Incidence Of Pituitary Tumors Research Articles

Clinically active pituitary tumors

The widespread use of diagnostic imaging has led to an increase in the incidence of pituitary tumors. The majority of incidentalomas are hormone-inactive (HI) pituitary microadenomas. The most common clinically relevant pituitary adenomas are prolactin-secreting, followed by HI, and far less common are growth hormone (GH)-, adrenocorticotropic hormone (ACTH)- and thyroid-stimulating hormone (TSH)-secreting adenomas. Pituitary adenomas are usually benign, although aggressive growth and invasion occurs in individual cases. Very rarely, they give rise to metastases and are then termed pituitary carcinomas. All pituitary tumors require endocrine testing for pituitary hormone excess. In addition to the medical history and clinical examination, laboratory diagnostics are very important. Symptoms such as irregular menstruation, loss of libido or galactorrhea often lead to the timely diagnosis of prolactinomas, and hyperprolactinemia can easily confirm the diagnosis (considering the differential diagnoses). Diagnosis is more difficult for all other hormone-secreting pituitary adenomas (acromegaly, Cushing's disease, TSHoma), as the symptoms are often non-specific (i.e., headaches, weight gain, fatigue, joint pain). Furthermore, comorbidities such as hypertension, diabetes, and depression are such widespread diseases that pituitary adenomas are rarely considered as the underlying cause. Timely diagnosis and appropriate treatment have asignificant impact on morbidity, mortality, and quality of life. Therefore, the role of primary care physicians is very important for achieving an early diagnosis. In addition, patients with pituitary adenomas should always be referred to endocrinologists to ensure optimal diagnosis as well as treatment.

Familial isolated pituitary adenoma is independent of Ahr genotype in a novel mouse model of disease

Human familial isolated pituitary adenoma (FIPA) has been linked to germline heterozygous mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP, also known as ARA9, XAP2, FKBP16, or FKBP37). To investigate the hypothesis that AIP is a pituitary adenoma tumor suppressor via its role in aryl hydrocarbon receptor (AHR) signaling, we have compared the pituitary phenotype of our global null Aip (AipΔC) mouse model with that of a conditional null Aip model (Aipfx/fx) carrying the same deletion, as well as pituitary phenotypes of Ahr global null and Arnt conditional null animals. We demonstrate that germline AipΔC heterozygosity results in a high incidence of pituitary tumors in both sexes, primarily somatotropinomas, at 16 months of age. Biallelic deletion of Aip in Pit-1 cells (Aipfx/fx:rGHRHRcre) increased pituitary tumor incidence and also accelerated tumor progression, supporting a loss-of-function/loss-of-heterozygosity model of tumorigenesis. Tumor development exhibited sexual dimorphism in wildtype and Aipfx/fx:rGHRHRcre animals. Despite the role of AHR as a tumor suppressor in other cancers, the observation that animals lacking AHR in all tissues, or ARNT in Pit-1 cells, do not develop somatotropinomas argues against the hypothesis that pituitary tumorigenesis in AIP-associated FIPA is related to decreased activities of either the Ahr or Arnt gene products.

Mini review of the pathogenesis, incidence, and treatment of Pituitary adenomas

In this review article, we are discussing the origin of pituitary tumors. We are showing the pathological transcription factors playing role in the differentiation of the pituitary cells. We are also describing the regulation of pituitary hormone secretion, describing the incidence of pituitary tumors, and at length describe the modern treatment of them with surgery, medications, or stereotactic radiosurgery (gamma knife) as well as a combination of different treatment modalities.

ACROMEGALY COMBINED WITH GIGANTISM ASSOCIATED WITH THE AIP-GENE MUTATION: A CLINICAL CASE

Pituitary gigantism is an extremely rare disorder: the incidence of pituitary tumors in children is approximately 0.1 in one million, and only about 1 to 10% of the pituitary tumors secrete the GH in childhood. Gigantism should be suspected if the patient's height is 3 standard deviations above the normal average height or 2 standard deviations above the corrected height of parents. When pituitary gigantism is suspected, the clinician should consider the presence of disorders, known to be associated with the GH-secreting pituitary tumors, including the McCune Albright syndrome (MAS), Carney complex (CNC), multiple endocrine neoplasia, types 1 and 4 (MEN 1, MEN 4), Familial isolated pituitary adenoma (FIPA), the paraganglioma, pheochromocytoma and pituitary adenoma association (PAA) due to succinate dehydrogenase defects, and X-linked acrogigantism (X-LAG). The molecular genetics of the AIP-associated FIPA, MAS, CNC, and MEN 1 has been extensively studied and reviewed, especially in children and young adults. The GH-secreting adenomas seem to be more invasive and aggressive in childhood than in adulthood. Data on a rare disease — gigantism combined with phenotypic signs of acromegaly in a young patient are presented. Clinical and laboratory parameters, data of histological and genetic analysis are described. Genetic analysis performed by AIP gene by Sequencing, proved a rare mutation in the locus of exons 1-6 of the AIP gene. The presented clinical case describes a rare fact of the AIP-gene mutation in the p.Cys238Tyr locus, which is associated with the occurrence of a giant pituitary adenoma in childhood. Aggressive growths of the pituitary tumor, its high proliferative and hormonal activity, clinical manifestations of gigantism in combination with severe phenotypic signs of acromegaly have also been noticed. Resistance to the therapy with somatostatin analogs has been revealed in this case. Considering the absence of genetic predisposition to a pituitary adenoma in the patient, this case can be regarded as a sporadic pituitary adenoma variant due to the abnormal AIP-gene expression and the disturbance of regulation during tumorigenesis.

Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase.

In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17β-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs. We found that, whereas 4-OH-E2 had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E2 has similar efficacy as E2 in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E2. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E2 (but not E2) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow Km value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E2 through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site.

Prevalence and Incidence of pituitary tumors: a nation-wide Population-based study using Korean National Health Insurance claims data

Prevalence and Incidence of pituitary tumors: a nation-wide Population-based study using Korean National Health Insurance claims data

Ethanol-Extracted Brazilian Propolis Exerts Protective Effects on Tumorigenesis in Wistar Hannover Rats.

The present study was conducted over a course of 104 weeks to estimate the carcinogenicity of ethanol-extracted Brazilian green propolis (EEP). Groups of 50 male and 50 female Wistar Hannover rats, 6-week-old at commencement were exposed to EEP at doses of 0, 0.5 or 2.5% in the diet. Survival rates of 0.5% and 2.5% EEP-treated male and female rats, respectively, were significantly higher than those of respective control groups. Overall histopathological evaluation of neoplasms in rat tissues after 2 years showed no significant increase of tumors or preneoplastic lesions in any organ of animals administered EEP. Significantly lower incidences of pituitary tumors in 0.5% EEP male and 2.5% EEP female groups, malignant lymphoma/leukemia in both 2.5% EEP-treated males and females and total thyroid tumors in 0.5% EEP male group were found. Administration of EEP caused significant decreases of lymphoid hyperplasia of the thymus and lymph nodes in 2.5% EEP-treated rats, tubular cell hyperplasia of kidneys in all EEP groups, and cortical hyperplasia of adrenals in EEP-treated females. In the blood, significant reduction of neutrophils in all EEP-treated males and band neutrophils in 2.5% EEP-treated females was found indicating lower levels of inflammation. Total cholesterol and triglicerides levels were significantly lower in the blood of 2.5% EEP-treated female rats. In conclusion, under the conditions of the 2-year feeding experiment, EEP was not carcinogenic, did not induce significant histopathological changes in any organ, and further exerted anti-inflammatory and antitumorigenic effects resulting in increase of survival of Wistar Hannover rats.

Historical distribution of central nervous system tumors in the Mexican National Institute of Neurology and Neurosurgery.

To determine the frequency of central nervous system (CNS) tumors in the first fifty years of the National Institute of Neurology and Neurosurgery of Mexico Manuel Velasco Suárez (Instituto Nacional de Neurología y Neurocirugía de México, INNN) from 1965 to 2014. A total of 16 116 institutional records of CNS tumors were analyzed. The frequency and distribution of CNS tumors were evaluated by tumor type, patient age and patient gender. The annual relationship between CNS tumors and surgical discharges (SD) over the last 20 years was estimated. The frequencies of most CNS tumors were consistent with those found worldwide, and the most common tumors were neuroepithelial tumors (33%), particularly astrocytic tumors (67%); meningeal tumors (26%); and pituitary tumors (20%). The incidence of pituitary tumors in these data was twice as high as that reported in other regions of the world, and the relationship between CNS tumors and SD was consistent over time (0.22-0.39). This study summarizes the largest sample of CNS tumor cases analyzed in Mexico and provides an important reference of the frequency of this tumor type in the country. This work will serve as a basis for conducting studies evaluating factors associated with the presence of CNS tumors and for identifying adequate public health interventions.

Descriptive epidemiology of pituitary tumors in the United States, 2004-2009.

Pituitary tumors are abnormal growths that develop in the pituitary gland. The Central Brain Tumor Registry of the United States (CBTRUS) contains the largest aggregation of population-based data on the incidence of primary CNS tumors in the US. These data were used to determine the incidence of tumors of the pituitary and associated trends between 2004 and 2009. Using incidence data from 49 population-based state cancer registries, 2004-2009, age-adjusted incidence rates per 100,000 population for pituitary tumors with ICD-O-3 (International Classification of Diseases for Oncology, Third Edition) histology codes 8040, 8140, 8146, 8246, 8260, 8270, 8271, 8272, 8280, 8281, 8290, 8300, 8310, 8323, 9492 (site C75.1 only), and 9582 were calculated overall and by patient sex, race, Hispanic ethnicity, and age at diagnosis. Corresponding annual percent change (APC) scores and 95% confidence intervals were also calculated using Joinpoint to characterize trends in incidence rates over time. Diagnostic confirmation by subregion of the US was also examined. The overall annual incidence rate increased from 2.52 (95% CI 2.46-2.58) in 2004 to 3.13 (95% CI 3.07-3.20) in 2009. Associated time trend yielded an APC of 4.25% (95% CI 2.91%-5.61%). When stratifying by patient sex, the annual incidence rate increased from 2.42 (95% CI 2.33-2.50) to 2.94 (95% CI 2.85-3.03) in men and 2.70 (95% CI 2.62-2.79) to 3.40 (95% CI 3.31-3.49) in women, with APCs of 4.35% (95% CI 3.21%-5.51%) and 4.34% (95% CI 2.23%-6.49%), respectively. When stratifying by race, the annual incidence rate increased from 2.31 (95% CI 2.25-2.37) to 2.81 (95% CI 2.74-2.88) in whites, 3.99 (95% CI 3.77-4.23) to 5.31 (95% CI 5.06-5.56) in blacks, 1.77 (95% CI 1.26-2.42) to 2.52 (95% CI 1.96-3.19) in American Indians or Alaska Natives, and 1.86 (95% CI 1.62-2.13) to 2.03 (95% CI 1.80-2.28) in Asians or Pacific Islanders, with APCs of 3.91% (95% CI 2.88%-4.95%), 5.25% (95% CI 3.19%-7.36%), 5.31% (95% CI -0.11% to 11.03%), and 2.40% (95% CI -3.20% to 8.31%), respectively. When stratifying by Hispanic ethnicity, the annual incidence rate increased from 2.46 (95% CI 2.40-2.52) to 3.03 (95% CI 2.97-3.10) in non-Hispanics and 3.12 (95% CI 2.91-3.34) to 4.01 (95% CI 3.80-4.24) in Hispanics, with APCs of 4.15% (95% CI 2.67%-5.65%) and 5.01% (95% CI 4.42%-5.60%), respectively. When stratifying by age at diagnosis, the incidence of pituitary tumor was highest for those 65-74 years old and lowest for those 15-24 years old, with corresponding overall age-adjusted incidence rates of 6.39 (95% CI 6.24-6.54) and 1.56 (95% CI 1.51-1.61), respectively. In this large patient cohort, the incidence of pituitary tumors reported between 2004 and 2009 was found to increase. Possible explanations for this increase include changes in documentation, changes in the diagnosis and registration of these tumors, improved diagnostics, improved data collection, increased awareness of pituitary diseases among physicians and the public, longer life expectancies, and/or an actual increase in the incidence of these tumors in the US population.

Late-life effects on rat reproductive system after developmental exposure to mixtures of endocrine disrupters

This study examined late-life effects of perinatal exposure of rats to a mixture of endocrine-disrupting contaminants. Four groups of 14 time-mated Wistar rats were exposed by gavage from gestation day 7 to pup day 22 to a mixture of 13 anti-androgenic and estrogenic chemicals including phthalates, pesticides, u.v.-filters, bisphenol A, parabens, and the drug paracetamol. The groups received vehicle (control), a mixture of all 13 chemicals at 150-times (TotalMix150) or 450-times (TotalMix450) high-end human exposure, or 450-times a mixture of nine predominantly anti-androgenic chemicals (AAMix450). Onset of puberty and estrous cyclicity at 9 and 12 months of age were assessed. Few female offspring showed significantly regular estrus cyclicity at 12 months of age in the TotalMix450 and AAMix450 groups compared with controls. In 19-month-old male offspring, epididymal sperm counts were lower than controls, and in ventral prostate an overrepresentation of findings related to hyperplasia was observed in exposed groups compared with controls, particularly in the group dosed with anti-androgens. A higher incidence of pituitary adenoma at 19 months of age was found in males and females in the AAMix450 group. Developmental exposure of rats to the highest dose of a human-relevant mixture of endocrine disrupters induced adverse effects late in life, manifested as earlier female reproductive senescence, reduced sperm counts, higher score for prostate atypical hyperplasia, and higher incidence of pituitary tumors. These delayed effects highlight the need for further studies on the role of endocrine disrupters in hormone-related disorders in aging humans.

Apoplexy in pituitary tumors, clinical and MRI analyses

AbstractPurpose The aim of the study is to evaluate the different types and incidence of pituitary tumors with apoplexy between 1988‐2009.Methods Retrospective data analysis from the notes of the neuro‐endocrine multidiciplinary workgroup and medical records of these patients treated by neurosurgeon or conservatively.Results complete notes were found from 5 years. Different ways of detection were found: the classic tumor pituitary apoplexy, accidental during MRI analyses and during surgery for an pituitary adenoma. Of the 82 macroadenomas, found in the notes over 5 years, in 17 cases an apoplexy was found, which is a higher incidency than described in the literature. From the in total 27 cases found during the 20 years period analysis, 15 cases had the classic pattern, with‐ at most‐ eyemovements disorders ; 10 cases had a subclinical pattern and were diagnosed by MRI, and or histopathological or biochemical; in 2 patients the mass was without tumor, and only hemorrhage.Conclusion Headache, eye motility disturbances and +/‐ chiasmal syndrome may pronounce in 20 % of the pituirary masses to an apoplexy. Because a pituirary mass frequently is managed with surgery, but conservative treatment is possible without complications, this differential diagnosis is important in neuro‐ophthalmological clinical practice. The different MRI patterns will demonstrated during the presentation.

Cooperation between Cyclin E and p27Kip1 in Pituitary Tumorigenesis

Cushing's disease is caused by glucocorticoid-resistant pituitary corticotroph adenomas. We have previously identified the loss of nuclear Brg1 as one mechanism that may lead to partial glucocorticoid resistance: this loss is observed in about 33% of human corticotroph adenomas. We now show that Brg1 loss of function correlates with cyclin E expression in corticotroph adenomas and with loss of the cell cycle inhibitor p27(Kip1) expression. Because Brg1 is thought to have tumor suppressor activity, the present study was undertaken to understand the putative contribution of cyclin E derepression produced by loss of Brg1 expression on adenoma development. Overexpression of cyclin E in pituitary proopiomelanocortin cells leads to abnormal reentry into cell cycle of differentiated proopiomelanocortin cells and to centrosome instability. These alterations are consistent with the intermediate lobe hyperplasia and anterior lobe adenomas that were observed in these pituitaries. When combined with the p27(Kip1) knockout, overexpression of cyclin E increased the incidence of pituitary tumors, their size, and their proliferation index. These results suggest that cyclin E up-regulation and p27(Kip1) loss-of-function act cooperatively on pituitary adenoma development.

Cigarette smoking and risk of acoustic neuromas and pituitary tumours in the Million Women Study

Background:The relationship between cigarette smoking and incidence of acoustic neuromas and pituitary tumours is uncertain.Methods:We examined the relation between smoking and risk of acoustic neuromas and pituitary tumours in a prospective study of 1.2 million middle-aged women in the United Kingdom.Results:Over 10.2 million person years of follow-up, 177 women were diagnosed with acoustic neuromas and 174 with pituitary tumours. Current smokers at recruitment were at significantly reduced risk of incident acoustic neuroma compared with never smokers (adjusted relative risk (RR)=0.41, 95% confidence interval (CI)=0.24–0.70, P=0.001). Past smokers did not have significantly different risk of acoustic neuroma than never smokers (RR=0.87, 95% CI=0.62–1.22, P=0.4). Smoking was not associated with incidence of pituitary tumours (RR in current vs never smokers=0.91, 95% CI=0.60–1.40, P=0.7).Conclusion:Women who smoke are at a significantly reduced risk of acoustic neuromas, but not of pituitary tumours, compared with never smokers. Acoustic neuromas are much rarer than the cancers that are increased among smokers.

Abstract 4191: Thymidylate synthase accelerates development of pituitary tumors in Men1 knockout mice

Abstract Thymidylate synthase (TS) is a key enzyme for DNA biosynthesis during cellular proliferation. Studies from our laboratory have demonstrated oncogenic activity of TS in mammalian cells (Cancer Cell, 5 p341, 2004) and in transgenic mice that overexpress human TS (hTS) (Oncogene v26 p4814, 2007). To investigate the in vivo role of TS in pituitary tumorigenesis, we crossed hTS transgenic mice with conditional Men1 knockout mice. We found that overexpression of hTS in fMen1−/− mice significantly decreased the age of onset and increased the incidence of pituitary tumors. fMen1−/−hTS mice developed adenoma and carcinoma as early as 6 and 7 month respectively, while the development of these tumor was not observed in fMen1−/− mice until after 8 month of age. By 8 months of age, 12.1% fMen1−/−hTS mice developed adenoma while no adenoma was observed in fMen1−/− mice. At 10 month of age, progression of pituitary adenoma to carcinoma occurred with higher incidence (51.6%) in fMen1−/−hTS as compared to fMen1−/− mice (18.2%) (p=0.013). Using immunohistochemistry and immunoblotting analysis we confirmed expression of ectopic hTS protein in pituitary tumors of fMen1−/−hTS mice. Our results demonstrated that TS enhances the development and progression of pituitary tumors and suggested that this transgenic model can be use to study the in vivo consequences of elevated hTS on DNA stability, to test how this relates to tumorigenesis, and to improve the use of hTS as a biomarker and therapeutic target. The impact of this work is that it would show that elevated hTS is playing an active role in promoting tumor cell proliferation and is not a simply a passive target for chemotherapy agents to induce cellular toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4191.

The Pathogenesis of Pituitary Tumors

Recently there has been significant progress in our understanding of pituitary development, physiology, and pathology. New information has helped to clarify the classification of pituitary tumors. Epidemiologic analyses have identified a much higher incidence of pituitary tumors than previously thought. We review the pathogenetic factors that have been implicated in pituitary tumorigenesis and the application of novel targeted therapies that underscore the increasingly important role of the pathologist in determining accurate diagnoses and facilitating appropriate treatment of patients with these disorders.

Aryl hydrocarbon receptor-interacting protein and pituitary adenomas: a population-based study on subjects exposed to dioxin after the Seveso, Italy, accident

The pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects. We investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin following an industrial accident in 1976. Through the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232 745). We identified 42 pituitary adenomas in the reference area, 1 prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9-45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5-7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3-1.8, P=0.48). The study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high-intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.

High prevalence rate of pituitary incidentaloma: Is it associated with the age-related decline of the sex hormones levels?

Incidental pituitary adenoma is the common finding during brain imaging. According to multistep model of pituitary tumourigenesis genetic alterations provide the initiating event that transforms cells while hormones play a role in promoting cell proliferation. Development of pituitary adenoma in a case of excessive hypophysiotrophic hormones production or reduced feedback suppression by target gland hormones emphasizes the importance of hormonal stimulation in pituitary tumourigenesis. Pituitary hyperplasia has been reported in pregnancy, hypothyroidism and conditions such as CRH or GHRH hypersecretion. Moreover, recent study reported one case of gonadotroph macroadenoma and two cases of gonadotroph cells hyperplasia in patients with Klinefelter syndrome probably due to protracted stimulation of gonadotroph cells because of lack of androgen feedback. Significant changes of the hypothalamic-pituitary-gonadal axis occurred with aging. In females, after menopause, estradiol level decreases by 35-fold and estrone level by 20-fold that results in increased gonadotropins levels. Similarly, FSH, but not LH, level is increased with advancing age in men, too, although the age-related difference in the level is less in comparison with women. Regarding these data, we hypothesised that high prevalence rate of pituitary incidentaloma in the elderly is associated with age-related decline in sex hormones levels and subsequent lack of feedback suppression leading to permanent gonadotrophs stimulation which is the crucial step in the pituitary tumour development. According to previously mentioned multistep model of pituitary tumourigenesis, incidentaloma will develop only in persons with already present intrinsic pituitary cell defects. However, further studies have to answer the questions of whether the incidence of pituitary tumours is more frequent in elderly, whether women with late onset menopause or those taking long-term hormone replacement therapy have lower rate of pituitary incidentaloma, and finally, is there any correlation between pituitary tumours incidence and serum concentrations of LH, FSH, bioavailable testosterone or estradiol.

Pituitary Tumor Transforming Gene Overexpression Facilitates Pituitary Tumor Development

Intrinsic and extrinsic stimuli result in profound pituitary growth changes ranging from hypoplasia to hyperplasia. Pituitary tumor transforming gene (PTTG) abundance correlates with pituitary trophic status. Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia. To test the impact of pituitary hyperplasia on tumor development, we crossbred alphaGSU.PTTG with Rb+/- mice, which develop pituitary tumors with high penetrance. Pituitary glands of resulting bitransgenic alphaGSU.PTTGxRb+/- mice were compared with monotransgenic alphaGSU.PTTG, Rb+/-, and wild-type mice. Confocal microscopy showed that PTTG-overexpressing cells have enlarged nuclei and marked redistribution of chromatin, and electron microscopy of alphaGSU.PTTG pituitaries showed enlarged gonadotrophs with prominent Golgi complexes and numerous secretory granules. These morphological findings were even more remarkable in alphaGSU.PTTGxRb+/- pituitaries. Mice from all four genotypes were sequentially imaged by magnetic resonance imaging to evaluate pituitary volume, and glands from alphaGSU.PTTGxRb+/- mice were the largest as early as 2 months of age (P = 0.0003). Cumulative incidence of pituitary tumors visualized by magnetic resonance imaging did not differ between Rb+/- and alphaGSU.PTTGxRb+/- mice. However, anterior lobe tumors determined after necropsy were 3.5 times more frequent in alphaGSU.PTTGxRb+/- than in Rb+/- mice (P = 0.0036), whereas the frequency of intermediate lobe tumors was similar. In summary, alphaGSU.PTTGxRb+/- pituitary glands exhibit enhanced cellular activity, increased volume, and higher prevalence of anterior pituitary tumors, indicating that changes in pituitary PTTG content directly relate to both pituitary trophic status and tumorigenic potential.

Morphology of the Pituitary Gland in Ferrets ( Mustela putorius furo) with Hyperadrenocorticism

Pituitary tumours are the cause of hyperadrenocorticism in a variety of species, but the role of the pituitary gland in hyperadrenocorticism in ferrets is not known. In this species, the disease is mediated by the action of excess gonadotrophins on the adrenal cortex and is characterized by an excessive secretion of sex steroids. In this study, the pituitary gland of four healthy control ferrets, intact or neutered, and 10 neutered ferrets with hyperadrenocorticism was examined histologically following immunohistochemical labelling for adrenocorticotrophic hormone, α-melanocyte-stimulating hormone, growth hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin. Immunohistochemistry revealed that somatotrophs, thyrotrophs and lactotrophs were the most abundant cell types of the pars distalis of the pituitary gland in the healthy ferrets. The distribution of corticotrophs was similar to that in the dog and man. In ferrets, as in dogs, the melanotrophic cell was almost the only cell type of the pars intermedia. Gonadotrophs were found in the pars distalis of neutered, but not intact ferrets. All the ferrets with hyperadrenocorticism had unilateral or bilateral alterations of the adrenal gland. In addition, in the pituitary gland of two of these ferrets a tumour was detected. These tumours were not immunolabelled by antibodies against any of the pituitary hormones, and had characteristics of the clinically non-functional gonadotroph tumours seen in man. In some of the other ferrets low pituitary immunoreactivity for gonadotrophic hormones was detected, which may have been due to the feedback of autonomous steroid secretion by the neoplastic transformation of the adrenal cortex. It is concluded that initially high concentrations of gonadotrophins resulting from castration may initiate hyperactivity of the adrenal cortex. The low incidence of pituitary tumours and the low density of gonadotrophin-positive cells in non-affected pituitary tissue in this study suggest that persistent hyperadrenocorticism is not dependent on persistent gonadotrophic stimulation.

Gene expression in aging kidney and pituitary

Gene expression in aging kidney and pituitary was determined by subtractive hybridization, DNA microarrays and RT-PCR. Kidneys and pituitary were removed from 10- and 30-month-old female WAG/Rij rats, which were free from chronic progressive nephrosis and had a low incidence of pituitary tumors with age. From 350 cDNA fragments isolated by subtractive hybridization, just one showed a more than twofold change in expression between 10 and 30 months. The use of a specific microarray with 4050 rodent genes also failed to detect downregulation lower than 0.5 or upregulation larger than 2.0 in aging rat kidney. Similarly, mRNA content for vasopressin V2 and V1 receptors, aquaporin 2 and 3, and adenylyl cyclase type VI was not significantly modified with age as determined by RT-PCR. In contrast, microarray analysis of pituitary mRNA expression showed upregulation of 11 genes with ratios equal to or greater than 2.0 and downregulation of 6 genes with ratios equal to or less than 0.5. Two cDNA sequences of unknown genes from the kidney subtractive library were part of the age-related up- and downregulated genes of the pituitary. Other genes were mainly related to cell differentiation, control of homeostasis, cellular signaling, endoplasmic reticulum trafficking and metabolism. These data indicated that mRNA expression is barely modified in aging kidney free from chronic progressive nephrosis, at least in the 0.5-2.0 range, in contrast to pituitary. They also suggest that the downregulation of proteins reported in aging kidneys free from gross disease is related to post-transcriptional changes.