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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 1 285-290
Copyright © 1999 by The Endocrine Society

Original Studies

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 Humans1

E. Ghigo, L. Gianotti, E. Arvat, J. Ramunni, M. R. Valetto, F. Broglio, M. Rolla, F. Cavagnini and E. E. Müller

Division of Endocrinology (E.G., L.G., E.A., J.R., M.R.V., F.B.), Department of Internal Medicine, University of Turin; Unit of Adolescentology (M.R.), University of Pisa; Division of Endocrinology (F.C.), San Luca Hospital; and Department of Pharmacology (E.E.M.), University of Milan, 20129 Milano, Italy

Address all correspondence and requests for reprints to: Prof. E. E. Müller, Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129, Milano, Italy.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The negative feedback exerted by insulin-like growth factor I (IGF-I) on GH secretion occurs at the pituitary, as well as the hypothalamic level, via stimulation of SS and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) administration inhibits basal GH secretion, at least in fasted humans, though its effect on the GH response to GHRH is still controversial. GH secretagogues (GHS) are peptidyl and nonpeptidyl molecules that act on specific receptors at the pituitary and/or the hypothalamic level. Contrary to GHRH, the GH-releasing activity of GHS is strong, reproducible, and even partially refractory to inhibitory influences such as exogenous somatostatin. We studied the effects of rhIGF-I administration (20 µg/kg sc at 0 min) on GH secretion, either spontaneous or stimulated by GHRH (2 µg/kg iv at +180 min) or Hexarelin (HEX, 2.0 µg/kg iv at +180 min), a GHS, in eight normal young women (age, mean ± SEM, 28.3 ± 1.2 yr; body mass index, 20.1 ± 0.5 kg/m2). rhIGF-I administration increased IGF-I levels (peak vs. baseline: 420.3 ± 30.5 vs. 274.4 ± 25.3 µg/L, P < 0.05) within the physiological range from +120 to +300 min. No variation in glucose or insulin levels was recorded. rhIGF-I did not reduce spontaneous GH secretion [areas under curves (AUC)0–300 min 140.6 ± 66.3 vs. 114.6 ± 32.1 µg/L·h], whereas it inhibited the GH response to both GHRH (AUC180–300 min 447.7 ± 159.4 vs. 715.9 ± 104.3 µg/L·h, P < 0.05) and HEX (620.3 ± 110.4 vs. 1705.9 ± 328.9 µg/L·h, P < 0.03). The percent inhibitory effect of rhIGF-I on the GH response to GHRH (41.7 ± 12.8%) was lower than that on the response to HEX (57.7 ± 11.0%). In fact, the GH response to GHRH alone was clearly lower than that to HEX alone (P < 0.05), whereas the GH responses to GHRH and HEX were similar after rhIGF-I. Our findings show that the sc administration of low rhIGF-I doses inhibits the GH response to GHRH and, even more, that to HEX; whereas, at least in this experimental design in fed conditions, it does not modify the spontaneous GH secretion. Because GHS generally show partial refractoriness to inhibitory inputs, including exogenous somatostatin, the present results point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IT IS well known that insulin-like growth factor I (IGF-I) exerts an inhibitory feedback action on GH secretion, both in animals and in humans (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). As regards the mechanisms underlying the negative IGF-I feedback on GH secretion, it has been demonstrated that this action may occur directly at the pituitary level through activation of IGF-I receptors, and it leads to inhibition of GH synthesis and release (1, 2, 3, 4, 10, 12, 13, 14). Indirect central nervous system-mediated mechanisms have also been demonstrated. In fact, in animals, IGF-I has been shown capable of acting at the hypothalamic level via stimulation of SS (1, 3, 15) and/or inhibition of GHRH release (4, 15, 16), though some authors reported that IGF-II is also needed to obtain these effects (17).

In humans, GH-resistant syndromes are often connoted by reduced IGF-I, despite increased GH secretion, which, in turn, probably reflects the abrogation of the negative IGF-I feedback action (18, 19). In keeping with this view, the administration of recombinant human IGF-I (rhIGF-I) has been already shown capable of inhibiting exaggerated GH secretion in patients with Laron’s syndrome, IDDM, malnutrition, and also fasted normal young and elderly subjects (7, 9, 11, 20, 21).

Data on the effects of rhIGF-I administration on the GH response to provocative stimuli in humans are instead scanty. In fact, though in different study protocols, the GH response to GHRH in normal subjects has been reported by some (6), but not by other (22) authors to be inhibited by rhIGF-I. Moreover, IGF-I-induced hypoglycemia stimulates GH secretion in normal subjects, as well as in patients with Laron’ syndrome (5, 23, 24), indicating that GH increase that follows hypoglycemia is refractory to the inhibitory action of rhIGF-I.

The aim of the present study was to further clarify the effects of rhIGF-I on both basal and stimulated GH secretion in humans. To this goal, in a group of normal women, we studied the effects of the sc administration of low-dose rhIGF-I on spontaneous somatotroph secretion and on the acute GH response to GHRH or Hexarelin (HEX), a synthetic hexapeptide belonging to the family of GH secretagogues (GHS) (25, 26, 27). The latter are synthetic peptidyl and nonpeptidyl molecules that possess a strong and reproducible GH-releasing effect and act on specific receptors at the pituitary and the hypothalamic level (14, 25, 26, 27, 28, 29, 30). It is of note that the GHS generally release GH more than GHRH and that the somatotroph response to GHS is even partially refractory to inhibitory influences, including that of exogenous somatostatin (26).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Drugs

Vials containing 1000 µg lyophilized rhIGF-I were kindly provided by Pharmacia & Upjohn, Inc. (Stockholm, Sweden). Vials containing 50 µg GHRH-29 were kindly provided by Serono (Roma, Italy). Vials containing 100 µg lyophilized HEX were kindly provided by Europeptides (Argenteuil, France).

Study protocol

Eight young, normally cycling women (age, mean ± SEM, 28.3 ± 1.2 yr; body mass index, 19.9 ± 0.5 kg/m2) were studied in their early 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 six test sessions at least 3 days apart: 1) placebo (sc at 0 min); 2) rhIGF-I administration (20 µg/kg sc at 0 min); 3) placebo + GHRH (2.0 µg/kg iv at +180 min); 4) rhIGF-I + GHRH; 5) placebo + HEX (2.0 µg/kg iv at + 180 min); and 6) rhIGF-I + HEX.

The tests were begun in the morning at 0830–0900 h, after an overnight fast and 30 min after an indwelling catether had been placed into an antecubital vein of the forearm, kept patent by slow infusion of isotonic saline.

Blood samples were drawn basally at -15 and 0 min and then every 15 min, up to +300 min.

Serum GH levels were measured at each time point in all sessions. Serum IGF-I, serum insulin, and plasma glucose levels were measured basally and then every 30 min, up to +300 min, in sessions 1 and 2.

Serum GH levels (µg/L) were measured in duplicate by immunoradiometric assay (hGH-CTK IRMA, Sorin Biomedica, 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 (µg/L) were measured in duplicate by RIA (Nichols Institute Diagnostics, San Juan Capistrano). 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 (mU/L) were measured in duplicate by immunoradiometric assays (Sorin Biomedica). The sensitivity of the assay was 2.5 ± 0.3 mU/L. Inter- and intraassay coefficients of variation were between 6.2 and 10.8% and between 5.5 and 10.6%, respectively.

Plasma glucose levels (mg/dL) were measured by 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, as well as areas under curves (AUC0–300 min or 180–300 min) calculated by trapezoidal integration.

The statistical analysis was carried out using nonparametric ANOVA (Wilcoxon test).

The results are expressed as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Basal GH and IGF-I, as well as basal glucose and insulin levels in different sessions, were similar (Fig. 1Go).



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  		Figure 1. Mean (± SEM) IGF-I, GH, blood glucose, and insulin levels after placebo or rhIGF-I (20 µg/kg sc at 0 min) administration in eight normal young women.

 
sc administration of rhIGF-I induced a clear-cut increase of serum IGF-I levels; basal serum IGF-I levels (274.4 ± 25.3 µg/L) increased significantly at +30 min (321.8 ± 30.1 µg/L, P < 0.02 vs. baseline), underwent a further rise, reaching the peak level at +120 min (420.3 ± 30.5 µg/L, P < 0.02 vs. baseline), and then remained similar up to +300 min (398.1 ± 27.8 µg/L). After rhIGF-I, serum IGF-I levels were still not significantly higher than the upper limits of the physiologic values (408 µg/L as 97th centile limit in a population of normal young adults 20–30 yr old) (Fig. 1aGo).

Serum GH levels underwent a prompt reduction after rhIGF-I (+30 min vs. baseline, 4.3 ± 1.6 vs. 7.4 ± 1.9 µg/L, P < 0.02), reaching the nadir at +270 min (0.4 ± 0.2 µg/L, P < 0.02). After placebo administration, GH levels progressively decreased (+90 min vs. baseline: 1.6 ± 1.2 vs. 7.3 ± 2.1 µg/L, P < 0.05), reaching the nadir at +180 min (0.2 ± 0.1 µg/L). Note that GH AUC after rhIGF-I overlapped with that after placebo (AUC0–300 min: 140.6 ± 66.3 vs. 120.2 ± 39.3 µg/L·h) (Fig. 1bGo).

The GH response to GHRH, recorded after rhIGF-I (peak180–300 min: 13.1 ± 4.5 µg/L, AUC180–300 min: 447.7 ± 159.4 µg/L·h), was significantly lower (P < 0.05 for both) than that recorded after placebo administration (peak180–300 min: 23.6 ± 2.9 µg/L; AUC180–300 min: 715.9 ± 104.3 µg/L·h) (Fig. 2Go, upper panel).



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  		Figure 2. Mean (± SEM) GH curves (µg/L) and AUCs (µg/L·h) after GHRH (1.0 µg/kg iv at +180 min) or HEX (2.0 µg/kg iv at +180 min), preceded by placebo or rhIGF-I (20 µg/kg sc at 0 min) administration in eight normal young women.

 
Similarly, the GH response to HEX after rhIGF-I (peak180–300 min: 23.9 ± 4.7 µg/L; AUC180–300 min: 620.3 ± 110.4 µg/L·h) was lower (P < 0.05 for both) than that after placebo administration (peak180–300 min: 64.7 ± 14.8 µg/L; AUC180–300 min: 1705.9 ± 328.9 µg/L·h) (Fig. 2Go, lower panel).

After placebo administration, the GH response to GHRH was clearly lower (P < 0.01) than that after HEX; whereas after rhIGF-I administration, both responses were similar (Fig. 2Go). In fact, the percentage inhibitory effect of rhIGF-I on the GHRH-induced GH response (41.7 ± 12.8%) was lower than that on the HEX-induced one (57.7 ± 11.0%), though this difference did not attain statistical significance.

The timing of the GH response to both GHRH and HEX after placebo was unaffected by rhIGF-I administration (Fig. 2Go).

The sc administration of rhIGF-I, as well as that of placebo, did not modify insulin and glucose levels (Fig. 1Go, c and d).

Side effects

All subjects experienced transient discomfort at the injection site after rhIGF-I administration, but no side effects were encountered with rhIGF-I; specifically, no symptoms of hypoglycemia were reported. Five subjects had a transient facial flushing after GHRH administration, whereas no side effect was recorded after HEX administration.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our present findings in humans demonstrate that a low sc rhIGF-I dose, which increases serum IGF-I levels within the normal range, inhibits the somatotroph responsiveness to GHRH and, even more, that to HEX, a synthetic GHS; whereas, at least in this experimental design in fed conditions, this dose does not modify the spontaneous GH secretion. These effects occurred in the absence of any variation of insulin and glucose levels.

The inhibitory effect of rhIGF-I administration on somatotroph secretion has been clearly demonstrated, both in animals after intracerebral administration (3, 8, 10) and in humans after iv and sc administration (6, 7, 9, 11, 20, 21). Notice that the increase in circulating IGF-I levels, induced by the low sc rhIGF-I dose administered in the present study, remained within the high-normal range; and it overlaps with that reported by other authors (6, 20, 21, 22, 31).

The inhibitory effect of high and low doses of rhIGF-I on spontaneous GH secretion has been clearly demonstrated by other authors in pathophysiological conditions such as Laron’s syndrome, IDDM, malnutrition, and even in fasted normal young and elderly subjects (7, 9, 11, 20, 21). All these conditions are connoted by exaggerated GH secretion, peripheral GH insensitivity, and reduced IGF-I synthesis and release (18, 19, 32). The reduction of IGF-I levels, in turn, abrogates the negative IGF-I feedback action on somatotroph secretion (3, 4) and could induce variations in the number of hypothalamic IGF-I receptors (12).

Our present findings would exclude any role of IGF-I on spontaneous GH secretion. In fact, a significant decrease of GH levels was found after rhIGF-I administration in normal subjects, but this overlapped with that found after placebo administration. Indeed, we found basal GH levels reproducibly elevated in our normal women; this agrees with the amplified GH pulsatility in young women (33) and could also be caused by the low normal body mass index in our group of normal women (34). Indeed, we can not rule out the possibility that an ultrasensitive GH assay and/or more prolonged sampling period could have evidenced some inhibitory effect of rhIGF-I (35). However, other data showed no significant changes in 24-h GH profile in fed normal subjects after rhIGF-I sc administration (22). On considering the clear inhibitory action of rhIGF-I on GH secretion in fasted subjects (9, 11), its lack in fed subjects could imply that the inhibitory effect of IGF-I on somatotroph function is triggered by GH hypersecretion, to prevent hyperstimulation of GH/IGF-I axis. This view fits well with other data in animals (8, 36, 37) and with evidence that the potent inhibitory influence of ß-adrenergic receptors on somatotroph function is not operative in basal conditions and is triggered by GH hypersecretion in humans (38).

Data about the effects of rhIGF-I administration on the GH response to provocative stimuli in humans are not conclusive, probably reflecting different study protocols, i.e. timing and doses of rhIGF-I administration, and timing and type of the applied stimulus on GH secretion. In fact, the GH response to GHRH in normal subjects has been reported to be inhibited after continuous infusion of 20 µg/kg sc rhIGF-I, in one study (6), but was found unaffected when a single sc dose of 40 µg/kg rhIGF-I was administered 24 h before (22). Moreover, there is indirect evidence suggesting that GH increase that follows hypoglycemia is refractory to the inhibitory effect of IGF-I. In fact, it has been demonstrated that IGF-I-induced hypoglycemia stimulates GH secretion in normal subjects, as well as in patients with Laron’ syndrome (6, 22, 24).

Our present data demonstrate that the GH response elicited by the maximal effective dose of GHRH is consistently blunted by an acute increase of circulating IGF-I levels within the normal range. There is a wealth of in vitro and in vivo animal data showing that IGF-I acts at either the pituitary or the hypothalamic level to inhibit GH release (1, 2, 3, 4, 8) via inhibition of GHRH and/or stimulation of somatostatin release (1, 2, 3, 4, 10, 13). Thus, the acute inhibitory effect of rhIGF-I on the GHRH-induced GH response could be mediated by the stimulatory effect on hypothalamic somatostatin release (1, 15).

Besides showing that the GH secretion elicited by a pure hypophysiotropic stimulus, i.e. GHRH, is sensitive to the inhibitory feedback action of IGF-I increase, the present study shows that rhIGF-I has a marked inhibitory effect on the somatotroph responsiveness to HEX. Notice that the percent inhibitory effect of rhIGF-I on the GH response to HEX tended to be significantly greater than to GHRH. In fact, after rhIGF-I, but not after placebo, the GH-releasing activity of the two peptides was similar.

It is impressive that the somatotroph response to HEX tends to show peculiar sensitivity to the inhibitory effect of rhIGF-I. In fact, in comparison with GHRH, the GH-releasing activity of GHS generally shows partial refractoriness to several inhibitory inputs, including exogenous somatostatin (26).

The GH-releasing activity of GHS is unlikely mediated by inhibition of hypothalamic somatostatin release (26), whereas it is more likely caused by functional antagonism of somatostatin activity at both the pituitary and the hypothalamic level (14, 25, 26, 27, 39, 40, 41). Thus, it is unlikely that the marked inhibitory effect of rhIGF-I on the GH response to GHS takes place via activation of somatostatinergic pathways.

There is evidence indicating the major role of GHRH activity in mediating the GH-releasing effect of GHS (25, 26, 27, 42, 43), which could also act via a natural, still unknown GHS-like ligand (25, 26, 27). Along this line, the marked inhibitory effect of rhIGF-I on the somatotroph responsiveness to HEX could be viewed as the result of an inhibitory effect of IGF-I on hypothalamic GHRH release (16), on somatotroph cells (1, 2, 3, 4, 10, 13), or possibly on the endogenous GHS-like ligand. On the other hand, the possibility that GH per se plays an ultrashort inhibitory feedback action (44) on the somatotrope response to GHS is unlikely; in fact, the GH-releasing effect of HEX is less sensitive than GHRH to the inhibitory effect of exogenous GH administration (26, 40, 41).

It has been shown that chronic treatment with nonpeptidyl GHS leads to attenuation of the GH-releasing activity, both in animals and in humans (26, 27, 45); and it has been hypothesized that enhanced negative IGF-I feedback action, rather than desensitization of GHS receptor, could account for this (27, 45, 46). Our present findings, showing peculiar sensitivity of HEX to the inhibitory action of rhIGF-I, agree with this hypothesis.

In conclusion, our present study demonstrates that acute IGF-I increase within the physiological range inhibits the somatotroph responsiveness to GHRH and, even more, that to HEX. The latter, like other GHS, generally shows partial refractoriness, even to exogenous somatostatin; thus, these findings point toward a peculiar sensitivity of GHS to the negative feedback action of IGF-I.


   Acknowledgments
 
The authors wish to thank Dr. Lidia Di Vito, Dr. Barbara Maccagno, Dr. Fabio Lanfranco, Dr. Angela Ida Pincelli, Dr. Deanna Belliti, and Dr. Maria Grazia Papini for their cooperation with the study; and Mrs. Marina Taliano for her skillful technical assistance.


   Footnotes
 
1 This work was supported by Pharmacia & Upjohn, Inc., Europeptides, CNR, MURST, and SMEM Foundation. Back

Received June 17, 1998.

Revised September 8, 1998.

Accepted September 17, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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