Benign Pituitary Tumors Research Articles

Epidemiology and aetiologies of hypopituitarism

Anterior Pituitary Hormone Deficiencies may be due to any lesion in this anatomical region, most commonly benign tumors like pituitary adenomas or craniopharyngiomas, and to surgical or radiation-based treatments of these tumors. Less frequently, cranial traumas, inflammatory or autoimmune processes like lymphocytic hypophysitis or genetic defects may cause pituitary deficits. The resulting pituitary hormone deficiencies may lead to severe clinical consequences with significant morbidity and often increased mortality despite recent therapeutic improvements. The large observational studies launched for the follow-up of patients treated by growth hormone have provided valuable epidemiological data. In recent years, new aetiologies of acquired hypopituitarism have been reported such as hypophysitis following targeted anticancer immune therapies. Hypopituitarism however remains predominantly a consequence of benign pituitary tumors and of their treatments.

A case of Rathke's cleft cyst presenting with amenorrhea

A 28-year-old female presented with Rathke’s cleft cysts (RCC) manifesting as primary amenorrhea and no development of secondary sexual characteristics. She had no symptoms of headache, visual disturbance, anosmia or galactorrhea.. The endocrinologic study demonstrated partial hypopituitarism. Magnetic resonance imaging revealed about 1.5 cm sized sellar and suprasellar cystic tumor, extending into the pituitary stalk. Its tentative diagnosis was benign pituitary cystic tumor, such as RCC. She underwent surgery by a transsphenoidal approach. Histological examination revealed a ciliated columnar epithelium those consistent with RCC. RCC is rarely symptomatic, but mechanical compression by the cyst or infl ammation itself causes headache, visual fi eld defects, or symptoms of pituitary dysfunction. The present case shows that RCC may manifest as hypogonadotropic hypogonadism.

Anacardic acid induces caspase-independent apoptosis and radiosensitizes pituitary adenoma cells

Pituitary adenomas, which are common intracranial tumors, are associated with significant patient morbidity due to hormone secretion or mass effect or as a complication of therapy. Epigenetic regulation has emerged as an important component of malignant tumor pathogenesis, although the contribution in the progression of benign pituitary tumors remains largely unexplored. The present study evaluates the effect of anacardic acid (6-pentadecyl salicylic acid), a natural histone acetyltransferase inhibitor, on pituitary adenoma cells. The concentration- and time-dependent effects of anacardic acid on the viability of GH3 and MMQ pituitary adenoma cells were determined by 3-(4,5-dimethylthiazoyl-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle phase distribution, protein expression, and percentage of apoptotic cells were assessed by flow cytometry and Western blotting. Colony forming assays were used to study the radiosensitizing effect of anacardic acid. The present study identifies a novel antiproliferative and cytotoxic effect of anacardic acid on pituitary adenoma cells. These effects were associated with an increase in poly([adenosine diphosphate]-ribose) polymerase cleavage, sub-G1 arrest, and annexin V staining, consistent with apoptotic cell death; however, the pancaspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone failed to reverse anacardic acid-induced cell death, suggesting a possible nonclassical apoptotic mechanism. Anacardic acid also reduced the expression of survivin and X-linked inhibitor of apoptosis protein, antiapoptotic proteins associated with cellular survival and radioresistance, and radiosensitized pituitary adenoma cells. These findings warrant further exploration of anacardic acid as a single agent or as an adjunct to radiation therapy for the treatment of pituitary tumors.

Clinical effectiveness and cost-effectiveness of pegvisomant for the treatment of acromegaly: a systematic review and economic evaluation

BackgroundAcromegaly, an orphan disease usually caused by a benign pituitary tumour, is characterised by hyper-secretion of growth hormone (GH) and insulin-like growth factor I (IGF-1). It is associated with reduced life expectancy, cardiovascular problems, a variety of insidiously progressing detrimental symptoms and metabolic malfunction. Treatments include surgery, radiotherapy and pharmacotherapy. Pegvisomant (PEG) is a genetically engineered GH analogue licensed as a third or fourth line option when other treatments have failed to normalise IGF-1 levels.MethodsEvidence about effectiveness and cost-effectiveness of PEG was systematically reviewed. Data were extracted from published studies and used for a narrative synthesis of evidence. A decision analytical economic model was identified and modified to assess the cost-effectiveness of PEG.ResultsOne RCT and 17 non-randomised studies were reviewed for effectiveness. PEG substantially reduced and rapidly normalised IGF-1 levels in the majority of patients, approximately doubled GH levels, and improved some of the signs and symptoms of the disease. Tumour size was unaffected at least in the short term. PEG had a generally safe adverse event profile but a few patients were withdrawn from treatment because of raised liver enzymes. An economic model was identified and adapted to estimate the lower limit for the cost-effectiveness of PEG treatment versus standard care. Over a 20 year time horizon the incremental cost-effectiveness ratio was £81,000/QALY and £212,000/LYG. To reduce this to £30K/QALY would require a reduction in drug cost by about one third.ConclusionPEG is highly effective for improving patients' IGF-1 level. Signs and symptoms of disease improve but evidence is lacking about long term effects on improved signs and symptoms of disease, quality of life, patient compliance and safety. Economic evaluation indicated that if current standards (UK) for determining cost-effectiveness of therapies were to be applied to PEG it would be considered not to represent good value for money.

Emerging drugs for acromegaly

Background: Acromegaly is due to growth hormone (GH) hypersecretion by a benign pituitary tumor (adenoma). Treatments include surgical removal of the adenoma (often incomplete when the tumor is large and/or invasive), radiotherapy of the pituitary region (sometimes effective only after > 10 years, and potentially causing cerebrovascular disease), and medical therapy. Methods: The scope of this article is to review the efficacy and safety of currently marketed drugs and to discuss the interest of new compounds. For this purpose, critical analysis of original articles and reviews was made and manufacturers were asked to provide all data that have been presented in congress and are not yet published. Results/conclusion: Somatostatin analogs (first octreotide and then lanreotide) have been used for 20 years to treat patients in whom surgery and/or radiotherapy has failed, and also as first-line therapy when other modalities are contraindicated or are unlikely to control GH and insulin-like growth factor-I (IGF-I) hypersecretion. Long-lasting formulations, requiring only one monthly injection, have greatly improved the convenience of these treatments. GH/IGF-I hypersecretion is controlled by these drugs in about 50% of patients, but the remaining patients require another treatment. Pegvisomant, a drug belonging to a totally different therapeutic class (GH-receptor antagonists) with a different mode of action, is effective in most of these patients. According to current research goals, new developmental drugs include new somatostatin analogs (SAs) with different somatostatin receptor selectivity, and chimeric molecules that are able to bind to both somatostatin and dopamine receptors.

Senescence Mediates Pituitary Hypoplasia and Restrains Pituitary Tumor Growth

Understanding factors subserving pituitary cell proliferation enables understanding mechanisms underlying uniquely benign pituitary tumors. Pituitary tumor-transforming gene (Pttg) deletion results in pituitary hypoplasia, low pituitary cell proliferation rates, and rescue of pituitary tumor development in Rb(+/-) mice. Pttg(-/-) pituitary glands exhibit ARF/p53/p21-dependent senescence pathway activation evidenced by up-regulated p19, cyclin D1, and Bcl-2 protein levels and p53 stabilization. High pituitary p21 levels in the absence of PTTG were associated with suppressed cyclin-dependent kinase 2 activity, Rb phosphorylation, and cyclin A expression, all required for cell cycle progression. Although senescence-associated beta-galactosidase was enhanced in Pttg-deficient pituitary glands, telomere lengths were increased. DNA damage signaling pathways were activated and aneuploidy was evident in the Pttg-deficient pituitary, triggering senescence-associated genes. To confirm the p21 dependency of decreased proliferation and senescence in the Pttg-null pituitary, mouse embryonic fibroblast (MEF) colony formation was tested in wild-type, Pttg(-/-), Rb(+/-), Rb(+/-)Pttg(-/-), and Rb(+/-)Pttg(-/-)p21(-/-) cells. Rb(+/-)Pttg(-/-) MEFs, unlike Rb(+/-) cells, failed to produce colonies and exhibited high levels of senescence. p21 deletion from Rb(+/-)Pttg(-/-) MEFs enhanced anchorage-independent cell growth, accompanied by a marked decrease in senescence. As cell proliferation assessed by bromodeoxyuridine incorporation was higher in Rb(+/-)Pttg(-/-)p21(-/-) relative to Rb(+/-)Pttg(-/-) pituitary glands, p21-dependent senescence provoked by Pttg deletion may underlie pituitary hypoplasia and decreased tumor development in Rb(+/-)Pttg(-/-) mice.

Oncogenesis and mutagenesis of pituitary tumors

Although pituitary tumors may be present in up to 10% of the population, the pathophysiology of these lesions is not well characterized. Pituitary tumors are composed of monoclonal cell populations with disrupted control of replication pathways. The oncogenes and tumor suppressor genes that are common in other malignancies (i.e. jun, fos, myc, and p53) are rarely involved in the development of these tumors. However, oncogenes, such as gsp, can be present in up to 40% of hormonally active adenomas. The process of pituitary oncogenesis further appears to involve oncogenes such as cyclin E, cyclin D1, and the pituitary tumor transforming gene (PTTG). Finally, the cAMP signaling cascade plays a significant role in generation of both benign and malignant pituitary tumors. In this review, the biology of pituitary adenomas is explored with a special emphasis on potential targets for the development of targeted therapeutics.

Recent developments in the therapy of acromegaly

Acromegaly, a condition due to growth hormone hypersecretion usually from a benign pituitary tumour, is associated with significant morbidity and mortality. Disease control leads to normalisation of life expectancy with a reduction in signs and symptoms. Treatment modalities include surgery, radiotherapy and medical management. Surgery is the primary treatment in most of the patients, with success rates of 61 – 91% reported for those with microadenomas who are operated on by a specialist pituitary surgeon; however, most patients have macroadenomas and, although benefiting from surgery, are not cured and require additional medical therapy. This review will focus on emerging concepts in the medical treatment of acromegaly.

Cell cycle dysregulation in pituitary oncogenesis.

The cell cycle is the process by which cells grow, replicate their genome and divide. The cell cycle control system is a cyclically-operating biochemical device constructed from a set of interacting proteins that induce and coordinate proper progression through the cycle, and includes cyclins, cyclin-dependent kinases (CDK) and their inhibitors (CDKI). There are mainly two families of CDKI, the INK family (INK4a/p16; INK4b/p15; INK4c/p18 and INK4d/p19) and the WAF/KIP family (WAF1/p21; KIP1/p27; KIP2/p57). Progression through the cell cycle is mainly dependent on fluctuations in the concentration of cyclins and CDKI achieved through the programmed degradation of these proteins by proteolysis within the ubiquitin-proteasome system. There is also a transcriptional regulation of cyclin expression, probably dependent on CDK phosphorylation. The p53 family--p53, p63 and p73--function as transcription factors that play a major role in regulating the response of mammalian cells to stressors and damage, in part through the transcriptional activation of genes involved in cell cycle control (e.g. p21), DNA repair, senescence, angiogenesis and apoptosis. Essential for the maintenance of euploidy during mitosis is human securin, identical to the product of the pituitary tumour-transforming gene (PTTG). Loss of regulation at the G1/S transition appears to be a common event among virtually all types of human tumours. Aberrations of one or more components of the pRb/p16/cyclin D1/CDK4 pathway seem to be a frequent event (80%) in pituitary tumours. The role of p27 is rather that of a haploinsufficient gene. p27-/- mice show an increased growth rate, due to increased cellularity, testicular and ovarian cell hyperplasia and infertility, and hyperplasia of the pituitary intermediate lobe with nearly 100% mortality caused by such a benign pituitary tumour. Although the p27 gene was not found to be mutated in human pituitary tumours and its mRNA expression was similar in tumour samples in comparison with normal pituitaries, the load of p27 protein expression in corticotroph adenomas and pituitary carcinomas was shown to be much lower than those in normal pituitary tissue or other types of pituitary adenoma, suggesting that post-translational processing of p27 accelerates its removal from the nucleus. In respect to p27 degradation and its cellular compartmentalization, several pathways have been explored. Malignant tumours are associated with increased nuclear immunostaining for Jun-activation binding protein-1 (Jab1) which is responsible for phosphorylated p27 export from the nucleus. Corticotrophinomas are characterized by massively increased phosphorylation of p27 on Thr187, but are not associated with changes in Jab1. Macrophage inhibitory factor (MIF), which binds and inactivates Jab1, was noted to be over-expressed in tumours with abundant Jab1, suggesting that it may be part of a compensatory mechanism to moderate Jab1 activity. Proteasomal degradation of p27 requires its ubiquitylation by the SCF ubiquitin ligase, with specific addressing by the F-box protein Skp2 and its co-factor Cks1. Pituitary tumours with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 immunostaining, suggesting that increased Skp2 could play at least a part in this process. No difference was observed in Cks1 mRNA levels between normal pituitaries and pituitary adenomas. The present data suggest that inhibition of growth and tumour development is sensitive not only to the absolute levels of p27 protein, but also to its cellular compartmentalization. Very recent findings from our group have established up-regulation of the serine-threonine kinase Akt in pituitary tumours compared to normal pituitary, which may cause phosphorylation of p27 on Thr157 and cytoplasmic retention of p27. PTTG protein is highly expressed in various human tumours, including pituitary tumours. While its mRNA levels are low in normal pituitary, increases in PTTG transcripts from more than 50% to more than 10-fold were recorded in the majority of a series of pituitary adenomas. Control of the cell cycle is a vital part of the cell's replication machinery. Disruption of this process is commonly seen in pituitary tumours and we are now beginning to identify regulatory elements which are likely to play a major role in pituitary oncogenesis.

Standard and molecular cytogenetics of endocrine tumors.

Standard cytogenetic data are reported for benign and malignant thyroid and pituitary tumors. These identified chromosomal rearrangements activating RET and PPAR gamma 1 in a subset of papillary (PTCs) and follicular thyroid carcinomas (FTCs) and amplification of PKC epsilon in FTCs. Increases in complex karyotypes accompany progression in thyroid lesions. For pituitary tumors, karyotypic abnormalities more often affect functioning than nonfunctioning tumors. Such differences extend into comparative genomic hybridization (CGH), with a similar distribution for chromosomal imbalances. CGH data are reported on all varieties of endocrine tumors, supporting some cytogenetic findings and adding new hotspots for genomic imbalances. Increases in genomic imbalance accompany clinical progression in malignant thyroid tumors, adult adrenocortical tumors, parathyroid tumors, and some pancreatic endocrine tumors (PETs), e.g., insulinomas. Pheochromocytoma and FTC show more losses than gains. Specific patterns of imbalances are emerging for gastrointestinal PETs regarding location and hormone status; for pheochromocytomas, medullary thyroid carcinomas, and parathyroid tumors regarding genetic syndrome association; and for pituitary tumors regarding hormone status.

Implications of DNA characterization of human acoustic neuromas.

Based on in vitro detection of cell-mediated immunity against human acoustic neuroma extract, a malignant potential of acoustic neuromas could be surmised, as malignant DNA patterns have been demonstrated in benign pituitary tumours. Flow-cytofluorometric characterization of the DNA content in 10 human acoustic neuromas, however, only revealed diploid cell lines and normal distributions of cells in different cell cycle phases. All acoustic neuromas were histopathology benign. The percentage of cells in S-phase (range: 1.8-8.3%, median: 3.6%) reflected a slow growth rate correlated neither to age, size of tumour, nor length of case history at time of surgery. These findings may in part be due to the analytical variation in the determinations of the S-phases. The investigation has not offered any explanation for the observed cell-mediated immunity against acoustic neuromas, and confirms that acoustic neuromas are benign tuours.

Aneuploid DNA pattern in human pituitary adenomas

The DNA contents of 29 histologically and ultrastructurally benign pituitary tumours were analyzed with flow-cytofluorometry.--Cytogenetic malignancy, i.e., aneuploidy, was found in 12 cases, independent of endocrinological type of tumour. In 17 cases a diploid DNA content occurred. In aneuploid tumours varying percentage of cells in S-phase was found indicating different growth patterns. Aneuploid DNA pattern was often found in young patients with a short case history. Our findings indicate that analysis of cellular DNA content may reflect the biological properties of pituitary tumours, independent of morphologic characteristics and type of hormone secretion.

Suicide, Cancer and Depression

SummaryA comparison has been made between persons aged 50 and over dying from suicide and a matched control group of persons dying from other violent causes with respect to the incidence of malignant neoplasms and benign intracranial tumours found at autopsy. Significantly more of the suicide cases were found to have cancer, meningiomas and benign pituitary tumours. The implications of this finding and the relationship between depression and neoplasia are discussed.

Tumours and hormonal changes produced in rats by subcutaneous injections of linoleic acid hydroperoxide

Linoleate hydroperoxide was given by repeated sc injection to two groups of rats. Those in the first group received a total dose of 200 mg and those in the second group a total dose of 353 mg. No tumours occured at the site of injection in the treated rats, but the incidence of malignant mammary tumours and of lymphosarcomas was increased among rats in the first group and that of benign mammary tumours and benign pituitary tumours was increased in the second group. These tumours occured late in the lifespan of the animals.The incidence of total mammary tumours and of total pituitary tumours increased as the dose of linoleate hydroperoxide was raised, but this increase was due to a greater number of benign rather than of malignant tumours. Enlargement of the pituitary gland, with increases in the proportion of eosinophilic cells in the pars anterior, in body-weight gain and body length, and in the proportion of rats with follicular cysts in their ovaries, also followed the administration of linoleate hydroperoxide. It is suggested that the pituitary and mammary tumours arose as a consequence of an induced hypothalamic disturbance, leading to mammosomatotrophic effects.

Osteogenic Sarcoma of the Skull Following Roentgen-Ray Therapy for Benign Pituitary Tumor

Osteogenic sarcoma of the skull is rare whether of spontaneous origin or following irradiation. In fact, it is almost unknown after irradiation of the skull or intracranial contents in any period of life. As a p r imary development, not associated with irradiation, it is also extremely rare, part icularly in the later decades of life and in individuals who do not have an associated Paget ' s disease of the skull. The pat ient in the present report did not have Paget ' s disease of the skull, was 57 years of age a t the t ime of death, and, 6 years after the beginning of roentgen-ray therapy for a verified chromophobe pi tui tary adenoma, had an osteogenic sarcoma of the skull, which was verified a t necropsy. The case report is accompanied by photomicrographs of the pi tui tary tumor and also several of the osteogenic sarcoma of the skull. I t is believed worthy of report because of its rar i ty and interest, and also to stress the importance of irradiating intracranial structures or neoplasms therein only when such therapy seems definitely or strongly indicated, as there always would appear to be a slight chance, and potential danger at least, of osteogenic sarcoma developing in the overlying skull when such roentgen therapy is carried out.