Pituitary Gland Tumors Research Articles

The effects of overfeeding and moderate dietary restriction on Sprague-Dawley rat survival, pathology, carcinogenicity, and the toxicity of pharmaceutical agents

Ad libitum (AL) overfeeding is the most significant uncontrolled variable effecting the rodent bioassay. There is a highly significant correlation between food consumption, the resultant body weight, and two-year survival in laboratory rats. We have studied the effects of AL overfeeding, moderate dietary restriction (DR) and several modified diets on Sprague-Dawley (SD) rat longevity, spontaneous disease, carcinogenesis and the toxicity of pharmaceuticals. AL feeding of diets varying in protein, fiber and metabolizable energy content did not significantly alter two-year rat survival. Moderate DR (within the range of reported AL food intake) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease and diet-related tumors compared to AL-fed rats. Moderate DR resulted in a similar incidence of spontaneous tumors by 2 years, however, the tumors were more likely to be incidental and not result in early mortality. There was a decreased, age-adjusted incidence of pituitary and mammary gland tumors, but tumor volume and growth time was similar between AL and DR groups indicating similar tumor progression with a delay in tumor onset. Moderate DR did not change Phase I and Phase II drug metabolizing enzyme levels and did not significantly alter the toxicological response to 5 pharmaceuticals tested at maximum tolerated doses (MTDs). Additional studies with 4 pharmaceutical candidates did demonstrate that moderate DR allowed higher doses of compounds to be given before classical MTDs were observed. However, toxicokinetic studies of two of these compounds demonstrated steady state systemic exposures that were either equal of higher in the moderate DR fed rats. These and other data indicate that the moderate DR fed SD rat is a more appropriately controlled rodent model for toxicity and carcinogenicity studies to assess human safety of candidate pharmaceuticals.

Prolactin receptors in human pituitary adenomas

In the rat, prolactin receptors (PRL-R) have been identified in normal pituitary cells and in anterior pituitary tumours induced by oestradiol. No published data are available concerning PRL-R in the human pituitary. The aim of our study was therefore to detect the presence of PRL-R in the normal human pituitary gland and human pituitary adenomas. Evaluation of free and total PRL-R in the normal pituitary gland and different pituitary tumours characterized by immunocytochemical analysis. Twenty-six unselected patients (14 M, 12 F) who underwent surgery for pituitary adenoma (3 prolactinomas, 4 GH-PRL adenomas, 5 GH adenomas, 1 ACTH adenoma, 9 glycoprotein and/or alpha-subunit adenomas, 4 null cells adenomas) were studied. Nine pituitaries from subjects whose death was unrelated to brain and endocrine diseases, were also studied as a control group in the PRL binding studies. Free PRL-R in microsomal membranes were determined by in-vitro radioreceptor assay using 125I-labelled human PRL as ligand. Total PRL-R were also measured in the same membrane fractions by removing endogenous PRL bound to its receptors using 4 M MgCl2. Serum PRL levels were also evaluated in all patients before surgery using an IRMA method. Specific binding values for PRL (free PRL-R) were 0.39 +/- 0.03% (range 0-1.96%) in the pituitary adenomas. These binding values were identical to those observed in normal pituitaries (0.38 +/- 0.07%, range 0.1-0.78%). Elevated PRL binding (1.25% and 1.96%) was found in two patients with PRL secreting adenomas and very high serum PRL levels (5768 and 11240 mU/I. No PRL binding was shown in 4 patients. Treatment of membranes with 4 M MgCl2 increased the specific binding (total PRL-R) in both pituitary tumours (0.5 +/- 0.11%; P < 0.001) and normal pituitaries (0.47 +/- 0.07%; P < 0.02). Our data have demonstrated the presence of prolactin receptors in normal cadaveric pituitary and in most pituitary adenomas, irrespective of histological classification. In particular, elevated prolactin receptor levels were shown in PRL-secreting tumours from patients with markedly increased serum PRL levels. Our study may support several lines of experimental evidence for a specific functional role for PRL in the growth of some pituitary adenomas.

The Effect of Body Weight on Tumor Incidence and Carcinogenicity Testing in B6C3F1 Mice and F344 Rats

The Effect of Body Weight on Tumor Incidence and Carcinogenicity Testing in B6C3F1 Mice and F344 Rats. Seilkop, S. K. (1995). Fundam. Appl. Toxicol. 24, 247-259.Associations between animal body weights and tumor incidence were examined using individual control animal data from 55 mouse and 53 rat studies conducted by the National Toxicology Program. Several statistically significant associations were found, the strongest of which were positive relationships between body weight and risk of liver tumors in both sexes of mice, pituitary gland tumors in both sexes of rats, and mammary gland tumors in female rats. The most compelling evidence that these relationships were causal in nature was the replication of the correlations across individual experiments. In addition, significant correlations between tumor occurrence and body weights occurred in animals as young as 9 weeks of age. Logistic regression models relating 12-month body weight to tumor risk were developed for the strongest relationships, and utilized in the reanalysis of tumor data from two National Toxicology Program studies with treatment-related decreases in body weight. A simulation study based on the logistic regression models indicated that statistical power to detect a treatment-related increase in tumor incidence can be seriously diminished when mean body weight in treated animals is depressed by as little as 10%. Conversely, when mean body weight in control animals is 10% lower than that of treated animals, false positive rates can increase to 20-30%. The severity of the effects of such commonly observed treatment-related disparities in body weight suggests that alternative data analysis methods or experimental designs should be considered to address this potential problem in carcinogenicity testing.

Developmental rescue of an embryonic-lethal mutation in the retinoblastoma gene in chimeric mice.

The requirement for a functional retinoblastoma gene, Rb-1, in murine development around days 12-15 of gestation precludes monitoring the effect of loss of Rb-1 function on later stages of development and on tumorigenesis in adult mice. Here we describe the developmental rescue of embryonic stem cells carrying two inactive Rb-1 alleles in chimeric mice. Rb-1- cells contributed substantially to most tissues in adult chimeras, including blood, liver and central nervous system, which were severely affected in pure Rb-1- embryos. The adult chimeric erythroid compartment appeared completely normal, but an increased number of nucleated red cells was observed during fetal liver erythropoiesis in highly chimeric embryos. No ostensive abnormalities were seen in the developing and adult CNS. However, the developing retina of chimeric Rb-1- embryos showed ectopic mitoses and substantial cell degeneration, while the contribution of Rb-1- cells to the adult retina was much reduced. Moreover, the formation of lens fibre cells was severely disturbed. No retinoblastomas developed in any of these mice. Instead, nearly all animals died of pituitary gland tumours which were exclusively derived from Rb-1- cells.

A transforming growth factor-alpha pathway is expressed in GH4C1 rat pituitary tumors and appears necessary for tumor formation.

Transforming growth factor-alpha (TGF alpha) is a growth regulatory peptide expressed largely as a high mol wt species in the anterior pituitary gland. The overall objective of this work was to test the hypothesis that altered expression of TGF alpha may play a role in the tumorigenicity of the GH4C1 cell line. We examined expression of TGF alpha in three related clones of pituitary tumor cells (GH1, GH3, and GH4C1) grown as transplantable tumors, the MtT/W5 tumor from which they were derived, and anterior pituitary glands of Wistar-Furth rats, the source of the MtT/W5 tumor. Wistar-Furth anterior pituitary, MtT/W5, GH1, GH3, and GH4C1 extracts all contained TGF alpha-specific immunoreactivity, which, when examined on sodium dodecyl sulfate-gel transfers, was of high relative mol wt, corresponding to incompletely processed TGF alpha. In neither the anterior pituitary nor the tumors was the fully processed 6-kilodalton TGF alpha form identified, indicating that mature TGF alpha is expressed to only a limited degree in normal and tumor pituitary tissue. We next determined whether a lack of receptors for TGF alpha may account for the MtT/W5 tumor phenotype in vivo. Scatchard analysis of [125I] epidermal growth factor ([125I]EGF) saturation isotherm binding identified a comparable class of sites in both the anterior pituitary gland and GH4C1 transplantable tumors. Specific binding sites were also found in MtT/W5, GH1, and GH3 tumors. Thus, the functional components of a TGF alpha pathway exist in both the anterior pituitary gland and GH4C1 transplantable tumors. We lastly examined whether a TGF alpha pathway plays a functional role in GH4C1 tumor formation. Toward this aim, we isolated TGF alpha-nonresponsive variants by two different selection schemes: one using a TGF alpha-toxin conjugate, and the other using a TGF alpha-inducible morphological phenotype. Each variant had decreased [125I]EGF specific binding and little or no EGF growth inhibitory response in vitro. We also isolated a mutagen-induced revertant from one of the variants based on expression of the TGF alpha-inducible morphological phenotype. These cells were found to have a normal complement of receptors and EGF growth inhibitory response in vitro. GH4C1, the two variants, and the revertant cells were inoculated into Wistar-Furth rats, and their growth observed for 8 weeks. The GH4C1 cells and the revertant formed tumors by 8 weeks, whereas the two variant cells failed to form tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Suprasellar Ectopic Pituitary Adenoma —Case Report—

A 33-year-old female presented with suprasellar ectopic pituitary adenoma manifesting as visual disturbances. Preoperative magnetic resonance imaging demonstrated intact pituitary gland and suprasellar cystic tumor, with a preoperative diagnosis of craniopharyngioma. At surgery, the tumor was identified as a suprasellar ectopic pituitary adenoma with intracapsular hematoma. There was no communication between the tumor and intrasellar structures. Total removal of the tumor immediately improved the severe visual disturbance. Ectopic pituitary adenoma should be considered in the differential diagnosis of a suprasellar lesion with intact pituitary gland.

Effect of angiogenesis inhibitor TNP-470 on vascular formation in pituitary tumors induced by estrogen in rats.

TNP-470 (TNP), an analog of fumagillin, inhibits cell proliferation and tumorigenesis in estrogen-induced pituitary tumors in rats. This study found that treatment with TNP or TNP and bromocriptine suppressed vascular formation in these pituitary tumors more than bromocriptine alone. TNP had a greater suppressive effect on vascular formation in pituitary tumors than in normal pituitary gland. Laminin and basic fibroblast growth factor (FGF) were detected around new blood vessels in normal pituitary gland and pituitary tumor. TNP did not completely suppress laminin or basic FGF expression. The effect of TNP on pituitary tumor may involve inhibition of vascular formation by mechanisms mediated by other factors in addition to basic FGF. Treatment with bromocriptine and TNP acts indirectly and directly on vascular formation and may provide a useful chemotherapeutic modality for pituitary tumors.

Early indicators for carcinogenesis in sex-hormone-sensitive organs

Hormones induce tumours in various target tissues in different species of laboratory animals in long-term toxicity studies. Examples of such tumours are: mammary gland tumours in beagle dogs after long-term treatment with progestogens or progestogen/oestrogen combinations; pituitary and mammary gland tumours in rats and mice after long-term treatment with oestrogens or progestogens with an oestrogenic partial effect; interstitial cell tumours in rats after chronic overstimulation by endogenous lutenising hormone; endometrial carcinomas in rats after chronic treatment with dopamine agonists. As a rule every hormone when given in excessive doses over prolonged periods can induce a tumour in the relevant target organs. Drugs or chemicals which stimulate or inhibit the endogenous hormone production of certain endocrine organs can have the same effect. Tumour induction can be a direct or indirect effect involving specific regulatory mechanisms. In general, the induction is preceded by excessive hyperlasia of the target tissue concerned or with regard to the pituitary where excess production of the stimulating hormone occurs. Tumour induction in chronic toxicity studies can usually be predicted by determining hormone levels in short-term studies. Hormones and drugs or chemicals which induce tumours when given in doses high enough to induce hyperlasia are unlikely to do so by a genotoxic mechanism.

Immunocytochemical studies on the pituitary gland and spontaneous pituitary tumors of sprague-dawley rats

The review of our studies indicates a predictive value of the pituitary gland and spontaneous pituitary tumors of Sprague-Dawley rats for detecting and evaluating the effects and interactions of estrogens and dopamine agonists on the pathogenesis, functional morphology and therapy of human pituitary tumors, such as prolactinomas, gonadotroph adenomas and null cell adenomas. The functional classification of spontaneous pituitary tumors in old female Sprague-Dawley rats reveals a diversity of hormone content and morphologic appearance. They seem to be useful models of the human disease.

Expression of the β-Subunit Gene of Murine Thyrotropin Results in Multiple Messenger Ribonucleic Acid Species which are Generated by Alternative Exon Splicing

The current studies reveal that expression of the mouse TSH beta-subunit gene in the pituitary gland and TtT97 murine thyrotropic tumor results in multiple mRNAs which arise by alternative splicing. This was deduced by 1) sequencing the extended products of TSH beta mRNA primed with an oligonucleotide complementary to the protein coding region and 2) demonstrating primer extension of oligonucleotides complementary to the optional exon junctions. These results, when correlated with the sequence of the TSH beta gene, revealed a structure comprising five exons and four introns. Exon 1, which is common to all of the mRNAs, and optional exons 2 and 3 code only for 5'-untranslated (UT) sequences, whereas exons 4 (includes one nucleotide of 5'-UT) and 5 encode the protein coding and 3'-UT regions. Multiple splicing events generate mRNAs with 5'-UT regions of 28, 69, 75, and 116 nucleotides which include exon 1, exons 1 and 3, exons 1 and 2, and exons 1, 2, and 3, respectively. In contrast, in the hypothyroid rat pituitary messages possessing optional exons were not detected, and thus the TSH beta mRNA with a 5'-UT region of 28 nucleotides predominated. We identified an additional transcriptional start site located 40 nucleotides upstream in both the mouse and rat TSH beta gene. Optional exon splicing was not detectable in transcripts initiated from the upstream start site of the murine gene. In the hypothyroid state, transcripts initiated at the upstream site were considerably less abundant than those initiated at the downstream site. Transcription from both start sites was inhibited by thyroid hormone in both mice and rats.

Increased creatine kinase activity in pituitary tumours of rat and man.

The demonstration that phosphocreatine is used as an energy source by rat PRL-secreting pituitary tumours prompted the study of the enzyme creatine kinase in both rat and human pituitary tumours. Rats treated with diethylstilbestrol developed greatly enlarged pituitaries and hyperprolactinaemia. Total creatine kinase was significantly increased and fractionation on diethylaminoethyl Sephadex showed that the 'brain' form was increased, whereas the 'muscle' and mitochondrial forms showed no change. Exposure to large concentrations of oestradiol caused similar changes in creatine kinase which increased over a period of 25 weeks. The total creatine kinase content of a series of human pituitary tumours was highly variable, but the mean value of 183 +/- 46 (SEM) units per gram protein was significantly higher than the mean for normal pituitary tissues (28.4 +/- 2.9). The brain:muscle isozyme ratio was measured in six human PRL-secreting tumours with a mean of 3.47 +/- 0.73, significantly higher than in 'non-functional' tumours (1.57 +/- 0.29) or normal tissue (1.77 +/- 0.28). Three of four GH-secreting tumours had a ratio below 0.6. The highest ratio found (8.66) was in an ACTH-secreting tumour. Previous reports have shown that oestradiol rapidly induces brain creatine kinase in oestrogen responsive tissues. This is not the case with the rat pituitary gland or oestrogen responsive human tumour cells in culture. Chronic oestrogen treatment, however, does increase creatine kinase in the proliferating gland and many human pituitary tumours have increased enzyme activity. These results suggest that the phosphocreatine/ATP system and in particular the brain isozyme of creatine kinase are of particular importance in lactotropes.

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The dietary and growth histories of noninbred male Charles River COBS rats permitted freedom of dietary choice throughout life were analyzed to determine the conditions associated with the spontaneous occurrence of anterior pituitary gland tumors (PT). The animals were allowed to regulate their protein intake apart from energy intake. Multivariable models were derived distinguishing rats that develop PT from those remaining free of tumors throughout life. Conventional fixed diet studies suggested that the quantity and quality of the diet consumed would be the best explanatory variables. However, body weight-related variables were found to be more important. The interacting, time-related conditions conductive to a high probability of PT occurrence included an unusually high growth rate associated with a high level of conversion of the food consumed into body mass during early life and a high intake of protein relative to body weight during early adult life. The accuracy in identifying rats with PT was even greater if mature body weight was included as an explanatory variable.

Evaluation of amitrole (aminotriazole) for potential carcinogenicity in orally dosed rats, mice, and golden hamsters

Amitrole was evaluated for carcinogenic potential in lifespan studies on Wistar rats, NMRI mice, and golden hamsters. At the start of the studies the animals were 6 weeks old. Amitrole was administered, mixed with pulverized chow, at dietary concentrations of 0, 1, 10, and 100 μg/g (ppm). Each treated group and control group consisted of 75 male and 75 female rats and mice and of 76 male and 76 female golden hamsters. Additional animals were used to evaluate the functional state of the thyroid. Somewhat lower body weights, slightly reduced survival times, and transient effects on thyroid function were observed in golden hamsters at 100 ppm. In mice, a slight increase in pituitary gland hyperemias was seen at 100 ppm; also an effect on thyroid function usually occurred at the same concentration. In rats, a very large number of cystic dilatations of follicles in the thyroid at 100 ppm and a dose-unrelated increase in hemorrhages and hyperemias in the pituitary gland were indicative of an effect of amitrole on these organs. The strongest effect of amitrole on thyroid function, as compared to golden hamsters and mice, was seen in rats at 100 ppm. At this concentration a highly increased number of thyroid and pituitary gland tumors was observed in rats. In golden hamsters and mice, no tumor induction was seen.

Computed tomography in the evaluation of the supraclinoid arteries in suprasellar pituitary gland tumors.

The demonstration of the supraclinoid arteries at CT in 38 patients with suprasellar lesions was evaluated. The anterior cerebral artery was visible in 8 per cent, the other supraclinoid arteries in about 80 per cent. In one patient cerebral angiography revealed a giant aneurysm which was erroneously considered as a suprasellar neoplasm at CT and encephalography. The demonstration of the supraclinoid arteries was often inadequate in large suprasellar tumors. Therefore, cerebral angiography is still necessary preoperatively in suprasellar pituitary lesions-at least at the state of technology represented by the Delta 25 Head Scanner.

Rhinological findings following transantrosphenoidal surgery of the pituitary gland.

Fifty patients with pituitary gland tumours on whom we operated via the transantrosphenoidal route, were rhinologically followed up with a view to revealing any conceivable functional impairments incurred by this method. Our investigations included rhinoscopy, endoscopy of the nasal and paranasal cavities and of the epipharynx, X-ray controls, and probes of the nn. olfactorius and trigeminus. Apart from the technical advantages of transantrosphenoidal pituitary gland surgery, the results also confirmed its benefit to functional performance.

Relative Effects of Whole-Body Sublethal Doses of 60-MeV Protons and 300-kVp X-Rays on Disease Incidence in RF Mice

Over 3100 young-adult female RF/Un mice were given wholebody exposure to 60-MeV protons or 300-kVp x rays (0 to 400 rads) and were observed for life- shortening effects and neoplastic and nonneoplastic diseases. Complete pathological examination was done on all animals, and 81% were examined histologically. Similar dose-response curves were seen for most diseases but, with the exception of ovarian tumor induction, x-rays were slightly more effective in inducing a specific disease than were protons. For life-shortening, x rays were more effective at all doses (0.34 to 0.80 day's life-shortening per rad) with the greatest difference in effect between x rays and protons found at the two lowest doses, 50 and 100 rads. X rays increased the combined incidences of thymic lymphoma and myeioid leukemia, but these leukemias did not account for all life-shortening at higher doses (100 to 400 rads); the remainder may be related to an increase in ovarian tumors. X rays were more effective than protons in inducing myeloid leukemias at 50 to 200 rads and thymic lymphoma at 300 to 400 rads with no differences at other doses. Maximum incidences were reached with x rays at 300 and 400 rads for thymic lymphoma and at 200more » rads for myeloid leukemia while there was no difference in effect between radiations on reticulum cell sarcoma and nonthymic lymphoma frequency. Combined observed incidences of all leukemias were not different from controls and irradiated groups at 50 rads, nor at 100 rads for protons, but increased at higher doses. Lung tumor incidence showed a negative dose-response due to the failure of animals to survive long enough to develop this usually nonfatal disease. Ovarian tumors were increased by all doses of both radiations and this was the only instance where protons were more effectlve than x rays; maximum response was seen at 100 rads for hoth radiations. Pituitary gland and harderian gland tumors may have been increased by radiation (P < 0.10 and <0.05, respectively), but the effect was not dose dependent. Nonneoplastic diseases showed little effect from radiation. Relative biological effectiveness (RBE) for 60-MeV protons was estimated at 0.63 for life-shortening, and at generally slightly less than 1.0 for all parameters, excluding ovarian tumors. Only thymic lymphoma, myeloid leukemia, and ovarian tumors were significantly increased by radiation, with suggested increases in harderian gland and pituitary gland tumors. Other pathological alterations in incidence and severity of disease would appear to be minimal when compared to nonirradiated populations. (auth)« less

Radiological assessment of the pituitary gland.

The treatment of pituitary gland tumours, particularly where there is no clinical evidence of supra-sellar extension, rarely involves an open surgical procedure. In these cases, pituitary ablation can be carried out by one of several methods including trans-sphenoidal and transethmoidal hypophysectomy, trans-sphenoidal cryosurgery, trans-sphenoidal yttrium implantation, external irradiation and transfrontal stereotactic yttrium implantation. Irrespective of the method employed, accurate investigation of the pituitary gland is essential, but this is particularly important with stereotactic implantation.

Influence of Protein and Caloric Intake upon Spontaneous Tumor Incidence of the Anterior Pituitary Gland of the Rat

The level of caloric intake and the proportion of protein in the diet was found to modify the incidence of spontaneous chromophobe adenomas of the anterior pituitary gland of the male rat. Three purified diets, differing only in the protein-calorie ratio, were employed. Each diet was provided throughout post-weaning life in ad libitum or in restricted but isocaloric amounts. Under ad libitum feeding conditions the highest incidence of chromophobe adenomas was found to be associated with the dietary group having the highest intake of food. Under restricted conditions tumor prevalence was directly related to the level of the protein component in the diet. Restriction in both caloric intake and protein intake depressed the incidence to the greatest extent. Among all six dietary groups, body weight of the rat early in life correlated directly with tumor prevalence of later life. In the ad libitum series, individuals of greater maximum body weight were more prone to anterior pituitary gland tumors than rats of lighter weight.