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Marcello D Bronstein

Publications and source records attributed to Marcello D Bronstein.

9 recordsLinked to original sources
PubMed2007

PTTG expression in different experimental and human prolactinomas in relation to dopaminergic control of lactotropes.

BACKGROUND: Pituitary tumor transforming gene (pttg) is a novel oncogene that is expressed at higher level in most of the tumors analyzed to date compared to normal tissues. Nevertheless, its expression in prolactinomas and its relation with the pituitary dopamine receptor 2 (D2R) are not well defined. We sought to determine the pituitary level of pttg in three different experimental models of prolactinomas with altered dopaminergic control of the pituitary: the dopaminergic D2R knockout female mouse, the estrogen-treated rat, and the senescent female rat. These three models shared the characteristics of increased pituitary weight, hyperprolactinemia, lactotrope hyperplasia and reduced or absent dopaminergic action at the pituitary level. We also studied samples from human macroprolactinomas, which were characterized as responsive or resistant to dopamine agonist therapy. RESULTS: When compared to female wild-type mice, pituitaries from female D2R knockout mice had decreased PTTG concentration, while no difference in pttg mRNA level was found. In senescent rats no difference in pituitary PTTG protein expression was found when compared to young rats. But, in young female rats treated with a synthetic estrogen (Diethylstylbestrol, 20 mg) PTTG protein expression was enhanced (P = 0.029). Therefore, in the three experimental models of prolactinomas, pituitary size was increased and there was hyperprolactinemia, but PTTG levels followed different patterns.Patients with macroprolactinomas were divided in those in which dopaminergic therapy normalized or failed to normalize prolactin levels (responsive and resistant, respectively). When pituitary pttg mRNA level was analyzed in these macroprolactinomas, no differences were found. We next analyzed estrogen action at the pituitary by measuring pituitary estrogen receptor alpha levels. The D2R knockout female mice have low estrogen levels and in accordance, pituitary estrogen receptors were increased (P = 0.047). On the other hand, in senescent rats estrogen levels were slightly though not significantly higher, and estrogen receptors were similar between groups. The estrogen-treated rats had high pharmacological levels of the synthetic estrogen, and estrogen receptors were markedly lower than in controls (P < 0.0001). Finally, in patients with dopamine resistant or responsive prolactinomas no significant differences in estrogen receptor alpha levels were found. Therefore, pituitary PTTG was increased only if estrogen action was increased, which correlated with a decrease in pituitary estrogen receptor level. CONCLUSION: We conclude that PTTG does not correlate with prolactin levels or tumor size in animal models of prolactinoma, and its pituitary content is not related to a decrease in dopaminergic control of the lactotrope, but may be influenced by estrogen action at the pituitary level. Therefore it is increased only in prolactinomas generated by estrogen treatment, and not in prolactinomas arising from deficient dopamine control, or in dopamine resistant compared with dopamine responsive human prolactinomas. These results are important in the search for reliable prognostic indicators for patients with pituitary adenomas which will make tumor-specific therapy possible, and help to elucidate the poorly understood phenomenon of pituitary tumorigenesis.

Adult↗
PubMed2006

[Pituitary tumorigenesis].

Pituitary adenomas, almost invariably adenomas, account for 10% to 15% of all intracranial neoplasms and are incidentally detected in up to 27% of non selected autopsies. They are morphologically classified as microadenomas (diameter < 1 cm) or macroadenomas, which can be enclosed, invasive and/or expansive. Functionally, they are classified as secreting adenomas (PRL, GH, ACTH, TSH, LH, and FSH, and those co-secreting two or more hormones), and clinically non secreting or "non functioning" tumors. Diagnosis is based on the hypersecretion phenotype (acromegaly, Cushing, etc), and on mass effect of macroadenomas leading to neurological disturbances, mainly visual complaints and headache. Pituitary tumorigenesis mechanisms include those of primary hypothalamic versus pituitary origin, the latter is supported by evidence of pituitary adenoma monoclonality, as well as the absence of hyperplastic tissue surrounding the surgically removed tumor, and the relative independence of tumor hypothalamic control. Nevertheless, a permissive role of the hypothalamus on tumor progression is also postulated. Several molecular mechanisms involved in pituitary tumorigenesis have been unraveled including oncogenes, tumor suppressor genes and growth factors involved in neoplastic development, and will be described in this review.

Adenoma↗
PubMed2006

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas.

In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

Adenoma↗
PubMed2006

Acromegaly: molecular expression of somatostatin receptor subtypes and treatment outcome.

About a third of acromegalic patients are resistant to the currently commercially available somatostatin analogs (SA) octreotide and lanreotide. Such resistance is related to an overall reduction of somatostatin receptor (SSTR) density or to a differentiated expression of SSTR subtypes. There are five known SSTR subtypes. SSTR2 and SSTR5 are usually expressed in GH-secreting pituitary tumors, and both octreotide and lanreotide bind preferentially to SSTR2 and, to a lesser extent, to SSTR5. SA inhibitory effects on GH secretion and tumor cell proliferation can occur together or be dissociated events, depending on the tumor expression of SSTR subtypes involved in each mechanism. The development of specific somatostatin subtypes analogs, mainly for SSTR5, of a SSTR2-SSTR5 bispecific compound, and of a "universal" analog with high affinity to SSTR1, 2, 3, and 5 showed preliminary, albeit promising results for the treatment of resistant somatotropic adenomas.

Acromegaly↗
PubMed2005

Human macroprolactin displays low biological activity via its homologous receptor in a new sensitive bioassay.

CONTEXT: Macroprolactinemia is a frequent finding in hyperprolactinemic individuals, usually without clinical impact. Data on biological activity of macroprolactin (bbPRL) are controversial and mostly based on a heterologous rat Nb2 cell bioassay. Biological activity of bbPRL observed in vitro but not in vivo may be due to its high molecular weight, preventing its passage through capillary barrier. Alternatively, bbPRL bioactivity may differ depending on the prolactin (PRL) receptor (PRLR) species specificity. OBJECTIVE: The objective of the study was to characterize the bioactivity of bbPRL in a homologous bioassay: Ba/F-3 cells stably expressing the human PRLR. DESIGN/SETTING/PATIENTS: Chromatography-purified bbPRL from macroprolactinemic individuals (group I, n = 18) and monomeric PRL from hyperprolactinemic patients without macroprolactinemia (group II, n = 5) were tested in Nb2 and Ba/F-LLP bioassays. Both groups were followed up at the neuroendocrinology outpatients' clinic. MAIN OUTCOME MEASURE: Biological activity of bbPRL presented in the two bioassays was measured. RESULTS: In group I, no patient had hypogonadism. Mean ratio bioactivity to immunoactivity of bbPRL in the Nb2 assay was 0.69. There was no dose-response in 15 of the 18 samples tested in Ba/F-LLP assay. In group II, three patients had galactorrhea and all five had hypogonadism. Mean ratio bioactivity to immunoactivity of monomeric PRL samples was 1.35 in Nb2 and 0.91 in Ba/F-LLP assay. CONCLUSION: Whereas both bioassays achieve similar results with respect to monomeric PRL activity, our results indicate that the activity displayed by bbPRL toward the rat receptor may be inappropriate because it is not observed in the human PRLR-mediated assay, consistent with the apparent absence of bioactivity in vivo.

Adult↗
PubMed2005

Treatment of acromegaly with octreotide-LAR: extensive experience in a Brazilian institution.

OBJECTIVE: Somatostatin analogues have become the mainstay of the medical treatment of acromegaly. The aim of our study was to evaluate the efficacy and tolerability of octreotide-LAR (OCT-LAR) treatment in acromegalic patients. DESIGN: Prospective open trial. PATIENTS AND METHODS: Eighty acromegalic patients (46 women; 18-80 years) were treated with OCT-LAR. Mean +/- SD duration of follow-up was 16.6 +/- 6.6 months (6-24 months). Twenty-eight patients received OCT-LAR as primary treatment. The target was to achieve normal IGF-I levels. Clinical activity was evaluated by symptom score and fasting samples for GH and IGF-I serum concentrations, obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging of the sella. A tumour volume reduction of at least 25% was considered significant. RESULTS: Clinical improvement was attained in most patients. Fifty-nine (74%) of them attained mean GH < 2.5 ng/ml and 33 (41%) achieved normal IGF-I by the 24th month of treatment. GH and IGF-I control increased throughout treatment. Regarding the 46 patients treated for at least 12 months there was a significant decrease of GH and IGF-I levels by the third month compared to basal levels, persisting with no subsequently variation. In the patient group that achieved normal serum IGF-1 during treatment (controlled group: n = 43) 20 patients maintained normal levels up to the latest follow-up, whereas 23 of them once again showed altered serum IGF-1-values of some measurements during follow-up, despite dose maintenance or elevation. Baseline percentage of the upper limit of IGF-I normal range, GH levels by the third month and length of treatment were predictive factors of IGF-I normalization. Tumour shrinkage occurred in 76% of primary patients. Among 21 diabetic patients, four worsened and five improved glycaemic control, based on glycated haemoglobin. One previously intolerant patient progressed to overt diabetes. Nine patients developed gall bladder sludge, other nine patients acquired microlithiasis and one patient developed gallstone pancreatitis. CONCLUSION: OCT-LAR is an effective agent in alleviating symptoms, suppressing GH, normalizing IGF-I and inducing tumour shrinkage in many acromegalic patients. Overall, OCT-LAR is well tolerated and should be recommended for nonsurgically cured acromegalics, and also be considered as primary therapy for selected cases, mainly for those with a low probability of surgical cure.

Acromegaly↗
PubMed2004

A meiotic recombination in a new isolated familial somatotropinoma kindred.

We report here the genetic findings of a new isolated familial somatotropinoma (IFS) kindred in which the mother (subject I:2) and one daughter (subject II:2) are affected; their ages at diagnosis were 25 and 14 years respectively. Additionally, patient I:2 developed virilization due to an androgen-secreting adrenocortical mass, presenting clinical and molecular features of sporadic adrenal carcinoma. To genotype this family and to narrow down the candidate interval of the putative IFS gene at 11q13, we performed haplotyping on the DNA from all five members of the family and allelotyping of one available somatotropinoma using polymorphic microsatellite markers from chromosome region 11q12.1-11q13.5. Results indicated that the disease haplotype, between markers D11S956 and D11S527, was transmitted from subject I:2 only to subject II:2. A meiotic recombination event was detected in the fraternal twin sister of II:2 (subject II:1), but her disease status is unknown. Since she is only 18 years old this genetic event cannot yet narrow down the area involved in the pathogenesis of IFS. Allelotyping of the somatotropinoma from II:2 revealed loss of the chromosome carrying the wild-type copy of the putative IFS gene inherited from her father. These results support the involvement of a tumor suppressor gene at 11q13.1-q13.3 in the pathogenesis of IFS.

Acromegaly↗
PubMed2002

Long-term follow-up of prolactinomas: normoprolactinemia after bromocriptine withdrawal.

Bromocriptine (BRC) and other dopamine agonist drugs are the first-choice treatment for prolactinomas. However, the major disadvantage is the need for prolonged therapy. We retrospectively studied 131 patients [62 microprolactinoma (MIC), 69 macroprolactinoma (MAC)], who achieved serum prolactin (PRL) normalization during BRC use. Twenty-seven percent of them (31% MIC and 69% MAC) underwent previous surgery. Twenty-seven patients (20.6%: 25.8% MIC and 15.9% MAC) persisted with normoprolactinemia after a median time of 44 months of BRC withdrawal. The median time of BRC use was 47 months. There were no statistically significant differences regarding age, gender, BRC initial dose, length of BRC use, tumor size, pregnancy during treatment, previous surgery, or radiotherapy among patients who persisted with normoprolactinemia and those who did not, using both univariate and multivariate analysis. BRC-induced prolactinoma cell alterations are highly controversial; and so, whether the mechanism of PRL normalization after BRC withdrawal is related to BRC use or whether it is attributable to natural history is a matter for debate. A periodic assessment of PRL levels during BRC (and other dopamine-agonist drugs) withdrawal is recommended to avoid the unnecessary maintenance of therapy in a subset of patients with prolactinomas.

Adolescent↗