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  1. 1. Diagnosis & Management of Growth Hormone Deficiency Consensus Workshop 17-21 October 1999 Growth Hormone Research Society
  2. 2. On behalf of Drs. Clayton, Cohen, Hintz, Laron, Sizonenko, and Tanaka, the GRS Council, and the attendees in the GRS Consensus meeting GRS Consensus Workshop
  3. 3. GRS Consensus Workshop Objectives <ul><li>To formulate consensus guidelines for the diagnosis and treatment of children and adolescents with severe and moderate GH deficiency </li></ul>
  4. 4. <ul><li>Pediatric & Adult Endocrinologists </li></ul><ul><li>Clinicians & Scientists </li></ul><ul><li>Representatives of LWPES, ESPE, JPES, APES, S-APES </li></ul><ul><li>Representatives from companies manufacturing rhGH </li></ul><ul><li>Participants from 13 countries </li></ul><ul><li>Totaling 44 </li></ul><ul><li>Pediatric & Adult Endocrinologists </li></ul><ul><li>Clinicians & Scientists </li></ul><ul><li>Representatives of LWPES, ESPE, JPES, APES, S-APES </li></ul><ul><li>Representatives from companies manufacturing rhGH </li></ul><ul><li>Participants from 13 countries </li></ul><ul><li>Totaling 44 </li></ul>Participants to the Consensus Workshop <ul><li>Pediatric & Adult Endocrinologists, Clinicians & Scientists </li></ul><ul><li>Representatives of LWPES, ESPE, JPES, APES, SAPES </li></ul><ul><li>Representatives from companies manufacturing rhGH </li></ul><ul><li>Participants from 13 countries </li></ul><ul><li>Totaling 44 </li></ul>
  5. 5. GRS consensus guidelines Diagnosis and treatment of childhood GHD <ul><li>Consensus document endorsed by </li></ul><ul><ul><li>GRS, Council of ESPE, LWPES, JSPE, SLEP, APEG </li></ul></ul><ul><li>Consensus document accepted by JCEM </li></ul><ul><li>Publication expected Q4 2000 </li></ul>
  6. 6. GRS Consensus Workshop Part One Diagnosis of Growth Hormone Deficiency
  7. 7. Auxological & Clinical Criteria (1) <ul><ul><li>Neonatal: Hypoglycemia, prolonged jaundice, microphallus, traumatic delivery </li></ul></ul><ul><ul><li>Cranial irradiation </li></ul></ul><ul><ul><li>Craniofacial midline abnormalities </li></ul></ul><ul><ul><li>Consanguinity &/or affected family member </li></ul></ul><ul><ul><li>Head trauma or CNS infection/infiltration </li></ul></ul>Short stature is defined as Height more than 2SD below the mean <ul><li>History & Physical Exam : </li></ul>
  8. 8. Auxological & Clinical Criteria (2) <ul><li>For immediate investigation : </li></ul><ul><li>Height > 3 SD below the mean </li></ul><ul><li>Height > 1.5 SD below mid-parental height </li></ul><ul><li>Height > 2 SD below mean & Height Velocity over 1 year > 1SD below mean for CA or Decrease in Ht SD > 0.5 over 1 year in those aged more than 2 years of age </li></ul>
  9. 9. Clinical & Auxological Criteria (3) <ul><li>In absence of short stature, Ht Velocity > 2 SD below the mean over 1 year or > 1.5 SD over 2 years </li></ul><ul><li>Signs of an intracranial lesion </li></ul><ul><li>Signs of multiple pituitary hormone deficiency </li></ul><ul><li>Neonatal symptoms & signs of GHD </li></ul><ul><li>For immediate investigation : </li></ul>
  10. 10. Clinical & Auxological Criteria (4) <ul><li>Use relevant population standards </li></ul><ul><li>Whenever possible update standards </li></ul><ul><li>Express as Standard Deviation Scores rather than percentiles </li></ul><ul><li>Need for longitudinal velocity standards </li></ul><ul><li>Interpretation of Growth data : </li></ul><ul><li>Biological markers, such as Body Composition, Bone Density & Bone Markers are NOT discriminatory for GHD </li></ul>
  11. 11. Evaluation for Genetic Disorders <ul><li>Early onset of growth failure </li></ul><ul><li>Possible family history & consanguinity </li></ul><ul><li>Height > 3 SD below the mean </li></ul><ul><li>Extremely low GH response to provocative tests, including GHRH, & very low IGF-I and IGFBP-3 </li></ul><ul><li>Tests (e.g. for Prop-1, Pit-1, HESX-1, etc...) becoming available  Bank DNA respecting ethical & legal considerations </li></ul>
  12. 12. Radiological Evaluation <ul><li>CNS imaging by MRI/CT </li></ul><ul><ul><li>Suspected intracranial lesion </li></ul></ul><ul><ul><li>Optic nerve hypoplasia/SOD </li></ul></ul><ul><ul><li>Other structural/developmental anomaly </li></ul></ul><ul><ul><li>Confirmed IGHD/MPHD </li></ul></ul><ul><li>Record </li></ul><ul><ul><li>Pituitary height &/or volume, stalk anatomy </li></ul></ul><ul><ul><li>Position of posterior pituitary bright signal </li></ul></ul><ul><li>Bone age on wrist XR </li></ul>
  13. 13. Biochemical Assessment of GHD (1) <ul><ul><li>GH reference preparation 22kD rhGH (88/625 3IU = 1mg) </li></ul></ul><ul><ul><li>Need WHO preparation for rhIGF-I </li></ul></ul><ul><ul><li>Clinician should be aware of methodology & performance in the diagnosis </li></ul></ul><ul><ul><li>Recommend assays measuring 22kD hGH with monoclonal antibodies </li></ul></ul><ul><ul><li>Immunofunctional GH assay requires further evaluation </li></ul></ul><ul><li>Assay considerations </li></ul>
  14. 14. Biochemical Assessment of GHD (2) <ul><li>Limit number of provocative agents (Arginine, Clonidine, Glucagon, Insulin & l-Dopa), but limited reference data are presently available for each test </li></ul><ul><li>Traditionally diagnosis of GHD made with peak GH < 10  g/L BUT this value needs revising for newer assays </li></ul><ul><li>Recognized that GH secretion is a continuum & that overlap exists in peak GH values between normal & GHD children </li></ul><ul><li>GH provocation tests </li></ul>
  15. 15. Biochemical Assessment of GHD (3) <ul><ul><li>Use reference ranges standardized for age & sex </li></ul></ul><ul><ul><li>Values > 2SD below the mean strongly suggest an abnormality in GH axis </li></ul></ul><ul><ul><li>BUT values within the normal range are seen in GHD </li></ul></ul><ul><ul><li>In the absence of a Gold Standard for GHD, integrate ALL available data </li></ul></ul><ul><li>IGF-I & IGFBP-3 values </li></ul>
  16. 16. Biochemical Assessment of GHD (4) <ul><ul><li>NO CONSENSUS has been yet established </li></ul></ul><ul><ul><li>But it is recognized that GHD is very difficult to diagnose in the peripubertal period when GH levels are frequently low </li></ul></ul><ul><li>Sex-Steroid Priming for GH Tests </li></ul>
  17. 17. Biochemical Assessment of GHD (5) <ul><ul><li>Urinary GH, serum IGF-II, IGFBP-2 & ALS may be useful in combination with other tests </li></ul></ul><ul><ul><li>Combination of Arginine & GHRH recognized as the most potent stimulus to GH </li></ul></ul><ul><ul><li>Evaluation of spontaneous GH secretion when GH & IGF data conflict, but Neurosecretory Dysfunction (without Cranial Radiotherapy) a rare diagnosis </li></ul></ul><ul><li>Other tests of the GH axis </li></ul>
  18. 18. Biochemical Assessment of GHD (6) <ul><ul><li>Nutritional status </li></ul></ul><ul><ul><li>Concomitant medication </li></ul></ul><ul><ul><li>Psychosocial conditions </li></ul></ul><ul><li>Confounding factors </li></ul>
  19. 19. The Process of Evaluation of the GH-IGF Axis <ul><li>Measure IGF-I/IGFBP-3 & carry out GH provocation tests </li></ul><ul><ul><li>For suspected IGHD, perform two GH tests </li></ul></ul><ul><ul><li>For established pathology, do one only </li></ul></ul><ul><ul><li>Check other pituitary function </li></ul></ul><ul><ul><li>Be alert to evolving hormone deficits </li></ul></ul><ul><ul><li>The combination of Normal GH but low IGF-I/IGFBP-3 is recognized - May need to consider GH treatment </li></ul></ul><ul><li>Once a decision to test is made </li></ul><ul><li>MRI (or CT) if GHD diagnosed </li></ul>
  20. 20. Conclusions Part One <ul><li>Diagnosis requires consideration of data from comprehensive assessment & investigation </li></ul><ul><li>Diagnosis of Severe GHD is usually straightforward </li></ul><ul><li>Well-defined clinical, auxological, biochemical & radiological abnormalities </li></ul><ul><li>Diagnosis of Moderate GHD can be associated with normal IGF axis & normal MRI </li></ul>
  21. 21. GRS Consensus Workshop Part Two Treatment of Growth Hormone Deficiency
  22. 22. Indications and Goals of GHD Rx <ul><li>Patients with proven GHD should be treated with rhGH as soon as possible after the diagnosis is made </li></ul><ul><li>Primary objectives of the therapy of GHD are: Normalization of height during childhood </li></ul><ul><li>Attainment of normal adult height </li></ul><ul><li>Normally growing patients with craniopharyngioma & GHD should be considered for therapy with GH for </li></ul><ul><li>Metabolic and body composition benefits </li></ul><ul><li>Enhancement of pubertal growth </li></ul>
  23. 23. Mode of Administration of GH <ul><li>Consideration should be given to dosing in  g/m 2 /day in patients with obesity </li></ul><ul><li>Daily subcutaneously in the evening </li></ul><ul><li>The dosage of GH should be expressed in  g (or mg)/kg/day </li></ul>
  24. 24. GH Dosing Under special circumstances, higher doses may be required . <ul><li>GH is routinely used in the range of 25-50  g/kg/day </li></ul>A dose-response relationship in terms of height velocity in the first two years of therapy has been clearly demonstrated within this range
  25. 25. The use of Prediction Models <ul><li>Prediction models are currently being investigated but need further evaluation </li></ul><ul><li>Prediction models of growth response might be useful for determination of the optimal individual starting dose </li></ul>
  26. 26. Evaluation of Response to GH <ul><li>The determination of the growth response to GH treatment is the single most important parameter in the monitoring of the child with GHD </li></ul><ul><li>Increase in height and change in height velocity are useful in clinical practice to assess the response to GH </li></ul><ul><li>For comparative purposes, data should be expressed as: the increase in (or  ) height SD/year </li></ul>
  27. 27. Monitoring GH-Rx <ul><li>For assurance of compliance and safety, monitoring serum IGF-I and IGFBP-3 levels is useful , although they do not always correlate well with the growth response . </li></ul><ul><li>IGF levels in GHD </li></ul>
  28. 28. Not indicated in Routine monitoring <ul><li>Serum leptin, </li></ul><ul><li>Bone markers </li></ul><ul><li>GH antibodies </li></ul><ul><li>Lipid profiles </li></ul><ul><li>Fasting insulin </li></ul><ul><li>Bone age </li></ul>Monitoring GH-Therapy
  29. 29. Summary for Monitoring GH Therapy <ul><li>Close follow-up with a pediatric endocrinologist every 3-6 months , in partnership with the pediatrician or primary care physician </li></ul><ul><li>Determination of growth response (change in height SDS ) </li></ul><ul><li>Monitoring serum IGF-I and IGFBP-3 levels </li></ul><ul><li>Screening for potential adverse effects </li></ul><ul><li>Evaluation of compliance </li></ul><ul><li>Consideration of dose adjustment based on IGF values, growth response, pubertal status, & comparison to growth prediction models </li></ul>
  30. 30. Factors affecting the response to GH <ul><ul><li>Every effort should be made to diagnose and treat children at the youngest possible age </li></ul></ul><ul><ul><li>It is very important to maximize height with GH therapy before the onset of puberty </li></ul></ul><ul><ul><li>If this is achieved, then modulation of the GH dose during puberty may not be necessary </li></ul></ul>
  31. 31. GH dose escalation Combined GH & GnRH-agonists Treatment of children entering puberty In the MPHD patient in whom puberty does not occur spontaneously, puberty should be initiated at the appropriate time after discussion with the patient Not fully tested and cannot be recommended at this time Role of gender Role of body composition Need further investigations
  32. 32. Management of MPHD <ul><li>In the patient with an initial diagnosis of isolated GHD, particularly those with an ectopic posterior pituitary or other developmental abnormalities, the clinician should be alert to the risk of the development of MPHD </li></ul><ul><li>Patients with suspected or proven multiple pituitary hormone deficiencies should be managed similarly to patients with isolated GHD </li></ul><ul><li>However, attention should be given to correct clinical recognition, treatment, and monitoring of additional hormonal deficiencies ( thyroxine, cortisol, sex steroids, and ADH ) </li></ul>
  33. 33. Safety Issues (1) <ul><li>Significant side effects of GH treatment in children are very rare </li></ul><ul><li>These include: benign intracranial hypertension, prepubertal gynecomastia, arthralgia, edema </li></ul><ul><li>Treatment with GH may unmask underlying hypothyroidism </li></ul>
  34. 34. Safety Issues (2) <ul><li>Careful history and physical examination are adequate to identify the presence of side-effects </li></ul><ul><li>Management of these side effects may include transient reduction of dosage or temporary discontinuation of GH </li></ul><ul><li>In the absence of other risk factors there is no evidence that GH recipients have increased risk of Leukemia, Brain tumor recurrence, Slipped capital femoral epiphysis, Diabetes </li></ul>
  35. 35. <ul><li>There is no evidence that GH replacement needs to be discontinued during intercurrent illness </li></ul><ul><li>Tumor survivors receiving GH should be followed in conjunction with an oncologist and a neurosurgeon when appropriate </li></ul>Safety Issues (3)
  36. 36. Re-testing (1) <ul><li>After attainment of final height, re-testing of the GH-IGF axis, using the adult GHD diagnostic criteria as defined by the Growth Hormone Research Society (GRS) consensus workshop on adult GHD in 1997 at Port Stephens should be undertaken by the pediatric endocrinologist using standard GH stimulation tests after an appropriate interval of 1 to 3 months off GH therapy </li></ul>
  37. 37. Re-testing (2) <ul><li>In places where an insulin tolerance test is mandatory for the patient to qualify for further GH therapy, this test should be performed </li></ul><ul><li>At the time of re-testing, other pituitary hormones and an IGF-I should also be measured </li></ul>
  38. 38. Transition to adult GHD care (1) <ul><ul><ul><li>The opportunity should be taken to assess body composition, bone mineral density, fasting lipids and insulin, before and after discontinuation of GH therapy </li></ul></ul></ul><ul><li>GH deficiency may or may not persist into adult life </li></ul><ul><ul><ul><li>GH has major metabolic actions, important for body composition and health in adults as in children </li></ul></ul></ul>
  39. 39. Transition to adult GHD care (2) <ul><li>When the diagnosis of adult GHD is established, continuation of GH therapy is recommended </li></ul><ul><li>Caution should be exercised when considering the decision of continuing GH therapy in conditions where there is a known risk of diabetes or malignancy </li></ul>
  40. 40. Conclusions regarding consensus (1) <ul><ul><ul><li>The approach to the diagnosis and treatment of GH deficiency in children is evolving </li></ul></ul></ul><ul><ul><ul><li>Clearly, many additional evidence-based clinical studies on the diagnosis and treatment of GHD will undoubtedly modify our approach </li></ul></ul></ul>
  41. 41. Conclusions regarding consensus (2) <ul><ul><ul><li>It will be the goal of the Growth Hormone Research Society, as well as the Pediatric Endocrine societies and Bodies, which have endorsed this document, to amend and revise this statement in coming years </li></ul></ul></ul>
  42. 42. GRS Consensus Workshop