Growth Hormone Therapy Place Holder

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Growth Hormone Therapy Place Holder

  1. 1. Growth Hormone Therapy: Bridging the Gap Between Children and Adults Peter J. Tebben MD Mayo Clinic, Rochester, MN June 3, 2007
  2. 2. Disclosures and discussion of off label use None Adult and Pediatric Endocrinology Height - 50%
  3. 3. Objectives <ul><li>Identify the clinical indications for GH therapy in children and adults. </li></ul><ul><li>Recognize which children are at risk for adult GHD and may benefit from GH therapy after achieving final adult height. </li></ul><ul><li>Describe the potential benefits of GH therapy in adolescents and young adults as well as understand the uncertainties regarding its use in this population. </li></ul>
  4. 4. Case <ul><li>6 3/12 y/o male </li></ul><ul><li>Sent for evaluation of short stature </li></ul><ul><li>Poor linear growth noted for the last year </li></ul><ul><li>Now has fallen below the 3 rd percentile </li></ul><ul><li>No family Hx of short stature </li></ul><ul><li>2 older healthy siblings </li></ul>
  5. 5. 105.3 cm 18.2 kg
  6. 6. Laboratory Data <ul><li>IGF-1 54 ng/mL (nl 88-474) </li></ul><ul><li>IGFBP-3 1.3 (nl 1.5-3.4) </li></ul><ul><li>TSH 2.6 mIU/L </li></ul><ul><li>FT4 1.2 ng/dL </li></ul><ul><li>Celiac Negative </li></ul>No other hormone deficiencies identified
  7. 7. Delayed bone age
  8. 8. Anterior pituitary is small in size. The infundibulum is thin. Normal location of posterior pituitary.
  9. 9. Indications for GH Therapy <ul><li>Growth hormone deficiency </li></ul><ul><li>Chronic renal insufficiency </li></ul><ul><li>Turner syndrome </li></ul><ul><li>Prader-Willi syndrome </li></ul><ul><li>Small for gestational age </li></ul><ul><li>Idiopathic short stature </li></ul>Children
  10. 10. Indications for GH Therapy <ul><li>Growth hormone deficiency </li></ul><ul><li>Chronic renal insufficiency </li></ul><ul><li>Turner syndrome </li></ul><ul><li>Prader-Willi syndrome </li></ul><ul><li>Small for gestational age </li></ul><ul><li>Idiopathic short stature </li></ul>Children
  11. 11. Indications for GH Therapy <ul><li>Growth hormone deficiency syndrome </li></ul><ul><li>HIV associated wasting </li></ul>Adults
  12. 12. Causes of GHD <ul><li>Idiopathic </li></ul><ul><li>Genetic </li></ul><ul><li>CNS Tumors </li></ul><ul><li>Radiation therapy </li></ul><ul><li>Trauma </li></ul><ul><li>Surgery </li></ul>
  13. 13. Making the Diagnosis <ul><li>Poor linear growth </li></ul><ul><li>Insulin-like Growth Factor 1 (IGF-1) </li></ul><ul><li>Insulin-like Growth Factor Binding Protein 3 (IGFBP-3) </li></ul><ul><li>Growth hormone stimulation testing </li></ul>Children
  14. 14. Growth Hormone Stimulation <ul><li>Insulin Tolerance Test (ITT) – “Gold Standard” </li></ul><ul><li>GHRH-Arginine </li></ul><ul><li>Arginine </li></ul><ul><li>L-DOPA </li></ul><ul><li>Clonidine </li></ul>
  15. 15. Growth Hormone Secretion Time of day Kerrigan JR, Rogol AD. Endocrine Reviews; 1992:13(2) 281-298
  16. 16. Insulin Tolerance Test 0 30 60 90 120 minutes Insulin (0.1 – 0.15 u/kg) Measure Growth Hormone and Glucose Children: Normal GH > 10 mcg/L Adults: Normal GH > 5 mcg/L
  17. 17. Growth Hormone Concentrations Kerrigan JR, Rogol AD. Endocrine Reviews; 1992:13(2) 281-298
  18. 18. <ul><li>Increased fat mass </li></ul><ul><li>Decreased lean mass </li></ul><ul><li>Lower Quality-of-Life </li></ul><ul><li>Abnormal lipids </li></ul><ul><li>Decreased bone density </li></ul>Signs/Symptoms of Adult GHD
  19. 19. Questions <ul><li>Do all children with GHD become adults with GHD? </li></ul><ul><li>Do fully grown adolescents/young adults benefit from GH therapy? </li></ul><ul><li>How should we treat patients in this transitional phase? </li></ul>
  20. 20. <ul><li>167 patients </li></ul><ul><li>GH treatment discontinued at least 6 weeks prior to retesting </li></ul><ul><li>Growth velocity < 1 cm per year </li></ul><ul><li>All other hormone deficiencies adequately treated for at least 6 months </li></ul>Attanasio AF. Clinical Endocrinology 2002 Does GHD Persist?
  21. 21. Attanasio AF. Clinical Endocrinology 2002 80% - GHD 20% - Normal Based on GH stimulation test or IGF-1
  22. 22. Does GHD Persist? Juul, A. JCEM 1997; 82(4) 1195-1201 <ul><li>108 patients </li></ul><ul><li>GH treatment discontinued at least 6 months prior to retesting </li></ul><ul><li>All other hormone deficiencies adequately treated for at least 6 months </li></ul>
  23. 23. 73% - GHD 27% - Normal Based on GH stimulation test Juul, A. JCEM 1997; 82(4) 1195-1201
  24. 24. 98% - GHD Juul, A. JCEM 1997; 82(4) 1195-1201 45% - Normal 55% - GHD Isolated GDH Multiple Pituitary Hormone Deficiencies
  25. 25. <ul><li>The prevalence of severe GHD in adults who received GH replacement in childhood. Nicolson et al. Clin Endo 1996. </li></ul><ul><li>Normal GH secretion in growth hormone insufficient children retested after completion of linear growth. Wacharasindhu et al . Clin Endo 1996. </li></ul><ul><li>Reevaluation of GH secretion in 69 adults diagnosed as GHD patients during childhood. Longbardi et al. JCEM 1996. </li></ul><ul><li>Growth Hormone Retesting and Auxological Data in 131 GH-Deficient Patients After Completion of Treatment. Tauber M et al. JCEM 1997 </li></ul>
  26. 26. GHD Does Persist <ul><li>However, not all children with GHD become adults with GHD. </li></ul><ul><li>Increased likelihood of persistent disease in patients with: </li></ul><ul><ul><li>Multiple hormone deficiencies </li></ul></ul><ul><ul><li>Genetic cause </li></ul></ul><ul><ul><li>Abnormal MRI findings </li></ul></ul><ul><ul><li>History of cranial XRT/Surgery </li></ul></ul>
  27. 27. Hypothalamus GHRH GH Pituitary Liver Bone IGF-1
  28. 28. Growth Hormone Research Society <ul><li>Retest after final adult height is achieved </li></ul><ul><li>Wait at least 1-3 months prior to retesting </li></ul><ul><li>Assess other pituitary hormones </li></ul><ul><li>Some may not require retesting: </li></ul><ul><ul><li>Multiple hormone deficiencies </li></ul></ul><ul><ul><li>Severe organic disease </li></ul></ul><ul><ul><li>Genetic defects </li></ul></ul>
  29. 29. AACE “ A stimulation test must be performed in most cases, unless the patient has persistent complete hypopituitarism.” “ Retesting must be performed prior to reinitiating GH treatment.”
  30. 30. Endocrine Society <ul><li>Measure IGF-1 after final adult height is attained </li></ul><ul><li>Discontinue GH therapy at least one month prior to measuring IGF-1 </li></ul><ul><li>Some may not require retesting with GH stim </li></ul><ul><ul><li>Multiple hormone deficiencies </li></ul></ul><ul><ul><li>Surgical or XRT induced GHD </li></ul></ul><ul><ul><li>Structural lesions of the hypothalamus or pituitary </li></ul></ul><ul><ul><li>Proven genetic disorder </li></ul></ul>
  31. 31. Questions <ul><li>Do all children with GHD become adults with GHD? </li></ul><ul><li>Do fully grown adolescents/young adults benefit from GH therapy? </li></ul><ul><li>How should we treat patients in this transitional phase? </li></ul>
  32. 32. Adult GHD Syndrome <ul><li>Increased fat mass </li></ul><ul><li>Decreased lean mass </li></ul><ul><li>Abnormal lipids </li></ul><ul><li>Decreased quality of life </li></ul><ul><li>Decreases exercise capacity </li></ul><ul><li>Decreased bone density </li></ul><ul><li>Increased cardiovascular morbidity </li></ul>
  33. 33. Continuation of GH replacement in GHD patients during transition from childhood to adulthood: A two year placebo-controlled trial. <ul><li>19 patients with childhood onset GHD </li></ul><ul><li>Retested for GHD after achievement of final adult height </li></ul><ul><li>Randomized, placebo controlled for first year </li></ul>Vahl et al. JCEM 2000; 85(5) 1874-1881
  34. 34. Study Design Childhood Year 1 Year 2 GH Treatment Retested 9 – GH 10 - Placebo All - GH Vahl et al. JCEM 2000; 85(5) 1874-1881
  35. 35. Measured Parameters <ul><li>Body composition </li></ul><ul><li>Muscle strength </li></ul><ul><li>Quality of life </li></ul><ul><li>IGF 1 </li></ul><ul><li>Lipids </li></ul><ul><li>Insulin, glucose, HbA1c </li></ul>Vahl et al. JCEM 2000; 85(5) 1874-1881
  36. 36. Results <ul><li>HDL increased at 24 months compared to baseline </li></ul><ul><li>No other changes in any parameter </li></ul>GH - GH Group Vahl et al. JCEM 2000; 85(5) 1874-1881
  37. 37. Results Placebo – GH Group Vahl et al. JCEM 2000; 85(5) 1874-1881
  38. 38. Results Placebo – GH Group <ul><li>Muscle Strength </li></ul><ul><ul><li>No changes in muscle strength or exercise capacity were observed </li></ul></ul>Vahl et al. JCEM 2000; 85(5) 1874-1881
  39. 39. Results Vahl et al. JCEM 2000; 85(5) 1874-1881 Placebo – GH Group <ul><li>Glucose, Insulin, and HbA1c </li></ul><ul><ul><li>Placebo: </li></ul></ul><ul><ul><ul><li>Decreased glucose (92 to 88 mg/dL) </li></ul></ul></ul><ul><ul><ul><li>No change in insulin or HbA1c </li></ul></ul></ul><ul><ul><li>GH: </li></ul></ul><ul><ul><ul><li>Increased glucose (88 to 95 mg/dL) </li></ul></ul></ul><ul><ul><ul><li>No change in insulin or HbA1c </li></ul></ul></ul>
  40. 40. Limited Efficacy of GH during the Transition of GHD Patients from Adolescence to Adulthood Mauras, N JCEM; 2005;90(7) 3946-3955 <ul><li>58 patients with childhood onset GHD </li></ul><ul><li>Retested with an ITT </li></ul><ul><li>20 mcg/kg/day or placebo </li></ul><ul><li>24 month trial </li></ul>
  41. 41. Limited Efficacy Mauras, N JCEM; 2005;90(7) 3946-3955 <ul><li>No difference at 24 months between GH treatment and Placebo in: </li></ul><ul><ul><li>Lean body mass </li></ul></ul><ul><ul><li>Fat mass </li></ul></ul><ul><ul><li>Bone mineral density </li></ul></ul><ul><ul><li>Exercise capacity </li></ul></ul><ul><ul><li>Grip strength </li></ul></ul><ul><ul><li>Lipids </li></ul></ul><ul><ul><li>Glucose </li></ul></ul>
  42. 42. Adult Growth Hormone (GH)-Deficient Patients Demonstrate Heterogeneity Between Childhood Onset and Adult Onset Before and During Human GH Treatment Attanasio et al. JCEM 1997; 82(1) 82-88 <ul><li>Compared childhood onset GHD to adult onset GHD </li></ul><ul><li>CO-GHD n=74 (off tx for at least 2 years) </li></ul><ul><li>AO-GHD n=99 </li></ul><ul><li>Randomized to placebo or GH for 6 months then all on GH </li></ul>
  43. 43. Baseline <ul><li>CO-GHD </li></ul><ul><ul><li>Younger (29 vs. 43 years) </li></ul></ul><ul><ul><li>Shorter (160 vs. 171 cm) </li></ul></ul><ul><ul><li>Lighter (63.8 vs. 84.9 kg) </li></ul></ul><ul><ul><li>Lower IGF1 and IGFBP3 </li></ul></ul><ul><ul><li>Higher HDL (36.5 vs. 31.9 mg/dL) </li></ul></ul><ul><ul><li>Better QOL scores for energy and mobility </li></ul></ul>Attanasio et al. JCEM 1997; 82(1) 82-88
  44. 44. Results <ul><ul><li>No change in QOL measures </li></ul></ul><ul><ul><li>No change in TC, HDL, or LDL </li></ul></ul><ul><ul><li>Fat mass decreased </li></ul></ul><ul><ul><li>Fewer side effects with treatment compared to AO-GHD </li></ul></ul>CO-GHD Placebo vs. GH treatment Attanasio et al. JCEM 1997; 82(1) 82-88
  45. 45. Results <ul><ul><li>Improved QOL </li></ul></ul><ul><ul><ul><li>Social isolation </li></ul></ul></ul><ul><ul><ul><li>Physical mobility </li></ul></ul></ul><ul><ul><li>Improved HDL </li></ul></ul><ul><ul><li>Lower fat mass </li></ul></ul><ul><ul><li>More side effects compared to CO-GHD </li></ul></ul>AO-GHD Placebo vs. GH treatment Attanasio et al. JCEM 1997; 82(1) 82-88
  46. 46. Lower Fat Mass Underwood, LE et al. JCEM 2003; 88(11) 5273-5280
  47. 47. Increased Lean Mass Underwood, LE et al. JCEM 2003; 88(11) 5273-5280
  48. 48. Treat Everybody Don’t Treat Anybody Treatment decisions and goals need to be individualized
  49. 49. Back to the patient Ht: 169 cm
  50. 50. Integrated Transitional Care <ul><li>Who? </li></ul><ul><li>What? </li></ul><ul><li>When? </li></ul><ul><li>Where? </li></ul><ul><li>Why? </li></ul>
  51. 51. Who? <ul><li>Children with GHD </li></ul><ul><li>Especially those with: </li></ul><ul><ul><li>MPHD </li></ul></ul><ul><ul><li>Abnormal MRI </li></ul></ul><ul><ul><li>Radiation Treatment </li></ul></ul>
  52. 52. What? <ul><li>Measure IGF-1 </li></ul><ul><li>Assess other pituitary hormones </li></ul><ul><li>GH stimulation testing in a selected population (IGHD) </li></ul>
  53. 53. What? <ul><li>Lipids </li></ul><ul><li>Glucose </li></ul><ul><li>Body composition (DEXA) </li></ul><ul><li>Bone density </li></ul><ul><li>Quality of life assessment </li></ul>Assess for signs/symptoms of adult GHD
  54. 54. When? <ul><li>When GH therapy is initiated </li></ul><ul><li>After height goals are met </li></ul><ul><li>Retest 1 – 3 months after GH therapy has been discontinued </li></ul>
  55. 55. Where? <ul><li>Initial discussion must be done by the Pediatric care team </li></ul><ul><li>Retesting can be performed by Pediatric or Adults Endocrine supervision </li></ul><ul><li>Ongoing care by Adult Endocrinology </li></ul>
  56. 56. Why? <ul><li>Why is or is not treatment being recommended </li></ul>
  57. 57. Potential Benefits <ul><li>Increased lean mass </li></ul><ul><li>Decreased fat mass </li></ul><ul><li>Improved bone density </li></ul><ul><li>Improved exercise capacity </li></ul><ul><li>Improved strength </li></ul><ul><li>Improved lipids </li></ul>However, studies have shown mixed results
  58. 58. Potential Harm <ul><li>Increased blood glucose </li></ul><ul><li>Insulin resistance </li></ul><ul><li>Edema </li></ul><ul><li>Arthralgias </li></ul><ul><li>Increased intracranial pressure </li></ul><ul><li>Malignancy </li></ul>
  59. 59. Drug Dose 1 Year of Tx Bones QOL Cholesterol Body composition $7520 $792 0.4 mg/d Somatropin 20 mg/d 70 mg/wk 40 mg/d Unlimited RAC Membership Simvastatin Fluoxetine Alendronate $280 $92 $972 $2136 vs. $7520 per year Other Considerations
  60. 60. Practical Approach <ul><li>Stop GH when height goals have been achieved </li></ul><ul><li>Measure IGF-1 in 1 to 3 months </li></ul><ul><li>Discuss with pt potential risks and benefits of continued GH therapy </li></ul><ul><li>If GH status is not clear – perform a GH stimulation test </li></ul>
  61. 61. Practical Approach <ul><li>Define treatment goals prior to initiating therapy </li></ul><ul><li>Reassess goals after 12 months </li></ul><ul><li>Consider stopping treatment if pre-defined goals are not met </li></ul>
  62. 62. Keys to Successful Transition <ul><li>Individualized treatment plan </li></ul><ul><ul><li>Complex patients </li></ul></ul><ul><li>Team approach </li></ul><ul><ul><li>Physicians </li></ul></ul><ul><ul><li>Nurses </li></ul></ul><ul><ul><li>Psychologists </li></ul></ul><ul><ul><li>Social workers </li></ul></ul><ul><li>Integrated care between Pediatric and Adults health care providers </li></ul>

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