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Effects of Human Growth Hormone in Men over 60 Years Old


Abstract and Figures

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
, M.D., A
G. F
, M.D., H
S. N
, M.D., G
A. G
, M.D.,
Y. L
, M.D., A
F. G
, D.D.S., R
A. S
, P
, M.D., I
W. R
, B.S.,
E. M
, P
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 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
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.
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;
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.
N middle and late adulthood all people experience
a series of progressive alterations in body composi-
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.
It has recently been pro-
posed, however, that reduced availability of growth hor-
mone in late adulthood may contribute to such
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-
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
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-
Plasma IGF-I concentrations decline with ad-
vancing age in healthy adults.
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.
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.
The concomitant decline in plasma concentrations of
both hormones supports the view that the decrease in
IGF-I results from diminished growth hormone secre-
Second, diminished secretion of growth hor-
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Copyright © 1990 Massachusetts Medical Society. All rights reserved.
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-
These alterations in body composition caused by
growth hormone deficiency can be reversed by re-
placement doses of the hormone, as experiments in
and adults 20 to 50 years old
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.
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.
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.
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.
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,
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.
‡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
§Measured according to the method of Nagraj et al.
¶Measured according to the method of Goldberg et al.
Measured at Nichols L aboratory, Los Angeles, according to the method of Furlanetto et al.
**Administered to group 1 only.
Table 1. Schedule of Tests during the Base-Line
and Treatment Periods.
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.
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.
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-
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.
(N = 12) G
(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
Arteriosclerotic heart disease*
Kidney stone
Hiatus hernia
Medications (no. of subjects)
Nonsteroidal antiinflammatory drug
Pilocarpine eyedrops
*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.
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
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Copyright © 1990 Massachusetts Medical Society. All rights reserved.
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).
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,
below-normal weight,
or liver disease,
a plasma IGF-I concentration of less
than 350 U per liter in older men generally signifies
that they secrete very little growth hormone.
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.
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
and was comparable to or
smaller than doses given previously
to children with growth hormone
and young adults.
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.
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.
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.
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.
Weight (kg) 1
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
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
29.0±6.4 20.6±5.6
28.0±4.0 0.05
2.4 (
5.7 to +0.8)
Sum of skin thickness at
four sites (mm) 1
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
Mid-shaft radius
Distal radius
Average, lumbar
vertebrae 1–4
Ward’s triangle
Greater trochanter
Femoral neck
+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
0.47±0.12 0.46±0.11
0.47±0.12 0.87
0.003 (
0.07 to +0.06)
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Copyright © 1990 Massachusetts Medical Society. All rights reserved.
sponses in children
and young adults
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.
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.
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
In young human subjects, an enlargement of
muscle and kidney induced by growth hormone has
been documented
; 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.
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,
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.
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.
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.
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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. ...
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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Premature ovarian failure (POF) is a mysterious disorder in women when the ovaries stop producing oocytes. Even though many causes are proposed as the pathogenesis of POF, the true underlying cause for the majority of POF cases has remained unidentified. Since POF severely interferes with fertility and it is a devastating diagnosis for women, itis necessary to develop new therapies to reduce the long-term health consequences from POF. To investigate the function and underlying mechanism of growth hormone (GH) in the development of ovaries, follicles, and oocytes under the condition of POF, we used the intraperitoneal injection of cisplatin to construct the POF mice model. Then, we assessed the function of GH in POF. Herein, we report that GH efficiently promoted the ovarian coefficient, development of follicles, and the number of oocytes. Mechanistically, GH prevented alternations of mitochondrial ultrastructure to stabilize the membrane potential, consequently reducing ROS level and early apoptosis of oocytes in POF mice. Furthermore, GH treatment stabilized the serum levels of Inhibin B (INHB) and anti-Mullerian hormone (AMH) and regulated the expressions of apoptosis-related factors, growth hormone receptor (GHR), and insulin-like growth factor-I (IGF - I). Thus, we concluded that GH supplementation promotes mitochondrial biogenesis to protect the oocyte from POF through the GHR/IGF-I signaling pathway.
... (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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The objective of this present study was to identify the ultrastructural changes of the gastrocnemius muscle, promoted by subcutaneous administration of growth hormone. We used 06 rats (Wistar Rats) randomly divided into 02 groups: sedentary rats without administration of GH (RSSH), rats with a sedentary lifestyle with administration of GH (RSCH). The subcutaneous administration of GH occurred in the period of eight weeks after the animals were sacrificed and the transverse section of the gastrocnemius muscle removed and prepared according to routine analysis transmission electron microscopy (TEM). The cuts were performed using Ultramicrotome sorvall Porter Blum MT2 and analyzed in the CM 100 Philips. The results of the administration of GH showed an increase in the diameter of the sarcoplasmic reticulum and accumulation of glycogen. Thus, it was concluded that the administration of GH accompanied causes of morphological alterations of muscle tissue examined, such as the changes in the dimensions and shape of the muscle fibers, increased thickness of the sarcoplasmic reticulum, accumulation of glycogen in the muscle fibers of the muscle gastrocnemius. Article History
... 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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In order to investigate the possible beneficial effects of GH administration on the aging process, 24-month-old rats of both sexes and 10-month-old SAMP8 mice were used. Male rats showed increased fat content and decreased lean body mass together with enhanced vasoconstriction and reduced vasodilation of their aortic rings compared to young adult animals. Chronic GH treatment for 10 weeks increased lean body mass and reduced fat weight together with inducing an enhancement of the vasodilatory response by increasing eNOS and a reduction of the constrictory responses. Old SAMP8 male mice also showed insulin resistance together with a decrease in insulin production by the endocrine pancreas and a reduced expression of differentiation parameters. GH treatment decreased plasma levels and increased pancreatic production of insulin and restored differentiation parameters in these animals. Ovariectomy plus low calcium diet in rabbits induced osteoporosis Titanium implants inserted into these rabbit tibiae showed after one month lesser bone to implant (BIC) surface and bone mineral density (BMD). Local application of GH in the surgical opening was able to increase BIC in the osteoporotic group. The hippocampus of old rats showed a reduction in the number of neurons and also in neurogenesis compared to young ones, together with an increase of caspases and a reduction of Bcl-2. GH treatment was able to enhance significantly only the total number of neurons. In conclusion, GH treatment was able to show beneficial effects in old animals on all the different organs and metabolic functions studied.
... 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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Osteoporosis (OP) is known as a silent disease in which the loss of bone mass and bone density does not cause obvious symptoms, resulting in insufficient treatment and preventive measures. The losses of bone mass and bone density become more severe over time and an only small percentage of patients are diagnosed when OP-related fractures occur. The high disability and mortality rates of OP-related fractures cause great psychological and physical damage and impose a heavy economic burden on individuals and society. Therefore, early intervention and treatment must be emphasized to achieve the overall goal of reducing the fracture risk. Anti-OP drugs are currently divided into three classes: antiresorptive agents, anabolic agents, and drugs with other mechanisms. In this review, research progress related to common anti-OP drugs in these three classes as well as targeted therapies is summarized to help researchers and clinicians understand their mechanisms of action and to promote pharmacological research and novel drug development.
... The role of the somatotropic axis has long been investigated in the context of healthspan and lifespan extension, dating back to the report on the positive impact that human growth hormone (HGH) has on the lean body mass when administered in late adulthood [13] that addresses the former, and a report of dwarf, growth hormone (GH)-deficient mice, addressing the latter [14]. The GH/insulin-like growth factor 1 (IGF-1) axis has been subject to extensive scrutiny, with numerous cellular and animal models being used to establish a positive link between disruption of its components and increased longevity, the details of which have been covered by comprehensive, in-depth reviews [15,16]. ...
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Cellular, small invertebrate and vertebrate models are a driving force in biogerontology studies. Using various models, such as yeasts, appropriate tissue culture cells, Drosophila, the nematode Caenorhabditis elegans and the mouse, has tremendously increased our knowledge around the relationship between diet, nutrient-response signaling pathways and lifespan regulation. In recent years, combinatorial drug treatments combined with mutagenesis, high-throughput screens, as well as multi-omics approaches, have provided unprecedented insights in cellular metabolism, development, differentiation, and aging. Scientists are, therefore, moving towards characterizing the fine architecture and cross-talks of growth and stress pathways towards identifying possible interventions that could lead to healthy aging and the amelioration of age-related diseases in humans. In this short review, we briefly examine recently uncovered knowledge around nutrient-response pathways, such as the Insulin Growth Factor (IGF) and the mechanistic Target of Rapamycin signaling pathways, as well as specific GWAS and some EWAS studies on lifespan and age-related disease that have enhanced our current understanding within the aging and biogerontology fields. We discuss what is learned from the rich and diverse generated data, as well as challenges and next frontiers in these scientific disciplines.
... For example, older individuals with sarcopenia are recommended to increase total daily protein intake from 0.8 to 1-1.5 g/ kg/day in conjunction with vitamin D supplementation and regular RT (20-30 min, thrice weekly) to slow and prevent atrophy [18]. There is also substantial evidence to show that pharmacological agents such as testosterone [19,20], nandrolone [21,22], and growth hormone [23,24] are effective in attenuating the effects of sarcopenia. However, little is known about the efficacy of dietary and pharmacological interventions in persons with motor complete SCI. ...
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Purpose: The purpose of this review was to compare all intervention modalities aimed at increasing skeletal muscle mass (SMM) in the paralysed limbs of persons with chronic (>1-year post-injury), motor complete SCI. Methods: A systematic review of EMBASE, MEDLINE, Scopus and SPORTDiscus databases was conducted from inception until December 2021. Published intervention studies aimed to increase SMM (measured by MRI, CT, ultrasound, muscle biopsy, or lean soft tissue mass by DXA) in the paralysed limbs of adults (>18 years) with SCI were included. Results: Fifty articles were included that, overall, demonstrated a high risk of bias. Studies were categorised into six groups: neuromuscular electrical stimulation (NMES) with and without external resistance, functional electrical stimulation cycling, walking and standing-based interventions, pharmacological treatments, and studies that compared or combined intervention modalities. Resistance training (RT) using NMES on the quadriceps produced the largest and most consistent increases in SMM of all intervention modalities. Conclusions: Current evidence suggests that clinical practise aiming to increase SMM in the paralysed limbs of persons with motor complete SCI should perform NMES-RT. However, more high-quality randomised control trials are needed to determine how training variables, such as exercise volume and intensity, can be optimised for increasing SMM.
Aging is associated with several changes in the endocrine system, possibly due to altering hormone secretion patterns, disordered feedback-feedforward networks, low sensitivity of tissues to hormone action, and reduced bioavailability of hormones. Overall, aging-related hormonal changes appear to worsen the frailty of aging, as they are associated with a reduction in bone and muscle mass, physical strength, and vitality. They may also be associated with increased visceral adiposity, insulin resistance, and therefore cardiometabolic disorders. However, clinical symptoms and signs of age-related endocrine alterations are difficult to distinguish from the effects of aging itself. Moreover, aging-related hormonal alterations may only be adaptive, as some studies show that people with certain hormonal profiles live longer. Studies have generally been contradictory in terms of the benefits of hormone replacement therapies in the elderly. Nevertheless, despite the paucity of high-quality evidence, hormonal preparations are being used for anti-aging purposes.
Dementia is not a single ailment, but a term that describes symptoms of impairment in memory, communication, and thinking, which occurs mainly in the elderly person. About 50 million people have dementia worldwide, and about ten million people are reported per day. The intensity of the symptoms varies from patient to patient. Hypertension and hyperlipidemia have been found to increase the risk of the emergence of dementia directly or indirectly. Further, the treatment with the antihypertensive and antihyperlipidemic drugs produces beneficial effects in the treatment of dementia. In the present chapter, the authors described the role of hypertension and hyperlipidemia in the pathogenesis of dementia and described the impact of antihypertensive and antihyperlipidemic drugs for the treatment of dementia.
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Neuroenhancement concerns the improvement of a person’s mental properties, abilities, and performance. The various techniques of neuroenhancement offer new opportunities of such improvement, but also come with substantive perils. Neuroenhancement thus involves significant normative challenges for individual persons as well as for society as a whole. This expert report provides a concise overview of the contemporary debate on neuroenhancement. It discusses the definition, techniques and targets of neuroenhancement and examines arguments for and against it at the level of individual persons, social interaction, and social policy.
The clinical characteristics and body composition of eight hypopituitary dwarfs (10.2-21.6 yr) were analyzed before and after 6 and 12 mo of growth hormone therapy. 2 IU 3 times/wk. Before treatment, growth rate was 1.8 +/- 0.7 cm/yr, height age was 2.0-12.8 yr less, and bone age 2.0-11.1 yr less than chronologic age. Total body water (TBW), lean body mass (LBM), extracellular water (ECW), and intracellular water (ICW) were below normal for chronologic age, but normal for height. Muscle mass (MM) was below normal for age and height. During HGH therapy, growth rate was 7.1 +/- 1.6 cm/yr in the first 6 mo and 7.8 +/- 1.4 cm/yr during the next 6 mo; the ratio of change in height age to change in chronologic age was greater than or equal to 1.0 in all patients and the ratio of change in bone age to change in height age was 1.2 in one patient and less than or equal to 1.0 in the others. TBW, LBM, ECW, and ICW increased according to height increments; however, MM increased at a faster rate than expected from the height gains. Also, a relative or absolute loss of total body fat was recorded during the first 6 mo of therapy. It is suggested (1) that among the body composition parameters studied, muscle mass is the tissue most closely reflecting the lack of HGH and also its therapeutic benefits and (2) evaluation of body composition in hypopituitary dwarfs in response to HGH therapy shows striking changes not reflected by the determination of stature or weight alone.
The development of a radioimmunoassay for somatomedin-C has for the first time made it possible to discriminate between serum concentrations of a single peptide or closely related group of peptides and the net somatomedin activity measured by less specific bioassay and radioreceptor techniques. Antibodies to human somatomedin-C were raised in rabbits using a somatomedin-C ovalbumin complex as the antigen. A variety of peptide hormones at concentrations up to 1 muM are not recognized by the antibody. Insulin at concentrations >0.1 muM cross reacts in a non-parallel fashion; purified somatomedin-A is only 3% as active as somatomedin-C; and radiolabeled cloned rat liver multiplication stimulating activity does not bind to the antibody. Immunoreactive somatomedin-C can also be quantitated in the sera of a variety of subhuman species. Unusual assay kinetics, which are manifest when reactants are incubated under classic "equilibrium" assay conditions, appear to result from the failure of (125)I-somatomedin-C to readily equilibrate with the somatomedin-C serum binding protein complex. It is, therefore, necessary to use nonequilibrium assay conditions to quantitate somatomedin-C in serum. With this assay it is possible to detect somatomedin-C in normal subjects using as little as 0.25 mul of unextracted serum. Serum somatomedin-C concentrations in normal subjects were lowest in cord blood and rose rapidly during the first 4 yr of life to near adult levels. In 23 normal adult volunteers, the mean serum somatomedin-C concentration was 1.50+/-0.10 U/ml (SEM) when compared to a pooled adult serum standard. 19 children with hypopituitary dwarfism had concentrations below 0.20 U/ml. 17 of these were below 0.1 U/ml, the lower limit of sensitivity of the assay. The mean concentration in 14 adults with active acromegaly was 6.28+/-0.37 U/ml (SEM), five times greater than the normal volunteers. Significant increases in serum somatomedin-C concentrations were observed in 8 of 10 hypopituitary children within 72 h after the parenteral administration of human growth hormone. Three patients with Cushing's disease had elevated serum somatomedin-C concentrations (2.61+/-0.14 U/ml [SEM]). Three patients with hyperprolactinemia had normal concentrations (1.74+/-0.11 U/ml [SEM]).The important new discovery brought to light by quantitation of immunoassayable somatomedin in patient sera is that all previously used assays detect, in addition to somatomedin-C, serum substances that are not under as stringent growth hormone control.
Forearm skin collagen, dermal thickness and collagen density were measured in a large number of normal subjects as a standard reference for future studies. Skin collagen decreased with age and was less in the females at all ages. There is a direct relationship between skin collagen and dermal thickness but variations in collagen density in disease limit the use of dermal thickness as a guide to changes in its collagen content.
We measured by photon absorptiometry the bone density at six sites in 65 nursing home men aged 57-85 y and in 25 independent community men aged 57-80 y. Average bone density in the community men ranged from 97% to 105% of age-matched normal men. In the nursing home men these values ranged from 71% to 92% of age-matched normal men (p less than 0.05 for comparison with the community men). About 50% of the nursing home men but none of the community men had a value less than 70% of age-matched normal men at one or more sites. Among the institutionalized men bone densities at all six sites (in g/cm2) were significantly (p less than 0.05) and directly correlated with body weight but were not significantly correlated with height, age, principal or secondary diagnoses, continuing medications, or functional level.
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.
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)
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.
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.