Rol de los fitoestrógenos en la calcificación vascular e interacciones óseo-vasculares / Role of phytoestrogens in vascular calcification and bonevascular interactions

La osteoporosis y las enfermedades cardiovasculares son patologías prevalentes en mujeres posmenopáusicas. La calcificación vascular es un proceso en el que se produce una distorsión de la arquitectura natural del tejido arterial con una transformación símil osteogénica. La fisiología vascular y la osteogénesis (formación y remodelación ósea) comparten una complejidad metabólica y funcional crítica, que ha sido poco explorada en forma conjunta, lo que ha impulsado la concepción del Eje Óseo-Vascular como nueva área de investigación, con una visión de estudio integradora con la finalidad de identificar vínculos entre ambos sistemas. En virtud de la controversia planteada sobre los riesgos/beneficios de la terapia de reemplazo hormonal para prevenir enfermedades asociadas a la menopausia, se ha incentivado la búsqueda de nuevas opciones de tratamiento. Los fitoestrógenos, como compuestos nutracéuticos, surgen como una potencial alternativa terapéutica. En particular, las isoflavonas presentan gran analogía estructural con el estrógeno humano 17ß-estradiol, lo que les permite unirse al receptor de estrógenos e inducir acciones estrogénicas tanto en células animales como humanas. Basado en la experiencia propia como en lo reportado en la bibliografía, este artículo analiza la información disponible sobre las acciones vasculares y óseas de los fitoestrógenos (específicamente la isoflavona genisteína), con una visión de ciencia traslacional. Es de esperar que los avances en el conocimiento derivado de la ciencia básica, en un futuro cercano, pueda contribuir a decisiones clínicas a favor de promover terapias naturales de potencial acción dual, para la prevención de enfermedades de alta prevalencia y significativo costo social y económico para la población. (AU)

Osteoporosis and cardiovascular diseases are prevalent diseases in postmenopausal women. Vascular calcification is a cellmediated process that leads to the loss of the natural architecture of the arterial vessels due to osteogenic transdifferentiation of smooth muscle cells, and matrix mineralization. Vascular physiology and osteogenesis (bone formation and remodeling) share a critical metabolic and functional complexity. Given the emerging integrative nature of the bonevascular axis, links between both systems are a matter of ongoing interest. In view of the controversy stated about the risks/benefits of hormone replacement therapy to prevent diseases associated with menopause, phytoestrogens arise as a potential natural therapeutic alternative. In particular, isoflavones have a strong structural analogy with the human estrogen 17ß-estradiol, that allows them to bind to the estrogen receptor and induce estrogenic actions in animal and human cells. Based in on our own experience and the information available in the literature, in this paper we provide an overview of the role of phytoestrogens on vascular and bone tissues, with focus on Genistein actions. We wish that the basic knowledge acquired may contribute to guide clinical decisions for the promotion of natural therapies for the treatment of diseases that conspire against human health. (AU)

Phytoestrogen -zearalanol ameliorates memory impairment and neuronal DNA oxidation in ovariectomized mice

OBJECTIVE: The aim of this study was to evaluate the effect of a novel phytoestrogen, α-Zearalanol, on Alzheimer's disease-related memory impairment and neuronal oxidation in ovariectomized mice. METHODS: Female C57/BL6 mice were ovariectomized or received sham operations and treatment with equivalent doses of 17β-estradiol or α-Zearalanol for 8 weeks. Their spatial learning and memory were analyzed using the Morris water maze test. The antioxidant enzyme activities and reactive oxygen species generation, neuronal DNA oxidation, and MutT homolog 1 expression in the hippocampus were measured. RESULTS: Treatment with 17β-estradiol or α-Zearalanol significantly improved spatial learning and memory performance in ovariectomized mice. In addition, 17β-estradiol and α-Zearalanol attenuated the decrease in antioxidant enzyme activities and increased reactive oxygen species production in ovariectomized mice. The findings indicated a significant elevation in hippocampi neuronal DNA oxidation and reduction in MutT homolog 1 expression in estrogen-deficient mice, but supplementation with 17β-estradiol or α-Zearalanol efficaciously ameliorated this situation. CONCLUSION: These results demonstrate that α-Zearalanol is potentially beneficial for improving memory impairments and neuronal oxidation damage in a manner similar to that of 17β-estradiol. Therefore, the compound may be a potential therapeutic agent that can ameliorate neurodegenerative disorders related to estrogen deficiency. .

Análise crítica dos efeitos da glycine max nas doenças cardiovasculares e seus fatores de risco / Critical analysis on the effects of glycine max in cardiovascular diseases and its risk factors

As doenças cardiovasculares (DCV) são as principais causas de morte em todo mundo e a mulher após a menopausa torna-se mais exposta, com a perda do papel protetor dos estrogênios, entre outros fatores de risco. Vários aspectos têm sido avaliados, no sentido de nortear as ações preventivas em atenção primária de saúde. Evidências têm demonstrado efeito da Glycine max, quer como alimento funcional (produtos à base de proteína de soja) ou fitomedicamento (extrato de soja rico em isoflavonas), na redução dos riscos de DCV. Nesta análise crítica de 66 estudos, obtidos por consulta no banco de dados Medline, no período de janeiro de 2000 até janeiro de 2007, visamos detalhar os efeitos da soja em diferentes marcadores de risco de DCV. Foi possível notar que a qualidade metodológica e a heterogenicidade dos trabalhos nos conduzem a comparações duvidosas, sem expressão estatística. No entanto, parece haver um impacto positivo da Glycine max em diversos parâmetros na prevenção da doença cardiovascular. A soja e os produtos dela derivados (isoflavonas) constituem possibilidade terapêutica na mulher após a menopausa, agregando melhora do risco de DCV.

Cardiovascular diseases (CVD) are the main causes of death worldwide and the postmenopausal women become more exposed due to deleterious hypoestrogenic effects. Several risk factors have been assessed, in order to guide preventive actions in primary healthcare. Evidences have demonstrated the Glycine max effects as functional nutrient (soy protein) of as patronized herbal drug (soy extract with isoflavonas) reducing the cardiovascular risks. In this critical analysis of 66 studies, obtained by consulting the Medline database, from January 2000 ultil January 2007, it was aimed to detail the soy effects in different risk markers of on CVD. It was noted that the methodological quality of work and heterogeneity lead in the dubious comparisons, without statistical expression. However, Glycien max seems to have a positive impact in some parameters in terms or prevention of CVD. The soybeans and products derived from it (isoflavones) are possible therapies in women after menopause, adding improves the risk of CVD.

¿Es posible encontrar un fitoestrógeno para la terapia de reemplazo hormonal, que disminuya el riesgo de cáncer?: tema de Proyecto Anillos de Investigación del Programa Bicentenario en Ciencia y Tecnología / Is it possible to find a phytoestrogen for hormone replacement therapy, decreasing cancer risk?: subject of Research Team Grant in Science and Technology from the Bicentennial Program in Science and Technology

Se describe una nueva línea de investigación que tiene como objetivo investigar principios activos presentes en especies vegetales chilenas, para identificar alguna(s) que produzcan los efectos farmacológicos deseables para su uso como terapia de reemplazo hormonal en mujeres peri o postmenopáusicas, pero que no aumenten, o incluso disminuyan, el riesgo de desarrollar cáncer mamario o endometrial. Esta posibilidad se basa en el hallazgo previo de nuestro equipo de investigadores de un nuevo tipo de receptores estrogénicos responsables de respuestas estrogénicas no genómicas y de nuestro hallazgo de diferencias entre los receptores estrogénicos citosólico-nucleares clásicos de los diferentes tipos celulares uterinos. Si existiera, como anteriormente se creía, un solo tipo de receptor de estrógenos, no sería posible el desarrollo de este nuevo fármaco estrogénico selectivo que buscamos, pues todos los receptores tendrían la misma afinidad por este agente, el que en consecuencia, induciría todas las respuestas a la estimulación estrogénica (incluyendo aquellas que deseamos prevenir, como las que presentan riesgo de desarrollo de cáncer), o que actuaría como antiestrógeno, antagonizando todas las respuestas a los estrógenos en el útero.

A new research line aimed at the investigation of active agents from Chilean plant species is described. The purpose is to indentify those agents inducing expected pharmacological effects in a hormone replacement therapy in peri- or post-menopausal women, but not increasing, or even decreasing, the risk for development of mammary or endometrial cancer. This possibility is based on previous findings from our research team of a new kind of estrogen receptors, responsible of non-genomic responses to estrogen, and our finding of differences between the classical cytosol-receptor estrogen receptors from the different uterine cell-types. If there exists one kind of estrogen receptors only in the uterus, as it was formerly accepted, then it is not possible to develop the selective estrogenic drug we search for, because all receptors would display the same affinity for this agent; therefore, it would induce all responses to estrogen stimulation (including those we wish to prevent, such as those presenting risk of cancer development), or would act as antiestrogen, antagonizing all responses to estrogen in the uterus.

Compuestos disruptores endocrinos y su participación en la programación del eje reproductivo / Endocrine disruptor compounds and their role on the developmental programming of the reproductive axis

Different perturbations during fetal and post natal development unleash endocrine adaptations that permanently alter metabolism, increasing the susceptibility to develop later disease, process known as "developmental programming"'. Endocrine disruptor compounds (EDC) are widely spread on the environment and display estrogenic, anti-estrogenic or anti-androgenic activity; they are lypophilyc and stored for long periods on the adipose tissue. Maternal exposure to EDC during pregnancy and lactation produces the exposure of the fetus and neonate through placenta and breast milk. Epidemiological and experimental studies have demonstrated reproductive alterations as a consequence of intrauterine and/or neonatal exposure to EDC. Diethystilbestrol (DES) is the best documented compound, this synthetic estrogen was administered to pregnant women at the BO and 60 to prevent miscarriage. It was implicated in urogenital abnormalities in children exposed in utero and withdrawn from the market. The "DES daughters" are women with high incidence of vaginal hypoplasia, spontaneous abortion, premature delivery, uterine malformation, menstrual abnormalities and low fertility. The "DES sons" show testicular dysgenesis syndrome, which is characterized by hypospadias, cryptorchidism and low semen quality. This entity is also associated to the fetal exposure to anti-androgens as flutamide. The effects on the reproductive axis depend on the stage of development and the window of exposure, as well as the dose and the compound. The wide distribution of EDC into the environment affects both human health and ecosystems in general, the study of their mechanisms of action is extremely important currently.

Diversas perturbaciones durante el desarrollo fetal y posnatal desencadenan adaptaciones endocrinas que modifican permanentemente el metabolismo, incrementando la susceptibilidad para el desarrollo de enfermedades, proceso conocido como "programación durante el desarrollo". Los compuestos disruptores endocrinos (CDE) se encuentran en el medio ambiente y presentan actividad estrogénica, antiestrogénica o antiandrogénica; son altamente lipofílicos y se almacenan por periodos prolongados en el tejido adiposo. La exposición materna a CDE durante el embarazo y la lactancia permite su paso al producto a través de la placenta y la leche materna. Estudios epidemiológicos y experimentales han demostrado alteraciones en el eje reproductivo como consecuencia de la exposición intrauterina y/o neonatal a CDE. El compuesto mejor documentado es el dietilestilbestrol (DES), este estrógeno sintético fue administrado a mujeres embarazadas durante los 50s y 60s y retirado del mercado por su implicación en anormalidades urogenitales de los bebés expuestos in útero. Las denominadas "hijas del DES" son mujeres con alta incidencia de hipoplasia vaginal, malformaciones uterinas, irregularidades menstruales, baja fertilidad y alta prevalencia de aborto espontáneo y parto prematuro. Por su parte, "los hijos del DES" presentan una entidad clínica conocida como síndrome de disgenesia testicular caracterizado por hipospadias, criptorquidia y baja calidad del semen. Este síndrome también se asocia a la exposición fetal a compuestos antiandrogénicos como la ñutamida. Los efectos en el eje reproductivo dependen del estadio de desarrollo y del tiempo de exposición, así como de la dosis y el compuesto del que se trate. La extensa presencia de CDE en el ambiente afecta la salud humana e impacta al ecosistema en general por lo cual es de suma importancia el estudio de los mecanismos involucrados en su acción.

Terapia de reposição hormonal e a mama / Hormonal replacement theraphy and the breast

A terapia de reposição hormonal (TRH) tem sido muito usada para alívio de sintomas climatéricos. Porém, como se sabe, os hormônios esteróides, principalmente os estrogênios, exercem ação promotora na carcinogênese mamária, a segurança da TRH em termos de risco de câncer de mama pode ser questionada. Nesta revisão de literatura, os autores concluíram que a TRH eleva discretamente o risco relativo de câncer de mama, podendo ser considerada quando as vantagens superarem as desvantagens. Mas, para mulheres com antecedente pessoal de câncer de mama ou com fatores predisponentes de alto risco, a TRH deve ser evitada, preferindo-se alternativas não-hormonais.

Hormonal replacement therapy (HRT) has been widely used for the 1llanagement of climateric symptoms. As it is known that steroid hormones, mainly estrogens, are promoting factors for mammary carcinogenesis, the safety of HRT in terms of risk for breast cancer may be cause of concern. In this review literature the authors concluded that HRT increases slightly the relative risk of breast cancer, and may by tailoring considered when the advantages exceed the disadvantages. Neverthless HRT should be avoided in women with personal history of breast cancer or presenting high risk predisposing factors, to whom non-hormonal alternatives are preferred.

Vegetables, fruits and phytoestrogens in the prevention of diseases.

The intake of 400-600 g/d of fruits and vegetables is associated with reduced incidence of many common forms of cancer, and diets rich in plant foods are also associated with a reduced risk of heart disease and many chronic diseases of ageing. These foods contain phytochemicals that have anti-cancer and anti-inflammatory properties which confer many health benefits. Many phytochemicals are colourful, and recommending a wide array of colourful fruits and vegetables is an easy way to communicate increased diversity of intake to the consumer. For example, red foods contain lycopene, the pigment in tomatoes, which is localized in the prostate gland and may be involved in maintaining prostate health, and which has also been linked with a decreased risk of cardiovascular disease. Green foods, including broccoli, Brussels sprouts and kale, contain glucosinolates which have also been associated with a decreased risk of cancer. Garlic and other white-green foods in the onion family contain allyl sulphides which may inhibit cancer cell growth. Other bioactive substances in green tea and soybeans have health benefits as well. Consumers are advised to ingest one serving of each of the seven colour groups daily, putting this recommendation within the United States National Cancer Institute and American Institute for Cancer Research guidelines of five to nine servings per day. Grouping plant foods by colour provides simplification, but it is also important as a method to help consumers make wise food choices and promote health.