A real-world study of the effects of endocrine therapy on liver function in breast cancer / 中华外科杂志

Objective: To compare the effect of different endocrine therapy drugs on liver function in patients with early breast cancer. Methods: A retrospective cohort study was conducted to include 4 318 patients with early breast cancer who received adjuvant endocrine therapy in Department of Breast Surgery, Peking Union Medical College Hospital from January 1, 2013 to December 31, 2021. All the patients were female, aged (51.2±11.3) years (range: 20 to 87 years), including 1 182 patients in the anastrozole group, 592 patients in the letrozole group, 332 patients in the exemestane group, and 2 212 patients in the toremifene group. The mixed effect model was used to analyze and compare the liver function levels of patients at baseline, 6, 12, 18, 24, 36, 48, 60 months of medication, and 1 year after drug withdrawal among the three aromatase inhibitors (anastrozole, letrozole, exemestane) and toremifene. Results: ALT and AST of the 4 groups were significantly higher than the baseline level at 6 months (all P<0.01), and there were no significant differences in total bilirubin, direct bilirubin and AST levels among all groups one year after drug withdrawal (P: 0.538, 0.718, 0.061, respectively). There was no significant difference in the effect of all groups on AST levels (F=2.474, P=0.061), and in the effect of three aromatase inhibitors (anastrozole, letrozole, and exemestane) on ALT levels (anastrozole vs. letrozole, P=0.182; anastrozole vs. exemestane, P=0.535; letrozole vs. exemestane, P=0.862). Anastrozole and letrozole had significantly higher effects on ALT levels than toremifene (P<0.01, P=0.009). The proportion of abnormal liver function in each group increased significantly at 6 months compared with baseline, and then the proportion showed a decreasing trend over time. Conclusions: Three aromatase inhibitors (anastrozole, letrozole, and exemestane) and toremifene can significantly increase the level of ALT and AST in patients with breast cancer, and the levels can gradually recover to the baseline after 1 year of drug withdrawal. The effect of non-steroidal aromatase inhibitors (anastrozole, letrozole) on ALT levels is greater than toremifene.

Síndrome dos ovários policísticos: particularidades no manejo da infertilidade / Polycystic ovary syndrome: particularities in the management of infertility

A síndrome dos ovários policísticos (SOP) é responsável por cerca de 80% dos casos de infertilidade anovulatória. Não há na literatura evidências suficientes para a definição do tratamento ideal da infertilidade na SOP, mas repete-se que deve ser iniciado por mudanças no estilo de vida, e frequentemente envolve a indução farmacológica da ovulação e, em casos selecionados, as técnicas de reprodução assistida e o drilling ovariano laparoscópico. Este texto pretende reunir informações atuais sobre o manejo da infertilidade em mulheres com SOP e, dessa forma, permitir ao ginecologista a escolha da melhor abordagem, de forma Individualizada e baseada nas melhores evidências disponíveis.(AU)

Pharmacological treatment for symptomatic adenomyosis: a systematic review / Tratamento farmacológico para adenomiose sintomática: revisão sistemática

Abstract Objective To assess the efficacy of non-surgical treatment for adenomyosis. Data Sources A search was performed by two authors in the Pubmed, Scopus, and Scielo databases and in the grey literature from inception to March 2018, with no language restriction. Selection of Studies We have included prospective randomized studies for treating symptomaticwomen with adenomyosis (abnormal uterine bleeding and/or pelvic pain) diagnosed by ultrasound or magnetic resonance imaging. Data Collection Studies were primarily selected by title and abstract. The articles that were eligible for inclusion were evaluated in their entirety, and their data was extracted for further processing and analysis. Data Synthesis From567retrieved records only 5 remained for analysis. The intervention groups were: levonorgestrel intrauterine system (LNG-IUS)(n= 2), dienogest (n= 2), and letrozole (n= 1). Levonorgestrel intrauterine system was effective to control bleeding when compared to hysterectomy or combined oral contraceptives (COCs). One study assessed chronic pelvic pain and reported that LNG-IUS was superior to COC to reduce symptoms. Regarding dienogest, it was efficient to reduce pelvic pain when compared to placebo or goserelin, but less effective to control bleeding than gonadotropin-releasing hormone (GnRH) analog. Letrozolewas as efficient asGnRHanalog to relieve dysmenorrhea and dyspareunia, but not for chronic pelvic pain. Reduction of uterine volumewas seen with aromatase inhibitors, GnRH analog, and LGN-IUD. Conclusion Levonorgestrel intrauterine system and dienogest have significantly improved the control of bleeding and pelvic pain, respectively, in women with adenomyosis. However, there is insufficient data from the retrieved studies to endorse eachmedication for this disease. Further randomized control tests (RCTs) are needed to address pharmacological treatment of adenomyosis.

Resumo Objetivo: Avaliar a eficácia de tratamento não cirúrgico para adenomiose. Fontes de dados: Uma pesquisa foi realizada por dois autores nas bases de dados Pubmed, Scopus, Scielo e na literatura cinzenta desde o início de cada base de dados até março de 2018, sem restrição de idioma. Seleção de estudos: Incluímos estudos prospectivos randomizados para tratamento de mulheres sintomáticas com adenomiose (sangramento uterino anormal e/ou dor pélvica) diagnosticadas por ultrassonografia ou ressonância magnética. Coleta de dados: Os estudos foram selecionados principalmente por título e resumo. Os artigos que preencheram os critérios de inclusão foram avaliados na íntegra, e seus dados foram extraídos para posterior processamento e análise. Síntese dos dados: De 567 registros recuperados, somente 5 permaneceram para análise. Os grupos de intervenção foram: sistema intrauterino de levonorgestrel (SIU-LNG) (n= 2), dienogest (n= 2), e letrozol (n= 1). O SIU-LNG foi efetivo no controle do sangramento quando comparado à histerectomia ou aos contraceptivos orais combinados (COCs).Umestudo avaliou a dor pélvica crônica e relatou que o SIU-LNGfoi superior ao COC para reduzir os sintomas.Emrelação ao dienogest, este foi eficienteemreduzir a dor pélvica quando comparado ao placebo ou à goserelina, mas foi menos eficaz no controle do sangramento do que o análogo do hormônio liberador de gonadotropina (GnRH). O letrozol foi tão eficiente quanto o análogo do GnRH para aliviar a dismenorreia e a dispareunia, mas não para a dor pélvica crônica. Redução do volume uterino foi observada com inibidores de aromatase, análogo de GnRH, e SIU-LNG. Conclusão: O SIU-LNG e dienogest apresentaram bons resultados para o controle de sangramento e dor pélvica, respectivamente, em mulheres com adenomiose. No entanto, não há dados suficientes para endossar cada medicação para tratar essa doença. Futuros estudos randomizados são necessários para avaliar o tratamento farmacológico da adenomiose.

Changes in Cardiac Autonomic Modulation in Women with Breast Cancer Using Aromatase Inhibitors and the Relation with Biochemical Variables / Alterações na Modulação Autonômica Cardíaca em Mulheres com Câncer de Mama em Uso de Inibidores de Aromatase e sua Relação com Variáveis Bioquímicas

Abstract Background: The use of autonomic modulation as a predictor of cardiovascular risk in women with breast cancer is important. Objective: To evaluate the cardiac autonomic modulation of postmenopausal women using aromatase inhibitors for breast cancer treatment, as well as its relation with the following biochemical variables. Methods: Postmenopausal women who did not have breast cancer (n = 33) and postmenopausal women with breast cancer (n = 15). For evaluation of the autonomic modulation the heart rate was recorded beat-to-beat for 30 minutes and the series of RR intervals obtained were used to calculate the following heart rate variability indices: Mean RR ms, SDNN (standard deviation of all normal RR intervals, expressed in milliseconds) ms, Mean HR, RMSSD (square root of the mean of the squared differences between adjacent normal RR interval) ms, NN50 (number of pairs of successive NNs that differ by more than 50 ms) count, pNN50% (proportion of NN50 divided by total number of NNs), RRtri (RR triangular), TINN (triangular interpolation of NN interval) ms, SD1 ms, SD2 ms, LF ms2, HF ms2, LH/HF ms2. The values of biochemical variables (fasting glycemia, triglycerides, HDL-cholesterol, and C-reactive protein) were analyzed by blood sample. Results: Lower values of heart rate variability indices were observed in postmenopausal women with breast cancer in relation to postmenopausal women who did not have breast cancer: Mean RR (p = 0.03); SDNN (p = 0.03); RMSSD (p = 0.03); NN50 count (p = 0.03); pNN50 % (p = 0.03); RRtri (p = 0.02); SD1 (p = 0.01); SD2 (p = 0.02); LF ms2 (p = 0.01); HF ms2 (p = 0.03).There was an inversely proportional correlation between the indices SDNN, SD2, and HFms2 with triglycerides (SDNN p = 0.04; SD2 p = 0.04; HF ms2 p = 0.04). No statistically significant correlations were found between heart rate variability indices and others variables. Statistical significance was set at 5% for all analyses. Conclusion: Women with breast cancer present reduced autonomic modulation and in these women of heart rate variability indices are inversely correlated with triglyceride values.

Resumo Fundamentos: A modulação autonômica como um preditor de risco cardiovascular em mulheres com câncer de mama é importante. Objetivos: Avaliar a modulação autonômica em mulheres pós-menopausa em uso de inibidores de aromatase como tratamento de câncer de mama, e sua relação com algumas variáveis bioquímicas. Métodos: Foram avaliadas mulheres pós-menopausa sem câncer de mama (n = 33) e mulheres pós-menopausa com câncer de mama (n = 15). Para avaliação da modulação autonômica, a frequência cardíaca (FC) foi registrada batimento a batimento por 30 minutos, e as séries de intervalos RR obtidas foram usadas para o cálculo dos seguintes índices de variabilidade da frequência cardíaca: média de RR ms, SDNN (desvio padrão de todos os intervalos RR normais) ms, FC, RMSSD (raiz quadrada da média das diferenças ao quadrado entre os intervalos RR normais adjacentes) ms, contagem NN50 (número de pares de NNs sucessivos que se diferem em mais de 50 ms), pNN50% (proporção de NN50 dividida pelo número total de NNs), RRtri (RR triangular), TINN (interpolação triangular do intervalo NN) ms, DP1 ms, DP2 ms, LF (baixa frequência) ms2, HF (alta frequência) ms2, LH/HF ms2. Os valores das variáveis bioquímicas (glicemia de jejum, triglicerídeos, HDL-colesterol, e proteína C reativa) foram analisadas das amostras de sangue. O nível de significância adotado nas análises estatísticas foi de 5%. Resultados: As mulheres pós-menopausa com câncer de mama apresentaram menores índices de variabilidade da frequência cardíaca em comparação àquelas sem câncer de mama: média de RR (p = 0,03); SDNN (p = 0,03); RMSSD (p = 0,03); contagem NN50 (p = 0,03); pNN50% (p = 0,03); RRtri (p = 0,02), DP1 (p = 0,01), DP2 (p = 0,02); LF ms2 (p = 0,01); HF ms2 (p = -0,03). Observou-se uma correlação inversamente proporcional dos índices SDNN, DP2 e HF ms2 com triglicerídeos (SDNN p = 0,04, DP2 p = 0,04; HF ms2 0,04). Não houve correlação significativa entre os índices de variabilidade da frequência cardíaca e as demais variáveis. Conclusão: Mulheres com câncer de mama apresentam modulação autonômica diminuída e índices de variabilidade da FC inversamente correlacionados com valores de triglicerídeos.

Manejo diagnóstico-terapéutico de las lesiones mamarias atípicas / Diagnostic-therapeutic Management of Atypical Breast Lesions

Las lesiones mamarias se dividen histológicamente en dos grandes grupos, malignas y benignas. Las lesiones malignas pueden ser de origen ductal o lobulillar, siendo el carcinoma ductal infiltrante la neoplasia invasiva más frecuente. Las lesiones benignas se clasifican en no proliferativas, proliferativas sin atipias y proliferativas con atipias. Dentro de los dos últimos grupos se encuentran entidades que conllevan un alto riesgo de desarrollar carcinoma de mama, como pueden ser la hiperplasia ductal atípica, la cicatriz radial o la neoplasia lobular. Revisamos en qué consisten dichas entidades y cuáles son sus características principales en imagen, fundamentalmente en mamografía y ecografía. Si tras realizar una biopsia se obtiene uno de esos diagnósticos histológicos, es importante analizar las características imagenológicas y el tipo de procedimiento realizado (número de cilindros obtenidos, calibre de aguja...), para realizar un adecuado manejo posterior. En algunos casos la actitud a seguir será la extirpación quirúrgica completa de la lesión, mientras que en otros se podrá realizar una extirpación percutánea (mediante biopsia con aguja de vacio), o incluso seguimiento estricto por imagen. Mediante diferentes casos mostraremos nuestra experiencia y analizaremos la literatura vigente para recordar esas entidades y llegar a un consenso adecuado sobre el manejo de las mismas.

Breast lesions are divided histologically into two large groups, malignant and benign. Malignant lesions may be of ductal or lobular origin, with infiltrating ductal carcinoma being the most frequent invasive neoplasm. Benign breast lesions are classified as proliferative, proliferative without atypia and proliferative with atypia. Within the last two classifications are entities that carry a high risk of developing breast carcinoma, such as atypical ductal hyperplasia, radial scar or lobular neoplasia. We review what these entities consist of and what are their fundamental characteristics in image, fundamentally in mammography and ultrasound. When we perform one of these histological diagnoses after a biopsy, it is important to analyze the radiological characteristics and the type of procedure performed (number of cylinders, needle gauge ...) to perform an appropriate posterior management. In some cases the attitude to be followed will be the complete surgical removal of the lesion, while in others a percutaneous excision (through vacuum needle biopsy) or even strict image follow-up may be performed. Through different cases we will show our experience and analyze current literature to remember these entities and reach an adequate management consensus.

Cáncer de mama avanzado receptor de estrógeno positivo: manejo sistémico actual / Systemic therapy for estrogen receptor positive advanced breast cancer

El cáncer de mama es la primera causa de muerte por cáncer en mujeres chilenas. Mientras la mayoría de las personas logra curarse de esta enfermedad, un 5% de los casos se presenta inicialmente con enfermedad avanzada y hasta un 20-30% de pacientes con enfermedad localizada pueden sufrir recurrencias sistémicas. La mayoría de las neoplasias mamarias son dependientes del estímulo estrogénico, de allí que la deprivación de estrógenos es la principal estrategia terapéutica. Recientemente, el uso de terapias molecularmente dirigidas en combinación con la terapia endocrina ha logrado mejorar los resultados de sobrevida del cáncer de mama avanzado, con menos efectos colaterales que aquellos producidos por la quimioterapia convencional. El conocimiento de los mecanismos de acción de estas nuevas terapias, sus toxicidades, vías de resistencia y selección de pacientes para lograr los mejores beneficios terapéuticos son aspectos relevantes en el manejo de la enfermedad. Presentamos una revisión del estado actual del manejo del cáncer de mama metastásico hormonodependiente con enfásis en el uso de terapias endocrinas combinadas con terapias moleculares.

Breast cancer is the leading cause of cancer death in Chilean women. While most patientes are cured, five percent of cases present with advanced disease initially and up to 20-30% of patients with localized disease may suffer systemic recurrences. The majority of breast neoplasms are dependent on the estrogenic stimulus, hence the deprivation of estrogen is the main therapeutic strategy. Recently, the use of molecular targeted therapies in combination with endocrine therapy has been successful in improving the survival outcomes of advanced breast cancer, with fewer side effects than those produced by conventional chemotherapy. Knowledge of the mechanisms of action of these new therapies, their toxicities, resistance pathways and patient selection to achieve the best therapeutic benefits are relevant aspects in the management of the disease. We present a review of the current state of management of hormone-dependent metastatic breast cancer with emphasis on the use of endocrine therapies combined with molecular therapies.

The use of aromatase inhibitors in boys with short stature: what to know before prescribing?

ABSTRACT Aromatase is a cytochrome P450 enzyme (CYP19A1 isoform) able to catalyze the conversion of androgens to estrogens. The aromatase gene mutations highlighted the action of estrogen as one of the main regulators of bone maturation and closure of bone plate. The use of aromatase inhibitors (AI) in boys with short stature has showed its capability to improve the predicted final height. Anastrozole (ANZ) and letrozole (LTZ) are nonsteroidal inhibitors able to bind reversibly to the heme group of cytochrome P450. In this review, we describe the pharmacokinetic profile of both drugs, discussing possible drug interactions between ANZ and LTZ with other drugs. AIs are triazolic compounds that can induce or suppress cytochrome P450 enzymes, interfering with metabolism of other compounds. Hydroxilation, N-dealkylation and glucoronidation are involved in the metabolism of AIs. Drug interactions can occur with azole antifungals, such as ketoconazole, by inhibiting CYP3A4 and by reducing the clearance of AIs. Antiepileptic drugs (lamotrigine, phenobarbital, and phenytoin) also inhibit aromatase. Concomitant use of phenobarbital or valproate has a synergistic effect on aromatase inhibition. Therefore, it is important to understand the pharmacokinetics of AIs, recognizing and avoiding possible drug interactions and offering a safer prescription profile of this class of aromatase inhibitors. Arch Endocrinol Metab. 2017;61(3):391-7.

Use of anastrozole in the chemoprevention and treatment of breast cancer: A literature review / Uso do anastrozol na quimioprevenção e no tratamento do câncer de mama: uma revisão da literatura

Summary Aromatase inhibitors have emerged as an alternative endocrine therapy for the treatment of hormone sensitive breast cancer in postmenopausal women. The use of third-generation inhibitors represented by exemestane, letrozol and anastrozole is currently indicated. Anastrozole is a nonsteroidal compound and a potent selective inhibitor of the aromatase enzyme. Although a few studies have shown that its pharmacodynamic and pharmacokinetic properties may be affected by interindividual variability, this drug has been recently used in all configurations of breast cancer treatment. In metastatic disease, it is currently considered the first-line treatment for postmenopausal women with estrogen receptor-positive breast tumors. Anastrozole has shown promising results in the adjuvant treatment of early-stage breast cancer in postmenopausal women. It has also achieved interesting results in the chemoprevention of the disease. Therefore, due to the importance of anastrozole both for endocrine treatment and chemoprevention of hormone-sensitive breast cancer in postmenopausal women, we proposed the current literature review in the SciELO and PubMed database of articles published in the last 10 years.

Resumo Os inibidores de aromatase têm emergido como uma endocrinoterapia alternativa para o tratamento de câncer de mama sensível a hormônios em mulheres pós-menopáusicas. A utilização de inibidores de terceira geração, representados por exemestano, letrozol e anastrozol, é atualmente indicada. Anastrozol é um composto não esteroide e um inibidor potente e seletivo da enzima aromatase. Embora alguns estudos tenham demonstrado que as suas propriedades farmacodinâmicas e farmacocinéticas podem ser afetadas pela variabilidade interindividual, esse fármaco tem sido recentemente utilizado em todas as configurações de tratamento do câncer de mama. Na doença metastática, é atualmente considerado o tratamento de primeira linha em mulheres pós-menopáusicas com tumores de mama e receptor de estrogênio positivo. O anastrozol tem mostrado resultados promissores no tratamento adjuvante do câncer de mama em estágio inicial em mulheres na pós-menopausa. Ele também conseguiu resultados interessantes na quimioprevenção da doença. Portanto, em virtude da importância do anastrozol tanto no tratamento endócrino quanto na quimioprevenção do câncer de mama hormoniossensível em mulheres na pós-menopausa, propusemos a atual revisão da literatura na base de dados SciELO e PubMed de artigos publicados nos últimos 10 anos.

Estrone and Estradiol Levels in Breast Cancer Patients Using Anastrozole Are Not Related to Body Mass Index / Níveis de estrona e estradiol em pacientes com câncer de mama usando anastrozol não estão relacionados ao índice de massa corpórea

ABSTRACT Objective: Obesity is associated with an increased risk for breast cancer. Recent studies have shown that aromatase inhibitors may be less effective in women with a high body mass index (BMI). The aim of this study was to establish the relationship between the BMI and plasma estrone and estradiol levels in postmenopausal women with hormone receptor-positive breast cancer using anastrozole. Methods: In this cohort study, the patients were divided into three groups according to BMI (normal weight, overweight and obese) to compare and correlate plasma hormone levels before starting anastrozole hormone therapy and three months after treatment. Plasma hormone levels were compared for age and use of chemotherapy. Results: A statistically significant reduction in estrone and estradiol levels was observed between baseline and three months after starting the anastrozole treatment (p < 0.05). There was no statistically significant difference in plasma estrone and estradiol levels among the BMI groups (p > 0.05), but a significant reduction in plasma estrone levels was observed after three-months' treatment relative to baseline in all groups, as well as a reduction in estradiol in the obese group (p < 0.05). The use of chemotherapy and age > 65 years had no influence on plasma steroid levels. Conclusion: Changes in estrone and estradiol levels in the studied groups were not associated with BMI, chemotherapy or age.

RESUMO Objetivo: A obesidade está associada com risco aumentado de câncer de mama. Estudos recentes têm mostrado que os inibidores de aromatase podem ser menos eficazes em mulheres com alto índice de massa corporal (IMC). O objetivo deste estudo foi estabelecer a relação entre o IMC e os níveis plasmáticos de estrona e estradiol em mulheres no período pós-menopausa com câncer de mama receptor hormonal positivo, em tratamento com anastrozol. Métodos: Este estudo de coorte acompanhou três grupos de pacientes de acordo com o seu IMC (peso normal, sobrepeso e obesidade), a fim de comparar e correlacionar as dosagens dos hormônios estrona e estradiol antes e após três meses do uso do anastrozol. Os níveis plasmáticos dos hormônios foram também relacionados à idade do paciente e ao uso da quimioterapia. Resultados: Redução estatisticamente significativa de estrona e estradiol foi observada entre os níveis basais e três meses após o início do tratamento com anastrozol (p < 0,05). Não houve diferença estatisticamente significativa entre os níveis plasmáticos de estrona e estradiol em relação ao IMC (p > 0,05), mas houve redução significativa entre os níveis plasmáticos basais de estrona após o tratamento em todos os grupos, e redução de estradiol no grupo de pacientes obesas (p < 0,05). A condução da quimioterapia e da idade acima de 65 anos não interfere com os níveis plasmáticos de esteroides. Conclusão: Os níveis plasmáticos de estrona e estradiol nos grupos estudados não foram alterados em termos de IMC, quimioterapia e idade.

Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review / Abordagem multidisciplinar em hormonioterapia neoadjuvante no câncer de mama: uma revisão

ABSTRACT Breast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HRþ) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemo-therapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2þ) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HRþ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.

RESUMO O câncer de mama é o mais comum, e a principal causa de mortalidade por câncer em mulheres de todo o mundo. Os tumores com receptor hormonal (RH) positivo representam o tipo mais comum desta doença. O benefício e as taxas de resposta à quimioterapia neoadjuvante variam de acordo com a expressão de RH, sendo mais baixa nos tumores luminais em comparação com tumores HER2 positivos ou triplo-negativos. A hormonioterapia neoadjuvante, uma opção para pacientes selecionados com tumores RH positivo localmente avançados, apresenta melhor perfil de tolerabilidade e segurança, e está associada com benefícios adicionais, como baixo custo e fácil acesso. Estes fatores são relevantes, uma vez que 70% das mortes por câncer de mama acontecem em mulheres de países pobres ou em desenvolvimento. Além disso, a hormonioterapia neoadjuvante vem sendo explorada como uma ferramenta científica, ao possibilitar o estudo de biomarcadores que podem predizer desfechos tanto para pacientes individuais quanto para ensaios clínicos em adjuvância. Este artigo de revisão detalha o conhecimento atual e as evidências mais relevantes sobre hormonioterapia neoadjuvante em câncer de mama, assim como perspectivas futuras nesta área.

Effect of letrozole in carcinogen-plus-estrogen-induced endometrial hyperplasia in mice

PURPOSE: To evaluate the effects of letrozole (Ltz) in carcinogen+estrogen-induced endometrial hyperplasia. METHODS: BALB/c female mice were divided into four groups of 12 animals each receiving an intrauterine dose of N-ethyl-N-nitrosourea (ENU) and weekly subcutaneous injections of estradiol hexaidrobenzoate (EHB), except for group I(control). The groups were divided in I (control), II (ENU+EHB), III (ENU+EHB+MPA) and IV (ENU+EHB+Ltz). Group III also received intramuscular injections of MPA (medroxy progesterone acetate) every four weeks, while group IV received oral doses of Ltz daily. At the end of 16 weeks, the animals were sacrificed, and blood samples were collected for the measurement of serum estradiol and progesterone levels. Uterine histological sections were made to evaluate the presence of endometrial proliferative lesions. Differences between groups were evaluated with student's t test, ANOVA and chi-square test. RESULTS: Groups ENU+EHB, ENU+EHB+MPA and ENU+EHB+Ltz showed varying degrees of endometrial hyperplasia. The incidence of hyperplasia in groups ENU+EHB and ENU+EHB+Ltz was higher and more severe than in group ENU+EHB+MPA. Control group showed lower levels of serum estradiol than the other groups. CONCLUSION: There was no evidence that letrozole could act as an antiestrogenic drug in the development of endometrial proliferative lesions.

Medical management of non-obstructive azoospermia

Non-obstructive azoospermia is diagnosed in approximately 10% of infertile men. It represents a failure of spermatogenesis within the testis and, from a management standpoint, is due to either a lack of appropriate stimulation by gonadotropins or an intrinsic testicular impairment. The former category of patients has hypogonadotropic hypogonadism and benefits from specific hormonal therapy. These men show a remarkable recovery of spermatogenic function with exogenously administered gonadotropins or gonadotropin-releasing hormone. This category of patients also includes some individuals whose spermatogenic potential has been suppressed by excess androgens or steroids, and they also benefit from medical management. The other, larger category of non-obstructive azoospermia consists of men with an intrinsic testicular impairment where empirical medical therapy yields little benefit. The primary role of medical management in these men is to improve the quantity and quality of sperm retrieved from their testis for in vitro fertilization. Gonadotropins and aromatase inhibitors show promise in achieving this end point.

Metástasis óseas múltiples de cáncer de mama: papel del CA 15.3 y respuesta a la hormonoterapia / Bone metastasis of breast carcinoma: role of tumoral marker CA 15.3 and hormonal therapy response

Las metástasis óseas suponen el 65-75 por ciento de casos de cáncer de mama avanzado. Los marcadores tumorales (CA 15.3, CEA) son útiles en el seguimiento de las pacientes y en la valoración de la respuesta al tratamiento. En el cáncer de mama metastásico de bajo grado, el tratamiento hormonal es la opción terapéutica más acertada debido a la baja toxicidad y alta probabilidad de respuesta generalmente de larga duración a la que se asocia. Se presenta el caso de una paciente con cáncer de mama tratado con cirugía, quimioterapia y radioterapia, asintomática durante el seguimiento y en la que metástasis óseas múltiples son detectadas a partir de una elevación del marcador CA 15.3. La hormonoterapia es el tratamiento pautado inicialmente con buena respuesta y tolerancia. Dicho tratamiento logra estabilizar las lesiones óseas durante 7 años y es precisamente al suspenderlo cuando aparecen nuevas lesiones también a nivel óseo detectadas de nuevo ante un incremento del marcador CA 15.3. La terapia hormonal pautada de nuevo vuelve a conseguir estabilizar las lesiones.

Bone metastases are involved in a 65-75 percent of advanced metastatic breast cancer cases. Tumoral markers (CEA, CA 15.3) are useful in the follow-up and evaluation of response to treatment. Hormonal therapy is the optimal treatment option in low grade metastatic breast cancer due to low toxicity and general long term good response. We present a breast cancer case treated with surgery, chemotherapy and radiotherapy. The patient was asymptomatic during the follow-up and multiple bone metastases were diagnosed as a result of an increased CA 15.3 marker found. Hormone therapy was the recommended initial treatment with good response and tolerance. Bone lesions remained stabilized for 7 years but after treatment suspension new bone lesions appeared. CA 15.3 marker had increased again. Reintroduction of hormonal therapy achieved again the stabilization of the lesions.

Collision of Three Histologically Distinct Endometrial Cancers of the Uterus

A collision tumor is defined by the presence of two separate masses in one organ, which are pathologically distinct. We described a 70-yr-old patient who complained of abnormal vaginal bleeding with a collision tumor of the uterine corpus. The patient received total hysterectomy, bilateral salphingo-oophorectomy, bilateral pelvic-paraaortic lymphadenectomy, omentectomy, and intraperitoneal chemotherapy. The uterine corpus revealed three separate masses, which were located at the fundus, anterior and posterior wall. Each tumor revealed three pathologically different components, which were malignant mixed mullerian tumor, papillary serous carcinoma, and endometrioid adenocarcinoma. Among these components, only the papillary serous carcinoma component invaded the underlying myometrium and metastasized to the regional lymph node. Adjuvant chemotherapy and radiation therapy were performed. The patient is still alive and has been healthy for the last 8 yr. We have reviewed previously reported cases of collision tumors which have occurred in the uterine corpus.

Terapia endócrina em câncer de mama avançado/recidivado / Endocrine therapy in advanced/recurrence breast cancer

Os autores fazem uma revisão da literatura sobre terapia endócrina em câncer de mama avançado/recidivado e atualizam o tratamento e toda a prática da indicação das armas terapêuticas dessa modalidade de tratamento.

The authors revised the literature about endocrine therapy in advanced/recurrence breast cancer and bring up therapy and the practice of therapeutics armies of this treatment modality.

Treatment of autonomous ovarian follicular cyst with long-term anastrozole therapy.

Functional follicular ovarian cysts are frequently reported in girls with peripheral precocious puberty (PP). These cysts are usually self-limiting and resolve spontaneously. Several drugs like antiestrogens (tamoxifen) and new aromatase inhibitors are seldom used for treatment. Here we report a girl with peripheral PP who presented with unilateral enlargement of the ovary and a recurrent autonomous ovarian cyst. No skin pigmentation or bone anomaly was noted. The patient was successfully treated with anastrozole, a highly selective aromatase inhibitor. No adverse reaction was noted. Anastrozole is a safe and tolerable drug especially used to suppress estrogen action.

Letrozole as a booster therapy in growth hormone deficiency.

A 13 year old boy presented to us with short stature. Evaluation revealed growth hormone (GH) deficiency. He was treated with GH replacement for 10 months and to further boost up the growth potential, an aromatase inhibitor Letrozole was added to GH therapy. After one year of combination therapy, patient had significant improvement in predicted adult height without a negative impact on pubertal progression.

O uso de tamoxifeno e inibidores da aromatase na terapia endócrina pra o câncer de mama / The use of tamoxifen and aromatae inhibitors for breast cancer endocrine therapy

A terapia endócrina para tumores de mama com receptores hormonais positivos é amplamente usada tanto de forma paliativa no câncer de mama metastático, quanto na adjuvância, para tumores iniciais. O tamoxifeno (TMX) tem sido usado como droga de escolha com este propósito há cerca de 30 anos com boa eficácia e perfil razoavelmente seguro. O desenvolvimento dos inibidores de aromatase (IAs) de terceira geração promoveu estudos comparativos que têm demonstrado superioridade dos IAs em relação ao TMX na adjuvância, favorecendo seu uso tanto em substituição, quanto de forma seqüencial. Em geral, os IAs são tão bem tolerados quanto o TMX, preocupando ainda questões como aumento de risco cardiovascular, de osteoporose e alterações no perfil lipídico. Nos últimos dois anos, importantes instituições como a American Society of Clinical Oncology (ASCO), o National Comprehensive Cancer Network (NCCN) e o Consenso Internacional de St. Gallen (Consenso de St. Gallen) passaram, em vista das evidências emergentes, a indicar o uso dos IAs em detrimento do TMX para as mulheres após a menopausa com tumores sensíveis ao tratamento endócrino.

Endocrine therapy for breast cancer with positive receptors has been widely applied either for advanced metastatic cancer as for initial tumors. For more than 30 years tamoxifen (TMX) has been the first choice for this purpose with an acceptable safety profile. The emerging third generation aromatase inhibitors (IA) promoted comparative trials which have proved the IA to be superior to TMX in the adjuvant setting - what supported its use both in substitution and in a sequential manner. Broadly, the IA are as well tolerated as TMX, still concerning issues as cardiovascular risk and osteoporosis increase and lipid profile changes. During the last couple of years, institutions as the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN) and the International St. Gallen Consensus have changed their recommendations advising the use of IA instead of TMX as a first choice treatment for post-menopause women with sensitive breast cancer.

O uso dos inibidores da aromatase na endometriose / The use of aromatase inhibitors in endometriosis

Endometriose é uma doença proliferativa e inflamatória crônica caracterizada por implantes de tecido endometrial fora da cavidade uterina. Afeta aproximadamente 10-15 porcento das mulheres em idade reprodutiva e é caracterizada clinicamente por dor pélvica e infertilidade. Apresenta etiologia multifatorial, entre as quais menstruação retrógrada, fatores genéticos, imunológicos e alterações intrínsecas do foco endometriótico, sendo a única certeza a sua dependência estrogênica. A aromatase é enzima chave na síntese de estrogênio, sendo responsável pela transformação de androstenediona e testosterona em estrona e estradiol, respectivamente, estando normalmente presente na granulosa do folículo ovariano, tecido gorduroso, fígado, fibroblastos da pele e cérebro. Baseado na demonstração da expressão aberrante desta enzima no foco endometriótico, a utilização de inibidores da aromatase vem sendo realizada para tratamento desta enigmática doença.