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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 12 4207-4211
Copyright © 1998 by The Endocrine Society

Original Studies

Adrenocorticotropin and Cortisol Hyperresponsiveness to Hexarelin in Patients with Cushing’s Disease Bearing a Pituitary Microadenoma, But Not in Those with Macroadenoma1

E. Arvat, R. Giordano, J. Ramunni, G. Arnaldi, A. Colao, R. Deghenghi, G. Lombardi, F. Mantero, F. Camanni and E. Ghigo

Division of Endocrinology, University of Turin, Ancona (G.A., F.M.), and Naples (A.C., G.L.), Italy; and Europeptides (R.D.), Argenteuil, France

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: camanni{at}pianeta.net


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We previously reported that in Cushing’s disease (CD) the ACTH- and cortisol (F)-releasing activity of Hexarelin (HEX), a GH secretagogue, is exaggerated with respect to that in normal subjects and is higher than that of human CRH (hCRH), but it is absent in Cushing’s syndrome. Our aim was to extend the study about the effects of HEX (2.0 µg/kg, iv) on ACTH and F secretion in 21 patients with CD (3 men and 18 women, 16–68 yr old). Based on magnetic resonance imaging, 15 CD patients had pituitary microadenoma, and 6 had macroadenoma. The results in CD patients were compared with those in 27 normal age-matched controls (NS; 10 men and 17 women, 24–69 yr old). Basal ACTH and F levels in CD were similar in patients with microadenom (mean ± SEM, 78.3 ± 7.2 pg/mL and 237.1 ± 23.6 µg/L, respectively) and macroadenoma (57.4 ± 9.0 pg/mL and 196.9 ± 20.1 µg/L, respectively) and were higher (P < 0.001) than those in NS (17.7 ± 2.0 pg/mL and 115.3 ± 6.7 µg/L, respectively). In microadenoma CD patients, HEX induced marked ACTH and F increases ({triangleup} peak, mean ± SEM: 261.2 ± 77.6 pg/mL and 226.1 ± 87.2 µg/L, respectively), which were higher (P < 0.04) than those induced by hCRH (45.6 ± 16.9 pg/mL and 84.6 ± 25.7 µg/L, respectively). Moreover, in microadenoma CD patients, the ACTH and F responses to HEX were higher (P < 0.001) than those in NS (18.5 ± 4.0 pg/mL and 36.1 ± 6.8 µg/L, respectively). In macroadenoma CD patients, HEX induced a slight, but significant increase (P < 0.02) in ACTH and F levels (33.9 ± 18.0 pg/mL and 89.6 ± 34.3 µg/L, respectively), which was not significantly different from that elicited by hCRH (20.0 ± 7.0 pg/mL and 54.8 ± 21.3 µg/L, respectively). In macroadenoma CD patients, the ACTH and F responses to HEX and hCRH were, in turn, similar to those in NS.

In conclusion, our findings demonstrate that the ACTH and F hyperresponsiveness to HEX is present in Cushing’s disease with micro-, but not macro- ACTH-secreting pituitary adenoma. This finding agrees with other evidence pointing toward differences in the hormonal behavior between micro- and ACTH-secreting pituitary macroadenomas.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH-RELEASING peptides and their nonpeptidyl mimetics [GH secretagogues (GHS)] are synthetic molecules that possess strong, dose-related, and reproducible GH-releasing activity after iv, sc, intranasal and oral administration in humans (1, 2, 3, 4, 5). GHS stimulate GH acting at both the pituitary and the hypothalamic level; at this level, as well as in other central nervous system (CNS) areas and in peripheral tissues, specific GHS receptors are present (6, 7, 8, 9, 10).

The activity of GHS is not fully specific. In fact, they also possess a slight effect on PRL and a more clear stimulatory effect on ACTH and cortisol (F) secretion (1, 2, 3, 4, 5). The latter, at least after acute administration, is similar to those of human CRH (hCRH), arginine vasopressin (AVP), and naloxone, which are well known ACTH secretagogues (11, 12, 13, 14).

The ACTH-releasing effect of GHS seems to be mediated by the CNS; in fact, it is lost after hypothalamo-pituitary disconnection in the pig (15), whereas GHS do not stimulate ACTH secretion from rat pituitary in vitro (16, 17). However, specific GHS receptors have recently been demonstrated in both human pituitary and ectopic ACTH-secreting adenoma (18). Although a CRH-mediated action of GHS has been indicated by studies in rats (19), data in humans suggest that the ACTH-releasing activity of GHS is at least partially independent of both CRH- and AVP-mediated mechanisms (11). Thus, other neurotransmitters and/or an endogenous GHS-like ligand could play an important role in the stimulatory effect of GHS on corticotroph secretion (2, 5, 20).

We have previously reported that in patients with Cushing’s disease (CD) the ACTH- and F-releasing activity of Hexarelin (HEX), a peptidyl GHS, is exaggerated with respect to that in normal subjects and is higher than that of hCRH, but it is absent in patients with Cushing’s syndrome due to a secreting adrenal tumor (13). On the other hand, in normal subjects the ACTH- and F-releasing effect of HEX is abolished after low dose dexamethasone pretreatment (20).

Our aim was to extend the study about the effects of HEX in patients with CD bearing pituitary ACTH-secreting micro- or macroadenomas.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Peptides and drugs

Vials containing 100 µg lyophilized HEX were provided by Europeptides (France). Vials containing 100 µg hCRH were purchased from Ferring (Germany).

Study design

Twenty-one patients with pituitary ACTH-dependent CD (3 men and 18 women, 16–68 yr; body mass index, 29.1 ± 1.7 kg/m2) were studied. Clinical details of the patients are reported in Table 1Go. Based on classical hormonal and magnetic resonance imaging findings, CD patients were diagnosed as having 1) pituitary ACTH-secreting microadenoma (cases 1–15), or 2) pituitary ACTH-secreting macroadenoma (cases 16–21) without evidence of hypopituitarism. In 18 patients the diagnosis of ACTH-secreting pituitary adenoma was confirmed by immune staining after transsphenoidal surgery; 3 other patients refused surgery and at present are receiving medical treatment. Twenty-seven normal subjects (NS; 10 men and 17 women, 24–69 yr; body mass index, 22.1 ± 1.2 kg/m2) were studied as a control group. The study was approved by an independent ethical committee, and informed consent was obtained from all subjects.


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  		Table 1. Clinical and hormonal details of the patients with Cushing’s disease

 
All subjects received the following treatments in different sessions, at least 3 days apart: 1) HEX (2.0 µg/kg, iv, at 0 min), and 2) hCRH (2.0 µg/kg, iv, at 0 min). The tests started between 0830–0900 h after an overnight fast and 30 min after venous cannulation kept patient by slow infusion of isotonic saline. Blood samples were taken in basal conditions (-15 and 0 min) and then every 15 min up to 120 min after HEX or hCRH administration. All samples from an individual subject were analyzed together for ACTH and F. GH levels were also assayed after HEX administration only.

Plasma ACTH levels were measured in duplicate by immunoradiometric assay (Allegro HS-ACTH, Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity of the assay was 1.0 pg/mL. The inter- and intraassay coefficients of variation ranged from 2.4–8.5% and from 3.9–9.9%, respectively.

Serum F levels were measured in duplicate by RIA (CORT-CTK 125, DiaSorin, Inc., Saluggia, Italy). The sensitivity of the assay was 5.0 µg/L. The inter- and intraassay coefficients of variation ranged from 4.3–6.8% and from 4.2–8.9%, respectively.

Serum GH levels were measured in duplicate by immunoradiometric assay (HGH-CTK IRMA, DiaSorin, Inc., Saluggia, Italy). The sensitivity of the assay was 0.15 µg/L. The inter- and intraassay coefficients of variation were 5.1–7.5% and 2.6–5.4%, respectively.

The hormonal responses are expressed as absolute values or as the maximum ({Delta}) peak above baseline levels. Statistical analysis was carried out using a nonparametric ANOVA (Kruskal-Wallis) and then Mann-Whitney and Wilcoxon tests where appropriate. Results are expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Basal hormonal levels

Basal ACTH and F levels in CD were similar in patients with microadenoma (mean ± SEM, 78.3 ± 7.2 pg/mL and 237.1 ± 23.6 µg/L, respectively) and macroadenoma (57.4 ± 9.0 pg/mL and 196.9 ± 20.1 µg/L, respectively) and were higher (P < 0.001) than those in NS (17.7 ± 2.0 pg/mL and 115.3 ± 6.7 µg/L, respectively).

Hormonal responses to HEX and hCRH

In NS, ACTH and F {Delta} peaks after HEX treatment (range, 1.0–112.9 pg/mL) were similar to those induced by hCRH (Table 2Go). In the whole CD group, ACTH and F responses to HEX (P < 0.001 vs. basal values) were greater than those observed in NS as well as after hCRH in NS and CD (P < 0.001). On the other hand, the ACTH and F responses to hCRH in CD patients were similar to those in NS (Table 2Go).


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  		Table 2. ACTH and cortisol responses ({Delta} peak, mean ± SEM) to HEX and hCRH in NS and CD

 
In microadenoma CD patients, as in the whole group, HEX induced marked ACTH and F increases (P < 0.001 vs. basal values) that were higher (P < 0.04) than those induced by hCRH. Moreover, in microadenoma CD patients, the ACTH and F responses to HEX were higher than those in NS (P < 0.001), whereas the ACTH and F responses to hCRH were not significantly different from those in NS (Table 2Go and Fig. 1Go).



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  		Figure 1. Mean (±SEM) ACTH and F levels after HEX or hCRH treatment in NS and patients with CD due to micro- or macroadenoma.

 
In macroadenoma CD patients, HEX induced a slight, but significant, increase in ACTH and F levels (P < 0.02 vs. basal values) that was not significantly different from that elicited by hCRH. The ACTH and F responses to HEX and hCRH were, in turn, not significantly different from those in NS (Table 2Go and Fig. 1Go).

Analyzing individual ACTH values, increased responses to HEX (more than the highest value of {Delta} peaks observed in NS) were recorded in 12 (cases 1–9 and 11–13) of 15 microadenoma patients (80%) and in 1 (case 19) of 6 macroadenoma patients (16.6%; Table 1Go).

The GH responses to HEX were similar in micro- and macroadenoma CD patients ({Delta} peak, 15.6 ± 5.5 and 16.3 ± 9.7 µg/L, respectively) and lower (P < 0.001) than those in NS (46.6 ± 6.8 µg/L; Fig. 2Go). No correlation was found between GH and ACTH or F responses to HEX in CD patients or in NS.



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  		Figure 2. Mean (±SEM) GH levels after HEX administration in NS and patients with CD due to micro- or macroadenoma.

 
Side-effects

Transient facial flushing was observed after both HEX and hCRH administration in 30% of the subjects. Mild sleepiness was recorded in 10% of the subjects after HEX administration.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The results of the present study demonstrate that ACTH and F hyperresponsiveness to HEX is present in patients with CD due to microadenoma, but not in those with CD due to ACTH-secreting pituitary macroadenoma. A comparison was made using the same doses of HEX and hCRH, and under these conditions, patients with microadenoma, but not those with macroadenoma, were more responsive to HEX than to hCRH. On the other hand, the GH response to HEX was reduced to the same extent in hypercortisolemic patients with micro- and macroadenoma.

The stimulatory effect of GHS on the activity of hypothalamic-pituitary-adrenal (HPA) axis has been clearly demonstrated in animals and humans (1, 2, 3, 4, 5). In humans it is similar to that of hCRH and AVP (11), which play the major role in the neural control of corticotrope secretion (21). In physiological conditions the stimulatory effect of GHS on the HPA axis is dependent on central mechanisms (15, 19), but seems to be independent of both CRH and AVP (11), at least in humans. Other neurotransmitters, such as NPY and {gamma}-aminobutyric acid, could play an important role in mediating the ACTH-releasing activity of GHS (20, 22). Moreover, the possibility that a putative endogenous GHS-like ligand per se plays a key role in the neural control of corticotropic function has also to be considered.

To strengthen the relevance of the ACTH-releasing activity of GHS, we have recently demonstrated that in patients with CD the ACTH and F responses to HEX are exaggerated with respect to those in normal subjects and are higher than those to hCRH (13). As the ACTH and F responses to HEX were absent in patients with Cushing’s syndrome due to F-secreting adrenal tumor and in two patients with ectopic ACTH-secreting tumor (13), this finding suggested the potential usefulness of testing with GHS in the diagnosis of Cushing’s syndrome.

The present results demonstrate that ACTH and F hyperresponsiveness to HEX is generally present only in patients bearing pituitary microadenoma. On the other hand, a marked ACTH-releasing effect of GHS was recently observed in some patients with Cushing’s syndrome due to ectopic ACTH-secreting tumor (personal communication) (23), in agreement with the finding of specific GHS receptors in these tumors (18). Therefore, this evidence makes unlikely the usefulness of testing with GHS in the differential diagnosis of Cushing’s syndrome.

The stimulatory effect of HEX on the HPA axis is lost after low dose dexamethasone treatment in normal young subjects (20) as well as in patients with Cushing’s syndrome due to F-secreting adrenal adenoma (13). This evidence indicates that the ACTH-releasing activity of GHS is generally sensitive to the negative glucocorticoid feedback, but this is not the case for hypercortisolemic patients with pituitary ACTH-secreting tumors, both micro- and macroadenoma. In fact, even in macroadenoma, the ACTH- and F-releasing effect of HEX is present and overlaps that in normal subjects despite the hypercortisolism.

The evidence that in physiological conditions the ACTH-releasing activity of GHS is mediated by a central mechanism (15, 16, 17, 19) suggests that even the ACTH and F hyperresponsiveness in microadenoma CD could be due to a CNS-mediated stimulatory effect of GHS. However, the presence of specific GHS receptors in human pituitary ACTH-secreting tumors (18) points toward the hypothesis of a direct action of HEX on tumoral corticotroph cells. In agreement with this hypothesis, it has been shown that in primary culture t cells from a human ectopic ACTH-secreting tumor displayed calcium influx in response to GH-releasing peptide-6 (23).

Our present findings further point toward a difference in the secretory behavior of micro- and ACTH-secreting macroadenomas (24, 25, 26). In fact, reduced corticotroph responsiveness to hCRH and sensitivity to dexamethasone have been reported in patients bearing an ACTH-secreting macroadenoma (24, 26), in whom the ACTH response to desmopressin seems enhanced (27). In the present study, the ACTH and F responses to hCRH were similar in patients bearing micro- and macroadenomas, but those to HEX were strikingly lower in patients with macroadenoma than in those with ACTH-secreting microadenoma. At present, the explanation of these differences is unclear. It may be hypothesized that in patients with macroadenoma an impaired function of the hypothalamo-pituitary unit is present; were this the case, in patients with microadenoma, but not in those with macroadenoma, synergy between endogenous CRH and HEX on corticotroph cells could theoretically have occurred. Moreover, a different sensitivity to the stimulatory effect of GHS in macroadenoma cells may not be excluded (25). On the other hand, discrepancies between magnetic resonance imaging and surgical findings have been recently reported (28). In the three patients with microadenoma in this study in whom the ACTH response to HEX overlaps that in NS (cases 10, 14, and 15), an invasive macroadenoma (cases 14 and 15) or a tumorous pituitary with stalk infiltration (case 10) was found at surgery.

Our present results also confirm that the GH-releasing activity of GHS is markedly reduced in patients with hypercortisolism (13, 23, 29) and show that the GH response to HEX in patients bearing micro- or ACTH-secreting pituitary macroadenoma is impaired to the same extent. The somatotrope hyporesponsiveness to HEX agrees with evidence that the GH response to all secretagogues known to date is strongly impaired in Cushing’s syndrome (29, 30, 31). This could be due to glucocorticoid-induced somatostatinergic hyperactivity (30, 32) or, more likely, to glucocorticoid-induced metabolic alterations such as elevated free fatty acid levels (32, 33, 34).

On the other hand, evidence that the GH response to HEX in patients with macroadenoma was similar to that in patients with microadenoma seems to indicate that in the former group no pituitary stalk interruption was present. In fact, stalk transection has been shown able to markedly impair the GH response to GHS in both animals and humans (15, 35, 36).

In conclusion, our results demonstrate that the ACTH and F hyperresponsiveness to HEX is present in CD patients with microadenoma, but not in those with ACTH-secreting pituitary macroadenoma. These findings agree with other evidence pointing toward differences in the hormonal behavior between microadenoma and ACTH-secreting pituitary macroadenoma.


   Acknowledgments
 
The authors thank Dr. A. Bertagna, Mrs. A. Barberis, and M. Taliano for their skillful technical assistance.


   Footnotes
 
1 This work was supported by grants from MURST (grant no. 9706151106), FSMEM, and Europeptides. Back

Received June 11, 1998.

Revised September 2, 1998.

Accepted September 9, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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G. Arnaldi, T. Mancini, B. Kola, G. Appolloni, S. Freddi, C. Concettoni, I. Bearzi, A. Masini, M. Boscaro, and F. Mantero
Cyclical Cushing's Syndrome in a Patient with a Bronchial Neuroendocrine Tumor (Typical Carcinoid) Expressing Ghrelin and Growth Hormone Secretagogue Receptors
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5834 - 5840.
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A. M. Pereira, M. O. van Aken, H. van Dulken, P. J. Schutte, N. R. Biermasz, J. W. A. Smit, F. Roelfsema, and J. A. Romijn
Long-Term Predictive Value of Postsurgical Cortisol Concentrations for Cure and Risk of Recurrence in Cushing's Disease
J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5858 - 5864.
[Abstract] [Full Text] [PDF]

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