The activation of somatostatinergic receptors by either somatostatin-14 or cortistatin-17 often inhibits ACTH hypersecretion in patients with Cushing’s disease

in European Journal of Endocrinology

Object: Somatostatin (SS) is known to inhibit GH and insulin, while its effect on corticotrope secretion is controversial: inhibition of ACTH secretion by agonists activating somatostatinergic receptors (sst)-2 and sst-5 was reported in vitro. Cortistatin (CST) not only binds all sst receptor subtypes but also possesses central actions that are not shared by SS.

Design: In nine patients with Cushing’s disease (CD), ACTH, cortisol, GH, insulin, and glucose levels were studied during 120-min i.v. infusion of SS-14 (2.0 μg/kg per h), CST-17 (2.0 μg/kg per h) or saline.

Results: Both SS or CST significantly affected the hypothalamic–pituitary–adrenal axis. Cortisol was decreased to the same extent by either SS or CST (P < 0.05). Both SS and CST decreased ACTH, although statistical difference was reached only during CST (P < 0.05). Analyzing the individual responses as Δareas under curve (ΔAUCs), a clear and consensual inhibition of ACTH and cortisol under either SS or CST was recorded in five out of nine patients. Both SS or CST inhibited (P < 0.05) insulin, that even showed a rebound (P < 0.01) at the end of infusion. GH was not modified by either peptide.

Conclusion: SS and CST often display similar inhibitory effects on the HPA axis in CD. The activation of sst receptors by both peptides is followed in almost 50% of patients by a remarkable inhibition of ACTH and cortisol hypersecretion. These findings reinforce the view that sst receptors are involved in the control of the secretory activity of tumoral corticotropic cells.

Abstract

Object: Somatostatin (SS) is known to inhibit GH and insulin, while its effect on corticotrope secretion is controversial: inhibition of ACTH secretion by agonists activating somatostatinergic receptors (sst)-2 and sst-5 was reported in vitro. Cortistatin (CST) not only binds all sst receptor subtypes but also possesses central actions that are not shared by SS.

Design: In nine patients with Cushing’s disease (CD), ACTH, cortisol, GH, insulin, and glucose levels were studied during 120-min i.v. infusion of SS-14 (2.0 μg/kg per h), CST-17 (2.0 μg/kg per h) or saline.

Results: Both SS or CST significantly affected the hypothalamic–pituitary–adrenal axis. Cortisol was decreased to the same extent by either SS or CST (P < 0.05). Both SS and CST decreased ACTH, although statistical difference was reached only during CST (P < 0.05). Analyzing the individual responses as Δareas under curve (ΔAUCs), a clear and consensual inhibition of ACTH and cortisol under either SS or CST was recorded in five out of nine patients. Both SS or CST inhibited (P < 0.05) insulin, that even showed a rebound (P < 0.01) at the end of infusion. GH was not modified by either peptide.

Conclusion: SS and CST often display similar inhibitory effects on the HPA axis in CD. The activation of sst receptors by both peptides is followed in almost 50% of patients by a remarkable inhibition of ACTH and cortisol hypersecretion. These findings reinforce the view that sst receptors are involved in the control of the secretory activity of tumoral corticotropic cells.

Introduction

The role of somatostatin (SS) in the regulation of corticotrope secretion, in both physiological and pathological conditions, is still a matter of active debate.

It has been shown that SS and SS analogs do not affect adrenocorticotropin (ACTH) and cortisol secretion in normal subjects (13), whereas in Cushing’s disease (CD) patients ACTH secretion is, at least partially, sensitive to the inhibitory effect of native SS and SS analogs (4). No significant inhibitory effect of octreotide, a preferential somatostatinergic receptor (sst)-2 agonist, has been generally demonstrated in patients with CD (48); this, however, would agree with hypercortisolism-induced sst-2 down-regulation (5). In fact, some inhibitory effect of octreotide on ACTH levels in Addison’s disease and Nelson’s syndrome has been reported (810). Indeed, sst-5 seems to play an important role in the regulation of basal and corticotrope releasing hormone (CRH)-induced ACTH release by primary cultures of human corticotrope adenomas as well as in corticotrope tumor cell lines, but not in normal corticotropes (2, 11, 12). Moreover, recent studies showed that pasireotide (SOM-230), a multi-receptor ligand SS analog displaying high affinity for sst subtypes 1–3 and 5, is able to significantly inhibit ACTH secretion in corticotropinomas in vitro as well as in vivo in some patients with CD (13, 14).

Cortistatin (CST) is a neuropeptide that represents a natural SS analog showing high structural similarity and binding with high affinity (ranging from 0.4 to 7.0 nM) to all SS receptor subtypes (1517). In agreement with this biochemical profile, it has been demonstrated that in humans as well as in animals, CST shares the same endocrine actions of SS, i.e., inhibiting growth hormone (GH) and insulin secretion in healthy young volunteers as well as in acromegalics and hyperprolactinemic patients (1820).

Interestingly, CST also exerts some distinct biological activities that are not shared with SS, for example some central actions (21). This evidence suggested the existence of a specific CST receptor; indeed, differently from SS, CST is able to bind to Mas-related gene X (MrgX)-2 receptor in various central and peripheral as well as in some neoplastic tissues (22, 23). Moreover, CST but not SS is also able to bind the GH secretagogs receptor (GHS-R) that mediates endocrine and non-endocrine actions of ghrelin, its natural ligand (24, 25). However, the physiological relevance, if any, of CST binding to these receptors is still unknown.

Based on the foregoing, in order to further investigate the role of SS receptor activation in patients with pituitary ACTH-dependent hypercortisolism, the effects of the infusion of either SS-14 or CST-17, the human CST form, on ACTH, cortisol, GH, insulin, and glucose levels were studied in a group of patients with CD.

Subjects and methods

Drugs

Vials containing CST-17 [Asp-Arg-Met-Pro-c(Cys-Arg-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Ser-Ser-Cys)-Lys-NH2] were purchased from Europeptides, Argenteuil, France; vials containing SS-14 [Ala-Gly-c(Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys)-OH] were purchased from Serono, Geneva, Switzerland.

Study protocol

Nine patients with CD (5 F and 4 M; 45.1 ± 4.3 years, BMI 29.8 ± 1.6 kg/m2) were studied; these were de novo patients who had not been studied before, and whose clinical details are reported in Table 1. The diagnosis of CD was made by international criteria, including elevated urinary free cortisol, normal or high plasma ACTH and serum cortisol levels, absence of suppression after low-dose dexamethasone test, and adequate suppression after high-dose dexamethasone test. Based on magnetic resonance imaging findings, CD patients were diagnosed as having a) pituitary ACTH-secreting microadenoma (cases 2, 3, 5, 6, and 7) or b) pituitary ACTH-secreting macroadenoma (cases 1, 4, 8, and 9). No patient had evidence of chiasmatic syndrome and hypopituitarism; no patient had been previously treated by surgery, radiotherapy, or medical treatment. According to the international criteria for the diagnosis of diabetes mellitus (DM) (26), three CD patients were normal glucose tolerant (N), three showed impaired glucose tolerance (IGT), and three had diabetes (DM). None of the patients underwent medical treatment influencing hormonal secretion at the time of testing. In all patients, the diagnosis of ACTH-secreting pituitary adenoma was confirmed by immunostaining after transsphenoidal surgery.

All patients gave their informed consent to participate in the study that had been approved by the Ethical Committee of the University of Turin in agreement with the Declaration of Helsinki.

All the patients underwent the following testing sessions in random order (using the second randomization plan generator available on www.randomization.com) at least 3 days apart:

a) Saline (250 ml infused over 120 min); b) SS-14 (2.0 μg/kg infused over 120 min) and c) CST-17 (2.0 μg/kg infused over 120 min). These were the same doses already administered in our previous studies in both normal (19) and acromegalic (20) subjects, showing similar hormonal and metabolic effects.

After an overnight fast, testing sessions began in the morning at 0830–0900 h, 30 min after an indwelling catheter had been placed into an antecubital vein of the forearm and kept clear by slow infusion of isotonic saline. Blood samples were taken every 15 min from −15 up to +150 min after starting infusion in all sessions; all samples from an individual subject were analyzed together and during the same assay section.

ACTH, cortisol, GH, insulin, and glucose levels were assayed at each time point in every testing session.

Plasma ACTH levels (pg/ml; 1 pg/ml × 0.22 = 1 pmol/l) were measured in duplicate by IRMA (Allegro HS-ACTH: Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). The sensitivity of the assay was 1 pg/ml. The inter-and intra-assay coefficients of variation ranged from 6.9 to 8.9% and from 1.1 to 3.0% respectively.

Serum cortisol levels (μg/dl; 1 μg/dl × 27.59 = 1 nmol/l) were measured in duplicate by RIA (CORT-CTK 125 RIA; Sorin Biomedica, Saluggia, Italy). The sensitivity of the assay was 0.04 μg/dl. The inter- and intra-assay coefficients of variation ranged from 6.6 to 7.5% and from 3.8 to 6.6% respectively.

Serum GH levels (μg/l) were measured in duplicate by IRMA (hGH-CTK IRMA, Sorin Biomedica). The sensitivity of the assay was 0.15 μg/l. The inter- and intra-assay coefficients of variation ranged from 2.9 to 4.5% and from 2.4 to 4.0% respectively.

Serum insulin levels (mU/l; 1 mU/l × 7.17 = 1 pmol/l) were measured in duplicate by IRMA (INSIK-5, Sorin Biomedica). The sensitivity of the assay was 2.5 mU/l. The inter- and intra-assay coefficients of variation ranged from 6.2 to 10.8% and from 5.5 to 10.6% respectively.

Plasma glucose levels (mg/dl; 1 mg/dl × 0.05 = 1 mmol/l) were measured by glucose-oxidase colorimetric method (GLUCOFIX, Menarini Diagnostici, Florence, Italy).

Urinary free cortisol (UFC) (μg/24 h; 1 μg/24 h × 2.76 = 1 nmol/d) was measured in duplicate by RIA (Cortisol Bridge; Biochem Immunosystems Company, Milan, Italy). The sensitivity of the assay was 2.67 μg/24 h. The inter- and intra-assay coefficients of variation ranged from 3.98 to 5.75% and from 2.64 to 8.67% respectively.

The hormonal responses are expressed as mean ±s.e.m. of absolute values, absolute, or delta ΔAUCs calculated by trapezoidal integration.

Statistical analysis

The statistical analysis was carried out using a non-parametric two-way ANOVA for repeated measures with time as a within-subject factor and treatment as a between-subject factor to analyze changes with time, and then Wilcoxon matched pairs test or Mann-Whitney U test as appropriate. SPSS (Statistical Package for the Social Science), version 13.0 was used for the analysis (27).

Results

Cortisol secretion was decreased to the same extent (P < 0.05) by either SS or CST infusion (ΔAUC; SS and CST versus saline: −403.4 ± 108.6 and −429.8 ± 182.1 vs 173.9 ± 71.5 μg/dl per h respectively). Both SS and CST also decreased ACTH secretion (−447.8 ± 854.4 and −720.5 ± 340.0 vs 519.3 ± 522.4 pg/ml per h), although statistical significance (P < 0.05) was reached during CST infusion only (Fig. 1).

Analyzing the individual responses in terms of ΔAUC, clear-cut and consensual inhibition of both ACTH and cortisol under either SS or CST was recorded in five out of nine patients (cases 1–5). Corticotrope refractoriness to either SS or CST was recorded in two out of nine patients (cases 8 and 9), both with a pituitary macroadenoma; one case showed some inhibition under SS but not under CST (case 6), while another showed some inhibition under CST but not under SS (case 7). When the individual responses were evaluated in terms of absolute AUC, variable but consensual inhibition of both ACTH and cortisol levels under either SS or CST was recorded in four out of nine patients (cases 2, 3, 4, and 5); refractoriness to either SS or CST was recorded in three out of nine patients (cases 1, 8, and 9); discordant responses to SS or CST persisted in the same two cases (Table 2).

Insulin secretion was inhibited (P < 0.05) by SS and CST (−1155.6 ± 197.3 and −962.2 ± 249.9 vs −7.2 ± 77.3 mU/l per h saline); insulin levels showed a significant rebound (P < 0.01) at the end of the administration of the two peptides (Fig. 2).

Glucose levels were unchanged under administration of both SS and CST (−913.9 ± 292.4 and −401.8 ± 261.9 vs −607.5 ± 241.5 mg/dl per h; data not shown).

Lower basal GH secretion was not significantly modified by SS and CST (−7.8 ± 7.9 and −3.7 ± 5.9 vs −3.4 ± 2.0 mg/dl per h; data not shown).

Side effects

No significant side effect was recorded in any subject. No medication was required and none had to stop any testing session.

Discussion

The results of the present study demonstrate that SS and CST often display similar inhibitory effects on the HPA axis in patients with CD: in fact, in almost 50% of patients a clear reduction of ACTH and cortisol levels was observed.

Data regarding the effects of SS receptors activation in patients with CD are controversial. No change in ACTH secretion has been observed in some studies where either native SS or octreotide, a preferential sst-2 agonist, was administered acutely (46). Instead, octreotide was able to exert some inhibitory effect on ACTH levels in other ACTH hypersecretory states, such as in Addison’s disease and Nelson’s syndrome (810). The lack of any effect of octreotide in CD would have an explanation. In fact, glucocorticoids exert negative modulation of sst-2 expression in corticotropic adenoma cells (5). Moreover, glucocorticoid receptor antagonists induce sensitivity to the inhibitory effect of SS on ACTH secretion from normal rat corticotropic cells (28). Thus, it is possible that the lack of ACTH inhibition under exposure to octreotide in CD simply reflects sst-2 down-regulation induced by hypercortisolism. Differently from sst-2, sst-5 have been found refractory to the negative influence of glucocorticoid; moreover, this receptor subtype has been supposed to play a more important role in the regulation of basal and stimulated ACTH release, at least in corticotrope tumors (12). In agreement with this assumption, another synthetic SS analog displaying high affinity for sst subtypes 1–3 and 5, pasireotide (SOM-230), has been found able to inhibit ACTH release from human corticotropinoma cells in vitro (13) and even in vivo in some patients with CD (14).

By studying the effects of native SS and CST, another natural ligand of all sst subtypes (16, 17), on the HPA axis we intended to further clarify whether play any significant role on ACTH and cortisol secretion in pituitary ACTH-dependent Cushing’s syndrome. The exposure of sst to either SS or CST also offered the possibility to test the reproducibility of the corticotropic response, if any, to these peptides. In fact, in patients with acromegaly as well as in normal subjects, the exposure to CST-17 and native SS led to reproducible inhibition of GH and insulin secretion and sometimes even of prolactin secretion (1820).

Our present findings indicate that either SS or CST infusion is followed by significant decrease of both mean ACTH and cortisol secretion in patients with CD, suggesting the activation of sst by both peptides. Unfortunately, we did not perform an in vitro study aimed at evaluating direct effects of both SS and CST on pituitary extracts of our patients, which, indeed, would throw light on our suggestion.

Actually, mean hormonal response reflected clear inhibition exerted by both peptides in five out of nine patients, some inhibition exerted by SS or CST in two cases, and no effect of any peptide in the remaining two cases, at least when ΔAUC were considered.

Analyzing the individual responses, SS and CST generally displayed the same concordant influence on ACTH and cortisol secretion. Thus, once again, it seems clear that SS and CST share the same endocrine actions, reflecting the activation of sst that are bound with almost equal affinity by both peptides (16, 17). This also implies that the inhibitory effect of sst activation on corticotropic function in patients with CD is reproducible. On the other hand, as CST has also been demonstrated to bind other specific receptors, e.g. MrgX2 and GH secretagogs-receptor type 1a (GHS-R1a) (2224), whether the activation of sst receptors by the peptide overrides any peculiar endocrine actions possibly mediated by the activation of these receptors remains, at present, unknown.

In terms of extent of inhibition, neither SS nor CST was able to normalize ACTH and cortisol hypersecretion in any patient; this could, however, simply reflect the short-term exposure to SS receptor agonists. In fact, preliminary data from Arnaldi et al. reported normalization of the HPA axis in some patients with CD under chronic treatment with pasireotide (14). Therefore, the possibility that treatment with SS analogs that also activate sst-5 and display more prolonged action (such as the new universal ligand pasireotide) could be effective for treatment of CD, at least in some cases, is open.

In our study, patients with CD exposed to SS or CST did not show any inhibition of GH secretion, but this would simply reflect the low somatotropic secretory function that connotes patients with hypercortisolism (29); on the other hand, GH measurement by an ultra-sensitive assay would likely be needed to record a significant inhibitory effect (30).

As expected, SS and CST displayed clear inhibitory effect on insulin secretion, while no significant change in glucose levels was recorded.

In conclusion, this study shows that SS and CST often display similar inhibitory effects on the HPA axis in patients with CD. In fact, in almost 50% of patients, the activation of SS receptors by both peptides is followed by a remarkable inhibition of ACTH and, in turn, cortisol hypersecretion. These findings reinforce the view that SS receptors are involved in the control of the secretory activity of tumoral corticotropic cells.

Acknowledgements

The present study was supported by MURST (Grant 2004–062974), University of Turin and SMEM Foundation. The authors wish to thank Dr A Bertagna and Mrs A Barberis for their skillful technical assistance.

Table 1

Clinical and hormonal details of the patients with Cushing’s disease.

Case (n)Age (years)SexBMI (kg/m2)ACTH (pg/ml)Cortisol (μg/dl)UFC (μg/24 h)GlycemicstatusImaging
ACTH, plasma concentrations at 0900 h (mean of two measurements; 1 pg/ml × 0.22 = 1 pmol/l; normal range 8–53 pg/ml); Cortisol, serum concentrations at 0900 h (mean of two measurements; 1 μg/dl × 27.59 = 1 nmol/l; normal range 8.8–26.0 μg/dl); UFC, urinary free cortisol (mean of two measurements; 1 μg/24 h × 2.76 = 1 nmol/d; normal range 30–150 μg/24 h); N, normal; IGT, impaired glucose tolerance; DM, diabetes mellitus.
147M2564.313.0196NMacroadenoma
227F2258.818.9262NMicroadenoma
329F3527.614.8183DMMicroadenoma
445F3283.022.5180IGTMacroadenoma
544F3234.921.6161NMicroadenoma
641F3549.816.9521IGTMicroadenoma
765M3417.012.9449DMMicroadenoma
863M25299.325.7294DMMacroadenoma
945M2868.529.0175IGTMacroadenoma
Mean45.129.878.119.5269
s.e.m.4.31.628.51.843.7
Table 2

Adrenocorticotropin (ACTH) and cortisol area under curves (AUCs) and ΔAUCs in patients with Cushing’s disease (CD) under infusion of somatostatin (SS), cortistatin (CST), or saline.

SSCSTSaline
Case (n)AUCsΔAUCsAUCsΔAUCsAUCsΔAUCs
ACTH (pg/ml; 1 pg/ml × 0.22 = 1 pmol/l); cortisol (μg/dl; 1 μg/dl × 27.59 = 1 nmol/l).
ACTH (pg/ml110 075.5−172.511 423.395.27755.84203.8
per h)23546.0−1014.02645.3665.34191.81407.8
32946.8−1973.32837.3−1002.84386.0138.0
44635.8−2672.34188.0−2412.06759.8−1064.3
53469.5−3202.52979.0−1857.04734.8258.8
63084.0−1884.04140.8264.86210.0270.0
72080.5604.51482.8−149.32664.8636.8
847 366.35186.345 408.8−1043.335 467.5−712.5
913 098.01098.010 394.5−645.511 415.0−465.0
Cortisol (μg/dl11619.9−502.81663.934.31442.4196.8
per h)2776.0−245.11455.6−1324.81863.1484.3
3689.2−532.3661.5−242.01832.045.2
41005.0−755.31385.2−765.11645.261.2
51266.0−398.41878.9−1199.01926.733.1
61146.6−825.01475.3−129.01709.3−115.8
71572.7−542.81096.8−417.61923.0531.0
83688.388.33460.832.43497.1239.1
92482.582.52242.5142.52190.790.7
Figure 1
Figure 1

Mean ( ± s.e.m ) Adrenocorticotropin (ACTH) (pg/ml; 1 pg/ml × 0.22 = 1 pmol/l) and cortisol (μg/dl; 1 μg/dl × 27.59 = 1 nmol/l) levels and ΔAUCs in Cushing’s disease patients under infusion of somatostatin (SS), cortistatin (CST), or saline. *P < 0.05 versus saline.

Citation: European Journal of Endocrinology eur j endocrinol 157, 4; 10.1530/EJE-07-0147

Figure 2
Figure 2

Mean ( ± s.e.m.) insulin levels (mU/l; 1 mU/l × 7.17 = 1 pmol/l) and ΔAUCs in Cushing’s disease patients under infusion of somatostatin (SS), cortistatin (CST), or saline. *P < 0.05 versussaline.

Citation: European Journal of Endocrinology eur j endocrinol 157, 4; 10.1530/EJE-07-0147

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    Mean ( ± s.e.m ) Adrenocorticotropin (ACTH) (pg/ml; 1 pg/ml × 0.22 = 1 pmol/l) and cortisol (μg/dl; 1 μg/dl × 27.59 = 1 nmol/l) levels and ΔAUCs in Cushing’s disease patients under infusion of somatostatin (SS), cortistatin (CST), or saline. *P < 0.05 versus saline.

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    Mean ( ± s.e.m.) insulin levels (mU/l; 1 mU/l × 7.17 = 1 pmol/l) and ΔAUCs in Cushing’s disease patients under infusion of somatostatin (SS), cortistatin (CST), or saline. *P < 0.05 versussaline.

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