Growth Hormone-producing Tumor Research Articles

Differential expression levels of β-catenin are associated with invasive behavior of both functional and non-functional pituitary neuroendocrine tumor (PitNET).

Although research continues to elucidate the molecular mechanism underlying pituitary tumor pathogenesis, limited information is available on the potential role and expression profile of β-catenin in functional and non-functional pituitary neuroendocrine tumors (PitNETs). In the current study, 104 pituitary samples (tumors and cadaveric healthy pituitary tissues) were included and the gene and protein expression levels of β-catenin were assessed by Real-Time PCR and immunohistochemistry, respectively. The correlation between expression level of β-catenin and tumor invasive feature and size as well as patient age, gender, and hormonal level was measured. The data showed that PitNET samples expressed higher levels of the β-catenin gene and protein compared to healthy pituitary tissues. Although there was no difference in β-catenin expression level between non-functioning (NF-PitNETs) and growth hormone-producing tumors (GH-PitNETs), both tumor types showed significantly elevated β-catenin levels compared to healthy pituitary tissues. The high level of β-catenin in the invasive functional and non-functional tumors is indicative of the association of β-catenin with PitNETs invasion. The expression pattern of the β-catenin gene and protein was consistently and significantly associated with these tumor types. The correlation between β-catenin and insulin-like growth factor 1 (IGF-1) in GH-PitNETs indicates the potential relevance of β-catenin and IGF-1 for GH-PitNETs. The simultaneous increase in the expression of β-catenin gene and protein level in PitNET tissues and their relationship to the tumor severity indicates the possible contributing role of β-catenin and its underlying signaling mediators in PitNET pathogenesis.

Status epilepticus and diabetes ketoacidosis: uncommon clinical presentations of acromegaly.

SummaryAcromegaly is a rare disease caused by hypersecretion of the growth hormone (GH). Most cases are caused by either pituitary microadenoma or macroadenoma. The GH producing tumors present with clinical manifestations of acromegaly due to excessive GH secretion or symptoms resulting from mass effects of the enlarging tumor. The physical changes are usually slow and, therefore, recognition of the disease is delayed. These adenomas are never malignant but can have significant morbidity and mortality. A subgroup of patients with acromegaly present with severe hyperglycemia resulting in diabetic ketoacidosis (DKA) which requires insulin. Rarely are pituitary tumors responsible for generalized convulsions except when they are too large. We hereby present two cases, the first is that of a 26-year-old female who presented with new onset status epilepticus, DKA with a 1-year history of diabetes mellitus (DM). On examination, she had clinical features of acromegaly. The second case is that of a 34-year-old female who presented with new onset status epilepticus, hyperglycemia with a history of recently diagnosed DM, and features of gigantism. In both cases, their diagnosis was confirmed by elevated serum GH and later by elevated insulin-like growth factor type 1 levels, and CT of the head demonstrating large pituitary macroadenoma. The importance of clinical history and examination, as well as investigations is vital in the recognition of acromegaly. The prognosis of acromegalic patients depends on early clinical recognition and tumor size reduction by either medical or surgical therapy.Learning pointsConditions such as status epilepticus and DKA may be clinical presentations in patients presenting with acromegaly.Seizures are rare in people with pituitary adenoma and typically occur when the tumor invades the suprasellar area due to mass effect on the brain.This article shows how best we were able to manage the acromegaly complications in a low resource setting.Hyperprolactinemia in acromegaly may be due to disruption of the normal dopaminergic inhibition of prolactin secretion due to mass effect of the macroadenoma, and around 25% of GH-secreting adenomas co-secrete prolactin.

Rapid and dramatic glucose‐lowering effect of bromocriptine in an inadequately controlled type 2 diabetes patient with prolactinoma

Dopamine receptor agonists are typically used to treat Parkinson’s disease and certain pituitary tumors, such as prolactinoma or a growth hormone‐producing tumor. A 53‐year‐old woman with a history of prolactinoma was referred to Kumamoto University Hospital (Kumamoto, Japan) with poorly controlled type 2 diabetes. Her glycated hemoglobin and serum prolactin levels were increased (8.8% and 160.3 ng/mL, respectively). Bromocriptine, a dopamine D2 receptor agonist, was administered to reduce her serum prolactin level. Because bromocriptine‐QR (quick release) has been approved for the treatment of type 2 diabetes mellitus in the USA, a continuous glucose monitoring system, FreeStyle Libre Pro, was utilized to examine the effect of bromocriptine on glycemic control. After the initial administration of bromocriptine, glucose levels were rapidly and dramatically ameliorated, and the time in range (70–180 mg/dL) improved from <50% to >90% between 1 week before and after the initial administration of bromocriptine.

Stem Cell Transcription Factor Sox2 Is Expressed in a Subset of Folliculo-stellate Cells of Growth Hormone-Producing Pituitary Neuroendocrine Tumours and Its Expression Shows No Association with Tumour Size or IGF1 Levels: a Clinicopathological Study of 109 Cases.

Sox2 is one of the transcription factors responsible for the maintenance of stem cell phenotype. It has been implicated as a marker of stem cells in normal pituitaries and pituitary neuroendocrine tumours. To explore the clinical significance of Sox2 expression in histological sections, we performed immunohistochemical detection of Sox2 in 113 pituitary neuroendocrine tumours from 109 patients with acromegaly. In 11 tumours, we performed double immunostaining for Sox2, annexin A1 and S100 protein. Tumours were characterised using the WHO classification system. Proliferative activity and invasion were assessed. The amount of immunoreactive cells was evaluated and correlated with tumour size and biochemical features (levels of IGF1, GH, prolactin, βTSH). Sox2+ cells were identified in 35/38 normal pituitaries adjacent to the tumours. In 36 tumours (33%), ≥ 1% of the cells expressed Sox2, in 24 cases (22%), Sox2+ cells comprised < 1% and 49 cases (45%) were negative. We found no significant differences between Sox2+ and Sox2- groups with respect to the age, initial levels of GH, IGF1, prolactin, βTSH, tumour size, invasion, proliferative activity or histological features. We observed a positive correlation between Sox2+ cell count and βTSH immunoreactive cells (r = 0.459, p< 0.001) that was further verified by multivariate analysis. Using double stain, the majority of Sox2+ cells coexpressed annexin A1 (average 89%) and S100 protein (average 76.2%) and showed morphological features of folliculo-stellate cells. Sox2+ cells are thus commonly present in growth hormone-producing tumours and normal pituitaries, and their amount does not have any prognostic significance. Most of these cells represent a subpopulation of folliculo-stellate cells, pointing out to their role as a possible stem cell population.

SAT-251 New Diagnosis of Acromegaly with DKA as Initial Presentation

Background: While diabetes mellitus from growth hormone related insulin resistance is not uncommon in GH secreting tumors, initial presentation with diabetic ketoacidosis is rare. Clinical Case: 31 YO male with no significant past medical history presented with c/o fatigue, 40 lb weight loss, polyuria, polydipsia. Clinical features of acromegaly with frontal bossing, protruding jaw, large hands and feet, thick spade like fingers, hammer toes, high arches and thickened fat pads on both feet were noted. Initial labs were consistent with DKA with anion of 31 mmol/L (0-20), blood glucose 241 mg/dl, bicarb 12 mmol/L (22-29), serum betahydroxy butyrate > 8 mmol/L (0-0.29), urine positive for glucose, ketones, protein. Patient was initially treated with IV insulin per DKA protocol, transitioned to subcutaneous insulin.MRI brain showed 2.1x1.3x2.1 cm pituitary macro adenoma. Labs showed elevated IGF1 LC/MS, S 1094 ng/ml (54-310), IGFBP3 14 mcg/ml (3.5-7), Z score IGF MS Mayo > 3 (-2 to +2), normal FSH 7.1 m unit/ml (1.5-12.4), normal LH 3.4 m unit/ml (1.7-8.6), normal prolactin 6 ng/ml (4-15), normal ACTH 10 pg/ml, cortisol 13.4 mcg/dl, low total testosterone 48.2 ng/dl (193-836), normal free testosterone 7.92 ng/dl (4.85-19), normal TSH 1.55 mc unit/ml (0.27-4.2) and free T4 1.17 ng/dl (0.93-1.7). The patient was discharged home on 120+ units of total daily dose of insulin, after initial hospital admission.He underwent trans sphenoidal resection of pituitary macro adenoma one month after his initial presentation. Surgical pathology confirmed growth hormone producing adenoma. He was successfully weaned off from insulin in one month following surgery. Conclusion: DKA is an unusual initial presentation of growth hormone producing tumors. As more cases are being reported it is important to be vigilant to look for DKA presentation in these patients and adjust/wean patients insulin once the growth hormone producing tumor is treated either with surgery or medications.

Pharmacokinetic analysis for the differentiation of pituitary microadenoma subtypes through dynamic contrast‑enhanced magnetic resonance imaging

The value of pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in distinguishing pituitary microadenoma subtypes was investigated in the present study. Pathology and follow-up outcomes were applied as the gold standard for differentiating between 76 patients with pituitary microadenomas (38 prolactin-producing tumors, 17 adrenocorticotropic hormone adenomas and 21 growth hormone-producing tumors) and 20 patients with normal pituitary glands. DCE-MRI was conducted to obtain the following quantitative permeability parameters: Volume transfer constant (Ktrans), rate constant (Kep) and extracellular extravascular volume fraction (Ve). Among the 76 cases included, 61 were visually diagnosed using conventional MRI. The Ktrans, Kep and Ve of the microadenoma cases were 0.472±0.292/min, 0.765±0.359/min and 0.792±0.345, respectively. The Ktrans, Kep and Ve of the normal control group were 0.902±0.238/min, 1.208±0.599/min and 0.928±0.378, respectively. The Ktrans and Kep of patients with microadenomas were significantly lower compared with those of the normal controls (P<0.05). However, the Ve of the two groups did not significantly differ. Subtype differentiation analysis revealed that patients with growth hormone-producing tumors exhibited the highest Ktrans value (P<0.05). Kep significantly differed between growth hormone-producing tumors and the other two subtypes (P<0.05), but did not significantly differ among three subtypes. Receiver-operator characteristic analysis indicated that the area under the curve values of Ktrans and Kep were 0.884 and 0.728, respectively. Sensitivity and specificity were 95.0 and 82.6%, respectively, when Ktrans was set to 0.614/min as the cut-off value, and when the Kep cut-off value was set to 0.985/min, sensitivity and specificity were 60.0 and 81.3%, respectively. In conclusion, Ktrans and Kep derived from DCE-MRI could be applied to detect and identify microadenoma subtypes. Ktrans better reflects the blood perfusion alterations exhibited by patients with different microadenoma subtypes.

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

Acromegaly is a disorder resulting from excessive production of growth hormone (GH) and consequent increase of insulin-like growth factor 1 (IGF-I), most frequently caused by pituitary adenomas. Elevated GH and IGF-I levels results in wide range of somatic, cardiovascular, endocrine, metabolic, and gastrointestinal morbidities. Subcutaneous implantation of the GH-secreting GC cell line in rats leads to the formation of tumors. GC tumor-bearing rats develop characteristics that resemble human acromegaly including gigantism and visceromegaly. However, GC tumors remain poorly characterized at a molecular level. In the present work, we report a detailed histological and molecular characterization of GC tumors using immunohistochemistry, molecular biology and imaging techniques. GC tumors display histopathological and molecular features of human GH-producing tumors, including hormone production, cell architecture, senescence activation and alterations in cell cycle gene expression. Furthermore, GC tumors cells displayed sensitivity to somatostatin analogues, drugs that are currently used in the treatment of human GH-producing adenomas, thus supporting the GC tumor model as a translational tool to evaluate therapeutic agents. The information obtained would help to maximize the usefulness of the GC rat model for research and preclinical studies in GH-secreting tumors.

Binasal Endoscopic Approach to the Sellar Region: Experience and Outcome Analysis of 80 Cases

A prospective study was performed on 80 cases of different types of sellar lesions during the period between January 2007 and December 2010. The binasal approach was used in all patients. Functioning lesions were diagnosed in 59 patients. The most common secretory tumors were prolactinomas (37 patients) followed by adrenocorticotropic hormone producing tumors (11 patients) and growth hormone producing tumors (11 patients). Nonfunctioning lesions included: 14 pituitary adenomas, 2 chordomas, 2 metastatic lesions (ovarian carcinoma and thyroid carcinoma), and 1 case of sarcoidosis, Rathke's cleft cyst, and craniopharyngioma. Seven nonfunctioning cases developed apoplexy. Among the 59 patients with functioning pituitary lesions, postoperative endocrinological control was achieved in 51 of them (86.5%) 3 months postoperatively with normalization of pituitary functions and complete tumor resection as proved by postoperative magnetic resonance imaging. Postoperative visual field defect improvement was achieved in 15 out of 23 patients (65.2%), including the cases with apoplexy, with complete tumor resection. Postoperative discomfort such as headache, vomiting, or dizziness was minimal and hospitalization period was 2 to 3 days. Postoperative leak continued in one patient in whom revision surgical repair was performed 7 days later. The merits, outcome, and limitations of the approach were discussed.

Growth suppression of mouse pituitary corticotroph tumor AtT20 cells by curcumin: a model for treating Cushing's disease.

BackgroundPituitary corticotroph tumors secrete excess adrenocorticotrophic hormone (ACTH) resulting in Cushing's disease (CD). Standard treatment includes surgery and, if not successful, radiotherapy, both of which have undesirable side effects and frequent recurrence of the tumor. Pharmacotherapy using PPARγ agonists, dopamine receptor agonists, retinoic acid or somatostatin analogs is still experimental. Curcumin, a commonly used food additive in South Asian cooking, has potent growth inhibitory effects on cell proliferation. Our laboratory recently demonstrated that curcumin inhibited growth and induced apoptosis in prolactin- and growth hormone-producing tumor cells [1]. Subsequently, Schaaf et.al. confirmed our findings and also showed the in vivo effectiveness of curcumin to suppress pituitary tumorigenesis. However the molecular mechanism that mediate this effect of curcumin are still unknown.Principal FindingsUsing the mouse corticotroph tumor cells, AtT20 cells, we report that curcumin had a robust, irreversible inhibitory effect on cell proliferation and clonogenic property. The curcumin-induced growth inhibition was accompanied by decreased NFκB activity. Further, curcumin down-regulated the pro-survival protein Bcl-xL, depolarized the mitochondrial membrane, increased PARP cleavage, which led to apoptotic cell death. Finally, curcumin had a concentration-dependent suppressive effect on ACTH secretion from AtT20 cells.ConclusionThe ability of curcumin to inhibit NFκB and induce apoptosis in pituitary corticotroph tumor cells leads us to propose developing it as a novel therapeutic agent for the treatment of CD.

Medical therapy: Options and uses

Since the initial use of medical treatment for acromegaly, several advances have been made in the understanding of the pathophysiology of growth hormone producing tumors, resulting in the development of multiple medical options and novel treatments. Currently there are three major classes of medication available for the treatment of acromegaly: somatostatin receptor ligands, growth hormone receptor antagonists, and dopamine agonists. Somatostatin receptor ligands are the treatment of choice for acromegaly due to their effectiveness in controlling growth hormone excess in approximately 60% of patients and their beneficial effects on tumor volume. Clinical trials have demonstrated efficacy of pegvisomant in up to 97% of patients, but long term data and safety have yet to be established. Dopamine agonists are inexpensive, but their use is hampered by their lack of efficacy compared to other medications. Medical therapy has an established role as adjuvant therapy after non-curative surgery, as well as primary therapy for selected patients unsuitable for surgical resection. Medical treatment to control growth hormone hypersecretion is often needed after radiation therapy until the effects are evident. Preliminary data suggest a potential role for medical treatment prior to surgical resection, surgical debulking to improve medical efficacy, and combination therapy with multiple medications from the three classes. More studies are required, however, to validate the utility of these approaches in treating acromegaly. With the available therapies, disease control can be achieved in nearly all patients with acromegaly.

Elevated expression of p21 (WAF1/Cip1) in hormonally active pituitary adenomas

Although most pituitary adenomas arise sporadically, molecular studies show alterations of known oncogenes and/or tumor suppressor genes in a small percentage of adenomas, and the molecular pathology of most is unknown. The p21 gene is a universal inhibitor of cyclin-dependent kinases and serves as a cell-cycle blocker and cell-growth inhibitor. Pituitary adenomas (n = 54) were immunophenotyped for hormone production (prolactin, growth hormone, adrenocorticotropin, thyrotropin, follicle-stimulating hormone, and luteinizing hormone), and expression of p21 was determined by immunohistochemistry. The percentage of cells expressing p21 for each tumor was evaluated blindly with regard to hormone status, and expression of p21 was then correlated with the results of hormone immunotyping. Results show a striking difference in the expression of p21 between immunonegative adenomas and hormone-producing tumors. Whereas 71% (10/14) of nonfunctional adenomas exhibit p21 expression in fewer than 5% of cells, 77% (31/40) of hormone-producing adenomas show expression in more than 25% of cells, and of these, 68% (21/31) show expression in more than 75% of cells. Overexpression of p21 is particularly striking for growth hormone-producing tumors, of which 92% (11/12) show expression in more than 75% of cells. Hormone-producing pituitary adenomas express much more p21 than do immunonegative adenomas. These high levels of p21 expression represent the most widespread molecular genetic alteration demonstrated to date in pituitary adenomas.

Gamma knife radiosurgery for pituitary adenoma: early results.

In recent years, gamma knife radiosurgery (GKRS) has emerged as an important treatment modality in the management of pituitary adenomas. Treatment results after performing GKRS and the complications of this procedure are reviewed. Between 1994 and 2002, a total of 78 patients with pituitary adenomas underwent a total of 84 GKRS procedures in our medical center. This patient group comprised 46 men (59%) and 32 women (41%). All patients were treated for recurrent or residual disease after surgery or radiotherapy, with 83% presenting with extensive tumor involvement. The cavernous sinus was involved in 75 patients (96%), and 22 patients (28%) had hormone-secreting adenomas. This latter subset of patients included 12 prolactinomas (15%), 6 growth-hormone secreting tumors (8%), and 4 adrenocorticotropic hormone-secreting tumors (5%). The median tumor volume was 2.3 cm(3), and the median radiation dose was 15 Gy defined to the 50% isodose line. The mean and median follow-up periods were 41 and 36 months, respectively. GKRS was tolerated well in these patients; acute toxicity was uncommon and of no clinical significance. Late toxicity was noted in three patients (4%) and consisted of VIth cranial nerve palsy. In two patients, there was spontaneous resolution of this palsy, and in one patient, it persisted for the entire 3-year duration of follow-up. Of the 15 patients who presented with cranial nerve dysfunction, 8 (53%) experienced complete recovery and 3 (20%) showed major improvement within 12 months of therapy. Tumor volume reduction was slow, with 30% of patients showing decreased tumor volume more than 3 years after undergoing GKRS. None of the 56 patients with nonfunctioning tumors showed progression in the treated volume, and 4 (18%) of the 22 hormone-secreting tumors relapsed (P = 0.008). Of the four patients with adrenocorticotropic hormone-secreting adenomas, therapy failed in two of them. All six patients with growth hormone-producing tumors responded well to therapy. Of the 12 patients with prolactinomas 10 (83%) had normalization of hormone level and 2 patients experienced increasing prolactin level. Two patients with prolactinomas had three normal pregnancies after undergoing GKRS. GKRS is a safe and effective therapy in selected patients with pituitary adenomas. None of the patients in our study experienced injury to the optic apparatus. A radiation dose higher than 15 Gy is probably needed to improve control of hormone-secreting adenomas. Longer follow-up is required for a more complete assessment of late toxicity and treatment efficacy.

Expression and alternative splicing of Pit-1 messenger ribonucleic acid in pituitary adenomas.

Twenty-eight human pituitary adenomas were analyzed for the expression of Pit-1 messenger ribonucleic acid (mRNA) by using reverse transcriptase-polymerase chain reaction analysis of frozen-section mRNA. Pit-1 mRNA was detected in all functioning tumors and in 9 of 11 nonfunctioning tumors. Pit-1 beta, which is a more active isoform of transcriptional factor for growth hormone than Pit- alpha and which arises from an alternative splicing mechanism, was detected in 14 of 17 functioning tumors and in 5 of 11 nonfunctioning tumors. The transcript that corresponds to Pit-1T, which increases thyroid-stimulating hormone beta promoter activity in rat thyrotropic tumor cells, was not found. There was no significant difference in the total Pit-1 (alpha+beta) mRNA expression level between functioning tumors and nonfunctioning tumors. Growth hormone-producing tumors and other pituitary adenomas also showed no significant difference in the Pit-1 beta/Pit-1 alpha expression ratio. Our data suggest that the major role of Pit-1 gene in pituitary adenoma might not be involved in the regulation of hormone production.

Galanin receptors from human pituitary tumors assayed with human galanin as ligand

Galanin (i.v.) elevates circulating growth hormone levels in humans, and human growth hormone producing tumors show galanin-like immunoreactivity. We have therefore investigated the presence of galanin receptors in sixteen human pituitary tumors. Specific binding of [ 125I]monoiodo-[Tyr 26]-porcine galanin was found in membranes from four clinically inactive and three growth hormone producing tumors. The affinity of human, rat and porcine galanin to these receptor sites was identical ( K d=0.9nM ). The rank order of potency of galanin receptor ligands was the same in the human pituitary tissue as in the rat and porcine pituitary, hypothalamus, pancreas and hippocampus. GTP (1 mM) or GMPP(NH)P (0.5 mM) lowered the apparent specific binding of [ 125I]galanin (0.2 nM), suggesting that the human pituitary galanin receptor is coupled via a G-protein similarly to galanin receptors in mouse, rat and pig. The possible significance of galanin receptors in pituitary tumors is discussed.

Expression of parathyroid hormone related peptide in human pituitary tumours.

The presence of parathyroid hormone related peptide (PTHrP) was studied in 20 patients with pituitary adenomas and one patient with pituitary adenocarcinoma. PTHrP expression was shown in almost all of the pituitary adenomas (95%) and in 100% (n = 7) growth hormone producing pituitary adenomas. A metastatic lesion from a pituitary growth hormone producing adenocarcinoma revealed strongly expressed PTHrP. It was weakly detected in normal pituitary cells in all of the specimens (n = 10). There was no significant correlation, however, between PTHrP expression and the clinical or pathological features of growth hormone producing tumours. Apart from an important role in the physiological function of the pituitary gland, PTHrP may be closely related to somatotroph tumorigenicity.

Cell-type-specific function of the C-type natriuretic peptide gene promoter in rat anterior pituitary-derived cultured cell lines.

The promoter function of the human C-type natriuretic peptide (CNP) gene in various cultured cells was examined by transient transfection assays. The CNP promoter functioned very effectively in GH3 cells, which originated from the growth hormone-producing tumor of the rat anterior pituitary and somatomammotroph phenotype, but functioned much less effectively in GH1 cells, another type of rat pituitary-derived cell with a somatotroph phenotype, and rat primary cardiocytes. The CNP promoter did not function at all in other cells, including AtT20 cells of murine pituitary corticotroph origin. Functional analyses of the deleted promoters with various 5' deletion breakpoints revealed the existence of at least two negative and one positive regulatory regions. Within the positive regulatory region (positions -54 to -19), which conferred 90% of the promoter activity in GH3 cells, two equipotent GC-rich cis elements (positions -49 to -45 and -40 to -35) were identified. Both sites shared half of the promoter activity and binding properties to the nuclear protein in GH3 cells. Rat anterior pituitary tissue contained the binding protein of the identified cis element, which was identical or similar to that of GH3 cells. With Southwestern (DNA-protein) analysis, a 70-kDa specific binding protein distinct from known factors such as SP-1, AP-2, and Pit-1 was identified in the nuclear extract of GH3 cells.

Cell-type-specific function of the C-type natriuretic peptide gene promoter in rat anterior pituitary-derived cultured cell lines.

The promoter function of the human C-type natriuretic peptide (CNP) gene in various cultured cells was examined by transient transfection assays. The CNP promoter functioned very effectively in GH3 cells, which originated from the growth hormone-producing tumor of the rat anterior pituitary and somatomammotroph phenotype, but functioned much less effectively in GH1 cells, another type of rat pituitary-derived cell with a somatotroph phenotype, and rat primary cardiocytes. The CNP promoter did not function at all in other cells, including AtT20 cells of murine pituitary corticotroph origin. Functional analyses of the deleted promoters with various 5' deletion breakpoints revealed the existence of at least two negative and one positive regulatory regions. Within the positive regulatory region (positions -54 to -19), which conferred 90% of the promoter activity in GH3 cells, two equipotent GC-rich cis elements (positions -49 to -45 and -40 to -35) were identified. Both sites shared half of the promoter activity and binding properties to the nuclear protein in GH3 cells. Rat anterior pituitary tissue contained the binding protein of the identified cis element, which was identical or similar to that of GH3 cells. With Southwestern (DNA-protein) analysis, a 70-kDa specific binding protein distinct from known factors such as SP-1, AP-2, and Pit-1 was identified in the nuclear extract of GH3 cells.

Pathology of growth hormone-producing tumors of the human pituitary.

This paper reviews the morphologic features of growth hormone-producing tumors of the human pituitary. These tumors are associated with elevated blood growth hormone levels and acromegaly or gigantism and can be classified into the following morphologically distinct entities by the combined application of histology, immunocytology, and electron microscopy: densely granulated growth hormone cell adenoma; sparsely granulated growth hormone cell adenoma; mixed growth hormone cell- prolactin cell-adenoma; acidophil stem cell adenoma; mammosomatotroph cell adenoma; growth hormone cell carcinoma; plurihormonal adenoma with growth hormone production.

Cardiac morphology in rats with growth hormone-producing tumours

Cardiac enlargement and dysfunction are common in patients with acromegaly. Whether these changes are a direct consequence of growth hormone excess is obscured by the high frequency of hypertension, diabetes mellitus, or atherosclerosis in acromegalic patients. In this study, the effects of chronic elevations of growth hormone (GH) upon the heart were studied in rats with GH-producing tumours implanted subcutaneously for 4 weeks. Geometric measurements and histology were employed to detect the presence of cardiac changes. Increased mass was observed in the tumour-bearing animals. When compared with controls, in tumour-bearing rats there were significantly greater (P less than 0.05) right (0.17 +/- 0.03 v. 0.13 +/- 0.01 g) and left (0.62 +/- 0.05 v. 0.50 +/- 0.04 g) ventricular weights, external cardiac dimensions, and myocardial fibre diameters (9.4 +/- 0.6 v. 8.3 +/- 0.4 micron). However, these increases were linearly-related to increased body mass in the tumour-bearing group so that the ratios of ventricular weights to body weight were similar in both groups. Furthermore, no pathologic changes such as myocardial fibrosis or asymmetric septal hypertrophy were present in the tumour-bearing rats. Thus, under the conditions of this study, growth hormone excess induced cardiac growth, which appeared to represent a manifestation of generalized body growth rather than a distinct pathologic process.

DNA and S-phase representation in human growth hormone producing pituitary adenomas.

The DNA contents of 33 pituitary adenomas from patients with acromegaly were analysed with flow-cytofluorometry. Degrees of ploidy and the proliferation rate, expressed as percentage of cells in S-phase, were determined. The aim was to compare these morphological and functional tumour properties with clinical and laboratory parameters to establish a possible relation and to further elucidate the characteristics of these tumours. In 15 tumours (45%) diploid DNA pattern were found, while 18 (55%) showed varying degrees of aneuploidy. The frequency of cells in S-phase showed wide variations and were equally distributed in diploid and aneuploid tumours. Duration of symptoms, age at diagnosis, preoperative growth hormone (GH)- and prolactin (Prl)-levels, tumour size and grade of invasive tumour growth as determined by radiological estimations, did not correlate to ploidy or grade of proliferation. The lack of correlation between DNA pattern and proliferation rate in relation to clinical, laboratory and radiological parameters in tumours causing acromegaly contrasts to the documented relation between the degree of ploidy, cells in proliferation and grade of malignancy reported in tumours of other sites. The 55% aneuploid GH producing tumours indicate a certain malignant transformation. The high frequency of cells in S-phase in several GH secreting tumours completes the malignant morphological and functional cell properties. The benign character of tumours causing acromegaly is therefore in contrast to these findings. The lack of clinical significance of the DNA pattern and the frequency of cells in proliferation in GH producing tumours and the benign character despite malignant cell properties in most of these tumours are difficult to explain.(ABSTRACT TRUNCATED AT 250 WORDS)