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PubMed1990

Association of hepatocellular carcinoma and a hyperplastic nodule after phosphate diethylstilbestrol therapy.

We treated a patient in whom a hepatocellular carcinoma and a hyperplastic nodule of the liver concomitantly grew in association with long term phosphate diethylstilbestrol therapy for a carcinoma of the prostate. A 72-year-old Japanese man was admitted for investigation of hepatic masses. A diagnosis of prostate carcinoma had been made seven years ago and phosphate diethylstilbestrol 200 mg daily had been prescribed. A small mass was first detected in the liver four years later and another mass appeared three years after the appearance of the first mass. Histology of the excised tissue showed the former mass to be a hyperplastic nodule and the latter one hepatocellular carcinoma. Findings of cirrhosis, hepatitis or fibrosis were nil but fatty metamorphosis of the hepatocytes was apparent. These histological changes were considered to be associated with long-term phosphate diethylstilbestrol therapy therefore careful follow-up using amazing diagnosis is recommended for patients on phosphate diethylstilbestrol therapy.

Aged↗

PubMed2001

Effects of diethylstilbestrol on the cytogenesis of prolactin cells in the pars distalis of the pituitary gland of the mouse.

This study was carried out to examine the developmental stage when prolactin cells differentiate in mice and to examine the effects of diethylstilbestrol on the development of prolactin cells in the fetal and neonatal pituitary glands. A small number of immunoreactive prolactin cells appeared first on embryonic day 15 in control (injected with oil) pituitary glands, whereas they did not increase in number until postnatal day 2. In diethylstilbestrol-treated mice (5 mg/kg body weight, 24 h before killing), a small number of immunoreactive prolactin cells were detectable as early as embryonic day 14, but not on day 13. They increased in number on embryonic days 15 and 16, and decreased markedly on days 17 and 18, followed by a rapid increase after birth. This transient reduction in the response to diethylstilbestrol was partially restored by treatment with metyrapone, a specific inhibitor of corticosteroid production. These results suggest that in the mouse: (1) differentiation of prolactin cells occurs between embryonic days 13 and 14, (2) prolactin gene expression is suppressed in the nascent prolactin cells presumably due to the presence of high levels of estrogen-binding protein, alpha-fetoprotein, and (3) prolactin gene expression is also suppressed by elevation of circulating glucocorticoids during the perinatal period. The present results suggest that, in the mouse, at least a proportion of prolactin cells are not derived from growth hormone cells, because the diethylstilbestrol-induced prolactin cells appear earlier than growth hormone gene expression.

Animals↗

PubMed1989

Colposcopic findings and intraepithelial neoplasia in diethylstilbestrol-exposed offspring. The Dutch experience.

Data from two regional diethylstilbestrol clinics for colposcopic evaluation of young women with a history of diethylstilbestrol exposure in utero are presented: A total of 224 subjects with a well-documented history were enrolled in this study. Structural anomalies of the cervix and vagina were found in 30%. Vaginal epithelial changes were colposcopically observed in 65%, including vaginal adenosis in 22%. The prevalence rate of abnormal cytologic findings in the study group was 9%. In half of these patients a low-grade intraepithelial neoplasia of the cervix and vagina was found. It was concluded that colposcopy in diethylstilbestrol-exposed offspring in inexperienced hands can result in many unnecessary biopsies. Therefore colposcopic examination should be performed by expert colposcopists in referral diethylstilbestrol centers.

Adult↗

PubMed1982

Diethylstilbestrol treatment increases the amount of choline kinase in rooster liver.

Studies have been performed on the mechanism by which diethylstilbestrol stimulates the activity of choline kinase in livers from cockerels. The enzyme was purified 700-900-fold by affinity chromatography. The increased enzyme activity could not be accounted for by diethylstilbestrol alteration of the kinetic constants of the enzyme. Rabbit antibody was raised to the purified enzyme. Titration studies with antiserum demonstrated a 2-fold increase in the amount of choline kinase in diethylstilbestrol-treated cytosol, which correlated with a 2-fold elevation of the activity of the enzyme. We conclude that diethylstilbestrol stimulates the activities of choline kinase in cockerel liver by corresponding increase in the amount of enzyme.

Animals↗

PubMed1979

Diethylstilbestrol and 11 derivatives: a mutagenicity study with Salmonella typhimurium.

Diethylstilbestrol was tested for mutagenicity with his- S. typhimurium strains under 10 different matabolic situations (no exogenous metabolizing system; S9 mix from liver homogenate of rats induced with Aroclor 1254, with or without inhibition of epoxide hydratase; liver and/or kidney S9 mix from control or hamsters treated with Aroclor 1254; horse-radish peroxidase + H2O2). Under none of these conditions did diethylstilbestrol give any indication of a mutagenic effect. Furthermore, 11 metabolites and other derivatives of diethylstilbestrol, 2 of them potent inducers of sister-chromatid exchange in cultured fibroblasts, were not mutagenic with any of the 4 tester strains (S. typhimurium TA100, TA98, TA1537, TA1535) in the presence or absence of S9 mix from liver homogenate of rats induced with Aroclor 1254. Thus, one of the few known human carcinogens is very resistant to detection by the mammalian enzyme-mediated Salmonella typhimurium mutagenicity test (Ames test). This is especially remarkable since the metabolizing systems used included: (1) some of very high metabolic activity (S9 mix from liver homogenate of rats and hamsters induced with Aroclor 1254); (2) metabolizing systems from organs susceptible to the carcinogenic activity of diethylstilbestrol (hamster kidney); as well as (3) a mixture of (1) and (2) in case both activities are required for the carcinogenic effect in the whole animal.

Diethylstilbestrol↗

PubMed1986

Determination of the distribution of fatty acids and diethylstilbestrol between serum albumin and alpha-fetoprotein by concanavalin A affinity chromatography.

The distribution of fatty acids and diethylstilbestrol between serum albumin and alpha-fetoprotein was measured in vitro by a new method based on the separation of the two proteins by virtue of the binding specificity of concanavalin A for the carbohydrate moiety of alpha-fetoprotein. Human and bovine proteins were investigated. It was found that palmitate and oleate were distributed almost equally between albumin and alpha-fetoprotein, while docosahexaenoate and diethylstilbestrol bound preferentially to alpha-fetoprotein even at an albumin: alpha-fetoprotein ratio of 10:1. The results confirm the binding specificity of alpha-fetoprotein for polyunsaturated fatty acids and also show that alpha-fetoprotein binds diethylstilbestrol much more strongly than albumin does. This suggests that alpha-fetoprotein may play a role in the fetal uptake of diethylstilbestrol.

Animals↗

PubMed1988

Clear cell adenocarcinoma of the vagina and cervix: incidence, undetected disease, and diethylstilbestrol.

We conducted an incidence study to determine the occurrence rates of clear cell adenocarcinoma (CCAC) of the vagina and cervix in young women (born in 1940 and thereafter), and a case-series analysis, focusing on the maternal history of pregnancy and delivery and in-utero exposure to diethylstilbestrol (DES). Overall, 10 cases of CCAC had been listed in the files of the Connecticut State Tumor Registry prior to the study, and each of the 10 cases were confirmed as valid. In addition, another 10 cases, all previously undetected, were found after the tissue slides of young women listed as having other cancers of the vagina and cervix were reviewed by expert pathologists, suggesting that prior estimates of the incidence rate for CCAC must be misleading unless special efforts are taken to identify undetected cases. The incidence rates of vaginal CCAC (11 cases total) were highest in 1975-1979, and decreased slightly during 1980-1982. In the cervix (nine cases total), the rate increased consistently since 1970. History of in-utero exposure to diethylstilbestrol was obtained for five of eight vaginal cases and four of eight cervical cases of CCAC. In all nine cases, exposure to diethylstilbestrol was associated with a history of bleeding during the pregnancy or prior miscarriage. We conclude that the finding of stable (or rising) incidence rates for CCAC occurring nearly 30 years after the marked decrease in diethylstilbestrol sales emphasizes the need for continued clinical and epidemiologic studies of the etiology and clinical course of CCAC.

Abortion, Spontaneous↗

PubMed2001

Involvement of K(ATP) channels in diethylstilbestrol-induced relaxation in rat aorta.

The estrogens prevent cardiovascular diseases that among other effects could be related to the modulation of the vascular tone via modifying ionic channel permeability. ATP-sensitive K(+) (K(ATP)) channels seem to be involved in diethylstilbestrol-induced relaxation in isolated rat aorta precontracted by noradrenaline (30 nM), since the effect is inhibited by glibenclamide (1--10 microM), and 1 mM tetraethylammonium, but not by 30 mM tetraethylammonium or paxilline. The antiestrogen tamoxifen, the inhibitor of protein kinase A, Rp-cAMPS, and the inhibitor of ornithine decarboxylase, difluoromethylornithine, antagonized diethylstilbestrol-induced relaxation. The association of glibenclamide with these compounds separately did not modify the effect of glibenclamide alone on diethylstilbestrol-induced relaxation. Functional K(ATP) channels are present in rat aorta, since diazoxide induced relaxation sensitive to glibenclamide. Papaverine, dibutyryl cyclic AMP and spermine relaxed isolated rat aorta although this was not sensitive to glibenclamide. The relaxation to forskolin was antagonized by glibenclamide. We conclude that diethylstilbestrol-induced relaxation in rat aorta is related to the modulation of K(ATP) channels. Cyclic AMP-dependent mechanisms and polyamine synthesis may mediate this modulation.

Animals↗

PubMed1986

Comparison of diethylstilbestrol, cyproterone acetate and medroxyprogesterone acetate in the treatment of advanced prostatic cancer: final analysis of a randomized phase III trial of the European Organization for Research on Treatment of Cancer Urological Group.

Patients with previously untreated category T3 to T4 Mo or Ml prostatic cancer were allocated randomly to receive 250 mg. cyproterone acetate per day, a loading dose of 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks followed by 100 mg. orally twice daily, or 1 mg. diethylstilbestrol 3 times daily in a phase III trial (protocol 30761) performed by the genitourinary tract cooperative group of the European Organization for Research on the Treatment of Cancer. Of 236 patients entered 210 were eligible: 75 received cyproterone acetate, 71 medroxyprogesterone acetate and 64 diethylstilbestrol. Local and distant tumor response, time to progression, survival and toxicity were assessed. Patients treated with medroxyprogesterone acetate had a less favorable course with a shorter duration of survival and time to progression than those treated with the other 2 drugs. There was no significant difference between diethylstilbestrol and cyproterone acetate. Cardiovascular side effects were reported more often in patients treated with diethylstilbestrol than in those treated with cyproterone acetate but severe and lethal cardiovascular toxicity was relatively low in all groups. Other side effects were negligible. Further studies are required to establish the influence of effective hormonal treatment upon survival.

Aged↗

PubMed1987

Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix. An update.

We reviewed 519 cases of clear-cell adenocarcinoma of the vagina and cervix identified by the Registry for Research on Hormonal Transplacental Carcinogenesis of the University of Chicago through June 30, 1985. In 60 percent of all cases the patient's mother had received diethylstilbestrol during pregnancy. An additional 12 percent of all mothers had been treated with another hormone or with an unidentified medication. Ninety-one percent of the cases in diethylstilbestrol-exposed women were diagnosed when the patient was between the ages of 15 and 27. The median age at diagnosis was 19.0 years. The risk that clear-cell adenocarcinoma will develop in an exposed female from birth through age 34 is 1 case per 1000 women. The temporal pattern of occurrence of clear-cell adenocarcinoma corresponds closely with that of the use of diethylstilbestrol for pregnancy support in the United States. The rarity of this tumor among exposed women suggests that diethylstilbestrol is not a complete carcinogen and that some other factor is also involved in the pathogenesis of clear-cell adenocarcinoma of the vagina and cervix.

Adenocarcinoma↗

PubMed1991

Vitamin C reduces the incidence and severity of renal tumors induced by estradiol or diethylstilbestrol.

The chronic administration of estradiol or diethylstilbestrol to male Syrian hamsters induces kidney tumors. The effect of vitamin C treatment on estrogen-induced carcinogenesis has been studied to elucidate the mechanism of tumor induction by estrogen. Vitamin C decreases the tumor incidence by approximately 50% but does not influence hormone-dependent growth of kidney tumors. Moreover, vitamin C lowers the concentration of diethylstilbestrol-4',4"-quinone, the genotoxic metabolite of diethylstilbestrol, in vitro and in Syrian hamsters treated with stilbene. Vitamin C also decreases the levels in hamsters of diethylstilbestrol-DNA adducts formed by the quinone metabolite. Estrogens may thus initiate tumors by their metabolic oxidation to corresponding quinone metabolites, which bind covalently to cellular macromolecules. Vitamin C may inhibit tumorigenesis by decreasing concentrations of quinone metabolites and their DNA adducts. Lowering quinone metabolite concentrations may also inhibit free radical generation by decreasing redox cycling between estrogens and their corresponding quinones.

Animals↗

PubMed1970

Interaction of staphylococcal alpha toxin and the estrogenic hormone diethylstilbestrol.

Previous work in this laboratory showed that diethylstilbestrol was capable of suppressing induced furunculosis in rabbits. The present study indicates that the synthetic estrogenic hormone diethylstilbestrol which is used for acne, estrogen deficiency, cancer, and other disorders, can reduce the cytolytic action of staphylococcal alpha toxin. The cytotoxic action of purified alpha toxin for tissue cultures was evaluated by use of such parameters as total and viable cell counts, glucose, and protein determination, and cytopathic effects (CPE) in the presence and absence of steroids. To 3-day-old primary rabbit baby kidney tissue cultures, 1 to 5 mug of diethylstilbestrol per ml was added; growth of tissue cultures in Eagles medium was continued till the 6th day, and then one tissue cytopathic dose per milliliter of alpha toxin was added, and the subsequent fate of tissue cultures was assayed. Such cultures yielded higher total and viable cell counts, utilized more glucose, and contained more protein than the control cultures. In control cultures, CPE was observed on the 3rd hr after the addition of alpha toxin, and it was complete in 24 hr, whereas in tissue cultures treated with diethylstilbestrol, the CPE was significantly reduced. The data presented in this study made possible the availability of a suppressor of the cytolytic action of alpha toxin and might be useful in assaying the action of alpha toxin in an in vitro inexpensive test system.

Animals↗

PubMed1995

Effects of some diethylstilbestrol metabolites and analogs on cytotoxicity and aneuploidy induction in Chinese hamster V79 cells.

We have previously reported the inhibitory effects of diethylstilbestrol (1) and optically active indenestrol derivatives on microtubule polymerization in vitro and their disruptive effect on cytoplasmic microtubules and cytotoxicity in cultured Chinese hamster V79 cells. In the present study, the cytotoxicities of (+-)-diethylstilbestrol oxide (2), (+)-, (-)- and (+-)-monomethyl ethers (4) of 2, (+-)-dimethyl ether (5) of 2, diethylstilbestrol pinacolone (3), E,E-dienestrol (6), Z,Z-dienestrol (7), meso-hexestrol (8), a mixture of (1R,1'S)4-hydroxyhexestrol and (1R,1'S)4'-hydroxyhexestrol (9), and the 4-hydroxy derivative (10) of diethylstilbestrol dimethyl ether were investigated in Chinese hamster V79 cells. The results indicated that the cytotoxic activity of 10 was the strongest of the compounds tested, although its activity was the almost same as that of 1. Moreover, as the activity of (-)-4 was greater than those of 2 and 1 monomethyl ethers, the effect of 4 on cytotoxic activities was elucidated. In conclusion, the present results indicate that the cytotoxic activities of hydroxylated metabolites are greater than those of each mother compound, although epoxidation of 1 leads to a product which can be broken down more readily than the parent compound.

Aneuploidy↗

PubMed1989

Mechanism of genotoxicity of diethylstilbestrol in vivo.

Diethylstilbestrol (DES) is a carcinogen in humans and rodents which has eluded mechanistic clarification of its carcinogenic action. In vitro and in vivo, binding of DES to DNA has been found previously, but covalent DNA adducts could not be identified. In this study, the nature of binding was investigated by 32P-postlabeling, a rapid and highly sensitive assay for covalent DNA damage, to distinguish between a genotoxic or epigenetic mechanism of carcinogenesis by DES. A unique and distinct DNA adduct pattern was observed in kidney, liver, uterus (or testes) of female (or male, respectively) Syrian hamsters treated with a single injection of DES (200 mg/kg body weight). This set of DNA adducts closely matched patterns generated in vitro by reaction of diethylstilbestrol-4',4''-quinone with DNA or 2'-deoxyguanosine 3'-monophosphate. The major and several minor DES-DNA adducts in vivo had identical chromatographic mobilities in 11 different solvent systems with corresponding adducts obtained in vitro. The major adduct spot, generated in vitro by reaction of diethylstilbestrol-4',4''-quinone and DNA, was chemically unstable (half-life at 37 degrees C: 4-5 days). The persistence in vivo of these DNA modifications was low (biological half-life: 14 h) presumably because of chemical instability in concert with DNA repair. After injection of identical dosages of DES, adduct concentrations were 4-6-fold higher in females than in males. These results demonstrate that DES is capable of covalently modifying DNA. Moreover, diethylstilbestrol-4',4"-quinone is the major reactive metabolic intermediate responsible for the genotoxic activity of DES. Tumors are expected to arise only in rapidly dividing cells due to the short biological lifetimes of DES-DNA adducts.

Animals↗

PubMed1985

Effects of pergolide on diethylstilbestrol-induced rat pituitary hyperplasia.

Hyperplastic anterior pituitary glands were produced in female rats by treatment with 10 mg of diethylstilbestrol in Silastic tubing. This led to increased numbers of immunoreactive prolactin cells and increased serum prolactin levels. After 6 weeks of diethylstilbestrol treatment, one group of rats was treated with daily injections of pergolide for 3 weeks. Pergolide produced a significant decrease in pituitary gland weight and in serum prolactin levels but did not change the percentage of prolactin cells significantly, compared with that of control rats. Ultrastructural studies showed a significant increase in the numbers of prolactin secretory granules and numerous large intracellular bodies with associated secretory granules in pituitaries from rats treated with pergolide. In one group of rats in which the diethylstilbestrol was discontinued for 3 weeks after 6 weeks of treatment there was a significant decrease in pituitary gland weight and serum prolactin and a significant decrease in the percentage of prolactin cells, compared with values in the rats treated with diethylstilbestrol for 9 weeks. These results indicate that pergolide causes decreased release of prolactin from secretory granules in anterior pituitary prolactin cells and an increase in the numbers of PRL secretory granules per cell but does not change the percentage of prolactin-producing pituitary cells after 3 weeks of treatment.

Animals↗

PubMedDate not supplied

[Mechanism of radioresistance of the hematopoietic system after treatment with diethylstilbestrol].

The effect of diethylstilbestrol on the hematopoietic system of intact animals and on dynamics of post-radiation hematopoiesis recovery was studied. The injection of diethylstilbestrol into unirradiated animals was shown to induce the decrease in CFUs and CFU-GM content in bone marrow, the increase in granulocyte-macrophage precursors number in spleen, the decrease in proliferative activity of hematopoietic precursor cells and the rise of CSF-GM levels in the sera at the period of optimal manifestation of radioprotective effect. Mice, which were protected by diethylstilbestrol, demonstrated much more powerful recovery of CFUs, CFU-GM numbers as well as myeloid and erythroid hematopoiesis series in comparison with irradiated control animals. It seems that radioprotective action of diethylstilbestrol is provided by the initial decrease of amount of early hematopoietic precursor cells as a result of suppression of their proliferative activity that causes the increase of endogenous growth and differentiation factors levels, which induce the changes in proliferation and differentiation of hematopoietic stem cells, providing the intensification of post-radiation hematopoiesis recovery.

Animals↗

PubMed1995

Effect of diethylstilbestrol or zeranol on fetal development, gestation duration, and number of offspring in NMRI mice.

OBJECTIVE: To evaluate the effects of diethylstilbestrol (DES) or alpha-zearalanol (zeranol) on fetal development, gestation duration, and number of offspring. DESIGN: Study effects of prenatal administration of DES or zeranol on various pre- and perinatal variables in an experimental group of mice, compared with effects in a control group. ANIMALS: Pregnant NMRI mice. PROCEDURE: Diethylstilbestrol or zeranol (150 mg/kg of body weight) or vehicle (controls) was administered SC to pregnant mice on days 9 and 10 of gestation. Fetuses from pregnant mice of each group were counted and weighed, and their size and head length were recorded. Additional pregnant mice delivered their fetuses naturally, and pups from each group were counted and their sex was determined. At the end of gestation, abortions were evaluated. All data were statistically analyzed. RESULTS: Mean number of fetuses was significantly lower (P < 0.0001) in DES-treated (4.59 +/- 0.48) than in control mice (8.33 +/- 0.49). Both estrogenic substances significantly reduced fetal size and weight (P < 0.0001), compared with control mice. Diethylstilbestrol significantly increased abortion frequency (P < 0.0001) and gestation duration (P < 0.0001), compared with values for control mice. A reduced number of live pups (P < 0.0001) from pregnant mice administered DES (5.48 +/- 0.38) or zeranol (5.97 +/- 0.49) was observed, compared with control mice (8.52 +/- 0.50), because of reduced number of male offspring (P < 0.0001). CONCLUSIONS: Diethylstilbestrol or zeranol administered during mid-pregnancy leads to decreased fetal weight and size and lower numbers of male offspring at birth. Likewise, DES induced a significant increase in abortions and gestation duration.

Animals↗

PubMed1977

Male genitourinary abnormalities and maternal diethylstilbestrol.

In view of the risk of vaginal cancer developing in young female subjects exposed in utero to maternally ingested diethylstilbestrol a pilot study was undertaken of male subjects similarly exposed. A healthy questionnaire was mailed to 306 male subjects whose mothers were known to have taken diethylstilbestrol in the early part of their pregnancies and to 231 age and sex-matched controls identified from the same record source. Although there was no increased history of cancer, heart disease or asthma when the groups were compared there was a higher incidence of reported urinary tract symptoms and genital abnormalities in the group exposed to diethylstilbestrol. The presence of these abnormalities was confirmed by physical examination of 15 respondents. Studies in experimental animals also have shown that in certain species maternally ingested stilbestrol may result in abnormalities of the genitaltensive clinical studies be undertaken to determine the level of risk, if any, to which many thousands of young men are subject.

Abnormalities, Drug-Induced↗