If this is achieved, then modulation of the GH dose durin

1
Growth Hormone Research Society
Diagnosis Management of Growth Hormone
Deficiency Consensus Workshop 17-21 October 1999
2
GRS Consensus Workshop
On behalf of Drs. Clayton, Cohen, Hintz, Laron,
Sizonenko, and Tanaka, the GRS Council, and the
attendees in the GRS Consensus meeting
3
GRS Consensus WorkshopObjectives

• To formulate consensus guidelines for the
  diagnosis and treatment of children and
  adolescents with severe and moderate GH deficiency

4
Participants to the Consensus Workshop

• Pediatric Adult Endocrinologists
• Clinicians Scientists
• Representatives of LWPES, ESPE, JPES, APES,
  S-APES
• Representatives from companies manufacturing rhGH
• Participants from 13 countries
• Totaling 44

• Pediatric Adult Endocrinologists
• Clinicians Scientists
• Representatives of LWPES, ESPE, JPES, APES,
  S-APES
• Representatives from companies manufacturing rhGH
• Participants from 13 countries
• Totaling 44

• Pediatric Adult Endocrinologists, Clinicians
  Scientists
• Representatives of LWPES, ESPE, JPES, APES, SAPES
• Representatives from companies manufacturing rhGH
• Participants from 13 countries
• Totaling 44

5
GRS consensus guidelinesDiagnosis and treatment
of childhood GHD

• Consensus document endorsed by
• GRS, Council of ESPE, LWPES, JSPE, SLEP, APEG
• Consensus document accepted by JCEM
• Publication expected Q4 2000

6
GRS Consensus Workshop
Part One Diagnosis of Growth Hormone Deficiency
7
Auxological Clinical Criteria (1)
Short stature is defined as Height more than 2SD
below the mean

• History Physical Exam

• Neonatal Hypoglycemia, prolonged jaundice,
  microphallus, traumatic delivery
• Cranial irradiation
• Craniofacial midline abnormalities
• Consanguinity /or affected family member
• Head trauma or CNS infection/infiltration

8
Auxological Clinical Criteria (2)

• For immediate investigation

• Height gt 3 SD below the mean
• Height gt 1.5 SD below mid-parental height
• Height gt 2 SD below mean Height Velocity over 1
  year gt 1SD below mean for CAor Decrease in Ht SD
  gt 0.5 over 1 yearin those aged more than 2 years
  of age

9
Clinical Auxological Criteria (3)

• For immediate investigation

• In absence of short stature, Ht Velocitygt 2 SD
  below the mean over 1 year or gt 1.5 SD over 2
  years
• Signs of an intracranial lesion
• Signs of multiple pituitary hormone deficiency
• Neonatal symptoms signs of GHD

10
Clinical Auxological Criteria (4)

• Interpretation of Growth data

• Use relevant population standards
• Whenever possible update standards
• Express as Standard Deviation Scores rather than
  percentiles
• Need for longitudinal velocity standards

• Biological markers, such as Body
  Composition,Bone Density Bone Markers are NOT
  discriminatory for GHD

11
Evaluation for Genetic Disorders

• Early onset of growth failure
• Possible family history consanguinity
• Height gt 3 SD below the mean
• Extremely low GH response to provocative tests,
  including GHRH, very low IGF-I and IGFBP-3
• Tests (e.g. for Prop-1, Pit-1, HESX-1, etc...)
  becoming available ? Bank DNA respecting ethical
  legal considerations

12
Radiological Evaluation

• Bone age on wrist XR

• CNS imaging by MRI/CT
• Suspected intracranial lesion
• Optic nerve hypoplasia/SOD
• Other structural/developmental anomaly
• Confirmed IGHD/MPHD
• Record
• Pituitary height /or volume, stalk anatomy
• Position of posterior pituitary bright signal

13
Biochemical Assessment of GHD (1)

• Assay considerations

• GH reference preparation 22kD rhGH (88/625 3IU
  1mg)
• Need WHO preparation for rhIGF-I
• Clinician should be aware of methodology
  performance in the diagnosis
• Recommend assays measuring 22kD hGH with
  monoclonal antibodies
• Immunofunctional GH assay requires further
  evaluation

14
Biochemical Assessment of GHD (2)

• GH provocation tests

• Limit number of provocative agents (Arginine,
  Clonidine, Glucagon, Insulin l-Dopa), but
  limited reference data are presently available
  for each test
• Traditionally diagnosis of GHD made with peak
  GHlt 10?g/L BUT this value needs revising for
  newer assays
• Recognized that GH secretion is a continuum
  that overlap exists in peak GH values between
  normal GHD children

15
Biochemical Assessment of GHD (3)

• IGF-I IGFBP-3 values

• Use reference ranges standardized for age sex
• Values gt 2SD below the mean strongly suggest an
  abnormality in GH axis
• BUT values within the normal range are seen in
  GHD
• In the absence of a Gold Standard for GHD,
  integrate ALL available data

16
Biochemical Assessment of GHD (4)

• Sex-Steroid Priming for GH Tests

• NO CONSENSUS has been yet established
• But it is recognized that GHD is very difficult
  to diagnose in the peripubertal period when GH
  levels are frequently low

17
Biochemical Assessment of GHD (5)

• Other tests of the GH axis

• Urinary GH, serum IGF-II, IGFBP-2 ALS may be
  useful in combination with other tests
• Combination of Arginine GHRH recognized as the
  most potent stimulus to GH
• Evaluation of spontaneous GH secretion when GH
  IGF data conflict, but Neurosecretory Dysfunction
  (without Cranial Radiotherapy) a rare diagnosis

18
Biochemical Assessment of GHD (6)

• Confounding factors

• Nutritional status
• Concomitant medication
• Psychosocial conditions

19
The Process of Evaluation of the GH-IGF Axis

• Once a decision to test is made

• Measure IGF-I/IGFBP-3 carry out GH provocation
  tests
• For suspected IGHD, perform two GH tests
• For established pathology, do one only
• Check other pituitary function
• Be alert to evolving hormone deficits
• The combination of Normal GH but low
  IGF-I/IGFBP-3 is recognized - May need to
  consider GH treatment

• MRI (or CT) if GHD diagnosed

20
Conclusions Part One

• Diagnosis of Severe GHD is usually
  straightforward
• Well-defined clinical, auxological, biochemical
  radiological abnormalities

• Diagnosis of Moderate GHD can be associated with
  normal IGF axis normal MRI

• Diagnosis requires consideration of data from
  comprehensive assessment investigation

21
GRS Consensus Workshop
Part Two Treatment of Growth Hormone Deficiency
22
Indications and Goals of GHD Rx

• Patients with proven GHD should be treated with
  rhGHas soon as possible after the diagnosis is
  made
• Primary objectives of the therapy of GHD
  areNormalization of height during childhood
• Attainment of normal adult height
• Normally growing patients with craniopharyngioma
  GHD should be considered for therapy with GH for
  
• Metabolic and body composition benefits
• Enhancement of pubertal growth

23
Mode of Administration of GH

• Daily subcutaneously in the evening

• The dosage of GH should be expressed in ?g (or
  mg)/kg/day

• Consideration should be given to dosing in
  ?g/m2/day in patients with obesity

24
GH Dosing

• GH is routinely used in the range of 25-50
  ?g/kg/day

A dose-response relationship in terms of height
velocity in the first two years of therapy has
been clearly demonstrated within this range
Under special circumstances, higher doses may be
required.
25
The use of Prediction Models

• Prediction models of growth response might be
  useful for determination of the optimal
  individual starting dose

• Prediction models are currently being
  investigated but need further evaluation

26
Evaluation of Response to GH

• The determination of the growth response to GH
  treatment is the single most important parameter
  in the monitoring of the child with GHD
• Increase in height and change in height velocity
  are useful in clinical practice to assess the
  response to GH
• For comparative purposes, data should be
  expressed as the increase in (or ?) height
  SD/year

27
Monitoring GH-Rx

• IGF levels in GHD

• 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.

28
Monitoring GH-Therapy
Not indicated in Routine monitoring

• Serum leptin,
• Bone markers
• GH antibodies
• Lipid profiles
• Fasting insulin
• Bone age

29
Summary for Monitoring GH Therapy

• Close follow-up with a pediatric endocrinologist
  every 3-6 months, in partnership with the
  pediatrician or primary care physician
• Determination of growth response (change in
  height SDS)
• Monitoring serum IGF-I and IGFBP-3 levels
• Screening for potential adverse effects
• Evaluation of compliance

• Consideration of dose adjustment based on IGF
  values, growth response, pubertal status,
  comparison to growth prediction models

30
Factors affecting the response to GH

• Every effort should be made to diagnose and treat
  children at the youngest possible age
• It is very important to maximize height with GH
  therapy before the onset of puberty
• If this is achieved, then modulation of the GH
  dose during puberty may not be necessary

31
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
GH dose escalation Combined GH GnRH-agonists
Not fully tested and cannot be recommended at
this time
Role of gender Role of body composition
Need further investigations
32
Management of MPHD

• Patients with suspected or proven multiple
  pituitary hormone deficiencies should be managed
  similarly to patients with isolated GHD

• However, attention should be given to correct
  clinical recognition, treatment, and monitoring
  of additional hormonal deficiencies (thyroxine,
  cortisol, sex steroids, and ADH)

• 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

33
Safety Issues (1)

• Treatment with GH may unmask underlying
  hypothyroidism

• Significant side effects of GH treatment in
  children are very rare
• These include benign intracranial
  hypertension, prepubertal gynecomastia, arthralg
  ia, edema

34
Safety Issues (2)

• Careful history and physical examination are
  adequate to identify the presence of side-effects
  
• Management of these side effects may include
  transient reduction of dosage or temporary
  discontinuation of GH

• In the absence of other risk factors there is no
  evidence that GH recipients have increased risk
  ofLeukemia,Brain tumor recurrence,Slipped
  capital femoral epiphysis,Diabetes

35
Safety Issues (3)

• Tumor survivors receiving GH should be followed
  in conjunction with an oncologist and a
  neurosurgeon when appropriate

• There is no evidence that GH replacement needs to
  be discontinued during intercurrent illness

36
Re-testing (1)

• 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

37
Re-testing (2)

• In places where an insulin tolerance test is
  mandatory for the patient to qualify for further
  GH therapy, this test should be performed

• At the time of re-testing, other pituitary
  hormones and an IGF-I should also be measured

38
Transition to adult GHD care (1)

• GH deficiency may or may not persist into adult
  life

• GH has major metabolic actions, important for
  body composition and health in adults as in
  children

• The opportunity should be taken to assess body
  composition, bone mineral density, fasting lipids
  and insulin, before and after discontinuation of
  GH therapy

39
Transition to adult GHD care (2)

• When the diagnosis of adult GHD is established,
  continuation of GH therapy is recommended

• Caution should be exercised when considering the
  decision of continuing GH therapy in conditions
  where there is a known risk of diabetes or
  malignancy

40
Conclusions regarding consensus (1)

• The approach to the diagnosis and treatment of GH
  deficiency in children is evolving
• Clearly, many additional evidence-based clinical
  studies on the diagnosis and treatment of GHD
  will undoubtedly modify our approach

41
Conclusions regarding consensus (2)

• 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

42
GRS Consensus Workshop