Stephen6.ppt

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Stephen6.ppt

  1. 1. © Growth Hormone Research Society 1 14th - 17th April 1997 Growth Hormone Research Society Port Stephen’s Consensus Workshop Port Stephen. New South Wales 14th - 17th April 1997 Australia
  2. 2. © Growth Hormone Research Society 2 14th - 17th April 1997 Participants• Andrea Attanasio (UK, Lilly) • Kenneth Attie (USA, Genetech) • Rob Baxter (Au, Kollings Institute) • Bengt-Ake Bengtsson (SE, GRS) • Allan Black (TGA Australia) • Sandra Blethen (USA, Genentech) • Lena Carlsson (SE, GRS) • Felipe Casanueva (Santiago U) • John Chipman (USA, Lilly) • Jens Christiansen (DK, GRS) • David Clemmons (USA, GRS) • Ross Cuneo (Au Brisbane U) • Dirk De Rijdt (NED, Pharmacia / Upjohn) • Ezio Ghigo (I, Turin University) • Mark Hartman (USA, Virginia Uni) • Elizabeth Hernberg-Stahl (SE, Pharmacia / Upjohn) • Ray Hintz (USA, Stanford University) • Ken Ho (Au, Garvan Institute) • David Hoffman (Au, Garvan Institute) • Minoru Irie (J, Toho University) • Jens Otto Jorgensen (DK, Aarhus Uni) • Anne-Marie Kappelgaard (DK, Novo Nordisk) • Zvi Laron (Israel, GRS) • Saul Malozowski(USA, FDA) • David Russell-Jones (UK, UMDS) • Steve Shalet (UK, Christie Hospital) • Pierre Sizonenko (CH, GRS) • Peter Sonksen (UK, GRS) • Christian Strasburger (GE, Innerstadt Hosp) • K Takano (J, Tokyo Women’s Hospital) • Michael Thorner (USA, University of Virginia)
  3. 3. © Growth Hormone Research Society 3 14th - 17th April 1997 Port Stephen’s Consensus Workshop • Objective: To develop consensus guidelines for: A. The diagnosis and B. The management of adults with growth hormone deficiency
  4. 4. © Growth Hormone Research Society 4 14th - 17th April 1997 Growth Hormone Research Society Port Stephen’s Consensus Workshop Recommendations
  5. 5. © Growth Hormone Research Society 5 14th - 17th April 1997 A. DIAGNOSIS of ADULT GROWTH HORMONE DEFICIENCY
  6. 6. © Growth Hormone Research Society 6 14th - 17th April 1997 Definition of Adult Growth Hormone Deficiency • Severe GH deficiency should be defined biochemically within an appropriate clinical context • Partial GH deficiency exists but further research is needed to distinguish it from physiological causes of reduced GH secretion (e.g.aging).
  7. 7. © Growth Hormone Research Society 7 14th - 17th April 1997 Definition of Adult Growth Hormone Deficiency • Clinical features include – alterations in body composition • reduced lean body mass & bone mineral density • increase in fat mass, particularly abdominal – dry skin with reduced sweating – reduced muscle strength & exercise performance – impaired sense of well-being and other psychological complaints
  8. 8. © Growth Hormone Research Society 8 14th - 17th April 1997 Patients who should be tested for Growth Hormone Deficiency • Those with evidence of hypothalamic or pituitary disease or cranial irradiation – likelihood of deficiency increases with number of pituitary hormone deficits • approaches 100% if 3-4 pituitary hormone deficits exist • Patients with childhood-onset growth hormone deficiency – all patients should be re-tested as adults before continuing treatment with GH
  9. 9. © Growth Hormone Research Society 9 14th - 17th April 1997 Biochemical Diagnosis of Adult GH Deficiency (GHD) • A. Dynamic tests of GH secretion – patients should be on stable & adequate replacement of other hormonal deficits before testing – the insulin tolerance test is the diagnostic test of choice – providing adequate hypoglycaemia is achieved, this test distinguishes GH deficiency from the reduced GH secretion with ageing & obesity
  10. 10. © Growth Hormone Research Society 10 14th - 17th April 1997 The Insulin Tolerance Test in GHD • Should be performed in experienced endocrine units where the test is performed frequently • Contraindicated in those with ECG evidence of ischaemic heart disease and in those with seizure disorders – in these people, alternative tests should be used
  11. 11. © Growth Hormone Research Society 11 14th - 17th April 1997 Insulin Tolerance Test - Definition of Severe GH Deficiency • Normal – peak GH response > 5 mcg/l • Severe GH deficiency – peak GH response < 3 mcg/l Defined with GH assays employing polyclonal competitive RIA’s. Cut-off values may need adjusting according to assay used
  12. 12. © Growth Hormone Research Society 12 14th - 17th April 1997 Alternative Provocative Tests in GHD • For use in those in whom Insulin Tolerance Test contraindicated – Arginine – Glucagon – Arginine plus GHRH – Others in development • Clonidine NOT recommended in adults as ineffective
  13. 13. © Growth Hormone Research Society 13 14th - 17th April 1997 Number of Provocative Tests Needed to Establish Diagnosis of GHD • One test only in adults with hypothalamic or pituitary disease and one or more pituitary hormonal deficits • Two test in adults with isolated GHD • One test in reconfirmation of childhood-onset GHD
  14. 14. © Growth Hormone Research Society 14 14th - 17th April 1997 Biochemical Diagnosis of Adult GH Deficiency (GHD) • B. Biochemical Markers of GH Action • Serum IGF-I – only of value with age-adjusted normal ranges – a normal serum IGF-I does not exclude GHD – a serum IGF-I below the normal range is suggestive of GHD (in absence of confounding conditions e.g. malnutrition, liver disease, hypothyroidism) – of greater value in presence of 2 or more hormonal deficiencies
  15. 15. © Growth Hormone Research Society 15 14th - 17th April 1997 Biochemical Diagnosis of Adult GH Deficiency (GHD) • B. Biochemical Markers of GH Action • Low serum IGF-I – additional provocative test required to establish diagnosis of GHD • Serum IGF binding protein 3 or acid labile sub- unit (ALS) have not yet been shown to offer any advantage over measurement of serum IGF-I
  16. 16. © Growth Hormone Research Society 16 14th - 17th April 1997 Standardisation of Assays : GH • GH immunoassay results vary between different assay methods • Recommended cut-off values for ITT based on results obtained with polyclonal RIA’s calibrated against IRP 80/505 (1mg = 2.6 U) • GRS advocates future use of rhGH IRP 88/624 (1mg = 3.0 U) • Results should be expressed in mass units • Further comparative studies are necessary
  17. 17. © Growth Hormone Research Society 17 14th - 17th April 1997 Standardisation of Assays : IGF-I • The presence of binding proteins interfere with measurement of serum IGF-I • At present removal of IGF-I before immunoassay is essential • New IGF-I assays are under development which may not require this • The recommended reference standard is IRP 87/518 • Results should be expressed in mass units
  18. 18. © Growth Hormone Research Society 18 14th - 17th April 1997 B. TREATMENT of GROWTH HORMONE DEFICIENCY in ADULTS
  19. 19. © Growth Hormone Research Society 19 14th - 17th April 1997 Treatment of Growth Hormone Deficiency in Adults • Patients who should be treated: – all patients with documented severe growth hormone deficiency • Goal of therapy: – to correct abnormalities associated with severe growth hormone deficiency
  20. 20. © Growth Hormone Research Society 20 14th - 17th April 1997 Dose Selection • Objective: – To maximise benefit and minimise side effects In practice, optimum dose varies greatly – sensitivity increase with age – men more sensitive than women
  21. 21. © Growth Hormone Research Society 21 14th - 17th April 1997 Starting GH Replacement • Start with a low dose – 0.15 - 0.30 mg / day (0.45 - 0.90 U / day) – subcutaneously at bedtime • Monitor response carefully – clinically and biochemically • Increase dose slowly – no more frequently than at monthly intervals
  22. 22. © Growth Hormone Research Society 22 14th - 17th April 1997 Target Dose of GH • Women aged 30 - 50 secrete on average 0.2 mg / day and men 0.1 mg / day • Sensitivity varies considerably between patients and probably between the sexes • The daily dose rarely exceeds 1 mg (3 U) • Doses used now are lower than previously and are no longer based on body weight or surface area
  23. 23. © Growth Hormone Research Society 23 14th - 17th April 1997 Monitoring Treatment Efficacy - Initial Assessment • Baseline – History from patient and partner (including quality of life) – Examination (including weight & girth) & biochemical investigations (IGF-1, lipids, TFT) – If possible, body composition & bone density by Dexa – MRI (or CT) if past or present pituitary pathology
  24. 24. © Growth Hormone Research Society 24 14th - 17th April 1997 Monitoring Treatment Efficacy - Biochemical Markers • IGF-1 still the best biochemical marker of growth hormone action • IGF BP3 less useful, ALS promising but needs further validation NB IGF-1 may be misleading in certain conditions – malabsorption / undernutrition – hypothyroidism & IDDM
  25. 25. © Growth Hormone Research Society 25 14th - 17th April 1997 Monitoring Treatment Efficacy - Importance of IGF-1 • Why monitor serum IGF-1? – important in order to avoid overdosing – aim to achieve and maintain IGF-1 values in normal range • Monitor every 1 to 2 months initially – once stable, every 6 to 12 months sufficient
  26. 26. © Growth Hormone Research Society 26 14th - 17th April 1997 Monitoring Treatment Efficacy - Clinical & Safety Issues (i) • Adults with GHD are fluid depleted • GH replacement results in fluid retention (physiological but warn patient in advance) • With the lower doses currently used excess fluid retention, arthralgia or nerve entrapment are uncommon • If problems occur, they either clear spontaneously or respond to reduced dose
  27. 27. © Growth Hormone Research Society 27 14th - 17th April 1997 Monitoring Treatment Efficacy - Clinical & Safety Issues (ii) • GH may effect insulin sensitivity, therefore monitor glycaemia from time to time • Although colon cancer rates are increased in acromegaly there is no evidence that GH replacement is associated with increased risk of malignancy • Current recommendations on cancer prevention and early diagnosis for the general population should be maintained
  28. 28. © Growth Hormone Research Society 28 14th - 17th April 1997 Monitoring Treatment Efficacy - Clinical & Safety Issues (iii) • Good clinical practice requires regular imaging of any residual pituitary tumour – GH replacement does not impose any need to intensify this • A baseline MRI or CT scan is to be recommended before GH replacement is started
  29. 29. © Growth Hormone Research Society 29 14th - 17th April 1997 Monitoring Treatment Efficacy - Clinical & Safety Issues (iv) • GH effects the action and metabolism of many other substances including hormones and medications • Alterations in dose requirements should therefore be anticipated – e.g... - increased conversion of T4 to fT3 - increased metabolism of cortisol - potentiation of testosterone?
  30. 30. © Growth Hormone Research Society 30 14th - 17th April 1997 Contraindications • Active malignancy • Benign intra-cranial hypertension • Proliferative or pre-proliferative diabetic retinopathy NB pregnancy is NOT a contraindication to GH replacement but it becomes unnecessary in the second trimester due to sufficient placental GH production
  31. 31. © Growth Hormone Research Society 31 14th - 17th April 1997 Long Term Care • GH replacement is most likely a lifelong treatment • Dose requirements are likely to change • Dosage needs careful monitoring in relation to increasing age & perceived benefits • If benefits are no longer tangible, a trial of withdrawal of GH may be indicated
  32. 32. © Growth Hormone Research Society 32 14th - 17th April 1997 Roles and Responsibilities • Those receiving GH replacement should remain under supervision of an endocrinologist specialising in pituitary disorders • This can be undertaken in partnership with an Internist or General Practitioner • Initial visits may need to be monthly but once stabilised can usually be reduced to one or two times a year

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