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Early retesting by GHRH + arginine test shows normal GH response in most children with idiopathic GH deficiency

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Abstract

Purpose

Most children with idiopathic isolated GH deficiency (IGHD) normalize GH response to stimulation tests when retested at the completion of growth. The objective of this study was to test the effectiveness of early retesting in challenging the diagnosis of idiopathic IGHD and critically review the diagnostic workup leading to this diagnosis in children with short stature.

Methods

We cross-sectionally retested 38 children with idiopathic IGHD and still on GH treatment. The initial diagnosis of idiopathic IGHD was based on subnormal GH responses to two stimulation tests and normal brain imaging or minor/nonspecific findings at magnetic resonance. The GH response normalization at retesting was considered as the main outcome measure. Clinical features of children who were falsely classified as idiopathic IGHD based on first GH testing were retrospectively analyzed.

Results

GH secretion was normal in 36/38 children (95 %). Two children showed slightly reduced peak GH responses and normal IGF-I levels. Fourteen children underwent GH retesting before puberty, 24 children during puberty.

Conclusion

The diagnostic process should be improved to minimize the rate of false positive at GH testing and, in case of unsatisfactory response to GH treatment, the diagnosis of isolated idiopathic GHD should be challenged with early retesting.

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References

  1. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hintz RL, Lafranchi S, Lippe B, Loriaux L, Melmed S (1995) Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 80:1532–1540

    CAS  PubMed  Google Scholar 

  2. Loche S, Bizzarri C, Maghnie M, Faedda A, Tzialla C, Autelli M, Casini MR, Cappa M (2002) Results of early reevaluation of growth hormone secretion in short children with apparent growth hormone deficiency. J Pediatr 140:445–449

    Article  CAS  PubMed  Google Scholar 

  3. Growth Hormone Research Society (2000) 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 85:3990–3993

    Google Scholar 

  4. Andersson AM, Orskov H, Ranke MB, Shalet S, Skakkebaek N (1995) Interpretation of growth hormone provocative tests: comparison of cut-off values in four European laboratories. Eur J Endocrinol 132:340–343

    Article  CAS  PubMed  Google Scholar 

  5. Barth JH, Smith JH, Clarkson P (1995) Wide diversity in measurements of growth hormone after stimulation tests in short children are due to assay variability. Ann Clin Biochem 32(Pt 4):369–372

    Article  CAS  PubMed  Google Scholar 

  6. Chevenne D, Beau N, Léger J, Porquet D (1993) Variability of serum human growth hormone levels in different commercial assays: specificity of growth hormone-releasing hormone stimulation. Horm Res 40:168–172

    Article  CAS  PubMed  Google Scholar 

  7. Illig R, Bucher H (1983) Testosterone priming of growth hormone release. Pediatr Adolesc Endocrinol 12:75–85

    Google Scholar 

  8. Martinez AS, Domené HM, Ropelato MG, Jasper HG, Pennisi PA, Escobar ME, Heinrich JJ (2000) Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency. J Clin Endocrinol Metab 85:4168–4172

    CAS  PubMed  Google Scholar 

  9. Kreitschmann-Andermahr I, Suarez P, Jennings R, Evers N, Brabant G (2010) GH/IGF-I regulation in obesity—mechanisms and practical consequences in children and adults. Horm Res Paediatr 73:153–160

    Article  CAS  PubMed  Google Scholar 

  10. Savage MO (2013) Insulin-like growth factors, nutrition and growth. World Rev Nutr Diet 106:52–59

    Article  PubMed  Google Scholar 

  11. Bang P, Ahmed SF, Argente J, Backeljauw P, Bettendorf M, Bona G, Coutant R, Rosenfeld RG, Walenkamp MJ, Savage MO (2012) Identification and management of poor response to growth-promoting therapy in children with short stature. Clin Endocrinol (Oxf). 77:169–181

    Article  CAS  PubMed  Google Scholar 

  12. Cacciari E, Tassoni P, Parisi G, Pirazzoli P, Zucchini S, Mandini M, Cicognani A, Balsamo A (1992) Pitfalls in diagnosing impaired growth hormone (GH) secretion: retesting after replacement therapy of 63 patients defined as GH deficient. J Clin Endocrinol Metab 74:1284–1289

    CAS  PubMed  Google Scholar 

  13. Longobardi S, Merola B, Pivonello R, Di Rella F, Di Somma C, Colao A, Ghigo E, Camanni F, Lombardi G (1996) Reevaluation of growth hormone (GH) secretion in 69 adults diagnosed as GH deficient during childhood. J Clin Endocrinol Metab 81:1244–1247

    CAS  PubMed  Google Scholar 

  14. Wacharasindhu S, Cotterill AM, Camacho-Hübner C, Besser GM, Savage MO (1996) Normal growth hormone secretion in growth hormone insufficient children retested after completion of linear growth. Clin Endocrinol (Oxf) 45:553–556

    Article  CAS  Google Scholar 

  15. Tauber M, Moulin P, Pienkowski C, Jouret B, Rochiccioli P (1997) Growth hormone (GH) retesting and auxological data in 131 GH-deficient patients after completion of treatment. J Clin Endocrinol Metab 82:352–356

    Article  CAS  PubMed  Google Scholar 

  16. Maghnie M, Strigazzi C, Tinelli C, Autelli M, Cisternino M, Loche S, Severi F (1999) Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 84:1324–1328

    Article  CAS  PubMed  Google Scholar 

  17. Aimaretti G, Baffoni C, Bellone S, Di Vito L, Corneli G, Arvat E, Benso L, Camanni F, Ghigo E (2000) Retesting young adults with childhood-onset growth hormone (GH) deficiency with GH-releasing-hormone-plus-arginine test. J Clin Endocrinol Metab 85:3693–3699

    CAS  PubMed  Google Scholar 

  18. Inzaghi E, Cianfarani S (2013) The challenge of growth hormone deficiency diagnosis and treatment during the transition from puberty into adulthood. Front Endocrinol (Lausanne) 4:34. doi:10.3389/fendo.2013.00034. eCollection 2013

    Google Scholar 

  19. Zucchini S, Pirazzoli P, Baronio F, Gennari M, Bal MO, Balsamo A, Gualandi S, Cicognani A (2006) 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 91:4271–4276

    Article  CAS  PubMed  Google Scholar 

  20. Cacciari E, Milani S, Balsamo A, Dammacco F, De Luca F, Chiarelli F, Pasquino AM, Tonini G, Vanelli M (2002) Italian cross-sectional growth charts for height, weight and BMI (6–20 y). Eur J Clin Nutr 56:171–180

    Article  CAS  PubMed  Google Scholar 

  21. Tanner JM, Whitehouse RH (1976) Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 51:170–179

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Tanner JM, Goldstein H, Whitehouse RH (1970) Standards for children’s height at ages 2–9 years allowing for heights of parents. Arch Dis Child 45:755–762

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Marshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Zachmann M, Prader A, Kind HP, Hafliger H, Budliger H (1974) Testicular volume during adolescence. Helv Paediatr Acta. 29:61–72

    CAS  PubMed  Google Scholar 

  25. Marin G, Domené HM, Barnes KM, Blackwell BJ, Cassorla FG, Cutler GB Jr (1994) The effects of estrogen priming and puberty on the growth hormone response to standardized treadmill exercise and arginine-insulin in normal girls and boys. J Clin Endocrinol Metab 79:537–541

    CAS  PubMed  Google Scholar 

  26. Bellone J, Aimaretti G, Bellone S, Baffoni C, Corneli G, Origlia C, Cappa M, Ghigo E (2000) Sequential administration of arginine and arginine plus GHRH to test somatotroph function in short children. J Endocrinol Invest 23:97–101

    Article  CAS  PubMed  Google Scholar 

  27. Coyne CP (2006) Comparative diagnostic pharmacology: clinical and research applications in living-system models. Wiley-Blackwell, Victoria, pp 157–160

  28. Maghnie M, Lindberg A, Koltowska-Häggström M, Ranke MB (2013) Magnetic resonance imaging of CNS in 15,043 children with GH deficiency in KIGS (Pfizer International Growth Database). Eur J Endocrinol 168:211–217

    Article  CAS  PubMed  Google Scholar 

  29. Maghnie M, Ghirardello S, Genovese E (2004) Magnetic resonance imaging of the hypothalamus-pituitary unit in children suspected of hypopituitarism: who, how and when to investigate. J Endocrinol Invest 27:496–509

    Article  CAS  PubMed  Google Scholar 

  30. Deal C, Hasselmann C, Pfäffle RW, Zimmermann AG, Quigley CA, Child CJ, Shavrikova EP, Cutler GB Jr, Blum WF (2013) Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study. Horm Res Paediatr 79:283–292

    Article  CAS  PubMed  Google Scholar 

  31. Di Iorgi N, Allegri AE, Napoli F, Bertelli E, Olivieri I, Rossi A, Maghnie M (2012) The use of neuroimaging for assessing disorders of pituitary development. Clin Endocrinol (Oxf) 76:161–176

    Article  Google Scholar 

  32. Greulich WW, Pyle SI (1971) Radiographic atlas of skeletal development of hand wrist, 2nd edn. Stanford University Press, Stanford

  33. Bedogni G, Giannone G, Maghnie M, Giacomozzi C, Di Iorgi N, Pedicelli S, Peschiaroli E, Melioli G, Muraca M, Cappa M, Cianfarani S (2012) Serum insulin-like growth factor-I (IGF-I) reference ranges for chemiluminescence assay in childhood and adolescence. Data from a population of in- and out-patients. Growth Horm IGF Res 22:134–138

    Article  CAS  PubMed  Google Scholar 

  34. Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson-Wikland K, Price DA (1999) Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS international board. Kabi pharmacia international growth study. J Clin Endocrinol Metab 84:1174–1183

    Article  CAS  PubMed  Google Scholar 

  35. Geffner ME, Dunger DB (2007) Future directions: growth prediction models. Horm Res 68(Suppl 5):51–56

    Article  PubMed  Google Scholar 

  36. Wu RH, St Louis Y, DiMartino-Nardi J, Wesoly S, Sobel EH, Sherman B, Saenger P (1990) Preservation of physiological growth hormone (GH) secretion in idiopathic short stature after recombinant GH therapy. J Clin Endocrinol Metab 70:1612–1615

    Article  CAS  PubMed  Google Scholar 

  37. Thomas M, Massa G, Maes M, Beckers D, Craen M, François I, Heinrichs C, Bourguignon JP; Belgian study group for paediatric endocrinology (BSGPE) (2003) Growth hormone (GH) secretion in patients with childhood-onset GH deficiency: retesting after one year of therapy and at final height. Horm Res 59:7–15

    Article  CAS  PubMed  Google Scholar 

  38. Ghigo E, Bellone J, Aimaretti G, Bellone S, Loche S, Cappa M, Bartolotta E, Dammacco F, Camanni F (1996) Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endocrinol Metab 81:3323–3327

    CAS  PubMed  Google Scholar 

  39. Giacomozzi C, Spadoni GL, Pedicelli S, Scirè G, Cristofori L, Peschiaroli E, Deodati A, Cambiaso P, Cappa M, Cianfarani S (2012) Responses to GHRH plus arginine test are more concordant with IGF-I circulating levels than responses to arginine and clonidine provocative tests. J Endocrinol Invest 35:742–747

    CAS  PubMed  Google Scholar 

  40. Cianfarani S, Tondinelli S, Spadoni GL, Scirè G, Boemi S, Boscherini B (2002) 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 (Oxf) 57:161–167

    Article  CAS  Google Scholar 

  41. Mitchell H, Dattani MT, Nanduri V, Hindmarsh PC, Preece MA, Brook CG (1999) Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency. Arch Dis Child 80:443–447

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Cianfarani S, Liguori A, Boemi S, Maghnie M, Iughetti L, Wasniewska M, Street ME, Zucchini S, Aimaretti G, Germani D (2005) Inaccuracy of insulin-like growth factor (IGF) binding protein (IGFBP)-3 assessment in the diagnosis of growth hormone (GH) deficiency from childhood to young adulthood: association to low GH dependency of IGF-II and presence of circulating IGFBP-3 18-kilodalton fragment. J Clin Endocrinol Metab 90:6028–6034

    Article  CAS  PubMed  Google Scholar 

  43. Blum WF, Deal C, Zimmermann AG, Shavrikova EP, Child CJ, Quigley CA, Drop SL, Cutler GB Jr, Rosenfeld RG (2013) Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency. Eur J Endocrinol 170:13–21

    Article  PubMed  Google Scholar 

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Conflict of interest

No conflict of interest to be declared.

Author information

Authors and Affiliations

  1. Unit of Endocrinology and Diabetes, Bambino Gesù Children’s Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy

    C. Bizzarri & M. Cappa

  2. D.P.U.O. Bambino Gesù Children’s Hospital, “Tor Vergata” University, Rome, Italy

    S. Pedicelli & S. Cianfarani

  3. Tor Vergata University, Rome, Italy

    B. Boscherini

  4. Clinical Epidemiology Unit, Liver Research Center, Basovizza and Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy

    G. Bedogni

  5. Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

    S. Cianfarani

Authors
  1. C. Bizzarri
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  2. S. Pedicelli
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  3. B. Boscherini
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  4. G. Bedogni
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  5. M. Cappa
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  6. S. Cianfarani
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Corresponding author

Correspondence to C. Bizzarri.

Additional information

C. Bizzarri and S. Pedicelli have contributed equally to this manuscript.

C. Bizzarri, M. Cappa and S. Cianfarani are ESPE members.

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Bizzarri, C., Pedicelli, S., Boscherini, B. et al. Early retesting by GHRH + arginine test shows normal GH response in most children with idiopathic GH deficiency. J Endocrinol Invest 38, 429–436 (2015). https://doi.org/10.1007/s40618-014-0205-3

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  • DOI: https://doi.org/10.1007/s40618-014-0205-3

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