MARCIO CARLOS MACHADO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
30 resultados
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- Pregnancy in Patients with Cushing's Syndrome(2018) MACHADO, Marcio Carlos; FRAGOSO, Maria Candida Barisson Vilares; BRONSTEIN, Marcello DelanoProgress in diagnosis and treatment of endocrine diseases has made pregnancy possible for women with endocrinopathies, including Cushing's syndrome (CS). The risk of maternal-fetal complications in patients who are not biochemically controlled, however, is substantial. Therefore, the surgical and/or medical control of hypercortisolism is mandatory before conceiving. A diagnosis of de novo CS during gestation is difficult because of changes in the hypothalamic-pituitary-adrenal axis during pregnancy, which may lead to some clinical features suggestive of CS along with abnormal laboratory test results. This article presents the diagnosis and management of CS during pregnancy.
- The effects of cabergoline in the presurgical and recurrence periods of Cushing's disease patients(2021) PEREIRA, Ana Julia Garcia; ANDRADE, Natalia Xavier Sant' Anna; MUSOLINO, Nina Rosa Castro; CESCATO, Valter Angelo Sperling; SILVA, Gilberto Ochman; FRAGOSO, Maria Candida; BRONSTEIN, Marcello D.; MACHADO, Marcio C.Background: The dopaminergic agonist cabergoline (CAB) has been used in the pharmacological treatment of Cushing's disease (CD). The effect is attributed to the frequent expression of the dopamine receptor subtype 2 in corticotroph tumors. However, in vivo studies have demonstrated the normalization of 24-h urinary cortisol (24-h UC) in approximately 30-40% of patients over the long term, mainly after surgical failure. Objective: To evaluate the effect of CAB as monotherapy in the early preoperative period and on the recurrence of CD. Methods: A single-center retrospective study was conducted in a tertiary referral center. Twenty-one patients with confirmed CD were included. The median age was 32 years (13-70), 86% were female, 10 had microadenomas, and 11 had macroadenomas. They were diagnosed from 1986 to 2016 and used CAB as monotherapy either in the preoperative period (n=7, CABi) or upon recurrence before any other treatment (n=14, CABr). A 'complete response' was considered 24-h UC normalization and a 'partial response' was considered a 24-h UC reduction of >50%. UC was obtained at the last follow-up evaluation. The normalization of late-night salivary cortisol (LNSC) after CAB use was evaluated in most patients, as well as the tumor diameter by pituitary MRI, before and after CAB treatment. Results: Complete response was achieved in 29% (6/21) of subjects after 14.9 +/- 16.4 months of treatment, with an average dose of 2.2 +/- 1.0 mg/week. Partial response occurred in 9.5% (2/21). LNSC normalized in 35% (6/17) of patients, and no variation in tumor diameter before and after CAB use was observed (n=13): 6.8 +/- 6.8 vs. 7.2 +/- 7.1 mm. There was no normalization of 24-h-UC in the CABi subgroup at the end of the treatment, whereas 43% (6/14) of patients in the CABr subgroup reached complete response. The CABi subgroup was treated for 4.7 +/- 1.9 months, and the CABr subgroup was treated for 20.1 +/- 18.1 months. Both groups were administered similar doses of CAB (CABi 2.1 +/- 0.9 and CABr 2.3 +/- 1.1 mg/week). Interestingly, the difference between the subgroups' complete response was evident early on in the three months of treatment: no patients in the CABi subgroup vs. 6/10 (60%) in the CABr subgroup (p=0.035), despite a lower dose in the CABr subgroup (1.1 vs. 1.6; p=0.008). The normalization of LNSC occurred in 20% of the CABi subgroup and in 42% of the CABr subgroup. Conclusions: The normalization of 24-h UC and LNSC occurred in approximately 30% of all patients, mainly in those who used CAB for the recurrence of CD. Despite the small number of subjects in the CABi subgroup, the absence of hormone control in this subgroup discourages the use of this medication as primary therapy or as a preoperative treatment option. PubMed Disclaimer
bookPart Corticotropinomas(2022) MACHADO, Márcio Carlos; FRAGOSO, Maria Candida Barisson VillaresbookPart Síndrome de Cushing(2017) CASTRO, Margaret de; MARTINS, Clarissa; ELIAS, Paula Condé Lamparelli; MACHADO, Marcio Carlos; FRAGOSO, Maria Candida Barrison Villares; MOREIRA, Ayrton Custódioarticle 13 Citação(ões) na Scopus Pregnancy and pituitary adenomas(2016) GLEZER, Andrea; JALLAD, Raquel S.; MACHADO, Marcio C.; FRAGOSO, Maria Candida; BRONSTEIN, Marcello D.Infertility is frequent in patients harboring pituitary adenomas. The mechanisms involved include hypogonadism secondary to hormonal hypersecretion (prolactin, growth hormone and cortisol), stalk disconnection and pituitary damage. With the improvement of clinical and surgical treatment, pregnancy in women harboring pituitary adenomas turned into a reality. Pituitary hormonal hyper- and hyposecretion influences pregnancy outcomes, as well as pregnancy can interfere on pituitary tumors, especially in prolactinomas. We review literature about specific follow-up and management in pregnant women harboring prolactinomas, acromegaly, or Cushings disease and the impact of clinical and surgical treatment on each condition.- 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
bookPart Doença de Cushing(2016) MACHADO, Márcio Carlos; FRAGOSO, Maria Candida B. Villares- Transcriptome analysis showed a Differential signature between invasive and non-invasive corticotrophinomas(2017) ARAUJO, Leonardo Jose Tadeu de; LERARIO, Antonio Marcondes; CASTRO, Margaret de; MARTINS, Clarissa Silva; BRONSTEIN, Marcello Delano; MACHADO, Marcio Carlos; TRARBACH, Ericka Barbosa; FRAGOSO, Maria Candida Barisson VillaresACTH-dependent hypercortisolism caused by a pituitary adenoma [Cushing's disease (CD)] is the most common cause of endogenous Cushing's syndrome. CD is often associated with several morbidities, including hypertension, diabetes, osteoporosis/bone fractures, secondary infections, and increased cardiovascular mortality. While the majority (approximate to 80%) of the corticotrophinomas visible on pituitary magnetic resonance imaging are microadenomas (MICs, <10 mm of diameter), some tumors are macroadenomas (MACs, >= 10 mm) with increased growth potential and invasiveness, exceptionally exhibiting malignant demeanor. In addition, larger and invasive MACs are associated with a significant increased risk of local complications, such as hypopituitarism and visual defects. Given the clinical and molecular heterogeneity of corticotrophinomas, the aim of this study was to investigate the pattern of genetic differential expression between MIC and MAC, including the invasiveness grade as a criterion for categorizing these tumors. In this study, were included tumor samples from patients with clinical, laboratorial, radiological, and histopathological diagnosis of hypercortisolism due to an ACTH-producing pituitary adenoma. Differential gene expression was studied using an Affymetrix microarray platform in 12 corticotrophinomas, classified as non-invasive MIC (n = 4) and MAC (n = 5), and invasive MAC (n = 3), according to modified Hardy criteria. Somatic mutations in USP8 were also investigated, but none of the patients exhibited USP8 variants. Differential expression analysis demonstrated that non-invasive MIC and MAC have a similar genetic signature, while invasive MACs exhibited a differential expression profile. Among the genes differentially expressed, we highlighted CCND2, ZNF676, DAPK1, and TIMP2, and their differential expression was validated through quantitative real-time PCR in another cohort of 15 non-invasive and 3 invasive cortocotrophinomas. We also identified potential biological pathways associated with growth and invasiveness, TGF-beta and G protein signaling pathways, DNA damage response pathway, and pathways associated with focal adhesion. Our study revealed a differential pattern of genetic signature in a subgroup of MAC, supporting a genetic influence on corticotrophinomas in patients with CD.
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