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PubMed1990

Vaginal bleeding and diethylstilbestrol exposure during pregnancy: relationship to genital tract clear cell adenocarcinoma and vaginal adenosis in daughters.

Comparing 186 cancer cases and 1772 cancer-free controls and reexamining several previously published studies, we found genital tract clear cell adenocarcinoma and vaginal adenosis to be moderately, but nonsignificantly, associated with vaginal gestational bleeding when in utero diethylstilbestrol exposure was statistically controlled. Considering the prevalence of diethylstilbestrol exposure in the general population, the relative risks of vaginal clear cell adenocarcinoma for in utero exposure were 365.6 and 459.0 when vaginal bleeding did and did not occur during the index pregnancy, respectively. The relative risks of vaginal adenosis for such diethylstilbestrol exposure were 15.4 and 92.8, respectively, for these women. The strong associations between in utero diethylstilbestrol exposure and both vaginal adenosis and genital tract clear cell adenocarcinoma cannot be attributed to the occurrence of problem pregnancy. However, among daughters exposed to diethylstilbestrol, maternal vaginal bleeding during the index pregnancy does appear to be associated with reduced risks of vaginal adenosis and vaginal clear cell adenocarcinoma.

Adenocarcinoma↗

PubMed1993

Conservative management and pregnancy outcome in diethylstilbestrol-exposed women with and without gross genital tract abnormalities.

OBJECTIVES: Our goal was to determine the effect of conservative management on pregnancy outcome in diethylstilbestrol-exposed women with and without gross structural lesions of the genital tract. STUDY DESIGN: The study included a case series of women prospectively enrolled over a 10-year period. RESULTS: Pregnancy outcome and both antepartum and intrapartum events occurring in a case series of 120 conservatively managed pregnancies in 50 diethylstilbestrol-exposed women were reviewed. Group A (n = 34, 89 pregnancies) consisted of women with gross upper or lower genital tract lesions associated with diethylstilbestrol exposure, whereas group B (n = 16, 31 pregnancies) consisted of women whose lesions were limited to colposcopic findings. Cerclage was limited to women with a history of cervical incompetence (n = 1, two pregnancies) or acute cervical change in the second trimester (one pregnancy). Women with cervical change occurring after 25 weeks' gestation were managed with bed rest. Group A experienced more spontaneous first-trimester losses than group B (25.8% vs 12.9%, p < 0.01), whereas group B had a greater gestational age at delivery (39.8 +/- 1.5 vs 37.3 +/- 3.8 weeks, p < 0.01) than group A. Overall, pregnancies surviving the first trimester (n = 94) resulted in delivery of a viable infant discharged home 92.2% of the time; 77.9% of pregnancies reached term. The perinatal loss rate was 1.3%. Preterm labor (6.5%) and preterm rupture of membranes (3.8%) resulted in an overall rate of preterm birth of 9.2%. There were no significant differences in length of any labor stage between groups, nor were there any differences in the use of oxytocin augmentation or cesarean section rates between groups. Postpartum hemorrhage and retained placenta were infrequent complications. CONCLUSIONS: The majority of pregnancy loss in diethylstilbestrol-exposed patients occurs in the first trimester. Cervical incompetence is an infrequent cause of pregnancy loss even in patients with gross structural abnormalities of the genital tract. Patients who had conservative management had good pregnancy outcomes. Prophylactic cerclage for all diethylstilbestrol-exposed patients should not be recommended.

Abnormalities, Drug-Induced↗

PubMed1985

Diethylstilbestrol induces metaphase arrest and inhibits microtubule assembly.

Diethylstilbestrol produced a dose-dependent increase in the mitotic index of the human prostatic tumour cell line DU 145. This is the result of metaphase arrest which may be induced by the action of diethylstilbestrol on spindle microtubules. Evidence is presented to show that diethylstilbestrol affects microtubules. Diethylstilbestrol completely inhibited the assembly of isolated brain microtubules although only partial disassembly could be induced. In contrast to other microtubule poisons, the inhibitory effect of diethylstilbestrol on taxol-induced self-assembly could be reversed by the addition of GTP.

Alkaloids↗

PubMed2004

Organizational effects of diethylstilbestrol on brain vasotocin and sexual behavior in male quail.

In Japanese quail, we previously described a sexual dimorphism of the parvocellular vasotocin system of the limbic region that, as the reproductive behavior, is steroid-sensitive and is organized during embryonic life by the exposure to estradiol. We verified in this study whether diethylstilbestrol, a chemical xenoestrogen, has analogous organizational effects on the vasotocin system of limbic regions and on copulatory behavior of male Japanese quail. We injected in the yolk sac of 3 day-old quail embryos diethylstilbestrol or estradiol benzoate (a treatment which suppresses male copulatory behavior in adulthood and reduces vasotocin innervation), or sesame oil (control). No further hormonal manipulations were performed after hatching. Sexual behavior was recorded in males at the age of 6 weeks. Estradiol- and diethylstilbestrol-treated males exhibited a total suppression of copulatory behavior. After behavioral tests, all males were sacrificed and brain sections processed for vasotocin immunocytochemistry. Significant decrease in the density of vasotocin immunoreactivity was detected in the medial preoptic nucleus, in the bed nucleus of stria terminalis, and in the lateral septum of diethylstilbestrol-treated males. The magnocellular vasotocin neurons were, in contrast, not affected. In conclusion, the present data demonstrate that embryonic treatment with diethylstilbestrol induces a full sex reversal of behavioral phenotype as well as a significant decrease of vasotocin expression in the preoptic-limbic region in male Japanese quail. Therefore, the parvocellular vasotocin system could represent an optimal model to investigate the effects of pollutants on neural circuits controlling reproductive functions.

Analysis of Variance↗

PubMed1986

A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer.

In a randomized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate (280 mg. twice daily for 8 weeks and 140 mg. twice daily thereafter) was compared to diethylstilbestrol (1 mg. 3 times daily) in patients with stages T3 to T4, M0 or M1 prostatic cancer. Of 248 patients entered 227 were evaluable for analysis: 115 received estramustine phosphate and 112 received diethylstilbestrol. The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol. There was no significant difference between treatments for response rate of metastases, interval to local progression, distant progression, over-all survival and death of carcinoma of the prostate. Duration of survival was correlated with the assessment of local response as determined by palpation. The response of distant lesions also was correlated closely with survival. Diethylstilbestrol (1 mg. 3 times daily) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate. This finding was especially obvious in patients who had no history of cardiovascular disease. Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate, including 6 in whom cessation of treatment was necessary. Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate, and to establish the best form of hormonal treatment for prostatic carcinoma.

Aged↗

PubMed2004

Age, sex and co-exposure to N-ethyl-N-nitrosourea influence mutations in the Alu repeat sequences in diethylstilbestrol-induced kidney tumors in Syrian hamsters.

We report, for the first time, mutations in the Alu repeat regions in the genome of kidney tumors induced by diethylstilbestrol in Syrian hamsters. Among the 66 loci amplified by 11 random primers, 28 loci exhibited insertions, deletions or losses or gains in intensity in the genome of kidney tumor tissues compared with normal kidney tissues from age-matched hamsters. Higher numbers of mutated Alu loci were observed in the tumors of old hamsters compared with young hamsters. In N-ethyl-N-nitrosourea- and diethylstilbestrol-treated hamsters deletion of a 0.59 kb locus amplified with primer OPC03 was observed in most of the female hamsters, but not in male hamsters. An insertion mutation of a 0.498 kb locus amplified with primer OPC03 was observed in 12 of 36 diethylstilbestrol-induced kidney tumors. The cloning and sequencing of the 0.498 kb locus amplified with primer OPC03 revealed that it had significant sequence similarity to the mouse RIKEN cDNA clone. These findings indicate that age, sex and co-exposure to N-ethyl-N-nitrosourea influence mutations in the Alu repeat sequences in the genome of diethylstilbestrol-induced kidney tumors in Syrian hamsters. Structural alterations in Alu repeats in critical target genes may be involved in diethylstilbestrol-induced carcinogenesis.

Age Factors↗

PubMed1996

Diethylstilbestrol and risk of fatal breast cancer in a prospective cohort of US women.

The authors examined the association between the use of diethylstilbestrol during pregnancy and the risk of subsequent fatal breast cancer in a large prospective study of US adults. After 9 years of follow-up, 1,574 cases of fatal breast cancer were observed among 501,536 gravid women who reported no prior history of cancer in 1982. Results from Cox proportional hazards models showed a positive association between a history of diethylstilbestrol exposure (reported by 3.9% of all women) and fatal breast cancer (adjusted rate ratio = 1.34, 95% confidence interval 1.06-1.69). This excess risk did not increase over time; women who were exposed more than 35 years ago (rate ratio = 1.35, 95% confidence interval 0.97-1.87) were not at greater risk than women who were exposed within the past 35 years (rate ratio = 1.39, 95% confidence interval 1.01-1.93). The positive association was not observed in women who used diethylstilbestrol before age 25 years but was seen at all other ages. The age of study participants did not modify the association between exposure and breast cancer, and there were no significant interactions between ever use of diethylstilbestrol and any of the other potential risk factors included in the analysis. These findings are consistent with those of several other studies of diethylstilbestrol exposure and breast cancer.

Adult↗

PubMed2003

Gonadectomy eliminates endothelium-dependent diethylstilbestrol-induced relaxant effect in rat aorta.

The effects of gender and castration of rats on diethylstilbestrol-induced, endothelium-dependent and endothelium-independent relaxation in rat aorta strips were studied. For this, male and female control and castrated rats were used. Diethylstilbestrol elicited a concentration-dependent (1-30 micromol/l) relaxation of isolated rat aorta. The effect was significantly higher in the presence of endothelium in aorta strips of the control group and also in female as compared with male rats. This effect is NO-dependent, since it is inhibited by N(G)-methyl-L-arginine. Castration of the rats suppressed the endothelium-dependent relaxation, and it was similar to that induced in the absence of endothelium. Acetylcholine-induced relaxation was not suppressed by castration. The acetylcholine-induced relaxation was decreased in aorta strips previously relaxed by diethylstilbestrol. There are no gender differences in the diethylstilbestrol-induced, endothelium-independent component of the relaxation, nor is it modified by the hormonal environment. Therefore, diethylstilbestrol-induced, endothelium-dependent relaxation in rat aorta strips is modulated by the hormonal status of the rats.

Acetylcholine↗

PubMedDate not supplied

The health effects of diethylstilbestrol revisited.

Although diethylstilbestrol has not been prescribed commonly for more than 25 years, its effects on the health of exposed persons are still important. In this article, we summarize current information about the major health effects of diethylstilbestrol exposure and delineate implications for nurses. Nurses can help to identify persons at risk from prior diethylstilbestrol exposure, facilitate comprehensive assessments of persons exposed to diethylstilbestrol, and share current information about diethylstilbestrol.

Adenocarcinoma, Clear Cell↗

PubMed1983

Effects of exogenous growth hormone and diethylstilbestrol on growth and carcass composition of growing lambs.

An 8-wk growth trial was conducted to assess the effects of ovine growth hormone (oGH; 7 mg/d, sc) on growth performance and carcass composition of normal, growing wether lambs. Diethylstilbestrol (DES; .1 mg/d, sc) and control lambs were included for comparisons. Plasma oGH levels at 8 wk were 1.9, 5.5 (P less than .05) and 138.1 ng/ml (P less than .001) for controls, DES and oGH lambs, respectively. Diethylstilbestrol did not increase plasma oGH until the fourth week. The oGH improved feed conversion 7.4% (FC; P less than .05), but did not alter average daily gain (ADG) or feed intake (ADF). Diethylstilbestrol increased ADG 15.3% (P less than .05) and improved FC 16.1% (P less than .01), with no effect on ADF. The primary effect of oGH on carcass composition was to decrease the quantity of fat 8.9% (P less than .05). In addition, oGH may have increased protein 6.5% (P less than .10) and moisture 4.0% (not significant). Diethylstilbestrol increased the quantity of carcass protein 10% (P less than .01) and moisture 8.7% (P less than .05), with no effect on fat. In these studies, the primary effect of exogenous oGH on normal, growing lambs was to reduce carcass fat, which may account for the observed improvement in FC. Diethylstilbestrol, at 1/70th of the oGH dose, was superior to oGH for improving FC (P less than .05) and ADG (P less than .10). Improvements in body weight of the lambs given DES were observed 2 wk before an increase in plasma oGH. In addition, DES, unlike exogenous oGH, did not alter the quantity of carcass fat. These observations do not support the concept that the mode of action of DES is through increased GH secretion.

Adipose Tissue↗

PubMed2003

[Voltammetric behaviors of diethylstilbestrol and its determination at multi-wall carbon nanotubes modified glassy carbon electrode].

AIM: To fabricate multi-wall carbon nanotube (MWNT) modified electrode and study the electrochemical behaviors of diethylstilbestrol at the MWNT-modified electrode. METHODS: Cyclic voltammetry and linear sweep voltammetry. RESULTS: The oxidation peak current of diethylstilbestrol increased remarkably and the peak potential shifted negatively at the MWNT-dihexadecyl hydrogen phosphate (DHP) modified glassy carbon electrode (GCE), in contrast to that at the bare GC electrode and DHP-modified GC electrode. The oxidation peak current is linear with the concentration of diethylstilbestrol over the range from 1 x 10(-8) to 2 x 10(-6) mol.L-1. The detection limit was 2.5 x 10(-9) mol.L-1. The relative standard deviation (n = 10) was 2.9% for 1 x 10(-6) mol.L-1 diethylstilbestrol. CONCLUSION: The MWNT-DHP modified GCE exhibits catalytic activity to the oxidation of diethylstilbestrol.

Carbon↗

PubMed1990

[Competitive affinity chromatography of human alpha fetoprotein on immobilized diethylstilbestrol].

Human alpha-fetoprotein (AFP) was isolated by affinity chromatography method on immobilized diethylstilbestrol from butanol extract of abortive material. Elution from the column was performed with 10% aqueous buffered butanol solution, pH 8.6. During one procedure human AFP-preparation containing about 10% of AFP and about 90% of albumin was obtained, with the yield about 60%. The preliminary incubation of extract of the abortive material with estrone raised AFP yield up to 85% with the increase of AFP content in the preparation up to 35%, and preincubation with estriol and estradiol caused the increase of the yield up to 88-92%, and AFP content in the preparation was 50% and 65%, respectively. The preincubation of human AFP with diethylstilbestrol lowers the yield of this protein, which testified to the possible binding of human AFP with free diethylstilbestrol; testosterone, hydrocortisone and desoxycorticosterone caused the increase of the yield of AFP. So the competitive variant of the affinity chromatography on immobilized diethylstilbestrol makes it possible to raise human AFP preparation purity and yield by decreasing the competition between AFP, and not binding free steroid hormones, ad albumin for immobilized diethylstilbestrol.

Abortion, Induced↗

PubMed1984

Males exposed in utero to diethylstilbestrol.

An increased frequency of various genitourinary anomalies, infertility, and testicular cancer among males has been reported to follow intrauterine exposure to diethylstilbestrol, but not all studies have confirmed an association. This study was designed to determine whether a cohort of males exposed in utero to diethylstilbestrol had a higher frequency of urogenital abnormalities than an unexposed cohort. Biases in selection of exposed and control participants were minimized. Of 828 exposed and 676 control men studied by medical-record review, 265 exposed men and 274 controls also underwent a special clinical examination. Overall, the data suggest that diethylstilbestrol exposure of males in utero did not increase their risk of genitourinary abnormalities, infertility, or testicular cancer. Previously reported increased frequencies of these abnormalities in diethylstilbestrol-exposed men may have resulted from selection biases or differences in diethylstilbestrol use, or both.

Abnormalities, Drug-Induced↗

PubMed1979

Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities.

Epididymal cysts and/or hypoplastic testes have been found in 31.5 per cent of 308 men exposed to diethylstilbestrol in utero, compared to 7.8 per cent of 307 placebo-exposed controls. Analyses of the spermatozoa have revealed severe pathological changes (Eliasson score greater than 10) in 134 diethylstilbestrol-exposed men (18 per cent) and 87 placebo-exposed men (8 per cent). Further investigation of the 26 diethylstilbestrol-exposed men with testicular hypoplasia has revealed that 65 per cent had a history of cryptorchidism. Only 1 of the 6 placebo-exposed controls with testicular hypoplasia had a history of testicular maldescent. Although none of our Diekmann's lying-in study group has had carcinoma to date one must keep in mind the reported increased risk of testicular carcinoma in testes that are or were cryptorchid. A 25-year-old man who was not part of the study group was treated recently by us for a testicular carcinoma ( mixed anaplastic seminoma plus embryonal cell carcinoma) and he had a history of diethylstilbestrol exposure in utero and cryptorchidism.

Abnormalities, Drug-Induced↗

PubMed1980

Enhancement of thrombocyte aggregation and thromboxane B2 synthesis by diethylstilbestrol.

Effect of diethylstilbestrol administration on thrombocyte aggregation and thromboxane B2 synthesis was investigated in atherosclerosis-susceptible pigeons. Platelet aggregatory response to arachidonic acid and synthesis of thromboxane B2 from 14C-arachidonic acid was enhanced in thrombocytes derived from diethylstilbestrol-treated pigeons. Platelet total phospholipid concentration was increased in pigeons with diethylstilbestrol treatment. Enhanced thromboxane synthesis might be responsible for increased platelet aggregation, which in turn might contribute to the severe atherosclerosis noted following diethylstilbestrol treatment in several avian species.

Animals↗

PubMed1982

Alterations in the subcellular distribution of Guanylate cyclase and its responsiveness to nitric oxide in diethylstilbestrol-induced renal tumors.

The cyclic GMP content of diethylstilbestrol-induced renal tumors in the male golden hamster was increased nearly 130-fold over that in kidney from control animals. Cyclic GMP in tumors was 91.80 +/- 19.18 pmoles cyclic GMP/mg protein compared to 0.72 +/- 0.07 in control kidneys. Cyclic AMP in tumors was also increased over control, however, to a much lesser degree (2.7-fold). In control kidneys, 84.6% of homogenate guanylate cyclase activity was recovered in the 100,000 X g supernatant fraction. Total homogenate guanylate cyclase activity from diethylstilbestrol-induced renal tumors was increased 5.5-fold over that in control kidneys and only 8.1% was associated with the 100,000 X g supernatant fraction. Neither the soluble or particulate guanylate cyclase from renal tumors could be activated by nitric oxide. The unresponsiveness of tumor guanylate cyclase to nitric oxide was independent of the cation cofactor, and not due to a shift in the dose response curve for nitric oxide. Responsiveness to nitric oxide was not restored by thiols, sugars, other proteins, or hemoglobin. Basal cyclic AMP formation by soluble guanylate cyclase from renal tumors was dramatically increased over that observed in control kidneys, and could not be increased further by nitric oxide. This is the first study of cyclic GMP and guanylate cyclase in a primary estrogen-induced tumor. The possibility that the changes observed in guanylate cyclase from diethylstilbestrol-induced renal tumors are related to in vivo activation of the enzyme by epoxide metabolites of diethylstilbestrol is discussed.

Animals↗

PubMed1980

Semiautomated method for analysis of enteric-coated and plain coated diethylstilbestrol tablets.

A semiautomated fluorometric method for the analysis of enteric-coated and plain coated diethylstilbestrol tablets is presented. To eliminate interferences from tablet excipients, diethylstilbestrol is extracted into an organic solvent and then into a basic aqueous solution. After UV irradiation, a product of diethylstilbestsrol is formed from which a fluorophore is produced chemically. The fluorescence is measured at an excitation wavelength of 335 nm and an emission wavelength of 410 nm. The coefficient of variation measured for the semiautomated procedure was 0.59%. Assay results agreed well with the USP procedure for tablets containing greater than 1 mg of diethylstilbestrol. Tablet dyes and excipients interfered in the USP procedure, which yielded low results for tablets containing less than 1 mg of diethylstilbestrol. Standard recovery data and assays of tablet composites showed that dyes and other excipients do not interfere with semiautomated procedure.

Autoanalysis↗

PubMed1993

In vitro characterization of estrogen induced Syrian hamster renal tumors: comparison with an immortalized cell line derived from diethylstilbestrol-treated adult hamster kidney.

Primary diethylstilbestrol-induced kidney tumors from Syrian hamsters were grown in vitro and maintained in culture for 6 mo. Combined immunohistochemical studies using antibodies to intermediate filaments and ultrastructural studies of tumor cells in culture exhibited characteristics similar to tumor cells in vivo. Furthermore, the cells manifested transformed properties in culture; they grew both as multilayered colonies attached to the tissue culture substrate and as floating multicellular colonies (spheroids). When cultured cells were injected into diethylstilbestrol-treated recipient hamsters, tumors developed at the injection sites. In contrast, renal tubules or whole kidney cortex from control hamsters cultured in the same medium underwent only short-term growth, with senescence developing after approximately 1 mo. However, cell cultures of kidney cortex from animals treated in vivo for 5 mo. with diethylstilbestrol formed a cell line. This diethylstilbestrol-induced cell line has been maintained in culture for 1.5 yr and has the following characteristics: a) it is anchorage-dependent, b) it is negative in in vivo tumorigenicity tests, and c) cultured cells are histochemically and ultrastructurally similar to cultured tumor cells. This culture system should prove to be of use in studying hormonal carcinogenesis in vitro.

Animals↗