Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.

SIX1 Regulates Aberrant Endometrial Epithelial Cell Differentiation and Cancer Latency Following Developmental Estrogenic Chemical Exposure.

Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal [cytokeratin (CK)14+/18-] and poorly differentiated features (CK14+/18+), strongly associating SIX1 with aberrant differentiation and cancer. Here, we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using Pgr-cre to generate conditional knockout mice lacking uterine Six1 (Six1 d/d). Interestingly, corn oil (CO) vehicle-treated Six1 d/d mice develop focal endometrial glandular dysplasia and features of carcinoma in situ as compared with CO wild-type Six1 (Six1 +/+) mice. Furthermore, Six1 d/d mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES Six1 +/+ mice. Although DES Six1 d/d mice had >10-fold fewer CK14+/18- basal cells within the uterine horns as compared with DES Six1 +/+ mice, the appearance of CK14+/18+ cells remained a feature of neoplastic lesions. These findings suggest that SIX1 is required for normal endometrial epithelial differentiation, CK14+/18+ cells act as a cancer progenitor population, and SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of CK14+/18+ cells. In human endometrial biopsies, 35% of malignancies showed CK14+/18+ expression, which positively correlated with tumor stage and grade and was not present in normal endometrium. IMPLICATIONS: Aberrant epithelial differentiation is a key feature in both the DES mouse model of endometrial cancer and human endometrial cancer. The association of CK14+/18+ cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.

Dietary acrylamide intake and the risk of endometrial or ovarian cancers in Japanese women.

A meta-analysis published in 2015 noted a marginally increased risk of endometrial and ovarian cancers in non-smoking women with dietary acrylamide intake, but only a few studies were included, and they were limited to Western countries. The aim of this study was to investigate the association between dietary acrylamide intake and endometrial or ovarian cancer risk in the Japan Public Health Center-based Prospective Study (JPHC Study). In this prospective cohort study, 47 185 participants aged 45-74 years at the follow-up starting point in the JPHC Study were enrolled. Dietary acrylamide intake was assessed using a validated food frequency questionnaire. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI). In participants with endometrial and ovarian cancer, the average follow-up periods were 15.5 and 15.6 years, respectively, and 161 and 122 cases of endometrial and ovarian cancer were diagnosed, respectively. Energy-adjusted dietary acrylamide intake was negatively associated with endometrial cancer, but the association disappeared after adjusting for coffee consumption with an adjusted HR for the highest vs lowest tertile of 0.85 (95%CI: 0.54-1.33). No association was observed, however, for ovarian cancer (adjusted HR, 0.77; 95%CI: 0.49-1.23). Furthermore, after stratifying by smoking status, coffee consumption, alcohol consumption, body mass index, and menopause status, no association was observed. Dietary acrylamide intake was not associated with the risk of endometrial or ovarian cancer in Japanese women with a relatively lower dietary intake of acrylamide compared with Western populations.

Detection of a negative correlation between prescription of Chinese herbal products containing coumestrol, genistein or daidzein and risk of subsequent endometrial cancer among tamoxifen-treated female breast cancer survivors in Taiwan between 1998 and 2008: A population-based study.

ETHNOPHARMACOLOGICAL RELEVANCE: Tamoxifen users sometimes seek complementary and alternative medicine advice for treatment of a variety of illness and co-administer with phytoestrogen-containing herbs, resulting in an increasing concern of its influence in subsequent endometrial cancer risk. Our study aims to determine the prevalence of Chinese herbal products containing coumestrol, genistein, or daidzein and their association with subsequent endometrial cancer risk among tamoxifen-treated breast cancer survivors in Taiwan. METHODS: We selected all patients who were newly diagnosed with invasive breast cancer and received tamoxifen treatment between January 1, 1998, and December 31, 2008, from the National Health Insurance Research Database. Among the 26,656 tamoxifen-treated breast cancer survivors, we evaluated the usage, frequency of service, and prescription of Chinese herbal products containing coumestrol, genistein, or daidzein. The logistic regression method was employed to calculate the odds ratios for utilization of those herbal products. Cox proportional hazard regression was set to calculate the hazard ratios of endometrial cancer associated with such usage. RESULTS: Of the patients surveyed, 36.2% (n=9652) of the tamoxifen-treated breast cancer survivors examined in the study had consumed Chinese herbal products containing coumestrol, genistein, or daidzein during the study period. Exposure to Ge Gen(Puerariae Radix) specifically was the most extensive. For it, the population consumed an average cumulative dose of above 180g. Compared to those who had never used Chinese herbal products, breast cancer survivors who had taken Chinese herbal products containing coumestrol, genistein, or daidzein concurrently with tamoxifen treatment did not have a higher hazard ratio for subsequent development of endometrial cancer. CONCLUSION: Among those tamoxifen-treated female breast cancer survivors in Taiwan, consumption of Chinese herbal products containing coumestrol, genistein, or daidzein is negatively correlated with subsequent endometrial cancer risk.

The use of Chinese herbal products and its influence on tamoxifen induced endometrial cancer risk among female breast cancer patients: a population-based study.

ETHNOPHARMACOLOGICAL RELEVANCE: The increased practice of traditional Chinese medicine (TCM) worldwide has raised concerns regarding herb-drug interactions. The purpose of our study was to analyze the use of Chinese herbal products (CHPs) and to estimate the influence of the use of CHP on tamoxifen induced endometrial cancer risk among female breast cancer patients in Taiwan. METHODS: All patients newly diagnosed with invasive breast cancer receiving tamoxifen treatment from January 1, 1998 to December 31, 2008 were selected from the National Health Insurance Research Database. The usage, frequency of service, and CHPs prescribed among the 20,466 tamoxifen-treated female breast cancer patients were analyzed. The logistic regression method was employed to estimate the odds ratios (ORs) for utilization of CHPs. Cox proportional hazard regression was performed to calculate the hazard ratios (HRs) for subsequent endometrial cancer for CHP non-users and CHP users among female breast cancer patients who had undergone tamoxifen treatment. RESULTS: More than half of the subjects had ever used a CHP. Jia-Wei-Xiao-Yao-San (Augmented Rambling Powder) and Shu-Jing-Huo-Xue-Tang (Channel-Coursing Blood-Quickening Decoction) were the two most commonly used CHPs. The HR for the development of endometrial cancer among CHP users was 0.50-fold (95% CI=0.38-0.64) compared to that of CHP non-users. CONCLUSION: More than half of the study subjects had ever used a CHP. Jia-Wei-Xiao-Yao-San was the most commonly used CHP. Among female breast cancer patients who had undergone tamoxifen therapy, CHP consumption decreased the risk of subsequent endometrial cancer. Exploring potential Chinese herb-tamoxifen interactions and integrating both healthcare approaches are beneficial to the overall health outcomes of tamoxifen-treated female breast cancer patients.

Dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal women: a prospective cohort study.

PURPOSE: Cadmium is a human lung carcinogen and possesses estrogen-like activity. This combination of carcinogenic and estrogenic activity makes cadmium a contaminant of high concern for hormone-related cancers. Diet and smoking are the main sources of cadmium exposure. The aim of this study was to investigate the association between dietary cadmium intake and risk of breast, endometrial and ovarian cancer in Danish postmenopausal woman. METHODS: We estimated dietary cadmium intake in the Diet, Cancer and Health cohort at enrolment 1993-97. The estimates were based on food frequency questionnaires and cadmium contents in all foods. Among 23,815 postmenopausal women we identified 1390 breast, 192 endometrial, and 146 ovarian cancer cases from enrolment through December 31, 2010 using the Danish Cancer Registry. Cox regression was used to analyse the association between dietary cadmium intake and cancer risk. RESULTS: Mean dietary cadmium intake was 14 µg/day. Cadmium was not associated with breast cancer, incidence rate ratio (IRR) = 0.99, 95% confidence interval (CI): 0.87-1.13 per 10 µg higher dietary cadmium intake/day; endometrial cancer, IRR = 1.08, 95% CI: 0.76-1.53; or ovarian cancer, IRR = 1.15, 95% CI: 0.78-1.70. We found a positive association between cadmium and endometrial cancer for the women with BMI<25 (IRR = 1.50, 95% CI: 0.94-2.39), whereas an inverse association was seen for the women with BMI≥25 (IRR = 0.69, 95% CI: 0.42-1.12); p value for interaction = 0.02. CONCLUSIONS: Our study does not indicate that our estimated dietary cadmium intake is associated with hormone-related cancers in women.

[Third generation selective estrogen receptor modulators: benefits beyond bone. II, endometrial action]. / Beneficio extraóseo de los moduladores selectivos del receptor estrogénico de tercera generación: II, acción en el endometrio.

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or third-generation SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450mg of CEE.

Hormonally active doses of isoflavone aglycones promote mammary and endometrial carcinogenesis and alter the molecular tumor environment in Donryu rats.

Our research is focused on modifying effects of an isoflavone aglycones (IAs)-rich extract at a hormonally active dose of 150 mg/kg body weight/day on mammary and endometrial carcinogenesis in female Donryu rats. IA administered for 2 weeks in a phytoestrogen-low diet exerted estrogenic activity and induced cell proliferation in the uterus of ovariectomized rats. Furthermore, administration for 4 weeks resulted in elevation of cell proliferation in the mammary glands of 7,12-dimethylbenz[a]anthracene (DMBA)-treated animals. Forty weeks of postpubertal administration of IA to 5-week-old rats after initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) caused significant increase of incidence and multiplicity of mammary adenocarcinoma, multiplicities of endometrial atypical hyperplasia, adenomatous polyps, and an increased trend of uterine adenocarcinomas. Liquid chromatography with tandem mass spectrometry and immunohistochemical analyses revealed significant elevation of tumorigenesis-related proteins such as S100 calcium-binding protein A8, kininogen 1, and annexins 1 and 2 in mammary adenocarcinomas and cadherin EGF LAG seven-pass G-type receptor 2, DEAD box polypeptide 1, and cysteine- and glycine-rich protein 1 in uterine proliferative lesions of IA-treated animals. Those changes are likely to be related to modulation of estrogen receptor (ER), AP1, nuclear factor-kappa B, and actin signaling pathways. Our results indicate that the postpubertal exposure of Donryu rats to IA at an estrogenic dose results in promotion of mammary and uterine carcinogenesis induced by DMBA and ENNG, which might be related to the activation of ER-dependent signaling and alteration of the molecular tumor environment in the mammary gland and endometrium.

Inhibitory effects of Hochu-ekki-to on endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17beta-estradiol in mice.

An evaluation of the effects of a traditional Chinese herbal medicine, Hochu-ekki-to (Bu-zong-yi-qi-tang) on endometrial carcinogenesis was performed in experiments with female mice. In the short-term experiment, dietary exposure of Hochu-ekki-to (0.2% for 2 weeks) decreased the estradiol-17beta (E2)-stimulated expression levels of c-jun (P<0.001), tumor necrosis factor (TNF)-alpha (P<0.005), estrogen receptors (ER)-alpha (P<0.001) and ER-beta (P<0.005), as determined by reverse transcription-polymerase chain reaction and a Southern blot analysis in the uteri of the ovarectomized mice. In the long-term experiment, the mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and then were divided into four groups. Group 1 (25 mice) was given a diet with Hochu-ekki-to and 5 ppm E2. Group 2 (25 mice) was given a diet with E2 alone. Group 3 (25 mice) was given a diet with Hochu-ekki-to alone. Group 4 (25 mice) was kept on the basal diet alone and treated as a control. The incidence of uterine endometrial cancer in the group with Hochu-ekki-to treatment was substantially lower than of the control group. The inhibitory effect of Hochu-ekki-to on endometrial carcinogenesis is thus suggested to decrease the expressions of c-jun, TNF-alpha, ER-alpha and -beta.

Toremifene: an evaluation of its safety profile.

Toremifene has been in clinical use for 8 years for the treatment of advanced hormone-sensitive breast cancer and the adjuvant treatment of early breast cancer. More than 350,000 patient treatment years have accumulated, sufficient to allow evaluation of its longer-term safety profile in comparison with tamoxifen and, where possible, with raloxifene and aromatase inhibitors. We reviewed all preclinical and clinical safety data from 1978 to 2004 and comparative clinical safety data between October 1995 and the end of 2004. Secondary endometrial cancer incidence was lower with toremifene than with tamoxifen and was similar to that with raloxifene. It is speculated that toremifene may unmask existing endometrial tumors rather than induce new events. The risk of stroke, pulmonary embolism, and cataract may be lower with toremifene than with tamoxifen and the risk of pulmonary embolism and deep vein thrombosis lower than with raloxifene. Beneficial estrogen agonistic effects were equivalent to those of tamoxifen regarding bone mineral density and superior regarding lipid profiles.

Preventive effect of Juzen-taiho-to on endometrial carcinogenesis in mice is based on Shimotsu-to constituent.

Juzen-taiho-to, a Kampo formula, originally consists of a mixture of Shimotsu-to and Shikunshi-to formulas together with two other crude ingredients. Juzen-taiho-to is reported to have a preventive effect on endometrial carcinogenesis in mice. Shimotsu-to exerts an inhibitory effect on estrogen-induced expression of c-fos, interleukin (IL)-1alpha and tumor necrosis factor (TNF)-alpha in uteri of ovarectomized mice. In the present study, short- and long-term experiments were designed to determine the effects of Juzen-taiho-to and Shimotsu-to on the estrogen-related endometrial carcinogenesis in mouse uteri, associated with the expression of cyclooxygenase (COX)-1 and -2. In the short-term experiment, exposure to Juzen-taiho-to or Shimotsu-to significantly reduced estradiol-17beta (E(2))-stimulated expressions of COX-2 mRNA (p<0.05) as well as the protein. However, no effects on the expression of COX-1 were observed. Shikunshi-to did not affect COX expression. In the long-term experiment, 90 female ICR mice were given N-methyl-N-nitrosourea (MNU) into their uterine corpora. The animals were divided into four groups as follows: group 1, a diet containing 0.07% Shimotsu-to and 5 ppm E(2); group 2, a diet containing 5 ppm E(2); group 3, a diet containing 0.07% Shimotsu-to; group 4 served as a control. Exposure of Shimotsu-to reduced the incidence of MNU- and E(2)-induced endometrial adenocarcinoma and atypical hyperplasia at the termination of the experiment (30 weeks). The above findings and our previous reports suggest that Shimotsu-to is responsible for the preventive effects of Juzen-taiho-to on estrogen-related endometrial carcinogenesis in mice, through the inhibition of estrogen-related COX-2 as well as c-fos, IL-1alpha and TNF-alpha expressions.

Potential risks and benefits of phytoestrogen-rich diets.

Interest in the physiological role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of non-steroidal oestrogens including isoflavones & lignans that are widely distributed within the plant kingdom. Data from animal and in vitro studies provide plausible mechanisms to explain how phytoestrogens may influence hormone dependent states, but although the clinical application of diets rich in these oestrogen mimics is in its infancy, data from preliminary studies suggest potential beneficial effects of importance to health. Phytoestrogens are strikingly similar in chemical structure to the mammalian oestrogen, oestradiol, and bind to oestrogen receptors (ER) with a preference for the more recently described ER beta. This suggests that these compounds may exert tissue specific effects. Numerous other biological effects independent of the ER (e.g. antioxidant capacity, antiproliferative and antiangiogenic effects) have been ascribed to these compounds. Whether phytoestrogens have any biological activity in humans, either hormonal or non hormonal is a contentious issue and there is currently a paucity of data on human exposure. Much of the available data on the absorption and metabolism of dietary phytoestrogens is of a qualitative nature; it is known that dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver, circulated in plasma and excreted in urine. Recent studies have addressed quantitatively what happens to isoflavones following ingestion--with pure compound and stable isotope data to compliment recent pharmacokinetic data for soy foods. The limited studies conducted so far in humans clearly confirm that soya isoflavones can exert hormonal effects. These effects may be of benefit in the prevention of many of the common diseases observed in Western populations (such as breast cancer, prostate cancer, menopausal symptoms, osteoporosis) where the diet is typically devoid of these biologically active naturally occurring compounds. However since biological effects are dependent on many factors including dose, duration of use, protein binding affinity, individual metabolism and intrinsic oestrogenic state, further clinical studies are necessary to determine the potential health effects of these compounds in specific population groups. However we currently know little about age related differences in exposure to these compounds and there are few guidelines on optimal dose for specific health outcomes.

Iron lactate induction of pancreatic and endometrial proliferative lesions and a lack of increased tumors in a 104-week carcinogenicity study in F344 rats.

Iron lactate has been used as a food additive for iron supplementation. The present study was conducted to determine whether it might have carcinogenic potential. A total of 150 male and 150 female Fischer 344 rats were divided into three groups and fed basal diet containing 0, 1 or 2% of iron lactate for 104 weeks. No iron lactate-induced tumors were observed in any groups, although the incidences of pancreatic acinar cell and endometrial gland hyperplasias were increased in males and females, respectively, in the 2% group. Thus our in vivo animal data indicate that iron lactate lacks carcinogenicity in male and female F344 rats. However, estrogenic effects might be concluded based on the data for endometrial lesions. In a second experiment, an estrogen responsive rat pituitary tumor cell line, MtT/Se, and a human breast cancer cell line, MCF-7, were therefore employed to examine the estrogenic potential of iron lactate with regard to receptor binding affinity and ERE-reporter gene activation. Results in both cases were negative. Further investigations are needed to elucidate the mechanisms of induction of pancreatic and endometrial proliferative lesions by iron lactate.

Phytoestrogen supplementation and endometrial cancer.

BACKGROUND: Phytoestrogens are increasingly used by patients as "natural" alternatives to hormone replacement. Attention in scientific and lay literature has focused on their potential to prevent menopausal symptoms, bone loss, heart disease, or breast cancer. Less is known about effects on the endometrium, specifically, whether prolonged exposure to phytoestrogens could promote hyperplasia or neoplasia, as does unopposed estrogen. CASE: We report the case of a woman diagnosed with grade 1 endometrioid adenocarcinoma of the endometrium whose history was notable for extensive use of supplemental phytoestrogens. CONCLUSION: The effects of phytoestrogens on endometrial tissue are not known. Given their increasing popularity and availability in concentrated form as dietary supplements, additional research is warranted before we can counsel our patients regarding the safety of such supplements.

Cell proliferation in cancer prevention; effects of preventive agents on estrogen-related endometrial carcinogenesis model and on an in vitro model in human colorectal cells.

Proto-oncogenes such as c-fos, c-jun and c-myc are known to relate to cell proliferation and differentiation. Some oriental herbal medicines like Glycyrrhizae radix or Juzen-taiho-to were found to suppress estradiol-17 beta (E2)-induced expression of c-fos/jun in uterine corpus and inhibited N-methyl-N-nitrosourea and E2-induced endometrial carcinogenesis in mice. It is suggested that the effects of such oriental drugs are exerted probably through suppression of estrogen-induced c-fos/jun expression and they are promising preventing agents for endometrial cancers. In the combined in vitro assay for cell proliferation (MTS assay) and apoptosis (DNA fragmentation) in human colorectal cancer cells (Colo 320), a number of naturally occurring chemopreventive agents such as curcumin, quercetin, auraptene, 1'-acetoxychavicol acetate (ACA) and indole-3-carbinol were shown to generate apoptosis as well as to inhibit cell proliferation. The results suggest a mode of action of these chemopreventive agents and also imply that such in vitro short term assay is useful for detection of new agents for cancer prevention.

Phytoestrogens and carcinogenesis-differential effects of genistein in experimental models of normal and malignant rat endometrium.

The phytoestrogen genistein was studied in normal and malignant experimental uterine models in vivo. The action of genistein on the uterus and vagina of ovariectomized DA/Han rats after 3 day oral administration (25, 50 or 100 mg/kg/BW/d) was compared to ethinyl oestradiol (0.1 mg/kg/BW/d). Effects on uterine and vaginal morphology, uterine growth and uterine gene expression were studied. A dose dependent increase of the uterine wet weight and the uterine and vaginal epithelial height, a dose dependent up-regulation of complement C3, down-regulation of clusterin mRNA expression and a stimulation of the vaginal cornification was observed after administration of genistein. Uterine gene expression and vaginal epithelium respond to genistein at doses where no significant effects on uterine wet weight were detectable. In general the vagina was more sensitive to genistein than the uterus. To analyse the action of genistein in malignant uterine tissue, the impact of a 28 d treatment with 50 mg/kg/d of genistein on the in-vivo tumour growth of RUCA I endometrial adenocarcinoma cells, following subcutaneous inoculation into syngeneic DA/Han rats, was assessed. In contrast to ethinyl oestradiol (0.1 mg/kg/BW/d), a dose of 50 mg/kg/BW/d of genistein did not affect tumour growth. Nevertheless C3 and TRPM2 mRNA expression in the tumour were both significantly stimulated by ethinyl oestradiol and genistein. In comparison to ovariectomized animals genistein up-regulated uterine wet weight and uterine dependent gene expression in tumour bearing animals. In conclusion, four independent uterine and vaginal parameters indicate genistein is a weak oestrogen receptor agonist in the uterus and vagina of female DA/Han rats, and evidence is provided for a selective oestrogen receptor modulator (SERM)-like action of genistein in normal and malignant uterine tissue.

Preventive effects of Juzen-taiho-to on N-methyl-N-nitrosourea and estradiol-17beta-induced endometrial carcinogenesis in mice.

Two experiments were conducted to determine effects of Juzen-taiho-to on endometrial carcinogenesis in mice. In the first experiment, Juzen-taiho-to treatment (2 weeks) decreased the levels of estradiol-17beta (E(2))-stimulated expression of c-fos/jun mRNA and their oncoproteins, determined by reverse transcription-polymerase chain reaction and Southern blot analysis, and the immunohistochemical method, in the uteri of ovarectomized mice. For the second experiment, 93 female ICR mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and were divided into four groups. Group 1 was given a diet containing 0.2% Juzen-taiho-to and 5 p.p.m. E(2). Group 2 was given a diet containing 5 p.p.m. E(2) alone. Group 3 was given a diet containing 0.2% Juzen-taiho-to alone. Group 4 was kept on the basal diet alone and treated as a control. Juzen-taiho-to treatment significantly decreased incidences of the uterine endometrial atypical (P<0.01), complex (P<0.05) and simple hyperplasias (P<0.01), under estrogenic stimulation. It is suggested that Juzen-taiho-to has an inhibitory effect on E2-related endometrial carcinogenesis in mice, relevantly through suppression of estrogen-induced c-fos/jun-expression.

[An alternative to postmenopausal Hormone Replacement Therapy? Selective Estrogens Receptors Modulators (SERMs)]. / Una alternativa alla terapia ormonale sostitutiva postmenopausale?

Hormone Replacement Therapy (HRT) represents the first and probably sole therapeutically approach for prevention and treatment of medical postmenopausal disease. Nevertheless, the adverse effects and the risks HRT associated, suggested, to clinical and pharmaceutical research new pharmacological treatment options. Actually a group of compounds, SERMs (Selective Estrogen Receptor Modulators), allows a large interest. These pharmacological agents, due to their estrogen agonist/antagonist properties, are able to bind Estrogen Receptors in female target tissues (bone, brain, heart, etc) with different actions; so, by these properties, SERMs represent actually a possible alternative to HRT.

Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen.

BACKGROUND: Tamoxifen increases the risk of endometrial cancer. However, few studies have produced reliable risk estimates by duration, dose, and recency of use, or addressed the prognosis of endometrial cancers in tamoxifen-treated women. METHODS: We did a nationwide case-control study on the risk and prognosis of endometrial cancer after tamoxifen use for breast cancer. Information on tamoxifen use and other risk factors for endometrial cancer was obtained from 309 women with endometrial cancer after breast cancer (cases), and 860 matched controls with breast cancer but without endometrial cancer. For 276 cases, we obtained tissue blocks of endometrial cancer to review the diagnosis, and used immunohistochemistry to examine hormone-receptor status and overexpression of p53. FINDINGS: Tamoxifen had been used by 108 (36.1%) of 299 cases and 245 (28.5%) controls (relative risk 1.5 [95% CI 1.1-2.0]). Risk of endometrial cancer increased with longer duration of tamoxifen use (p < 0.001), with relative risks of 2.0 (1.2-3.2) for 2-5 years and 6.9 (2.4-19.4) for at least 5 years compared with non-users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users (> or = 2 years) than in non-users (17.4% vs 5.4%, p=0.006). Long-term users were more likely than non-users to have had malignant mixed mesodermal tumours or sarcomas of the endometrium (15.4% vs 2.9%, p < or = 0.02), p53-positive tumours (31.4% vs 18.2%, p=0.05), and negative oestrogen-receptor concentrations (60.8% vs 26.2%, p < or = 0.001). 3-year endometrial-cancer-specific survival was significantly worse for long-term tamoxifen users than for non-users (76% for > or = 5 years, 85% for 2-5 years vs 94% for non-users, p=0.02). INTERPRETATION: Long-term tamoxifen users have a worse prognosis of endometrial cancers, which seems to be due to less favourable histology and higher stage. However, the benefit of tamoxifen on breast-cancer survival far outweighs the increased mortality from endometrial cancer. Nevertheless, we seriously question widespread use of tamoxifen as a preventive agent against breast cancer in healthy women.