Types Of Pituitary Tumors Research Articles

Leukemia inhibitory factor regulates prolactin secretion in prolactinoma and lactotroph cells.

Leukemia inhibitory factor (LIF) stimulates the hypothalamic-pituitary-adrenal axis, and transgenic mice overexpressing pituitary LIF develop Cushing-like syndrome accompanied by reduced prolactin (PRL) expression. Effects of LIF were, therefore, tested on PRL expression in human prolactinomas and normal and tumorous rat lactotrophs. Normal human pituitary tissue expressed LIF, as well as the LIF receptor (LIFR) signaling subunits, gp130 and LIFR. Although all of 19 prolactinomas tested expressed gp130 and LIFR subunit mRNA and immunoreactive protein, only 3 of 19 prolactinomas expressed LIF mRNA. All of four prolactinomas had no detectable LIF immunoreactivity, in contrast to all other pituitary tumor types that expressed LIF. LIF (5 nM) treatment reduced PRL secretion in primary human prolactinoma cultures by up to 42% (P < 0.0005), an effect that was surprisingly blocked by sulpiride, a D2-like dopamine receptor antagonist. LIF (5 nM) also suppressed PRL levels in primary rat pituitary cultures by 70% (P < 0.005), and in rat MMQ pituitary tumor cells, and this effect was also reversed by sulpiride (200 micro M). D2R agonist suppression of PRL was not additive with LIF. GH levels in these cells were unchanged by LIF, consistent with a selective effect on PRL. Transfection of human long-form D2R into an LIF-resistant MMQ cell clone restored LIF responsiveness. These results show that even though human prolactinomas express gp130 and LIFR, and respond to exogenous LIF, albeit less than normal lactotrophs, they are largely devoid of LIF. These observations indicate a role for LIF in loss of autocrine PRL suppression contributing to unrestrained prolactinomas PRL secretion. Moreover, PRL suppression by LIF may be mediated by gp130 and D2R interaction.

Medical management of pituitary adenomas: structural and ultrastructural changes.

The morphology of the various pituitary cell types is highly dynamic and allows recognition of many cellular functions. Most pituitary cells show morphologic changes that reflect stimulation or inhibition by hormones. Drugs have also been shown to alter the morphology of several pituitary tumor types, allowing a measure of therapeutic efficiency and a careful dissection of the mechanisms of action of various medical therapies. In some cases, these morphologic alterations can evoke diagnostic problems.

Medical therapy of gonadotropin-producing and nonfunctioning pituitary adenomas.

Clinically nonfunctioning pituitary adenomas are one of the most common types of pituitary tumors. Unless they present with symptoms related to local mass effect, most tumors are detected incidentally when imaging studies are performed for other reasons. Although clinically nonfunctioning, most of these tumors have evidence, in vitro, of gonadotropin hormone or glycoprotein subunit production. The gonadotropins or their monomer submits rarely cause clinically identifiable effects. When these tumors present as macroadenomas, often with associated mass effect and hypopituitarism, primary therapy is neurosurgery. The role for medical therapy will be reviewed here.

Myosin XVA Expression in the Pituitary and in Other Neuroendocrine Tissues and Tumors

The myosin superfamily of molecular motor proteins includes conventional myosins and several classes of unconventional myosins. Recent studies have characterized the human and mouse unconventional myosin XVA, which has a role in the formation and/or maintenance of the unique actin-rich structures of inner ear sensory hair cells. Myosin XVA is also highly expressed in human anterior pituitary cells. In this study we examined the distribution of myosin XVA protein and mRNA in normal and neoplastic human pituitaries and other neuroendocrine cells and tumors. Myosin XVA was expressed in all types of normal anterior pituitary cells and pituitary tumors and in other neuroendocrine cells and tumors including those of the adrenal medulla, parathyroid, and pancreatic islets. Most nonneuroendocrine tissues examined including liver cells were negative for myosin XVA protein and mRNA, although the distal and proximal tubules of normal kidneys showed moderate immunoreactivity for myosin XVA. Ultrastructural immunohistochemistry localized myosin XVA in association with secretory granules of human anterior pituitary cells and human pituitary tumors. These data suggest that in neuroendocrine cells myosin XVA may have a role in secretory granule movement and/or secretion.

Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction.

Pituitary adenomas account for approximately 10% of intracranial tumors, but little is known of the oncogenesis of these tumors. The identification of tumor-specific genes may further elucidate the pathways of tumor formation. We used complementary DNA microarrays to examine gene expression profiles in nonfunctioning, PRL, GH, and ACTH secreting adenomas, compared with normal pituitary. Microarray analysis showed that 128 of 7075 genes examined were differentially expressed. We then analyzed three genes with unique expression patterns and oncogenic importance by RT-real time quantitative PCR in 37 pituitaries. Folate receptor gene was significantly overexpressed in nonfunctioning adenomas but was significantly underexpressed in PRL and GH adenomas, compared with controls and to other tumors. The ornithine decarboxylase gene was significantly overexpressed in GH adenomas, compared with other tumor subtypes but was significantly underexpressed in ACTH adenomas. C-mer proto-oncogene tyrosine kinase gene was significantly overexpressed in ACTH adenomas but was significantly underexpressed in PRL adenomas. We have shown that at least three genes involved in carcinogenesis in other tissues are also aberrantly regulated in the major types of pituitary tumors. The evaluation of candidate genes that emerge from these experiments provides a rational approach to investigate those genes significant in tumorigenesis.

A Fatal Malignant Macroprolactinoma in a Female Patient: Case Report and Review of the Literature

Prolactinomas, the most common type of pituitary tumor, are prevalent in women. Macroprolactinomas, which often present with misleading and polymorphic symptoms, occur mainly in men. We review the literature on pituitary prolactin-carcinomas in women, and include a case-report of a 27 year old woman who underwent radical trans-sphenoidal excision of a large invasive macroprolactinoma. Postoperative evaluation of pituitary function showed normal PRL levels associated to hypopituitarism. Three years later, PRL levels increased associated with gross visual defects and a second operation with radiotherapy was done. Bromocriptine normalized PRL levels, and no recurrence was seen on CT/MRI for seven years. When she was 37 years old, the patient became resistant to dopamine-agonists, and the adenoma recurred with invasion of the cavernous sinus and a left frontal mass. Surgical removal of the frontal PRL-secreting metastasis reduced PRL levels to normal associated with quinagolide treatment. Two years later, a progressive increase in PRL levels heralded further expansion of the pituitary mass. The patient underwent a surgical debulking procedure followed by gamma-knife radiosurgery. Two months later, sudden rhinorrhea and visual loss occurred followed by coma. New growth of the pituitary neoplasm was evident. Three months later she died of thromboembolic events. Various causes of resistance to dopamine agonists are known. We suggest that the sudden loss of sensitivity to chronic dopamine-agonist treatment is a sign of the malignant transformation of a macroprolactinoma.

Role of matrix metalloproteinase 9 in pituitary tumor behavior.

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are able to degrade the extracellular matrix and allow angiogenesis and tumor invasion. The vast majority of pituitary tumors are benign and do not metastasize to distant sites, although they may invade locally. The aim of this study was to determine whether expression of the collagenase MMP-9 may play a role in allowing angiogenesis and invasion by different pituitary tumor types. Tumor expression of MMP-9 was investigated using a monoclonal antibody on a series of well-characterized paraffin-embedded sections of pituitary tumors. Invasive macroprolactinomas (n = 11) were significantly more likely to express MMP-9 than noninvasive macroprolactinomas (n = 8) (P = 0.003). Invasive macroprolactinomas showed higher-density MMP-9 staining than noninvasive tumors (P < 0.05). MMP-9 expression did not differ between noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP-9 expression was related to aggressive tumor behavior. It was higher in invasive macroprolactinomas (P = 0.003) when compared with noninvasive macroprolactinomas or the normal anterior pituitary gland. In addition, although there was no difference in whether MMP-9 was present or not when nonfunctioning adenomas that recurred were compared with those that did not, samples of recurrent tumor at the second presentation were more likely to express MMP-9 (P = 0.01). Pituitary carcinomas were significantly more likely to be MMP-9 positive compared with normal anterior pituitary gland (P = 0.05), but there was no difference from invasive adenomas. Angiogenesis assessed by vascular density was related to MMP-9 expression (P < 0.05). In summary, we have shown the presence of MMP-9 expression in some invasive and recurrent pituitary adenomas, and in the majority of pituitary carcinoma. The mechanisms whereby MMP-9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remains to be elucidated. However, these observations suggest that a future potential therapeutic strategy for some pituitary tumors may be administration of a synthetic MMP-9 inhibitor.

The modern concept of the pathogenesis of pituitary tumors

Pituitary tumors are a fairly common and often very severe form of neuroendocrine pathology. They make up about 10% of all intracranial tumors detected in clinical practice. They are found at autopsy in 10-20% of cases. Therefore, elucidation of the fundamental mechanisms of the pathogenesis of various types of pituitary tumors, the characteristics of their cellular biology and the development on this basis of effective approaches to their diagnosis, monitoring and treatment are one of the priorities in endocrinology.

Clinical review 110: Diagnosis and treatment of pituitary tumors.

We are fortunate to have multiple safe and effective therapeutic options available for the treatment of pituitary tumors. These options include medical therapy, transsphenoidal surgery and radiotherapy. The treatment of choice depends on the type of pituitary tumor. The majority, of PRL-secreting tumors can be effectively treated with dopamine agonists. Transsphenoidal surgery is also an effective option for patients who are resistant to or intolerant of these drugs. Transsphenoidal surgery remains the treatment of choice for the majority of patients with GH, ACTH, and TSH-secreting tumors and for large nonsecreting tumors. Medical therapy with somatostatin analogs and/or dopamine agonists should be undertaken in patients with persistent elevations of GH and IGF-I levels; radiotherapy should be considered for patients with significant residual tumor in whom medical therapy is unsuccessful. Radiotherapy is also indicated for ACTH-secreting tumors not cured by surgery; medical therapy with ketoconazole and other adrenal enzyme inhibitors can be used as adjunctive therapy to lower cortisol levels. Postoperative radiotherapy for nonsecreting tumors is also an option if there is considerable residual tumor or evidence of tumor growth on follow-up MRI. Evaluation and treatment of hypopituitarism is an important part of the management of all patients with pituitary tumors. Patients also should be monitored for the development of new deficits, particularly after radiotherapy. The development of new medical therapies, such as GH antagonists, as well as refinements of surgical, radiotherapy, and imaging techniques should continue to improve our management of pituitary tumors.

Recent developments in gene therapy: applications for the treatment of pituitary tumours.

Pituitary tumours are normally benign, highly differentiated and slow growing neoplasms. Nevertheless, as many as half of them will show evidence of local invasion into the surrounding structures. Despite their benign growth characteristics and slow clinical progression, pituitary tumours commonly cause serious morbidity. The mass effects of large tumours, including headache and visual failure from optic chiasm compression, may cause lifelong disability. Hormone hypersecretion or deficiency causes major clinical problems that often require expensive and long-term medical therapy. Major advances have been made in the therapy of pituitary tumours over the past 20-30 years, but despite this, their treatment often remains an unsatisfactory compromise in practice. There is, therefore, a place for improvements in therapy, and to this end, gene therapy may come to hold a significant place in the future treatment of human pituitary tumours. With the development of new gene delivery vehicles, this concept can now be explored with a view to treating specific types of pituitary tumours.

MEDICAL THERAPY FOR GONADOTROPH AND THYROTROPH TUMORS

Gonadotroph adenomas, a common type of pituitary tumor, are not associated with syndromes of hormonal hypersecretion and thus present as pituitary macroadenomas with mass effects, or as incidentally discovered pituitary masses. When indicated, primary therapy is neurosurgery, but there may be a limited role for medical therapy in patients with residual disease. Thyrotroph adenomas are rare neoplasms that present with hyperthyroidism and local mass effects. Medical therapy may be effective in controlling tumor growth and in achieving euthyroidism, when surgery or radiation, or both, do not control the tumor.

Twenty‐four‐month oral carcinogenicity study of ebrotidine in rats

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species. Teratogenesis Carcinog. Mutagen. 18:263–277, 1998. © 1998 Wiley-Liss, Inc.

Twenty-four-month oral carcinogenicity study of ebrotidine in rats

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species.

New Directions in the Treatment of Hyperprolactinemia

The introduction of the prototype dopamine agonist drug, bromocriptine, to treat hyperprolactinemia resulted in a different therapeutic approach to this disorder. The subsequent introduction of other dopamine agonist drugs has provided alternatives for patients unable to tolerate bromocriptine. During the course of medical therapy, specific issues may arise including drug dose, the need for gonadal steroid replacement, pregnancy, and the role of surgery and/or radiation therapy. Although the majority of patients have an excellent response to medical therapy, some have only a partial response and require additional treatments; in selected patients surgery and/or pituitary radiation may be required. As with all types of pituitary tumors, multimodality therapy may be necessary to treat this disorder effectively.

Transsphenoidal selective adenomectomy is the treatment of choice in patients with Cushing's disease. Considerations concerning preoperative medical treatment and the long-term follow-up.

Cushing’s observation, that most patients with the disease named after him harbor small basophilic pituitary adenomas, has been confirmed by the success of transsphenoidal surgery in the majority of patients. Monoclonality of such tumors supports the concept of a primary pituitary origin of the disease, which indeed then should be cured after their selective removal. It has become evident that ACTH secretion by the normal corticotrophs surrounding these microadenomas is suppressed in most cases and that this suppression persists for many months after the selective removal of ACTH-secreting microadenomas before a gradual normalization occurs. This initial period after surgery is accompanied by clinically evident hypocortisolism to a degree that is seldom achieved more thoroughly after surgery on other types of pituitary tumors. A gradual return to normal of the diurnal rhythm of ACTH and cortisol, of the response to an insulin-induced hypoglycemia, of daily adrenal cortisol production, as well as a return to normal sensitivity of the restored hypothalamopituitary adrenal axis to low dose dexamethasone supports the concept of a real cure in these patients. Most series describing the results of selective removal of ACTH-secreting tumors by transsphenoidal surgery report an overall percentage of immediate remission of about 75%. Amongst the therapeutic failures a small group of patients can be identified in whom the diagnosis of pituitary-dependent Cushing’s disease was wrong after all. This group includes individuals with occult tumors secreting ACTH and/or CRH ectopically, patients with primary glucocorticoid receptor resistance, and patients with secondary autonomous adrenocortical lesions. The majority of therapeutic failures, however, are neurosurgical. Several categories can be recognized: patients in whom extensive pituitary exploration did not reveal an adenoma, patients in whom the tumor could not be completely removed (in many of these cases invasive tumor penetration of bone or surrounding tissue made selective removal technically impossible), and finally an undetermined number of patients with a seemingly discrete lesion that was, in retrospect at microscopical examination, surrounded by hyperplastic corticotrophs. There is no ideal therapy for patients with Cushing’s dis

Marginally elevated prolactin levels require magnetic resonance imaging and evaluation for acromegaly

Marginal elevations in serum PRL concentration represent a particularly difficult diagnostic dilemma. In most cases, mild hyperprolactinemia is not associated with organic disease. Patients with menstrual disturbances, galactorrhea, and confirmed elevations in serum PRL should have a screening TSH to rule out primary hypothyroidism (5). In cases where there is no clear etiology of hyperprolactinemia, an MRI should be performed. Magnetic resonance imaging with gadolinium is more sensitive and specific than CT scanning in detecting all types of pituitary tumors and is the study of choice (4). Further, a serum IGF-1 level (or OGTT) should be obtained when clinical symptoms and/or a pituitary mass suggest the possibility of acromegaly. An individual with abnormal GH screening tests but an unremarkable MRI would be subjected to an especially careful follow-up, including IGF-1 and PRL levels every 6 to 12 months. In this way, early tumor growth may be detected making a surgical cure more likely (Fig. 1). Although we have stressed the importance of GH-producing tumors as a cause of hyperprolactinemia, other tumor types of the pituitary may do so as well. Most of these will be detected by MRI.

The retinoblastoma gene in human pituitary tumors.

Functional inactivation of the retinoblastoma (RB) tumor suppressor gene is important in the pathogenesis of many human tumors. Recently, the frequent occurrence of pituitary tumors was reported in mice genetically engineered to have one defective RB allele, a genetic background analogous to that of patients with familial retinoblastoma. The molecular pathogenesis of human pituitary tumors is largely unknown, and the potential role of RB gene inactivation in these neoplasms has not been examined. Consequently, we studied 20 human pituitary tumors (12 clinically nonfunctioning tumors, 4 somatotroph adenomas, 2 prolactinomas, and 2 corticotroph adenomas) for tumor-specific allelic loss of the RB gene using a highly informative polymorphic locus within the gene. Control leukocyte DNA samples from 18 of these 20 patients were heterozygous at this locus, permitting genetic evaluation of their paired tumor specimens. In contrast to the pituitary tumors in the mouse model, none of these 18 human tumors exhibited RB allelic loss. These findings indicate that RB gene inactivation probably does not play an important role in the pathogenesis of common types of human pituitary tumors.

Incidental Visualization of Pituitary Tumors During Brain SPECT Imaging with Tc-99m HMPAO

In three female patients, 70, 72, and 81 years old, with proven large pituitary tumors, Tc-99m hexamethylpropylene amineoxime (HMPAO) brain SPECT was performed because of clinical signs of disturbed brain perfusion. In all three cases, an increased uptake was found in the pituitary tumor; to our knowledge, this has not been reported in the literature. We did not see an increased uptake in other patients with various types of pituitary tumors.

Use of DES-treated rats as an animal model for assessment of pituitary adenoma imaging agents

Prolactin (PRL) secreting pituitary adenomas are the most common type of pituitary tumors. An imaging agent which specifically localized in prolactinomas would be of considerable clinical value for both initial detection and also for monitoring the effects of dopamine agonist therapy. Tritiated spiroperidol ( 3HSp) was selected for initial evaluation as a possible imaging agent based on: (1) demonstrated localization in the pituitary and (2) demonstrated binding to human PRL-secreting tumor tissue. DES was implanted in Fischer F344 rats and induced prolactinoma formation was evidenced by increased pituitary weight, elevated serum PRL levels and by an increase in the proportion of PRL-secreting cells in the pituitary. 3HSp concentrations in pituitary and other tissues of DES-treated rats were assessed in female rats and correlation studies showed that a 5-fold increase in serum PRL was associated with a 6-fold increase in both pituitary weight and % dose/organ accumulation of 3HSp. The number of pituitary D 2 receptors per mg of protein in tissue homogenates was similar in both normal and DES-treated females. A blocking study with (+)-butaclamol demonstrated a D 2 receptor-mediated component to 3HSp localization. In summary, an animal model for prolactinoma was characterized. An assessment of 3HSp accumulation indicates that radiolabelled spiroperidol shows excellent potential for detecting PRL-secreting tumors of the pituitary.

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 Ca 2+-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.