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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 4 1674-1683
Copyright © 2004 by The Endocrine Society

Dopamine Receptor Expression and Function in Clinically Nonfunctioning Pituitary Tumors: Comparison with the Effectiveness of Cabergoline Treatment

Rosario Pivonello, Carmela Matrone, Mariagiovanna Filippella, Luigi M. Cavallo, Carolina Di Somma, Paolo Cappabianca, Annamaria Colao, Lucio Annunziato and Gaetano Lombardi

Departments of Molecular and Clinical Endocrinology and Oncology (R.P., M.F., C.D.S., A.C., G.L.); Neuroscience, Section of Pharmacology (R.P., C.M., L.A.); and Neurosurgery (L.M.C., P.C.), "Federico II" University of Naples, Naples 80131, Italy

Address all correspondence and requests for reprints to: Rosario Pivonello, M.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University, Via Sergio Pansini, 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The aim of this study was to correlate dopamine receptors and D2 isoform expression with the cabergoline effect on {alpha}-subunit secretion in vitro and tumor mass in vivo in clinically nonfunctioning pituitary tumors.

Eighteen patients were subjected to neurosurgery, and a tumor sample was used for dopamine receptor and D2 isoform expression evaluation by RT-PCR and the in vitro functional studies. After neurosurgery, nine of 18 patients with persistent tumor were treated with cabergoline and tumor mass was evaluated before and after 1 yr treatment.

D2 receptor was expressed in 67% of cases. D2long was found in 50%, D2short in 17%, and both D2 isoforms in 33% of cases. D4 receptor was also expressed in 17% of cases. The in vitro inhibition of {alpha}-subunit concentration was found in 56% of cases and was associated with D2 expression ({chi}2 = 5.6; P < 0.05). After 1 yr of cabergoline treatment, tumor shrinkage was evident in 56% of patients and was associated with D2 expression ({chi}2 = 5.6; P < 0.05). The expression of D2short rather than D2long isoform is associated with the most favorable response of the tumor to cabergoline treatment.

In conclusion, this study demonstrates D2 receptor expression and function in nearly 70% of cases, suggesting a role of this drug in the treatment schedule of clinically nonfunctioning pituitary tumors.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE DOPAMINE RECEPTOR (DR) family includes five different receptor subtypes, D1–D5, which are classified as two subgroups on the basis of their molecular, biochemical, and pharmacological characteristics: D1-like, including D1 and D5 receptors, and D2-like, including D2, D3, and D4 receptors. D2 receptor exists as two different isoforms generated by alternative splicing: the long (D2long) and the short (D2short) isoforms (1). D2 isoforms differ in the presence or absence of a stretch of 29 amino acids in the third cytoplasmic loop, involved in G protein receptor coupling. The two D2 isoforms may be associated with different intracellular signaling transduction mechanisms and therefore elicit different effects after binding with dopamine agonists (1).

The D2 receptor is expressed in the anterior and intermediate lobes of the pituitary gland, where it mediates the tonic inhibitory control of hypothalamic dopamine on prolactin (PRL) and MSH secretion, respectively (1). The presence of functional D2 receptors on tumoral PRL-secreting cells (2, 3) led to a major therapeutic application in the treatment of PRL-secreting pituitary tumors. Indeed, medical therapy with dopamine agonists represents the choice treatment of these tumors because it is effective in suppressing PRL secretion and inducing tumor shrinkage in the vast majority of cases (4, 5, 6). Moreover, among the different dopamine agonists, the most recently developed cabergoline has been demonstrated to be more effective than the shorter-acting and less potent bromocriptine in the treatment of prolactinomas (7, 8).

D2 receptors are also expressed in non-PRL-secreting pituitary tumors (9, 10). However, results of bromocriptine treatment of GH- and ACTH-secreting pituitary tumors have been controversial (11, 12, 13, 14, 15, 16). On the other hand, the recent use of cabergoline, demonstrated to be more effective than bromocriptine, has led to a reevaluation of treating other tumor types with dopaminergic drugs (12, 17, 18).

The D2 receptor is expressed in most clinically nonfunctioning pituitary tumors, although conflicting and disappointing results have been reported on the effectiveness of their treatment with bromocriptine (16, 19, 20, 21, 22, 23). However, heterogeneous D2 isoform expression has been demonstrated in these tumors, in which D2short seems more favorable than D2long expression for in vitro growth inhibitory response to bromocriptine (24). Moreover, cabergoline treatment has recently been demonstrated to induce tumor shrinkage in about half of the cases, suggesting improved effectiveness of cabergoline over bromocriptine in the treatment of this category of pituitary tumors as well (25).

The current study has been designed with a 2-fold purpose: 1) to evaluate DR and D2 isoform expression in clinically nonfunctioning pituitary tumors; and 2) to correlate DR and D2 isoforms expression with in vitro effects of cabergoline administration on {alpha}-subunit secretion in cultured tumoral cells and with the in vivo effect of cabergoline treatment on tumor mass, clinical features, and visual field parameters, in a group of patients harboring residual clinically nonfunctioning pituitary tumors after unsuccessful surgery.


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

Eighteen patients (10 males and eight females; age range, 30–65 yr; mean, 51.6 ± 0.6 yr; median, 51.5 yr) with a diagnosis of clinically nonfunctioning pituitary tumor entered the study. The diagnosis of clinically nonfunctioning pituitary tumor was based on the following: 1) detection of a pituitary tumor by magnetic resonance imaging (MRI) with or without local tumor signs, such as headache, visual acuity deficiency, or visual field defects; 2) the absence of clinical characteristics of GH, TSH, or ACTH hypersecretion; and 3) the presence of normal or low circulating GH and IGF-I, TSH or thyroid hormones, and ACTH and cortisol levels (26). Indeed, all patients harbored a pituitary adenoma, classified as macroadenoma (maximal diameter range, 1.2–4.0 cm). The pituitary macroadenoma was intrasellar in seven cases, whereas there was suprasellar extension in six cases and a supra- and parasellar extension in the remaining five cases. Headache was present in all cases but one, and asthenia was reported by eight patients, whereas visual acuity impairment was found in six and clear-cut visual field defects in 12 patients. Mild hyperprolactinemia (PRL levels, 42.3 ± 3.0 µg/liter) was present in 10 patients, without clinical features of PRL excess. No clinical signs of hypopituitarism were present in any case, although the presence of hormonally diagnosed hypothyroidism, hypoadrenalism, and hypogonadism was detected in three, two, and five cases, respectively. Replacement therapy with cortisone acetate was started in the two patients with hypoadrenalism. All patients were subjected to pituitary neurosurgery by a transsphenoidal approach for the removal of the macroadenoma. Histological and immunohistochemical study of the lesion removed by neurosurgery was performed in all cases. The diagnosis of clinically nonfunctioning pituitary adenoma was confirmed on the basis of the presence of histological characteristics of a pituitary adenoma with no significant immunoreactive GH, PRL, TSH, or ACTH expression within the tumor. After neurosurgery, complete disappearance of the pituitary macroadenoma was evident in nine patients, whereas residual tumor tissue was detected in the remaining nine patients by MRI. The residual tumor had a maximal diameter ranging from 7.5–30 mm and was intrasellar in three cases, suprasellar in one case, parasellar in two cases, and supra- and parasellar in the remaining three of the nine cases. Among these nine cases not cured by neurosurgery, headache was present in seven and asthenia reported by seven, whereas visual acuity impairment was found in three and clear-cut visual field defects in five patients. Residual pituitary function was evaluated in all nine patients 1 month after neurosurgery, and the presence of the following were demonstrated: central diabetes insipidus (two cases), hypothyroidism (two cases), hypoadrenalism (three cases), hypogonadism (seven cases), and GH deficiency (seven cases). All patients with postsurgical hypopituitarism were given standard therapy for the respective hormone deficiencies. The adequacy of this replacement therapy was monitored every 15 d during the following 2 months and was then monitored monthly. The presence of mild hyperprolactinemia was detected in five patients (PRL levels, 38.2 ± 2.2 µg/liter), without clinical features of PRL excess. The patients’ profiles are shown in Table 1Go.


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  		TABLE 1. Patients’ clinical profile at diagnosis of clinically nonfunctioning pituitary tumors

 
Samples

Pituitary tumor specimens were obtained at the time of tumor excision from the 18 patients who entered the study. Fresh samples of these specimens were obtained directly at surgery. A sample was quickly frozen on dry ice and stored at –80 C for RT-PCR study. An additional sample was used for establishing primary pituitary tumor cultures in cases with sufficient material for this study.

Study design

The study protocol was in accordance with the Helsinki Doctrine on Human Experimentation. Patients were included in the study after informed consent had been obtained. The study protocol included the following: 1) DR and D2 isoform expression in clinically nonfunctioning pituitary tumors, evaluated by RT-PCR performed on the frozen tissue collected at the time of neurosurgery (18 cases); 2) evaluation of the in vitro effect of cabergoline on {alpha}-subunit secretion by the cultured pituitary tumor cells in all cases with detectable {alpha}-subunit (nine cases); and 3) evaluation of in vivo effects of cabergoline treatment on tumor mass in patients with residual tumor after neurosurgery (nine cases). A comparison between DR and D2 isoform expression and results of the in vitro and in vivo functional studies was also performed.

RT-PCR

mRNA was isolated using Dynabeads Oligo (dT)25 (Dynal AS Biotech, Oslo, Norway) from a frozen tissue sample. Cells were lysed for 2 min on ice in a buffer containing 100 mM Tris-HCl (pH 8), 500 mM LiCl, 10 mM EDTA (pH 8), 1% lithium dodecyl sulfate (LiDS), 5 mM dithiothreitol, and 5 U/100 µl ribonuclease inhibitor (HT Biotechnology Ltd., Cambridge, UK). The mixture was centrifugated at 14,000 rpm for 1 min to remove cell debris. One hundred microliter prewashed Dynabeads Oligo (dT)25 were added to the supernatant, and the mixture was incubated for 5 min on ice. Thereafter, beads were collected with a magnet, washed three times with 10 mM Tris HCl (pH 8), 0.15 M LiCl, 1 mM EDTA and 0.1% LiDS and once with a similar buffer from which LiDS was omitted. mRNA was eluted from the beads in 50 ml of a 2-mM EDTA solution (pH 8) during 2 min at 65 C. To avoid contamination by genomic DNA, the isolated poly A+ mRNA was subjected to a second purification by RNA capture on a fresh aliquot of prewashed Dynabeads Oligo (dT)25, and the captured RNA was washed as above described. cDNA was synthesized using the poly A+ mRNA captured on the Dynabeads Oligo (dT)25 in a buffer containing 50 mM Tris-HCl (pH 8.3), 100 mM KCl, 4 mM dithiothreitol, 10 mM MgCl2, 1 mM of each deoxynucleotide triphosphate, 10 U ribonuclease inhibitor, and 2 U Super Reverse Transcriptase (HT Biotechnology Ltd.) in a final volume of 20 µl. This mixture was incubated for 1 h at 42 C. One tenth from each cDNA library immobilized on the paramagnetic beads was used for each amplification. The amplification reaction mixture contained cDNA template, 0.5 U SuperTaq (HT Biotechnology Ltd.), 50 µM of each deoxynucleotide triphosphate (HT Biotechnology Ltd.), 5 pmol of each of a pair of oligonucleotide primers specific for human D1–D5 receptor subtype or the hypoxanthine ribosyl transferase (HPRT) in a buffer of 10 mM Tris-HCl (pH 9), 50 mM KCl, 2 mM MgCl2, 0.01% (wt/vol) gelatin, 0.1% Triton X-100 in a final volume of 50 µl. The sequences of the primers for D1–D5 and HPRT are listed in Table 2Go. The PCR was carried out in a DNA thermal cycler with heated lid (Perkin-Elmer Cetus Instruments, Gouda, The Netherlands). After an initial denaturation at 94 C for 5 min, the samples were subjected to 40 cycles of denaturation at 94 C for 1 min, annealing for 2 min at 60 C, and extension for 1 min at 72 C. After a final extension for 10 min at 72 C, 10-µl aliquots of resulting PCR products were analyzed by electrophoresis on 1.5% agarose gels stained with ethidium bromide. Several controls were included in the RT-PCR experiments. To ascertain that no detectable genomic DNA was present in the poly A+ mRNA preparation for two DR subtypes, D1 and D5, whose genes are intron-less, the cDNA reactions were also performed without reverse transcriptase and amplified with each primer pair. Amplification of cDNA samples with the HPRT-specific primers served as positive controls for the quality of cDNA. To exclude contamination of the PCR mixtures, reactions were also performed in the absence of DNA template in parallel with cDNA samples. As positive controls for the PCR of the DR subtypes and HPRT, 0.01 µg of human brain cDNA was amplified in parallel with the cDNA samples of each examined clinically nonfunctioning pituitary tumor.


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  		TABLE 2. Specific oligonucleotide primers for DR subtypes (D1–D5) and controls used in the RT-PCR study

 
Cell dispersion and cell culture

Tumor tissue specimens were freshly placed in Hanks’ balanced salt solution (Life Technologies Ltd., Paisley, Scotland, UK), supplemented with human serum albumin 5% (Laboratories MABIO International, Tourcoing Cedex, France), penicillin (105 U/liter), and Fungizone (0.5 mg/liter). After careful removal of blood clots, specimens were minced and washed several times with the Hanks’ balanced salt solution and human serum albumin. The minced tissue was enzymatically dissociated with dispase (1000 U/liter) for 1–2 h at 37 C. After removal of erythrocytes by centrifugation on a Ficoll gradient DMEM (Life Technologies Ltd.) containing 10% vol/vol fetal calf serum and penicillin/streptomycin and were incubated at 37 C in a humid CO2 incubator for 24–48 h to allow them to attach to the bottom of plate wells. Medium was then removed and replaced with 1 ml fresh DMEM, test substances were added, and cells were reincubated at 37 C for 72 h. Afterward, medium was collected and stored at –20 C for measurement of {alpha}-subunit secretion. In all experiments, cabergoline was added to the cell cultures at concentrations ranging from 10–12 to 10–6 M. Baseline {alpha}-subunit concentration (measured in the medium not containing test substances) was compared with the {alpha}-subunit concentrations measured in medium containing the different concentrations of cabergoline. {alpha}-Subunit concentration inhibition was evaluated in a semiquantitative manner as follows: less than 25%, absent; 25–50%, mild; more than 50%, notable. {alpha}-Subunit concentrations inhibition higher than 25% of baseline was considered significant.

Hormone assays

{alpha}-Subunit was measured by immunoradiometric assay using an Immunotech (Marseille, France) kit. The sensitivity of the assay was 0.02 mUI/ml, and specificity was higher than 99.9% because of cross-reactivity with FSH, LH, TSH, and chorionic gonadotropin lower than 0.1% and that with ß-subunit nearly 0%. The intraassay coefficient ranged from 4.3–6.8%, whereas the interassay coefficient ranged from 2.77–8.6%.

Treatment protocol

Cabergoline was administered at an initial dose of 1 mg/wk for 1 month and afterward increased to 3 mg/wk, in case of good drug tolerability by patients. Treatment was started at least 3 months after neurosurgery, when a pituitary MRI clearly showed the presence of a residual tumor without any possible misinterpretation of postsurgical changes. Clinical symptoms and visual fields were evaluated every 3 months, and pituitary MRI for evaluation of tumor growth pattern was performed after 6 and 12 months. An exact measurement of tumor volume was performed before and after 12 months of cabergoline treatment.

Visual field evaluation

Visual field was evaluated, after a complete basal ophthalmic examination, including visual acuity evaluation, pupillary reflexes tests, applanation tonometry, and funduscopy, by Goldmann perimetry and automatic static perimetry (Humphrey perimetry) examinations. Particularly, defects of Goldmann perimetry and indexes of automatic static perimetry, namely mean defect (MD), pattern SD (PSD), short-term fluctuations (SF), and corrected pattern SD (CPSD), were evaluated. The MD displays the reduction of mean sensibility of visual field compared with normal sensibility for the same age of the patient. The PSD shows how the shape of the visual field differs from the normal shape for the same age of the patient. The SF is an index of coherence of the collaboration of the patient, whereas the CPSD shows how the shape of visual field differs from the normal shape for the same patient age after correction of the SF. Goldmann and static perimetry were compared in cases with pituitary adenoma, and identical results with the two techniques have been obtained (27).

Tumor mass evaluation

Tumor mass was evaluated by a dynamic pituitary MRI. The MRI examination was performed by a 0.5 Tesla MRI unit (Vectra, General Electric Global Research, Niskayuna, NY) by means of T1-dependent gradient-echo acquisitions (repetition time = 180 msec, echo time = 12 msec, flip angle = 90°) with 3-mm-thick, contiguous sections on the coronal plane and with an in-plane resolution of 0.9 mm. These acquisitions were repeated before and after the administration of 0.1 mM/kg of body weight of gadolinium dietilen-tiamino-pentacetate analyzing pituitary perfusion over time with a temporal resolution of 57 sec. Tumor volume was calculated according to Lundin and Pedersen (28) using the following formula: [(longitudinal diameter x transversal diameter x anteroposterior diameter) x 1/2]. Residual tumor shrinkage was defined as reduction of baseline volume, evaluated in a semiquantitative manner as follows: less than 25%, absent; 25–50%, mild; more than 50%, notable (16). Tumor shrinkage higher than 25% of baseline was considered significant.

Statistical analysis

Data are shown as mean ± SE. The intergroup and intragroup comparisons have been performed by ANOVA for unpaired and paired data, respectively. The association studies were performed using {chi}2 test. Significance was set at 5%.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
RT-PCR study

D2 was expressed in 12 of 18 cases (67%). D2long was found in six (50%), D2short in two (17%), and both D2 isoforms in four cases (33%). D4 was expressed in three cases (17%) associated with expression of both D2short and/or D2long in all three cases. Expression of other DR was not found in one case. The results of RT-PCR study are summarized in Table 3Go.


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  		TABLE 3. DR expression by RT-PCR and in vitro {alpha}-subunit secretion in clinically nonfunctioning pituitary tumors

 
In vitro effectiveness of cabergoline on {alpha}-subunit secretion

Dose-dependent inhibition of {alpha}-subunit secretion was found in five of nine cases (56%) after cabergoline addition. The maximal inhibition was higher than 50% in three cases and between 25 and 50% in the remaining two cases. Inhibition of {alpha}-subunit secretion was significant (P < 0.05) at the concentration of 10–8 M of cabergoline in all cases. D2 expression correlated with {alpha}-subunit secretion inhibition ({chi}2 = 5.6; P < 0.05), as also demonstrated by a difference in {alpha}-subunit secretion inhibition between cases with and those without D2 expression (P < 0.01; Fig. 1Go). In addition, the {alpha}-subunit secretion inhibition differed between the cases expressing and those not expressing D2short isoform (P < 0.05), the former associated with a higher inhibition than the latter ones (Fig. 1Go). Particularly, D2 expression was found in all five cases (100%) with a response to cabergoline and in one of the four cases (25%) not responsive to cabergoline, which expressed D2long isoform. D2short was detected in the three cases with a notable inhibition and in one of the two cases with a mild inhibition, whereas the presence of only D2long isoform was found in the remaining case with mild inhibition of {alpha}-subunit concentration.



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  		FIG. 1. In vitro inhibition of {alpha}-subunit secretion after 72-h cabergoline administration in the totality of the cases, in cases with D2 compared with those without D2 expression, and in the cases with D2short compared with those with only D2long expression. The values are expressed as percentage of maximal inhibition compared with baseline.

 
In vivo effectiveness of cabergoline treatment

Clinical features. Improved clinical features were observed in patients before and after 1 yr of cabergoline treatment; headache disappeared in five of the seven (71%) patients with headache at baseline, and visual acuity improved in two of three (67%) patients with impairment of visual acuity at baseline. Asthenia improved in two patients, probably related to the starting and stabilization of replacement treatments for pituitary deficiencies, but persisted or worsened in the other two patients, who already reported this symptom at study entry.

Visual field evaluation. A significant improvement of visual fields after 1 yr of cabergoline treatment was observed in four of five (80%) patients with a baseline clear-cut visual field defect, as evaluated by Goldmann perimetry. At Humphrey perimetry, improved MD (P < 0.01), PSD (P < 0.01), and CPSD (P < 0.01) was observed in patients after 1 yr cabergoline treatment compared with baseline evaluation (Fig. 2Go). Particularly, MD improved in all patients (100%), whereas PSD and CPSD improved in 13 of the 18 eyes (72%) examined, with a bilateral improvement in five patients, monolateral improvement in three patients, and no improvement in the remaining five patients. Visual field parameter changes did not correlate with D2 expression, and no difference was found between cases expressing and those not expressing the D2short isoform in the pituitary tumor.



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  		FIG. 2. Visual field parameters at baseline ({square}) and after 1 yr cabergoline treatment ({blacksquare}).

 
Tumor mass evaluation. Significant tumor shrinkage was observed in five of nine (56%) patients after 1 yr cabergoline treatment. Particularly, a notable tumor reduction was found in two patients, and a mild tumor reduction was found in three patients. Conversely, slight but not significant tumor shrinkage was observed in one patient, and a slight tumor size increase was observed in the remaining three patients. D2 expression was associated with tumor shrinkage in this group of patients ({chi}2 = 5.6; P < 0.05), and a significant difference in tumor shrinkage was detected between cases expressing and those not expressing D2 receptor (P < 0.01; Fig. 3Go). In particular, all cases with significant tumor shrinkage were associated with D2 expression, and all but one case without a significant tumor shrinkage did not express D2 receptor. Moreover, a relevant although not significant difference in tumor shrinkage was found between patients expressing and those not expressing the D2short isoform, i.e. the two cases with high tumor shrinkage and one of the three with moderate tumor shrinkage associated with D2short expression (Fig. 3Go). The effect of cabergoline treatment on the tumor mass in patients with clinically nonfunctioning pituitary tumors are summarized in Table 4Go. Two exemplary cases of tumor mass changes evaluated by MRI after 1 yr of cabergoline treatment and the comparison with DR expression of these tumors at RT-PCR are shown in Fig. 4Go.



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  		FIG. 3. In vivo tumor shrinkage after 1 yr cabergoline treatment in the totality of the cases, in cases with D2 compared with those without D2 expression, and in the cases with D2short compared with those with only D2long expression. The values are expressed as percentage of volume reduction compared with baseline.

 

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  		TABLE 4. D2 expression and in vivo tumor shrinkage in patients not cured by surgery with clinically nonfunctioning pituitary tumors

 


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  		FIG. 4. Exemplary cases of tumor mass changes after 1 yr cabergoline treatment and comparison with the expression of DR in the tumor as evaluated at the RT-PCR study. D2i = D2 receptor isoforms (D2short and long). Case 1 represents a case not responsive to cabergoline with a maximal diameter reduction of 0% and a tumor volume increase of 4% of baseline; the RT-PCR shows no expression of any dopamine receptor in the tumor. Case 3 represents a case responsive to cabergoline with a maximal diameter reduction of 36% and a tumor volume decrease of 52% of baseline; the RT-PCR shows the expression of D2long, and D2short, and D4 in the tumor. MW, Molecular weight; D, diameter.

 
Treatment compliance. Treatment with cabergoline had no major side effects. Minor symptoms, including asthenia and dizziness or mild hypotension, were reported in three patients. Routine laboratory examination showed no change, whereas PRL levels were suppressed in all patients during cabergoline treatment, independent of baseline PRL levels (4.0 ± 0.2 µg/liter). However, no patients discontinued therapy because of side effects.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The results of the current study demonstrate the following regarding clinically nonfunctioning pituitary tumors: 1) D2 receptors are expressed in nearly 70% of cases; 2) 1 yr of cabergoline treatment induces a significant clinical and visual improvement in 70–80% and tumor shrinkage in nearly 60% of cases; and 3) the expression of D2short isoform is associated with the most favorable response to cabergoline treatment.

The biological basis of the effectiveness of dopamine agonists in the treatment of pituitary tumors is determined by tumor DR expression. In the pituitary, the response to dopamine agonists is related to activity of the D2 receptor (1, 29, 30). In PRL-secreting pituitary tumors, the presence of abundant D2 receptors explains the good therapeutic response to dopamine agonists, which inhibits PRL secretion and leads to tumor shrinkage (4, 5, 6, 16). Resistance to dopamine agonists in these tumors may be explained either by the absence or small amount of D2 receptors or their functional inactivity (31). D2 receptors have also been demonstrated in GH-secreting pituitary tumors (9), although their response to dopamine agonists is not as marked as in PRL-secreting pituitary tumors (11, 12, 16). We recently demonstrated that D2 receptors are also expressed in ACTH-secreting pituitary tumors (10). However, controversial results on the effectiveness of dopamine agonists in these tumors have been reported (13, 14, 15, 16).

The majority of studies on the effectiveness of dopamine agonists on pituitary tumors have used the classical dopamine agonist bromocriptine. However, a relatively recent dopamine agonist, cabergoline, which possesses a higher specificity and affinity for the D2 receptor and a longer duration of action, has been clearly demonstrated to be more effective and better tolerated than bromocriptine in the treatment of pituitary tumors (32). This evidence has been largely reported in PRL-secreting pituitary tumors (4, 5, 6, 7, 8). Moreover, the resistance of GH-secreting pituitary tumors to dopamine agonists has been demonstrated to be overcome in some patients by using cabergoline instead of bromocriptine (17, 18). Also, cabergoline has been demonstrated recently to be more effective than bromocriptine in the treatment of ACTH-secreting pituitary tumors (10). In addition, cabergoline was reported to induce significant shrinkage of a silent ACTH pituitary tumor (33) and an ACTH-secreting pituitary tumor that developed after bilateral adrenalectomy in a patient cured from Cushing’s disease (34).

Clinically nonfunctioning pituitary tumors are a category of pituitary tumors not associated with a specific clinical or biochemical feature of pituitary hormone hypersecretion (26). However, they represent a very heterogeneous group of tumors because a consistent proportion of them has been shown to secrete low amounts of intact FSH and LH and/or their {alpha}- and ß-subunits either in vitro or in vivo. In these tumors, D2 receptors are expressed in a large number of cases, as demonstrated both in vitro by receptor-ligand binding studies and in vivo by scintigraphic studies using radiolabeled dopamine analogs (19, 20, 35, 36). However, the therapeutic use of dopamine agonists in different clinical trials have given disappointing and conflicting results. Importantly, the majority of studies on dopamine agonist treatment in these tumors were performed with bromocriptine, which inhibited hormone secretion in vitro and in vivo in a consistent percentage of cases but inhibited in vitro tumoral cell growth and reduced in vivo tumoral mass only in a minority of patients (16, 19, 21, 22, 23, 37). In particular, bromocriptine sporadically induced tumor shrinkage only by using high doses of the drug. Therefore, these studies are limited by the fact that bromocriptine at such high doses is not well tolerated due to the occurrence of severe side effects. On the other hand, the nonergot derivative D2 selective dopamine agonist quinagolide has also been used in the treatment of clinically nonfunctioning pituitary tumors. Quinagolide induced a short-term inhibition of gonadotropins and/or {alpha}-subunit secretion in 80%, tumor shrinkage in 20%, and tumor stabilization in 60% of cases (38). However, a long-term study demonstrated that quinagolide does not prevent progressive tumor increase in the majority of patients (39). On the other hand, pituitary tumor uptake at scintigraphy with radiolabeled dopamine analog 123I-metoxybenzamide was predictive of hormone inhibition and tumor shrinkage in patients with clinically nonfunctioning pituitary tumors (40, 41). In most studies evaluating the effect of dopamine agonist treatment in these tumors, the stringent criterion of a tumor mass reduction of at least 25% has been considered the definition of significant tumor shrinkage. However, it has been recently reported that, considering significant tumor shrinkage of at least 10%, the treatment of these tumors with cabergoline at the maximal dose of 1 mg/wk for 1 yr induced tumor shrinkage in nearly 60% of cases, although tumor shrinkage of 25% occurred in less than 10% of cases (25). In this regard, it must be considered that some minor tumor shrinkage observed in previous study with any dopamine agonist can be due to the action of the drugs on normal lactotroph surrounding the tumor. The current study demonstrated that 1 yr of cabergoline treatment at the dose of 3 mg/wk induced a more than 25% tumor shrinkage in 56% of patients with clinically nonfunctioning pituitary tumors. All these patients had a relevant tumor shrinkage, nearly 50–60%, with the exception of one case, who had a 29% decrease of tumor volume. This evidence seems to exclude the possibility of a shrinkage of normal lactotroph surrounding the tumors in the cases included in the current study. The discrepancy between the current and the previous study investigating the cabergoline effectiveness in these tumors may be explained by the different dose of cabergoline administered in the two groups of patients. An important finding demonstrated for the first time in the current study is that tumor shrinkage by cabergoline treatment is accompanied by a significant correlation with D2 receptor expression. The results of this study also demonstrate that cabergoline treatment significantly improved clinical features, particularly headache, and visual function in 70–80% of patients, independently of tumor shrinkage, suggesting a possible direct effect of cabergoline on headache and visual function in these patients. This effect on clinical and visual parameters is better than that reported in previous studies using bromocriptine or quinagolide and even more favorable than that reported in the study using 1 mg/wk cabergoline. It is noteworthy that previous data suggested that clinical features and visual field improvements after surgery alone may progressively improve in the months after the operation (42). Therefore, the possibility cannot be ruled out that the improvement in clinical features and visual field observed after cabergoline treatment in the patients in this study also may be related to a delayed effect of surgery.

Dopamine agonist resistance in clinically nonfunctioning tumors may be due to similar D2 receptor structure and function abnormalities demonstrated in resistant PRL-secreting pituitary tumors. However, a possible influence of a different expression pattern of D2 receptor isoforms also has been postulated. Indeed, the D2 receptor belongs to the family of the G protein-coupled receptors and acts through inhibiting AMP cyclase enzyme (1, 43). Alternative splicing of the gene product encoding for the D2 receptor leads to two subtypes of the receptor, D2short and D2long (1, 44). In the normal pituitary, the D2 receptor was found in more than 75% of the whole pituitary cells, indicating that it is not expressed only in lactotroph and melanotroph cells, which represent not more than 30% of all pituitary cells (24). Moreover, both D2 receptor isoforms have been found, with a predominant expression of D2long isoform (24). Conversely, in clinically nonfunctioning pituitary tumors, D2 receptor expression was lower than in the normal pituitary, and the ratio between D2long and D2short was heterogeneous, being also in some cases only D2long or D2short expressed (24). This evidence suggests that changes in the mechanism of alternative D2 splicing may occur during tumorigenesis of these tumors. These changes might also influence the sensitivity of tumoral cells to dopamine agonists. Indeed, the affinity of dopamine and dopamine agonists for D2 receptor isoforms is nearly identical (45), but the intracellular signaling pathways activated by the binding of the receptor with the ligand seems to be different for each isoform. In fact, the two D2 receptor isoforms are differently coupled to G proteins, such as Gs{alpha}, Gi{alpha}2, and Gi{alpha}3, which differentially regulate adenylyl cyclase and K and Ca flux. Therefore, heterogeneous G protein coupling would allow a variable second-messenger activation by the two D2 receptor isoforms (46, 47). An heterogeneous dopamine signal transduction has been observed in clinically nonfunctioning pituitary tumors (48). In addition, dopamine agonists induce in vitro growth suppression of cells derived from these tumors only in cases of isolated or predominant expression of D2short, suggesting that this D2 isoform favors the growth-suppressive response in this category of pituitary tumors (24). The results of the current study are in line with this hypothesis because inhibition of {alpha}-subunit secretion in vitro as well as the in vivo tumor shrinkage was greater in cases expressing D2short isoform. The cases resistant to cabergoline administration either in vitro or in vivo were those not expressing D2 receptor, or only expressing D2long isoform. On the basis of these results, it may be hypothesized that the D2short isoform plays a pivotal role in the control of hormone secretion and cell growth inhibition and that the lack of D2short isoform expression or an increased D2long/D2short ratio may contribute to dopamine agonist resistance of clinically nonfunctioning pituitary tumors.

The current study confirms that cabergoline is more effective and better tolerated than bromocriptine also in the treatment of clinically nonfunctioning pituitary tumors. The reasons for the superiority of cabergoline compared with bromocriptine have not been completely clarified. The majority of the studies comparing the behavior of the two drugs found in the different pharmacokinetic and pharmacodynamic characteristics the explanation of their different effectiveness and tolerability. However, different hypotheses could be postulated. First, the current study has confirmed the possible key role of D2 receptor isoforms ratio in the expression pattern of these tumors. Cabergoline might activate D2short isoform better than bromocriptine. This seems to be supported by the evidence that the cases expressing D2short isoform are associated with the better clinical response to cabergoline. Second, the current study demonstrated that D4 may be coexpressed with D2 receptors, possibly having an additive or synergistic effect, in these tumors. Cabergoline might activate D4 receptor better than bromocriptine. This seems to be supported by the evidence that both cases expressing D4 receptor had a significant clinical response to cabergoline. Moreover, the possibility cannot be ruled out that cabergoline induces cell apoptosis more than does bromocriptine through the activation of D2short and/or D4 receptors. Finally, G protein-coupled receptors, including D2 receptors, have been recently demonstrated to form homo- or heterodimers with the same or different receptors, respectively (49, 50). The formation of these dimers seems to be a receptor agonist-dependent process and seems to induce a potentiation of the action mediated by the receptors (49, 50). On these bases, the possibility that cabergoline rather than bromocriptine is able to induce D2 dimerization, expressing its relevant effectiveness, can be considered. However, all these hypotheses need to be confirmed by appropriate studies before drawing definitive conclusions.

In conclusion, the current study demonstrates the expression and function of the D2 receptor in nearly 70% of clinically nonfunctioning pituitary tumors. The demonstration of an effectiveness of chronic treatment with the dopamine agonist cabergoline in improving clinical syndrome in about 70% of cases, improving visual field impairment in 80% of cases, and inducing tumor shrinkage in nearly 60% of cases, strongly supports the possible therapeutic use of this drug in the management of residual clinically nonfunctioning pituitary tumors after unsuccessful surgery.


   Acknowledgments
 
We are grateful to Professor Leo J. Hofland and Steven W. J. Lamberts for the expertise on the methodology of reverse transcriptase-polymerase chain reaction and in vitro studies and Professsor Shlomo Melmed for revising the manuscript. We are greatly indebted to Pharmacia-Pfizer for providing the dopamine agonist drug cabergoline for the experimental studies.

This work was supported in part by Grant 2003-068735 from the Italian Minister of University and Research.


   Footnotes
 
Abbreviations: CPSD, Corrected pattern SD; DR, dopamine receptor(s); HPRT, hypoxanthine ribosyl transferase; LiDS, lithium dodecyl sulfate; MD, mean defect; MRI, magnetic resonance imaging; PRL, prolactin; PSD, pattern SD; SF, short-term fluctuation(s).

Received May 19, 2003.

Accepted December 30, 2003.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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