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PubMed1984

3-Hydroxy-3-methyl-glutaryl coenzyme A reductase activity in chicks fed coumestrol, a phytoestrogen.

Coumestrol was examined for its effects upon cholesterol metabolism. Chicks (60) were fed control and coumestrol test diets with added levels of cholesterol for 3 weeks. In the first trial, dietary treatments of 0 ppm coumestrol, 10 ppm coumestrol, 10 ppm coumestrol plus 1% cholesterol, and 1% cholesterol resulted in plasma cholesterol levels of 144, 127, 179, and 193 mg/dl, respectively. Growth rates of chicks were not affected by treatments. The percent ether extract of liver was significantly elevated in chicks fed the diet containing 10 ppm coumestrol and 1% cholesterol. Copper and zinc in liver was reduced in chicks receiving either added dietary coumestrol or cholesterol. A second trial compared diets with 0, .05, .5, 5, and 50 ppm coumestrol. Plasma levels of cholesterol in chicks at 3 wks were 156, 152, 149, 145, and 115 mg/dl, respectively. Liver 3-hydroxy-3-methyl-glutaryl coenzyme A ( HMGCoA ) reductase activity in chicks fed 50 ppm coumestrol was elevated at Day 15 but had returned to control level by Day 21. Maximal HMGCoA reductase activity was found at 2000 hr and least activity at 0400 and 1400 hr. Peak HMGCoA reductase activity appeared strongly influenced by time of feed intake. Apparently, changes in HMGCoA reductase activity are secondary responses to reduced plasma cholesterol due to dietary coumestrol.

Animals↗

PubMed1999

Effects of phytoestrogen-coumestrol on lipid and carbohydrate metabolism in young ovariectomized rats may be independent of its estrogenicity.

Two groups of young ovariectomized female rats received one of two treatments. The first group was fed coumestrol in lab chow (200 microg of coumestrol per day) for 14 days; the second group received coumestrol (40 mg/L) via perfusion medium. There was a significant increase (78% compared with the control group) in the uterine weight after coumestrol treatment, which supports the estrogen-like activity of coumestrol. Phytoestrogen diminished the liver and skeletal muscle glycogen contents by 18% and 29%, respectively, and increased the blood glucose level by 24%. Glycogenolytic activity of coumestrol was observed when it acted directly on the liver areas. Although phytoestrogen did not influence insulin and glucagon blood level, liver and to some degree muscle susceptibility to insulin (measured as hormone binding by insulin receptors) was decreased. Coumestrol increased the content of triglycerides in muscle by 113% and enhanced the liver lipid synthesis from glucose by 179%. Liver cholesterol concentration was increased both after coumestrol feeding (by 12%) and when it acted directly on the liver (by 16%). These observations suggest that coumestrol is in general anabolic with regard to lipid and catabolic within-carbohydrate metabolism of young ovariectomized female rats. Based on the results of this study, it is concluded that influence of coumestrol on lipid and carbohydrate metabolism of ovariectomized rats is in part not related to its estrogenic action.

Journal Article↗

PubMed1999

Induction of hyperplasia and increased DNA content in the uterus of immature rats exposed to coumestrol.

Administration of the phytoestrogen coumestrol to ovariectomized rats leads to increases in both wet and dry uterine weights in the absence of an increase in uterine DNA content, as reported by Markaverich et al. [Effects of Coumestrol on Estrogen Receptor Function and Uterine Growth in Ovariectomized Rats. Environ Health Perspect 103:574-581 (1995)]. It was not possible to know if the observed atypical uterotrophic response of coumestrol was associated uniquely with the ovariectomized uterotrophic assay protocol. This question is answered in the present paper. Two experiments are described in which three daily oral gavage administrations of 60 mg/kg/day coumestrol to immature AP rats were followed by assessment of the reproductive tract on the fourth day. In both experiments coumestrol increased uterine fluid content and increased the weights of the uterus, cervix, and vagina. In addition, bromodeoxyuridine staining of uterine sections enabled confirmation of uterine hyperplasia for the coumestrol-treated animals. In the second experiment, total uterine DNA was determined; it doubled in the coumestrol-treated animals. Estradiol benzoate acted as the positive control agent for both of these experiments, and in each case it gave similar responses to those seen for coumestrol. We conclude that the uterotrophic activity of the phytoestrogen coumestrol in the immature intact rat is typical of the activity of the natural estrogen estradiol.

Animals↗

PubMed1993

In situ localization of the estrogen receptor in living cells with the fluorescent phytoestrogen coumestrol.

Coumestrol is a naturally occurring plant coumarin that displays high affinity for the hormone-binding site of the human estrogen receptor (hER), for which it serves as a potent non-steroidal agonist. Coumestrol emits intense blue fluorescence when bound to this protein, making it ideally suited for use as a cytological stain to detect ER in fixed and intact cells. Conditions are reported for the efficient detection of recombinant ER protein artificially expressed in cultured cells by calcium phosphate-mediated transfection. Coumestrol fluorescence co-localizes with hER protein detected by indirect immunofluorescence with an hER-specific anti-peptide antiserum, confirming the specificity of this reagent. Fluorescence from ER occupied by coumestrol shows a predominantly nuclear distribution, even when the receptor protein is cross-linked in situ by fixation with glutaraldehyde plus paraformaldehyde before coumestrol exposure. This corroborates previous conclusions, based on indirect immunofluorescence analysis, that the ER remains nuclear in the absence of hormone. Examination of the pattern of coumestrol staining in mitotic cells further indicates that hER remains associated with condensed chromatin. Such observations illustrate the potential for using coumestrol to investigate real-time effects of a variety of physiological stimuli on the subcellular distribution of hER in living cells.

Cell Line↗

PubMed2006

Gonadotrophin levels and morphological testicular features in rats after different doses of the phytoestrogen coumestrol.

INTRODUCTION: Phytoestrogens are a wide variety of chemical compounds, mainly isoflavonoids, from a vegetable source. Their name makes reference to their ability to induce estrogenic responses in mammals. Coumestrol is a phytoestrogen that can be found in high concentrations in the dietary elements of cattle. Some endocrine alterations have been reported for cows and ewes after ingestion of vegetables with high concentrations of coumestrol. However, these studies have been made mainly in females. OBJECTIVE: To analyze some features of the masculine endocrine response in rats after several doses of the phytoestrogen coumestrol. DESIGN: Adult male rats were injected with several doses of coumestrol. Plasma gonadotrophins (LH/FSH) and testosterone levels were assessed. In addition, morphology of the testicles was analyzed. SETTING: Experiments were done in the facilities of the neurosciences area at the University. RESULTS: No significant changes were observed in gonadotrophin levels after the administration of coumestrol. Testosterone levels showed a significant decrease with the higher doses. Morphological analysis showed an inhibitory effect on spermatogenesis expressed mainly in the right testicle. Testicular volume decreased and the tubular area increased significantly after coumestrol treatment. CONCLUSIONS: These results suggest that the endocrine effect of coumestrol is mainly expressed in peripheral targets in male rats. In addition, the possible mediation of estrogen beta receptors is discussed.

Animals↗

PubMed2007

Effects of coumestrol on neonatal and adult mice osteoblasts activities.

Estrogen replacement therapy has been shown to reduce postmenopausal osteoporosis. In the present study, we examined the effects of the phytoestrogen coumestrol on neonatal and adult osteoblasts metabolism. Two different sources of osteoblast cells (neonatal mice calvaria and adult mice long bone) cultures were used in this study. The effects of coumestrol on the cellular activities were analyzed by the mitochondrial tetrazolium (MTT) assay, secretion of alkaline phosphatase (ALP), intracellular calcium content (Ca), and the gene expression of bone matrix protein, estrogen receptors (ER-alpha, ER-beta), and osteoprotegerin (OPG) and osteoprotegerin ligand (OPGL). The results showed that the proliferation of neonatal mice osteoblast cells was enhanced by treatment of coumestrol. In the presence of 10(-9)M coumestrol, the osteoblast proliferation attained 139.5% of the control and that the coumestrol can increase the intracellular calcium contents. Type I collagen gene expression was upregulated 167% at the 1st day's culture; ALP gene expression was upregulated 360% at the 7th day's culture; while the osteocalcin gene expression was upregulated 222% at the 14th day's culture. When adult mice osteoblasts were cultured in the presence of 10(-9)M coumestrol, the osteoblasts population increased significantly earlier and attained its maximal effect at the 21st day's culture with 207.4% of control group. The content of ER-beta and osteoprotegerin secretion by neonatal mice control cells gradually increased during osteoblasts differentiation, whereas the ER-alpha and OPGL content were decreased in this study. The cellular responses to the estradiol and counmestrol were quite different in the osteoblasts derived from different age.

Animals↗

PubMed1997

Neonatal exposure to coumestrol, a phytoestrogen, does not alter spermatogenic potential in rats.

The objective of this study was to determine the effects of neonatal exposure to phytoestrogens on male reproductive function as adults. Male rats were injected either with 100 micrograms coumestrol or DMSO (controls) daily during their first 5 d of life. Pituitary gland, testes, sex accessory organs, and blood were collected on d 60 of life. Serum testosterone, LH, and FSH levels were determined by RIA. Levels of steady-state mRNA for gonadotrophin subunits (LH beta and FSH beta were determined by Northern blot analysis and quantified by a scanning densitometer. Coumestrol had no effect on weights of testes and sex accessory organs, or sperm count. Similarly, there were no significant differences among serum concentrations of testosterone, LH beta and FSH of coumestrol-treated rats and those of controls. Whereas steady state levels of LH beta mRNA in coumestrol-treated rats did not differ from those of controls, steady state levels of FSH beta mRNA increased (37%) in treated animals. However, the augmented FSH beta mRNA expression in coumestrol-treated rats did not negatively affect reproductive potential in male rats. We conclude that neonatal exposure to coumestrol does not alter reproductive organ structure or spermatogenic potential in male rats.

Animals↗

PubMed2004

Effects of the phytoestrogen coumestrol on RANK-ligand-induced differentiation of osteoclasts.

Phytoestrogens, which have structural similarity to 17beta-estradiol, have been reported to act as agonists/antagonists of estrogen in animals and humans. Estrogen is known to have an important role in maintaining bone mass, because the concentration of serum estrogen decreases after menopause and the estrogen deficiency causes bone loss. In this study, we investigated the effects of coumestrol and other phytoestrogens on osteoclast differentiation using estrogen receptor alpha-transfected RAW264.7 (RAW264.7-ERalpha) cells. When the cells were cultured with the receptor activator of nuclear factor kappa B-ligand (RANKL), both formation of tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells and TRAP activity were increased compared with control cells that were cultured in the absence of RANKL. Coumestrol decreased RANKL-induced formation of TRAP-positive multinucleated cells and TRAP activity dose-dependently. RANKL-stimulated RAW264.7-ERalpha cells formed resorption pits on calcium phosphate films and the pit formation was inhibited by coumestrol in a dose-dependent manner. RT-PCR analyses revealed that coumestrol (10 microM) decreased mRNA levels of calcitonin receptor (CTR) and matrix metalloproteinase-9 (MMP9) in RANKL-treated cells. In addition, pretreatment of coumestrol decreased RANKL-induced phosphorylation of extracellular signal-regulated kinases/p44/42 (ERK1/2). These results suggest that coumestrol has an inhibitory effect on the differentiation of osteoclasts, at least partially via ERK1/2 pathway.

Acid Phosphatase↗

PubMed2001

Evaluation of the genotoxicity of the phytoestrogen, coumestrol, in AHH-1 TK(+/-) human lymphoblastoid cells.

Coumestrol, a phytoestrogen found in high levels in alfalfa and red clover, is of concern since endocrine disorders have been observed in farm animals exposed to high levels of phytoestrogens. Previous studies found that coumestrol was an effective inducer of DNA strand breaks, micronuclei, and mutations in the Hypoxanthine phosphoribosyl transferase (HPRT) gene of Chinese hamster ovary cells. In the experiments presented here, we extended the previous studies to examine the effect of coumestrol exposure on AHH-1 TK(+/-) human lymphoblastoid cells. Micronuclei were induced with the highest frequency occurring at day 2 after exposure. Flow cytometric analysis of annexin V-FITC-7-aminoactinomycin D stained cells indicated that the primary pathway of cell death was by apoptosis. Mutations were induced in the Thymidine Kinase (TK) gene and were due primarily to the induction of clones with the slow-growth phenotype. Subsequent molecular analysis revealed the loss of exon 4 in the coumestrol-induced clones, indicative of loss-of heterozygosity and consistent with a proposed inhibition of topoisomerase-II activity as a mechanism of action for coumestrol. Taken together, these results suggest that coumestrol exhibits both mutagenic and clastogenic properties in cultured human lymphoblastoid cells.

Base Sequence↗

PubMedDate not supplied

Neurobehavioral actions of coumestrol and related isoflavonoids in rodents.

Isoflavonoids are plant estrogens that are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. As weak estrogen agonists/antagonists with a range of other enzymatic activities, the isoflavonoids provide a useful model for the actions of endocrine disruptors. This paper reviews the responses of rodents to diets containing coumestrol or an isoflavone supplement in comparison to animals fed the phytoestrogen-free AIN76A diet. Neural mechanisms were investigated by examining isoflavonoid effects on ER(alpha)-dependent (regulation of oxytocin receptor [OTR] binding in the ventromedial nucleus of the hypothalamus [VMN]) and ERbeta-dependent (regulation of ERbeta mRNA in the paraventricular nucleus [PVN]) endpoints. Activational as well as organizational effects on sexual behavior and gonadotropin secretion were observed for coumestrol. Treatment of rat dams with a 100-ppm coumestrol diet from birth to postnatal day (PND) 21 induced premature anovulation in female offspring, and treatment from birth to PND 10 suppressed sexual behavior in male offspring. One-week treatment of ovariectomized (OVX) female rats with the same coumestrol diet increased ERbeta mRNA expression in the PVN, an effect opposite to that of estradiol. Ten days of treatment with a 200-ppm coumestrol diet increased LH secretion in OVX wild-type mice, an effect opposite to the normal negative feedback effects of estradiol. No effects were observed in ER(alpha) knockout (ER(alpha)KO)-OVX females, indicating that coumestrol's action on LH was mediated through ER(alpha). Similar activational effects were observed for the isoflavone diet. The lordotic response to estrogen was significantly reduced by 2 days of treatment of OVX adult females with an isoflavone diet providing 13 ppm genistein and 33 ppm daidzein. One week of treatment with the same isoflavone diet produced an effect opposite to that of estradiol in the PVN, increasing ERbeta mRNA expression above control levels. These investigations show that, in spite of their preferential affinity for ERbeta, isoflavonoids act through both ER(alpha) and ERbeta. Moreover, their neurobehavioral actions were antiestrogenic, either antagonizing or producing an action in opposition to that of estradiol. This work demonstrates that even small, physiologically relevant exposure levels can alter estrogen-dependent gene expression in the brain and complex behavior.

Animals↗

PubMed1984

Estrogenicity of coumestrol in the mouse: fluorescence detection of interaction with estrogen receptors.

The estrogenicity of coumestrol, a fluorescent phytoestrogen, has been examined in murine uteri. Coumestrol competed with 17 beta-[3H]estradiol for binding to cytoplasmic estrogen receptors, caused cytoplasmic estrogen receptors to associate with chromatin in the nucleus, and induced progesterone receptors. By use of size-exclusion high-performance liquid chromatography (SEHPLC), the interaction of coumestrol with estrogen receptors was examined directly by monitoring the fluorescence associated with macromolecules having properties characteristic of estrogen receptors. These analyses were made possible by the addition of dimethylformamide to the elution buffer, at a concentration (7.5%) which improved recoveries but did not interfere with estrogen receptor binding. It was possible to detect fluorescent coumestrol at approximately 0.5 nM. All determinations were performed with preparations in which estrogen receptor activity was 3-10 nM. Exposure of these preparations to coumestrol (50 nM) resulted in the elution of increased fluorescent activity in the regions where estrogen receptors eluted during SEHPLC. This fluorescent activity was reduced when diethylstilbestrol, 17 beta-estradiol, hexestrol, or tamoxifen was present as a competitor (2 microM) but was unaffected by testosterone or progesterone. Diethylstilbestrol reduced fluorescence below endogenous base lines and thereby displayed a fluorescence quench property which was not observed with other ligands. When hepatic and renal estrogen receptor preparations were used, the injected receptor activity was observed to be the major limiting factor in detecting the interaction of coumestrol with estrogen receptors. These observations are relevant to attempts to visualize estrogen receptors in tumor cells and demonstrate that accepted biochemical criteria for ligand-receptor interaction can be satisfied when fluorescent ligands are examined.

Animals↗

PubMed1990

Reproductive abnormalities in female mice exposed neonatally to various doses of coumestrol.

Female C57BL/Crgl mice were neonatally exposed to various doses of coumestrol to determine the threshold doses required for the occurrence of reproductive tract abnormalities. Newborn mice received daily subcutaneous injections of 10(-3), 10(-2), 8 X 10(-2), 10(-1), 1, 5, 25, 50, and 100 micrograms coumestrol in 0.005 ml dimethyl sulfoxide (DMSO) or DMSO alone, or received no treatment for the first 5 d of life. Some of the animals were ovariectomized at 40 d of age. Mice were killed at 20-22 mo of age. All neonatal doses of coumestrol advanced vaginal opening before that of controls. At 2 and 20-22 mo of age, doses greater than or equal to 25 micrograms consistently resulted in ovary-independent persistent vaginal cornification as judged by vaginal smears. Intact untreated and DMSO-treated control mice exhibited aging changes in the genital tract, some cervical adenosis and early cervicovaginal pegs and downgrowths, uterine cystic glandular hyperplasia, corpora lutea, and scattered areas of ovarian ceroid deposition. Intact mice receiving neonatal coumestrol exhibited cervicovaginal pegs and downgrowths (at all doses with the exception of 25 and 50 micrograms), cervical adenosis (at doses greater than or equal to 8 X 10(-2) micrograms), uterine squamous metaplasia (significant at doses greater than or equal to 50 micrograms), and a decrease in uterine cystic glandular hyperplasia (significant at doses greater than or equal to 25 micrograms). The levels of 10(-1), 5, and 100 micrograms neonatal coumestrol daily resulted in hemorrhagic follicles. An increase in ovarian ceroid deposition (significant at doses greater than or equal to 5 micrograms) was observed. At 40 d and 20-22 mo of age, corpora lutea were consistently absent from the 100-micrograms-treated animals. Most of the ovariectomized untreated and DMSO-treated control animals showed typical castrate-like morphology of the genital tract, with the majority of the control mice exhibiting uterine cystic glandular hyperplasia. Ovariectomized mice receiving coumestrol neonatally exhibited various degrees of cervicovaginal alterations: pegs and downgrowths (significant at all doses with the exception of 10(-1) micrograms), endometrial collagen deposition (significant at greater than or equal to 25 micrograms), and reduced or absent uterine glands (significant at 10(-3), and 10(-11), and at all doses greater than or equal to 5 micrograms).

Age Factors↗

PubMed2001

Coumestrol antagonizes neuroendocrine actions of estrogen via the estrogen receptor alpha.

The phytoestrogen coumestrol has estrogenic actions on peripheral reproductive tissues. Yet in the brain this compound has both estrogenic and anti-estrogenic effects. We used estrogen receptor alpha knockout mice (ERalphaKO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ERalpha. Female wild-type (WT) and ERalphaKO mice were ovariectomized and treated with estradiol (E2), dietary coumestrol, both, or neither compound. Ten days later the animals were sacrificed, blood was collected, and brain tissues were perfused. Fixed brains were sectioned and immunocytochemistry was employed to quantify progesterone receptors (PR) in the medial preoptic (POA) and ventromedial nucleus of the hypothalamus (VMN). Plasma was assayed for luteinizing hormone (LH). Estrogen treatment induced PR immunoreactivity in both regions in brains of WT females. In ERalphaKO mice, lower levels of PR were induced. The stimulatory effects of E2 on PR were attenuated in the POA by cotreatment with coumestrol, and the same trend was noted in the VMN. WT ovariectomized females treated with E2 had low levels of LH, while LH was high in untreated females and even higher in ovariectomized females treated with coumestrol. ERalphaKO females in all treatment groups had high levels of LH. Taken together, the results show that coumestrol has anti-estrogenic actions in the brain and pituitary and that ERalpha mediates these effects.

Animals↗

PubMed1985

Gonadotrophin release in ovariectomized ewes fed different amounts of coumestrol.

Three experiments were conducted to study changes in pulsatile secretion of LH and FSH during the breeding season or anoestrus in ovariectomized Ile-de-France ewes fed different amounts of the phyto-oestrogen coumestrol. In Exp. 1, conducted during the breeding season, ewes (3-4 per group) were fed lucerne supplying 4, 18 or 30 mg coumestrol per ewe per day for 15 days. Experiments 2 and 3 were conducted during seasonal anoestrus. In Exp. 2, ewes (4 per group) were fed lucerne supplying coumestrol concentrations ranging from 4 to 38 mg/ewe/day for 15 days. In Exp. 3, ewes (10 per group) were fed lucerne supplying 14 or 125 mg coumestrol/ewe/day for 15 days. During the breeding season, an increased concentration of coumestrol in the diet significantly decreased the amplitude of LH pulses. There were no effects on LH pulse frequency or on FSH concentrations. During seasonal anoestrus, there were no significant effects on LH pulse frequency, or amplitude and no significant effect on FSH concentration. These results show that high concentrations of coumestrol in lucerne diets would not explain seasonal variation in LH pulse frequency in ovariectomized ewes. However, lucerne diets with increased coumestrol concentrations can influence LH release during the breeding season.

Anestrus↗

PubMed1995

Binding properties of coumestrol to expressed human estrogen receptor.

We have studied the binding of coumestrol, an inherently fluorescent analog of 17 beta-estradiol, to human estrogen receptor (hER) in extracts of transfected cultured cells. The binding of coumestrol to the hER as well as its dissociation from the receptor can be directly determined by the change in fluorescence intensity of the probe. In agreement with previous studies using calf uterine extracts, we find that coumestrol binds to the receptor with a ten-fold lower affinity than 17 beta-estradiol. However, the rate of dissociation appears to be close to that of the native ligand. Coumestrol can accept energy from Trp residues in the excited state and, using a C530W hER mutant, we have confirmed that residue 530 is close to the ligand-binding pocket. We also find that the presence of saturating amounts of the specific DNA binding sites (ERE) did not significantly alter the binding affinity of coumestrol to either wild type hER or the C530W mutant.

Animals↗

PubMed1999

Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol.

Estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) are differentially distributed in the brain and likely mediate different estrogen-dependent processes. ERbeta is abundant in the bed nucleus of the stria terminalis, medial preoptic nucleus, paraventricular nucleus of the hypothalamus and the amygdala of the rat. In the paraventricular nucleus, which is devoid of ERalpha, ERbeta is colocalized with the neuropeptides, oxytocin and vasopressin, suggesting a potential functional role for ERbeta in the regulation of these peptides. We examined the regulation of ERbeta mRNA expression in the rat brain by 17beta-estradiol and the phytoestrogen, coumestrol. 17beta-Estradiol treatment decreased ERbeta mRNA in situ hybridization signal by 44.5% in the paraventricular nucleus of the hypothalamus (PVN), but had no effect in the bed nucleus of the stria terminalis (BnST) or the medial preoptic nucleus (MPA). In contrast, dietary exposure to coumestrol increased ERbeta mRNA signal by 47.5% in the PVN but had no effect in the BnST or the MPA. These data demonstrate that like ERalpha, ERbeta is down regulated by estrogen in a region specific manner in the rat brain. Furthermore, exposure to coumestrol may modulate ERbeta-dependent processes by acting as an anti-estrogen at ERbeta. This data contradicts results from cell transfection assays which suggest an estrogenic activity of coumestrol on ERbeta, indicating that the mode of action may be tissue specific, or that metabolism of dietary coumestrol may alter its effects. Because the highest concentrations of phytoestrogens are found in legumes, vegetables and grains, they are most prevalent in vegetarian and traditional Asian diets. Understanding the neuroendocrine effects of phytoestrogens is particularly important now that they are being marketed as a natural alternative to estrogen replacement therapy and sold in highly concentrated pills and powders.

Animals↗

PubMed2002

Comparison of the oestrogenic effects of infant milk formulae, oestradiol and the phytoestrogen coumestrol delivered continuously in the drinking water to ovariectomised mice.

The potential oestrogenic effects of infant milk formulae, coumestrol and oestradiol delivered in the drinking water were investigated in ovariectomised mice. None of the infant formulae tested (three soya, two cow's milk) produced any uterotrophic or mitotic responses in the reproductive tract, although the soya milks displayed weak oestrogenic activity in vitro. Studies of the interactions between coumestrol and oestradiol were undertaken to investigate claims that phytoestrogens may act as oestrogen antagonists. The responses to coumestrol (100 g/ml drinking water) and 17-oestradiol (100 ng/ml) given separately were similar. Combined administration begun simultaneously produced only additive effects on uterine weight and cell proliferation in the vagina and uterus. While pretreatment with coumestrol for 24 h reduced the mitotic response of the uterus 48 h after placement of an oestradiol implant, the uterine weight increase was unaffected and the apparent reduction in mitoses reflected the natural fluctuations in the underlying cycle of cell proliferation. These studies indicate that coumestrol acts as a typical oestrogen and shows only additive effects with oestradiol. The results also indicate that infant soya milk formulae do not constitute a large enough source of oestrogenic compounds to invoke oestrogenic effects in the reproductive tract of mature mice.

Animals↗

PubMed2002

Daidzein, coumestrol and zearalenone affect lipogenesis and lipolysis in rat adipocytes.

Daidzein, coumestrol and zearalenone - compounds called phytoestrogens, considered as active biological factors affecting many important physiological and biochemical processes appeared to be also significant regulators of adipocyte metabolism. In our experiments the influence of daidzein (0.01, 0.1 and 1 mM), coumestrol (0.001, 0.01 and 0.1 mM), zearalenone (0.01, 0.1 and 1 mM) and estradiol (0.01, 0.1 and 1 mM) on basal and insulin-stimulated (1 nM) lipogenesis from glucose and acetate was tested in adipocytes isolated from growing (160 +/- 5 g b.w) male Wistar rats. All tested compounds significantly attenuated glucose conversion to lipids. In the case of daidzein and coumestrol, this effect was probably due to inhibition of glycolysis. Daidzein (0.01, 0.1 and 1 mM), coumestrol (0.01 and 0.1 mM) and zearalenone (0.01, 0.1 and 1 mM) affected also basal and epinephrine-stimulated (1 microM) lipolysis. Daidzein (0.01 and 1 mM) augmented basal glycerides breakdown in adipocytes. The epinephrine-induced lipolysis was dependent on daidzein concentration and its stimulatory (0.1 mM) or inhibitory (1 mM) influence was observed. Zearalenone changed lipolysis only at the concentration of 1 mM and its effect was contradictory in the absence or presence of epinephrine (the stimulatory or inhibitory effect, respectively). Results obtained in experiments with inhibitors (insulin, 1 nM and H-89, 50 microM) and activators (dibutyryl-cAMP, 1 mM and forskolin, 1 microM) of lipolysis allowed us to assume that daidzein augmented basal lipolysis acting on PKA activity. The inhibitory effect of daidzein and zearalenone on epinephrine-induced lipolysis is probably due to restriction of HSL action. The influence of coumestrol on glycerides breakdown was less marked. Estradiol augmented only epinephrine-stimulated lipolysis.

Adipocytes↗