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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-1358
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 4 1412-1417
Copyright © 2008 by The Endocrine Society

BRIEF REPORT

Correlation of in Vitro and in Vivo Somatotropic Adenoma Responsiveness to Somatostatin Analogs and Dopamine Agonists with Immunohistochemical Evaluation of Somatostatin and Dopamine Receptors and Electron Microscopy

Diego Ferone, Wouter W. de Herder, Rosario Pivonello, Johan M. Kros, Peter M. van Koetsveld, Ton de Jong, Francesco Minuto, Annamaria Colao, Steven W. J. Lamberts and Leo J. Hofland

Departments of Internal Medicine (D.F., W.W.d.H., P.M.v.K., S.W.J.L., L.J.H.) and Pathology (J.M.K., T.d.J.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Department of Molecular and Clinical Endocrinology and Oncology (R.P., A.C.) "Federico II" University, 80131 Naples, Italy; and Department of Endocrinological and Medical Sciences and Center of Excellence for Biomedical Research (F.M.), University of Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Diego Ferone, M.D., Ph.D., Department of Endocrinology and Medical Sciences, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy. E-mail: ferone{at}unige.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective and Patients: Twenty-four pituitary adenomas from acromegalic patients (13 females, 11 males; age range 19–65 yr) were characterized for somatostatin receptor subtype 2A (sst2A), dopamine D2 receptor (D2R), GH, and prolactin (PRL) expression by immunohistochemistry, and results correlated with the in vitro and in vivo hormone responses to octreotide and quinagolide. In nine cases, GH and PRL content was further studied by immunoelectron microscopy.

Results: Immunoreactivity was semiquantitatively scored as 2 (>50% stained cells), 1 (10–50% stained cells), and 0 (<10% stained cells). Sst2A was scored as 2 in 13 cases, 1 in 10, and 0 in one; D2R was scored as 2 in 13 cases, 1 in nine, and 0 in 2; GH was 2 in 15 cases and 1 in nine; PRL was 2 in six cases, 1 in 13, and 0 in 5. Sst2A was positively correlated with in vitro (P = 0.003) and in vivo (P = 0.006) percent GH suppression by octreotide and with the chronic suppression of IGF-I by somatostatin analogs (P =0.008). D2R was positively correlated with in vitro percent GH (P =0.000) and PRL (P =0.005) suppression by quinagolide. Electron microscopy revealed two pure somatotroph adenomas, five somatomammotrophs with a variable coexpression of GH and PRL in the same cells, and two tumors consisting of mixed cell types, which were less sensitive to quinagolide and octreotide.

Conclusion: Sst2A and D2R are frequently coexpressed in adenomas from acromegalic patients, and immunohistochemistry may be helpful in characterizing receptor expression in pituitary adenomas to select patients responsive to different treatments.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
First-line medical therapy in acromegaly generally consists of somatostatin analogs (SSAs), dopamine agonists (DAs), or combinations and should result in suppression of the elevated GH and IGF-I levels and/or significant tumor reduction (1).

The response to SSAs depends on the presence of a sufficiently high number of somatostatin receptors subtypes (sst1–5) on the tumor cells. GH secretion is regulated through ligand binding of somatostatin to both sst2 and sst5, whereas octreotide and lanreotide bind preferentially sst2 (2). The GH-lowering effect by these drugs is positively correlated with the level of expression of sst2 mRNA (3, 4, 5).

DAs have been largely used for the treatment of pituitary tumors, particularly prolactinomas, and the responsiveness depends on the expression of dopamine D2 receptors (D2R) on tumor cells. This subtype is also responsible for the paradoxical DA-suppressive activity on GH in tumors of acromegalic patients (6).

SSAs are more effective than DAs in lowering GH and normalizing IGF-I. However, DAs can be orally administered at lower costs (7). The additive effect in lowering GH suggests that the combination of SSAs and DAs might be useful in selected patients (7). Hyperprolactinemia in acromegaly might be caused by anatomical or functional hypothalamo-pituitary disconnection, presence of mixed GH/prolactin (PRL)-secreting tumors, or mammosomatotroph adenomas (8, 9).

The availability of subtype-specific antibodies to sst2 and D2R provides new tools to evaluate the receptor profile in those adenomas that have been unsuccessfully operated and need additional medical control (10, 11).

In this study we characterized a series of pituitary adenomas from acromegalic patients by immunohistochemistry for GH, PRL, sst2A, and D2R expression. In a subgroup of these tumors, we evaluated the intracellular localization of GH and PRL granules using immunoelectron microscopy (EM) to determine which tumors coexpress sst2A and D2R in GH- and GH/PRL-secreting pituitary adenomas and whether the truly mixed GH/PRL-secreting adenomas represent a subgroup preferentially sensitive to DA. Immunohistochemical findings were correlated with clinical response to medical therapy as well as in vitro hormonal response to octreotide and quinagolide to establish whether the receptor expression phenotype is indicative of tailoring the adjuvant medical therapy.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and treatments

We selected 24 acromegalic patients (13 females and 11 males, age ranging 19–65 yr, Table 1Go) who underwent neurosurgery. In these patients, in vitro tumor response to octreotide and quinagolide as well as short- and long-term in vivo hormonal response to SSAs and/or DAs were available. Postoperative SSA treatment was continued for at least 6 months in 18 patients, whereas two were treated with DAs, and four did not receive any postoperative treatment (Table 1Go). These latter six patients were not included in the long-term study. No patient had received radiotherapy before or during the study period. Informed consent was obtained from all patients.


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  		TABLE 1. Patient characteristics, treatment details, immunohistochemical and electron microscopy findings, and hormonal response

 
The acute octreotide and quinagolide tests were performed, on alternate days, as reported elsewhere (12). After the tests, six patients started sc octreotide treatment (Sandostatin; Novartis, Basel, Switzerland) 12 patients long-acting SSAs: 11 octreotide long-acting release (LAR; Sandostatin LAR) and one lanreotide (Somatuline Autogel; Ipsen, Kleve, Germany) (Table 1Go). All patients were evaluated after 3, 6, 9, and 12 months. The maximum dose of Sandostatin was 0.2 mg three times a day, that of Sandostatin LAR 30 mg every 4 wk, and that of Somatuline Autogel 60 mg every 28 d.

Cell cultures

GH-secreting pituitary adenoma tissue was collected during operation, and cells were isolated as previously described (13). A 72-h incubation without or with octreotide or quinagolide (10 nM) in 1 ml culture medium was performed in quadruplicate. Thereafter the medium was collected and stored at –20 C until analysis. The results of each experiment were expressed as the percent suppression, compared with control untreated wells.

Assays

GH and PRL were determined by use of a nonisotopic, automatic chemiluminescence immunoassay system (Immulite; Diagnostic Products Corp., Los Angeles, CA). IGF-I was determined with a commercially available nonextraction immunoradiometric assay (Diagnostic Systems Laboratories, Inc., Webster, TX).

Immunohistochemistry

Immunohistochemistry was performed on paraffin-embedded sections (5 µm) as previously described (11, 14). GH, PRL, sst2A, and D2R immunoreactivity was semiquantitatively scored as 2 (>50% stained cells), 1 (10–50% stained cells), and 0 (<10% stained cells) by three investigators.

Immunoelectron microscopy

Tissues were fixed in buffered, 1% acrolin, 0.4% glutaraldehyde solution (pH 7.2) for 4 h at 4 C and stored in 1 M sucrose 0.1 M phosphate buffer. Samples were dehydrated up to 100% alcohol under lowering temperature to –35 C and infiltrated by Lowicryl. Polymerization was performed for 24 h at –35 C, followed by reverse transcription for 72 h. Semithin (1 µm) slides were stained with toluidin blue for orientation, and subsequently ultrathin slides were mounted on carbon-coated, formfar-covered, one-hole grids. To block aldehyde groups, the grids were incubated with 0.14 glycine/1 M phosphate buffer (pH 7.2) followed by incubation with 5% normal serum at room temperature for 20 min. Incubation with primary antibodies included PRL (dilution 1:80) or GH (dilution 1:20) for 1 h at room temperature. Samples were rinsed with 0.14 M glycine 0.1 M phosphate buffer (pH 7.2). Visualization was achieved by incubation of 10-nm colloidal, gold-labeled, goat-antimouse serum (GaMau 10 nm, 1:20) for 1 h at room temperature. After incubation, samples were rinsed with 0.1 M phosphate buffer (pH 7.2)/aquadest. Finally, the grids were contrasted using uranyl acetate and lead citrate. For EM, a Morgagni 268 D T105 D32 electron microscope (Philips, Best, The Netherlands) was used. Areas of the same cells were compared for GH and PRL positivity.

Statistical analysis

Statistical analysis was carried out by SPSS (version 12 for Windows; SPSS Inc., Chicago, IL). All the data are expressed as mean ± SD, unless otherwise specified. The difference between percent GH and PRL in vitro suppression by octreotide and quinagolide, compared with baseline, was analyzed by the Wilcoxon matched-paired test. The {chi}2 test was used to calculate the association between immunohistochemistry score and the in vitro and in vivo response to SSAs and DAs. Correlation analysis was performed using Spearman’s and Pearson tests.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
In vivo therapy

Basal mean GH levels were 30.5 ± 4.7 (range 2.2 ± 0.2 to 76.4 ± 1.0 µg/liter), and basal mean PRL levels, available in 18 patients, were 24.5 ± 18.2 (range 0.7 ± 0.02 to 333.4 ± 8.1 µg/liter). Percent GH suppression during the octreotide test ranged from –4 to 95.3%, whereas GH suppression during the quinagolide ranged from –14.1 to 92.9% (Table 1Go). After long-term SSA therapy, IGF-I levels normalized in nine patients (responders), reduced more than 50% in six patients (partial responders), and reduced less than 50% in the remaining patients (poor responders). Patient treatments and dosages are reported in Table 1Go.

In vitro functional studies

In cultures mean GH secretion was 925.1 ± 194.6 (range 52.5 ± 0.2 to 3742.2 ± 11.8 µg/liter), whereas PRL was detectable in 14 cases with a mean secretion of 213.2 ± 92.6 (range 1.2 ± 0.01 to 561.7 ± 11.9 µg/liter). GH suppression by octreotide ranged from 8.5 to 73.7%, and quinagolide from –15.6 to 61.9% (Table 1Go). PRL suppression by octreotide ranged from 6.4 to 73.9%, and quinagolide from 12.0 to 70.8%.

Immunohistochemistry

GH immunoreactivity was scored 2 in 15 cases and 1 in the remaining nine; PRL was scored 2 in six cases, 1 in 13, and 0 in the remaining five. Sst2A and D2R were detected in 23 and 22 of the 24 tumors, respectively. In most tumors sst2A colocalized with D2R. Sst2A showed the highest score, namely 2, in 13 of 24 cases, whereas it was scored 1 in 10, and 0 in one. D2R showed the highest score, namely 2 in 13 of 24 cases, whereas it was scored 1 in nine and 0 in the remaining two (Table 1Go). Mainly complete or incomplete membrane-bound as well as cytoplasmic immunoreactivity was noted in all tumors but not all cells. Figure 1Go shows, together with histology and EM, an exemplary case (patient 20, Table 1Go).


Figure 1
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  		FIG. 1. Upper panel, Immunohistochemical detection of GH, PRL, sst2A, and D2R in a somatotroph pituitary adenoma. A, Hematoxylin-eosin. B, Homogeneous GH immunoreactivity. C, PRL immunoreactivity in scattered cells, sections developed with 3,3'-diaminobenzidine. D, Homogeneous sst2A immunoreactivity. E, Homogeneous D2R immunoreactivity. F and G, Adjacent sections showing displacement of immunostaining after preabsorption of the antibodies with 100 nM of the respective peptide antigens (no. 20, Table 1Go). Sections developed with New Fucsine/Naphtol AS-MX. The sections are slightly counterstained with hematoxylin. Magnification, x200. Lower panel, EM study in semithin sections of pituitary tumors showing the hormone content in the same granules characterizing a somatomammotroph adenoma. In this case of somatomammotroph adenoma (no. 23, Table 1Go), immunogold particles identified GH (A–C) or PRL (D–F) in the same granules in the same cell. Three magnifications: x4,400 (A and D); x11,000 (B and E); x22,000 (C and F).

 
EM study

EM studies revealed two pure somatotrophs, five somatomammotrophs with a variable expression of PRL in the same cells containing GH, and two tumors formed by mixed cell types containing either GH and PRL or single hormones (Fig. 1Go). The in vitro GH suppression by octreotide in the two somatotrophs was significantly higher than that obtained with quinagolide, and both normalized IGF-I levels with octreotide. The two mixed tumors showed similar sensitivity to octreotide and quinagolide both in vitro and in vivo, but GH levels were suppressed less than in the pure somatotroph adenomas. SSAs did not normalize IGF-I in these patients. The five somatomammotrophs heterogeneously responded to both octreotide and quinagolide, and three of four chronically treated with octreotide normalized IGF-I, whereas in one IGF-I was reduced more than 50% (Table 1Go).

A significant association was found: between sst2A score and in vitro ({chi}2, 7.92; P = 0.02) and in vivo ({chi}2, 6.76; P = 0.03) GH suppression by octreotide as well as with IGF-I suppression during SSAs ({chi}2, 6.10; P = 0.01), and between D2R score and in vitro GH ({chi}2, 15.65; P = 0.000) and PRL ({chi}2, 6.37; P = 0.04) suppression by quinagolide as well as in vitro GH suppression by octreotide ({chi}2, 6.46; P = 0.04). Moreover, sst2A was positively correlated with the in vitro (P = 0.003) and in vivo (P = 0.006) GH suppression by octreotide (Fig. 2Go, A and B) as well as with the IGF-I suppression by SSAs (P = 0.008). Moreover, in vitro GH suppression by octreotide was positively correlated with the in vivo GH response to octreotide (P = 0.009), which was positively correlated with IGF-I suppression by SSA treatment (P = 0.017). D2R immunoreactivity was positively correlated with the in vitro GH (P = 0.000) and PRL (P = 0.005) suppression by quinagolide (Fig. 2Go, C and D), whereas D2R was not correlated with the in vivo response to quinagolide. Surprisingly, D2R was also positively correlated with in vitro GH response to octreotide (P = 0.01) (Fig. 2EGo), whereas in vitro GH suppression by octreotide was positively correlated with in vitro GH suppression by quinagolide (P = 0.003) (Fig. 2FGo).


Figure 2
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  		FIG. 2. Box plots show the median, interquartile range, outliers ({circ}, cases with values between 1.5 and three box lengths from the upper or lower edge of the box), and extreme cases (*, cases with values more than three box lengths from the upper or lower edge of the box) of individual variables. The box length is the interquartile range. A, Positive correlation between the percentage of GH suppression by octreotide in vitro and sst2A immunohistochemistry (IHC) score. B, Positive correlation between the percentage of GH suppression by octreotide in vivo and sst2A immunohistochemistry score. C, Positive correlation between the percentage of GH suppression by quinagolide in vitro and D2R immunohistochemistry score. D, Positive correlation between the percentage PRL suppression by quinagolide in vitro and D2R immunohistochemistry score. E, Positive correlation between the percentage of GH suppression by octreotide in vitro and D2R immunohistochemistry score. F, Positive correlation between the percentage of GH suppression by octreotide in vitro and the percentage of GH suppression by quinagolide in vitro.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The acute bromocriptine and octreotide tests are unable to predict the long-term GH response to chronic medical therapy (12, 15). PRL cosecretion and/or presence of PRL immunoreactivity in tumor specimens seem indicative of positive response to DAs or hint at combining DA and SSA in patients inadequately controlled by SSA monotherapy. However, two recent studies did not show any correlation between hyperprolactinemia and response to therapies (16, 17). In the present study, we found a positive correlation between sst2A and both the in vitro and in vivo sensitivity of GH to octreotide in acromegalic patients. Sst2A immunoreactivity was also correlated with control of IGF-I by chronic SSA therapy. Similarly, D2R immunoreactivity positively correlated with the in vitro GH and PRL suppression by quinagolide. However, D2R was not correlated with the in vivo GH response to quinagolide, suggesting that the in vivo sensitivity to DAs might be affected by other mechanisms. Indeed, heterogeneity as well as coexpression of other specific receptor subtypes might influence the activity of sst2 and D2R. For example, a relative higher expression of sst3 or sst5 may promote an antiproliferative effect of SSAs despite the lack in controlling hormone secretion (18, 19).

Octreotide and lanreotide bind predominantly to sst2, whereas quinagolide and cabergoline bind predominantly to D2R. Emerging data have demonstrated heterodimerization of somatostatin receptors and DRs (20). In support of this hypothesis is the finding that D2R was positively correlated with in vitro GH sensitivity to octreotide. Moreover, in vitro GH suppression by octreotide positively correlated with in vitro GH suppression by quinagolide. PRL staining did not correlate with D2R or the acute in vivo or in vitro sensitivity of both GH and PRL to quinagolide.

By EM study, we have identified two pure somatotroph adenomas, five somatomammotrophs, and two truly mixed GH/PRL tumors. Although the number of cases is too low to draw definitive conclusions, the mixed tumors seem more resistant to SSAs, whereas almost no difference in sensitivity to octreotide and quinagolide was observed in somatotroph and somatomammotroph tumors. This might be due to the lower density of sst2 in mixed tumors or an interfering role of other receptor subtypes.

In conclusion, immunohistochemistry is a useful method to characterize receptor expression in pituitary adenomas to optimize postoperative medical therapies. Receptor characterization can be used for studying the mechanisms regulating the different responses to therapy, particularly when new compounds with specific receptor binding profiles become available in the near future.


   Footnotes
 
Current address for D.F.: Department of Endocrinological and Medical Sciences and Center of Excellence for Biomedical Research, University of Genova, Genova, Italy.

Disclosure Statement: D.F., W.W.d.H., R.P., J.M.K., P.M.v.K., T.d.J., F.M., A.C., S.W.J.L., and L.J.H. have nothing to declare.

First Published Online January 22, 2008

Abbreviations: DA, Dopamine agonist; D2R, dopamine D2 receptor; EM, electron microscopy; LAR, long-acting release; PRL, prolactin; SSA, somatostatin analog; sst2A, somatostatin receptor subtype 2A.

Received June 19, 2007.

Accepted January 15, 2008.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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