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Circulating IGF-I and IGFBP-3: Evolving Clinical Applications A. Paul Durham Dir. Scientific Publications San José, 2005
A “Laboratory Medicine” Perspective <ul><li>IGF-I and IGFBP-3 </li></ul><ul><ul><li>Insulin-like Growth Factor I (Somatome...
Agenda <ul><li>Background (Biochemistry & Physiology) </li></ul><ul><li>Modern Assay Methods, Limitations </li></ul><ul><l...
Background: Some Basic Biochemistry and Physiology
Proinsulin, IGF-I and IGF-II Lowe. Sci & Med 1996;3(2):62.
IGF and Insulin Receptors Le Roith. NEJM 1997;336:633.
IGF-I, IGFBP-3 and ALS Production The liver accounts for most of the IGF-I in circulation. San José, 2005
Formation of Ternary Complex After: Ranke, Elmlinger. Horm Res 1997:48(S4):9. : Acid Labile Subunit
IGFBP Proteases — e.g. PSA After: Ranke, Elmlinger. Horm Res 1997:48(S4):9.
IGFBP: Cell Binding After: Ranke, Elmlinger. Horm Res 1997:48(S4):9.
Impact of Liver Transplantation Weber et al. Horm Res 2002;57:105. IGFBP-3 IGF-I Before After Before After
Bone — the Growth Plate Daci et al. Horm Res 2002;58(S1):44.
IGF-I and Bone Mineral Density (BMD) Muñoz-Torres et al. Clin Endo 2001;55:759. N = 154 ambulatory postmenopausal women
Nutritional Status <ul><li>Competing control systems </li></ul><ul><ul><li>Growth hormone (GH) secretion </li></ul></ul><u...
Response to Nutritional Intervention Clemmons et al. Am J Clin Nutr 1985;41:191. N = 6   Crohn’s disease,  relapsing pancr...
Modern Assay Methods for GH, IGF-I, IGFBP-3: Prospects for Harmonization?
Growth Hormone Assays <ul><li>Specificity — monoclonal/polyclonal IMAs </li></ul><ul><ul><li>Lower values than RIAs (1st g...
Growth Hormone Assays <ul><li>Standardize to WHO 98/574 (2nd IS) </li></ul><ul><ul><li>Recombinant human 22 kDa growth hor...
(Total) IGF-I Assays <ul><li>Displace IGF-I from IGFBPs </li></ul><ul><li>Prevent IGFBPs & fragments from interfering </li...
Free IGF-I Assays <ul><li>So far, no compelling need: in some contexts, IGF-I / IGFBP-3 ratio serves as a proxy </li></ul>...
Derived Values: IGF-I / IGFBP-3 Ratio <ul><li>An index of — circulating! — free IGF-I </li></ul><ul><ul><li>Based on two r...
IGFBP-3 Assays <ul><li>Molecular weight? </li></ul><ul><ul><li>Circulates in two glycosylated forms, approximately 42 and ...
Molecular Weights, Conversion Factors <ul><li>Analyte Mass to Molar Units </li></ul><ul><li>IGF-I , 7.649 kDa µg/L  x  0.1...
Molar Sum of IGF-I and IGF-II Renehan et al. Clin Endo 2001;55:469. line of  identity San José, 2005
Interpretive Frameworks: Age-related Reference Distributions
Reference Ranges — Assay-Specific <ul><li>…  because perfect agreement is elusive! </li></ul><ul><li>GRS Consensus (1999):...
Growth Chart “ The use of DS specific growth charts is important for diagnosis of associated diseases, such as coeliac dis...
National Height Velocity Standards Hermanussen et al. Horm Res 2002;58:71. Differences partly due to data analysis!
Cyclical Prepubertal Growth Butler et al. Ann Hum Biol 1990;17:177.
IGF-I Children Elmlinger, 2002.
Elmlinger, 2002. IGFBP-3 Children
Elmlinger, 2002. Ratio Children
Elmlinger, 2002. IGF-I  Adults
Elmlinger, 2002. IGFBP-3 Adults
Ratio Adults  Elmlinger, 2002.
Elmlinger, 2002. IGF-I
Gender, Age, Pubertal Stage Löfqvist et al. JCEM 2001;86:5870. San José, 2005
Cancer, Cardiovascular and Other Emerging Applications
Prostate Cancer (PCa) Detection ? <ul><li>149 men with PCa from cohort study PSA: 1.75–13.5 µg/L </li></ul><ul><li>Combini...
Risk Factor for Epithelial Cancers ? <ul><li>High IGF-I, low IGFBP-3 </li></ul><ul><li>High ratio suggests increased free ...
Colorectal Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
Lung Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
Breast Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
Prostate Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
Insulin Resistance Hypothesis Redrawn from: Barnard et al. Obesity Reviews 2002;3:303. San José, 2005
Risk for Ischemic Heart Disease (IHD) <ul><li>DAN-MONICA </li></ul><ul><ul><li>Nested case-control study </li></ul></ul><u...
Risk for Congestive Heart Failure (CHF) <ul><li>Framingham Heart Study </li></ul><ul><ul><li>Prospective, community-based ...
Cardiovascular Risk <ul><li>Low IGF-I is bad — and high IGFBP-3 </li></ul><ul><ul><li>Opposite to the situation for cancer...
Some IGF-I Research Topics <ul><li>Metabolic syndrome (“Syndrome X”) </li></ul><ul><ul><li>insulin resistance </li></ul></...
Growth Hormone Excess: Acromegaly and Gigantism
Robert Pershing Wadlow, 1918 – 1940 Alton’s Gentle Giant: 272 cm (8 ft 11   in) www.altonweb.com/history/wadlow
Acromegaly – Mortality <ul><li>Associated with uncontrolled GH secretion </li></ul><ul><ul><li>Cardiovascular disease: 60%...
IGF-I / IGFBP-3 Ratio Marzullo et al. JCEM 2001;86:3001. Age (years)     Active   “ Cured”
Glucose Suppression Test (OGTT) Holl et al. Horm Res 1999;51:20.
Acromegaly — Major Treatment Goals <ul><li>Reduce or eliminate tumor mass </li></ul><ul><li>Suppress GH to < 1.0 µg/L duri...
Acromegaly — GH / IGF-I Discrepancies <ul><li>16 patients, newly diagnosed acromegaly </li></ul><ul><li>GH < 1.0 µg/L in O...
Normal Adult — Pulsatile, Low Nadir Dimaraki et al. JCEM 2002;87:3537. Mean GH = 0.7 µg/L IGF-I = 113 µg/L
After: Dimaraki et al. JCEM 2002;87:3537.
Circadian Variation Juul et al. JCEM 1998;83:4408. San José, 2005
After: Oscarsson et al. Clin Endo 1997;46:63. 50 – 67y >1 year N = 5 28 – 52y 1 week N = 6
Lessons from Acromegaly <ul><li>IGF-I elevations suggest GH hypersecretion </li></ul><ul><ul><li>May be more sensitive to ...
Growth Hormone Receptor Antagonist Drake et al. Trends Endocrinol Metab 2001;12:408. Pegvisomant (B2036 - PEG) for acromeg...
GHD, GHI: Growth Hormone Deficiency Growth Hormone Insensitivity
“ The Little Women of Loja” — NEJM 1990 Zvi Laron. JCEM 1999;84:4397. Arlan Rosenbloom, Jaime Guevara-Aguirre. JCEM 1994;7...
Rosenbloom, Guevara-Aguirre. JCEM 1994;79:695
“IGF Deficiency” <ul><li>GH Deficiency </li></ul><ul><ul><li>Isolated GHD (IGHD) </li></ul></ul><ul><ul><li>Multiple Pitui...
GH Deficiency — rhGH Therapy <ul><li>Children </li></ul><ul><ul><li>Promote linear growth (increased stature) . . . </li><...
Institute rhGH Therapy in a Child . . . <ul><li>. . . classically, only after demonstrating GHD </li></ul><ul><li>Cannot r...
Growth Hormone Stimulation Tests <ul><li>Not “physiological” </li></ul><ul><li>Poor reproducibility </li></ul><ul><li>Too ...
Children with GHD Ranke, Schweizer, Elmlinger et al. Horm Res 2000;54:60. N = 187 Growth Hormone  Deficiency
Children with TS, ISS, IUGR N = 205 Ranke, Schweizer, Elmlinger et al. Horm Res 2000;54:60. TS: Turner syndrome ISS: Idiop...
Adult Growth Hormone Deficiency Hilding et al. JCEM 1999;84:2013. IGF-I
Managing and Optimizing rhGH and rhIGF-I Therapy
Some Approved Indications for rhGH <ul><li>Growth hormone deficiency (GHD) —  Children </li></ul><ul><li>Prader-Willi synd...
Prader-Willi Syndrome (PWS) Low GHD-induced IGF-I levels masked by obesity
The Rice Twins, Greg and John Los Angeles Times 2005 Nov 24: B10 (Photo: John Viles,  Fox ). Spondyloepiphyseal dysplasia ...
Individualizing rhGH Dose in an Adult <ul><li>Start with low dose, titrate upwards </li></ul><ul><li>Aim for IGF-I  within...
Adult GHD Murray et al. Clin Endo 2000;52:537. Pretreatment IGF-I   versus GH dose required to normalize IGF-I
Monitoring rhGH Therapy in a Child <ul><li>Measure IGF-I and IGFBP-3 routinely “for assurance of compliance and safety” </...
Optimizing rhGH Therapy in a Child  <ul><li>Adjust dose to maximize intended benefit </li></ul><ul><ul><li>Even if this en...
Ranke, Schweizer, Elmlinger et al. Horm Res 2001;55:115. Development of IGF Parameters, on a Group Basis San José, 2005
One-year Growth Study: IGF-I Gelander, Blum et al. Pediatr Res 1999;45:377. N = 65
One-year Growth Study: IGFBP-3 N = 65 Gelander, Blum et al. Pediatr Res 1999;45:377.
Predicting Growth Response Kriström, Löfqvist et al. JCEM 2001;86:4963. San José, 2005 Spontaneous GH Profile
Predicting Growth Response Kriström, Löfqvist et al. JCEM 2001;86:4963. Based, in part, on peak levels in spontaneous GH p...
Conclusions: GH, IGF-I and IGFBP-3 Assay Requirements
GH Assays: Current Norm <ul><li>Immunometric, with “2nd generation” LoD </li></ul><ul><ul><li>Capable of quantifying even ...
GH Assays: Reference Values <ul><li>Single measurements </li></ul><ul><ul><li>Not for routine use — of  very  limited valu...
IGF-I, IGFBP-3, Ratio: Reference Values <ul><li>Rigorous, detailed, assay-specific </li></ul><ul><li>Calculated as a funct...
Special thanks to: Prof. Martin W. Elmlinger, University of Tübingen. Rubén Alvarado & Oswaldo von Breymann, DPC Medlab Ce...
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Pseudo-Bullet Ref San José, 2005
Patch Ref San José, 2005
Graph – Small Knight  Ref San José, 2005
xx Arial 20, *not* Bold Resize, *no* Word Wrap Light Turquoise (5.5): RGB=204, 255, 255 Transparency 0 Box: Black 2.25 Arr...
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  1. 1. Circulating IGF-I and IGFBP-3: Evolving Clinical Applications A. Paul Durham Dir. Scientific Publications San José, 2005
  2. 2. A “Laboratory Medicine” Perspective <ul><li>IGF-I and IGFBP-3 </li></ul><ul><ul><li>Insulin-like Growth Factor I (Somatomedin-C) </li></ul></ul><ul><ul><li>Insulin-like Growth Factor Binding Protein 3 </li></ul></ul><ul><ul><li>Also: IGF-I / IGFBP-3 ratio </li></ul></ul><ul><li>Measurements in serum or plasma </li></ul><ul><ul><li>Systemic (circulation) versus local (tissue) </li></ul></ul><ul><li>Clinical interpretation </li></ul><ul><ul><li>Maximize patient-specific information </li></ul></ul><ul><li>Focus on growth-related applications </li></ul>
  3. 3. Agenda <ul><li>Background (Biochemistry & Physiology) </li></ul><ul><li>Modern Assay Methods, Limitations </li></ul><ul><li>Interpretive Frameworks (Reference Ranges) </li></ul><ul><li>Emerging Applications (Cancer, Cardiac, ...) </li></ul><ul><li>Acromegaly (Growth Hormone Excess) </li></ul><ul><li>Growth Hormone Deficiency (GHD) </li></ul><ul><li>Optimizing rhGH Therapy </li></ul><ul><li>Conclusions: Assay Requirements </li></ul>
  4. 4. Background: Some Basic Biochemistry and Physiology
  5. 5. Proinsulin, IGF-I and IGF-II Lowe. Sci & Med 1996;3(2):62.
  6. 6. IGF and Insulin Receptors Le Roith. NEJM 1997;336:633.
  7. 7. IGF-I, IGFBP-3 and ALS Production The liver accounts for most of the IGF-I in circulation. San José, 2005
  8. 8. Formation of Ternary Complex After: Ranke, Elmlinger. Horm Res 1997:48(S4):9. : Acid Labile Subunit
  9. 9. IGFBP Proteases — e.g. PSA After: Ranke, Elmlinger. Horm Res 1997:48(S4):9.
  10. 10. IGFBP: Cell Binding After: Ranke, Elmlinger. Horm Res 1997:48(S4):9.
  11. 11. Impact of Liver Transplantation Weber et al. Horm Res 2002;57:105. IGFBP-3 IGF-I Before After Before After
  12. 12. Bone — the Growth Plate Daci et al. Horm Res 2002;58(S1):44.
  13. 13. IGF-I and Bone Mineral Density (BMD) Muñoz-Torres et al. Clin Endo 2001;55:759. N = 154 ambulatory postmenopausal women
  14. 14. Nutritional Status <ul><li>Competing control systems </li></ul><ul><ul><li>Growth hormone (GH) secretion </li></ul></ul><ul><ul><li>Nutritional status . . . and inflammation </li></ul></ul><ul><li>Malnutrition: lower IGF-I </li></ul><ul><ul><li>Anorexia nervosa, cachexia (wasting), chronic renal failure </li></ul></ul><ul><li>Obesity: tendency towards higher IGF-I </li></ul><ul><li>IGF-I levels can serve as an index of nutritional status </li></ul>
  15. 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. 16. Modern Assay Methods for GH, IGF-I, IGFBP-3: Prospects for Harmonization?
  17. 17. Growth Hormone Assays <ul><li>Specificity — monoclonal/polyclonal IMAs </li></ul><ul><ul><li>Lower values than RIAs (1st generation assays) </li></ul></ul><ul><li>Low-end precision — LoD (detection limit) </li></ul><ul><ul><li>2nd generation (“ultrasensitive”) assays </li></ul></ul><ul><li>Standardization — more than one WHO prep </li></ul><ul><ul><li>Conversion (& confusion) between µg/L, mIU/L </li></ul></ul><ul><li>Age- and sex-related variation </li></ul><ul><li>Stimulation & suppression testing </li></ul><ul><li>Spontaneous profiles </li></ul>
  18. 18. Growth Hormone Assays <ul><li>Standardize to WHO 98/574 (2nd IS) </li></ul><ul><ul><li>Recombinant human 22 kDa growth hormone </li></ul></ul><ul><ul><li>Same as 88/624 — supercedes 80/505 </li></ul></ul><ul><li>Relative abundance of isoforms in circulation* </li></ul><ul><ul><li>22 kDa (1–192): 43 % </li></ul></ul><ul><ul><li>20 kDa (missing 32–46): 8 % </li></ul></ul><ul><ul><li>Homodimers: 29 % ... </li></ul></ul><ul><ul><li>Balance may shift somewhat in acromegaly </li></ul></ul><ul><ul><li>Absolute specificity for 22 kDa form may miss bioactive GH peaks** </li></ul></ul>**Wood, Ann Clin Biochem 2001;38:471. *De Palo. Clin Chim Acta 2005 (Epub).
  19. 19. (Total) IGF-I Assays <ul><li>Displace IGF-I from IGFBPs </li></ul><ul><li>Prevent IGFBPs & fragments from interfering </li></ul><ul><ul><li>Acid chromatography / extraction / pretreatment </li></ul></ul><ul><ul><li>Chemical blocking, with IGF-II </li></ul></ul><ul><ul><li>Immunometric assay, mono/poly or mono/mono </li></ul></ul><ul><li>Standardize to WHO 87/518 </li></ul><ul><ul><li>Need for rhIGF-I based WHO preparation </li></ul></ul>Chestnut, Quarmby. J Immunol Methods 2002;259:11.
  20. 20. Free IGF-I Assays <ul><li>So far, no compelling need: in some contexts, IGF-I / IGFBP-3 ratio serves as a proxy </li></ul><ul><li>Would require: reference ranges, validation </li></ul><ul><li>Discrepancies: direct versus ultrafiltration </li></ul><ul><ul><li>Chronic renal failure, anorexia nervosa </li></ul></ul><ul><li>“ Are we hunting a ghost ? ” * </li></ul><ul><ul><li>Free hormone model too simplistic here . . . . </li></ul></ul>Frystyk et al. GHIR 2001;11:117. *Bang et al. Horm Res 2001;55(S2):84.
  21. 21. Derived Values: IGF-I / IGFBP-3 Ratio <ul><li>An index of — circulating! — free IGF-I </li></ul><ul><ul><li>Based on two readily validated assays </li></ul></ul><ul><ul><li>Analogous to: T4/TBG, Testosterone/SHBG </li></ul></ul><ul><ul><li>Not applicable in all contexts </li></ul></ul><ul><li>Are processes in bone, breast, prostate, etc. reflected in the blood stream? </li></ul><ul><ul><li>The systemic -versus- local theme </li></ul></ul><ul><li>Clinical interest of extreme ratios </li></ul><ul><ul><li>Possible discordance between IGF-I, IGFBP-3 </li></ul></ul><ul><ul><li>Risk assessment, e.g. for cancer </li></ul></ul>
  22. 22. IGFBP-3 Assays <ul><li>Molecular weight? </li></ul><ul><ul><li>Circulates in two glycosylated forms, approximately 42 and 44 kDa* </li></ul></ul><ul><ul><li>Deglycosylated: 28.75 kDa </li></ul></ul><ul><li>Choice for standardization affects conversion factor and numerical values (but not pattern) for molar ratio </li></ul><ul><li>Standardize to WHO 93/560 </li></ul><ul><ul><li>deglycosylated form </li></ul></ul>*Elmlinger. Pers comm, 2002.
  23. 23. Molecular Weights, Conversion Factors <ul><li>Analyte Mass to Molar Units </li></ul><ul><li>IGF-I , 7.649 kDa µg/L x 0.1307  nmol/L </li></ul><ul><li>IGFBP-3 , 43 kDa mg/L x 23.26  nmol/L glycosylated Molar ratio µg/mg x 0.5619  %M/M </li></ul><ul><li>IGFBP-3 , 28.75 kDa mg/L x 34.78  nmol/L deglycosylated (WHO 93/560) Molar ratio µg/mg x 0.3759  %M/M </li></ul>
  24. 24. Molar Sum of IGF-I and IGF-II Renehan et al. Clin Endo 2001;55:469. line of identity San José, 2005
  25. 25. Interpretive Frameworks: Age-related Reference Distributions
  26. 26. Reference Ranges — Assay-Specific <ul><li>… because perfect agreement is elusive! </li></ul><ul><li>GRS Consensus (1999): SD Scores (SDS) as function of age and sex are essential for IGF-I and IGFBP-3 assays </li></ul><ul><li>“ Growth standards” for laboratory results </li></ul><ul><ul><li>Age, sex, pubertal status (Tanner Stage), etc. </li></ul></ul><ul><ul><li>Full characterization of distributions </li></ul></ul><ul><ul><li>Not just a pair of “reference limits” </li></ul></ul><ul><li>Culture shock for clinical chemists! </li></ul>www.GhResearchSociety.org/bin/Consensus.asp
  27. 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. 28. National Height Velocity Standards Hermanussen et al. Horm Res 2002;58:71. Differences partly due to data analysis!
  29. 29. Cyclical Prepubertal Growth Butler et al. Ann Hum Biol 1990;17:177.
  30. 30. IGF-I Children Elmlinger, 2002.
  31. 31. Elmlinger, 2002. IGFBP-3 Children
  32. 32. Elmlinger, 2002. Ratio Children
  33. 33. Elmlinger, 2002. IGF-I Adults
  34. 34. Elmlinger, 2002. IGFBP-3 Adults
  35. 35. Ratio Adults Elmlinger, 2002.
  36. 36. Elmlinger, 2002. IGF-I
  37. 37. Gender, Age, Pubertal Stage Löfqvist et al. JCEM 2001;86:5870. San José, 2005
  38. 38. Cancer, Cardiovascular and Other Emerging Applications
  39. 39. Prostate Cancer (PCa) Detection ? <ul><li>149 men with PCa from cohort study PSA: 1.75–13.5 µg/L </li></ul><ul><li>Combining IGF-I and/or IGFBP-3 with (total) PSA and/or free PSA </li></ul><ul><li>did not enhance sensitivity or specificity for predicting future occurrence of PCa </li></ul><ul><li>Distinguish: </li></ul><ul><ul><li>Usefulness ( added value) in screening/ diagnosis </li></ul></ul><ul><ul><li>Usefulness in risk assessment/management </li></ul></ul>Stattin, Stenman et al. JCEM 2001;86:5745.
  40. 40. Risk Factor for Epithelial Cancers ? <ul><li>High IGF-I, low IGFBP-3 </li></ul><ul><li>High ratio suggests increased free IGF-I </li></ul><ul><ul><li>enhanced growth for tumor cells </li></ul></ul><ul><ul><li>reduced apoptosis (programmed cell death) </li></ul></ul><ul><ul><li>reduced protection from IGFBP-3 </li></ul></ul><ul><li>Questions: </li></ul><ul><ul><li>Same pattern for all (epithelial) cancers? </li></ul></ul><ul><ul><li>Do systemic (circulating) levels/relationships reflect local (tissue) situation? </li></ul></ul>
  41. 41. Colorectal Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
  42. 42. Lung Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
  43. 43. Breast Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
  44. 44. Prostate Cancer Risk Pollak et al. Nature 2004;4:505 (Table 1). San José, 2005
  45. 45. Insulin Resistance Hypothesis Redrawn from: Barnard et al. Obesity Reviews 2002;3:303. San José, 2005
  46. 46. Risk for Ischemic Heart Disease (IHD) <ul><li>DAN-MONICA </li></ul><ul><ul><li>Nested case-control study </li></ul></ul><ul><li>Low IGF-I & high IGFBP-3 associated with increased risk of developing IHD in 15 years </li></ul><ul><ul><li>Relative Risk = 4.05 (95% CI: 1.5–11.2) </li></ul></ul>Juul et al, Circulation 2002;106:939.
  47. 47. Risk for Congestive Heart Failure (CHF) <ul><li>Framingham Heart Study </li></ul><ul><ul><li>Prospective, community-based investigation </li></ul></ul><ul><li>Elderly people without previous myocardial infarction </li></ul><ul><ul><li>N = 717, mean age: 78.4y, 67% women </li></ul></ul><ul><li>Conclusion: Circulating IGF-I inversely related to CHF risk </li></ul>Vasan et al. Ann Intern Med 2003;139:642.
  48. 48. Cardiovascular Risk <ul><li>Low IGF-I is bad — and high IGFBP-3 </li></ul><ul><ul><li>Opposite to the situation for cancer </li></ul></ul><ul><li>But high IGF-I is also bad for the heart </li></ul><ul><ul><li>As shown by experience with acromegaly </li></ul></ul><ul><li>A “U-shaped” risk profile </li></ul><ul><ul><li>Similar to T4, TSH where both high and low values for these hormones are undesirable </li></ul></ul>
  49. 49. Some IGF-I Research Topics <ul><li>Metabolic syndrome (“Syndrome X”) </li></ul><ul><ul><li>insulin resistance </li></ul></ul><ul><li>Relation to inflammation markers </li></ul><ul><ul><li>e.g., hsCRP, IL-6 </li></ul></ul><ul><li>Diabetes — the insulin connection </li></ul><ul><li>Diabetic sequelae — e.g., retinopathy </li></ul><ul><li>Osteoporosis and frailty </li></ul><ul><li>Polycystic ovary syndrome (PCOS) and assisted reproduction </li></ul>
  50. 50. Growth Hormone Excess: Acromegaly and Gigantism
  51. 51. Robert Pershing Wadlow, 1918 – 1940 Alton’s Gentle Giant: 272 cm (8 ft 11 in) www.altonweb.com/history/wadlow
  52. 52. Acromegaly – Mortality <ul><li>Associated with uncontrolled GH secretion </li></ul><ul><ul><li>Cardiovascular disease: 60% </li></ul></ul><ul><ul><li>Respiratory disease: 25% </li></ul></ul><ul><ul><li>Malignancy: 15% </li></ul></ul>Melmed. JCEM 2001;86:2929.
  53. 53. IGF-I / IGFBP-3 Ratio Marzullo et al. JCEM 2001;86:3001. Age (years)   Active   “ Cured”
  54. 54. Glucose Suppression Test (OGTT) Holl et al. Horm Res 1999;51:20.
  55. 55. Acromegaly — Major Treatment Goals <ul><li>Reduce or eliminate tumor mass </li></ul><ul><li>Suppress GH to < 1.0 µg/L during OGTT </li></ul><ul><li>Normalize IGF-I levels </li></ul><ul><ul><li>i.e., target age-related reference range </li></ul></ul><ul><li>Deal with cardiovascular, pulmonary, and metabolic derangements </li></ul>Giustina et al. JCEM 2000;85:526. Melmed. JCEM 2002;87:4054.
  56. 56. Acromegaly — GH / IGF-I Discrepancies <ul><li>16 patients, newly diagnosed acromegaly </li></ul><ul><li>GH < 1.0 µg/L in OGTT, or: mean 24h integrated GH < 2.5 µg/L </li></ul><ul><li>Elevated IGF-I </li></ul><ul><li>Proposed revisions: </li></ul><ul><ul><li>Lower cutoff, ca. 0.3 µg/L, in OGTT </li></ul></ul><ul><ul><li>Nadir, not mean, of spontaneous levels </li></ul></ul>Dimaraki et al. JCEM 2002;87:3537. Trainer. JCEM 2002;87:3534.
  57. 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. 58. After: Dimaraki et al. JCEM 2002;87:3537.
  59. 59. Circadian Variation Juul et al. JCEM 1998;83:4408. San José, 2005
  60. 60. After: Oscarsson et al. Clin Endo 1997;46:63. 50 – 67y >1 year N = 5 28 – 52y 1 week N = 6
  61. 61. Lessons from Acromegaly <ul><li>IGF-I elevations suggest GH hypersecretion </li></ul><ul><ul><li>May be more sensitive to milder forms than GH suppression tests </li></ul></ul><ul><li>IGF-I and IGFBP-3 usually concur </li></ul><ul><li>Judging acromegaly treatments </li></ul><ul><ul><li>Surgery, radiation, medications </li></ul></ul><ul><ul><li>How completely & how rapidly does it restore IGF-I to age-related normal levels? </li></ul></ul>
  62. 62. Growth Hormone Receptor Antagonist Drake et al. Trends Endocrinol Metab 2001;12:408. Pegvisomant (B2036 - PEG) for acromegaly
  63. 63. GHD, GHI: Growth Hormone Deficiency Growth Hormone Insensitivity
  64. 64. “ The Little Women of Loja” — NEJM 1990 Zvi Laron. JCEM 1999;84:4397. Arlan Rosenbloom, Jaime Guevara-Aguirre. JCEM 1994;79:695.
  65. 65. Rosenbloom, Guevara-Aguirre. JCEM 1994;79:695
  66. 66. “IGF Deficiency” <ul><li>GH Deficiency </li></ul><ul><ul><li>Isolated GHD (IGHD) </li></ul></ul><ul><ul><li>Multiple Pituitary Hormone Deficiency (MPHD) </li></ul></ul><ul><li>GH Insensitivity: </li></ul><ul><ul><li>Primary: GH Receptor Defects (GHRD) </li></ul></ul><ul><ul><ul><li>Laron syndrome, and many variants </li></ul></ul></ul><ul><ul><li>Secondary: malnutrition, liver disease, chronic disease, etc. </li></ul></ul><ul><li>IGF-I Defects or Resistance </li></ul>After: Rosenfeld.
  67. 67. GH Deficiency — rhGH Therapy <ul><li>Children </li></ul><ul><ul><li>Promote linear growth (increased stature) . . . </li></ul></ul><ul><ul><li>but also normal bone maturation </li></ul></ul><ul><li>Adults </li></ul><ul><ul><li>Improve body composition, etc. </li></ul></ul><ul><li>GHD represents a spectrum! </li></ul><ul><li>rhIGF-I for GHRD (Laron syndrome, etc.) </li></ul><ul><ul><li>Alone — or in combination with IGFBP-3 to avoid high circulating free IGF-I levels </li></ul></ul>
  68. 68. Institute rhGH Therapy in a Child . . . <ul><li>. . . classically, only after demonstrating GHD </li></ul><ul><li>Cannot rely solely on IGF-I, IGFBP-3 </li></ul><ul><ul><li>Normal IGF-I & IGFBP-3: compatible with “moderate” or “partial” GHD </li></ul></ul><ul><ul><li>Low IGF-I & IGFBP-3: may be due to causes other than GHD! </li></ul></ul><ul><li>Biochemical assessment typically includes </li></ul><ul><ul><li>IGF-I & IGFBP-3 determinations </li></ul></ul><ul><ul><li>Two GH stimulation tests — one for MPHD (multiple pituitary hormone deficiencies) </li></ul></ul>Sizonenko et al. GHIR 2001;11:137. GRS Consensus: JCEM 2000;85:3990.
  69. 69. Growth Hormone Stimulation Tests <ul><li>Not “physiological” </li></ul><ul><li>Poor reproducibility </li></ul><ul><li>Too many combinations, formats, GH assays </li></ul><ul><li>Expensive, invasive, sometimes hazardous </li></ul><ul><li>Cutoffs in general use are “arbitrary” </li></ul><ul><ul><li>Not based on sex- & age-related studies of specific protocols and GH methodologies </li></ul></ul><ul><ul><li>No hope for rigorous pediatric ref. range studies </li></ul></ul><ul><li>Why not study spontaneous GH secretion instead of resorting to stimulation testing? </li></ul>
  70. 70. Children with GHD Ranke, Schweizer, Elmlinger et al. Horm Res 2000;54:60. N = 187 Growth Hormone Deficiency
  71. 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. 72. Adult Growth Hormone Deficiency Hilding et al. JCEM 1999;84:2013. IGF-I
  73. 73. Managing and Optimizing rhGH and rhIGF-I Therapy
  74. 74. Some Approved Indications for rhGH <ul><li>Growth hormone deficiency (GHD) — Children </li></ul><ul><li>Prader-Willi syndrome (PWS) </li></ul><ul><li>Turner syndrome (TS)* </li></ul><ul><li>Small for Gestational Age (SGA)* </li></ul><ul><li>Chronic renal failure (CRF)* </li></ul><ul><li>Idiopathic short staure (ISS): </li></ul><ul><ul><li>short, healthy, PAH < 5'3 (M), < 4'11 (F)* </li></ul></ul><ul><li>Growth hormone deficiency (GHD) — Adults </li></ul><ul><li>Cachexia due to HIV, severe burns, trauma </li></ul>www.medscape.com/druginfo — somatropin * GHD not assumed PAH: average parental height
  75. 75. Prader-Willi Syndrome (PWS) Low GHD-induced IGF-I levels masked by obesity
  76. 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
  77. 77. Individualizing rhGH Dose in an Adult <ul><li>Start with low dose, titrate upwards </li></ul><ul><li>Aim for IGF-I within normal limits for age to minimize side effects and long-term risks </li></ul><ul><ul><li>“ within” — preferably well within . . . </li></ul></ul><ul><ul><li>Final dose may depend on sex, age, steroids </li></ul></ul><ul><li>This is a “replacement” strategy </li></ul><ul><ul><li>IGF-I as a surrogate for GH action </li></ul></ul>GRS Consensus: JCEM 1998;83:379.
  78. 78. Adult GHD Murray et al. Clin Endo 2000;52:537. Pretreatment IGF-I versus GH dose required to normalize IGF-I
  79. 79. Monitoring rhGH Therapy in a Child <ul><li>Measure IGF-I and IGFBP-3 routinely “for assurance of compliance and safety” </li></ul><ul><ul><li>Not for dose adjustment </li></ul></ul><ul><li>Dose based on weight: mg per kg per day </li></ul><ul><ul><li>Go by surface area to accommodate obesity </li></ul></ul><ul><ul><li>Don’t consider sex, age, pubertal status </li></ul></ul><ul><li>“Herd dosing”* </li></ul>Tanaka et al. GHIR 2002;12:323. GRS Consensus: JCEM 2000;85:3990. *Cohen et al. JCEM 2002;87:90.
  80. 80. Optimizing rhGH Therapy in a Child <ul><li>Adjust dose to maximize intended benefit </li></ul><ul><ul><li>Even if this entails supra-normal IGF-I levels </li></ul></ul><ul><ul><li>Side effects less common in children </li></ul></ul><ul><li>“ Prediction Models” </li></ul><ul><ul><li>Regression relationships: </li></ul></ul><ul><ul><li>Growth response — as a function of: </li></ul></ul><ul><ul><ul><li>Auxological variables (height, etc.) and </li></ul></ul></ul><ul><ul><ul><li>Peak GH, in spontaneous GH secretion profile </li></ul></ul></ul>Kriström, Löfqvist et al. JCEM 2001;86:4963.
  81. 81. Ranke, Schweizer, Elmlinger et al. Horm Res 2001;55:115. Development of IGF Parameters, on a Group Basis San José, 2005
  82. 82. One-year Growth Study: IGF-I Gelander, Blum et al. Pediatr Res 1999;45:377. N = 65
  83. 83. One-year Growth Study: IGFBP-3 N = 65 Gelander, Blum et al. Pediatr Res 1999;45:377.
  84. 84. Predicting Growth Response Kriström, Löfqvist et al. JCEM 2001;86:4963. San José, 2005 Spontaneous GH Profile
  85. 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. 86. Conclusions: GH, IGF-I and IGFBP-3 Assay Requirements
  87. 87. GH Assays: Current Norm <ul><li>Immunometric, with “2nd generation” LoD </li></ul><ul><ul><li>Capable of quantifying even lowest (nadir) levels </li></ul></ul><ul><li>Standardized to 98/574, but broad specificity: </li></ul><ul><ul><li>Reactive with 20 kDa as well as 22 kDa isoforms </li></ul></ul><ul><li>Automation desirable </li></ul><ul><ul><li>Applications generate series of measurements </li></ul></ul><ul><ul><ul><li>Stimulation & suppression testing </li></ul></ul></ul><ul><ul><ul><li>Spontaneous profiles </li></ul></ul></ul>
  88. 88. GH Assays: Reference Values <ul><li>Single measurements </li></ul><ul><ul><li>Not for routine use — of very limited value! </li></ul></ul><ul><li>Stimulation & suppression tests </li></ul><ul><ul><li>Not for routine use — interpretable? </li></ul></ul><ul><ul><li>Pediatric normal values difficult to establish </li></ul></ul><ul><ul><ul><li>Internal Review Board (IRB) restrictions </li></ul></ul></ul><ul><li>Spontaneous profiles </li></ul><ul><ul><li>Not for routine use — underutilized? </li></ul></ul><ul><ul><li>Peak values and distribution </li></ul></ul>
  89. 89. IGF-I, IGFBP-3, Ratio: Reference Values <ul><li>Rigorous, detailed, assay-specific </li></ul><ul><li>Calculated as a function of </li></ul><ul><ul><li>Age, sex (where appropriate), Tanner stage </li></ul></ul><ul><li>Distributions, not just intervals </li></ul><ul><ul><li>Similar to growth charts for height, enabling translation of concentrations into centiles & Standard Deviation Scores (SDS) </li></ul></ul><ul><li>National and regional studies desirable </li></ul><ul><ul><li>Nutritional and other demographical variations </li></ul></ul>
  90. 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. 91. Bullet Ref
  92. 92. Pseudo-Bullet Ref San José, 2005
  93. 93. Patch Ref San José, 2005
  94. 94. Graph – Small Knight Ref San José, 2005
  95. 95. xx Arial 20, *not* Bold Resize, *no* Word Wrap Light Turquoise (5.5): RGB=204, 255, 255 Transparency 0 Box: Black 2.25 Arrow: Black 2.5 xROMx Same, but: Bold White No Line xx xx Title32B Title32B <ul><li>BulletOne29 </li></ul>Reference xBOLDx xx <ul><li>BulletOne29 </li></ul>xTNR29x xTNR29x xTNR31x San José, 2005

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