Diagnosis & Management ofGrowth Hormone Deficiency

Consensus Workshop17-21 October 1999

Growth Hormone Research Society

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

GRS Consensus WorkshopObjectives

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

• 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

Participants to the Consensus Workshop

• Pediatric & Adult Endocrinologists, Clinicians & Scientists

• Representatives of LWPES, ESPE, JPES, APES, SAPES

• Representatives from companies manufacturing rhGH

• Participants from 13 countries

• Totaling 44

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

GRS Consensus Workshop

Part One

Diagnosis of

Growth Hormone Deficiency

Auxological & Clinical Criteria (1)

Neonatal: Hypoglycemia, prolonged jaundice, microphallus, traumatic delivery

Cranial irradiation Craniofacial midline abnormalities Consanguinity &/or affected family member Head trauma or CNS infection/infiltration

Neonatal: Hypoglycemia, prolonged jaundice, microphallus, traumatic delivery

Cranial irradiation Craniofacial midline abnormalities Consanguinity &/or affected family member Head trauma or CNS infection/infiltration

Short stature is defined as Height more than 2SD below the mean

•History & Physical Exam :

Auxological & Clinical Criteria (2)

•For immediate investigation :

Height > 3 SD below the mean Height > 1.5 SD below mid-parental height Height > 2 SD below mean

& Height Velocity over 1 year > 1SD below mean for CAor Decrease in Ht SD > 0.5 over 1 yearin those aged more than 2 years of age

Height > 3 SD below the mean Height > 1.5 SD below mid-parental height Height > 2 SD below mean

& Height Velocity over 1 year > 1SD below mean for CAor Decrease in Ht SD > 0.5 over 1 yearin those aged more than 2 years of age

Clinical & Auxological Criteria (3)

In absence of short stature, Ht Velocity> 2 SD below the mean over 1 year or > 1.5 SD over 2 years

Signs of an intracranial lesion Signs of multiple pituitary hormone

deficiency Neonatal symptoms & signs of GHD

In absence of short stature, Ht Velocity> 2 SD below the mean over 1 year or > 1.5 SD over 2 years

Signs of an intracranial lesion Signs of multiple pituitary hormone

deficiency Neonatal symptoms & signs of GHD

• For immediate investigation :

Clinical & Auxological Criteria (4)

• Use relevant population standards• Whenever possible update standards• Express as Standard Deviation Scores rather

than percentiles• Need for longitudinal velocity standards

• Use relevant population standards• Whenever possible update standards• Express as Standard Deviation Scores rather

than percentiles• Need for longitudinal velocity standards

• Interpretation of Growth data :

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

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

Evaluation for Genetic Disorders

• Early onset of growth failure• Possible family history & consanguinity• Height > 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

• Early onset of growth failure• Possible family history & consanguinity• Height > 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

Radiological Evaluation

• CNS imaging by MRI/CTSuspected intracranial lesionOptic nerve hypoplasia/SODOther structural/developmental anomalyConfirmed IGHD/MPHD

• Record– Pituitary height &/or volume, stalk anatomy– Position of posterior pituitary bright signal

• CNS imaging by MRI/CTSuspected intracranial lesionOptic nerve hypoplasia/SODOther structural/developmental anomalyConfirmed IGHD/MPHD

• Record– Pituitary height &/or volume, stalk anatomy– Position of posterior pituitary bright signal

• Bone age on wrist XR• Bone age on wrist XR

Biochemical Assessment of GHD (1)

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

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

• Assay considerations

Biochemical Assessment of GHD (2)

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 GH< 10g/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

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 GH< 10g/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

• GH provocation tests

Biochemical Assessment of GHD (3)

Use reference ranges standardized for age & sex Values > 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

Use reference ranges standardized for age & sex Values > 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

• IGF-I & IGFBP-3 values

Biochemical Assessment of GHD (4)

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

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

• Sex-Steroid Priming for GH Tests

Biochemical Assessment of GHD (5)

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

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

• Other tests of the GH axis

Biochemical Assessment of GHD (6)

Nutritional status

Concomitant medication

Psychosocial conditions

Nutritional status

Concomitant medication

Psychosocial conditions

• Confounding factors

The Process of Evaluation of the GH-IGF Axis

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

• Once a decision to test is made

MRI (or CT) if GHD diagnosed

Conclusions Part One

Diagnosis requires consideration of data from comprehensive assessment & investigation

Diagnosis of Severe GHD is usually straightforwardWell-defined clinical, auxological, biochemical & radiological abnormalities

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

GRS Consensus Workshop

Part Two

Treatment of

Growth Hormone Deficiency

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 are:

Normalization 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

Patients with proven GHD should be treated with rhGHas soon as possible after the diagnosis is made

Primary objectives of the therapy of GHD are:

Normalization 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

Mode of Administration of GH

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

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

• Daily subcutaneously in the evening• Daily subcutaneously in the evening

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

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

GH Dosing

Under special circumstances, higher doses may be

required.Under special circumstances, higher doses may be

required.

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

A dose-response relationship in terms of height velocity in the first two years of therapy has been clearly demonstrated within this range

The use of Prediction Models

• Prediction models are currently being investigated but need further evaluation

• Prediction models are currently being investigated but need further evaluation

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

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

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

• 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

Monitoring GH-Rx

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.

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.

• IGF levels in GHD

Not indicated in Routine monitoring

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

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

Monitoring GH-Therapy

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

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

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

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

• 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

GH dose escalationCombined GH & GnRH-agonistsGH dose escalationCombined 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

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 compositionRole of gender Role of body composition

Need further investigations

Management of MPHD

• 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

• 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

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

• 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)

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

Safety Issues (1)

• Significant side effects of GH treatment in children are very rare

• These include:benign intracranial hypertension,prepubertal gynecomastia,arthralgia,edema

• Significant side effects of GH treatment in children are very rare

• These include:benign intracranial hypertension,prepubertal gynecomastia,arthralgia,edema

• Treatment with GH may unmask underlying hypothyroidism

• Treatment with GH may unmask underlying hypothyroidism

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

• 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

• 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

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

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

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

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

Safety Issues (3)

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

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

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

• 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

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

Transition to adult GHD care (1)

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

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

• GH deficiency may or may not persist into adult life

• 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

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

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

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

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

GRS Consensus Workshop