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Growth Hormone Deficiency – Difficulties in Diagnosis and Management

Published Online: June 6th 2011 European Endocrinology, 2008; 4(2):90-2; DOI: http://doi.org/10.17925/EE.2008.04.02.90
Authors: Mehul Dattani, Anitha Kumaran
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Abstract
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Abstract:
Overview

Growth hormone (GH) secreted by the pituitary gland is the principal mediator of somatic growth in childhood. Growth hormone deficiency (GHD) has an incidence of approximately one in 3,000-4000.1,2 This may be an overestimate, as reversibility of GH deficiency has been reported in 25-75% of children with GHD.3 It may occur in isolation (IGHD), or in combination with other hormone deficiencies (multiple pituitary hormone deficiency [MPHD]).

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Additionally, it can occur in association with other congenital abnormalities such as forebrain defects, optic nerve hypoplasia or cleft lip and palate. A threshold of height standard deviation score (SDS) equal to or below 2.0 (3rd percentile) will identify 14% of children with an organic cause of growth failure.4,5 After excluding chronic, non-endocrine causes of growth failure, these children should be assessed for GHD if there is an association of poor growth velocity (height velocity >1 SD below mean for chronological age).6

Diagnosis

Additionally, it can occur in association with other congenital abnormalities such as forebrain defects, optic nerve hypoplasia or cleft lip and palate. A threshold of height standard deviation score (SDS) equal to or below 2.0 (3rd percentile) will identify 14% of children with an organic cause of growth failure.4,5 After excluding chronic, non-endocrine causes of growth failure, these children should be assessed for GHD if there is an association of poor growth velocity (height velocity >1 SD below mean for chronological age).6

Diagnosis
The diagnosis of GHD in children has been the subject of controversy for decades. Diagnosis can be extremely difficult owing to the fallibility, lack of reproducibility and poor sensitivity and specificity of the various biochemical tests involved. Accurate height measurements with appropriate measuring devices plotted on appropriate charts by staff trained in auxology are imperative to diagnose growth failure.7 Serial measurements over at least six months to one year are necessary for calculating height velocity.8

Thyroxine and cortisol are necessary for regulation of the GH1 gene, so normal concentrations of these hormones are necessary before testing for GH deficiency. Random GH measurements are unhelpful in diagnosing GHD due to the pulsatile nature of GH secretion. Urinary GH secretion lacks adequate sensitivity and specificity for the diagnosis of GHD.9

The commonly used method to diagnose GHD is growth hormone provocation testing. The National Institute for Clinical Excellence in the UK (NICE) recommends that at least two tests of GH provocation must be performed to diagnose GHD. There is at present no satisfactory solution if the two provocation tests produce conflicting results. The cut-off value to diagnose GHD is any value less than or equal to 5–6.7mcg/l (15;20mU/l). This is an arbitrary cut-off value as even normal children can have low peak GH values.10 This cut-off value may be used independently of the type of test and assay methodology involved, which makes interpretation difficult as it is well known that there is not only considerable inter- and intra-individual variation with these tests, but the cut-offs used also vary depending on the assay used.8,11 These tests are considered to be non-physiological as they are not representative of the normal secretory pattern of pituitary GH. Additionally, the tests can be associated with significant morbidity and even mortality.12

While provocation tests can diagnose complete GHD, the boundaries between partial GHD, idiopathic short stature and constitutional delay of growth and puberty are blurred. Additionally, in children with neurosecretory dysfunction of GH secretion, the diagnosis can be missed as they have a normal GH response to stimulation but have decreased spontaneous GH secretion.6 The influence of age and sex steroids on GH testing is another area of debate. Although the consensus statement of the Growth Hormone Research Society6 does not recommend sex steroid priming prior to GH testing, it has been shown that 61% of normal pre-pubertal children failed to raise their peak GH level above 7.2ng/ml following three provocation tests.10 Hence, sex steroid priming is still practised despite a lack of consensus. Variation in GH concentrations is marked with the use of different GH assays in different studies.13;17 The assays in use detect immunologically active hGH, which may not reflect true biological activity. Immunofunctional assays (IFAs) represent an advance as they detect hGH capable of binding to its receptor. A comparison of IFAs with immunoradiometric assays demonstrates different GH concentrations within the same serum sample.18

The GH-dependent growth factors insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) lack adequate sensitivity for the diagnosis of GHD but have a combined specificity of 90%, which would indicate GHD if values are subnormal

and other contributing causes (nutrition, renal and hepatic dysfunction and underlying disease) are excluded.9,19;21 IGF-1 concentrations are highly age-dependent, with very low concentrations in early childhood and a dramatic increase in puberty.17,22 However, a combination of HV and IGF-1 concentrations has a high sensitivity (95%) and specificity (96%) in diagnosing GHD, and may replace the need for a second growth provocation test.23

Imaging
Bone age estimated by X-ray of the left wrist and hand is a useful tool in the evaluation of all children with growth failure. Recently, the use of magnetic resonance imaging (MRI) has helped enormously in the diagnosis of GHD and related disorders. Abnormalities are associated with both IGHD and MPHD. Common abnormalities are a small anterior pituitary gland, attenuated or absent pituitary stalk and an ectopic or undescended posterior pituitary.24,25 Suspicion of intracranial tumours, infiltrative disorders and structural abnormalities should also prompt an MR of the central nervous system.

Genetics
Recent advances in our knowledge of the developmental processes regulating normal pituitary development have led to the identification of a number of genetic causes of GHD and hypopituitarism. For instance, mutations in the developmental gene HESX1 are associated with septo
optic dysplasia (SOD), MPHD and IGHD, while mutations in the genes SOX3, LHX3, LHX4, PROP1 and POU1F1 are associated with variable forms of hypopituitarism. Mutations in the genes encoding GH and the growth-hormone-releasing hormone receptor (GHRHR) are associated with IGHD.26 However, variability of phenotypes and penetrance, as well as the rarity of mutations, suggests that genotyping cannot currently be used for the diagnosis of GHD. Currently, the gold standard for diagnosis is a combination of clinical, auxological, biochemical and radiological data that support GHD.6

Treatment
The unlimited supply of recombinant human growth hormone (rhGH) introduced in 1985 has led to optimal dosing and adequate duration of treatment with a good safety profile. Children treated early have good catch-up growth and normal final adult height (FAH). The recommended dose of rhGH for use in GHD is 20–30µg/kg/day. A dose of 0.18mg/kg/week rhGH has been shown to be sufficient to reach FAH within two SDS of the normal population.27 The variables that influence final height are dose of GH, duration of treatment, height SDS at the start of treatment, bone age delay, height at puberty onset, midparental height and first year of treatment growth velocity (GV), all of which showed a positive correlation; age at start of treatment and maximum GH peak in stimulation tests are negatively correlated.28-34

Another possible factor influencing hGH responsiveness and final height is a polymorphic variant resulting in the deletion of exon 3 in the gene encoding the growth hormone receptor (GHR gene). The two main polymorphic variants in GHR result in the retention (GHRfl) or deletion of exon 3 (GHRd3).35 In children born small for gestational age (SGA), the GHRd3 genotype has shown increased responsiveness to GH therapy.36 In children with GHD and MPHD, the presence of GHRd3 genotype has generated data ranging from no influence on GH responsiveness35,37-39 to improved first-year growth velocity and an increase of 0.9 SDS in final height compared with GHRfl genotype.40 It is unclear if the dose of GH or the severity of GHD might contribute to these conflicting reports.

GHD has been shown to reverse in 25-75% of GHD patients, when re-tested after a washout period of one to three months.3 Recent data show that 36% of children diagnosed with isolated GHD without alterations in pituitary anatomy on MRI normalised on re-testing of their GH-IGF axis at puberty, and discontinuation of rhGH in these children did not significantly alter their final height.41 This could indicate the presence of a transient GH deficiency that corrects under the influence of pubertal steroids, or reflect the lack of reproducibility of the biochemical tests. This might validate earlier withdrawal of treatment, especially in children with partial GHD.

Recently, the continuation of GH treatment in adults with persisting GHD has been recommended by the National Institute for Clinical Excellence (NICE) in the UK. In adults, GHD has been associated with increased fat mass, decreased lean body mass, increased triglycerides and high-density lipoprotein contributing to cardiovascular morbidity.42 Reduction in bone density and exercise capacity secondary to reduced muscle mass has also been reported.43-45 It is well known that GHD has a significant impact on quality of life and is associated with reduced energy levels, concentration and emotion. NICE guidelines recommend that GH treatment should be considered only in adults who have fulfiled criteria on a quality of life questionnaire. rhGH has shown to improve body composition, lipid profile, bone density, quality of life and cardiovascular morbidity.46-49 The Growth Hormone Research Society recommends a lower dose of 0.15-0.30mg/day to minimise side effects,6 with subsequent optimisation of the dose based on IGF1 concentrations.

Currently, it is recommended that GH secretion should be reassessed at the end of statural growth, and GH therapy continued only in cases of severe GHD (peak GH<3mcg/l); individuals with moderate GHD (peak 3-7mcg/l) should be followed up by an adult endocrinologist.50-52

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There is no need for re-testing in patients with MPHD, GHD due to a congenital lesion or a genetic mutation, and GHD secondary to radiotherapy, surgery or a mass lesion as it is unlikely that their GH deficiency will reverse.

Conclusion
In summary, the diagnosis of GHD in children and adults can be subject to several fallacies and careful consideration of clinical, auxological, biochemical and radiological data is required for appropriate diagnosis. Understanding the role of growth hormone in metabolic and psychological aspects of GHD has led to better management of GHD in adulthood but long-term follow up is required to assess the impact of rhGH on lifespan in GHD adults and the safety profile of prolonged treatment. With further advances in medical technology, better investigation modalities might emerge, with a consequent impact on management.

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References

  1. Lindsay R, Feldkamp M, Harris D, et al., Utah Growth Study: growth standards and the prevalence of growth hormone deficiency, J Pediatr, 1994;125(1):29–35.
  2. Vimpani GV, Vimpani AF, Pocock SJ, et al., Differences in physical characteristics, perinatal histories, and social backgrounds between children with growth hormone deficiency and constitutional short stature, Arch Dis Child, 1981;56(12): 922–8.
  3. de Boer H, van der Veen EA, Why retest young adults with childhood-onset growth hormone deficiency?, J Clin Endocrinol Metab, 1997;82(7):2032–6.
  4. Voss LD, Growth hormone therapy for the short normal child: who needs it and who wants it? The case against growth hormone therapy, J Pediatr, 2000;136(1):103–6.
  5. Voss LD, Mulligan J, Betts PR, Wilkin TJ, Poor growth in school entrants as an index of organic disease: the Wessex growth study, BMJ, 1992;305:1400–1402.
  6. GH Research Society, Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society, J Clin Endocrinol Metab, 2000;85:3990–93.
  7. Tanner JM, Whitehouse RH, Clinical longitudinal standard for height, weight, height velocity and weight velocity and the stage of puberty, Arch Dis Child, 1976;51:170–79.
  8. Hindmarsh PC, Swift PG, An assessment of growth hormone provocation tests, Arch Dis Child, 1995;72(4):327–62.
  9. Tillmann V, Buckler JM, Kibirige MS, et al., Biochemical tests in the diagnosis of childhood growth hormone deficiency, J Clin Endocrinol Metab, 1997;82(2):531–5.
  10. Marin G, Domene HM, Barnes KM, et al., The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine insulinin normal girls and boys, J Clin Endocrinol Metab, 1994;79:537–41.
  11. Dattani MT, Pringle PJ, Hindmarsh PC, What is a normal stimulated growth hormone concentration?, J Endocrinol, 1992;133:447–50.
  12. Shah A, Stanhope R, Matthew D, Hazards of pharmacological tests of growth hormone secretion in childhood, Br Med J, 1992;304:173–4
  13. Andersson AM, Orskov H, Ranke MB, et al., Interpretation of growth hormone provocative tests: comparison of cut-off values in four european laboratories, Eur J Endocrinol, 1995;132: 340–43.
  14. Ebdrup L, Fisker S, Sorensen HH, et al., Variety in growth hormone determinations due to use of different immunoassays and to the interference of growth hormone-binding protein, Horm Res, 1999;51(Suppl. 1):20–26.
  15. Jansson C, Boguszewski C, Rosberg S, et al., Growth hormone (gh) assays: Influence of standard preparations, gh isoforms, assay characteristics, and gh-binding protein, Clin Chem, 1997;43:950–56.
  16. Preece MA, Making a rational diagnosis of growth-hormone deficiency, J Pediatr, 1997;131:S61–4.
  17. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, et al., Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited, J Clin Endocrinol Metab, 1995;80:1532–40.
  18. Stark S, Willig RP, Growth hormone determination in children using an immunofunctional assay in comparison to conventional assays, Horm Res, 2007;68(4):171–7.
  19. Mitchell H, Dattani MT, Nanduri V, et al., Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency, Arch Dis Childhood, 1999;80:443–4.
  20. Cianfarani S, Liguori, A, Germani D, IGF-I and IGFBP-3Assessment in the Management of Childhood Onset Growth Hormone Deficiency, Cianfarani S, Clemmons DR, Savage MO (eds): IGF-I and IGF Binding Proteins, Basic Research and Clinical Management, Endocr Dev, 2005;9:66–75.
  21. Hauffa BP, Lehmann N, Bettendorf M, et al., German KIGS Board/Medical Outcome Study Group, Central laboratory reassessment of IGF-I, IGF-binding protein-3, and GH serum concentrations measured at local treatment centers in growth-impaired children: implications for the agreement between outpatient screening and the results of somatotropic axis functional testing, Eur J Endocrinol, 2007;157(5):597–603.
  22. Bala RM, Lopatka J, Leung A, et al., Serum immunoreactive somatomedin-C levels in normal adults, pregnant women at term, children at various ages and children with constitutionally delayed growth, J Clin Endocrinol Metab, 1981;52:508–12.
  23. Cianfarani S, Tondinell T, Spadoni GL, et al., Height velocity and IGF-I assessment in the diagnosis of childhood onset GH insufficiency: do we still need a second GH stimulation test?, Clin Endocrinol, 2002;57(2):161–7
  24. Osorio MG, Marui S, Jorge AA, et al., Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes, J Clin Endocrinol Metab, 2002;87(11): 5076–84.
  25. Hamilton J, Chitayat D, Blaser S, et al., Familial growth hormone deficiency associated with MRI abnormalities, Am J Med Genet, 1998;80(2):128–32.
  26. Kelberman D, Dattani MT, The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism, Ann Med, 2006;38(8):560–77.
  27. Rachmiel M, Rota V, Atenafu E, et al., Final Height in Children with Idiopathic Growth Hormone Deficiency Treated with a Fixed Dose of Recombinant Growth Hormone, Horm Res, 2007;68:236–43.
  28. Wit J M, Kamp GA, Rikken B, Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature, Pediatr Res, 1996;39(2):295–302.
  29. Cutfield W, Lindberg A, Albertsson WK, et al., Final height in idiopathic growth hormone deficiency: the KIGS experience. KIGS International Board, Acta Paediatr, 1999;88(428):72–5.
  30. Tanaka T, Cohen P, Clayton PE, et al., Diagnosis and management of growth hormone deficiency in childhood and adolescence-part 2: growth hormone treatment in growth hormone deficient children, Growth Horm, 2002;12(5):323–41.
  31. Thomas M, Massa G, Bourguignon JP, et al., Final height in children with idiopathic growth hormone deficiency treated with recombinant human growth hormone: the Belgian experience, Horm Res, 2001;55(2):88–94.
  32. Saenger P, Growth hormone in growth hormone deficiency, BMJ, 2002;325:58–9.
  33. Cacciari E, Zucchini S, Cicognani A, et al., Birth weight affects final height in patients treated for growth hormone deficiency, Clin Endocrinol, 1999;51(6):733–9.
  34. Ranke MB, Schweizer R, Wollmann HA, Schwarze P, Dosing of growth hormone in growth hormone deficiency, Horm Res, 1999;51(Suppl. 3):70–74.
  35. de Graaff LC, Meyer S, Els C, et al., GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age, Clin Endocrinol, 2008;68(6):930–34.
  36. Dos Santos C, Essioux L, Teinturier C, et al., A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone, Nat Genet,2004;36:720–24
  37. Pilotta A, Mella P, Filisetti M, et al., Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children, J Clin Endocrinol Metab, 2006;91: 1178–80.
  38. Ito Y, Makita Y, Matsuo K, et al., Influence of the exon 3 deleted isoform of GH receptor gene on growth response to GH in Japanese children, Horm Res, 2006;65.
  39. Räz B, Janner M, Petkovic V, Lochmatter D, et al., Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency, J Clin Endocrinol Metab, 200893(3):974–80.
  40. Jorge AA, Marchisotti FG, Montenegro LR, et al., Growth hormone (GH) pharmacogenetics: Influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency, J Clin Endocrinol Metab, 2006;91(3):795–6.
  41. Zucchini S, Pirazzoli P, Baronio F, et al., Effect on adult height of pubertal growth hormone retesting and withdrawal of therapy in patients with previously diagnosed growth hormone deficiency, J Clin Endocrinol Metab, 2006;91(11):4271–6.
  42. Colao A, Di Somma C, Spiezia S, et al., Growth hormone treatment on atherosclerosis: results of a five-year open, prospective, controlled study in male patients with severe growth hormone deficiency, J Clin Endocrinol Metab, 2008; 93(9):3416–24
  43. Rosen T, Bosaeus I, Tolli J, et al., Increased body fat mass and decreased extracellular fluid volume in adults with growth hormone deficiency, Clin Endocrinol, 1993;38(1):63–71.
  44. Rosen T, Hansson T, Granhed H, et al., Reduced bone mineral content in adult patients with growth hormone deficiency”, Acta Endocrinol (Copenh), 1993;129(3):201–6.
  45. Attanasio AF, Lamberts SW, Matranga AM, et al., Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment, Adult Growth Hormone Deficiency Study Group, J Clin Endocrinol Metab, 1997;82(1):82–8.
  46. Bengtsson BA, Eden S, Lonn L, et al., Treatment of Adults with Growth Hormone (GH) Deficiency with Recombinant Human GH, J Clin Endocrinol Metabol, 1993;76;309–17.
  47. Salomon F, Cuneo RC, Hesp R, et al., The Effects of Treatment with Recombinant Human Growth Hormone on Body Composition and Metabolism in Adults with Growth Hormone Deficiency, N Eng J Med, 1989;321:1797–1803.
  48. Amato G, Carella C, Fazio S, 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 Metabol, 1993;77:1671–6.
  49. Widowson WM, Gibney J, The Effect of Growth Hormone Replacement on Exercise Capacity in Patients with GH Deficiency: A Metaanalysis, J Clin Endocrinol Metab, 2008;93(11):4413–17.
  50. Allen DB, Issues in the transition from childhood to adult growth hormone therapy, Pediatrics, 1999;104:1004–10.
  51. Monson JP, Hindmarsh P, The assessment of growth hormone deficiency in children and adults with particular reference to the transitional period, Clin Endocrinol, 2000;53(5):545–7.
  52. Rosenfeld RG, Transitioning patients with childhood-onset growth hormone deficiency to treatment in adulthood, J Pediatr Endocrinol Metab, 2002;15(Suppl. 5):1361–5.

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