Hyperinsulinemia Tends to Induce Growth Without Growth Hormone in Children with Brain Tumors After Neurosurgery

  • Norishi Ueda
  • Hideyuki Iwayama
Part of the Tumors of the Central Nervous System book series (TCNS, volume 12)


Hypothalamo-pituitary dysfunction is commonly seen in children with brain tumors after neurosurgery, resulting in endocrine disorders, including growth hormone deficiency (GHD). GHD causes growth failure, and thus the majority of the patients need GH replacement therapy. Despite GHD, some patients grow normally or excessively, which has been recognized as growth without GH (GWGH). Since hyperinsulinemia is highly associated with the patients with GWGH, it has been considered to play an important role for promoting linear growth. However, the causes of hyperinsulinemia associated with GWGH and the mechanisms of GWGH remain elusive. The data to date collectively suggest that the location of brain tumors and/or the mode of surgery, insulin resistance associated with obesity, insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-1 and −3, leptin and prolactin (PRL) may contribute to the regulation of insulin secretion in patients with GWGH. Besides its metabolic effects, insulin exerts the diverse effects as a growth factor, including proliferation and differentiation of osteoblasts, leading to acceleration of linear growth. Interaction between insulin- and IGF-I-induced signaling pathways and of insulin with other hormonal factors such as leptin or PRL may play a crucial role for promoting linear growth in patients with GWGH. Despite normal or excessive linear growth, patients with GWGH still have metabolic abnormalities and retarded bone maturation. It remains elusive whether GH replacement therapy solves these problems and enables the patients to reach normal height in adulthood. Better understanding for the mechanisms of GWGH is essential to improve the quality of life of patients with GWGH. Because of a lack of accumulating data, further studies would be necessary to clarify the clinical characteristics and the mechanisms of GWGH in more detail in the future.


Insulin Secretion Linear Growth Growth Hormone Deficiency Precocious Puberty Growth Spurt 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are grateful to Drs. T. Kamijo and H. Mizuno for their helpful suggestions.


  1. Araki K, Koga M, Okada T, Kurashige T, Naruse K, Hiroi M (2000) A boy with normal growth in spite of growth hormone deficiency after resection of a suprasellar teratoma. Endocr J 47(Suppl):S101–S104PubMedCrossRefGoogle Scholar
  2. Ben-Jonathan N, LaPensee CR, LaPensee EW (2008) What can we learn from rodents about prolactin in humans? Endocr Rev 29:1–41PubMedCentralPubMedCrossRefGoogle Scholar
  3. Blethen SL, Weldon VV (1986) Outcome in children with normal growth following removal of a craniopharyngioma. Am J Med Sci 292:21–24PubMedCrossRefGoogle Scholar
  4. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA (1998) Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev 19:225–268PubMedCrossRefGoogle Scholar
  5. Bucher H, Zapf J, Torresani T, Prader A, Froesch ER, Illig R (1983) Insulin-like growth factors I and II, prolactin, and insulin in 19 growth hormone-deficient children with excessive, normal, or decreased longitudinal growth after operation for craniopharyngioma. N Eng J Med 309:1142–1146CrossRefGoogle Scholar
  6. Carmel PW, Antunes JL, Chang CH (1982) Craniopharyngiomas in children. Neurosurgery 11:382–389PubMedCrossRefGoogle Scholar
  7. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, GH Insensitivity Syndrome Collaborative Group (2007) Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab 92:902–910PubMedCrossRefGoogle Scholar
  8. Costin G, Kogut MD, Phillips LS, Daughaday WH (1976) Craniopharyngioma: the role of insulin in promoting postoperative growth. J Clin Endocrinol Metab 42:370–379PubMedCrossRefGoogle Scholar
  9. DeVile CJ, Grant DB, Hayward RD, Stanhope R (1996) Growth and endocrine sequelae of craniopharyngioma. Arch Dis Child 75:108–114PubMedCentralPubMedCrossRefGoogle Scholar
  10. Di Battista E, Naselli A, Queirolo S, Gallarotti F, Garré ML, Milanaccio C, Cama A (2006) Endocrine and growth features in childhood craniopharyngioma: a mono-institutional study. J Pediatr Endocrinol Metab 19(Suppl 1):431–437PubMedGoogle Scholar
  11. Finkelstein JW, Kream J, Ludan A, Hellman L (1972) Sulfation factor (somatomedin): an explanation for continued growth in the absence of immunoassayable growth hormone in patients with hypothalamic tumors. J Clin Endocrinol Metab 35:13–17PubMedCrossRefGoogle Scholar
  12. Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Brüning JC, Clemens TL (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319PubMedCentralPubMedCrossRefGoogle Scholar
  13. Giustina A, Mazziotti G, Canalis E (2008) Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 29:535–559PubMedCentralPubMedCrossRefGoogle Scholar
  14. Gluckman PD, Holdaway IM (1976) Prolactin and somatomedin studies in the syndrome of growth hormone-independent growth. Clin Endocrinol (Oxf) 5:545–549CrossRefGoogle Scholar
  15. Gonc EN, Yordam N, Ozon A, Alikasifoglu A, Kandemir N (2004) Endocrinological outcome of different treatment options in children with craniopharyngioma: a retrospective analysis of 66 cases. Pediatr Neurosurg 40:112–119PubMedCrossRefGoogle Scholar
  16. Holmes LB, Frantz AG, Rabkin MT, Soeldner JS, Crawford JD (1968) Normal growth with subnormal growth-hormone levels. N Engl J Med 279:559–566PubMedCrossRefGoogle Scholar
  17. Iwayama H, Kamijo T, Ueda N (2011) Hyperinsulinemia may promote growth without GH in children after resection of suprasellar brain tumors. Endocrine 40:130–133PubMedCrossRefGoogle Scholar
  18. Kawai M, Rosen CJ (2009) Insulin-like growth factor-I and bone: lessons from mice and men. Pediatr Nephrol 24:1277–1285PubMedCrossRefGoogle Scholar
  19. Kenny FM, Iturzaeta NF, Mintz D, Drash A, Garces LY, Susen A, Askari HA (1968) Iatrogenic hypopituitarism in craniopharyngioma: unexplained catch-up growth in three children. J Pediatr 72:766–775PubMedCrossRefGoogle Scholar
  20. 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 73:153–160PubMedCrossRefGoogle Scholar
  21. Laron Z (2008) Insulin-a growth hormone. Arch Physiol Biochem 114:11–16PubMedCrossRefGoogle Scholar
  22. Lyen KR, Grant DB (1982) Endocrine function, morbidity, and mortality after surgery for craniopharyngioma. Arch Dis Child 57:837–841PubMedCentralPubMedCrossRefGoogle Scholar
  23. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, Hamnvik OP, Koniaris A (2011) Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab 301:E567–E584PubMedCentralPubMedCrossRefGoogle Scholar
  24. Matson DD (1964) Craniopharyngioma. Clin Neurosurg 10:116–129PubMedGoogle Scholar
  25. Nagasaki K, Tsumanuma I, Yoneoka Y, Jinguji S, Ogawa Y, Kikuchi T, Uchiyama M (2010) Metabolic effects of growth hormone replacement in two pediatric patients with growth without growth hormone. Endocr J 57:771–775PubMedCrossRefGoogle Scholar
  26. Pavlou M, Tsatsoulis A, Efstathiadou Z, Bitsis S, Papadopoulou ZL (2001) A study of the growth-promoting and metabolic effects of growth hormone (GH) in a patient with the “growth without GH” syndrome. Growth Horm IGF Res 11:225–230PubMedCrossRefGoogle Scholar
  27. Pinto G, Bussières L, Recasens C, Souberbielle JC, Zerah M, Brauner R (2000) Hormonal factors influencing weight and growth pattern in craniopharyngioma. Horm Res 53:163–169PubMedCrossRefGoogle Scholar
  28. Roth C, Wilken B, Hanefeld F, Schröter W, Leonhardt U (1998) Hyperphagia in children with craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of appetite. Eur J Endocrinol 138:89–91PubMedCrossRefGoogle Scholar
  29. Saenger P, Levine LS, Wiedemann E, Schwartz E, New MI (1974) Growth with absent growth hormone by radioimmunoassay. J Pediatr 85:137–138PubMedCrossRefGoogle Scholar
  30. Schoenle EJ, Zapf J, Prader A, Torresani T, Werder EA, Zachmann M (1995) Replacement of growth hormone (GH) in normally growing GH-deficient patients operated for craniopharyngioma. J Clin Endocrinol Metab 80:374–378PubMedGoogle Scholar
  31. Siddle K (2011) Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol 47:R1–R10PubMedCrossRefGoogle Scholar
  32. Simoneau-Roy J, O’Gorman C, Pencharz P, Adeli K, Daneman D, Hamilton J (2010) Insulin sensitivity and secretion in children and adolescents with hypothalamic obesity following treatment for craniopharyngioma. Clin Endocrinol (Oxf) 72:364–370CrossRefGoogle Scholar
  33. Sorensen K, Aksglaede L, Petersen JH, Andersson AM, Juul A (2012) Serum IGFI and insulin levels in girls with normal and precocious puberty. Eur J Endocrinol 166:903–910PubMedCrossRefGoogle Scholar
  34. Sorva R (1988) Children with craniopharyngioma. Early growth failure and rapid postoperative weight gain. Acta Paediatr Scand 77:587–592PubMedCrossRefGoogle Scholar
  35. Srinivasan S, Ogle GD, Garnett SP, Briody JN, Lee JW, Cowell CT (2004) Features of the metabolic syndrome after childhood craniopharyngioma. J Clin Endocrinol Metab 89:81–86PubMedCrossRefGoogle Scholar
  36. Stahnke N, Grubel G, Lagenstein I, Willig RP (1984) Long-term follow-up of children with craniopharyngioma. Eur J Pediatr 142:179–185PubMedCrossRefGoogle Scholar
  37. Su PH, Chen JY, Yu JS, Chen SJ, Yang SF (2011) Leptin expression and leptin receptor gene polymorphisms in growth hormone deficiency patients. Hum Genet 129:455–462PubMedCrossRefGoogle Scholar
  38. Thomsett MJ, Conte FA, Kaplan SL, Grumbach MM (1980) Endocrine and neurologic outcome in childhood craniopharyngioma: review of effect of treatment in 42 patients. J Pediatr 97:728–735PubMedCrossRefGoogle Scholar
  39. Tiulpakov AN, Mazerkina NA, Brook CGD, Hindmarsh PC, Peterkova VA, Gorelyshev SK (1998) Growth in children with craniopharyngioma following surgery. Clin Endocrinol (Oxf) 49:733–738CrossRefGoogle Scholar
  40. Trivin C, Busiah K, Mahlaoui N, Recasens C, Souberbielle JC, Zerah M, Sainte-Rose C, Brauner R (2009) Childhood craniopharyngioma: greater hypothalamic involvement before surgery is associated with higher homeostasis model insulin resistance index. BMC Pediatr 9:24PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of PediatricsPublic Central Hospital of Matto IshikawaHakusanJapan
  2. 2.Department of Pediatrics, Neonatology and Congenital DisordersNagoya City UniversityMizho-ku, NagoyaJapan

Personalised recommendations