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Endocrinology

Growth hormone deficiency in children

This article examines the management of growth hormone deficiency in children. The causes, clinical features and issues surrounding the use of growth hormone are discussed. A second article, to be published at a later date, will cover the treatment of growth hormone deficiency in adults

By A. Mehta, MD, MRCP and P. Hindmarsh, MD, FRCP

The importance of monitoring growth and weight in childhood and its progression into adulthood cannot be overemphasised. A record of consecutive accurate heights and weights over time yields more information than isolated measurements.
Short stature has been defined as a height below the 0.4th centile of the 1990 Growth Reference Charts.1While this group requires an explanation for their short stature, the process can be refined by consideration of their growth rate. Children with an abnormal growth velocity warrant a more detailed assessment for a pathological cause. A simple classification distinguishes short stature into two main categories:

  • Children who are short but growing with a normal velocity
  • Children who are short and growing with an abnormal growth velocity

The former includes children with genetic short stature and constitutional delay. The latter includes children who have an hormonal abnormality, a dysmorphic syndrome, intrauterine growth restriction and/or systemic chronic illnesses.

Growth hormone (GH)

Human GH is a single chain polypeptide of 191 amino acid residues with two disulphide bridges.2 It is secreted by the somatotrophs of the anterior pituitary gland under the control of the hypothalamic peptides GH releasing hormone (GHRH), somatostatin and the recently discovered peptide, Ghrelin.3
Under normal physiological conditions, GH is secreted in approximately eight peaks each day with low basal levels in between these pulses.
Various pharmacological and physiological factors, such as exercise, stress, high protein meals and prolonged fasting are potent stimulators of GH secretion. Nearly 50 per cent of the daily GH secretion occurs during the early hours of the night following the onset of deep sleep.4
GH circulates mainly in an unbound form. Approximately 25 per cent is bound to a high affinity protein - GH binding protein (GHBP). This protein is structurally similar to the extracellular domain of the GH receptor.5
The growth promoting effects of GH are mediated through a family of insulin-like growth factors (principally IGF-1).6These peptides are structurally similar to insulin and share similar metabolic activity. IGF-1 and its binding proteins (principally IGFBP-3) correlate well with spontaneous GH secretion.7 The effects of GH are shown in Panel 1.

Panel 1: Growth hormone effects

  • Stimulation of linear growth
  • Lipolysis
  • Stimulation of protein synthesis
  • Hyperglycaemia
  • Improved bone mineralisation and bone density
  • Reduction of fat mass
  • Improved lean body mass
  • Altered insulin sensitivity

Classic GH deficiency

Growth hormone deficiency (GHD) encompasses a group of different pathologies, all with failure of or a reduction in GH secretion. It may occur singly or in combination with other pituitary hormone deficiencies and may be sporadic or familial. It may be congenital or acquired as a result of trauma, infiltrations (eg, disseminated tuberculosis, sarcoidosis, haemochromatosis) , tumour or radiation therapy. The pathology arises either as a result of abnormalities in the pituitary GH-producing cells or in the hypothalamus, ie, in the GHRH cells. Despite the large number of aetiologies, the majority of GH deficient children have “idiopathic” GH deficiency.

Features suggestive of GHD

Clinical featuresMost children with GHD have normal body proportions and features. However certain characteristics, if present, are suggestive of GHD.

  • Short stature
  • Poor growth velocity
  • Delayed bone maturation
  • Immature facial appearance with a small midface and frontal bossing (prominence)
  • Increased subcutaneous fat
  • Delayed dentition
  • Micropenis
  • Sparse and thin hair
  • A poor appetite

Auxological parameters The following auxological parameters are suggestive of GHD.8

  • Severe growth retardation with a height less than three standard deviations below the mean for chronological age
  • Moderate growth retardation (height less than two standard deviations below mean) and a growth rate that is persistently (more than two years) below the 25th height velocity centile
  • Severe growth deceleration (height velocity over one year below the 3rd centile)

Neonatal presentation A characteristic neonatal presentation of GHD would be a newborn baby with unexplained hypoglycaemia, prolonged hyperbilirubinaemia, clinical appearance suggestive of GHD, microphallus and cryptorchidism. A turbulent neonatal course and hyponatraemia may point towards additional pituitary hormone deficiencies.

Developmental abnormality Every child with a midline facial defect should be considered at risk of having pituitary hormone deficiencies. This is because the pituitary gland is derived from midline structures and a defective development of these structures leads to an abnormal pituitary gland itself. GHD is also seen as an association with several other developmental defects.

Post cranial irradiation Initially, all children treated for a neoplastic disease show some growth failure because of both the disease itself and as a result of the radiation and/or chemotherapy. This is followed by a second phase of growth failure due to GHD, as a result of cranial and craniospinal irradiation. This GHD is directly related to the dose of the radiation received.

Failure of pubertal growth Failure of a pubertal growth spurt by mid-puberty is a feature suggestive of GHD

Pituitary abnormalities Evidence of other pituitary hormone abnormalities would suggest GHD.

Some of the developmental defects associated with GHD are shown in Panel 2.

Panel 2: Some developmental defects associated with GHD

  • Optic nerve hypoplasia - a developmental defect of the optic nerve which leads to defective vision
  • Anosmia - loss of smell
  • Anencephaly - a large defect in the skull with a rudimentary brain
  • Holoprosencephaly - a developmental defect of the midline cleavage of the forebrain
  • Single central incisor
  • Cleft lip and palate
  • Hypospadias - a congenital abnormality of the penis

Diagnosis of GHD

GH deficiency is a difficult diagnosis. It requires a combination of the above clinical and auxological parameters coupled with biochemical investigations.

GH provocation testing In view of the complex nature of pulsatile GH secretion, a single blood sample for GH measurement is not informative. Various pharmacological stimuli such as insulin, glucagon, arginine, clonidine, and GHRH are powerful stimulators of GH secretion and help to evaluate the hypothalamic-pituitary axis. These should only be conducted in specialist centres by experienced personnel. There is considerable variability in the different types of assay used to measure GH so each laboratory needs to set its own threshold for defining GHD. This adds to the difficulty and variability in the diagnosis of GHD worldwide. Finally there are false positive and negative results with any of these tests so that “normal” children with normal growth patterns can have a GH response on pharmacological testing that could support a diagnosis of GHD. Generally, a peak GH response of less than 20 mU/L or less than 5-10mg/L is considered evidence of GHD.9,10

Spontaneous GH secretion Spontaneous GH secretory studies are done by measuring blood samples every 15 to 20 minutes for 24 hours or for 12 hours overnight. Because of the laborious nature of testing, this technique remains primarily a research tool. However, it can be useful in children who have a growth pattern suggestive of GHD but normal results in stimulation studies. In such a situation, measuring GH secretion can identify a subgroup of children with growth hormone neurosecretory dysfunction (GHNSD) who are short, have a poor growth velocity, delayed bone age but normal GH results on provocation testing.11,12

Urinary GH secretion Urinary GH secretion has been found to correlate significantly with IGF-1 levels and growth velocity provided that renal function is not impaired. However, there are wide inter-day variations and difficulties with interpretation.

Other investigations Other investigations that are carried out in the diagnosis of GHD are:

  • IGF-1 and IGFBP-3 levels corrected for age and sex
  • Bone age for evidence of delayed skeletal maturation
  • MRI of the brain for evidence of pituitary hypoplasia
  • DNA studies for gene deletions

GH therapy

Crude extracts of human growth hormone were first used to treat GHD nearly 40 years ago. With the emergence of commercially produced recombinant GH therapy (rhGH), there have been major improvements in the treatment of short children. On the other hand, there has also been an increased awareness of the need for careful evaluation of the effect and benefit of GH usage in non-GH deficient children.
Recombinant GH was approved in the United States in 1985. Its launch eliminated the risk of Creutzfeld Jakob disease (CJD), a disease linked with previous crude pituitary extracts.13
The increased availability of the recombinant form of GH has allowed research into its usage in a number of conditions that do not fit strict definitions of GHD, eg, intrauterine growth restriction (IUGR), skeletal dysplasias, Noonans syndrome and Prader Willi syndrome.
The licensed indications for GH are outlined in Panel 3.

Panel 3: Current licensed indications for GH therapy in Europe

  • GHD
  • Chronic renal failure in children
  • Turner syndrome

Effects Early treatment of GHD with daily subcutaneous injections of an adequate dose of GH can, in most instances, normalise growth and will achieve an adult height within the predicted target height. The key to success is early diagnosis. Treatment commenced within the first two years of life will normalise height in the short and long term and allow the child to reach its genetic height potential. In the short term, GH therapy can restore lean body mass, reduce excess and abnormal body fat and prevent hypoglycaemia.14,15
GHD in adulthood causes increased obesity, reduces muscle tone and strength, causes low self esteem and increases the risk of cardiovascular mortality and osteoporosis. The increased cardiovascular mortality stems from an increased body fat mass, increased abdominal fat, elevated free fatty acids and elevated total and low density lipoprotein cholesterol.16,17 Recombinant GH has also made replacement therapy in these adults a feasible, albeit, in some people’s eyes, a controversial option.

Dosage and method of administration There continues to be marked variability in the dosage calculation and expression worldwide. In some countries, the dosage is calculated per kg body weight, while other countries use body surface area. To complicate the situation further, the dose calculated may be expressed as either international units (IU) or as milligrams (mg). The WHO and European Pharmacopeia have implemented a change in this dosage expression from IU to mg. This change will be fully implemented by mid 2001 (3IU=1mg).
Data from previous studies indicate that a daily dosage of 0.67mg/m2 (2IU/m2) or 0.024mg/kg (0.071IU/kg) provide satisfactory catch-up and an adult height SDS (standard deviation score) between -0.5 and -1.9,10,18 The dose is administered subcutaneously and given at bedtime to mimic normal peak GH physiology.
Evening GH injections have been shown to have greater peak levels than morning administration.19

Side effects of treatment GH treatment with rhGH is essentially safe.20 There is no risk of CJD, as seen with the previous crude pituitary extracts. Benign intracranial hypertension, salt and water retention and a few cases of acute pancreatitis have been reported.21,22 A common hip disorder, slipped capital femoral epiphysis, can occur in adolescence (see Panel 4).
Hypothyroidism may occur because of transient or persistent decreases in serum thyroxine levels. Thyroid function should be monitored to detect poor response to GH. An increase in cortisol to cortisone conversion has also been noted. This has important implications for the management of patients already on thyroxine and hydrocortisone whose dosing schedules may need revision.
The risk of hyperinsulinism, glucose intolerance and type II diabetes as a result of the diabetogenic role of GH requires ongoing evaluation. There is no evidence that the prevalence of type I diabetes mellitus is increased.
A possible increased risk of leukaemia has been suggested in a small sample from Japan but this has not been confirmed in further Japanese studies, nor in much larger European/United States data sets.23

Panel 4: Potential side effects of GH treatment

  • Salt and water retention
  • Possible glucose intolerance and hyperinsulinism
  • Pseudotumor cerebri
  • Antibody formation and growth attenuation
  • Hypothyroidism
  • Acute pancreatitis
  • Slipped capital femoral epiphysis

Response and monitoring The response to growth hormone treatment is influenced by:

  • Age at the start of treatment
  • Severity of GHD
  • Duration of the disease
  • Genetic potential (parental height)
  • Dose and frequency of administration of rhGH

Since height at puberty also influences final height, normalisation of growth prior to the onset of puberty is important.
Careful measurements and growth velocity need to be monitored on each visit. Bone age evaluation shows an improvement in the skeletal maturation.

Panel 5: Other statural disorders for which GH has been investigated

  • Intrauterine growth restriction
  • Turner syndrome
  • Idiopathic short stature
  • Other short stature syndrome
    • ??Russel-Silver syndrome
    • ??Down’s syndrome
    • ??Noonan syndrome
  • Skeletal dysplasias
    • ??Achondroplasia
    • ??Hypochondroplasia
    • ??Spondyloepiphyseal dysplasia
  • Chronic illnesses
    • ??Chronic renal failure
    • ??Cystic fibrosis
    • ??Rheumatoid arthritis
    • ??Post-transplant patients
    • ??Catabolic states
  • Promotion of healing
    • ??Burns
    • ??Intensive care patients
  • Neural tube defects
  • GHD in adults

Intrauterine growth restriction

Approximately 8 per cent of children born small for gestational age do not catch-up and grow into short adults. Included in this group are children born with dysmorphic syndromes, such as Russel Silver syndrome.24
The Kabi International Growth Study data have clearly shown an involvement of the GH/IGF-1 axis in this lack of postnatal catch-up in children where GH secretion and/or sensitivity are decreased.25,26,27 GH treatment of these children in two multicentre studies was shown to induce catch-up growth. The response was dose dependent and greatest in younger children. The short-term growth did not occur at the expense of final height which was consistently increased.28 The dosage recommended was 0.1-0.3IU/kg/day (0.03-0.1mg/kg/day).
No data on final height are available and no controlled studies have been conducted long-term to determine final height.

Turner syndrome

Almost all girls with Turner syndrome29,30,31 have a final height of 142-147cm without treatment and demonstrate a poor growth velocity in childhood and adolescence. The reasons for the short stature are possibly a failure to respond to growth factors at a tissue level or decreased spontaneous GH secretion. A disorder of the GH/IGF-1 axis is a less likely explanation.
There is considerable controversy about GH treatment in Turner syndrome. Growth acceleration occurs with higher than normal rhGH doses (4IU/m2/day), which could favour GH insensitivity as a causative factor. Oestrogen therapy, necessary for complete physical development, causes rapid closure of the epiphysis (growing sector of the bone). It has no role in the sole treatment of short stature, although timing of its commencement can strongly influence final height.
Anabolic steroids, such as oxandrolone, have been used for a long time in the treatment of short stature. They increase growth velocity by a direct action on the growth plates in doses of 0.5mg/kg/day orally.
Oxandrolone also acts synergistically with GH for reasons that are not completely understood. Since final height in Turner syndrome is inversely correlated with age at the onset of GH therapy, oxandrolone can also shorten the duration of GH treatment by augmenting its effects.
At present there are no good randomised controlled studies to indicate the magnitude of the rhGH treatment effect in Turner syndrome.

Chronic renal disease

Chronic renal failure is now a licensed indication for the use of GH.32 A combination of poor nutrition, acidosis, anaemia and GH insensitivity is thought to be responsible for the poor growth velocity in such cases. GH in a dose of 4 IU/m2/day has no adverse effect on renal function and improves growth. The best response has been seen in those children who are not severely growth retarded.

Skeletal dysplasia

Children with skeletal dysplasias have abnormal body proportions with a shortening of either the spine, limbs or both. A diagnosis is made by skeletal survey. Several studies of GH treatment in skeletal dysplasias, such as achondroplasia and hypochondroplasia, have shown conflicting results. An initial acceleration of growth is followed by a decline and final response is only modest. The doses needed are much higher than for classical GH deficiency. Compared with limb lengthening the GH effects are disappointing and this, coupled with the potential problems of inducing further disproportionate growth, suggests that GH should not be routinely offered to these patients.

Idiopathic short stature

GH treatment in idiopathic short stature (where there is normal GH secretion) has been shown to accelerate bone age and puberty. Again, the initial acceleration in growth velocity was followed by a gradual decline and ultimate height increase was only about 3cm. Best responses were seen in younger children and treatment should be ideally started at the earliest opportunity and restricted to pre-puberty patients. As the overall effect is minimal and as the children are not disadvantaged by their short stature, there is no indication for treating these patients with rhGH.33,34

Glucocorticoid treated children

Steroids are used as a treatment for various chronic illnesses and they lead to growth failure. They promote catabolism, inhibit collagen syntheses, impair the action of IGF-1 and suppress GH secretion.
GH treatment increases growth velocity, especially in the first few years of treatment, in those on moderate steroid doses. However, the diabetogenic risk of GH and glucocorticoids together needs further evaluation.

Other indications

GH responses in other short stature syndromes, such as Down’s, and Noonan syndromes, have all shown similar responses to those observed with Turner syndrome.35
GH’s role in children with catabolic states, severe burns, patients on total parenteral nutrition and paediatric intensive care units is under further trial.36 GH has been shown to promote healing and hence improve the clinical course.
Other areas of interest that might show a therapeutic response are cystic fibrosis, chronic arthritis and spina bifida.37

Other therapies for GHD

Panel 6 outlines the other types of interventional therapy used in GHD

Panel 6: Other interventional therapy in GHD

  • Anabolic steroids
  • IGF-1
  • GHRH
  • Surgery and limb lengthening
  • Delaying puberty

Ethical issues

It is obvious from the above studies that rhGH will be used for several conditions other than just GHD. There is controversy regarding its justification, especially where the responses are only moderate and where carefully controlled randomised studies have not been conducted.The dilemma whether or not to treat needs careful consideration of cost-benefit ratios, long-term side effects, benefits in relation to final height and other options available.
The question as to whether short children suffer physically or emotionally as a result of their short stature is debatable. Is to be taller, to be better?38

Dr Mehta is specialist registrar in paediatric endocrinology and Dr Hindmarsh is consultant paediatric endocrinologist, Great Ormond Street Hospital for Children NHS trust, London.

References

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3.Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;40:656-60.
4.Martha PMJ, Gorman KM, Blizzard RM, Rogol AD, Veldhuis JD. Endogenous growth hormone secretion and clearance rates in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status and body mass. J Clin Endocrinol Metab 1992;74:336-44.
5.Brook CGD, editor. Clinical paediatric endocrinology. 3rd ed. Oxford: Blackwell Scientific Publications;1995.
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10.Saggese G, Ranke MB, Saenger P, Rosenfeld RG. Tanaka T, Chaussain JL et al. Diagnosis and treatment of growth hormone deficiency in children and adolescents: towards a consensus. Horm Res 1998;50:320-40.
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14.Boot AM, Engels MAMJ, Boerma GJM, Krenning EP, de Muinck Keizer-Schrama SMPF. Changes in bone mineral density, bone composition and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab 1997;82:2423-8.
15.Saggese G, Barancelli GI, Bertelloni S, Cinquanta L, De Nero G. Effects of long term treatment with growth hormone on bone and mineral metabolism in children with growth hormone deficiency. J Pediatr 1993;122:37-45.
16.Amato G, Carella C, Fazio S, La Montagna G, Cittadini A, Sabatini D et al. Body composition, bone metabolism and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 1993;77:1671-6.
17.Jorgensen JO, Pedersen SA, Thuesen L, Jorgensen J, Ingemann-Hansen T, Skakkebaek NE et al. Beneficial effects of growth hormone (GH) treatment in GH deficient adults. Lancet 1989;1:1221-5.
18.Gertner JM. Growth hormone treatment in children. Trends Endocrinol Metab 1997;8:92-7.
19.Jorgensen JO, Muller N, Lauritzen T, Alberi KJ, Orskov H, Christiansen JH. Evening vs morning injections of growth hormone (GH) in GH-deficient patients: effects on 24 hour patterns of circulating hormones and metabolites. J Clin Endocrinol Metab 1990;70:207-14.
20.Ritzen EM, Czernichow P, Preece M, Ranke MB, Wit JM. Safety of human growth hormone therapy. Horm Res 1993;39:92-3.
21.Malozowski S, Hung W, Stadel BV. Acute pancreatitis associated with growth hormone therapy for short stature. N Engl J Med 1995;332:401-2.
22.Malozowski S, Tanner LA, Wysowski D, Fleming GA. Growth Hormone, insulin like growth factor-1 and benign intracranial hypertension. N Engl J Med 1993;329:665.
23.Blethen SL. Leukemia in children treated with growth hormone. Trend Endocrinol Metab 1998;9:367-70.
24.Albertsson-Wikland K, Wennergren G, Wennergren M, Vilbergsson G, Rosberg S. Longitudinal follow-up of growth in children born small for gestational age. Acta Paediatr 1993;82:438-43.
25.Albertsson-Wikland K. Growth hormone secretion and growth hormone treatment in children with intrauterine growth retardation. Acta Paediatr Scand 1989;349:35-41.
26.Ackland FM, Stanhope R, Eyre C, Hamill G, Jones J, Preece MA. Physiological growth hormone secretion in children with short stature and intrauterine growth retardation. Horm Res 1988;30:241-5.
27.Chatelain PG, Cauderay MC, de Zegher F, Claris O, Salle B, Tauber M et al. Growth hormone secretion and sensitivity in children born small for gestational age. Acta Paediatr Suppl 1996;417:15-6.
28.Chatelain PG, Job JC, Blanchard J, Ducret JP, Olivier M, Sagnard L et al. Dose dependant catch-up growth after two years of growth hormone treatment in intrauterine growth retarded children. J Clin Endocrinol Metab 1994;78:1454-60.
29.Massa G, Otten BJ, de Muinck Keizer-Schrama SMPF, Delamarre-van de Waal HA, Jansen M, Vulsma T et al. Treatment with two growth hormone regimens in girls with Turner’s Syndrome; final height results. Horm Res 1995;43:144-6.
30.Summary of United States FDA hearing on the use of growth hormone in girls with Turner’s syndrome. Rockville: Food and Drug Administration, 1997.
31.Van de Brock J, Massa G, Attanasio A, Mastranga A, Chaussain JL, Price DA et al. Final height after long term growth hormone treatment in Turner’s syndrome. J Pediatr 1995;1276:729-35.
32.Fine RN, Kohaut EC, Brown DF, Perlman AJ. Growth after recombinant growth hormone treatment in children with chronic renal failure: Report of a multicentre randomized double-blind placebo-controlled study. J Pediatr 1994;124:374-82.
33.Hindmarsh P, Brook CGD. Final height of short normal children treated with growth hormone. Lancet 1996;348:13-6.
34.Ranke MB, Grauer ML, Kistner K, Blum WF, Wollmann HA. Spontaneous adult height in idiopathic short stature. Horm Res 1995;44:152-7.
35.Castells S, Torrado C, Bastian W, Wisniewski KE. Growth hormone deficiency in Down’s syndrome children, J Intell Disability Res 1992;36:29-43.
36.Ramirez RJ, Wolfe SE, Barrow RE, Herndon DN. Growth hormone treatment in pediatric burns: A safe therapeutic approach. Ann Surg 1998;228:439-48.
37.Butenandt O. Rheumatoid arthritis and growth retardation in children: treatment with human growth hormone. Eur J Pediatr 1979;130:28.
38.Allen DB. Determining who needs growth hormone. Med Ethics Pediatrician 1991;2:6-7.

Citation: The Pharmaceutical Journal URI: 20001867

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