Isoflavonas como tratamento alternativo na sintomatologia climatérica: uma revisão sistemática / Isoflavones as alternative treatment in climacteric symptomatology: a systematic review

O climatério é uma fase natural da vida da mulher que ocorre entre os 40 e 65 anos de idade e é caracterizado pela transição entre a fase reprodutiva e não reprodutiva. Neste período, devido às alterações hormonais, ocorrem alterações biológicas, endócrinas e clínicas. Sintomas vasomotores são típicos do hipoestrogenismo e podem interferir negativamente na qualidade de vida das mulheres. Este estudo teve como objetivo revisar os resultados dos estudos de intervenção que utilizaram isoflavonas na sintomatologia de mulheres climatéricas não usuárias de Terapia de Reposição Hormonal (TRH). Realizou-se uma revisão sistemática de artigos publicados entre os anos de 2008 e 2019 na base de dados PubMed. Foram encontrados 169 estudos, e considerando os critérios de inclusão, 18 artigos foram selecionados, em que houve intervenção com isoflavonas por meio de cápsulas e/ou suplementos ou alimentos para tratamento da síndrome climatérica. Foram verificados resultados positivos nos sintomas globais, com destaque para sintomas vasomotores, em mais da metade dos estudos avaliados, em que doses entre 45 mg a 160 mg diárias de isoflavonas por pelo menos 12 semanas foram administradas, especificadamente nas mulheres no período da pós-menopausa.

The climacteric is a natural phase during women’s life, which occurs between 40 and 65 years. It is characterized by the transition from their reproductive to non-reproductive phase. In this period, due to hormonal changes, biological, endocrine and clinical modifications also occur. Vasomotor symptoms are characteristic of hypoestrogenism and can negatively affect women’s quality of life. This study aimed to review the results of intervention studies which used isoflavones to treat the symptoms of climacteric women who did not undergo Hormone Replacement Therapy (HRT). A systematic review of articles published between 2008 and 2019 in the PubMed database was carried out. 169 studies were found, and considering the inclusion criteria, 18 articles were selected, in which it was described isoflavones intervention with capsules and/ or supplements or foods for the treatment of climacteric syndrome. Positive results were observed regarding to global symptoms, with emphasis on vasomotor symptoms in more than half of the studies, in which daily doses of isoflavones, between 45 mg to 160 mg, for at least 12 weeks, were administered specifically in postmenopausal women.

Effects of the phytoestrogen genistein on the development of the reproductive system of Sprague Dawley rats

OBJECTIVES: Genistein is known to influence reproductive system development through its binding affinity for estrogen receptors. The present study aimed to further explore the effect of Genistein on the development of the reproductive system of experimental rats. METHODS: Eighteen post-weaning female Sprague Dawley rats were divided into the following groups: (i) a control group that received vehicle (distilled water and Tween 80); (ii) a group treated with 10 mg/kg body weight (BW) of Genistein (Gen 10); and (iii) a group treated with a higher dose of Genistein (Gen 100). The rats were treated daily for three weeks from postnatal day 22 (P22) to P42. After the animals were sacrificed, blood samples were collected, and the uteri and ovaries were harvested and subjected to light microscopy and immunohistochemical study. RESULTS: A reduction of the mean weekly BW gain and organ weights (uteri and ovaries) were observed in the Gen 10 group compared to the control group; these findings were reversed in the Gen 100 group. Follicle stimulating hormone and estrogen levels were increased in the Gen 10 group and reduced in the Gen 100 group. Luteinizing hormone was reduced in both groups of Genistein-treated animals, and there was a significant difference between the Gen 10 and control groups (p<0.05). These findings were consistent with increased atretic follicular count, a decreased number of corpus luteum and down-regulation of estrogen receptors-a in the uterine tissues of the Genistein-treated animals compared to the control animals. CONCLUSION: Post-weaning exposure to Genistein could affect the development of the reproductive system of ovarian-intact experimental rats because of its action on the hypothalamic-pituitary-gonadal axis by regulating hormones and estrogen receptors.

Isoflavonas de soya y salud humana: cáncer de mama y sincronización de la pubertad / Soy isoflavones and human health: breast cancer and puberty timing

Background: Accumulated exposure to high levels of estrogen is associated with an increased incidence of breast cancer. Thus, factors such as early puberty, late menopause and hormone replacement therapy are considered to be risk factors, whereas early childbirth, breastfeeding and puberty at a later age are known to consistently decrease the lifetime breast cancer risk. Epidemiological studies suggest that consumption of isoflavones correlates with a lower incidence of breast cancer. Data from human intervention studies show that the effects of isoflavones on early breast cancer markers differ between pre- and post-menopausal women. The reports from experimental animals (rats and mice) on mammary tumors are variable. These results taken together with heterogeneous outcomes of human interventions, have led to a controversy surrounding the intake of isoflavones to reduce breast cancer risk. This review summarizes recent studies and analyzes factors that could explain the variability of results. In mammary tissue, from the cellular endocrine viewpoint, we analyze the effect of isoflavones on the estrogen receptor and their capacity to act as agonists or antagonists. On the issue of puberty timing, we analyze the mechanisms by which girls, but not boys, with higher prepuberal isoflavone intakes appear to enter puberty at a later age.

Efeitos de altas doses de genisteína sobre o epitélio mamário de ratas / Effects of high doses of genistein on mammary gland of female rat

OBJETIVO: avaliar os efeitos de altas doses de genisteína sobre o epitélio mamário de ratas adultas. MÉTODOS: após 28 dias da ooforectomia, cinquenta ratas adultas foram divididas em cinco grupos, a saber: um controle (Ctrl), três que receberam genisteína (GEN) nas doses de 46 mg/kg (GEN46), 125 mg/kg (GEN125) e 250 mg/kg (GEN250), e um que recebeu estrogênios conjugados equinos na dose de 50 µg/kg (ECE). As substâncias foram administradas diariamente durante 30 dias consecutivos por gavagem e na última semana de tratamento foi efetuado exame colpocitológico durante sete dias consecutivos. Após o tratamento, os animais foram anestesiados, amostras de sangue foram retiradas para determinação do estradiol e da progesterona, e o primeiro par de mamas inguinais retirado e processado para análise histomorfométrica. Os dados obtidos foram submetidos à análise de variância complementada pelo teste de Tukey-Kramer (p<0,05). RESULTADOS: nos grupos Ctrl e tratados com as diferentes doses de GEN as mamas apresentaram-se atróficas, no entanto mostraram-se desenvolvidas no grupo ECE, onde se notou a presença de inúmeros ductos e alvéolos mamários contendo material eosinófilo em seu interior. A morfometria mostrou maior área de parênquima mamário no grupo ECE (98.870,1±550,4 µm²* por mm²; p<0,05) comparado aos outros grupos (Ctrl=36.875,6±443,4; GEN46=37.001,7±557,4; GEN125=36.480,8±658,3 e GEN250=37.502,8±669,3). O mesmo ocorreu em relação ao número de alvéolos e ductos mamários no grupo ECE (33,2±6,9* por mm²; p<0,05) em relação aos outros grupos (Ctrl=10,4±2,1, GEN 46=11,2±3,1; GEN 125=11,6±2,1 e GEN 250=12,3±2,3). Os níveis de estradiol mostraram-se aumentados no grupo ECE em relação aos outros grupos (9,4±1,7 pg/mL; p<0,05), sendo que os níveis séricos de progesterona mostraram-se semelhantes em todos os grupos de estudo. CONCLUSÃO: a administração de genisteína em altas doses não apresentou efeito proliferativo no tecido mamário de ratas.

PURPOSE: to evaluate the effects of high doses of genistein on the mammary glands of adult female rats. METHODS: Twenty-eight days after oophorectomy, 50 adult female rats were divided into five groups, as follows: a control group (Ctrl), three rats that received genistein (GEN) at the doses of 46 mg/kg (GEN46;), 125 mg/kg (GEN125) and 250 mg/kg (GEN250); one group received conjugated equine estrogen at the dose of 50 µg/g (ECE50). The substances were administered daily for 30 consecutive days by gavage and in the last week of the period of treatment, colpocytological exams were carried out for seven consecutive days. After treatment, the animals were anesthetized, blood samples were collected for estradiol and progesterone determination and the first pair of inguinal mammary glands was removed and processed for histomorphometric analysis. Collected data were subjected to analysis of variance supplemented by the Tukey-Kramer test (p<0.05). RESULTS: the ctrl group and the ones treated with different doses of GEN showed atrophic mammary glands, whereas the glands were more developed in the ECE group, where numerous mammary ducts and alveoli were observed. Morphometry showed a larger area of mammary parenchyma in the ECE group (98.870.1±550.4 µm²* per mm²; p<0.05) compared with other groups (Ctrl=36.875.6±443.4; GEN46=37.001.7±557.4; GEN125=36.480.8±658.3 and GEN250=37.502.8±669.3). The same occurred in the number of alveoli in the ECE group (33.2±6.9* per mm²; p<0.05) compared to the other groups (Ctrl=10.4±2.1, GEN46=11.2±3.1; GEN125=11.6±2.1 and GEN250=12.3±2.3). The estradiol level was higher in the ECE group compared to the other groups (9.4±1.7 pg/mL; p<0.05), whereas serum levels of progesterone were similar in all groups. CONCLUSION: the administration of genistein at high doses had no trophic effect on the mammary glands of rats.

Lactantes menores alimentados con fórmula de soya: evaluación de hormonas tiroideas / Infants fed with soy formula: evaluation of thyroid hormones

La alimentación a base de soya, se ha relacionado con alteración de la función tiroidea, debido a la presencia de fitoestrógenos en su composición. Es por ello, que el presente estudio tiene como objetivo determinar la función tiroidea en lactantes menores de 6 meses alimentados con fórmula infantil a base de soya. Es un estudio descriptivo, transversal. Se evaluaron 28 lactantes que recibieron fórmula infantil de soya, como única alimentación. Variables utilizadas: edad, sexo, Graffar-Méndez Castellano, motivo de indicación de la fórmula, dilución, onzas diarias ingeridas, determinación de T3-libre y T4-libre y TSH sérico. Para el análisis estadístico se aplicó t de Student para un nivel de significación estadística de p<0,05. Los valores séricos de T3 y T4 libres se mantuvieron dentro de rangos normales. 7% de la muestra mostró valores elevados de TSH, no siendo estadísticamente significativo. No existió relación estadística entre el consumo de fórmula de soya y función tiroidea. Sin embargo, en la muestra estudiadados de los pacientes presentaron aumento de los niveles de TSH, por lo que no se puede descartar la posibilidad de una asociación dado lo limitado de la muestra.

Feeding with soy has been related to alteration of thyroid function. The objective of this study was to determine thyroid functionalism in babies under 6 months of age fed with infantile soy based formula. Descriptive, cross-sectional, non experimental study. Twenty eight babies who received exclusively infantile soy based formula were evaluated. Variables studied were: age, gender, socio-economical level, reason for the prescription of soy formula, dilution, daily ounces, determination of free T3, T4 and TSH. For the statistic analysis, Student’s t test was applied for a statistical significance level of p<0.05. Serum free T3 and T4 were within normal ranges. 7% of the sample showed elevated levels of TSH, with no statistic significance. there was no statistical relationship between consumption of soy formula and thyroid function. However, two patients had increased levels of TSH and therefore, the possibility of an association cannot be ruled out given the small size of the sample.

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.

Hormonas femeninas y cáncer de mama: estado de la polémica y evidencias en 2008: ¿qué responder a las pacientes? / Female hormones and breast cancer: controversies and evidences at 2008: what to answer to our patients?

The use of Hormone Replacement Therapy (HRT) has evolved from a massive utilization to a restricted use under very precise medical indications, in the light of the deletereous effects its indiscriminate prescription could entail. It is not beneficial for secondary prevention, but rather implies additional cardiocerebrovascular risks, and therefore it must be preferentially employed during perimenopausic and non-late periods, in the smallest possible dose and only over short periods of time, restricting its prescription to women presenting with severe estrogen deprivation syndrome or to osteoporotic patients intolerant to calcium and bifosfonates therapy. Breast cancer risk -which is low- is related to a estrogen therapy extended for more than seven years or associated with the use of progesterone for a period exceeding five years. Personal medical records of breast cancer imply absolute contraindication. Currently there are no research work supporting the safe use of phytoestrogens as an alternative therapy. It is likely that in upcoming days transdermal estrogen administration associated with natural progesterone could allow an increased use of them, but for the time being there are no massive studies supporting their recommendation.

El uso de terapia de reemplazo hormonal ha evolucionado desde su empleo masivo a un uso restringido bajo indicaciones precisas, a la luz de los efectos deletéreos que pudiera significar su indicación indiscriminada. No es de utilidad en la prevención secundaria y más bien representa riesgos adicionales cardiovasculares y cerebro vasculares, por lo que se debe emplear de preferencia en el periodo peri-menopáusico y no tardío, en la menor dosis posible y por el menor tiempo necesario, restringiendo su indicación a las mujeres con síntomas de deprivación estrogénica severa o a mujeres osteoporóticas que no toleran la terapia de calcio y bifosfonatos. El riesgo de cáncer de mama -que es bajo- está relacionado con una terapia estrogénica prolongada de 7 años o más o en asociación con el empleo de progesterona por más de 5 años. Antecedentes personales de cáncer de mama representan una contraindicación absoluta. No hay trabajos a la fecha que apoyen el empleo sin riesgo de fitoestrógenos como una terapia alternativa al uso de estrógenos. Es posible que en el futuro la administración transdérmica de los estrógenos, asociado a progesteronas naturales permitan su mayor utilización, pero aún no se dispone de estudios masivos que aprueben su recomendación.

Ingestão excessiva de fitoestrógenos e telarca precoce: relato de caso com possível correlação / High intake of phytoestrogens and precocious thelarche: case report with a possible correlation

Telarca precoce, desenvolvimento mamário antes dos 8 anos de idade, apresenta dois picos de incidência, nos dois primeiros anos de vida e após os 6 anos de idade. Uma menina de 4,75 anos apresentou-se com telarca associada à ingestão excessiva de fitoestrógenos. O desenvolvimento puberal M2P1-2, os níveis hormonais e o US pélvico eram compatíveis com puberdade precoce periférica. Durante o seguimento, observou-se ingestão diária de alimentos baseados em soja (> 40 mg fitoestrógenos/dia). Soja contém fitoestrógenos, principalmente genisteína e daidzeína. Embora menos potentes do que o estradiol, sua concentração pode ser 13.000 a 22.000 vezes maior em crianças alimentadas somente com fórmulas baseadas em soja. Os pais foram aconselhados a reduzir para uma vez na semana o seu fornecimento na dieta. O desenvolvimento puberal cessou em M2-3P1 e a paciente, com 8,66 anos, continua a desenvolver-se com idades óssea e cronológica equivalentes. Questões relacionadas à segurança alimentar, principalmente de alimentos baseados em soja, permanecem sem respostas precisas. Embora sejam conhecidas as etiologias da puberdade precoce não progressiva e da telarca prematura, neste caso esteve fortemente relacionada à ingestão excessiva de soja e de outros alimentos ricos em fitoestrógenos que poderiam ter desencadeado a telarca atuando como desreguladores endócrinos.

Precocious thelarche is the breast development before 8 years of age with two peaks of incidence during the first two years of life and after 6 years of age. A 4.75-year-old girl presented with thelarche associated to an excessive intake of phytoestrogens (phye). Tanner development B2P1-2, hormonal levels and pelvic US were compatible with peripheral precocious puberty. During follow-up, a daily intake of soy-based foods was observed (> 40 mg phye/day). Soy is rich in phytoestrogens, mainly genistein and daidzein. Although phye are less strong than estradiol, its concentration could be from 13,000 to 22,000 times stronger in children fed only by soy-based formulas. Parents were advised and soy intake was reduced to once a week. Progression of pubertal development ceased at B2-3P1. The patient, now 8.66 years old, keeps growing with similar bone and chronological ages. Some questions related to industrial food security, mainly the soy-based food, remain without precise answer. Although it is well known the entity of non-progressive precocious puberty and premature thelarche, pubertal development in this case was strongly related to excessive daily intake of soy and other phye-rich food that could trigger puberty as endocrine disruptor.

Assessing phytochemical intake in a group of Mexican women

OBJECTIVE: Identify the content of selected phytochemicals (PHYs) in Mexican foods and evaluate the reliability of a food frequency questionnaire (FFQ) in assessing PHYs intake among Mexican women. MATERIAL AND METHODS: Values for PHYs content were obtained from four different data sets. PHYs intake was assessed in 50 women of reproductive age enrolled in a longitudinal cohort study. Values were obtained from a FFQ administered twice, one year apart in order to evaluate its reliability. Selected PHYs included flavonol (FOL), flavones (FES), flavanol (FAL), secoisolariciresinol (SE), matairesinol (MA), lariciresinol (LA), pinoresinol (PI), cynamic acid (CA) and coumestrol (CU). RESULTS: Daily PHYs intake ranged from 1.3 µg ± 0.9 for MA to 116.3 ± 43.8 mg for CA. The adjusted correlation coefficients ranged from 0.17 for FAL to 0.47 for LA. Pinto beans, oranges, hot sauce, broccoli, apples and onions were the main sources of the selected PHYs daily intake. DISCUSSION: The results of this study contribute to our understanding of the consumption of PHYs in the Mexican diet, and would help evaluate their potential health impact.

OBJETIVO: Crear una base de datos con el contenido de nueve fitoestrógenos (FIT) presentes en alimentos mexicanos y calcular su ingestión y reproducibilidad en 50 mujeres participantes en un estudio de cohorte en México. MATERIAL Y MÉTODOS: Los FIT seleccionados incluyeron flavonol (FOL), flavones (FES), flavanol (FAL), secoisolariciresinol (SE), matairesinol (MA), lariciresinol (LA), pinoresinol (PI), ácido cinámico (CA) y coumestrol (CU). El contenido de estos compuestos se obtuvo de cuatro diferentes fuentes de datos. La ingestión diaria se estimó a través de un cuestionario de frecuencia de consumo de alimentos, aplicado en dos oportunidades con una diferencia de un año a cada participante. La reproducibilidad en el reporte de cada FIT se estimó mediante coeficientes de correlación intraclase ajustados por residuales de energía. RESULTADOS: La media de consumo de los FIT seleccionados varió de 1.3 ± 0.8 µg/d de MA hasta 116.3 ± 43.8 mg/d de CA. La reproducibilidad varió desde 0.17 para FAL hasta 0.47 para LA. Las principales fuentes de FIT fueron frijoles, naranja, salsa picante, brócoli, manzana y cebolla. DISCUSION: Este es el primer estudio que calcula la ingestión de FIT en México y podría constituir una herramienta útil para la futura evaluación de su efecto en la salud.

Plasma levels of genistein following a single dose of soy extract capsule in Indian women.

BACKGROUND & OBJECTIVE: Soy isoflavones are being used as therapy for menopausal syndrome in many countries. Marketed preparations show variability in bioavailability and there are variations in kinetics due to ethnicity and diet. Inspite of soy isoflavone being available in the Indian market there are no studies to show whether the preparation is likely to be effective in women. This study was carried out to determine circulating levels of genistein, a bioactive soy isoflavone, in Indian women after a single dose of soy extract. METHODS: Six healthy vegetarian women volunteers, between 36 and 62 yr and with a mean body mass index (BMI) 25.01+/-2.02 (kg/m2), were enrolled after an informed consent. Women with antibiotic or Soy food intake within 1 month of study were excluded. A single dose of standardized soy extract capsule containing 64.12 mg of total isoflavones (genistein content equivalent to 31.76 mg) was ingested under supervised fasting condition and multiple blood samples were collected at 0, 1, 2, 4, 6, 8 and 24 h. Genistein levels were measured by high performance liquid chromatography (HPLC) method with a detection level of 2.5 ng/100 microl of injection volume. The intra- and inter-assay coefficients of variation were < 5.32 per cent. RESULTS: Genistein was detected (10.3 to 16.2 ng/ml) in 3 volunteers in baseline samples. Within one hour genistein levels rose from 42 ng to 215 ng/ml with a maximum concentration of 117 to 380 ng/ml at 4 to 8 h. A secondary peak suggestive of enterohepatic circulation was seen between 4 and 6 h in 2 out of 6 volunteers. The mean Cmax was 315.5 +/- 57.1 ng/ml. All women had detectable levels from 25.2 to 109.3 ng/ml at 24 h. INTERPRETATION & CONCLUSION: Our study showed adequate circulating levels of genistein in Indian vegetarian women after a single dose of soy extract. Variability in plasma levels of the soy isoflavones may explain differences in responses to therapy.