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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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... Age-related decline in the secretion of growth hormone (GH) [6], a condition called somatopause, plays a role in both primary and secondary sarcopenia. Since GH is a strong anabolic agent in muscle, GH treatment increases lean body mass [7][8][9][10] and decreases relative adipose-tissue mass [9,10]. The known side effects of pharmacological GH, however, are fluid retention and insulin resistance, which are dose dependent. ...
... Age-related decline in the secretion of growth hormone (GH) [6], a condition called somatopause, plays a role in both primary and secondary sarcopenia. Since GH is a strong anabolic agent in muscle, GH treatment increases lean body mass [7][8][9][10] and decreases relative adipose-tissue mass [9,10]. The known side effects of pharmacological GH, however, are fluid retention and insulin resistance, which are dose dependent. ...
Full-text available
Sarcopenia is an age-related condition characterized by progressive loss of muscle mass and strength. Age-related decline in the secretion of growth hormone (GH), a condition called somatopause, is thought to play a role in sarcopenia. As pharmacological GH has adverse effects, we attempted to increase physiological GH. While the relationship between chewing and ghrelin levels has been studied, there are no reports on the relationship between chewing and GH. The aim of this study was to clarify the effects of chewing on the muscle anabolic hormones serum GH and plasma ghrelin. Thirteen healthy adults ingested a chewy nutrition bar containing 5.56 g of protein, 12.71 g of carbohydrate, and 0.09 g of fat on two different days, chewing before swallowing in one trial and swallowing without chewing in the other. Blood samples were taken before and after ingestion (0, 15, 30, and 60 min); GH, acylated ghrelin, glucose, insulin, amino acids, and lactate were measured. Two-way repeated ANOVA revealed a significant difference in the GH concentrations between the “Chew trial” and “Swallow trial” in females (p = 0.0054). However, post-hoc analyses found no statistically significant difference at each time point. The area under the curve of the percentage increase in GH was significantly increased in the “Chew trial” compared with the “Swallow trial” in females (12,203 ± 15,402% min vs. 3735 ± 988% min, p = 0.0488). Chewing had no effect on glucose, insulin, amino acids, or lactate concentrations. Thus, we found that chewing a protein supplement rather than swallowing it without chewing elevates the blood GH concentration. These results serve as a rationale for larger research and longitudinal studies to confirm the impacts of chewing on GH secretion.
... Serum GH levels are high in the mid-fetus stage and at birth, and then decline rapidly within a few weeks to reach prepubertal levels by 6 months of age, and then peak at puberty. GH secretion after puberty is inversely proportional to age (6), with GH secretion decreasing gradually by approximately 15% every decade after the third decade of life. Therefore, some scholars suspect that reduced GH secretion is among the important causes of human aging. ...
... The effects of GH on the human body are not limited to promoting human growth and development; in fact, GH improved symptoms of atherosclerosis, enhanced bone density and bone remodeling, and reduced the risk of fracture (7). rhGH leads to increased muscle strength, fat metabolism, bone density, and skin thickness in middle-aged and elderly patients (6). Rosen et al. (8) found that rhGH also led to more energy, emotional stability, and sexual function in middle-aged and elderly people. ...
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Aging is a biological process in which the environment interacts with the body to cause a progressive decline in effective physiological function. Aging in the human body can lead to a dysfunction of the vital organ systems, resulting in the onset of age-related diseases, such as neurodegenerative and cardiovascular diseases, which can seriously affect an individual’s quality of life. The endocrine system acts on specific targets through hormones and related major functional factors in its pathways, which play biological roles in coordinating cellular interactions, metabolism, growth, and aging. Aging is the result of a combination of many pathological, physiological, and psychological processes, among which the endocrine system can achieve a bidirectional effect on the aging process by regulating the hormone levels in the body. In this paper, we explored the mechanisms of growth hormone, thyroid hormone, and estrogen in the aging process to provide a reference for the exploration of endocrine mechanisms related to aging.
... Somatotropin (Genotropin) GH receptor activation [506] 168. ...
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Demonstrating biosimilarity entails comprehensive analytical evaluations, clinical pharmacolo-gy profiling, and efficacy testing for at least one medical indication in patients. These require-ments are stipulated by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The costliest element—efficacy testing—can be waived if other compliance benchmarks are satisfied, including comparing functional pharmacodynamic (PD) biomarkers, even when they do not di-rectly correlate with clinical outcomes. Most biological drugs, such as monoclonal antibodies (mAbs), lack identifiable PD biomarkers. The FDA has employed various 'omics' technologies to identify potential PD biomarkers, including proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. Although these efforts provide a robust scientific basis for estab-lishing biosimilarity, they are neither practical nor necessarily superior to existing functional biomarkers, such as receptor binding and mode-of-action outcomes. As we report for the first time, these functional biomarkers can effectively serve as PD indicators for all FDA-licensed bio-logical drugs. We recommend that the FDA consider officially listing these functional biomarkers to expedite and reduce the cost of biosimilar development, thereby increasing the accessibility of biological drugs. PD surrogates, like the receptor binding and pharmacokinetic profiles, are more robust and offer a rational solution to finding PD markers to compare for establishing biosimi-larity.
...  Several studies and systematic reviews [43][44][45]  Taking in totality of evidences, international guidelines strongly recommend against the use of GHRT to treat ageing, ageing-related conditions, or as performance enhancer [3]. ...
... 63 Noteworthy, adenoviral delivery of telomerase in aged mice was demonstrated to enhance cardiac function after acute myocardial infarction, improve muscle coordination and kidney and liver performance, reduce insulin resistance and subcutaneous fat reduction, increase bone mineral density, and extend life expectancy without triggering a growth in cancer frequency. 3,72 In the early 1990s, the potential of human growth hormone (hGH) as an anti-aging agent acting to increase lean body mass, decrease adipose tissue mass, and increase bone mineral density was reported 44 , and hGH supplements became available, sparking controversy questioning their safety and effectiveness. Later on, aging research was focused on the genetic pathways of aging, revealing a complex system of intracellular signaling pathways and higher-order processes. ...
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Aging is a dynamic, time-dependent process characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Anti-aging research has a long history throughout civilization, with many efforts put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified and multiple strategies aiming to promoting healthy aging and extending the lifespan including lifestyle adjustments, medical treatments, and social programs, have been developed. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent research. We review the advances in knowledge and delineate trends in research advancement on aging factors and attributes, as well as the anti-aging strategies across time, geography, and development pipelines. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, the age-associated diseases, with attention to brain aging and brain health support, as well as the major biochemical processes associated with aging. We further assess the state-of-the-art anti-aging strategies and explore their correlations with age-related diseases. Well-recognized and novel, currently evaluated anti-aging agents have been summarized. Finally, we review clinical applications of anti-aging products with their development pipelines. We hope this review will be helpful for apprehending the current knowledge in the field of aging progression and prevention, in effort to further solve the remaining challenges and fulfil its potential.
... Moreover, GH can promote the secretion of thymosin by thymic stromal cells, stimulate the production of antibodies by B lymphocytes, improve the activities of natural killer cells (NK cells) and macrophages, and thus participate in the function regulation of the immune system in the human body [28]. GH also has the effect of anti-aging [33,34] and regulates emotional and behavioral activities [35]. GH is also one of the important stress hormones secreted by adenohypophysis. ...
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Human growth hormone (GH) is the indispensable hormone for the maintenance of normal physiological functions of the human body, including the growth, development, metabolism, and even immunoregulation. The GH is synthesized, secreted, and stored by somatotroph cells in adenohypophysis. Abnormal GH is associated with various GH-related diseases, such as acromegaly, dwarfism, diabetes, and cancer. Currently, some studies found there are dozens or even hundreds of GH proteoforms in tissue and serum as well as a series of GH-binding protein (GHBP) proteoforms and GH receptor (GHR) proteoforms were also identified. The structure-function relationship of protein hormone proteoforms is significantly important to reveal their overall physiological and pathophysiological mechanisms. We propose the use of proteoformics to study the relationship between every GH proteoform and different physiological/pathophysiological states to clarify the pathogenic mechanism of GH-related disease such as pituitary neuroendocrine tumor and conduct precise molecular classification to promote predictive preventive personalized medicine (PPPM / 3P medicine). This article reviews GH proteoformics in GH-related disease such as pituitary neuroendocrine tumor, which has the potential role to provide novel insight into pathogenic mechanism, discover novel therapeutic targets, identify effective GH proteoform biomarker for patient stratification, predictive diagnosis, and prognostic assessment, improve therapy method, and further accelerate the development of 3P medicine.
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Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.
Thanks to increasing life expectancy with its concomitant number of aging men, medicine is forced to focus more strongly on the endocrine situation of this age group. In men, although there is no climacteric, there is a gradual decline in testosterone, and levels may well remain within the normal range of younger men. In some men, however, levels fall below normal. When this occurs in conjunction with characteristic symptoms, it may be genuine late-onset hypogonadism (LOH) or functional hypogonadism. In these cases, testosterone substitution may be considered and must be closely monitored.
Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are the frontline treatment of sarcopenia, with no drug currently approved for this indication. However, new therapeutic options are emerging. In this review, we evidenced that only very few trials have focused on sarcopenia/sarcopenic patients. Most drug trials were performed in different clinical older populations (e.g., men with hypogonadism, post-menopausal women at risk for osteoporosis), and their efficacy were tested separately on the components of sarcopenia (muscle mass, muscle strength and physical performances). Results from trials testing the effects of Testosterone, Selective Androgen Receptor Modulators (SARMs), Estrogen, Dehydroepiandrosterone (DHEA), Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), GH Secretagogue (GHS), drug targeting Myostatin and Activin receptor pathway, Vitamin D, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), or β-blockers, were compiled. Although some drugs have been effective in improving muscle mass and/or strength, this was not translated into clinically relevant improvements on physical performance. Finally, some promising molecules investigated in on-going clinical trials and in pre-clinical phase were summarized, including apelin and irisin.
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.