Growth Hormone Deficiency: Pediatric to Adult Transition

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Growth Hormone DeficiencyPediatric to Adult
Transition

• J. Paul Frindik, MD, CDE, FACE

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Traditional GH Treatment

• GH deficiency is a pediatric problem
• GH therapy discontinued after final height
• Patient discharged from pediatric endocrinology
  GH clinic

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ObjectivesGH Deficiency Pediatric to Adult

• Consequences of stopping GH therapy
• Adult GHD syndrome Adult Onset (AO) vs.
  Childhood Onset (CO)
• Effects of GH on adults with CO-GHD
• Pediatric to adult transition

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GH Deficiency Pediatric to AdultObjectives

• Consequences of stopping GH
• Adult Onset (AO) GHD vs. Childhood Onset (CO)
• Effects of GH on adults with CO-GHD
• Adult transition

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Consequences of Stopping GH Therapy in CO-GHD 1

• Summary of seven controlled studies of prolonged
  GH deficiency in adults with CO-GHD n 276 (4
  females)
• Mean age range 26 to 28 years old
• Mean peak GH range 1.8 to lt 5
• Mean duration off GH gt 5 to 8.8 years

JCEM 822032, 1997.
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Consequences of Stopping GH Therapy in CO-GHD 2a

• Increased
• SC, intraabdominal fat (n 46)
• LDL, cholesterol (n64)
• Decreased
• muscle mass (n46), bone density (n100), cardiac
  function (n18), cognitive function (n48)

JCEM 822032, 1997.
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Consequences of Stopping GH Therapy in CO-GHD 2b

• Increased
• SC fat (75), intraabdominal fat (85)
• LDL, cholesterol ( 20)
• Decreased
• muscle mass (- 20), bone density (- 10),
  cognitive function (- 15)

JCEM 822032, 1997.
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Adult Onset vs Childhood Onset GHD

• 173 GHD patients
• Adult Onset (age 43.5 10 years)
• no previous GHD or GH treatment
• symptoms of at least one years duration
• Childhood Onset (age 28.8 8 years)
• GH therapy until final height
• no GH in at least two years

JCEM 8282, 1997
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Adult Onset vs Childhood Onset GHD Etiologies of
Adult Onset GHD

• Post surgical intervention 81.6
• Adenoma 56.1
• Craniopharyngioma 19.4
• Other tumors / cysts 6.1
• Post TB, histiocytosis 2.0
• Trauma / Empty Sella 9.2
• Idiopathic 7.2

JCEM 8282, 1997
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Adult Onset vs Childhood Onset GHD Etiologies of
Childhood Onset GHD

• Idiopathic 89.6
• Isolated GHD 28.4
• GHD plus TSH deficiency 10.4
• GHD plus LH/FSH deficiency 6.0
• MPHD 44.8
• Trauma / Empty Sella 6.0
• Craniopharyngioma, other tumors 4.4

JCEM 8282, 1997
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Adult Onset vs Childhood Onset GHD Phenotypes

• Adult
• normal heights
• normal lean body mass
• increased body fat

• Childhood
• 50 heights lt 2 SD
• decreased LBM
• increased body fat

JCEM 8282, 1997
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Adult Onset vs Childhood Onset GHD Baseline
Chemistries

• Adult
• decreased IGF-I
• normal IGFBP-3
• increased total cholesterol
• decreased HDL
• abnormal in 72

• Childhood
• decreased IGF-I
• decreased IGFBP-3
• increased total cholesterol
• low normal HDL
• abnormal in 54

JCEM 8282, 1997
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Adult GHD Syndrome in Previously Treated CO-GHD

• Combination of sub-optimal replacement during
  childhood / adolescence plus
• Prolonged GHD after discontinuation of GH therapy
  at final height
• May be preventable or reversible

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Effects of GH Therapy in Adults with CO-GHD 1

• Body composition
• reduction in mean total body percent fat and mean
  trunk percent fat
• increases in mean total body percent lean mass
• no changes in body fat or lean mass with placebo

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Effects of GH Therapy in Adults with CO-GHD 2

• Lipid metabolism
• decreases in total cholesterol, LDL cholesterol,
  and LDLHDL ratio compared to baseline after 12
  months
• no effect on HDL or triglycerides
• decrease in total cholesterol only in patients
  with initially elevated cholesterol

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Effects of GH Therapy in Adults with CO- GHD 3

• Bone Mineral Density (BMD)
• GH increases bone turnover
• initial decreased BMD due to remodeling
• increased BMD after one year of treatment
• Increased BMD persists after prolonged (4-5 yrs)
  GH therapy
• JCEM 842373, 1999

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Pediatric to Adult Transition

• Rationale for Treatment
• Patient selection
• risk factors for adult GHD syndrome
• previous vs. current CO-GHD patients
• Diagnostic testing to confirm adult GHD
• Health care providers
• adult vs. pediatric endocrinologists

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Adult Onset vs Childhood Onset GHD Rationale for
Treatment

• Adult Onset
• reverse the symptoms of acquired GHD
• Childhood Onset
• reverse the symptoms of prolonged GHD
• prevent the development of adult GHD syndrome

JCEM 8282, 1997
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Patient SelectionRisk Factors for Adult GHD in
CO-GHD

• Severity of childhood GHD
• Majority with adult GHD syndrome had peak GH
  values less than 5 ng/dl as children
• Patients with partial GHD (peak GH 5-10 ng/dl
  as children) are less likely to develop adult GHD
  syndrome
• Etiology of childhood GHD

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Patient SelectionPrevious CO-GHD Patients

• Identify patients
• database search, chart reviews
• outreach via educational mailings, seminars
• Screen for risk factors, symptoms
• Offer retesting
• high risk or symptomatic patients

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Patient SelectionCurrent CO-GHD Patients

• Introduce concept of adult GHD
• Screen for risk factors
• Clinical follow-up after discontinuation of
  growth hormone
• Offer retesting
• high risk or symptomatic patients

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Retesting Adults with CO-GHDObjectives

• Confirm diagnosis of adult GHD
• diagnostic criteria for GHD adults differs from
  that of GHD children
• Identify childhood transient GHD
• CO-GHD patients with normal GH response to
  retesting are not at risk for adult GHD
• Insurance documentation

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Stimulation Testing Criteria for Adult GHD

• Peak GH value less than 5 ng/dl is considered
  diagnostic of adult GHD
• Majority of healthy adults respond with values
  over 5 ng/dl to stimulation
• Patients with adult GHD syndrome have peak values
  of less than 5 ng/dl after stimulation

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GH Retesting in Children with Idiopathic GHD

• 13 out of 53 (24.5) had normal GH response to 2
  provocative stimuli
• JCEM 741284, 1992.
• 44 out of 132 (28.9) had normal GH response
• JCEM 791663, 1994.

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GH Retesting Results in Adultswith History of
CO-GHD
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Retesting Adults with CO-GHDSummary

• CO-GHD does not always adult GHD
• about 60 of former CO-GHD patients will respond
  normally upon retesting as an adult (peak GH
  value over 5 ng/dl)
• JCEM 822032, 1997.
• Retesting of CO-GHD is mandatory to establish a
  diagnosis of adult GHD

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Pharmacological GH StimulationTesting for Adult
GHD 1

• Insulin Tolerance Test
• highly accurate for adult GHD diagnosis
• Lancet 3431064 1994
• adverse hypoglycemia rare (0.2) in adults
• Hoffman et al 1996
• not recommended for patients over 65 years

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Pharmacological GH StimulationTesting for Adult
GHD 2

• Arginine Tolerance Test
• response similar to insulin tolerance test,
  without risk of hypoglycemia
• Glucagon, levo-dopa, GHRH
• results in adults less well characterized

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Pharmacological GH StimulationTesting for Adult
GHD 3

• Avoid clonidine in suspected adult GHD
• Produced peak GH response in healthy adults
  identical to placebo
• Clin Endocrinol 45557 1996

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Transition of CO-GH DeficiencyCurrent
Recommendations

• No proven treatment strategy to prevent adult GHD
  syndrome in CO-GHD

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Transition of CO-GH DeficiencyCurrent
Recommendations

• Discontinue GH after final height
• Monitor for development of symptoms
• body composition, serum lipids, physical and
  psychological performance
• Retest to verify adult GHD

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Adults with CO-GH DeficiencyGH Dosage
Recommendations

• Dosage much less than for treatment of pediatric
  GHD
• Starting dose is 0.006 mg/kg/day
• maximum of 0.025 mg/kg/d lt 35 years old
• maximum of 0.0125 mg/kg/d gt 35 years old

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Adult GH DeficiencySummary

• Growth Hormone its not just for kids anymore