Journal ofGerontology: MEDICAL SCIENCES Copyright 1998 by The Geronlological Society of America

1998, Vol. 53A, No. 3, M183-M187

Side Effects Resulting From the Use

of Growth Hormone and Insulin-like Growth Factor-I
as Combined Therapy to Frail Elderly Patients
Dennis H. Sullivan,12 William J. Carter,12 Winston R. Warr,1 and Linda H. Williams12

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'Geriatric Research, Education and Clinical Center, John L. McClellan Memorial Veterans Hospital,
department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

Background. The objective of this study was to examine the relationship between serum IGF-I concentration and
the incidence of side effects of therapy with recombinant human growth hormone (rhGH) and recombinant human
insulin-like growth factor-I (rhIGF-I).

Methods. Thirteen high-risk, undernourished elderly males were started on a 15-day course of rhGH and rhIGF-I by
subcutaneous injection. The dose of rhGH was held constant at .0125 mg/kg/day, whereas the dose of rhIGF-I was
increased in a stepwise fashion from 10 |xg/kg to the targeted dose of 40 u.g/kg twice a day.

Results. Nine subjects completed the protocol and reached the full target dose of both hormones. Fluid retention,
gynecomastia, and orthostatic hypotension were the most common complications. The hormone injections increased
the serum concentration of IGF-I (from 72.7 ± 40.9 to 483.7 ±251.4 T)g/ml, p = .001) and IGFBP-3 (from 1.82 ± 0.66
to 2.72 ±1.18 mg/L,/? = .012), and decreased serum albumin (from 34.3 ± 5.5 to 31.4 ± 4.6 g/L, p = .009). The magni-
tude of the initial increase in the serum IGF-I concentration was a powerful risk factor for severe orthostatic hypoten-
sion, diffuse myalgias, and drug-induced hepatitis. There was no association between the serum IGF-I concentration
and fluid retention or gynecomastia.

Conclusions. Treatment of the undernourished frail elderly with the anabolic agents rhGH and rhIGF-I at the speci-
fied dosages may produce undesirable side effects including fluid retention, gynecomastia, and orthostatic hypotension.
Although these agents hold therapeutic promise, they must be used with caution in this high-risk population.

T HE anabolic agents recombinant human growth hor-

mone (rhGH) and recombinant human insulin-like
growth factor-I (rhIGF-I) may be useful adjuvants in the
treatment of undernourished elderly patients recuperating
from a serious illness. When used alone or in combination,
these agents promote nitrogen retention and may accelerate
muscle accretion and functional recovery (1-5). However,
there is very little experience using such agents to treat frail
elderly hospitalized patients. The objectives of this non-
blinded experiment were to establish the safety of a treat-
ment regimen consisting of rhGH and rhIGF-I in a speci-
fied dosage range and to determine the relationship
between the serum IGF-I concentration and the incidence
of side effects.
METHODS
Patients
Undernourished, frail elderly patients admitted to a geri-
atric rehabilitation and recuperative care unit (GRU) were
targeted for study entry. All subjects were metabolically
stable, free of metastatic cancer and limiting end organ dis-
ease, and had experienced a recent functional decline as a
consequence of an acute illness from which they were recu-
perating. The exclusion criteria were: (a) a nutrient intake
(on an admission three-day calorie count) less than 90% of
predicted requirements [as described previously (6)]; (b)
uncontrolled diabetes; (c) severe cognitive impairment;
and, (d) ambulation judged to be an unattainable goal.
Thirteen subjects met all inclusion and exclusion criteria
and were recruited into the study. Each received oral and
written explanations of the nature of the study and the pos-
sible risk involved prior to signing an informed consent, in
accordance with the ethical standards of the Subcommittee
on Human Studies, Little Rock (AR) VA Hospital, and the
Human Research Advisory Committee of the University of
Arkansas for Medical Sciences. The age, race, and gender
of each study subject are shown in Table 1. All subjects
were male, and 83% were White. The mean age of the
study population (± SD) was 77 ± 4 years (range 70-86).
Based on the outcomes model developed in previous GRU
studies (7), all 13 subjects were high-risk patients. The
average predicted probability of developing an in-hospital
complication for this group was 39 ± 18%.
Protocol
In addition to the standard comprehensive GRU admis-
sion assessment, which included a complete history and
physical exam, each subject completed an evaluation of
functional status using the Katz Index of ADL scale (8), a
set of 14 anthropometric measurements (9), and a bioelec-
trical impedance study (Bio-Analogies, Inc, Beverton, OR,
Model ELG-82). All anthropometric measurements were
obtained by the same individual using a standardized mea-

M183
M184 SULLIVANETAL.

Table 1. Profile of the 13 Study Subjects

Day 1 Day 5 Day 16* Complication

Days
of Study Weight IGF-I IGFBP3 IGF-I IGFBP3 IGF-I IGFBP3 category j
O
Subject Age Race Completed (kg) BMI (T)g/ml) (mg/L) Cng/mi) (mg/L) Cng/mi) (mg/L) A B c
1 73 W 0 48.2 13.6 121.0 — — — — — 0 0 0
2 86 W 0 70.0 24.9 45.4 — — — — — 0 0 0
3 75 W 2 67.3 20.7 12.2 — — — — — 1 0 0
4 81 B 16 14.8 37.5 1.1 64.5 1.5 147.0 1.4 0 0 0

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46.5
5 83 B 16 68.0 21.2 17.4 1.2 90.6 1.4 415.0 1.7 0 1 0
6 80 W 16 53.2 17.8 77.8 1.2 132.0 1.3 157.0 1.0 0 0 1
7 76 W 16 45.3 14.7 68.2 1.9 150.0 2.6 318.0 2.3 0 1 0
8* 75 W 11 46.5 16.1 30.0 0.8 218.0 1.4 148.0 1.4 0 1 0
9 76 W 16 66.5 22.3 45.0 1.7 247.0 2.7 568.0 3.6 1 0 0
10 70 W 16 63.0 18.3 111.0 2.2 292.0 2.8 762.0 3.0 0 0 1
11 79 W 16 50.0 17.3 155.0 3.2 305.0 3.6 880.0 4.1 0 0 1
12 74 W 16 63.1 21.2 66.4 1.7 419.0 2.5 520.0 4.2 1 0 0
13 78 W 16 73.0 24.5 76.0 2.2 481.0 3.0 586.0 3.2 1 0 0

•Study day 11 labs used for subject 8.

f0 = no complication, 1 = complication.
Category A complication = orthostatic hypotension, diffuse myalgias, or drug-induced hepatitis.
Category B complication = worsening congestive heart failure or peripheral edema requiring treatment with furosemide.
Category C complication = post-discharge gynecomastia.

surement protocol as described previously (9). Total body
water, lean body mass, and fat mass were calculated based
on the results of the bioelectrical impedance study.
After the body composition studies were completed, each
subject was started on a 15-day course of rhGH (Nutropin,
gift from Genentech, South San Francisco, CA) and rhlGF-
I (also a gift from Genentech). The dose of each hormone
was based on ideal body weight (IBW) or actual weight,
whichever was lower. Each study subject received .0125
mg/kg/day of rhGH by subcutaneous injection at 0700
hours throughout their 15-day course (or until early with-
drawal). Beginning on study day 1, each study subject was
started on rhIGF-I at 10 |xg/kg given subcutaneously twice
a day at 0700 and 1900 hours (for a total daily dose of 20
(xg/kg). If tolerated, the dose was increased to 20 |xg/kg
subcutaneously b.i.d. on day 5, and 40 |xg/kg subcuta-
neously b.i.d. on day 9. As described subsequently, the
development of complications in some of the subjects
resulted in a temporary suspension or discontinuation of
both drugs.
Prior to receiving the first dose of the study drugs, fasting
blood specimens were obtained for determination of serum
IGF-I and insulin-like growth factor binding proteins 1, 2,
and 3 (IGFBP-1, -2, and -3) concentration and a chemistry
profile including electrolytes (K+,Na+, Cl~, CO2), albumin,
total protein, glucose, phosphorus, calcium, and liver func-
tion studies. The chemistry profile was measured by autoana-
lyzer using standard laboratory techniques. Throughout the
study, the fasting blood specimens for determination of IGF-I
and IGFBPs were promptly centrifuged and stored at -70°C
until assayed. The batched specimens were assayed at one
time. After acid-ethanol extraction from its carrier proteins,
IGF-I was measured by radioimmunoassay kits obtained
from the Nichols Institute of Diagnostics (San Juan Capis-
trano, CA) (10). In our lab, this assay has an intra-assay coef-
ficient of variation of 5.4%, and the inter-assay coefficient of
variation of 12.7%. According to normative data provided by
the manufacturer, the mean IGF-I value for a population of
healthy volunteers (ages 40-67 years) is 148.6 T|g/mL (95%
confidence interval 54.0-328.5) (10). The lower limit of sen-
sitivity of the assay is approximately 1.4 T|g/ml. The IGFBP
assays were performed by Endocrine Sciences Laboratory
(Kalabosa Hills, CA). IGFBP-3 was measured by a competi-
tive binding radioimmunoassay using rabbit polyclonal antis-
era specific for human IGFBP-3 and purified recombinant
human IGFBP-3 as tracer (11). The intra- and interassay
coefficients of variation from this lab are 9% and 10%,
respectively. The lower limit of sensitivity of the assay is 0.3
mg/ml. IGFBP-2 was measured in the same fashion by a
competitive binding radioimmunoassay. The intra- and
interassay coefficients of variation are 6.6% and 8.9%,
respectively. The lower limit of sensitivity of the assay is 50
nig/ml. IGFBP-1 was measured using a two-site immuno-
chemiluminometric assay (ICMA). In this procedure,
IGFBP-1 present in the sample is "sandwiched" between
pairs of monoclonal antibodies that are either immobilized
on polystyrene beads or in liquid phase and labeled with a
chemiluminscent tag. The intra- and interassay coefficients
of variation are 5.4% and 12.7%, respectively. The lower
limit of sensitivity of the assay is .01 T}g/ml.
Each day the patient received rhIGF-I/rhGH the follow-
ing measurements were obtained: (a) fasting weight; (b)
fasting glucose and potassium; and (c) a fingerstick blood
glucose measured by glucometer at 1130, 1600, 2230, and
0300 hours. On study days 1, 5, 10, and 16, the admission
serum profile was repeated prior to the next dose of rhlGF-
I. For the first three patients, vital signs were obtained every
hour for 3 hours after each injection of rhIGF-I, and a
serum potassium was obtained 1.5-2 hours after the first
rhIGF-I injection of the day on study days 1, 5, and 10. In
no case did the 2-hour post-treatment serum potassium
decline to less than 3.5 mmol/L.
 GROWTH HORMONE AND IGF-I THERAPY
Throughout the study, each patient was monitored for the
development of adverse reactions to rhGH and rhIGF-I
administration including facial or peripheral edema, tem-
poromandibular joint pain, arthralgias, myalgias, flushing,
worsening orthostatic hypotension, fatigue, headaches,
dyspnea, tachycardia, benign intracranial hypertension, and
gynecomastia. On the last day of the protocol, the func-
tional assessment and bioelectrical impedance study were
repeated. After discharge from the hospital, subjects were
followed on a scheduled basis by phone for 6 months to
determine if they developed gynecomastia or any of the
other above-mentioned symptoms.
Statistics
The data were analyzed using SAS Institute software (12).
Univariate repeated measures analysis of variance (with no
grouping factor) was used to test for significant differences in
serum IGF-I and binding protein concentrations over time.
When more than two time points were involved, Tukey's Stu-
dentized range was used for post-hoc testing for significant
differences between time groupings. The unpaired r-test was
used to compare complication-group means for serum pro-
tein concentrations. The results are reported as means, stan-
dard deviations, and p-values for the contrasts of interest.
Pearson's correlation coefficient and least squares regression
were used to evaluate the correlation between admission
variables and change in serum IGF-I concentration.
RESULTS
Clinical Outcomes
Four subjects were withdrawn prior to completing the pro-
tocol (Table 1). Two were withdrawn on the first day because
of medical instability (subject 1 had recurrence of undiag-
nosed chest pain, and subject 2 had recurrence of orthostatic
hypotension after intravenous fluids were discontinued).
Subject 3, with idiopathic thrombocytopenia, was withdrawn
on the third day because of profound orthostatic hypotension,
anemia, and guaiac positive stools. Although a subacute gas-
trointestinal bleed secondary to gastritis was determined to
be the probable cause of the anemia, the rhIGF-I may have
contributed to the orthostatic hypotension. A fourth subject
(subject 8) was withdrawn on the eleventh day because of an
exacerbation of respiratory distress secondary to chronic
restrictive pulmonary disease, worsening congestive heart
failure, and aspiration pneumonia. Although initially stabi-
lized, he developed similar complications a week later and
died. Because of his frail state, this subject had been started
on half of the calculated initial dose of both rhGH and
rhIGF-I (.00625 mg/kg/day and 5 |xg/kg b.i.d., respectively).
These reduced dosages were well tolerated, and the full cal-
culated initial dose of both hormones was initiated on day 5.
No further dosage adjustments were made prior to the onset
of his clinical deterioration. Although fluid retention caused
by the hormone injections may have contributed to his initial
bout of congestive heart failure, his death was not believed to
be related to the study medications.
Nine subjects completed the protocol and reached the
full target dose of both hormones. Fluid retention, gyneco-
mastia, and orthostatic hypotension were the most common
M185
complications developing in this group. Subjects 5 and 7
developed peripheral edema and other signs of congestive
heart failure during the second week of the protocol. After
treatment with furosemide, both returned to baseline and
were able to complete the study. Four subjects developed
transient tender gynecomastia during (subject 5) or within 7
to 14 days after completing the study (subjects 6, 10, and
11). Two were evaluated and found to have normal serum
testosterone, follicle-stimulating hormone (FSH), luteiniz-
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ing hormone (LH), and prolactin levels Study medications
were withheld for two days from subject 13 because of
hypokalemia and orthostatic hypotension. After three of
four antihypertensives were discontinued and his blood
pressure stabilized, the subject resumed the protocol with-
out further problems.
Two other subjects developed complications that ap-
peared to be caused by the study medications. Subject 9,
who had a history of a left hemispheric cerebral vascular
accident (CVA), developed a constant dull pain in his right
arm and side on study day 11. Within four days of receiving
the last dose of the. study medications his symptoms
resolved completely. Subject 12 had a rise in serum glu-
tamic-oxaloacetic transaminase (SGOT) and serum glu-
tamic-pyruvic transaminase (SGPT) between the 10th and
15th study day peaking at 1.5-2.0 times normal, which
immediately returned to baseline 24 hours after the last
dose of hormones. During this same time period, this sub-
ject also developed mild fasting hyperglycemia. He had
longstanding insulin-requiring diabetes, but had been taken
off insulin earlier in the hospitalization because of poor
nutrient intake, weight loss, and hypoglycemia. At admis-
sion to the GRU, his appetite was adequate (i.e., met the
study entry criteria) and his blood sugars were well con-
trolled without insulin. The hyperglycemia developed in
parallel with a progressive improvement in his appetite and
was readily controlled with reinstitution of insulin at the
previously used dose. No subject developed hypoglycemia.
Relationship Between Serum Hormone Concentrations
and Complications
The effect of the hormone therapy on the serum IGF-I
concentration and the relationship between serum IGF-I and
the risk of developing a complication were examined. Ten
subjects were included in these analyses, the nine subjects
who completed the protocol and subject 8, who was with-
drawn on the 11th day (Table 1). For all 10 subjects, serum
IGF-I and IGFBP-3 rose significantly by day 16 (Tabie 2),
and the degree of change was directly correlated with the risk
of developing severe orthostatic hypotension, diffuse myal-
gias, or drug-induced hepatitis. Compared to the other seven
subjects within the study completion group, the three sub-
jects who developed such complications had significantly
higher concentrations of serum IGF-I on day five (382.3 ±
121.2 vs 178.9 ± 95.0 Tig/ml, p = .020), a greater increase in
the concentration of serum IGF-I from study admission to
day five (319.9 ± 105.4 vs 107.9 ± 64.4 T|g/ml, p = .004) and
a more marked change in the ratio of IGF-I to IGFBP-3 by
the fifth study day (106.4 ± 35.9 vs 46.6 ± 35.2 fig/mg, p =
.040). The relationship between complications and the IGF-I
concentration on day 16 did not reach significance.
M186 SULLIVANETAL.
Table 2. Serum IGF-I and Binding Protein Concentration in Response to Therapy in 10 Subjects Completing Study
Day 1 Day 5
IGF-I Cng/ml) 68.4 ± 40.9 239.9 ±137.6
IGFBP-1 Cng/ml)§ 44.9 ± 31.2 37.2 ± 39.0
IGFBP-2 Cng/ml)§ 1457.2 ±473.1 1311.0 ± 494.9
IGFBP-3 (mg/mL)§ 1.72 ± 0.70 2.28 ± 0.81
*Serum binding proteins were not measured on day 10.
fProbability that the measurements are the same over time as determined by ANOVA with repeated measures.
JDays 1, 5, and 16 are all significantly different from each other by post-hoc analysis (see text for details).
§IGFBP—Insulin-like growth factor binding protein.
Of the 13 admission variables evaluated (Table 3), the
triceps skinfold thickness was the most powerful predictor
of the change in the serum concentration of IGF-I from
study admission to day 5. The greater the amount of subcu-
taneous fat, the greater the day 5 serum IGF-I concentration
Although the hormone therapy appeared to cause or con-
tribute to the development of other complications, the risk of
developing such complications was not correlated with the
serum IGF-I concentration on any study day or the change
in IGF-I from study admission to completion. A premorbid
condition predisposing to fluid retention was a risk factor for
the development of worsening peripheral edema and con-
gestive heart failure and was present in all three of the sub-
jects who required treatment with furosemide.
DISCUSSION
All subjects who entered this study had clinically signifi-
cant protein-energy nutritional deficits and multiple comor-
bid conditions that placed them in a high-risk category.
Their average expected probability of developing a clini-
cally significant in-hospital complication was nearly 40%.
These patients were targeted for study because they repre-
sent a clinically important high-risk group. Up to 61% of
hospitalized elderly patients have similar protein-energy
nutritional deficits at admission or develop them prior to
discharge (13). Such patients are at increased risk of devel-
oping life-threatening in-hospital complications with the
likelihood increasing in direct proportion to the severity of
the nutritional deficits (7,14,15). For those undernourished
elderly patients who survive hospitalization, their nutri-
tional deficits place them at increased risk of early hospital
readmission and one-year mortality (16,17). Establishing
the feasibility and safety of rhGH and rhIGF-I in the treat-
ment of undernourished elderly patients is the first step in
evaluating the potential benefits of this therapeutic combi-
nation in improving outcomes in this high-risk population.
The rationale for using rhGH and rhIGF-I as combined
therapy for undernourished frail elderly patients is sup-
ported by a recent study, which demonstrated that the com-
bination of rhGH and rhIGF-I treatment in calorically
restricted humans is substantially more anabolic than either
agent used alone (3). This may be partially related to the
fact that with liver disease (18), sepsis (19), severe trauma
or illness (20), and starvation, there is an uncoupling of the
GH/somatomedin axis. Although GH levels may rise con-
siderably, the plasma concentration of IGF-I remains de-
pressed. Because the subjects targeted for this study were
Day 10* Day 16 pt value
408.7 ±221.5
—
450.1 ±259.7 .oou
.654
39.5 ± 37.6
— 1151.3 ±575.1 .080
— 2.59 ± 1.19 .001$
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all undernourished and still recuperating from recent ill-
nesses, they are unlikely to have an optimal IGF-I response
to rhGH administration. As with the calorie-restricted sub-
jects, combined therapy is likely to be more effective than
either agent used alone.
The findings from this study suggest that frail elderly
patients appear to be at particular risk for developing unto-
ward effects of rhGH and rhIGF-I therapy. Several of the
subjects developed fluid retention, gynecomastia, or ortho-
static hypotension during or immediately after participating
in the study. In all cases, the rhGH and rhIGF-I combina-
tion appeared to cause, or at least contribute to, these prob-
lems. Each of these conditions is a known side effect of
rhGH or rhIGF-I therapy (3,21-23).
In a retrospective evaluation of the relationship between
clinical response and serum hormone concentrations, we
found that certain complications, notably severe orthostatic
hypotension, diffuse myalgias, and drug-induced hepatitis,
developed in the subjects with the most marked initial
increase in serum IGF-I concentration and IGF-I to IGFBP-
3 ratio. The relationship between IGF-I concentration on
day 16 and the development of such complications was less
marked. This suggests that these complications were a
result of the rapid rise in the free serum concentration of
IGF-I. In the population evaluated in this study, all subjects
were at, or were less than, their ideal body weight. For this
reason, total body weight was used as the basis for calculat-
ing the dose of both rhGH and rhIGF-I. Consequently, thin-
ner subjects received a relatively smaller dose of both hor-
mones in relationship to lean body mass. This difference in
dosage was apparently significant, as reflected by the fact
that body fat mass (as indicated by triceps skinfolds, BMI,
or body composition analysis) was a strong predictor of
serum IGF-I concentration. To avoid these types of compli-
cations, it may be important to use a lower dose of one or
both hormones, titrate the dosage upward more slowly, or
base the dosage on lean body mass. The likelihood of clini-
cally significant fluid retention or gynecomastia was not
related to the rate of change or peak serum IGF-I concen-
tration. The risk of developing complications needs further
evaluation in controlled trials.
In this study, none of the subjects developed hypogly-
cemia. However, only subjects who were maintaining an
adequate nutrient intake were recruited into the study. In the
future, it will be important to examine the effects of com-
bined therapy with rhGH and rhIGF-I on glucose
metabolism in patients on less than optimal nutrient intakes.
A possible benefit of rhGH/rhIGF-I therapy might be the
 GROWTH HORMONE AND IGF-I THERAPY M187

Table 3. Factors Predictive of Change tor I by use of both agents simultaneously. J Clin Invest 1993;91:
in Serum IGF-I Concentration From Study Admission to Day 5 391-396.
4. Pape GS, Friedman M, Underwood LE, Clemmons DR. The effect of
Correlation growth hormone on weight gain and pulmonary function in patients
Admission Variable p- value Coefficient with chronic obstructive lung disease. Chest. 1991 ;99:1495— 1500.
5. Jiang ZM, He GZ, Zhang SY, et al. Low-dose growth hormone and
Serum albumin .914 .04 hypocaloric nutrition attenuate the protein-catabolic response after
Weight .061 .61 major operation. Ann Surg. 1989;210:513-524.
Body mass index .020 .72 6. Sullivan DH. The utility of an admission assessment to predict in-hos-
Weight as a percentage of usual weight .150 -.49 pital nutrient intake. J Am GeriatrSoc. 1994;42:478-480.
Weight as a percentage of ideal weight .017 .73 7. Sullivan DH, Walls RC. Impact of nutritional status on morbidity in a

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Percentage of body mass as fat .058 .62
Percentage of weight lost in previous year .863 .06
Waist-to-hip ratio .808 -.09
Age .196 -.45
Katz Index of ADL score* .654 -.16
Biceps skinfold thickness .006 .80
Thigh skinfold thickness .033 .67
Triceps skinfold thickness .002 .84
* ADL = activities of daily living.
attainment of positive nitrogen balance and repletion of lean
body mass at a relatively low volitional nutrient intake such
as that which many frail recuperating patients are likely to
maintain. The patients who entered this study were repre-
sentative of elderly high-risk male patients. Whether the
results are applicable to females is yet to be established.
Although the anabolic agents rhGH and rhIGF-I hold
therapeutic promise, they must be used with caution in the
undernourished frail elderly. Combination therapy with
these agents in the specified dosages is associated with the
development of fluid retention, gynecomastia, and ortho-
static hypotension. Using a lower dose or dosing these hor-
mones on the basis of lean body mass may reduce the inci-
dence of complications.
ACKNOWLEDGMENTS
This research was supported in part by a grant from the Department of
Veterans Affairs, a faculty development grant from the University of
Arkansas for Medical Sciences, and Genentech, Inc. The authors are grate-
ful to the clinical staff on the GRU, J. L. McClellan Memorial Veterans
Hospital, for their assistance with this project; to Dr. Robert C. Walls,
Division of Biometry, Department of Medicine, University of Arkansas for
Medical Sciences, for his review of the statistical procedures used in this
report; and especially Melinda Bopp and Leigh Hite, Division of Aging,
Department of Medicine, University of Arkansas for Medical Sciences, for
their hard work and dedication to this study and review of this report.
Address correspondence to Dr. Dennis H. Sullivan, Geriatric Research,
Education and Clinical Center (182/LR), John L. McClellan Memorial
Veterans Hospital, 4300 West 7th Street, Little Rock, AR 72205.
REFERENCES
1. Clemmons DR, Underwood LE. Role of insulin-like growth factors
and growth hormone in reversing catabolic states. Horm Res. 1992;38
(Suppl 2):37^0.
2. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH. Growth hor-
mone treatment in growth hormone-deficient adults. I. Effects on mus-
cle mass and strength. J Appl Physiol. 1991;70:688-694.
3. Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement
of the anabolic effects of growth hormone and insulin-like growth fac-
population of geriatric rehabilitation patients. J Am Geriatr Soc. 1994;
42:471^77.
8. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW, Cleveland
MA. Studies of illness in the aged. The index of ADL: a standardized
measure of biological and psychosocial function. JAMA. 1963; 185:
914-919.
9. Sullivan DH, Patch GA, Baden AL, Lipschitz DA. An approach to
assessing the reliability of anthropometries in elderly patients. J Am
GeriatrSoc. 1989;37:607-613.
10. Furlanetto RW, Underwood LE, Van Wyk JJ, D'Ercole AJ. Estimation
of somatomedin-C levels in normal and patients with pituitary disease
by radioimmunoassay. J Clin Invest. 1977;60:648-657.
11. Leinskold T, Permert J, Olaison G, Larsson J. Effect of postoperative
insulin-like growth factor I supplementation on protein metabolism in
humans. BrJSurg. 1995:82:921-925.
12. SAS Institute. Users Guide: Statistics, Version 6. 4th ed., vol. 2. Cary,
NC: SAS Institute, Inc.
13. Bienia R, Ratcliff S, Barbour GL, Kummer M. Malnutrition in the
hospitalized geriatric patient. J Am GeriatrSoc. 1982;30:433-436.
14. Seltzer MH, Slocum BA, Cataldi-Betcher EL, Filed C, Gerson N.
Instant nutritional assessment: absolute weight loss and surgical mor-
tality. J Parenter Enteral Nutr. 1982;6:218-221.
15. Anderson CF, Moxness K, Meister J, Burritt MF. The sensitivity and
the specificity of nutrition-related variables in the relationship to the
duration of hospital stay and the rate of complications. Mayo Clin
Proc. 1984:59:477-483.
16. Sullivan DH, Walls RC, Lipschitz DA. Protein-energy undernutrition
and the risk of mortality within one year of hospital discharge in a
select population of geriatric rehabilitation patients. Am J Clin Nutr.
1991:53:599-605.
17. Sullivan DH. Risk factors for early hospital readmission in a select
population of geriatric rehabilitation patients: the significance of nutri-
tional status. J Am Geriatr Soc. 1992;40:792-798.
18. Takano K, Hizuka N, Shizume K, Hayashi N, Motoike Y, Obata H:
Serum somatomedin peptides measured by somatomedin-A radiore-
ceptor assay in chronic liver disease. J Clin Endocrinol Metab. 1977;
45:828-832.
19. Dahn MS, Lange MP, Jacobs LA. Insulinlike growth factor 1 produc-
tion is inhibited in human sepsis. Arch Surg. 1988;123:1409—1419.
20. Ross R, Miell J, Freeman E, et al. Critically ill patients have high
basal growth hormone levels with attenuated oscillatory activity asso-
ciated with low levels of insulin-like growth factor-I. Clin Endocrinol.
1991:35:47-54.
21. Jorgensen JOL, Pedersen SA, Thuesen L, et al. Beneficial effects of
growth hormone treatment in GH-deficient adults. Lancet. 1989; 1:
1221-1225.
22. Marcus R, Butterfield G, Holloway L, et al. Effects of short term
administration of recombinant human growth hormone to elderly peo-
ple. / Clin Endocrinol Metab. 1990;70:519-527.
23. Jabri N, Schalch DS, Schwartz SL, et al. Adverse effects of recombi-
nant human insulin-like growth factor I in obese insulin-resistant type
II diabetic patients. Diabetes. 1994;43:369-374.
Received November 18, 1996
Accepted October 6, 1997