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PubMed1985

Dearylation and other cleavage reactions of diethylstilbestrol: novel oxidative pathways mediated by peroxidases.

Oxidation of diethylstilbestrol (I) by peroxidases from horseradish or mouse uterus in the presence of H2O2 in vitro leads to Z,Z-dienestrol (II) and to a number of cleavage products, five of which were identified by g.l.c.-mass spectrometry and comparison with authentic reference compounds as 4-hydroxybenzoic acid (III), 4'-hydroxypropiophenone (IV), 1'(4'-hydroxyphenyl)-propan-1-on-2-ol (V), 1-(4'-hydroxyphenyl)-propan-1,2-dione (VI) and 3-(4'-hydroxyphenyl)-hex-2-en-4-one (VII). The formation of 3-(4'-hydroxyphenyl)-hex-2-en-4-one (VII) from diethylstilbestrol is the first reported example of a metabolic dearylation reaction. The amount of cleavage products depends on the excess of H2O2 used. The amount of H2O2 does not affect the extent of binding of diethylstilbestrol to DNA as mediated by peroxidases. The syntheses of V, VI and VII are described.

Animals↗

PubMed1990

Influence of neonatal diethylstilbestrol treatment on prolactin receptor levels in the mouse male reproductive system.

Neonatal exposure to the synthetic estrogen, diethylstilbestrol, is known to affect the structure of the male reproductive system; thus, changes may also occur in the levels of hormone receptors. Prolactin receptor levels from the reproductive systems of male BALB/c mice exposed neonatally to diethylstilbestrol were analyzed. Neonatal exposure to diethylstilbestrol caused significant decreases (i) in prolactin receptor levels in the seminal vesicle, ductus deferens, and anterior and ventral prostates and (ii) in tissue weight and protein content in reproductive organs other than the ventral prostate.

Animals↗

PubMed1976

Effect of diethylstilbestrol, ascorbic acid and vitamin E on serum lipid patterns.

The effects of relatively high concentration of vitamin C, vitamin E and diethylstilbestrol, and various combinations of cholestyramine and diethylstilbestrol on the lipid compositions of chicken serum were studied were studied. After DES injection (at concentrations as low as 1 mg/day for 7 days), levels of triglycerides, phospholipids and cholesterol were much higher, the effect being much more pronounced in the hens. Cholestyramine caused a fourfold decrease in cholesterol in females, a 25% reduction males. DES consistently caused a redistribution of the esterfied fatty acids, increasing the percentage of oleic and reducing percentages of stearic and lionelic acids. Preparative TLC analysis of all constituents showed other variations in fatty acid composition, but there was no other common pattern of change. Vitamin E in the diet caused a significant rise in triglycerides and phospholipids in DES treated birds. When vitamins E and C were fed, triglyceride and phospholipid values decreased. Cholesterol concentration did not vary significantly. With birds receiving both vitamins, diethylstilbestrol seemes to have less effect in causing the shift to increase percentage of oleic acids in the total esterified fatty acids.

Animals↗

PubMed1976

Calcium balance in the quail (Coturnix coturnix japonica). 1, Influence of sex and diethylstilbestrol.

Young adult male and laying female quail, fed with a diet containing 2.64% Ca and 0.70% P, were used to study nutritive utilization, corporal calcium retention and endogenous excretion, calcemia, laying and properties of the egg (including the shell structure), mineralization of the femur bone, as well as the influence of diethylstilbestrol upon these parameters. The coefficient of nutritive utilization (C.N.U.) in the female was high and logically superior to that of the male, while the corporal retention was quite similar for both sexes. Most of the Ca absorbed (81.8%) and not excreted in urine, went to the egg and only 18.2% remained in the body. The diethylstilbestrol caused a big reduction of the C.N.U. in the female, but not in the male, parallel to an inhibition of laying, and an increase of corporal retention of used calcium. In both sexes the calcemia surprisingly increased, and the calcium level of the femur bone was higher, and even though the cortical osseous zone was slightly wider, the effect of treatment was noticeable, particularly in the medular tissue, which incremented in the female and appeared in the male. When quail were fed a calcium-restricted diet, the endogenous excretion of this mineral was small in the case of the female and significantly smaller in the male. This situation suppressed egg laying and resulted in a clearly decreased bone mineralization. The ingestion of diethylstilbestrol before feeding a diet poor in calcium provoked an increase of the endogenous excretion of calcium in both female and male quail.

Animals↗

PubMed1998

Urinary excretion of diethylstilbestrol in the ostrich.

Stilboestrol tablets (20 x 1 mg) were given to 4 ostriches. Urine was collected over a period of 8 days and stored frozen at-20 degrees C pending analysis. Analyses were performed on a gas chromatograph-mass selective detector for the presence of parent compound and/or metabolites. Diethylstilbestrol and its metabolite, dienestrol, were detected in urine; dienestrol only for 1 day but diethylstilbestrol for 8 days after administration. Residue analysis for the use of diethylstilbestrol as growth promoter can be performed on the urine of ostriches by scanning for parent compound only since it can be detected longer than the metabolite.

Animals↗

PubMed1999

A phase 1-2 trial of diethylstilbestrol plus low dose warfarin in advanced prostate carcinoma.

PURPOSE: This prospective study was designed to determine the safety and efficacy of low dose warfarin in the prophylaxis of thromboembolic disease in patients receiving diethylstilbestrol therapy for advanced prostatic carcinoma. MATERIALS AND METHODS: Patients were stratified to receive 1 mg. warfarin and 3 mg. diethyl-stilbestrol daily (younger than 65 years) or 1 mg. warfarin and 2 mg. diethylstilbestrol daily (older than 65 years). Efficacy of therapy was determined by measuring serum prostate specific antigen (PSA), testosterone and international normalized ratio. Patients were monitored for signs and symptoms of hypercoagulability, bleeding and fluid retention. RESULTS: Of the 32 patients enrolled in the study 6 were lost to followup and 4 died of advanced prostatic disease (2), pneumonia (1) and myocardial infarction (1). Patients were followed for a total of 272 months. Median patient age was 73.5 years. Median pretreatment serum PSA was 95.4 microg./l. with a median pretreatment serum testosterone value of 12.9 nmol./l. After 3 months of therapy the median serum PSA was 1.5 microg./l. with a median serum testosterone value of 0.1 nmol./l. Adverse events were common. In 10 patients (31%) clinically significant proximal deep venous thrombosis developed, 2 (7%) had a myocardial infarction, 2 (7%) had transient ischemic attacks, 1 had new prolonged chest pain and 1 had marked dyspnea due to congestive heart failure. Clotting factor assays performed in a subset of 7 patients demonstrated that factor VII failed to normalize. CONCLUSIONS: The significant thromboembolic toxicity associated with the hypercoagulable state induced by diethylstilbestrol is not reduced by fixed low dose warfarin therapy.

Adult↗

PubMed1975

Effects of diethylstilbestrol and testosterone propionate implanted in the hypothalamus on spermatogenesis in rats.

Small quantities of diethylstilbestrol and testosterone proprionate were implanted into the hypothalamic arcuate nucleus of male rats of the Wistar-Imamichi strain at 43 days of age. The animals were sacrificed at 64 or 76 days of age. Diethylstilbestrol suppressed the development of all genital organs and disturbed spermatogenesis. The damage was found to have recovered slightly in rats sacrificed at 76 days of age. Testosterone propionate was also effective for the atrophy of some genital organs. Its influence was not so severe as that of diethylstilbestrol. It extinguished almost completely 33 days after implantation. On the contrary, the numbers of spermatogonia and spermatocytes per cross section of the seminiferous tubule were smaller at 76 days than at 64 days of age. The diameter of the seminiferous tubule in the rat implanted with testosterone propionate was longer at 76 days than at 64 days of age. Therefore, the tubular diameter did not always represent the quantity or quality of spermatogenesis. The results also suggested that spermatogenesis might have been disturbed in some of the rats in which androgen was considered to be secreted almost normally.

Animals↗

PubMed1992

[Affinity chromatography of mouse and rat alpha-fetoproteins on immobilized diethylstilbestrol].

Alpha-fetoproteins (AFP) from amniotic fluid of mouse and rat demonstrate high affinity and specificity during their binding with immobilized diethylstilbestrol, which allows to isolate these two proteins by one step using the method of affinity chromatography on Sepharose with immobilized diethylstilbestrol. Meanwhile the yield of mouse AFP was 42%, and rat AFP--75%. The preliminary incubation of the amniotic fluid of rat and mouse with free estradiol results in abrupt fall of AFP outcome, which may testify to the binding of estradiol and diethylstilbestrol by the same receptor sites on AFP molecule.

Amniotic Fluid↗

PubMed1992

Effect of mesulergine on prolactin secretion and dopamine D2 receptors-adaptive changes in diethylstilbestrol-induced hyperplasia of the rat anterior pituitary.

Mesulergine (N,N-dimethylsulphamide-N'-1,6-dimethyl-ergoline-8 alpha-yl) is an active semisynthetic ergot derivative with lower antiprolactin potency compared with bromocriptine or pergolide. Since no data are yet available on the effects of mesulergine on pituitary dopamine receptors, the present study has been designated to elucidate the influence of this drug on prolactin secretion in vivo and in vitro and 3H-spiperone binding by the anterior pituitary gland in female Wistar rats with experimentally induced hyperprolactinemia. Three weeks after bilateral ovariectomy and subcutaneous implantation of silastic tubes, containing 10 mg of diethylstilbestrol, a dramatic rise in serum prolactin levels was observed (1.67 +/- 0.23 vs. 80.82 +/- 3.80 ng/ml; P less than 0.001). Mesulergine attenuated the stimulatory effect of diethylstilbestrol on serum prolactin level in a time- and dose-dependent fashion. At concentration range between 10(-5) and 10(-7) M it also inhibited prolactin secretion from cultured rat pituitary cells to the medium during 180 min incubation in a dose-dependent manner. Scatchard analyses performed on the in vitro 3H-spiperone binding kinetics in a dispersed anterior pituitary cell culture, prepared from the pituitaries from rats treated for four weeks with diethylstilbestrol, showed that chronic mesulergine treatment (in dose of 3.0 mg/kg injected s.c. for 10 days) induced a significant decrease in the number of dopamine D2-binding sites (Bmax 28.00 +/- 4.20 vs. 42.80 +/- 4.76 fmol/10(6) cells; P less than 0.01) without any changes in D2-receptor affinity. Our results suggested that antiprolactin activity of mesulergine in vivo and in vitro is probably associated with agonistic effect of this drug on D2-dopamine receptors.

Animals↗

PubMed2003

Spontaneous rupture of a first-trimester gravid uterus in a woman exposed to diethylstilbestrol in utero. A case report.

BACKGROUND: Poor reproductive outcome was well documented in several studies of women exposed to diethylstilbestrol in utero. Spontaneous rupture of an unscarred uterus is rare and very uncommon in the first trimester of pregnancy. CASE: Spontaneous rupture of the uterus was diagnosed in a 28-year-old nullipara who developed acute abdominal pain at 12 weeks' gestation. She was known to have been exposed to diethylstilbestrol in utero. Laparotomy revealed the rupture in the anterior fundal area of the uterus. Both tubes were normal. CONCLUSION: Several spontaneous ruptures have been described, but this is the first case of first-trimester spontaneous rupture of an unscarred uterus in a diethylstilbestrol-exposed woman.

Adult↗

PubMed1988

Evaluation of the cytotoxic activity of diethylstilbestrol and its mono- and diphosphate towards prostatic carcinoma cells.

To evaluate a possible direct cytotoxic effect of diethylstilbestrol diphosphate (DESDP) in the treatment of prostate cancer we exposed three prostatic carcinoma cell lines (LNCaP, DU 145, and PC-3), 2 nonprostatic neoplastic cell lines (KB and EJ), and one nontransformed cell line (MRC-5) to diethylstilbestrol (DES), diethylstilbestrol monophosphate, and DESDP at levels occurring in patients' sera during p.o. DES therapy (2 to 5 ng/ml) or DESDP infusions (1 to 20 micrograms/ml), respectively. With 5 ng/ml of DES no effect was seen in LNCaP cells, even after 14 days of exposure. In contrast, drug levels attained during DESDP infusions showed marked, dose-dependent cytotoxicity towards all cell lines under study. Prostatic cells were not exceptionally sensitive. High-dose DES slightly stimulated the synthesis of prostatic acid phosphatase in LNCaP cells. Formation of foci of polygonal cells was induced by 5 micrograms/ml of DES in cultures of MRC-5 fibroblasts. We conclude that, at high doses, DES liberated from DESDP acts upon a regulatory or metabolic mechanism common to many if not all human cells. Preferential sensitivity of prostate cancer cells in vivo may be due to high local phosphatase activity and/or DES accumulation in prostatic tissue.

Acid Phosphatase↗

PubMed1983

Mechanism of diethylstilbestrol carcinogenicity as studied with the fluorinated analogue E-3',3",5',5"-tetrafluorodiethylstilbestrol.

E-3',3",5',5"-Tetrafluorodiethylstilbestrol (TF-DES), a structural analogue of diethylstilbestrol synthesized as a possible noncarcinogenic estrogen, was found to induce renal clear-cell carcinoma in Syrian hamster. The tumor induction frequency of TF-DES was the same as that of diethylstilbestrol, although the induction period was longer (approximately 9 months) than that of diethylstilbestrol (approximately 6 months). TF-DES was estrogenic and was found to support in vivo growth of estrogen-dependent H-301 cells, a cell line derived from the primary estrogen-induced and -dependent renal clear-cell carcinoma of male Syrian hamster. These data established the ability of TF-DES not only to induce tumors but also to promote estrogen-dependent tumor growth after the initiation process. Oxidation of TF-DES to TF-DES quinone was catalyzed by horseradish peroxidase. The structure of this metabolic intermediate was confirmed by comparison with synthesized TF-DES quinone. This intermediate was very unstable (half-life in methanol, 24 min; half-life in water, 4 min) and rearranged to Z,Z-3',3",5',5"-tetrafluorodienestrol. Based on the experiments with the fluorinated derivative, it is postulated that stilbestrol estrogens induce tumors via metabolic oxidation to quinone intermediates, which then may interact with DNA or other cellular targets.

Adenocarcinoma↗

PubMedDate not supplied

[Effect of diethylstilbestrol on conformation of the hemoglobin molecule].

The paper deals with the results obtained while measuring the surface presssure of hemoglobin monolayers containing diethylstilbestrol. It is shown that insignificant additions of diethylstilbestrol change the shape of the surface hemoglobin pressure isoterm. The addition of diethylstilbestrol to hemoglobin causes a considerable increase in the limiting value of the area corresponding to the substance mass unit in the monolayer. The time passed from the moment of components mixing till deposing the substance upon the interphase affects the value of the area.

Diethylstilbestrol↗

PubMed1995

Complete remission of hormone refractory adenocarcinoma of the prostate in response to withdrawal of diethylstilbestrol.

The phenomenon of regression of adenocarcinoma of the prostate after the withdrawal of antiandrogens is well documented. However, to our knowledge we report the first case of durable complete remission of hormone refractory prostate cancer after cessation of diethylstilbestrol. The drug was discontinued because the patient had disease progression while on diethylstilbestrol and withdrawal resulted in durable remission. In more than 3 years of followup since discontinuing diethylstilbestrol there has been no evidence of clinical or biochemical recurrence.

Adenocarcinoma↗

PubMed1980

Effects of diethylstilbestrol and estramustine phosphate on serum sex hormone binding globulin and testosterone levels in prostate cancer patients.

Serum testosterone-estradiol binding globulin and total testosterone were measured in 2 groups of male controls (less than 50 and more than 65 years old) and in 7 groups of prostatic cancer patients treated with various endocrine manipulation procedures, including orchiectomy, and estramustine phosphate and diethylstibestrol therapy. There were 133 individuals studied. Total serum testosterone levels were significantly higher in the younger versus the older control group and testosterone-estradiol binding globulin levels were significantly higher in the older men. Whereas orchiectomy reduced serum testosterone to low concentrations (72 plus or minus 11 ng. per 100 ml.) testosterone-estradiol binding globulin levels were not altered. In contrast, estramustine phosphate and diethylstilbestrol therapy, when administered to intact or castrated patients, resulted in depressed testosterone and markedly elevated testosterone-estradiol binding globulin serum levels, particularly in those patients receiving estramustine phosphate (less than 35 ng. per 100 ml. and more than 6 micrograms per 100 ml., respectively). These studies led to the conclusion that diethylstilbestrol or estramustine phosphate therapy is significantly more effective than orchiectomy in eliciting a concomitant elevation of testosterone-estradiol binding globulin and a depression of total testosterone. Even though free serum testosterone was not measured in the present study the law of mass action would indicate that in those patients with high testosterone-estradiol binding globulin (more than 5 microgram. per 100 ml.) and low total testosterone levels (less than 80 ng. per 100 ml.) the availability of biologically active (unbound steroid) testosterone would be negligible.

Adult↗

PubMed1981

Dysplasia and cytologic findings in 4,589 young women enrolled in diethylstilbestrol-adenosis (DESAD) project.

This report presents the cytologic findings and the rates of dysplasia for 4,589 young women enrolled in the National Cooperative Diethylstilbestrol-Adenosis (DESAD) Project. Mucinous columnar cells and/or metaplastic squamous cells with or without mucinous droplets were encountered in 22% of vaginal scrape smears from all diethylstilbestrol (DES)-exposed participants identified by review of prenatal records and in 43% of women in whom vaginal epithelial changes (VEC) were observed by colposcopy or by iodine staining. The frequency of cellular findings in the vaginal scrape smears was closely related to the timing of the administration of the DES to the mother. With increasing age of the daughters, the overall frequencies of both the mucinous and metaplastic cells decreased; relative to each other, an increasing proportion was metaplastic squamous cells. These data suggest that, as the women grow older, vaginal adenosis regresses by the process of squamous metaplasia. Endometrial type cells were found in 2% of vaginal scrape smears. Their cyclical occurrence during the menstrual cycle and lack of correlation with the presence of VEC indicated an origin from the uterine corpus rather than the tuboendometrial type of adenosis. Squamous cell dysplasia of the vagina and cervix was detected by biopsy or scrape smear specimens in 1.8% of DES-exposed women in the record review group. The rate of unexposed women was twice as high. In general, the rates of dysplasia were higher in the cervix than vagina, and the more severe degrees of dysplasia were encountered only in those women who were referred to the DESAD Project or who themselves requested entry. Four patients who were referred or who themselves requested entry were found to have clear cell adenocarcinoma of the vagina. The vaginal smear provided the first clue to the presence of an abnormality in three of them.

Adenocarcinoma↗

PubMed1984

Structural anomalies of the cervix and vagina in women enrolled in the Diethylstilbestrol Adenosis (DESAD) Project.

Among women exposed in utero to diethylstilbestrol (DES) and enrolled in the Diethylstilbestrol Adenosis (DESAD) Project, structural anomalies of the cervix or vagina were found in 25% of the 1,655 subjects identified by review of prenatal records, 43% of the 800 who themselves requested entry into the project, and 49% of the 1,089 referred by physicians but in only 2% of the 963 control subjects. Among the 367 cases found by record review to have complete information on the DES exposure, multivariate analysis indicated close association of the anomalies with the gestational week of first exposure and the total dose. Also, the prevalence rate of the anomalies was lower among subjects who had been pregnant and higher among those with later age at menarche.

Abnormalities, Drug-Induced↗

PubMed1993

Luteinizing hormone-releasing hormone agonists in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose diethylstilbestrol.

BACKGROUND: In response to the first administration of a luteinizing hormone-releasing hormone (LHRH) agonist, the secretion of pituitary gonadotropin increases sharply and gives rise to a transient surge in the concentration of serum testosterone. This effect reaches a peak 4 to 7 days after the start of therapy and results in the onset of clinical symptoms and signs of tumor flare in 5% to 10% of patients. METHODS: To determine whether the effects of the LHRH-induced flare reaction are preventable, cyproterone acetate (100 mg) and low-dose diethylstilbestrol (0.1 mg) were administered daily for 4 weeks to inhibit the pituitary before the initiation of therapy with a depot LHRH agonist, goserelin acetate (3.6 mg every 4 weeks). Diethylstilbestrol was stopped after 8 weeks to eliminate associated minor toxicity while administration of cyproterone acetate was continued to suppress vasomotor symptoms. Twenty-four men with histologically confirmed prostate cancer were enrolled in the study: 6 with Stage C, 2 with Stage D1, and 16 with Stage D2 disease. RESULTS: Lead-in therapy reduced the concentration of serum testosterone into the castrate range within 1 week, and no significant change was observed in the mean level after administration of goserelin acetate. Neither was there an effect on the initial rate of normalization of serum prostate specific antigen (PSA); normal PSA values were obtained in 50% of patients after 10 weeks and in 70% after 32 weeks. In the subgroup of patients with Stage D2 disease, longer median survival was predicted by a normal serum PSA, either stable or decreasing, after 32 weeks of treatment. The regimen was well tolerated with a low incidence of hot flushes. CONCLUSIONS: These results imply that in the absence of LHRH-induced tumor flare, prognosis is related to the ability of therapy to maintain a PSA nadir in the normal range.

Acid Phosphatase↗