Biomedical subjects

D Seidlová-Wuttke

Publications and source records attributed to D Seidlová-Wuttke.

13 recordsLinked to original sources

PubMed2006

[Pharmacological potential of phytoestrogens in the treatment of prostate cancer].

INTRODUCTION: Phytoestrogenes are plant-derived compounds that have been shown to exert an antiproliferative potential on prostate cancer cells, although the exact mechanisms are still unclear. In prostate cancer cells proliferation is regulated by modulation of the IGF-1 receptor (IGF-R-1) by the androgen receptor (AR) and its co-activator prostate derived Ets factor (PDEF). Phytooestrogenes interact with these mechanisms as demonstrated exemplarily in the presented study with the isoflavone tectorigenin derived from Belamcanda chinensis. MATERIAL AND METHODS: Cultured androgen-sensitive LNCaP prostate cancer cells were treated with tectorigenin of 100 microM for 24 hours. The mRNA-expression of AR, PSA, PDEF, hTERT, TIMP-3 and IGF-R-1 were quantified by real-time RT-PCR. Furthermore, the expression or activity of PSA, telomerase and IGF-R-1 was measured on the protein level. In addition, we investigated in nude mice the influence of a diet of extracts of Belamcanda chinensis on the growth of subcutaneously injected LNCaP cells versus a control group of animals fed with a soy-free diet. RESULTS: In cultured LNCaP cells treatment with tectorigenin resulted in a significant down-regulation of the gene expression of AR, PDEF, PSA, IGF-R-1 and hTERT. On the protein level PSA secretion and the activity of telomerase and IGF-R-1 expression was also decreased. The gene expression of TIMP-3 was distinctly up-regulated by tectorigenin. Nude mice fed with Belamcanda chinensis extract showed a significantly decreased incidence and tumor growth compared to controls. CONCLUSIONS: Tectorigenin shows an inhibition of the IGF-1-R modulated cell proliferation of PCa-Cells, due to modulation of the activity the co-activator PDEF independently from the AR. Furthermore, tectorigenin has pro-apoptotic effects and decreases tissue invasion by up-regulation of TIMP-3. Therefore, phytooestrogenes are an interesting option in the therapy of prostate especially advanced prostate cancer.

Animals↗

PubMed2005

Comparison of effects of estradiol (E2) with those of octylmethoxycinnamate (OMC) and 4-methylbenzylidene camphor (4MBC)--2 filters of UV light - on several uterine, vaginal and bone parameters.

OMC and 4MBC are 2 absorbers of ultraviolet light which are used in unknown quantities in sunscreens, cosmetics and plastic products to protect against UV light-induced damage of the skin or of fragrances or plastic material. From there, they were shown to reach surface water and/or by direct contamination or ingestion the human. Under various conditions in mice and rats, both substances were shown to be estrogenic. Therefore, we compared in vitro and in vivo the effects of chronic application of these compounds at 2 doses with those of E2, all administered via food. No signs of toxicity were observed under application of 0.6 mg E2, 57.5 or 275 mg of OMC, 57.5 or 250 mg of 4MBC; these amounts were ingested with 21 g of control food, 17.8 g E2 food, 20.6 g or 22.3 g OMC food and 23.7 or 22.8 g 4MBC food. In the uterus, vagina and bone, E2 exerted the expected stimulatory effects which were minimally shared by OMC and 4MBC in the uterus and vagina as assessed by histology and determination of a variety of estrogen-regulated genes such as insulin-like growth factor-1, progesterone receptor and estrogen receptor beta. In the bone, OMC had no effect, while 4MBC shared the antiosteoporotic effects of E2 as measured by quantitative computer tomography in the metaphysis of the tibia. The mechanism of action of 4MBC, however, appears to be different as E2 reduced serum osteocalcin and the C-terminal breakdown products of collagen-1alpha1 which were both increased by 4MBC. Taken together, these data indicate a very weak estrogenic effect of OMC and 4MBC in the uterus and in the vagina but not in the bone where 4MBC exerted antiosteoporotic effects by a different mechanism than E2.

Animals↗

PubMed2005

Effects of estradiol-17beta, testosterone and a black cohosh preparation on bone and prostate in orchidectomized rats.

Estradiol (E2) and testosterone (T) effectively prevent orchidectomy (orx) induced osteoporosis. T, however, stimulates prostate proliferation which may lead to malignancy. We showed that a Cimicifuga racemosa (CR) preparation had bone-sparing effects without exerting estrogenic effects in the uterus. We studied therefore whether a CR preparation has also antiosteoporotic effects in orx rats substituted with E2, T or CR via pelleted food over a period of 3 months. Average daily intake per animal was: T: 25 mg; E2: 0.325 mg, CR low dose: 33 mg; CR high dose: 133 mg. E2, T and CR at the high dose partially prevented development of osteoporosis as measured by quantitative computer tomography in the metaphysis of the tibia. E2, but not T or CR reduced serum osteocalcin and the metabolic products of collagen-1alpha1. Gene expression of collagen-1alpha1 and tartrate-resistant acid phosphatase was decreased by E2 and the higher dose of the CR extract but increased in the T-treated animals. In the prostate T inhibited androgen receptor, estrogen receptor alpha and insulin-like growth factor-1 gene expression but stimulated the expression of the ERbeta gene. These effects were not shared by E2 or both doses of the CR extract. It is concluded that E2, T and CR exert antiosteoporotic effects in the metaphysis of the tibia of orx rats. T has profound effects in the prostate which were not seen in the E2- and CR-treated animals. Therefore, the Cimicifuga racemosa extract BNO 1055 may be useful to prevent osteoporosis in aged male patients with reduced testosterone production.

Analysis of Variance↗

PubMed2004

Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone.

UNLABELLED: Contradictory results whether the endocrine disrupters (ED) benzophenone-2 (BP2), bisphenol A (BPA) and dibutylphtalate (DBP) exert estrogenic effects have been published. Selective estrogen receptor modulators (SERMs) exert estrogenic effects in some but not in all organs and ED may be SERMs. Therefore, we studied their binding properties to recombinant ERalpha and ERbeta protein and their effects in the uterus, vagina and bone of ovariectomized rats. BP2 bound to both receptor subtypes, while BPA had a relatively high ERbeta selectivity. DBP did not bind to ERalpha but with a low affinity to ERbeta. In the uterus, only E2 and BP2 increased uterine weight and the complement C3 but decreased ERbeta gene expression. Discrete effects of BPA and DBP in the uterus were found upon histological examination. In the vagina, BP2 but not BPA and DBP had clear estrogenic effects. E2 and BP2 had antiosteoporotic effects in the metaphysis of the tibia. The serum surrogate parameters of bone metabolism, i.e. osteocalcin and the cross (rat) laps were significantly reduced by E2, an effect shared with BP2 but not by the two other EDs. THE CONCLUSION: BP2 acts as ERalpha and ERbeta agonist mimicking effects of E2, while the effects of BPA and DBP are not pure estrogenic.

Animals↗

PubMed2004

Belamcanda chinensis and the thereof purified tectorigenin have selective estrogen receptor modulator activities.

Belamcanda chinensis (BC) belongs to the family of iridaceae and the isoflavone tectorigenin has been isolated from the rhizome of this plant. Whether this isoflavone has estrogenic, possibly selective estrogen receptor modulator activities and if so, whether they are mediated via the estrogen receptor alpha or beta is unknown at present. Therefore, we performed binding studies with recombinant human ERalpha and ERbeta to show that tectorigenin binds to both receptor subtypes. In ERalpha-expressing MCF7 and ERbeta-expressing MDA-MB231 reporter gene transfected cells tectorigenin causes transactivation. When given intravenously to ovariectomized (ovx) rats, it inhibits pulsatile pituitary LH secretion. In postmenopausal women estrogen-unopposed LH pulses correlate with hot flushes. Therefore, suppression of pulsatile LH secretion may be beneficial in women suffering from hot flushes. Upon chronic application to ovx rats a BC extract containing 5% Belamcanda at a daily dose of 33 mg or 130 mg of the extract had no effect on uterine weight or on estrogen-regulated uterine gene expression while estrogenic effects in the bone, on bone mineral density of the metaphysis of the tibia could be established. Hence, tectorigenin may have antiosteoporotic effects also in postmenopausal women. Immunohistochemical staining of proliferating cell nuclear antigen--a proliferation marker--in the mammary gland did not indicate a mammotrophic effect of the tectorigenin-containing BC extract at both tested doses. In summary, tectorigenin or the B. chinensis extract containing tectorigenin had a strong hypothalamotropic and osteotropic effect but no effect in the uterus or the mammary gland. Therefore, tectorigenin may be in the future a clinically useful selective estrogen receptor modulator.

Animals↗

PubMed2004

In vivo properties of the urinary bladder wall and their modulation by estradiol and raloxifene in a rat model.

OBJECTIVES: Urinary incontinence is a common symptom of urogenital aging that affects a considerable proportion of postmenopausal women. Morphological and morphometrical modulation of the bladder by estrogen are known. Yet data showing that this translates into changes of in vivo function of the urinary bladder are missing. METHODS: We measured urodynamic parameters in anaesthetized, surviving rats. Following ovariectomy animals were divided into three groups and fed either an estradiol-, raloxifene-, or unsupplemented soy-free formula for ten weeks. Via a transurethral catheter the intravesical pressure was recorded during a stretch period (the urinary bladder was filled), and a one-minute isometric accommodation period immediately after the filling period. Upon termination of the experiment upper and lower halves of the bladder were processed histologically. RESULTS: The estrogen-, and raloxifene-treated animals showed significantly higher pressures in responses to rapid stretch. Bladder compliance during the isometric period on the other hand was not significantly affected by these treatments. Thickness of the epithelial layer, collagen content and muscle bundles were significantly increased by estrogen and raloxifene treatment. CONCLUSIONS: This is a good animal model to investigate modulation of detrusor muscle contractility and stiffness. Both estradiol and raloxifene increase bladder contractility. Urinary bladder morphology indicates that estrogen acts primarily in the upper half of this organ since significant effects on collagen content and muscle fibers are only found in this part.

Animals↗

PubMed2004

Urodynamic effects of estradiol (E2) in ovariectomized (ovx) rats.

Whether estrogens have a beneficial effect in the urinary bladder to prevent or to delay occurrence of urinary bladder incontinence is an open question. Good animal models are missing. Therefore, in ovariectomized (ovx) rats we studied the effects of estradiol (E2) administered with food for 3 mo on urodynamic properties of the urinary bladder and the urethra. A biluminal catheter with one outlet in the bladder and another in the urethra in juxtaposition to the external sphincter was inserted in isoflurane anaesthetized animals. Within 2 x 30 s (1 min apart) 0.5 mL Ringer's solution was infused into the bladder and the inner vesicular and urethral pressure were recorded. In comparison to ovx estradiol-treated rats, ovx animals had significantly (p < 0.05) lower vesicular and urethral pressure. In the sham-treated ovx animals vesicular and urethral pressures were unstable and appeared uncoordinated, whereas estrogens increased vesicular and urethral pressure in a coordinated way, such that in these animals leaked volume was significantly lower than in the sham-treated ovx animals. By means of quantitative RT-PCR we demonstrate that the upper and lower part of the bladder and the urethra express estrogen receptor of the alpha- and beta-subtype (ER alpha and beta) and nerve growth factor, which is associated with painful sensations in inflamed urinary bladders. E2 downregulated both ERs in the bladder but not in the urethra, while NGF gene expression was downregulated in the urethra but unaffected by E2 in the bladder. It is concluded that estrogen deprivation causes uncoordinated function of the detrusor and sphincter muscles and that this effect can be prevented by estradiol.

Animals↗

PubMed2003

Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and uterus.

OBJECTIVES: Hormone replacement therapy (HRT) has therapeutic effects on climacteric complaints and prevents osteoporosis. Owing to the increased risks of breast cancer and cardiovascular diseases, patients look for alternatives. Cimicifuga racemosa (CR) preparations might be an alternative, because they proved to reduce climacteric complaints as efficiently as conjugated estrogens without exerting estrogenic effects in the uterus. Whether CR has positive effects on bone and in fat tissue is currently unknown. Therefore, osteoprotective effects of the CR extract BNO 1055 and an influence on fat tissue were studied in ovariectomized rats. METHODS: Bone mineral density (BMD) of the tibia of ovariectomized (ovx) rats was determined by computer-assisted tomography (CT). CT scans of fat depots were perimetrically quantified. Bone turnover (osteocalcin, crosslaps) and lipocyte activity (leptin) were also determined. Uterine weights were measured and gene expression of estrogen-regulated uterine genes (IGF-1, ERbeta) was determined by RT-PCR. RESULTS: Treatment of the ovx rats over a period of 3 months with E(2) and the CR extract BNO 1055 showed osteoprotective effects; both significantly reduced the loss of BMD in tibia. Serum osteocalcin levels were significantly reduced by both treatments, whereas only E(2), but not BNO 1055, reduced serum crosslaps. A paratibial fat depot and serum leptin concentration were also significantly reduced. In contrast to E(2), the CR extract showed no effect on uterine weight and gene expression of E(2)-regulated genes. CONCLUSION: The CR extract BNO 1055 exerted estrogenic effects in the bone (particularly in osteoblasts) and in fat tissue, but not in the uterus of ovx rats. The extract appears to contain rat organ-specific selective estrogen receptor modulators (SERMs), and if these findings can be approved in human it may be an alternative to HRT.

Adipose Tissue↗

PubMed2003

The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.

OBJECTIVES: In the present study, therapeutic effects of the Cimicifuga racemosa preparation CR BNO 1055 (Klimadynon/Menofem) on climacteric complaints, bone metabolism and endometrium will be compared with those of conjugated estrogens (CE) and placebo. The question whether CR BNO 1055 contains substances with selective estrogen receptor modulator (SERM) activity will be investigated. METHODS: Sixty-two evaluable postmenopausal women were included in the double-blind, randomized, multicentre study, and treated either with CR BNO 1055 (daily dose corresponding to 40 mg herbal drug), 0.6 mg CE, or matching placebo, for 3 months. Menopausal symptoms were assessed by the menopause rating scale (MRS) and a diary. Levels of CrossLaps (marker of bone degradation) were determined by ELECSYS system and bone-specific alkaline phosphatase (marker of bone formation) by an enzymatic assay. Endometrial thickness was measured via transvaginal ultrasound; vaginal cytology was also studied. The primary efficacy criterion was the change from baseline to end point in the MRS. Change from baseline was analyzed for the secondary variables too. RESULTS: CR BNO 1055 proved to be equipotent to CE and superior to placebo in reducing climacteric complaints. Under both verum preparations, beneficial effects on bone metabolism have been observed in the serum. CR BNO 1055 had no effect on endometrial thickness, which was significantly increased by CE. Vaginal superficial cells were increased under CE and CR BNO 1055 treatment. CONCLUSION: The results concerning climacteric complaints and on bone metabolism indicate an equipotent effect of CR BNO 1055 in comparison to 0.6 mg CE per day. It is proposed that CR BNO 1055 contains substances with SERM activity, i.e. with desired effects in the brain/hypothalamus, in the bone and in the vagina, but without exerting uterotrophic effects.

Administration, Oral↗

PubMed2003

Silymarin is a selective estrogen receptor beta (ERbeta) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats.

Silymarin is a widely used standardized mixture of flavonolignans and its major component Silybinin binds to cytosolic estrogen receptors. Here, we demonstrate that this binding is exclusive to the estrogen receptor beta (ERbeta). Treatment of ovariectomized (ovx) rats with silymarin or estradiol (E2) may allow differentiation of biological effects mediated by the ERalpha or ERbeta. E2 inhibited serum LH, cholesterol, LDL and HDL concentrations in the blood and increased gene expression of IGF1, HbEGF and C3 in the uterus, while silymarin was totally ineffective or antagonistic in altering these parameters. Both, E2 and silymarin inhibited expression of uterine ERbeta gene. Hence, in the pituitary, liver (where the lipoproteins are synthesized) and uterus E2 acts primarily via the ERalpha. Exclusive estrogenic effects of silymarin were observed in the metaphysis of the femur (MF), on osteoblast parameters (gene expression of IGF1, TGFbeta1, osteoprotegerin, collagen-1alpha1, osteocalcin (OC)) and on the osteoclast activity marker tartrate resistant acid phosphatase (TRAP) gene expression of adult ovx rats. Our RT-PCR method detects ERbeta gene expression in all organs including developing bones but not in the MF of adult ovx rats. We conclude therefore, that the effects of silymarin in this part of the bone cannot be exerted via the ERalpha because it does not bind to this receptor subtype. Despite the failure to detect ERbeta mRNA in the MF of our animals the possibility exists that ERbeta protein is present and may mediate the effects of silymarin. Another possibility may be that the effect of silymarin and therefore possibly also of E2 in the MF may be mediated via other possibly not yet identified receptors or via an ERbeta splice variant which is not detected by our PCR-method.

Animals↗

PubMed2003

Chaste tree (Vitex agnus-castus)--pharmacology and clinical indications.

Extracts of the fruits of chaste tree (Vitex agnus castus = AC) are widely used to treat premenstrual symptoms. Double-blind placebo-controlled studies indicate that one of the most common premenstrual symptoms, i.e. premenstrual mastodynia (mastalgia) is beneficially influenced by an AC extract. In addition, numerous less rigidly controlled studies indicate that AC extracts have also beneficial effects on other psychic and somatic symptoms of the PMS. Premenstrual mastodynia is most likely due to a latent hyperprolactinemia, i.e. patients release more than physiologic amounts of prolactin in response to stressful situations and during deep sleep phases which appear to stimulate the mammary gland. Premenstrually this unphysiological prolactin release is so high that the serum prolactin levels often approach heights which are misinterpreted as prolactinomas. Since AC extracts were shown to have beneficial effects on premenstrual mastodynia serum prolactin levels in such patients were also studied in one double-blind, placebo-controlled clinical study. Serum prolactin levels were indeed reduced in the patients treated with the extract. The search for the prolactin-suppressive principle(s) yielded a number of compounds with dopaminergic properties: they bound to recombinant DA2-receptor protein and suppressed prolactin release from cultivated lactotrophs as well as in animal experiments. The search for the chemical identity of the dopaminergic compounds resulted in isolation of a number of diterpenes of which some clerodadienols were most important for the prolactin-suppressive effects. They were almost identical in their prolactin-suppressive properties than dopamine itself. Hence, it is concluded that dopaminergic compounds present in Vitex agnus castus are clinically the important compounds which improve premenstrual mastodynia and possibly also other symptoms of the premenstrual syndrome.

Animals↗

PubMed2002

Phytoestrogens for hormone replacement therapy?

Due to some severe side effects "classical" hormone replacement therapy (HRT) is currently being challenged by a therapy with phytoestrogens. Particularly soy and red clover derived isoflavones are advertised as selective estrogen receptor modulators (SERMs) with only desired and no undesired estrogenic effects. Evidence that this is the case however is scarce. Most studies investigating climacteric complaints did not find beneficial effects. A proposed beneficial effect on mammary cancer is unproven. The majority of studies however indicate an antiosteoporotic effect of isoflavones, while putative beneficial effects in the cardiovascular system are questionable due to the fact that estradiol which--like isoflavones--increase HDL and decrease LDL concentrations appear not to prevent arteriosclerosis in the human. In the urogenital tract, including the vagina, soy and red clover derived isoflavones are without effects. Cimicifuga racemosa extracts are traditionally used for the treatment of climacteric complaints. Evidence is now available that the yet unknown compounds in Cimicifuga racemosa extracts prevent climacteric complaints and may also have antiosteoporotic effects.

Bone and Bones↗

PubMed2001

LH pulses and the corpus luteum: the luteal phase deficiency LPD).

The proper function of the GnRH pulse generator in the hypothalamus is essential for normal ovarian function, hence also for proper function of the corpus luteum. During the luteal phase LH pulses stimulate progesterone release, which is essential for normal endometrial transformation. Approximately one-half of all luteal phase deficiencies (LPD) are due to improper function of the GnRH pulse generator. Obviously, following ovulation the increased serum progesterone levels oversuppress the GnRH pulse generator, resulting in too few LH pulses and therefore improper luteal function. Also, latent hyperprolactinemia may lead to an LPD which can be effectively treated with plant extracts containing dopaminergic (prolactin-suppressing) compounds. Our increasing knowledge of auto- and paracrine mechanisms between nonsteroidogenic and steroidogenic cells now allow subclassification of LPDs of ovarian origin. The so-called small luteal cells are LH-responsive. If they develop improperly the regularly occurring LH pulses are unable to stimulate progesterone secretion from the small luteal cells, which results in what we call the small luteal cell defect. In addition, there is also evidence that the large luteal cells may function improperly. Hence, basal progesterone release is too low while LH-stimulated progesterone release from the small luteal cells appears to be intact. This subclassification of luteal phase deficiency results in the suggestion of different treatments. In cases where the corpus luteum is LH-responsive, such as the hypothalamic corpus luteum insufficiency and the large luteal cell defect, HCG treatment or pulsatile treatment with GnRH is advisable. In the case of LH/hCG-unresponsive small luteal cell defect a progesterone substitution is suggested.

Animals↗