MARCELLO DELANO BRONSTEIN
Projetos de Pesquisa
Unidades Organizacionais
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
23 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 23
- Cabergoline and prolactinomas: lack of association between DRD2 polymorphisms and response to treatment(2017) BUENO, C. B. F.; TRARBACH, E. B.; BRONSTEIN, M. D.; GLEZER, A.Background About 80% of prolactinomas respond to dopamine agonists (DA) with hormonal normalization and tumor shrinkage. Mechanisms of DA resistance include reduction of dopamine receptor subtype 2 (DRD2) expression, short and long isoform ratio and post-receptor mechanisms. It was suggested that polymorphisms in the gene encoding dopamine receptor subtype 2 gene (DRD2) could be associated with variable effectiveness of cabergoline (CAB). Objective To assess the influence of DRD2 polymorphisms in responsiveness of CAB treatment in patients with prolactinoma. Study design and patients Cross-sectional retrospective case-control study analyzing the frequency of five DRD2 polymorphisms in 148 patients with prolactinoma and 349 healthy subjects. The association of genetic variants and clinical characteristics with CAB responsiveness was performed in 118 patients (mean age at diagnosis 29 years; range 11-61 years) with hormonal evaluation. Patients with prolactin (PRL) normalization were considered as responders. Results No association in genotypes and allele proportions was found comparing patients and controls. On pharmacogenetic study, 118 patients on CAB were included and 20% were non-responders. No association was found between clinical characteristics (gender, age, PRL level and tumor size at diagnosis) and polymorphisms of DRD2 with CAB responsiveness. Otherwise, there was association between polymorphisms rs1076560 (allele A) and rs1800497 (allele T) and the presence of macroadenomas. Conclusion No correlation was found between DRD2 polymorphisms and CAB responsiveness in patients with prolactinoma. More data are necessary in order to assess the influence of DRD2 genotyping on DA treatment response.
- The Pituitary Gland in Pregnancy(2022) GLEZER, A.; BRONSTEIN, M. D.During pregnancy, pituitary morphology and function are modified by placental hormonal secretion. Pituitary volume is increased due to lactotroph hypertrophy and hyperplasia. Placental sex steroids inhibit GnRH and gonadotropin secretion. The placenta secretes a variant isoform of GH, increasing IGF-1 levels. TSH secretion decreases in the first trimester, secondary to thyroid stimulation by human chorionic gonadotropin. Hepatic production of thyroid-binding globulin is stimulated by estrogens, increasing total T4 and T3. Placental CRH stimulates pituitary and placental ACTH, increasing cortisol levels throughout pregnancy. Infertility is common in patients harboring pituitary tumors. Pathophysiology includes hormonal hypersecretion and tumoral mass effect. Hypopituitarism can also result from surgery and/or radiotherapy for pituitary adenoma treatment. Hyperprolactinemia, occurring in prolactinomas, the most common subtype of pituitary adenomas, and other pituitary tumors, inhibits GnRH pulsatility. Different mechanisms seem to play a role in hypogonadism of patients harboring acromegaly: tumoral gonadotroph compression, hyperprolactinemia, and GH/IGF-1 excess disrupting gonadal axis. In Cushing's disease, hypogonadism is mainly due to the negative impact of hypercortisolism and hyperandrogenism in the gonadotrophic axis. Clinically nonfunctioning pituitary tumors seldom are associated with pregnancy. In pituitary adenomas, treatment is often necessary to control hormonal hypersecretion and tumor mass effect related to infertility. Other causes of infertility include lymphocytic hypophysitis and Sheehan's syndrome. This chapter reviews the pathophysiology, diagnosis, and therapeutic approaches for women with pituitary diseases, before and during pregnancy, in order to induce fertility and avoid the deleterious effects of hormonal hyper- or hyposecretion. © 2022 Elsevier Inc. All rights reserved.
- Pituitary autoimmune disease: nuances in clinical presentation(2012) GLEZER, A.; BRONSTEIN, M. D.Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH.
- A consensus on the diagnosis and treatment of acromegaly complications(2013) MELMED, S.; CASANUEVA, F. F.; KLIBANSKI, A.; BRONSTEIN, M. D.; CHANSON, P.; LAMBERTS, S. W.; STRASBURGER, C. J.; WASS, J. A. H.; GIUSTINA, A.In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed.
- Ketoconazole Treatment Decreases the Viability of Immortalized Pituitary Cell Lines Associated with an Increased Expression of Apoptosis-Related Genes and Cell Cycle Inhibitors(2015) GUZZO, M. F.; CARVALHO, L. R.; BRONSTEIN, M. D.Ketoconazole, which was initially developed as an antifungal agent, is a potent inhibitor of adrenal steroidogenesis and has therefore been used in the management of Cushing's disease. Surprisingly, the reduction of cortisol levels during ketoconazole treatment is not accompanied by the expected elevation in plasma adrenocorticotrophic hormone (ACTH) at the loss of negative cortisol feedback from corticotrophic cells, suggesting a direct effect of ketoconazole on these cells. To characterize the direct effects of ketoconazole, we evaluated its invitro effect on cell viability using the pituitary tumoural cell lines AtT-20 (which secretes ACTH), GH3 (which secretes growth hormone and prolactin) and T3.1 (which secretes -subunit) and we also determined the expression levels of genes involved in apoptosis and DNA replication by the quantitative reverse transcription polymerase chain reaction (qRT-PCR). We also evaluated ACTH levels in AtT-20 cells during ketoconazole treatment. We observed a ketoconazole concentration-dependent decrease in pituitary cell viability and reduced ACTH levels in AtT-20 cells after removal of the drug. We also observed increased expression of cell death receptors (e.g. Fas, tumour necrosis factor receptor) and caspases (e.g., caspase-6, caspase-7, caspase-9), suggesting activation of the apoptosis pathway. In addition, we observed increased gene expression of the cell cycle inhibitors p21 and p27 in GH3 cells and increased expression of p21 in T3.1 cells. In conclusion, our findings suggest that ketoconazole significantly reduces cell viability in a concentration-dependent manner in pituitary tumour cell lines and is associated with an increase in apoptosis- and cell cycle regulation-related gene expression.
- Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study(2014) COLAO, A.; BRONSTEIN, M. D.; FREDA, P.; GU, F.; SHEN, C. -C.; GADELHA, M.; FLESERIU, M.; LELY, A. J. van der; FARRALL, A. J.; RESENDIZ, K. Hermosillo; RUFFIN, M.; CHEN, Y.; SHEPPARD, M.Context: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. Objective: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. Design and Setting: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. Patients: A total of 358 patients with medically naive acromegaly (GH > 5 mu g/L or GH nadir >= 1 mu g/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. Interventions: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH >= 2.5 mu g/L and/or IGF-1 was above the upper limit of normal. Main Outcome Measure: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 mu g/L and normal IGF-1) at month 12. Results: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 mu g/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). Conclusions: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
- Disorders of Prolactin Secretion and Prolactinomas(2015) BRONSTEIN, M. D.
- Pituitary Physiology During Pregnancy and Lactation(2020) JALLAD, R. S.; GLEZER, A.; MACHADO, M. C.; BRONSTEIN, M. D.Pregnancy promotes a physiologic increase in the size of the maternal pituitary gland, especially the adenohypophysis, mainly due to estrogenic stimulation of lactotrophs. Prolactin promotes mammary gland differentiation and ensures milk production after delivery. Hyperprolactinemia inhibits gonadotrophin secretion. Placental growth hormone has a key role in the maternal adaptation, being closely related to fetal growth, and is a potential candidate to mediate insulin resistance observed in late pregnancy. Normal gestation is considered a state of hypercortisolism due to physiological activation of the hypothalamic-pituitary-adrenal axis. Although important changes in the physiology of the pituitary-thyroid axis occur, mainly due to the increase in chorionic gonadotrophin and thyroxin-binding globulin levels, the normal pregnant woman usually remains euthyroid. Gonadotrophin secretion is inhibited, preventing the stimulation of new ovarian follicles and, consequently, ovulation throughout the gestation period. The increase in antidiuretic hormone during pregnancy is balanced by placental vasopressinase activity, keeping plasma levels similar to that in nonpregnant subjects. Serum oxytocin concentrations gradually increase during gestation and reach peak values during labor. In conclusion, pregnancy is a state of integration of three complex and physiological neuroendocrine compartments: maternal, placental, and fetal. Each plays a critical role in maintaining the health of the embryo/fetus, placenta, and mother up to delivery. © 2020 Elsevier Inc. All rights reserved.
- Pituitary Disorders During Pregnancy and Lactation(2020) JALLAD, R. S.; GLEZER, A.; MACHADO, M. C.; BRONSTEIN, M. D.The presence of a pituitary adenoma may affect the course of pregnancy, as the hormonal changes related to these tumors may lead to early termination of pregnancy due to failure to implant or maintain the conceptus or early embryo. The age-adjusted incidence rate of pituitary adenomas is estimated to be 3.4 cases per 100,000 inhabitants per year. They are usually benign adenomas, with a peak incidence in young women of childbearing age. The management of pituitary adenomas during pregnancy depends on its clinical presentation and should be adapted to the individual case. Most pregnant women with pituitary adenomas can be safely observed with frequent neuro-ophthalmologic assessments and MRI, if needed. Among women with pituitary adenomas, prolactin (PRL)-secreting pituitary adenomas (prolactinomas) are the most common. Dopamine agonists (DAs) are the gold standard treatment for prolactinomas; they normalize serum PRL levels, leading to tumor shrinkage in more than 80% of cases and restoration of eugonadism. In micro- and intrasellar macroprolactinomas, DA is usually withdrawn when pregnancy is confirmed. In pregnant women with acromegaly, hormonal control is often achieved in most patients, allowing the withdrawal of clinical treatment. Due to similar clinical features and changes in the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, the diagnosis of Cushing disease (CD) during gestation can be difficult. Similar to nonpregnant women, surgery is the first treatment option for CD during pregnancy, if complications develop. Overall, pregnancy in women harboring clinically nonfunctioning tumors is a rare event. Causes of hypopituitarism that are most specific to pregnancy include lymphocytic hypophysitis and postpartum pituitary infarction (Sheehan’s syndrome). During pregnancy, the priority for hormonal replacement should be glucocorticoid, followed by thyroid hormone. Doses should be adjusted throughout pregnancy based on the severity and nature of the condition. For this reason, it is necessary to follow these patients regularly and closely during pregnancy. Central or nephrogenic diabetes insipidus (DI) can also be observed during pregnancy. Therefore, a detailed medical history is essential for the differential diagnoses of DI. Primary polydipsia and head trauma should be excluded. Ingestion of drugs such as lithium, mannitol, diuretics, and anticholinergic drugs should be questioned. Management of pituitary disease during pregnancy in otherwise healthy women poses difficult challenges from various perspectives. However, a multidisciplinary approach, involving the endocrinologist, obstetrician, neurosurgeon, and anesthesiologist, will allow a better outcome for both mother and fetus during pregnancy. © 2020 Elsevier Inc. All rights reserved.
- Resolution of Cyclicity After Pasireotide LAR in a Patient With Cushing Disease(2021) MACHADO, M. C.; CESCATO, V. A. S.; FRAGOSO, M. C. B. V.; BRONSTEIN, M. D.Objective: The cyclicity (CIC) of cortisol spontaneously occurs in a minority of patients with Cushing syndrome (CS). When it arises, diagnostic and therapeutic approaches become more challenging. This study aimed to report a patient with Cushing disease (CD) who achieved normalization of cortisol and CIC pattern with pasireotide long-acting release (pasi/LAR). Methods: A 43-year-old female patient related an 8-month history of CS. An 8-mm pituitary nodule depicted by magnetic resonance imaging, serum cortisol suppression of >50% after 8 mg of dexamethasone therapy, and the absence of other lesions were compatible with a CD diagnosis. The patient presented with a CIC pattern with 1 episode before and 17 episodes after an unsuccessful pituitary surgery. Results: Medical treatment with cabergoline alone up to 3.5 mg/wk and a combined treatment with ketoconazole 400 mg/d did not improve CIC CS. Pasi/LAR was initiated at a dose of 20 mg/mo. A few days after the first dose, the patient experienced symptoms suggestive of adrenal insufficiency. The medication and dose were maintained for 24 months. During this period, there was a normalization of UFC levels and progressive clinical improvement. Additionally, new episodes of CIC were not observed. Conclusion: A CD patient with a challenging issue of CIC was reported. The condition was not controlled after pituitary surgery and by the combined treatment with cabergoline and ketoconazole, although hypercortisolism was abated by the continuous use of pasi/LAR. To our knowledge, this is the first report as regards the use of this medication to control CIC in a patient with CD. © 2021 AACE
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