Full text of DOI:10.1007/BF03343801

J. Endocrinol. Invest. 24: 1-7, 2001
Effect of acute elevation of IGF-I on circulating GH, TSH,
insulin, IGF-II and IGFBP-3 levels in non-endocrine short
stature (NESS)
K. Hanew* and A. Tanaka**
*Hanew Endocrine Clinic and **The Second Department of Internal Medicine, Tohoku University School
of Medicine, Sendai, Japan
ABSTRACT. It is not clear whether acute and slight
elevation of serum IGF-I, which does not affect
blood glucose levels, modulates circulating GH
levels. To clarify this, small doses of recombinant
human IGF-I (rhIGF-I, 5 μg/kg, iv) were adminis-
tered as a bolus to 10 children with non-endocrine
short stature (NESS) (5 males and 5 females,
11.2 0.7 yr old) after an overnight fast. Phy-
siological saline was administered intravenously
to sex- and age-matched NESS controls (5 males
and 5 females, 10.9 0.7 yr old). The changes of
serum GH, TSH, PRL, IGF-I, IGF-II, IGFBP-3, T4, T3
and plasma glucose levels after the administration
were compared to those of the control subjects.
Serum IGF-I levels increased significantly from 15
to 150 min after injection compared to those in
the control group. The peak value was observed
at 15 min (ꢀ increment, 74.6 11.8 μg/l). At 15 min
after the injection, serum insulin was suppressed
significantly (p<0.05), although plasma glucose
levels were not modified significantly. Serum TSH
showed a significant decrease by rhIGF-I at 15 min
and 60 min, whereas serum T4 and T3 levels were
not modified. Serum GH was also significantly sup-
pressed at 60 min (p<0.02) and showed a rebound
increase at 120 min (p<0.05). Serum IGFBP-3 lev-
els after rhIGF-I were higher than controls at 90
min and 150 min. No significant changes of serum
PRL, IGF-II, (IGF-I plus IGF-II)/ IGFBP-3 ratios were
observed after the IGF-I injection compared to
controls. These results indicate that circulating
IGF-I is a physiological regulator of GH secretion
in normal children, since the changes of IGF-I after
the small doses of rhIGF-I administration were
within physiological ranges and did not affect plas-
ma glucose levels.
(J. Endocrinol. Invest. 24: 1-7, 2001)
©2001, Editrice Kurtis
INTRODUCTION
al. (4) reported that subcutaneous administration of
20 μg/kg of rhIGF-I inhibits either spontaneous GH
secretion or stimulated GH secretion induced by
GHRH and Hexarelin in normal young women with-
out causing hypoglycemia.
Growth hormone secretion is mainly regulated by
hypothalamic GHRH, somatostatin and IGF-I (1, 2).
The physiological role of circulating IGF-I in humans
is not well characterized.
The administration of large amounts of recombi-
nant human IGF-I (rhIGF-I) stimulates circulating GH
secretion through hypoglycemia in normal subjects
(3). The effects of rhIGF-I on spontaneous GH se-
cretion have therefore been studied under the pre-
vention of hypoglycemia by either glucose clamp
methods (1) or food intake (2). Recently, Ghigo et
So far, it has been reported that iv infusion of 3
μg/kg/h of rhIGF-I is the minimal dose to inhibit GH
secretion in normal adults , but that this dose still
has a glucose lowering effect in minor cases (5, 6).
The physiological role of IGF-I on GH secretion in
normal children is largely unknown. Limited studies
have been carried out in patients with GH insensi-
tivity syndrome. In these individuals, large amounts
of rhIGF-I suppress fasting serum concentration of
GH (7, 8). However, the activities of hypothalamic
GHRH, SS neurons and pituitary somatotrophs, and
IGF-I clearance are considered to be different from
those of normal children due to the GH receptor ab-
normality and IGFBP-3 deficiency.
Key-words: Short stature, IGF-I, GH, TSH, IGFBP-3.
Correspondence: Dr. Kunihiko Hanew, Director of the Hanew Endocrine
Clinic, Hasekura-cho 2-5, Aoba-ku, Sendai, 980-0824, Japan.
E-mail: hanew@alnet.kojin.or.jp
Accepted April 25, 2000.
1

K. Hanew and A. Tanaka
Therefore, we examined circulating GH, TSH, PRL,
Insulin, IGF-II and IGFBP-3 responses, in non-en-
docrine short stature (NESS) children, to a bolus in-
jection of 5 μg/kg of rhIGF-I which has no effect on
fasting plasma glucose levels. This dose causes a
steep elevation of serum IGF-I levels and might be
suitable to see acute and direct effects of IGF-I on
pituitary somatotrophs.
Data are expressed as the mean SE. Statistical anal-
ysis was carried out using analysis of variance followed
by Student/Neumann-Keuls test or Fisher’s random-
ization test where appropriate for statistical compar-
isons between two groups or within a group.
RESULTS
This is the first report to examine serum GH re-
sponses to rhIGF-I in NESS.
After the administration of rhIGF-I, serum IGF-I lev-
els in NESS increased significantly from 15 to 150
min compared to those in the control study (Fig.
1A). As -30 min and 0 min values of each parame-
ter before IGF-I or saline study were quite similar
(p=not significant=NS), 0 min values alone were
shown in each figure. The peak value was observed
at 15 min ranging from 87.4 to 541.6 μg/l, and the
mean value was significantly higher than that of the
control subjects (IGF-I vs saline, baseline 259.4 33.8
vs 247.5 34.3, p=NS; ꢀ increment, 75.2 9.9 vs
-2.5 5.4 μg/l, p<0.01).
At 15 and 30 min after the injection, serum insulin
was suppressed significantly (IGF-I vs saline, baseli-
ne, 5.2 0.9 vs 4.8 0.4, p=NS; ꢀ increment at 15 min,
-2.3 0.7 vs -0.5 0.2, p<0.05; at 30 min, -1.6 0.5 vs
0.2 0.4 μU/ml, p<0.05) (Fig. 1B). Within the IGF-I
study, 15 and 30 min values are also significantly
lower than that of 0 min value (both p<0.025). Con-
comitant with the decrease of insulin, plasma glu-
cose levels increased transiently at 30 min (IGF-I vs
saline, baseline, 85.5 2.5 vs 83.0 1.7; ꢀ increment,
2.4 1.2 vs 0.2 0.6 mg/ml), but it was not statisti-
cally significant compared to control subjects (Fig.
1C).
Serum TSH was significantly suppressed by rhIGF-I
at 15 min (IGF-I vs saline, baseline, 1.65 0.17 vs
1.36 0.22, p=NS; ꢀ increment, -0.18 0.04 vs
-0.09 0.04 μU/ml, p<0.01) and 60 min (ꢀ incre-
ment, -0.44 0.10 vs -0.160 0.10 μU/ml, p<0.05)
(Fig. 2A). Within the IGF-I study, all values from 15
to 150 min were significantly lower than that of 0
min value (p<0.05 to 0.005). In this study, NESS chil-
dren showed -17.0 2.1% of TSH decrease at 30 min
from the basal level and the nadir value (-26.7 3.5%)
was at 90 min after the IGF-I injection.
However, serum T4 and T3 levels at 0 min and 150
min were not changed in either IGF-I (T4: 7.8 0.3 vs
7.4 0.3μg/dl; T3: 141 7 vs 128 7 ng/dl) or control
groups (T4: 7.7 0.3 vs 7.2 0.3 μg/dl; T3:143 7 vs
128 7 ng/dl).
MATERIALS AND METHODS
Ten NESS patients (5 males and 5 females, range 9-
14 yr old, mean SE=11.2 0.7 yr old) and age-and
sex-matched 10 NESS patients as control (5 males
and 5 females, range 9-13 yr old, mean SE=10.9 0.7
yr old), all healthy and non-obese, were studied.
The study was approved by the independent Local
Ethics Commitee in Sendai and informed consent
was obtained from every parent and/or subject. In
all NESS patients, height standard deviation score
(HtSDS) was below -2SD, and Ht velocity for chro-
nological age ranged from low to low-normal, but
GH responses, at least to two provocative stimuli
[classical tests, (clonidine, insulin tolerance test (ITT),
arginine tolerance test (ATT), L-dopa and gluca-
gon); and GHRH] were normal (>10 μg/l to classical
tests, and >15 μg/l to GHRH), and plasma IGF-I lev-
els were within normal ranges.
Intravenous cannula were inserted into the antecu-
bital vein from 08:30 h after an overnight fast, and
rhIGF-I (rhIGF-I, Fujisawa, Tokyo) (5 μg/kg, iv) was ad-
ministered as a bolus at 09:00 h to these subjects.
Physiological saline was administered intravenously
to the control NESS patients. Blood samples were
obtained 30 and 0 min before the IGF-I injection and
15, 30, 45, 60, 90, 120 and 150 min after the injec-
tion. Serum samples were kept frozen at -20 C until
assay. Serum GH, TSH, PRL, IGF-I, IGF-II, IGFBP-3,
T4, T3, insulin and plasma glucose were measured
with commercial IRMA kits [Daiichi: GH, PRL, IGF-I
(by acid etanol extraction method), IGF-II, IGFBP-3
and insulin], Immunofluorometric assay kits (Pharma-
cia: TSH, T4, T3) and the glucose dehydrogenase
method, respectively.
The minimal detectable level, the intra- and in-
terassay coefficients of variation were 0.006 μg/l,
2.2% and 3.5% for GH; 0.02 mU/l, 2.5% and 3.8%
for TSH; 0.3 μg/l, 3.2% and 5.6% for PRl; 0.2 μg/l,
2.0% and 2.1% for IGF-I; 0.1 μg/l, 3.2% and 4.8%
for IGF-II; 0.925 μg/l, 2.8% and 3.4% for IGFBP-3;
1.0 mU/l, 1.6% and 2.2% for insulin; 0.2 μg/dl, 3.0%
and 6.1% for T4; and 8.0 ng/dl, 2.9% and 6.7% for
T3, respectively (9, 10).
Serum GH showed a gradual decrease from 15 min
and reached statistical significance at 60 min (IGF-I
vs saline, baseline, 1.7 0.4 vs 1.8 0.4 μg/dl; ꢀ in-
crement at 60 min, -1.0 0.3 vs 1.3 0.8, p<0.05).
Rebound increases occurred at 120 min (ꢀ increment,
8.7 4.2 vs 0.6 0.7 μg/dl, p<0.05) (Fig. 2B). Within
2

GH response to rhIGF-I in NESS
100
80
60
40
20
0
A
0.2
0.0
A
rhIGF-I
-0.2
-0.4
-0.6
-0.8
Control
IGF-I
IGF-I
Control
-20
-40
2
1
B
rhIGF-I
14
12
10
8
B
0
IGF-I
-1
-2
-3
-4
IGF-I
Control
6
rhIGF-I
4
Control
2
0
-2
0.2
0.0
C
6
4
C
rhIGF-I
rhIGF-I
2
IGF-I
-0.2
-0.4
-0.6
-0.8
0
-2
-4
-6
-8
Control
Control
IGF-I
0
30
60
90
120
150
0
15 30 45 60
90
120
150
Time (min)
Time (min)
Fig. 2 - Mean ( SE) serum TSH (A), GH (B) and IGFBP-3 (C) lev-
els after an iv bolus injection of recombinant human IGF-I
(rhIGF-I) (5 μg/kg) in 10 subjects with non-endocrine short
stature (NESS, closed circles). Open circles: saline administration
in NESS controls, no.=10, *p<0.05, **p<0.01.
Fig. 1 - Mean ( SE) serum IGF-I (A), insulin (B) and plasma glu-
cose (C) levels after an iv bolus injection of recombinant human
IGF-I (rhIGF-I) (5 μg/kg) in 10 subjects with non-endocrine short
stature (NESS, closed circles). Open circles: saline administration
in NESS controls, no.=10; *p<0.05; **p<0.01.
controls at 90 min (IGF-I vs saline, baseline, 2.728
0.155 vs 2.674 0.181, p=NS; ꢀ increment at 90 min,
0.017 0.064 vs -0.196 0.075 mg/l, p<0.05) and 150
min (ꢀ increment, 0.021 0.060 vs -0.176 0.049 mg/l,
p<0.05) (Fig. 2C).
No significant changes of serum IGF-II, and (IGF-I
plus IGF-II)/IGFBP-3 ratios were observed after IGF-
I injection compared with controls (data not shown).
the IGF-I study, GH values were significantly lower [at
30 (p<0.01), 45 (p<0.01) and 60 min (p<0.005)] or
higher [at 120 min (p<0.05)] than 0 min value. The %
decrease of GH from the basal level at 30 min was
-43.4 5.5 and the nadir was -58.8 7.6 at 60 min.
Serum PRL levels were not modified by the admin-
istration of exogenous rhIGF-I (data not shown).
Serum IGFBP-3 levels after rhIGF-I were higher than
3

K. Hanew and A. Tanaka
DISCUSSION
galic patients [who are more sensitive to SS com-
pared with normal young adults (19)] was -37%
(26) and the maximal decrement was -68% at 75
min. In contrast, NESS patients showed much
greater GH decrease at 30 min (-43.4%) and sim-
ilar maximal decrement (-58.8%) at 60 min fol-
lowing the rhIGF-I injection. Therefore, it is plau-
sible that IGF-I exerts the GH inhibitory effects
directly on somatotrophs, although the coexis-
tence of other GH inhibitory mechanism through
the release of hypothalamic SS inhibition cannot
be ruled out completely.
It is not clear whether IGF-I-induced inhibition of
hypothalamic GHRH release is participating in the
GH decrease or not (1, 21, 22). The rebound of the
GH increase observed 120 min after IGF-I injection
might be due to the steep IGF-I decline from 15 to
30 min after reaching peak and gradual decline
thereafter, probably due to the short half life (ap-
proximately 10-16.6 min) of the free form of IGF-I
(1, 27). Such rapid rebound GH phenomenon after
suppression is also observed concomitantly with
the cessation of IGF-I infusion (4).
In this study, a bolus injection of 5 μg/kg of rhIGF-I
significantly increased serum IGF-I levels and de-
creased insulin levels transiently in NESS patients.
It has been reported that circulating insulin in man
is suppressed by much larger amounts of rhIGF-I
(3, 11-13), probably by the direct action of IGF-I on
pancreatic β-cells (14, 15). At the dose used in this
study, plasma glucose levels are not suppressed.
Rather, the levels were increased transiently, al-
though it was not statistically significant. It appears
that, with the doses used in this study, the insulin-
suppressive action of IGF-I was more dominant than
the insulin-like action of IGF-I.
Serum TSH secretion in this study was significantly
suppressed by rhIGF-I injection. This is compatible
with previous reports (2, 16, 17), although there is
a report that IGF-I does not inhibit the release of
TSH from the rat pituitary in vitro (18). After the be-
ginning of rhIGF-I injection, TSH response occurred
promptly, and it was followed by a slight rebound
increase. It is well known that SS inhibits TSH se-
cretion (2, 18, 19). Previously, we reported that nor-
mal young adults showed -34% of TSH decrease
from baseline at 30 min after subcutaneous admin-
istration of SS-analog (SMS 201-995) with the nadir
value (-54%) at 180 min (19). In this study, NESS chil-
dren showed much smaller 30 min decreases (-17.0%)
and a higher nadir value (-26.7% at 90 min). From
these results we can not draw valid conclusions re-
garding the site of action of IGF-I, but it is con-
ceivable that IGF-I exerts direct inhibition on thy-
rotrophs or indirect inhibition through the hy-
pothalamic SS release.
As other mechanisms of IGF-I-induced TSH sup-
pression, IGF-I-induced T4 to T3 conversion (5’ deio-
dination) in thyrotrophs should be considered (16)
although we and Klinger et al. (17) did not observe
any changes of peripheral T4 and T3 levels after IGF-I
administration. However, since GH induces signifi-
cant changes of thyroid hormone carriers, thyrox-
ine binding globulin and transthyretin (20), mea-
surement of free T4 and free T3 might provide bet-
ter information regarding the effects of IGF-I on thy-
roid function.
Serum GH showed significant suppression 60 min
after rhIGF-I administration followed by a re-
bound increase. It has been reported that IGF-I
can inhibit GH release through different path-
ways, i.e. inhibition of hypothalamic GHRH (1, 21,
22) and the stimulation of hypothalamic somato-
statin (2, 18) or through the direct inhibition of pi-
tuitary somatotrophs (18, 23-25). We previously
showed that the percent decrease of GH at 30
min after an intravenous SS infusion in acrome-
As the peak IGF-I levels achieved (87.4 to 541.6
μg/l) were considered to be within the physiologi-
cal range of age-matched controls (60-731 μg/L), it
is highly conceivable that circulating IGF-I is a phys-
iological regulator of GH secretion.
In this study, acute administration of rhIGF-I did not
increase serum IGFBP-3 levels but blocked the phy-
siological decrease of the levels despite the signi-
ficant fall of serum GH (major regulator of IGFBP-3)
(28-30). There are many controversial results re-
garding the effects of IGF-I on IGFBP-3 levels, i.e.
inhibition (31, 32), stimulation (28, 33, 34), or no ef-
fects (4, 35). The reason of these contradictory ob-
servations are not clear. However, our acute exam-
ination suggests that exogenously administered
IGF-I binds to circulating IGFBP-3 (and acid labile
subunit: ALS) and such a complex may inhibit the
degradation of circulating IGFBP-3. Related to this,
the free form of IGFBP-3 has a very short half life,
but when bound with IGF and ALS its half life is pro-
longed (34).
It is reported that high levels of IGF-I are associat-
ed with a correspondingly rapid decrease in IGF-II
probably through a direct and indirect inhibition
(via GH suppression) or by displacement from its
binding proteins (9, 33, 34, 36, 37). However, in this
study plasma IGF-II levels after the IGF-I injection
were not statistically different from those of the con-
trol study. While the reason for these contradicto-
ry results is not clear, the study design including
subjects, dose and mode of IGF-I administration
might be factors.
4

GH response to rhIGF-I in NESS
5. Chapman I.M., Hartman M.L., Pieper K.S., Skiles E.H.,
Pezzoli S.S., Hinz R.L., Thorner M.O.
The ratio of (IGF-I plus IGF-II)/IGFBP-3 has been
reported to be constant (38, 39). This was con-
firmed in IGF-I and control groups throughout the
study.
Whilst the PRL molecule has close similarity with
GH, small doses of rhIGF-I did not lower serum PRL
levels, although PRL responds to large iv bolus in-
jection of rhIGF-I in patients with GH receptor de-
ficiency (40). This may imply that somatotrophs and
lactotrophs have distinctly different sensitivity to
IGF-I, and that IGF-I does not have a significant
physiological role in PRL secretion.
Recovery of growth hormone release from sup-
pression by exogenous insulin-like growth factor I
(IGF-I): evidence for a suppressive action of free
rather than bound IGF-I.
J. Clin. Endocrinol. Metab. 1998, 83: 2836-2842.
6. Chapman I.M., Hartman M.L., Pezzoli S.S., Harrell
F.E.Jr., Hinz R.L., Alberti K.G.M.M., Thorner M.O.
Effect of aging on the sensitivity of growth hormo-
ne secretion to insulin-like growth factor (IGF)-I ne-
gative feedback.
J. Clin. Endocrinol. Metab. 1997, 82: 2996-3004.
These results indicate that circulating IGF-I is a
physiological regulator of GH secretion in normal
children. The changes of IGF-I after the small dos-
es of rhIGF-I administration did not affect plasma
glucose levels and were thought to be within the
physiological ranges. The possible regulatory roles of
circulating IGF-I on plasma TSH, insulin and IGFBP-3
are also considered.
7. Laron Z., Klinger B., Jensen L.T., Erster B.
Biochemical and hormonal changes induced by
one week of administration of rIGF-I to patients
with Laron type dwarfism.
Clin. Endocrinol. 1991, 35: 145-160.
8. Walker J.L., Ginalska-Malinowska M., Romer T.E.,
Pucilowska J.B., Underwood L.E.
Effects of the infusion of insulin-like growth factor
I in a child with growth hormone insensitivity syn-
drome (Laron dwarfism).
ACKNOWLEDGMENTS
N. Engl. J. Med. 1991, 324: 1483-1488.
9. Hanew K., Tanaka A., Utsumi A., Sugawara A.,
Abe K.
We thank Dr. Gordon B. Coutts for his careful review of our
manuscript, and the staff of Hanew Endocrine Clinic for their
help in performing this study.
Plasma GH responses to human GHRH-antagonist
in normal subjects.
Eur. J. Endocrinol. 1994, 134: 67-72.
10. Fujieda K, Shimatsu A, Hanew K, Tanaka T., Yokoya
S., Miyachi Y., Hizuka N., Hasegawa Y., Tachibana
K., Ohyama K., Seino Y., Kato Y., Nishi Y., Khono
H., Irie M.
REFERENCES
Clinical evaluation of serum IGF-I, IGF-II and IGFBP-3
measured by IRMA kits in childhood.
Clin. Endocrinol. (Tokyo) 1996, 44: 1229-1239.
1. Hartman M.L., Clayton P.E., Johnson M.L.,
Celniker A., Perlman A.J., Alberti K.G.M.M.,
Thorner M.O.
A low dose euglycemic infusion of recombinant hu-
man insulin-like growth factor I rapidly suppresses
fasting-enhanced pulsatile growth hormone secre-
tion in humans.
11. Vaccarello M.A., Diamond F.B., Guevara-Aguirre
J. Jr., Rosenbloom A.L., Fielder P.J., Gargosky S.,
Cohen P., Wilson K., Rosenfeld R.G.
Hormonal and metabolic effects and pharmacoki-
netics of recombinant insulin-like growth factor-I in
growth hormone receptor deficiency/Laron syn-
drome.
J. Clin. Invest. 1993, 91: 2453-2462.
2. Bermann M., Jaffe C.A., Tsai W., DeMott-Friberg R.,
Barkan A.L.
J. Clin. Endocrinol. Metab. 1993, 77: 273-280.
Negative feedback regulation of pulsatile growth
hormone secretion by insulin-like growth factor I.
J. Clin. Invest. 1994, 94: 138-145.
12. Boulware S.D., Tamborlane W.V., Matthews L.S.,
Sherwin R.
Diverse effects of insulin-like growth factor-I on glu-
cose, lipid, and amino acid metabolism.
Am. J. Physiol. 1992, 262: E130-E133.
3. Guller H.-P., Zapf J., Froesch E.R.
Short-term metabolic effects of recombinant human
insulin-like growth factor I in healthy adults.
N. Engl. J. Med. 1987, 317: 137-140.
13. Guller H.P., Wettstein K., Schurr W., Zapf J.,
Froesch E.R.
4. Ghigo E., Gianotti L., Arvat E., Ramunni J., Valetto
M.R., Broglio F., Rolla M., Cavagnini F., Muller E.E.
Effects of recombinant human insulin-like growth fac-
tor I administration on growth hormone (GH) secre-
tion, both spontaneous and stimulated by GH-re-
leasing hormone or hexarelin, a peptidyl GH secre-
tagogue, in humans.
Recombinant human insulin-like growth factor I: ef-
fects in normal subjects and implications for use in
patients.
In: Raizada M.K., LeRoith D. (Eds.), Molecular biolo-
gy and physiology of insulin and insulin-like growth
factors.
Plenum Press, New York, 1991, p. 97.
J. Clin. Endocrinol. Metab. 1999, 84: 285-290.
5

K. Hanew and A. Tanaka
14. Van Schravendijk C.F.H., Frories A., Van den Brande
J.L., Pipeleers D.G.
24. Yamashita S., Weiss M., Melmed S.
Insulin-like growth factor I regulates growth hormone
secretion and messenger ribonucleic acid levels in
human pituitary tumor cells.
Evidence for the presence of type I insulin-like growth
factor receptors on rat pancreatic A and B cells.
Endocrinology 1987, 121: 1784-1788.
J. Clin. Endocrinol. Metab. 1986, 63: 730-735.
25. Yamashita S., Melmed S.
15. Van Schravendijk C.F.H., Heylen L., Van den Brande
J.L., Pipeleers D.G.
Insulin-like growth factor I action on rat anterior pi-
tuitary cells: suppression of growth hormone secre-
tion and messenger ribonucleic acid levels.
Endocrinology 1986, 118: 176-182.
Direct effect of insulin and insulin-like growth fac-
tor-I on the secretory activity of rat pancreatic be-
ta cells.
Diabetologia 1990, 33: 649-653.
26. Hanew K., Kokubun M., Sasaki A., Mouri T.,
Yoshinaga K.
16. Jaffe C., Ocampo-Lim B., Guo W., Krueger K., Sugahara
I., DeMott-Friberg R., Bermann M., Barkan A.L.
Regulatory mechanisms of growth hormone secre-
tion are sexually dimorphic.
The spectrum of pituitary growth hormone respons-
es to pharmacological stimuli in acromegaly.
J. Clin. Endocrinol. Metab. 1980, 51: 292-297.
J. Clin. Invest. 1998, 102: 153-164.
27. Guller H.P., Zapf J., Schmid C., Froesch E.R.
Insulin-like growth factor I and II in healthy man.
Estimation of half-lives and production rates.
Acta Endocrinol. (Copenh.) 1989, 121: 753-758.
28. Gucev Z.S., Oh Y., Kelley K.M., Labarta J.I., Vorwerk
P., Rosenfeld R.G.
17. Klinger B., Ionesco A., Anin S., Laron Z.
Effect of insulin-like growth factor I on the thyroid
axis in patients with Laron-type dwarfism and healthy
subjects.
Acta Endocrinol. (Copenh.) 1992, 127: 515-519.
Evidence for insulin-like growth factor (IGF-I)-inde-
pendent transcriptional regulation of IGF binding
protein-3 by growth hormone in SKHEP-1 human
hepatocarcinoma cells.
18. Berelowitz M., Szabo M., Frohman L.A., Firestone S.,
Chu L., Hinz R.L.
Somatomedin C mediates growth hormone negative
feedback by effects on both the hypothalamus and
pituitary.
Endocrinology 1997, 138: 1464-1470.
29. Rosenfeld R.G.
Science 1981, 212: 1279-1281.
IGF-I treatment of growth hormone insensitivity.
In: Takano K., Hizuka N., Takahashi S-I. (Eds.), Mole-
cular mechanisms to regulate the activities of insulin-
like growth factors.
19. Hanew K., Utsumi A., Sugawara A., Shimizu Y., Ikeda
H., Abe K.
The evaluation of hypothalamic somatostatin tone
using pyridostigmine and thyrotropin releasing hor-
mone in patients with acromegaly.
Elsevier Science, Amsterdam, 1998, p. 359.
30. Baxter R.C., Martin J.L.
J. Endocrinol. Invest. 1994, 17: 313-321.
Radioimmunoassay of growth hormone-dependent
insulin-like growth factor binding protein in human
plasma.
20. Vranckx R., Rouaze-Romet M., Savu L., Mechighel P.,
Maya M., Nunez E.A.
Regulation of rat thyroxine-binding globulin and
transthyretin: studies in thyroidectomized and hy-
pophysectomized rats given tri-iodothyronine or/and
growth hormone.
J. Clin. Invest. 1986, 78: 1504-1512.
31. Baxter R.C., Hizuka N., Takano K., Holman S.R.,
Asakawa K.
Responses of insulin-like growth factor binding pro-
tein-1 (IGFBP-1) and IGFBP-3 complex to adminis-
tration of insulin-like growth factor-I.
J. Endocrinol. 1994, 142: 77-84.
21. Sato M., Frohman L.A.
Differential effects of central and peripheral admin-
istration of growth hormone (GH) and insulin-like
growth factor on hypothalamic GH-releasing hor-
mone and somatostatin gene expression in GH-de-
ficient dwarf rats.
Acta Endocrinol. (Copenagh.) 1993, 128: 101-118.
32. Kupfer S.R., Underwood L.E., Baxter R.C., Clemmons
D.R.
Enhancement of anabolic effects of growth hormone
and insulin-like growth factor-I by use of both agents
simultaneously.
Endocrinology 1993, 133: 793-799.
22. Shibasaki T., Yamauchi N., Hotta M., Masuda A.,
Imaki T., Demura H., Ling N., Shizume K.
J. Clin. Invest. 1993, 91: 391-396.
33. Cheetham T.D., Taylor A., Holly J.M.P., Clayton K.,
Cwyfan-Hughes S., Dunger D.B.
In vitro release of growth hormone-releasing factor from
rat hypothalamus: effect of insulin-like growth factor I.
Regul. Pept. 1986, 15: 47-53.
The effects of recombinant human insulin-like growth
factor-I (IGF-I) administration on the levels of IGF-I,
IGF-II and IGF-binding proteins in adolescents with
insulin-dependent diabetes mellitus.
23. Morita S., Yamashita S., Melmed S.
Insulin-like growth factor-I action on rat anterior pitu-
itary cells: effects of intracellular messengers on growth
hormone secretion and messenger RNA levels.
Endocrinology 1987, 121: 2000-2006.
J. Endocrinol. 1994, 142: 367-374.
34. Cheetham T.D., Holly J.M.P., Baxter R.C., Meadows
K., Jones J.
6

GH response to rhIGF-I in NESS
The effects of recombinant human IGF-I administra-
tion on concentrations of acid labile subunit, IGF
binding protein-3, IGF-I, IGF-II and proteolysis of IGF
binding protein-3 in adolescents with insulin-depen-
dent diabetes mellitus.
37. Zenobi P.D., Glatz E., Riesen W.F., Roder M., Froesch
E.R.
Insulin-like growth factor-I improves glucose, lipid
metabolism in type 2 diabetes mellitus.
J. Clin. Invest. 1992, 90: 2234-2241.
J. Endocrinol. 1998, 157: 81-87.
38. Baxter R.C., Martin J.L.
Structure of the Mr 140,000 growth hormone-de-
pendent insulin-like growth factor binding protein
complex: Determination by reconstitution and affin-
ity-labeling.
35. Guevara-Aguirre J., Vasconez O., Martinez V.,
Martinez A.L., Rosenbloom A.L., Diamond F.B. Jr.,
Gargosky S.E., Nonoshita L., Rosenfeld R.G.
A randomized, double blind, placebo-controlled tri-
al on safety and efficacy of recombinant human in-
sulin-like growth factor-I in children with growth hor-
mone receptor deficiency.
Proc. Natl. Acad. Sci. 1989, 86: 6898-6902.
39. Baxter R.C.
The insulin-like growth factors and their binding pro-
teins.
J. Clin. Endocrinol. Metab. 1995, 80: 1393-1398.
Comp. Biochem. Physiol. 1988, 91B: 229-235.
36. Guller H-P., Schmid C., Zapf J., Froesch E.R.
Effects of recombinant insulin-like growth factor I on
insulin secretion and renal function in normal human
subjects.
40. Silbergeld A., Klinger B., Schwartz H., Laron Z.
Serum prolactin in patients with Laron-type dwarfism:
Effect of insulin-like growth factor I.
Proc. Natl. Acad. Sci. 1989, 86: 2868-2872.
Horm. Res. 1992, 37: 160-164.
7