Journal of Endocrinological Investigation

, Volume 42, Issue 9, pp 1067–1076 | Cite as

First-year predictors of health-related quality of life changes in short-statured children treated with human growth hormone

  • J. QuitmannEmail author
  • J. Bloemeke
  • H.-G. Dörr
  • M. Bullinger
  • S. Witt
  • N. Silva
Original Article



Little attention has been directed towards examining the impact of predictors on change in health-related quality of life (HRQOL) within the course of growth hormone (GH) treatment in pediatric short stature. We aimed to assess changes in HRQOL and its sociodemographic, clinical and psychosocial predictors in children and adolescents diagnosed with growth hormone deficiency (GHD), and born short for gestational age (SGA) before and 12-month after start of GH treatment from the parents’ perspective. Results were compared with an untreated group with idiopathic short stature (ISS). In this prospective multicenter study, 152 parents of children/adolescents (aged 4–18 years) provided data on their children’s HRQOL at baseline and at 12-month follow-up.


Repeated-measures multivariate analyses of covariance were performed to examine parent-reported HRQOL changes from baseline to 1-year after treatment and hierarchical linear regressions to identify the predictors of HRQOL changes.


Results showed that parents of children that were treated with GH report an increase in their children’s HRQOL after 1 year. Changes in HRQOL were mostly explained by psychosocial predictors followed by sociodemographic and clinical variables. Specifically, the diagnosis SGA significantly predicted a greater increase in parent-reported HRQOL. Furthermore, a lower caregiving burden significantly predicted a decrease in parent-reported HRQOL.


In conclusion, a substantial percentage of explained variance in HRQOL relates to psychosocial and sociodemographic predictors. However, there appears to be other important factors that are predictors of HRQOL, which need to be determined in large, population-based samples.


Short stature Growth hormone treatment Children and adolescents HRQOL Predictors of change 



The QoLISSY prospective project would like to thank the children, parents, and staff from the participating clinical centers for their participation and contributions. Besides, we thank Dr. Ilker Akkurt, Dr. Desiree Dunstheimer, Dr. Christian Vogel, Dr. Volker Böttcher, Dr. Ursula Kuhnle Krahl, PD. Dr. Markus Bettendorf, Prof. Dr. Eckhard Schönau, Dr. Susanne Fricke-Otto, Dr. Alexandra Keller and Prof. Dr. Klaus Mohnike who helped to conduct the study, as well as Prof. Dr. H. Wollmann, Dr. Anja Rohenkohl and Dr. Rachel Sommer for supporting and helping to realize the study.


This study was sponsored by Pfizer, Inc. and while the authors received research funding for the conduct of the study, no financial support was given for the writing of this manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Access to the QoLISSY instrument

QoLISSY is a joint initiative between Pfizer Limited and the University Medical Center Hamburg–Eppendorf. Copyright Pfizer Limited all rights reserved. The European QoLISSY instrument, together with comprehensive information of its development and validation process is published in the QoLISSY’s User’s Manual (Pabst Science Publishers, Lengerich, 2013). The Manual, which is available upon request, includes QoLISSY child and parent forms, as well as scoring information (


  1. 1.
    Wit JM, Clayton PE, Rogol AD, Savage MO, Saenger PH, Cohen P (2008) Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 18:89–110. CrossRefPubMedGoogle Scholar
  2. 2.
    Stanley T (2012) Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes 19:47–52CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    QoLISSY Group (2017) Quality of life of short statured children and adolescents during growth hormone treatment: final study report. Medical University Center Hamburg-Eppendorf, HamburgGoogle Scholar
  4. 4.
    Lee JM, Chernausek SD, Hokken-Koelega AC, Czernichow P (2003) International small for gestational age advisory board consensus development conference statement: management of short children born small for gestational age, April 24 Oct 1, 2001. Pediatrics 111:1253–1261CrossRefPubMedGoogle Scholar
  5. 5.
    Binder G (2010) Störungen des Wachstums. In: Hiort O, Danne T, Wabitsch M (eds) Pädiatrische Endokrinologie und Diabetologie. Springer, Berlin, pp 261–281CrossRefGoogle Scholar
  6. 6.
    Pedicelli S, Peschiaroli E, Violi E, Cianfarani S (2009) Controversies in the definition and treatment of idiopathic short stature (ISS). J Clin Res Pediatr Endocrinol 1:105–115. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ranke MB (1996) Towards a consensus on the definition of idiopathic short stature. Horm Res 45:64–66CrossRefPubMedGoogle Scholar
  8. 8.
    Kang MJ (2017) Novel genetic causes of idiopathic short stature. Ann Pediatr Endocrinol Metab 22:153–157CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cuttler L, Silvers JB, Singh J, Marrero U, Finkelstein B, Tannin G, Neuhauser D (1996) Short stature and growth hormone therapy. A national study of physician recommendation patterns. JAMA 276:531–537CrossRefPubMedGoogle Scholar
  10. 10.
    Finkelstein BS, Singh J, Silvers JB, Marreroa U, Neuhauser D, Cuttler L (1999) Patient attitudes and preferences regarding treatment: GH therapy for childhood short stature. Horm Res 51:67–72PubMedGoogle Scholar
  11. 11.
    Hardin D, Woo J, Butsch R, Huett B (2007) Current Prescribing practices and opinions about growth hormone therapy: results of a nationwide survey of paediatric endocrinologists. Clin Endocrinol (Oxf) 66:85–94Google Scholar
  12. 12.
    Lee JM, Appugliese D, Coleman SM, Kaciroti N, Corwyn RF, Bradley RH, Sandberg DE, Lumeng JC (2009) Short stature in a population-based cohort: social, emotional and behavioral functioning. Pediatrics 124:903–910. CrossRefPubMedGoogle Scholar
  13. 13.
    Maghnie M, Labarta JI, Koledova E, Rohrer TR (2018) Short stature diagnosis and referral. Front Endocrinol (Lausanne). CrossRefGoogle Scholar
  14. 14.
    Ranke Wit J (2018) Growth hormone—past, present and future. Nat Rev Endocrinol 14:285–300CrossRefPubMedGoogle Scholar
  15. 15.
    Migliaretti G, Ditaranto S, Guiot C, Vannelli S, Matarazzo P, Cappello N, Stura I, Cavallo F (2018) Long-term response to recombinant human growth hormone treatment: a new predictive mathematical method. J Endcrinol Investig 41:839–848. CrossRefGoogle Scholar
  16. 16.
    Wit JM, Reiter EO, Ross JL, Saenger PH, Savage MO, Rogol AD, Cohen P (2008) Idiopathic short stature: management and growth hormone treatment. Growth Horm IGF Res 18:111–135CrossRefPubMedGoogle Scholar
  17. 17.
    Ranke M, Lindberg A, Tanaka T, Camacho-Hübner C, Dunger D, Geffner M (2017) Baseline characteristics and gender differences in prepubertal children treated with growth hormone in Europe, USA, and Japan: 25 Years’ KIGS ® experience (1987–2012) and review. Horm Res Paediatr 87:30–41CrossRefPubMedGoogle Scholar
  18. 18.
    Kim JE, Suh B-K, Ko C, Lee K, Shin C, Hwang J, Kim H, Chung W, Kim C, Han H, Kwon N, Cho S, Yoo H, Jun D (2018) Recombinant growth hormone therapy for prepubertal children with idiopathic short stature in Korea: a phase III randomized trial. J Endcrinol Investig 41:475–483CrossRefGoogle Scholar
  19. 19.
    Brod M, Alolga SL, Beck JF, Wilkinson L, Hojbjerre L, Rasmussen MH (2017) Understanding the burden of illness for child growth hormone deficiency. Qual Life Res 26:1673–1686CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Abe S, Okumura A, Mukae T, Nakazawa T, Niijima S, Yamashiro Y, Shimizu T (2009) Depressive tendency in children with growth hormone deficiency. J Paediatr Child Health 45:636–640CrossRefPubMedGoogle Scholar
  21. 21.
    Attanasio AF, Shavrikova EP, Blum WF, Shalet SM (2005) Quality of life in childhood onset growth hormone-deficient patients in the transition phase from childhood to adulthood. J Clin Endocrinol Metab 90:4525–4529CrossRefPubMedGoogle Scholar
  22. 22.
    Brütt AL, Sandberg DE, Chaplin J, Wollmann H, Noeker M, Koltowska-Haggstrom M, Bullinger M (2009) Assessment of health-related quality of life and patient satisfaction in children and adolescents with growth hormone deficiency or idiopathic short stature—part 1: a critical evaluation of available tools. Horm Res 72:65–73PubMedGoogle Scholar
  23. 23.
    Voss LD, Mulligan J (2000) Bullying in school: are short pupils at risk? Questionnaire study in a cohort. BMJ 320:612–613CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Christensen TL, Djurhuus CB, Clayton P, Christiansen JS (2007) An evaluation of the relationship between adult height and health-related quality of life in the general UK population. Clin Endocrinol (Oxf) 67:407–412CrossRefGoogle Scholar
  25. 25.
    Bullinger M, Dellenmark Blom M, Feigerlova E, Herdman M, Lunde C, Mimoun E, Pleil A, Power M, Quitmann J, Rohenkohl A, Sanz D, Skoropadskaya A, Wollmann H, Chaplin J (2010) Assessing quality of life in short stature youth-the QoLiSSY project focus group and cognitive debriefing experience. Value Health 13:63CrossRefGoogle Scholar
  26. 26.
    Quitmann J, Rohenkohl A, Sommer R, Bullinger M, Silva N (2016) Explaining parent-child (dis)agreement in generic and short stature-specific health related quality of life reports: do family and social relationships matter? Health Qual Life Outcomes 14:150CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Silva N, Bullinger M, Sommer R, Rohenkohl A, Witt S, Quitmann J (2018) Children’s psychosocial functioning and parents’ quality of life in paediatric short stature: the mediating role of caregiving stress. Clin Psychol Psychother 25:e107–e118CrossRefPubMedGoogle Scholar
  28. 28.
    Silva N, Bullinger M, Quitmann J, Ravens-Sieberer U, Rohenkohl A (2013) HRQoL of European children and adolescents with short stature as assessed with generic (KIDSCREEN) and chronic-generic (DISABKIDS) instruments. Expert Rev Pharmacoecon Outcomes Res 13:817–827CrossRefPubMedGoogle Scholar
  29. 29.
    Sandberg DE, Colsman M (2005) Growth hormone treatment of short stature: status of the quality of life rationale. Horm Res 63:275–283PubMedGoogle Scholar
  30. 30.
    Bullinger M (2002) Assessing health related quality of life in medicine. An overview over concepts, methods and applications in international research. Restor Neurol Neurosci 20:93–101PubMedGoogle Scholar
  31. 31.
    Quitmann J, Bullinger M, Sommer R, Rohenkohl A, Silva N (2016) Associations between psychological problems and quality of life in pediatric short stature from patients’ and parents’ perspectives. PLoS One 11:e0153953CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sheppard L, Eiser C, Davies HA, Carney S, Clarke SA, Urquhart T, Ryder MJ, Stoner A, Wright NP, Butler G (2006) The effects of growth hormone treatment on health-related quality of life in children. Horm Res 65:243–249PubMedGoogle Scholar
  33. 33.
    Stephen MD, Varni JW, Limbers CA, Yafi M, Heptulla RA, Renukuntla VS, Bell CS, Brosnan PG (2011) Health-related quality of life and cognitive functioning in pediatric short stature: comparison of growth-hormone-naive, growth-hormone-treated, and healthy samples. Eur J Pediatr 170:351–358CrossRefPubMedGoogle Scholar
  34. 34.
    Geisler A, Lass N, Reinsch N, Uysal Y, Singer V, Ravens-Sieberer U, Reinehr T (2012) Quality of life in children and adolescents with growth hormone deficiency: association with growth hormone treatment. Horm Res Paediatr 78:94–99CrossRefPubMedGoogle Scholar
  35. 35.
    Al-Uzri A, Matheson M, Gipson DS, Mendley SR, Hooper SR, Yadin O, Rozansky DJ, Moxey-Mims M, Furth SL, Warady BA, Gerson AC, Chronic Kidney Disease in Children Study G (2013) The impact of short stature on health-related quality of life in children with chronic kidney disease. J Pediatr 163(736–741):e731Google Scholar
  36. 36.
    Sommer R, Daubmann A, Quitmann J, Ravens- Sieberer U, Bullinger M (2015) Understanding the impact of statural height on health-related quality of life in German adolescents: a population-based analysis. Eur J Pediatr 174:875–882CrossRefPubMedGoogle Scholar
  37. 37.
    Chaplin JE, Kristrom B, Jonsson B, Hagglof B, Tuvemo T, Aronson AS, Dahlgren J, Albertsson-Wikland K (2011) Improvements in behaviour and self-esteem following growth hormone treatment in short prepubertal children. Horm Res Paediatr 75:291–303CrossRefPubMedGoogle Scholar
  38. 38.
    Coste J, Pouchot J, Carel JC (2012) Height and health-related quality of life: a nationwide population study. J Clin Endocrinol Metab 97:3231–3239CrossRefPubMedGoogle Scholar
  39. 39.
    Leiberman E, Pilpel D, Carel CA, Levi E, Zadik Z (1993) Coping and satisfaction with growth hormone therapy among short- stature children. Horm Res 40:128–135CrossRefPubMedGoogle Scholar
  40. 40.
    Rekers-Mombarg LTM, Busschbach JVV, Massa GG, Dicke J, Wit JM, Group DGHW (1998) Quality of life of young adults with idiopathic short stature: effect of growth hormone treatment. Acta Paediatr 87:865–870CrossRefPubMedGoogle Scholar
  41. 41.
    Visser-van Balen H, Sinnema G, Geenen R (2006) Growing up with idiopathic short stature: psychosocial development and hormone treatment; a critical review. Arch Dis Child 91:433–439CrossRefPubMedGoogle Scholar
  42. 42.
    The KIDSCREEN Group Europe (2006) The KIDSCREEN questionnaires: Quality of life for children and adolescents—Handbook. Pabst Science Publishers, LengrichGoogle Scholar
  43. 43.
    Cole TJ (1990) The LMS method for constructing normalized growth standards. Eur J Clin Nutr 44:45–60PubMedGoogle Scholar
  44. 44.
    Kromeyer-Hausschild K, Wabitsch M, Kunze D, Geller F, Geiß H, Hesse V (2001) Perzentile für den Body-mass-Index für das Kindes- und Jugendalter unter Heranziehung verschiedener deutsche Stichproben. Monatsschr Kinderheilkd 147:807–820CrossRefGoogle Scholar
  45. 45.
    Bullinger M, Quitmann J, Power M, Herdman M, Mimoun E, DeBusk K, Feigerlova E, Lunde C, Dellenmark-Blom M, Sanz D, Rohenkohl A, Pleil A, Wollmann H, Chaplin JE (2013) Assessing the quality of life of health-referred children and adolescents with short stature: development and psychometric testing of the QoLISSY instrument. Health Qual Life Outcomes 11:76CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sommer R, Blömeke J, Bullinger M, Quitmann J (2018) The psychometric evaluation of the quality of life in short stature youth (QoLISSY) instrument for German children born small for gestational age. J Endcrinol Investig 41:1185–1191CrossRefGoogle Scholar
  47. 47.
    Bullinger M, Sommer R, Pleil A, Mauras N, Ross J, Newfield R, Silverman L, Rohenkohl A, Fox J, Quitmann J (2015) Evaluation of the American-english quality of life in short stature youth (QoLISSY) questionnaire in the United States. Health Qual Life Outcomes. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Rohenkohl A, De Schepper J, Vanderfaeillie J, Fricke K, Hendrickx S, Lagrou K, Bullinger M, Quitmann J, Group TQS (2014) Validation of the flemish version of the quality of life in short stature youth (QoLISSY) QUESTIONNAIRE. Acta Clin Belg 69:177–182CrossRefPubMedGoogle Scholar
  49. 49.
    Rohenkohl A, Stalman S, Kamp G, Bullinger M, Quitmann J (2016) Psychometric performance of the quality of life in short stature youth (QoLISSY) questionnaire in the Netherlands. Eur J Pediatr 175:347–354CrossRefPubMedGoogle Scholar
  50. 50.
    Quitmann J, Gianmmarco A, Maghnie M, Napoli F, Di Giovanno I, Carducci C, Mohn A, Bullinger M, Sommer R (2017) The cross cultural adaptation and validation of the Italian quality of life in short stature youth (QoLISSY) questionnaire. J Endocrinol Invest 40:1077–1084CrossRefPubMedGoogle Scholar
  51. 51.
    The European QoLISSY Group (2013) Quality of life in short stature youth. In: The QoLISSY questionnaire—User’s manual. Pabst Science Publishers, LengerichGoogle Scholar
  52. 52.
    IBM Corp (2012) IBM SPSS statistics for windows. 21.0 edn. IBM Corp., Armonk, NYGoogle Scholar
  53. 53.
    Mukaka M (2012) A guide to appropriate use of correlation coefficient in medical research. Malawi Med J 24:69–71PubMedPubMedCentralGoogle Scholar
  54. 54.
    Cohen J (1992) A power primer. Psychol Bull 112:155–159. CrossRefPubMedGoogle Scholar
  55. 55.
    Thomas M, Beckers D, Brachet C, Dotremont H, Lebrethon MC, Lysy P, Massa G, Reynaert N, Rooman R, van der Straaten S, Roelants M, De Schepper J (2018) Adult height after growth hormone treatment at pubertal onset in short adolescents born small for gestational age: results from a belgian registry-based study. Int J Endocrinol. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Zanelli SA, Rogol AD (2017) Short children born small for gestational age outcomes in the era of growth hormone therapy. Growth Hormon IGF Res 38:8–13CrossRefGoogle Scholar
  57. 57.
    Hwang IT (2014) Efficacy and safety of growth hormone treatment for children born small for gestational age. Korean J Pediatr 57:379–383CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Houk CP, Lee PA (2012) Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes. Int J Pediatr Endocrinol 2012:11CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Cutfield WS, Lindberg A, Rapaport R, Wajnrajch MP, Saenger P (2006) Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res 65(Suppl 3):153–159PubMedGoogle Scholar
  60. 60.
    Ross J, Lee PA, Gut R, Germak J (2010) Factors influencing the one- and two-year growth response in children treated with growth hormone: analysis from an observational study. Int J Pediatr Endocrinol 2010:494656. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    de Ridder MA, Stijnen T, Hokken-Koelega AC (2007) Prediction of adult height in growth-hormone-treated children with growth hormone deficiency. J Clin Endocrinol Metab 92:925–931CrossRefPubMedGoogle Scholar
  62. 62.
    Ranke MB, Lindberg A, Cowell CT, Wikland KA, Reiter EO, Wilton P, Price DA (2003) Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 88:125–131CrossRefPubMedGoogle Scholar
  63. 63.
    Jung HJ, Rosilio M, Blum W, Drop S (2008) Grwoth hormone treatment for short stature in children born small for gestational age. Adv Ther 25:951–978CrossRefPubMedGoogle Scholar
  64. 64.
    Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A (2003) Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 88:3584–3590. CrossRefPubMedGoogle Scholar
  65. 65.
    Barthel D, Ravens-Sieberer U, Nolte S, Thyen U, Klein M, Walter O, Meyrose AK, Rose M, Otto C (2018) Predictors of health-related quality of life in chronically ill children and adolescents over time. J Psychosom Res 109:63–70CrossRefPubMedGoogle Scholar
  66. 66.
    Shiba K, Kondo N, Kondo K (2016) Informal and formal social support and caregiver burden: the AGES caregiver survey. J Epidemiol 26:622–628CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Piran P, Khademi Z, Tayari N, Mansouri N (2017) Caregiving burden of children with chronic diseases. Electron Phys 9:5380–5387CrossRefGoogle Scholar
  68. 68.
    Silva N, Carona C, Crespo C, Canavarro MC (2015) Caregiving burden and uplifts: a contradiction or a protective partnership for the quality of life of parents and their children with asthma? J Fam Psychol 29:151–161CrossRefPubMedGoogle Scholar
  69. 69.
    Eiser C, Varni JW (2013) Health-related quality of life and symptom reporting: similarities and differences between children and their parents. Eur J Pediatr 172:1299–1304CrossRefPubMedGoogle Scholar
  70. 70.
    Fisher M, Mello MP, Dykens EM (2014) Who reports it best? A comparison between parent-report, self-report, and the real life social behaviors of adults with williams syndrome. Res Dev Disabil 35:3276–3284CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Mohseni S, Heydari Z, Qorbani M, Radfar M (2018) Adherence to growth hormone therapy in children and its potential barriers. J Pediatr Endocrinol Metab 26:13–20CrossRefGoogle Scholar
  72. 72.
    Higginson IJ, Carr AJ (2001) Measuring quality of life: using quality of life measures in the clinical setting. BMJ (Clin Res ed) 322:1297–1300CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2019

Authors and Affiliations

  • J. Quitmann
    • 1
    Email author
  • J. Bloemeke
    • 1
  • H.-G. Dörr
    • 2
  • M. Bullinger
    • 1
  • S. Witt
    • 1
  • N. Silva
    • 1
    • 3
  1. 1.Center for Psychosocial Medicine, Institute for Medical PsychologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Division Paediatric EndocrinologyHospital for Children and Adolescents, University Erlangen-NürnbergErlangenGermany
  3. 3.Faculty of Psychology and Education Sciences, Center for Research in Neuropsychology and Cognitive Behavioral InterventionUniversity of CoimbraCoimbraPortugal

Personalised recommendations