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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1837
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1595-1599
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Cortistatin-17 and Somatostatin-14 Display the Same Effects on Growth Hormone, Prolactin, and Insulin Secretion in Patients with Acromegaly or Prolactinoma

S. Grottoli, V. Gasco, F. Broglio, R. Baldelli, F. Ragazzoni, F. Gallenca, A. Mainolfi, F. Prodam, G. Muccioli and E. Ghigo

Department of Internal Medicine, Division of Endocrinology and Metabolism (S.G., V.G., F.B., R.B., F.R., F.G., A.M., F.P., E.G.), and Department of Anatomy, Pharmacology and Forensic Medicine (G.M.), University of Turin, 10126 Turin, Italy

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, San Giovanni Battista–Molinette Hospital, C.so Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Cortistatin binds all somatostatin receptor subtypes but also has particular central actions; moreover, a specific cortistatin receptor has also been discovered.

Objective: We compared the endocrine effects of cortistatin-17 with those of somatostatin-14 in patients with acromegaly (ACRO) or prolactinoma (PRLOMA). Normal subjects (NS) were studied as control group.

Design: All subjects underwent the following tests: 1) saline, 2) somatostatin-14 (2.0 µg/kg·h iv, 0–120 min) and 3) cortistatin-17 (2.0 µg/kg·h iv, 0–120 min) infusion.

Results: Cortistatin-17 and somatostatin-14 inhibited GH secretion to the same extent in ACRO (P < 0.05) and NS (P < 0.01). Cortistatin-17 and somatostatin-14 inhibited PRL secretion in PRLOMA (P < 0.05), to some extent in ACRO (P value not significant), but not in NS. Insulin secretion was inhibited by both cortistatin-17 and somatostatin-14 to the same extent in all groups (P < 0.05).

Conclusions: Cortistatin-17 and somatostatin-14 display the same effects on GH, PRL, and insulin secretion in patients with ACRO or PRLOMA.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SOMATOSTATIN (SS) EXERTS its actions via five receptor subtypes (sst 1–5) distributed at both the central and peripheral level (1).

Cortistatin (CST) is a neuropeptide expressed in the cortex and hippocampus but also in other tissues such as the endocrine pancreas and the immune system (2, 3, 4, 5). CST-17, CST-14, and CST-29 bind all sst-r subtypes with an affinity close to that of SS and therefore share all SS actions (2, 3). However, CST also exerts distinct biological activities, suggesting the existence of a CST-specific receptor (2, 3). Unlike SS, CST increases slow-wave sleep and reduces locomotor activity (3). Moreover, CST and SS are often coexpressed by the same neuron, but they are regulated by different stimuli (3, 6). An orphan receptor named MrgX2 has been proved to selectively bind both CST-17 and CST-14 but not SS (7). MrgX2 is expressed in dorsal root ganglions but also in other tissues such as testes, small intestine, spinal cord, pancreas, lungs, heart, thymus, and colon (7).

In human tissues, CST-17 and CST-14, but not SS, bind also the GH secretagogue receptor (GHS-R) (8); ghrelin, its natural ligand, stimulates GH secretion but also exerts other endocrine and nonendocrine actions including stimulatory effect on prolactin (PRL) release, influence on insulin secretion, and hyperglycemic effect (9). Interplay between the ghrelin system and CST would therefore be possible.

In healthy young volunteers, CST-17 and SS have the same inhibitory effect on GH and insulin secretion (10, 11), suggesting that, at least in physiological conditions, the activation of sst receptors by CST overrides potential endocrine peculiarity of CST that would take place via the activation of other specific receptors (e.g. MrgX2 and/or GHS-R).

To look for further differences between CST and SS, we studied the effects of CST-17 and SS-14 on GH, PRL, and insulin secretion as well as on glucose levels in patients with acromegaly (ACRO) or prolactinoma (PRLOMA). In fact, discrepancy between CST and SS (where SS is inactive) would indicate that specific CST receptors are present and mediate that peculiar action. Thus, we paid attention to compare the effects of CST and SS also at the individual level.


   Subjects and Methods
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 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Eight patients with active ACRO [three males and five females; age (mean ± SEM), 51.4 ± 4.5 yr (range, 36–67 yr); body mass index (BMI) (mean ± SEM), 28.4 ± 1.8 kg/m2 (range, 23.4–37.7 kg/m2)] and five patients with hyperprolactinemia due to a pituitary PRL-secreting adenoma (PRLOMA) [two males and three females; age (mean ± SEM), 42.2 ± 7.3 yr (range, 28–67 yr); BMI (mean ± SEM), 29.8 ± 2.9 kg/m2 (range, 23–36.7 kg/m2)] were studied.

Active ACRO was diagnosed in the appropriate clinical context on the basis of elevated GH levels showing no suppression after oral glucose load, elevated IGF-I levels, and evidence of a pituitary adenoma on magnetic resonance imaging.

Pathological hyperprolactinemia secondary to a pituitary PRL-secreting microadenoma was diagnosed in the appropriate clinical context by persistently elevated PRL levels and evidence of pituitary microadenoma on magnetic resonance imaging. No subject had showed chiasmatic syndrome or hypopituitarism; none had previously been treated.

Six normal subjects (NS) [males; age, 28.7 ± 2.9 yr (range, 22–35 yr); BMI, 23.4 ± 0.8 kg/m2 (range, 20–26 kg/m2)] were also studied as control group. The data in NS have already been published (11).

All subjects gave their informed consent to participate in the study; the study was approved by an independent Ethical Committee.

All subjects underwent the following testing sessions in random order at least 3 d apart: 1) saline infusion or 2) CST-17 or 3) SS-14 infusion (2.0 µg/kg·h iv over 120 min, from 0 to +120 min).

Testing sessions began at 0830–0900 h, and blood samples were taken every 15 min from –15 up to +150 min. The studies were carried out single blind.

GH, PRL, and insulin levels were measured by immunoradiometric assay, plasma glucose levels by glucooxidase colorimetric method at each time point, with methods detailed elsewhere (11).

The hormonal responses (mean ± SEM) are expressed as absolute levels or areas under curves (AUCs) calculated by trapezoidal integration. Statistical analysis was carried out using nonparametric ANOVA (Friedman test) and then the Wilcoxon test, as appropriate.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal GH (20.9 ± 6.6 µg/liter), IGF-I (849.4 ± 93.3 µg/liter), PRL (24.1 ± 5.2 µg/liter), insulin (23.7 ± 2.8 mU/liter), and glucose (114.6 ± 6.8 mg/dl) levels in ACRO were higher than in NS (P < 0.05). Three of eight ACRO subjects had hyperprolactinemia (24.0, 51.5, and 88.4 µg/liter at baseline).

Basal PRL (167.7 ± 36.5 µg/liter), insulin (22.9 ± 3.0 mU/liter), and glucose (91.4 ± 2.8 mg/dl) levels in PRLOMA were higher than in NS (P < 0.05).

Both CST-17 and SS-14 inhibited GH hypersecretion in ACRO (P < 0.05) (Table 1Go). Refractoriness to the inhibitory effect of both CST and SS was recorded in one case (Fig. 1Go).


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  		TABLE 1. GH, PRL, insulin, and glucose AUC0–120 (mean ± SEM) during CST-17, SS-14, and saline infusion in ACRO patients, patients with PRLOMA, and NS

 

Figure 1
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  		FIG. 1. Individual GH AUCs 0–120 min in normo- and hyperprolactinemic ACRO patients (upper and lower panels, respectively) under infusion of CST-17, SS-14, or saline.

 
CST-17 and SS-14 partially inhibited GH secretion in NS (P < 0.01) but not in PRLOMA (Table 1Go).

At the end of either CST or SS infusion, GH levels in ACRO as well as in NS recovered to baseline levels.

CST-17 and SS-14 did not significantly reduce PRL secretion in ACRO or in NS. On the other hand, significant PRL inhibition (P < 0.05) was observed in PRLOMA (Table 1Go).

CST and SS inhibited PRL secretion in some ACRO, regardless of their normo- or hyperprolactinemia (Fig. 2Go).


Figure 2
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  		FIG. 2. Individual PRL AUCs 0–120 min in normo- and hyperprolactinemic ACRO patients (upper and middle panels, respectively) and in patients with PRLOMA (lower panel) under infusion of CST-17 or SS-14 or saline (1 µg/liter = 43.5 pmol/liter).

 
Insulin secretion was inhibited by CST-17 and SS-14 to the same extent either in ACRO (P < 0.05) or in PRLOMA (P < 0.01) (Table 1Go). A similar reduction in insulin secretion (P < 0.05) during CST or SS infusion was recorded also in NS (Table 1Go). The percent insulin inhibition was similar in all groups. A rebound effect (P < 0.05) in insulin secretion after CST or SS infusion was recorded in all groups (peak vs. baseline for CST and SS was, respectively, for ACRO, 49.9 ± 11.5 vs. 22.8 ± 4.2 and 57.4 ± 11.1 vs. 24.4 ± 5.0 mU/liter; for PRLOMA, 46.2 ± 13.3 vs. 19.9 ± 3.7 and 54.8 ± 16.1 vs. 21.7 ± 3.2 mU/liter; and for NS, 20.2 ± 1.6 vs. 13.3 ± 0.9 mU/liter and 23.8 ± 6.4 vs. 11.8 ± 1.6 mU/liter).

Glucose levels did not change in any group during the infusion of CST or SS.

No relevant side effect was recorded in any subject. No medication was required.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study shows that GH and insulin secretion are inhibited in the same manner by both SS-14 and CST-17 in normal or hyperprolactinemic acromegalics as well as in control subjects. In patients with PRLOMA, both CST and SS inhibit insulin secretion. PRL secretion was inhibited during SS-14 and CST-17 infusion in patients with PRLOMA and in some ACRO subjects. Glucose levels were unchanged during SS or CST infusion. No divergent effect between CST and SS was recorded.

Cortistatin binds all sst-r subtypes with an affinity close to that of SS (2, 3) but exerts also distinct activities in agreement with the existence of a specific CST receptor (7). CST but not SS also binds the ghrelin receptor GHS-R1a (8).

CST-17 and CST-14 share the same inhibitory effect of SS on GH and insulin secretion in physiological conditions (Refs. 10 , 11 and present data); however, CST activates all sst receptors, and this would mask its theoretical endocrine peculiarities exerted via the activation of other receptors. Even single discrepancy between CST and SS (where SS is inactive) would indicate that specific CST receptors mediate that peculiar action. In fact, GH-secreting tumors are sometimes resistant to SS but able to express TRH and GnRH receptors; accordingly, the GH response to SS and its analogs or TRH, GnRH, and ghrelin/GHS may vary tumor by tumor (12, 13, 14). On the other hand, sst-r are unlikely to play major role in the control of PRL (10) but tumoral lactotroph secretion is sometimes influenced by sst-r activation, namely sst 5 (15, 16).

Herein we show that CST-17 and SS-14 always have the same effect on GH and insulin secretion and even to some extent on PRL secretion in ACRO as well as in patients with PRLOMA. No patient showed any response to CST that was not shared by SS. Therefore, CST is really unlikely to differ from SS in terms of endocrine action.

Evidence that PRL secretion is inhibited by CST and SS in some ACRO is not surprising (1). PRL hypersecretion in patients with PRLOMA is generally insensitive to SS analogs (17, 18), but we found significant PRL inhibition in PRLOMA under CST as well SS infusion. Unlike common SS analogs that mostly activate sst 2 (1), CST and SS activate all sst-r subtypes (3); this agrees with the hypothesis that sst 5 per se plays a major role in the control of PRL release from pure PRLOMA (15).

In this study, hyperinsulinism in patients with PRLOMA was as marked as that in ACRO (19, 20); in both groups, CST and SS markedly inhibited insulin secretion. That PRL has major impact on pancreatic ß-cells and that hyperprolactinemia as well as GH excess is associated with hyperinsulinism and insulin resistance is widely accepted (19, 20). In both conditions, sst-r activation inhibited insulin hypersecretion without any change in glucose levels; this implies some improvement in insulin sensitivity, as suggested by some authors (20).

In conclusion, CST and SS display the same effects on GH, insulin, and sometimes PRL secretion in ACRO and PRLOMA. Thus, in terms of endocrine actions, CST and SS show no differences but only identities.


   Footnotes
 
This work was supported by a grant from University of Turin, MIUR 2002 (Rome, Italy) and Fondazione per lo Studio delle Malattie Endocrino Metaboliche (FSMEM).

S.G., V.G., F.B., R.B., F.R., F.G., A.M., F.P., G.M., and E.G. have nothing to declare.

First Published Online January 31, 2006

Abbreviations: ACRO, Acromegaly; AUC, area under the curve; BMI, body mass index; CST, cortistatin; GHS-R, GH secretagogue receptor; NS, normal subjects; PRLOMA, prolactinoma; SS, somatostatin.

Received August 16, 2005.

Accepted January 20, 2006.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Patel YC 1999 Somatostatin and its receptor family. Front Neuroendocrinol 20:157–198[CrossRef][Medline]
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  6. Calbet M, Guadano-Ferraz A, Spier AD, Maj M, Sutcliffe JG, Przewlocki R, de Lecea L 1999 Cortistatin and somatostatin mRNAs are differentially regulated in response to kainate. Brain Res Mol Brain Res 72:55–64[Medline]
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