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Effects of Human Growth Hormone in Men over 60 Years Old

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The declining activity of the growth hormone--insulin-like growth factor I (IGF-I) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging. To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma IGF-I concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight subcutaneously three times a week, and 9 men (group 2) received no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites. In group 1, the mean plasma IGF-I level rose into the youthful range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in adipose-tissue mass, and a 1.6 percent increase in average lumbar vertebral bone density (P less than 0.05 in each instance). Skin thickness increased 7.1 percent (P = 0.07). There was no significant change in the bone density of the radius or proximal femur. In group 2 there was no significant change in lean body mass, the mass of adipose tissue, skin thickness, or bone density during treatment. Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age.
Content may be subject to copyright.
Volume 323 JULY 5, 1990 Number 1
©Copyright, 1990, by the Massachusetts Medical Society
EFFECTS OF HUMAN GROWTH HORMONE IN MEN OVER 60 YEARS OLD
D
ANIEL
R
UDMAN
, M.D., A
XEL
G. F
ELLER
, M.D., H
OSKOTE
S. N
AGRAJ
, M.D., G
REGORY
A. G
ERGANS
, M.D.,
P
ARDEE
Y. L
ALITHA
, M.D., A
LLEN
F. G
OLDBERG
, D.D.S., R
OBERT
A. S
CHLENKER
, P
H
.D.,
L
ESTER
C
OHN
, M.D., I
NGE
W. R
UDMAN
, B.S.,
AND
D
ALE
E. M
ATTSON
, P
H
.D.
Abstract
Background.
The declining activity of the
growth hormone–insulin-like growth factor I (IGF-I) axis
with advancing age may contribute to the decrease in lean
body mass and the increase in mass of adipose tissue that
occur with aging.
Methods.
To test this hypothesis, we studied 21
healthy men from 61 to 81 years old who had plasma
IGF-I concentrations of less than 350 U per liter during
a six-month base-line period and a six-month treatment
period that followed. During the treatment period, 12 men
(group 1) received approximately 0.03 mg of biosynthetic
human growth hormone per kilogram of body weight sub-
cutaneously three times a week, and 9 men (group 2) re-
ceived no treatment. Plasma IGF-I levels were measured
monthly. At the end of each period we measured lean
body mass, the mass of adipose tissue, skin thickness
(epidermis plus dermis), and bone density at nine skeletal
sites.
Results.
In group 1, the mean plasma IGF-I level rose
into the youthful range of 500 to 1500 U per liter during
treatment, whereas in group 2 it remained below 350 U per
liter. The administration of human growth hormone for six
months in group 1 was accompanied by an 8.8 percent
increase in lean body mass, a 14.4 percent decrease in
adipose-tissue mass, and a 1.6 percent increase in aver-
age lumbar vertebral bone density (P<0.05 in each in-
stance). Skin thickness increased 7.1 percent (P = 0.07).
There was no significant change in the bone density of the
radius or proximal femur. In group 2 there was no signifi-
cant change in lean body mass, the mass of adipose tis-
sue, skin thickness, or bone density during treatment.
Conclusions.
Diminished secretion of growth hor-
mone is responsible in part for the decrease of lean body
mass, the expansion of adipose-tissue mass, and the thin-
ning of the skin that occur in old age. (N Engl J Med 1990;
323:1-6.)
From the Department of Medicine, Medical College of Wisconsin, Milwaukee
(D.R., I.W.R.); the Medical Service, Veterans Affairs Medical Center, Milwaukee
(D.R.); the Department of Medicine, Chicago Medical School, North Chicago
(A.G.F., H.S.N., G.A.G., P.Y.L., L.C.); the Medicine (A.G.F., H.S.N., P.Y.L.), Nu-
clear Medicine (G.A.G.), and Dental (A.F.G.) Services, Veterans Affairs Medical
Center, North Chicago; the Argonne National Laboratory, Argonne, Ill. (R.A.S.);
and the Epidemiology– Biometry Program, University of Illinois School of Public
Health, Chicago (D.E.M.).
Supported by grants from the Department of Veterans Affairs and Eli Lilly and
Co., and by a grant (1D31 PE95008-02) from the Public Health Service.
I
N middle and late adulthood all people experience
a series of progressive alterations in body composi-
tion.
1
The lean body mass shrinks and the mass of
adipose tissue expands. The contraction in lean body
mass reflects atrophic processes in skeletal muscle, liv-
er, kidney, spleen, skin, and bone.
These structural changes have been considered un-
avoidable results of aging.
1
It has recently been pro-
posed, however, that reduced availability of growth hor-
mone in late adulthood may contribute to such
changes.
1,2
This proposal is based on two lines of evi-
dence. First, after about the age of 30, the secretion of
growth hormone by the pituitary gland tends to de-
cline.
1,3,4
Since growth hormone is secreted in pulses,
mostly during the early hours of sleep, it is difficult to
measure the 24-hour secretion of the substance direct-
ly. Growth hormone secretion can be measured indi-
rectly, however, by measuring the plasma concentration
of insulin-like growth factor I (IGF-I, also known as so-
matomedin C), which is produced and released by the
liver and perhaps other tissues in response to growth
hormone.
5
There is little diurnal variation in the plas-
ma IGF-I concentration, and measurements of it are
therefore a convenient indicator of growth hormone se-
cretion.
5
Plasma IGF-I concentrations decline with ad-
vancing age in healthy adults.
1,4,6
Less than 5 percent
of the healthy men 20 to 40 years old have plasma
IGF-I values of less than 350 U per liter, but the values
are below this figure in 30 percent of the healthy men
over 60.
4
Likewise, the nocturnal pulses of growth hor-
mone secretion become smaller or disappear with ad-
vanced age. If the plasma concentration of IGF-I falls
below 350 U per liter in older adults, no spontaneous
circulating pulses of growth hormone can be detected
by currently available radioimmunoassay methods.
4
The concomitant decline in plasma concentrations of
both hormones supports the view that the decrease in
IGF-I results from diminished growth hormone secre-
tion.
4,6
Second, diminished secretion of growth hor-
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Copyright © 1990 Massachusetts Medical Society. All rights reserved.
2 THE NEW ENGLAND JOURNAL OF MEDICINE July 5, 1990
mone is accompanied not only by a fall in the plasma
IGF-I concentration, but also by atrophy of the lean
body mass and expansion of the mass of adipose tis-
sue.
1
These alterations in body composition caused by
growth hormone deficiency can be reversed by re-
placement doses of the hormone, as experiments in
rodents,
7
children,
8,9
and adults 20 to 50 years old
10-13
have shown. These findings suggest that the atrophy
of the lean body mass and its component organs and
the enlargement of the mass of adipose tissue that are
characteristic of the elderly result at least in part from
diminished secretion of growth hormone.
1,2
If so, the
age-related changes in body composition should be
correctable in part by the administration of human
growth hormone, now readily available as a biosyn-
thetic product.
14
In this study we administered biosynthetic human
growth hormone for six months to 12 healthy men from
61 to 81 years old whose plasma IGF-I concentrations
were below 350 U per liter, and we measured the ef-
fects on plasma IGF-I concentration, lean body mass,
adipose-tissue mass, skin (dermal plus epidermal)
thickness, regional bone density, and mandibular-
height ratio (the height of the alveolar ridge divided by
the total height of the mandible). The measurement of
the mandible was included to test the hypothesis that
the age-related involution of dental bone results in part
from the loss of stimulation by growth hormone.
1
In ad-
dition, the men were monitored for possible adverse ef-
fects of the hormone by means of interviews, physical
examinations, and standard laboratory tests. Nine men
matched for age and with similar plasma IGF-I concen-
trations served as controls.
M
ETHODS
Subjects
Healthy men who were 61 or older and living in the community
were recruited through newspaper advertisements followed by an in-
terview. Entry criteria (available from the authors on request) includ-
ed body weight of 90 to 120 percent of the standard for age, the abil-
ity to administer growth hormone to oneself subcutaneously, and the
absence of indications of major disease. Ninety-five men who an-
swered the advertisements met criteria that could be ascertained by
interview. Their plasma IGF-I concentrations were then determined
twice at an interval of four weeks. Consistent with the results of a
previous study,
13
the plasma IGF-I values in these men ranged from
100 to 2400 U per liter, with an average of 500 U per liter. Thirty-
three of the men had plasma IGF-I values of less than 350 U per liter
on both occasions. These 33 men were then further evaluated by a
medical-history taking, physical examination, differential blood
count, urinalysis, blood-chemistry tests, chest radiography, and elec-
trocardiography. Twenty-six subjects (1 black and 25 white) met all
the entry criteria and were enrolled in the 12-month protocol sum-
marized in Table 1.
Study Periods
The men were seen at regular intervals and tested as shown in Ta-
ble 1 during the first week of the first, third, and sixth months of the
base-line period. Five men dropped out of the study during these six
months (four for personal reasons and one because carcinoma of the
prostate was detected).
At the beginning of the seventh month, the 21 men who had
completed the base-line period were randomly assigned to group 1
(growth hormone group) or group 2 (control group) in a ratio of 3 to
2. The randomization table was generated by a computer program
such that in each group of five men, three would be assigned to the
growth hormone group and two to the control group. All 21 men (12
in group 1 and 9 in group 2) completed the treatment period and
constitute the study group for this report. Their clinical character-
istics are summarized in Table 2. During the first week of the sev-
enth month, the men in group 1 were instructed in the subcutane-
ous administration of recombinant biosynthetic human growth
hormone (2.6 IU per milligram of hormone; Eli Lilly). The initial
dose was 0.03 mg per kilogram of body weight, injected three times
a week at 8 a.m., the interval between injections being either one
or two days. A sample of venous blood for plasma IGF-I assay was
obtained each month 24 hours after a growth hormone injection. If
the IGF-I level was below 500 U per liter, the dose of hormone was
increased by 25 percent; if the IGF-I level was above 1500 U per li-
ter, the dose was reduced by 25 percent. The men in group 2 re-
ceived no injections. The schedule of tests for both groups during
the treatment period is shown in Table 1.
At the start of the base-line period, the project dietitian instructed
each man to follow a diet that furnished 25 to 30 kcal per kilogram.
The distribution of kilocalories among protein, carbohydrate, and fat
was approximately 15 percent, 50 percent, and 35 percent, respec-
tively. At each scheduled visit shown in Table 1, the dietitian analyzed
each man’s diet on the basis of a 24-hour dietary recall and instructed
the subjects again about the standard diet. The men were told not
to alter their lifestyles (including their use of tobacco or alcohol and
their level of physical activity) during the 12-month study period.
The study protocol was carried out with the informed consent of
each subject and with the approval of the human-research commit-
tees of the Medical College of Wisconsin, the Chicago Medical
School, and the Veterans Affairs Medical Centers in North Chicago
and Milwaukee.
Statistical Analysis
The methods used to measure each response variable and the lo-
cations where the tests were performed are described in Table 1.
*Tests included a complete bloo d count, hematocrit, blood in dexes, and the measurement af-
ter an overnight fast of plasma glucose, urea nitrogen, creatinine, uric acid, sodium, potassium,
chloride, carbon dioxide, phosphate, calcium, total protein, albumin, alkaline phosphatase, as-
partate aminotransferase, lactic dehydrogenase, bilirubin, cholesterol, triglyceride high-density
lipoprotein cholesterol, and glycosylated hemoglobin levels. Tests were performed at the
North Chicago Veterans Affairs Medical Center laboratories.
†Total body potassium levels (lean body mass and adipose-tissue mass) were measured
according to the method of Flynn et al.
15
‡Calculated as the sum of the skin thicknesses of the right and left dorsal hand and right and
left volar forearm measured w ith a Harpenden caliper according to the method o f Lawrence and
Shuster.
16
§Measured according to the method of Nagraj et al.
17
¶Measured according to the method of Goldberg et al.
18
Measured at Nichols L aboratory, Los Angeles, according to the method of Furlanetto et al.
19
**Administered to group 1 only.
Table 1. Schedule of Tests during the Base-Line
and Treatment Periods.
T
EST
B
ASE
-L
INE
P
ERIOD
T
REATMENT
P
ERIOD
MO
1
MO
3
MO
6
MO
7
MO
8
MO
9
MO
10
MO
11
MO
12
Physical examination x x x xxxxxx
Hematology* xxx xxxxxx
Urinalysis* xxx xxxxxx
Blood chemistry* xxx xxxxxx
Chest radiography x x x
Electrocardiography x x x
Echocardiography x x x
Total body potassium† x x
Skin thickness‡ x x
Bone density*§ x x
Mandibular-height ratio*¶ x x
Plasma IGF-I x x x xxxxxx
Biosynthetic growth
hormone** xxxxxx
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Copyright © 1990 Massachusetts Medical Society. All rights reserved.
Vol. 323 No. 1 EFFECTS OF HUMAN GROWTH HORMONE IN MEN — RUDMAN ET AL. 3
The interassay coefficients of variation for the response variables
were as follows: plasma IGF-I, 7.2 percent; lean body mass, 3.6 per-
cent; adipose-tissue mass, 6.9 percent; skin thickness, 5.4 percent;
and bone density, 2.3 percent (average of nine measured sites).
P values based on two-tailed, matched-pair t-tests were calculat-
ed for the comparisons between the 6-month and 12-month values
in group 1 and group 2. In addition, for each response variable the
6-month value was subtracted from the 12-month value to repre-
sent the change in each subject. P values based on two-tailed, un-
equal-variance, independent-sample t-tests were then calculated
for the comparison of the changes in response variables between
groups 1 and 2.
R
ESULTS
Clinical Observations
All the men remained healthy, and none had any
changes in the results of differential blood count, uri-
nalysis, blood-chemistry profile, chest radiography,
electrocardiography, or echocardiography during the
12-month protocol. Specifically, none had edema, fast-
ing hyperglycemia (>6.6 mmol of glucose per liter),
an increase in blood pressure to more than 160/90
mm Hg, ventricular hypertrophy, or a local reaction to
human growth hormone, nor did their serum cholester-
ol or triglyceride concentrations change significantly. In
group 1, however, both the mean (±SE) systolic blood
pressure and fasting plasma glucose concentration
were significantly higher (P<0.05 by matched-pair t-
test) at the end of the experimental period than at the
end of the base-line period (127.2±5.2 vs. 119.1±3.6
mm Hg and 5.8±0.2 vs. 5.4±0.2 mmol per liter, re-
spectively).
Plasma IGF-I Concentration
In group 1, the mean plasma IGF-I concentration
ranged from 200 to 250 U per liter throughout the
base-line period (Table 3). Within one month after the
administration of growth hormone had been initiated,
the mean IGF-I level rose to 830 U per liter (P<0.05),
and it remained near this value for the next five
months. Eight of the 12 men in group 1 required no
adjustment in their initial dose of growth hormone.
Two required an upward adjustment of 25 percent,
and two required a downward adjustment of 25 per-
cent. The mean plasma IGF-I concentration in group
2 remained in the range of 180 to 300 U per liter
throughout the base-line and treatment periods.
Lean Body Mass, Adipose-Tissue Mass, Skin Thickness,
Bone Density, and Mandibular-Height Ratio
Table 4 shows the mean values for the other re-
sponse variables at the end of the base-line period (6
months) and the end of the treatment period (12
months). There was no significant change in weight in
either group. In group 1, several response variables
had changed significantly after 12 months. Lean body
mass and the average density of the lumbar vertebrae
increased by 8.8 percent (P<0.0005) and 1.6 percent
(P<0.04), respectively, and adipose-tissue mass de-
creased by 14.4 percent (P<0.005). The sum of skin
thicknesses at four sites increased 7.1 percent (P =
0.07). The small average change in lumbar vertebral
bone density (only 0.02 g per square centimeter) was
statistically significant because of very little variability
in individual results. The bone density of the radius
and proximal femur and the ratio of the height of the
alveolar ridge to total mandibular height did not
change significantly. In group 2 none of these variables
changed significantly. The change in the lean body
mass was significantly greater in group 1 than in
group 2 (P<0.018), but the differences in changes in
skin thickness and adipose-tissue mass between
groups did not reach statistical significance in this
small series (P = 0.10 and 0.13, respectively).
*Defined as a history of myocardial infarction or electrocardiographic abnormality ascribed
to coronary artery disease.
Table 2. Clinical Characteristics of the Study Subjects.
C
HARACTERISTIC
G
ROUP
1
(N = 12) G
ROUP
2
(N = 9)
Median age (range) 67 (61–73) 68 (65–81)
Percent of ideal body weight —
median (range) 103 (94–120) 105 (99–117)
Medical conditions (no. of subjects)
Degenerative joint disease
Benign prostatic hypertrophy
Glaucoma
Cataract
Arteriosclerotic heart disease*
Gallstones
Kidney stone
Hiatus hernia
5
3
1
2
3
0
1
0
2
1
1
1
1
1
1
1
Medications (no. of subjects)
Nonsteroidal antiinflammatory drug
Pilocarpine eyedrops
Cimetidine
3
1
0
1
1
1
*Values are means ±SD. †P<0.05 for the comparison between groups.
Table 3. Effect of the Administration of Human Growth Hormone on Plasma IGF-I Concentrations in Healthy Older Men.
*
G
ROUP
P
LASMA
IGF-I
BASE
-
LINE
PERIOD TREATMENT
PERIOD
mo 1 mo 3 mo 6 mo 7 mo 8 mo 9 mo 10 mo 11 mo 12
units per liter
Group 1 240±86 230±97 230±66 830±339† 680±180† 720±350† 810±305† 810±192† 910±312†
Group 2 240±69 240±126 240±108 200±126 220±123 240±177 180±126 240±186 300±201
Downloaded from www.nejm.org on December 01, 2003.
Copyright © 1990 Massachusetts Medical Society. All rights reserved.
4 THE NEW ENGLAND JOURNAL OF MEDICINE July 5, 1990
D
ISCUSSION
The 21 men studied were representative of the ap-
proximately one third of all men 60 to 80 years old who
have plasma IGF-I concentrations of less than 350 U
per liter (as compared with a range of 500 to 1500 U per
liter in healthy men 20 to 40 years old).
4
Our findings
cannot be generalized to the approximately two thirds
of all men over 60 who have plasma IGF-I concentra-
tions of more than 350 U per liter or to women of a
similar age. Furthermore, our entry criteria focused
the study on an overtly healthy subgroup of older men.
In the absence of obesity,
4
below-normal weight,
20
or liver disease,
21
a plasma IGF-I concentration of less
than 350 U per liter in older men generally signifies
that they secrete very little growth hormone.
4
To verify
this explanation for the low plasma IGF-I concentration
in these men, it would be necessary to measure serum
growth hormone levels at frequent intervals for 24
hours or to determine the 24-hour urinary excretion of
growth hormone. We did not do this, but Ho et al. found
that the 24-hour integrated serum growth hormone lev-
el was markedly lower in the men over 55 than in men
18 to 33 years old.
22
An alternative explanation for a low
plasma IGF-I concentration is decreased production of
plasma IGF-I binding proteins. Most of the IGF-I plas-
ma is bound to these proteins, but their concentrations
vary little in healthy people who eat a normal diet.
In the 12 men in group 1, initially
low plasma IGF-I concentrations
were raised to the normal range for
young adult men by the dose of
growth hormone administered, with
no evidence of tachyphylaxis or hor-
mone resistance. The dose, approxi-
mately 0.03 mg per kilogram three
times a week, was based on pub-
lished estimates of the rate of
growth hormone secretion in young
men
23
and was comparable to or
smaller than doses given previously
to children with growth hormone
deficiency
24,25
and young adults.
10-13
The plasma IGF-I responses to this
dose in these older men were similar
in magnitude to those in younger
people. That ‘‘replacement’’ rather
than pharmacologic doses were be-
ing administered was confirmed by
the plasma IGF-I measurements,
which remained within the range for
healthy young adults (500 to 1500 U
per liter) throughout the treatment
period (Table 3). We conclude that
in aging men with low plasma IGF-I
concentrations hepatic responsive-
ness to human growth hormone is
not impaired, and the decline in
plasma IGF-I concentrations in such
men results from growth hormone
deficiency rather than growth hor-
mone resistance. The increase in plasma IGF-I levels
that occurs when growth hormone is administered to
children with growth hormone deficiency reflects not
only augmented hepatic production of IGF-I, but also
increased production of one of the binding proteins
that transport IGF-I.
26
The extent to which the pro-
duction of IGF-I binding protein is increased by the
administration of growth hormone has not yet been
studied in adults.
At the beginning of our study, adverse reactions to
human growth hormone were thought to be unlikely
because physiologic doses were being used. Further-
more, similar or larger doses have not caused undes-
ired reactions in children or young adults.
10-14,25
Never-
theless, it remained possible that this dose, when
given for six months to older subjects, might cause
some manifestation of hypersomatotropism, such as
edema, hypertension, diabetes, or cardiomegaly.
27-29
Although none of these conditions developed, there
were small increases in the mean systolic blood pres-
sure and fasting plasma glucose concentration of the
group of men who received growth hormone.
The magnitude of the increases in lean body mass
and the decreases in adipose-tissue mass (8.8 and –14.2
percent above and below base line, respectively) in the
aging men who received human growth hormone for
six months was similar to the magnitude of these re-
*Plus–minus values are means ±SD.
†P values are for the change from base line, by matched-pair t-test.
‡The difference in changes (12-month value minus 6-month value) is the average change in group 1 minus the average
change in group 2. Values in parentheses are 95 percent confidence intervals, calculated by independent-sample, unequal-
variance t-tests.
Table 4. Effect of the Administration of Human Growth Hormone on Weight, Lean
Body Mass, Adipose-Tissue Mass, Skin Thickness, and Bone Density in Healthy
Older Men.
*
V
ARIABLE
G
ROUP
E
ND
OF
B
ASE
-L
INE
P
ERIOD
E
ND
OF
T
REATMENT
P
ERIOD
P V
ALUE
†D
IFFERENCE
IN
C
HANGES
Weight (kg) 1
277.2±11.4
83.3±11.1 78.2±12.1
83.3±9.7 0.26
0.97 +1.0 (
1.4 to +3.4)
Lean body mass (kg) 1
253.0±7.4
54.2±7.1 57.7±9.1
55.2±7.3 0.0005
0.17 +3.7 (+0.7 to +6.6)
Adipose-tissue mass (kg) 1
224.1±5.0
29.0±6.4 20.6±5.6
28.0±4.0 0.05
0.43
2.4 (
5.7 to +0.8)
Sum of skin thickness at
four sites (mm) 1
29.9±1.2
9.3±0.9 10.6±1.5
9.23±0.80 0.07
0.69 +0.8 (
0.1 to +1.7)
Bone density (g/cm
2
)
Mid-shaft radius
Distal radius
Average, lumbar
vertebrae 1–4
Ward’s triangle
Greater trochanter
Femoral neck
1
2
1
2
1
2
1
2
1
2
1
2
0.74±0.10
0.76±0.10
0.37±0.07
0.34±0.04
1.23±0.12
1.29±0.25
0.70±0.14
0.70±0.17
0.85±0.13
0.81±0.15
0.92±0.15
0.89±0.14
0.74±0.12
0.71±0.07
0.36±0.08
0.33±0.05
1.25±0.13
1.29±0.26
0.69±0.13
0.70±0.17
0.85±0.13
0.81±0.13
0.91±0.14
0.85±0.14
0.85
0.09
0.12
0.26
0.04
0.64
0.15
0.69
0.72
0.55
0.53
0.14
+0.04 (
0.02 to +0.10)
0.004 (
0.03 to +0.02)
+0.006 (
0.04 to +0.05)
0.018 (
0.08 to +0.05)
+0.007 (
0.05 to +0.03)
0.029 (
0.08 to +0.03)
Mandibular-height ratio 1
20.45±0.15
0.47±0.12 0.46±0.11
0.47±0.12 0.87
0.98
0.003 (
0.07 to +0.06)
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Vol. 323 No. 1 EFFECTS OF HUMAN GROWTH HORMONE IN MEN — RUDMAN ET AL. 5
sponses in children
8,9
and young adults
10-13
treated
with similar or lower doses for three to six months, a
comparison that provides further evidence that tissue
responsiveness to growth hormone and IGF-I is not al-
tered in older men. Until now, the evidence for such a
conclusion came only from short-term nitrogen-bal-
ance experiments.
14,30-32
Salomon et al. reported that the administration of
human growth hormone in a dose of 0.49 unit per kilo-
gram per week (0.19 mg per kilogram per week) for six
months to adults 20 to 50 years old who had growth
hormone deficiency lowered the serum cholesterol con-
centration significantly.
13
Serum cholesterol concentra-
tions did not change in our study, in which the dose of
growth hormone was about half as large (0.9 mg per
kilogram per week). The divergent results could reflect
differences in the subjects’ ages, the degree of growth
hormone deficiency, the dose of hormone, or all three.
In rodents, the increase in lean body mass in re-
sponse to growth hormone is due to increases in the
volume of skeletal muscle, skin, liver, kidney, and
spleen.
1,7
In young human subjects, an enlargement of
muscle and kidney induced by growth hormone has
been documented
8-12
; other organs have not yet been
assessed. The reduction in adipose-tissue mass when
children with growth hormone deficiency are treated
with human growth hormone is associated with a re-
distribution of adipose tissue from abdominal to pe-
ripheral areas.
31
It is not known, however, whether the
increase in lean body mass and the decrease in adi-
pose-tissue mass are qualitatively as well as quantita-
tively similar in old and young human subjects.
Biosynthetic human growth hormone had no detect-
able effect on the bone density of the radius or proxi-
mal femur in the aging men, but it increased the den-
sity of the lumbar vertebrae by about 1.6 percent.
Although the decrease in bone density with advancing
age in men may be due in part to diminished secretion
of growth hormone,
1,33
longer periods of administration
of human growth hormone will be required before a fi-
nal conclusion can be drawn regarding its efficacy in
reversing that decrease. A similar interpretation applies
to the lack of increase in the mandibular-height ratio.
The findings in this study are consistent with the hy-
pothesis that the decrease in lean body mass, the in-
crease in adipose-tissue mass, and the thinning of the
skin that occur in older men are caused in part by re-
duced activity of the growth hormone–IGF-I axis, and
can be restored in part by the administration of human
growth hormone.
1,2
The effects of six months of human
growth hormone on lean body mass and adipose-tissue
mass were equivalent in magnitude to the changes in-
curred during 10 to 20 years of aging.
1,34,35
Among the
questions that remain to be addressed are the follow-
ing: What will be the benefits and what will be the na-
ture and frequency of any adverse effects when larger
numbers of elderly subjects and other doses of human
growth hormone are studied? What organs are respon-
sible for the increase in lean body mass, and do their
functional capacities change as well? Only when such
questions are answered can the possible benefits of hu-
man growth hormone in the elderly be explored. Since
atrophy of muscle and skin contributes to the frailty of
older people, the potential benefits of growth hormone
merit continuing attention and investigation.
We are indebted to Dr. Ruth Hartmann, Milwaukee Veterans Af-
fairs Medical Center, for assistance in the preparation of this report.
R
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... Here, we explore the possible effects of progerin on the somatotroph axis, which diminishes in aging and aging-related disorders (12,13). We find that progerin accumulates outside of the nucleus and progressively impairs the insulin-like growth factor 1 (IGF-1)/ Akt signaling pathway by interacting with IGF-1 receptor (IGF-1R). ...
... The importance of the somatotroph axis (growth hormone and IGF-1) in maintaining organismal homeostasis is evidenced by its attenuation in normal aging (12) and premature aging (41). Besides decreased IGF-1, few other factors are known to be involved in diminished IGF-1/Akt signaling. ...
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Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24 −/− mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA -associated progeroid disorders.
... The rst puri cation method of GH was developed in 1956 (9). After that, GH has been clinically used to cure the growth retardation of children and adults with the shortage of GH (10). ...
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... (Marcus et al., 1990;Russell et al., 1996; Butterfield et al., 1997) and increases lean mass and decreases fat mass(Crist et al., 1988;Richelsen et al., 1994; Holloway et al., 1994; Lange et al., 2000;Rudman et al., 1990; Jørgensen et al., 1989;Yarasheski et al., 1995).An increase in the thickness of the sarcoplasmic reticulum (T-tubules) was observed in this study (Figure 1) may demonstrate that the increase of fluid retention the intercellular of muscle fiber. The use of GH causes, on body composition of the fluid retention in muscle tissue(Marcus et al., 1990). ...
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... These data are consistent with previous studies from our laboratory [24] observing the effects of GH administration on body composition. GH treatment for both GHD adults and elderly people has been shown to improve several parameters related to body composition [11,25], for example reducing waist perimeter, which has been proven to be a strong predictor of cardiovascular risk [26]. The SGI increase that was seen in our data in old GH-treated rats was also associated with an enhancement in body weight gain as compared to the weight loss observed in old untreated animals; this confirms that in old rats GH exerts a more important anabolic activity on muscles than lipolytic effects on fat tissue. ...
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... A growth hormone deficiency in adults leads to a decreased bone mineral density; however, it is not clear whether growth hormone supplementation is beneficial for aging-related bone loss. Clinical studies have shown that growth hormone activates osteoblasts and stimulates bone remodeling in older men, women, and postmenopausal patients with OP but has no long-term effects on the spine and proximal femur bone density (Brixen, Nielsen, Mosekilde, & Flyvbjerg, 1990;Rudman et al., 1990;Ghiron et al., 1995). A meta-analysis has shown that the incidence of adverse events in patients treated with growth hormone was 24.8 ± 28.6% compared to 6.1 ± 7.8% in the control group. ...
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We evaluated the effects of recombinant human GH (rhGH) in 16 men and women more than 60 yr of age. After 10 days of dietary equilibration and control collections, subjects were randomly assigned to receive 0.03, 0.06, or 0.12 mg/kg rhGH by daily injection for 7 days. A brisk rise in circulating somatomedin-C (insulin-like growth factor-I) occurred in all subjects, and this rise was dose dependent. rhGH produced striking changes in nitrogen retention, sodium excretion, and the parathyroid-vitamin D axis. Twenty-four-hour urinary nitrogen excretion decreased from 8.00 +/- 0.33 to 5.01 +/- 0.33 g (P less than 0.001), and sodium excretion decreased from 45.9 +/- 2.96 to 21.2 +/- 3.48 mmol/day (P less than 0.001). Serum calcium concentrations did not change, but serum inorganic phosphorus levels of 1.08 +/- 0.04 mmol/L at baseline increased significantly after rhGH treatment to 1.33 +/- 0.04 mmol/L (P less than 0.001). Increases were also observed in circulating PTH (53.2 +/- 6 vs. 39.5 +/- 4.2 ng/L; P less than 0.01) and calcitriol (82.8 vs. 65.8 pmol/L; P less than 0.05). A rise in serum osteocalcin (10.3 +/- .86 vs. 8.0 +/- 0.5 micrograms/L; P less than 0.05) was accompanied by increased urinary excretion of hydroxyproline (628 +/- 63 vs. 406 +/- 44 mumol/day; P less than 0.01). Despite the reduction in sodium excretion, marked increases were observed in urinary calcium (6.04 +/- 0.97 vs. 3.27 +/- 0.40 mmol/day; P less than 0.01). rhGH significantly impaired oral glucose tolerance and reduced insulin sensitivity, but was otherwise well tolerated and produced no systematic changes in weight or blood pressure. The results of this study indicate that rhGH requires further study as a potential agent for attenuating or reversing the loss of muscle and bone in elderly people.
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Somatomedin-C (Sm-C) or insulin-like growth factor-I, GH and physical fitness decline with age. Physical fitness and muscle strength are important determinants of bone density, and the age-related decline in bone density may be related in part to a decline in fitness and muscle strength. Also, Sm-C has been shown to stimulate osteoblasts in vitro and may effect skeletal muscle mass. We postulated that the age-related decline in GH and Sm-C levels may be related to an age-related decline in physical fitness and/or muscle strength, and the effect of physical fitness and muscle strength on bone may be mediated by Sm-C. We, therefore, examined the relationship between circulating GH and Sm-C levels and physical fitness, as determined by predicted maximal oxygen uptake (VO2max) in 134 normal women, 34 of whom were postmenopausal. In a subgroup of 62 women overall muscle strength was estimated as the sum of the Z-sores for biceps, quadriceps, and grip strength. Overall muscle strength correlated with GH levels (r = 0.28; P less than 0.02), but not with Sm-C levels. There was a significant positive relationship between plasma Sm-C levels and VO2max in all women (r = 0.47; P less than 0.001) and in the postmenopausal group alone (r = 0.05; P less than 0.01). Although there was a significant negative relationship between Sm-C and age (r = -0.36; P = 0.001), VO2max was a better independent predictor than age (r = 0.47; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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Total body potassium (TBK) data calculated from longitudinal measurements over 18 y of 40K by whole-body counting of 564 male and 61 female healthy humans in a 2-pi liquid scintillation counter show little change in females younger than 50 y compared with males of those ages. Males show less TBK from 41 y onward as they age, with most rapid rate of loss between 41 and 60 y. Females have a rapid loss of TBK when they are older than 60 y; the loss is at a greater rate than that of males. Percent total body fat calculated from total body weight and lean body mass (LBM) derived from TBK document greater adiposity in females at all ages except ages 51-60 y when females are similar to males in change in percent fat per year per centimeter.
Article
A double-blind, placebo-controlled, crossover study on the effects of 4 months' growth hormone (GH) treatment was carried out in 22 GH-deficient adults (8 women, 14 men; mean [SEM] age 23.8 [1.2] years). 1 patient was withdrawn because of oedema. Mean total body weight of the other 21 did not change, whereas mean muscle volume of the thigh, estimated by computerised tomography (CT), was significantly higher after GH than after placebo (70.0 [3.7] vs 66.3 [3.1] ml/0.8 cm cross-sectional slice). The mean adipose tissue volume of the thigh and subscapular skinfold thickness fell significantly during GH treatment. Growth hormone caused a small increase in the isometric strength of the quadriceps muscles and a significant rise in exercise capacity (60.8 [7.2] vs 54.2 [6.6] kJ). The heart rate both at rest and after maximum exercise was low during the placebo period and increased significantly during GH treatment. Blood pressure and echocardiographic wall mass of the left ventricle did not change during the study. Growth hormone increased both mean glomerular filtration rate and renal plasma flow from a subnormal level on placebo to a level comparable with that of an age-matched control group. The filtration fraction did not change. Urinary albumin excretion was in the low normal range and was not affected by GH treatment. Finally, GH treatment normalised mean circulating levels of insulin-like growth factor 1 (IGF-1), which were low after the placebo period (96 [9] micrograms/l placebo; 224 [28] micrograms/l GH). These findings suggest that GH, in a conventional replacement dose, has several potentially beneficial effects in GH-deficient adults and therefore encourage future long-term trials.