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PubMed2006

[A preliminary study on the effect of prepubertal exposure of male rats to diethylstilbestrol on the apoptosis of spermatogenic cells after sexual maturation and its mechanism].

OBJECTIVE: To preliminarily study the effect of prepubertal exposure of male SD (Sprague-Dawley) rats to diethylstilbestrol (DES) on the apoptosis of spermatogenic cells after sexual maturation and its mechanism. METHODS: Thirty 21-day-old male SD rats were randomly divided into 4 experimental groups, DES 0.01, 0.1, 1.0 and 10.0 microg/(kg x d) and 1 control group. The experimental groups were injected (s.c.) with different doses of DES (dissolved in corn oil) during prepuberty [from postnatal day (PND) 22 to PND 35] and the control group with medium only. The apoptosis and related proteins Bcl-2 and Bax expressions of testicular spermatogenic cells were studied with TUNEL and immunohistochemistry after the rats sexual maturation (at PND 64). RESULTS: Compared with the control group, the apoptosis of testicular spermatogenic cells in the DES 0.01 microg/kg group had no difference, but significantly increased in the DES 0.1, 1.0 and 10.0 microg/kg groups and the apoptosis increased with the increase of DES dose. In the control and DES 0.01 microg/kg groups, Bax protein expressed weakly but Bcl-2 protein strongly in spermatogenic cells. With the increase of DES exposure, Bax protein expression in spermatogenic cells increased but Bcl-2 protein expression decreased. CONCLUSION: Prepubertal exposure of SD rats to inappropriate dose of DES can make the apoptosis of spermatogenic cells increase after sexual maturation. Bax and Bcl-2 proteins participate in the apoptotic course caused by prepubertal DES exposure.

Animals↗

PubMedDate not supplied

In vitro fertilization of oocytes from polyovular follicles in mouse ovaries exposed neonatally to diethylstilbestrol.

In 35-day-old female ICR/JCL mice given 5 daily injections of 1 microgram diethylstilbestrol (DES) from the day of birth, a significantly higher incidence of polyovular follicles was found in the ovaries than in those of age-matched control mice. Gap junctions of granulosa cells of mature follicles in neonatally DES-exposed mice were larger than those of the controls. When stimulated by gonadotropins (PMSG and hCG) and caged with males, the number of tubal embryos in DES-exposed mice was less, but the rate of fertilization and development was not different compared to the controls. Division of oocytes collected from the ovaries of 40-day-old DES-exposed and control mice after stimulation of gonadotropins was examined 24 to 72 h after in vitro insemination to ascertain whether fertilization had occurred in oocytes from polyovular follicles. Seventy-seven % of oocytes from uniovular follicles of control mice developed up to 8-cell stage embryos following in vitro insemination; 66% of those from similar follicles of DES-exposed mice developed into the same stage. By contrast, only 47% of oocytes from polyovular follicles of DES-exposed mice showed the division up to 8-cell stage 72 h after insemination, indicating a significantly lower fertilization rate compared to the oocytes from uniovular follicles of control and DES-exposed mice. Without insemination, oocytes taken from the same pools in these experiments never divided during the period of manipulation and incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Acute and chronic effects of diethylstilbestrol on serum levels of alpha melanocyte stimulating hormone and prolactin in the hamster.

Continuous exposure to diethylstilbestrol (DES) induces renal tumors in male hamsters. The tumor formation is preceded by an increase in pituitary weight and elevation of the pituitary hormones-alpha melanocyte stimulating hormone (aMSH) and prolactin (Pr1). A decline in Pr1 (to normal levels) but not aMSH then accompanies the development of tumors and the enlargement of the intermediate lobe of the pituitary. Hypophysectomy, castration and thymectomy reduced serum levels of aMSH. DES administered for one week increased the serum levels of both hormones in normal and castrated animals, but not in hypophysectomized hamsters.

Adenocarcinoma↗

PubMed1991

[Refocusing on the gynecological and obstetrical consequences of intrauterine exposure to diethylstilbestrol (DES)].

The oncological and obstetrical follow-up is described of 321 patients who presented between 1981 and 1988 in the St Radboud Hospital with a history of intrauterine diethylstilbestrol(DES) exposure. In 45 out of 321 cases cytological abnormalities were found including 20 cases of cervical intraepithelial neoplasia (CIN). No relation could be established between CIN and the extension of the cervical adenosis. Twenty-two percent of 87 evaluable pregnancies terminated in spontaneous abortion, 13 percent of the patients delivered immaturely and 27 percent prematurely. These percentages were significantly higher than in the rest of the hospital population. The consequences of intrauterine exposure to DES are discussed. Full examination of the patients is advised, including colposcopy and hysterosalpingography. If abnormalities are present it is advised to offer a timely cerclage in case of pregnancy.

Adenocarcinoma↗

PubMed1990

[Ingestion of diethylstilbestrol during pregnancy. Its responsibility in the testicular feminization syndrome].

We report the cases of two women who had testicular feminization with remnants of Müllerian ducts and whose mothers had received diethylstilbestrol (DES) during the first trimester of pregnancy. At laparotomy, masses were removed which had the microscopic appearances of testes and Fallopian tubes, and were confirmed as such at histology. There were three possible explanations for these genetic abnormalities: deficient antimüllerian hormone (AMH) secretion (or lack of sensitivity of Müllerian ducts to AMH); early testicular descent with regression of Müllerian ducts beyond the efficacy margin of AMH; exposure to DES in utero during the first trimester of pregnancy. In these two women, the most likely explanation seems to be the last one.

Adult↗

PubMed1990

Role of the mitochondrial bc1-complex in the cytotoxic action of diethylstilbestrol-diphosphate toward prostatic carcinoma cells.

In previous work (P. Schulz et al., Cancer Res., 48: 2867-2870, 1988) we have demonstrated that diethylstilbestrol (DES), DES-monophosphate, and DES-diphosphate (DESDP) are generally cytotoxic at concentrations attained in patients' sera during therapeutic DESDP infusions for progressed carcinoma of the prostate. We have extended this work and addressed two questions: (a) Is DESDP itself a completely nontoxic prodrug which has to be transformed into the active species DES by a phosphatase? (b) Which metabolic or regulatory mechanism in a cell is the target of DES action? Using cell cultures in phosphatase-depleted media we could provide evidence that DESDP exerts cytotoxic activity only after conversion to DES. Oxygen electrode experiments and difference spectra with intact mitochondria demonstrated that DES did not act as an uncoupler, but inhibited electron flow from ubiquinone to cytochrome c1. Phenomena previously observed in DES-treated cells could be explained by distortion of the energy metabolism.

Acid Phosphatase↗

PubMed1990

Phenotypic differences in upper genital tract abnormalities and reproductive history in dizygotic twins exposed to diethylstilbestrol in utero. A case report.

Major phenotypic variations in reproductive function and upper genital tract abnormalities were found between 30-year-old dizygotic twins exposed in utero to diethylstilbestrol (DES). The women were exposed to maternal DES doses of 12.5-50.0 mg daily starting from the 12th gestational week as documented in the original antepartum obstetric office records. Twin A had primary involuntary infertility of over four years' duration associated with a severe DES uterine deformity on hysterosalpingography (HSG). A complete evaluation demonstrated all other infertility investigations to be normal. Twin B had two term pregnancies but a significant history of reproductive loss, including three miscarriages and one ectopic pregnancy. HSG demonstrated mild DES-induced changes. Cervical adenosis was observed only in the more severely affected twin.

Abnormalities, Drug-Induced↗

PubMed1975

Gas-liquid chromatographic determination of diethylstilbestrol in molasses-based liquid feed supplements.

A gas-liquid chromatographic (GLC) method is described for the determination of diethylstilbestrol (DES) in molasses-based liquid feed supplements, using dienestrol diacetate as the internal standard. A sample equivalent to 110 mug DES was diluted, acidified with dilute sulfuric acid, extracted with chloroform, and subjected to basic sodium acetate cleanup. The bis-(trimethylsilyl) acetamide derivative was prepared and determined by GLC. Interfering peaks and/or low recoveries were found to be related to emulsions and the procedure incorporates centrifugation to minimize these.

Animal Feed↗

PubMedDate not supplied

The histochemical and ultrastructural characterization of hyaline material in the endometrium of mice fed diethylstilbestrol.

Histochemistry and electron microscopy were used to examine hyaline material within the endometrium of mice continuously fed diethylstilbestrol (DES). Virgin female mice were fed diets containing 0, 320 or 640 ppb DES from 4 weeks of age. All animals reported on in this study were sacrificed when moribund and ranged from 622 to 762 days of age. Irregular deposits of hyaline material were seen throughout the connective tissue stroma with frequent accumulations seen immediately beneath the surface epithelial membrane and around blood vessels. The material was characterized by a paucity of cells and fibrous material but exhibited an eosinophilic reaction and was PAS-positive. Histochemistry indicated collagen was present even though electron microscopy revealed a homogeneous, amorphous structure virtually devoid of a fibrous component. Numerous plasma cells were seen in close proximity to macrophages and lymphocytes. This material was probably a product of collagen degradation and a subsequent immune response elicited in the endometrium.

Administration, Oral↗

PubMed1989

F0 "proton channel" of rat liver mitochondria. Rapid purification of a functional complex and a study of its interaction with the unique probe diethylstilbestrol.

The F0 portion of the rat liver mitochondrial ATP synthase (F0F1-ATPase) has been purified by a rapid, high yield procedure. F0 is selectively extracted from inner membrane vesicles with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) after prior treatment of the vesicles with guanidine HCl to remove F1. The resultant F0 is functional in proton translocation assays and separates in sodium dodecyl sulfate-polyacrylamide gel electrophoresis into four major and three minor Coomassie-stainable bands, all with apparent molecular masses below 30 kDa. This CHAPS-purified F0 preparation was characterized in detail for its capacity to interact with the unique probe diethylstilbestrol (DES) which, depending on conditions, has been shown to interact with rat liver F0F1 to either inhibit or promote ATP hydrolysis (McEnery, M. W., and Pedersen, P.L. (1986) J. Biol. Chem. 261, 1745-1752). DES-inhibitory sensitivity could be conferred on F1-ATPase activity with the same concentration dependence on F0 as conferral of oligomycin sensitivity. DES was shown also to inhibit the magnitude of valinomycin induced proton influx, while initiating proton efflux in asolectin vesicles reconstituted with F0 and loaded with K+. The potency of DES in producing the latter effects was shown to be highly dependent on hydroxyl groups in "para" positions of the two benzene rings within the DES molecule. Finally, in the absence of F0, DES was shown to act as a catalyst of proton influx in K+-loaded asolectin vesicles upon addition of valinomycin. A model based on the structure of DES is presented to account for both the inhibitory and uncoupling properties of this compound.

Animals↗

PubMedDate not supplied

Diethylstilbestrol exposure and the risk of clear cell cervical and vaginal adenocarcinoma.

Data from two case-control studies that showed an association between in utero diethylstilbestrol (DES) exposure and clear cell vaginal cancer are evaluated. Neither study considered the cancer risk according to the reasons for prescribing DES and therefore cannot be used to infer any cause-and-effect relationship between DES exposure and vaginal cancer. Neither these studies nor any other studies have specifically evaluated the risk of clear cell cervical cancer to DES-exposed women. For DES-exposed women the risk of vaginal and cervical cancer is 0.5-2.0 cases per 1000 DES-exposed women; comparable data are not available for non-DES-exposed women.

Adenocarcinoma↗

PubMed1989

Ultrasound surveillance of the cervix during pregnancy in diethylstilbestrol-exposed offspring.

Twenty-three diethylstilbestrol (DES)-exposed patients were evaluated through 27 pregnancies to determine their eligibility for admission to a prospective protocol that combined serial ultrasound surveillance of the lower uterine segment-cervical complex with periodic pelvic examinations to diagnose cervical incompetency. Of these, 21 pregnant women, including seven vaginectomy patients, were matched to 84 low-risk controls to determine the following: 1) the effect of DES exposure on reproductive performance, 2) the efficacy of ultrasound selection of cerclage candidates, and 3) the influence of previous partial vaginectomy on reproductive outcome. Five DES-exposed patients were diagnosed as having cervical incompetency and had cerclages placed. There were no missed diagnoses of cervical incompetency. The DES-exposed patients delivered statistically earlier in gestation than did controls (268 +/- 13 versus 276 +/- 10 days). It was not evident that this difference was important clinically, as there were no neonatal deaths, very low birth weight infants, second-trimester losses, or deliveries before 252 days (36 weeks) among the study patients. Previous vaginectomy did not affect the frequency of the diagnosis of cervical failure or the neonatal outcome. After ultrasound surveillance and treatment for incompetent cervix, a majority of our patients delivered at term without cerclage placement. Therefore, routine cerclage placement is not recommended. Knowledge of the ultrasound criteria for diagnosing cervical incompetency is required.

Adult↗

PubMed1977

Effects of the simultaneous administration of diethylstilbestrol and prednisolone on serum enzymes in Duchenne's muscular dystrophy.

The effects of diethylstilbestrol (DES) and prednisolone (Pr), administered alone or in combination, on the serum enzyme activities in Duchenne's muscular dystrophy (DMD) have been evaluated. When DES and Pr were given simultaneously to four boys with DMD, the mean creatine phosphokinase and lactate dehydrogenase levels fell to about one half those achieved with either agent alone. No untoward or unexpected side effects were encountered. These observations, and our previous demonstration that both agents reduce enzyme efflux from skeletal muscle, give promise that a safe combination therapy may be found to approximately normalize the serum in DMD. This will permit us to test the hypothesis that lowering the serum enzymes, by reducing their loss from skeletal muscle, will slow or arrest the muscle deterioration characteristic of this disease.

Child↗

PubMed1989

Inhibition of glycolysis induced by diethylstilbestrol in anaerobically grown yeast.

In anaerobically grown yeast cells which lack functional mitochondria, the presence of diethylstilbestrol (DES) depressed glycolysis. The addition of the inhibitor markedly increased the cellular concentration of glycolytic intermediates which are formed prior to the pyruvate kinase step as well as to bring about an increase in the [ATP]/[ADP] ratio. Under these conditions an 18 fold decrease in the mass action ratio for pyruvate kinase [( pyruvate] [ATP]/[phosphoenolpyruvate] [ADP]) was noted, however, there was little if any effect on the other glycolytic enzymes. These results suggest that the depression of anaerobic glycolysis caused by DES results from a blockage at the level of the regulatory enzyme pyruvate kinase through a modification of its intracellular environment.

Anaerobiosis↗

PubMed1989

Pancytopenia, rash and fever caused by diethylstilbestrol used for prostate cancer.

Pancytopenia, rash, and fever developed in a 66-year-old man being treated for metastatic prostate cancer with diethylstilbestrol (DES). Only the withdrawal of DES resulted in the prompt resolution of symptoms, signs, and laboratory manifestations. Both immunologic and endocrinologic mechanisms are implicated and must be considered by physicians using DES for the palliative management of prostate cancer.

Adenocarcinoma↗

PubMed1989

[A case report of advanced breast cancer effectively treated by chemo-endocrine therapy with diethylstilbestrol diphosphate and cyclophosphamide].

A woman more than 5 years postmenopausal with right advanced breast cancer (T4, T3, M1, stage IV) was treated with a mild chemo-endocrine therapy. The regimen consisted of diethylstilbestrol diphosphate (Honvan) at 15 mg/day orally and cyclophosphamide at 100 mg/day orally. By the sixth month after administration, both the right breast cancer and multiple lymph node metastases completely disappeared. The change of hormonal therapy from Honvan, as estrogen, to tamoxifen, as antiestrogen, was done 2 years and 9 months after the beginning of initial treatment. The breast cancer recurred 9 months after the change of treatment. At that time, Honvan was again administered instead of tamoxifen. Complete remission was again obtained for 6 months beginning 2 months after the change of drugs, but then the tumor recurred. Although combination chemotherapy was undertaken, the patient died 5 years after initial treatment. These results suggest that chemoendocrine therapy using a low dose of Honvan and cyclophosphamide is effective for advanced breast carcinoma.

Administration, Oral↗

PubMed1988

Development of cervical and vaginal squamous cell neoplasia as a late consequence of in utero exposure to diethylstilbestrol.

During the last 14 years, several articles have given contradictory reports on prevalence rates of squamous cell neoplasia of the cervix and vagina in diethylstilbestrol (DES)-exposed progeny. In 1984, the DES-Adenosis (DESAD) Project found that the incidence of cervical and vaginal intraepithelial neoplasia in DES-exposed daughters was twice as high as in a comparison group of unexposed women. This was also associated with a higher rate of herpes simplex virus and human papillomavirus infections. Possible hypotheses on the etiology of the increased incidence of squamous neoplasia are discussed.

Carcinoma, Squamous Cell↗

PubMed1979

Carcinogenic effects of diethylstilbestrol in male Syrian golden hamsters and European hamsters.

The tumorigenic effects of sc-implanted diethylstilbestrol (DES) on male Syrian golden hamsters and European hamsters were compared. The adenohypophyses, kidneys, and testes of both species showed neoplastic responses to DES treatment. European hamsters were more sensitive than were Syrian hamsters, inasmuch as the European hamsters had a higher tumor incidence. The testicular tumors were all Leydig cell adenomas and seemed to depend on the coincident occurrence of hypophyseal neoplasms (all composed of gonadotropic cells). Of the European hamsters tested, 29% also developed liver tumors (hepatocellular adenomas, carcinomas, and cholangiocarcinomas.

Animals↗