Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis.

Introduction: The first-line treatment for Cushing's disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response. Methods: We searched for articles that evaluated ketoconazole use in Cushing's disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels. Results: After applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism. Conclusion: Ketoconazole can be considered a safe and efficacious option for Cushing's disease treatment after pituitary surgery. Systematic review registration: https://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).

Evaluation of ketoconazole as a treatment for Cushing's disease in a retrospective cohort.

Objective: The first-line treatment for Cushing's disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%, even in those with real initial remission. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and the treatment response to ketoconazole in Cushing's disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital. Patients and methods: This was a retrospective cohort of Cushing's disease patients with active hypercortisolism who used ketoconazole at any stage of follow-up. Patients who were followed up for less than 7 days, who did not adhere to treatment, or who were lost to follow-up were excluded. Results: Of the 172 Cushing's disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, five of whom (15%) had also undergone radiotherapy; seven used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years. A total of 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to nine others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Only four patients had serious adverse effects that warranted discontinuation. There were 20 confirmed episodes of hypokalemia among 10/33 patients (30%). Conclusion: Ketoconazole effectively controlled hypercortisolism in 66% of Cushing's disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out. Hypokalemia is a frequent metabolic effect not yet described in other series, which should be monitored during treatment.

Metabolic effects of antihyperglycemic agents and mortality: meta-analysis of randomized controlled trials.

The effects of antihyperglycemic medications on cardiovascular events and mortality are heterogeneous and their effects on intermediate factors might explain these differences. This systematic review explores the relationship between metabolic factors, mechanism of action, and mortality effects of antihyperglycemic medications in type 2 diabetes. Randomized trials assessing the effects of antihyperglycemic medications on all-cause or cardiovascular mortality in type 2 diabetes were included. Myocardial infarction, stroke, and heart failure were secondary outcomes. The effects of medications on HbA1c, severe hypoglycemia (SH), body weight, systolic blood pressure (SBP), and mechanism of action were evaluated. Meta-analyses and meta-regressions were performed grouping studies according to the above-cited factors. All-cause mortality was lower for medications that reduced HbA1c, SH, body weight, and SBP. Decreased cardiovascular mortality was associated with lower HbA1c, SH, SBP. Myocardial infarction and stroke were also associated with favorable metabolic profile. These findings were not confirmed in meta-regression models. Medications associated with lower SH, body weight and SBP had a lower risk of heart failure. In conclusion, medications with better metabolic profile were associated with reduced all-cause and cardiovascular mortality. These findings are based on indirect comparisons and must be applied cautiously.

Controversial issues in the management of hyperprolactinemia and prolactinomas - An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism.

Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.

Controversial issues in the management of hyperprolactinemia and prolactinomas - An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism

ABSTRACT Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.

Características clínicas de pacientes obstétricas admitidas em uma Unidade de Tratamento Intensivo Terciária: revisão de dez anos / Clinical features and results of obstetric patients admitted to a Tertiary Intensive Care Unit: ten-year review

Introdução: Taxas significativas de morbimortalidade materna ainda podem ser observadas no período gestacional. Um indicador importante de morbidade materna é a necessidade de transferência de paciente obstétrica para a Unidade de Terapia Intensiva. O objetivo do estudo foi avaliar os desfechos maternos e perinatais relacionados a pacientes obstétricas admitidas em unidade de cuidados intensivos. Mé-todos: Estudo observacional e consecutivo das pacientes obstétricas admitidas na Unidade de Tratamento Intensivo do Hospital Geral da Universidade de Caxias do Sul, de Março/1998 a Dezembro/2008. Foram analisadas variáveis maternas, obstétricas e neonatais. As variáveis contínuas foram apresentadas sob a forma de porcentagens e as categóricas, sob a forma de proporções. Foi realizado o cálculo de intervalo de confiança com nível de significância (alfa) de 5%. Resultados: no Hospital Geral, no período citado, ocorreram 17.071 nascimentos e 2.758 internações em Unidade de Tratamento Intensivo, sendo que dessas, 87 (3,2%) estiveram relacionadas a complicações da gravidez ou abortos. O principal motivo de internação hospitalar foram as síndromes hipertensivas (70,1%); de óbito, a coagulação intravascular disseminada e o choque séptico. A média da idade materna foi 26,8±7,8; 45 (51,7%) eram nulíparas; 21 (27,6%) apresentaram algum tipo de complicação intraparto. A taxa de mortalidade materna foi de 8,1% (n=7) e a de mortalidade perinatal foi de 22,4% (n=17). Conclusões: Oitenta e sete pacientes obstétricas necessitaram de tratamento intensivo. Fundamentalmente, eram pacientes nulíparas, hipertensas, com pouca escolaridade e assistência pré-natal inadequada. Sete (8,1%) pacientes morreram durante a estada hospitalar.

Introduction: Significant rates of maternal morbidity and mortality still occur during pregnancy. An important indicator of maternal morbidity is the need for transfer of obstetric patients to the Intensive Care Unit. The aim of the study was to evaluate maternal and perinatal outcomes related to obstetric patients admitted to intensive care units. Methods: An observational study of consecutive patients admitted to the obstetric intensive care unit of the General Hospital of the University of Caxias do Sul, from March/1998 to December/2008. Maternal, obstetric and neonatal variables were analyzed. Continuous variables were presented as percentages, and categorical variables as proportions. Confidence interval with significance level (alpha) at 5% was calculated. Results: In the general Hospital, in the mentioned period, there were 17,071 births and 2,758 admissions to the Intensive Care Unit, and of these, 87 (3.2%) were related to complications of pregnancy or abortion. The main reason for hospital admission were hypertensive disorders (70.1%); for death, disseminated intravascular coagulation and septic shock. The mean maternal age was 26.8 ± 7.8; 45 (51.7%) were nulliparous; and 21 (27.6%) had some type of intrapartum complication. The maternal mortality rate was 8.1% (n = 7) and the perinatal mortality rate was 22.4% (n = 17). Conclusions: Eighty-seven obstetric patients required intensive care. Fundamentally, they were nulliparous, hypertensive, with poor education and inadequate prenatal care. Seven (8.1%) patients died during their hospital stay.

Factores de riesgo asociados a traumatismo al nacimiento / Risk factors associated with birth trauma

ANTECEDENTES: Se define trauma al nacimiento las lesiones sufridas por el feto durante el trabajo de parto o expulsión. OBJETIVO: Identificar los factores de riesgo asociados a lesiones originadas durante el nacimiento en recién nacidos. MÉTODO: Estudio casos y controles, realizado en el período de julio/2004 a diciembre/2005, en la División de Ginecología y Obstetricia del Hospital General de Caxias do Sul/ Facultad de Medicina, Universidad de Caxias do Sul, RS, Brasil. Fueron analizadas variables maternas, del parto y fetales, utilizando el programa estadístico SPSS versión 19.0. Los factores que obtuvieron nivel significativo <0,10 en los análisis bivariado fueron insertas en la regresión logística. Se utilizó el modelo de entrada por bloques (block entry) para selección del modelo final de la regresión. RESULTADOS: En el período citado nacieron 2.137 infantes, 26 de ellos (1,2%) sufrieron trauma al nacimiento. La fractura de clavícula fue la lesión más frecuente (n=14; 53,8%), seguida del cefalohematoma (n=5; 19,2%). Las variables gasométricas no presentaron diferencia estadística. En la regresión logística, las únicas variables independientes asociadas a traumatismo al nacimiento fueron parto vaginal (OR-A: 11,08; IC95%: 2,45-49,98; p=0,002) y perímetro torácico >33 cm (OR-A: 3,36; IC95%: 1,35-9,73; p=0,010). CONCLUSIÓN: Los factores de riesgo asociados a lesiones durante el nacimiento involucran el parto vaginal y el perímetro torácico igual o superior a 33cm.

BACKGROUND: Obstetrics injuries can be defined as fetal lesions suffered by the fetus during labor or expulsion. OBJECTIVE: Identify risk factors for fetal birth trauma. METHOD: Case-control study conducted from July 2004 to December 2005. We analyzed maternal and fetal variables using software SPSS 19.0. The variables showing a significance level <0.10 in the bivariate analysis were included in the logistic regression analysis. We used the block entry model for selection of the final regression model. RESULTS: During these period, we identified 2137 births and 26 (1.2%) were related to fetal birth injury. Clavicle fracture was the most frequent injury (n = 14; 53.8%), followed by cephalohematoma (n = 5; 19.2%). Umbilical cord blood gas analysis did not show statistical significance. In the regression analysis of the variables that had significance level <0.10, the only independent variables associated with fetal birth injury were vaginal delivery (OR-A: 11.08; 95%CI: 2.45-49.98; p=0.002) and thorax circumference > 33 cm (OR-A: 3.36; 95%CI: 1.35-9.73; p=0.010). CONCLUSION: The risk factors for fetal birth injury were vaginal delivery and chest circumference equal to or larger than 33 cm. Other variables were not associated with the outcome in discussion.

Fatores de risco para tocotraumatismo materno / Risk factors to maternal birth injury

Os tocotraumatismos maternos acometem com mais frequência partes moles da genitália materna e, por isso, estão relacionados a substancial morbidade, como nos casos de rupturas perineais, vaginais e cervicais. A mortalidade é representada principalmente pela ruptura uterina. O objetivo deste estudo foi identificar os fatores de risco relacionados ao tocotraumatismo materno. Métodos: Estudo caso-controle, realizado em uma enfermaria de puerpério, no período de julho/2004 a dezembro/2005. Foram avaliadas variáveis maternas e fetais. As variáveis categóricas foram apresentadas como proporções, as com distribuição normal como média e desvio padrão, e as sem distribuição normal como mediana e intervalo interquartil. Para verificação das variáveis associadas ao tocotraumatismo materno, foram conduzidas análises bivariadas, com o teste qui-quadrado. Resultados: Dentre 2.137 puérperas, foram identificados 37 casos (1,7%) de tocotraumatismo. As lesões de primeiro e segundo graus foram as mais prevalentes (n=29; 78,4%). Foi observado um caso de ruptura uterina. As variáveis: a) segundo período de trabalho de parto inferior a 30 minutos, b) peso fetal entre 3.000g e 3.499 g, c) comprimento fetal entre 46 cm e 50 cm e d) perímetro torácico ≥33 cm estiveram associadas ao tocotraumatismo materno na análise bivariada, mas não tiveram significância quando da regressão logística. Conclusão: As lesões de primeiro e segundo graus foram as mais prevalentes (n=29). Parto vaginal, multiparidade e perímetro cefálico ≥33 cm foram identificados como fatores de risco independentes para lesão materna.

Maternal birth injuries affect most often the soft parts of the maternal genitalia and therefore are related to substantial morbidity, such as in cases of perineal, vaginal and cervical ruptures. Mortality is mainly represented by uterine rupture. The aim of this study was to identify risk factors related to maternal birth trauma. Methods: A case-control study conducted in a postpartum ward from Jul 2004 to Dec 2005. Maternal and fetal variables were evaluated. Categorical variables were shown as proportions, those with normal distribution as mean and standard deviation, and those without normal distribution as median and interquartile range. In order to check the variables associated with maternal birth trauma, bivariate analysis was conducted with the chi-square test. Results: Of 2,137 women, 37 cases (1.7%) of maternal birth trauma were identified. Lesions of first and second degrees were the most prevalent (n = 29, 78.4%). One case of uterine rupture was found. Variables (a) second period of labor less than 30 minutes, (b) fetal weight between 3,000 g and 3,499 g, (c) fetal length between 50 cm and 46 cm) and (d) chest girth ≥ 33 cm were associated with maternal birth trauma in the bivariate analysis, but had no significance in the logistic regression. Conclusion: First and second degrees lesions were the most prevalent (n = 29). Vaginal delivery, multiparity and head circumference ≥ 33 cm were identified as independent risk factors for maternal injury.