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.

Terapia endocrina para la prevención primaria del cáncer de seno: Revisión sistemática y metaanálisis actualizado / Endocrine therapy for primary prevention of breast cancer: Systematic review and updated meta-analysis

Introducción. Debido a que el cáncer de seno es una enfermedad asociada a una significativa tasa de morbilidad y mortalidad cuando se diagnostica en el período sintomático, se han hecho enormes esfuerzos orientados hacia la prevención primaria de esta enfermedad. Métodos. Se realizó una búsqueda de todos los experimentos clínicos aleatorizados que evaluaran la eficacia de la terapia endocrina para la reducción del riesgo de desarrollar cáncer de seno. La calidad metodológica de los estudios seleccionados fue valorada utilizando la herramienta de la Colaboración Cochrane para medir el riesgo de sesgo en ensayos aleatorizados. Se evaluó la heterogeneidad de los estudios primarios elegibles utilizando los estadísticos T², I², H². El sesgo de publicación fue evaluado mediante el test de Harbord y mediante la gráfica de funnel plot. La medida de efecto utilizada en este metaanálisis fue el riesgo relativo (RR) con el cálculo de los intervalos de confianza (IC) del 95%. Resultados. Encontramos doce experimentos clínicos aleatorizados que reclutaron a 68.180 mujeres, las cuales fueron asignadas al azar para recibir algún tipo terapia endocrina para reducir el riesgo de desarrollar cáncer de seno o placebo. La terapia endocrina en conjunto redujo el riesgo proporcional de cáncer de seno (invasivo más in situ) en un 42 %, resultado estadísticamente significativo RR 0,58 (IC95% 0,50 ­ 0,69). Conclusiones. La terapia endocrina es el manejo estándar de prevención en mujeres sanas con riesgo de desarrollar cáncer de seno no hereditario.

Introduction. Because breast cancer is a disease associated with a significant morbidity and mortality rate when diagnosed in the symptomatic period, enormous efforts have been made towards the primary prevention of this disease. Methods. A search was conducted for all randomized clinical trials evaluating the efficacy of endocrine therapy in reducing the risk of developing breast cancer. The methodological quality of the selected studies was assessed using the Cochrane Collaboration tool to assess risk of bias in randomized trials. Heterogeneity of eligible primary studies was assessed using the T², I², H² statistics. Publication bias was evaluated using the Harbord test and the funnel plot. The effect measure used in this meta-analysis was the relative risk (RR) with the calculation of the 95% confidence intervals (CI).Results. We found twelve randomized clinical trials that recruited 68,180 women who were randomly assigned to receive some type of endocrine therapy to reduce the risk of developing breast cancer or placebo. Endocrine therapy as a whole reduced the proportional risk of breast cancer (invasive plus in situ) by 42%, a statistically significant result RR 0.58 (95% CI 0.50 - 0.69). Conclusions. Endocrine therapy is the standard preventive management in healthy women at risk of developing non-hereditary breast cancer.

Perinatal exposure to an aromatase inhibitor glyphosate-base herbicide reduced male and female social behavior in juvenile age and the sexual behavior at adult female rats / Exposição perinatal ao inibidor da aromatase a base de glifosato reduz o comportamento social de machos e fêmeas e o comportamento sexual de ratas

Objectives: The herbicide glyphosate, a pesticide used in agriculture to control weeds, both in food crops and in other agricultural areas, has been identified as an endocrine modulator through the inhibition of aromatase activity and the activation of estrogen receptors. The present study examined the effects of a glyphosate-based herbicide (Roundup® (GLY-BH) on sexual dimorphism of rats after perinatal exposure to low and high GLY-BH in males and females offspring. Methods: Two groups of pregnant rats were treated with two doses of GLY-BH (50 or 150 mg/kg) from day 15 of gestation (GD15) to postnatal day 7 (PND7). Play fighting behavior was observed at the juvenile stage and during social and sexual behaviors in adulthood. Results: Perinatal GLY-BH exposure reduced male and female body weight at 28, 75, and 90 days of age. The play fighting behavior was decreased in both sexes, but female rats were more affected. The sexual behaviors were reduced only in females. Conclusions: Perinatal exposure to both doses of GLY-BH promoted sexually dimorphic effects in both juvenile and adulthood stages. These effects were attributed to the inhibition of aromatase activity induced by exposure to GLY-BH in the perinatal period.(AU)

Objetivos: O glifosato é um herbicida não seletivo, usado em muitas culturas alimentares e não alimentares e em áreas não agrícolas, sendo que os produtos a base de glifosato atuam como moduladores das funções endócrinas por meio da inibição da atividade da aromatase e da ativação de receptores de estrógeno. O presente estudo avaliou os efeitos do herbicida Roundup® (GLY-BH) à base de glifosato, em comportamentos sexualmente dimórficos de ratos após exposição perinatal a doses baixas e altas de GLY-BH no período perinatal. Métodos: Ratas prenhas foram tratadas com 50 ou 150 mg/kg de GLY-BH do 15º dia de gestação (GD15) ao 7º dia de lactação (LD7). O comportamento de luta/brincar foi observado na fase juvenil e os comportamentos social e sexual na idade adulta. Resultados: a exposição perinatal a GLY-BH reduziu o peso corporal de machos e fêmeas aos 28, 75 e 90 dias de idade. O comportamento de luta/brincar diminuiu em ambos os sexos, sendo as ratas foram as mais afetadas. O comportamento sexual foi reduzido apenas nas fêmeas. Conclusões: A exposição perinatal a ambas as doses do GLY- BH promoveu tanto na idade juvenil como na idade adulta, efeitos sexualmente dimórficos. Esses efeitos foram atribuídos à inibição da atividade da aromatase induzida exposição perinatal ao GLY-BH.(AU)

Parâmetros clínicos, periodontais, nutricionais e imaginológicos em pacientes em uso de inibidores de aromatase / Clinical, periodontal, nutritional and imaginological parameters in patients using aromatase inhibitors

A osteoporose é uma doença sistêmica multifatorial, caracterizada pela redução da massa óssea. A osteoporose pode ser primária ou secundária ao uso de medicamentos como os inibidores de aromatase. Estes medicamentos interferem com a conversão de andrógenos a estrogênios, reduzindo a produção destes e sendo indicados para tratamento do câncer de mama dependente de estrógeno. O diagnóstico da osteoporose é baseado em critérios densitométricos da Organização Mundial de Saúde com referência na classificação do T-score, realizada pela técnica de absorciometria de energia dupla de raios X (DXA). Por se tratar de uma doença sistêmica, a osteoporose também afeta os ossos maxilares. Entretanto, a ocorrência e extensão de perda de estrutura do osso alveolar na osteoporose, bem como o risco destes pacientes à doença periodontal e perdas dentárias não estão claramente definidos. Este estudo teve como objetivo identificar os parâmetros clínicos, periodontais, nutricionais e bioquímicos envolvidos na perda óssea em pacientes em uso de inibidores de aromatase. A perda óssea foi avaliada por absorciometria dupla de raios-X (DXA). Foram coletados dados sobre estado nutricional, antropométrico, bucal e periodontal e qualidade de vida relacionada à saúde bucal (OHRQoL). Citocinas e adipocinas foram quantificadas na saliva e soro. Foi realizado um estudo transversal do tipo caso-controle, com um grupo de comparação, no serviço de densitometria óssea do Hospital Mater Dei, no período de 2018 a 2021. A amostra foi constituída por 72 mulheres divididas em dois grupos: em uso de inibidores de aromatase (IAs) (n=40) e pacientes sem uso de inibidores de aromatase (controle) (n=32). Do total da amostra, 39 pacientes (57,4%) foram diagnosticados com perda de massa óssea. Os resultados mostraram que as mulheres idosas em uso de inibidores de aromatase (p=0,009) e fumantes (p=0,034) apresentaram maior perda óssea. Não houve diferença significativa entre os grupos considerando-se as comorbidades analisadas. A análise antropométrica demonstrou que os indivíduos em uso de inibidores de aromatase com perda óssea apresentaram menor peso (p=0,028). O modelo de regressão revelou que a única variável que explica a perda óssea é o uso de antirreabsortivos sendo a perda óssea significativamente reduzida nos indivíduos que usaram esse medicamento (p=0,022). Embora a frequência de periodontite tenha sido semelhante comparando todos os grupos, maiores valores de IL-6 (p=0,004); IL-1ß (p=0,002) e IL-33 (p=0,006) na saliva foram relacionados à pior condição periodontal. Indivíduos que usaram inibidores de aromatase foram 1,18 mais propensos a relatar uma melhor qualidade de vida relacionada à saúde bucal (OHRQoL) do que os controles. Conclusão: Enquanto idade avançada, tabagismo e menor peso são fatores associados à perda óssea, o uso de antirreabsortivos foi fator protetor em indivíduos em uso de inibidores de aromatase.

Osteoporosis is a multifactorial systemic disease characterized by reduced bone mass. Osteoporosis can be primary or secondary to the use of drugs such as aromatase inhibitors. These drugs interfere with the conversion of androgens to estrogens, reducing their production and are indicated for the treatment of estrogen-dependent breast cancer. The diagnosis of osteoporosis is based on densitometric criteria of the World Health Organization with reference to the T-score classification, performed by the technique of dual energy x-ray absorptiometry (DXA). Because it is a systemic disease, osteoporosis also affects the jaw bones. However, the occurrence and extent of loss of alveolar bone structure in osteoporosis, as well as the risk of these patients for periodontal disease and tooth loss, are not clearly defined. This study aimed to identify clinical, periodontal, nutritional and biochemical determinants involved with bone loss in patients using aromatase inhibitors. Bone loss was assessed by dual X- ray absorptiometry (DXA). Data on nutritional, anthropometric, oral and periodontal status and oral health-related quality of life (OHRQoL) were collected. Cytokines and adipokines were quantified in saliva and serum. A cross-sectional case-control type study, with a comparison group, was conducted at the bone densitometry service of Hospital Mater Dei from 2018 to 2021. The sample consisted of 72 women divided into two groups: using aromatase inhibitors (AIs) (n=40) and patients not using aromatase inhibitors (control) (n=32). Of the total sample, 39 patients (57.4%) were diagnosed with bone loss. The results showed that elderly women using aromatase inhibitors (p=0.009) and smokers (p=0.034) had greater bone loss. There was no significant difference between the groups considering the analyzed comorbidities. Anthropometric analysis showed that individuals using aromatase inhibitors with bone loss had lower weight (p=0.028). The regression model revealed that the only variable that explains bone loss is the use of antiresorptive drugs, with bone loss significantly reduced in individuals who used this medication (p=0.022). Although the frequency of periodontitis was similar comparing all groups, higher values of IL-6 (p=0.004); IL-1ß (p=0.002) and IL-33 (p=0.006) in saliva were related to worse periodontal status. Subjects who used aromatase inhibitors were 1.18 times more likely to report a better oral health-related quality of life (OHRQoL) than controls. Conclusion: While advanced age, smoking and lower weight are factors associated with bone loss, the use of antiresorptives was a protective factor in individuals using aromatase inhibitors.

Use of aromatase inhibitors in patients with breast cancer is associated with deterioration of bone microarchitecture and density

ABSTRACT Objective: To evaluate changes in bone density and architecture in postmenopausal women with breast cancer (BC) and use of aromatase inhibitor (AI). Subjects and methods: Thirty-four postmenopausal women with BC, without bone metastasis, renal function impairment and who were not receiving bone-active drugs were selected from a population of 523 outpatients treated for BC. According to the presence of hormonal receptors, HER2 and Ki67, seventeen had positive hormonal receptors and received anastrozole (AI group), and seventeen were triple-negative receptors (non-AI group), previously treated with chemotherapy. Areal bone mineral density (aBMD) and vertebral fracture assessment (VFA) analyses were performed by DXA; vBMD and bone microarchitecture were evaluated by HR-pQCT. Fracture risk was estimated using the FRAX tool. Results: No patient referred previous low-impact fracture, and VFA detected one moderate vertebral fracture in a non-AI patient. AI patients showed lower aBMD and BMD T-scores at the hip and 33% radius and a higher proportion of osteoporosis diagnosis on DXA (47%) vs non-AI (17.6%). AI group had significantly lower values for vBMD at the entire, cortical and trabecular bone compartments, cortical and trabecular thickness and BV/TV. They also had a higher risk for major fractures and for hip fractures estimated by FRAX. Several HR-pQCT parameters evaluated at distal radius and distal tibia were significantly associated with fracture risk. Conclusion: AI is associated with alterations in bone density and microarchitecture of both the cortical and trabecular compartments. These findings explain the overall increase in fracture risk in this specific population.

Parâmetros imaginológicos em pacientes com alteração de massa óssea / Imaginological parameters in patients with bone mass alteration

Os inibidores de aromatase (IAs) são medicamentos mais comumente utilizados para tratamento para pacientes com câncer de mama. Os IAs atuam inibindo a enzima aromatase, que é responsável pela conversão de hormônios esteroidais. Vários estudos mostram a importância do estrógeno para a formação óssea. Acredita-se que a privação do estrógeno possa ter um efeito deletério no osso causando o aumento da reabsorção óssea, diminuição da densidade mineral óssea (DMO) e com isso o aumento do risco de osteoporose e fraturas. A osteoporose é uma doença sistêmica multifatorial caracterizada pela redução da massa óssea e desorganização estrutural do tecido ósseo. O diagnóstico da osteoporose é baseado em critérios densitométricos da Organização Mundial de Saúde (OMS) com referência na classificação do T-score, realizada pela técnica de absorciometria de energia dupla de raios X (DXA), cujo valor avalia a DMO. Por se tratar de uma doença sistêmica, a osteoporose também afeta os ossos maxilares. Desta forma, o trabalho tem como objetivo avaliar parâmetros imaginológicos em pacientes mulheres que fazem tratamento com; IAs e encaminhadas para investigação de perda de massa óssea em um hospital de referência no tratamento dessas pacientes. Foram avaliadas 40 mulheres sob terapia com IAs. Foram avaliados índices radiomorfométricos (IR) de tomografia computadorizada de feixe cônico (TCFC) e análise fractal (AF) para algumas regiões de interesse (RI), espessura da cortical mandibular (ECM) e índice cortical mandibular (ICM) em radiografias panorâmicas digitais (RPD). Todas as pacientes foram submetidas ao exame DXA para avaliar a condição de DMO e divididas nos grupos: normal e baixa DMO. Para cada IR e para as RI da dimensão fractal, foram estabelecidas a curva característica de operação do receptor (ROC), a área sob a curva (AUC), a sensibilidade e a especificidade com seus receptivos intervalos de confiança. Os valores de AUC para os índices de RPD variaram de 52,6%-75,8%. O índice com a maior AUC foi a ECM, apresentando sensibilidade de 38,1%-100,0% e especificidade de 36,8%-84,2%. Para a AF, a RI do trabeculado total teve a maior sensibilidade, enquanto a RI anterior ao forame mentual teve a maior especificidade. Na análise da TCFC, os valores de AUC variaram de 51,8%-62,0%. Os índices com a AUC mais elevada foram o índice molar (M), com sensibilidade 18,1%-61,6% e especificidade de 66,9%-98,7% e o índice anterior (A) com sensibidade de 25,7%- 70,2% e especificidade de 48,8%-90,9%. O índice da sínfise (S) apresentou a maior sensibilidade e o índice posterior (P) apreentou a maior especificidade. Os índices de tomografia computadorizada inferior (ITC I) apresentou sensibilidade e especificidade razoáveis. Assim a ECM, a AF das RI do ângulo da mandíbula e do trabeculado total da RPD, bem como os índices ITC (I), M, P e A na TCFC mostraram-se úteis para identificar mulheres na pós-menopausa que usavam AI com baixa DMO.

Aromatase inhibitors (AIs) are the most commonly used drugs to treat breast cancer patients. AIs work by inhibiting the aromatase enzyme, which is responsible for converting steroid hormones. Several studies show the importance of estrogen for bone formation. It is believed that estrogen deprivation can have a deleterious effect on bone, causing increased bone resorption, decreased bone mineral density (BMD) and thus an increased risk of osteoporosis and fractures. Osteoporosis is a multifactorial systemic disease characterized by reduced bone mass and structural disorganization of bone tissue. The diagnosis of osteoporosis is based on densitometric criteria of the World Health Organization (WHO) with reference to the T- score classification, performed by the dual energy X-ray absorptiometry (DXA) technique, whose value assesses the BMD. As it is a systemic disease, osteoporosis also affects the maxillary bones. Thus, the study aims to evaluate imaging parameters in female patients undergoing treatment with AIs and referred for investigation of bone mass loss in a reference hospital in the treatment of these patients. Forty women undergoing therapy with AIs were evaluated. Radiomorphometric indices (RI) of cone beam computed tomography (CBCT) and fractal dimension (FD) were evaluated for some regions of interest (ROI), mandibular cortical width (MCW) and mandibular cortical index (MCI) in digital panoramic radiographs (DPR). All patients underwent the DXA exam to assess the status of BMD and divided into groups: normal and low BMD. The AUC values for the DPR indices ranged from 52.6%-75.8%. The index with the highest AUC was the mandibular cortical width ([MCW]; sensitivity: 38.1%-100.0%; specificity: 36.8%-84.2%). For FD, the total trabecular index had the greatest sensitivity, while the index anterior to the mental foramen (MF) had the highest specificity. In CBCT analysis, the values of AUC ranged from 51.8%-62.0%. The indices with the highest AUC were the molar index (M, sensitivity: 18.1%-61.6% and specificity: 66.9%-98.7%) and anterior (A, sensitivity: 25.7%-70.2% and specificity 48.8%-90.9%). The symphysis (S) index had the highest sensitivity, and the posterior (P) index presented the highest specificity. Sensitivity and specificity reasonable were obtained to computed tomography index (Inferior) [CTI (I)]. The MCW, FD of ROI of the mandible angle and total mandibular in the DPR, as well as the CTI (I), M, P, and A indices in the CBCT are useful to identify postmenopausal women who were using AI with low BMD.

The morphology of paca (Cuniculus paca) testis with high dose of letrozole an aromatase inhibitor / La morfología del testículo de paca (Cuniculus paca) con altas dosis de letrozol, un inhibidor de la aromatasa

SUMMARY: The study reported the influence of the high and acute dose of Letrozole on the testis morphology in paca (Cuniculus paca), an aromatase inhibitor that reduces the endogenous estrogen, the essential hormone for spermatogenesis. Morphological changes were observed in seminiferous epithelium with germ cells with apoptotic characteristics and presence of vacuoles and nuclei in pycnose.

RESUMEN: El objetivo de este estudio fue analizar la influencia de una dosis alta de Letrozol en la morfología de los testículos de la paca (Cuniculus paca), un inhibidor de la aromatasa que reduce el estrógeno endógeno, la hormona esencial para la espermatogénesis. Se observaron cambios morfológicos en el epitelio seminífero con células germinales con características apoptóticas y la presencia de vacuolas y núcleos en picnosis.

Urinary incontinence and overactive bladder symptoms in women with breast cancer being treated with oral hormone therapy / Incontinência urinária e sintomas de bexiga hiperativa em mulheres com câncer de mama em tratamento com terapia hormonal oral

Abstract Objective: The objective of the present study is to observe the frequency and severity of urinary symptoms in women with breast cancer (BC) being treated with oral hormone therapy, associating them to drug adherence. Methods: The participants were interviewed once from June to October 2016. The evaluation of urinary symptoms was performed by two questionnaires: International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF) and International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OAB). Adherence was evaluated by the Morisky-Green method. Statistical analysis was performed by the Mann-Whitney test, linear regression, and Spearman correlation. Results: Fifty-eight women were interviewed: 42 treated with tamoxifen and 16 with aromatase inhibitor. Twenty-seven women (46.5%) presented urinary incontinence symptoms and 15 (25.8%) presented stress urinary incontinence (SUI). Fourteen (24.1%) women had symptoms of overactive bladder (OAB). There was no statistical difference in symptoms between both treatments and duration of treatments. Higher scores in the ICIQ-SF questionnaire were associated with low/medium adherence and advanced age. Higher scores in the ICIQ-OAB questionnaire were associated with low/medium adherence. Conclusion: The present study showed a high prevalence of urinary symptoms, such as urinary incontinence and OAB, associated with low/medium adherence and older age in women with BC being treated with oral hormone therapy. Health professionals should be alert to these symptoms since it could influence life quality and adherence to treatment.

Resumo Objetivo: O objetivo do presente estudo foi observar a frequência e a gravidade dos sintomas urinários em mulheres com câncer de mama em uso de terapia hormonal oral, associando estes com a adesão ao tratamento. Métodos: As pacientes foram entrevistadas uma única vez, entre junho e outubro de 2016. A avaliação dos sintomas urinários foi realizada por dois questionários: International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF, na sigla em inglês) e o Questionário Sobre Bexiga Hiperativa (ICIQ-OAB, na sigla em inglês). A adesão foi avaliada pelo método Morisky-Green. A análise estatística foi realizada pelo teste de Mann-Whitney, regressão linear e correlação de Spearman. Resultados: Foram entrevistadas 58 mulheres: 42 tratadas com tamoxifeno e 16 com inibidor de aromatase. Vinte e sete mulheres (46,5%) apresentaram sintomas de incontinência urinária (IU) e 15 (25,8%) apresentaram incontinência urinária por estresse (IUS). Quatorze (24,1%) das mulheres tinham sintomas de bexiga hiperativa. Não houve diferença estatística nos sintomas entre os tratamentos e a duração dos tratamentos. Os escores mais elevados no questionário ICIQ-SF estiveram associados à baixa/média adesão e à idade avançada. Os escores mais elevados no questionário da ICIQ-OAB foram associados à baixa/média adesão. Conclusão: O presente estudo mostrou alta prevalência de sintomas urinários, como IU e bexiga hiperativa, associadas à baixa/média adesão e à idade mais avançada em mulheres com câncer de mama em tratamento com hormonioterapia oral. Os profissionais de saúde devem estar atentos a esses sintomas, pois eles podem influenciar a qualidade de vida e a adesão ao tratamento.

Uso de testosterona en mujeres: un comentario sobre el consenso global sobre el uso de la terapia de testosterona para mujeres / Global consensus position statement on the use of testosterone therapy for women

Las mujeres han sido tratadas por décadas con testosterona intentando aliviar una gran variedad de síntomas con riesgos y beneficios inciertos. En la mayoría de los países, la testosterona se prescribe "off-label", de modo que las mujeres están utilizando compuestos y dosis ideadas para tratamientos en hombres. En este sentido, varias sociedades médicas de distintos continentes adoptaron recientemente por consenso una toma de posición sobre los beneficios y potenciales riesgos de la terapia con testosterona en la mujer, explorar las áreas de incertidumbre e identificar prácticas de prescripción con potencial de causar daño. Las recomendaciones con respecto a los beneficios y riesgos de la terapia con testosterona se basan en los resultados de ensayos clínicos controlados con placebo de al menos 12 semanas de duración. A continuación se comentan las recomendaciones. (AU)

There are currently no clear established indications for testosterone replacement therapy for women. Nonetheless, clinicians have been treating women with testosterone to alleviate a variety of symptoms for decades with uncertainty regarding its benefits and risks. In most countries, testosterone therapy is prescribed off-label, which means that women are using testosterone formulations or compounds approved for men with a modified dose for women. Due to these issues, there was a need for a global Consensus Position Statement on testosterone therapy for women based on the available evidence from placebo randomized controlled trials (RCTs). This Position Statement was developed to inform health care professionals about the benefits and potential risks of testosterone therapy intended for women. The aim of the Consensus was to provide clear guidance as to which women might benefit from testosterone therapy; to identify symptoms, signs, and certain conditions for which the evidence does not support the prescription of testosterone; to explore areas of uncertainty, and to identify any prescribing practices that have the potential to cause harm. (AU)

Predicting the Benefit of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer Patients with Phosphorylated S6K1 Expression Status / 한국유방암학회지

PURPOSE: Phosphorylated ribosomal S6 kinase 1 (pS6K1) is a major downstream regulator of the mammalian target of rapamycin (mTOR) pathway. Recent studies have addressed the role of S6K1 in adipogenesis. pS6K1 may affect the outcome of estrogen depletion therapy in patients with hormone-sensitive breast cancer due to its association with adipogenesis and increased local estrogen levels. This study aimed to investigate the potential of pS6K1 as a predictive marker of adjuvant aromatase inhibitor (AI) therapy outcome in postmenopausal or ovarian function-suppressed patients with hormone-sensitive breast cancer.METHODS: Medical records were retrospectively reviewed in postmenopausal or ovarian function-suppressed patients with estrogen receptor-positive and node-positive primary breast cancer. pS6K1 expression status was scored on a scale from 0 (negative) to 3+ (positive) based on immunohistochemical analysis.RESULTS: A total of 428 patients were eligible. The median follow-up duration was 44 months (range, 1–90). In patients with positive pS6K1 expression, AIs significantly improved disease-free survival (DFS) compared to selective estrogen receptor modulators (SERMs) (5 year-DFS: 83.5% vs. 50.7%, p = 0.016). However, there was no benefit of AIs on DFS in the pS6K1 negative group (5 year-DFS 87.6% vs. 91.4%, p = 0.630). On multivariate analysis, AI therapy remained a significant predictor for DFS in the pS6K1 positive group (hazard ratio, 0.39; 95% confidence interval, 0.16–0.96; p = 0.041). pS6K1 was more effective in predicting the benefit of AI therapy in patients with ages < 50 (p = 0.021) compared to those with ages ≥ 50 (p = 0.188).CONCLUSION: pS6K1 expression may predict AI therapy outcomes and serve as a potential predictive marker for adjuvant endocrine therapy in postmenopausal and ovarian function-suppressed patients with hormone-sensitive breast cancer. AIs may be more effective in patients with pS6K1 positive tumors, while SERM could be considered an alternative option for patients with pS6K1 negative tumors.

Reconsideration of the third-generation non-steroidal aromatase inhibitors in pediatrics / 浙江大学学报·医学版

Aromatase is the rate-limiting enzyme in estrogen biosynthesis. The third generation aromatase inhibitors (AIs), represented by letrozoleand and anastrozole, can combine with aromatase, effectively reducing the estrogen level in the body. Because of its high efficiency, selectivity and reversibility, it has been used in the treatment of McCune-Albright syndrome, familial male-limited precocious puberty, gynecomastia, and adolescent boy with short stature. The good efficacy and safety of AIs have been observed. However, so far the drug instructions of AIs usually do not show indications for children; there are risks of adverse reactions involving liver and kidney function, lipid metabolism, hyperandrogenemia and bone metabolism; especially the long-term effects on reproductive system and bone metabolism are still not clear. Therefore, it is necessary to prescribe it carefully and follow up closely. It was not recommended that AIs be routinely used to improve adult height of adolescent boy with short stature. And more clinical evidences are needed for the safety and effectiveness of AIs prescribed in pediatrics.

Efficacy and safety of letrozole in treatment of McCune-Albright syndrome girls with peripheral precocious puberty / 浙江大学学报·医学版

OBJECTIVE@#To evaluate the efficacy and safety of the third-generation aromatase inhibitor letrozole in the treatment of McCune-Albright syndrome (MAS) girls with peripheral precocious puberty.@*METHODS@#Twenty-one MAS girls with peripheral precocious puberty treated in Pediatrics Department of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine from March 2012 to June 2017 were enrolled in the study. Patients presented with repeated vaginal bleeding, premature breast enlargement, café-au-lait spots or dysplasia of bone fibers, and low levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and the congenital adrenal hyperplasia, estrogen-producing tumors, and exogenous estrogen intake were excluded. Letrozole were administrated at a dose of 0.5-2 mg·m ·d for 6 to 12 months. The patients were observed for changes in breast staging, vaginal bleeding, sex hormone levels, liver function and bone age changes, and changes in uterine and ovarian volume.@*RESULTS@#After treatment, bone age/chronological age (BA/CA)was decreased from 1.23±0.30 to 1.11±0.18 ( < 0.01); the predicted adult height (PAH) increased from (156.2±5.9)cm to (158.4±2.1)cm after treatment ( < 0.05); the vaginal bleeding was reduced and the estradiol level decreased, while the teststosterone level and the uterus showed no significant increase, and no adverse reactions such as ovarian torsion and abnormal liver function were observed.@*CONCLUSIONS@#Precocious puberty is one of the most common endocrine manifestations in MAS. Our findings suggest that letrozole may be an effective and safe therapy to precocious puberty in girls with McCune-Albright Syndrome.

Aromatase inhibitors combined with growth hormone in treatment of adolescent boys with short stature / 浙江大学学报·医学版

OBJECTIVE@#To assess the efficacy and safety of aromatase inhibitors (AIs) combined growth hormone in treatment of adolescent boys with short stature.@*METHODS@#One hundred and fifty-one short stature pubertal boys with age of 10-14 years and bone age of 13-15 years, who were admitted to the Department of Pediatrics, the First Affiliated Hospital, Zhejiang University School of Medicine, were included in this trial. According to their own or parents' intention, the children were divided into recombinant human growth hormone (rhGH)+AI group ( =108) and rhGH group ( =43). All children were injected subcutaneously with rhGH 0.15-0.2 IU·kg ·d , and those in rhGH+AI group were additionally given 2.5 mg/d letrozole or 1 mg/d anastrozole, orally for 12 months or longer. The children were followed-up every 3 months. During the follow-up visit, the predicted adult height (PAH), sex hormone level, glucose and lipid metabolism, and other indicators were measured, and adverse reactions were monitored.@*RESULTS@#After intervention, there were significant differences in ΔBA(bone age)/ΔCA(chronological age), ΔHtSDS (height standard deviation score based on bone age)and ΔPAH between rhGH+AI group and the rhGH group( < 0.05 or < 0.01). During follow-up, 63.9%of the children in the rhGH+AI group had elevated uric acid and 51.9%had decreased high-density lipoprotein (HDL); 25.9%showed severe acne, excitement, hyperactivity and irritability, 11.1%had knee pain; 4.6%had fracture; 2.8%had mild renal dysfunction; 1.9%had inactivity, drowsiness, memory loss and performance decline; 1.9%showed mild abnormal liver function; 0.9%showed impaired fasting glucose; 0.9%showed granulocytopenia. In the rhGH group, 11.6%of the children presented with knee pain and 2.3%with impaired fasting glucose.@*CONCLUSIONS@#AI combined with rhGH can delay the growth of BA and effectively improve the PAH of adolescent boys with larger bone age. However, the occurrence of adverse reactions of AI should be closely monitored during treatment.

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.

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)

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.

PARAGON (ANZGOG-0903): a phase 2 study of anastrozole in asymptomatic patients with estrogen and progesterone receptor-positive recurrent ovarian cancer and CA125 progression / 부인종양

OBJECTIVE: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER+). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER+ and/or progesterone receptor (PR)-positive (PR+) recurrent/metastatic gynecological cancers. METHODS: Postmenopausal women with ER+ and/or PR+ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%–48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1–3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8–11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6 months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS. CONCLUSION: A subset of asymptomatic patients with ER+ and/or PR+ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents.

A pilot study of gonadotropin-releasing hormone agonist combined with aromatase inhibitor as fertility-sparing treatment in obese patients with endometrial cancer / 부인종양

OBJECTIVE: This study aims to evaluate the effects and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH agonist) combined with aromatase inhibitor (AI) in preserving the fertility of obese women with grade 1 endometrial cancer (EC). METHODS: This study recruited obese EC patients who wished to preserve their fertility. The treatment regimen consisted of intramuscular GnRH agonist 3.75 mg every 4 weeks and oral AI 2.5 mg daily. The maintenance regimen was the same as the initial treatment regimen. Primary outcomes included response rate, time to complete response (CR), and time to recurrence; pregnancy outcomes included the time to pregnancy, pregnancy rate and live birth rate. RESULTS: Six obese patients with EC were included in this study, with the age (mean±standard deviation [SD]) of 30.5±3.3 years and body mass index (mean±SD) of 35.0±1.4 kg/m2. CR rate was 100%, and time to CR was 3–6 months. None of the patients had recurrence after a median follow-up of 4.0 years (range, 1.3–7.0 years). The most common side effects were menopause-like symptoms. Among these patients, no weight gain was observed during treatment. The pregnancy rate and live birth rate was 50.0% and 75.0%, respectively, with a median time to pregnancy of 2.4 years (range, 1.0–5.5 years). CONCLUSION: The combination of GnRH agonist and AI demonstrated promising long-term effect in young obese EC patients who wished to preserve their fertility. No weight gain side effects were observed. Further studies with a larger sample size are needed to fully evaluate this novel treatment regimen.