The document discusses insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), their roles in growth and metabolism, and emerging clinical applications of measuring their levels in serum. It covers background biochemistry, modern assay methods and reference ranges, and applications in conditions like cancer, heart disease, and growth hormone disorders like acromegaly and growth hormone deficiency.

1. Circulating IGF-I and IGFBP-3: Evolving Clinical Applications A. Paul Durham Dir. Scientific Publications San José, 2005

4. Background: Some Basic Biochemistry and Physiology

5. Proinsulin, IGF-I and IGF-II Lowe. Sci & Med 1996;3(2):62.

6. IGF and Insulin Receptors Le Roith. NEJM 1997;336:633.

7. IGF-I, IGFBP-3 and ALS Production The liver accounts for most of the IGF-I in circulation. San José, 2005

8. Formation of Ternary Complex After: Ranke, Elmlinger. Horm Res 1997:48(S4):9. : Acid Labile Subunit

9. IGFBP Proteases — e.g. PSA After: Ranke, Elmlinger. Horm Res 1997:48(S4):9.

10. IGFBP: Cell Binding After: Ranke, Elmlinger. Horm Res 1997:48(S4):9.

11. Impact of Liver Transplantation Weber et al. Horm Res 2002;57:105. IGFBP-3 IGF-I Before After Before After

12. Bone — the Growth Plate Daci et al. Horm Res 2002;58(S1):44.

13. IGF-I and Bone Mineral Density (BMD) Muñoz-Torres et al. Clin Endo 2001;55:759. N = 154 ambulatory postmenopausal women

15. Response to Nutritional Intervention Clemmons et al. Am J Clin Nutr 1985;41:191. N = 6 Crohn’s disease, relapsing pancreatitis, postgastrectomy syndrome IGF-I Prealbumin Retinol-binding protein Transferrin

16. Modern Assay Methods for GH, IGF-I, IGFBP-3: Prospects for Harmonization?

24. Molar Sum of IGF-I and IGF-II Renehan et al. Clin Endo 2001;55:469. line of identity San José, 2005

25. Interpretive Frameworks: Age-related Reference Distributions

27. Growth Chart “ The use of DS specific growth charts is important for diagnosis of associated diseases, such as coeliac disease and hypothyroidism, which may further impair growth.” Myrelid et al. Arch Dis Child 2002;87:97. Height, Boys Down Syndrome Children San José, 2005

28. National Height Velocity Standards Hermanussen et al. Horm Res 2002;58:71. Differences partly due to data analysis!

29. Cyclical Prepubertal Growth Butler et al. Ann Hum Biol 1990;17:177.

30. IGF-I Children Elmlinger, 2002.

31. Elmlinger, 2002. IGFBP-3 Children

32. Elmlinger, 2002. Ratio Children

33. Elmlinger, 2002. IGF-I Adults

34. Elmlinger, 2002. IGFBP-3 Adults

35. Ratio Adults Elmlinger, 2002.

36. Elmlinger, 2002. IGF-I

37. Gender, Age, Pubertal Stage Löfqvist et al. JCEM 2001;86:5870. San José, 2005

38. Cancer, Cardiovascular and Other Emerging Applications

41. Colorectal Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005

42. Lung Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005

43. Breast Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005

44. Prostate Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005

45. Insulin Resistance Hypothesis Redrawn from: Barnard et al. Obesity Reviews 2002;3:303. San José, 2005

50. Growth Hormone Excess: Acromegaly and Gigantism

51. Robert Pershing Wadlow, 1918 – 1940 Alton’s Gentle Giant: 272 cm (8 ft 11 in) www.altonweb.com/history/wadlow

53. IGF-I / IGFBP-3 Ratio Marzullo et al. JCEM 2001;86:3001. Age (years)   Active   “ Cured”

54. Glucose Suppression Test (OGTT) Holl et al. Horm Res 1999;51:20.

57. Normal Adult — Pulsatile, Low Nadir Dimaraki et al. JCEM 2002;87:3537. Mean GH = 0.7 µg/L IGF-I = 113 µg/L

58. After: Dimaraki et al. JCEM 2002;87:3537.

59. Circadian Variation Juul et al. JCEM 1998;83:4408. San José, 2005

60. After: Oscarsson et al. Clin Endo 1997;46:63. 50 – 67y >1 year N = 5 28 – 52y 1 week N = 6

62. Growth Hormone Receptor Antagonist Drake et al. Trends Endocrinol Metab 2001;12:408. Pegvisomant (B2036 - PEG) for acromegaly

63. GHD, GHI: Growth Hormone Deficiency Growth Hormone Insensitivity

64. “ The Little Women of Loja” — NEJM 1990 Zvi Laron. JCEM 1999;84:4397. Arlan Rosenbloom, Jaime Guevara-Aguirre. JCEM 1994;79:695.

65. Rosenbloom, Guevara-Aguirre. JCEM 1994;79:695

70. Children with GHD Ranke, Schweizer, Elmlinger et al. Horm Res 2000;54:60. N = 187 Growth Hormone Deficiency

71. Children with TS, ISS, IUGR N = 205 Ranke, Schweizer, Elmlinger et al. Horm Res 2000;54:60. TS: Turner syndrome ISS: Idiopathic short stature IUGR: Intrauterine growth retardation Non-GHD . . .

72. Adult Growth Hormone Deficiency Hilding et al. JCEM 1999;84:2013. IGF-I

73. Managing and Optimizing rhGH and rhIGF-I Therapy

75. Prader-Willi Syndrome (PWS) Low GHD-induced IGF-I levels masked by obesity

76. The Rice Twins, Greg and John Los Angeles Times 2005 Nov 24: B10 (Photo: John Viles, Fox ). Spondyloepiphyseal dysplasia (SED), not achondroplasia. 173 cm (5 ft 8 in)* *Combined height

78. Adult GHD Murray et al. Clin Endo 2000;52:537. Pretreatment IGF-I versus GH dose required to normalize IGF-I

81. Ranke, Schweizer, Elmlinger et al. Horm Res 2001;55:115. Development of IGF Parameters, on a Group Basis San José, 2005

82. One-year Growth Study: IGF-I Gelander, Blum et al. Pediatr Res 1999;45:377. N = 65

83. One-year Growth Study: IGFBP-3 N = 65 Gelander, Blum et al. Pediatr Res 1999;45:377.

84. Predicting Growth Response Kriström, Löfqvist et al. JCEM 2001;86:4963. San José, 2005 Spontaneous GH Profile

85. Predicting Growth Response Kriström, Löfqvist et al. JCEM 2001;86:4963. Based, in part, on peak levels in spontaneous GH profiles of various durations.

86. Conclusions: GH, IGF-I and IGFBP-3 Assay Requirements

90. Special thanks to: Prof. Martin W. Elmlinger, University of Tübingen. Rubén Alvarado & Oswaldo von Breymann, DPC Medlab Centroamérica, San José. Jeff Sherin, Michelle Muse & Roma Levy, DPC, Los Angeles. Visit: www.DPCweb.com , Technical Documents Fb29d San José, 2005

91. Bullet Ref

92. Pseudo-Bullet Ref San José, 2005

93. Patch Ref San José, 2005

94. Graph – Small Knight Ref San José, 2005