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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3604-3608
Copyright © 2000 by The Endocrine Society

Original Studies

Arginine Counteracts the Inhibitory Effect of Recombinant Human Insulin-Like Growth Factor I on the Somatotroph Responsiveness to Growth Hormone-Releasing Hormone in Humans1

Laura Gianotti, Mauro Maccario, Fabio Lanfranco, Josefina Ramunni, Lidia Di Vito, Silvia Grottoli, Eugenio Edoardo Muller, Ezio Ghigo and Emanuela Arvat

Division of Endocrinology, Department of Internal Medicine, University of Turin, 10126 Turin, Italy; and Department of Pharmacology, University of Milan (E.E.M.), 20100 Milan, Italy

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, Corso Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Insulin-like growth factor I (IGF-I) exerts a negative feedback effect on GH secretion via either direct actions at the pituitary level or indirect ones at the hypothalamic level, through stimulation of somatostatin (SS) and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) in humans inhibits spontaneous GH secretion as well as the GH response to GHRH and even more to GH/GH-releasing peptides, whose main action is on the hypothalamus, antagonizing SS and enhancing GHRH activity. The aim of the present study was to further clarify in humans the mechanisms underlying IGF-I-induced inhibition of somatotroph secretion. In six normal young volunteers (all women; mean ± SEM: age, 28.3 ± 1.2 yr; body mass index, 21.3 ± 1.2 kg/m2) we studied the GH response to GHRH (1 µg/kg, iv, at 0 min), both alone and combined with arginine (ARG; 0.5 g/kg, iv, from 0–30 min), which probably acts via inhibition of hypothalamic SS release, after pretreatment with rhIGF-I (20 µg/kg, sc, at -180 min) or placebo. rhIGF-I increased circulating IGF-I levels (peak at -60 vs. -180 min: 54.9 ± 3.9 vs. 35.9 ± 3.3 mmol/L; P < 0.05) to a reproducible extent, and these levels remained stable and within the normal range until 90 min. The mean GH concentration over 3 h (from -180 to 0 min) before ARG and/or GHRH was not modified by placebo or rhIGF-I. After placebo, the GH response to GHRH (peak, 23.6 ± 2.9 µg/L) was strikingly enhanced (P < 0.05) by ARG coadministration (69.6 ± 9.9 µg/L). rhIGF-I blunted the GH response to GHRH (13.1 ± 4.5 µg/L; P < 0.05), whereas that to GHRH plus ARG was not modified (59.5 ± 8.9 µg/L), although it occurred with some delay. Mean glucose and insulin concentrations were not modified by either placebo or rhIGF-I. In conclusion, ARG counteracts the inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH in humans. These findings suggest that the acute inhibitory effect of rhIGF-I on the GH response to GHRH takes place on the hypothalamus, possibly via enhancement of SS release, and that ARG overrides this action.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INSULIN-LIKE growth factor I (IGF-I) exerts an inhibitory feedback action on GH secretion in both animals and humans (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). The mechanisms underlying this effect include a direct action on the pituitary, where IGF-I activates IGF-I receptors and inhibits GH synthesis and release (1, 2, 3, 4, 11, 15, 16). In addition, an indirect central nervous system (CNS)-mediated IGF-I action has been demonstrated. In fact, IGF-I has specific IGF-I receptors in the CNS, and animal data have shown that it acts on the hypothalamus to stimulate somatostatin (SS) release (1, 3, 17) and/or inhibit GHRH release (4, 17, 18).

In humans, apart from GH deficiency, in conditions of peripheral GH insensitivity, reduced IGF-I secretion is often coupled with increased GH secretion, probably due to lack of the negative IGF-I feedback effect (19, 20, 21, 22). In fact, the administration of recombinant human IGF-I (rhIGF-I) is able to inhibit the GH secretion in patients with Laron’s syndrome, insulin-dependent diabetes mellitus, malnutrition, and critical illness and even in fasted normal subjects (7, 8, 23, 24, 25).

In fed normal subjects, rhIGF-I administration inhibits the GHRH-induced GH response (6, 13, 14). Lack of an inhibitory effect of rhIGF-I on the GH secretion stimulated by GHRH in women has been reported by some (13), but not by others (14). It has also been shown that the inhibitory effect of rhIGF-I on the GH-releasing effect of hexarelin, a peptidyl GH secretagogue (GHS), is even more marked than that exerted on the GH response to GHRH (14); this finding is noteworthy considering that GH secretagogues mainly act on the hypothalamus at least partially via enhanced firing of GHRH-secreting neurons and functional antagonism of SS activity (26, 27, 28).

On the other hand, indirect evidence in children with Laron’s dwarfism indicates that the stimulatory effect of hypoglycemia on GH secretion is refractory to the inhibitory action of rhIGF-I (29, 30). As the GH-releasing effect of hypoglycemia probably reflects concomitant inhibition of hypothalamic SS release and activation of GHRH-secreting neurons (31, 32, 33), it has been hypothesized that these mechanisms are not counteracted by IGF-I.

Based on the foregoing, the aim of the present study was to further clarify the mechanism by which IGF-I inhibits GH secretion in humans. To this goal, in healthy young women we studied the effect of a low dose of rhIGF-I on the GH response to GHRH given alone or combined with arginine (ARG). In fact, there is evidence, although indirect, indicating that ARG acts via inhibition of hypothalamic SS release (31, 32, 33).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
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). Vials containing 30 g (in 100 mL solution) arginine hydrochloride (Arginine, Damor, Naples, Italy) were purchased from Damor (Naples, Italy).

Study protocol

Six normal young women (mean ± SEM: age, 28.3 ± 1.2 yr; body mass index, 21.3 ± 1.2 kg/m2) were studied in the early follicular phase. All subjects gave their informed consent to participate in the study, which had been approved by an independent ethical committee.

All subjects underwent the following six testing sessions in random order and at least 3 days apart: placebo (saline, 1 mL, sc, at -180 min), rhIGF-I (20 µg/kg, sc, at -180 min), placebo (at -180 min) followed by GHRH (1 µg/kg, iv, at 0 min), placebo (at -180 min) followed by GHRH (at 0 min) plus ARG (0.5 g/kg, iv, up to a maximum of 30 g from 0–30 min), rhIGF-I (at -180 min) followed by GHRH (at 0 min), and rhIGF-I (at -180) followed by GHRH (at 0 min) plus ARG (from 0–30 min). The tests were begun in the morning at 0830–0900 h after overnight fasting and 30 min after an indwelling catheter had been placed into an antecubital vein of the forearm and kept patent by slow infusion of isotonic saline. Blood samples were drawn basally at every 15 min from -180 to +90 min.

Serum GH levels were measured at each time point in all sessions. Serum IGF-I, serum insulin, and plasma glucose levels were measured every 30 min from -180 to 90 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 (nanomoles per L; 1 µg/L x 0.1307 = 1 nmol/L) were measured in duplicate by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). All samples were treated with acid-ethanol to avoid interference by binding proteins. The sensitivity of the assay was 0.01 nmol/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; 1 mU/L x 7.175 = 1 pmol/L) were measured in duplicate by immunoradiometric assays (Sorin). The sensitivity of insulin assay was 17.9 ± 2.2 pmol/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; 1 mg/dL x 0.05551 = 1 mmol/L) were measured by the glucose oxidase colorimetric method (GLUCOFIX, Menarini Diagnostics, Firenze, Italy).

All samples from an individual subject were analyzed together. The hormonal responses are expressed as absolute values of circulating GH levels induced by stimuli. Statistical analysis was carried out using nonparametric ANOVA (Wilcoxon test). The results are expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The administration of rhIGF-I increased circulating IGF-I levels (mean ± SEM peak at -60 vs. -180 min, 54.9 ± 3.9 vs. 35.9 ± 3.3 nmol/L; P < 0.05) to a reproducible extent, and IGF-I levels remained within the normal range until 90 min (Table 1Go). GH concentrations from -180 to 90 min after both placebo and rhIGF-I administration were similar. In fact, an overlapping significant (P < 0.05) decrease in basal GH levels was recorded after both placebo and rhIGF-I (Table 1Go). After placebo, the GH response to GHRH (23.6 ± 2.9 µg/L) was markedly potentiated (P < 0.05) by ARG coadministration (69.6 ± 9.9 µg/L; Fig. 1Go).


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  		Table 1. Mean (±SEM) IGF-I, GH, insulin, and blood glucose levels after placebo or rhIGF-I (20 µg/kg, sc, at -180 min) in six normal subjects

 


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  		Figure 1. Mean (±SEM) GH curves (micrograms per L) and AUCs (micrograms per L/h) after GHRH alone (1 µg/kg, iv, at 0 min; upper panel) or combined with arginine (0.5 g/kg, iv, from 0–30 min; lower panel), preceded by placebo ({circ}) or rhIGF-I (•; 20 µg/kg, sc, at -180 min) administration in six normal young adults. *, P < 0.05.

 
The GH response to GHRH was significantly blunted by pretreatment with rhIGF-I (13.1 ± 4.5 µg/L; P < 0.05), which, in turn, did not modify somatotroph responsiveness to the combined administration of GHRH and ARG (59.5 ± 8.9 µg/L). However, pretreatment with rhIGF-I induced a nonsignificant delay in the timing of peak GH after GHRH plus ARG treatment (Fig. 1Go).

When evaluated as the area under the curve (AUC), the results showed the differences reported above (Fig. 1Go), although the GH AUC recorded after the combined administration of GHRH and arginine preceded by rhIGF-I seemed slightly blunted.

Mean glucose and insulin concentrations from -180 to 90 min were not modified by either placebo or rhIGF-I (Table 1Go).

Side effects

Four subjects experienced transient discomfort at the injection site after rhIGF-I administration, but no major side-effects were recorded. Five subjects had transient facial flushing after GHRH administration. No side-effects were observed after ARG coadministration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study show that arginine counteracts the inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH in humans. In agreement with previous studies (6, 10, 14, 23, 34), the rhIGF-I dose we administered in this study increased circulating IGF-I levels within the normal range, indicating that we were investigating the effects of physiological increases in IGF-I levels on stimulated somatotroph release.

The inhibitory effect of rhIGF-I on somatotroph secretion has clearly been demonstrated (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). In humans, high and low doses of rhIGF-I inhibit spontaneous GH secretion in pathophysiological conditions such as Laron’s syndrome, insulin-dependent diabetes mellitus, malnutrition, and critical illness and even in fasted normal subjects (7, 8, 23, 24, 25). Moreover, it has been shown that rhIGF-I administration inhibits both basal and stimulated GH secretion in normal fed subjects; in fact, low rhIGF-I doses were shown to blunt the GH response to ARG (35), GHRH (6, 13, 14), and peptidyl GH secretagogues (14). As anticipated, the marked inhibitory effect of rhIGF-I on the GH response to GHS is noticeable (14), because they mainly act at the hypothalamic level and show a GH-releasing effect that is generally refractory to inhibitory inputs, including exogenous SS (26, 27, 28).

In our experimental conditions, differently from other researches (9, 13), no inhibitory effect of rhIGF-I on spontaneous GH secretion was recorded, although the use of an ultrasensitive assay might have allowed us to disclose some effect (36). In agreement with other studies (6, 14), the GH response to the maximal effective dose of GHRH was significantly inhibited by rhIGF-I. By contrast, no inhibitory effect of rhIGF-I on the somatotroph responsiveness to GHRH was recorded when the neurohormone was administered in combination with ARG, which strikingly potentiated its GH-releasing effect.

There is evidence, although indirect, suggesting that ARG potentiated both basal and GHRH-stimulated somatotroph secretion acting via inhibition of hypothalamic SS release (37, 38). In fact, ARG does not release GH from pituitary cells in culture (38), whereas in humans it counteracts the SS-mediated negative GH autofeedback mechanism (37, 39) as well as the inhibitory effect of glucose (40), which is likely to take place via an increase in SS release (31, 32, 33). Moreover, ARG fully restores the reduced somatotroph responsiveness to GHRH in aging (37), in which absolute or relative somatostatin hyperactivity has been demonstrated (41, 42, 43), but it has no interaction with cholinergic agonists, such as pyridostigmine, which potentiate GH secretion via inhibition of hypothalamic SS release (31, 32, 33, 44).

Thus, evidence that ARG counteracts the inhibitory effect of rhIGF-I on the GH response to GHRH suggests that this effect occurs via an increase in hypothalamic SS, in agreement with previous animal experiments (1, 3). This hypothesis does not disagree with evidence that rhIGF-I abolishes the GH response to ARG alone in normal subjects (35). In fact, the latter is also abolished during the infusion of a GHRH antagonist (45). As IGF-I has been shown to be able to inhibit hypothalamic GHRH release (17, 18, 46), the GH response to ARG alone could have been abolished after rhIGF-I pretreatment by blockade of GHRH neuronal function even in the presence of reduced SS release. This hypothesis is supported by evidence that both inhibition of hypothalamic SS release as well as passive immunization against SS lead to an increase in GH by triggering the activity of GHRH-secreting neurons, which possess both SSt1 and SSt2 receptor sites (32, 33, 47). In animals, IGF-I inhibits the stimulated somatotroph release via an increase in SS concomitant with a reduction of GHRH release from the hypothalamus (1, 3, 4, 17, 18). Moreover, the inhibitory action of rhIGF-I on somatotroph secretion in children with Laron’s dwarfism is overridden by hypoglycemia (29, 30), which probably leads to concomitant inhibition of hypothalamic SS release and activation of GHRH-secreting neurons (31, 32, 33). As definite direct evidence that ARG acts via inhibition of hypothalamic SS release is still missing, we cannot rule out the possibility that unknown mechanisms underlie ARG activity and its ability to counteract the acute inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH.

In conclusion, this study shows that ARG overrides the inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH in humans. These findings indicate that the acute inhibitory effect of acute rhIGF-I administration on somatotroph secretion takes place on the hypothalamus, where concomitant triggering of SS release and inhibition of GHRH-secreting neurons might play a major role.


   Acknowledgments
 
We thank Dr. Fabio Broglio, Barbara Maccagno, and Maria Rosa Valetto for their cooperation during the study; and Mrs. Marina Taliano for her skillful technical assistance.


   Footnotes
 
1 This work was supported by Pharmacia & Upjohn, Inc., MURST (ex 60%{approx} es. fin. 95), and the Fondazione per lo Studio delle Malattie Endocrino-Metaboliche. Back

Received March 15, 2000.

Revised June 2, 2000.

Accepted June 15, 2000.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Distinctive Inhibitory Mechanisms of Age and Relative Visceral Adiposity on Growth Hormone Secretion in Pre- and Postmenopausal Women Studied under a Hypogonadal Clamp
J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6006 - 6013.
[Abstract] [Full Text] [PDF]

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 Eur J EndocrinolHome page
J. D Veldhuis, D. M Keenan, K. Mielke, J. M Miles, and C. Y Bowers
Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy
Eur. J. Endocrinol., October 1, 2005; 153(4): 577 - 586.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, A. Iranmanesh, and C. Y. Bowers
Joint Mechanisms of Impaired Growth-Hormone Pulse Renewal in Aging Men
J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4177 - 4183.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
C. Soares-Welch, L. Farhy, K. L. Mielke, F. H. Mahmud, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis
Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults
J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2225 - 2232.
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 Endocr. Rev.Home page
J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers
Endocrine Control of Body Composition in Infancy, Childhood, and Puberty
Endocr. Rev., February 1, 2005; 26(1): 114 - 146.
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 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, J. Y. Weltman, A. L. Weltman, A. Iranmanesh, E. E. Muller, and C. Y. Bowers
Age and Secretagogue Type Jointly Determine Dynamic Growth Hormone Responses to Exogenous Insulin-Like Growth Factor-Negative Feedback in Healthy Men
J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5542 - 5548.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
D. Erickson, D. M. Keenan, K. Mielke, K. Bradford, C. Y. Bowers, J. M. Miles, and J. D. Veldhuis
Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Postmenopausal Compared with Premenopausal Women Studied under an Experimental Estradiol Clamp
J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4746 - 4754.
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 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, S. M. Anderson, P. Kok, A. Iranmanesh, J. Frystyk, H. Orskov, and D. M. Keenan
Estradiol Supplementation Modulates Growth Hormone (GH) Secretory-Burst Waveform and Recombinant Human Insulin-Like Growth Factor-I-Enforced Suppression of Endogenously Driven GH Release in Postmenopausal Women
J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1312 - 1318.
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 Am. J. Physiol. Endocrinol. Metab.Home page
R. Nass, S. S. Pezzoli, I. M. Chapman, J. Patrie, R. L. Hintz, M. L. Hartman, and M. O. Thorner
IGF-I does not affect the net increase in GH release in response to arginine
Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E702 - E710.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. D. Veldhuis, M. Bidlingmaier, S. M. Anderson, Z. Wu, and C. J. Strasburger
Lowering Total Plasma Insulin-Like Growth Factor I Concentrations by Way of a Novel, Potent, and Selective Growth Hormone (GH) Receptor Antagonist, Pegvisomant (B2036-Peg), Augments the Amplitude of GH Secretory Bursts and Elevates Basal/Nonpulsatile GH Release in Healthy Women and Men
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3304 - 3310.
[Abstract] [Full Text] [PDF]

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