Diethylstilbestrol cis-trans isomerization and estrogen activity of diethylstilbestrol isomers.
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Anhydrides↗
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Results for “DIETHYLSTILBESTROL”
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Cyclodextrins as diethylstilbestrol carrier system: characterization of diethylstilbestrol-cyclodextrins complexes.
PURPOSE: The in vitro formation of DES-cyclodextrins inclusion complexes was characterized using lipoxygenase as enzymatic system. METHODS: DES-cyclodextrins complexes were obtained in aqueous solution. RESULTS: The addition of cyclodextrins to the reaction medium had an inhibitory effect on DES oxidation by lipoxygenase due to the drug's complexation into the cyclodextrin cavity. This inhibitory effect depends on the complexation constant between DES and the cyclodextrins type used. In this case, beta-, 2-hydroxypropyl-beta- and gamma-cyclodextrins have similar complexation constants and therefore produce the same inhibitory effect. Moreover, depending on the type of cyclodextrins used, the solubility of DES can be enhanced up to 956 times, while the lipoxygenase activity remains constant. CONCLUSIONS: These results suggest that the system described may be used as a controlled-release delivery system for DES, since it may diminish the local and systemic adverse side effects caused by high concentrations of the drug.
Cyclodextrins↗
Bioavailability, distribution and pharmacokinetics of diethylstilbestrol converted from diethylstilbestrol diphosphate in patients with prostatic cancer.
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Antineoplastic Agents↗
Gas chromatographic determination of diethylstilbestrol dimethyl ether in diethylstilbestrol.
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Chromatography, Gas↗
Gas-liquid chromatographic determination of diethylstilbestrol monomethyl ether in diethylstilbestrol.
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Alkalies↗
Inhibitory effect of diethylstilbestrol on histamine release by rat mast cells and its relation to the cellular ATP content.
The effect of diethylstilbestrol, a synthetic estrogen, on mast cell secretion was investigated. The results showed that 50 microM diethylstilbestrol inhibited histamine release from rat peritoneal mast cells in the presence and absence of glucose, but did not affect 45Ca uptake stimulated by concanavalin A. Diethylstilbestrol also inhibited histamine release induced by compound 48/80, exogenous ATP, or ionophore A23187. Since estradiol benzoate, hexestrol and daidzein were not inhibitory, the inhibitory action of diethylstilbestrol must be independent of its estrogenic activity. The ATP content of mast cells decreased to less than 0.1 nmol/10(6) cells on treatment with 50 microM diethylstilbestrol at 37 degrees C for 15 min. This effect of diethylstilbestrol in decreasing the ATP content of mast cells correlated well with its inhibitory effect on histamine release. Diethylstilbestrol at 50 microM depleted the cells of ATP at 37 degrees C, but not at 0 degrees C, whereas [3H]diethylstilbestrol ( [monoethyl-3H]diethylstilbestrol) binding to rat mast cells was the same at 0 and 37 degrees C. It is concluded that diethylstilbestrol reduced the ATP content of rat mast cells by inhibiting metabolism of the cells, and consequently inhibited degranulation.
Adenosine Triphosphate↗
Metabolism of diethylstilbestrol by horseradish peroxidase and prostaglandin-H synthase. Generation of a free radical intermediate and its interaction with glutathione.
Diethylstilbestrol is carcinogenic in rodents and in humans and its peroxidatic oxidation in utero has been associated with its carcinogenic activity. Horseradish peroxidase-catalyzed oxidation of [14C]diethylstilbestrol and [14C]diethylstilbestrol analogs induced binding of radiolabel to DNA only when the compound contained a free hydroxy group (Metzler, M., and Epe, B. (1984) Chem. Biol. Interact. 50, 351-360). We have found that horseradish peroxidase or prostaglandin-H synthase-catalyzed oxidation of diethylstilbestrol in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide caused the generation of an ESR signal indicative of a free radical intermediate (aN = 14.9 G, aH = 18.3 G). The identity of the trapped radical could not be identified on the basis of published hyperfine coupling constants, but the observation that horseradish peroxidase-catalyzed oxidation of 1-naphthol produced an identical ESR signal suggests that the radical was either a phenoxy or phenoxy-derived radical. During horseradish peroxidase-catalyzed oxidation of diethylstilbestrol in the presence of glutathione the thiol reduced the diethylstilbestrol radical to generate a thiyl radical. This was shown by a thiol-dependent oxygen uptake during horseradish peroxidase-catalyzed oxidation of diethylstilbestrol and the observation of an ESR signal consistent with 5,5-dimethylpyrroline-N-oxide-glutathionyl radical adduct formation. A diethylstilbestrol analog devoid of free hydroxy groups, namely diethylstilbestrol dipropionate, did not produce an ESR signal above control levels during horseradish peroxidase-catalyzed metabolism in the presence of 5,5-dimethylpyrroline-N-oxide. Thus, free radicals are formed during peroxidatic oxidation of diethylstilbestrol and must be considered as possible determinants of the genotoxic activity of this compound.
Carbon Radioisotopes↗
Analysis of diethylstilbestrol, dienestrol and hexestrol in biological samples by immunoaffinity extraction and gas chromatography-negative-ion chemical ionization mass spectrometry.
A method has been developed for the detection of diethylstilbestrol, together with dienestrol and hexestrol, using extraction with a single immunoaffinity column containing antibodies raised against diethylstilbestrol, followed by gas chromatography-negative-ion chemical ionization mass spectrometry. Immunoaffinity columns were prepared by coupling immunoglobulin G fractions obtained from rabbit antisera with a Sepharose matrix. The immunizing agent was synthesized by introducing a carboxyl group into the diethylstilbestrol molecule and coupling this product to bovine serum albumin. The columns were used for immunoadsorption of diethylstilbestrol and other estrogens, after dilution of samples with phosphate buffer, and were eluted with acetone-water (95:5 v/v). A derivatization method suitable for gas chromatographic-mass spectrometric analysis of diethylstilbestrol and other estrogens was developed using pentafluorobenzyl bromide and ethanolic potassium hydroxide as reagents. The derivatives obtained were detectable at the sub-picogram level using gas chromatography with negative-ion chemical ionization mass spectrometry. Recoveries of cis- and trans-diethylstilbestrol, dienestrol and hexestrol from the immunoaffinity columns, determined after extraction from urine, plasma and buffer, ranged from 28 to 96%. The sensitivity for diethylstilbestrol in urine samples was ca. 10 ppt. The method was applied to the analysis of urine from calves given a single dose of 10 mg of diethylstilbestrol. Free and glucuronic acid conjugated diethylstilbestrol decreased with time, but their ratio was variable.
Animals↗
Fertility in men exposed prenatally to diethylstilbestrol.
BACKGROUND: Prenatal exposure to diethylstilbestrol causes infertility in male mice and has been associated with malformations of the genital tract in men. However, little is known about the fertility of men who have been exposed prenatally to diethylstilbestrol. METHODS: In 1950 through 1952, 1646 pregnant women were enrolled in a randomized, placebo-controlled clinical trial of diethylstilbestrol at Chicago Lying-in Hospital. We interviewed men who were born to the women during that study about their fertility. RESULTS: Four decades after their birth, we were able to trace 548 of the surviving sons (68 percent). Ninety percent consented to be interviewed (253 who had been exposed to diethylstilbestrol in utero and 241 who had not been exposed). Congenital malformations of the genitalia were reported three times as often by the diethylstilbestrol-exposed men as by the sons of the women in the placebo group. Within the exposed group, malformations were reported twice as often among those exposed to diethylstilbestrol before the 11th week of gestation as among those exposed later (P = 0.05). Men with genital malformations were nonetheless as fertile as other men. The diethylstilbestrol-exposed men (with or without genital malformations) had no impairment of fertility by any measure, including whether they had ever impregnated a women, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception in the most recent pregnancy of the female partner. Finally, diethylstilbestrol-exposed men had no impairment of sexual function, as indicated, for example, by the frequency of intercourse or reported episodes of decreased libido. CONCLUSIONS: High doses of diethylstilbestrol did not lead to impairment of fertility or sexual function in adult men who had been exposed to the drug in utero.
Abnormalities, Drug-Induced↗
Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment.
Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 microg/pup/d) or tamoxifen (10 microg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor-alpha (ER-alpha) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-alpha expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers.
Animals↗
Biliary excretion of diethylstilbestrol in the rhesus monkey.
The biliary excretion of diethylstilbestrol in the bile fistula rhesus monkey was investigated during exogenous taurocholate- and taurodehydrocholate-induced choleresis. Following intravenous administration, 36% of the dose was excreted into the bile (as diethylstilbestrol monoglucuronide) and 53% in the urine (as diethylstilbestrol monoglucuronide plus more polar unidentified metabolites). During the steady-state infusion of diethylstilbestrol, with taurocholate-induced choleresis, a bile flow dependent transport for the biliary excretion of diethylstilbestrol monoglucuronide was observed. Evidence for carrier-mediated transport of this metabolite was a bile-to-blood concentration ratio which ranged from 228 to 279 during steady-state experiments. In vitro experiments indicated that diethylstilbestrol monoglucuronide forms an association with taurocholate, as well as the micellar structures of bile, resulting in a severalfold enhancement of solubility above that in aqueous buffer alone. Taurodehydrocholate, a non-micelle-forming bile salt, did not interact with this metabolite and had no effect on its solubility. Substitution of taurodehydrocholate for taurocholate during the steady-state infusion of diethylstilbestrol produced no significant changes in the transport of diethylstilbestrol monoglucuronide from blood to bile.
Animals↗
Mechanisms of diethylstilbestrol-induced relaxation in rat aorta smooth muscle.
The mechanisms of diethylstilbestrol (1 to 30 microM)-induced relaxation on noradrenaline (30 nM)-raised tone in the rat aorta smooth muscle were studied. Neither the increase of calcium content in the medium (3, 6 and 9 mM) nor Bay K 8644 (3, 10 and 100 nM) reversed diethylstilbestrol relaxation. Tamoxifen (3 microM), the quaternary derivate (tamoxifen ethyl bromide, 3 microM), actinomycin D (30 microM), cycloheximide (100 microM), Rp-cAMPS (30 microM), TPCK (1 microM) and difluoromethylornithine (1 mM) inhibited diethylstilbestrol-induced relaxation. Incubation with 2 microg/ml pertussis toxin, propranolol (1 microM), H-7 (10 microM), 2',3'- and 2',5'-dideoxiadenosine (10 and 30 microM, respectively) and methylene blue (10 microM) did not modify diethylstilbestrol-induced relaxation. Our results showed that presumably an activation of membrane mechanisms, protein kinase A activation, genomic mechanisms and polyamine synthesis might participate in diethylstilbestrol-elicited relaxation in addition to the increase in K(ATP) permeability, as previously described. Actinomycin D produces a synergistic effect, with tamoxifen, difluoromethylornithine and glibenclamide antagonizing the effect of diethylstilbestrol. In the case of the association of actinomycin D and glibenclamide, the antagonism of relaxation is complete. The fact that tamoxifen- and difluoromethylornithine-dependent mechanisms participate in diethylstilbestrol relaxation inhibited by glibenclamide suggests that two transduction pathways are involved in the relaxation. Therefore, K(ATP) channels and genomic mechanisms, both modulated by cyclic AMP (cAMP)-dependent mechanisms, are associated with diethylstilbestrol relaxation.
Animals↗
Neonatal diethylstilbestrol alters blood pressure and CNS drinking response in SHR and WKY rats.
Neonatal SHR and WKY rats were treated with diethylstilbestrol or propylene glycol (controls). Control SHR had higher blood pressures than WKY rats. Neonatal diethylstilbestrol treatment delayed the onset and full expression of hypertension in the male SHR but had no effect on blood pressure in the other animals. Neonatal diethylstilbestrol treatment had an adverse effect on body weights of male SHR and WKY rats through 98 days of age (not statistically decreased thereafter). Adult female SHR and WKY rats treated neonatally with diethylstilbestrol had body weights significantly greater than the control females. Neonatal treatment with diethylstilbestrol resulted in precocious puberty in female SHR and WKY rats. Control female SHR and WKY rats and female SHR treated neonatally with diethylstilbestrol had attenuated angiotensin - II induced drinking response from the central administration of estrogen in adulthood. The angiotensin II - induced drinking response was not significantly attenuated by central estrogen in adult WKY females exposed neonatally to diethylstilbestrol. Neonatal diethylstilbestrol treatment of WKY female rats appears to have altered neuroendocrine secretions that control CNS drinking behavior.
Angiotensin II↗
Diethylstilbestrol exposure.
Diethylstilbestrol is a synthetic nonsteroidal estrogen that was used to prevent miscarriage and other pregnancy complications between 1938 and 1971 in the United States. In 1971, the U.S. Food and Drug Administration issued a warning about the use of diethylstilbestrol during pregnancy after a relationship between exposure to this synthetic estrogen and the development of clear cell adenocarcinoma of the vagina and cervix was found in young women whose mothers had taken diethylstilbestrol while they were pregnant. Although diethylstilbestrol has not been given to pregnant women in the United States for more than 30 years, its effects continue to be seen. Women who took diethylstilbestrol during pregnancy have a slightly higher risk of breast cancer than the general population and therefore should be encouraged to have regular mammography. Women who were exposed to diethylstilbestrol in utero may have structural reproductive tract anomalies, an increased infertility rate, and poor pregnancy outcomes. However, the majority of these women have been able to deliver successfully. Recommendations for gynecologic examinations include vaginal and cervical digital palpation, which may provide the only evidence of clear cell adenocarcinoma. Initial colposcopic examination should be considered; if the findings are abnormal, colposcopy should be repeated annually. If the initial colposcopic examination is normal, annual cervical and vaginal cytology is recommended. Because of the higher risk of spontaneous abortion, ectopic pregnancy, and preterm delivery, obstetric consultation may be required for pregnant women who had in utero diethylstilbestrol exposure. The male offspring of women who took diethylstilbestrol during pregnancy have an increased incidence of genital abnormalities and a possibly increased risk of prostate and testicular cancer. Routine prostate cancer screening and testicular self-examination should be encouraged.
Breast Neoplasms↗
Oestrogen supplementation, mainly diethylstilbestrol, for preventing miscarriages and other adverse pregnancy outcomes.
BACKGROUND: Laboratory evidence in the 1940s demonstrated a positive role of placental hormones in the continuation of pregnancy. It was suggested that diethylstilbestrol was the oestrogen of choice for prevention of miscarriages. Observational studies were carried out with apparently positive results, on which clinical practice was based. This led to a worldwide usage of diethylstilbestrol despite controlled studies with contrary findings. OBJECTIVES: To determine the effects of antenatal administration of oestrogens, mainly diethylstilbestrol, on high risk and unselected pregnancy as regards miscarriages and other outcomes. SEARCH STRATEGY: We searched the Pregnancy and Childbirth Group Specialised Register of controlled trials in November 2002. SELECTION CRITERIA: Randomised and quasi-randomised trials were included. DATA COLLECTION AND ANALYSIS: Both reviewers extracted data from the studies identified that met the selection criteria, and the data were analysed using the RevMan software. MAIN RESULTS: Miscarriage, preterm labour, low birthweight and stillbirth or neonatal death were not positively influenced by the intervention (diethylstilbestrol) as compared to the control group. Diethylstilbestrol in utero exposure led to increased rate of miscarriage and preterm birth. There was also an increase in the numbers of babies weighing less than 2500 grams. The maternal outcome in terms of pre-eclampsia was not influenced. Exposed female offsprings have a non-significant trend towards more cancer of the genital tract and cancer other than of the genital tract. Primary infertility, adenosis of the vagina/cervix in female offsprings, and testicular abnormality in male offsprings were significantly higher in those exposed to diethylstilbestrol before birth. REVIEWER'S CONCLUSIONS: There was no benefit with the use of diethylstilbestrol in preventing miscarriages. Both short and long-term adverse outcomes in exposed offsprings were demonstration of the harm that this intervention caused women and their offspring during its usage.
Abortion, Spontaneous↗
Effect of ovarian steroids and diethylstilbestrol on the contractile responses of the human myometrium and intramyometrial arteries.
Estriol, estradiol, progesterone and diethylstilbestrol in the concentration range of 0.2-40 microM inhibited the spontaneous contractions of the myometrium in a dose-dependent manner but the differences in IC50 values obtained with different hormones were not statistically significant. All these hormones caused a concentration-dependent inhibition of the K(+)-induced contraction. The IC50 values were lowest for diethylstilbestrol and highest for estriol. Vasopressin at concentrations of 1.5 x 10(-6) - 1.8 x 10(-3) U/ml stimulated myometrial contractions. These responses were also inhibited by ovarian steroids and diethylstilbestrol. The IC50 values for estriol and progesterone were significantly higher than for estradiol or diethylstilbestrol. The values for estriol and progesterone did not differ significantly. In the uterine arteries, which lacked spontaneous activity, ovarian steroids and diethylstilbestrol inhibited contractions induced by K+ depolarization. As with myometrium, the lowest effect was observed with estriol and the highest with diethylstilbestrol. A dose-dependent inhibition by all four hormones (0.2-40 microM) of vasopressin-induced contractile responses of the uterine arteries was observed. With the lowest concentration of progesterone, however, the arterial response to vasopressin was enhanced. The increases by progesterone (0.02 and 0.2 microM) of responses induced by vasopressin were statistically significant (P < 0.05). The present data strongly suggest that, in human myometrium and uterine arteries, ovarian steroids and diethylstilbestrol cause a more pronounced inhibition of receptor-mediated than of voltage-dependent Ca2+ channels. The increase by a very low (physiological) concentration of progesterone of vasopressin-induced responses in both myometrium and arteries may be of significance in the pathophysiology of dysmenorrhea.
Arteries↗
Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero.
The in utero effects of diethylstilbestrol on the human male genital tract are reported in our followup study of male offspring of mothers treated with diethylstilbestrol. Anatomical and functional abnormalities were significantly greater in male patients exposed to diethylstilbestrol compared to male controls whose mothers were all participants in a prospective, randomized double-blind study on the effects of diethylstilbestrol on pregnancy at our hospital during the early 1950s. Epididymal cysts, hypotrophic testes and capsular induration of the testes were among the more common genital lesions found in more than 25 per cent of 159 male patients exposed to diethylstilbestrol compared to a 6.8 per cent incidence in 161 male controls. Spermatozoal analysis revealed severe pathological changes (Eliasson score more than 10) in 32 per cent of 31 patients exposed to diethylstilbestrol and 0 per cent of 20 male controls. Abnormal findings on physical examination combined with severe sperm abnormalities (Eliasson score more than 10) were found in 23 per cent of the male patients exposed to diethylstilbestrol versus none of the male controls. Cytologic examinations revealed no malignant cells from urine samples before and after prostatic massage or ejaculation, prostatic fluids and aspirates from epididymal cysts.
Abnormalities, Drug-Induced↗
Prenatal exposure to diethylstilbestrol decreases the number of estrogen receptor alpha-containing neurons innervating the ovary in rat celiac ganglion.
Recently, we reported that, in rats, transplacental exposure to diethylstilbestrol, a potent synthetic estrogen, decreases the density of the ovarian sympathetic nerve network compared to that in control rats not exposed to diethylstilbestrol. To clarify the mechanism of the decrease in the density, we performed a series of experiments using rats prenatally exposed to diethylstilbestrol and unexposed control rats. First, a retrograde tract tracer, Fast Blue, was microinjected into the ovaries of both groups of rats at four months of age, and the number of Fast Blue-positive neurons in the celiac ganglion was counted. The number of neurons in the ganglion was smaller in diethylstilbestrol-exposed rats than in the controls. Second, double labeling of the neurons with antibody against estrogen receptor alpha and Fast Blue in the celiac ganglion was carried out in both groups of rats. The results showed that estrogen receptor alpha-containing neurons in the ganglion innervated the ovary, and their number was decreased selectively by prenatal diethylstilbestrol exposure. Finally, a decrease in the celiac ganglion volume in rats prenatally exposed to diethylstilbestrol was also detected on day 23 of gestation, as compared to the volume in the control rats. From these observations, we propose that prenatal exposure to diethylstilbestrol can induce a loss of estrogen receptor alpha-containing neurons innervating the ovary during development, resulting in paucity of the neural network in the ovary.
Amidines↗