Growth Hormone Therapy Place Holder

Growth Hormone Therapy:Growth Hormone Therapy:

Bridging the Gap Between Bridging the Gap Between Children and AdultsChildren and Adults

Peter J. Tebben MDMayo Clinic, Rochester, MN

June 3, 2007

Disclosures and Disclosures and discussion of off label use discussion of off label use

NoneNone

Adult and Pediatric EndocrinologyAdult and Pediatric Endocrinology

Height - 50%Height - 50%

Objectives Objectives

•Identify the clinical indications for GH Identify the clinical indications for GH therapy in children and adults.therapy in children and adults.

•Recognize which children are at risk for Recognize which children are at risk for adult GHD and may benefit from GH therapy adult GHD and may benefit from GH therapy after achieving final adult height.after achieving final adult height.

•Describe the potential benefits of GH Describe the potential benefits of GH therapy in adolescents and young adults as therapy in adolescents and young adults as well as understand the uncertainties well as understand the uncertainties regarding its use in this population.regarding its use in this population.

Case Case

•6 3/12 y/o male6 3/12 y/o male•Sent for evaluation of short statureSent for evaluation of short stature•Poor linear growth noted for the last yearPoor linear growth noted for the last year•Now has fallen below the 3Now has fallen below the 3rdrd percentile percentile

•No family Hx of short statureNo family Hx of short stature•2 older healthy siblings2 older healthy siblings

105.3 cm105.3 cm18.2 kg18.2 kg

Laboratory Data Laboratory Data

•IGF-1IGF-1 54 ng/mL (nl 88-474)54 ng/mL (nl 88-474)•IGFBP-3 IGFBP-3 1.3 (nl 1.5-3.4)1.3 (nl 1.5-3.4)•TSHTSH 2.6 mIU/L2.6 mIU/L•FT4FT4 1.2 ng/dL1.2 ng/dL•CeliacCeliac NegativeNegative

No other hormone deficiencies identified No other hormone deficiencies identified

Delayed bone Delayed bone age age

Anterior pituitary is small in size.Anterior pituitary is small in size.The infundibulum is thin.The infundibulum is thin.Normal location of posterior pituitary.Normal location of posterior pituitary.

Indications for GH TherapyIndications for GH Therapy

•Growth hormone deficiencyGrowth hormone deficiency•Chronic renal insufficiencyChronic renal insufficiency•Turner syndromeTurner syndrome•Prader-Willi syndromePrader-Willi syndrome•Small for gestational ageSmall for gestational age•Idiopathic short statureIdiopathic short stature

ChildrChildrenen


•Growth hormone deficiencyGrowth hormone deficiency•Chronic renal insufficiencyChronic renal insufficiency•Turner syndromeTurner syndrome•Prader-Willi syndromePrader-Willi syndrome•Small for gestational ageSmall for gestational age•Idiopathic short statureIdiopathic short stature

ChildrChildrenen

•Growth hormone deficiency syndromeGrowth hormone deficiency syndrome•HIV associated wastingHIV associated wasting

AdulAdultsts


Causes of GHD Causes of GHD

•IdiopathicIdiopathic•GeneticGenetic•CNS TumorsCNS Tumors•Radiation therapyRadiation therapy•TraumaTrauma•SurgerySurgery

Making the Diagnosis Making the Diagnosis

•Poor linear growthPoor linear growth•Insulin-like Growth Factor 1 (IGF-1)Insulin-like Growth Factor 1 (IGF-1)•Insulin-like Growth Factor Binding Insulin-like Growth Factor Binding

Protein 3 (IGFBP-3)Protein 3 (IGFBP-3)•Growth hormone stimulation Growth hormone stimulation

testingtesting

ChildrChildrenen

Growth Hormone Stimulation Growth Hormone Stimulation

•Insulin Tolerance Test (ITT) – Insulin Tolerance Test (ITT) – “Gold Standard”“Gold Standard”•GHRH-ArginineGHRH-Arginine•ArginineArginine•L-DOPAL-DOPA•ClonidineClonidine

Growth Hormone Growth Hormone Secretion Secretion

Time of Time of dayday

Kerrigan JR, Rogol AD. Endocrine Reviews; 1992:13(2) 281-298

Insulin Tolerance Test Insulin Tolerance Test

0 30 60 90 1200 30 60 90 120

minuminutestes

InsulinInsulin(0.1 – 0.15 u/kg)(0.1 – 0.15 u/kg)

Measure Growth Hormone and GlucoseMeasure Growth Hormone and Glucose

Children: Normal GH > 10 mcg/LChildren: Normal GH > 10 mcg/LAdults: Normal GH > 5 mcg/LAdults: Normal GH > 5 mcg/L

Growth Hormone Growth Hormone Concentrations Concentrations

Kerrigan JR, Rogol AD. Endocrine Reviews; 1992:13(2) 281-298

•Increased fat massIncreased fat mass•Decreased lean massDecreased lean mass•Lower Quality-of-LifeLower Quality-of-Life•Abnormal lipidsAbnormal lipids•Decreased bone densityDecreased bone density

Signs/Symptoms of Adult Signs/Symptoms of Adult GHDGHD

Questions Questions 1.1. Do all children with GHD become Do all children with GHD become

adults with GHD?adults with GHD?

2.2. Do fully grown adolescents/young Do fully grown adolescents/young adults benefit from GH therapy?adults benefit from GH therapy?

3.3. How should we treat patients in How should we treat patients in this transitional phase?this transitional phase?

•167 patients167 patients•GH treatment discontinued at least 6 weeks GH treatment discontinued at least 6 weeks

prior to retestingprior to retesting•Growth velocity < 1 cm per yearGrowth velocity < 1 cm per year•All other hormone deficiencies adequately All other hormone deficiencies adequately

treated for at least 6 monthstreated for at least 6 months

Attanasio AF. Attanasio AF. Clinical EndocrinologyClinical Endocrinology 2002 2002

Does GHD Persist? Does GHD Persist?

Attanasio AF. Attanasio AF. Clinical EndocrinologyClinical Endocrinology 2002 2002

80% - GHD80% - GHD

20% - Normal20% - Normal

Based on GH stimulation test or IGF-1Based on GH stimulation test or IGF-1

Does GHD Persist? Does GHD Persist?

Juul, A. Juul, A. JCEMJCEM 1997; 82(4) 1195-1201 1997; 82(4) 1195-1201

•108 patients108 patients•GH treatment discontinued at least 6 months GH treatment discontinued at least 6 months

prior to retestingprior to retesting•All other hormone deficiencies adequately All other hormone deficiencies adequately

treated for at least 6 monthstreated for at least 6 months

73% - GHD73% - GHD


Based on GH stimulation testBased on GH stimulation test


98% - GHD98% - GHD



55% - GHD55% - GHD

Isolated GDHIsolated GDH Multiple Pituitary Multiple Pituitary Hormone DeficienciesHormone Deficiencies

• The prevalence of severe GHD in adults who received GH The prevalence of severe GHD in adults who received GH replacement in childhood. Nicolson replacement in childhood. Nicolson et al.et al. Clin EndoClin Endo 1996. 1996.

• Normal GH secretion in growth hormone insufficient children Normal GH secretion in growth hormone insufficient children retested after completion of linear growth. Wacharasindhu retested after completion of linear growth. Wacharasindhu et et alal. . Clin EndoClin Endo 1996. 1996.

• Reevaluation of GH secretion in 69 adults diagnosed as GHD Reevaluation of GH secretion in 69 adults diagnosed as GHD patients during childhood. Longbardi patients during childhood. Longbardi et al.et al. JCEM JCEM 1996. 1996.

• Growth Hormone Retesting and Auxological Data in 131 GH-Growth Hormone Retesting and Auxological Data in 131 GH-Deficient Patients After Completion of Treatment. Tauber M Deficient Patients After Completion of Treatment. Tauber M et et al. JCEMal. JCEM 1997 1997

GHD Does PersistGHD Does Persist

• However, not However, not allall children with GHD children with GHD become adults with GHD.become adults with GHD.

• Increased likelihood of persistent Increased likelihood of persistent disease in patients with:disease in patients with:

•Multiple hormone deficienciesMultiple hormone deficiencies•Genetic causeGenetic cause•Abnormal MRI findingsAbnormal MRI findings•History of cranial XRT/SurgeryHistory of cranial XRT/Surgery

HypothalamusHypothalamus

GHRHGHRH

GHGH

PituitaryPituitary

LiverLiver

BoneBone

IGF-1IGF-1

Growth Hormone Research SocietyGrowth Hormone Research Society

• Retest after final adult height is achievedRetest after final adult height is achieved• Wait at least 1-3 months prior to retestingWait at least 1-3 months prior to retesting• Assess other pituitary hormonesAssess other pituitary hormones• Some may not require retesting:Some may not require retesting:

• Multiple hormone deficienciesMultiple hormone deficiencies• Severe organic diseaseSevere organic disease• Genetic defectsGenetic defects

AACEAACE

““A stimulation test must be performed A stimulation test must be performed in most cases, unless the patient has in most cases, unless the patient has persistent complete hypopituitarism.” persistent complete hypopituitarism.”

““Retesting must be performed prior to Retesting must be performed prior to reinitiating GH treatment.”reinitiating GH treatment.”

Endocrine Society Endocrine Society

•Measure IGF-1 after final adult height is Measure IGF-1 after final adult height is attainedattained

•Discontinue GH therapy at least one month Discontinue GH therapy at least one month prior to measuring IGF-1prior to measuring IGF-1

•Some may not require retesting with GH stimSome may not require retesting with GH stim•Multiple hormone deficienciesMultiple hormone deficiencies•Surgical or XRT induced GHDSurgical or XRT induced GHD•Structural lesions of the hypothalamus or Structural lesions of the hypothalamus or

pituitarypituitary•Proven genetic disorderProven genetic disorder

Questions Questions 1.1. Do all children with GHD become Do all children with GHD become

adults with GHD?adults with GHD?

2.2. Do fully grown adolescents/young Do fully grown adolescents/young adults benefit from GH therapy? adults benefit from GH therapy?

3.3.How should we treat patients in this How should we treat patients in this transitional phase?transitional phase?

Adult GHD Syndrome Adult GHD Syndrome

• Increased fat massIncreased fat mass• Decreased lean massDecreased lean mass• Abnormal lipidsAbnormal lipids• Decreased quality of lifeDecreased quality of life• Decreases exercise capacityDecreases exercise capacity• Decreased bone densityDecreased bone density• Increased cardiovascular morbidityIncreased cardiovascular morbidity

Continuation of GH replacement in GHD patients Continuation of GH replacement in GHD patients during transition from childhood to adulthood: A during transition from childhood to adulthood: A

two year placebo-controlled trial.two year placebo-controlled trial.

• 19 patients with childhood onset GHD19 patients with childhood onset GHD• Retested for GHD after achievement Retested for GHD after achievement

of final adult heightof final adult height• Randomized, placebo controlled for Randomized, placebo controlled for

first yearfirst year

Vahl et al. Vahl et al. JCEMJCEM 2000; 85(5) 1874-1881 2000; 85(5) 1874-1881

Study DesignStudy Design

ChildhoodChildhood Year 1Year 1 Year 2Year 2

GH TreatmentGH Treatment

RetestedRetested

9 – GH9 – GH10 - Placebo10 - Placebo All - GHAll - GH


Measured Parameters Measured Parameters

•Body compositionBody composition•Muscle strengthMuscle strength•Quality of lifeQuality of life•IGF 1IGF 1•LipidsLipids•Insulin, glucose, HbA1cInsulin, glucose, HbA1c


Results Results

• HDL increased at 24 months HDL increased at 24 months compared to baselinecompared to baseline

• No other changes in any parameterNo other changes in any parameter

GH - GH GroupGH - GH Group


Results Results Placebo – GH GroupPlacebo – GH Group


Results Results Placebo – GH GroupPlacebo – GH Group

Muscle StrengthMuscle Strength •No changes in muscle strength or No changes in muscle strength or

exercise capacity were observedexercise capacity were observed


Results Results


Placebo – GH GroupPlacebo – GH Group

Glucose, Insulin, and HbA1cGlucose, Insulin, and HbA1c • Placebo:Placebo:

• Decreased glucose (92 to 88 Decreased glucose (92 to 88 mg/dL)mg/dL)

• No change in insulin or HbA1cNo change in insulin or HbA1c• GH:GH:

• Increased glucose (88 to 95 mg/dL)Increased glucose (88 to 95 mg/dL)• No change in insulin or HbA1cNo change in insulin or HbA1c

Mauras, N JCEM; 2005;90(7) 3946-3955

• 58 patients with childhood onset GHD58 patients with childhood onset GHD• Retested with an ITTRetested with an ITT• 20 mcg/kg/day or placebo 20 mcg/kg/day or placebo • 24 month trial24 month trial

Limited Efficacy of GH during the Limited Efficacy of GH during the Transition of GHD Patients from Transition of GHD Patients from

Adolescence to Adulthood Adolescence to Adulthood

Mauras, N JCEM; 2005;90(7) 3946-3955

No difference at 24 months between No difference at 24 months between GH treatment and Placebo in:GH treatment and Placebo in:

• Lean body massLean body mass• Fat massFat mass• Bone mineral densityBone mineral density• Exercise capacityExercise capacity• Grip strengthGrip strength• LipidsLipids• GlucoseGlucose

Limited Efficacy Limited Efficacy

Adult Growth Hormone (GH)-Deficient Patients Demonstrate Heterogeneity Between Childhood

Onset and Adult Onset Before and During Human GH Treatment

Attanasio et al. JCEM 1997; 82(1) 82-88

• Compared childhood onset GHD to adult Compared childhood onset GHD to adult onset GHDonset GHD

• CO-GHD n=74 (off tx for at least 2 years)CO-GHD n=74 (off tx for at least 2 years)• AO-GHD n=99AO-GHD n=99• Randomized to placebo or GH for 6 Randomized to placebo or GH for 6

months then all on GHmonths then all on GH

Baseline Baseline CO-GHDCO-GHD • Younger (29 vs. 43 years)Younger (29 vs. 43 years)• Shorter (160 vs. 171 cm)Shorter (160 vs. 171 cm)• Lighter (63.8 vs. 84.9 kg)Lighter (63.8 vs. 84.9 kg)• Lower IGF1 and IGFBP3Lower IGF1 and IGFBP3• Higher HDL (36.5 vs. 31.9 mg/dL)Higher HDL (36.5 vs. 31.9 mg/dL)• Better QOL scores for energy and Better QOL scores for energy and

mobilitymobility


Results Results

• No change in QOL measuresNo change in QOL measures• No change in TC, HDL, or LDLNo change in TC, HDL, or LDL• Fat mass decreasedFat mass decreased• Fewer side effects with treatment Fewer side effects with treatment

compared to AO-GHDcompared to AO-GHD

CO-GHDCO-GHD Placebo vs. GH treatmentPlacebo vs. GH treatment


Results Results

• Improved QOLImproved QOL•Social isolationSocial isolation•Physical mobilityPhysical mobility

• Improved HDLImproved HDL• Lower fat massLower fat mass• More side effects compared to CO-GHDMore side effects compared to CO-GHD

AO-GHDAO-GHD Placebo vs. GH treatmentPlacebo vs. GH treatment


Lower Fat MassLower Fat Mass

Underwood, LE et al. JCEM 2003; 88(11) 5273-5280

Increased Lean MassIncreased Lean Mass

Underwood, LE et al. JCEM 2003; 88(11) 5273-5280

Treat EverybodyTreat Everybody Don’t TreatDon’t TreatAnybodyAnybody

Treatment decisions and goals Treatment decisions and goals need to be individualized need to be individualized

Back to the Back to the

patientpatient

Ht: 169 cmHt: 169 cm

Integrated Integrated Transitional Care Transitional Care

• Who?Who?• What?What?• When?When?• Where?Where?• Why?Why?

Who? Who?

• Children with GHDChildren with GHD• Especially those with:Especially those with:

• MPHDMPHD• Abnormal MRIAbnormal MRI• Radiation TreatmentRadiation Treatment

What? What?

• Measure IGF-1Measure IGF-1• Assess other pituitary Assess other pituitary

hormoneshormones• GH stimulation testing in a GH stimulation testing in a

selected population (IGHD)selected population (IGHD)

What? What?

• LipidsLipids• GlucoseGlucose• Body composition (DEXA)Body composition (DEXA)• Bone densityBone density• Quality of life assessmentQuality of life assessment

Assess for signs/symptoms of Assess for signs/symptoms of adult GHDadult GHD

When? When?

• When GH therapy is initiatedWhen GH therapy is initiated• After height goals are metAfter height goals are met• Retest 1 – 3 months after GH therapy Retest 1 – 3 months after GH therapy

has been discontinuedhas been discontinued

Where? Where?

• Initial discussion Initial discussion mustmust be done by be done by the Pediatric care teamthe Pediatric care team

• Retesting can be performed by Retesting can be performed by Pediatric or Adults Endocrine Pediatric or Adults Endocrine supervisionsupervision

• Ongoing care by Adult EndocrinologyOngoing care by Adult Endocrinology

Why? Why?

• Why is or is not treatment being Why is or is not treatment being recommendedrecommended

Potential Benefits Potential Benefits • Increased lean massIncreased lean mass• Decreased fat massDecreased fat mass• Improved bone densityImproved bone density• Improved exercise capacityImproved exercise capacity• Improved strengthImproved strength• Improved lipidsImproved lipids

However, studies have shown mixed results However, studies have shown mixed results

Potential Harm Potential Harm

• Increased blood glucoseIncreased blood glucose• Insulin resistanceInsulin resistance• EdemaEdema• ArthralgiasArthralgias• Increased intracranial pressureIncreased intracranial pressure• MalignancyMalignancy

Drug Dose 1 Year of TxDrug Dose 1 Year of Tx

BonesBones

QOLQOL

CholesterolCholesterol

Body Body compositioncomposition

$7520$7520

$792$792

0.4 mg/d0.4 mg/dSomatropinSomatropin

20 mg/d20 mg/d

70 mg/wk70 mg/wk

40 mg/d40 mg/d

UnlimitedUnlimitedRACRACMembershipMembership

SimvastatinSimvastatin

FluoxetineFluoxetine

AlendronateAlendronate

$280$280

$92$92

$972$972

$2136 vs. $7520 per year$2136 vs. $7520 per year

Other ConsiderationsOther Considerations

Practical Approach Practical Approach • Stop GH when height goals have been Stop GH when height goals have been

achievedachieved• Measure IGF-1 in 1 to 3 months Measure IGF-1 in 1 to 3 months • Discuss with pt potential risks and Discuss with pt potential risks and

benefits of continued GH therapybenefits of continued GH therapy• If GH status is not clear – perform a GH If GH status is not clear – perform a GH

stimulation test stimulation test

Practical Approach Practical Approach • Define treatment goals prior to initiating Define treatment goals prior to initiating

therapytherapy• Reassess goals after 12 monthsReassess goals after 12 months• Consider stopping treatment if pre-Consider stopping treatment if pre-

defined goals are not met defined goals are not met

Keys to Successful Keys to Successful TransitionTransition

• Individualized treatment planIndividualized treatment plan• Complex patientsComplex patients

• Team approachTeam approach• PhysiciansPhysicians• NursesNurses• PsychologistsPsychologists• Social workersSocial workers

• Integrated care between Pediatric and Integrated care between Pediatric and Adults health care providers Adults health care providers

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