The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 581-584
Copyright © 2004 by The Endocrine Society
A Case of Dopamine Agonists Inhibiting Pancreatic Polypeptide Secretion from an Islet Cell Tumor
Ram D. Pathak,
Tuan Huy Tran and
Alan L. Burshell
Department of Internal Medicine, Section on Endocrinology and Metabolic Diseases, Ochsner Clinic Foundation, New Orleans, Louisiana 70121
Address all correspondence and requests for reprints to: Alan Burshell, M.D., Endocrinology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, Louisiana 70121. E-mail: Aburshell{at}ochsner.org.
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Abstract
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A patient with a large prolactinoma developed a metastatic islet cell tumor secreting pancreatic polypeptide. Dopamine agonist drugs reduced the prolactin levels to normal, caused a 7-fold decrease in the pancreatic polypeptide levels, and inhibited the liver metastases. Elevated chromogranin A levels also normalized on the higher doses of bromocriptine. Dopamine receptors are found in many endocrine tissues, and the expression of dopamine-2 receptor on endocrine tumors establishes the potential for response to dopamine agonist treatment. The relatively benign risk profile of dopaminergic agents makes further testing of these drugs to treat neuroendocrine tumors a worthwhile endeavor.
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Introduction
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PANCREATIC POLYPEPTIDE (PP) is a common hormone secreted by islet cell neoplasms (1). Neuroendocrine tumors tend to be slow growing and are usually treated surgically (2). Once liver metastases are present, surgery is unlikely to yield a cure (3). Other treatment options include the following: somatostatin (4), arterial embolization (5), radiation (6, 7), and chemotherapeutic agents, including 5- fluorouracil and streptozocin (8, 9). None of these options alter the long-term prognosis and may have significant adverse effects (2). Long-acting somatostatin analogs may decrease hormonal secretion and are well tolerated. However, these benefits tend to be short lived, tumor size is unaffected, gallstones may be induced, and therapy is expensive (2). Dopamine receptors are present in many neuroendocrine tumors, and dopamine agonists have been shown to inhibit both hormone secretion and growth of tumors. The best data are for prolactinomas. We describe a woman who had both a prolactinoma and a metastatic islet cell tumor secreting PP that demonstrated a 2-yr response to dopaminergic treatment.
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Case Report
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A 68-yr-old woman was seen in the endocrinology clinic for evaluation of both metastatic islet cell tumor and prolactinoma in April 2001. Severe iron deficiency anemia with hemoglobin level of 8.7 gm/dl had been diagnosed 3 months before from an indeterminate bleeding site, with negative upper and lower gastrointestinal endoscopy. A computed tomography (CT) scan of the abdomen showed a 2.0 x 1.0-cm lesion in the pancreatic head with multiple lesions in the liver compatible with metastatic disease. Liver tissue obtained by a CT-guided biopsy stained strongly for chromogranin and synaptophysin but not for carcinoembryonic antigen, suggesting a neuroendocrine tumor.
She attained menarche at the age of 14 yr and had regular menses until her early twenties. She was amenorrheic by the age of 27 yr and sought advice for infertility. At the age of 42 yr, she developed intermittent dull retroorbital headaches. A neurological examination revealed no deficits, and visual fields were normal. Skull x-rays showed an enlarged sella turcica, with erosion of the posterior sellar floor, both posterior clinoids, and dorsum sellae. A right carotid arteriogram confirmed a destroyed sella and showed a faint tumor blush in the sellar region suggesting a pituitary tumor. Hormonal studies for Cushing’s syndrome were negative, and prolactin (PRL) testing was not yet available. The patient received no further evaluation or treatment for the next 25 yr. Review of systems revealed occasional tiredness, mild right-sided abdominal pain, but no nausea or vomiting. She denied flushing, diarrhea, or palpitations. She had occasional headaches, which responded to analgesic medication, but no blurring of vision, dizziness, seizures, or loss of consciousness. There was no history of galactorrhea, heat or cold intolerance, increase in ring or shoe size, or change in facial features. She had been recently diagnosed with hypertension. Her family history was negative for multiple endocrine neoplasia. Her medications included hydrochlorothiazide, triamterene, pantoprazole, acetaminophen, and hydrocodone.
Physical examination revealed a well-developed, alert, and oriented woman. Visual fields were bilaterally normal by confrontation and by Goldman visual fields. There was no focal neurological deficit. Neck examination revealed a normal thyroid without any palpable nodules. Her abdomen was soft, without hepatomegaly or any palpable masses. There was a 6-mm facial angiofibroma but no skin collagenoma. Laboratory data showed the following levels and normative data: PRL, 9580 ng/ml (1.8–20, postmenopausal); PP, 8085 pg/ml (<312); chromogranin A (CgA), 32.3 ng/ml (2.6–14.3); LH, less than 0.1 mIU/ml 6–54(6–54, postmenopausal); FSH, 1.7 mIU/ml 23–116(23–116, postmenopausal); fasting gastrin, 105 pg/ml (<100); ionized calcium (Ca), 5.2 mg/dl (4.4–5.2); and PTH, 16.2 pg/ml (10–65). Thyroid function tests, 0800 h cortisol, GH, IGF1, somatostatin, serotonin, glucagon, calcitonin, total calcium, 24-h urinary 5-HIAA, and complete metabolic profile were all normal (for conversion from metric to SI units, multiply PRL by 44.4, PP by 0.24, Ca by 0.25, PTH by 0.102, and all others by 1.0).
A magnetic resonance imaging of the pituitary gland revealed a homogeneously enhancing macroadenoma extending to sphenoid sinus, without suprasellar extension. A CT of the abdomen showed a 2.0 x 1.0-cm cystic mass in the pancreatic head and multiple hepatic lesions with the largest being 3.0 cm in diameter. A whole-body octreotide scan revealed intense uptake in the pancreatic head area and liver. The largest liver lesion was in the left lobe and measured 7.0 x 2.0 cm. There were three additional discrete lesions with heterogeneity of the remaining liver tissue.
The patient was diagnosed with having both a prolactinoma and an islet cell cancer metastatic to the liver primarily producing PP. Multiple endocrine neoplasia, type 1, syndrome (MEN 1; Werner syndrome) was considered, but there was no evidence of hyperparathyroidism, and family history was negative. MEN-1 gene testing revealed no mutation by direct sequencing. She was treated with dopaminergic agonist bromocriptine (Parlodel) or cabergoline (Dostinex) for the prolactinoma (Table 1
). The patient preferred observation to debulking surgery or chemotherapy. Her hyperprolactinemia responded to dopaminergic drugs (Table 1). The PP levels also declined. The CgA level was initially 2.25 times the upper limit of normal, and the last measure was 24.5 ng/ml (6.0–39.0). Abdominal CT scans at 34 and 74 wk after initial presentation showed no increase in tumor size, with the possibility of slight improvement in liver metastasis at 74 wk. Repeat CT scan at 90 wk revealed only two large metastatic lesions unchanged from previous study with disappearance of the smaller lesions. Magnetic resonance imaging of the pituitary gland at 74 wk showed no change in size of the pituitary adenoma.
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Discussion
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This large prolactinoma had been present for at least 26 yr. As expected, the hyperprolactinemia responded well to conventional dopaminergic agonist treatment. Surprisingly, the grossly elevated PP levels also decreased during dopamine agonist treatment, although not to the same extent as the PRL levels. The stabilization of hepatic metastasis and the decline in PP levels suggest that bromocriptine and cabergoline inhibited the growth of the metastatic islet cell tumor and the secretion of the PP. CgA levels declined into the normal range after dopaminergic therapy. CgA may be secreted by either the islet cells or pituitary adenomas. However, prolactinomas generally secrete chromagranin B and lack CgA (10). In our patient, the CgA likely originated from the pancreas (11).
Although the patient demonstrated two components of the MEN 1 syndrome, namely pituitary and pancreatic tumors, we do not feel that this was the likely diagnosis. The patient had high normal calcium levels and low normal PTH levels while receiving a thiazide diuretic. These findings are not suggestive of primary hyperparathyroidism, which is the most common and usually the earliest manifestation of this syndrome. In addition, the MEN 1 gene study was negative, and there was no family history of pituitary, pancreatic, or parathyroid disease. However, variants such as MEN 1-Burin with a high prevalence of pituitary prolactinomas and late manifestation of the other components are well described (12).
We postulate that D2 receptors may have been present on the pancreatic tumor of our patient, and treatment with bromocriptine or cabergoline had an inhibitory effect leading to a substantial decrease in PP. Cabergoline binds more selectively to the D2 receptor than bromocriptine, and because cabergoline was effective in lowering the PP levels, D2 receptor is probably crucial. The variability of PP levels may be related to the erratic intake of cabergoline, as evidenced by the PRL levels also rising during the same period. The higher bromocriptine doses (7.5 and 10 mg/d) resulted in the lowest levels of PP and PRL (Table 1
). The slow response of PP levels to varying doses of dopaminergic therapies suggests that the maximal dopaminergic effects may take weeks to develop and recede. Interestingly, the CgA level, which was initially 2.25 times the upper limit of normal, declined to mid-normal range on higher bromocriptine doses. Dopaminergic withdrawal was not attempted because of the potential for growth of the large prolactinoma.
There are multiple examples of dopamine agonists affecting endocrine cells and tissues via D2 receptors. The inhibitory effects of dopamine on adenohypophysial cells are mediated via dopamine subtype 2 receptor (13). In human neuroendocrine pancreatic cell line BON, Lemmer et al. (14) have shown expression of D2 and D5 receptors, transmembrane dopamine transporter, and mRNA of dopamine receptors D1 to D5. They found that the D2 receptor agonist drug quinpirole decreased intracellular cAMP levels, suggesting that D2 receptor activation causes inactivation of pancreatic neuroendocrine cells. Fiorentini et al. (15) recently reported that prolactinoma cell lines that respond have D2 receptors. They also suggested that the regulator of D2 gene may not be confined to pituitary tumors but may extend to other systems. In a patient with ACTH-secreting pituitary adenoma with D2 receptor intensity similar to that of prolactinoma controls, cabergoline treatment was noted to be highly effective (16). Cabergoline, a predominantly D2 receptor agonist, has been shown to decrease IGF1 levels to normal in 39% of patients with pituitary tumor and acromegaly. It was effective in up to 50% cases cosecreting GH and PRL (17).
D2 receptors have been identified on normal human adrenal glands, pheochromocytomas, and aldosterone-producing adenomas (18), and also on neuroblastoma (19), meningioma (20), and teratocarcinoma cells (21). Furthermore, it has been shown that activation of D2 receptors inhibits aldosterone secretion and activation of D4 receptors increases it (18). Farrell et al. (22) noted that bromocriptine suppressed ACTH precursor peptide secretion from ACTH-secreting small cell lung cancer in vitro in a dose-dependent manner. Bromocriptine has also been shown to be effective in suppressing ACTH secretion in a patient with lung carcinoid (23). Antiproliferative function for dopamine regulated through D2 receptor activation has been described in mice (24). However, bromocriptine was ineffective in decreasing gastrin levels in two patients with gastrinomas, but their D2 receptor status was not known (25). Thus, dopamine receptors are found in many endocrine tissues, and the expression of D2 receptor on endocrine tumors establishes the potential for response to dopamine agonist treatment.
An alternative explanation may be that PRL receptors exist on the pancreatic tumor tissue, and high levels of PRL led to secretion of PP. Pancreatic islets are known to enlarge during pregnancy (26). However, we believe that this is less likely, because the PP levels continued to be significantly elevated even when PRL levels were low normal, and high-dose dopaminergic therapy caused declines in PP levels when the PRL level was suppressed.
We do not know whether the above response is a unique feature of this patient’s tumor, or whether it is applicable to all tumors secreting PP or other secretory neuroendocrine tumors. The relatively benign risk profile of dopaminergic agents makes further testing of this hypothesis a worthwhile endeavor.
In conclusion, we describe a patient with a large prolactinoma for many years, who subsequently developed a metastatic pancreatic tumor secreting PP. Dopamine agonist drugs reduced both the PRL levels to normal and significantly decreased the PP levels and inhibited the liver metastases. Further studies are required to evaluate the role of dopamine agonist drugs in the management of other functioning neuroendocrine tumors.
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Footnotes
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Abbreviations: CgA, Chromogranin A; CT, computed tomography; MEN 1, multiple endocrine neoplasia, type 1; PP, pancreatic polypeptide; PRL, prolactin.
Received June 16, 2003.
Accepted November 6, 2003.
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Abstract
Introduction
