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Growth hormone treatment in GHdeficiency adults

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Growth hormone replacement therapy in adult-onset GH ... History of acromegaly. Fasting blood glucose = 140 mg/dl. Carpal tunnel syndrome. Malignancy ... – PowerPoint PPT presentation

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Title: Growth hormone treatment in GHdeficiency adults

1
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

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

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

13
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
17
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
20
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
26

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

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

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

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 )

30
Conclusion
31

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

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

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

36
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

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

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

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

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