Transcript Growth Hormone Research Society

Growth Hormone Research Society
Port Stephen’s Consensus Workshop
Port Stephen. New South Wales
14th - 17th April 1997
Australia
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14th - 17th April 1997
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Participants
• Elizabeth Hernberg-Stahl (SE, Pharmacia / Upjohn)
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)
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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)
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
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Growth Hormone Research Society
Port Stephen’s Consensus Workshop
Recommendations
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A. DIAGNOSIS of ADULT
GROWTH HORMONE
DEFICIENCY
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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).
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Definition of Adult Growth Hormone
Deficiency
• Clinical features include
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alterations in body composition
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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
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Patients who should be tested for
Growth Hormone Deficiency
• Those with evidence of hypothalamic or pituitary
disease or cranial irradiation
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likelihood of deficiency increases with number of
pituitary hormone deficits
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approaches 100% if 3-4 pituitary hormone deficits exist
• Patients with childhood-onset growth hormone
deficiency
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all patients should be re-tested as adults before continuing
treatment with GH
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Biochemical Diagnosis of Adult
GH Deficiency (GHD)
• A. Dynamic tests of GH secretion
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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
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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
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in these people, alternative tests should be used
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Insulin Tolerance Test Definition of Severe GH Deficiency
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peak GH response > 5 mcg/l
• Severe GH deficiency
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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
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Alternative Provocative Tests in GHD
• For use in those in whom Insulin Tolerance Test
contraindicated
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Arginine
Glucagon
Arginine plus GHRH
Others in development
• Clonidine NOT recommended in adults as
ineffective
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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
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Biochemical Diagnosis of Adult
GH Deficiency (GHD)
• B. Biochemical Markers of GH Action
• Serum IGF-I
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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
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Biochemical Diagnosis of Adult
GH Deficiency (GHD)
• B. Biochemical Markers of GH Action
• Low serum IGF-I
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additional provocative test required to establish
diagnosis of GHD
• Serum IGF binding protein 3 or acid labile subunit (ALS) have not yet been shown to offer any
advantage over measurement of serum IGF-I
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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
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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
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B. TREATMENT of GROWTH
HORMONE DEFICIENCY in
ADULTS
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Treatment of Growth Hormone
Deficiency in Adults
• Patients who should be treated:
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all patients with documented severe growth
hormone deficiency
• Goal of therapy:
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to correct abnormalities associated with severe
growth hormone deficiency
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Dose Selection
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To maximise benefit and minimise side effects
In practice, optimum dose varies greatly
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sensitivity increase with age
men more sensitive than women
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Starting GH Replacement
• Start with a low dose
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0.15 - 0.30 mg / day (0.45 - 0.90 U / day)
subcutaneously at bedtime
• Monitor response carefully
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clinically and biochemically
• Increase dose slowly
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no more frequently than at monthly intervals
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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
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Monitoring Treatment Efficacy Initial Assessment
• Baseline
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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
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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
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malabsorption / undernutrition
hypothyroidism & IDDM
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Monitoring Treatment Efficacy Importance of IGF-1
• Why monitor serum IGF-1?
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important in order to avoid overdosing
aim to achieve and maintain IGF-1 values in normal
range
• Monitor every 1 to 2 months initially
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once stable, every 6 to 12 months sufficient
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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
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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
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Monitoring Treatment Efficacy Clinical & Safety Issues (iii)
• Good clinical practice requires regular imaging of
any residual pituitary tumour
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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
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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
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e.g...
- increased conversion of T4 to fT3
- increased metabolism of cortisol
- potentiation of testosterone?
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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
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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
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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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