Osthole prevents tamoxifen-induced liver injury in mice.

Tamoxifen (TMX) is an antiestrogen drug that is used in the treatment and prevention of all stages of estrogen-dependent breast cancer. Adverse effects of TMX include hepatotoxicity. In this study, we investigated the therapeutic effects of osthole, isolated from medicinal plants especially Fructus Cnidii, on TMX-induced acute liver injury in mice. Mice were injected with osthole (100 mg/kg, ip) or vehicle, followed by TMX (90 mg/kg, ip) 24 h later. We showed that a single injection of TMX-induced liver injury and oxidative stress. Pretreatment with osthole attenuated TMX-induced liver injury evidenced by dose-dependent reduction of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Pretreatment with osthole also blunted TMX-induced oxidative stress, evidenced by significant increase of reduced glutathione (GSH) as well as reduction of malondialdehyde (MDA) and hydrogen peroxide (H2O2). Consistently, osthole significantly enhanced the expressions of antioxidant genes (GPX1, SOD2, GCL-c, and G6pdh), but suppressed those of pro-oxidant genes (NOX2 and ACOX). Furthermore, osthole inhibited the production of inflammatory cytokines, reduced the metabolic activation of TMX, and promoted its clearance. We further revealed that osthole elevated hepatic cAMP and cGMP levels, but inhibition of PKA or PKG failed to abolish the hepatoprotective effect of osthole. Meanwhile, prominent phosphorylation of p38 was observed in liver in response to TMX, which was significantly inhibited by osthole. Pretreatment with SB203580, a p38 inhibitor, significantly attenuated TMX-induced increase of ALT and AST activities, reduced oxidative stress, and reversed the alterations of gene expression caused by TMX. Moreover, pretreatment with L-buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, partly reversed the effect of osthole on TMX-induced liver injury. Consistently, pretreatment with N-acetyl-L-cysteine (NAC) significantly attenuated TMX-induced increase in ALT and AST activities. Notably, both BSO and NAC had no detectable effect on the phosphorylation levels of p38. Collectively, our results suggest that osthole prevents TMX hepatotoxicity by suppressing p38 activation and subsequently reducing TMX-induced oxidative damage.

Stearoyl-CoA desaturase-1, a novel target of omega-3 fatty acids for reducing breast cancer risk in obese postmenopausal women.

BACKGROUND/OBJECTIVES: Conversion of saturated fatty acids to monounsaturated fatty acids by the enzyme stearoyl-Co-A-desaturase (SCD-1) is emerging as a major factor in promoting carcinogenesis including breast cancer. The aim of our study was to explore the regulation of SCD-1 by Raloxifene and omega-3 fatty acids in women at increased risk of breast cancer based on high breast density. SUBJECTS/METHODS: As a reflection of SCD-1 activity, we measured the ratios of palmitoleic acid (C16:1n7) to palmitic acid (C16:0) (SCD-16) and oleic acid (C18:1n9) to steric acid (C18:0) (SCD-18) in plasma samples of postmenopausal women enrolled in our clinical trial (NCT00723398) designed to test the effects of the antiestrogen, Raloxifene and/or the omega-3 preparation Lovaza, on breast density, a validated biomarker of breast cancer risk. RESULTS: We report that Lovaza but not Raloxifene-reduced SCD-16 and SCD-18 for the 2-year duration of the trial. Importantly, decreasing levels of SCD-16 and SCD-18 were associated with a progressive reduction in breast density but only in obese women (body mass index ⩾30). CONCLUSIONS: Body mass index-related factors play an important role in the reduction of breast density and hence breast cancer risk by omega-3 fatty acids. SCD-1 may be a useful biomarker in future clinical trials testing the benefit of nutritional interventions in reducing obesity-associated breast cancer risk.

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.

Letrozole combined with gonadotropin-releasing hormone analog for metastatic male breast cancer.

The role of aromatase inhibitors combined with gonadotropin-releasing hormone analog in metastatic male breast cancer patients remains unknown. In this retrospective study we evaluated the activity of letrozole combined with a gonadotropin-releasing hormone analog as a first- or second-line therapy for metastatic male breast cancer patients. 19 men entered the study. We did not observe any grade 3 or 4 adverse events. 2 patients (10.5 %) had complete response, 7 patients (36.8 %) experienced a partial response, 7 patients (36.8 %) had stable disease lasting ≥ 6 months, and 3 patients (15.8 %) had progressive disease. Overall, the disease control rate was 84.2 %. Median progression-free survival was 12.5 months (95 % CI 8.2-16.9), median overall survival was 35.8 months (95 % CI 24.4-49.2), 1- and 2-year survival rates were 89.5 and 67 %, respectively. Interestingly, 3 out of 4 patients treated with the combination following disease progression while on aromatase inhibitor monotherapy confirmed or improved the best overall response observed in the first-line setting. The combination of letrozole and gonadotropin-releasing hormone analog is effective and safe in hormone-receptor positive, metastatic male breast cancer patients.

The antiestrogen 4-hydroxytamoxifen protects against isotretinoin-induced permeability transition and bioenergetic dysfunction of liver mitochondria: comparison with tamoxifen.

The combination of isotretinoin (13-cis-retinoic acid) with antiestrogens seems to be a promising strategy for cancer chemotherapy. The aim of the study was to evaluate the effects of isotretinoin alone or in combination with 4-hydroxytamoxifen (OHTAM) and with its prodrug tamoxifen (TAM), on the functions of rat liver mitochondria, i.e., mitochondrial permeability transition (MPT), bioenergetic functions and adenine nucleotide translocase (ANT). Isotretinoin (5 nmol/mg protein) induced the Ca²âº-dependent MPT pore opening in mitochondria energized with succinate, which was prevented by OHTAM, cyclosporine A, TAM and ANT ligands. When mitochondria were energized with glutamate/malate and in the absence of added Ca²âº isotretinoin decreased the state 3 respiration, the ATP levels, the active ANT content and increased the lag phase of the phosphorylation cycle, demonstrating that isotretinoin decreased the mitochondrial phosphorylation efficiency. These changes of isotretinoin in bioenergetic parameters were not significant in the presence of succinate. The effects of isotretinoin at 5 nmol/mg protein on the Ca²âº-dependent MPT and phosphorylative efficacy may be related with interactions with the ANT. Above 10 nmol/mg protein isotretinoin strongly diminished the active ANT content, decreased the Δψ, inhibited the complex I and induced proton leak through the Fo fraction of complex V. The combination of OHTAM with isotretinoin only induced significant changes in the energy production systems at concentrations ≥5 nmol isotretinoin/mg protein. Therefore, our results suggest that isotretinoin-associated liver toxicity is possibly related with mitochondrial dysfunctions and that the combination with OHTAM may contribute to decrease its toxicity.

Osteoporose no climatério II: prevenção e tratamento / Osteoporosis in postmenopausal II: prevention and treatment

A osteoporose é uma doença que pode acarretar um enorme prejuízo na qualidade de vida dos pacientes em função das alterações no tecido ósseo, levando à fragilidade mecânica e consequente predisposição a fraturas e dor. Hoje, dispomos de medidas preventivas, do uso de suplementos e de várias drogas aprovadas para terapia farmacológica da osteoporose, no período pós-menopausa, revisadas neste artigo. Essas drogas apresentam características antirreabsortivas (bisfosfonatos, terapia estrogênica, agonistas seletivos dos receptores de estrogênio - SERM -, calcitonina e denozumabe), anabólicas (teriparatida - PTH) ou ambas, simultaneamente (ranelato de estrôncio). A terapia estrogênica (TE) e a terapia com os bisfosfonatos compreendem as primeiras linhas de medicamentos utilizadas para prevenção e tratamento da osteoporose no climatério. Os medicamentos de segunda linha ficam reservados aos casos com evolução desfavorável com uso de TE e/ou bisfosfonatos, ou quando essas pacientes apresentem alguma enfermidade óssea associada (osteoporose secundária), necessitando de tratamento específico. Na falha ou impossibilidade da utilização dos medicamentos de segunda linha podemos utilizar o ranelato de estrôncio ou o denozumabe, pesando que os riscos dessas drogas precisam ser mais bem estudados

Osteoporosis is a disease that can cause a great loss of quality of life of patients according to the changes in bone tissue leading to mechanical fragility and consequent susceptibility to fractures and pain. Today, we offer preventive measures, the use of supplements and several drugs approved for pharmacologic therapy for osteoporosis in postmenopausal, reviewed in this article. These drugs have anti resorptive characteristics (bisphosphonates, estrogen, selective estrogen receptor modulators - SERM -, calcitonin and denozumab), anabolic (teriparatide - PTH) or both, simultaneously (strontium ranelate). Estrogen therapy (ET) and therapy with bisphosphonates comprise the first line drugs used for prevention and treatment of osteoporosis in the climacteric. The second-line drugs are reserved to cases with unfavorable outcome with the use of TE and/or bisphosphonates, or when these patients have a disease associated with bone (secondary osteoporosis), requiring specific treatment. In the failure or inability of use of second-line drugs, we can use the strontium ranelate or denozumab, weighing the risks of these drugs that need to be further studied

Screening for in vivo (anti)estrogenic and (anti)androgenic activities of Tropaeolum majus L. and its effect on uterine contractility.

ETHNOPHARMACOLOGICAL RELEVANCE: Tropaeolum majus L. (Tropaeolaceae) is a medicinal herb popularly used in Brazil for treatment of inflammatory and cardiovascular diseases. Despite some published data on its efficacy, there are still few toxicological data describing the safety of this plant. The aim of this study was to evaluate the (anti)estrogenic and (anti)androgenic activity of the hydroethanolic extract obtained from Tropaeolum majus L. (HETM), as well as its possible effects on uterine contractility. MATERIALS AND METHODS: Three experimental protocols were performed, (a) uterotrophic assay, (b) Hershberger assay and (c) an ex vivo test to investigate the effects of maternal administration of HETM on uterine contractility at the end of pregnancy. In all protocols three doses of the HETM were administered to Wistar rats: 3, 30 and 300mg/kg. RESULTS: In vivo tests for detection of (anti)androgenic and (anti)estrogenic activities did not show any significant alterations. Similarly, no alterations were observed on uterine contractility induced by oxytocin and arachidonic acid. CONCLUSIONS: HETM was unable to produce (anti)estrogenic or (anti)androgenic activities in the short-term in vivo screening assays performed. In addition, there was no evidence that HETM can affect uterine contractility following gestational exposure of rats.

Bevacizumab for the first-line treatment of human epidermal growth factor receptor 2-negative advanced breast cancer.

PURPOSE OF REVIEW: Breast cancer is the most common cancer in women worldwide and its incidence is increasing as a result of the continued adoption of lifestyles associated with increased risk factors. Approximately, 75% of breast cancers do not express the human epidermal growth factor receptor 2 (HER2), including hormone receptor-positive and triple-negative tumors. HER2-negative breast cancers are resistant to, or eventually become resistant to, existing targeted treatments such as HER2-targeted agents and hormone therapies, and, as a consequence, are associated with poorer outcomes than HER2-positive breast cancer. Bevacizumab is a humanized monoclonal antibody that recognizes vascular endothelial growth factor-A, a rate-limiting step in pathological angiogenesis such as tumor growth. As angiogenic pathways become more complex as breast cancer progresses, angiogenesis inhibitors should be initiated earlier in the disease course. This review will discuss the evidence for bevacizumab as first-line therapy in metastatic breast cancer, with a particular focus on patients with HER2-negative disease. RECENT FINDINGS: Bevacizumab, when administered in combination with first-line standard chemotherapy, significantly increases progression-free survival and overall response rate in patients with metastatic breast cancer. SUMMARY: Novel targeted therapies that are appropriate to HER2-negative breast cancer, such as bevacizumab, may represent valuable therapeutic options in the clinical management of metastatic breast cancer.

Developments in the systemic treatment of endometrial cancer.

Systemic treatment represents the cornerstone of endometrial cancer management in advanced, relapsed and metastatic disease, which is still characterized by poor prognosis. Progestins remain an effective option for patients with low grade, estrogen and/or progesterone receptor positive disease, with some of them achieving prolonged survival. Platinum compounds, anthracyclines and more recently taxanes have been implemented in combination regimens achieving response rates more than 50% and resulting in overall survival above 1 year in randomized trials. Adjuvant chemotherapy with the same agents may be useful for patients with early stage disease and high-risk features, such as high grade or non-endometrioid histology. Combination of chemotherapeutic agents with radiotherapy remains investigational. Hematologic, cardiac toxicity and neurotoxicity represent the main concern of chemotherapy and increase the risk for treatment-related morbidity and death, especially in pretreated patients bearing substantial co-morbidities. The gradual elucidation of the molecular aspects of endometrial carcinogenesis has led to the development of novel, selective antineoplastic agents, targeting specific molecular pathways and mediators of signal transduction implemented in cell proliferation, survival and angiogenesis. In the current review, we report on the recent advances regarding systemic therapy of endometrial carcinoma with special emphasis on results of large, randomized phase III clinical trials. Biomarkers with potent prognostic significance or predictive value for response to treatment are presented and novel molecular agents showing promising results in early clinical trials are discussed.

Effect of long-time administration of tibolone on vaginal cytology of castrated rats.

PURPOSE: To evaluate the estrogenic effect of tibolone administered at high-dose and long-term through cytological examination of vaginal epithelium of castrated rats. METHODS: 15 adult Wistar rats were submitted to bilateral oophorectomy 30 days before starting the experiment. The rats were then randomly divided in two groups. Experimental rats (n = 9) orally received 1 mg tibolone/day; control rats (n = 6) just received carboxymethylcellulose. Vaginal smears were collected from all rats on days 0, 1-6, 30, 60, 90 and 120 of the experiment. RESULTS: On day 0, smears from all rats were atrophic, classified as anestrus, and remained this type in the control group until day 120. In the tibolone group, on day 3 all the rats had vaginal cytology similar to estrus and maintained the same aspect till day 90. CONCLUSION: Tibolone has estrogenic action in the vaginal epithelium which is already evident after the first dose and remains without major changes over time.

A new generalization of Weibull distribution with application to a breast cancer data set.

In this article, we propose a new generalization of the Weibull distribution, which incorporates the exponentiated Weibull distribution introduced by Mudholkar and Srivastava (IEEE Trans. Reliab. 1993; 42:299-302) as a special case. We refer to the new family of distributions as the beta-Weibull distribution. We investigate the potential usefulness of the beta-Weibull distribution for modeling censored survival data from biomedical studies. Several other generalizations of the standard two-parameter Weibull distribution are compared with regards to maximum likelihood inference of the cumulative incidence function, under the setting of competing risks. These Weibull-based parametric models are fit to a breast cancer data set from the National Surgical Adjuvant Breast and Bowel Project. In terms of statistical significance of the treatment effect and model adequacy, all generalized models lead to similar conclusions, suggesting that the beta-Weibull family is a reasonable candidate for modeling survival data.

[Adjuvant endocrine therapy in postmenopausal hormone-sensitive breast cancer: to start, to switch or to extend?]. / A posztmenopauzális hormonérzékeny emlôrák adjuváns endokrin kezelése: kezdeni, váltani, kiterjeszteni?

From the big randomized clinical trials there are evidences that adjuvant endocrine therapy for hormone-sensitive early breast cancer in postmenopausal women should include an aromatase inhibitor (AI). Anastrozole or letrozole should be used upfront for 5 years (ATAC and BIG 1-98), the sequential approach of tamoxifen for 2-3 years, followed by anastrozole or exemestane for 2-3 years is a reasonable alternative (ABCSG8, ARNO 95, IES, ITA), and mostly in patients with node-positive disease completing 5 years of tamoxifen should be offered letrozole up to 4-5 years (MA-17). In each of these trials incorporation of an AI resulted in significant improvement in study endpoints. Further results will be needed to establish the optimal beneficial effect, use, duration and safety of adjuvant AI therapies.

Utilidad de los fitoestrógenos en la reducción de la presión arterial. Revisión sistemática y metaanálisis / Usefulness of phyto-oestrogens in reduction of blood pressure. Systematic review and meta-analysis

Objetivos. Determinar si el tratamiento con fitoestrógenos o proteína de soja logra descensos de la presión arterial. Diseño. Se realizó una revisión sistemática, valorando todos los estudios observacionales y ensayos clínicos, y un metaanálisis para evaluar la variación de la presión arterial en pacientes tratados con fitoestrógenos. Búsqueda. Se usó una estrategia de búsqueda con los términos «fitoestrógenos» o «comidas de soja» e «hipertensión» o «tensión arterial». Fuentes de datos. Se utilizaron las bases de datos MEDLINE, EMBASE, Cochrane Database y OVID sin restricción temporal ni de idioma. Se realizó una búsqueda manual de las referencias de los artículos de interés. Selección de estudios. Dos evaluadores independientes analizaron los trabajos obtenidos en la búsqueda. Extracción de datos. Se aplicó la escala de Jadad a los ensayos clínicos, y se extrajeron los datos numéricos del texto o referidos en tablas. Se valoró qué artículos observacionales y experimentales mostraban descenso de la presión arterial con fitoestrógenos y cuáles no. Se realizó el metaanálisis, extrayendo de cada estudio datos de tamaño muestral, diferencia de presión arterial tras la intervención y basalmente y desviación estándar. Se usó la diferencia ponderada de medias con el modelo de efectos aleatorios. Se utilizó el programa Review Manager v4.2.9. Resultados. No se observaron variaciones significativas de la presión arterial, tanto sistólica (­1,20 mmHg; intervalo de confianza [IC] del 95%, ­2,80 a 0,41 mmHg) como diastólica (­1,31 mmHg; IC del 95%, ­2,73 a 0,11); si las hay, estas variaciones parecen clínicamente poco importantes. También hay un grado importante de heterogeneidad, tanto estadística como clínica. Conclusiones. No hay diferencias estadísticamente significativas ni clínicamente importantes de presión arterial en tratados con fitoestrógenos frente a no tratados

Objectives. To determine whether treatment with phyto-oestrogens or soya protein succeeds in lowering blood pressure. Design. A systematic review, evaluating all the observation studies and clinical trials, was conducted, followed by a meta-analysis to evaluate blood pressure variations in patients treated with phyto-oestrogens. Search. The search strategy adopted used the terms "phyto-oestrogens," "soya meals," "hypertension," and "blood pressure." Data sources. The data bases MEDLINE, EMBASE, Cochrane, OVID were used, without time or language restrictions. References in the relevant articles were searched for manually. Study selection. Two independent reviewers analysed the studies found in the search. Data extraction. The Jadad scale was used for the clinical trials and the numerical data in the text or referred to in tables were extracted. Evaluation was made of which observational and experimental articles showed a drop in blood pressure with phyto-oestrogens and which did not. In the meta-analysis, data on sample size, difference in blood pressure before and after intervention and standard deviation were extracted from each study. The weighted difference of means was used with the model of randomised effects. The Review Manager v4.2.9 programme was used. Results. No significant variations in blood pressure were found, whether systolic (­1.20 mm Hg; 95% CI, ­2.80 to 0.41 mm Hg) or diastolic (­1.31 mm Hg; 95% CI, ­2.73 to 0.11). If there were any variations, they are clinically of little importance. There was also an important degree of both statistical and clinical heterogeneity. Conclusions. There are no statistically significant or clinically important differences in blood pressure between patients treated with phyto-oestrogens and those not treated

Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial.

BACKGROUND: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. METHODS: Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]); 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF); 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF); 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. RESULTS: Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00; P = .05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). CONCLUSIONS: Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy.

Equol production capability is associated with favorable vascular function in postmenopausal women using tibolone; no effect with soy supplementation.

OBJECTIVE: Equol, a gut bacterial metabolite of isoflavone daidzein, may improve health through changes in vascular function and in estrogen metabolism. Tibolone, a synthetic steroid alternative for the treatment of postmenopausal symptoms, causes a different estrogenic milieu than estrogen and may affect vascular health. We studied the effects of equol production and soy supplementation on vascular function in postmenopausal women under long-term tibolone use. METHODS: We screened 110 women using tibolone for 3-60 months for high equol production capacity with a one-week soy challenge. Twenty women with high equol production capacity (4-fold elevation in equol level) and 20 comparable control women without this capacity were treated in a randomized placebo-controlled cross-over trial with a soy drink (52 g of soy protein containing 112 mg of isoflavones) or placebo for 8 weeks. Arterial stiffness and endothelial function were assessed before and after soy and placebo supplementation with pulse-wave analysis. RESULTS: Prior to soy supplementation arterial stiffness, expressed as augmentation index, was lower (p=0.01) in equol producers (25.9+/-1.1%) than non-equol producers (29.6+/-0.9%). Similarly, endothelial function index was better at baseline (p=0.009) in these women (72.3+/-5.3%) compared to women lacking equol production capacity (55.2+/-3.8%). Soy supplementation had no effect on arterial stiffness or endothelial function in either group. CONCLUSION: In postmenopausal tibolone users, endogenous equol production capability is associated with favorable vascular function. This phenomenon was not affected by soy and thus, equol producing capacity may be an independent vascular health marker, at least in postmenopausal women using tibolone.

Individual differences in equol production capability modulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation.

OBJECTIVES: Equol, a gut bacterial metabolite of the isoflavone daidzein, has been associated with beneficial health effects. Recent studies indicate that women with intestinal capacity to convert daidzein to equol also have the capacity to alter steroid metabolism and bioavailability of estrogens. METHODS: We evaluated whether individual equol production capability, while not consuming soy supplement, was associated with lower blood pressure in postmenopausal women using tibolone. In addition, in a randomized, placebo-controlled, cross-over trial we assessed the effect of soy supplementation on blood pressure in both equol-producing (n = 20) and non-equol-producing (n = 20) women using tibolone. Blood pressure was recorded with a validated oscillometric technique. RESULTS: The circulating equol levels rose 20-fold in the equol producers and 1.9-fold in the non-equol producers. At baseline, systolic blood pressure (129.9 +/- 2.6 vs. 138.5 +/- 3.1 mmHg, p = 0.02), diastolic blood pressure (72.2 +/- 1.5 vs. 76.6 +/- 1.3 mmHg, p = 0.01) and mean arterial blood pressure (93.5 +/- 1.7 vs. 99.9 +/- 1.8 mmHg, p = 0.007) were lower in equol producers compared to non-equol producers. Soy supplementation had no effect on blood pressure in either group, whereas the baseline differences persisted. CONCLUSIONS: Postmenopausal women using tibolone characterized as equol producers had lower blood pressure compared to non-equol producers. Soy supplementation for 2 months had no blood pressure-lowering effect.

Performance-enhancing drugs and supplements in women and girls.

Performance-enhancing substance use has been frequently discussed in the media. High-profile professional athletes have tested positive for performance-enhancing substances, while surveys indicate an escalating incidence of use among amateur athletes. Several articles have reviewed this concern in men's sports; however, this article discusses performance-enhancing drug and supplement use by women and girls.

Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallel-controlled study versus tibolone.

OBJECTIVE: To investigate the efficacy-safety balance of the isopropanolic extract of Actaea (=Cimicifuga) racemosa (iCR, Remifemin) in comparison with tibolone in Chinese women with climacteric complaints. METHOD: The randomized, double-blind, controlled 3-month study in 5 centers of 3 cities in China enrolled 244 menopausal patients aged 40-60 years and with a Kupperman Menopause Index (KMI)>or=15. The participants were assigned to either iCR corresponding to 40 mg crude drug/day (N=122) or tibolone 2.5mg/day (N=122) orally. The primary endpoint was the combination of the Mann-Whitney values (MWV) of the KMI and the frequency of adverse events (benefit-risk balance) at end of treatment (MWV>0.5 shows superiority; MWV>0.36 shows non-inferiority). RESULTS: KMI decreased from 24.7+/-6.1 to 11.2+/-6.2 and 7.7+/-5.8 (iCR) and to 11.2+/-7.2 and 7.5+/-6.8 (tibolone) at 4 and 12 weeks. This remarkable and clinically relevant improvement was similar in both treatment groups (MWV=0.47; 95% CI=0.39-0.54; p(non-inferiority)=0.002) showing statistical significant non-inferiority of iCR to tibolone. The KMI-responder rate was similar in both groups (84% and 85%). The safety evaluation showed for both groups a good safety and tolerability profile, however, there is a significant lower incidence of adverse events (p<0.0001) in favor of the herbal treatment. None of the postmenopausal iCR patients experienced vaginal bleeding in contrast to tibolone (17 cases). Breast and abdominal pain as well as leukorrhea was mostly observed in the tibolone group (p=0.015, p=0.008, p=0.002). No serious adverse event was observed in the iCR-group, however, two occurred in the tibolone-group. The benefit-risk balance for iCR was significantly (p=0.01) superior to tibolone (MWV=0.56; 95% confidence interval [0.51-0.62]). CONCLUSION: The efficacy of iCR (medicinal product Remifemin) is as good as tibolone for the treatment of climacteric complaints, even for moderate to severe symptoms, whereby iCR is clearly superior regarding the safety profile. This iCR containing medicinal product is an excellent option for treatment of climacteric complaints which has now for the first time been verified in Asian women.