The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 167-171
Copyright © 2001 by The Endocrine Society
Effects of Recombinant Human Insulin-Like Growth Factor I Administration on the Growth Hormone (GH) Response to GH-Releasing Hormone in Obesity1
M. Maccario,
F. Tassone,
L. Gianotti,
F. Lanfranco,
S. Grottoli,
E. Arvat,
E. E. Muller and
E. Ghigo
Division of Endocrinology and Metabolism, Department of Internal
Medicine, University of Turin, Turin; and Department of Pharmacology,
University of Milan, Milan, Italy
Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it
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Abstract
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Circulating GH levels are reduced in obesity due to true reduction of
the 24-h GH production rate. GH insufficiency in obesity might reflect
neuroendocrine abnormalities and/or alterations in peripheral hormones
and metabolic factors. The somatotroph response to provocative stimuli
including GHRH is markedly blunted in obese patients. However, the
somatotroph responsiveness to GHRH in obesity shows also peculiar
refractoriness to the inhibitory effect of glucose load. In this
present study we aimed at verifying the effect of low dose rhIGF-I (20
µg/kg, sc, at 0 min) on the GH response to GHRH (1 µg/kg, iv, at
180 min) in obesity. With this goal in mind, six obese women with
abdominal adiposity [OB; age (mean ± SEM), 32.3
± 4.4 yr; body mass index, 32.8 ± 2.3 kg/m2] were
studied. The effects of recombinant human insulin-like growth factor I
(rhIGF-I) administration on circulating total IGF-I, insulin, and
glucose levels were also evaluated. The results in OB were compared
with those recorded in age-matched lean women (NW; age, 28.3 ±
1.2 yr; body mass index, 20.1 ± 0.5 kg/m2), in whom
the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I
levels in OB were similar to those in NW (199.7 ± 33.3
vs. 274.4 ± 25.3 µg/L). The mean GH
concentration over 3 h (from 0–180 min) in OB was lower than that
in NW (0.9 ± 0.4 vs. 2.6 ± 0.8 µg/L;
P = NS). Administration of GHRH induced a GH
response in OB lower than that in NW (area under the curve from
180–270 min, 576.5 ± 137.5 vs. 1315.9 ±
189.9 µg/L·min; P < 0.02). Administration of
rhIGF-I increased circulating IGF-I levels in both groups to the same
percent extent (326.8 ± 28.3 and 420.3 ± 26.5 µg/L in OB
and NW, respectively). rhIGF-I administration inhibited the GH response
to GHRH in OB (240.1 ± 99.6 µg/L; P <
0.05) as well as in NW (730.2 ± 288.1 µg/L;
P < 0.05), although it failed to lower the mean GH
concentration over 3 h in either OB or NW. After rhIGF-I the GH
response to GHRH in OB was slight and was still lower
(P < 0.05) than that in NW; in fact, the percent
decreases were similar in both groups (44.21 ± 14.06 and
48.21 ± 13.95 µg/L, in OB and NW, respectively). The mean
insulin (107.1 ± 21.9 and 36.8 ± 7.2 pmol/L), but not
glucose (4.0 ± 0.3 and 4.1 ± 0.1 mmol/L), levels calculated
over 270 min, were higher (P = 0.005) in OB than in
NW; rhIGF-I administration did not modify insulin and glucose levels in
either group. Our study shows that the sc administration of a low
rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese
as well as in normal subjects, indicating that somatotroph sensitivity
to the inhibitory effect of rhIGF-I is preserved in obesity.
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Introduction
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CIRCULATING GH levels are reduced in
obesity as a reflection of true reduction of the 24-h GH production
rate (1). GH insufficiency in obesity could denote
neuroendocrine abnormalities, including a hyperactive somatostatinergic
tone and/or, more likely, a state of GHRH hypoactivity
(2, 3, 4). On the other hand, recent evidence favors the view
that alterations in peripheral hormones and metabolic factors could
also play a major role; they include enhanced negative free
insulin-like growth factor I (IGF-I) feedback, hyperinsulinism,
alterations in leptin activity and elevated free fatty acids
(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15).
In obesity, not only spontaneous GH secretion, but also the somatotroph
response to provocative stimuli, including GHRH and GH-releasing
peptide, is markedly blunted (16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27), sometimes to
levels similar to those recorded in patients with GH deficiency
(28). Interestingly, in the obese subjects, the low
somatotroph responsiveness to either GHRH or arginine shows a peculiar
refractoriness to the inhibitory effect of glucose load
(29), whereas the GH response to the same stimuli is
normally inhibited by pirenzepine, a muscarinic antagonist, which is
likely to act via somatostatin release as well as by exogenous
somatostatin (30).
It is well known that IGF-I exerts an inhibitory feedback action on
somatotroph secretion, being capable of inhibiting the GH responses to
GHRH, arginine and GH-releasing peptides in normal subjects
(31, 32, 33) and also in conditions of peripheral GH
resistance, which are generally refractory to the inhibitory effect of
glucose load (34, 35, 36, 37).
The inhibitory action of IGF-I on somatotroph secretion may occur
directly at the pituitary level through activation of IGF-I receptors
and lead to inhibition of GH synthesis and release
(39, 40, 41, 42, 43, 44, 45, 46). On the other hand, indirect central nervous
system-mediated actions of recombinant human IGF-I (rhIGF-I) have been
clearly demonstrated, which include enhancement of hypothalamic
somatostatin release (40, 42, 44) and/or inhibition of
GHRH release (39, 47, 48).
Based on the foregoing, we sought in the present study to verify the
effect of a low rhIGF-I dose on the GH response to GHRH in obesity. The
effects of rhIGF-I administration on circulating total IGF-I, insulin,
and glucose levels were also evaluated. The results in obese patients
were compared with those recorded in age-matched lean women, in whom
the inhibitory effect of rhIGF-I had been previously demonstrated
(31).
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Subjects and Methods
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Drugs
Vials containing 1000 µg lyophilized rhIGF-I were provided by
Pharmacia & Upjohn, Inc. (Stockholm, Sweden). Vials
containing 50 µg GHRH-29 were provided by Serono (Rome, Italy).
Study protocols
Six obese women with abdominal adiposity [OB; age (mean ±
SEM), 32.3 ± 4.4 yr; body mass index, 32.8 ±
2.3 kg/m2] took part in the study. Eight normal
young women (NW; age, 28.3 ± 1.2 yr; body mass index, 20.1
± 0.5 kg/m2) were studied as controls. The
results obtained in these subjects have been published
(31). All women had regular menses and were studied in the
early follicular phase (between days 2 and 6 of the same follicular
phase). All subjects gave their written informed consent to participate
in the study, which had been approved by an independent ethical
committee. All subjects underwent the following test sessions at least
3 days apart: 1) placebo (sc at 0 min) plus GHRH (1 µg/kg, iv, at 180
min), and 2) rhIGF-I (20 µg/kg, sc, at 0 min) plus GHRH. The order of
the sessions was randomized. The tests were begun in the morning at
0830–0900 h after an overnight fast and 30 min after an indwelling
catheter had been inserted into an antecubital vein of the forearm kept
patent by slow infusion of isotonic saline. Blood samples were drawn
basally at 0 min, then every 30 min up to 180 min, and then every 15
min up to 270 min. Serum GH levels were measured at each time point in
all sessions. Serum IGF-I, serum insulin, and plasma glucose levels
were measured under baseline conditions and then every 30 min up to 270
min in all sessions. Serum GH levels (micrograms per L) were measured
in duplicate by immunoradiometric assay (hGH-CTK IRMA, SORIN, Saluggia,
Italy). The sensitivity of the assay was 0.15 µg/L. The inter- and
intraassay coefficients of variation were 2.9–4.5% and 2.4–4.0%,
respectively. Serum IGF-I levels (micrograms per L) were measured in
duplicate by RIA (Nichols Institute Diagnostics, San Juan
Capistrano, CA). All samples were extracted with acid-ethanol to avoid
interference by binding proteins. The sensitivity of the assay was 0.1
µg/L. The inter- and intraassay coefficients of variation were
10.1–15.7% and 7.6–15.5%, respectively. Serum insulin levels
(picomoles per L) were measured in duplicate by immunoradiometric
assays (Sorin Biomedica, Saluggia, Italy). The sensitivity of the assay
was 17.9 ± 2.2 mU/L. Inter- and intraassay coefficients of
variation were between 6.2–10.8% and between 5.5–10.6%,
respectively. Plasma glucose levels (millimoles per L) were measured by
a glucose-oxidase colorimetric method (GLUCOFIX, Menarini Diagnostics,
Firenze, Italy). All samples from an individual subject were analyzed
in a single batch.
The hormonal responses are expressed as absolute values as well as
areas under the curve calculated by trapezoidal integration.
Statistical analysis was carried out using nonparametric ANOVA
(Mann-Whitney ANOVA, Wilcoxon signed rank test). The results are
expressed as the mean ± SEM.
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Results
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Basal IGF-I levels in OB were similar to those in NW (199.7
± 33.3 vs. 274.4 ± 25.3 µg/L). The mean GH
concentration over 3 h (from 0–180 min) in OB was lower than that
in NW (mGHc, 0.9 ± 0.4 vs. 2.6 ± 0.8 µg/L),
but this difference did not attain statistical significance.
Administration of GHRH induced a GH response in OB lower than that in
NW (area under the curve from 180–270 min, 576.5 ± 137.5
vs. 1315.9 ± 189.9 µg/L·min; P <
0.02; Fig. 1
). Administration of rhIGF-I
increased circulating IGF-I levels in both groups to the same percent
extent (326.8 ± 28.3 and 420.3 ± 26.5 µg/L in OB and NW,
respectively; Fig. 2). After rhIGF-I
administration the mGHc over 3 h was not significantly reduced in
either OB or NW (1.0 ± 0.5 and 3.2 ± 1.0 µg/L,
respectively). rhIGF-I administration inhibited the GH response to GHRH
in OB (240.1 ± 99.6 µg/L; P < 0.05) as well as
in NW (730.2 ± 288.1 µg/L; P < 0.05; Fig. 1).
After rhIGF-I the GH response to GHRH in OB was slight and still lower
(P < 0.05) than that in NW; in fact, the percent
decrease was similar in both groups (44.21 ± 14.06 and 48.21
± 13.95 in OB and NS, respectively; Fig. 1). Mean insulin (107.1
± 21.9 and 36.8 ± 7.2 pmol/L), but not glucose, levels (4.0
± 0.3 and 4.1 ± 0.1 mmol/L) calculated over 270 min were higher
(P = 0.005) in OB than in NW. Administration of rhIGF-I
did not modify mean insulin and glucose levels in either OB or
NW (Fig. 2).
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Figure 1. Mean (±SEM) serum GH levels
after GHRH (2 µg/kg, iv, at 180 min) alone or preceded by rhIGF-I (20
µg/kg, sc, at 0 min) in obese patients and normal subjects.
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Figure 2. Mean (±SEM) serum IGF-I,
insulin, and plasma glucose levels after placebo or rhIGF-I (20
µg/kg, sc, at 0 min) in obese patients.
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Side effects
All subjects experienced transient discomfort at the injection
site after rhIGF-I administration, but no systemic side effects were
observed. Five normal subjects and two OB patients had transient facial
flushes after GHRH administration.
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Discussion
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Our study shows that the sc administration of a low rhIGF-I dose
inhibits the somatotroph responsiveness to GHRH in both obese and
normal subjects. The low IGF-I dose that elicited an increase in
circulating IGF-I levels within the normal range did not modify insulin
and glucose levels in either obese or normal subjects.
The inhibitory feedback action of rhIGF-I administration on GH
secretion has been widely demonstrated in humans after iv and sc
administration (31, 32, 34, 35, 36, 37). The inhibition of
spontaneous GH secretion has been shown in normal fasted humans as well
as in pathophysiological conditions such as Laron’s syndrome,
insulin-dependent diabetes mellitus, malnutrition, and anorexia nervosa
(34, 35, 36, 37, 49). Moreover, the inhibitory effect of rhIGF-I
on the somatotroph response to GHRH has been shown in normal and
anorectic subjects (49), although this effect may depend
on the timing of rhIGF-I pretreatment (50). It is
noteworthy that the inhibitory effect of rhIGF-I in humans takes place
even after the administration of a low dose, after which, as in the
present study, circulating IGF-I levels do not exceed the normal range
(31).
Although IGF-I may exert its inhibitory feedback action directly at the
pituitary level (39, 40, 41, 42), there is evidence that it
generally modulates somatotroph secretion mainly via central nervous
system-mediated actions, which include concomitant inhibition of the
activity of GHRH-secreting neurons and stimulation of hypothalamic
somatostatin release (40, 47, 48, 51). Accordingly, it has
been demonstrated that in humans rhIGF-I is capable of inhibiting the
GH response to GHRH alone or to arginine alone (31, 33), which is
likely to act via inhibition of hypothalamic somatostatin release.
However, it does not inhibit the secretory effects of either the
combined administration of GHRH and arginine (52) or of
hypoglycemia (34, 53), a multifactorial stimulus that
triggers GHRH-secreting neurons and inhibits somatostatin release
(54).
The marked insufficiency of both spontaneous and stimulated GH
secretion in obesity might reflect neuroendocrine abnormalities,
including a hyperactive somatostatinergic tone and/or GHRH hypoactivity
(2, 3, 4), although abnormalities in peripheral hormones and
metabolic factors could play a major role. The latter abnormalities
could include enhanced negative free IGF-I feedback, hyperinsulinism,
alterations in leptin activity, and elevated free fatty acids
(5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15).
Paradoxically, in obesity the low somatotroph responsiveness to
provocative stimuli is coupled with a peculiar refractoriness to the
inhibitory effect of hyperglycemia (29). In fact, the low
GH response to GHRH is not inhibited by previous glucose load, although
it is normally abolished by pirenzepine, a muscarinic antagonist, as
well as exogenous somatostatin (30).
Taking also into account the hypothesis that the GH hyposecretory state
in obese patients would reflect an exaggerated negative feedback of
high circulating free IGF-I levels (5), we aimed at
verifying whether a low rhIGF-I dose could inhibit the GH response to
GHRH in obese patients. Our present data show that the sensitivity to
the inhibitory effect of IGF-I is preserved in obesity. In fact, in
obese patients after rhIGF-I administration the GH response to GHRH was
lower than that in normal subjects, but the percent inhibitory effect
was similar in the two groups.
In obese as well as normal subjects no significant inhibitory effect of
rhIGF-I on spontaneous GH secretion before GHRH administration was
recorded. However, this finding should be examined with caution,
because we did not use an ultrasensitive GH assay that might better
investigate some inhibitory effect of rhIGF-I on low spontaneous GH
levels (55). On the other hand, our study of spontaneous
GH secretion was probably too short, and thus we might have missed
recording a significant number of GH peaks that could have been
inhibited by rhIGF-I (56). The clear inhibitory effect of
a low rhIGF-I dose, which raised circulating IGF-I levels within the
normal range, on the somatotroph responsiveness to GHRH may challenge
the hypothesis that GH insufficiency in obesity reflects an enhanced
negative feedback by high free IGF-I levels (5). However,
this hypothesis cannot be definitively ruled out, as we did not measure
free IGF-I levels. On the other hand, as the GH response to GHRH in
obese patients was inhibited by rhIGF-I in the present study as well as
by pirenzepine or exogenous somatostatin in previous studies
(30), the present results indirectly strengthen the
peculiar refractoriness of somatotroph secretion to the inhibitory
effect of a glucose load.
It has been shown that a high rhIGF-I dose inhibits insulin
secretion in normal subjects (57), whereas the
insulin-sensitizing effect of IGF-I has also been demonstrated
(58). Although we used a rhIGF-I dose that had been
previously shown to be devoid of any inhibitory effect on insulin and
glucose levels in normal and anorectic subjects (31, 49),
an inhibitory effect on the insulin hypersecretion that connotes
obesity could be foreseen. Our results show that 20 µg/kg rhIGF-I,
sc, does not modify insulin hypersecretion and glucose levels in obese
patients, at least after acute administration.
In conclusion, the present study shows that the inhibitory effect of
rhIGF-I on the GH response to GHRH is preserved in obese patients in
whom somatotroph hyporesponsiveness to all provocative stimuli known to
date as well as peculiar refractoriness to the inhibitory effect of
glucose load have been demonstrated. This would make it less likely
that the GH hyposecretion of obesity is due to a greater somatotroph
inhibition by circulating IGF-I levels.
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Footnotes
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1 This work was supported by Pharmacia & Upjohn, Inc.,
CNR (Grant 98.03040.CT04, Rome, Italy), Ministero
Universitá e Ricerca Scientifica e Technologica (Grant
9706151106, Rome, Italy), and the SMEM Foundation. 
Received June 15, 2000.
Revised September 18, 2000.
Accepted September 21, 2000.
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References
|
|---|
-
Veldhuis JD, Iranmanesh A, Ho KKY, Waters MJ,
Johnson ML, Lizarralde G. 1991 Dual defects in pulsatile growth
hormone secretion and clearance subserve the hyposomatotropism of
obesity in man. J Clin Endocrinol Metab. 72:51–59.[Abstract/Free Full Text]
-
Berelowitz M, Finkelstein JA, Thominet JL, Ting NC,
Hirth J, Frohman LA. Impaired growth hormone secretion in
spontaneous experimental obesity: a result of increased somatostatin
(SRIF) tone [Abstract 16]. Proc of the 64th Annual Meet of The
Endocrine Soc. 1983; 84.
-
Tannenbaum GS, Lapointe M, Gurd W, Finkelstein JA. 1990 Mechanism of impaired growth hormone secretion in genetically
obese Zucker rats: roles of growth hormone-releasing factor and
somatostatin. Endocrinology. 127:3087–3095.[Abstract/Free Full Text]
-
Ghigo E, Procopio M, Maccario M, et al. 1993 Repetitive GHRH administration fails to increase to GHRH in obese
subjects. Evidence for a somatotrope defect in obesity? Horm Metab Res. 25:305–308.[Medline]
-
Frystyk J, Skjaerbaek E, Mogensen CE, Orskov H. 1995 Free insulin-like growth factor in human obesity. Metabolism.
44(Suppl 4):37–44.
-
Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. 1994 Effect of insulin on the hepatic production of insulin-like growth
factor binding protein-1 (IGFBP-1), IGFBP-3 and IGF-I in
insulin-dependent diabetics. J Clin Endocrinol Metab. 79:872–878.[Abstract]
-
Maccario M, Arvat E, Procopio M, et al. 1995 Metabolic Modulation of growth hormone-releasing activity of hexarelin
in man. Metabolism. 44:134–138.[CrossRef][Medline]
-
Maccario M, Procopio M, Grottoli S, et al. 1996 Effects of acipimox, an antilipolytic drug, on the growth hormone (GH).
Response to GH-releasing hormone alone or combined with arginine in
obesity. Metabolism. 45:342–346.[CrossRef][Medline]
-
Casanueva FF, Dieguez C. 1999 Neuroendocrine
regulation and actions of leptin. Front Neuroendocrinol. 20:317–363.[CrossRef][Medline]
-
Cordido F, Peino R, Penalva A, Alvarez CV, Casanueva FF,
Dieguez C. 1996 Impaired growth hormone secretion in obese
subjects is partially reversed by acipimox-mediated plasma free fatty
acid depression. J Clin Endocrinol Metab. 81:914–918.[Abstract]
-
Nam SY, Lee EJ, Kim KR, et al. 1996 Long-term
administration of acipimox potentiates growth hormone response to
growth hormone-releasing hormone by decreasing serum free fatty acid in
obesity. Metabolism. 45:594–597.[CrossRef][Medline]
-
Alvarez CV, Mallo F, Burguera B, Caciedo L, Dieguez C,
Casanueva FF. 1991 Evidence for a direct pituitary inhibition by
free fatty acid of in vivo growth hormone responses to growth
hormone-releasing hormone in the rat. Neuroendocrinology. 53:185–189.[CrossRef][Medline]
-
Andreotti AC, Lanzi R, Manzoni AF, Caumo A, Moreschi A,
Pontiroli AE. 1994 Acute pharmacological blockade of lypolisis
normalizes nocturnal growth hormone levels and pulsatily in obese
subjects. Metabolism. 43:1207–1213.[CrossRef][Medline]
-
Yamashita S, Melmed S. 1986 Effect of insulin on
rat anterior pituitary cells. Diabetes. 35:440–447.[Abstract]
-
Diamond MP, Hallarman L, Starick-Zych K, et al. 1991 Suppression of counterregulatory hormone response to hypoglycemia
by insulin per se. J Clin Endocrinol Metab. 72:1388–1390.[Abstract/Free Full Text]
-
Copinschi G, Wegienka LC, Hane S, Forsham PH. 1967 Effect of arginine on serum levels of insulin and growth hormone in
obese subjects. Metabolism. 16:485.[CrossRef][Medline]
-
Bell JP, Donald RA, Espiner EA. 1970 Pituitary
response to insulin-induced hypoglycemia in obese subjects before and
after fasting. J Clin Endocrinol Metab. 31:546–551.[Abstract/Free Full Text]
-
Mims RB, Stein RB, Bethune JE. 1973 The effect of a
single dose of L-dopa on pituitary hormones in acromegaly,
obesity and in normal subjects. J Clin Endocrinol Metab. 37:34–39.[Abstract/Free Full Text]
-
Topper E, Gil-Ad I, Bauman B, Josefaberg Z, Laron
Z. 1984 Plasma growth hormone response to oral clonidine as
compared to insulin hypoglycemia in obese children and adolescents. Horm Metab Res. 1:127–130.
-
Finer H, Price P, Grossman A, Besser GM. 1987 The
effects of enkephalin analogue on pituitary hormone release in human
obesity. Horm Metab Res. 19:68–70.[Medline]
-
Ghigo E, Mazza E, Corrias A, et al. 1989 Effect of
cholinergic enhancement by pyridostigmine on growth hormone secretion
obese adults and children. Metabolism. 38:631–633.[CrossRef][Medline]
-
Loche S, Pintus S, Cella SG, et al. 1990 The effect
of galanin on baseline and GHRH-induced growth hormone secretion in
obese children. Clin Endocrinol (Oxf). 33:187–192.[Medline]
-
Dieguez C, Mallo F, Senaris R, et al. 1996 Role of
glucocorticoids in the neuroregulation of growth hormone secretion.
J Pediatr Endocrinol Metab. 9(Suppl 3):255–260.
-
Williams T, Berelowitz M, Joffe SN, et al. 1984 Impaired growth hormone releasing factor in obesity. N Engl J
Med. 311:1403–1407.[Abstract]
-
Cordido F, Casanueva FF, Dieguez C. 1989 Cholinergic receptor activation by pyridostigmine restores growth
hormone (GH) responsiveness to GH-releasing hormone administration in
obese subjects. J Clin Endocrinol Metab. 68:290–293.[Abstract/Free Full Text]
-
Ghigo E, Goffi S, Nicolosi M, et al. 1990 GH
responsiveness to combined administration of arginine and GHRH does not
vary with age in man. J Clin Endocrinol Metab. 71:1481–1485.[Abstract/Free Full Text]
-
Cordido F, Penalva A, Dieguez C, Casanueva FF. 1993 Massive growth hormone (GH) discharge in obese subjects after the
combined administration of GH-releasing hormone and GHRP-6: evidence
for a marked somatotroph secretory capability in obesity. J Clin
Endocrinol Metab. 76:819–823.[Abstract]
-
Procopio M, Maccario M, Savio P, et al. 1998 GH
response to GHRH combined with pyridostigmine or arginine in different
conditions of low somatotrope secretion in adulthood: obesity and
Cushing’s syndrome in comparison with hypopituitarism. Panminerva Med. 40:13–17.[Medline]
-
Grottoli S, Procopio M, Maccario M, et al. 1997 In
obesity, glucose load loses its early inhibitory, but maintains its
late stimulatory, effect on somatotrope secretion. J Clin
Endocrinol Metab. 82:2261–2265.[Abstract/Free Full Text]
-
Maccario M, Procopio M, Grottoli S, et al. 1995 In
obesity the somatotrope response to either growth hormone-releasing
hormone or arginine is inhibited by somatostatin or pirenzepine but not
by glucose. J Clin Endocrinol Metab. 80:3774–3778.[Abstract]
-
Ghigo E, Gianotti L, Arvat E, et al. 1999 Effects
of recombinant human insulin-like growth factor I administration on
growth hormone (GH) secretion, both spontaneous and stimulated by
GH-releasing hormone or hexarelin, a peptidyl GH secretagogue, in
humans. J Clin Endocrinol Metab. 84:285–290.[Abstract/Free Full Text]
-
Guler HP, Schmid C, Zapf J, Froesch ER. 1989 Effect
of recombinant insulin-like growth factor I on insulin secretion and
renal function in normal human subjects. Proc Natl Acad Sci USA. 86:2868–2872.[Abstract/Free Full Text]
-
Nass RM, Pezzoli SS, Chapman IM, Hartman ML, Thorner
MO. 1998 IGF-I attenuates the GH response to arginine. Proceedings
of the 80th Annual Meeting of The Endocrine Society, New Orleans, LA;
73.
-
Laron Z, Klinger B, Jensen LT, Erster B. 1991 Biochemical and hormonal changes induced by one week of administration
of rhIGF-I to patients with Laron type dwarfism. Clin Endocrinol (Oxf).
35;145–150.
-
Hartman ML, Clayton PE, Johnson ML, et al. 1993 A
low dose euglycemic infusion of recombinant human insulin-like growth
factor I rapidly suppresses fasting-enhanced pulsatile growth hormone
secretion in humans. J Clin Invest. 91:2453–2462.
-
Vaccarello MA, Diamond FB, Guevara-Aguirre J, et
al. 1993 Hormonal and metabolic effects and pharmacokinetics of
recombinant insulin-like growth factor-I in growth hormone receptor
deficiency/Laron syndrome. J Clin Endocrinol Metab. 77:273–280.[Abstract]
-
Cheetham TD, Connors M, Clayton K, Watts A, Dunger
DB. 1997 The relationship between overnight GH levels and insulin
concentrations in adolescents with insulin-dependent diabetes mellitus
(IDDM) and the impact of recombinant human insulin-like growth factor-I
(rhIGF-I). Clin Endocrinol (Oxf). 46:415–424.[CrossRef][Medline]
-
Deleted in proof.
-
Ceda GP, Davis RG, Rosenfeld RG, Hoffman AR. 1987 The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis:
evidence for rapid inhibition of GHRH-elicited GH release by
insulin-like growth factors I and II. Endocrinology. 120:1658–1662.[Abstract/Free Full Text]
-
Berelowitz M, Szabo M, Frohman LA, Firestone S, Hintz
RL. 1981 Somatomedin-C mediates growth hormone negative feedback
by effects on both the hypothalamus and the pituitary. Science. 212:1279–1281.[Abstract/Free Full Text]
-
Abe H, Molitch ME, Van Wyk JJ, Underwood LE. 1983 Human growth hormone and somatomedin C suppress the spontaneous release
of growth hormone in unanesthetized rats. Endocrinology. 113:1319–1324.[Abstract/Free Full Text]
-
Tannembaum GS, Guyda HJ, Posner BI. 1983 Insulin-like growth factors: a role in growth hormone negative feedback
and body weight regulation via brain. Science. 220:77–79.[Abstract/Free Full Text]
-
Yamashita S, Melmed S. 1986 Insulin-like growth
factor I action on rat anterior pituitary cells: suppression of
growth hormone secretion and messenger ribonucleic acid levels. Endocrinology. 118:176–182.[Abstract/Free Full Text]
-
Fletcher TP, Thomas GB, Dunshea FR, Moore LG, Clarke
IJ. 1995 IGF feedback effects on growth hormone secretion in ewes:
evidence for action at the pituitary but not the hypothalamic level. J
Endocrinol. 144:323–331.[Abstract/Free Full Text]
-
Bohannon NJ, Figlewicz DP, Corp ES, Wilcox BJ, Porte Jr
D, Baskin DG. 1986 Identification of binding sites for an
insulin-like growth factor (IGF-I) in the median eminence of the rat
brain by quantitative autoradiography. Endocrinology. 119:943–945.[Abstract/Free Full Text]
-
Shimon I, Yan X, Melmed S. 1998 Human fetal
pituitary expresses functional growth hormone-releasing peptide
receptors. J Clin Endocrinol Metab. 83:174–178.[Abstract/Free Full Text]
-
Sato M, Frohman LA. 1993 Differential effects of
central and peripheral administration of GH and insulin-like growth
factor on hypothalamic GH-releasing hormone and somatostatin gene
expression in GH-deficient dwarf rats. Endocrinology. 133:793–799.[Abstract/Free Full Text]
-
Shibasaki T, Yamauchi N, Hotta M, et al. 1986 In
vitro release of growth hormone-releasing factor from rat hypothalamus:
effect of insulin-like growth factor-I. Regul Pept. 15:47–51.[CrossRef][Medline]
-
Gianotti L, Pincelli AI, Scacchi M, et al. 2000 Effects of recombinant human insulin-like growth factor I
administration on spontaneous and growth hormone (GH)-releasing
hormone-stimulated GH secretion in anorexia nervosa. J Clin
Endocrinol Metab. 85:2805–2809.[Abstract/Free Full Text]
-
Trainer PJ, Holly J, Medbak S, Rees LH, Besser GM. 1994 The effect of recombinant IGF-I on anterior pituitary function in
healthy volunteers. Clin Endocrinol (Oxf). 41:801–807.[Medline]
-
Frohman LA, Jansson JO. 1986 Growth
hormone-releasing hormone. Endocr Rev. 7:223–231.[Abstract/Free Full Text]
-
Gianotti L, Maccario M, Lanfranco F, et al. 2000 Arginine counteracts the inhibitory effect of recombinant human
insulin-like growth factor I on the somatotroph responsiveness to
growth hormone-releasing hormone in humans. J Clin Endocrinol
Metab. 85:3597–3603.[Abstract/Free Full Text]
-
Laron Z, Klinger B, Silbergeld A, Lewin R, Erster B,
Gil-Ad I. 1990 Intravenous administration of recombinant IGF-I
lowers serum GHRH and TSH. Acta Endocrinol (Copenh). 123:378–382.[Abstract/Free Full Text]
-
Muller EE, Nistico G. 1989 Neurotransmitter
regulation of the anterior pituitary. In: Nistico G, ed. Brain
messengers and the pituitary. San Diego: Academic Press; 404–537.
-
Veldhuis JD. 1996 New modalities for
understanding dynamic regulation of the somatotropic (GH) axis:
explication of gender differences in GH neuroregulation in the human.
J Pediatr Endocrinol Metab. 9(Suppl 3):237–253.
-
Pincus SM, Hartman ML, Roelfsema F, et al. 1999 Hormone pulsatility discrimination via coarse and short time sampling.
Am J Physiol. 277:E948—E957.
-
Bianda TL, Hussain MA, Keller A, et al. 1996 Insulin-like growth factor-I in man enhances lipid mobilization and
oxidation induced by a growth hormone pulse. Diabetologia. 39:961–969.[Medline]
-
Hussain MO, Schmitz O, Mengel A, et al. 1993 Insulin-like growth factor I stimulates lipid oxidation, reduces
protein oxidation, and enhances insulin sensitivity in humans. J
Clin Invest. 92:2249–2256.
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Abstract
Introduction
