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Two-Month Treatment of Obese Subjects with the Oral Growth Hormone (GH) Secretagogue MK-677 Increases GH Secretion, Fat-Free Mass, and Energy Expenditure 1

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Obesity is associated with blunted GH secretion, unfavorable body composition, and increased cardiovascular mortality. The objective of this study was to investigate the effects of oral treatment with the GH secretagogue MK-677 on GH secretion and body composition in otherwise healthy obese males. The study was randomized, double blind, parallel, and placebo controlled. Twenty-four obese males, aged 18-50 yr, with body mass indexes greater than 30 kg/m2 and waist/hip ratios greater than 0.95, were treated with MK-677 25 mg (n = 12) or placebo (n = 12) daily for 8 weeks. Serum insulin-like growth factor I (IGF-I) increased approximately 40% with MK-677 treatment (P < 0.001 vs. placebo). Serum IGF-binding protein-3 was also significantly increased (P < or = 0.001 vs. placebo). GH and PRL (peak and area under the curve values) were significantly increased after the initial dose of MK-677. Significant increases, with the exception of peak PRL, persisted at 2 and 8 weeks of treatment. The increases in GH and PRL after the initial dose were significantly greater than the increase seen after multiple doses. Serum and urinary concentrations of cortisol were not increased at 2 and 8 weeks (P = NS, vs. placebo). Fat-free mass increased significantly in the MK-677 treatment group when determined with dual energy x-ray absorptiometry (P < 0.01) or using a four-compartment model (P < 0.05). Total and visceral fat were not significantly changed with active therapy. The basal metabolic rate was significantly increased at 2 weeks of MK-677 treatment (P = 0.01) but not at 8 weeks (P = 0.1). Fasting concentrations of glucose and insulin were unchanged, whereas an oral glucose tolerance test showed impairment of glucose homeostasis at 2 and 8 weeks. We conclude that 2-month treatment with MK-677 in healthy obese males caused a sustained increase in serum levels of GH, IGF-I, and IGF-binding protein-3. The effects on cortisol secretion were transient. Changes in body composition and energy expenditure were of an anabolic nature, with a sustained increase in fat-free mass and a transient increase in basal metabolic rate. Further studies are needed to evaluate whether a higher dose of MK-677 or a more prolonged treatment period can promote a reduction in body fat.
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Two-Month Treatment of Obese Subjects with the Oral
Growth Hormone (GH) Secretagogue MK-677 Increases
GH Secretion, Fat-Free Mass, and Energy Expenditure*
J. SVENSSON, L. LO
¨
NN, J.-O. JANSSON, G. MURPHY, D. WYSS, D. KRUPA,
K. CERCHIO, W. POLVINO, B. GERTZ, I. BOSEAUS, L. SJO
¨
STRO
¨
M, AND
B.-Å. BENGTSSON
Research Centre for Endocrinology and Metabolism (J.S., J.-O.J., B.-Å.B.), Departments of Radiology
(L.L.), Clinical Nutrition (I.B.), and Internal Medicine (L.S.), Sahlgrenska University Hospital,
Go¨teborg, Sweden; and Merck Research Laboratories (G.M., D.W., D.K., K.C., W.P., B.G.), Rahway,
New Jersey 07065
ABSTRACT
Obesity is associated with blunted GH secretion, unfavorable body
composition, and increased cardiovascular mortality. The objective of
this study was to investigate the effects of oral treatment with the GH
secretagogue MK-677 on GH secretion and body composition in oth-
erwise healthy obese males. The study was randomized, double blind,
parallel, and placebo controlled. Twenty-four obese males, aged
18–50 yr, with body mass indexes greater than 30 kg/m
2
and waist/hip
ratios greater than 0.95, were treated with MK-677 25 mg (n 5 12)
or placebo (n 5 12) daily for 8 weeks.
Serum insulin-like growth factor I (IGF-I) increased approximately
40% with MK-677 treatment (P , 0.001 vs. placebo). Serum IGF-
binding protein-3 was also significantly increased (P # 0.001 vs.
placebo). GH and PRL (peak and area under the curve values) were
significantly increased after the initial dose of MK-677. Significant
increases, with the exception of peak PRL, persisted at 2 and 8 weeks
of treatment. The increases in GH and PRL after the initial dose were
significantly greater than the increase seen after multiple doses.
Serum and urinary concentrations of cortisol were not increased at 2
and 8 weeks (P 5 NS, vs. placebo). Fat-free mass increased signifi-
cantly in the MK-677 treatment group when determined with dual
energy x-ray absorptiometry (P , 0.01) or using a four-compartment
model (P , 0.05). Total and visceral fat were not significantly changed
with active therapy. The basal metabolic rate was significantly in-
creased at 2 weeks of MK-677 treatment (P 5 0.01) but not at 8 weeks
(P 5 0.1). Fasting concentrations of glucose and insulin were un-
changed, whereas an oral glucose tolerance test showed impairment
of glucose homeostasis at 2 and 8 weeks.
We conclude that 2-month treatmentwithMK-677 in healthy obese
males caused a sustained increase in serum levels of GH, IGF-I, and
IGF-binding protein-3. The effects on cortisol secretion were tran-
sient. Changes in body composition and energy expenditure were of
an anabolic nature, with a sustained increase in fat-free mass and a
transient increase in basal metabolic rate. Further studies are needed
to evaluate whether a higher dose of MK-677 or a more prolonged
treatment period can promote a reduction in body fat. (J Clin Endo-
crinol Metab 83: 362–369, 1998)
G
H-RELEASING peptides (GHRPs), including the well
known hexapeptide GHRP-6, were first discovered by
Bowers et al. (1–3). Other GHRPs, such as GHRP-1, GHRP-2,
and hexarelin (4, 5), and nonpeptidyl GH secretagogues,
such as orally active MK-677 (6 8), have since been devel-
oped. Recently, a specific GHRP receptor has been identified
(9), although the natural ligand to this receptor has not yet
been identified.
In obesity, GH secretion is blunted, with a decrease in the
amount of GH secreted per burst without any major impact
on GH secretory burst frequency (10). GH release is also
blunted after administration of most GH secretagogues (Ref.
11 and references therein). It has been shown, however, that
GHRP-6 elicits a larger increase in GH secretion than GHRH
after single dose administration, and their combined admin-
istration produces a massive GH response in obese subjects
(12).
Striking similarities exist between obesity in males and
adult GH deficiency, such as an increased amount of body
fat, insulin resistance, and increased cardiovascular mortal-
ity (13–17). GH treatment has demonstrated favorable effects
on most features of GH deficiency in adults (15) and signif-
icant improvement of the various perturbations associated
with abdominal/visceral obesity (18).
In the present study we investigated whether 2-month
treatment with the oral GH secretagogue MK-677 can induce
a significant GH response capable of affecting body compo-
sition and energy expenditure in healthy obese males.
Subjects and Methods
Subjects
Twenty-four males, 1949 yr of age with body mass indexes (BMIs)
greater than 30 kg/m
2
and waist/hip ratios greater than 0.95, were
studied. They were recruited using advertisements in local newspapers.
Exclusion criteria included fasting blood glucose above 6.4 mmol/L and
blood pressure greater than 165/95 mm Hg. Except for obesity, all
subjects were in good general health, and none used concomitant
medication.
Received June 19, 1997. Revision received October 2, 1997. Accepted
October 14, 1997.
Address all correspondence and requests for reprints to: Dr. Johan
Svensson, Research Centre for Endocrinology and Metabolism,
Sahlgrenska University Hospital, S-413 45 Go¨teborg, Sweden.
* Presented in part at the Second International Meeting of the Growth
Hormone Research Society, London, UK, November 1996. This work
was supported by grants from the Swedish Medical Research Council
(nos. 11621 and 9894) and Merck Research Laboratories.
0021-972X/98/$03.00/0 Vol. 83, No. 2
Journal of Clinical Endocrinology and Metabolism Printed in U.S.A.
Copyright © 1998 by The Endocrine Society
362
Two subjects were discontinued from the study after approximately
1–2 weeks. One subject had a 3-fold increase in serum alanine amino-
transferase (ALT) and aspartate aminotransferase (AST), both of which
decreased spontaneously to prestudy values after discontinuation of
treatment with the study drug (MK-677). Of note, this subject had vi-
olated the protocol by ingesting alcohol around the time of the elevation
of AST and ALT. One subject was discontinued when hypothyroidism
was diagnosed based on a prestudy T
4
value, and the subject was given
appropriate T
4
replacement therapy. The two discontinued subjects
were replaced by two new subjects who received the same treatment as
the subjects they replaced.
Study design
This was an 8-week, randomized, double blind, parallel, and placebo-
controlled trial of the oral administration of MK-677 in healthy obese
subjects. Subjects were randomized to receive oral MK-677 (25 mg) or
a matching dose of placebo daily for 8 weeks (n 5 12/group). The dose
was administered with 150 mL water between 0800 0900 h. Compliance
was checked by weekly tablet counts. The study was approved by the
ethics committee at the University of Go¨teborg and by the Swedish
Medical Products Agency (Uppsala, Sweden). Informed consent was
obtained from each subject before the start of the study.
Study protocol
The subjects were instructed not to change their ordinary daily caloric
intake or physical activity during this study. In this study, GH secretion,
body composition, energy expenditure, and glucose homeostasis are
reported; these are the primary end points of this study. The secondary
end points are bone metabolism, thyroid hormones, and lipid profiles;
these will be reported elsewhere.
Before the start of the study, subjects underwent a complete physical
examination with laboratory safety assessments. Subjects were in the
fasted state and voided their bladder before the measurements. Body
weight was measured to the nearest 0.1 kg using a 6800 Digital Indicator
(Detecto Scale, Webb City, MO). Body height was measured barefoot
and to the nearest 0.01 cm. BMI was calculated as body weight divided
by the square of body height. Waist circumference was measured in the
standing position with a flexible plastic tape placed midway between the
lower rib margin and the iliac crest, and hip girth was measured at the
widest part of the hip. Systolic and diastolic blood pressures were
measured after at least 10 min of supine rest, using the sphygmoma-
nometric cuff method.
The patients were studied as out-patients. At baseline, 2 weeks, and
8 weeks, blood samples were drawn pretreatment for measurement
of GH, insulin-like growth factor I (IGF-I; also measured at 1 week),
IGF-binding protein-3 (IGFBP-3), free fatty acids (FFA), glycerol, and
b
-hydroxybutyrate. Eight-hour profiles of GH, PRL, and cortisol were
performed after the first intake of study drug and after tablet intake at
2 and 8 weeks. At baseline, 2 weeks, and 8 weeks, 24-h urine was
collected, an oral glucose tolerance test (OGTT) was performed, basal
metabolic rate (BMR) and total body nitrogen (TBN) were measured, and
body composition was evaluated by dual energy x-ray absorptiometry
(DEXA) and a four-compartment model. Abdominal computed tomog-
raphy scans were conducted at baseline and 8 weeks. Daily caloric intake
was assessed at baseline, 4 weeks, and 8 weeks. Body weight measure-
ments and laboratory assessments were performed weekly.
Eight-hour serum profiles of GH, PRL, and cortisol were determined
after an overnight fast. Venous blood samples were drawn before treat-
ment and 30, 60, 90, 120, 240, and 480 min after administration of the
daily dose of MK-677 or placebo. The area under the curve (AUC) for
each hormone was calculated using the trapezoidal rule.
Total body fat and fat-free mass (FFM) were assessed with DEXA
measurements, using software version 1.31 for the Lunar DPX-L
(Scanexport Medical, Helsingborg, Sweden). The scanner (system no.
7156) had precision errors of 1.7% for total body fat and 0.7% for FFM,
as determined by duplicate examinations in 10 healthy subjects.
The four-compartment model used is based on total body potassium
(TBK) and total body water (TBW) assessments as previously described
by Bruce et al. (19). TBK was assessed using a whole body counter
[coefficient of variation (CV) 5 2.2%], and TBW was determined by the
isotope dilution of tritiated water (CV 5 3.2%).
Visceral fat mass was determined by means of a Philips Tomoscan 350
(Philips Medical Systems, Eindhover, the Netherlands) using the fol-
lowing settings: 120 kV, 300 mA, and 12-mm slice thickness. Five scans
were conducted while the subject remained in a recumbent position, as
described previously by Chowdbury et al. (20). Images from the com-
puted tomography scanner were transferred to a Philips Stand Alone
Viewing System (SAVS) analyzing unit. Total abdominal visceral fat
volume was then determined (20). Sagittal diameter was measured at the
L4–L5 level.
TBN was measured by in vivo neutron activation as previously
described (21, 22). The measurement error was approximately 64%
(21, 22).
BMR was determined by indirect calorimetry, using a computerized,
ventilated, open hood system (Deltatrac, Datex, Helsinki, Finland). The
measurements were made in the morning after an overnight fast and
after at least 15 min of rest in the supine position. Respiratory data were
collected each minute for 30 min. The calculations used were described
by Ferrannini (23). The overall se of a single determination was 4%, as
calculated from 2 determinations on consecutive days in 20 healthy
subjects. The technical error of the system, verified at specified intervals
by calibrated ethanol combustion experiments, was approximately 3%.
Daily caloric intake was evaluated using standardized, self-admin-
istered dietary questionnaires, as described by Lindroos et al. (24).
OGTTs using 75 g glucose dissolved in water were performed after
an overnight fast. Venous blood samples were drawn for glucose and
insulin determinations at 0, 30, 60, 90, and 120 min.
Biochemical assays
Serum GH was determined by a polyclonal antibody-based immu-
noradiometric assay (Pharmacia, Uppsala, Sweden). The detection limit
of the assay was 0.3 mIU/L, and the total CV was 5.3% for a serum pool
with 19.8 mIU/L. Serum IGF-I was measured by RIA after acid-ethanol
extraction (Endocrine Sciences, Calabasas Hills, CA). At mean serum
IGF-I concentrations of 26, 299, and 330
m
g/L, the within-assay CVs were
20%, 5.9%, and 5.6%, respectively. At mean serum IGF-I concentrations
of 24, 279, and 307
m
g/L, the between-assay CVs were 28%, 7.7%, and
8.2%, respectively. Serum IGFBP-3 was measured by RIA (Endocrine
Sciences). The intraassay CV was 5.1%, and the interassay CV was 7.8%
at a mean serum IGFBP-3 concentration of 2.7 mg/L. Serum PRL was
measured by RIA (Diagnostic Products Corp., Los Angeles, CA), with
a total CV of 6%. Serum cortisol was determined by RIA (Farmos Di-
agnostica, Turku, Finland), with a total CV of 6%. Urinary free cortisol
was measured by RIA after extraction and chromatography (Endocrine
Sciences). Urinary 17-hydroxycorticosteroids were measured as Porter-
Silber chromogens after enzymatic hydrolysis and purification (Endo-
crine Sciences). Serum insulin was determined by RIA (Phadebas, Phar-
macia, Sweden), and blood glucose was measured using the glucose-
6-phosphate dehydrogenase method (Kebo Laboratory, Stockholm,
Sweden). Plasma FFA and glycerol were measured using enzymatic
methods (NEFAC, Wako, Neuss, Germany; and Boehringer Mannheim,
Mannheim, Germany, respectively). Plasma
b
-hydroxybutyrate was de-
termined enzymatically as described by Li et al. (25).
Statistical analysis
The descriptive statistical results are presented as the mean and sem.
Where appropriate, a logarithmic transformation was performed before
statistical analysis. Logarithmically transformed data (peak GH, GH
AUC, serum IGF-I, and IGFBP-3) are presented as the geometric mean 6
sem. Unpaired t tests were used to assess between-group differences.
Differences in baseline were accounted for by analyzing the percent
change from baseline for all variables except the hormone profiles, for
which the absolute values were analyzed. Within-group differences
were analyzed using paired t tests. Correlations were calculated using
Pearson’s linear regression coefficient. A two-tailed P , 0.05 was con-
sidered significant.
Results
The two groups were matched with regard to mean age,
weight, height, BMI, and waist/hip ratio (Table 1).
MK-677 TREATMENT OF OBESE SUBJECTS 363
Compliance and side-effects
Compliance data were available for all 24 subjects and
indicated greater than 99% compliance. MK-677 treatment
was generally well tolerated. Five subjects had clinical
and/or laboratory adverse experiences with MK-677 admin-
istration that the investigator considered drug related; all
were of mild intensity, and none required medical treatment.
One subject in the treatment group had transient gastritis at
4 weeks and transient mild sweating at 6 weeks, and 1 subject
had a glucose concentration of 10 mmol/L after 6 weeks of
MK-677 treatment, which spontaneously decreased 1 week
later. Three subjects in the treatment group had asympto-
matic, transient increases in ALT and/or AST.
GH-IGF-I axis (Table 2 and Fig. 1)
Peak serum GH and serum GH AUC after MK-677 ad-
ministration were significantly increased compared with
those after placebo treatment throughout the study period (Ta-
ble 2). In the treatment group, peak serum GH and serum GH
AUC were significantly reduced after 2 weeks of treatment
compared to the results after the first dose of MK-677 (P , 0.01
and P , 0.001, respectively), but there were no significant dif-
ferences between 2 and 8 weeks. Serum IGF-I and IGFBP-3 were
both significantly increased throughout the study period (P ,
0.001 and P # 0.001, respectively; Fig. 1). There was a significant
positive correlation between baseline serum IGF-I and IGFBP-3
(r 5 0.57, P , 0.01), and a marginally significant positive cor-
relation (r 5 0.56, P , 0.06) was found in the MK-677 treatment
group between the increases in serum IGF-I and IGFBP-3 at 8
weeks of treatment.
PRL and cortisol (Table 2)
Peak serum PRL and serum PRL AUC were significantly
higher in the treatment group than in the placebo group after
the first administration of MK-677 (P , 0.001). These in-
creases after the initial dose of MK-677 were significantly
greater than the increases after multiple doses of MK-677.
After 2 and 8 weeks of treatment, only PRL AUC remained
increased vs. that after placebo administration (P 5 0.01).
Peak serum cortisol and serum cortisol AUCs were sig-
nificantly increased compared with those after placebo
treatment after the first administration of MK-677
(P , 0.001). After 2 and 8 weeks of treatment, there were
no significant differences compared with placebo values
(Table 2). No significant effects were elicited by MK-677
on urinary free cortisol and 17-hydroxycorticosteroids
(Table 2).
TABLE 1. Baseline characteristics of the cohort or 24 obese
males treated with MK-677 25 mg or placebo daily for 8 weeks
Subject characteristics MK-677 Placebo
Age (yr) 36.8 (2.7) 39.0 (2.4)
BW (kg) 99.3 (2.3) 103.4 (2.1)
Ht (cm) 176.0 (2.1) 178.6 (1.4)
BMI (kg/m
2
) 32.0 (0.4) 32.5 (0.5)
Waist/hip ratio 1.04 (0.02) 1.00 (0.01)
Serum IGF-I (
m
g/L) 150.3 (12.1) 156.4 (8.2)
Serum IGFBP-3 (mg/L) 2.8 (0.1) 2.8 (0.1)
All values are presented as the mean (6SEM). No statistically sig-
nificant differences were found between the MK-677 group and the
placebo group using unpaired t tests.
TABLE 2. Serum peak and AUC values of GH, PRL, and cortisol and 24-h urine collections of free cortisol and 17-hydroxycorticosteroids
(17-OHCS) during 2 months of treatment with MK-677 (25 mg) or placebo daily in obese males
Variable Initiation of treatment 2 weeks 8 weeks Reference range
Peak GH (mIU/L)
MK-677 65.4 (13.1)
a
17.0 (3.3)
a
14.3 (3.9)
a
No reference range exists
Placebo 2.0 (0.8) 1.5 (0.8) 0.9 (0.4)
GH AUC (mIUzh/L)
MK-677 144.4 (32.1)
a
33.1 (5.0)
a
29.0 (7.5)
a
No reference range exists
Placebo 7.1 (2.2) 5.8 (2.3) 3.8 (1.0)
Peak PRL (mIU/L)
MK-677 737 (59)
a
358 (24) 372 (35) ,300
Placebo 224 (29) 290 (51) 282 (50)
PRL AUC (mIUzh/L)
MK-677 3565 (259)
a
2135 (157)
a
2015 (196)
b
No reference range exists
Placebo 1097 (143) 1261 (170) 1252 (162)
Peak cortisol (nmol/L)
MK-677 634 (34)
a
329 (21) 357 (30) 200800
Placebo 313 (20) 329 (28) 296 (15)
Cortisol AUC (nmolzh/L)
MK-677 3439 (235)
a
1977 (109) 2129 (129) No reference range exists
Placebo 1901 (108) 1971 (116) 1806 (90)
Urinary free cortisol/creatinine ratio (10
26
)
MK-677 26.2 (3.0) 17.7 (2.0) 21.4 (3.3) No reference range exists
Placebo 18.5 (2.6) 14.9 (2.2) 15.4 (1.3)
17-OHCS/creatinine ratio (10
23
)
MK-677 6.0 (0.5) 6.2 (0.7) 6.8 (0.6) No reference range exists
Placebo 3.8 (0.3) 3.6 (0.4) 4.1 (0.4)
The hormonal profiles were performed after tablet intake, whereas the urine collections were made before tablet intake. All values are
presented as the mean (SEM). P values are based on a between-group analysis of the absolute values for the hormonal profiles. For the urine
collection values, a between-group analysis of the percent change from baseline was performed. Note that GH peak and AUC values are presented
as the geometric mean.
a
P , 0.001.
b
P # 0.01.
364 SVENSSON ET AL.
JCE&M1998
Vol 83 No 2
Body composition, blood pressure, and BMR (Table 3 and
Figs. 2–4)
The treatment group showed a weight gain of 2.7 kg at 8
weeks of MK-677 treatment (P , 0.01 vs. placebo; Table 3).
At the poststudy visit 1 week after the end of treatment, BW
was still significantly increased compared to baseline values
in the treatment group (1.8 kg), although this did not achieve
statistical significance compared with the change in BW in
the placebo group. Sagittal diameter, visceral fat volume,
TBN, and TBW did not change, whereas TBK was increased
in response to treatment (Table 3). Systolic blood pressure
was not changed, whereas diastolic blood pressure and heart
rate were increased by MK-677 at 8 weeks (P , 0.05 vs.
placebo; Table 3).
TABLE 3. Body weight, sagittal diameter, abdominal visceral fat
volume, total body nitrogen (TBN), total body water (TBW), total
body potassium (TBK), blood pressure, and heart rate during 2
months of treatment with MK-677 (25 mg) or placebo daily in
obese males
Variable Baseline 2 weeks 8 weeks
BW (kg)
MK-677 99.3 (2.3) 100.9 (2.3)
a
102.0 (2.4)
b
Placebo 103.4 (2.1) 102.8 (1.9) 103.1 (1.8)
Sagittal diameter (cm)
MK-677 26.2 (0.4) ND 26.2 (0.7)
Placebo 24.8 (0.4) ND 25.0 (0.4)
Visceral fat vol (L)
MK-677 5.54 (0.58) ND 5.32 (0.59)
Placebo 4.79 (0.40) ND 4.75 (0.39)
TBN (kg)
MK-677 1.85 (0.06) 1.91 (0.05) 1.92 (0.06)
Placebo 2.02 (0.06) 1.96 (0.08) 2.07 (0.06)
TBW (kg)
MK-677 50.6 (1.9) 54.6 (1.2) 55.2 (1.6)
Placebo 53.4 (1.0) 56.0 (1.7) 55.8 (1.5)
TBK (mmol)
MK-677 4390 (134) 4493 (138)
b
4539 (129)
c
Placebo 4778 (122) 4694 (141) 4739 (127)
Systolic blood pressure
(mm Hg)
MK-677 131.2 (3.2) 129.1 (1.9) 134.1 (4.7)
Placebo 124.4 (3.1) 126.5 (3.4) 134.2 (3.4)
Diastolic blood pressure
(mm Hg)
MK-677 78.8 (3.4) 79.0 (2.5) 83.7 (3.2)
c
Placebo 80.6 (2.1) 78.8 (2.7) 79.0 (2.7)
Heart rate (beats/min)
MK-677 58.6 (2.7) 62.5 (3.6) 61.3 (3.0)
c
Placebo 60.0 (2.5) 62.5 (2.3) 55.9 (1.8)
Values are presented as the mean (6SEM). P values are based on
a between-group analysis of the percent change from baseline. ND,
Not determined.
a
P , 0.001.
b
P , 0.01.
c
P , 0.05.
FIG. 2. Correlations a) in the total study population at baseline, be-
tween serum IGF-I and visceral fat volume (r 520.5; P , 0.01); and
b) in the MK-677 treatment group, between the percent change in
serum IGF-I and the percent change in visceral fat volume at the end
of the study period (r 520.7; P , 0.01). Note the logarithmic scale
for the x-axis in a.
FIG. 1. Serum concentrations of IGF-I
and IGFBP-3 during 2-month treat-
ment with MK-677 (25 mg) or placebo
daily in obese males. The vertical bars
indicate the SE for the mean values
shown. P values are based on a be-
tween-group analysis of percent change
from baseline. ***, P # 0.001.
MK-677 TREATMENT OF OBESE SUBJECTS 365
At baseline, visceral fat volume correlated negatively with
serum IGF-I (r 520.5; P , 0.01; Fig. 2a), and in the MK-677
treatment group, a strong negative correlation was found
between the percent change in visceral fat volume and the
percent change in serum IGF-I at the end of the study period
(r 520.7; P , 0.01; Fig. 2b).
FFM increased about 3 kg in the treatment group com-
pared with that in the placebo group (P , 0.01; Fig. 3a). In
contrast, total body fat, as assessed from DEXA measure-
ments, was not changed by MK-677 treatment (Fig. 3b). BCM
derived from the four-compartment model increased about
1kg(P , 0.05) in the treatment group (Fig. 3c). No significant
effects were elicited by MK-677 treatment on total body fat
when derived from the four-compartment model (Fig 3d).
BMR was increased by MK-677 at 2 weeks of treatment
(P 5 0.01 compared with placebo) even after correction for
the increase in FFM (P , 0.05; Fig. 4).
Glucose homeostasis (Table 4)
No significant effects were seen on fasting blood glucose,
serum insulin, or insulin AUC after OGTT. However, the 2-h
concentration of blood glucose during the OGTT was in-
creased at both 2 and 8 weeks of treatment, and blood glucose
AUC and the 2-h serum insulin during OGTT were increased
after 2 weeks, but not after 8 weeks, of treatment (Table 4).
Daily caloric intake and plasma concentrations of FFA
Total daily caloric intake, as assessed using dietary ques-
tionnaires, remained unchanged during the study (data not
shown). Daily intakes of fat, protein, and carbohydrates were
also not changed by MK-677 (data not shown). Fasting con-
centrations of FFA, glycerol, and
b
-hydroxybutyrate were
not changed by MK-677 compared to baseline values or
compared to placebo values (data not shown).
Discussion
We have shown that 2-month treatment of healthy obese
males with the oral GH secretagogue MK-677 produced a
significant GH response throughout the study period, capa-
ble of increasing serum IGF-I and IGFBP-3 and FFM. BMR
was increased at 2 weeks, but not at 8 weeks. Body fat was
not significantly changed. Diastolic blood pressure and heart
rate were increased at 8 weeks. The effects on cortisol se-
cretion were transient, whereas a minor increase in PRL
levels was found throughout the study period. Basal values
of fasting blood glucose and insulin were unchanged, but the
OGTT showed an impairment of glucose homeostasis at 2
weeks and, with some attenuation, at 8 weeks of treatment.
Previously, short term administration of GHRP-6 (26),
hexarelin (5), and nonpeptide substance L-692,429 (27) as
well as 2 weeks of MK-677 treatment (8) have been found to
increase GH secretion. In the present study, GH levels were
increased by MK-677 treatment throughout the 8-week study
period, even though the GH response to MK-677 was lower
at 2 and 8 weeks compared to the initial response. It is
possible that the negative feedback that IGF-I exerts on GH
secretion (28) could explain this dampening in GH response
to MK-677 administration. Such a mechanism would also be
supported by the constant level of increased serum IGF-I
found throughout the study. A homologous desensitization
after infusion of GHRP has previously been reported (29, 30).
It is unknown whether desensitization contributed to the
decrease in the GH response between initiation and 2 weeks
of treatment in this study. In any case, the response to oral
MK-677 was not abolished even after 8 weeks of treatment,
which may also indicate that MK-677 does not deplete the
pituitary reserve of GH, possibly because of a stimulatory
effect on GH synthesis.
Previously, single dose administration of GH secreta-
gogues (5, 26, 27) and 2-week treatment with MK-677 (8)
produced small increases in PRL levels. In the present study,
a similar initial increase in PRL was found, but at 2 and 8
weeks, only the PRL AUC, not peak PRL, remained in-
creased. These findings indicate that there is a minor effect
on PRL secretion that persists after 8 weeks of treatment,
possibly the result of MK-677 affecting pituitary somato-
mammotrops (31, 32).
The present study confirms that the stimulatory effect of
GHRP-related compounds on cortisol secretion is transient.
Increased cortisol levels have been noted after single dose
administration of GHRPs (26, 27), but not after 1 (7) or 2 (8)
FIG. 3. Body composition during 2-month treatment with MK-677
(25 mg) or placebo daily in obese subjects. a and b show FFM and body
fat, respectively, as assessed by DEXA. c and d show body cell mass
and body fat, respectively, as calculated using the four-compartment
model. The vertical bars indicate the SE for the mean values shown.
P values are based on a between-group analysis of the percent change
from baseline. *, P , 0.05; **, P , 0.01.
366 SVENSSON ET AL.
JCE&M1998
Vol 83 No 2
weeks of MK-677 treatment. In the present study, an increase
in serum cortisol was demonstrated after the first MK-677
administration, but no increase was found at 2 and 8 weeks.
Moreover, urinary cortisol was unchanged throughout the
study. These results are clinically important with regard to
the safety of MK-677, as visceral obesity is accompanied by
relative hypercortisolism (33).
An anabolic effect was seen on FFM in the treatment
group, with a maximum increase of 3 kg measured by DEXA
scan, corresponding to the increase in body weight of this
cohort. This was expected from experience with GH treat-
ment of GH-deficient adults (15) and elderly subjects (34, 35).
The increase in FFM is not explained by an increase in body
water, since TBW estimations did not show any significant
difference between the groups. However, it is possible that
the decrease in body weight in the treatment group from the
study end to the poststudy visit (0.9 kg) at least in part can
be explained by loss of water. It is also possible that different
estimations of body water can explain part of the difference
(1.5 kg) between DEXA and the four-compartment model in
estimating the increases in FFM and body cell mass,
respectively.
Body fat was unchanged, which was unexpected based on
the results of previous studies of GH treatment of GH-de-
ficient adults (15) and obese males (18). GH induces lipolysis
with an increase in FFA levels (36), but no increase in FFA
levels or glycerol was observed in this study to support
increased lipolysis with MK-677 treatment. Previously, con-
tinuous infusion of GH has been shown to produce a greater
reduction in total body fat than sc GH injections in a study
of GH-deficient adults (37). Therefore, it is possible that the
GH secretory pattern produced by MK-677 is less effective in
inducing lipolysis and body fat reduction.
A strong negative correlation was found between the
changes in serum IGF-I and visceral fat in the treatment
group. Correlation analysis showed that a greater than 30
35% increase in serum IGF-I was needed to reduce visceral
fat mass. This suggests that a higher dose of MK-677, result-
ing in enhanced levels of serum GH and IGF-I, may cause a
reduction in visceral fat. In obese males, GH treatment re-
duces the visceral fat mass over a 9-month period (18), and
it is possible that a more prolonged MK-677 treatment period
could cause a decrease in visceral fat.
GHRH stimulates food intake in rats (38), and it has re-
cently been found that the newly developed GHRP KP-102
stimulates feeding in rats (39). GHRP-6 injection activates
neuropeptide Y cells in the rat arcuate nucleus (40), which
could indicate a positive effect on appetite (41). It is difficult
to explain our present findings of increases in body weight,
FFM, and BMR in combination with unchanged body fat
without a concomitant increase in food intake. The dietary
questionnaires used, however, did not indicate any such
effect, but they may not be sufficiently sensitive.
The increase in diastolic blood pressure found after treat-
ment with a GH secretagogue in the present study is unex-
pected, as GH treatment has been shown to reduce periph-
eral vascular resistance (42). However, the current study was
FIG. 4. BMR (a) and BMR corrected for
the increase in FFM (b) during 2-month
treatment with MK-677 (25 mg) or pla-
cebo daily in 24 obese males. The ver-
tical bars indicate the SE for the mean
values shown. P values are based on a
between-group analysis of the percent
change from baseline. *, P , 0.05; **
P 5 0.01.
TABLE 4. Effects of 2 months of treatment with MK-677 (25 mg)
or placebo daily in obese males on oral glucose tolerance test
Variable Baseline 2 weeks 8 weeks
Basal blood glucose
(mmol/L)
MK-677 4.2 (0.1) 4.3 (0.2) 4.3 (0.2)
Placebo 4.3 (0.2) 4.2 (0.1) 4.3 (0.1)
Blood glucose 120
(mmol/L)
MK-677 5.2 (0.3) 7.8 (0.7)
a
7.0 (0.7)
b
Placebo 6.4 (0.5) 5.4 (0.6) 6.2 (0.6)
Blood glucose AUC
(mmolzh/L)
MK-677 13.3 (0.8) 15.2 (1.2)
c
14.9 (1.2)
Placebo 13.9 (0.7) 13.0 (0.8) 13.9 (0.9)
Basal insulin (mIU/L)
MK-677 14.2 (2.0) 19.4 (2.9) 16.4 (2.5)
Placebo 11.6 (1.1) 12.9 (1.3) 12.2 (1.1)
Insulin 120 (mIU/L)
MK-677 54.4 (10.2) 92.6 (12.6)
b
77.0 (14.3)
Placebo 59.5 (7.7) 45.6 (7.4) 68.2 (12.0)
Insulin AUC (mIUzh/L)
MK-677 126 (21) 155 (14) 141 (17)
Placebo 114 (12) 125 (14) 136 (16)
All values are presented as the mean (6SEM). P values are based
on a between-group analysis of percent change from baseline. Note
that serum levels of insulin are given. Blood glucose 120 and insulin
120 are the respective values 2 h after oral administration of a 75-g
glucose solution. Blood glucose AUC and insulin AUC also refer to the
OGTT.
a
P , 0.001.
b
P , 0.05.
c
P , 0.01.
MK-677 TREATMENT OF OBESE SUBJECTS 367
conducted in a relatively small number of subjects, and the
effect of MK-677 on blood pressure should be confirmed in
a larger study. It cannot be excluded that longer term treat-
ment with MK-677 could affect blood pressure in a more
favorable way if a reduction of visceral fat is achieved.
Past studies have shown an increase in BMR during GH
treatment of GH-deficient adults (15). We observed an in-
crease in BMR at 2 weeks of treatment even when corrected
for the increase in FFM. However, there was no significant
increase in BMR at study end. This could be explained by the
lower GH response to MK-677 at 2 and 8 weeks of treatment
compared to the response at the first administration. In a
9-month study of GH treatment of obese males, a similar
decrease in BMR responsiveness was observed (43). There-
fore, it is possible that a down-regulation of the initial in-
crease in BMR occurs during long term GH or MK-677 treat-
ment of obese subjects, an effect not seen with GH treatment
in adult GH deficiency.
Fasting levels of glucose and insulin were unchanged in
the present study, but the OGTT demonstrated an impaired
glucose homeostasis after 2 and 8 weeks of MK-677 treat-
ment. The tendency to an improvement from 2 to 8 weeks of
treatment is probably not explainable by changes in GH
secretion, because the GH response to MK-677 was similar at
2 and 8 weeks of treatment. A similar pattern has been
observed in a study of GH deficiency, in which an initial
deterioration of insulin resistance was restored to baseline
values after 6 months of GH treatment (44). Skeletal muscle
is the major site of glucose disposal (45), IGF-I stimulates
glucose transport into skeletal muscle in vitro (46), and GH
treatment of hypophysectomized rats increases the propor-
tion of insulin-sensitive type I muscle fibers (47). Therefore,
the increase in FFM found in the present study or any related
changes in muscle metabolism or morphology that may have
occurred might help to explain the improvement in glucose
homeostasis between 2 and 8 weeks of treatment.
We concluded that 2-month treatment with the oral GH
secretagogue MK-677 was generally well tolerated in healthy
obese males. MK-677 treatment elicited a significant GH re-
sponse, followed by increases in serum IGF-I and IGFBP-3,
whereas effects on cortisol secretion were transient. Changes
in body composition and energy expenditure were of an
anabolic nature, with a sustained increase in FFM and a
transient increase in BMR. Further studies are needed to
evaluate whether body fat can be affected by a higher dose
of or more prolonged treatment with MK-677.
Acknowledgments
We are indebted to Lena Wire´n, Anne Rose´n, Ingrid Hansson, and
Annika Reibring at the Research Centre for Endocrinology and Metab-
olism for their skillful technical support. We thank Anna-Karin Lindroos
for analyzing the dietary questionnaires.
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MK-677 TREATMENT OF OBESE SUBJECTS 369
... The reported use of these peptides in humans is limited, but studies have demonstrated improvements in body mass and anti-catabolic effects by GHS-R agonists such as the novel oral compound MK-0677 (Murphy et al., , 2001Nass et al., 2008;Svensson et al., 1998). GHRP-2 has also shown promising anti-catabolic effects-a case report of GHRP-2 use in a patient with anorexia nervosa reported increased body weight, muscle, and fat mass (Haruta et al., 2015). ...
... Safety studies performed using MK-0677 established an excellent safety profile en route to clinical development (Smith, 2005). MK-0677 had relatively few and mild adverse events such as dizziness, stomachache, and transient increases in aspartate transaminase (AST)/alanine transaminase (ALT) in trials in healthy young men, obese men, elderly men and women, and osteoporotic women (Chapman et al., 1996;Murphy et al., 1998Murphy et al., , 2001Svensson et al., 1998). Safety concerns relating to an increased incidence of congestive heart failure (CHF; 4 in the treatment group vs. 1 in the placebo group) was seen in one trial of MK-0677 in patients above 60 years of age with hip fracture (Adunsky et al., 2011). ...
... MK-0677 raises serum IGF-1 levels in both beagles and humans (Chapman et al., 1996;Hickey et al., 1997;Smith, 2005). The drug also increases lean mass in obese males and the elderly, increases bone density in osteoporotic women, and has anti-catabolic effects in the setting of diet-induced nitrogen wasting (Murphy et al., , 2001Nass et al., 2008;Svensson et al., 1998). MK-0677 currently lacks FDA approval and is not yet commercially available, but other, not-yet FDA-approved GHSs are available for clinical use. ...
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... In adipösen diabetischen ob/ob Mäusen, die aufgrund einer Mutation kein Leptin produzieren, verbessert das Knockout des Ghrl die Insulinsekretion (Sun et al., 2006;Ma et al., 2011). Eine chronische Behandlung mit GHS-R Agonisten induziert Hyperglykämie und Insulinresistenz in gesunden älteren Menschen (Chapman et al., 1996;Svensson et al., 1998;Muller et al., 2001). Im Gegensatz dazu führt eine Blockade des Rezeptors (GHS-R Knockout Mäuse) zu einem Anstieg der Insulinsekretion und einer Normalisierung des Blutzuckerspiegels (Longo et al., 2011). ...
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Purpose Growth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats. Materials and Methods The serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects. Results Oral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However, oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagogue receptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression. Conclusion Our results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatory effect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS.
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Introduction: Growth hormone (GH) increases lean body mass, decreases fat mass, increases exercise tolerance and maximum oxygen uptake, enhances muscle strength, and improves linear growth. Long-term studies of GH administration offer conflicting results on its safety, which has led to strict Food and Drug Administration criteria for GH use. The potential drawbacks of exogenous GH use are believed to be due in part to impaired regulatory feedback. Aim: To review the literature on GH secretagogues (GHSs), which include GH-releasing peptides and the orally available small-molecule drug ibutamoren mesylate. Methods: Review of clinical studies on the safety and efficacy of GHSs in human subjects. Main outcome measure: Report on the physiologic changes from GHS use in human subjects including its safety profile. Results: GHSs promote pulsatile release of GH that is subject to negative feedback and can prevent supra-therapeutic levels of GH and their sequelae. To date, few long-term, rigorously controlled studies have examined the efficacy and safety of GHSs, although GHSs might improve growth velocity in children, stimulate appetite, improve lean mass in wasting states and in obese individuals, decrease bone turnover, increase fat-free mass, and improve sleep. Available studies indicate that GHSs are well tolerated, with some concern for increases in blood glucose because of decreases in insulin sensitivity. Conclusion: Further work is needed to better understand the long-term impact of GHSs on human anatomy and physiology and more specifically in the context of a diversity of clinical scenarios. Furthermore, the safety of these compounds with long-term use, including evaluation of cancer incidence and mortality, is needed. Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sex Med Rev 2017;X:XXX-XXX.
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Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.
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L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of the GH secretagogue, GH-releasing peptide-6. The safety and GH secretory activity of L-692,429 (0.001-1.0 mg/kg, i.v.) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 micrograms/L or more after 1 microgram/kg, i.v. GH-releasing hormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-controlled, alternating panel fashion to 3 panels of 8 subjects each. Dose-dependent GH secretion was observed with a threshold dose of 0.05 mg/kg (4 of 6 subjects responded with peak GH > 7 micrograms/L), and 0.2 mg/kg produced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 micrograms/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 micrograms/L; n = 8). The GH peak was seen 30-45 min after initiation of the infusion. Small transien...
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The effects of GH treatment on energy expenditure in abdominal obesity were examined in a randomized double-blind placebo controlled trial. Energy expenditure was determined by indirect calorimetry in a computerized ventilated open-hood system. Body composition was determined from total body potassium. Results: At baseline the mean BMR was significantly lower than the calculated reference value (1890±34 vs 1950±31 kcal/24h; p<0.05). In response to the GH treatment total body fat decreased by 9.2±2.4% (p = 0.03) but no alterations was observed in fat free mass. Basal metabolic rate increased by 7.3±2.1% (p<0.01) after 6 weeks. During the same period lipid-oxidation increased with a mean of 37±15% (p<0.05). Between 6 weeks and 6 months BMR was essentially unchanged. After 9 months BMR was not different from baseline values and lipid-oxidation only tended to be increased. The increase in BMR between baseline and 6 weeks was related to the increase in IGF-1 (r = 0.51; p<0.05), PIIIp (r = 0.65; p<0.01) and the freeT3/freeT4 ratio (r = 0.60; p<0.05). Summary: It is concluded that the blunted GH secretion in abdominal obesity seems to be associated with a low basal metabolic rate. A temporary normalization of the energy expenditure level was experienced during the first 6 months of GH treatment.
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Recent evidence suggests that growth hormone-releasing peptides (GHRPs) mimic an unidentified native GH-releasing hormone (GHRH)-amplifying hormone. GHRH has been shown to stimulate food intake acting on the central nervous system. The present studies were conducted to test the hypothesis that GHRPs may also potentiate the central effect of GHRH on feeding in free-feeding rats. Intracerebroventricular (ICV) administration of picomole doses of a newly developed GHRP, KP-102, or human GHRH stimulated feeding, but the phenomenon was not reproduced by systemic injection. A prior ICV injection of a GHRH antagonist completely prevented the increase of food intake evoked by GHRH, but this pretreatment did not influence the increase in food intake induced by KP-102. When maximally effective doses of GHRH and KP-102 were co-administered ICV, the amount of food intake increased significantly compared with after ICV injection of a maximum dose of either peptide alone. These findings suggest that GHRPs stimulate food intake via a specific receptor for GHRPs in the central nervous system and amplify the central effect of GHRH on feeding.
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A set up forin vivo determination of nitrogen has been built. Phantoms containing different amounts of nitrogen have been measured as well as a volunteer in a pilot study. A total body protein content of 18.8 kg was calculated, to be compared with 17.0 kg estimated from potassium measurements.
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Recombinant human growth hormone (GH) is routinely administered as daily subcutaneous injections to patients with GH deficiency (GHD). However, in the hypophysectomized rat, pulsatile and continuous infusion of GH has been shown to differ in terms of the magnitude of effect on longitudinal bone growth, serum insulin-like growth factor-I (IGF-I) concentrations, and hepatic metabolism. The aim of the present study was to compare the effects of daily injections and continuous infusion of GH in GHD adults on previously well-documented GH-dependent factors. Recombinant human GH (0.25 U/kg/wk) was administered to nine men with GHD for 14 days in two different ways, ie, as a daily subcutaneous injection at 8 pm and as a continuous subcutaneous infusion, with 1 month of washout between treatments. Blood samples and tests were performed in the morning after an overnight fast before the start of GH treatment (day 0) and on day 2 and day 14 of treatment. An oral glucose tolerance test (OGTT) was performed on day 0 and day 14. Daily injections and continuous infusion of GH exerted similar effects in terms of body weight and body composition. The two modes of administration resulted in similar daily urinary GH excretion and similar serum GH concentrations in the morning. GH binding protein (GHBP) concentrations did not change significantly during the various treatment periods. Serum IGF-I and IGF-I binding protein (IGFBP)-3 concentrations increased to a greater degree during continuous infusion of GH versus daily injections. Serum IGFBP-1 concentrations decreased to a similar degree during the two modes of administration. Serum concentrations of free triiodothyronine and total triiodothyronine (T3) increased and free thyroxine (T4) decreased to a similar degree, independent of the mode of administration. However, total T4 concentrations were unchanged during both modes of treatment. Serum thyrotropin (TSH) concentrations decreased during continuous infusion, and there was a similar nonsignificant decrease during daily injections of GH. Fasting free fatty acid (FFA) levels increased during treatment with one daily injection of GH, but there was no significant effect from continuous infusion. Results of measurements of fasting concentrations of blood glucose and oral glucose tolerance (OGT) indicated a more impaired glucose tolerance after daily injections of GH versus continuous infusion. In conclusion, continuous infusion and daily injections of GH have similar effects on the variables described, but the magnitude of the effects differs.