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To investigate the impact of Humulus Lupulus L. hydroalcoholic extract on the body weights, reproductive organs, sperm quality and hormone levels in male rats.By simple random sampling method, seventy male Sprague-Dawley rats were randomly assigned to 7 groups including control group [distilled water, 1 mL/(kg•d)], Tween 80 group [25% Tween 80 solution, 1 mL/(kg•d)], olive oil group [olive oil, 1 mL/(kg•d)], diethyl stilbestrol (DES) group [DES, 100 μg/(kg•body weight)], H50, H150 and H450 [50, 150 and 400 mg/(kg•d) of Humulus Lupulus L extract, respectively]. The administration was performed via gavage once daily for 7 weeks. Body and reproductive organs weights including testes, seminal vesicles, epididymis and prostate were weighted and epididymal sperm quality were determined by digital balance. Blood samples were collected and serum free testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estrogen (E2) levels were measured by rat specific enzyme-linked immunosorbent assay.The percentage increase in mean body weights of rats in the DES and H50, H150 and H450 groups decreased significantly compared to olive oil and Tween 80 groups (all P0.05). The weights of seminal vesicle, epididymis and testes in rats receiving H50 were significantly higher than the control group (P0.05 or P0.01). The sperm count in the rats receiving H50 was significantly lower than the control group (P0.05). The sperm motile characteristics of the rats receiving hydroalcoholic extract at and DES were significantly lower than those of the control or rats receiving vehicles (all P0.05). In H50, H150, H450 and DES groups, T and LH levels were decreased, and E2 was significantly increased compared to the control (P0.05 or P0.01). The FSH level did not change in all groups (P0.05).Humulus Lupulus L. extract significantly increased the seminal vesicle and testes weights and reduced the sperm motility.

Humulus lupulus L. is a plant from cannabinaceac family which is grown in Iran as well as most regions round the world. The present study aimed at examining effects of hydroalcoholic extract of Humulus lupulus L. hops on blood pictures in male rats. Rats were randomly assigned to seven groups of ten, including one control group (no treatment). All of the six groups under the study were exposed 7 weeks to 25% tween 80° solution (1 ml/kg/day), olive oil (1 ml/kg/day), hydroalcoholic extract of Humulus lupulus L. (H) at 50, 150, or 450 mg/kg/day, as well as Di Ethyl Stilbestrol (DES) (100 μg/Kg BW). Having performed the experiments, the researcher removed rats’ blood serums from the due blood samples and kept them all frozen for usage. After all, results were analyzed by one way-ANOVA statistical method (p

Cladistic analysis allows inference of the structure of an ancestral steroid that acts as a ligand for the ancestral receptor., The origin of ancient ligand/receptor couples is often analyzed via reconstruction of ancient receptors and, when ligands are products of metabolic pathways, they are not supposed to evolve. However, because metabolic pathways are inherited by descent with modification, their structure can be compared using cladistic analysis. Using this approach, we studied the evolution of steroid hormones. We show that side-chain cleavage is common to most vertebrate steroids, whereas aromatization was co-opted for estrogen synthesis from a more ancient pathway. The ancestral products of aromatic activity were aromatized steroids with a side chain, which we named “paraestrols.” We synthesized paraestrol A and show that it effectively binds and activates the ancestral steroid receptor. Our study opens the way to comparative studies of biologically active small molecules.

A series of structurally simple bibenzyl-diol and stilbene-diol core molecules, structural analogs of the well-known hexestrol and diethylstilbestrol non-steroidal estrogens, were prepared and evaluated as estrogen receptor (ER) subtype-selective ligands. Analysis of their ERalpha and ERbeta binding showed that certain substitution patterns engendered binding affinities that were100-fold selective for ERbeta. When further investigated in cell-based gene transcription assays, some molecules showed similarly high relative transcriptional potency selectivity in favor of ERbeta. Interestingly, the most ERbeta-selective molecules were those bearing non-polar substituents on one of the internal carbon atoms. These compounds should be useful probes for determining the physiological roles of ERbeta, and they might lead to the development of more selective and thus safer pharmaceuticals.

A method was developed, using commercially available immunoaffinity chromatography cleanup cartridges, followed by detection by gas chroma- tography/mass spectrometry, to screen for resi- dues of the hormone growth promotants diethyl- stilbestrol, dienestrol, hexestrol, and zeranol in bovine urine. The single-laboratory, in-house vali- dation included assessment of recoveries, repeat- ability, linearity of response, detection capability, and specificity (cross-reactivity) with a suite of an- tibiotics and other hormonal growth promotants. The method was validated for screening at a target concentration of 2.0 g/L in urine. The detection capabilities for the analytes were diethylstilbestrol, 0.24; dienestrol, 0.15; hexestrol, 0.84; and zeranol, 0.28 g/L. food animals is banned in the European Union (EU), and no residues of these substances are allowed in meat products sold there. To meet EU requirements, cattle producers in a number of exporting countries have developed "hormone-free cattle" programs, where animals are certified to have been grown to market weight without the use of HGPs. National authorities are required to collect and test bovine urine for the presence of these HGPs in order to demonstrate that cattle raised for ex- port to the EU are free of these substances (2, 3). For cattle to be acceptable to the EU, the HGPs must not be detectable in urine by a method capable of detecting residues at a concen- tration of 2.0 g/L or higher (4). This level defines the mini- mum required performance limit (MRPL) for the analytical method. To meet the EU regulations, the Canadian Food In- spectionAgency(CFIA)requiredasuitablescreeningmethod for these HGPs in bovine urine. An existing CFIA method for DES, DIEN, HEX, and ZER in tissue, based on a method by Covey et al. (5), was extended to bovine urine. The original gas chromatography/mass spec- trometry(GC/MS)determinationoftheanalyteswasretained, and a new sample preparation methodology, based on com- mercially available immunoaffinity chromatography (IAC) columns, was incorporated into the method. This approach was adopted to minimize the amount of time and resources needed to develop and validate the method, and reduce famil- iarization time for the technical staff. The new screening method was validated for the reliability of detection of the analytes at a concentration of 2.0 g/L in fortified blank urine samples. The single-laboratory, in-house validation included assessment of recoveries, repeatability, linearity of response, detection capability (CC), and selectivity. METHOD

Cadmium is a very important m etal toxin and environmental pollutant. In rodents, the acute and chronic toxic effects of cadmium are pronounced in several tissues including the lung, liver, kidney, prostate, and testes. The toxic effects of cadmium can be modulated by pretreatments or concurrent treatments with various m etallic and nonmetallic substances. This review focuses on theeffects of steroid hormones and steroid antagonists on cadmium toxicity in vivo. Steroids can have a variety of effects on cadmium toxicity including both mitigation and exacerbation of the adverse effects of this metal. Steroids or steroid antagonists that have been reported to modify cadmium toxicity include testosterone, progesterone, cyproterone, estradiol, and stilbestrol. Some steroids, like dexam ethasone and corticosterone, are inducers of metallothionein (MT), a cadmium-binding protein thought to be im portant in cadm ium tolerance. From these reports several possible mechanisms have been proposed to explain the m odul...

Primary dysmenorrhea is one of the most frequent gynecological disorders in young women. Chinese herbal medicine has the advantage in terms of multi-targeting efficacy, lower toxicity, as well as lower cost. Core licorice is the hard and atropurpureus heart part in root and rootstock of Glycyrrhiza uralensis Fisch (Leguminosae), having a therapeutic effect on dysmenorrhea.This experiment indicated the spasmolytic effect of core licorice aqueous extract (CLE) on spontaneous rhythmic contractions and spasmogen-provoked contractions of stilbestrol primed, estrogen-dominated, non-pregnant mouse isolated uterine horns and its spasmolytic mechanism.We investigated the spasmolytic effect of CLE (0.025-0.1 mg/mL) on spontaneous contractions and potassium chloride (KCl, 40 mM), acetylcholine (ACh, 5 μg/mL), carbachol (CCh, 5 μg/mL), oxytocin (OT, 2 U/L) or bradykinin (5 ng/mL)-provoked contractions of mouse isolated uterine horns. Contractions were recorded by tension force transducers using Biolap 420F software on a PC.Our present study showed that graded, escalated concentrations of CLE (0.025-0.1 mg/mL) significantly inhibited the amplitude of spontaneous phasic contractions (15.03-55.10%), as well as the contractions produced by KCl (40 mM; 20.16-53.99%), ACh (5 μg/mL; 14.65-48.32%), CCh (5 μg/mL; 38.40-76.70%), OT (2 U/L; 21.53-58.49%) or bradykinin (5 ng/mL; 58.01-79.44%) of the estrogen-dominated isolated mice uterine horn preparations in a concentration-related manner.The spasmolytic effect of CLE observed in the present study lends pharmacological support to the traditional use of core licorice in the management, control and treatment of primary dysmenorrhea.

In psychobiological research on sexual orientation, the prenatal hormone theory has a central posi tion. This article examines the hypothesis that prenatal estrogens contribute to the development of human sexual orientation. Several groups of women with a history of prenatal exposure to diethyl stilbestrol (DES), a nonsteroidal synthetic estrogen, were compared with several samples of control women in the context of a comprehensive study of the psychiatric and psychologic effects of prenatal DES. Various aspects of sexual orientation were assessed by systematic interview. Consistently across samples, more DES-exposed women than controls were rated as bisexual or homosexual (scores 2-6 on Kinsey-format scales ranging from 0 to 6). The data are compatible with the hypothesis that prenatal estrogens may play a role in the development of human sexual orientation

The first example of hormonal dependency of breast cancer can be dated back as far as 1896, when Dr. G.T. Beatson observed and described the reduction of breast cancer progression in a premenopausal patient after bilateral oophorectomy (Beatson 1896). It was an indication that the ovaries produced something in a woman’s body that fueled breast cancer growth. This phenomenon was reconfirmed in a collected series of patients with advanced breast cancer following oophorectomy (Boyd 1900), however there was only a 30% percent response. In 1916 Lathrop and Loeb demonstrated in mice, that ovarian function has an influence on the growth of mammary glands and tumorigenesis, and that castration of immature female mice has delayed the evolution of mammary tumors (Lathrop 1916). However, the chemical control mechanisms of breast cancer progression and the relevance of ovarian function remained uncertain, until the first animal models were introduced to test the effects of oophorectomy and estrogenic properties of different chemical compounds under precise laboratory conditions (Allen 1923). This model allowed the indentification the ovarian hormone, which induced estrus in oophorectomized mice, estrogen. In subsequent years during the 1930s and 1940s many other compounds, including diethylstilbestrol, and triphenylethylene derivatives would be identified as estrogens utilizing the ovariectomized mouse model (Robson 1937; Dodds 1938). The connection between the beneficial effects of oophorectomy as a treatment for advanced breast cancer provoked questions about the actual role of estrogen and other estrogenic compounds in breast cancer growth. High dose estrogen therapy was the first chemical therapy (“chemotherapy”) to treat any cancer successfully. In 1944 Haddow (Haddow 1944) published the results of his clinical trial with the synthetic estrogens triphenylchlorethylene, triphenylmethylethylene, and diethylstilbestrol. He found that 10 out of 22 post-menopausal patients with advanced mammary carcinomas, who were treated with triphenylchlorethylene, had significant regression of tumor growth. Five patients out of 14 who were treated with high dose stilbestrol produced similar responses. The finding that high doses of synthetic estrogens induced regression of tumor growth in some, but not all postmenopausal patients with breast cancer (30% of patients responded to therapy favorably) was similar to the random responsiveness of oophorectomy in premenopausal patients with metastatic breast cancer (Boyd 1900). However, Haddow (Haddow 1944) noted that the first successful use of a chemical therapy to treat breast and prostate cancers

THE ABDOMINAL fibroids which are produced in the guinea pig by estrogens (Lipschutz and Iglesias, 1938) may easily be prevented by the administration of certain cortical steroids such as desoxycorticosterone and dehydrocorticosterone (work of Lipschutz, Nunez, Vargas and Zanartu; see review by Lipschutz, 1944). Since 28 different steroids have been extracted from the adrenal cortex (Reichstein and Shoppee, 1944) of which 6 or 7 have cortical activity, the question arose as to the role of these steroids in the system of anti-tumoral auto-defense by the maintenance of the steroid balance, in accordance, 0 with the concept of Lipschiitz (1943). We proposed to attack this problem by removing the adrenal glands from guinea pigs which were to be treated afterward with fibromatogenic quantities of estrogen. But in order to study the question experimentally, it was necessary to replace the adrenal cortex with a steroid possessing cortical activity but lacking any antifibromatogenic action.

Directions are given for the preparation of stilbestryl‐bis (diethylaminoethyl) ether dihydrochloride, and hexylresorcinol‐bis (diethylaminoethyl) ether. In vitro tests showed that the stilbestrol derivative is bactericidal against Mycobacterium tuberculosis var, hominis i n concentration of 1:50,000; against cultures of the M. tuberculosis which had been pretreated with alkali, 1:50,000; against Eberthella typhosa, 1:5000 and against Staphylococcus aureus, 1: 5000. The corresponding minimum effective concentrations of the hexylresorcinol derivative were 1:50,000 (M. tuberculosis); 1:100,000 (M. tuberculosis pretreated with alkali); 1:50,000 (E. typhosa; and 1:10,000 (S. aureus). The compounds appeared to be bactericidal rather than bacteriostatic against all three organisms. Preliminary tests indicated that the stilbestrol derivative, administered intraperitoneally to castrated female rats, was neither estrogenic nor toxic in doses of 10, 50, or 100 micrograms.

1. The noted fall of the erythrocyte count, haemoglobin and haematocrit levels after stilbestrol indicate that this hormone disturbs erythropoiesis, probably by depressing the maturation of erythroid cells in the bone marrow. 2. The reaction of the erythrocyte system of birds intoxicated with Ekatin indicates that this pesticide has a haemolytic influence on the morphotic elements of the blood. 3. Estrogenisation enhances the action of Ekatin on the erythrocyte system by as it seems increasing the susceptibility of the red blood cells to the haemolytic action of this pesticide. 4. The high heterophilic leucocytosis in birds receiving stilbestrol is evidence that this hormone causes by an increased release of corticoids, hyperplasia of the granulopoietic tissue in the bone marrow and depresses the marrow barrier for heterophils. 5. Changes in the leucocyte system of quails intoxicated with Ekatin indicate a stressogenic action of this poison. 6. The reaction of the latter system to Ekatin administered after estrogenisation seems to be an indication that stilbestrol reduces the susceptibility of the quails to the stressogenic action of the pesticide.

Antioxidant and estrogenic effects of formononetin on ovariectomized mice have been investigated in the present study. The adult female Kunming mice were divided into 5 groups: sham-operated group, ovariectomized group, stilbestrol replacement therapy group (0.20 mg/kg day), low-dose formononetin group (0.05 g/kg day) and high-dose formononetin group (0.5 g/kg day). The mice in the latter 4 groups were ovariectomized. The drug was given by oral administration for 6 months. Estrogenic effect was determined by the change of uterine weight, and oxidant effects were determined by the content of SOD, GSH-Px, CAT and MDA. The intake of formononetin increased the uterine weight of the mice significantly as well as the content of SOD, GSH-Px, CAT, and reduced MDA in body. Formononetin had obvious antioxidant effects and estrogenic effect, and the estrogenic effect was not dosage-related.

The ability of certain man-made chemicals to mimic the effects of natural steroid hormones and their potential to disrupt the delicate balance of the endocrine system in animals are of increasing concern. The growing list of reported hormone-mimics includes the alkylphenolic (AP) compounds, a small number of which have been reported to be weakly estrogenic. In their most basic form, APs are composed of an alkyl group, which can vary in size, branching, and position, joined to a phenolic ring. The aim of this project was to identify the important structural features responsible for the estrogenic activity of AP chemicals. This was achieved by incubating APs with different structural features in a medium containing a previously described estrogen-inducible strain of yeast (Saccharomyces cerevisiae) expressing the human estrogen receptor and comparing their activity spectrophotometrically by the resulting color change of the medium. The results were compared to the effects of the main natural estrogen 17b-estradiol. The data indicate that both the position (para> meta> ortho) and branching (tertiary>secondary 5normal) of the alkyl group affect estrogenicity. Optimal estrogenic activity requires a single tertiary branched alkyl group composed of between 6 and 8 carbons located at the para position on an otherwise unhindered phenol ring. The results are discussed in relation to the purity and composition of the chemicals tested. In the early 1930s, scientists began synthesizing compounds based on the phenanthrene nucleus of steroidal estrogens in an attempt to produce substances with similar properties and considerable clinical value. Estrogenic activity was assessed by subcutaneous administration of chemicals (dissolved in sesame oil) to ovariectomized rats that were then observed for the onset of estrus (1). It soon became apparent that the phenanthrene condensed ring structure was not required for estrogenic activity, with the discovery that diphenyl and diphenyl methane derivatives (2) and stilbene derivatives (3‐6) containing two hydroxyl groups in the para positions (e.g. 4,49-dihydroxy diphenyl) were also active. The substituted derivative of stilbene (4,49-dihydroxystilbene) was renamed stilbestrol and was used as the parent compound in the production of another series of estrogenic compounds, including 4,49-dihydroxydiethylstilbene (later known as diethylstilbestrol), which is still one of the most potent man-made estrogens. During this period, the first references to active compounds containing only one benzene ring, such as para-hydroxy propenyl benzene (anol) (7) and some of the alkylphenolic compounds, are found (8). It seems that this information was long forgotten, until it recently resurfaced within the context of endocrine disruption.

This study documents the hepatic morphology and the ultrastructure of a model of hepatic fibrosis in rabbits. Rabbits were given a cholesterol-supplemented diet (1%), a stilbestrol diet (10 mg subcutaneously twice a week), or both treatments simultaneously for 7 weeks. Rabbits given the combined treatment developed sinusoidal and portal fibrosis with only a mild disturbance of acinar vascular relationships. Ultrastructurally, there was marked widening of the spaces of Disse by collagen fibers, basement membrane material adjacent to endothelial cells and hepatocytes, blunted hepatocellular microvilli, activated stellate cells, lipid droplets in endothelial cells and hepatocytes, and degranulated platelets in sinusoids. The hepatic hydroxyproline content was markedly increased (12.0 +/- 5.2 vs. 4.8 +/- 1.5 mmol/g of liver dry weight; P < .001). Plasma bile acids were markedly increased (222 +/- 180 vs. 12 +/- 5 in controls; P < .001). Dipyridamole (25 mg every 12 hours) that was given in addition to cholesterol and stilbestrol decreased the hepatic collagen content (-49% and -48%, in two experiments; P < .05 in both) and splenomegaly. This model provides a reliable method for the production of extensive sinusoidal fibrosis with capillarization of sinusoids. Hepatocellular degeneration is only mild to moderate, and fibrosis occurs slowly without the sudden pathological changes that occur with other models of hepatic fibrosis, such as with the administration of CCl4 or galactosamine. The mechanism of injury may involve the accumulation of bile salts or the generation of free radicals from cholesterol oxidation products. The possibility that the sinusoidal release of platelet-derived factors may have a role in the activation of stellate cells (lipocytes) is supported by the suppression of fibrogenesis by dipyridamole.

We assessed hepatic functions and systemic and splanchnic hemodynamics in a new model of hepatic sinusoidal fibrosis. Fibrosis was induced by the simultaneous administration for 8 weeks of diethyl-stilbestrol (DES) (10 mg twice weekly, subcutaneously) and cholesterol-supplemented diet (1%) in rabbits. A marked and progressive impairment of hepatic function was observed during the 8 weeks of treatment with a significant decrease in indocyanine green (ICG) systemic clearance (-89%; P.001) and aminopyrine elimination (-69%; P.001). In fibrotic animals, hyperdynamic circulation was found with an increased cardiac output (+73%, P0.01) and a decreased peripheral vascular resistance (-50%; P.005), as evaluated by the microsphere technique in animals that were awake. The total portal venous inflow was not significantly modified in fibrotic rabbits. However, since there was a marked increase in the liver weight, the portal venous inflow was significantly decreased when expressed per gram of liver weight (-30%; P.05). In contrast, the hepatic artery blood flow was markedly increased, even when expressed per gram of liver weight (+95%; P.01). Portal pressure was significantly increased in treated rabbits (from 7.4 +/- .4 to 14.4 +/- .6 mm Hg, P.01). This new experimental model could prove useful to evaluate the influence of extensive perisinusoidal fibrosis on exchanges between plasma and hepatocytes, particularly of protein-bound substances.