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PubMed1984

Urinary tract evaluation of diethylstilbestrol-exposed female progeny followed in a colposcopy clinic.

Structural abnormalities of the upper genital tract in diethylstilbestrol-exposed (DES-exposed) female progeny have been noted. Since upper genital tract anomalies are often associated with upper urinary tract anomalies, intravenous pyelography was obtained in 102 DES-exposed patients at our institution to determine the incidence of upper urinary tract anomalies. Only two patients had duplication of the ureter. Since this incidence is not greater than that expected in an unexposed population, intravenous pyelogram studies are not routinely recommended for DES-exposed patients.

Abnormalities, Drug-Induced↗

PubMed1984

Molecular structures of metabolites and analogues of diethylstilbestrol and their relationship to receptor binding and biological activity.

A series of indanyl derivatives of diethylstilbestrol (DES) have recently been identified as inv vivo metabolites of DES. These compounds are of interest because they possess effective uterine estrogen receptor-binding affinity but poor biological activity. The X-ray crystal structures of three of these derivatives were determined and their conformations were compared with those of estradiol and DES. The more active derivatives, indenestrol A (I) and indenestrol B (II) have nearly identical conformations, in which the overall molecule is highly planar, the phenyl ring is twisted out of the plane of the indene rings by approximately 30 degrees, and the distance between the hydroxyl groups is 11.6 A. In the least active derivative, idanestrol (III), the methyl, ethyl, and phenyl substituents were found to be in the same side of the indane ring so that the molecule is constrained to an L-shape. The crystallographically observed conformations of I, II, III, DES, and estradiol, their competative binding affinities, and their in vivo biological activities are consistent with the proposal that the steroid A-ring plays a dominant role in initiating receptor binding while the D-ring orientation relative to the A-ring has a more decisive influence upon activity. The reduction in estrogen receptor-binding affinity and associated reduced activity of III is almost certainly due to its L-shape conformation. The extended conformation of I and II in which both phenolic rings are exposed permitting ready access to both surfaces of either ring probably accounts for the ability of these derivatives to compete so successfully with estradiol for estrogen receptor binding. There are eight different ways in which the molecules of the racemic mixtures of I and II could initiate receptor binding. The reduced biological activity of I and II is probably due to the fact that not all eight binding orientations are compatible with eliciting estrogenic response. Comparison of the observed conformations of I, II, DES, and estradiol suggests that it is the alpha-ring of I and II that minics the steroid A-ring in receptor binding, and that two of the four possible alpha-ring/A-ring matches are most conducive to eliciting hormone activity.

Animals↗

PubMed1983

Uterine tumors in old female mice exposed prenatally to diethylstilbestrol.

Pregnant strain CD-1 mice were treated with diethylstilbestrol (DES) or vehicle. Their female offspring were raised to old age and autopsied when terminally ill. Squamous metaplasia and adenomyosis were more common in uteri of these old mice exposed prenatally to DES than in control mice. Tumors of the uterine horns were seen in 17 of 143 DES-exposed mice and in 3 of 64 control mice. The controls had only leiomyomas, whereas 14 of the DES-exposed mice had adenocarcinomas. There were 5 cervical adenocarcinomas and 1 vaginal adenocarcinoma among treated mice but none in the control mice. Thus the effects of prenatal exposure to DES interacted with the effects of aging to produce a relatively high frequency of uterine adenocarcinoma.

Adenocarcinoma↗

PubMed1983

In vivo selection of androgen-insensitive cells in R3327-G rat prostate tumors: diethylstilbestrol diphosphate treatment versus orchiectomy.

Tumors grown in diethylstilbestrol diphosphate (DES)-treated rats grew significantly more slowly than tumors grown in orchiectomized animals, and tumors grown in orchiectomized animals grew significantly more slowly than tumors grown in controls (intact male rats). When these tumors (phase I) were dispersed and reimplanted into DES-treated, orchiectomized, or control rats in all possible combinations (phase II), a partial selection of androgen-insensitive cells was observed in tumors grown in DES-treated animals. Tumors grown in DES-treated phase I animals responded significantly less to DES treatment or orchiectomy in phase II. In contrast, tumors from phase I orchiectomized animals showed the same responses to orchiectomy in phase II. Since the administration of exogenous testosterone propionate prevented the growth rate inhibitory effects of both DES treatment and orchiectomy, the added effect of DES seemed to be antiandrogenic.

Adenocarcinoma↗

PubMed1983

Induction of hepatic tumors by diethylstilbestrol alone or in synergism with n-nitrosobutylurea in castrated male WF rats.

Inbred male WF rats were castrated at 40 days of age and divided into 5 groups. Group I was given no further treatment. Groups III, IV, and V received pellet implants of 5.0 mg diethylstilbestrol (DES) concurrently with castration. At 50-55 days of age, groups II, IV, and V were given drinking water containing 5.0 mg N-nitrosobutylurea (NBU) per day for 30 days (subthreshold dose). At the termination of NBU treatment, group V further received daily sc injections of 2-bromoergocryptine (CB-154; 0.4 mg/100 g body wt) four times a week throughout the experiment. None of castrated rats or rats castrated and treated with NBU alone developed hepatic tumors (HT) and pituitary tumors (PT). Incidences of HT and PT in groups III, IV, and V were 4/9 (44%) and 7/9 (78%), 15/17 (88%) and 12/17 (71%), and 17/20 (85%) and 4/20 (20%), respectively. The treatment of DES alone resulted in the concurrent development of HT and PT in castrated male rats (group III), and further NBU treatment significantly increased the incidence of HT (group IV). CB-154 treatment did not change the incidence of HT, the number of HT per rat, and the liver weight, although it significantly reduced the incidence of PT, the pituitary weight, and the serum prolactin level in castrated male rats given DES and NBU (group V). These results indicate that DES itself had a direct carcinogenic effect on the liver; this effect was not mediated by prolactin, and NBU increased the effect of DES in this process.

Animals↗

PubMed1984

Inhibitory effect of antiestrogen on hepatic tumorigenesis in WF rats treated with diethylstilbestrol alone or in combination with N-nitrosobutylurea.

Four groups of inbred male WF rats were castrated and received sc implantations of diethylstilbestrol [(DES) CAS: 56-53-1; alpha,alpha'-diethyl-4,4'-stilbenediol] at 40 days of age. Group I was given no further treatment; groups II and IV were treated with antiestrogen (AntiE) clomiphene citrate simultaneously with DES treatment. At 50-55 days of age, groups III and IV were given drinking water containing N-nitrosobutylurea [(NBU) CAS: 869-01-2; 1-butyl-1-nitrosourea] for 30 days. Castrated male rats or rats castrated and treated with NBU alone developed neither hepatic tumors (HT) nor pituitary tumors (PT). When AntiE was administered, incidences of HT and PT, size and the total number of HT, and mean pituitary weight were significantly reduced in rats given DES alone and in rats given DES with NBU. AntiE treatment changed the distribution in the histologic classification of hepatocellular lesions: Neoplastic nodules, instead of hepatocellular carcinomas, were predominant. The results indicate that AntiE was effective in the inhibition of hepatic and pituitary tumorigenesis associated with DES treatment. Our previous study has shown that prolactin was not involved in this hepatic tumorigenesis. Therefore, these studies provide evidence that the carcinogenic effect of DES on the liver cell is direct and that HT are regulated in development and growth by AntiE treatment.

Animals↗

PubMed1984

Tumors of female offspring of mice exposed prenatally to diethylstilbestrol.

Strain CD-1 female mice exposed prenatally to diethylstilbestrol (DES) (CAS: 56-53-1; alpha,alpha'-diethyl-4,4'-stilbenediol) were mated to unexposed males. Female offspring of these matings were raised to the stage of terminal illness. They were never exposed to DES and so have been referred to as "DES-lineage mice." Ten uterine adenocarcinomas and 5 ovarian cystadenocarcinomas were found in 40 DES-lineage mice. These findings were significantly different from the absence of such tumors in 24 "vehicle-lineage" mice whose mothers had received injections only of oil and alcohol. The types of tumors that commonly occur spontaneously in the CD-1 strain appeared with comparable frequency in the 2 groups of mice. The DES-lineage mice did not show the increased frequency of adenomyosis and squamous metaplasia of the uterus, nor the reduced frequency of corpora lutea seen in mice exposed prenatally to DES.

Adenocarcinoma↗

PubMed1984

Effect of immunosuppression on neonatally diethylstilbestrol-induced genital tract lesion and tumor development in female mice.

Neonatal treatment of female rodents with the synthetic estrogen diethylstilbestrol [(DES) CAS: 56-53-1; alpha, alpha'-diethyl-4,4'-dimethoxystilbene] results in immunodeficiency that persists into adulthood, along with progressive development of genital tract lesions. DES-induced immunosuppression was examined as a possible promoter of genital tract lesion and tumor development in BALB/cCrgl female mice. Secondary suppression of T-cell immunity after neonatal DES treatment failed to increase lesion incidence or to promote genital tract tumor development in 8-month-old mice. Although hyperplastic lesions were present in 70% of the genital tracts from DES-treated mice at 8 months of age, apparently few neoplastic cells are present at this time, since transplantation of genital tracts from these animals into syngeneic hosts did not yield tumors. To reduce the possibility that potential tumors were too immunogenic to survive in the syngeneic hosts, genital tract pieces from 12-month-old DES-treated female mice were transplanted into immunosuppressed hosts; only 1 tumor resulted. The tumor was a mixed adenocarcinoma, squamous cell carcinoma, and sarcoma and was immunogenic. These results suggest that immunosurveillance by T-cells is relatively unimportant in DES-induced genital tract lesion development.

Animals↗

PubMed1984

Effects of 17 beta-estradiol and diethylstilbestrol on concurrent development of hepatic, mammary, and pituitary tumors in WF rats: evidence for differential effect on liver.

17 beta-Estradiol [(E2) CAS: 50-28-2; estradiol] and diethylstilbestrol [(DES) CAS: 56-53-1; alpha-alpha'-diethyl-4,4'-stilbenediol] were compared to determine their tumor-inducing abilities in tissue. After castration at 40 days of age, inbred male WF rats received a pellet of either 5.0 mg DES or 5.0 mg E2. Approximately half of the rats that had been given DES or E2 were further given at 50-55 days of age 5.0 mg N-nitrosobutylurea [(NBU) CAS: 869-01-2; 1-butyl-1-nitrosourea] in their drinking water each day for 30 days. None of the castrated rats given E2 alone developed hepatic tumors (HT). Even further addition of NBU did not elicit any HT. Conversely, E2 treatment as well as DES treatment, whether administrated alone or in combination with NBU, resulted in an increase in the incidence of pituitary tumors (PT) and in the mean pituitary weight. The data indicate that E2 was ineffective in inducing HT in castrated male rats, whereas E2 showed an ability to induce PT similar to that of DES. In addition, E2 was not as able to induce as many mammary tumors as DES was able to induce. There was no significant synergism between E2 and NBU in contrast to that between DES and NBU in mammary tumorigenesis, whereas these two estrogens had a similar effect in causing an increase in the pituitary weight. This study, therefore, suggests that the carcinogenic effect of estrogens may not always correlate with their estrogenic effect and further confirms the noninvolvement of prolactin in hepatic tumorigenesis.

Animals↗

PubMed1983

Clear cell adenocarcinoma of the cervix unrelated to diethylstilbestrol exposure.

Twenty-three cases of clear cell adenocarcinoma unrelated to diethylstilbestrol (DES) exposure are described. The microscopic appearance of clear cell and hobnail-shaped cells arranged in a solid, tubular, microcystic, or papillary pattern is diagnostic. Four of the tumors were associated with mesonephric remnants, but none could be demonstrated to arise in them. The age range of the patients, 13 to 80 years, serves as a reminder that DES is not an etiologic factor in many cases and that the disease can occur in older women. Nulliparous patients were unexpectedly common (67% of the total), and the survival rate at ten years was 57%.

Adenocarcinoma↗

PubMed1983

Radiologic diagnosis of diethylstilbestrol induced teratogenesis in rats.

Radiographs were used for the assessment of diethylstilbestrol-induced teratogenesis of the urogenital system of rats. Lesions such as female hypospadias were demonstrable with a 4:1 magnification of radiographs that were not observed using subgross dissection and histologic step sections.

Abnormalities, Drug-Induced↗

PubMed1980

Interaction of dimethylbenzanthracene and diethylstilbestrol on mammary adenocarcinoma formation in female ACI rats.

It has been reported that X-irradiation and diethylstilbestrol (DES) act synergistically on mammary adenocarcinoma formation in female ACI rats. The physical carcinogen, X-irratiation, was replaced by a chemical carcinogen, dimethylbenzanthracene (DMBA), and their interaction was studied in this system. Thirty-three female ACI rats were given 13.3 mg of DMBA per 100 grams of body weight. A total of 10 mammary adenocarcinomas were found, 8 in rats with a single mammary adenocarcinoma and 2 in a single rat, over a 266-day study period. Twenty-nine rats were implanted with a cholesterol pellet containing 5 mg of DES, and a total of 47 mammary adenocarcinomas were found, 5 in rats with a single mammary adenocarcinoma and 42 in 5 rats with 2 or more mammary adenocarcinomas. Twenty-four rats were given a combined treatment of both compounds, DES 2 days before DMBA, and a total of 12l mammary adenocarcinomas were found, 2 in rats with a single mammary adenocarcinoma and 124 in 18 rats with 2 or more mammary adenocarcinomas. The interaction between DMBA and DES was interpreted to be synergistic in regard to the proportion of rats with one or more mammary adenocarcinomas, the proportion of rats with two or more mammary adenocarcinomas, and the median times of appearance of both first and second mammary adenocarcinomas. These interactions between DMBA and DES resemble the previously reported synergistic interactions between radiation and DES on mammary adenocarcinoma formation in female ACI rats.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1981

Prenatal exposure to diethylstilbestrol: ovarian-independent growth of mammary tumors induced by 7,12-dimethylbenz[a]anthracene.

The effects of ovariectomy on the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors were investigated after rats ahd been exposed prenatally to diethylstilbestrol (DES). Pregnant rats were inoculated with either DES (total dose: 1.2 micrograms) in sesame oil or with the vehicle alone on days 10 and 13 of gestation. Female offspring were given 2 gastric intubations of DMBA (10 mg each) 1 week apart beginning at 50 plus or minus 1 days of age. When the average diameter of a mammary tumor exceeded 2 cm, the animal was ovariectomized. The initial response of most tumors in both the DES-exposed and control groups to ovariectomy was size regression. The growth of 7 tumors that arose soon after DMBA treatment in each group was studied for 12-20 weeks after ovariectomy. Whereas only 1 tumor from the control group resumed active growth after the initial regression period, 6 tumors in the DES-exposed group overcame the initial effects of ovariectomy and began to grow again. Thus ovariectomy appeared to be less effective in producing sustained control growth in DMBA-induced mammary tumors in rats exposed prenatally to DES.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1982

Oxidative metabolism of diethylstilbestrol by prostaglandin synthetase.

The cooxidative metabolism of the transplacental carcinogen, diethylstilbestrol (DES), was examined using ram seminal vesicle microsomes. The major extractable metabolite was beta-dienestrol (Z,Z-DIES) and represented about 35% of the added DES in 3-min incubations supplemented with arachidonic acid. Its formation was dependent upon the presence of arachidonic acid, whereas reduced nicotinamide adenine dinucleotide phosphate failed to elicit Z,Z-DIES above background. Indomethacin and 1-phenyl-3-pyrazolidone, known inhibitors of prostaglandin synthetase, blocked Z,Z-DIES formation, probably by inhibiting the cyclooxygenase and the hydroperoxidase activities, respectively. Hydrogen peroxide and 15-hydroperoxyarachidonic acid (cosubstrates of the prostaglandin synthetase-hydroperoxidase), when replacing arachidonic acid in incubations, also supported oxidative metabolism of DES catalyzed by ram seminal vesicle microsomes. 1-Phenyl-3-pyrazolidone, but not indomethacin, inhibited the 15-hydroxyperoxyarachidonic acid-dependent formation of Z,Z-DIES. Incubation conditions which supported efficient Z,Z-DIES formation also resulted in the formation of 3,3-di(p-hydroxyphenyl)hexan-4-one and the cis-isomer of DES as well as nonextractable, protein-associated radioactivity indicating the presence of reactive intermediates. The implications of the peroxidative metabolism of DES for its toxic activity are obvious.

Animals↗

PubMed1978

Incompetent cervix in offspring exposed to diethylstilbestrol in utero.

Five patients with malformation and hypoplasia of the cervix due to diethylstilbestrol (DES)-exposure in utero developed cervical incompetency during the second trimester. Four of the patients were managed successfully during pregnancy with a modified Shirodkar cerclage procedure which was performed at the first sign of cervical effacement and dilitation. The fifth patient, who had lost 2 pregnancies because of cervical incompentency, underwent a modified Lash procedure and permanent cerclage in the nonpregnant state and was delivered at term by primary cesarean section. In view of the large number of women exposed to DES who have grossly abnormal-appearing and hypoplastic cervices, it is important for obstetricians to be aware of this potential complication in order to avoid second trimester losses which could be prevented by prompt surgical intervention.

Adult↗

PubMed1983

Effect of in-utero exposure to diethylstilbestrol on age at onset of puberty and on postpubertal hormone levels in boys.

A group of boys exposed to diethylstilbestrol (DES) in utero who had earlier been found to have urogenital abnormalities were studied for evidence of later effects of DES on their health, physical development and hormonal status. They showed no difference in age at onset of puberty, development of sexual characteristics or hormone levels from boys of the same age who had not been exposed to DES. However, the exposed group tended to have smaller testes.

Adolescent↗

PubMed1983

Receptor status and subsequent sensitivity of subclones of MCF-7 human breast cancer cells surviving exposure to diethylstilbestrol.

The estrogen receptor (ER)-positive human breast cancer cell line MCF-7 was incubated continuously in the presence of pharmacological concentrations of diethylstilbestrol (DES) in an attempt to correlate receptor status with DES sensitivity. It was consistently observed that cytotoxicity occurred at DES concentrations greater than 5 X 10(-6)M; however, a small percentage of cells, both from the wild-type MCF-7 line and from subclones derived in soft agar from single MCF-7 cells, survived, with altered morphology, up to 4 months of continuous exposure to DES concentrations ranging from 5 X 10(-6) to 1 X 10(-4)M. Characterization of seven regenerated surviving cell populations suggested that they remained ER positive; no evidence could be found for a block in the pathway of hormonal activation, as determined by progesterone receptor induction, to explain the ability of these cells to survive DES. Three regenerated cell populations were reexposed to DES. Two remained as sensitive to growth inhibition as untreated parent cells from which they were derived; however, one of these, designated MCF-7(35-1), was found to have autonomously high progesterone receptor (463 +/- 94 fmol/mg of cytosol; Kd = 1.8 +/- 0.2 X 10(-9)M) which was not significantly stimulated by the addition of 1 X 10(-8)M 17beta-estradiol for 72 hr. The third population, designated MCF-7(35-3), which survived initial exposure to 5 X 10(-5)M DES for 109 days and which remained ER positive (27 +/- 3 fmol/mg of cytosol; Kd = 0.8 +/- 0.2 X 10(-10)M) and progesterone receptor inducible, demonstrated significantly decreased sensitivity (p = 0.025) on reexposure to DES; conversely, significantly increased sensitivity (p less than 0.03) to the antiestrogen tamoxifen was observed. The mechanisms by which some MCF-7 cells survive prolonged exposure to DES are not certain; the data suggest that there is no clear relationship between ER status and sensitivity to DES and that there is no way of predicting the ultimate status of cells surviving DES treatment.

Breast Neoplasms↗

PubMed1983

Sister chromatid exchanges and cell division delays induced by diethylstilbestrol, estradiol, and estriol in human lymphocytes.

It had been found previously that exposure of human lymphocytes in vitro to diethylstilbestrol (DES), a synthetic estrogen and known human carcinogen, led to the induction of sister chromatid exchanges. More sister chromatid exchanges were induced in cells from pregnant women than from men. To see if the effects of DES could be induced by other estrogens, lymphocytes from a man and a pregnant woman were treated in vitro with the natural estrogens estradiol and estriol. These did not induce sister chromatid exchanges. To see if the presence of exogenous female hormones might be responsible for the increase in DES-induced sister chromatid exchanges seen in cells from pregnant women, lymphocytes from a man and a pregnant woman were also treated in vitro simultaneously with DES, estradiol, estriol, and progesterone. Treatments with these exogenous hormones did not alter the number of DES-induced sister chromatid exchanges. Our previous studies showed that DES also inhibits in vitro proliferation of lymphocytes. The results reported here show that estradiol also strongly inhibits this proliferation but that estriol is only a weak inhibitor. The cause of delayed cell proliferation induced by DES and estradiol was 2-fold: some of the cells were delayed in phytohemagglutinin-mediated blast cell transformation but, additionally, most cells had a prolonged cell cycle because of an extended G2 phase. These studies also showed that DES, but not estradiol or estriol, induced a low level of polyploidy in human lymphocytes.

Cell Cycle↗