1990 Dr. Daniel Rudman Study
New England Journal of Medicine,
Volume 323 July 5, 1990 Number 1
EFFECTS OF HUMAN GROWTH HORMONE IN MEN OVER 60 YEARS OLD
Daniel Rudman, M.D., Axel G. Feller, M.D., Hoskote S. Nagraj,
M.D., Gregory A. Gergans, M.D., Pardee Y. Lalitha, M.D., Allen F. Goldberg,
D.D.S., Robert A. Schlenker, Ph.D., Lester Cohn, M.D.,
Inge W. Rudman, B.S., and Dale E. Mattson, Ph.D.
Abstract Background.
The declining activity of the growth hormone-insulin-like growth factor
1 (IGF-1) axis with advancing age may contribute to the decrease in lean
body mass and the increase in mass of adipose tissue that occur with aging.
Methods. To test
this hypothesis, we studied IGF-1 plasma with 21 healthy men from 61 to
81 years old who had plasma IGF-1 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-1 levels were measured monthly. At the
end of each period, we measured lean body mass, the mass of adipose tissue,
skin thickness (epidermis plus dermis), and bone density at nine skeletal
sites.
Results. In group
1, the mean plasma IGF-1 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<0.05 in each instance).
Skin thickness increased .1 percent (P = 0.0). 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.
Conclusions. 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
occurs in old age. (New England Journal of Medicine, 1990; 323:1-6).
In middle and late adulthood, all
people experience a series of progressive alterations in body composition.
The lean body mass shrinks and the mass of adipose tissue expands. The
contraction in lean body mass reflects atrophic processes in skeletal
muscle, liver, kidney, spleen, skin, and bone.
These structural changes have been
considered unavoidable results of aging. It has recently been proposed,
however, that reduced availability of growth hormone in late adulthood
may contribute to such changes. This proposal is based on two lines of
evidence. First, after about the age of 30, the secretion of growth hormone
by the pituitary gland tends to decline. 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 directly. Growth hormone
secretion can be measured indirectly, however measure the 24-hour secretion
of the substance measure the 24-hour secretion of the substance directly.
Growth hormone secretion can be measured indirectly, however, by measuring
the plasma concentration of insulin-like growth factor I (IGF-I, also
known as somatomedin C), which is produced and released by the liver and
perhaps other tissues in response to growth hormone. There is little diurnal
variation in the plasma IGF-I concentration, and measurements of it are
therefore a convenient indicator of growth hormone secretion. Plasma IGF-I
concentrations decline with advancing 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 hormone secretion becomes smaller or disappear with advanced
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 secretion.
Second, diminished secretion of growth hormone 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 tissue. These alterations
in body composition caused by growth hormone deficiency can be reversed
by replacement doses of the hormone, as experiments in rodents, children,
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 biosynthetic 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 effects on plasma IGF-I concentration, lean boy 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). In addition, the men
were monitored for possible adverse effects of the hormone by means of
interviews physical examinations, and standard laboratory tests. Nine
men matched for age and with similar plasma IGF-I concentrations served
as controls.
Methods
Subjects
Healthy men who were 61 or older
and living in the community were recruited through newspaper advertisements
followed by an interview. Entry criteria (available from the authors on
request) included body weight of 90 to 120 percent of the standard for
age, the ability to administer growth hormone to oneself subcutaneously,
and the absence of indications of major disease. Ninety-five men who answered
the advertisement 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 electrocardiography. Twenty-six subjects (1 black and 25 white) met
all the entry criteria and were enrolled in the 12-month protocol summarized
in Table 1.
Study Periods
The men were seen at regular intervals
and tested as shown in Table 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).
Table 1. Schedule of Tests During the Base-Line and Treatment
Periods
SUNDAY, JUNE 16, 1990 7:08:56 AM SUNDAY, JUNE 16, 1990 7:08:56
AM SUNDAY, JUNE 16, 1990 7:08:56 AM
Test |
Base Line Period |
Treatment Period |
|
Mo |
Mo |
Mo |
Mo |
Mo |
Mo |
Mo |
Mo |
Mo |
|
1 |
3 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
Physical Examination |
x |
x |
x |
x |
x |
x |
x |
x |
x |
Hematology* |
x |
x |
x |
x |
x |
x |
x |
x |
x |
Urinalysis* |
x |
x |
x |
x |
x |
x |
x |
x |
x |
Blood Chemistry* |
x |
x |
x |
x |
x |
x |
x |
x |
x |
Chest radiography |
x |
|
x |
|
|
|
|
|
x |
Electrocardiography |
x |
|
x |
|
|
|
|
|
x |
Echocardiography |
x |
|
x |
|
|
|
|
|
x |
Total body
potassium† |
|
|
x |
|
|
|
|
|
x |
Skin thickness‡ |
|
|
x |
|
|
|
|
|
x |
Bone density*Š |
|
|
x |
|
|
|
|
|
x |
Mandibular-heightratio*þ` |
|
|
x |
|
|
|
|
|
x |
Plasma IFG1¶ |
x |
x |
x |
x |
x |
x |
x |
x |
x |
Biosynthecic growth hormone** |
|
|
|
x |
x |
x |
x |
x |
x |
† Total body potassium levels (lean body
mass and adipose tissue-mass) were measured according to the method of
Flynn et al. 15
‡ Calculated at the sum of skin thickness
of the right and left dorsal hand and left volar forearm measured with
a Harpenden caliper according to the method of Lawrence and Shuster.16
*Š Measured according to the method of
Nagraj et al.17
*þ` Measured according to the method of
Goldberg et al.18
¶ Measured at Nichols Laboratory, Los
Angeles, according to the method of Furlanetto et al.19
** Administered to group 1 only.
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 continue
the study group for this report. Their clinical characteristics are summarized
in Table 2. During the first week of the seventh month, the men in group
1 were instructed in the subcuntaneious 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 8a.m., the interval between injections being either
one or two days. A sample of venious 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 w as increased
by 25 percent; if the IGF-I level was above 1500 U per liter, the dose
was reduced by 25 percent. The men in group 2 received no injections.
The schedule of tests of both groups during the treatment period is shown
in Table 1.
At the start of the base-line period,
the project dietician instructed each man to follow a diet that furnished
25 to 30 k.cal per kilogram. The distribution of kilocalories among protein,
carbohydrate, and fat was approximately 15 percent, 50 percent, and 35
percent, respectively. At each scheduled visit shown in Table 1, the dietitian
analyzed each man's diet on the basis of a 24-hours 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 or 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 committees of the Medical College of Wisconsin, the
Chicago Medical School, and the Veterans Affairs Medical Centers in North
Chicago and Milwaukee.
Table 2. Clinical Characteristics
of the Study Subjects.
Characteristic |
Group1 (N=12) |
Group2 (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 |
5 |
2 |
Benign prostatic
hypertrophy |
3 |
1 |
Glaucoma |
1 |
1 |
Cataract |
2 |
1 |
Arterioscleotic heart disease* |
3 |
1 |
Gallstones |
0 |
1 |
Kidney stone |
1 |
1 |
Hiatus hernia |
0 |
1 |
|
Medications (no. of subjects) |
|
|
Nonsteroidal antiinflamitory drug |
3 |
1 |
Pilocarpine eyedrops |
1 |
1 |
Cimetidine |
0 |
1 |
* Defined as history of myocardial infraction
or electrocardiographic abnormality ascribed to coronary artery disease.
Statistical Analysis
The methods used to measure each
response variable and the locations where the tests were performed are
described in Table 1. The interassay coeficients of variation for the
response variables were as follows: plasma IGF-I, 7.2 percent; lean body
mass, 3.6 percent; 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 calculated for the comparisons between the 6-month and 12-month
values in group1 and group 2. In addition, for each response variable
the 6-month value was subtracted from the 12-month value to represent
the change in each subject. P values based on two-tailed, unequalvariance,
independent-sample t-tests were then calculated for the comparison of
the changes in response variables between groups 1 and 2.
Results
Clinical Observations
All the men remained healthy, and none had any changes in the results
of differential blood count, urinalysis, blood-chemistry profile, chest
radiography, electrocardiography, or echocardiography during the 12-month
protocol. Specifically, none had edema, fasting 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 cholesterol or triglyceride concentrations
change significantly. In group 1, however, both the men (" 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" 3.6mm
Hg and 5.8" 0.2 vs. 5.4" 0.2 mmol per liter, respectively).
Table 3. Effect of the Administration of Human Growth Hormone
on Plasma IGF-1 Concentrations in Healthy Older Men*
|
Plasma IGF-1 |
|
Base Line Period |
Treatment Period |
|
Mo 1 |
Mo. 3 |
Mo.6 |
Mo.7 |
Mo.8 |
Group 1 |
240 +-86 |
230+-97 |
230+-66 |
830 +-339H |
680+-180H |
|
Mo. 9 |
Mo.10 |
Mo.11 |
Mo.12 |
|
|
720+-350H |
810+-305H |
810+-192H |
910+-312H |
|
Group 2 |
Mo 1 |
Mo. 3 |
Mo. 6 |
Mo. 7 |
Mo.8 |
|
240+-69 |
240+-126 |
240+-108 |
200+-126 |
220+-123 |
|
Mo. 9 |
Mo.10 |
Mo.11 |
Mo.12 |
|
|
240+-177 |
180+-126 |
240+-186 |
300+-201 |
|
*Values are means +-SD
HP<0.05 for the comparison between groups
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 percent. 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 response 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 decreased
by 14.4 percent (P<0.005). The sum of skin thicknesses at four sites
increased .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).
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
Variable |
Group |
End of Base Line
Period |
End of Base Line
Period |
P ValueH |
Difference in ChangesI |
Weight (kg) |
1 2 |
77.2+-11.4 83.3+-11.1 |
78.2+-12.1 83.3+-9.7 |
0.26 0.97 |
+1.0 (-1.4 to
3.4) |
Lean Body Mass
(kg) |
1 2 |
53.0+-7.4 54.2+-7.1 |
57.7+-9.1 55.2+-7.3 |
0.05 0.17 |
+3.7 (+0.7 to
+6.6) |
Adipose Tissue
Mass (kg) |
1 2 |
24.1+-5.0 29.0+-6.4 |
20.6+-5.6 28.0+-4.0 |
0.05 0.43 |
-2.4 (-5.7 to
+0.8) |
Sum of Skin Thickness
at four Sites (mm) |
1 2 |
9.9+-1.2 9.3+-0.9 |
10.6+-1.5 9.23+-0.80 |
0.07 0.69 |
+0.8 (-0.1 to
+1.7) |
Bone Density (g/cm2)
Mid-shaft radius |
1 2 |
0.74+-0.10 0.76+-0.10 |
0.74+-0.12 0.71+-0.07 |
0.85 0.09 |
+0.40 (-0.02 to
+0.10) |
Distal radius |
1 2 |
0.37+-0.07 0.34+-0.04 |
0.36+-0.08 0.33+-0.05 |
0.12 0.26 |
-0.004 (-0.03
to +0.02) |
Average lumbar
vertebrae 1-4 |
1 2 |
1.23+-0.12 1.29+-0.25 |
1.25+-0.13 1.29+-0.26 |
0.04 0.64 |
+0.006 (-0.04
to +0.05) |
Ward's Triangle |
1 2 |
0.70+-0.14 0.70+-0.17 |
0.69+-0.13 0.70+-0.17 |
0.15 0.69 |
-0.018 (-0.08
to +0.05) |
Greater trochanter |
1 2 |
0.85+-0.13 0.81+-0.15 |
0.85+-0.13 0.81+-0.13 |
0.72 0.55 |
+0.007 (-0.05
to +0.03) |
Fremoral neck |
1 2 |
0.92+-0.15 0.89+-0.14 |
0.91+-0.14 0.85+-0.14 |
0.53 0.14 |
-0.029 (-0.08
to +0.03) |
Mandibular height ratio |
1 2 |
0.45+-0.15 0.47+-0.12 |
0.46+-0.11 0.47+-0.12 |
0.87 0.98 |
-0.003 (-0.07
to +0.06) |
* Plus-minus values are means +-SD
HP values are for the
change from base line, by matched pair 1-test
I The difference in
changes (12 month value minus 6 month value) is the average in group 1
minus the average change in group 2. Values in parentheses are 95 percent
confidence intervals, calculated by independent-sample, unequal-variance
1-test.
Discussion
The 21 men studied were representative
of the approximately 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 IGFK-I concentrations of more than
350 U per liter or to women of a similar age. Furthermore, our entry criteria
focused the study on an overly 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 level 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 plasma 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 hormone resistance. The dose, approximately 0.03 mg
per kilogram three times a week, was based on published estimates of the
rate of growth hormone secretion in young men and was comparable to or
smaller than doses given previously to children with growth hormone deficiency
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 being 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 responsiveness to human growth hormone is not impaired,
and the decline in plasma IGF-1 concentrations in such men results from
growth hormone deficiency rather than growth hormone resistance. The increase
in plasma IGF-1 levels that occurs when growth hormone is administered
to children with growth hormone deficiency reflects not only augmented
hepatic production of IGF-1, but also increased production of one of the
binding proteins that transport IGF-1. The extent to which the production
of IGF-1 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. Furthermore, similar or larger
doses have not caused undesired reactions in children or young adults.
Nevertheless, 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,k or cardiomegaly. Although none
of these conditions developed, there were small increases in the mean
systolic blood pressure 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 responses in children and young adults treated with similar or
lower doses for three to six months, a comparison that provides further
evidence that tissue responsiveness to growth hormone and IGFK-I is not
altered in older men. Until now, the evidence for such a conclusion came
only from short-term nitrogen-balance experiments.
Salomon et al. reported that the
administration of human growth hormone in a dose of 0.49 unit per kilogram
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
concentration significantly. Serum cholesterol concentrations did not
change in our study, in which the does 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 response to growth hormone is due to increases in the volume
of skeletal muscle, skin, liver, kidney, and spleen. 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 redistribution of adipose
tissue from abdominal to peripheral areas. It is not known however, whether
the increase in lean body mass and the decrease in adipose-tissue mass
are qualitatively as well as quantitatively similar in old and young human
subjects.
Biosynthetic human growth hormone
had no detectable effect on the bone density of the radius or proximal
femur in the aging men but it increased the density 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 final 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 hypothesis that the decrease in lean body mass, the
increase in adipose-tissue mass, and the thinning of the skin that occur
in older men are caused in part by reduced 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 incurred during 10 to 20 years of aging. Among the questions that
remain to be addressed are the following: What will be the benefits and
what will be the nature and frequency of any adverse effects when larger
numbers of elderly subjects and other doses of human growth hormones are
studied? What organs are responsible 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 human 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.
|