Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among 288 patients with prolactinoma (aged 12-62 years; 242 women), 27 were diagnosed as resistant to bromocriptine as their plasma prolactin (PRL) levels remained elevated despite long-term (3 months or more) treatment at high doses (> or = 15 mg daily). These 18 women and 9 men, aged 29 +/- 9 years (mean +/- SD, range 13-50), followed-up for 8 +/- 4 years, had microadenomas (n = 6) or macroadenomas. They were treated by dopamine agonists alone (n = 6) or associated with surgical or radiation therapy. In 8 cases repetitive surgical treatments were necessary. Among the 24 patients who were treated with the nonergot dopamine agonist CV 205-502 after unsuccessful bromocriptine treatment, half of them (9 women, 3 men) resumed normal PRL levels on doses ranging from 0.15 to 0.45 mg/day. Despite daily doses of CV 205-502 from 0.3 to 0.525 mg, the remaining patients were not normalized by this drug which did not prevent tumor growth in 4 of them. Two patients died from invasive cerebral extensions of their tumor and a third had vertebral metastases with positive anti-PRL immunostaining. It is concluded that bromocriptine-resistant prolactinomas represent the most severe aspect of this disease and that a more powerful dopamine agonist like CV 205-502 is effective in only a fraction of these patients.
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PMID:Prolactinomas and resistance to dopamine agonists. 130 23

Experience with PRL-secreting macroadenomas in the pediatric and adolescent population is limited. Although use of synthetic GH after treatment of central nervous system tumors in children without active disease is accepted practice, reports of GH use in patients with central nervous system tumors in situ are rare. Furthermore, the effect of GH on tumor growth is not known. We report GH treatment (10 and 11.5 months), concomitant with bromocriptine (BC; dopamine agonist) therapy in two children, a 15.5-yr-old male and a 15.5-yr-old female, with PRL-secreting macroadenomas in situ. Surgical resection was deemed undesirable because of the risk of major morbidity due to the large size of the tumors and the close proximity to major vessels. Both patients were GH deficient and had heights below the fifth percentile coupled with arrested pubertal progress. During BC therapy, a decrease in tumor size and a reduction in serum PRL levels occurred in both patients, which continued after the addition of GH treatment. Neither patient experienced changes in visual acuity during combined treatment, and both experienced marked improvement in growth velocity. We conclude that in children with PRL-secreting tumors and GH deficiency in whom surgery is not advised, combined treatment with BC and GH appears to be safe and efficacious. To our knowledge, these patients represent the first report of the combined therapeutic use of BC and GH as the primary mode of treatment in children with prolactinoma in situ with documented GH deficiency.
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PMID:Combined bromocriptine and growth hormone (GH) treatment in GH-deficient children with macroprolactinoma in situ. 161 34

Positron emission tomography (PET) allows to detect in coincidence photons issued from annihilation between positrons and electrons nearby situated. Tomographic detection (plane by plane) and tomographic reconstruction will lead to the quantitation of radioactive distribution per voxel, in the organ of interest. Recent tomographs can acquire simultaneously several transaxial slices, with a high sensitivity and a spatial resolution of 3-5 mm. Commonly used positron emitters have a short half-life: 2, 10, 20 and 110 min for 150, 13N, 11C and 18F, respectively. The use of these isotopes requires on line production of radionuclides and synthesis of selected molecules. In endocrinology, PET allows among others to study noninvasively the receptor density of hormone-dependent neoplasms such as breast, uterus, prostate tumors and prolactinomas. These last tumors represent a particular entity because of several combined characteristics: high turnover rate of amino acids, high density of dopaminergic receptors and response to bromocriptine (analogue of dopamine inhibiting the secretion of prolactin) in relation to the level of receptors. Because PET permits to evaluate the density of dopaminergic receptors and the metabolism of amino acids, theoretical response of the prolactinoma to bromocriptine can be predicted, the achieved therapeutic efficacy can be estimated and the long-term follow up of tumor growth can be assessed. This example illustrates the clinical value of PET in endocrinology.
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PMID:[Methods and clinical applications of positron emission tomography in endocrinology]. 229 30

Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Resistance to bromocriptine in prolactinomas. 276 Jan 67

Three animal models of pituitary tumors were compared: the spontaneous prolactinoma in Wistar/Furth (W/Fu) rats, an estrogen-induced transplantable tumor in the Fischer rat (MtTF4), and a spontaneous prolactin transplantable tumor in the W/Fu rat (SMtTW1). The spontaneous prolactinoma in W/Fu rats is interesting in that it resembles the human prolactinoma by its morphological characteristics, its benign nature, and its secretion of prolactin alone. It may be useful to study the initial factors of tumorigenesis but it is very expensive and the variability of tumor growth makes it difficult to plan experiments. The MtTF4 tumor is an easy model to study because it is transplantable but this tumor differs from most human pituitary tumors by its induction by estrogen, its malignancy, its undifferentiated aspect and its secretion of ACTH, GH, and prolactin. The SMtTW1 tumor, a new model of transplantable tumor, is close to the human pituitary tumor because the initial tumor is spontaneous, the transplanted tumors are benign and well differentiated. They secrete prolactin only. These transplantable tumors are valuable for studying the factors of growth. Since no single tumor system is a perfect model, researchers have to work on different models each of which is appropriate for investigating specific problems.
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PMID:Animal models of human pituitary tumors. 307 May 14

Twenty patients with a novel, frequently aggressive type of pituitary adenoma, termed silent subtype 3 adenoma on the basis of fine structural criteria, are reported. The surgically removed tumors were studied by morphological techniques, and the findings were correlated with clinical and biochemical data. All tumors were macroadenomas, often with parasellar extension. The histologically diffuse tumors frequently exhibited focal immunopositivity for one or more adenohypophysial hormones, although the majority of adenoma cells were negative. The tumors had characteristic electron microscopic features, assuring specific diagnosis and delineating this tumor type as a distinct ultrastructural entity. The tumors were removed from 9 women and 11 men (median ages, 27 and 41 yr, respectively). In all women, mild to moderate hyperprolactinemia and its sequelae were present from the early phase of the disease, leading to the erroneous diagnosis of prolactinoma. Bromocriptine therapy (3 patients) reduced serum PRL levels to normal, but failed to halt tumor growth. In men, most adenomas were nonfunctioning; 4 men had mild to moderate hyperprolactinemia. Three men had elevated serum GH levels and acromegaly, suggestive of multidirectional differentiation. Although the putative cell type giving rise to silent subtype 3 adenomas is not known, the tumor should be recognized to avoid erroneous diagnosis and inappropriate treatment.
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PMID:A novel type of pituitary adenoma: morphological features and clinical correlations. 337 77

Men with PRL-producing macroadenomas often present with hypogonadism and impotence. This report documents exacerbation of a PRL-secreting tumor after two separate 200-mg testosterone enanthate (T) injections despite continued bromocriptine (BRC) therapy. A 37-yr-old man with a 60-mm invasive tumor and a serum PRL level of 13,969 +/- 332 ng/ml (mean +/- SD) responded to BRC therapy with rapid disappearance of visual field defect, headache, and facial pain as well as decrease in serum PRL to 5,103 +/- 1,446 ng/ml. T injection was followed by severe headache, facial pain, and increase in PRL to 13,471 ng/ml. Visual field deterioration and increased tumor size (height, 40-43 mm) by computed tomography were documented. A relationship between T injection and exacerbation of the prolactinoma was not recognized until after a second T injection 3 months later. After that therapy, baseline PRL increased from 6,900 to 12,995 ng/ml. The hypothesis that T was aromatized to estradiol, directly stimulating lactotrophs, was supported by an increase in serum estradiol from 24 to 51 pg/ml after the second T injection. Although T treatment is accepted as appropriate therapy for hypogonadism in men with prolactinomas, it may not only interfere with the response of the tumor to BRC therapy, but even stimulate tumor growth and secretion.
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PMID:Testosterone-related exacerbation of a prolactin-producing macroadenoma: possible role for estrogen. 379 56

The most effective therapy of human prolactinomas is represented by dopamine D-2 receptor agonists; there is, however, a population of nonresponder patients who require surgical intervention. In the present study, we report that prolactinomas totally resistant to pharmacological therapy have a high potential of both growing in soft agar and forming tumors in nude mice and lack D-2 receptors for dopamine. These tumors express the receptors for nerve growth factor (NGF) and are sensitive to its differentiating activity. After exposure to NGF for 4 days, prolactinoma cells decreased their proliferation rate, lost their capability to form colonies in soft agar, lost their tumorigenic activity in nude mice, and reexpressed the lactotroph-specific D-2 receptor protein inhibiting prolactin release. These effects were permanent after NGF withdrawal and were reproducible in vivo in nude mice transplanted with the tumors. NGF in fact remarkably and lastingly depressed tumor growth and induced expression of D-2 receptors when injected intravenously once a day for 5 days into prolactinoma-bearing nude mice. These data suggest that NGF may induce a long-lasting switch of gene expression in human prolactinomas, modifying their transforming phenotype and reverting them to more differentiated, less malignant, dopamine-sensitive lactotroph-like cells. The possibility thus arises that short-term treatment with NGF may restore the refractory patients to conventional pharmacological therapy with D-2 agonists.
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PMID:Nerve growth factor suppresses the transforming phenotype of human prolactinomas. 836 48

We have shown previously that human prolactinomas express transforming sequences of the heparin-binding secretory transforming gene (hst) which encodes fibroblast growth factor-4 (FGF-4). To elucidate the role of hst in pituitary tumorigenesis we treated primary rat pituitary and pituitary tumor cell cultures with recombinant FGF-4 and also stably transfected pituitary cell lines with full-length human hst cDNA. Transfectants were screened for hst mRNA expression and FGF-4 production. FGF-4 (0.1-50 ng/ml) caused a dose-dependent 2.5-fold increase of prolactin (PRL) secretion (P < 0.001) in GH4 cells and up to 60% (P < 0.05) in primary cultures, while decreasing growth hormone release (P < 0.001). GH4 hst transfectants displayed markedly enhanced basal PRL secretion (threefold, P < 0.001) and also proliferated faster (P < 0.001). FGF-4 treatment of wild-type GH4 cells, transiently transfected with an expression construct (rPRL.luc) containing a luciferase reporter driven by the rPRL promoter, resulted in a dose-dependent increase of up to 3.3-fold in PRL transcriptional activity. Tumors derived from in vivo subcutaneous injection of GH4 hst-transfected cells strongly expressing FGF-4 grew more aggressively as assessed by histologic invasiveness and proliferating cell nuclear antigen staining (P < 0.01). The results indicate that hst overexpression mediates lactotrope tumor growth and potently stimulates PRL synthesis. Thus, hst may directly facilitate prolactinoma development via paracrine or autocrine action of its secreted protein, FGF-4.
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PMID:Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription. 855 Aug 32

Prolactinomas in women commonly present as small intrasellar tumors, but are usually much larger in men. This discrepancy has generally been attributed to differences in the delay before diagnosis. However, studies comparing clinical and pathological correlates of growth of these tumors in both sexes are lacking. We conducted a retrospective study comparing 45 men and 51 women bearing prolactinoma to determine whether the predominance of large tumors in men was due to a delay in diagnosis or, rather, to a fundamental sex-related difference in tumor growth. Basal PRL levels (mean +/- SEM, 2789 +/- 573 ng/mL) and mean tumor diameter (26 +/- 2 mm) were significantly higher in men than in women (292 +/- 74 ng/mL and 10 +/- 1 mm, respectively; P < 0.001), but were not correlated to the age at diagnosis or the duration of symptoms. Giant tumors (n = 8) occurred in males only. The frequencies of bromocriptine-resistant tumors (30 vs.5%; P < 0.01) and invasive macroadenomas (52 vs.27%; P < 0.001) were significantly greater in men than those in women. Lastly, macroprolactinomas in males exhibited higher indexes of proliferating cells by Ki-67 immunoreactivity (2.6 +/- 1.1% of positive nuclei) than did similar tumors in female patients (0.4 +/- 0.2%; P = 0.08). We conclude that the predominance of large prolactinomas in men is due to a high frequency of rapidly growing tumors, which are often invasive and frequently bromocriptine resistant.
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PMID:Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. 1129 30


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