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Departments of Internal Medicine and Nuclear Medicine, 1 Erasmus MC, Rotterdam, The Netherlands
(Correspondence should be addressed to W W de Herder who is now at the Sector of Endocrinology, Department of Internal Medicine, Erasmus MC, S-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands; Email: w.w.deherder{at}erasmusmc.nl)
This paper was presented at a symposium held at the Erasmus Medical Center, Rotterdam, The Netherlands, 2005. The symposium was jointly organized by LJ Hofland, Erasmus Medical Center, and A Colao, Federico II University of Naples, Italy. Ipsen partially supported the publication of these proceedings.
Abstract
Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using 123I-S-(–)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide (123I-IBZM) and 123I-epidepride. 123I-epidepride is generally superior to 123I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, 123I-IBZM and 123I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with 11C-N-raclopride and 11C-N-methylspiperone.
Introduction
Pituitary adenomas are subclassified according to hormonal hypersecretion into clinically functioning and clinically non-functioning. Among the hormone products secreted are: prolactin (PRL), growth hormone (GH), adrenocorticotrophic hormone (ACTH), thyroid-stimulating hormone (TSH), gonadotrophins (luteinizing hormone and follicle-stimulating hormone) or glycoprotein hormone subunits.
In the field of nuclear medicine, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) techniques have become available for the study of dopamine D2 and D3 receptors and somatostatin receptor subtype expression. For a review on the latter, see reference (1).
Dopamine D2 receptors
The expression of functionally active dopamine D2 receptors has been demonstrated in PRL-, GH-, ACTH-, TSH-secreting and clinically non-functioning pituitary tumours (2–11). The presence of high numbers of high-affinity D2 receptors on prolactinomas, some GH-, TSH-and ACTH-secreting tumours is the pharmacological basis for therapy with dopamine receptor agonist drugs, like the ergot-derived substances bromocriptine, pergolide and cabergoline and the nonergot dopamine agonist quinagolide (7).
Dopamine D2 receptor SPECT
Several centres, including our own, have shown that D2 receptor scintigraphy of pituitary adenomas is feasible by SPECT using 123I-S-(–)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-hydroxy-3-iodo-6-methoxybenzamide (123I-IBZM; 12–15). In a patient with a metastatic malignant macroprolactinoma, 123I-IBZM SPECT failed to visualize the primary tumour, whereas the uptake in a metastasis was lower than that observed for the striatum. A partial response of this metastatic tumour to quinagolide could be demonstrated in vivo and in vitro (16). In another patient with a mixed TSH/
-SU/PRL-secreting pituitary macroadenoma, SPECT with 123I-IBZM and 111In-DTPA-pentetreotide both visualized the tumour (17). An acute in vivo response of the tumour to octreotide and bromocriptine could be demonstrated. However, long-term combined treatment did not result in tumour regression or a decrease in circulating hormone levels (17). Thus, the demonstration of receptors in vivo in these patients did not positively predict the outcome of medical therapy with these two receptor agonists. We have performed scintigraphy using 123I-IBZM in a series of 37 patients with pituitary tumours (5 patients with PRL-secreting macroadenomas, 2 patients with PRL-secreting microadenomas, 17 patients with clinically non-functioning pituitary adenomas (NFPAs), 12 patients with GH-secreting adenomas and 1 patient with a TSH-secreting macroadenoma; (15)). SPECT showed significant uptake of 123I-IBZM in the pituitary region in three out of five macroprolactinoma patients. These results correlated closely with the response of plasma PRL levels to quinagolide. In two scan-positive prolactinoma patients, repeated SPECTs during therapy with quinagolide showed a reduction in the pituitary uptake of 123I-IBZM. Pituitary SPECT was negative in the two microprolactinoma patients who responded to quinagolide administration. In 4 out of 17 patients with NFPA, significant uptake of the radioligand in the pituitary region was observed. In two out of three scan-positive NFPA patients, who were treated with quinagolide, shrinkage of the pituitary tumours was observed. Treatment with quinagolide resulted in stabilization of tumour growth in the other scan-positive patients. Four out of seventeen patients with NFPA and a negative SPECT were treated with quinagolide. Tumour growth was observed in one patient and tumour size did not change in the other three patients. The pituitary region of none of the 12 acromegaly patients showed significant uptake of 123I-IBZM (15).
Panza and co-workers have performed pituitary scintigraphy with 123I-IBZM in two patients with mixed GH/PRL-secreting pituitary tumours and acromegaly (18). One patient showed high pituitary uptake of 123I-IBZM and >80% GH suppression was observed after a single dose of bromocriptine. Combined therapy with bromocriptine and octreotide also resulted in significant tumour regression. Another patient had negative 123I-IBZM scintigraphy and in this patient, there was no GH response to a single bromocriptine dose. In this patient, combined octreotide and bromocriptine therapy also resulted in tumour regression (18).
Ferone and co-workers have performed pituitary scintigraphy with 123I-IBZM in four patients with mixed GH/PRL-secreting pituitary tumours and acromegaly (19). One patient showed high pituitary uptake of 123I-IBZM. In this patient, cabergoline therapy failed to normalize pathologically elevated GH levels. Another patient only showed slight pituitary uptake of 123I-IBZM. In this patient quinagolide reduced, but did not normalize, pathologically elevated GH levels. In two other patients, 123I-IBZM scintigraphy was negative and neither cabergoline nor quinagolide therapy was effective (19).
These studies demonstrate that the sensitivity of 123I-IBZM SPECT for imaging pituitary adenomas is rather poor, which presumably results from the relatively low target:background ratio of 123I-IBZM binding (12–15).
These studies also show that the clinical usefulness of 123I-IBZM scintigraphy for predicting the clinical efficacy of dopamine agonists in patients with NFPAs or acromegaly is limited.
Consequently, investigators have been actively testing SPECT radiopharmaceuticals for the D2 receptor which show higher receptor affinity. Another substituted benzamide derivative, epidepride, 123I-(S)-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-iodo-2, 3-dimethoxybenzamide (123I-epidepride) has shown to provide high target-to-background uptake and hence high image quality (20–22). Subsequent D2 receptor scintigraphic studies were performed using 123I-epidepride (20, 21). Pirker and co-workers have reported a high sensitivity of 123I-epidepride SPECT for demonstrating dopamine receptors on pituitary tumours (23). We have compared pituitary SPECT after 123I-epidepride and 123I-IBZM in NFPAs in the same 15 patients. Four dopamine agonist-sensitive macroprolactinomas were used as positive controls (24). In parallel with studies demonstrating a much greater relative striatal uptake of 123I-epidepride than of 123I-IBZM (25), we have also observed a much higher uptake of 123I-epidepride in NFPAs and macroprolactinomas than of 123I-IBZM (24). All four macroprolactinomas showed pituitary uptake of 123I-epidepride, but pituitary uptake of 123I-IBZM was only demonstrated in one of these tumours (24). The pituitary region of 9 out of 15 NFPA patients showed significant uptake of 123I-epidepride, but the uptake of 123I-IBZM was only shown in 6 out of 15 patients (24). Therefore, we concluded that 123I-epidepride is superior to 123I-IBZM for the visualization of D2 receptors on pituitary macroadenomas, and that therefore 123I-epidepride should be the radioligand of choice for D2 receptor SPECT studies in pituitary tumour patients (24).
We have subsequently studied the correlation between the results of 123I-epidepride scintigraphy and the radiological response to dopamine agonists in 18 NFPAs (26). Patients were treated with either cabergoline (1–2 mg/week) or quinagolide (150–300 µg/day) for a mean period of 89.7 months (range: 34–187 months). Pituitary uptake of 123I-epidepride varied from slight uptake, classified as grade 0, to very high, classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three patients; grade 2 in ten patients and grade 3 uptake in one patient. NFPA stabilization or shrinkage with dopamine agonist therapy showed no significant difference between grades 0, 1 and 2 tumours (mean tumour stabilization or shrinkage: 31, 30 and 36% respectively) (26). We concluded that 123I-epidepride scintigraphy is not useful to predict the response to long-term dopaminergic treatment in NFPA patients (26). However, when we considered a decrease in tumour size ranging from 0 to 20% as tumour stabilization and >20% decrease in tumour size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three NFPAs with grade 1 uptake and eight out of ten NFPAs with grade 2 uptake showed tumour shrinkage (26).
As with 123I-IBZM scintigraphy, the clinical usefulness of 123I-epidepride scintigraphy for predicting the clinical efficacy of dopamine agonists in selected patients with NFPAs is therefore limited.
Discrimination of NFPAs from other pathologies in the sellar region is generally not difficult when modern MRI protocols are applied. 123I-epidepride scintigraphy, however, might still be useful in specific situations – for discrimination of scar tissue from NFPA recurrence or residual NFPA, or for the differential diagnosis between pituitary tumours and metastases (Fig. 1
) for example.
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Muhr and co-workers and Bergström and co-workers have performed PET studies with 11C-labelled dopamine D2 antagonists such as 11C-N-raclopride and 11C-N-methylspiperone for in vivo measurement of D2 receptors in prolactinomas and GH-secreting pituitary adenomas (27–30). They have demonstrated higher dopamine receptor binding in patients responsive to dopamine agonists than in therapy-resistant patients (27–30). In a patient with a malignant prolactinoma, presenting with multiple intracranial metastases, these techniques clearly visualized the primary tumour as well as a number of metastases. Bromocriptine treatment resulted in tumour regression, a decrease in circulating PRL levels and a decrease in 11C-N-labelled dopamine antagonist binding as determined in vivo by PET (31).
References
This article has been cited by other articles:
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  D. Ferone, R. Pivonello, E. Resmini, M. Boschetti, A. Rebora, M. Albertelli, V. Albanese, A. Colao, M. D Culler, and F. Minuto Preclinical and clinical experiences with the role of dopamine receptors in the treatment of pituitary adenomas Eur. J. Endocrinol., April 1, 2007; 156(suppl_1): S37 - S43. [Abstract] [Full Text] [PDF]
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