Isolated growth hormone deficiency (GHD) in childhood and adolescence: Recent advances

Endocrine Reviews

Volumn 35, Issue 3, 2014, Pages 376-432

  Alatzoglou, Kyriaki S ^a   Webb, Emma Alice ^a   Le Tissier, Paul ^a,b   Dattani, Mehul T ^a  

^a UNIVERSITY COLLEGE LONDON   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

FIALURIDINE; GLUCOCORTICOID; GROWTH HORMONE; GROWTH HORMONE RELEASING FACTOR RECEPTOR; RECOMBINANT GROWTH HORMONE; SOMATOMEDIN C; TRANSCRIPTION FACTOR; HUMAN GROWTH HORMONE;

ACUTE GRANULOCYTIC LEUKEMIA; ADOLESCENT DISEASE; BODY COMPOSITION; BODY HEIGHT; BONE DENSITY; BRAIN TUMOR; CARDIOVASCULAR DISEASE; CHILDHOOD DISEASE; COGNITION; DRUG DOSE TITRATION; DRUG SAFETY; FIBROMYXOSARCOMA; GENE MUTATION; GENETIC ASSOCIATION; GROWTH HORMONE BLOOD LEVEL; GROWTH HORMONE DEFICIENCY; HUMAN; HYPOPHYSIS CELL; KIDNEY CANCER; LONGEVITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHODGKIN LYMPHOMA; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; ORGANOGENESIS; PHARMACOGENOMICS; PITUITARY DEVELOPMENT; PRIORITY JOURNAL; REVIEW; RHABDOMYOSARCOMA; SECOND CANCER; SEMINOMA; SOMATOTROPE; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; ADOLESCENT; ANIMAL; CHILD; DWARFISM, PITUITARY; GENETICS;

ADOLESCENT; ANIMALS; CHILD; DWARFISM, PITUITARY; HUMAN GROWTH HORMONE; HUMANS;

EID: 84901503065     PISSN: None     EISSN: 0163769X     Source Type: Journal    
DOI: 10.1210/er.2013-1067     Document Type: Review

References (493)

1. Growth Hormone 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. GH Research Society. J Clin Endocrinol Metab. 2000;85:3990-3993.
2. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev. 1998;19:717-797.
3. Kelberman D, Rizzoti K, Lovell-Badge R, Robinson IC, Dattani MT. Genetic regulation of pituitary gland development in human and mouse. Endocr Rev. 2009;30:790-829.
4. Stanley T. Diagnosis of growth hormone deficiency in childhood. Curr Opin Endocrinol Diabetes Obes. 2012; 19:47-52.
5. Shalet SM, Toogood A, Rahim A, Brennan BM. The diagnosis of growth hormone deficiency in children and adults. Endocr Rev. 1998;19:203-223.
6. Alatzoglou KS, Dattani MT. Genetic causes and treatment of isolated growth hormone deficiency-an update. Nat Rev Endocrinol. 2010;6:562-576.
7. Japón MA, Rubinstein M, Low MJ. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J Histochem Cytochem. 1994;42:1117-1125.
8. Zhu X, Gleiberman AS, Rosenfeld MG. Molecular physiology of pituitary development: signaling and transcriptional networks. Physiol Rev. 2007;87:933-963.
9. Davis SW, Mortensen AH, Camper SA. Birthdating studies reshape models for pituitary gland cell specification. Dev Biol. 2011;352:215-227.
10. Magoulas C, McGuinness L, Balthasar N, et al. A secreted fluorescent reporter targeted to pituitary growth hormone cells in transgenic mice. Endocrinology. 2000;141:4681-4689.
11. Bonnefont X, Lacampagne A, Sanchez-Hormigo A, et al. Revealing the large-scale network organization of growth hormone-secreting cells. Proc Natl Acad Sci U S A. 2005; 102:16880-16885.
12. Le Tissier PR, Hodson DJ, Lafont C, Fontanaud P, Schaeffer M, Mollard P. Anterior pituitary cell networks. Front Neuroendocrinol. 2012;33:252-266.
13. Le Tissier PR, Carmignac DF, Lilley S, et al. Hypothalamic growth hormone-releasing hormone (GHRH) deficiency: targeted ablation of GHRH neurons in mice using a viral ion channel transgene. Mol Endocrinol. 2005;19:1251-1262.
14. Waite E, Lafont C, Carmignac D, et al. Different degrees of somatotroph ablation compromise pituitary growth hormone cell network structure and other pituitary endocrine cell types. Endocrinology. 2010;151:234-243.
15. Chauvet N, El-Yandouzi T, Mathieu MN, et al. Characterization of adherens junction protein expression and localization in pituitary cell networks. J Endocrinol. 2009; 202:375-387.
16. Budry L, Lafont C, El Yandouzi T, et al. Related pituitary cell lineages develop into interdigitated 3D cell networks. Proc Natl Acad Sci U S A. 2011;108:12515-12520.
17. Lafont C, Desarménien MG, Cassou M, et al. Cellular in vivo imaging reveals coordinated regulation of pituitary microcirculation and GH cell network function. Proc Natl Acad Sci U S A. 2010;107:4465-4470.
18. Hodson DJ, Schaeffer M, Romano N, et al. Existence of long-lasting experience-dependent plasticity in endocrine cell networks. Nat Commun. 2012;3:605.
19. Sanchez-Cardenas C, Fontanaud P, He Z, et al. Pituitary growth hormone network responses are sexually dimorphic and regulated by gonadal steroids in adulthood. Proc Natl Acad Sci U S A. 2010;107:21878-21883.
20. Gouty-Colomer LA, Méry PF, Storme E, et al. Specific involvement of gonadal hormones in the functional matura- tion of growth hormone releasing hormone (GHRH) neurons. Endocrinology. 2010;151:5762-5774.
21. Bouyer K, Loudes C, Robinson IC, Epelbaum J, Faivre-Bauman A. Sexually dimorphic distribution of sst2A somatostatin receptors on growth hormone-releasing hormone neurons in mice. Endocrinology. 2006;147: 2670-2674.
22. Schaeffer M, Hodson DJ, Meunier AC, et al. Influence of estrogens on GH-cell network dynamics in females: a live in situ imaging approach. Endocrinology. 2011;152: 4789-4799.
23. Ward RD, Stone BM, Raetzman LT, Camper SA. Cell proliferation and vascularization in mouse models of pituitary hormone deficiency. Mol Endocrinol. 2006;20:1378-1390.
24. Schwartz J. Intercellular communication in the anterior pituitary. Endocr Rev. 2000;21:488-513.
25. Kappeler L, De Magalhaes FC, Dupont J, et al. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol. 2008;6:e254.
26. Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk. J Neuroendocrinol. 2008;20:1-70.
27. Cimini V. Neuropeptides in anterior pituitary development. Int J Dev Neurosci. 2003;21:291-301.
28. Lazarini F, Tham TN, Casanova P, Arenzana-Seisdedos F, Dubois-Dalcq M. Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia. 2003;42:139-148.
29. Lee Y, Kim JM, Lee EJ. Functional expression of CXCR4 in somatotrophs: CXCL12 activates GH gene, GH production and secretion, and cellular proliferation. J Endocrinol. 2008;199:191-199.
30. Horiguchi K, Ilmiawati C, Fujiwara K, Tsukada T, Kikuchi M, Yashiro T. Expression of chemokine CXCL12 and its receptor CXCR4 in folliculostellate (FS) cells of the rat anterior pituitary gland: the CXCL12/CXCR4 axis induces interconnection of FS cells. Endocrinology. 2012; 153:1717-1724.
31. Howard AD, Wang R, Pong SS, et al. Identification of receptors for neuromedin U and its role in feeding. Nature. 2000;406:70-74.
32. Wren AM, Small CJ, Abbott CR, et al. Hypothalamic actions of neuromedin U. Endocrinology. 2002;143:4227-4234.
33. Reyes R, Valladares F, Gutiérrez R, Gonzalez M, Bello AR. Immunohistochemical distribution of regulatory peptides in the human fetal adenohypophysis. J Anat. 2008;212: 817-826.
34. Nogami H, Hisano S. Functional maturation of growth hormone cells in the anterior pituitary gland of the fetus. Growth Horm IGF Res. 2008;18:379-388.
35. Bilezikjian LM, Justice NJ, Blackler AN, Wiater E, Vale WW. Cell-type specific modulation of pituitary cells by activin, inhibin and follistatin. Mol Cell Endocrinol. 2012; 359:43-52.
36. Barbieri F, Bajetto A, Porcile C, Pattarozzi A, Schettini G, Florio T. Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function. J Mol Endocrinol. 2007;38:383-389.
37. Mazziotti G, Giustina A. Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol. 2013;9:265-276.
38. Porter TE. Regulation of pituitary somatotroph differentiation by hormones of peripheral endocrine glands. Domest Anim Endocrinol. 2005;29:52-62.
39. Vakili H, Jin Y, Nagy JI, Cattini PA. Transgenic mice expressing the human growth hormone gene provide a model system to study human growth hormone synthesis and secretion in non-tumor-derived pituitary cells: differential effects of dexamethasone and thyroid hormone. Mol Cell Endocrinol. 2011;345:48-57.
40. Vakili H, Cattini PA. The hidden but positive role for glucocorticoids in the regulation of growth hormone-producing cells. Mol Cell Endocrinol. 2012;363:1-9.
41. Jenkins SA, Muchow M, Richards MP, McMurtry JP, Porter TE. Administration of adrenocorticotropic hormone during chicken embryonic development prematurely induces pituitary growth hormone cells. Endocrinology. 2007;148:3914-3921.
42. Nogami H, Inoue K, Kawamura K. Involvement of glucocorticoid- induced factor(s) in the stimulation of growth hormone expression in the fetal rat pituitary gland in vitro. Endocrinology. 1997;138:1810-1815.
43. Suga H, Kadoshima T, Minaguchi M, et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature. 2011;480:57-62.
44. Bossis I, Nishimura S, Muchow M, Porter TE. Pituitary expression of type I and type II glucocorticoid receptors during chicken embryonic development and their involvement in growth hormone cell differentiation. Endocrinology. 2004;145:3523-3531.
45. Erdmann G, Schütz G, Berger S. Loss of glucocorticoid receptor function in the pituitary results in early postnatal lethality. Endocrinology. 2008;149:3446-3451.
46. Eliard PH, Marchand MJ, Rousseau GG, et al. Binding of the human glucocorticoid receptor to defined regions in the human growth hormone and placental lactogen genes. DNA. 1985;4:409-417.
47. Moore DD, Marks AR, Buckley DI, Kapler G, Payvar F, Goodman HM. The first intron of the human growth hormone gene contains a binding site for glucocorticoid receptor. Proc Natl Acad Sci U S A. 1985;82:699-702.
48. Gutierrez-Hartmann A, Duval DL, Bradford AP. ETS transcription factors in endocrine systems. Trends Endocrinol Metab. 2007;18:150-158.
49. Yang X, Jin Y, Cattini PA. Appearance of the pituitary factor Pit-1 increases chromatin remodeling at hypersensitive site III in the human GH locus. J Mol Endocrinol. 2010;45:19-32.
50. Ellestad LE, Carre W, Muchow M, et al. Gene expression profiling during cellular differentiation in the embryonic pituitary gland using cDNA microarrays. Physiol Genomics. 2006;25:414-425.
51. Ellestad LE, Porter TE. Ras-dva is a novel Pit-1-and glucocorticoid- regulated gene in the embryonic anterior pituitary gland. Endocrinology. 2013;154:308-319.
52. McEachern R, Drouin J, Metherell L, Huot C, Van Vliet G, Deal C. Severe cortisol deficiency associated with reversible growth hormone deficiency in two infants: what is the link? J Clin Endocrinol Metab. 2011;96:2670-2674.
53. McMahon SK, Pretorius CJ, Ungerer JP, et al. Neonatal complete generalized glucocorticoid resistance and growth hormone deficiency caused by a novel homozygous mutation in Helix 12 of the ligand binding domain of the glucocorticoid receptor gene (NR3C1). J Clin Endocrinol Metab. 2010;95:297-302.
54. Stojilkovic SS, Murano T, Gonzalez-Iglesias AE, et al. Multiple roles of Gi/o protein-coupled receptors in control of action potential secretion coupling in pituitary lactotrophs. Ann N Y Acad Sci. 2009;1152:174-186.
55. Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22:724-763.
56. Garcia-Tornadú I, Perez-Millan MI, Recouvreux V, et al. New insights into the endocrine and metabolic roles of dopamineD2receptors gained from the Drd2 mouse. Neuroendocrinology. 2010;92:207-214.
57. Díaz-Torga G, Feierstein C, Libertun C, et al. Disruption of the D2 dopamine receptor alters GH and IGF-I secretion and causes dwarfism in male mice. Endocrinology. 2002; 143:1270-1279.
58. García-Tornadú I, Rubinstein M, Gaylinn BD, et al. GHin the dwarf dopaminergic D2 receptor knockout mouse: somatotrope population, GH release, and responsiveness to GH-releasing factors and somatostatin. J Endocrinol. 2006;190:611-619.
59. Phelps CJ, Romero MI, Hurley DL. Growth hormone-releasing hormone-producing and dopaminergic neurones in the mouse arcuate nucleus are independently regulated populations. J Neuroendocrinol. 2003;15:280-288.
60. Deltondo J, Por I, Hu W, et al. Associations between the human growth hormone-releasing hormone- and neuropeptide-Y-immunoreactive systems in the human diencephalon: a possible morphological substrate of the impact of stress on growth. Neuroscience. 2008;153:1146-1152.
61. Dudas B, Baker M, Rotoli G, Grignol G, Bohn MC, Merchenthaler I. Distribution and morphology of the catecholaminergic neural elements in the human hypothalamus. Neuroscience. 2010;171:187-195.
62. Anderson D, Baker M, Grignol G, Hu W, Merchenthaler I, Dudas B. Distribution and morphology of the juxtapositions between growth hormone-releasing hormone-(GHRH)-immunoreactive neuronal elements. Growth Horm IGF Res. 2010;20:356-359.
63. Rotoli G, Grignol G, Hu W, Merchenthaler I, Dudas B. Catecholaminergic axonal varicosities appear to innervate growth hormone-releasing hormone-immunoreactive neurons in the human hypothalamus: the possible morphological substrate of the stress-suppressed growth. J Clin Endocrinol Metab. 2011;96:E1606-E1611.
64. Albanese A, Hamill G, Jones J, Skuse D, Matthews DR, Stanhope R. Reversibility of physiological growth hormone secretion in children with psychosocial dwarfism. Clin Endocrinol (Oxf). 1994;40:687-692.
65. Gohlke BC, Frazer FL, Stanhope R. Growth hormone secretion and long-term growth data in children with psychosocial short stature treated by different changes in environment. J Pediatr Endocrinol Metab. 2004;17:637-643.
66. Callewaere C, Banisadr G, Rostène W, Parsadaniantz SM. Chemokines and chemokine receptors in the brain: implication in neuroendocrine regulation. J Mol Endocrinol. 2007;38:355-363.
67. Sawada T, Koike K, Kanda Y, et al. In vitro effects of CINC/gro, a member of the interleukin-8 family, on hormone secretion by rat anterior pituitary cells. Biochem Biophys Res Commun. 1994;202:155-160.
68. Massa A, Casagrande S, Bajetto A, et al. SDF-1 controls pituitary cell proliferation through the activation of ERK1/2 and the Ca2+-dependent, cytosolic tyrosine kinase Pyk2. Ann N Y Acad Sci. 2006;1090:385-398.
69. Ansell PJ, Zhou Y, Schjeide BM, et al. Regulation of growth hormone expression by Δ-like protein 1 (Dlk1). Mol Cell Endocrinol. 2007;271:55-63.
70. Moon YS, Smas CM, Lee K, et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol Cell Biol. 2002;22:5585-5592.
71. Puertas-Avendaño RA, González-Gómez MJ, Ruvira MD, et al. Role of the non-canonical notch ligand delta-like protein 1 in hormone-producing cells of the adult male mouse pituitary. J Neuroendocrinol. 2011;23:849-859.
72. Cheung LY, Rizzoti K, Lovell-Badge R, Le Tissier PR. Pituitary phenotypes of mice lacking the notch signalling ligand delta-like 1 homologue. J Neuroendocrinol. 2013; 25:391-401.
73. McGuinness L, Magoulas C, Sesay AK, et al. Autosomal dominant growth hormone deficiency disrupts secretory vesicles in vitro and in vivo in transgenic mice. Endocrinology. 2003;144:720-731.
74. Alba M, Salvatori R. Amouse with targeted ablation of the growth hormone-releasing hormone gene: a new model of isolated growth hormone deficiency. Endocrinology. 2004;145:4134-4143.
75. Borrelli E, Heyman RA, Arias C, Sawchenko PE, Evans RM. Transgenic mice with inducible dwarfism. Nature. 1989;339:538-541.
76. Castinetti F, Davis SW, Brue T, Camper SA. Pituitary stem cell update and potential implications for treating hypopituitarism. Endocr Rev. 2011;32:453-471.
77. Vankelecom H, Gremeaux L. Stem cells in the pituitary gland: a burgeoning field. Gen Comp Endocrinol. 2010; 166:478-488.
78. Gremeaux L, Fu Q, Chen J, Vankelecom H. Activated phenotype of the pituitary stem/progenitor cell compartment during the early-postnatal maturation phase of the gland. Stem Cells Dev. 2012;21:801-813.
79. Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson IC. SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci U S A. 2008;105:2907-2912.
80. Pevny L, Placzek M. SOX genes and neural progenitor identity. Curr Opin Neurobiol. 2005;15:7-13.
81. Favaro R, Valotta M, Ferri AL, et al. Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci. 2009;12: 1248-1256.
82. Fu Q, Gremeaux L, Luque RM, et al. The adult pituitary shows stem/progenitor cell activation in response to injury and is capable of regeneration. Endocrinology. 2012;153: 3224-3235.
83. Mullis PE. Genetics of growth hormone deficiency. Endocrinol Metab Clin North Am. 2007;36:17-36.
84. Alatzoglou KS, Turton JP, Kelberman D, et al. Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency. J Clin Endocrinol Metab. 2009;94:3191-3199.
85. Horan M, Millar DS, Hedderich J, et al. Human growth hormone 1 (GH1) gene expression: complex haplotypedependent influence of polymorphic variation in the proximal promoter and locus control region. Hum Mutat. 2003;21:408-423.
86. Shewchuk BM, Liebhaber SA, Cooke NE. Specification of unique Pit-1 activity in the hGH locus control region. Proc Natl Acad Sci U S A. 2002;99:11784-11789.
87. Cattini PA, Yang X, Jin Y, Detillieux KA. Regulation of the human growth hormone gene family: possible role for Pit-1 in early stages of pituitary-specific expression and repression. Neuroendocrinology. 2006;83:145-153.
88. Procter AM, Phillips JA 3rd, Cooper DN. The molecular genetics of growth hormone deficiency. HumGenet. 1998; 103:255-272.
89. Wagner JK, Eblé A, Hindmarsh PC, Mullis PE. Prevalence of human GH-1 gene alterations in patients with isolated growth hormone deficiency. Pediatr Res. 1998;43:105-110.
90. Phillips JA 3rd, Cogan JD. Genetic basis of endocrine disease. 6. Molecular basis of familial human growth hormone deficiency. J Clin Endocrinol Metab. 1994;78:11-16.
91. Laron Z, Kelijman M, Pertzelan A, Keret R, Shoffner JM, Parks JS. Human growth hormone gene deletion without antibody formation or growth arrest during treatment-a new disease entity? Isr J Med Sci. 1985;21:999-1006.
92. Igarashi Y, Ogawa M, Kamijo T, et al. A new mutation causing inherited growth hormone deficiency: a compound heterozygote of a 6.7 kb deletion and a two base deletion in the third exon of the GH-1 gene. HumMol Genet. 1993; 2:1073-1074.
93. Iughetti L, Sobrier ML, Predieri B, et al. Complex disease phenotype revealed by GH deficiency associated with a novel and unusual defect in the GH-1 gene. Clin Endocrinol (Oxf). 2008;69:170-172.
94. Cogan JD, Phillips JA 3rd, Sakati N, Frisch H, Schober E, Milner RD. Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency. J Clin Endocrinol Metab. 1993;76:1224-1228.
95. Leiberman E, Pesler D, Parvari R, et al. Short stature in carriers of recessive mutation causing familial isolated growth hormone deficiency. Am J Med Genet. 2000;90: 188-192.
96. Phillips JA 3rd, Hjelle BL, Seeburg PH, Zachmann M. Molecular basis for familial isolated growth hormone deficiency. Proc Natl Acad Sci U S A. 1981;78:6372-6375.
97. Kamijo T, Phillips JA 3rd. Detection of molecular heterogeneity in GH-1 gene deletions by analysis of polymerase chain reaction amplification products. J Clin Endocrinol Metab. 1992;74:786-789.
98. He YA, Chen SS, Wang YX, Lin XY, Wang DF. A Chinese familial growth hormone deficiency with a deletion of 7.1 kb of DNA. J Med Genet. 1990;27:151-154.
99. Braga S, Phillips JA 3rd, Joss E, Schwarz H, Zuppinger K. Familial growth hormone deficiency resulting from a 7.6 kb deletion within the growth hormone gene cluster. Am J Med Genet. 1986;25:443-452.
100. Goossens M, Brauner R, Czernichow P, Duquesnoy P, Rappaport R. Isolated growth hormone (GH) deficiency type1Aassociated with a double deletion in thehuman GH gene cluster. J Clin Endocrinol Metab. 1986;62:712-716.
101. Duquesnoy P, Amselem S, Gourmelen M, Le BY, Goossens M. A frameshift mutation causing isolated growth hormone deficiency type 1A. Am J Hum Genet. 1990;47: A110.
102. Akinci A, Kanaka C, Eblé A, Akar N, Vidinlisan S, Mullis PE. Isolated growth hormone (GH) deficiency type IA associated with a 45-kilobase gene deletion within thehuman GH gene cluster. J Clin Endocrinol Metab. 1992;75:437-441.
103. Lee MS, Wajnrajch MP, Kim SS, et al. Autosomal dominant growth hormone (GH) deficiency type II: the Del32-71-GH deletion mutant suppresses secretion of wild-type GH. Endocrinology. 2000;141:883-890.
104. Ryther RC, McGuinness LM, Phillips JA 3rd, et al. Disruption of exon definition produces a dominant-negative growth hormone isoform that causes somatotroph death and IGHD II. Hum Genet. 2003;113:140-148.
105. Moseley CT, Mullis PE, Prince MA, Phillips JA 3rd. An exon splice enhancer mutation causes autosomal dominant GH deficiency. J Clin Endocrinol Metab. 2002;87:847-852.
106. Takahashi I, Takahashi T, Komatsu M, Sato T, Takada G. An exonic mutation of the GH-1 gene causing familial isolated growth hormone deficiency type II. Clin Genet. 2002; 61:222-225.
107. Shariat N, Holladay CD, Cleary RK, Phillips JA 3rd, Patton JG. Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function. Clin Genet. 2008;74:539-545.
108. Petkovic V, Lochmatter D, Turton J, et al. Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency. J Clin Endocrinol Metab. 2007;92:4427-4435.
109. Millar DS, Lewis MD, Horan M, et al. Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature. Hum Mutat. 2003;21:424-440.
110. Ryther RC, Flynt AS, Harris BD, Phillips JA 3rd, Patton JG. GH1splicing is regulated by multiple enhancers whose mutation produces a dominant-negative GH isoform that can be degraded by allele-specific small interfering RNA (siRNA). Endocrinology. 2004;145:2988-2996.
111. Cogan JD, Prince MA, Lekhakula S, et al. A novel mechanism of aberrant pre-mRNA splicing in humans. Hum Mol Genet. 1997;6:909-912.
112. McCarthy EM, Phillips JA 3rd. Characterization of an intron splice enhancer that regulates alternative splicing of human GH pre-mRNA. Hum Mol Genet. 1998;7:1491-1496.
113. Vivenza D, Guazzarotti L, Godi M, et al. A novel deletion in theGH1gene including the IVS3 branch site responsible for autosomal dominant isolated growth hormone deficiency. J Clin Endocrinol Metab. 2006;91:980-986.
114. Salemi S, YousefiS, Eblé A, Deladoëy J, Mullis PE. Impact of del32-71-GH (exon 3 skipped GH) on intracellularGH distribution, secretion and cell viability: a quantitative confocal microscopy analysis. Horm Res. 2006;65:132-141.
115. Salemi S, YousefiS, Lochmatter D, et al. Isolated autosomal dominant growth hormone deficiency: stimulating mutant GH-1 gene expression drives GH-1 splice-site selection, cell proliferation, and apoptosis. Endocrinology. 2007;148:45-53.
116. Takahashi Y, Kaji H, Okimura Y, Goji K, Abe H, Chihara K. Brief report: short stature caused by a mutant growth hormone. N Engl J Med. 1996;334:432-436.
117. Miyata I, Cogan JD, Prince MA, Kamijo T, Ogawa M, Phillips JA 3rd. Detection of growth hormone gene defects by dideoxy fingerprinting (ddF). Endocr J. 1997;44:149-154.
118. Takahashi Y, Shirono H, Arisaka O, et al. Biologically inactive growth hormone caused by an amino acid substitution. J Clin Invest. 1997;100:1159-1165.
119. Lewis MD, Horan M, Millar DS, et al. A novel dysfunctional growth hormone variant (Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway. J Clin Endocrinol Metab. 2004;89:1068-1075.
120. Petkovic V, Thevis M, Lochmatter D, et al. GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity. Eur J Endocrinol. 2007;157(Suppl 1):S67-S74.
121. Deladoëy J, Stocker P, Mullis PE. Autosomal dominant GH deficiency due to an Arg183His GH-1 gene mutation: clinical and molecular evidence of impaired regulated GH secretion. J Clin Endocrinol Metab. 2001;86:3941-3947.
122. Zhu YL, Conway-Campbell B, Waters MJ, Dannies PS. Prolonged retention after aggregation into secretory granules of human R183H-growth hormone (GH), a mutant that causes autosomal dominant GH deficiency type II. Endocrinology. 2002;143:4243-4248.
123. Salemi S, YousefiS, Baltensperger K, et al. Variability of isolated autosomal dominant GH deficiency (IGHD II): impact of the P89LGHmutation on clinical follow-up and GH secretion. Eur J Endocrinol. 2005;153:791-802.
124. Petkovic V, Godi M, Pandey AV, et al. Growth hormone (GH) deficiency type II: a novel GH-1 gene mutation (GHR178H) affecting secretion and action. J Clin Endocrinol Metab. 2010;95:731-739.
125. Petkovic V, Miletta MC, Boot AM, et al. Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH. Eur J Endocrinol. 2013;168: K35-K43.
126. Petkovic V, Eblé A, Pandey AV, et al. A novel GH-1 gene mutation (GH-P59L) causes partial GH deficiency type II combined with bioinactive GH syndrome. Growth Horm IGF Res. 2011;21:160-166.
127. Binder G, Nagel BH, Ranke MB, Mullis PE. Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin. Eur J Endocrinol. 2002;147:755-760.
128. Hess O, Hujeirat Y, Wajnrajch MP, et al. Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene. J Clin Endocrinol Metab. 2007;92:4387-4393.
129. Hamid R, Phillips JA 3rd, Holladay C, et al. A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II. J Clin Endocrinol Metab. 2009;94:4728-4734.
130. Binder G, Keller E, Mix M, et al. Isolated GH deficiency with dominant inheritance: new mutations, new insights. J Clin Endocrinol Metab. 2001;86:3877-3881.
131. Mullis PE, Robinson IC, Salemi S, et al. Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study. J Clin Endocrinol Metab. 2005;90:2089-2096.
132. Turton JP, Buchanan CR, Robinson IC, Aylwin SJ, Dattani MT. Evolution of gonadotropin deficiency in a patient with type II autosomal dominant GH deficiency. Eur J Endocrinol. 2006;155:793-799.
133. Petkovic V, Godi M, Lochmatter D, et al. Growth Hormone (GH)-Releasing Hormone Increases the Expression of the Dominant-NegativeGHIsoform in Cases of Isolated GH Deficiency due to GH Splice-Site Mutations. Endocrinology. 2010;151:2650-2658.
134. Poling JS, Phillips JA 3rd, Cogan JD, Hamid R. Pharmacologic correction of dominant-negative GH1 deficiency causing mutations. Clin Transl Sci. 2011;4:175-179.
135. Shariat N, Ryther RC, Phillips JA 3rd, Robinson IC, Patton JG. Rescue of pituitary function in a mouse model of isolated growth hormone deficiency type II by RNA interference. Endocrinology. 2008;149:580-586.
136. Lochmatter D, Strom M, Eblé A, et al. Isolated GH deficiency type II: knockdown of the harmful Delta3GH recovers wt-GH secretion in rat tumor pituitary cells. Endocrinology. 2010;151:4400-4409.
137. Solloso A, Barreiro L, Seoane R, et al. GHRHproliferative action on somatotrophs is cell-type specific and dependent on Pit-1/GHF-1 expression. J Cell Physiol. 2008;215:140-150.
138. Wajnrajch MP, Gertner JM, Harbison MD, Chua SC Jr, Leibel RL. Nonsense mutation in the human growth hormone- releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet. 1996;12: 88-90.
139. Godi M, Mellone S, Petri A, et al. Arecurrent signal peptide mutation in the growth hormone releasing hormone receptor with defective translocation to the cell surface and isolated growth hormone deficiency. J Clin Endocrinol Metab. 2009;94:3939-3947.
140. Salvatori R, Fan X, Veldhuis JD, Couch R. Serum GH response to pharmacological stimuli and physical exercise in two siblings with two new inactivating mutations in the GH-releasing hormone receptor gene. Eur J Endocrinol. 2002;147:591-596.
141. Soneda A, Adachi M, Muroya K, et al. Novel compound heterozygous mutations of the growth hormone-releasing hormone receptor gene in a case of isolated growth hormone deficiency. GrowthHormIGF Res. 2013;23:89-97.
142. Salvatori R, Fan X, Phillips JA 3rd, Prince M, Levine MA. Isolated growth hormone (GH) deficiency due to compound heterozygosity for two new mutations in the GHreleasing hormone receptor gene. Clin Endocrinol (Oxf). 2001;54:681-687.
143. Salvatori R, Fan X, Phillips JA 3rd, et al. Three new mutations in the gene for the growth hormone (GH)-releasing hormone receptor in familial isolated GH deficiency type Ib. J Clin Endocrinol Metab. 2001;86:273-279.
144. Carakushansky M, Whatmore AJ, Clayton PE, et al. Anew missense mutation in the growth hormone-releasing hormone receptor gene in familial isolatedGHdeficiency. Eur J Endocrinol. 2003;148:25-30.
145. Haskin O, Lazar L, Jaber L, et al. A new mutation in the growth hormone-releasing hormone receptor gene in two Israeli Arab families. J Endocrinol Invest. 2006;29:122-130.
146. Hilal L, Hajaji Y, Vie-Luton MP, et al. Unusual phenotypic features in a patient with a novel splice mutation in the GHRHR gene. Mol Med. 2008;14:286-292.
147. Wang Q, Diao Y, Xu Z, et al. Identification of a novel splicing mutation in the growth hormone (GH)-releasing hormone receptor gene in a Chinese family with pituitary dwarfism. Mol Cell Endocrinol. 2009;313:50-56.
148. Alba M, Hall CM, Whatmore AJ, Clayton PE, Price DA, Salvatori R. Variability in anterior pituitary size within members of a family withGHdeficiency due to anewsplice mutation in the GHRH receptor gene. Clin Endocrinol (Oxf). 2004;60:470-475.
149. Shohreh R, Sherafat-Kazemzadeh R, Jee YH, Blitz A, Salvatori R. A novel frame shift mutation in the GHRH receptor gene in familial isolated GH deficiency: early occurrence of anterior pituitary hypoplasia. J Clin Endocrinol Metab. 2011;96:2982-2986.
150. Horikawa R. Isolated GH deficiency due to inactivating mutation of GHRH receptor [in Japanese]. Nippon Rinsho. 2002;60:297-305.
151. Salvatori R, Fan X, Mullis PE, Haile A, Levine MA. Decreased expression of the GHRH receptor gene due to a mutation in a Pit-1 binding site. Mol Endocrinol. 2002; 16:450-458.
152. Salvatori R, Hayashida CY, Aguiar-Oliveira MH, et al. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J Clin Endocrinol Metab. 1999;84:917-923.
153. Salvatori R, Aguiar-Oliveira MH, Monte LV, et al. Detection of a recurring mutation in the human growth hormone- releasing hormone receptor gene. Clin Endocrinol (Oxf). 2002;57:77-80.
154. Maheshwari HG, Silverman BL, Dupuis J, Baumann G. Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab. 1998;83:4065-4074.
155. Kamijo T, Hayashi Y, Seo H, et al. A nonsense mutation (E72X) in growth hormone releasing hormone receptor (GHRHR) gene is the major cause of familial isolated growth hormone deficiency in Western region of India: founder effect suggested by analysis of dinucleotide repeat polymorphism close toGHRHRgene. Growth Horm IGF Res. 2004;14:394-401.
156. Inoue H, Kangawa N, Kinouchi A, et al. Identification and functional analysis of novel human growth hormone-releasing hormone receptor (GHRHR) gene mutations in Japanese subjects with short stature. Clin Endocrinol (Oxf). 2011;74:223-233.
157. Marui S, Trarbach EB, Boguszewski MC, et al. GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects. Horm Res Paediatr. 2012;78:165-172.
158. Gondo RG, Aguiar-Oliveira MH, Hayashida CY, et al. Growth hormone-releasing peptide-2 stimulates GH secretion in GH-deficient patients with mutated GH-releasing hormone receptor. J Clin Endocrinol Metab. 2001;86: 3279-3283.
159. Gois MB Jr, Salvatori R, Aguiar-Oliveira MH, et al. The consequences of growth hormone-releasing hormone receptor haploinsufficiency for bone quality and insulin resistance. Clin Endocrinol (Oxf). 2012;77:379-384.
160. Pereira RM, Aguiar-Oliveira MH, Sagazio A, et al. Heterozygosity for a mutation in the growth hormonereleasing hormone receptor gene does not influence adult stature, but affects body composition. J Clin Endocrinol Metab. 2007;92:2353-2357.
161. Alba M, Salvatori R. Naturally-occurring missense mutations in the human growth hormone-releasing hormone receptor alter ligand binding. J Endocrinol. 2005;186: 515-521.
162. Camats N, Fernandez-Cancio M, Carrascosa A, et al. Contribution of human growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to isolated severe growth hormone deficiency (ISGHD) and normal adult height. Clin Endocrinol (Oxf). 2012;77:564-574.
163. Johansson A, Jonasson I, Gyllensten U. Extended haplotypes in the growth hormone releasing hormone receptor gene (GHRHR) are associated with normal variation in height. PLoS One. 2009;4:e4464.
164. Kelberman D, de Castro SC, Huang S, et al. SOX2 plays a critical role in the pituitary, forebrain, and eye during human embryonic development. J Clin Endocrinol Metab. 2008;93:1865-1873.
165. Woods KS, Cundall M, Turton J, et al. Over- and underdosage ofSOX3is associated with infundibular hypoplasia and hypopituitarism. Am J Hum Genet. 2005;76:833-849.
166. Dateki S, Kosaka K, Hasegawa K, et al. Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. J Clin Endocrinol Metab. 2010;95:756-764.
167. Thomas PQ, Dattani MT, Brickman JM, et al. HeterozygousHESX1mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet. 2001;10:39-45.
168. Idrees F, Bloch-Zupan A, Free SL, et al. Anovel homeobox mutation in the PITX2 gene in a family with Axenfeld-Rieger syndrome associated with brain, ocular, and dental phenotypes. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:184-191.
169. Pfaeffle RW, Hunter CS, Savage JJ, et al. Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab. 2008;93:1062-1071.
170. Kelberman D, Rizzoti K, Avilion A, et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo- pituitary-gonadal axis in mice and humans. J Clin Invest. 2006;116:2442-2445.
171. Stewart DM, Tian L, Notarangelo LD, Nelson DL. X-linked hypogammaglobulinemia and isolated growth hormone deficiency: an update. Immunol Res. 2008;40: 262-270.
172. Alatzoglou KS, Kelberman D, Cowell CT, et al. Increased transactivation associated with SOX3 polyalanine tract deletion in a patient with hypopituitarism. J Clin Endocrinol Metab. 2011;96:E685-E690.
173. McNay DE, Turton JP, Kelberman D, et al. HESX1 mutations are anuncommoncause of septooptic dysplasia and hypopituitarism. J Clin Endocrinol Metab. 2007;92:691-697.
174. Dateki S, Fukami M, Sato N, Muroya K, Adachi M, Ogata T. OTX2 mutation in a patient with anophthalmia, short stature, and partial growth hormone deficiency: functional studies using the IRBP, HESX1, and POU1F1 promoters. J Clin Endocrinol Metab. 2008;93:3697-3702.
175. Ashkenazi-Hoffnung L, Lebenthal Y, Wyatt AW, et al. A novel loss-of-function mutation in OTX2 in a patient with anophthalmia and isolated growth hormone deficiency. Hum Genet. 2010;127:721-729.
176. Sobrier ML, Attié-Bitach T, Netchine I, Encha-Razavi F, Vekemans M, Amselem S. Pathophysiology of syndromic combined pituitary hormone deficiency due to a LHX3 defect in light of LHX3 and LHX4 expression during early human development. Gene Expr Patterns. 2004;5:279-284.
177. Jayakody SA, Andoniadou CL, Gaston-Massuet C, et al. SOX2 regulates the hypothalamic-pituitary axis at multiple levels. J Clin Invest. 2012;122:3635-3646.
178. Flück C, Deladoey J, Rutishauser K, et al. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-Cys at codon 120 (R120C). J Clin Endocrinol Metab. 1998;83:3727-3734.
179. Prince KL, Walvoord EC, Rhodes SJ. The role of homeodomain transcription factors in heritable pituitary disease. Nat Rev Endocrinol. 2011;7:727-737.
180. Turton JP, Reynaud R, Mehta A, et al. Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. J Clin Endocrinol Metab. 2005;90:4762-4770.
181. França MM, Jorge AA, Alatzoglou KS, et al. Absence of GH-releasing hormone (GHRH) mutations in selected patients with isolated GH deficiency. J Clin Endocrinol Metab. 2011;96:E1457-E1460.
182. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85:495-522.
183. Zizzari P, Halem H, Taylor J, et al. Endogenous ghrelin regulates episodic growth hormone (GH) secretion by amplifyingGHPulse amplitude: evidence from antagonism of theGHsecretagogue-R1a receptor. Endocrinology. 2005; 146:3836-3842.
184. Pantel J, Legendre M, Cabrol S, et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest. 2006;116:760-768.
185. Pantel J, Legendre M, Nivot S, et al. Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. J Clin Endocrinol Metab. 2009;94:4334-4341.
186. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol. 2003;23:7973-7981.
187. Mohamadi A, Martari M, Holladay CD, Phillips JA 3rd, Mullis PE, Salvatori R. Mutation analysis of the muscarinic cholinergic receptor genes in isolated growth hormone deficiency type IB. J Clin Endocrinol Metab. 2009;94:2565-2570.
188. Lettre G, Jackson AU, Gieger C, et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet. 2008;40:584-591.
189. Lango AH, Estrada K, Lettre G, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467:832-838.
190. Li O, Li J, Dröge P. DNA architectural factor and protooncogene HMGA2 regulates key developmental genes in pluripotent human embryonic stem cells. FEBS Lett. 2007; 581:3533-3537.
191. Lanktree MB, Guo Y, Murtaza M, et al. Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height. Am J Hum Genet. 2011;88:6-18.
192. Gorbenko del Blanco D, de GraaffLC, Posthouwer D, Visser TJ, Hokken-Koelega AC. Isolated GH deficiency: mutation screening and copy number analysis of HMGA2 and CDK6 genes. Eur J Endocrinol. 2011;165:537-544.
193. Brants JR, Ayoubi TA, Chada K, Marchal K, Van de Ven WJ, Petit MM. Differential regulation of the insulin-like growth factor II mRNA-binding protein genes by architectural transcription factor HMGA2. FEBS Lett. 2004; 569:277-283.
194. Taylor M, Couto-Silva AC, Adan L, et al. Hypothalamicpituitary lesions in pediatric patients: endocrine symptoms often precede neuro-ophthalmic presenting symptoms. J Pediatr. 2012;161:855-863.
195. Einaudi S, Bondone C. The effects of head trauma on hypothalamic- pituitary function in children and adolescents. Curr Opin Pediatr. 2007;19:465-470.
196. Aimaretti G, Ambrosio MR, Di Somma C, et al. Hypopituitarism induced by traumatic brain injury in the transition phase. J Endocrinol Invest. 2005;28:984-989.
197. Karavitaki N, Cudlip S, Adams CB, Wass JA. Craniopharyngiomas. Endocr Rev. 2006;27:371-397.
198. Sekine S, Shibata T, Kokubu A, et al. Craniopharyngiomas of adamantinomatous type harbor β-catenin gene mutations. Am J Pathol. 2002;161:1997-2001.
199. Buslei R, Nolde M, Hofmann B, et al. Common mutations of β-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathol. 2005;109:589-597.
200. Gaston-Massuet C, Andoniadou CL, Signore M, et al. Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci U S A. 2011;108:11482-11487.
201. Olson LE, Tollkuhn J, Scafoglio C, et al. Homeodomainmediated β-catenin-dependent switching events dictate cell-lineage determination. Cell. 2006;125:593-605.
202. Klose M, Juul A, Struck J, Morgenthaler NG, Kosteljanetz M, Feldt-Rasmussen U. Acute and long-term pituitary insufficiency in traumatic brain injury: a prospective singlecentre study. Clin Endocrinol (Oxf). 2007;67:598-606.
203. Tanriverdi F, Senyurek H, Unluhizarci K, Selcuklu A, Casanueva FF, Kelestimur F. High risk of hypopituitarism after traumatic brain injury: a prospective investigation of anterior pituitary function in the acute phase and 12 months after trauma. J Clin Endocrinol Metab. 2006;91: 2105-2111.
204. Agha A, Thompson CJ. Anterior pituitary dysfunction following traumatic brain injury (TBI). Clin Endocrinol (Oxf). 2006;64:481-488.
205. Einaudi S, Matarazzo P, Peretta P, et al. Hypothalamohypophysial dysfunction after traumatic brain injury in children and adolescents: a preliminary retrospective and prospective study. J Pediatr Endocrinol Metab. 2006;19: 691-703.
206. Niederland T, Makovi H, Gál V, Andréka B, Abrahám CS, Kovács J. Abnormalities of pituitary function after traumatic brain injury in children. J Neurotrauma. 2007;24: 119-127.
207. McDonald A, Lindell M, Dunger DB, Acerini CL. Traumatic brain injury is a rarely reported cause of growth hormone deficiency. J Pediatr. 2008;152:590-593.
208. Norwood KW, Deboer MD, Gurka MJ, et al. Traumatic brain injury in children and adolescents: surveillance for pituitary dysfunction. Clin Pediatr (Phila). 2010;49: 1044-1049.
209. Fofanova OV, Evgrafov OV, Polyakov AV, Peterkova VA, Dedov II. A novel splicing mutation in exon 4 (456GA) of the GH1 gene in a patient with congenital isolated growth hormone deficiency. Hormones (Athens). 2006;5: 288-294.
210. Caturegli P, Newschaffer C, Olivi A, Pomper MG, Burger PC, Rose NR. Autoimmune hypophysitis. Endocr Rev. 2005;26:599-614.
211. Bensing S, Fetissov SO, Mulder J, et al. Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1. Proc Natl Acad Sci U S A. 2007;104:949-954.
212. Smith CJ, Bensing S, Burns C, et al. Identification of TPIT and other novel autoantigens in lymphocytic hypophysitis: immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays. Eur J Endocrinol. 2012;166:391-398.
213. Quintos JB, Grover M, Boney CM, Salas M. Autoimmune polyglandular syndrome type 3 and growth hormone deficiency. Pediatr Diabetes. 2010;11:438-442.
214. O'Dwyer DT, McElduffP, Peterson P, Perheentupa J, Crock PA. Pituitary autoantibodies in autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED). Acta Biomed. 2007;78(Suppl 1):248-254.
215. De Bellis A, Salerno M, Conte M, et al. Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature. J Clin Endocrinol Metab. 2006;91:2484-2489.
216. Yamamoto M, Iguchi G, Takeno R, et al. Adult combined GH, prolactin, and TSH deficiency associated with circulating PIT-1 antibody in humans. J Clin Invest. 2011;121: 113-119.
217. Wit JM, Kiess W, Mullis P. Genetic evaluation of short stature. Best Pract Res Clin Endocrinol Metab. 2011;25: 1-17.
218. Richmond EJ, Rogol AD. Growth hormone deficiency in children. Pituitary. 2008;11:115-120.
219. Loche S, Bizzarri C, Maghnie M, et al. Results of early reevaluation of growth hormone secretion in short children with apparent growth hormone deficiency. J Pediatr. 2002;140:445-449.
220. Gelwane G, Garel C, Chevenne D, et al. Subnormal serum insulin-like growth factor-I levels in young adults with childhood-onset nonacquired growth hormone (GH) deficiency who recover normal gh secretion may indicate less severe but persistent pituitary failure. J Clin Endocrinol Metab. 2007;92:3788-3795.
221. Maghnie M, Strigazzi C, Tinelli C, et al. 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. 1999;84:1324-1328.
222. 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;91:4271-4276.
223. Secco A, Di Iorgi N, Napoli F, et al. Reassessment of the growth hormone status in young adults with childhoodonset growth hormone deficiency: reappraisal of insulin tolerance testing. J Clin Endocrinol Metab. 2009;94: 4195-4204.
224. Quigley CA, Zagar AJ, Liu CC, et al. United States multicenter study of factors predicting the persistence of GH deficiency during the transition period between childhood and adulthood. Int J Pediatr Endocrinol. 2013;2013:6.
225. Attanasio AF, Howell S, Bates PC, et al. Confirmation of severe GH deficiency after final height in patients diagnosed as GH deficient during childhood. Clin Endocrinol (Oxf). 2002;56:503-507.
226. Müller A, Scholz M, Blankenstein O, et al. Harmonization of growth hormone measurements with different immunoassays by data adjustment. Clin Chem Lab Med. 2011; 49:1135-1142.
227. Bidlingmaier M, Strasburger CJ. Growth hormone assays: current methodologies and their limitations. Pituitary. 2007;10:115-119.
228. Bidlingmaier M, Freda PU. Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth Horm IGF Res. 2010;20:19-25.
229. Clemmons DR. Consensus statement on the standardization and evaluation of growth hormone and insulin-like growth factor assays. Clin Chem. 2011;57:555-559.
230. Amed S, Delvin E, Hamilton J. Variation in growth hormone immunoassays in clinical practice in Canada. Horm Res. 2008;69:290-294.
231. Tanaka T, Tachibana K, Shimatsu A, et al. A nationwide attempt to standardize growth hormone assays. HormRes. 2005;64(Suppl 2):6-11.
232. Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr. 2003;143:415-421.
233. Wilson DM, Frane J. A brief review of the use and utility of growth hormone stimulation testing in theNCGS:dowe need to do provocative GH testing? Growth Horm IGF Res. 2005;15(Suppl A):S21-S25.
234. Ogilvy-Stuart AL, Hands SJ, Adcock CJ, et al. Insulin, insulin- like growth factor I (IGF-I), IGF-binding protein-1, growth hormone, and feeding in the newborn. J Clin Endocrinol Metab. 1998;83:3550-3557.
235. Binder G, Weidenkeller M, Blumenstock G, Langkamp M, Weber K, Franz AR. Rational approach to the diagnosis of severe growth hormone deficiency in the newborn. J Clin Endocrinol Metab. 2010;95:2219-2226.
236. Marin G, Domené HM, Barnes KM, Blackwell BJ, Cassorla FG, Cutler GB Jr. 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. 1994;79:537-541.
237. Martínez AS, Domené HM, Ropelato MG, et al. Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency. J Clin Endocrinol Metab. 2000;85:4168-4172.
238. Molina S, Paoli M, Camacho N, Arata-Bellabarba G, Lanes R. Is testosterone and estrogen priming prior to clonidine useful in the evaluation of the growth hormone status of short peripubertal children? J Pediatr Endocrinol Metab. 2008;21:257-266.
239. Müller G, Keller A, Reich A, et al. Priming with testosterone enhances stimulated growth hormone secretion in boys with delayed puberty. J Pediatr Endocrinol Metab. 2004;17:77-83.
240. Gonc EN, Kandemir N, Ozon A, Alikasifoglu A. Final heights of boys with normal growth hormone responses to provocative tests following priming. J Pediatr Endocrinol Metab. 2008;21:963-971.
241. Gönç EN, Yordam N, Kandemir N, Alikasifoglu A. Comparison of stimulated growth hormone levels in primed versus unprimed provocative tests. Effect of various testosterone doses on growth hormone levels. Horm Res. 2001;56:32-37.
242. van Stralen MM, te Velde SJ, van Nassau F, et al. Weight status of European preschool children and associations with family demographics and energy balance-related behaviours: a pooled analysis of six European studies. Obes Rev. 2012;13(Suppl 1):29-41.
243. de Onis M, Blössner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr. 2010;92:1257-1264.
244. Argente J, Caballo N, Barrios V, et al. Multiple endocrine abnormalities of the growth hormone and insulin-like growth factor axis in prepubertal children with exogenous obesity: effect of short- and long-term weight reduction. J Clin Endocrinol Metab. 1997;82:2076-2083.
245. Radetti G, Bozzola M, Pasquino B, et al. Growth hormone bioactivity, insulin-like growth factors (IGFs), and IGF binding proteins in obese children. Metabolism. 1998;47: 1490-1493.
246. Albertsson-Wikland K, Rosberg S, Karlberg J, Groth T. Analysis of 24-hour growth hormone profiles in healthy boys and girls of normal stature: relation to puberty. J Clin Endocrinol Metab. 1994;78:1195-1201.
247. Kreitschmann-Andermahr I, Suarez P, Jennings R, Evers N, Brabant G. GH/IGF-I regulation in obesity-mechanisms and practical consequences in children and adults. Horm Res Paediatr. 2010;73:153-160.
248. Misra M, Bredella MA, Tsai P, Mendes N, Miller KK, Klibanski A. Lower growth hormone and higher cortisol are associated with greater visceral adiposity, intramyocellular lipids, and insulin resistance in overweight girls. Am J Physiol Endocrinol Metab. 2008;295:E385-E392.
249. Bonert VS, ElashoffJD, Barnett P, Melmed S. Body mass index determines evoked growth hormone (GH) responsiveness in normal healthy male subjects: diagnostic caveat for adult GH deficiency. J Clin Endocrinol Metab. 2004; 89:3397-3401.
250. Corneli G, Di Somma C, Baldelli R, et al. The cut-offlimits of the GH response to GH-releasing hormone-arginine test related to body mass index. Eur J Endocrinol. 2005;153: 257-264.
251. Ho KK. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Eur J Endocrinol. 2007;157:695-700.
252. Qu XD, Gaw Gonzalo IT, Al Sayed MY, et al. Influence of body mass index and gender on growth hormone (GH) responses to GH-releasing hormone plus arginine and insulin tolerance tests. J Clin Endocrinol Metab. 2005;90: 1563-1569.
253. Gasco V, Beccuti G, Baldini C, et al. Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults. Eur J Endocrinol. 2013;168:23-30.
254. Stanley TL, Levitsky LL, Grinspoon SK, Misra M. Effect of body mass index on peak growth hormone response to provocative testing in children with short stature. J Clin Endocrinol Metab. 2009;94:4875-4881.
255. Lee HS, Hwang JS. Influence of body mass index on growth hormone responses to classic provocative tests in children with short stature. Neuroendocrinology. 2011;93:259-264.
256. Loche S, Guzzetti C, Pilia S, et al. Effect of body mass index on the growth hormone response to clonidine stimulation testing in children with short stature. Clin Endocrinol (Oxf). 2011;74:726-731.
257. Maghnie M, Pennati MC, Civardi E, et al. GH response to ghrelin in subjects with congenital GH deficiency: evidence that ghrelin action requires hypothalamic-pituitary connections. Eur J Endocrinol. 2007;156:449-454.
258. Müller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone secretion. Physiol Rev. 1999;79:511-607.
259. Alderete TL, Byrd-Williams CE, Toledo-Corral CM, Conti DV, Weigensberg MJ, Goran MI. Relationships between IGF-1 and IGFBP-1 and adiposity in obese African-American and Latino adolescents. Obesity (Silver Spring). 2011;19:933-938.
260. Maghnie M, Aimaretti G, Bellone S, et al. Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement. Eur J Endocrinol. 2005;152:589-596.
261. Clayton PE, Cuneo RC, Juul A, Monson JP, Shalet SM, Tauber M. Consensus statement on the management of the GH-treated adolescent in the transition to adult care. Eur J Endocrinol. 2005;152:165-170.
262. Di Iorgi N, Secco A, Napoli F, et al. Deterioration of growth hormone (GH) response and anterior pituitary function in young adults with childhood-onset GH defi- ciency and ectopic posterior pituitary: a two-year prospective follow-up study. J Clin Endocrinol Metab. 2007;92: 3875-3884.
263. Mehta A, Hindmarsh PC, Mehta H, et al. Congenital hypopituitarism: clinical, molecular and neuroradiological correlates. Clin Endocrinol (Oxf). 2009;71:376-382.
264. Léger J, Danner S, Simon D, Garel C, Czernichow P. Do all patients with childhood-onset growth hormone deficiency (GHD) and ectopic neurohypophysis have persistent GHD in adulthood? J Clin Endocrinol Metab. 2005;90:650-656.
265. Carel JC, Ecosse E, Nicolino M, et al. Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. BMJ. 2002;325:70.
266. 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;55:88-94.
267. Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB. Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database. J Clin Endocrinol Metab. 2006;91:2047-2054.
268. Hindmarsh PC, Dattani MT. Use of growth hormone in children. Nat Clin Pract Endocrinol Metab. 2006;2:260-268.
269. Cohen P, Bright GM, Rogol AD, Kappelgaard AM, Rosenfeld RG. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab. 2002;87:90-98.
270. Radetti G, Buzi F, Paganini C, Pilotta A, Felappi B. Treatment of GH-deficient children with two different GH doses: effect on final height and cost-benefit implications. Eur J Endocrinol. 2003;148:515-518.
271. Mauras N, Attie KM, Reiter EO, Saenger P, Baptista J. High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. J Clin Endocrinol Metab. 2000;85:3653-3660.
272. Coelho R, Brook CG, Preece MA, Stanhope RG, Dattani MT, Hindmarsh PC. A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency. Horm Res. 2008;70:85-88.
273. Darendeliler F, Berberoglu M, Ocal G, et al. Response to growth hormone with respect to pubertal status on increased dose in idiopathic growth hormone deficiency: an analysis of Turkish children in the KIGS database (Pfizer International Growth Study). J Pediatr Endocrinol Metab. 2005;18:949-954.
274. Howard SR, Butler GE. An analysis of the clinical and cost effectiveness of growth hormone replacement therapy before and during puberty: should we increase the dose? Horm Res Paediatr. 2013;79:75-82.
275. Wikland KA, Kriström B, Rosberg S, Svensson B, Nierop AF. Validated multivariate models predicting the growth response to GH treatment in individual short children with a broad range in GH secretion capacities. Pediatr Res. 2000;48:475-484.
276. Ranke MB, Lindberg A, Chatelain P, et al. 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. 1999; 84:1174-1183.
277. Ranke MB, Lindberg A. Predicting growth in response to growth hormone treatment. Growth Horm IGF Res. 2009;19:1-11.
278. de Ridder MA, Stijnen T, Hokken-Koelega AC. Prediction of adult height in growth-hormone-treated children with growth hormone deficiency. J Clin Endocrinol Metab. 2007;92:925-931.
279. Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG. Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study. J Clin Endocrinol Metab. 2007;92: 2480-2486.
280. Kriström B, Aronson AS, Dahlgren J, et al. Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature. J Clin Endocrinol Metab. 2009; 94:483-490.
281. Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG. Height velocity targets from the national cooperative growth study for first-year growth hormone responses in short children. J Clin Endocrinol Metab. 2008;93:352-357.
282. Ranke MB, Lindberg A; KIGS International Board. Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metab. 2010;95:1229-1237.
283. Ranke MB, Lindberg A, Mullis PE, et al. Towards optimal treatment with growth hormone in short children and adolescents: evidence and theses. Horm Res Paediatr. 2013; 79:51-67.
284. Gardner J, Ashraf A, You Z, McCormick K. Changes in plasma FGF23 in growth hormone deficient children during rh GH therapy. J Pediatr Endocrinol Metab. 2011;24: 645-650.
285. Xiao Y, Dong Z, Lu W, et al. Measurement of aminoterminal propeptide of C-type natriuretic peptide in patients with idiopathic short stature or isolated growth hormone deficiency. J Pediatr Endocrinol Metab. 2011;24: 989-994.
286. Cruz-Topete D, Jorgensen JO, Christensen B, et al. Identification of new biomarkers of low-dose GH replacement therapy in GH-deficient patients. J Clin Endocrinol Metab. 2011;96:2089-2097.
287. Hellgren G, Andersson B, Nierop AF, Dahlgren J, Hochberg Z, Albertsson-Wikland K. A proteomic approach identified growth hormone-dependent nutrition markers in children with idiopathic short stature. Proteome Sci. 2008;6:35.
288. Lanes R, Marcano H, Villaroel O, et al. Circulating levels of high-sensitivity C-reactive protein and soluble markers of vascular endothelial cell activation in growth hormonedeficient adolescents. Horm Res. 2008;70:230-235.
289. Abd Rahman S, Schirra HJ, Lichanska AM, Huynh T, Leong GM. Urine metabonomic profiling of a female adolescent with PIT-1 mutation before and during growth hormone therapy: insights into the metabolic effects of growth hormone. Growth Horm IGF Res. 2013;23:29-36.
290. Whatmore AJ, Patel L, Clayton PE. A pilot study to evaluate gene expression profiles in peripheral blood mononuclear cells (PBMCs) from children with GH deficiency and Turner syndrome in response to GH treatment. Clin Endocrinol (Oxf). 2009;70:429-434.
291. Stevens A, Clayton P, Tato L, et al. Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome. Pharmacogenomics J. 2014;14:54-62.
292. Fernandez-Perez L, Novoa J, Stahlberg N, et al. The effect of in vivo growth hormone treatment on blood gene expression in adults with growth hormone deficiency reveals potential biomarkers to monitor growth hormone therapy. Clin Endocrinol (Oxf). 2010;72:800-806.
293. Cutfield WS, Derraik JG, Gunn AJ, et al. Non-compliance with growth hormone treatment in children is common and impairs linear growth. PLoS One. 2011;6:e16223.
294. Fisher BG, Acerini CL. Understanding the growth hormone therapy adherence paradigm: a systematic review. Horm Res Paediatr. 2013;79:189-196.
295. Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V. Defects in growth hormone receptor signaling. Trends Endocrinol Metab. 2007;18:134-141.
296. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougnères P. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet. 2004;36:720-724.
297. Blum WF, Machinis K, Shavrikova EP, et al. The growth response to growth hormone (GH) treatment in children with isolated GH deficiency is independent of the presence of the exon 3-minus isoform of the GH receptor. J Clin Endocrinol Metab. 2006;91:4171-4174.
298. Pantel J, Machinis K, Sobrier ML, Duquesnoy P, Goossens M, Amselem S. Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J Biol Chem. 2000;275:18664-18669.
299. Jorge AA, Marchisotti FG, Montenegro LR, Carvalho LR, Mendonca BB, Arnhold IJ. 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;91:1076-1080.
300. 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;91:1178-1180.
301. Carrascosa A, Audí L, Fernández-Cancio M, et al. The exon 3-deleted/full-length growth hormone receptor polymorphism did not influence growth response to growth hormone therapy over two years in prepubertal short children born at term with adequate weight and length for gestational age. J Clin Endocrinol Metab. 2008;93:764-770.
302. Wan L, Chen WC, Tsai Y, et al. Growth hormone (GH) receptor C. 1319 GT polymorphism, but not exon 3 retention or deletion is associated with better first-year growth response to GH therapy in patients with GH deficiency. Pediatr Res. 2007;62:735-740.
303. Marchisotti FG, Jorge AA, Montenegro LR, et al. Comparison between weight-based and IGF-I-based growth hormone(GH)dosing in the treatment of children with GH deficiency and influence of exon 3 deleted GH receptor variant. Growth Horm IGF Res. 2009;19:179-186.
304. de GraaffLC, Meyer S, Els C, Hokken-Koelega AC. GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age. Clin Endocrinol (Oxf). 2008;68:930-934.
305. Wassenaar MJ, Dekkers OM, Pereira AM, et al. Impact of the exon 3-deleted growth hormone (GH) receptor polymorphism on baseline height and the growth response to recombinant human GH therapy in GH-deficient (GHD) and non-GHD children with short stature: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2009; 94:3721-3730.
306. Räz B, Janner M, Petkovic V, 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. 2008;93: 974-980.
307. Costalonga EF, Antonini SR, Guerra-Junior G, Mendonca BB, Arnhold IJ, Jorge AA. The - 202 Aallele of insulin-like growth factor binding protein-3 (IGFBP3) promoter polymorphism is associated with higher IGFBP-3 serum levels and better growth response to growth hormone treatment in patients with severe growth hormone deficiency. J Clin Endocrinol Metab. 2009;94:588-595.
308. Miletta MC, Scheidegger UA, Giordano M, et al. Association of the (CA)n repeat polymorphism of insulin-like growth factor-I and - 202 A/C IGF-binding protein-3 promoter polymorphism with adult height in patients with severe growth hormone deficiency. Clin Endocrinol (Oxf). 2012;76:683-690.
309. Costalonga EF, Antonini SR, Guerra G Jr, et al. Growth hormone pharmacogenetics: the interactive effect of a microsatellite in the IGF1 promoter region with the GHR-exon 3 and - 202 A/C IGFBP3 variants on treatment outcomes of children with severe GH deficiency. Pharmacogenomics J. 2012; 12:439-445.
310. Su PH, Yang SF, Yu JS, Chen SJ, Chen JY. Apolymorphism in the leptin receptor gene at position 223 is associated with growth hormone replacement therapy responsiveness in idiopathic short stature and growth hormone deficiency patients. Eur J Med Genet. 2012;55:682-687.
311. Alvarez-Nava F, Marcano H, Pardo T, et al. GHR and VDRgenes do not contribute to the growth hormone (GH) response in GH deficient and Turner syndrome patients. J Pediatr Endocrinol Metab. 2010;23:773-782.
312. Aberg D. Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis. EndocrDev. 2010;17:63-76.
313. Aberg MA, Aberg ND, Palmer TD, et al. IGF-I has a direct proliferative effect in adult hippocampal progenitor cells. Mol Cell Neurosci. 2003;24:23-40.
314. Ransome MI, Goldshmit Y, Bartlett PF, Waters MJ, Turnley AM. Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness. Eur J Neurosci. 2004;19:2069-2079.
315. Molina DP, Ariwodola OJ, Linville C, et al. Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats. Neurobiol Aging. 2012; 33:1938-1949.
316. Aberg ND, Blomstrand F, Aberg MA, Bjorklund U, Carlsson B, Carlsson-Skwirut C, Bang P, Ronnback L, Eriksson PS. Insulin-like growth factor-I increases astrocyte intercellular gap junctional communication and connexin43 expression in vitro. J Neurosci Res. 2003; 74:12-22.
317. Russo VC, Gluckman PD, Feldman EL, Werther GA. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 2005;26:916-943.
318. Lai Z, Roos P, Zhai O, et al. Age-related reduction of human growth hormone-binding sites in the human brain. Brain Res. 1993;621:260-266.
319. Lobie PE, García-Aragón J, Lincoln DT, Barnard R, Wilcox JN, Waters MJ. Localization and ontogeny of growth hormone receptor gene expression in the central nervous system. Brain Res Dev Brain Res. 1993;74:225-233.
320. Pan W, Yu Y, Cain CM, Nyberg F, Couraud PO, Kastin AJ. Permeation of growth hormone across the blood-brain barrier. Endocrinology. 2005;146:4898-4904.
321. Donahue CP, Kosik KS, Shors TJ. Growth hormone is produced within the hippocampus where it responds to age, sex, and stress. Proc Natl Acad Sci U S A. 2006;103: 6031-6036.
322. Enhamre E, Carlsson A, Grönbladh A, Watanabe H, Hallberg M, Nyberg F. The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments. Neurosci Lett. 2012;523:82-86.
323. van Dam PS, de Winter CF, de Vries R, et al. Childhoodonset growth hormone deficiency, cognitive function and brain N-acetylaspartate. Psychoneuroendocrinology. 2005; 30:357-363.
324. Lagrou K, Xhrouet-Heinrichs D, Massa G, et al. Quality of life and retrospective perception of the effect of growth hormone treatment in adult patients with childhood growth hormone deficiency. J Pediatr Endocrinol Metab. 2001;14(Suppl 5):1249-1260.
325. Lijffijt M, Van Dam PS, Kenemans JL, et al. Somatotropicaxis deficiency affects brain substrates of selective attention in childhood-onset growth hormone deficient patients. Neurosci Lett. 2003;353:123-126.
326. Sathiavageeswaran M, Burman P, Lawrence D, et al. Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: a placebo-controlled 12-month study. Eur J Endocrinol. 2007;156:439-447.
327. Quik EH, Valk GD, Drent ML, et al. Reduced growth hormone secretion after cranial irradiation contributes to neurocognitive dysfunction. Growth Horm IGF Res. 2012;22:42-47.
328. Moreau OK, Cortet-Rudelli C, Yollin E, Merlen E, Daveluy W, Rousseaux M. Growth hormone replacement therapy in patients with traumatic brain injury. J Neurotrauma. 2013;30:998-1006.
329. Golgeli A, Tanriverdi F, Suer C, et al. Utility of P300 auditory event related potential latency in detecting cognitive dysfunction in growth hormone (GH) deficient patients with Sheehan's syndrome and effects of GH replacement therapy. Eur J Endocrinol. 2004;150:153-159.
330. Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Drent ML. Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study. Neuroendocrinology. 2006;83:12-19.
331. Reimunde P, Quintana A, Castañón B, et al. Effects of growth hormone (GH) replacement and cognitive rehabilitation in patients with cognitive disorders after traumatic brain injury. Brain Inj. 2011;25:65-73.
332. Sugisaki T, Noguchi T, Tsukada Y. Cerebral myelinogenesis in the Snell dwarf mouse: stimulatory effects of GH and T4 restricted to the first 20 days of postnatal life. Neurochem Res. 1985;10:767-778.
333. Noguchi T, Sugisaki T, Nishikawa N, Tsukada Y. Restoration of microcephalic cerebrum with hypomyelination in the growth hormone-deficient mouse (lit): stimulatory effects of GH restricted to the first 20 days of postnatal life. Neurochem Res. 1988;13:249-252.
334. Lehman DM, Hale DE, Cody JT, Harrison JM, Leach RJ. Molecular, morphometric and functional analyses demonstrate that the growth hormone deficient little mouse is not hypomyelinated. Brain Res Dev Brain Res. 1999;116: 191-199.
335. Sun LY, Evans MS, Hsieh J, Panici J, Bartke A. Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice. Endocrinology. 2005;146:1138-1144.
336. Takeuchi T, Suzuki H, Sakurai S, Nogami H, Okuma S, Ishikawa H. Molecular mechanism of growth hormone (GH) deficiency in the spontaneous dwarf rat: detection of abnormal splicing of GH messenger ribonucleic acid by the polymerase chain reaction. Endocrinology. 1990; 126:31-38.
337. Li E, Kim DH, Cai M, et al. Hippocampus-dependent spatial learning andmemoryare impaired in growth hormonedeficient spontaneous dwarf rats. Endocr J. 2011;58:257-267.
338. Nieves-Martinez E, Sonntag WE, Wilson A, et al. Earlyonset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation. J Endocrinol. 2010;204:31-36.
339. Le Grevès M, Zhou Q, Berg M, et al. Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMD Areceptor subunit and PSD-95 gene transcript levels. Exp Brain Res. 2006;173:267-273.
340. Li RC, Guo SZ, Raccurt M, et al. Exogenous growth hormone attenuates cognitive deficits induced by intermittent hypoxia in rats. Neuroscience. 2011;196:237-250.
341. Yan H, Mitschelen M, Bixler GV, et al. Circulating IGF1 regulates hippocampal IGF1 levels and brain gene expression during adolescence. J Endocrinol. 2011;211:27-37.
342. Aberg ND, Johansson I, Aberg MA, et al. Peripheral administration of GH induces cell proliferation in the brain of adult hypophysectomized rats. J Endocrinol. 2009;201: 141-150.
343. Walser M, Hansén A, Svensson PA, et al. Peripheral ad- ministration of bovine GH regulates the expression of cerebrocortical beta-globin, GABAB receptor 1, and the Lissencephaly-1 protein (LIS-1) in adult hypophysectomized rats. Growth Horm IGF Res. 2011;21:16-24.
344. Le Grevès M, Steensland P, Le Grevès P, Nyberg F. Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats. Proc Natl Acad Sci U S A. 2002;99:7119-7123.
345. Mahmoud GS, Grover LM. Growth hormone enhances excitatory synaptic transmission in area CA1 of rat hippocampus. J Neurophysiol. 2006;95:2962-2974.
346. Grönbladh A, Johansson J, Nyberg F, Hallberg M. Recombinant human growth hormone affects the density and functionality of GABAB receptors in the male rat brain. Neuroendocrinology. 2013;97:203-211.
347. 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;87:5076-5084.
348. Enhamre-Brolin E, Carlsson A, Hallberg M, Nyberg F. Growth hormone reverses streptozotocin-induced cognitive impairments in male mice. Behav Brain Res. 2013; 238:273-278.
349. Whitman BY, Myers S, Carrel A, Allen D. The behavioral impact of growth hormone treatment for children and adolescents with Prader-Willi syndrome: a 2-year, controlled study. Pediatrics. 2002;109:E35.
350. Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, et al. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial and longitudinal study. J Clin Endocrinol Metab. 2012;97:2307-2314.
351. van Pareren YK, Duivenvoorden HJ, Slijper FS, Koot HM, Hokken-Koelega AC. Intelligence and psychosocial functioning during long-term growth hormone therapy in children born small for gestational age. J Clin Endocrinol Metab. 2004;89:5295-5302.
352. Hokken-Koelega A, van Pareren Y, Arends N. Effects of growth hormone treatment on cognitive function and head circumference in children born small for gestational age. Horm Res. 2005;64(Suppl 3):95-99.
353. Huisman J, Aukema EJ, Deijen JB, et al. The usefulness of growth hormone treatment for psychological status in young adult survivors of childhood leukaemia: an openlabel study. BMC Pediatr. 2008;8:25.
354. Stabler B, Siegel PT, Clopper RR, Stoppani CE, Compton PG, Underwood LE. Behavior change after growth hormone treatment of children with short stature. J Pediatr. 1998;133:366-373.
355. Andronikof-Sanglade A, Fjellestad-Paulsen A, Ricard-Malivoir S, Evain-Brion D. Specific abnormalities in a visual motor psychological test in short children with abnormal growth hormone secretion. Acta Paediatr. 1997; 86:154-159.
356. Puga González B, Ferrández Longás A, Oyarzábal M, Nosas R; Grupo Colaborativo Español. The effects of growth hormone deficiency and growth hormone replacement therapy on intellectual ability, personality and adjustment in children. Pediatr Endocrinol Rev. 2010;7: 328-338.
357. Webb EA, O'Reilly MA, Clayden JD, et al. Effect of growth hormone deficiency on brain structure, motor function and cognition. Brain. 2012;135:216-227.
358. Beaulieu C. The basis of anisotropic water diffusion in the nervous system - a technical review. NMR Biomed. 2002; 15:435-455.
359. Laron Z, Galatzer A. Effect of hGH on head circumference and IQ in isolated growth hormone deficiency. Early Hum Dev. 1981;5:211-214.
360. Arwert LI, Veltman DJ, Deijen JB, van Dam PS, Delemarre- van deWaal HA, Drent ML. Growth hormone deficiency and memory functioning in adults visualized by functional magnetic resonance imaging. Neuroendocrinology. 2005;82:32-40.
361. Deepak D, Daousi C, Javadpour M, et al. The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency. Growth Horm IGF Res. 2010;20:220-225.
362. Colao A, Di Somma C, Salerno M, Spinelli L, Orio F, Lombardi G. The cardiovascular risk of GH-deficient adolescents. J Clin Endocrinol Metab. 2002;87:3650-3655.
363. Colao A, Di Somma C, Cuocolo A, et al. The severity of growth hormone deficiency correlates with the severity of cardiac impairment in 100 adult patients with hypopituitarism: an observational, case-control study. J Clin Endocrinol Metab. 2004;89:5998-6004.
364. Colao A. The GH-IGF-I axis and the cardiovascular system: clinical implications. Clin Endocrinol (Oxf). 2008; 69:347-358.
365. Gola M, Bonadonna S, Doga M, Giustina A. Clinical review: Growth hormone and cardiovascular risk factors. J Clin Endocrinol Metab. 2005;90:1864-1870.
366. Colao A, Di Somma C, Pivonello R, et al. The cardiovascular risk of adult GH deficiency (GHD) improved after GH replacement and worsened in untreated GHD: a 12-month prospective study. J Clin Endocrinol Metab. 2002; 87:1088-1093.
367. Johannsson G, Albertsson-Wikland K, Bengtsson BA. Discontinuation of growth hormone (GH) treatment: metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. Swedish Study Group for Growth Hormone Treatment in Children. J Clin Endocrinol Metab. 1999;84:4516-4524.
368. Lanes R, Gunczler P, Lopez E, Esaa S, Villaroel O, Revel-Chion R. Cardiac mass and function, carotid artery intimamedia thickness, and lipoprotein levels in growth hormone- deficient adolescents. J Clin Endocrinol Metab. 2001;86:1061-1065.
369. Carroll PV, Drake WM, Maher KT, et al. Comparison of continuation or cessation of growth hormone (GH) therapy on body composition and metabolic status in adolescents with severe GH deficiency at completion of linear growth. J Clin Endocrinol Metab. 2004;89:3890-3895.
370. Nygren A, Sunnegårdh J, Albertsson-Wikland K, Berggren H, Isgaard J. Relative cardiac expression of growth hormone receptor and insulin-like growth factor-I mRNA in congenital heart disease. J Endocrinol Invest. 2008;31: 196-200.
371. Shulman DI, Root AW, Diamond FB, Bercu BB, Martinez R, Boucek RJ Jr. Effects of one year of recombinant human growth hormone (GH) therapy on cardiac mass and function in children with classical GH deficiency. J Clin Endocrinol Metab. 2003;88:4095-4099.
372. Ozdemir O, Abaci A, Hizli S, et al. Cardiac functions in children with growth hormone deficiency before and during growth hormone-replacement therapy. Pediatr Cardiol. 2011;32:766-771.
373. Salerno M, Esposito V, Spinelli L, et al. Left ventricular mass and function in children with GH deficiency before and during 12 months GH replacement therapy. Clin Endocrinol (Oxf). 2004;60:630-636.
374. Salerno M, Esposito V, Farina V, et al. Improvement of cardiac performance and cardiovascular risk factors in children withGHdeficiency after two years of GHreplacement therapy: an observational, open, prospective, casecontrol study. J Clin Endocrinol Metab. 2006;91:1288-1295.
375. Capalbo D, LoVecchio A, Farina V, et al. Subtle alterations of cardiac performance in children with growth hormone deficiency: results of a two-year prospective, case-control study. J Clin Endocrinol Metab. 2009;94:3347-3355.
376. Nygren A, Sunnegardh J, Teien D, et al. Rapid cardiovascular effects of growth hormone treatment in short prepubertal children: impact of treatment duration. Clin Endocrinol (Oxf). 2012;77:877-884.
377. Charlton HM, Clark RG, Robinson IC, et al. Growth hormone- deficient dwarfism in the rat: a new mutation. J Endocrinol. 1988;119:51-58.
378. Groban L, Lin M, Kassik KA, Ingram RL, Sonntag WE. Early-onset growth hormone deficiency results in diastolic dysfunction in adult-life and is prevented by growth hormone supplementation. Growth Horm IGF Res. 2011;21: 81-88.
379. Koltowska-Häggström M, Geffner ME, Jönsson P, et al. Discontinuation of growth hormone (GH) treatment during the transition phase is an important factor determining the phenotype of young adults with nonidiopathic childhood- onset GH deficiency. J Clin Endocrinol Metab. 2010;95:2646-2654.
380. Gleeson H, Barreto ES, Salvatori R, et al. Metabolic effects of growth hormone (GH) replacement in children and adolescents with severe isolated GH deficiency due to a GHRH receptor mutation. Clin Endocrinol (Oxf). 2007; 66:466-474.
381. Attanasio AF, Shavrikova E, Blum WF, et al. Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients. J Clin Endocrinol Metab. 2004; 89:4857-4862.
382. Mauras N, Pescovitz OH, Allada V, Messig M, Wajnrajch MP, Lippe B. Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial. J Clin Endocrinol Metab. 2005;90:3946-3955.
383. van der Sluis IM, Boot AM, Hop WC, De Rijke YB, Krenning EP, de Muinck Keizer-Schrama SM. Long-term effects of growth hormone therapy on bone mineral density, body composition, and serum lipid levels in growth hormone deficient children: a 6-year follow-up study. Horm Res. 2002;58:207-214.
384. Lanes R, Paoli M, Carrillo E, Villaroel O, Palacios A. Peripheral inflammatory and fibrinolytic markers in adolescents with growth hormone deficiency: relation to postprandial dyslipidemia. J Pediatr. 2004;145:657-661.
385. Andiran N, Yordam N. TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy. GrowthHormIGF Res. 2007;17:149-153.
386. Pagani S, Meazza C, Travaglino P, De Benedetti F, Tinelli C, Bozzola M. Serum cytokine levels in GH-deficient children during substitutive GH therapy. Eur J Endocrinol. 2005;152:207-210.
387. López-Siguero JP, López-Canti LF, Espino R, et al. Effect of recombinant growth hormone on leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α and ghrelin levels in growth hormone-deficient children. J Endocrinol Invest. 2011;34:300-306.
388. Ciresi A, Amato MC, Criscimanna A, et al. Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency. Eur J Endocrinol. 2007;156:353-360.
389. Esposito V, Di Biase S, Lettiero T, Labella D, Simeone R, Salerno M. Serum homocysteine concentrations in children with growth hormone (GH) deficiency before and after 12 months GH replacement. Clin Endocrinol (Oxf). 2004;61:607-611.
390. Nozue H, Kamoda T, Matsui A. Serum resistin concentrations in growth hormone-deficient children during growth hormone replacement therapy. Metabolism. 2007; 56:1514-1517.
391. Cañete R, Valle M, Martos R, Sánchez-Carrión A, Cañete MD, van Donkelaar EL. Short-term effects of GH treatment on coagulation, fibrinolysis, inflammation biomarkers, and insulin resistance status in prepubertal children with GH deficiency. Eur J Endocrinol. 2012;167:255-260.
392. Lanes R, Soros A, Flores K, Gunczler P, Carrillo E, Bandel J. Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: apparent effects of growth hormone treatment on these parameters. J Clin Endocrinol Metab. 2005;90:3978-3982.
393. Szczepaniska KJ, Tołwinska J, Urban M, Gardziejczyk M, Głowi&nska B. Cardiac mass and function, carotid artery intima media thickness, homocysteine and lipoprotein levels in children and adolescents with growth hormone deficiency. J Pediatr Endocrinol Metab. 2004;17:1405-1413.
394. Bachrach LK, Ward LM. Clinical review 1: Bisphosphonate use in childhood osteoporosis. J Clin Endocrinol Metab. 2009;94:400-409.
395. Högler W, Briody J, Moore B, Lu PW, Cowell CT. Effect of growth hormone therapy and puberty on bone and body composition in children with idiopathic short stature and growth hormone deficiency. Bone. 2005;37:642-650.
396. Boot AM, Engels MA, Boerma GJ, Krenning EP, De Muinck Keizer-Schrama SM. Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab. 1997;82:2423-2428.
397. Baroncelli GI, Bertelloni S, Sodini F, Saggese G. Lumbar bone mineral density at final height and prevalence of fractures in treated children with GH deficiency. J Clin Endocrinol Metab. 2002;87:3624-3631.
398. Hulthén L, Bengtsson BA, Sunnerhagen KS, Hallberg L, Grimby G, Johannsson G. GHis needed for the maturation of muscle mass and strength in adolescents. J Clin Endocrinol Metab. 2001;86:4765-4770.
399. Schweizer R, Martin DD, Haase M, et al. Similar effects of long-term exogenous growth hormone (GH) on bone and muscle parameters: a pQCT study of GH-deficient and small-for-gestational-age (SGA) children. Bone. 2007;41: 875-881.
400. Maheshwari HG, Bouillon R, Nijs J, Oganov VS, Bakulin AV, Baumann G. The Impact of congenital, severe, untreated growth hormone (GH) deficiency on bone size and density in young adults: insights from genetic GH-releasing hormone receptor deficiency. J Clin Endocrinol Metab. 2003;88:2614-2618.
401. Baim S, Binkley N, Bilezikian JP, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom. 2008;11:75-91.
402. Fricke O, Schoenau E. The 'functional muscle-bone unit': probing the relevance of mechanical signals for bone development in children and adolescents. GrowthHormIGF Res. 2007;17:1-9.
403. Gahlot M, Khadgawat R, Ramot R, et al. The effect of growth hormone deficiency on size-corrected bone mineral measures in pre-pubertal children. Osteoporos Int. 2012; 23:2211-2217.
404. Schweizer R, Martin DD, Schwarze CP, et al. Cortical bone density is normal in prepubertal children with growth hormone (GH) deficiency, but initially decreases during GH replacement due to early bone remodeling. J Clin Endocrinol Metab. 2003;88:5266-5272.
405. Hogler W, Shaw N. Childhood growth hormone deficiency, bone density, structures and fractures: scrutinizing the evidence. Clin Endocrinol (Oxf). 2010;72:281-289.
406. Bouillon R, Koledova E, Bezlepkina O, et al. Bone status and fracture prevalence in Russian adults with childhoodonset growth hormone deficiency. J Clin Endocrinol Metab. 2004;89:4993-4998.
407. Ross J, Czernichow P, Biller BM, Colao A, Reiter E, Kiess W. Growth hormone: health considerations beyond height gain. Pediatrics. 2010;125:e906-e918.
408. Hoos MB, Westerterp KR, Gerver WJ. Short-term effects of growth hormone on body composition as a predictor of growth. J Clin Endocrinol Metab. 2003;88:2569-2572.
409. Ernst MA, Simons MY, Gerver AJ, Zandwijken GR, Zimmermann LJ, Gerver WJ. Change in total body water as a predictive tool for growth hormone treatment response. Horm Res Paediatr. 2012;78:18-23.
410. Esen I, Demirel F, Tepe D, Kara O, Koc N. The association between growth response to growth hormone and baseline body composition of children with growth hormone deficiency. Growth Horm IGF Res. 2013;23:196-199.
411. Collett-Solberg PF. Update in growth hormone therapy of children. J Clin Endocrinol Metab. 2011;96:573-579.
412. Rosenfeld RG, Cohen P, Robison LL, et al. Long-term surveillance of growth hormone therapy. J Clin Endocrinol Metab. 2012;97:68-72.
413. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in children. J Clin Endocrinol Metab. 2010;95: 167-177.
414. Darendeliler F, Karagiannis G, Wilton P. Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. Horm Res. 2007; 68(Suppl 5):41-47.
415. Pitukcheewanont P, Desrosiers P, Steelman J, et al. Issues and trends in pediatric growth hormone therapy-an update from the GHMonitor observational registry. Pediatr Endocrinol Rev. 2008;5(Suppl 2):702-707.
416. Luger A, Feldt-Rasmussen U, Abs R, et al. Lessons learned from 15 years of KIMS and 5 years of ACROSTUDY. Horm Res Paediatr. 2011;76(Suppl 1):33-38.
417. Wyatt D. Lessons from the national cooperative growth study. Eur J Endocrinol. 2004;151(Suppl 1):S55-S59.
418. Bolar K, Hoffman AR, Maneatis T, Lippe B. Long-term safety of recombinant human growth hormone in turner syndrome. J Clin Endocrinol Metab. 2008;93:344-351.
419. Bannink EM, van der Palen RL, Mulder PG, de Muinck Keizer-Schrama SM. Long-term follow-up of GH-treated girls with Turner syndrome: metabolic consequences. Horm Res. 2009;71:343-349.
420. de Lind van Wijngaarden RF, Siemensma EP, Festen DA, et al. Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi syndrome. J Clin Endocrinol Metab. 2009;94:4205-4215.
421. Salvatoni A, Veronelli E, Nosetti L, et al. Short-term effects of growth hormone treatment on the upper airways of non severely obese children with Prader-Willi syndrome. J Endocrinol Invest. 2009;32:601-605.
422. Hauffa BP, Knaup K, Lehmann N, Neudorf U, Nagel B. Effects of growth hormone therapy on cardiac dimensions in children and adolescents with Prader-Willi syndrome. Horm Res Paediatr. 2011;75:56-62.
423. Fine RN, Ho M, Tejani A, Blethen S. Adverse events with rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease. J Pediatr. 2003;142: 539-545.
424. Seikaly MG, Salhab N, Warady BA, Stablein D. Use of rhGHin children with chronic kidney disease: lessons from NAPRTCS. Pediatr Nephrol. 2007;22:1195-1204.
425. Alangari A, Abobaker A, Kanegane H, Miyawaki T. Xlinked lymphoproliferative disease associated with hypogammaglobulinemia and growth-hormone deficiency. Eur J Pediatr. 2006;165:165-167.
426. Tanaka T, Yokoya S, Seino Y, et al. Long-term efficacy and safety of two doses of growth hormone in short Japanese children born small for gestational age. Horm Res Paediatr. 2011;76:411-418.
427. Hokken-Koelega A, van Pareren Y, Arends N, Boonstra V. Efficacy and safety of long-term continuous growth hormone treatment of children born small for gestational age. Horm Res. 2004;62(Suppl 3):149-154.
428. Cutfield WS, Lindberg A, Rapaport R, Wajnrajch MP, Saenger P. Safety of growth hormone treatment in children born small for gestational age: the US trial and KIGS analysis. Horm Res. 2006;65(Suppl 3):153-159.
429. Kemp SF, Kuntze J, Attie KM, et al. Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab. 2005;90: 5247-5253.
430. Quigley CA, Gill AM, Crowe BJ, et al. Safety of growth hormone treatment in pediatric patients with idiopathic short stature. J Clin Endocrinol Metab. 2005;90:5188-5196.
431. Robison LL, Armstrong GT, Boice JD, et al. The Childhood Cancer Survivor Study: a National Cancer Institutesupported resource for outcome and intervention research. J Clin Oncol. 2009;27:2308-2318.
432. Sklar CA, Mertens AC, Mitby P, et al. Risk of disease recurrence and second neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab. 2002;87:3136-3141.
433. Mackenzie S, Craven T, Gattamaneni HR, Swindell R, Shalet SM, Brabant G. Long-term safety of growth hormone replacement after CNS irradiation. J Clin Endocrinol Metab. 2011;96:2756-2761.
434. Ergun-Longmire B, Mertens AC, Mitby P, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. J Clin Endocrinol Metab. 2006; 91:3494-3498.
435. Allen DB. Growth hormone post-marketing surveillance: safety, sales, and the unfinished task ahead. J Clin Endocrinol Metab. 2010;95:52-55.
436. Cutfield WS, Wilton P, Bennmarker H, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet. 2000;355:610-613.
437. Child CJ, Zimmermann AG, Scott RS, Cutler GB Jr, Battelino T, Blum WF. Prevalence and incidence of diabetes mellitus in GH-treated children and adolescents: analysis from the GeNeSIS observational research program. J Clin Endocrinol Metab. 2011;96:E1025-E1034.
438. Neu A, Feldhahn L, Ehehalt S, Hub R, Ranke MB. Type 2 diabetes mellitus in children and adolescents is still a rare disease in Germany: a population-based assessment of the prevalence of type 2 diabetes and MODY in patients aged 0-20 years. Pediatr Diabetes. 2009;10:468-473.
439. Writing Group for the SEARCH for Diabetes in Youth Study Group; Dabelea D, Bell RA, D'Agostino RB Jr, et al. Incidence of diabetes in youth in the United States. JAMA. 2007;297:2716-2724.
440. SEARCH for Diabetes in Youth Study Group; Liese AD, D'Agostino RB Jr, Hamman RF, et al. The burden of diabetes mellitus among US youth: prevalence estimates from theSEARCHfor Diabetes in Youth Study. Pediatrics. 2006;118:1510-1518.
441. Smith TL, Drum ML, Lipton RB. Incidence of childhood type I and non-type 1 diabetes mellitus in a diverse population: the Chicago Childhood Diabetes Registry, 1994 to 2003. J Pediatr Endocrinol Metab. 2007;20:1093-1107.
442. Luger A, Mattsson AF, Koltowska-Häggström M, et al. Incidence of diabetes mellitus and evolution of glucose parameters in growth hormone-deficient subjects during growth hormone replacement therapy: a long-term observational study. Diabetes Care. 2012;35:57-62.
443. Clayton PE, Banerjee I, Murray PG, Renehan AG. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol. 2011;7:11-24.
444. Kleinberg DL, Wood TL, Furth PA, Lee AV. Growth hormone and insulin-like growth factor-I in the transition from normal mammary development to preneoplastic mammary lesions. Endocr Rev. 2009;30:51-74.
445. Baik M, Yu JH, Hennighausen L. Growth hormone-STAT5 regulation of growth, hepatocellular carcinoma, and liver metabolism. Ann N Y Acad Sci. 2011;1229:29-37.
446. Gallagher EJ, LeRoith D. Minireview: IGF, insulin, and cancer. Endocrinology. 2011;152:2546-2551.
447. Renehan AG, Brennan BM. Acromegaly, growth hormone and cancer risk. Best Pract Res Clin Endocrinol Metab. 2008;22:639-657.
448. Wilton P, Mattsson AF, Darendeliler F. Growth hormone treatment in children is not associated with an increase in the incidence of cancer: experience from KIGS (Pfizer International Growth Database). J Pediatr. 2010;157:265-270.
449. Møller N, Jørgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009;30:152-177.
450. Lombardi G, Tauchmanova L, Di Somma C, et al. Somatopause: dismetabolic and bone effects. J Endocrinol Invest. 2005;28:36-42.
451. Sherlock M, Ayuk J, Tomlinson JW, et al. Mortality in patients with pituitary disease. Endocr Rev. 2010;31:301-342.
452. Tomlinson JW, Holden N, Hills RK, et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet. 2001;357:425-431.
453. Stochholm K, Gravholt CH, Laursen T, et al. Mortality and GH deficiency: a nationwide study. Eur J Endocrinol. 2007;157:9-18.
454. Svensson J, Bengtsson BA, Rosén T, Odén A, Johannsson G. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab. 2004;89: 3306-3312.
455. van Heemst D, Beekman M, Mooijaart SP, et al. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell. 2005;4:79-85.
456. Holzenberger M, Dupont J, Ducos B, et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003;421:182-187.
457. Zhou Y, Xu BC, Maheshwari HG, et al. A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A. 1997;94:13215-13220.
458. Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, Bartke A. Long-lived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor I/insulin signaling and caloric restriction. Endocrinology. 2005;146:851-860.
459. Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS. Extending the lifespan of long-lived mice. Nature. 2001;414:412.
460. Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM. Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in longlived mutant mice. FASEB J. 2010;24:5073-5079.
461. Suh Y, Atzmon G, Cho MO, H et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008;105:3438-3442.
462. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3:70ra13.
463. Steuerman R, Shevah O, Laron Z. Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies. Eur J Endocrinol. 2011;164: 485-489.
464. Krzisnik C, Grguric S, Cvijovic K, Laron Z. Longevity of the hypopituitary patients from the island Krk: a follow-up study. Pediatr Endocrinol Rev. 2010;7:357-362.
465. Aguiar-Oliveira MH, Oliveira FT, Pereira RM, et al. Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J Clin Endocrinol Metab. 2010;95:714-721.
466. Jeay S, Sonenshein GE, Postel-Vinay MC, Kelly PA, Baixeras E. Growth hormone can act as a cytokine controlling survival and proliferation of immune cells: new insights into signaling pathways. Mol Cell Endocrinol. 2002;188: 1-7.
467. Hattori N. Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Horm IGF Res. 2009;19:187-197.
468. Besson A, Salemi S, Gallati S, et al. Reduced longevity in untreated patients with isolated growth hormone deficiency. J Clin Endocrinol Metab. 2003;88:3664-3667.
469. Carel JC, Ecosse E, Landier F, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. J Clin Endocrinol Metab. 2012;97:416-425.
470. Sävendahl L, Maes M, Albertsson-Wikland K, et al. Longterm mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: preliminary report of 3 countries participating in the EU SAGhE study. J Clin Endocrinol Metab. 2012;97: E213-E217.
471. Behringer RR, Mathews LS, Palmiter RD, Brinster RL. Dwarf mice produced by genetic ablation of growth hormone- expressing cells. Genes Dev. 1988;2:453-461.
472. Luque RM, Lin Q, Cordoba-Chacon J, et al. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One. 2011;6:e15767.
473. Bouchoucha YX, Charnay P, Gilardi-Hebenstreit P. Ablation of Egr2-positive cells in male mouse anterior pituitary leads to atypical isolated GH deficiency. Endocrinology. 2013;154:270-282.
474. Godfrey P, Rahal JO, Beamer WG, Copeland NG, Jenkins NA, Mayo KE. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet. 1993;4:227-232.
475. Li H, Zeitler PS, Valerius MT, Small K, Potter SS. Gsh-1, an orphan Hox gene, is required for normal pituitary development. EMBO J. 1996;15:714-724.
476. Wettschureck N, Moers A, Wallenwein B, Parlow AF, Maser-Gluth C, Offermanns S. Loss of Gq/11 family G proteins in the nervous system causes pituitary somatotroph hypoplasia and dwarfism in mice. Mol Cell Biol. 2005;25:1942-1948.
477. Roelfsema F, Biermasz NR, Veldman RG, et al. Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role fornon-GHRHinputs into the generation of GH pulses. J Clin Endocrinol Metab. 2001; 86:2459-2464.
478. Gautam D, Jeon J, Starost MF, et al. Neuronal M3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth. Proc Natl Acad Sci U S A. 2009;106:6398-6403.
479. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci U S A. 2004;101:4679-4684.
480. Yang H, Dixit VD, Patel K, et al. Reduction in hypophyseal growth hormone and prolactin expression due to deficiency in ghrelin receptor signaling is associated with Pit-1 suppression: relevance to the immune system. Brain Behav Immun. 2008;22:1138-1145.
481. Seurin D, Froment P, Bluet-Pajot MT, Epelbaum J, Monget P, Binoux M. Functional alteration of the somatotrophic axis in transgenic mice with liver-specific expression of human insulin-like growth factor binding protein-1. Pediatr Res. 2002;52:168-174.
482. Balthasar N, Mery PF, Magoulas CB, et al. Growth hormone- releasing hormone (GHRH) neurons in GHRH-enhanced green fluorescent protein transgenic mice: a ventral hypothalamic network. Endocrinology. 2003;144:2728-2740.
483. McElvaine AT, Korytko AI, Kilen SM, Cuttler L, Mayo KE. Pituitary-specific expression and Pit-1 regulation of the rat growth hormone-releasing hormone receptor gene. Mol Endocrinol. 2007;21:1969-1983.
484. Tsubahara M, Hayashi Y, Niijima S, et al. Isolated growth hormone deficiency in two siblings because of paternal mosaicism for a mutation in the GH1 gene. Clin Endocrinol (Oxf). 2012;76:420-424.
485. Gucev Z, Tasic V, Saranac L, et al. A novel GH1 mutation in a family with isolated growth hormone deficiency type II. Horm Res Paediatr. 2012;77:200-204.
486. Besson A, Salemi S, Deladoëy J, V et al. Short stature caused by a biologically inactive mutant growth hormone (GHC53S). J Clin Endocrinol Metab. 2005;90:2493-2499.
487. Fofanova OV, Evgrafov OV, Polyakov AV, Poltaraus AB, Peterkova VA, Dedov II. A novel IVS2-2AT splicing mutation in the GH-1 gene in familial isolated growth hormone deficiency type II in the spectrum of other splicing mutations in the Russian population. J Clin Endocrinol Metab. 2003;88:820-826.
488. Cogan JD, Ramel B, Lehto M, et al. A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency-a clinical research center study. J Clin Endocrinol Metab. 1995;80:3591-3595.
489. Binder G, Ranke MB. Screening for growth hormone (GH) gene splice-site mutations in sporadic cases with severe isolated GH deficiency using ectopic transcript analysis. J Clin Endocrinol Metab. 1995;80:1247-1252.
490. Hayashi Y, Yamamoto M, Ohmori S, Kamijo T, Ogawa M, Seo H. Inhibition of growth hormone (GH) secretion by a mutant GH-I gene product in neuroendocrine cells containing secretory granules: an implication for isolated GH deficiency inherited in an autosomal dominant manner. J Clin Endocrinol Metab. 1999;84:2134-2139.
491. Hayashi Y, Kamijo T, Yamamoto M, et al. A novel mutation at the donor splice site of intron 3 of the GH-I gene in a patient with isolated growth hormone deficiency. Growth Horm IGF Res. 1999;9:434-437.
492. Cogan JD, Phillips JA 3rd, Schenkman SS, Milner RD, Sakati N. Familial growth hormone deficiency: a model of dominant and recessive mutations affecting a monomeric protein. J Clin Endocrinol Metab. 1994;79:1261-1265.
493. Katsumata N, Matsuo S, Sato N, Tanaka T. A novel and de novo splice-donor site mutation in intron 3 of the GH-1 gene in a patient with isolated growth hormone deficiency. Growth Horm IGF Res. 2001;11:378-383.