Growth hormone treatment in GHdeficiency adults

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Growth hormone treatment in GH-deficiency adults

• Journal reading
• R5 ???
• 2004-6-2

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Growth hormone replacement therapy in adult-onset
GH deficiency effects on body composition in men
and women in a double-blind, randomized,
placebo-controlled trial

• Journal of the clinical endocrinology
  metabolism 89(5)20482056 ,2004

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• Adult GH deficiency (AGHD) ---
• Abnormal body composition
• fat mass , visceral fat ?
• lean body mass ?
• Strength , exercise capacity ?
• Altered lipid metabolism
• Increased cardiovascular disease
• Diminished quality of life , social isolation ,
  decreased energy
• BMD? ? 3-fold increase in bone fracture rate

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• Short-term GH replacement therapy in adult
  ?Beneficial effects on body composition, fate
  distribution , quality of life
• GH at least 18 months ? improvement in bone
  mineral content and BMD

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Subjects and methods

• 19931995
• Multicenter, radomized, placebo-controlled,
  double blind study
• Age 1870 y/o
• Inclusion criteria ---
• AGHD ( result of hypothalamic-pituitary disease)
• Two GH stimulation tests --- maximal GH lt 5ng/ml
  
• Clonidine, Levodopa, insulin tolerance test,
  arginine stimulation test
• No previous history of GH therapy
• No change in steroid , thyroid hormone, or
  gonadal hormone replacement therapy within 2
  months before study entry
• Gonadal steroid replacement therapy could be
  started no later than 12 months before entry
• 12 lead EKG, CBC, serum chemistry test ? normal

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Subjects and methods

• Exclusion criteria
• Psychological or physical impairment
• History of acromegaly
• Fasting blood glucose gt 140 mg/dl
• Carpal tunnel syndrome
• Malignancy
• Methods
• Daily sc injections of recombinant human GH
  (somatropin) or placebo for 12 months
• GH
• initial dose 0.0125 mg/kg.d for the first month
• Increased to 0.025 mg/kg.d if tolerable
• Decreased to 0.00625 mg/kg.d if adverse events

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Subjects and methods

• Primary endpoints
• A reduction in the proportion of body mass
  composed of fat
• An increase in maximum voluntary thigh muscle
  force production and endurance
• Improved of quality of life
• Beck Depression Index, the Nottingham Health
  Profile, the General Well-being Schedule, the
  Paffenbarger Questionnaire, the National Health
  Interview Survey , Trail-Making Tests
• Additional efficacy measures
• Serum IGF-I SD score
• Anthropomorphic measurement
• Weight, height, BMI, ring size, hip/waist ratio,
  midarm circumference, skinfold thickness.
• BMD ( DXA)

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Results
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• Baseline IGF-1
• 52 of men and 75 of women lt -2SDS
• 15 of men and 27 of women lt-4SDS ( normal
  range for age )
• Women lt men
• Women taking estrogen lower IGF-I SDS
• Baseline cholesterol
• 59 of men and 66 of women gt 200mg/dl
• Baseline anthropometric and body composition
• 62 of subjects , BMI gt 25 kg/m2
• 64 of men , total body fat gt 25
• 90 of women , total body fat gt 30
• Baseline BMD
• 51 of subjects -- Spine T-score lt -1
• 64 of subjects -- femoral T-scorelt -1

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GH dose

• 79 of subjects 0.0125 mg/kg.d
• 21 of subjects 0.00625 mg/kg.d ( because of
  edema )
• Compliance high ( only 5 missing more than
  10 of injections)

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Change in serum IGF-I SDS
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Strength and endurance and quality of life

• GH did not produce a significant change in
  strength and endurance ( data not shown)
• Quality of life
• Generally normal at baseline
• Did not change with GH therapy

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Changes in body composition
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Changes in body composition

• No significant changes were observed in BMD
  measurement in GH treatment women and men

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Changes in anthropometric measurement

• Skinfold thickness ? significantly decreased from
  baseline
• GH-treated men at month 6
• GH-treated women at month 9

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Changes in serum lipids
9 mg/dl
-3 mg/dl
-15 mg/dl
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Safety

• Adverse events
• 2 subjects edema
• 1 subjects arthritis
• 4 subjects arthritis-like syndrome
• 3 subjects carpal tunnel syndrome
• 2 subjects increasing suprasellar mass size
• 1 subject abnormal glucose tolerance test
• 1 subject Graves disease

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• No significant change in renal function , blood
  chemistry, urinalysis
• No significant change in physical examination
• A small increase ( 5 bpm) in mean pulse rate in
  GH group
• No acromegalic change seen on x-ray
• Ring size increase
• Antibodies to GH not detected

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Discussion
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• GH replacement therapy at a dose of 0.00625 or
  0.0125 mg/kg.d
• produced significant changes in body composition
  ( total body and trunk fat?, lean body mass?)
• LDL cholesterol , LDL/HDL ratio improved
• improved cardiovascular risk profile

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• Discrepant effects of GH replacement therapy
  between men and women
• Premenopausal women are resistance to the effects
  of GH
• Oral estrogen decrease the ability of GH therapy
  to stimulate IGF-I levels
• Woman may need a higher replacment dose of GH
• No significant changes in BMD
• Other study more prolonged GH dose lead to
  increased BMD

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• Weight-based dosing regimens have recently been
  criticized
• Leading to excessively high IGF-I ? increased
  incidence of adverse events
• GH secretion is negatively correlated with BMI ?
  weight based dose may be nonphysiologic
• GH replacement therapy in adult should be
  titrated to achieve a target IGF-I within 2 SD of
  the mean for age and gender-matched control

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• Testosterone stimulate IGF-I production
• Oral estrogen increase GH secretion and
  decrease IGF-I
• women with AGHD in premenopausal
  age can be treated with transdermal estrogen (
  do not lead to GH resistance )

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Conclusion
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• GH replacement therapy
• Improve body composition
• Improve serum lipid profile
• Did not affect exercise performance or quality of
  life
• some of these changes were
  small ? similar effect may be more easily
  achieved by lifestyle modification and oral
  lipid-lowering agent

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• Other investigators
• Improvement of quality of life ( long-term
  therapy)
• Regression of carotid artery intimal thickness
• Increase BMD after 18 months of GH therapy
• GH dose should be individualized
• Starting at a dose of 0.20.4mg/d (0.003 mg/kg)
• Titrated with the goal of normalizing IGF-I

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Impact of growth hormone treatment on
cardiovascular risk factors in GH-deficient
adults A metaanalysis of blinded, randomized,
placebo-controlled trials

• The journal of clinical endocrinology
  metabolism 89(5)2192-2199,2004

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• AGHD patients exhibit cardiovascular risk
  factors ( abdominal obesity, hypercholesterolemia,
  hypertriglyceridemia)
• GH replacement therapy
• Reduce cardiovascular risk factor
• Adverse effect insulin resistance , increased
  volemia

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Subjects and methods

• Inclusion criteria
• all blinded , randomized , placebo-controlled
  trials, published up to August 2003
• patients aged over 17 yr with GHD corresponding
  to less than 5 ug/liter after stimulation

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Results

• 37 blinded, randomized, placebo-controlled trials
  

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Discussion
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• GH treatment
• Small but statistically significant beneficial
  effect of GH treatment on lean and fat body mass
  , LDL , total cholesterol , diastolic blood
  pressure
• Significant increased plasma glucose and insulin
  levels

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• Effects on LDL cholesterol and total cholesterol
  were variable
• Half showed o significant difference
• Overall effect size ? beneficial effect
• No effect on HDL, or triglyceride was observed
• Most study mild fluid retention
• The relationship between blood pressure and GH
  therapy
• No significant effect was noted in most studies
• One trial ? hypertension
• One trial ? decrease in diastolic blood pressure
• Overall effect size ? decrease in diastolic blood
  pressure, no change in systolic blood pressure

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• The relationship between blood pressure and GH
  therapy may be due to
• Stimulation of the Renin-aldosterone system
• Increase in NO formation
• Decrease in intima-media thickness

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• The effect of GH on fasting insulin and glucose
• Varied
• One trial 2 case of incident diabetes
• Overall effect sizes ? significant increase in
  glucose and insulin during GH treatment
• Men were more sensitive to the effect of GH on
  insulin sensitivity
• Not support previous suggestions that insulin
  resistance falls during low-dose and long-term GH
  therapy

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• Young patients may be more sensitive than older
  patients to GH treatment
• Beneficial effects on body mass, cholesterol,
  blood pressure increased with the duration of
  treatment , whereas adverse effects remained at a
  similar level
• GH treatment seemed to be more beneficial in AGHD
  than in adults with childhood-onset GHD .
• No difference in GH effects between patients with
  multiple hormone deficiency and those with
  isolated GHD