Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.

No description available.

Background: Phytoestrogens are diphenolic compounds found in plants with a structure and molecular weight similar to oestradiol which enables them to bind to the oestrogen receptor. Isoflavonoids occur mainly within the legume family with highest concentration in soybeans. Lignans are found in a range of plant foods and the richest known source is linseed. Few studies have been published on intake of isoflavonoids and none were located on intake of lignans in Australian women. The validity of methods designed to estimate intake can be assessed using urinary excretion of isoflavonoids and lignans as studies have found an association between intake and excretion of isoflavonoids and lignans. It has been proposed that, through their ability to act like oestrogen, phytoestrogens could decrease bone turnover and attenuate the loss of bone mineral density (BMD) at menopause. The aims of this research were to determine the pattern of intake of isoflavonoids and lignans in 500 women from food and supplements and to assess a questionnaire used to estimate intake using excretion in a sub-sample of 141 women. Associations between usual intake or excretion of isoflavonoids and lignans and biomarkers of bone health were also examined. Methods: A cross-sectional study was conducted involving 500 women aged 40-80 years participating in the Longitudinal Assessment of Ageing in Women (LAW), a 5 year study being conducted in the Betty Byrne Henderson Centre at the Royal Brisbane and Women's Hospital. Subjects were randomly selected from the electoral role and stratified into ten year age groups. Intake of isoflavonoids and lignans from food and supplements was assessed using a specially designed questionnaire containing 110 items. Values for individual items were obtained from published literature and summed to provide average daily intakes of isoflavonoids and lignans (mg/d). A sub-sample of 141 women was recruited to take part in the assessment of the association between phytoestrogen intake and excretion. Participants collected three 24-h urine samples spaced over one week. Samples were analysed using high performance liquid chromatography MS/MS for seven isoflavonoids and four lignans. Bone mineral densities (BMD) of the femur neck, total hip and lumbar spine were measured by dual energy x-ray absorptiometry. Bone formation was assessed using serum bone alkaline phosphatase (bone ALP) and osteocalcin (OC) and bone resorption was assessed using deoxypyridinoline (DPD) and urinary excretion of N-terminal cross-linking telopeptide of type-I collagen (NTX). Potential confounding factors were also evaluated. Statistical analyses were conducted using SPSS for windows (version 10). Participants were defined as consumers if they reported intake of one or more serves of soy or linseed in the prior month. Differences in socio-demographic and lifestyle characteristics between groups were assessed using ANOVA and Chi Square tests. Associations between intake and excretion of phytoestrogens were assessed using Spearman's rank-order correlations () for non-normal data. Phytoestrogen intake was categorised into four groups for the assessment of the association with markers of bone health. Associations between phytoestrogen excretion and markers of bone health were assessed using Pearson's product moment correlations for normal data (r) and Spearman's rank-order correlations for non-normal data. A value of P < 0.05 was taken as statistically significant. Results: Consumption of soy food was reported by 40% and consumption of linseed by 34% of women. Median (range) intakes among soy/linseed consumers for isoflavonoids, 3.87 (0-173) mg/d, and lignans, 2.40 (0.1-33) mg/d, were significantly higher than corresponding intakes among non consumers of 0.005 (0-2.6) and 1.57 (0.4-4.7) mg/d, respectively (P < 0.001). Soy/linseed consumers reported higher intakes of energy (P=0.043), dietary fibre (P=0.003) and polyunsaturated fat (P=0.004); and a higher level of physical activity (P=0.006), SEP (P < 0.001), education (P < 0.001) and supplement use (P < 0.001). Use of non-prescription supplements for menopause in the previous month was reported by 13% of women. A review of supplements available for treatment of menopause indicated that use of soy, red clover, black cohosh and sage could have a role in treatment of menopause symptoms. Evidence supporting the presence of oestrogenic components was available for soy and red clover isoflavonoids only. There was a significant association between intake and excretion of isoflavonoids within the total group (r=0.207, P < 0.05), with a stronger association in soy consumers (r=0.364, P < 0.01). Excretion of isoflavonoids was detected in women who did not report known intake of soy foods, suggesting isoflavonoids could be derived in small amounts from other plant foods or use of soy as an ingredient in processed foods. There was no significant association between intake and excretion of lignans, however both intake and excretion were associated with dietary fibre (r=0.303 and r=0.230, respectively, P < 0.01 for both). Bone ALP was higher among the very low isoflavonoid intake group (P=0.005) for the total sample (P=0.005) and women with BMI≤25 kg/m2 (P=0.002). Data also demonstrated an inverse association between excretion of isoflavonoids and NTX within women with BMI≤25 kg/m2 (r=-0.33, P < 0.05). There was a positive association between lignan excretion and bone ALP in the total sample (r=0.21, P < 0.05) which was strengthened in women with osteoporosis/osteopenia (r=0.41, P < 0.05) and a positive association between lignan excretion and DPD among women with BMI≤25 kg/m2 (ρ=0.28, P < 0.05) All associations remained significant after adjustment for confounding. Conclusions: Few women who chose phytoestrogen-rich foods consumed amounts similar to women with traditional soy-based diets although some achieved high intakes with supplements. Women who consumed soy or linseed foods differed in lifestyle and sociodemographic characteristics that could influence the association with disease in epidemiological studies. Results indicated that the phytoestrogen questionnaire was useful for assessment of isoflavonoids but was not acceptably precise for measurement of lignans. Findings suggest that there is an inverse association between isoflavonoid status and bone ALP and NTX although the precise mechanism of action has not been clarified. The association between lignan intake and bone is less well understood; however findings of a positive association with bone ALP indicate that further research on the lignan content of foods and the inclusion of lignans in studies is warranted.

The inclusion of soya as a dietary protein source in the formulated feed, Abfeed® S34 (Marifeed Pty (Ltd), Hermanus) for farmed abalone, Haliotis midae has resulted in larger gonads during reproductive seasons compared to the gonads of abalone fed kelp or diets that included fishmeal as the only main protein source. The aim of this study was to determine if the isoflavones present in the soya were responsible for this increase in gonad size and the subsequent effects on farmed abalone growth. Animals weighing between 40-50 g were fed one of seven isonitrogenous and isoenergetic diets containing either 0, 25, 50 or 100 percent of the soya component of the commercial feed (Abfeed® S34, Marifeed Pty (Ltd), Hermanus) from September 2013 to March 2014. An additional three diets were formulated to include crystalline isoflavone (ISO). These diets were identical to the 0 percent soya diet (i.e. the fishmeal only diet - FM), only ISO was included at the same rate that ISO occurred in the three soya diets. Data were analysed using a multiple forward stepwise regression analysis (MSR) to test the effects of ISO concentration, soya concentration, time, sex, time by concentration interaction and sex by concentration interaction on growth and gonad development and to identify those variables that most contributed to the model. The inclusion of crystalline ISO failed to promote larger gonads and had no effect on abalone growth, while growth and gonad development was dose dependent on soya inclusion rates with sex and time contributing to the models. Mean monthly weight gain in males correlated with increasing soya concentrations (c) (MSR, y = 3.24 + 0.002c, r2 = 0.23, p = 0.03), ranging from 3.11 ± 0.55 g abalone-1 month-1 to 4.43 ± 0.46 g abalone-1 month-1, while both male and female monthly length gain was not influenced by soya concentration with an overall mean of 1.62 ± 0.05 mm abalone-1 month-1 (MSR, p = 0.05 and p = 0.81, respectively). By December, the whole body mass, meat mass and visceral mass in both males and females decreased with increasing soya levels. However, by February, female whole body mass, meat mass and visceral mass positively correlated with soya levels. At the end of the study, male abalone fed FM with soya equivalent to the commercial feed had the highest whole body mass (69.00 ± 2.48 g abalone-1), meat mass (41.80 ± 1.12 g abalone-1), visceral mass (9.00 ± 2.47 g abalone-1) and gonad bulk index (42.70 ± 9.82 g abalone-1), while females were not influenced by soya concentrations with an overall whole body mass of 63.46 ± 0.79 g abalone-1. Weight loss was observed in all treatments between February and March, probably due to a spawning event. The moisture content in the meat was not influenced by treatment, however, visceral water loss was effected by both ISO and soya concentration with time and sex contributing to the model. The visceral water loss of females fed graded levels of soya decreased as a function of soya from December to March, and from December to February for males, whereas females fed ISO-enriched diets decreased as a function of ISO concentration (c) at the end of the study from 74.98 ± 0.88 to 73.10 ± 0.75 percent (MSR, y = 74.97 – 0.0025c, r2 = 0.20, p = 0.048). The inclusion of crystalline ISO had no significant effect on oogenesis in female farmed Haliotis midae, while the distribution of the predominant oocyte stage, stage 7 (second last stage prior to spawning) was dose-dependent in abalone fed increasing soya concentration (c) (MSR, y = 33.38 + 0.03c, r2 = 0.32, F(1, 18) = 8.52, p = 0.01). The increase in stage 7 oocytes in abalone fed FM with soya did not reduce the number of oocytes (44.96 ± 3.01 oocytes mm-2) present within the lumen, while the number of oocytes (o) in abalone fed the FM-only based diets decreased with increasing abundance of stage 7 oocytes (MSR, y = 58.28 – 0.48c, r2 = 0.38, F(1, 18) = 12.51, p = 0.002), possibly due to the increase in size of the oocytes with thicker jelly coats. This study provided evidence that crystalline isoflavone had no influence on abalone gonad development over five months, while soya had a dose-dependent effect on growth, gonad mass and oogenesis in farmed Haliotis midae. Formulated abalone feed could be manipulated at certain times of the year to obtain maximum growth. These implications and further studies were discussed.

Linseed meal (LSM) was fed to ovariectomized ewes exposed to estradiol 17-ß (E2) implants over time, and LSM was supplemented to beef cows during late gestation and early lactation to evaluate the estrogenic potential of the phytoestrogen secoisolariciresinol diglycoside (SDG) found in LSM. Forty-eight ovariectomized ewes were fed a diet containing 12.5% LSM for 0, 1, 7, or 14 d and implanted with estradiol-17ß (E2) for 0, 6, or 24 h before tissue collection. Uterine cellular proliferation, vascularity, and the expression of the angiogenic factors and their receptors were recorded. There was an interaction of LSM and E2 on uterine mass (P = 0.05). At 24 h of E2 exposure, proliferation was reduced (P < 0.001) when ewes were fed for 14 d compared to being fed 0 or 1 days. There was a LSM x E2 interaction (P ≤ 0.03) on VEGF receptor-2 (KDR) and hasicfihrohlast growth factor receptor (FGFR2) decreasing by 24 h E2 exposure. Exposure of LSM and E2 may impact the estrogenic response of sensitive tissue. Two studies were conducted to examine the effects of supplementing beef cows with LSM during late gestation or early lactation on calf growth and development. In Experiment 1, multiparous cows received either LSM or a control (CON) supplement (approximately 10% diet dry matter) for the last 60 d of gestation. Offspring weights, ADG, heifer age at puberty, conception percentage and steer carcass characteristics were recorded. In Experiment 2, multiparous cows received LSM or CON supplements (approximately 10% diet dry matter) during the first 60 d of lactation, and only heifer calf development performance was observed and recorded. Heifer calf weight, average daily gain, and attainment of puberty were assessed. For both experiments, birth weight, weaning weight and ADG were not affected (P > 0.31) by LSM supplementation. While final body weights were heavier (P = 0.04) for steer calves in Experiment 1, there was no effect (P = 0.09) of supplementation on carcass characteristics. In Experiment 1 and 2, attainment of puberty in heifer calves was not influenced (P > 0.58) by supplement type. Linseed meal supplementation during late gestation or early lactation does not appear to have a negative impact on calf growth, onset of puberty in heifer calves, or steer carcass quality, implicating that it may make a good supplement choice in cattle.

A dietary supplement is a product that contains nutrients (e.g. vitamins, minerals, herbs, amino acids or fatty acids) intended to supplement the diet. The aim of the diploma thesis was to suggest a prescription for preparation of three types of dietary supplements which are used to reduce of climacteric symptoms, their production and determination of energetic (nutrition) value on account of detected content of proteins, fats and saccharides in dietary supplements. A part of the diploma thesis was to suggest suitable wrapping and price of prepared dietary supplements. The three dietary supplements were used for analyses, namely capsules, herb syrup and herb drops. The content of proteins was determined by Kjeldahl´s method, total fats were determined by Soxhlet extraction and saccharides were determined by titration with potassium permanganate (Bertrand´s method). Dietary supplements in form of capsules were particular analysed on content of heavy metals (lead, cadmium and arsenal). In herbal drops was in addition determined alcohol content (ethanol). There was from the measured data found out, dietary supplement in form of capsules was chosen as the product with the lowest energetic (nutrition) value.

Indiana University-Purdue University Indianapolis (IUPUI) / Phytoestrogens that abound in soy products, legumes, and chickpeas can induce biologic responses in animals and humans due to structural similarity to 17β-estradiol. Although experimental studies suggest that phytoestrogen intake may alter the risk of cancer and cardiovascular disease, few epidemiologic studies have investigated this research question. This dissertation investigated the associations of intake of total and individual phytoestrogens and their urinary biomarkers with these chronic conditions using data previously collected from two US national cohort studies (NHANES and PLCO). Utilizing NHANES data with urinary phytoestrogen concentrations and follow-up mortality, Cox proportional hazards regression (HR; 95% CI) were performed to evaluate the association between total cancer, cardiovascular disease, and all-cause mortality and urinary phytoestrogens. After adjustment for confounders, it was found that higher concentrations of lignans were associated with a reduced risk of death from cardiovascular disease (0.48; 0.24-0.97), whereas higher concentrations of isoflavones (2.14; 1.03-4.47) and daidzein (2.05; 1.02-4.11) were associated with an increased risk. A reduction in all-cause mortality was observed for elevated concentrations of lignans (0.65; 0.43-0.96) and enterolactone (0.65; 0.44-0.97). Utilizing PLCO data and dietary phytoestrogens, Cox proportional hazards regression examined the associations between dietary phytoestrogens and the risk of prostate cancer incidence. After adjustment for confounders, a positive association was found between dietary intake of isoflavones (1.58; 1.11-2.24), genistein (1.42; 1.02-1.98), daidzein (1.62; 1.13-2.32), and glycitein (1.53; 1.09-2.15) and the risk of advanced prostate cancer. Conversely, an inverse association existed between dietary intake of genistein and the risk of non-advanced prostate cancer (0.88; 0.78-0.99) and total prostate cancer (0.90; 0.81-1.00). C-reactive protein (CRP) concentration levels rise in response to inflammation and higher levels are a risk factor for some cancers and cardiovascular disease reported in epidemiologic studies. Logistic regression performed on NHANES data evaluated the association between CRP and urinary phytoestrogen concentrations. Higher concentrations of total and individual phytoestrogens were associated with lower concentrations of CRP. In summary, dietary intake of some phytoestrogens significantly modulates prostate cancer risk and cardiovascular disease mortality. It is possible that these associations may be in part mediated through the influence of phytoestrogen intake on circulating levels of C-reactive protein.

Made available in DSpace on 2017-07-21T19:59:54Z (GMT). No. of bitstreams: 1 Camila Juraszeck.pdf: 2382188 bytes, checksum: de4167e36249ed23da96ba41c11fe677 (MD5) Previous issue date: 2011-04-19 / Genistein has estrogenic activity and can bind to estrogen receptors (ER), so it is considered a phytoestrogen. ER have been reported in macrophages and in that sense, the estrogens modulate immune responses. Despite the sexual dimorphism of the immune responses in females and males is well established, there are few studies that elucidate the role of bioactive compounds such as genistein among the genders. We investigated the effects of genistein on mice macrophage functionality, benchmarking males and females, which are divided into three groups according to sex and stage of the estrous cycle. First we checked the cytotoxicity,employing the technique of MTT reduction, in the following compounds: genistein, quercetin and 17-estradiol in the presence or absence of lipopolysaccharide (LPS). And none of these altered cell viability. To test the functionality of macrophages, the cells were treated for 24 h with two concentrations of genistein and quercetin (5M and 10M) as well as two concentrations of 17-estradiol (0,01 and 10 M), besides the control of the vehicle, the dimethylsulfoxide (DMSO) at 0,5%. The macrophages’ funtion standarts determined by spectrophotometry were the NO production in both basal and LPS induced, the production of H2O2 induced by LPS and by light microscopy was evaluated the phagocytic ability of macrophages, which were challenged to phagocytize Zymosan particles opsonized or not, after two hours of treatments. The results show a inhibition percentage of basal NO production in macrophages treated with genistein 10M, 34% and 40% for males and females in diestrus, respectively. In the macrophages obtained from females in proestrus quercetin treatment alone (in lower and higher concentration) showed a decrease in basal NO production significantly compared to control, with inhibition of 24% and 34% respectively. As NO production induced by LPS, macrophages from males showed significant inhibition of production with all treatments (except quercetin 5 μM), while in females in diestrus, treatments genistein (5 and 10 μM) and quercetin (5 and 10 μM ), this parameter significantly decreased functional macrophages, with values corresponding respectively to 25%, 30%, 17% and 31%. Once in females in proestrus, basal NO production induced by LPS and was inhibited only by quercetin (10M). All treatments of macrophages collected from the male reduced the production of H2O2 and genistein inhibition percentage of 10M of 27%. In females in diestrus was observed that treatment with genistein 5 e 10 M and quercetin 10M inhibited respectively 29%, 32% and 37% the production of H2O2. The H2O2 production by macrophages from females in proestrus was significantly inhibited by all treatments (except estradiol 0,01 ηM and quercetin 10M), and the percentage inhibition of genistein 5 e 10M was 22%. The phagocytic activity of macrophages was not affected by treatment with genistein for either group. Our results suggest that NO production, macrophages premodulated by exposure to 17-estradiol, the effect of genistein is less pronounced, may possible be explained by downregulation of ER in ex vivo treatments. In conclusion we can infer that, the use of genistein should account for sex, and therefore variations in serum hormone concentrations of 17-estradiol (sexual cycle) in females. / A genisteína têm atividades estrogênicas, e pode se ligar aos receptores de estrogênio (RE), por isso é considerada um fitoestrógeno. RE têm sido relatados em macrófagos e nesse sentido, os estrogênios modulam as respostas imunes. Apesar do dimorfismo sexual das respostas imunes de fêmeas e machos estar bem estabelecido, existem poucos estudos que elucidem o papel de compostos bioativos como a genisteína entre os sexos. Neste estudo, investigamos os efeitos da genisteína na funcionalidade de macrófagos de ratos, avaliando comparativamente machos e fêmeas, sendo estes divididos em três grupos de acordo com o sexo e a fase do ciclo estral. Primeiramente verificamos a citotoxicidade, empregando a técnica de redução do MTT, dos seguintes compostos: genisteína, quercetina e 17-estradiol, na presença ou ausência de lipopolissacarídeo (LPS). E nenhum destes alterou a viabilidade celular. Para o ensaio da funcionalidade dos macrófagos, as células foram tratadas por 24 horas com duas concentrações de genisteína e quercetina (5M e 10M), como também duas concentrações de 17-estradiol (0,01 e 10 M), além do controle do veículo, o dimetilsulfoxido (DMSO) na concentração de 0,5%. Dos parâmetros de funcionalidade dos macrófagos, foram determinadas por espectrofotometria a produção de NO tanto basal quanto a induzida por LPS, bem como a produção de H2O2 induzida por LPS, e por microscopia de luz realizou-se a avaliação da capacidade fagocítica dos macrófagos, que foram desafiados a fagocitar partículas de Zimosan opsonizadas ou não, após tratamentos de 2 horas. Os resultados encontrados revelam uma porcentagem de inibição da produção de NO basal de macrófagos tratados com genisteína 10 M de 34% e 40%, para machos e fêmeas em diestro, respectivamente. Nos macrófagos obtidos das fêmeas em proestro apenas o tratamento quercetina (em menor e maior concentração) apresentou diminuição na produção de NO basal significativa em relação ao controle, com inibição de 24% e 34% respectivamente. Quanto a produção de NO induzida por LPS, macrófagos de machos apresentaram inibição significativa da produção com todos os tratamentos (exceto quercetina 5M), enquanto nas fêmeas em diestro, os tratamentos genisteína (5 e 10 M) e quercetina (5 e 10 M), diminuíram significativamente esse parâmetro funcional de macrófagos, com os valores correspondentes respectivamente a 25%, 30%, 17% e 31%. Já nas fêmeas em proestro, a produção de NO basal e induzida por LPS foi apenas inibida pela quercetina (10M). Todos os tratamentos dos macrófagos obtidos de machos reduziram a produção de H2O2, sendo porcentagem de inibição da genisteína 10 μM de 27%. Nas fêmeas em diestro observa-se que os tratamentos com genisteína 5 e 10M e quercetina 10 M inibiram respectivamente em 29%, 32% e 37% a produção de H2O2. A produção de H2O2 pelos macrófagos das fêmeas em proestro foi inibida significativamente por todos os tratamentos (exceto estradiol 0,01 M e quercetina 10 M), sendo que a porcentagem de inibição da genisteína 5 e 10 M foi de 22%. A atividade fagocítica dos macrófagos não foi influenciada pelo tratamento com a genisteína para nenhum dos grupos. Nossos resultados são sugestivos de que a produção de NO nos macrófagos prémodulados pela exposição ao hormônio estradiol o efeito da genisteína é menos acentuado, podendo ser explicado por possível downregulation dos RE em tratamentos ex vivo. Em conclusão podemos inferir que para o emprego da genisteína deve se levar em consideração o sexo, e por conseguinte, a variação da concentração hormonal sérica de 17-estradiol (ciclo sexual) em fêmeas.

Abstract not available

Eine ständig steigende Nachfrage nach einer auf pflanzlichen Stoffen basierenden Hormonersatztherapie für menopausale Beschwerden, macht eine verstärkte Untersuchung sogenannter Phytoöstrogene erforderlich. Bei den hier untersuchten Substanzen handelt es sich um die chemisch synthetisierten Flavanone 6-(1,1-Dimethylallyl)Naringenin (6DMAN) und 8-Prenylnaringenin (8PN), die ursprünglich in Pflanzen identifiziert wurden. 7-Oxyprenylnaringenin-4'-Azetat (7OPN) ist ein weiteres Mitglied dieser Stoffgruppe, zu dem jedoch bisher noch praktisch keine Daten vorlagen. Ebenfalls in die Untersuchungen einbezogen wurde ein isopropanolischer Extrakt aus dem Rhizom von Cimicifuga racemosa (L.) Nutt. (iCR), der schon seit langer Zeit erfolgreich zur Bekämpfung menopausaler Beschwerden eingesetzt wird, dessen Wirkmechanismus jedoch unbekannt ist und zu dem bisher noch wenige molekulare Daten bezüglich der Wirkung auf einzelne Zielorgane, insbesondere nach einer Behandlung über einen längeren Zeitraum vorliegen. Die durchgeführten Untersuchungen betrafen zum Einen den Uterus als eines der Hauptzielorgane weiblicher Sexualhormone und zum Anderen die Vena cava, repräsentativ für das Gefäßsystem. Als Modellorganismus wurden Ratten gewählt. Dabei wurde die Genexpression Östrogen (E2)-regulierter Gene auf mRNA-Ebene mittels Real-Time-PCR bestimmt. Die Wirkung von 7OPN wurde in einem in vitro-System (MVLN-Zellen) und im Uterus getestet. Zusätzlich wurden humane Nabelschnurvenen-Endothelzellen als in vitro-Modell für das Gefäßsystem eingesetzt. Mit ihnen wurde die Wirkung der Testsubstanzen auf Angiogenese und Differenzierung getestet. Die durch die E2 hervorgerufenen Effekte entsprachen weitestgehend den Erwartungen. Es konnte sowohl eine Zunahme des Uterusgewichts der Ratten als auch eine Regulation der Expression von Proliferationsmarkern und E2-abhängig regulierten Genen im Uterus auf mRNA-Ebene festgestellt werden. Auch im Gefäßsystem konnte sowohl eine Regulation E2-abhängig exprimierter Gene beobachtet werden, als auch ein proliferationsfördernde und differentiationsfördernde Wirkung auf venöse Endothelzellen in vitro. Die untersuchten Flavanone zeigten einen von den vorhandenen funktionalen Gruppen abhängigen Effekt auf die E2-regulierten Prozesse und Gene. Während es sich bei 8PN um eine rein östrogen wirkende Substanz zu handeln scheint, wirkt 6DMAN offenbar als selektiver Östrogenrezeptor-Modulator (SERM) und zeigt für einen Einsatz in der HRT sehr interessante Eigenschaften, da weder ein uterotrophe Wirkung in vivo, noch eine angiogene Wirkung in vitro beobachtet werden konnte, während gleichzeitig eine östrogene, potentiell kardioprotektive Wirkung auf die Genexpression im Gefäßsystem gezeigt werden konnte. Auch 7OPN zeigt ein differenziertes Wirkmuster. Ein in vitro-Reportergentest in einer stabil transfizierten Brustkrebszellinie deutete auf eine in Abhängigkeit von der Konzentration E2-antagonistische oder agonistische Wirkung hin. Die Genexpressionsstudien im Uterus der Versuchstiere nach dreitägiger Behandlung zeigten, daß die Wirkung von 7OPN jedoch auch abhängig vom untersuchten Gen ist. Da auch dieses Flavanon keine uterotrophe Wirkung zu besitzen scheint, ist 7OPN ebenfalls eine interessante Zielsubstanz weiterer Untersuchungen im Hinblick auf die Anwendung in der HRT. Für den in einem Arzneimittel enthaltenen Extrakt iCR konnte in einem 17-tägigen Tierversuch keine östrogene Wirkung auf Uterus und Gefäßsystem gezeigt werden. Während eine Anwendung dieses Extrakts zur Behandlung menopausaler Beschwerden im Lichte dieser Ergebnisse und langjähriger praktischer Erfahrungen zwar sicher erscheint, bleibt der Wirkmechanismus von iCR weiterhin unbekannt.