronic diseases such as renal failure, and newer indications such as juvenile chronic arthritis, cystic fibrosis, skeletal dysplasias and congenital adrenal hyperplasia. Condition-specific dose ranges are used. GH deficiency is still principally a clinical diagnosis, needing accurate measurements to demonstrate growth failure supported by tests of poor GH secretory ability. Compliance is improved with a wide range of attractive injection devices.
Advances in the administration of growth hormone treatment Initially, GH treatment was given by a standard subcutaneous injection syringe and needle requiring dilution of the freeze-dried GH powder with solvent. Considerable investment by the pharmaceutical industry together with feedback from families and health-care professionals has meant that a wide range of injection devices is now available. GH comes in ready-mixed solution or self-mixing vials administered by pen devices (resembling insulin pens), automatic and programmable injection devices, and needle-free injectors whereby a fine jet of GH is ‘transjected’ through the skin under high pressure. This latter system is not entirely pain-free and can give cause minor bruising, but is helpful for children or parents with ‘needle phobia’.2
Keywords growth; growth hormone; insulin-like growth factor-1; safety; transition; quality of life
Introduction Human growth hormone (GH) has been used in the treatment of growth disorders for the last 50 years. Biosynthetic GH became available in unlimited quantities in 1985 and this has made the treatment of children with poor growth much more successful. Details about conditions for which GH is licensed and approved by the UK National Institute for Health and Clinical Excellence (NICE) since the guidance was issued in 2002 can be found on the NICE website (www.nice.org.uk). This review incorporates what was known up to that time with the advances in the last 5 years. General considerations are dealt with first, followed by the diagnosis and treatment of specific conditions.
New developments Since GH currently needs to be given by daily subcutaneous injection, research is continuing to formulate a depot preparation lasting for weeks or months. With the discovery of GH-releasing short peptides (e.g. hexarelin, gastrin-releasing peptide 6), it was hoped that one of these secretogogues would be superior to GH, which has a relatively short half-life. However, the prolonged half-lives of depot GH and secretogogues were found to induce a semi-acromegalic state. It is now realized that it is the pulsatility of GH secretion from the anterior pituitary that is important. Between GH pulses (which occur at approximately 120 minute intervals), the concentration of GH drops to zero and this is important in preventing levels of the target hormone, insulin-like growth factor-1 (IGF1), becoming excessive. Therefore, though clinical phase trials are under way, for the immediate future GH treatment will be delivered in a similar manner to at present.
Safety of growth hormone treatment A unique feature of GH treatment is the extensive safety surveillance that has occurred; far greater attention has been given to this form of therapy than to any other. Concern first arose with the development of Creutzfeldt–Jakob disease in young adults who had received pituitary-derived GH. This treatment was withdrawn in 1985 and a national surveillance programme
Growth hormone deficiency Simple replacement therapy accounts for more than one-half of all prescriptions for GH. GH deficiency may be idiopathic isolated (arising from deletions of the GH gene) or associated with congenital central brain malformations such as septo-optic dysplasia
Gary Butler MD FRCPCH is Professor of Paediatrics and Growth, Institute of Health Sciences, University of Reading and Department of Paediatrics, Royal Berkshire Hospital NHS Foundation Trust, Reading RG1 5AN UK.
PAEDIATRICS AND CHILD HEALTH 17:9
356
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
in which GH deficiency is often combined with other anterior pituitary hormone deficits. Paradoxical GH deficiency may arise from mutations in the GH receptor gene. These children have extreme short stature and poor growth, with a phenotype (Laron syndrome) resulting in very low IGF-1 levels but extremely high GH levels. In such cases, the treatment is a synthetic IGF-1 and IGF-binding protein 3 combination. The details of this condition are beyond the scope of this review. Acquired GH deficiency usually arises from insults to the pituitary gland such as traumatic brain injury that cause disruption of the pituitary stalk, surgery, or cranial irradiation for a brain tumour. The tends principally to affect hypothalamic GHreleasing hormone secretion. GH deficiency can also result from toxic drug treatments such as cancer chemotherapy. Diagnosis GH deficiency should always be positively excluded when there are congenital mid-brain abnormalities, and since presentation with clinical growth failure may take some years, GH secretion in these patients should be reviewed no less frequently than every 2 years from diagnosis. GH deficiency is present from 2 years after the end of cancer treatment in 80% of childhood cancer survivors in whom significant amounts of cranial irradiation have been used (>30 Gy). Regular prospective surveillance programmes are mandatory. Neonatal hypoglycaemia may occur as a result of GH and adrenocorticotrophic hormone–cortisol deficiency as part of congenital hypopituitarism, and replacement with GH and hydrocortisone must be started immediately. Most children with idiopathic isolated GH deficiency present with short stature and growth failure. This may not occur until the second or third year of life, as the major influence driving IGF-1 secretion in early infancy is nutrition. GH assumes principal responsibility for controlling growth only in the second year of life. Clinical features of GH deficiency are short stature, hypoplasia of the mid-face causing immature-looking facies, normal body proportions and central obesity with characteristic marbling of the fat (Figure 1); in boys, there may also be genital hypoplasia or undescended testes. Height velocity is often less then 4 cm/year, and significantly below the usual range of height velocity in children of this age. Other causes of growth failure must be excluded. Routine biochemistry, haematology, and thyroid and liver function tests are required together with antibody titres to exclude cryptic coeliac disease. Random IGF-1 levels may be confusing. Low levels may have high sensitivity, confirming a diagnosis of GH deficiency, but exhibit poor specificity as a screening test since many short normal children without GH deficiency have low IGF-1 levels. GH deficiency is thus principally a clinical diagnosis based on the demonstration of growth failure, and this requires accurate serial measurements of height and weight for a minimum of 3 months (usually 6 months to 1 year) so that normal growth variations can be confidently excluded.
Figure 1 Classical phenotype of a short girl with growth hormone deficiency. Note the central obesity with ‘marbling’ of the fat and midfacial hypoplasia.
occur unless proper precautions are undertaken. GH provocation tests are not routine and should be performed only in units that are familiar with their conduct and have dedicated staff attending solely to the child under investigation who are familiar with the procedures for safe management of side effects such as hypoglycaemia. GH secretagogues include glucagon, clonidine, arginine, and insulin, which on account of its central action in inducing hypoglycaemia is regarded as a gold standard against which other tests are compared. Demonstration of GH deficiency should be followed by pituitary imaging using MRI to exclude destructive intracranial lesions and abnormalities of hypothalamic-pituitary development. Interpretation of test results GH is usually measured in plasma by sensitive immunoradiometric assays, each with its own standardization and local reference ranges. Although assays define a cut-off below which the diagnosis of GH deficiency may be considered, it is important to recognize firstly that these tests have poor reproducibility and secondly that the normal range of physiological GH secretion
Investigations According to current guidance, demonstration of biochemical GH deficiency is required to confirm the diagnosis before initiation of replacement therapy. The GH stimulation test is a major investigation for a child and may carry risks, as unexpected deaths can
PAEDIATRICS AND CHILD HEALTH 17:9
357
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
varies considerably throughout life. Secretion is much higher in younger children and adolescents and relatively low in the years before the adolescent growth spurt, often regarded as a period of physiological GH deficiency. Thus, a pubertal patient whose peak GH level is at the threshold for the diagnosis of GH deficiency in a prepubertal child may have a significant deficit compared with other adolescents of the same age and stage of puberty who should be undergoing a period of much more rapid growth. A false diagnosis of GH deficiency can be made in the peri-pubertal period during the so-called prepubertal lag in which spontaneous GH deficiency wanes and growth velocity may be the lower limit of normal even in children of normal stature. It is therefore customary to prime the pituitary with sex steroids to prevent false diagnoses. This similar to the situation in those who have the full deficiency.
Management of the transition of adolescents into adult practice GH treatment was traditionally stopped at the end of growth, initially because supplies were limited but also because it was thought that GH had effects on physical growth only. It is now known that that is not the case and that there are many cardiovascular, muscular and skeletal health benefits. Another significant direct action of GH is improved sense of well-being, energy levels and quality of life. In the UK, evaluation of secondary phenomena, and particularly quality of life, have an important role in deciding eligibility for continuation of GH treatment into adult life. However, the fact that GH is a daily injectable treatment and is extremely expensive prompted an evaluation of its cost-effectiveness, and the following approach to transition was devised and has been endorsed by NICE. At the end of growth, usually defined as a height velocity of less than 2 cm/year, GH treatment should be stopped and symptoms such as lethargy, tiredness and reduced drive, mental functioning and libido should be assessed after at least 4 weeks to allow washout. IGF-1 levels are measured and a GH provocation test (using a powerful secretagogue such as glucagon or insulin) is conducted. In many cases, GH secretion will have returned to normal or near normal, and continuation of treatment is not warranted since the side effects of GH deficiency are not usually noticed in this situation. When isolated GH deficiency is re-confirmed, GH replacement may need to be considered, but in the adult low-dose regimen. A low re-instatement dose is chosen that is titrated against IGF-1 levels over 3 months so that the level moves into the upper part of the predicted normal range (the target). If the patient is over 25 years of age, it is a requirement in England that the adult GH deficiency quality-of-life assessment (AGHDA) questionnaire is administered. If the score is poor (>11/25), the patient is eligible for GH treatment provided a seven-point improvement in quality of life can be demonstrated over a 6 month period. Long-term data on changes in bone and cardiovascular health are currently being collected.
Treatment outcomes and prediction of response Despite more than 20 years of experience with biosynthetic GH replacement therapy, children with GH deficiency may expect to growth to a final height within the normal population range but 0.6 standard deviations below their mid-parental height. In a recent analysis of final height data in 1258 patients from the KIGS database,3 pre-treatment height standard deviation scores (SDSs) ranged between –4.0 and 0. Adult height SDSs after GH cessation of GH therapy were between –0.7 and –2.1. Although this is a significant improvement over historical attempts to treat these individuals, there seem to be key ages at which height gain can be optimized. The greatest improvement in growth is seen in the first year of treatment in children who are the shortest, in those growing most slowly and in those in whom the response to GH during the provocation test was the lowest.4 Starting GH at the standard dose of 25–35 μg/kg/day at a younger age was associated with a greater first-year response and also with more total height gained. This is a strong argument for retaining growth screening of all children, focused particularly at the pre-school years when initial growth failure can occur. The other phase of significant growth is during puberty. Although there is a physiological increase in GH secretion in normal adolescents, there does not appear to be an improvement in the gain of total pubertal growth when the dose of GH is increased during this period.5 Since pubertal growth is when the greatest increase in height occurs, attempts have been made to prolong this period by delaying the onset and progression of puberty using gonadotrophin-releasing hormone analogues. These have not been successful, however, suggesting that, in patients with GH deficiency and spontaneous puberty occurring at the normal time, manipulating the timing of adolescence has no effect on final height.6
Quality of life GH seems to have direct effects on the functioning of the CNS. Children starting GH treatment show an improvement on some quality-of-life scales together with an increase in their energy levels and physical activity.7 GH treatment has also been associated with an improvement in some quality-of-life measures in adolescents born small for gestational age who are treated with GH,8 but similar improvements have not been seen in young women with Turner’s syndrome following GH treatment in childhood and adolescence.9
Growth hormone treatment in other licensed and approved indications
Other considerations Although GH may have beneficial effects on the cardiovascular system in adult patients, the potential benefit in children is not known. Bone mineral density (BMD) increases during childhood and adolescence directly as a result of the actions of GH and sex hormones and normal calcium homeostasis. Full bone mineralization may not be acquired by the time growth stops; hence, continuing treatment into young adult life to improve BMD has been considered. Trials to resolve this issue are ongoing.
PAEDIATRICS AND CHILD HEALTH 17:9
Turner’s syndrome Turner’s syndrome is associated with progressive growth failure throughout childhood. Evidence suggests that this may be partially arrested by GH treatment. Many trials have been conducted to ascertain the optimal treatment regimen.10 The largest was in France, where 700 girls were followed to final height.11 The mean adult height was 149.9±6.1 cm; that Is, 8.5 cm above the projected height. Only 10% underwent spontaneous puberty 358
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
that did not require oestrogen supplementation for ovarian failure. The conclusion was that early initiation of GH treatment (at a dose of 50 μg/kg/day) and induction of puberty at a normal physiological age were important features of success.
height and are growing with a borderline slow or slow height velocity. However, in the absence of any other identifiable pathology, they exhibit apparently normal GH secretion on provocative testing. It seems that there must be an overlap between borderline GH deficiency (partial GH deficiency) and idiopathic short stature. Numerous clinical trials have shown that idiopathic short stature patients can respond to GH treatment equally as well as children with GH deficiency.16 Initial trials attempting to increase final height by delaying puberty with gonadotrophin-releasing hormone analogues have not yet shown any significant success.17 However, delaying puberty and boosting growth with GH has shown improvements in adopted girls with early puberty.18
Chronic kidney disease Regardless of whether they are receiving dialysis, children with chronic kidney disease may show growth failure due to GH resistance. This can be partially overcome with GH treatment given at the upper end of the therapeutic range (50 μg/kg/day). An updated Cochrane systematic review in 200612 confirmed that a significant improvement in growth can be seen in the first 2 years of life, and as treatment continues over subsequent years further improvements in growth may occur. However, increasing numbers of children progress to renal transplantation, and at that point GH treatment is usually stopped to ascertain whether catch-up growth will occur. Initial evidence suggests that the height gained with GH treatment before transplantation is maintained after the procedure.
Other new indications for growth hormone treatment GH is a powerful stimulant of childhood growth and anabolism and has been considered in several chronic diseases, including those in which weight gain may also be poor. Recent studies have demonstrated beneficial effects on growth and health in children with juvenile chronic arthritis or cystic fibrosis,19 and have shown improved growth in children with congenital adrenal hyperplasia.20
Prader–Willi syndrome GH treatment in Prader–Willi syndrome is exceptional in that it is directed not only at increasing height gain but also at improving body composition and possibly promoting cognitive and psychomotor development.13 Improvements in non-growth-related areas have always been difficult to verify. Accelerated language development has been shown in young patients receiving GH treatment (35 μg/kg/day) associated with faster head growth, increased lean body mass acquisition and reduced body fat. Patients treated before their first birthday walked earlier than controls.
Skeletal dysplasia GH treatment has led to a modest improvement in conditions in which there is mild skeletal dysplasia such as hypochondroplasia, Turner’s syndrome and Noonan’s syndrome.21 The modest increases in stature contrast with the significant gains seen in children with GH deficiency. Similar improvements were hoped for in major skeletal dysplasias such as achondroplasia, in which major gains in height can be achieved only by surgical limb lengthening. Over 5 years, GH treatment can achieve height increases of 1.4–1.9 standard deviations, thereby not only preventing further growth failure but also producing gains comparable to those seen in Turner’s syndrome and idiopathic short stature.22 This may be considered as a future new indication.
Small for gestational age One of the more challenging indications for GH treatment is in children born small for gestational age (<2 standard deviations for birthweight and/or birth length) who subsequently fail to show catch-up growth. The causes are multifactorial and cases include preterm sick infants from neonatal ICUs whose growth does not recover.14 Concern has been expressed in this group of patients that GH treatment may accelerate the development of cardiovascular risk factors. This worry arose since infants who were of low birthweight and showed rapid weight gain in the first year of life were those who were more susceptible to metabolic syndrome (cardiovascular disease, hypertension, type 2 diabetes and hyperlipidaemia) (the Barker hypothesis). The few studies that have reported to final height have shown significant gains in height, especially with higher GH doses (35–50 μg/ kg/day). Although small reductions in insulin sensitivity can be demonstrated on treatment, so far no significant detrimental factors have been identified, and many of the changes noted have reversed when GH treatment is stopped.15 It is suggested that continued surveillance is required in these patients.
Conclusions The use of GH as a therapeutic agent has expanded considerably over the last 50 years and especially since it became available in unlimited quantities. Growth by its very nature takes a long time, so current published final height data tend to reflect ‘yesterday’s’ treatment regimens. If children are to reach their full genetic potential, we need to further refine our approach, especially in two important periods: catch-up after the initiation of treatment, and in adolescence. The potentially most exciting new developments are in the field of chronic disease, and increasing numbers of indications for GH treatment will become apparent. As management of primary conditions improves, children are surviving with a better quality of life, and this does not need to be diminished by less than optimal growth. We now have the possibility of redressing this balance. ◆
Future directions of growth hormone therapy Idiopathic short stature (non-growth hormone-deficient short stature) This category is defined as children of height less than –2.5 standard deviations below the mean who are short for their mid-parental
PAEDIATRICS AND CHILD HEALTH 17:9
References 1 Wilton P. Adverse events. In: Ranke MB, ed. Treatment with recombinant human growth hormone in children and adolescents: 20 years of KIGS. Basel: Karger; 2007, p. 432–41.
359
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
adulthood: a consensus statement of the International Societies of Paediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007; 92: 804–10. 15 Cutfield WS, Lindberg A, Rapaport R, et al. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res 2006; 65(suppl 3): 153–9. 16 Kemp SF, Kuntze J, Attee KM, et al. Efficacy and safety results of long term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab 2005; 90: 5243. 17 Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol 2006: 254–255, 226–33. 18 Tuvemo T, Jonsson B, Gustafsson J, et al. Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty. Acta Paediatr 2004; 93: 1456–62. 19 Hardin DS, Adams-Huet B, Brown D, et al. Growth hormone treatment improves growth and clinical status in pre-pubertal children with cystic fibrosis: results of a multicenter randomized controlled trial. J Clin Endocrinol Metab 2006; 91: 4925–9. 20 Lin-Su K, Vogiatzi MG, Marshall I, et al. Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2005; 90: 3318–25. 21 Osio D, Dahlgren J, Wikland KA, et al. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr 2005; 94: 1232–7. 22 Hertel NT, Eklof O, Ivarsson S, et al. Growth hormone treatment in 35 pre-pubertal children with achondroplasia: a 5 year study doseresponse trial. Acta Paediatr 2005; 94: 1402–10.
2 Wickramasuria BP, Casey A, Akhtar S, et al. Factors determining patient choice of device for GH therapy. Horm Res 2006; 65: 18–22. 3 Reiter EO, Price DA, Wilton P, et al. Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab 2006; 91: 2047–54. 4 Cole TJ, Hindmarsh PC, Dunger DB. Growth hormone (GH) provocation tests and the response to GH treatment in GH deficiency. Arch Dis Child 2004; 89: 1024–7. 5 Darendelier F, Berberoglu M, Ocal G, et al. Response to growth hormone with respect to pubertal status on increased dose in idiopathic growth hormone deficiency: an analysis of Turkish children in the KIGS database (Pfizer International Growth Study). J Pediatr Endocrinol Metab 2005; 18: 949–54. 6 Reiter EO, Lindberg A, Ranke MB, et al. The KIGS experience with the addition of gonadotrophin-releasing hormone agnosists to growth hormone (GH) treatment of children with idiopathic GH deficiency. Horm Res 2003; 60(suppl 1): 68–73. 7 Sheppard L, Eiser C, Davies HA, et al. The effects of growth hormone treatment on health-related quality of life in children. Horm Res 2006; 65: 243–9. 8 Basnnink EM, van Pareren YK, Theunissen NC, et al. Quality of life in adolescents born small for gestational age: does growth hormone make a difference. Horm Res 2005; 64: 166–74. 9 Carel JC, Ecosse E, Bastie-Sigec I, et al. Quality of life determinants in young women with Turner’s syndrome after growth hormone treatment: results of the Sta Tur population-based cohort study. J Clin Endocrinol Metab 2005; 90: 1992–7. 10 Pasquino AM, Pucarelli I, Segni M, et al. Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group. J Endocrinol Invest 2005; 28: 350–6. 11 Soriano-Guillan L, Coste J, Ecosse E, et al. Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone. J Clin Endocrinol Metab 2005; 90: 5197–204. 12 Vimalachandra D, Hodson EM, Willis NS, et al. Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev 2006; 3: CD003264. 13 Myers SE, Whitman BY, Carrel AL, et al. Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits. Am J Med Genet A 2006; 13: [Epub ahead of print]. 14 Clayton PE, Cianfarni P, Johannsson G, et al. Management of the child born small for gestational age child (SGA) through to
PAEDIATRICS AND CHILD HEALTH 17:9
Practice points • GH deficiency is a clinical diagnosis and should be considered in any short child who is growing subnormally • GH stimulation tests should be performed only to confirm the clinical diagnosis of GH deficiency and require careful preparation and monitoring • GH treatment may be successful in promoting growth in other clinical conditions even when the patient does not have GH deficiency
360
© 2007 Elsevier Ltd. All rights reserved.
Indications for growth hormone therapy
continues to monitor the outcomes of the 1900 patients treated with these preparations of GH, which were extracted from post mortem samples of human pituitary tissue. With the subsequent introduction of biosynthetic GH, public reassurance was required that this episode would not be repeated, and postmarketing safety surveillance was established in conjunction with the pharmaceutical industry. The largest and most extensive of these programmes, the Pfizer International Growth Study (KIGS), has been running for 20 years and has shown that GH is a very safe and effective replacement therapy.1 It has also been demonstrated that, when GH is given in supraphysiological amounts to over-drive growth in conditions such as Turner’s syndrome, no excess of side effects Is seen. In addition, no excess of relapses is seen in children treated for growth failure arising from treatment for cancer. This venture has been a remarkable success and is a testimony to the success of good joint working relationships between the pharmaceutical industry and the health-care professions.
Gary Butler
Abstract Treatment with biosynthetic growth hormone (GH) has been extended in the last 20 years to a wide range of indications. Hormone replacement in GH deficiency, congenital or acquired, can allow children to grow to a normal adult height, though treatment regimen refinements are still required. Extensive post-marketing surveillance has revealed an impressive safety record. Other successful indications include Turner’s syndrome and growth failure associated with chronic diseases such as renal failure, and newer indications such as juvenile chronic arthritis, cystic fibrosis, skeletal dysplasias and congenital adrenal hyperplasia. Condition-specific dose ranges are used. GH deficiency is still principally a clinical diagnosis, needing accurate measurements to demonstrate growth failure supported by tests of poor GH secretory ability. Compliance is improved with a wide range of attractive injection devices.
Advances in the administration of growth hormone treatment Initially, GH treatment was given by a standard subcutaneous injection syringe and needle requiring dilution of the freeze-dried GH powder with solvent. Considerable investment by the pharmaceutical industry together with feedback from families and health-care professionals has meant that a wide range of injection devices is now available. GH comes in ready-mixed solution or self-mixing vials administered by pen devices (resembling insulin pens), automatic and programmable injection devices, and needle-free injectors whereby a fine jet of GH is ‘transjected’ through the skin under high pressure. This latter system is not entirely pain-free and can give cause minor bruising, but is helpful for children or parents with ‘needle phobia’.2
Keywords growth; growth hormone; insulin-like growth factor-1; safety; transition; quality of life
Introduction Human growth hormone (GH) has been used in the treatment of growth disorders for the last 50 years. Biosynthetic GH became available in unlimited quantities in 1985 and this has made the treatment of children with poor growth much more successful. Details about conditions for which GH is licensed and approved by the UK National Institute for Health and Clinical Excellence (NICE) since the guidance was issued in 2002 can be found on the NICE website (www.nice.org.uk). This review incorporates what was known up to that time with the advances in the last 5 years. General considerations are dealt with first, followed by the diagnosis and treatment of specific conditions.
New developments Since GH currently needs to be given by daily subcutaneous injection, research is continuing to formulate a depot preparation lasting for weeks or months. With the discovery of GH-releasing short peptides (e.g. hexarelin, gastrin-releasing peptide 6), it was hoped that one of these secretogogues would be superior to GH, which has a relatively short half-life. However, the prolonged half-lives of depot GH and secretogogues were found to induce a semi-acromegalic state. It is now realized that it is the pulsatility of GH secretion from the anterior pituitary that is important. Between GH pulses (which occur at approximately 120 minute intervals), the concentration of GH drops to zero and this is important in preventing levels of the target hormone, insulin-like growth factor-1 (IGF1), becoming excessive. Therefore, though clinical phase trials are under way, for the immediate future GH treatment will be delivered in a similar manner to at present.
Safety of growth hormone treatment A unique feature of GH treatment is the extensive safety surveillance that has occurred; far greater attention has been given to this form of therapy than to any other. Concern first arose with the development of Creutzfeldt–Jakob disease in young adults who had received pituitary-derived GH. This treatment was withdrawn in 1985 and a national surveillance programme
Growth hormone deficiency Simple replacement therapy accounts for more than one-half of all prescriptions for GH. GH deficiency may be idiopathic isolated (arising from deletions of the GH gene) or associated with congenital central brain malformations such as septo-optic dysplasia
Gary Butler MD FRCPCH is Professor of Paediatrics and Growth, Institute of Health Sciences, University of Reading and Department of Paediatrics, Royal Berkshire Hospital NHS Foundation Trust, Reading RG1 5AN UK.
PAEDIATRICS AND CHILD HEALTH 17:9
356
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
in which GH deficiency is often combined with other anterior pituitary hormone deficits. Paradoxical GH deficiency may arise from mutations in the GH receptor gene. These children have extreme short stature and poor growth, with a phenotype (Laron syndrome) resulting in very low IGF-1 levels but extremely high GH levels. In such cases, the treatment is a synthetic IGF-1 and IGF-binding protein 3 combination. The details of this condition are beyond the scope of this review. Acquired GH deficiency usually arises from insults to the pituitary gland such as traumatic brain injury that cause disruption of the pituitary stalk, surgery, or cranial irradiation for a brain tumour. The tends principally to affect hypothalamic GHreleasing hormone secretion. GH deficiency can also result from toxic drug treatments such as cancer chemotherapy. Diagnosis GH deficiency should always be positively excluded when there are congenital mid-brain abnormalities, and since presentation with clinical growth failure may take some years, GH secretion in these patients should be reviewed no less frequently than every 2 years from diagnosis. GH deficiency is present from 2 years after the end of cancer treatment in 80% of childhood cancer survivors in whom significant amounts of cranial irradiation have been used (>30 Gy). Regular prospective surveillance programmes are mandatory. Neonatal hypoglycaemia may occur as a result of GH and adrenocorticotrophic hormone–cortisol deficiency as part of congenital hypopituitarism, and replacement with GH and hydrocortisone must be started immediately. Most children with idiopathic isolated GH deficiency present with short stature and growth failure. This may not occur until the second or third year of life, as the major influence driving IGF-1 secretion in early infancy is nutrition. GH assumes principal responsibility for controlling growth only in the second year of life. Clinical features of GH deficiency are short stature, hypoplasia of the mid-face causing immature-looking facies, normal body proportions and central obesity with characteristic marbling of the fat (Figure 1); in boys, there may also be genital hypoplasia or undescended testes. Height velocity is often less then 4 cm/year, and significantly below the usual range of height velocity in children of this age. Other causes of growth failure must be excluded. Routine biochemistry, haematology, and thyroid and liver function tests are required together with antibody titres to exclude cryptic coeliac disease. Random IGF-1 levels may be confusing. Low levels may have high sensitivity, confirming a diagnosis of GH deficiency, but exhibit poor specificity as a screening test since many short normal children without GH deficiency have low IGF-1 levels. GH deficiency is thus principally a clinical diagnosis based on the demonstration of growth failure, and this requires accurate serial measurements of height and weight for a minimum of 3 months (usually 6 months to 1 year) so that normal growth variations can be confidently excluded.
Figure 1 Classical phenotype of a short girl with growth hormone deficiency. Note the central obesity with ‘marbling’ of the fat and midfacial hypoplasia.
occur unless proper precautions are undertaken. GH provocation tests are not routine and should be performed only in units that are familiar with their conduct and have dedicated staff attending solely to the child under investigation who are familiar with the procedures for safe management of side effects such as hypoglycaemia. GH secretagogues include glucagon, clonidine, arginine, and insulin, which on account of its central action in inducing hypoglycaemia is regarded as a gold standard against which other tests are compared. Demonstration of GH deficiency should be followed by pituitary imaging using MRI to exclude destructive intracranial lesions and abnormalities of hypothalamic-pituitary development. Interpretation of test results GH is usually measured in plasma by sensitive immunoradiometric assays, each with its own standardization and local reference ranges. Although assays define a cut-off below which the diagnosis of GH deficiency may be considered, it is important to recognize firstly that these tests have poor reproducibility and secondly that the normal range of physiological GH secretion
Investigations According to current guidance, demonstration of biochemical GH deficiency is required to confirm the diagnosis before initiation of replacement therapy. The GH stimulation test is a major investigation for a child and may carry risks, as unexpected deaths can
PAEDIATRICS AND CHILD HEALTH 17:9
357
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
varies considerably throughout life. Secretion is much higher in younger children and adolescents and relatively low in the years before the adolescent growth spurt, often regarded as a period of physiological GH deficiency. Thus, a pubertal patient whose peak GH level is at the threshold for the diagnosis of GH deficiency in a prepubertal child may have a significant deficit compared with other adolescents of the same age and stage of puberty who should be undergoing a period of much more rapid growth. A false diagnosis of GH deficiency can be made in the peri-pubertal period during the so-called prepubertal lag in which spontaneous GH deficiency wanes and growth velocity may be the lower limit of normal even in children of normal stature. It is therefore customary to prime the pituitary with sex steroids to prevent false diagnoses. This similar to the situation in those who have the full deficiency.
Management of the transition of adolescents into adult practice GH treatment was traditionally stopped at the end of growth, initially because supplies were limited but also because it was thought that GH had effects on physical growth only. It is now known that that is not the case and that there are many cardiovascular, muscular and skeletal health benefits. Another significant direct action of GH is improved sense of well-being, energy levels and quality of life. In the UK, evaluation of secondary phenomena, and particularly quality of life, have an important role in deciding eligibility for continuation of GH treatment into adult life. However, the fact that GH is a daily injectable treatment and is extremely expensive prompted an evaluation of its cost-effectiveness, and the following approach to transition was devised and has been endorsed by NICE. At the end of growth, usually defined as a height velocity of less than 2 cm/year, GH treatment should be stopped and symptoms such as lethargy, tiredness and reduced drive, mental functioning and libido should be assessed after at least 4 weeks to allow washout. IGF-1 levels are measured and a GH provocation test (using a powerful secretagogue such as glucagon or insulin) is conducted. In many cases, GH secretion will have returned to normal or near normal, and continuation of treatment is not warranted since the side effects of GH deficiency are not usually noticed in this situation. When isolated GH deficiency is re-confirmed, GH replacement may need to be considered, but in the adult low-dose regimen. A low re-instatement dose is chosen that is titrated against IGF-1 levels over 3 months so that the level moves into the upper part of the predicted normal range (the target). If the patient is over 25 years of age, it is a requirement in England that the adult GH deficiency quality-of-life assessment (AGHDA) questionnaire is administered. If the score is poor (>11/25), the patient is eligible for GH treatment provided a seven-point improvement in quality of life can be demonstrated over a 6 month period. Long-term data on changes in bone and cardiovascular health are currently being collected.
Treatment outcomes and prediction of response Despite more than 20 years of experience with biosynthetic GH replacement therapy, children with GH deficiency may expect to growth to a final height within the normal population range but 0.6 standard deviations below their mid-parental height. In a recent analysis of final height data in 1258 patients from the KIGS database,3 pre-treatment height standard deviation scores (SDSs) ranged between –4.0 and 0. Adult height SDSs after GH cessation of GH therapy were between –0.7 and –2.1. Although this is a significant improvement over historical attempts to treat these individuals, there seem to be key ages at which height gain can be optimized. The greatest improvement in growth is seen in the first year of treatment in children who are the shortest, in those growing most slowly and in those in whom the response to GH during the provocation test was the lowest.4 Starting GH at the standard dose of 25–35 μg/kg/day at a younger age was associated with a greater first-year response and also with more total height gained. This is a strong argument for retaining growth screening of all children, focused particularly at the pre-school years when initial growth failure can occur. The other phase of significant growth is during puberty. Although there is a physiological increase in GH secretion in normal adolescents, there does not appear to be an improvement in the gain of total pubertal growth when the dose of GH is increased during this period.5 Since pubertal growth is when the greatest increase in height occurs, attempts have been made to prolong this period by delaying the onset and progression of puberty using gonadotrophin-releasing hormone analogues. These have not been successful, however, suggesting that, in patients with GH deficiency and spontaneous puberty occurring at the normal time, manipulating the timing of adolescence has no effect on final height.6
Quality of life GH seems to have direct effects on the functioning of the CNS. Children starting GH treatment show an improvement on some quality-of-life scales together with an increase in their energy levels and physical activity.7 GH treatment has also been associated with an improvement in some quality-of-life measures in adolescents born small for gestational age who are treated with GH,8 but similar improvements have not been seen in young women with Turner’s syndrome following GH treatment in childhood and adolescence.9
Growth hormone treatment in other licensed and approved indications
Other considerations Although GH may have beneficial effects on the cardiovascular system in adult patients, the potential benefit in children is not known. Bone mineral density (BMD) increases during childhood and adolescence directly as a result of the actions of GH and sex hormones and normal calcium homeostasis. Full bone mineralization may not be acquired by the time growth stops; hence, continuing treatment into young adult life to improve BMD has been considered. Trials to resolve this issue are ongoing.
PAEDIATRICS AND CHILD HEALTH 17:9
Turner’s syndrome Turner’s syndrome is associated with progressive growth failure throughout childhood. Evidence suggests that this may be partially arrested by GH treatment. Many trials have been conducted to ascertain the optimal treatment regimen.10 The largest was in France, where 700 girls were followed to final height.11 The mean adult height was 149.9±6.1 cm; that Is, 8.5 cm above the projected height. Only 10% underwent spontaneous puberty 358
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
that did not require oestrogen supplementation for ovarian failure. The conclusion was that early initiation of GH treatment (at a dose of 50 μg/kg/day) and induction of puberty at a normal physiological age were important features of success.
height and are growing with a borderline slow or slow height velocity. However, in the absence of any other identifiable pathology, they exhibit apparently normal GH secretion on provocative testing. It seems that there must be an overlap between borderline GH deficiency (partial GH deficiency) and idiopathic short stature. Numerous clinical trials have shown that idiopathic short stature patients can respond to GH treatment equally as well as children with GH deficiency.16 Initial trials attempting to increase final height by delaying puberty with gonadotrophin-releasing hormone analogues have not yet shown any significant success.17 However, delaying puberty and boosting growth with GH has shown improvements in adopted girls with early puberty.18
Chronic kidney disease Regardless of whether they are receiving dialysis, children with chronic kidney disease may show growth failure due to GH resistance. This can be partially overcome with GH treatment given at the upper end of the therapeutic range (50 μg/kg/day). An updated Cochrane systematic review in 200612 confirmed that a significant improvement in growth can be seen in the first 2 years of life, and as treatment continues over subsequent years further improvements in growth may occur. However, increasing numbers of children progress to renal transplantation, and at that point GH treatment is usually stopped to ascertain whether catch-up growth will occur. Initial evidence suggests that the height gained with GH treatment before transplantation is maintained after the procedure.
Other new indications for growth hormone treatment GH is a powerful stimulant of childhood growth and anabolism and has been considered in several chronic diseases, including those in which weight gain may also be poor. Recent studies have demonstrated beneficial effects on growth and health in children with juvenile chronic arthritis or cystic fibrosis,19 and have shown improved growth in children with congenital adrenal hyperplasia.20
Prader–Willi syndrome GH treatment in Prader–Willi syndrome is exceptional in that it is directed not only at increasing height gain but also at improving body composition and possibly promoting cognitive and psychomotor development.13 Improvements in non-growth-related areas have always been difficult to verify. Accelerated language development has been shown in young patients receiving GH treatment (35 μg/kg/day) associated with faster head growth, increased lean body mass acquisition and reduced body fat. Patients treated before their first birthday walked earlier than controls.
Skeletal dysplasia GH treatment has led to a modest improvement in conditions in which there is mild skeletal dysplasia such as hypochondroplasia, Turner’s syndrome and Noonan’s syndrome.21 The modest increases in stature contrast with the significant gains seen in children with GH deficiency. Similar improvements were hoped for in major skeletal dysplasias such as achondroplasia, in which major gains in height can be achieved only by surgical limb lengthening. Over 5 years, GH treatment can achieve height increases of 1.4–1.9 standard deviations, thereby not only preventing further growth failure but also producing gains comparable to those seen in Turner’s syndrome and idiopathic short stature.22 This may be considered as a future new indication.
Small for gestational age One of the more challenging indications for GH treatment is in children born small for gestational age (<2 standard deviations for birthweight and/or birth length) who subsequently fail to show catch-up growth. The causes are multifactorial and cases include preterm sick infants from neonatal ICUs whose growth does not recover.14 Concern has been expressed in this group of patients that GH treatment may accelerate the development of cardiovascular risk factors. This worry arose since infants who were of low birthweight and showed rapid weight gain in the first year of life were those who were more susceptible to metabolic syndrome (cardiovascular disease, hypertension, type 2 diabetes and hyperlipidaemia) (the Barker hypothesis). The few studies that have reported to final height have shown significant gains in height, especially with higher GH doses (35–50 μg/ kg/day). Although small reductions in insulin sensitivity can be demonstrated on treatment, so far no significant detrimental factors have been identified, and many of the changes noted have reversed when GH treatment is stopped.15 It is suggested that continued surveillance is required in these patients.
Conclusions The use of GH as a therapeutic agent has expanded considerably over the last 50 years and especially since it became available in unlimited quantities. Growth by its very nature takes a long time, so current published final height data tend to reflect ‘yesterday’s’ treatment regimens. If children are to reach their full genetic potential, we need to further refine our approach, especially in two important periods: catch-up after the initiation of treatment, and in adolescence. The potentially most exciting new developments are in the field of chronic disease, and increasing numbers of indications for GH treatment will become apparent. As management of primary conditions improves, children are surviving with a better quality of life, and this does not need to be diminished by less than optimal growth. We now have the possibility of redressing this balance. ◆
Future directions of growth hormone therapy Idiopathic short stature (non-growth hormone-deficient short stature) This category is defined as children of height less than –2.5 standard deviations below the mean who are short for their mid-parental
PAEDIATRICS AND CHILD HEALTH 17:9
References 1 Wilton P. Adverse events. In: Ranke MB, ed. Treatment with recombinant human growth hormone in children and adolescents: 20 years of KIGS. Basel: Karger; 2007, p. 432–41.
359
© 2007 Elsevier Ltd. All rights reserved.
symposium: endocrinology
adulthood: a consensus statement of the International Societies of Paediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007; 92: 804–10. 15 Cutfield WS, Lindberg A, Rapaport R, et al. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res 2006; 65(suppl 3): 153–9. 16 Kemp SF, Kuntze J, Attee KM, et al. Efficacy and safety results of long term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab 2005; 90: 5243. 17 Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: a controversial issue. Mol Cell Endocrinol 2006: 254–255, 226–33. 18 Tuvemo T, Jonsson B, Gustafsson J, et al. Final height after combined growth hormone and GnRH analogue treatment in adopted girls with early puberty. Acta Paediatr 2004; 93: 1456–62. 19 Hardin DS, Adams-Huet B, Brown D, et al. Growth hormone treatment improves growth and clinical status in pre-pubertal children with cystic fibrosis: results of a multicenter randomized controlled trial. J Clin Endocrinol Metab 2006; 91: 4925–9. 20 Lin-Su K, Vogiatzi MG, Marshall I, et al. Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2005; 90: 3318–25. 21 Osio D, Dahlgren J, Wikland KA, et al. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr 2005; 94: 1232–7. 22 Hertel NT, Eklof O, Ivarsson S, et al. Growth hormone treatment in 35 pre-pubertal children with achondroplasia: a 5 year study doseresponse trial. Acta Paediatr 2005; 94: 1402–10.
2 Wickramasuria BP, Casey A, Akhtar S, et al. Factors determining patient choice of device for GH therapy. Horm Res 2006; 65: 18–22. 3 Reiter EO, Price DA, Wilton P, et al. Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab 2006; 91: 2047–54. 4 Cole TJ, Hindmarsh PC, Dunger DB. Growth hormone (GH) provocation tests and the response to GH treatment in GH deficiency. Arch Dis Child 2004; 89: 1024–7. 5 Darendelier F, Berberoglu M, Ocal G, et al. Response to growth hormone with respect to pubertal status on increased dose in idiopathic growth hormone deficiency: an analysis of Turkish children in the KIGS database (Pfizer International Growth Study). J Pediatr Endocrinol Metab 2005; 18: 949–54. 6 Reiter EO, Lindberg A, Ranke MB, et al. The KIGS experience with the addition of gonadotrophin-releasing hormone agnosists to growth hormone (GH) treatment of children with idiopathic GH deficiency. Horm Res 2003; 60(suppl 1): 68–73. 7 Sheppard L, Eiser C, Davies HA, et al. The effects of growth hormone treatment on health-related quality of life in children. Horm Res 2006; 65: 243–9. 8 Basnnink EM, van Pareren YK, Theunissen NC, et al. Quality of life in adolescents born small for gestational age: does growth hormone make a difference. Horm Res 2005; 64: 166–74. 9 Carel JC, Ecosse E, Bastie-Sigec I, et al. Quality of life determinants in young women with Turner’s syndrome after growth hormone treatment: results of the Sta Tur population-based cohort study. J Clin Endocrinol Metab 2005; 90: 1992–7. 10 Pasquino AM, Pucarelli I, Segni M, et al. Adult height in sixty girls with Turner syndrome treated with growth hormone matched with an untreated group. J Endocrinol Invest 2005; 28: 350–6. 11 Soriano-Guillan L, Coste J, Ecosse E, et al. Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone. J Clin Endocrinol Metab 2005; 90: 5197–204. 12 Vimalachandra D, Hodson EM, Willis NS, et al. Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev 2006; 3: CD003264. 13 Myers SE, Whitman BY, Carrel AL, et al. Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits. Am J Med Genet A 2006; 13: [Epub ahead of print]. 14 Clayton PE, Cianfarni P, Johannsson G, et al. Management of the child born small for gestational age child (SGA) through to
PAEDIATRICS AND CHILD HEALTH 17:9
Practice points • GH deficiency is a clinical diagnosis and should be considered in any short child who is growing subnormally • GH stimulation tests should be performed only to confirm the clinical diagnosis of GH deficiency and require careful preparation and monitoring • GH treatment may be successful in promoting growth in other clinical conditions even when the patient does not have GH deficiency
360
© 2007 Elsevier Ltd. All rights reserved.