Unusual clinical presentations of giant prolactinomas

Giant prolactinomas are rare pituitary tumors which have scarcely been reported in the literature. We describe three men with unusual presenting features of prolactin-secreting giant pituitary adenomas: prolonged and increasingly disturbing intolerance to light and noise; strange behavior and mood disturbances; and rhinorrhea followed by a finding of cerebrospinal fluid leakage. Treatment with dopamine agonist alleviated all symptoms, with concomitant suppression of plasma prolactin levels and a significant reduction in tumor mass. These cases emphasize the importance of considering unusual symptoms in the differential diagnosis of giant prolactinomas and the effectiveness of medical treatment.     

Medical therapy of glycoprotein hormone-secreting pituitary tumors

Glycoprotein hormone adenomas represent approximately 25% of all pituitary adenomas. Although surgery and radiation are the primary therapeutic modalities, there is an important need for the development of adjunctive medical therapy for these tumors. Investigations have focused on the suppression of GPH synthesis and secretion by hypothalamic regulatory factors in an attempt to decrease tumor mass. Although GnRH agonist analogues have not produced consistent GPH suppression, they may be valuable tools to investigate the regulation of intact GPH and subunit secretion in these tumors. Preliminary reports have shown that analogues of dopamine and somatostatin may be therapeutically useful. However, careful in vivo and in vitro characterization of tumors within this very heterogeneous group and correlation with their response to treatment are needed to establish guidelines for effective medical therapy.     

Altered balance between thyrotropin-releasing hormone and dopamine in prolactinomas and other pituitary tumors compared to normal pituitaries

We measured TRH and dopamine (DA) concentrations in prolactinomas and other pituitary tumors in order to further understand the roles of these two factors in the hormone hypersecretion and growth of these tumors. The mean TRH concentration (by RIA) in 16 prolactinomas was 247 +/- 92 (+/- SE) fmol/mg cell protein (range, 10-1297), near that found in normal pituitary tissue. The prolactinoma TRH content did not correlate with the patient's tumor size or plasma PRL level. By contrast, DA assayed by high pressure liquid chromatography was present in normal pituitary tissue (7.3 +/- 3.5 pmol/mg cell protein), but was very low or undetectable in the prolactinomas (23 fmol/mg cell protein or less). 3,4-Dihydroxyphenylacetic acid, also assayed by high pressure liquid chromatography, was undetectable in both normal pituitary tissue and prolactinomas. This imbalance between TRH and DA content also was found in GH-secreting and nonsecreting adenomas. The TRH content in 18 GH-secreting tumors (24 +/- 6 fmol/mg) was considerably lower than that in the prolactinomas (P less than 0.001). In 8 nonsecreting adenomas, the mean TRH concentration was 109 +/- 28 fmol/mg, about half of that in the prolactinomas. In those 2 types of adenomas, DA also was nearly undetectable (less than or equal to 73 fmol/mg cell protein). We conclude that the imbalance between TRH and DA contents in prolactinomas compared to those in normal pituitary tissue might participate in the mechanisms leading to hypersecretion of PRL and the growth of all types of pituitary adenomas.     

Expression of prolactin-releasing peptide and its receptor messenger ribonucleic acid in normal human pituitary and pituitary adenomas

The recently identified PRL-releasing peptide (PrRP) is the first hypothalamic peptide hormone that specifically stimulates PRL production from the pituitary gland. Similar to other hypothalamic regulatory hormones, it acts through its specific seven-transmembrane domain, G protein-coupled receptor. Using RT-PCR, we examined messenger ribonucleic acid (mRNA) expression of PrRP and its receptor in normal human pituitary tissue and in pituitary tumors. PrRP mRNA was expressed in all five normal pituitary glands examined. In contrast, PrRP mRNA was detected in only 5 of 11 of the human prolactinomas. All 5 prolactinomas expressing PrRP were responsive to dopamine agonist treatment, whereas PrRP-negative prolactinomas were non- or partially responsive. PrRP mRNA was also detected in 6 of 13 GH-secreting tumors and 5 of 10 clinically nonfunctioning tumors investigated. PrRP receptor mRNA was found in all the normal and neoplastic human pituitary samples studied. The production of PrRP and its receptor by normal and neoplastic pituitary tissue raises the question of whether it may regulate PRL production in an autocrine/paracrine manner in pituitary tissue. Further investigation of PrRP and its receptor expression and function will be needed to clarify its potential role in regulating PRL secretion in normal human lactotrophs and pituitary tumors.     

Radiosurgery for pituitary adenomas

Pituitary adenomas represent nearly 15% of all intracranial tumors. Multimodal treatment includes microsurgery, medical management and radiotherapy. Microsurgery is the primary recommendation for nonfunctioning and most of functioning adenomas, except for prolactinomas that are usually managed with dopamine agonist drugs. However, about 30% of patients require additional treatment after microsurgery for recurrent or residual tumors. In these cases, fractionated radiation therapy has been the traditional treatment. More recently, radiosurgery has been established as a treatment option. Radiosurgery allows the delivery of prescribed dose with high precision strictly to the target and spares the surrounding tissues. Therefore, the risks of hypopituitarism, visual damage and vasculopathy are significantly lower. Furthermore, the latency of the radiation response after radiosurgery is substantially shorter than that of fractionated radiotherapy. The goal of this review is to define the efficacy, safety and role of radiosurgery for treatment of pituitary adenomas and to present the preliminary results of our institution.     

Effects of thyrotropin-releasing hormone and gonadotropin-releasing hormone on inositol phospholipid turnover in endocrinologically inactive pituitary adenomas and prolactinomas

We examined the effects of GnRH and TRH on inositol phospholipid turnover in 11 endocrinologically inactive pituitary adenomas and 5 prolactinomas. In 9 of the 11 nonsecreting adenomas, GnRH induced a significant increase in inositol phospholipid turnover; of those that responded, increased inositol phospholipid turnover in response to TRH occurred in 6. Neither of the 2 prolactinomas exposed to GnRH responded to GnRH, whereas all 5 prolactinomas responded to TRH. These findings demonstrate the presence of functional GnRH receptors on endocrinologically inactive pituitary adenomas. The phosphatidyl inositol-linked receptor status of these tumors differs from that of prolactinomas. These receptors may offer a possible target for therapeutic intervention in endocrinologically inactive adenomas.     

Management of aggressive pituitary adenomas: current treatment strategies

Aggressive pituitary adenomas are notoriously difficult to manage due to their size, invasiveness, speed of growth and high frequency of recurrence. Except for prolactinomas, surgery (usually transsphenoidal but sometimes transcranial) is the first-line option, but re-growth of aggressive tumors is almost inevitable and monitoring and repeat surgery is required to control symptoms. In prolactinomas, dopamine agonists are the first-line treatment and they normalize prolactin levels in most patients even with macroprolactinomas. Somatostatin analogues offer another pharmacotherapy for pituitary adenomas either for primary therapy, pre-operatively to reduce the tumor volume and make it more amenable to surgical removal, or post-surgery to control re-expansion. When surgery and pharmacotherapy fail, radiotherapy is a useful third-line strategy that reduces recurrence, while extreme pituitary adenomas with metastases may potentially be managed with chemotherapy (although more data are needed). A combination of these therapies will be required for aggressive pituitary adenomas and careful follow-up is essential.     

Expression of Aromatase P450 is Increased in Spontaneous Prolactinomas of Aged Rats

We have recently reported the presence of aromatase P450 in the rat hypophysis. This enzyme is responsible for the aromatization of testosterone to estradiol. Since the induction of prolactinomas has been demonstrated in the rat following chronic treatment with estradiol, the aim of the present study was to analyze whether a relationship exists between the presence of pituitary aromatase and the appearance of spontaneous prolactinomas in aged rats. Of a series of 90 adenomas studied, 53% showed prolactin immunoreactive cells and were classified as prolactinomas; only 33% of the adenomas were pure prolactinomas and the other 20% were multi-hormonal protactinomas. Moreover, 60% of the adenomas were aromatase-positive tumors. Interestingly, 100% of the pure prolactinomas were aromatase-positive while only 60% of the multi-hormonal prolactinomas expressed the enzyme. Western blotting with anti-aromatase antibodies revealed a 3.8-fold increase in expression of aromatase in pituitary tumors as compared to normal rat pituitary gland. Double immunohistochemical labeling detected the coexistence of prolactin and aromatase P450 in prolactinoma cells. ACTH- and LH-positive adenomas were considered as controls; only multi-hormonal ACTH and LH tumors display aromatase-positive cells and all of these also contained prolactin-positive cells. Our results demonstrate for the first time that aromatase is expressed in pituitary adenomas and that it is related to the functional nature of the tumor, especially in the case of pure prolactinomas, suggesting the possibility that an abnormally high conversion of testosterone into estradiol in pituitary cells may contribute to the genesis of spontaneous prolactinomas in aged rats.     

An electrophysiological study of cultured human pituitary cells

The electrophysiological properties of tumoral pituitary cells were studied in 4 types of human adenomas including prolactinomas, growth-hormone-secreting tumors, adrenocorticotropinhormone-secreting adenoma and “non-functioning” tumors. Only 9% of the cells from prolactinomas and ACTH tumors were excitable but they never elicited spontaneous action potentials. These cells did not respond to substances known to act on the hormone-releasing process (thyreoliberin, dopamine). However, 37% of the cells cultured from growth-hormone-secreting adenomas and from “non-functioning” tumors displayed action potentials. The action potential was calcium-dependent i.e., it was blocked by cobalt, nickel and methoxyverapamil and could be recorded in a sodium-free medium. Thyreoliberin triggered action potentials, whereas dopamine and γ-aminobutyric acid inhibited electrical activity.These results show that human tumoral pituitary cells in culture are able to generate Ca²⁺-dependent action potentials. The data from growth-hormone-secreting tumors are in good agreement with the stimulus-secretion coupling concept; however, differences in the response of cells cultured from other types of human pituitary tumors suggest that each type of adenoma has specialized membrane properties.     

THE EFFECT OF DOPAMINE AGONIST THERAPY ON LARGE FUNCTIONLESS PITUITARY TUMOURS

Fifteen patients (12 male) with large pituitary tumours and serum prolactin levels below 1000 mU/l were given dopamine agonist therapy (bromocriptine, mesulergine or pergolide) for a mean of 9 months (range 3-36 months). Serum prolactin became undetectable in all. Despite this, significant suprasellar extensions and any associated neurological defect remained in 14 patients, who therefore were referred for surgery. In one patient there was evidence of spontaneous pituitary infarction unrelated to dopamine agonist therapy. At operation 12 patients had apparently functionless pituitary adenomas which failed to immunostain for prolactin, one had an epidermoid cyst and one a Rathke's pouch cyst. We conclude that patients with large pituitary tumours and only a mildly elevated serum prolactin are unlikely to have prolactinomas, and that such tumours are not likely to show significant tumour shrinkage with medical treatment with dopamine agonists.     

Management of resistant prolactinomas

Resistance to dopamine agonists occurs in a subset of patients with prolactin-secreting pituitary tumors. The resistance is mediated by loss of pituitary D2 receptors and occurs in both microadenomas and macroadenomas. Cabergoline is the most effective dopamine agonist and tumors that do not respond to bromocriptine or quinagolide frequently respond to cabergoline. Treatment options include maximizing the dose of the dopamine agonist, changing agonists, trans-sphenoidal surgery and radiation therapy. The goal of therapy is to restore and maintain gonadal and neurologic function, and this might occur in the absence of a normal prolactin level or a significant change in tumor size. Trans-sphenoidal pituitary surgery should be reserved for patients who are intolerant of medical therapy, or in whom this has failed. Radiation therapy has a limited role in treatment of resistant prolactinomas and should be reserved for patients in whom medical and surgical therapy has failed.     

Misinterpretation of prolactin levels leading to management errors in patients with sellar enlargement

Serum prolactin concentrations and clinical features were correlated with the histopathologic diagnosis in 128 patients, without acromegaly or Cushing's syndrome, referred for surgical treatment of a presumed pituitary adenoma. A serum prolactin concentration of more than 8,000 mU/liter was always due to a prolactin-secreting adenoma. Prolactin levels of less than 8,000 mU/liter occurred with a variety of pathologic diagnoses. Fifteen patients had lesions other than pituitary adenomas, most commonly intrasellar craniopharyngioma; 10 of these had modest hyperprolactinaemia (maximum, 5,260 mU/liter) and four had received inappropriate bromocriptine therapy. Adenomas that were not prolactinomas frequently caused mild hyperprolactinaemia, although this was usually less than 3,000 mU/liter; three of these patients, however, had serum prolactin concentrations greater than this (maximum, 8,000 mU/liter). If the serum prolactin concentration is less than 3,000 mU/liter in the presence of significant pituitary enlargement, surgical removal is essential for both diagnosis and treatment since only prolactin-secreting adenomas are likely to shrink with dopamine agonist therapy. A serum prolactin concentration between 3,000 and 8,000 mU/liter is consistent with any diagnosis, whether the fossa is greatly enlarged or not, and great care must be taken with dopamine agonist therapy in such patients.     

Treatment of pituitary tumors: dopamine agonists

The neurotransmitter/neuromodulator dopamine plays an important role in both the central nervous system and the periphery. In the hypothalamopituitary system its function is a dominant and tonic inhibitory regulation of pituitary hormone secretion including prolactin- and proopiomelanocortin-derived hormones. It is well known that dopamine agonists, such as bromocriptine, pergolide, quinagolide, cabergoline, and lisuride, can inhibit PRL secretion by binding to the D(2) dopamine receptors located on normal as well as tumorous pituitary cells. Moreover, they can effectively decrease excessive PRL secretion as well as the size of the tumor in patients having prolactinoma. Furthermore, dopamine agonists can also be used in other pituitary tumors. The major requirement for its use is that the tumor cells should express D(2) receptors. Therefore, in addition to prolactinomas, targets of dopamine agonist therapy are somatotroph tumors, nonfunctioning pituitary tumors, corticotroph pituitary tumors, Nelson's syndrome, gonadotropinomas, and thyrotropin-secreting pituitary tumors. It is also an option for the treatment of pituitary disease during pregnancy. Differences between the effectiveness and the resistance of different dopaminergic agents as well as the future perspectives of them in the therapy of pituitary tumors are discussed.     

Management of pituitary tumors in pregnancy

Pituitary tumors, usually adenomas, account for about 10-15% of all intracranial tumors. Their treatment, which includes surgery, medicine or radiotherapy, either isolated or in combination, aims to halt tumor growth or achieve tumor shrinkage, as well as control hormone hypersecretion or ensure hormone replacement. Such approaches have made pregnancy possible for women with pituitary adenomas. Medical therapy with dopamine agonists is the treatment of choice for most patients with prolactinomas, with surgery reserved for individuals resistant to drugs. On the other hand, surgery before conception is indicated as a first-line approach in patients with acromegaly, Cushing disease or clinically nonfunctioning pituitary macroadenomas. In these patient populations, medical therapy with somatostatin analogues (acromegaly) or drugs that target the adrenal glands, such as metyrapone and ketoconazole (Cushing disease), should be reserved for those in whom surgery is unsuccessful or contraindicated.     

Tissue kallikrein is associated with prolactin-secreting cells within human growth hormone-secreting adenomas.

Tissue kallikrein is a serine protease which may be involved in the intracellular processing of prolactin in the anterior pituitary gland. The expression of tissue kallikrein, in the rat, is promoted by oestrogen and inhibited by dopamine. Human and rat prolactinomas contain markedly increased amounts of tissue kallikrein; this is comparatively reduced if patients are pretreated with the dopamine agonist, bromocriptine, before surgery. Some GH-secreting adenomas are mixed and also contain prolactin-secreting cells. We therefore investigated 27 GH-immunostaining human pituitary adenomas for the presence of immunoreactive tissue kallikrein. Sixteen of the adenomas had positive immunostaining for prolactin; eight of these patients had associated clinical hyperprolactinaemia before the tumour was removed. Tissue kallikrein immunoreactivity was found in ten adenomas, all of which also had prolactin immunopositivity. There was a close relationship between the percentage of cells staining for prolactin and tissue kallikrein but not for GH. A further eight adenomas had patchy positivity, i.e. less than 1% of cells immunostained for tissue kallikrein and six of these also had some prolactin-staining cells. Nine out of eleven purely GH-staining adenomas had no tissue kallikrein immunopositivity, the remaining two showing patchy staining. A review of bromocriptine responsiveness, as assessed by mean GH hormone levels during oral glucose tolerance tests before and after therapy was commenced, indicated that patients with adenomas which stained for prolactin and tissue kallikrein were more likely to respond to bromocriptine than those which failed to do so.     

Reduced expression levels of the cell-cycle inhibitor p27Kip1 in human pituitary adenomas

The molecular mechanisms leading to increased cellular proliferation rates and, thus, tumor formation in the anterior pituitary gland are poorly understood. The cyclin-dependent kinase inhibitor p27Kip1 is a key molecule regulating the G1 phase of the cell cycle in many cell types. Furthermore, it was shown that p27 knock-out mice develop pro-opiomelanocortin-positive pituitary tumors. In an effort to clarify the role of p27 in the normal and tumorous human pituitary, we studied the expression of p27 by immunohistochemistry, using a highly specific mouse monoclonal anti-human p27 antibody. Normal pituitaries and 54 pituitary adenomas (twelve somatotrope adenomas, nine prolactinomas, twelve corticotrope adenomas, three TSH-producing tumors, six gonadotrope adenomas, six null cell adenomas, and six oncocytomas) were analyzed. p27 expression was determined semiquantitatively with regard to both the percentage of positive cells and the intensity of the staining. Normal human pituitaries showed strong expression of p27 in most nuclei. In contrast, the levels of p27 were reduced in the majority of the tumors analyzed. Twenty-two tumors (six somatotrope adenomas, five prolactinomas, four corticotrope adenomas, two TSH-producing tumors, two gonadotrope adenomas, and three null cell adenomas) were completely p27-negative. In 18 tumors, p27 expression was found in < or = 10% of the cells. In the other ten tumors, 11-80% of the cells were p27-positive. In summary, we were able to demonstrate reduced expression levels of the cell-cycle inhibitor p27 in tumors derived from all pituitary cell types. Our data indicate that p27 may be an important regulator of cellular proliferation in the anterior pituitary, the underexpression of which could play a role in pituitary tumorigenesis.     

Ambulatory diagnosis and outpatient management of patients with hypophyseal adenomas

In 88 patients with adenomas of the pituitary gland, among them 24 hormone-inactive tumours, 27 somatotropic adenomas and 37 prolactinomas, anamnestic data, clinical, endocrinologic and localisation-diagnostic findings as well as therapeutic measures were evaluated. Main symptoms were headache and visual disturbances. 78 of the 88 patients with adenomas of the pituitary gland were able to work at the time, when the diagnosis was made. In about 32% of the patients partial defects of the visual field were present and in 35% in the cranial computed tomogram a suprasellar and parasellar, respectively, expansion of the tumour and thus an advanced stage of the disease was established. The number of the residual findings and recidivations, respectively was great in all the three forms of the adenomas of the pituitary gland. In the prolactinomas and the somatotropic adenomas of the pituitary gland a medicamentous secondary therapy with dopamine agonists is possible. The therapy with bromocriptine reveals good results particularly in prolactinomas.     

Malignant prolactinoma: case report and review of the literature

Pituitary carcinomas are extremely rare. In general, the initial clinical, biochemical, and histological characteristics are of minimal utility in distinguishing benign adenomas from pituitary carcinomas. We describe a 63-year-old woman with a macroprolactinoma, who presented with diplopia and blurred vision. This unusual initial presentation and the subsequent aggressive clinical course, with diffuse local and distant intramedullary metastases, prompted us in retrospect to make a detailed analysis of the therapeutic interventions and histology. In addition, we reviewed all available literature on published cases of malignant prolactinoma and detailed their epidemiological, clinical, and histopathological characteristics. In brief, it is postulated that pituitary carcinomas arise from the transformation of initially large, but benign, adenomas. Unusual and/or atypical clinical manifestations appear to occur more frequently. In vivo, the development of dopamine agonist resistance in invasive macroprolactinoma is indicative of malignancy and should prompt the clinician to perform a biopsy of the tumor. For pituitary tumors that exhibit high mitotic activity, increased Ki-67 and/or p53 immunoreactivity, it may be useful to denote these tumors as 'atypical' prolactinomas to raise the possibility of future malignant development.     

Ras mutations in human pituitary tumors.

The cellular basis for pituitary neoplasia is poorly understood. Mutations that activate the ras protooncogenes have been identified in a number of different types of human cancers and potentially represent one of the genetic alterations that occur in pituitary tumors. In this study we examined 19 pituitary tumors for the occurrence of ras mutations. The tumor types included 11 nonfunctioning adenomas, 6 somatotroph adenomas, and 2 prolactinomas. Each of the three ras genes (K-ras, N-ras, and H-ras) was amplified from pituitary tumor DNA using the polymerase chain reaction. Oligonucleotide-specific hybridization was used to screen for mutations that inhibit GTPase activity and cause activation of the ras oncogene. No ras mutations were observed in 18 of the pituitary adenomas. However, a mutation was identified in codon 12 of the H-ras gene (Gly to Val) in a recurrent prolactinoma that was highly invasive and ultimately proved to be fatal. We conclude that ras mutations are uncommon in pituitary adenomas, but may provide a marker for highly invasive tumors.