© 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

© 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)

© 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

© Growth Hormone Research Society 4 14th - 17th April 1997 Growth Hormone Research Society Port Stephen’s Consensus Workshop Recommendations

© Growth Hormone Research Society 5 14th - 17th April 1997 A.DIAGNOSIS of ADULT GROWTH HORMONE DEFICIENCY

© 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).

© 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

© 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

© 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

© 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

© 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

© 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

© 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

© 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

© 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

© 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

© 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

© Growth Hormone Research Society 18 14th - 17th April 1997 B.TREATMENT of GROWTH HORMONE DEFICIENCY in ADULTS

© 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

© 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

© Growth Hormone Research Society 21 14th - 17th April 1997 Starting GH Replacement Start with a low dose – mg / day ( U / day) – subcutaneously at bedtime Monitor response carefully – clinically and biochemically Increase dose slowly – no more frequently than at monthly intervals

© Growth Hormone Research Society 22 14th - 17th April 1997 Target Dose of GH Women aged 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

© 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

© 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

© 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

© 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

© 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

© 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

© 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?

© 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

© 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

© 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