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1
Growth hormone replacement therapy in elderly growth hormone
deficient patients: a systematic review
Nieke E. Kokshoorn, Nienke R. Biermasz, Ferdinand Roelfsema, Johannes W.A. Smit, Alberto
M. Pereira and Johannes A. Romijn
Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center,
Leiden, The Netherlands
Abbreviated title: rhGH treatment of GHD elderly
Word count: 3504
Corresponding author: N.E. Kokshoorn, MD
Department of Endocrinology and Metabolic Diseases C4-R
28 Hilding A, Hall K, Wivall-Helleryd IL, Saaf M, Melin AL & Thoren M. Serum
levels of insulin-like growth factor I in 152 patients with growth hormone
deficiency, aged 19-82 years, in relation to those in healthy subjects. J Clin
Endocrinol Metab 1999 84 2013-2019.
29 Bruce A, Andersson M, Arvidsson B & Isaksson B. Body composition. Prediction
of normal body potassium, body water and body fat in adults on the basis of body
height, body weight and age. Scand J Clin Lab Invest 1980 40 461-473.
30 Finucane FM, Liew A, Thornton E, Rogers B, Tormey W & Agha A. Clinical
insights into the safety and utility of the insulin tolerance test (ITT) in the
assessment of the hypothalamo-pituitary-adrenal axis. Clin Endocrinol (Oxf) 2008
69 603-607.
31 Eskes SA, Tomasoa NB, Endert E, Geskus RB, Fliers E & Wiersinga WM.
Establishment of reference values for endocrine tests. Part VII: growth hormone
deficiency. Neth J Med 2009 67 127-133.
32 Toogood AA, Jones J, O'Neill PA, Thorner MO & Shalet SM. The diagnosis of
severe growth hormone deficiency in elderly patients with hypothalamic-pituitary
disease. Clin Endocrinol (Oxf) 1998 48 569-576.
33 Ghigo E, Goffi S, Nicolosi M, Arvat E, Valente F, Mazza E et al. Growth hormone
(GH) responsiveness to combined administration of arginine and GH-releasing
Page 19 of 25
20
hormone does not vary with age in man. J Clin Endocrinol Metab 1990 71 1481-
1485.
34 Colao A, Di SC, Savastano S, Rota F, Savanelli MC, Aimaretti G et al. A
reappraisal of diagnosing GH deficiency in adults: role of gender, age, waist
circumference, and body mass index. J Clin Endocrinol Metab 2009 94 4414-4422.
35 Packard CJ, Ford I, Robertson M, Shepherd J, Blauw GJ, Murphy MB et al. Plasma
lipoproteins and apolipoproteins as predictors of cardiovascular risk and treatment
benefit in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).
Circulation 2005 112 3058-3065.
36 Bartke A & Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol
2004 63 189-225.
37 Bartke A. Growth hormone and aging: a challenging controversy. Clin Interv Aging
2008 3 659-665.
38 Bonkowski MS, Pamenter RW, Rocha JS, Masternak MM, Panici JA & Bartke A.
Long-lived growth hormone receptor knockout mice show a delay in age-related
changes of body composition and bone characteristics. J Gerontol A Biol Sci Med
Sci 2006 61 562-567.
39 Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A & Kopchick JJ.
Deletion, but not antagonism, of the mouse growth hormone receptor results in
severely decreased body weights, insulin, and insulin-like growth factor I levels and
increased life span. Endocrinology 2003 144 3799-3810.
40 Rollo CD. Growth negatively impacts the life span of mammals. Evol Dev 2002 4
55-61.
41 Brosnahan MM & Paradis MR. Assessment of clinical characteristics, management
practices, and activities of geriatric horses. J Am Vet Med Assoc 2003 223 99-103.
42 Greer KA, Canterberry SC & Murphy KE. Statistical analysis regarding the effects
of height and weight on life span of the domestic dog. Res Vet Sci 2007 82 208-214.
43 Patronek GJ, Waters DJ & Glickman LT. Comparative longevity of pet dogs and
humans: implications for gerontology research. J Gerontol A Biol Sci Med Sci 1997
52 B171-B178.
44 Dekkers OM, Biermasz NR, Pereira AM, Romijn JA & Vandenbroucke JP.
Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab 2008 93 61-67.
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Figure 1 Summary of study assessment and exclusion stages
Page 21 of 25
1
Figure 1 Summary of study assessment and exclusion stages
534 relevant studies identified and screened
129 potentially relevant studies retrieved for more detailed
assessment
403 excluded based on title and abstract No rhGH replacement therapy and/or age < 60 yr (n=324) Reviews (n=77)2 papers not possible to obtain
14 studies remained
11 studies included
6 papers used identical patient cohort; results were combined
89 excluded because of age; included patients > 60 yr however data could not be extracted26 studies did not fulfill inclusion criteria
Page 22 of 25
Table 1 Studies on rhGH therapy in elderly patients with GHD
Author Patients Definition GHD
Treatment
duration Dose IGF-I SDS
Evaluation Effect of treatment
Metabolic Syndrome
Anthropometrics Lipids Bone
Body
composition
QoL/
Cognition
Götherström
et al; 201012
n= 24
M: 11
65 (61-74) yr
ITT(n=22)
GHRH-pyr (n=1)
Low IGF-I (n=2)
Peak GH<3 μg/l
10 yr
Mean initial dose
0.72 mg/day in 5
years ↓ 0.37
mg/day
Aim normalizing
IGF-I SDS (-2 to +2)
and BC
After 10 yrs:
↑ -1.10(1.08) to
1.17(1.52)
Physical exam.
BC (DEXA)
Muscle
strength*
BW: ↓
Height: ↓
BMI: =
- - BF:↓
LBM:↑
-
Götherström et
al; 200519
5 yr 4-comp model:
BF, BCM, and
ECW: =
Koltowska et al;
200910
(KIMS)
n= 64 > 60 yr
n=286 < 60 yr
ITT
Arginine
GHRH
Glucagon
Peak GH<3 μg/l
6 yr Mean after 1 yr:
0.26-0.40 mg/day
Baseline:
-1.3(1.19) to -
2.1(1.75)
After 1 year:
0.8(1.4) to
0.5(1.31)
QoL (AGHDA)
- - - - Both
groups:
AGDHA: +
Feldt-
Rasmussen et
al; 200411
(KIMS)
n= 125 > 65 yr
n= 2469 < 65 yr
M: 1249
ITT
Arginine
GHRH
Glucagon
Peak GH<3 μg/l
12 months
Mean 0.2 mg/day
Titration based on
clinical response
and IGF-I SDS
Baseline:
Between 0 and -4
After 12 months:
Between -2 and+2
Physical exam.
Lipids
BC (DEXA)
QoL (AGHDA)
Both groups:
Waist (n=114): ↓
W/H-ratio: ↓
BP:
< 65 yr: DBP ↓ F
> 65 yr: DBP ↓ M
TC (n=107): ↓
LDL: ↓
HDL; TG: =
- Both groups:
LBM (n=47): ↑
Both
groups:
AGHDA
(n=98): +
Monson et al;
200321
(KIMS)
n= 135 > 65 yr
(65-74)
M: 83
n= 1395 < 65 yr
ITT 55%
Arginine 14%
Glucagon 5%
Other 26 %
Peak GH<3 μg/l
12 months
Start dose max
0.042 - 0.083 mg/
kg/week
Baseline:
M: median -1.60
(-3.19 to +0.28)
F: median -1.78
(-3.81 to 0.06)
After 1 yr:
Between -2 and +3
Physical exam.
Lipids
QoL (AGHDA)
Both groups:
Waist (n=93): ↓
W/H-ratio: ↓
BP(n=123):
< 65 yr: DBP ↓ F
> 65 yr: DBP ↓ M
TC: ↓
LDL (n=78): ↓
HDL; TG: =
- - Both
groups:
AGHDA
(n=78): +
Monson et al;
200015
(KIMS)
n= 64
68 (65-82) yr
n= 863 < 65 yr
ITT 44%
Arginine 19%
GHRH 13%
Glucagon 11%
Peak GH<3 μg/l
> 6 months
Mean:
0.37 mg /day
Titration based on
clinical response
and IGF-I SDS
Between -2 and+2 6 months
(n=64):
BP
QoL (AGHDA)
12 months
(n=22):
Lipids
Bone
Waist:
< 65 yr ↓
Only F > 65 yr ↓
BP:
> 65 yr: DBP↓ M
TC: ↓
LDL: ↓
HDL; TG: =
- - Both
groups:
AGHDA: +
Page 23 of 25
Sathiavageeswa
ran et al; 200717
n= 34
M: 22
66 (60-77) yr
n=16 rGH
n=18 placebo
ITT
Arginine
Peak GH<3 μg/l
12 months
Mean:
0.16 mg/day
(0.10-0.30)
Titration based on
IGF-I SDS
Target:
Between +1 and+2
Fasting glucose,
insulin, HbA1c
Cognitive
function
Mood
HbA1c, insulin,
fasting glucose: no
differences
- - Cognition:
No
benefits
Franco et al;
200622
n= 24
M: 15
68 (65-75) yr
n= 24
M: 15
37 (27-46) yr
ITT (n = 41)
GHRH (n=3),
Glucagon (n=1)
Peak GH<3 μg/l
2 yr
Mean:
0.31(0.03) mg/day
Normalizing age
adjusted IGF-I
levels and BC
Target:
Between 0 and +2
Physical exam.
BC (DEXA)
Bone (DEXA)
Lipids
Glucose metab
Both groups:
BW: =
Waist: ↓
W/H-ratio: ↓
Transient BP ↓
> 65 yr:
LDL: ↓
TC: ↓
Both groups:
Osteocalcin
:↑
Calcium: ↑
PTH:
unaffected
BMD: no
differences
Both groups:
No differences
-
White et al;
200523
n= 10
M: 5
60-68 yr
n= 22
M: 6
26-57 yr
ITT
Peak GH<3 μg/l
12 months Mean:
0.29(0.03) mg/day
Maintaining IGF-I
within 2 SD of age
related ref range
Baseline:
Mean -2.72 ± 1.17
After 1 month:
Mean -0.38 ± 0.96
Bone - Both groups:
PTH target-
organ
sensitivity:
↑**
- -
Elzgyri et al ;
200416
n= 31
M: 25
68 (60-79) yr
GHRH test n=29
ITT n=2
Peak GH< 3 μg/l
6 months
GH: n=15
Placebo:
n=16
12 months
GH: n=28
1 month: 0.017
5 months: 0.033
mg/kg/week
1 month 0.017
11 months 0.033
mg/kg/week
Normal range IGF-
I assessed by n=
448 healthy
subjects (20-96 yr)
Baseline:
All patients below
normal mean for
age
6 months:
6.9 to 18.5 nmol/l
(10.4-32.8)
12 months:
Mean 18.8±1.6
BP, heart rate
Lipids
ECG
Exercise tests
6 and 12 months
No changes on
cardiac noninvasive
structural and
functional
parameters.
6 months
Both groups:
TC: ↓
LDL:↓
LDL/HDL ratio:
↓
12 months
TC: ↓
LDL: ↓
HDL: ↑
-
Fernholm et al;
200013
BC (DEXA)
Bone
BP: = BMD: no
changes
Markers
bone
formation:
↑
6 and 12
months:
Only in M
Placebo: no
response
GH groups:
LBM:↑
TBF:↓
De Marinis et
al ; 200224
n= 11
M: 6
60-78 yr
n= 39
M: 19
18-57 yr
GHRH-arg
Peak GH<15 μg/l
12 months
0.06 - 0.12
IU/kg/wk
Keep IGF-I levels
in psychological
range for age and
sex
NR BMI
Waist
BC
BMI: =
W/H ratio: =
- - No changes -
Page 24 of 25
Gill et al ;
199914
n= 12
M: 9
68 (62–85) yr
Arginine
Peak GH<3 μg/l
9 months
Acute study:
single bolus 0.1
mg/kg/BW
Chronic study:
0.17 mg/day
0.33 mg/day
0.5 mg/day,
Each dose 3
months
Relationship age
and IGF-I assessed
in group n=124
(60-87 yr) with
specific
equations***
Baseline:
Between -2 and 0
0.17 mg/day:
normal limits
0.33 mg/day: n=2
> +2
0.50 mg/day: n=6
> +2
BC (DEXA)
QoL (AHGDA)
FM: ↓
LBM:↑
AGHDA: +
Toogood et al;
1999
Leptin
Insulin
BC (DEXA)
Acute study:
Leptin: ↑
Insulin: ↑
Chronic study:
Leptin: =
Insulin: ↑
AGHDA; Assessment of Growth Hormone Deficiency in Adults, BC; body composition, BCM; body cell mass, BF; body fat, BMD; bone mineral density, BMI; body mass index, BP; blood pressure, BW; body weight, DBP; diastolic blood
pressure, DEXA; Dual energy X-ray absorptiometry, ECW; extra cellular water, FM; fat mass, GH; growth hormone, GHRH; growth hormone releasing hormone, HDL; high density lipoprotein, IGF-I; insulin-like growth factor -1, ITT;
insulin tolerance test, LBM; lean body mass, LDL; low density lipoprotein, M; male, PTH; parathyroid hormone, QoL; quality of life, SBP; systolic blood pressure, TC; total cholesterol, TG; triglycerides, W/H; waist/hip; =, no changes.
* Outcome evaluation muscle strength: -Transient ↑ isometric knee flexor strength and ↑ muscle strength reversed age-related decline in muscle strength. Proximal leg muscle responded more markedly than distal arm muscle